Abstract:
This invention provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the invention is concerned with indoleoxoacetyl piperazine derivatives. These compounds possess unique antiviral activity, whether used alone or in combination with other antivirals, antiinfectives, immunomodulators or HIV entry inhibitors. More particularly, the present invention relates to the treatment of HIV and AIDS.

Description:
CROSS REFERENCE TO RELATED APPLICATION 
     This application claims the benefit of U.S. Provisional Application No. 60/139,213 filed Jun. 15, 1999. 
    
    
     BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     This invention provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the invention is concerned with indoleoxoacetyl piperazine derivatives. These compounds possess unique antiviral activity, whether used alone or in combination with other antivirals, antiinfectives, immunomodulators or HIV entry inhibitors. More particularly, the present invention relates to the treatment of HIV and AIDS. 
     2. Background Art 
     HIV-1 (human immunodeficiency virus-1) infection remains a major medical problem, with an estimated 33.4 million people infected worldwide. Currently available HIV drugs include six nucleoside reverse transcriptase (RT) inhibitors (zidovudine, didanosine, stavudine, lamivudine, zalcitabine and abacavir), three non-nucleoside reverse transcriptase inhibitors (nevirapine, delavirdine and efavirenz) as well as five peptidomimetic protease inhibitors (saquinavir, indinavir, ritonavir, nelfinavir and amprenavir). Each of these drugs can only transiently restrain viral replication if used alone. However, when used in combination, these drugs have a profound effect on disease progression. In fact, significant reductions in death rates among AIDS patients have been recently documented. Despite these results, 30 to 50% of patients ultimately fail combination drug therapies. Insufficient drug potency, non-compliance, restricted tissue penetration and drug-specific limitations within certain cell types (e.g. most nucleoside analogs cannot be phosphorylated in resting cells) may account for the incomplete suppression of sensitive viruses. Furthermore, the high replication rate and rapid turnover of HIV-1 combined with the frequent incorporation of mutations, leads to the appearance of drug-resistant variants and treatment failures when suboptimal drug concentrations are present (Larder and Kemp, Gulick, Morris-Jones, et al, Kuritzkes, Vacca and Condra, Schinazi, et al and Flexner, Ref. 6-12). Therefore, novel anti-HIV agents exhibiting distinct resistance patterns, and favorable pharmacokinetic as well as safety profiles are needed to provide more treatment options. 
     Currently marketed HIV-1 drugs are dominated by either nucleoside reverse transcriptase inhibitors or peptidomimetic protease inhibitors. Non-nucleoside reverse transcriptase inhibitors have recently gained an increasingly important role in the therapy of HIV infections. At least 30 different classes of NNRTIs have been published in the literature (DeClercq, Ref. 13). Dipyridodiazepinone (nevirapine), benzoxazinone (efavirenz) and bis(heteroaryl) piperazine derivatives (delavirdine) are already approved for clinical use. In addition, several indole derivatives including indole-3-sulfones, piperazino indoles, pyrazino indoles, and 5H-indolo[3,2-b][1,5]benzothiazepine derivatives have been reported as HIV-1 reverse transciptase inhibitors (Greenlee et al, Ref. 1, Williams et al, Ref. 2, Romero et al, Ref. 3, Font et al, Ref. 14, Romero et al, Ref. 15, Young et al, Ref. 16, Genin et al, Ref. 17, and Silvestri et al, Ref. 18). Indole 2-carboxamides have also been described as inhibitors of cell adhesion and HIV infection (Boschelli et al. in U.S. Pat. No. 5,424,329, Ref. 4). Finally, 3-substituted indole natural products (Semicochliodinol A and B, didemethylasterriquinone and isocochliodinol) were disclosed as inhibitors of HIV-1 protease (Fredenhagen et al, Ref. 19). However, nothing in these references can be construed to disclose or suggest the novel compounds of this invention and their use to inhibit antiviral infection, including HIV infection. 
     Structurally related compounds have been disclosed previously (Brewster et al, Ref. 20, Archibald et al, Ref. 21, American Home Products in GB 1126245, Ref. 5). However, the structures differ from those claimed herein in that they are symmetrical bis(3-indolylglyoxamides) rather than unsymmetrical aroyl indoleoxoacetyl piperazine derivatives, and there is no mention of use for treating antiviral infections. Interestingly, the indole moiety present in the compounds disclosed here is the common feature of many non-nucleoside HIV-1 reverse transcriptase inhibitors including Delavirdine from Upjohn (Dueweke et al. 1992, 1993, Ref. 22 and 23). 
     Additionally, the following compounds are available commercially but have not been reported as being useful as pharmaceuticals, and more specifically for antiviral use in mammals. 
     Compound LJ952 (available from Menai Organics Ltd., Gwynedd, North Wales):                           
     Compound TRI-29586 (available from Tripos):                           
     REFERENCES CITED 
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     3. Romero, D. L.; Thomas, R. C., Preparation of substituted indoles as anti-AIDS pharmaceuticals. PCT WO 93/01181. 
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     SUMMARY DESCRIPTION OF THE INVENTION 
     It has now been surprisingly found that compounds of formula I, or pharmaceutically acceptable salts thereof, are effective antiviral agents, particularly for treating HIV, whether used alone or in combination with other antivirals, antiinfectives, immunomodulators or HIV entry inhibitors. 
     The present invention comprises compounds of formula I, or pharmaceutically acceptable salts thereof,                           
     wherein: 
     R 1 , R 2 , R 3 , R 4  and R 5  are each independently H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 2 -C 6  alkenyl, C 3 -C 6  cycloalkenyl, C 2 -C 6  alkynyl, halogen, CN, nitro, COOR 6  or XR 7 , each of said alkyl and cycloalkyl being optionally substituted with one to three same or different halogen, amino, OH, CN or NO 2 ; 
     R 6  is H, C 1 -C 6  alkyl, or C 3 -C 6  cycloalkyl, benzyl, each of said alkyl, cycloalkyl and benzyl being optionally substituted with one to three same or different halogen, amino, OH, CN or NO 2 ; 
     X is O, S or NR 6 R 7 ; 
     R 7  is H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 2 -C 6  alkenyl, C 3 -C 6  cycloalkenyl, C 2 -C 6  alkynyl or C(O)R 8 , each of said alkyl and cycloalkyl being optionally substituted with one to three same or different halogen, OH, amino, CN or NO 2 ; 
     R 8  is H, C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl; 
     —W— is                           
     R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22  are each independently H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 2 -C 6  alkenyl, C 3 -C 6  cycloalkenyl, C 2 -C 6  alkynyl, CR 23 R 24 OR 25 , COR 26 , COOR 27  or C(O)NR 28 R 29 , each of said alkyl and cycloalkyl being optionally substituted with one to three same or different halogen, amino, OH, CN or NO 2 ; 
     R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29  are each independently H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 2 -C 6  alkenyl, C 3 -C 6  cycloalkenyl or C 2 -C 6  alkynyl; 
     Ar is a 4-7 membered aromatic ring which may contain one to five heteroatoms independently selected from the group consisting of O, S, N or NR 6 , wherein said aromatic ring is optionally fused to group B; 
     B is an aromatic group selected from the group consisiting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, and anthracenyl; or a heteroaryl group selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimnidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl; 
     B and said 4-7 membered aromatic ring may each independently contain one to five substituents which are each independently selected from R 30  R 31 , R 32 , R 33  or R 34 ; 
     R a  and R b  are each independently H, C 1-6  alkyl or phenyl; 
     Z is 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl, 2-methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, or pyrimidyl; and p is 0-2; 
     R 30  R 31 , R 32 , R 33 , and R 34  are each independently H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 2 -C 6  alkenyl, C 3 -C 6  cycloalkenyl, C 2 -C 6  alkynyl, halogen, CN, nitro, C(O)R 35 , COXR 36 , hydroxyl, COOR 6 , hydroxymethyl, trifluoromethyl, trifluoromethoxy, O—[(C 1 -C 4 )-straight or branched alkyl], O-benzyl, O-phenyl, 1,2-methylenedioxy, OC(O)C 1-6  alkyl, SC(O)C 1-6  alkyl, S(O) m  C 1-6  alkyl, S(O) 2  NR a R b , amino, carboxyl, O-Z, CH 2 —(CH 2 ) p -Z, O—(CH 2 ) p -Z, (CH 2 ) p —O-Z, CH═CH-Z or XR 37 , each of said alkyl and cycloalkyl being optionally substituted with one to three same or different halogen, amino, OH, CN or NO 2 ; 
     m is 0-2; 
     R 35  and R 36  are each independently H, C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl; 
     R 37  is H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 2 -C 6  alkenyl, C 3 -C 6  cycloalkenyl, C 2 -C 6  alkynyl, C(O)R 38  or C(O)OR 39 , each of said alkyl and cycloalkyl being optionally substituted with one to three same or different halogen, amino, OH, CN or NO 2 ; 
     R 38 , R 39  are each independently H, C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl, each of said alkyl and cycloalkyl being optionally substituted with one to three same or different halogen, amino, OH, CN or NO 2 ; provided R 39  is not H; 
     R 40  is (CH 2 ) n —Y, where n is 0-6; 
     Y is selected from: 
     (1) H, C 1-6  alkyl, C 3-6  cycloalkyl, C 2-6  alkenyl, C 3-6  cycloalkenyl, C 2-6  alkynyl, halogen, CN, nitro, Ar, COOR 6 , COOAr, —CONR a R b , TR 6 , NR a R b , —NC(O)NR a R b , —OC(O)R 6 , —C[N(R a ) 2 ]=N-T-R b , XR 6 , —C(O)R 6 , —C(O)Ar, —S(O)R a  or —S(O) 2 R a , provided when Y is —S(O)R a  or —S(O) 2 R a  then R a  is not H; and 
     (2) a 4-7 membered heterocyclic ring, optionally substituted with R 6 , which may contain 1-3 heteroatoms selected from the group consisting of O, S, SO, SO 2 , N, and NR 41 , wherein R 41  is selected from the group consisting of hydrogen, (C 1 -C 4 )-straight or branched alkyl, (C 2 -C 4 )-straight or branched alkenyl or alkynyl; 
     T is S or O; 
     provided R 1 -R 5 , R 9 -R 16  and R 30 -R 34  are not all H at the same time and Ar is phenyl; and 
     provided R 1 -R 5 , R 9 -R 16  and R 30 -R 34  are not all H at the same time and Ar is 2-furyl. 
     Another embodiment of the invention is a pharmaceutical formulation which comprises an antiviral effective amount of a compound of formula I. 
     Another embodiment of the invention is a pharmaceutical formulation useful for treating infection of HIV which additionally comprises an antiviral effective amount of an AIDS treatment agent selected from the group consisting of: 
     (a) an AIDS antiviral agent; 
     (b) an anti-infective agent; 
     (c) an immunomodulator; and 
     (d) HIV entry inhibitors. 
     Another embodiment of the invention is a method for treating mammals infected with a virus (e.g. HIV), comprising administering to said mammal an antiviral effective amount of a compound of formula II, or pharmaceutically acceptable salts thereof,                           
     wherein: 
     R 1 , R 2 , R 3 , R 4  and R 5  are each independently H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 2 -C 6  alkenyl, C 3 -C 6  cycloalkenyl, C 2 -C 6  alkynyl, halogen, CN, nitro, COOR 6  or XR 7 , each of said alkyl and cycloalkyl being optionally substituted with one to three same or different halogen, amino, OH, CN or NO 2 ; 
     R 6 is H, C 1 -C 6  alkyl, or C 3 -C 6  cycloalkyl, benzyl, each of said alkyl, cycloalkyl and benzyl being optionally substituted with one to three same or different halogen, amino, OH, CN or NO 2 ; 
     X is O, S or NR 6 R 7 ; 
     R 7 is H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 2 -C 6  alkenyl, C 3 -C 6  cycloalkenyl, C 2 -C 6  alkynyl or C(O)R 8 , each of said alkyl and cycloalkyl being optionally substituted with one to three same or different halogen, OH, amino, CN or NO 2 ; 
     R 8  is H, C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl; 
     —W— is                           
     R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22  are each independently H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 2 -C 6  alkenyl, C 3 -C 6  cycloalkenyl, C 2 -C 6  alkynyl, CR 23 R 24 OR 25 , COR 26 , COOR 27  or C(O)NR 28 R 29 , each of said alkyl and cycloalkyl being optionally substituted with one to three same or different halogen, amino, OH, CN or NO 2 ; 
     R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29  are each independently H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 2 -C 6  alkenyl, C 3 -C 6  cycloalkenyl or C 2 -C 6  alkynyl; 
     Ar is a 4-7 membered aromatic ring which may contain one to five heteroatoms independently selected from the group consisting of O, S, N or NR 6 , wherein said aromatic ring is optionally fused to group B; 
     B is an aromatic group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, and anthracenyl; or a heteroaryl group selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl; 
     B and said 4-7 membered aromatic ring may each independently contain one to five substituents which are each independently selected from R 3 o R 31 , R 32 , R 33  or R 34 ; 
     R a  and R b  are each independently H, C 1-6  alkyl or phenyl; 
     Z is 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl, 2-methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, or pyrimidyl; and p is 0-2; 
     R 30  R 31 , R 32 , R 33 , and R 34  are each independently H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 2 -C 6  alkenyl, C 3 -C 6  cycloalkenyl, C 2 -C 6  alkynyl, halogen, CN, nitro, C(O)R 35 , COXR 36 , hydroxyl, COOR 6 , hydroxymethyl, trifluoromethyl, trifluoromethoxy, O—[(C 1 -C 4 )-straight or branched alkyl], O-benzyl, O-phenyl, 1,2-methylenedioxy, OC(O)C 1-6  alkyl, SC(O)C 1-6  alkyl, S(O) m  C 1-6  alkyl, S(O) 2  NR a R b , amino, carboxyl, O-Z, CH 2 —(CH 2 ) p -Z, O-(CH 2 ) p -Z, (CH 2 ) p -O-Z, CH═CH-Z or XR 37 , each of said alkyl and cycloalkyl being optionally substituted with one to three same or different halogen, amino, OH, CN or NO 2 ; 
     m is 0-2; 
     R 35  and R 36  are each independently H, C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl; 
     R 37  is H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 2 -C 6  alkenyl, C 3 -C 6  cydloalkenyl, C 2 -C 6  alkynyl, C(O)R 38  or C(O)OR 39 , each of said alkyl and cycloalkyl being optionally substituted with one to three same or different halogen, amino, OH, CN or NO 2 ; 
     R 38 , R 39  are each independently H, C 1 -C 6  alkyl or C 3 -C 6  cycloalkyl, each of said alkyl and cycloalkyl being optionally substituted with one to three same or different halogen, amino, OH, CN or NO 2 ; provided R 39  is not H; 
     R 40  is (CH 2 ) n —Y, where n is 0-6; 
     Y is selected from: 
     (1) H, C 1-6 alkyl, C 3-6  cycloalkyl, C 2-6  alkenyl, C 3-6  cycloalkenyl, C 2-6  alkynyl, halogen, CN, nitro, Ar, COOR 6 , COOAr, —CONR a R b , TR 6 , NR a R b , —NC(O)NR a R b , —OC(O)R 6 , —C[N(R a ) 2 ]=N-T-R b , XR 6 , —C(O)R 6 , —C(O)Ar, —S(O)R a  or S(O) 2 R a , provided when Y is —S(O)R a  or —S(O) 2 R a  then R a  is not H; and 
     (2) a 4-7 membered heterocyclic ring, optionally substituted with R 6 , which may contain 1-3 heteroatoms selected from the group consisting of O, S, SO, SO 2 , N, and NR 41 , wherein R 41  is selected from the group consisting of hydrogen, (C 1 -C 4 )-straight or branched alkyl, (C 2 -C 4 )-straight or branched alkenyl or alkynyl; and 
     T is S or O. 
     In a preferred embodiment, compounds of formula I and II include those where Ar is phenyl, furyl, isoxazolyl, thiophenyl, pyrazolyl, pyridyl, benzofuryl, benzothiophenyl, indolyl, pyrazinyl, thiazolyl, imidazolyl, thiadiazolyl. 
     Also preferred are compounds of formulas I and II wherein 
     W is                           
     R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , and R 15  are each H; and 
     R 16  is methyl. 
     Also preferred are compounds of formulas I and II wherein R 2  is H, fluoro or methoxy. 
     Also preferred are compounds of formulas I and II wherein R 1 , R 3  and R 4  are each H. 
     DETAILED DESCRIPTION OF THE INVENTION 
     The synthesis procedures and anti-HIV-1 activities of the novel indoleoxoacetyl piperazine analogs of formula I are summarized below. 
     Chemistry 
     The present invention comprises compounds of formula I, their pharmaceutical formulations, and their use in patients suffering from or susceptible to HIV. The compounds of formula I which include pharmaceutically acceptable salts thereof,                           
     The term “C 1-6  alkyl” as used herein and in the claims (unless the context indicates otherwise) mean straight or branched chain alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl and the like. Similarly, “C 2-6  alkenyl” and “C 2-6  alkynyl” include straight or branched chain groups. 
     The term “pharmaceutically acceptable salt” as used herein and in the claims is intended to include nontoxic base addition salts. Suitable salts include those derived from organic and inorganic acids such as, without limitation, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lactic acid, sulfinic acid, citric acid, maleic acid, fumaric acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, and the like. 
     “Halogen” refers to chlorine, bromine, iodine or fluorine. 
     In the method of the present invention, the term “antiviral effective amount” means the total amount of each active component of the method that is sufficient to show a meaningful patient benefit, i.e., healing of acute conditions characterized by inhibition of antiviral infection, including HIV infection. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the desired antiviral effect, whether administered in combination, serially or simultaneously. The terms “treat, treating, treatment” as used herein and in the claims means preventing or ameliorating diseases associated with viral infection, including HIV infection. 
     The present invention is also directed to combinations of the compounds with one or more agents useful in the treatment of AIDS. For example, the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the AIDS antivirals, 
     
       
         
               
             
               
               
               
             
           
               
                   
               
               
                 ANTIVIRALS 
               
             
          
           
               
                 Drug Name 
                 Manufacturer 
                 Indication 
               
               
                   
               
               
                 097 
                 Hoechst/Bayer 
                 HIV infection, 
               
               
                   
                   
                 AIDS, ARC 
               
               
                   
                   
                 (non-nucleoside 
               
               
                   
                   
                 reverse tran- 
               
               
                   
                   
                 scriptase (RT) 
               
               
                   
                   
                 inhibitor) 
               
               
                 Amprenivir 
                 Glaxo Wellcome 
                 HIV infection, 
               
               
                 141 W94 
                   
                 AIDS, ARC 
               
               
                 GW 141 
                   
                 (protease inhibitor) 
               
               
                 Abacavir (1592U89) 
                 Glaxo Wellcome 
                 HIV infection, 
               
               
                 GW 1592 
                   
                 AIDS, ARC 
               
               
                   
                   
                 (RT inhibitor) 
               
               
                 Acemannan 
                 Carrington Labs 
                 ARC 
               
               
                   
                 (Irving, TX) 
               
               
                 Acyclovir 
                 Burroughs Wellcome 
                 HIV infection, AIDS, 
               
               
                   
                   
                 ARC, in combination 
               
               
                   
                   
                 with AZT 
               
               
                 AD-439 
                 Tanox Biosystems 
                 HIV infection, AIDS, 
               
               
                   
                   
                 ARC 
               
               
                 AD-519 
                 Tanox Biosystems 
                 HIV infection, AIDS, 
               
               
                   
                   
                 ARC 
               
               
                 Adefovir dipivoxil 
                 Gilead Sciences 
                 HIV infection 
               
               
                 AL-721 
                 Ethigen 
                 ARC, PGL 
               
               
                   
                 (Los Angeles, CA) 
                 HIV positive, AIDS 
               
               
                 Alpha Interferon 
                 Glaxo Wellcome 
                 Kaposi&#39;s sarcoma, 
               
               
                   
                   
                 HIV in combination 
               
               
                   
                   
                 w/Retrovir 
               
               
                 Ansamycin 
                 Adria Laboratories 
                 ARC 
               
               
                 LM 427 
                 (Dublin, OH) 
               
               
                   
                 Erbamont 
               
               
                   
                 (Stamford, CT) 
               
               
                 Antibody which 
                 Advanced Biotherapy 
                 AIDS, ARC 
               
               
                 Neutralizes pH 
                 Concepts 
               
               
                 Labile alpha aberrant 
                 (Rockville, MD) 
               
               
                 Interferon 
               
               
                 AR177 
                 Aronex Pharm 
                 HIV infection, AIDS, 
               
               
                   
                   
                 ARC 
               
               
                 Beta-fluoro-ddA 
                 Nat&#39;l Cancer Institute 
                 AIDS-associated 
               
               
                   
                   
                 diseases 
               
               
                 BMS-232623 
                 Bristol-Myers Squibb/ 
                 HIV infection, 
               
               
                 (CGP-73547) 
                 Novartis 
                 AIDS, ARC 
               
               
                   
                   
                 (protease inhibitor) 
               
               
                 BMS-234475 
                 Bristol-Myers Squibb/ 
                 HIV infection, 
               
               
                 (CGP-61755) 
                 Novartis 
                 AIDS, ARC 
               
               
                   
                   
                 (protease inhibitor) 
               
               
                 CI-1012 
                 Warner-Lambert 
                 HIV-1 infection 
               
               
                 Cidofovir 
                 Gilead Science 
                 CMV retinitis, 
               
               
                   
                   
                 herpes, 
               
               
                   
                   
                 papillomavirus 
               
               
                 Curdlan sulfate 
                 AJI Pharma USA 
                 HIV infection 
               
               
                 Cytomegalovirus 
                 MedImmune 
                 CMV retinitis 
               
               
                 Immune globin 
               
               
                 Cytovene 
                 Syntex 
                 Sight threatening 
               
               
                 Ganciclovir 
                   
                 CMV 
               
               
                   
                   
                 peripheral CMV 
               
               
                   
                   
                 retinitis 
               
               
                 Delaviridine 
                 Pharmacia-Upjohn 
                 HIV infection, 
               
               
                   
                   
                 AIDS, ARC 
               
               
                   
                   
                 (RT inhibitor) 
               
               
                 Dextran Sulfate 
                 Ueno Fine Chem. 
                 AIDS, ARC, HIV 
               
               
                   
                 Ind. Ltd. (Osaka, 
                 positive 
               
               
                   
                 Japan) 
                 asymptomatic 
               
               
                 ddC 
                 Hoffman-La Roche 
                 HIV infection, AIDS, 
               
               
                 Dideoxycyfidine 
                   
                 ARC 
               
               
                 ddI 
                 Bristol-Myers Squibb 
                 HIV infection, AIDS, 
               
               
                 Dideoxyinosine 
                   
                 ARC; combination 
               
               
                   
                   
                 with AZT/d4T 
               
               
                 DMP-450 
                 AVID 
                 HIV infection, 
               
               
                   
                 (Camden, NJ) 
                 AIDS, ARC 
               
               
                   
                   
                 (protease inhibitor) 
               
               
                 Efavirenz 
                 DuPont Merck 
                 HIV infection, 
               
               
                 (DMP 266) 
                   
                 AIDS, ARC 
               
               
                 (-)6-Chloro-4-(S)- 
                   
                 (non-nucleoside RT 
               
               
                 cyclopropylethynyl- 
                   
                 inhibitor) 
               
               
                 4(S)-trifluoro- 
               
               
                 methyl-1,4-dihydro- 
               
               
                 2H-3,1-benzoxazin- 
               
               
                 2-one, STOCRINE 
               
               
                 EL10 
                 Elan Corp, PLC 
                 HIV infection 
               
               
                   
                 (Gainesville, GA) 
               
               
                 Famciclovir 
                 Smith Kline 
                 herpes zoster, 
               
               
                   
                   
                 herpes simplex 
               
               
                 FTC 
                 Emory University 
                 HIV infection, 
               
               
                   
                   
                 AIDS, ARC 
               
               
                   
                   
                 (reverse transcriptase 
               
               
                   
                   
                 inhibitor) 
               
               
                 GS 840 
                 Gilead 
                 HIV infection, 
               
               
                   
                   
                 AIDS, ARC 
               
               
                   
                   
                 (reverse transcriptase 
               
               
                   
                   
                 inhibitor) 
               
               
                 HBY097 
                 Hoechst Marion 
                 HIV infection, 
               
               
                   
                 Roussel 
                 AIDS, ARC 
               
               
                   
                   
                 (non-nucleoside 
               
               
                   
                   
                 reverse transcriptase 
               
               
                   
                   
                 inhibitor) 
               
               
                 Hypericin 
                 VIMRx Pharm. 
                 HIV infection, AIDS, 
               
               
                   
                   
                 ARC 
               
               
                 Recombinant Human 
                 Triton Biosciences 
                 AIDS, Kaposi&#39;s 
               
               
                 Interferon Beta 
                 (Almeda, CA) 
                 sarcoma, ARC 
               
               
                 Interferon alfa-n3 
                 Interferon Sciences 
                 ARC, AIDS 
               
               
                 Indinavir 
                 Merck 
                 HIV infection, AIDS, 
               
               
                   
                   
                 ARC, asymptomatic 
               
               
                   
                   
                 HIV positive, also in 
               
               
                   
                   
                 combination with 
               
               
                   
                   
                 AZT/ddI/ddC 
               
               
                 ISIS 2922 
                 ISIS Pharmaceuticals 
                 CMV retinitis 
               
               
                 KNI-272 
                 Nat&#39;l Cancer Institute 
                 HIV-assoc. diseases 
               
               
                 Lamivudine, 3TC 
                 Glaxo Wellcome 
                 HIV infection, 
               
               
                   
                   
                 AIDS, ARC 
               
               
                   
                   
                 (reverse 
               
               
                   
                   
                 transcriptase 
               
               
                   
                   
                 inhibitor); also 
               
               
                   
                   
                 with AZT 
               
               
                 Lobucavir 
                 Bristol-Myers Squibb 
                 CMV infection 
               
               
                 Nelfinavir 
                 Agouron 
                 HIV infection, 
               
               
                   
                 Pharmaceuticals 
                 AIDS, ARC 
               
               
                   
                   
                 (protease inhibitor) 
               
               
                 Nevirapine 
                 Boeheringer 
                 HIV infection, 
               
               
                   
                 Ingleheim 
                 AIDS, ARC 
               
               
                   
                   
                 (RT inhibitor) 
               
               
                 Novapren 
                 Novaferon Labs, Inc. 
                 HIV inhibitor 
               
               
                   
                 (Akron, OH) 
               
               
                 Peptide T 
                 Peninsula Labs 
                 AIDS 
               
               
                 Octapeptide 
                 (Belmont, CA) 
               
               
                 Sequence 
               
               
                 Trisodium 
                 Astra Pharm. 
                 CMV retinitis, HIV 
               
               
                 Phosphonoformate 
                 Products, Inc. 
                 infection, other CMV 
               
               
                   
                   
                 infections 
               
               
                 PNU-440690 
                 Pharmacia Upjohn 
                 HIV infection, 
               
               
                   
                   
                 AIDS, ARC 
               
               
                   
                   
                 (protease inhibitor) 
               
               
                 Probucol 
                 Vyrex 
                 HIV infection, AIDS 
               
               
                 RBC-CD4 
                 Sheffield Med. 
                 HIV infection, 
               
               
                   
                 Tech (Houston, TX) 
                 AIDS, ARC 
               
               
                 Ritonavir 
                 Abbott 
                 HIV infection, 
               
               
                   
                   
                 AIDS, ARC 
               
               
                   
                   
                 (protease inhibitor) 
               
               
                 Saquinavir 
                 Hoffmann- 
                 HIV infection, 
               
               
                   
                 LaRoche 
                 AIDS, ARC 
               
               
                   
                   
                 (protease inhibitor) 
               
               
                 Stavudine; d4T 
                 Bristol-Myers Squibb 
                 HIV infection, AIDS, 
               
               
                 Didehydrodeoxy- 
                   
                 ARC 
               
               
                 thymidine 
               
               
                 Valaciclovir 
                 Glaxo Wellcome 
                 Genital HSV &amp; CMV 
               
               
                   
                   
                 infections 
               
               
                 Virazole 
                 Viratek/ICN 
                 asymptomatic HIV 
               
               
                 Ribavirin 
                 (Costa Mesa, CA) 
                 positive, LAS, ARC 
               
               
                 VX-478 
                 Vertex 
                 HIV infection, AIDS, 
               
               
                   
                   
                 ARC 
               
               
                 Zalcitabine 
                 Hoffmann-LaRoche 
                 HIV infection, AIDS, 
               
               
                   
                   
                 ARC, with AZT 
               
               
                 Zidovudine; AZT 
                 Glaxo Wellcome 
                 HIV infection, AIDS, 
               
               
                   
                   
                 ARC, Kaposi&#39;s 
               
               
                   
                   
                 sarcoma, in 
               
               
                   
                   
                 combination with 
               
               
                   
                   
                 other therapies 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
             
           
               
                   
               
               
                 IMMUNOMODULATORS 
               
             
          
           
               
                 Drug Name 
                 Manufacturer 
                 Indication 
               
               
                   
               
               
                 AS-101 
                 Wyeth-Ayerst 
                 AIDS 
               
               
                 Bropirimine 
                 Pharmacia Upjohn 
                 Advanced AIDS 
               
               
                 Acemannan 
                 Carrington Labs, Inc. 
                 AIDS, ARC 
               
               
                   
                 (Irving, TX) 
               
               
                 CL246,738 
                 American Cyanamid 
                 AIDS, Kaposi&#39;s 
               
               
                   
                 Lederle Labs 
                 sarcoma 
               
               
                 EL10 
                 Elan Corp, PLC 
                 HIV infection 
               
               
                   
                 (Gainesville, GA) 
               
               
                 FP-21399 
                 Fuki ImmunoPharm 
                 Blocks HIV fusion 
               
               
                   
                   
                 with CD4+ cells 
               
               
                 Gamma Interferon 
                 Genentech 
                 ARC, in combination 
               
               
                   
                   
                 w/TNF (tumor 
               
               
                   
                   
                 necrosis factor) 
               
               
                 Granulocyte 
                 Genetics Institute 
                 AIDS 
               
               
                 Macrophage Colony 
                 Sandoz 
               
               
                 Stimulating Factor 
               
               
                 Granulocyte 
                 Hoechst-Roussel 
                 AIDS 
               
               
                 Macrophage Colony 
                 Immunex 
               
               
                 Stimulating Factor 
               
               
                 Granulocyte 
                 Schering-Plough 
                 AIDS, 
               
               
                 Macrophage Colony 
                   
                 combination 
               
               
                 Stimulating Factor 
                   
                 w/AZT 
               
               
                 HIV Core Particle 
                 Rorer 
                 Seropositive HIV 
               
               
                 Immunostimulant 
               
               
                 IL-2 
                 Cetus 
                 AIDS, in combination 
               
               
                 Interleukin-2 
                   
                 w/AZT 
               
               
                 JL-2 
                 Hoffman-LaRoche 
                 AIDS, ARC, HIV, in 
               
               
                 Interleukin-2 
                 Immunex 
                 combination w/AZT 
               
               
                 IL-2 
                 Chiron 
                 AIDS, increase in 
               
               
                 Interleukin-2 
                   
                 CD4 cell counts 
               
               
                 (aldeslukin) 
               
               
                 Immune Globulin 
                 Cutter Biological 
                 Pediatric AIDS, in 
               
               
                 Intravenous 
                 (Berkeley, CA) 
                 combination w/AZT 
               
               
                 (human) 
               
               
                 IMREG-1 
                 Imreg 
                 AIDS, Kaposi&#39;s 
               
               
                   
                 (New Orleans, LA) 
                 sarcoma, ARC, PGL 
               
               
                 IMREG-2 
                 Imreg 
                 AIDS, Kaposi&#39;s 
               
               
                   
                 (New Orleans, LA) 
                 sarcoma, ARC, PGL 
               
               
                 Imuthiol Diethyl 
                 Merieux Institute 
                 AIDS, ARC 
               
               
                 Dithio Carbamate 
               
               
                 Alpha-2 
                 Schering Plough 
                 Kaposi&#39;s sarcoma 
               
               
                 Interferon 
                   
                 w/AZT, AIDS 
               
               
                 Methionine- 
                 TNI Pharmaceutical 
                 AIDS, ARC 
               
               
                 Enkephalin 
                 (Chicago, IL) 
               
               
                 MTP-PE 
                 Ciba-Geigy Corp. 
                 Kaposi&#39;s sarcoma 
               
               
                 Muramyl-Tripeptide 
               
               
                 Granulocyte 
                 Amgen 
                 AIDS, in combination 
               
               
                 Colony Stimulating 
                   
                 w/AZT 
               
               
                 Factor 
               
               
                 Remune 
                 Immune Response 
                 Immunotherapeutic 
               
               
                   
                 Corp. 
               
               
                 rCD4 
                 Genentech 
                 AIDS, ARC 
               
               
                 Recombinant 
               
               
                 Soluble Human CD4 
               
               
                 rCD4-IgG 
                   
                 AIDS, ARC 
               
               
                 hybrids 
               
               
                 Recombinant 
                 Biogen 
                 AIDS, ARC 
               
               
                 Soluble Human CD4 
               
               
                 Interferon 
                 Hoffman-LaRoche 
                 Kaposi&#39;s sarcoma 
               
               
                 Alfa 2a 
                   
                 AIDS, ARC, 
               
               
                   
                   
                 in combination 
               
               
                   
                   
                 w/AZT 
               
               
                 SK &amp; F106528 
                 Smith Kline 
                 HIV infection 
               
               
                 Soluble T4 
               
               
                 Thymopentin 
                 Immunobiology 
                 HIV infection 
               
               
                   
                 Research Institute 
               
               
                   
                 (Annandale, NJ) 
               
               
                 Tumor Necrosis 
                 Genentech 
                 ARC, in combination 
               
               
                 Factor; TNF 
                   
                 w/gamma Interferon 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
             
           
               
                   
               
               
                 ANTI-INFECTIVES 
               
             
          
           
               
                 Drug Name 
                 Manufacturer 
                 Indication 
               
               
                   
               
               
                 Clindamycin with 
                 Pharmacia Upjohn 
                 PCP 
               
               
                 Primaquine 
               
               
                 Fluconazole 
                 Pfizer 
                 Cryptococcal 
               
               
                   
                   
                 meningitis, 
               
               
                   
                   
                 candidiasis 
               
               
                 Pastille 
                 Squibb Corp. 
                 Prevention of 
               
               
                 Nystatin Pastille 
                   
                 oral candidiasis 
               
               
                 Ornidyl 
                 Merrell Dow 
                 PCP 
               
               
                 Eflornithine 
               
               
                 Pentamidine 
                 LyphoMed 
                 PCP treatment 
               
               
                 Isethionate (IM &amp; IV) 
                 (Rosemont, IL) 
               
               
                 Trimethoprim 
                   
                 Antibacterial 
               
               
                 Trimethoprim/sulfa 
                   
                 Antibacterial 
               
               
                 Piritrexim 
                 Burroughs Wellcome 
                 PCP treatment 
               
               
                 Pentamidine 
                 Fisons Corporation 
                 PCP prophylaxis 
               
               
                 Isethionate for 
               
               
                 Inhalation 
               
               
                 Spiramycin 
                 Rhone-Poulenc 
                 Cryptosporidial 
               
               
                   
                   
                 diarrhea 
               
               
                 Intraconazole- 
                 Janssen-Pharm. 
                 Histoplasmosis; 
               
               
                 R51211 
                   
                 cryptococcal 
               
               
                   
                   
                 Meningitis 
               
               
                 Trimetrexate 
                 Warner-Lambert 
                 PCP 
               
               
                 Daunorubicin 
                 NeXstar, Sequus 
                 Kaposi&#39;s sarcoma 
               
               
                 Recombinant Human 
                 Ortho Pharm. Corp. 
                 Severe anemia 
               
               
                 Erythropoietin 
                   
                 assoc. with AZT 
               
               
                   
                   
                 Therapy 
               
               
                 Recombinant Human 
                 Serono 
                 AIDS-related 
               
               
                 Growth Hormone 
                   
                 wasting, cachexia 
               
               
                 Megestrol Acetate 
                 Bristol-Myers Squibb 
                 Treatment of 
               
               
                   
                   
                 Anorexia assoc. 
               
               
                   
                   
                 W/AIDS 
               
               
                 Testosterone 
                 Alza, Smith Kline 
                 AIDS-related wasting 
               
               
                 Total Enteral 
                 Norwich Eaton 
                 Diarrhea and 
               
               
                 Nutrition 
                 Pharmaceuticals 
                 malabsorption 
               
               
                   
                   
                 Related to AIDS 
               
               
                   
               
             
          
         
       
     
     Additionally, the compounds of the invention herein may be used in combination with another class of agents for treating AIDS which are called HIV entry inhibitors. Examples of such HIV entry inhibitors are discussed in DRUGS OF THE FUTURE 1999, 24(12), pp. 1355-1362; CELL, Vol. 9, pp. 243-246, Oct. 29, 1999; and DRUG DISCOVERY TODAY, Vol. 5, No. 5, May 2000, pp. 183-194. 
     It will be understood that the scope of combinations of the compounds of this invention with AIDS antivirals, immunomodulators, anti-infectives, HIV entry inhibitors or vaccines is not limited to the list in the above Table, but includes in principle any combination with any pharmaceutical composition useful for the treatment of AIDS. 
     Preferred combinations are simultaneous or alternating treatments of with a compound of the present invention and an inhibitor of HIV protease and/or a non-nucleoside inhibitor of HIV reverse transcriptase. An optional fourth component in the combination is a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddI. A preferred inhibitor of HIV protease is indinavir, which is the sulfate salt of N-(2(R)-hydroxy-1-(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)-N′-(t-butylcarboxamido)-piperazinyl))-pentaneamide ethanolate, and is synthesized according to U.S. Pat. No. 5,413,999. Indinavir is generally administered at a dosage of 800 mg three times a day. Other preferred protease inhibitors are nelfinavir and ritonavir. Another preferred inhibitor of HIV protease is saquinavir which is administered in a dosage of 600 or 1200 mg tid. Preferred non-nucleoside inhibitors of HIV reverse transcriptase include efavirenz. The preparation of ddC, ddI and AZT are also described in EPO 0,484,071. These combinations may have unexpected effects on limiting the spread and degree of infection of HIV. Preferred combinations include those with the following (1) indinavir with efavirenz, and, optionally, AZT and/or 3TC and/or ddI and/or ddC; (2) indinavir, and any of AZT and/or ddI and/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3) stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and 141W94 and 1592U89; (5) zidovudine and lamivudine. 
     In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s). 
     Procedures for making compounds of formula I are shown in Schemes 1-13, and further exemplified in Tables 5-8.                           
     Starting indoles 1 (Scheme 1) are known or are readily prepared according to literature procedures, such as those described in Cribble, G. (Ref. 24) or Bantoli et al (Ref. 36). The indoles 1 are treated with oxalyl chloride in either THF (tetrahydrofuran) or ether to afford the desired glyoxyl chlorides 2 according to literature procedures (Lingens, F. et al, Ref. 25). The intermediate glyoxyl chlorides 2 are then coupled with benzoyl piperazine 3 (Desai, M. et al, Ref. 26) under basic conditions to afford 4.                           
     Treatment of indole-3-glyoxyl chloride 2 (Scheme 2) with tert-butyl 1-piperazinecarboxylate 5 affords the coupled product 6. Deprotection of the Boc group of 6 is effected with 20% (trifluoroacetic acid) TFA/CH 2 Cl 2  to yield 7. This product is then coupled with carboxylic acid in the presence of polymer supported 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (P-EDC) to afford products 8.                           
     For Examples 58-81, piperazine 7 (Scheme 3) was treated with Boc-protected aminobenzoic acid in the presence of EDC to afford 8a. A portion of the resulting product was separated and subjected to TFA in order to remove the Boc group, thus yielding amino derivatives 9.                           
     For Examples 82-89, piperazine 7 (Scheme 4) was treated with acetoxybenzoic acid in the presence of EDC to afford 8b. A portion of the resulting product was separated and subjected to LiOM hydrolysis in order to remove the acetate group, thus yielding hydroxy derivatives 10. 
     Examples containing substituted piperazines are prepared using the general procedures outlined in Schemes 5-13. 
     Substituted piperazines are either commercially available from Aldrich, Co. or prepared according to literature procedures (Behun et al, Ref. 31(a), Scheme 5, eq. 01). Hydrogenation of alkyl substituted pyrazines under 40 to 50 psi pressure in ethanol afforded substituted piperazines. When the substituent was an ester or amide, the pyrazine systems could be partially reduced to the tetrahydropyrazine (Rossen et al, Ref. 31(b), Scheme 5, eq. 02). The carbonyl substituted piperazines could be obtained under the same conditions described above by using commercially available dibenzyl piperazines (Scheme 5, eq. 03).                           
     2-Trifluoromethylpiperazine (Jenneskens et al., Ref. 31c) was prepared through a four step route (Scheme 6). Using Lewis acid TiCl 4 , N,N′-dibenzylethylenediamine 11 reacted with trifluoropyruvates 12 to afford hemiacetal 13, which was reduced at room temperature by Et3SiH in CF3COOH to lactam 14. LiAlH 4  treatment then reduced lactam 14 to 1,4-dibenzyl-2-trifluoromethylpiperazine 15. Finally, hydrogenation of compound 15 in HOAc gave the desired product 2-trifluoromethylpiperazine 16.                           
     Mono-benzoylation of symmetric substituted piperazines could be achieved by using one of the following procedures (Scheme 7). (a) Treatment of a solution of piperazine in acetic acid with acetyl chloride afforded the desired mon-benzoylated piperazine (Desai et al. Ref. 26, Scheme 7, eq. 04). (b) Symmetric piperazines were treated with 2 equivalents of n-butyllithium, followed by the addition of benzoyl chloride at room temperature (Wang et al, Ref. 32, Scheme 7, eq. 05).                           
     Mono-benzoylation of unsymmetric substituted piperazines could be achieved by using one of the following procedures (Scheme 8), in which all the methods were exemplified by mono-alkyl substituted piperazines. (a) Unsymmetric piperazines were treated with 2 equivalents of n-butyllithium, followed by the addition of benzoyl chloride at room temperature to afford a mixture of two regioisomers, which could be separated by chromatography (Wang et al, Ref. 32 and 33(b), Scheme 8 eq. 06); (b) Benzoic acid was converted to its pentafluorophenyl ester, and then further reaction with 2-alkylpiperazine to provide the mono-benzoylpiperazines with the benzoyl group at the less hindered nitrogen (Adamczyk et al, Ref. 33(a), Scheme 8, eq. 07); (c) A mixture of piperazine and methyl benzoate was treated with dialkylaluminum chloride in methylene chloride for 2-4 days to yield the mono-benzoylpiperazine with the benzoyl group at the less hindered nitrogen (Scheme 8, eq. 08); (d) Unsymmetric piperazines were treated with 2 equivalents of n-butyllithium, followed by subsequent addition of triethylsilyl chloride and benzoyl chloride in THF at room temperature to afford mono-benzoylpiperazines with the benzoyl group at the more hindered nitrogen (Wang et al, Ref. 33(b), Scheme 8, eq. 09). When the substituent at position 2 was a ester or amide, the mono-benzoylation with benzoyl chloride occurred at the less hindered nitrogen of the piperazine with triethylamine as base in THF (Scheme 8, eq. 10).                           
     In the case of tetrahydropyrazines (Scheme 9, eq. 11), mono-benzoylation occurred at the more hindered nitrogen under the same conditions as those in equation 10 of Scheme 8, in the well precedented manner. (Rossen et al, Ref. 31(b)).                           
     Furthermore, the ester group can be selectively reduced by NaBH 4  in the presence of the benzamide (Masuzawa et al, Ref. 34), which is shown in Scheme 10.                           
     Hydrolysis of Ester Group to Acid: 
     The ester groups on either the piperazine linkers or on the indole nucleus could be hydrolyzed to the corresponding acid under basic conditions such as K 2 CO 3  (Scheme 11, eq. 13) or NaOMe (Scheme 11, eq. 14) as bases in MeOH and water.                           
     Coupling Reaction:                           
     Reaction of glyoxyl chloride 2 with substituted benzoyl piperazines or tetrahydropyrazines (17) in CH2Cl2 using i-Pr2NEt as base afforded the desired products 18. 
     In the case of coupling reactions using 3-hydroxylmethylbenzoylpiperazine, the hydroxyl group was temporarily protected as its TMS (trimethylsilyl) ether with BSTFA (N,O-bistrimethylsilyl)fluoroacetamide) (Furber et al, Ref. 35). The unprotected nitrogen atom was then reacted with glyoxyl chlorides 2 to form the desired diamides. During workup, the TMS masking group was removed to give free hydroxylmethylpiperazine diamides 19 (Scheme 13).                           
     Antiviral Activity 
     The antiviral activity of the compounds of Examples 1-34 was determined in MT-2 cells (a CD4 positive T-lymphocytic cell line) acutely infected by the BRU strain of HIV-1 in the presence of 10 μM compound. The virus yields were quantitated 6 days after infection using a reverse transcriptase assay (Potts, Ref. 27). The anti-viral results are summarized in Table 1, shown below. Cytotoxicity was determined by incubating cells in the presence of serially diluted compound and cell viability determined using an XTT dye reduction assay (Weislow, Ref. 28). The 50% cytotoxicity concentrations of all compounds were significantly higher than 10 μM, indicating that the compounds are relatively non-toxic. 
     The antiviral activity of the compounds of Examples 35-215 was determined in HeLa CD4 CCR 5  cells infected by single-round infectious HIV-1 reporter virus in the presence of compound at concentrations≦10 μM. The virus infection was quantified 3 days after infection by measuring luciferase expression from integrated viral DNA in the infected cells (Chen et al, Ref. 41). The percent inhibition for each compound was calculated by quantifying the level of luciferase expression in cells infected in the presence of each compound as a percentage of that observed for cells infected in the absence of compound and subtracting such a determined value from 100. Compounds exhibiting anti-viral activity without appreciable toxicity at concentrations ≦10 μM are presented in Tables 1-4 and 9-13. 
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 % 
               
               
                 Example 
                   
                   
                   
                 Inhibition 
               
               
                 # 
                 R 1   
                 R 2   
                 R 3   
                 @  10 uM  
               
               
                   
               
             
          
           
               
                 1 
                 H 
                 H 
                 H 
                 &gt;98 
               
               
                 2 
                 H 
                 H 
                 2,6-Difluoro- 
                 66.8 
               
               
                 3 
                 H 
                 H 
                 2,4-Difluoro- 
                 28.5 
               
               
                 4 
                 H 
                 H 
                 2-Fluoro-3- 
                 91.2 
               
               
                   
                   
                   
                 chloro- 
               
               
                 5 
                 H 
                 H 
                 2-Fluoro- 
                 &gt;98 
               
               
                 6 
                 H 
                 H 
                 2-Acetoxy- 
                 65.4 
               
               
                 7 
                 H 
                 H 
                 2-Hydroxy- 
                 88 
               
               
                 8 
                 H 
                 H 
                 3-Chloro-4- 
                 46 
               
               
                   
                   
                   
                 fluoro- 
               
               
                 9 
                 H 
                 H 
                 3-Fluoro-4- 
                 23.4 
               
               
                   
                   
                   
                 methyl- 
               
               
                 10 
                 H 
                 H 
                 3,4-Difluoro- 
                 32.7 
               
               
                 11 
                 H 
                 H 
                 3-Fluoro- 
                 92.5 
               
               
                 12 
                 H 
                 H 
                 3-Bromo- 
                 88.4 
               
               
                 13 
                 H 
                 H 
                 4-Hydroxy- 
                 87.7 
               
               
                 14 
                 H 
                 H 
                 4-Fluoro- 
                 73.6 
               
               
                 15 
                 H 
                 H 
                 4-Methyl- 
                 61.8 
               
               
                 16 
                 H 
                 H 
                 4-tertButyl- 
                 47.9 
               
               
                 17 
                 H 
                 H 
                 4-Acetoxy- 
                 91.5 
               
               
                 18 
                 2-Methyl- 
                 H 
                 H 
                 54.9 
               
               
                 19 
                 4-Fluoro- 
                 H 
                 H 
                 &gt;98 
               
               
                 20 
                 4-Chloro- 
                 H 
                 H 
                 &gt;98 
               
               
                 21 
                 4-Nitro- 
                 H 
                 H 
                 88.3 
               
               
                 22 
                 5,6-Diacetoxy- 
                 H 
                 H 
                 34 
               
               
                 23 
                 5-Fluoro- 
                 H 
                 H 
                 94.6 
               
               
                 24 
                 5-Acetoxy- 
                 H 
                 H 
                 75.8 
               
               
                 25 
                 5-Methyl- 
                 H 
                 H 
                 49.5 
               
               
                 26 
                 5-Bromo- 
                 H 
                 H 
                 &gt;98 
               
               
                 27 
                 5-Chloro- 
                 H 
                 H 
                 95.8 
               
               
                 28 
                 6-Fluoro- 
                 H 
                 H 
                 &gt;98 
               
               
                 29 
                 6-Chloro- 
                 H 
                 H 
                 95.6 
               
               
                 30 
                 6-Methoxy- 
                 H 
                 H 
                 96.4 
               
               
                 31 
                 7-Chloro- 
                 H 
                 H 
                 &gt;98 
               
               
                 32 
                 7-Carboethoxy- 
                 H 
                 H 
                 &gt;98 
               
               
                 33 
                 7-Ethyl- 
                 H 
                 H 
                 &gt;98 
               
               
                 34 
                 7-Methyl- 
                 H 
                 H 
                 &gt;98 
               
               
                 35 
                 7-Bromo 
                 H 
                 H 
                 &gt;98 
               
               
                 36 
                 7-Methoxy 
                 H 
                 H 
                 &gt;98 
               
               
                 37 
                 6-Trifluoromethyl 
                 H 
                 H 
                 38 
               
               
                 38 
                 7-Fluoro 
                 H 
                 H 
                 &gt;98 
               
               
                 39 
                 4,7-Dimethoxy 
                 H 
                 H 
                 &gt;98 
               
               
                 40 
                 5,6-Dichloro 
                 H 
                 H 
                 &gt;98 
               
               
                 41 
                 4-Bromo 
                 H 
                 H 
                 &gt;98 
               
               
                 42 
                 4,6-Difluoro 
                 H 
                 H 
                 &gt;98 
               
               
                 43 
                 5-Fluoro-6-chloro 
                 H 
                 H 
                 60 
               
               
                 44 
                 5,6-Difluoro 
                 H 
                 H 
                 63 
               
               
                 45 
                 4,5,6,7-tetrafluoro 
                 H 
                 H 
                 &gt;98 
               
               
                 46 
                 4,7-Difluoro 
                 H 
                 H 
                 &gt;98 
               
               
                 47 
                 4-Methoxy 
                 H 
                 H 
                 &gt;98 
               
               
                 48 
                 5-Fluoro-7-bromo 
                 H 
                 H 
                 75 
               
               
                 49 
                 4-Fluoro-7-methyl 
                 H 
                 H 
                 &gt;98 
               
               
                 50 
                 4,6-Difluoro-5- 
                 H 
                 H 
                 97 
               
               
                   
                 Bromo 
               
               
                 51 
                 4-Fluoro-7- 
                 H 
                 H 
                 &gt;98 
               
               
                   
                 trifluoroethoxy 
               
               
                 52 
                 4-Methoxy-7-chloro 
                 H 
                 H 
                 &gt;98 
               
               
                 53 
                 4-ethoxy 
                 H 
                 H 
                 &gt;98 
               
               
                 54 
                 4-methoxy-7-bromo 
                 H 
                 H 
                 &gt;98 
               
               
                 55 
                 4-Bromo-7-fluoro 
                 H 
                 H 
                 97 
               
               
                 56 
                 4-Fluoro-7-methoxy 
                 H 
                 H 
                 &gt;98 
               
               
                 57 
                 4- 
                 H 
                 H 
                 &gt;98 
               
               
                   
                 Trifluoromethoxy- 
               
               
                   
                 7-bromo 
               
               
                 58 
                 4-Fluoro 
                 H 
                 4-NHC(O)OBu-t 
                 95 
               
               
                 59 
                 4-Chloro 
                 H 
                 2- 
                 51 
               
               
                   
                   
                   
                 NHC(O)OBu-t 
               
               
                 60 
                 4-Chloro 
                 H 
                 3- 
                 97 
               
               
                   
                   
                   
                 NHC(O)OBu-t 
               
               
                 61 
                 4-Chloro 
                 H 
                 4- 
                 93 
               
               
                   
                   
                   
                 NHC(O)OBu-t 
               
               
                 62 
                 4-Fluoro 
                 H 
                 2- 
                 51 
               
               
                   
                   
                   
                 NHC(O)OBu-t 
               
               
                 63 
                 4-Fluoro 
                 H 
                 3- 
                 98 
               
               
                   
                   
                   
                 NHC(O)OBu-t 
               
               
                 64 
                 4-Methoxy 
                 Me 
                 3- 
                 95 
               
               
                   
                   
                   
                 NHC(O)OBu-t 
               
               
                 65 
                 4-Fluoro 
                 H 
                 2-Amino 
                 84 
               
               
                 66 
                 4-Fluoro 
                 H 
                 3-Amino 
                 &gt;98 
               
               
                 67 
                 4-Fluoro 
                 H 
                 4-Amino 
                 &gt;98 
               
               
                 68 
                 4-Chloro 
                 H 
                 2-Amino 
                 75 
               
               
                 69 
                 4-Chloro 
                 H 
                 3-Amino 
                 &gt;98 
               
               
                 70 
                 4-Chloro 
                 H 
                 4-Amino 
                 98 
               
               
                 71 
                 H 
                 H 
                 2-Amino 
                 36 
               
               
                 72 
                 H 
                 H 
                 3-Amino 
                 87 
               
               
                 73 
                 4,7-Difluoro 
                 H 
                 3-Amino 
                 &gt;98 
               
               
                 74 
                 4,7-Difluoro 
                 Me 
                 3-Amino 
                 &gt;98 
               
               
                 75 
                 4,7-Difluoro 
                 Me 
                 4-Amino 
                 &gt;98 
               
               
                 76 
                 4-Fluoro 
                 Me 
                 3-Amino 
                 &gt;98 
               
               
                 77 
                 4-Methoxy-7- 
                 Me 
                 3-Amino 
                 &gt;98 
               
               
                   
                 Chloro 
               
               
                 78 
                 4-Methoxy-7- 
                 Me 
                 4-Amino 
                 &gt;98 
               
               
                 79 
                 4-Methoxy 
                 Me 
                 3-Amino 
                 &gt;98 
               
               
                 80 
                 4-Fluoro-7- 
                 Me 
                 3-Amino 
                 &gt;98 
               
               
                   
                 Methoxy 
               
               
                 81 
                 4-Fluoro-7- 
                 Me 
                 4-Amino 
                 &gt;98 
               
               
                   
                 Methoxy 
               
               
                 82 
                 4-Fluoro 
                 H 
                 2-Acetoxy 
                 91 
               
               
                 83 
                 4-Fluoro 
                 H 
                 3-Acetoxy 
                 &gt;98 
               
               
                 84 
                 4-Fluoro 
                 H 
                 4-Acetoxy 
                 98 
               
               
                 85 
                 4-Chloro 
                 H 
                 4-Acetoxy 
                 93 
               
               
                 86 
                 4-Chloro 
                 H 
                 3-Acetoxy 
                 &gt;98 
               
               
                 87 
                 4-Fluoro 
                 H 
                 2-OH 
                 86 
               
               
                 88 
                 4-Fluoro 
                 H 
                 3-OH 
                 &gt;98 
               
               
                 89 
                 4-Fluoro 
                 H 
                 4-OH 
                 95 
               
               
                 90 
                 4-Fluoro-7- 
                 H 
                 H 
                 &gt;98 
               
               
                   
                 carboxaldehyde  
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 % 
               
               
                 Example 
                   
                   
                 Inhibition 
               
               
                 # 
                 R 1   
                 W 
                 @  10 uM  
               
               
                   
               
             
          
           
               
                 91 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 92 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 94 
               
               
                   
               
               
                 93 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 94 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 95 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 96 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 97 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 97 
               
               
                   
               
               
                 98 
                 4-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 84 
               
               
                   
               
               
                 99 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 89 
               
               
                   
               
               
                 100 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 86 
               
               
                   
               
               
                 101 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 74 
               
               
                   
               
               
                 102 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 103 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 104 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 105 
                 7-OMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 106 
                 4,7- Difluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 107 
                 4,5,6,7- tetrafluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 108 
                 4,5,6,7- tetrafluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 109 
                 7-Nitro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 110 
                 7-Ethyl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 111 
                 7-OMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 112 
                 7-Nitro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 84 
               
               
                   
               
               
                 113 
                 6-Chloro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 81 
               
               
                   
               
               
                 114 
                 5,6- Dichloro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 89 
               
               
                   
               
               
                 115 
                 4-Chloro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 79 
               
               
                   
               
               
                 116 
                 4-Chloro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 77 
               
               
                   
               
               
                 117 
                 5,6- dichloro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 89 
               
               
                   
               
               
                 118 
                 5-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 69 
               
               
                   
               
               
                 119 
                 7-Ethyl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 72 
               
               
                   
               
               
                 120 
                 4-Bromo 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 58 
               
               
                   
               
               
                 121 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 92 
               
               
                   
               
               
                 122 
                 4-Br 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 40 
               
               
                   
               
               
                 123 
                 5-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 95 
               
               
                   
               
               
                 124 
                 6-Chloro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 125 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 126 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 127 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 95 
               
               
                   
               
               
                 128 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 95 
               
               
                   
               
               
                 129 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 81 
               
               
                   
               
               
                 130 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 77 
               
               
                   
               
               
                 131 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 63 
               
               
                   
               
               
                 132 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 59 
               
               
                   
               
               
                 133 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 92 
               
               
                   
               
               
                 134 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 87 
               
               
                   
               
               
                 135 
                 4-OMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 136 
                 4-OMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 137 
                 7-COOH 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 138 
                 4-Fluoro-7- methyl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 139 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 140 
                 7-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 141 
                 7-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 96 
               
               
                   
               
               
                 142 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 143 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 91 
               
               
                   
               
               
                 144 
                 4-fluoro-7- bromo 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 145 
                 4-Fluoro-7- COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 146 
                 4-Fluoro-7- COOH 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 147 
                 4-Fluoro-7- OMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98  
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 % 
               
               
                   
                   
                   
                 Inhibition 
               
               
                 Entry 
                 R 
                 Ar 
                 at 10 μM  
               
               
                   
               
             
          
           
               
                 148 
                 4-Fluoro 
                 3-Thiophenyl 
                 &gt;98 
               
               
                 149 
                 4-Fluoro 
                 1,2,3-Thiadiazolyl 
                 88 
               
               
                 150 
                 4-Fluoro 
                 2-(4-Methoxy)- 
                 81 
               
               
                   
                   
                 thiophenyl 
               
               
                 151 
                 4-Fluoro 
                 2-(5-Methylthio)- 
                 75 
               
               
                   
                   
                 thiophenyl 
               
               
                 152 
                 4-Fluoro 
                 2-(3-Bromo)- 
                 97 
               
               
                   
                   
                 thiophenyl 
               
               
                 153 
                 4-Fluoro 
                 2-(5-Bromo)- 
                 &gt;98 
               
               
                   
                   
                 thiophenyl 
               
               
                 154 
                 4-Fluoro 
                 2-Pyrazinyl 
                 80 
               
               
                 155 
                 4-Fluoro 
                 2-(5-Methyl)- 
                 &gt;98 
               
               
                   
                   
                 thiophenyl 
               
               
                 156 
                 4-Fluoro 
                 2-(5-Chloro)- 
                 &gt;98 
               
               
                   
                   
                 thiophenyl 
               
               
                 157 
                 4-Fluoro 
                 2-Indolyl 
                 70 
               
               
                 158 
                 4-Fluoro 
                 4-(2-Methyl)- 
                 92 
               
               
                   
                   
                 thiazolyl 
               
               
                 159 
                 4-Fluoro 
                 4-Thiazolyl 
                 &gt;98 
               
               
                 160 
                 4-Fluoro 
                 4-Pyridyl 
                 98 
               
               
                 161 
                 4-Fluoro 
                 3-(6-Methyl)- 
                 94 
               
               
                   
                   
                 pyridyl 
               
               
                 162 
                 4-Fluoro 
                 3-Pyridyl 
                 97 
               
               
                 163 
                 4-Fluoro 
                 5-Isoxazolyl 
                 90 
               
               
                 164 
                 4-Fluoro 
                 2-Furanyl 
                 &gt;98 
               
               
                 165 
                 4-Fluoro 
                 3-Pyrazolyl 
                 92 
               
               
                 166 
                 4-Fluoro 
                 2-Pyridyl 
                 &gt;98 
               
               
                 167 
                 4-Fluoro 
                 3-Furanyl 
                 &gt;98 
               
               
                 168 
                 4-Fluoro 
                 2-Thiophenyl 
                 &gt;98 
               
               
                 169 
                 4-Fluoro 
                 2-Benzofuranyl 
                 80 
               
               
                 170 
                 4-Fluoro 
                 2-(5-Bromo)- 
                 &gt;98 
               
               
                   
                   
                 furanyl 
               
               
                 171 
                 4-Fluoro 
                 2-(3-Methyl)- 
                 &gt;98 
               
               
                   
                   
                 furanyl 
               
               
                 172 
                 4-Fluoro 
                 2-(3-Chloro)- 
                 &gt;98 
               
               
                   
                   
                 thiophenyl 
               
               
                 173 
                 4-Fluoro 
                 3-(5-Chloro-4- 
                 &gt;98 
               
               
                   
                   
                 methoxy)- 
               
               
                   
                   
                 thiophenyl 
               
               
                 174 
                 4-Fluoro 
                 2-(5-Chloro)- 
                 &gt;98 
               
               
                   
                   
                 furanyl 
               
               
                 175 
                 4-Chloro 
                 3-Thiophenyl 
                 &gt;98 
               
               
                 176 
                 4-Chloro 
                 2-[5-(Pyrid-2-yl)]- 
                 86 
               
               
                   
                   
                 thiophenyl 
               
               
                 177 
                 4-Chloro 
                 2-Thieno[3,2-B]- 
                 &gt;98 
               
               
                   
                   
                 thiophenyl 
               
               
                 178 
                 4-Chloro 
                 2-(5-Methylthio)- 
                 93 
               
               
                   
                   
                 thiophenyl 
               
               
                 179 
                 4-Chloro 
                 2-(5-Bromo)- 
                 &gt;98 
               
               
                   
                   
                 thiophenyl 
               
               
                 180 
                 4-Chloro 
                 2-Pyrazinyl 
                 76 
               
               
                 181 
                 4-Chloro 
                 2-Pyridyl 
                 96 
               
               
                 182 
                 4-Chloro 
                 2- 
                 89 
               
               
                   
                   
                 Benzothiophenyl 
               
               
                 183 
                 4-Chloro 
                 2-(5-Chloro)- 
                 &gt;98 
               
               
                   
                   
                 thiophenyl 
               
               
                 184 
                 4-Chloro 
                 2-(3-Chloro)- 
                 94 
               
               
                   
                   
                 thiophenyl 
               
               
                 185 
                 4-Chloro 
                 2-Indolyl 
                 85 
               
               
                 186 
                 4-Chloro 
                 4-(2-Methyl)- 
                 91 
               
               
                   
                   
                 thiazolyl 
               
               
                 187 
                 4-Chloro 
                 4-Thiazolyl 
                 98 
               
               
                 188 
                 4,7-Difluoro 
                 2-(5-Chloro)- 
                 &gt;98 
               
               
                   
                   
                 furanyl 
               
               
                 189 
                 4,7-Difluoro 
                 2-(5-Bromo)- 
                 &gt;98 
               
               
                   
                   
                 furanyl 
               
               
                 190 
                 4,7-Difluoro 
                 2-furanyl 
                 &gt;98 
               
               
                 191 
                 4,7-Difluoro 
                 2-Pyridyl 
                 95 
               
               
                 192 
                 4,7-Difluoro 
                 2-(3,4-Dichloro)- 
                 &gt;98 
               
               
                   
                   
                 furanyl 
               
               
                 193 
                 4,7-Difluoro 
                 2-(5- 
                 &gt;98 
               
               
                   
                   
                 Trifluoromethyl)- 
               
               
                   
                   
                 furanyl 
               
               
                 194 
                 4,7-Difluoro 
                 2-(4,5-Dimethyl)- 
                 &gt;98 
               
               
                   
                   
                 furanyl 
               
               
                 195 
                 4-Fluoro 
                 2-Imidazolyl 
                 71  
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 % 
               
               
                   
                   
                   
                 Inhibition 
               
               
                 Entry 
                 R 
                 Ar 
                 @  10 μM  
               
               
                   
               
             
          
           
               
                 196 
                 4,7- 
                 2-Pyridyl 
                 &gt;98 
               
               
                   
                 difluoro 
               
               
                 197 
                 4-Fluoro-7- 
                 2-Pyridyl 
                 93 
               
               
                   
                 methyl 
               
               
                 198 
                 4,7- 
                 2-(5-Bromo)- 
                 &gt;98 
               
               
                   
                 Difluoro 
                 furanyl 
               
               
                 199 
                 4,7- 
                 2-(5-Bromo)- 
                 &gt;98 
               
               
                   
                 Dimethoxy 
                 furanyl 
               
               
                 200 
                 7-COOMe 
                 2-(5-Bromo)- 
                 &gt;98 
               
               
                   
                   
                 furanyl 
               
               
                 201 
                 4,7- 
                 2-Pyridyl 
                 &gt;98 
               
               
                   
                 Difluoro 
               
               
                 202 
                 4-Fluoro 
                 2-Pyridyl 
                 &gt;98 
               
               
                 203 
                 4-Chloro 
                 2-Pyridyl 
                 80 
               
               
                 204 
                 4-Bromo 
                 2-Pyridyl 
                 50 
               
               
                 205 
                 5-Fluoro 
                 2-Pyridyl 
                 61 
               
               
                 206 
                 6-Chloro 
                 2-Pyridyl 
                 88 
               
               
                 207 
                 7-Fluoro 
                 2-Pyridyl 
                 &gt;98 
               
               
                 208 
                 7-Methoxy 
                 2-Pyridyl 
                 &gt;98 
               
               
                 209 
                 7-Methyl 
                 2-Pyridyl 
                 &gt;98 
               
               
                 210 
                 7-Ethyl 
                 2-Pyridyl 
                 88 
               
               
                 211 
                 4-methoxy- 
                 2-Pyridyl 
                 &gt;98 
               
               
                   
                 7-chloro 
               
               
                 212 
                 7-cyano 
                 2-Pyridyl 
                 &gt;98 
               
               
                 213 
                 4-Methoxy 
                 2-Pyridyl 
                 &gt;98 
               
               
                 214 
                 4- 
                 2-Pyridyl 
                 &gt;98 
               
               
                   
                 Methoxy- 
               
               
                   
                 7-Bromo 
               
               
                 215 
                 4-Fluoro-7- 
                 2-Pyridyl 
                 &gt;98 
               
               
                   
                 Methoxy  
               
               
                   
               
             
          
         
       
     
    
    
     EXPERIMENTAL PROCEDURES 
     Biology 
     Abbreviations 
     “μM” means micromolar; 
     “μci” means microcurie; 
     “ml” means milliliter; 
     “μl” means microliter; 
     “μg” means microgram; 
     “M” means molar; 
     “μm” means micromolar; 
     “mM” means millimolar; 
     “a” refers to percent inhibition data as representing the mean values of at least two experiments with duplicate determinations in each experiment. 
     “RT” refers to reverse transcriptase. 
     The materials and experimental procedures used to obtain the anti-viral results for Examples 1-34 are described below. 
     Cells—MT-2 T cell lines propagated in Roswell Park Memorial Institute (RPMI) 1640 medium (Life Technologies, Gaithersburg, Md.) containing 10% fetal Bovine serum (FBS, Sigma, St. Louis, Mo.). 
     Virus—The laboratory HIV-1 strain BRU was titrated using an infectivity assay (johnson, V. A. and R. E. Byrington, 1990). 
     Experiment 
     1. MT-2 cells (Harada, et al, Ref. 30) were infected by HIV-1 BRU at a multiplicity of infection (MOI) of 0.005 in RPMI 1640 medium containing 10% fetal Bovine serum at a concentration of 1×10 5  cells/ml. 
     2. Compound was added to 100 μl RPMI 1640 media containing 10% fetal Bovine serum per well in a 96 well plate at a concentration of 20 μM. 
     3. 100 μl of 1×10 5 /ml infected MT-2 cells were added to each well in such plates, resulting in a final cell concentration of 5×10 4  cells/ml and a final compound concentration of 10 μM. 
     4. Samples were incubated at 37° C. and harvested 6 days after infection. 
     5. HIV-1 replication was quantified by measuring the HIV-1 reverse transcriptase (RT) activity present in cell-free supernatants (Potts, et al, Ref. 27). For each sample, 20 μl of cell-free supernatant was added to 40 μl RT cocktail [42 μM Tris(hydroxymethyl) aminomethane pH 7.8 (Sigma, St. Louis, Mo.), 63 μM potassium chloride (Mallinckrodt, Paris Ky.), 2 μM dithiothreitol (Sigma, St. Louis, Mo.), 4 μM magnesium chloride (Mallinckrodt, Paris Ky.), 4 μg/ml polyadenylic acid (Pharmacia, Piscataway, N.J.), 1.3 μg/ml oligonucleotide deoxythymidinel 2-18 (Pharmacia, Piscataway, N.J.), 0.04% (octylphenoxy)-polyethoxyethanol (Nonidet P40, Sigma, St. Louis, Mo.), and 17 μCi/ml 3H-deoxythymidine 5′-triphosphate (NEN, Boston, Mass.)]. Assays were incubated for 1 hour at 37° C. and then 1 μl portions of each reaction were spotted on diethylaminoethyl cellulose (DE-81) filter paper (Whatman, Hillsboro, Oreg.), allowed to dry, washed four times with 0.3 M sodium chloride (Fisher Scientific, Pittsburgh, Pa.), 30 mM sodium citrate pH 7.0 (Sigma, St. Louis, Mo.), followed by two washes in 95% ethanol. Bound radioactivity was quantified by scintillation counting. 
     6. The percent inhibition for each compound was calculated by quantifying the level of HIV-1 replication in the presence of each compound as a percentage of the no compound control and subtracting such a determined value from 100. 
     7. To determine the cytotoxicity of compounds, uninfected cells were incubated with a series of concentrations of each compound for 3-6 days. Cell viability was determined by the XTT {2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide} dye reduction method (Weislow et al, Ref. 28). The percentage of living cells in compound containing wells compared to untreated controls was determined. The 50% cytotoxic concentration was calculated as the concentration of drug that decreased the percentage of living cells to 50% of those in untreated cells. 
     The materials and methods for determination of anti-viral activity for examples 35-215 are described below: 
     Cells: 
     Virus production—Human embryonic Kidney cell line, 293, propagated in Dulbecco&#39;s Modified Eagle Medium (Life Technologies, Gaithersburg, Md.) containing 10% fetal Bovine serum (FBS, Sigma, St. Louis, Mo.). 
     Virus infection—Human epithelial cell line, HeLa, expressing the HIV-1 receptors CD4 and CCR5 was propagated in Dulbecco&#39;s Modified Eagle Medium (Life Technologies, Gaithersburg, Md.) containing 10% fetal Bovine serum (FBS, Sigma, St. Louis, Mo.) and supplemented with 0.2 mg/ml Geneticin (Life Technologies, Gaithersburg, Md.) and 0.4 mg/ml Zeocin (Invitrogen, Carlsbad, Calif.). 
     Virus-Replication defective reporter virus was produced by co-transfecting human embryonic Kidney 293 cells with an HIV-1 envelope DNA expression vector and a proviral cDNA containing an envelope deletion mutation and the luciferase reporter gene inserted in place of HIV-1 nef sequences (Chen, 1994). Transfections were performed using lipofectAMINE PLUS reagent as described by the manufacturer (Life Technologies, Gaithersburg, Md.). 
     Experiment 
     1. Compound was added to HeLa CD4 CCR 5  cells plated in 96 well plates at a cell density of 5×10 4  cells per well in 100 ul Dulbecco&#39;s Modified Eagle Medium containing 10% fetal Bovine serum at a concentration of &lt;20 uM. 
     2. 100 ul of replication defective reporter virus in Dulbecco&#39;s Modified Eagle Medium was then added to the plated cells and compound at a multiplicity of infection (MOI) of 0.01, resulting in a final volume of 200 ul per well and a final compound concentration of &lt;10 uM. 
     3. Samples were harvested 72 hours after infection. 
     4. Viral infection was monitored by measuring luciferase expression from viral DNA in the infected cells using a luciferase reporter gene assay kit (Roche Molecular Biochemicals, Indianapolis, Ind.). Infected cell supernatants were removed and 50 ul of Dulbecco&#39;s Modified Eagle Medium (without phenol red) and 50 ul of luciferase assay reagent reconstituted as described by the manufacturer (Roche Molecular Biochemicals, Indianapolis, Ind.) was added per well. Luciferase activity was then quantified by measuring luminescence using a Wallac microbeta scintillation counter. 
     5. The percent inhibition for each compound was calculated by quantifying the level of luciferase expression in cells infected in the presence of each compound as a percentage of that observed for cells infected in the absence of compound and subtracting such a determined value from 100. 
     References 
     Chen, B. K., Saksela, K., Andino, R., and D. Baltimore. 1994. Distinct modes of human immunodeficiency type 1 proviral latency revealed by superinfection of nonproductively infected celllines with recombinant luciferase-encoding viruses. J. Virol. 68:654-660 (Ref. 37). 
     Chemistry 
     General: Unless otherwise noted, solvents and reagents were used directly as obtained from commercial sources, and reactions were performed under the nitrogen atmosphere. Flash chromatography was conducted on Silica gel 60 (0.040-0.063 particle size; EM Science supply).  1 H NMR spectra were recorded at 500 MHz, unless otherwise noted, and the chemical shifts are reported relative to residual solvent signals. The following standard acronyms were employed to describe the multiplicity patterns: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), b (broad), app (apparent). The coupling constant (J) is in hertz. 
     All Liquid Chromatography (LC) data were recorded on a Shimadzu LC-10AS liquid chromotograph using a SPD-10AV UV-Vis detector and Mass Spectrometry (MS) data were determined with a Micromass Platform for LC in electrospray mode. 
     LC/MS Method (i.e., Compound Identification) 
     Unless otherwise noted, all compounds were analyzed using the following conditions: 
     Column: YMC ODS S7 3.0×50 mm column 
     Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B 
     Gradient time: 2 minutes 
     Hold time: 1 minute 
     Flow rate: 5 mL/min 
     Detector Wavelength: 220 nm 
     Solvent A: 10% MeOH/90% H 2 O/0.1% Trifluoroacetic Acid 
     Solvent B: 10% H 2 O/90% MEOH/0.1% Trifluoroacetic Acid 
     When noted, the following conditions were used for HPLC analysis: 
     Method A: Column YMC ODS-A C18 S7 3.0×50 min 
     Start%B=0/Finish%B=100 
     Method B: Column YMC ODS-A C18 S7 3.0×50 min 
     Start%B=30/Finish%B=100 
     Method C: Column PHX-LUNA C18 4.6×30 mm 
     Start%B=0/Finish%B=100 
     Compounds purified by preparative HPLC were diluted in methanol (1.2 mL) and purified using the following methods on a Shimadzu LC-10A automated preparative HPLC system. 
     Preparative HPLC Method (i.e., Compound Purification) 
     Purification Method: Initial gradient (40% B, 60% A) ramp to final gradient (100% B, 0% A) over 20 minutes, hold for 3 minutes (100% B, 0% A) 
     Solvent A: 10% MeOH/90% H 2 O/0.1% Trifluoroacetic Acid 
     Solvent B: 10% H 2 O/90% MeOH/0.1% Trifluoroacetic Acid 
     Column: YMC C18 S5 20×100 mm column 
     Detector Wavelength: 220 nm 
     Indoles were either commercially available, or were prepared using known chemistry such as the method of Bartoli (Ref. 36) or as described by Gribble (Ref. 24) 
     Representative indole syntheses are shown below. 
     Preparation of 4-Fluoro-7-methyl Indole 
     Step A                           
     A flame dried 50 ml three neck flask was charged with BCl3 (44 mmol, 44 ml, 1 M in benzene) and 10 mL dry benzene at rt. under N2. The mixture was cooled down to 0° C. followed by dropwise addition of 5-fluoro-2-methylaniline(5 g, 40 mmol) in 10 ml dry benzene over 10 min, chloroacetonitrile (2.18 g, 48 mmol) over 2 min and AlCl3 in one portion. After stirring at 0° C. for 5 min, the ice-bath was removed and the mixture was refluxed for 6 hr under N2. The resulted mixture was cooled down to rt. and poured into EtOAc/1N HCl (300 mL, 50:50 v:v with ice). After separation, the aqueous phase was extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (100 mL), brine (2×100 mL), and dried with MgSO4. The solvent was removed in vacuo, and the crude intermediate was used directly in next step without further purification. 
     Step B                           
     The above residue was dissolved in 100 mL ETOH. Then the mixture was cooled down to 0° C., followed by dropwise addition of NaBH4 in 2 ml H2O. After stirring at 0° C. for 1 hr, the reaction was quenched with H2O (10 ml). The solvent was removed in vacuo and the residue was dissolved in EtOAc (150 ml), and washed with brine (2×50 ml). The organic layer was dried with MgSO4, the solvent was removed, and the expected reduced intermediate was used directly in next cyclization step. 
     Step C:                           
     The above intermediate, a yellow oil, was dissolved in 100 ml EtOH, followed by addition of K2CO3 (11.0 g, 80 mmol). The mixture was refluxed under N2 for 2 hr, and cooled down to rt. The solids were removed by filtering through celite, and the resulted solution was concentrated in vacuo. The residue was dissolved in EtOAc (200 mL), washed with brine (2×50 ml) and dried over MgSO4. The solvent was removed in vacuo and gave a brown oil which was purified by flash chromotography (12% EtOAc in hexanes), to yield 2.3 g (39% overall yield) of pure product. M+H, 150.0; Retention time, 1.297 min. 
     Synthesis of 4-Ethoxyindole 
     
       
                 
         
             
             
         
      
     
     An oven dried two neck flask was charged with 5 ml DMF and NaH (66 mg, 60% in oil, 1.65 mmol). The mixture was cooled down to 0° C., followed by dropwise addition of 4-hydroxy indole (200 mg, 1.5 mmol) in 5 ml DMF over 10 second. After stirring for 30 min under N2, bromoethane in 2 ml DMF was added dropwise, and the reaction was allowed to warm to rt. with continued stirring for 2 hr. Removal of the solvent in vacuo, followed by aqueous work up afforded crude 4-ethoxyindole which was purified by prep. HPLC to afford 201 mg (83%) of pure 4-ethxyindole; HPLC retention time, 1.190 min. 
     Synthesis of 4-Fluoro-7-carbomethoxy Indole 
     Step A:                           
     A mixture of 4-fluoro-7-bromoindole (600 mg, 2.8 mmol) and CuCN (1.004 g, 11.2 mmol) in DMF (4 ml) was refluxed for 16 hours. After cooling to room temperature, the reaction mixture was poured into a solution of ammonia in MeOH (30 ml, sat.) and the residue removed by filtration. The filtrate was added to a mixture of water (20 ml)/ammonia (20 ml, sat. aq.) and extracted with EtOAc/Ether (1/1) until TLC analysis showed no product in the aqueous phase. The combined organic extracts were washed with brine (2×200 ml) and water (200 ml), dried (MgSO 4 ); evaporation in zacuo gave 4-fluoro-7-cyanoindole as a tan yellow solid (310 mg, 69%). 
     Step B                           
     To a solution of KOH (13.04 g, 0.232 mol) in 14% H 2 O/EtOH (50 ml) was added 4-fluoro-7-cyanoindole (900 mg, 5.60 mmol). The resulting mixture was refluxed for 12 hours, slowly cooled to room temperature, and concentrated in vacuo to about 30 ml. The residue was acidified to pH 2 with HCl (˜5.5 N aq.). The precipitate was filtered, washed with excess of water, and dried under high vacuum to afford 4-fluoro-7-carboxyindole as a white solid (100% conversion). The material was used without further purification. 
     Step C                           
     To a suspension of 4-fluoro-7-carboxyindole in a mixture of MeOH (18 ml)/PhH (62 ml) was added (trimethylsilyl)diazomethane (8.8 ml, 17.6 mmol, 2 M in hexane). The resulting mixture was stirred at room temperature for 30 min., quenched with excess acetic acid and evaporated in vacuo. The crude oily material was purified by flash chromatography using a gradient elution (Hexane to 10% EtOAc/Hexane) to afford methyl (4-fluoro)indole-7-carboxylate as a white solid (1.04 g, 83% two steps) 
     Preparation of 4-Fluoroindole-7-carboxaldehyde 
     
       
                 
         
             
             
         
      
     
     To a solution of 4-fluoro-7-bromoindole (1.0 g, 4.7 mmol) in THF (5 mL) at −78° C. was added n-BuLi (5.6 mL, 2.5M in hexanes) dropwise. The mixture was stirred for 15 min at −78° C., was allowed to warm to 5° C. for 30 min and was then re-cooled to −78° C. DMF (1.8 mL) was then added and the mixture was allowed to warm to room temperature slowly. The reaction was quenched with water and was extracted with ether. The organic phase was dried over MgSO4, filtered and concentrated to afford 4-fluoroindole-7-carboxaldehyde. 
     General Procedure for Preparation of Examples 1-17 in Table 5 
     Step A                           
     To commercially available indole-3-glyoxylyl chloride I (3 gram, 14.45 mmol) in CH 2 Cl 2  at room temperature was added tert-butyl 1-piperazinecarboxylate (2.7 gram, 14.45 mmol) and diisopropylethylamine (2.76 ml, 15.9 mmol). The light-brown color solution was stirred for 2 hr at room temperature after which time LC/MS analysis indicated the completion of the reaction. The solvent was removed in vacuo and the resulting residue was diluted with ethyl acetate (250 ml) and diethylether (250 ml). The organic solution was then washed with water (100 ml×3) and brine (50 ml), dried over MgSO 4 , filtered and concentrated. To the light-yellow solid was then added 30 ml of 20% trifluoroacetic acid in CH 2 Cl 2 . The solution was concentrated and the light-brown solid was dried in vacuo to give 3.5 g (95%) of product II. LC/MS analysis indicated this product was 100% pure and it was used for the next reaction without further purification. 
     Step B                           
     To piperazine indole-3-glyoxylamide II (0.03 mmol) was added resin-bound 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (P-EDC) (0.21 mmol) and carboxylic acid (RCOOH) (0.06 mmol) in dichloroethane (DCE) (1 mL) or DMF (dimethylformamide) (1 mL) in cases where the carboxylic acids are not soluble in DCE. The reaction was shaken for 12 hr at room temperature. The product III was filtered and concentrated. Products with purity less than 70% were diluted in methanol and purified using a Shimadzu automated preparative HPLC System. 
     2) General Procedure for Preparation of Examples 18-56 in Table 5 
     Step A.                           
     To a solution of substituted indole IV (1 eq) in dry Et 2 O was dropwise added oxalylchloride (1.2 eq) at 0° C. After 5 min., the reaction mixture was warmed to room temperature, or heated to 35° C. overnight if necessary. The intermediate substituted-indole-3-glyoxylyl chloride V, 10 which was formed as a solid, was filtered and washed with dry ether (2×1 ml) to remove excessive oxalyl chloride. The product was then dried under vacuum to give desired glyoxyl chlorides V. 
     In cases where reaction in Et 2 O was unsuccessful, the following procedure was adopted: To a solution of substituted indole IV (1 eq) in dry THF (tetrahydrofuran) solvent was dropwise added oxalyl chloride (1.2 eq) at 0° C. After 5 min., the reaction was warmed to room temperature, or heated to ˜70° C. under nitrogen if necessary. After concentration in vacuo, the resulting crude intermediate V was submitted to next step without further treatment. 
     Step B                           
     To a solution of indole glyoxyl chloride V (1 eq) in dry THF was added benzoylpiperazine (1 eq) at room temperature. Then the mixture was cooled down to 0° C., followed by dropwise addition of diisopropylamine (1.3 eq). After 5 min., the reaction mixture was warmed to room temperature and was shaken for 3 hr. The resulting crude products VI were purified by preparative HPLC and characterized as shown in Table 5. 
     General Procedure for Preparation of Examples 58-63 in Table 5 
     Step A                           
     To glyoxyl chloride V (1 equiv.) in CH 2 Cl 2  at room temperature was added tert-butyl 1-piperazinecarboxylate (1 equiv) and diisopropylethylamine (1.2 equiv). The solution was stirred for 2 hr at room temperature after which time LC/MS analysis indicated the completion of the reaction. The solvent was removed in vacuo and the resulting residue was diluted with ethyl acetate and diethylether. The organic solution was then washed with water (100 ml×3) and brine (50 ml), dried over MgSO 4 , filtered and concentrated. To the solid was then added 30 ml of 20% trifluoroacetic acid in CH 2 Cl 2 . The solution was concentrated and the light-brown solid was dried in vacuo to give glyoxamide VII. 
     Step B                           
     To piperazine glyoxamide VII (0.1 mmol, 1 eq) in DMF (1 mL) at room temperature was added EDC (1.5 eq) and Boc-aminobenzoic acid (1.5 eq). The reaction mixture was stirred at room temperature for 16 hours. The crude product was then purified by preparative HPLC to afford product VIII. 
     General Procedure for Preparation of Examples 65-73 in Table 5 
     
       
                 
         
             
             
         
      
     
     To Boc-protected derivative VIII (0.03 mmol) was added 50% TFA/CH 2 Cl 2  (1.5 mL). The reaction mixture was stirred at room temperature for 16 hours. The product was then concentrated in vacuo to afford product IX as its TFA salt. The purity of IX was sufficient that no further purification was necessary. 
     General Procedure for Preparation of Examples 82-86 in Table 5 
     
       
                 
         
             
             
         
      
     
     To piperazine glyoxamide VII (0.1 mmol, 1 eq) in DMF (1 mL) at room temperature was added EDC (1.5 eq) and acetoxybenzoic acid (1.5 eq). The reaction mixture was stirred at room temperature for 16 hours. The crude product was then purified by preparative HPLC to afford product X. 
     General Procedure for Preparation of Examples 87-89 in Table 5 
     
       
                 
         
             
             
         
      
     
     To acetate-protected derivative X (0.03 mmol, 1 eq) was added aqueous LiOH (3 eq) in THF/MeOH (1.5 mL, 1:1). The reaction mixture was stirred at room temperature for 16 hours. The crude product was then purified by preparative HPLC to afford product XI. 
     General Procedure for Preparation of Examples 64 and 74-81 in Table 5 
     Step A                           
     To a solution of Boc-protected amino benzoic acid (5 mmol) in DMF (10 mL) at room temperature was added pentafluorophenol (5 mmol) followed by EDC (5 mmol). The reaction mixture was stirred at room temperature for 3 h. The crude product was diluted with CH2Cl2 and was washed with water, 0.1 M HCl and brine. The organic phase was dried over MgSO4, filetered and concentrated. The pentafluorophenyl ester XII was used in the following reaction without further purification. 
     Step B                           
     To a stirred solution (R)-2-methylpiperazine in DMF (15 mL) at room temperature was added a solution of pentafluorophenyl ester XII in DMF (2 mL) dropwise. The reaction mixture was stirred at room temperature for 16 hours. The crude product was diluted with CH2Cl2 and was washed with Na2CO3 (sat) and brine. The organic phase was dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (50% EtOAc/Hexane—10% MeOH/EtOAc) to afford product XIII. 
     Step C                           
     To indole-3-glyoxyl chloride V (1 eq.) in CH2Cl2 was added acylpiperazine XII followed by i-Pr 2 NEt (3 eq.). The reaction mixture was stirred at room temperature for 5 hours, was then diluted with methanol and product XIV was purified by preparative HPLC. 
     Step D                           
     To Boc-protected derivative XIV (˜0.03 mmol) was added 50% TFA/CH 2 Cl 2  (1.5 mL). The reaction mixture was stirred at room temperature for 16 hours. The product was then concentrated in vacuo to afford product XV. The purity of XV was sufficient that no further purification was necessary. 
     Procedure for the Synthesis of Examples 57 and 90 in Table 5. 
     Step A                           
     To substituted indole IV (1 equiv) in CH 2 Cl 2  at 0° C. was added ethyl chloroxalate (2 equiv) dropwise followed by addition of AlCl 3  (2 equiv). The reaction was stirred at 0° C. and was then allowed to warm to room temperature overnight. The reaction was quenched by dropwise addition of HCl (1N). The crude material was extracted with EtOAc and was washed with water, dried over MgSO4, filtered and concentrated. The crude product was then recrystallised from EtOAc/Hexanes to afford ester XVI. 
     Step B                           
     To ester XVI (1 equiv) in EtOH was added NaOH (2.5 equiv, 10N) dropwise. The reaction mixture was stirred at rt for 30 min and was then heated to 45° C. for an additional 90 min. The product was concentrated in vacuo. The resulting residue was partitioned between EtOAc and water. The organic layer was separated and was washed with water, dried over MgSO4, filtered and concentrated to afford acid XVII. 
     Step C                           
     To acid XVII (1 equiv) in DMF was added benzoyl pierazine (1.2 equiv) followed by DEPBT (1.2 equiv) and i-Pr2NEt (2 equiv). The reaction mixture was stirred at room temperature for 2 h. It was then diluted with EtOAc, was washed with water and brine, dried over MgSO4, filtered and concentrated. The crude product was then purified by flash chromatography (EtOAc/MeOH, 95:5) to afford the desired product XVIII. 
     
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 5 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 HPLC 
                 MS 
               
               
                   
                   
                   
                   
                 Retention 
                 Data 
               
               
                 Example 
                   
                   
                   
                 Time 
                 (M + 
               
               
                 # 
                 R 1   
                 R 2   
                 R 3   
                 (min) 
                 H) +   
               
               
                   
               
             
          
           
               
                 1 
                 H 
                 H 
                 H 
                 1.13 
                 362 
               
               
                 2 
                 H 
                 H 
                 2,6- 
                 1.36 
                 398 
               
               
                   
                   
                   
                 Difluoro- 
               
               
                 3 
                 H 
                 H 
                 2,4- 
                 1.43 
                 398 
               
               
                   
                   
                   
                 Difluoro 
               
               
                 4 
                 H 
                 H 
                 2-Fluoro-3- 
                 1.54 
                 415 
               
               
                   
                   
                   
                 chloro- 
               
               
                 5 
                 H 
                 H 
                 2-Fluoro- 
                 1.42 
                 380 
               
               
                 6 
                 H 
                 H 
                 2-Acetoxy- 
                 1.63 
                 378 
               
               
                 7 
                 H 
                 H 
                 2-Hydroxy- 
                 1.25 
                 378 
               
               
                 8 
                 H 
                 H 
                 3-Chloro- 
                 1.56 
                 415 
               
               
                   
                   
                   
                 4-fluoro- 
               
               
                 9 
                 H 
                 H 
                 3-Fluoro-4- 
                 1.54 
                 394 
               
               
                   
                   
                   
                 methyl- 
               
               
                 10 
                 H 
                 H 
                 3,4- 
                 1.45 
                 398 
               
               
                   
                   
                   
                 Difluoro 
               
               
                 11 
                 H 
                 H 
                 3-Fluoro- 
                 1.44 
                 380 
               
               
                 12 
                 H 
                 H 
                 3-Bromo- 
                 1.56 
                 442 
               
               
                 13 
                 H 
                 H 
                 4-Hydroxy- 
                 1.17 
                 378 
               
               
                 14 
                 H 
                 H 
                 4-Fluoro- 
                 1.43 
                 380 
               
               
                 15 
                 H 
                 H 
                 4-Methyl- 
                 1.34 
                 376 
               
               
                 16 
                 H 
                 H 
                 4-tertButyl- 
                 1.76 
                 419 
               
               
                 17 
                 H 
                 H 
                 4-Acetoxy- 
                 1.58 
                 420 
               
               
                 18 
                 2-Methyl- 
                 H 
                 H 
                 1.86 
                 376 
               
               
                 19 
                 4-Fluoro- 
                 H 
                 H 
                 1.21 
                 380 
               
               
                 20 
                 4-Chloro- 
                 H 
                 H 
                 1.35 
                 397 
               
               
                 21 
                 4-Nitro- 
                 H 
                 H 
                 1.16 
                 407 
               
               
                 22 
                 5,6-Diacetoxy- 
                 H 
                 H 
                 1.78 
                 478 
               
               
                 23 
                 5-Fluoro- 
                 H 
                 H 
                 1.69 
                 380 
               
               
                 24 
                 5-Acetoxy- 
                 H 
                 H 
                 1.76 
                 420 
               
               
                 25 
                 5-Methyl- 
                 H 
                 H 
                 1.37 
                 376 
               
               
                 26 
                 5-Bromo- 
                 H 
                 H 
                 1.51 
                 442 
               
               
                 27 
                 5-Chloro- 
                 H 
                 H 
                 1.58 
                 396 
               
               
                 28 
                 6-Fluoro- 
                 H 
                 H 
                 1.80 
                 380 
               
               
                 29 
                 6-Chloro- 
                 H 
                 H 
                 2.01 
                 396 
               
               
                 30 
                 6-Methoxy- 
                 H 
                 H 
                 1.28 
                 392 
               
               
                 31 
                 7-Chloro- 
                 H 
                 H 
                 1.50 
                 397 
               
               
                 32 
                 7-Carboethoxy- 
                 H 
                 H 
                 1.41 
                 380 
               
               
                 33 
                 7-Ethyl- 
                 H 
                 H 
                 1.57 
                 390 
               
               
                 34 
                 7-Methyl- 
                 H 
                 H 
                 1.47 
                 376 
               
               
                 35 
                 7-Bromo 
                 H 
                 H 
                 1.54 
                 442 
               
               
                 36 
                 7-Methoxy 
                 H 
                 H 
                 1.37 
                 392 
               
               
                 37 
                 6-Trifluoromethyl 
                 H 
                 H 
                 ND 
                 430 
               
               
                 38 
                 7-Fluoro 
                 H 
                 H 
                 1.59 
                 380 
               
               
                 39 
                 4,7-Dimethoxy 
                 H 
                 H 
                 1.30 
                 422 
               
               
                 40 
                 5,6-Dichloro 
                 H 
                 H 
                 1.86 
                 432 
               
               
                 41 
                 4-Bromo 
                 H 
                 H 
                 1.62 
                 440 
               
               
                 42 
                 4,6-Difluoro 
                 H 
                 H 
                 1.44 
                 398 
               
               
                 43 
                 5-Fluoro-6-chloro 
                 H 
                 H 
                 1.52 
                 414 
               
               
                 44 
                 5,6-Difluoro 
                 H 
                 H 
                 ND 
                 398 
               
               
                 45 
                 4,5,6,7-tetrafluoro 
                 H 
                 H 
                 1.54 
                 434 
               
               
                 46 
                 4,7-Difluoro 
                 H 
                 H 
                 1.30 
                 398 
               
               
                 47 
                 4-Methoxy 
                 H 
                 H 
                 1.23 
                 392 
               
               
                 48 
                 5-Fluoro-7-bromo 
                 H 
                 H 
                 ND 
                 ND 
               
               
                 49 
                 4-Fluoro-7-methyl 
                 H 
                 H 
                 1.34 
                 394 
               
               
                 50 
                 4,6-Difluoro-5- 
                 H 
                 H 
                 1.63 
                 477 
               
               
                   
                 Bromo 
               
               
                 51 
                 4-Fluoro-7- 
                 H 
                 H 
                 1.44 
                 478 
               
               
                   
                 trifluoroethoxy 
               
               
                 52 
                 4-Methoxy-7- 
                 H 
                 H 
                 1.36 
                 426 
               
               
                   
                 chloro 
               
               
                 53 
                 4-ethoxy 
                 H 
                 H 
                 1.28 
                 406 
               
               
                 54 
                 4-methoxy-7- 
                 H 
                 H 
                 1.35 
                 471 
               
               
                   
                 bromo 
               
               
                 55 
                 4-Bromo-7-fluoro 
                 H 
                 H 
                 1.45 
                 458 
               
               
                 56 
                 4-Fluoro-7- 
                 H 
                 H 
                 1.29 
                 410 
               
               
                   
                 methoxy 
               
               
                 57 
                 4- 
                 H 
                 H 
                 ND 
                 525 
               
               
                   
                 Trifluoromethoxy- 
               
               
                   
                 7-bromo 
               
               
                 58 
                 4-Fluoro 
                 H 
                 4- 
                 1.43 
                 495 
               
               
                   
                   
                   
                 NHC(O)O 
               
               
                   
                   
                   
                 Bu-t 
               
               
                 59 
                 4-Chloro 
                 H 
                 2- 
                 1.56 
                 511 
               
               
                   
                   
                   
                 NHC(O)O 
               
               
                   
                   
                   
                 Bu-t 
               
               
                 60 
                 4-Chloro 
                 H 
                 3- 
                 1.55 
                 511 
               
               
                   
                   
                   
                 NHC(O)O 
               
               
                   
                   
                   
                 Bu-t 
               
               
                 61 
                 4-Chloro 
                 H 
                 4- 
                 1.54 
                 511 
               
               
                   
                   
                   
                 NHC(O)O 
               
               
                   
                   
                   
                 Bu-t 
               
               
                 62 
                 4-Fluoro 
                 H 
                 2- 
                 1.42 
                 495 
               
               
                   
                   
                   
                 NHC(O)O 
               
               
                   
                   
                   
                 Bu-t 
               
               
                 63 
                 4-Fluoro 
                 H 
                 3- 
                 1.44 
                 495 
               
               
                   
                   
                   
                 NHC(O)O 
               
               
                   
                   
                   
                 Bu-t 
               
               
                 64 
                 4-Methoxy 
                 Me 
                 3- 
                 1.46 
                 522 
               
               
                   
                   
                   
                 NHC(O)O 
               
               
                   
                   
                   
                 Bu-t 
               
               
                 65 
                 4-Fluoro 
                 H 
                 2-Amino 
                 1.07 
                 395 
               
               
                 66 
                 4-Fluoro 
                 H 
                 3-Amino 
                 0.91 
                 395 
               
               
                 67 
                 4-Fluoro 
                 H 
                 4-Amino 
                 0.86 
                 395 
               
               
                 68 
                 4-Chloro 
                 H 
                 2-Amino 
                 1.21 
                 411 
               
               
                 69 
                 4-Chloro 
                 H 
                 3-Amino 
                 1.06 
                 411 
               
               
                 70 
                 4-Chloro 
                 H 
                 4-Amino 
                 1.03 
                 411 
               
               
                 71 
                 H 
                 H 
                 2-Amino 
                 1.12 
                 377 
               
               
                 72 
                 H 
                 H 
                 3-Amino 
                 0.93 
                 377 
               
               
                 73 
                 4,7-Difluoro 
                 H 
                 3-Amino 
                 0.98 
                 413 
               
               
                 74 
                 4,7-Difluoro 
                 Me 
                 3-Amino 
                 1.02 
                 427 
               
               
                 75 
                 4,7-Difluoro 
                 Me 
                 4-Amino 
                 1.01 
                 427 
               
               
                 76 
                 4-Fluoro 
                 Me 
                 3-Amino 
                 0.97 
                 409 
               
               
                 77 
                 4-Methoxy-7- 
                 Me 
                 3-Amino 
                 1.11 
                 455 
               
               
                   
                 Chloro 
               
               
                 78 
                 4-Methoxy-7- 
                 Me 
                 4-Amino 
                 1.11 
                 455 
               
               
                   
                 Chloro 
               
               
                 79 
                 4-Methoxy 
                 Me 
                 3-Amino 
                 0.93 
                 421 
               
               
                 80 
                 4-Fluoro-7- 
                 Me 
                 3-Amino 
                 1.05 
                 439 
               
               
                   
                 Methoxy 
               
               
                 81 
                 4-Fluoro-7- 
                 Me 
                 4-Amino 
                 1.04 
                 439 
               
               
                   
                 Methoxy 
               
               
                 82 
                 4-Fluoro 
                 H 
                 2-Acetoxy 
                 1.18 
                 438 
               
               
                 83 
                 4-Fluoro 
                 H 
                 3-Acetoxy 
                 1.17 
                 438 
               
               
                 84 
                 4-Fluoro 
                 H 
                 4-Acetoxy 
                 1.16 
                 438 
               
               
                 85 
                 4-Chloro 
                 H 
                 4-Acetoxy 
                 1.28 
                 454 
               
               
                 86 
                 4-Chloro 
                 H 
                 3-Acetoxy 
                 1.29 
                 454 
               
               
                 87 
                 4-Fluoro 
                 H 
                 2-OH 
                 1.17 
                 396 
               
               
                 88 
                 4-Fluoro 
                 H 
                 3-OH 
                 1.13 
                 396 
               
               
                 89 
                 4-Fluoro 
                 H 
                 4-OH 
                 1.09 
                 396 
               
               
                 90 
                 4-Fluoro-7- 
                 H 
                 H 
                 0.79 
                 408 
               
               
                   
                 carboxaldehyde  
               
               
                   
               
               
                 (M +  H) +   refers to the molecular ion peak in positive ionization mode. ND means not determined.  
               
             
          
         
       
     
     Procedure for Synthesis of Compounds in Table 6 
     A. Preparation of Substituted Piperazines: 
     Preparation of 2-Alkylpiperazines 
     
       
                 
         
             
             
         
      
     
     5 g of 2-alkyl pyrazine (46.3 mmol, from Pyrazine Specialties, Inc.) was dissolved in 200 ml of 95% ethanol with 500 mg 10% palladium on active carbon. The reaction mixture was hydrogenated under pressure (40-50 psi) for 2 days. The solid was filtered and removed. The filtrate was concentrated to afford 2-alkyl piperazine, which did not require further purification. 
     2-ethylpiperazine XIX:  1 H NMR (500 MHz, CD 3 OD) δ 2.89 (t, J=15.05 Hz, 1H), 2.85 (d, J=15.11 Hz, 2H), 2.75 (t, J=11.80 Hz, 1H), 2.65 (t, J=11.90 Hz, 1H), 2.48 (m, 1H), 2.28 (t, J=6.12 Hz, 1H), 1.35 (m, 2H), 0.93 (t, J=7.55 Hz, 3H).                           
     2-propylpiperazine XX:  1 H NMR (300 MHz, CDCl 3 ) δ 3.00-2.60 (m, 6H), 2.65 (t, J=10.20 Hz, 1H), 1.70 (m, 2H), 1.30 (m, 2H), 0.92 (t, J=6.9 Hz, 3H).                           
     2-iso-propylpiperazine XXI:  1 H NMR (300 MHz, CDCl 3 ) δ 3.03-2.30 (m, 7H), 1.50 (m, 1H), 0.91 (dd, J=6.60 &amp; 6.60 Hz, 3H).                           
     2-iso-butylpiperazine XXII:  1 H NMR (500 MHz, CD 3 OD) δ 3.00-2.62 (m, 6H), 2.28 (t, J=10.55 Hz, 1H), 1.68 (m, 1H), 1.38 (m, 2H), 0.92 (dd, J=6.65 &amp; 6.55 Hz, 3H).                           
     2-tert-butylpiperaine XXIII:  1 H NMR (500 MHz, CD 3 OD) δ 2.96 (d, J=11.85 Hz, 2H), 2.80 (d, J=12.05 Hz, 1H), 2.74 (t, J=11.75 Hz, 1H), 2.63 (t, J=11.95 Hz, 1H), 2.41 (t, J=11.85 Hz, 1H), 2.31 (d, J=13.91 Hz, 1H), 0.92 (s, 9H).                           
     2-pentylpiperazine XXIV::  1 H NMR (500 MHz, CD 3 OD) δ 2.89 (m, 2H), 2.83 (d, J=11.95 Hz, 1H), 2.75 (t, J=11.80 Hz, 1H), 2.65 (t, J=11.85 Hz, 1H), 2.56 (m, 1H), 2.28 (t, J=12.3 Hz, 1H), 1.35 (m, 8H), 0.90 (t, J=7.15 Hz, 3H).                           
     Preparation of 2-Methoxycarbonyltetrahydropyrazine XXV 
     
       
                 
         
             
             
         
      
     
     5 g of pyrazine carboxylic acid methyl ester (36.2 mmol, from Lancaster, Inc.) was dissolved in 200 ml of 95% ethanol with 500mg 10% palladium on active carbon. The reaction mixture was hydrogenated under pressure (40-50 psi) for 2 days. The solid was filtered and removed. The filtrate was concentrated to afford methoxycarbonyltetrahydropyrazine XXV, which was sufficiently pure enough for subsequent reactions. 
     2-Methoxycarbonyltetrahydropyrazine XXV:  1 H NMR (300 MHz, CD 3 OD) δ 7.10(s, 1H), 4.84 (b, 2H), 3.66 (s, 3H), 3.29 (t, J=6.0 Hz, 2H), 3.08 (t, J=6.0 Hz, 2H);  13 C NMR (75 MHz, CD 3 OD) δ 166.1, 130.8, 105.4, 48.4, 40.6, 40.0; MS m/z: (M+H) +  calcd for C 6 H 11 N 2 O 2 : 143.08, found 143.09. HPLC retention time 0.11 (Method C).                           
     Preparation of 2-Ethoxycarbonylpiperazine XXVI 
     
       
                 
         
             
             
         
      
     
     5 g of N,N′-dibenzylpiperazine carbhoxylic acid ethyl ester (14.8 mmol, from Maybridge Chemical Company Ltd.) was dissolved in 200 ml of 95% ethanol with 500 mg 10% palladium on active carbon. The reaction mixture was hydrogenated under pressure (40-50 psi) for 2 days. The solid was filtered and removed. The filtrate was concentrated to afford 2-ethoxycarbonylpiperazine XXVI, which was sufficiently pure for subsequent reactions. 
     2-Ethoxycarbonylpiperazine XXVI:  1 H NMR (300 MHz, CD 3 OD) δ 4.20 (q, J=7.20 Hz, 2H), 3.46-2.60 (m, 7H), 1.27 (t, J=6.9 Hz, 3H.).                           
     Preparation of 2-Trifluoromethylpiperazine XXVII 
     Step 1:                           
     To a solution of N,N′-dibenzylethylenediamine (1.51 ml, 6.41 mmol), methyl 3,3,3-trifluoro-2-oxopropanate (1.0 g, 6.41 mmol) and triethylamine (1.78 ml, 12.8 mmol) in dichloromethane (100 ml) was added via a syringe titanium chloride (1M in CH 2 Cl 2 , 3.21 ml, 3.21 mmol). The reaction was stirred for 8 hours and the solvents were removed in vacuo. The residue was carried to the next step without further purification. 
     Step 2:                           
     The crude product (200 mg, &lt;0.55 mmol) from the previous step was dissolved in TFA (5 ml). An excess of triethylsilane (0.88 ml, 5.5 mmol) was then added. After 30 minutes, TFA was removed under vaccum and the residue was carried to the next step without further purification. 
     Step 3:                           
     The crude product (&lt;0.55 mmol) from step 2 was suspended in ether. LiAlH 4  (1M in THF, 0.55 ml, 0.55 mmol) was then added at room temperature. After stirring for 8 hours, the reaction was quenched with saturated NaHCO 3  solution. The aqueous layer was extracted with EtOAc. Organic layers were combined, dried over MgSO 4  and concentrated to give a residue, which was carried to the next step without purification. 
     Step 4:                           
     The crude product from the step 3 was dissolved in HOAc (20 ml) with 10 mg 10% palladium on active carbon. The reaction mixture was hydrogenated under pressure (40-50 psi) for 8 hours. The solid was filtered and removed. The filtrate was concentrated to afford 2-trifluoromethylpiperazine XXVII as a HOAc salt, which was pure enough for the further reactions. 
     2-Trifluoromethylpiperazine XXVII as its HOAc (2 equivalents) salt:  1 H NMR (300 MHz, CD 3 OD) δ 3.80-2.80 (m, 7H), 1.95 (s, 6H);  13 C NMR (75 MHz, CD 3 OD) δ 174.5, 53.8, 53.3, 42.7, 41.3, 40.8, 19.8; HRMS m/z: (M+H) +  calcd for C 5 H 10 F 3 N 2 : 155.0796, found 155.0801.                           
     B. Mono-benzoylation of Piperazine Derivatives: 
     Unless otherwise started, substituted piperazine were mono-benzoylated using the following procedures: 
     Preparation of Benzoylpiperazines XXVIII and XXIX 
     
       
                 
         
             
             
         
      
     
     To a stirred solution of substituted piperazine (1.0 g, 11.6 mmol) in dry THF (50 ml) under argon was added 2.5M n-BuLi in THF (10.23 ml, 25.5 mmol) at room temperature. After stirring for 1 hour at room temperature, benzoyl chloride (1.27 ml, 11.0 mmol) was added to the solution of dianion and the reaction mixture was stirred for an additional 10 minutes. The reaction mixture was quenched with MEOH, and the solvents evaporated. The residue was partitioned between EtOAc (50 ml) and sat. NaHCO 3 . The aqueous layer was saturated with NaCl and extracted with EtOAc (2×30 ml). The organic layer was dried over MgSO 4  and concentrated to afford the crude product benzoylpiperazine, which was generally of sufficient purity to be used directly without further purification. Chromatography on a silica gel column (EtOAc/MeOH/Et 3 N, 7:3:1) gave the purified product. 
     Preparation of Benzoylpiperazine XXXIII and XLIII 
     
       
                 
         
             
             
         
      
     
     To a stirred solution of 2-isopropylpiperazine (1.0 g, 7.81 mmol) in dry THF (50 mL), maintained at room temperature under argon atmosphere, was added a solution of 2.5 M n-BuLi in THF (6.88 mL, 17.2 mmol). After stirring for 30 minutes at room temperature, benzoyl chloride (0.86 ml, 7.42 mmol) was added and the reaction mixture stirred for an additional 10 minutes. The reaction mixture was then quenched with MeOH, the solvents were evaporated in vacuo and the residue was purified by silica gel flash chromatography. Elution with a mixture of EtOAc and MeOH (1:1) afforded product XXXIII (0.62 g, 36% yield) and XLIII (0.3 g, 17% yield). Benzoyl piperazines XXXIII, XXXIV, XXXV, XXXVI, XXXVII were prepared using the same procedure as that outlined above. 
     Preparation of Benzoylpiperazines XXXI, XXXII, XXXVIII, 
     
       
                 
         
             
             
         
      
     
     Commercially available benzoic acid (4.8 g, 40 mmol), pentafluorophenol (7.4 g, 40 mmol) and EDAC (7.6 g, 40 mmol) were combined in 60 ml of dry DMF. The mixture was stirred at room temperature for 2 hours. To this solution, 2-methylpiperazine (4.0 g, 40 mmol) in 30 ml of DMF was added slowly and the reaction mixture was stirred at room temperature for 12 hours. 
     Evaporation of DMF gave a residue which was diluted with 400 ml of EtOAc and washed with water (2×100 nm). The organic phase was dried over anhydrous MgSO4 and concentrated in vacuo to provide a crude product, which was purified by column chromatography with EtOAc/MeOH (100:1) and then EtOAc/MeOH (10:1) to give 4.8 g of product XX in 60% yield. 
     Preparation of Benzoylpiperazine XXX 
     
       
                 
         
             
             
         
      
     
     To a stirred solution of 2-methylpiperazine (10.0 g, 0.1 mol) in dry CH 2 Cl 2  (500 ml) under argon was added a solution of 1.0 M Me 2 AlCl or Et 2 AlCl in hexanes (100 ml, 0.1 mmol) and methyl benzoate (12.4 ml, 0.1 mmol) at room temperature. The reaction mixture was then stirred for 2 days before 2N NaOH (200 ml) was added. Aqueous layer was extracted with EtOAc (3×100 ml). The combined organic layer was dried over MgSO 4  and concentration of solution provided 20.0 g of crude product (98%), with was pure enough for the further reactions. 
     Preparation of N-Benzoyl-cis-2,6-dimethylpiperazine XLVII 
     
       
                 
         
             
             
         
      
     
     To a stirred solution of 2,6-di-methylpiperazine (0.82 g, 7.2 mmol) in dry THF (50 mL), maintained at room temperature under an argon atmosphere, was added a solution of 2.5 M n-BuLi in THF (6.3 mL, 15.8 mmol). After stirring for 30 minutes at room temperature, trimethylsilyl chloride (1.0 mL, 7.9 mmol) was added and the reaction mixture stirred for one hour before the addition of benzoyl chloride (0.80 mL, 6.9 mmol). After 10 minutes, the reaction mixture was quenched with MeOH and the solvents were evaporated in vacuo. The residue was purified by silica gel flash column chromatography eluting with a mixture of EtOAc and MeOH (1:1) to provide product XLVII (1.48 g, 99% yield). Benzoyl piperazines XL, XLI, XLII, XLIII, XLIV, XLV, and XLVI were synthesised using the same procedure as outlined above. 
     Preparation of Benzoylpiperazine XXXIX 
     
       
                 
         
             
             
         
      
     
     To a stirred solution of 2-ethoxycarbonylpiperazine (4.6 g, 29.1 mmol) in dry methylene chloride (200 mL), was added benzoyl chloride (3.55 ml, 29.1 mmol) and triethylamine (2 ml) sequentially. After stirring for 8 hours at room temperature, a saturated NaHCO 3  solution was added and the aqueous phase was extracted with ethyl acetate (3×200 ml). The organic layers were combined, dried over MgSO 4  and concentrated to give a crude mixture, which included the desired product XXXIX. The crude was then used for the further reaction without purification. 
     Preparation of Benzoylpiperazine XLVIII 
     
       
                 
         
             
             
         
      
     
     To a stirred solution of 2-methoxycarbonyltetrahydropyrazine (1.0 g, 7.0 mmol) in dry methylene chloride (50 ml), was added benzoyl chloride 0.76 ml, 6.7 mmol) and triethylamine (5 ml) sequentially. After stirring for 8 hours at room temperature, a saturated NaHCO 3  solution was added and the aqueous phase was extracted with ethyl acetate (3×20 ml). The organic layers were combined, dried over MgSO 4  and concentrated to give a crude mixture, which included the desired product XLVII. The crude was then used for the further reaction without purification. 
     Preparation of 3-Hydroxylmethyl-benzoylpiperazine XLIX 
     
       
                 
         
             
             
         
      
     
     To a stirred solution of 3-ethoxycarbonyl-benzoylpiperazine XLIX (200 mg, 0.76 mmol) in THF (5 ml), was added lithium chloride (36 mg, 0.84 mmol), NaBH4 (32 mg, 0.84 mmol) and EtOH (5 ml) sequentially. After stirring for 8 hours at room temperature, a saturated NaHCO 3  solution was added and the aqueous phase was extracted with ethyl acetate (3×20 ml). The organic layers were combined, dried over MgSO 4  and concentrated to give a crude mixture, which was used for the further reaction without purification. 
     Characterization of Mono-Benzoylated Piperazine Derivatives 
     N-Benzoylpiperazine XXVIII:  1 H NMR (300 MHz, CD 3 OD) δ 7.37 (m, 5H), 3.73 (br s, 2H), 3.42 (br s, 2H), 2,85 (br s, 4H);  13 C NMR (75 MHz, CD 3 OD) δ 170.9, 135.0, 129.6, 128.2, 126.5, 44.5; HRMS m/z: (M+H) +  calcd for C 11 H 15 N 2 O 191.1184, found 191.1181.                           
     N-(Benzoyl)-trans-2,5-Dimethylpiperazine XXIX.  1 H NMR (300 MHz, CD 3 OD) δ 7.50-7.28 (m, 5H), 4.38 (br s, 1H), 3.70 (br s, 1H), 3.40-3.20 (m, 3H), 2.57 (dd, 1H, J=12.96, 1.98 Hz), 1,35 (d, 3H, J=6.87 Hz), 1.22 (d, 3H, J=6.78 Hz);  13 C NMR (75 MHz, CD 3 OD) δ 171.9, 135.9, 129.3, 128.3, 126.0, 47.6, 46.7, 43.8, 42.3, 14.7, 14.3; HRMS m/z: (M+H) +  calcd for C 13 H 19 N 2 O 219.1497, found 219.1499.                           
     N-(Benzoyl)-3-methylpiperazine XXX.  1 H NMR (300 MHz, CD 3 OD) δ 7.45 (m, 5H), 4.50 (d, 1H, J=10.8 Hz), 3.60 (b, 1H), 3.33-2.60 (m, 5H), 1.16-0.98 (m, 3H);  13 C NMR (75 MHz, CD 3 OD) δ 170.9, 135.3, 129.6, 128.3, 126.5, 54.0, 50.6, 50.1, 45.0, 44.4, 41.7, 17.50; HRMS m/z: (M+H) +  calcd for C 12 H 17 N 2 O 205.1341, found 205.1336.                           
     N-(Benzoyl)-3-ethylpiperazine XXXI.  1 H NMR (300 MHz, CD 3 OD) δ 7.47 (m, 5H), 4.55 (b, 1H), 3.64 (b, 1H), 3.36-2.59 (m, 5H), 1.51-0.82 (m, 5H);  13 C NMR (75 MHz, CD 3 OD) δ 171.5, 135.8, 130.1, 128.8, 126.9, 57.2, 56.7, 52.9, 47.1, 45.5, 42.5, 26.4, 26.0, 9.3; HRMS m/z: (M+H) +  calcd for C 13 H 19 N 2 O 219.1497, found 219.1495.                           
     N-(Benzoyl)-3-propylpiperazine XXXII.  1 H NMR (300 MHz, CD 3 OD) δ 7.45 (m, 5H), 4.53 (t, 1H, J=13.44 Hz), 3.64 (b, 1H), 3.17-2.64 (m, 5H), 1.46-0.86 (m, 7H);  13 C NMR (75 MHz, CD 3 OD) δ 171.4, 135.9, 130.1, 128.8, 126.9, 55.4, 54.9, 53.2, 45.6, 45.0, 42.6, 35.8, 35.3, 18.8, 13.4; HRMS m/z: (M+H) +  calcd for C 14 H 21 N 2 O 233.1654, found 233.1652.                           
     N-(Benzoyl)-3-iso-propylpiperazine XXXIII.  1 H NMR (300 MHz, CD 3 OD) δ 7.45 (m, 5H), 4.30 (m, 1H), 3.64 (m, 1H), 3.10-2.40 (m, 5H), 1.70-0.75 (m, 7H);  13 C NMR (75 MHz, CD 3 OD) δ 171.5, 135.9, 130.5, 129.3, 126.9, 61.7, 61.1, 51.2, 45.9, 45.4, 42.5, 31.2, 30.7, 18.3; HRMS m/z: (M+H) +  calcd for C 14 H 21 N 2 O 233.1654, found 233.1654.                           
     N-(Benzoyl)-3-pentylpiperazine XXXIV.  1 H NMR (300 MHz, CD 3 OD) δ 7.47 (m, 5H), 4.50 (t, 1H, J=17.85 Hz), 3.62 (b, 1H), 3.17-2.64 (m, 5H), 1.46-0.87 (m, 11H);  13 C NMR (75 MHz, CD 3 OD) δ 171.4, 135.9, 130.1, 129.3, 126.8, 55.6, 55.2, 53.1, 45.6, 45.0, 42.5, 33.6, 33.0, 32.0, 28.9, 25.9, 25.3, 22.6, 13.4; HRMS m/z: (M+H) +  calcd for C 16 H 25 N 2 O 261.1967, found 261.1969.                           
     N-(Benzoyl)-3-iso-butylpiperazine XXXV. MS m/z: (M+H) +  calcd for C 15 H 23 N 2 O: 247.18, found 247.22. HPLC retention time: 1.04 minutes (Method C).                           
     N-(Benzoyl)-3-tert-butylpiperazine XXXVI.  1 H NMR (300 MHz, CD 3 OD) δ 7.45 (m, 5H), 4.70 (m, 1H), 3.66 (m, 1H), 3.17-2.43 (m, 5H), 1.17-0.84 (m, 9H);  13 C NMR (75 MHz, CD 3 OD) δ 171.6, 135.9, 131.0, 129.4, 126.9, 65.3, 64.6, 49.6, 46.5, 45.9, 43.7, 42.3, 32.7.25.7; HRMS m/z: (M+H) +  calcd for C 15 H 23 N 2 O 247.1810, found 247.1815.                           
     N-(Benzoyl)-cis-3,5-di-methylpiperazine XXXVII.  1 H NMR (300 MHz, CD 3 OD) δ 7.43 (m, 5H), 4.55 (d, 1H,J=12.0 Hz), 3.55 (d, 1H, J=9.60 Hz), 2.74-2.38 (m, 5H), 1.13-0.94 (m, 6H);  13 C NMR (75 MHz, CD 3 OD) δ 170.5, 135.5, 129.6, 128.3, 126.6, 53.4, 50.9, 50.2, 17.7, 17.3; HRMS m/z: (M+H) +  calcd for C 13 H 19 N 2 O 219.1497, found 219.1492.                           
     N-(Benzoyl)-3-trifluoromethylpiperazine XXXVIII. MS m/z: (M+H) +  calcd for C 12 H 14 F 3 N 2 O: 259.11, found 259.05. HPLC retention time: 0.65 minutes (Method A).                           
     N-(Benzoyl)-3-ethoxycarbonylpiperazine XXXIX. MS m/z: (M+H) +  calcd for C 14 H 19 N 2 O 3 : 263.14, found 263.20. HPLC retention time: 0.80 minutes (Method C).                           
     N-(Benzoyl)-2-methylpiperazine XL.  1 H NMR (300 MHz, CD 3 OD) δ 7.47 (m, 5H), 3.30-2.70 (m, 7H), 1.36 (d, 3H, J=6.90 Hz);  13 C NMR (75 MHz, CD 3 OD) δ 171.0, 135.4, 129.7, 128.5, 126.3, 48.5, 44.3, 14.5; HRMS m/z: (M+H) +  calcd for C 12 H 17 N 2 O 205.1341, found 205.1341.                           
     N-(Benzoyl)-2-ethylpiperazine XLI.  1 H NMR (300 MHz, CD 3 OD) δ 7.49 (m, 5H), 3.34-2.80 (m, 7H), 2.10-1.70 (m, 2H), 0.85 (b, 3H);  13 C NMR (75 MHz, CD 3 OD) δ 171.5, 135.1, 129.8, 128.5, 126.5, 48.5, 46.0, 43.9, 21.8, 9.6; HRMS m/z: (M+H) +  calcd for C 13 H 19 N 2 O 219.1497, found 219.1501.                           
     N-(Benzoyl)-2-propylpiperazine XLII.  1 H NMR (300 MHz, CD 3 OD) δ 7.50 (m, 5H), 3.60-2.80 (m, 7H), 2.10-0.70 (m, 7H); 13C NMR (75 MHz, CD 3 OD) δ 172.5, 135.0, 129.9, 128.6, 126.7, 48.7, 46.2, 43.8, 30.9, 18.9, 13.1; HRMS m/z: (M+H) +  calcd for C 14 H 21 N 2 O 233.1654, found 233.1650.                           
     N-(Benzoyl)-2-iso-propylpiperazine XLIII.  1 NMR (300 MHz, CD 3 OD) δ 7.50 (b, 5H), 4.40 (m, 1H), 3.60-2.50 (m, 6H), 1.10-0.70 (m, 7H);  13 C NMR (75 MHz, CD 3 OD) δ 171.1, 135.0, 130.0, 128.7, 127.0, 60.6, 54.1, 43.9, 42.3, 25.4, 19.3, 18.4; HRMS m/z: (M+H) +  calcd for C 14 H 21 N 2 O 233.1654, found 233.1653.                           
     N-(Benzoyl)-2-pentylpiperazine XLIV.  1 H NMR (300 MHz, CD 3 OD) δ 7.47 (b, 5H), 3.40-2.80 (m, 7H), 2.10-0.70 (m, 11H); 13C NMR (75 MHz, CD 3 OD) δ 71.2, 135.0, 129.9, 128.6, 126.7, 48.7, 46.2, 43.8, 31.0, 28.8, 25.3, 22.2, 13.4; HRMS m/z: (M+H) +  calcd for C 16 H 25 N 2 O 261.1967, found 261.1970.                           
     N-(Benzoyl)-2-iso-butylpiperazine XLV. MS m/z: (M+H) +  calcd for C 15 H 23 N 2 O: 247.18, found 247.23. HPLC retention time: 1.06 minutes (Method C).                           
     N-(Benzoyl)-2-tert-butylpiperazine XLVI.  1 H NMR (300 MHz, CD 3 OD) δ 7.45 (m, 5H), 4.53 (t, 1H, J=5.70 Hz), 3.60-2.60 (m, 6H), 1.14 (s, 9H);  13 C NMR (75 MHz, CD 3 OD) δ 173.5, 136.7, 129.9, 128.9, 126.6, 55.9, 44.8, 44.5, 42.7, 36.5, 27.8; HRMS m/z: (M+H) +  calcd for C 15 H 23 N 2 O 247.1810, found 247.1808.                           
     N-(Benzoyl)-cis-2,6-di-methylpiperazine XLVII.  1 H NMR (300 MHz, CD 3 OD) δ 7.45 (m, 5H), 4.18 (b, 2H), 2.85 (m, 4H), 1.33 (d, 6H, J=6.90 Hz);  13 C NMR (75 MHz, CD 3 OD) δ 172.0, 136.7, 128.9, 128.3, 125.8, 49.1, 47.1, 19.2; HRMS m/z: (M+H) +  calcd for C 13 H 19 N 2 O 219.1497, found 219.1491.                           
     N-(Benzoyl)-3-methoxycarbonyltetrahydropyrazine XLVIII. MS m/z: (M+H) +  calcd for C 13 H 15 N 2 O 3 : 247.11, found 247.13. HPLC retention time: 1.00 minutes (Method C).                           
     3-Hydroxylmethyl-benzoylpiperazine XLIX. MS m/z: (M+H) +  calcd for C 12 H 17 N 2 O 2 : 221.13, found 221.17. HPLC retention time: 0.32 minutes (Method C).                           
     C. Coupling of Mono-benzoyl Piperazines with Glyoxyl Chlorides                           
     To a solution of indole glyoxoyl chloride V (1 eq) in dry CH 2 Cl 2  was added substituted benzoylpiperazine (1 eq) at room temperature. The mixture was then cooled down to 0° C., followed by dropwise addition of diisopropylamine (1.3 eq). After 5 min., the reaction mixture was warmed to room temperature and was shaken for 3 hr. The resulting crude products XL were purified by preparative HPLC and characterized as shown in Table 6. 
     Preparation of N-(Benzoyl)-3-hydroxylmethyl-N′-[(7-methoxycarbonyl-indol-3-yl)-oxoacetyl]-piperazine Example 98 
     
       
                 
         
             
             
         
      
     
     To a stirred solution of 3-hydroxylmethyl-benzoylpiperazine XLIX (8.0 mg, 0.036 mmol) in acetonitrile (5 ml) was added BSTFA (8.1 mg, 0.036 mmol). After stirring for 30 minutes at room temperature, (7-methoxycarbonyl-indol-3-yl)-oxoacetyl chloride (8.1 mg, 0.036 mmol) and pyridine (0.5 ml) were added. The reaction was stirred for another 2 hours at room temperature. Concentration under vaccum provided a residue, which was then purified by Shimazu HPLC purification system to give 2 mg of N-(benzoyl)-3-hydroxylmethyl-N′-[(7-methoxycarbonyl-indol-3-yl)-oxoacetyl]-piperazine (Example 98). 
     D. Hydrolysis of Ester Group to Acid Group: 
     Preparation of N-(Benzoyl)-3-hydroxycarbonyl-N′-[(4-fluoro-indol-3-yl)-oxoacetyl]-piperazine (Example 101) 
     
       
                 
         
             
             
         
      
     
     To a stirred solution of N-(benzoyl)-3-ethoxycarbonyl-N′-[(4-fluoro-indol-3-yl)-oxoacetyl]-piperazine (100 mg, 0.02 mmol) in methanol (1 ml) and water (1 ml), was added potassium carbonate (9 mg, 0.06 mmol). After stirring for 8 hours at room temperature, the product was concentrated in vacuo to give a residue which was purified by preparative HPLC to yield 2 mg of N-(benzoyl)-3-hydroxycarbonyl-N′-[(4-fluoro-indol-3-yl)-oxoacetyl]-piperazine (Example 101). 
     Preparation of N-(Benzoyl)-3-(R)-methyl-N′-[(7-hydroxycarbonyl-indol-3-yl)-oxoacetyl]-piperazine (Example 137) 
     
       
                 
         
             
             
         
      
     
     To a stirred solution of N-(benzoyl)-3-(R)-methyl-N′-[(7-methoxycarbonyl-indol-3-yl)-oxoacetyl]-piperazine (20 mg, 0.05 mmol) in 0.5N sodium methoxide in methanol (5 ml), was added 0.5 ml of water. After stirring for 8 hours at room temperature, 10% HCl was added to the reaction mixture to pH=6. N-(benzoyl)-3-(R)-methyl-N ′-[(7-hydroxycarbonyl-indol-3-yl)-oxoacetyl]-piperazine (Example 137) precipated out from the solution, which was collected via filtration. 
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 6 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 HPLC 
                   
               
               
                 Exam- 
                   
                   
                 retention 
               
               
                 ple 
                   
                   
                 time 
                 MS Data 
               
               
                 # 
                 R1 
                 W 
                 (min) 
                 (M+H) +   
               
               
                   
               
             
          
           
               
                 91 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.27 A   
                 394 
               
               
                   
               
               
                 92 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.32 A   
                 408 
               
               
                   
               
               
                 93 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 0.92 B   
                 394 
               
               
                   
               
               
                 94 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.32 A   
                 394 
               
               
                   
               
               
                 95 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.32 A   
                 394 
               
               
                   
               
               
                 96 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.29 A   
                 408 
               
               
                   
               
               
                 97 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.29 A   
                 408 
               
               
                   
               
               
                 98 
                 4-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.44 A   
                 450 
               
               
                   
               
               
                 99 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.23 A   
                 432 
               
               
                   
               
               
                 100 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.60 A   
                 492 
               
               
                   
               
               
                 101 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.25 A   
                 424 
               
               
                   
               
               
                 102 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.41 B   
                 434 
               
               
                   
               
               
                 103 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.39 A   
                 434 
               
               
                   
               
               
                 104 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.57 A   
                 434 
               
               
                   
               
               
                 105 
                 7-OMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.55 
                 406 
               
               
                   
               
               
                 106 
                 4,7-difluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.33 
                 412 
               
               
                   
               
               
                 107 
                 4,5,6,7- tetrafluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.57 
                 448 
               
               
                   
               
               
                 108 
                 4,5,6,7- tetrafluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.58 
                 448 
               
               
                   
               
               
                 109 
                 7-Nitro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.48 
                 421 
               
               
                   
               
               
                 110 
                 7-Ethyl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.58 
                 404 
               
               
                   
               
               
                 111 
                 7-OMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.39 
                 406 
               
               
                   
               
               
                 112 
                 7-Nitro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.49 
                 421 
               
               
                   
               
               
                 113 
                 6-Chloro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.55 
                 411 
               
               
                   
               
               
                 114 
                 5,6-dichloro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.71 
                 446 
               
               
                   
               
               
                 115 
                 4-Chloro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.45 
                 410 
               
               
                   
               
               
                 116 
                 4-Chloro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.45 
                 410 
               
               
                   
               
               
                 117 
                 5,6-dichloro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.72 
                 446 
               
               
                   
               
               
                 118 
                 5-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.43 
                 394 
               
               
                   
               
               
                 119 
                 7-Ethyl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.55 
                 1.67 
               
               
                   
               
               
                 120 
                 4-Bromo 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.48 
                 456 
               
               
                   
               
               
                 121 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.62 A   
                 476 
               
               
                   
               
               
                 122 
                 4-Br 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.48 
                 456 
               
               
                   
               
               
                 123 
                 5-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.42 
                 394 
               
               
                   
               
               
                 124 
                 6-Chloro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.57 
                 410 
               
               
                   
               
               
                 125 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.61 A   
                 448 
               
               
                   
               
               
                 126 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.69 A   
                 462 
               
               
                   
               
               
                 127 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.67 A   
                 462 
               
               
                   
               
               
                 128 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.69 A   
                 462 
               
               
                   
               
               
                 129 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.76 A   
                 476 
               
               
                   
               
               
                 130 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.76 A   
                 476 
               
               
                   
               
               
                 131 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.71 A   
                 476 
               
               
                   
               
               
                 132 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.84 A   
                 490 
               
               
                   
               
               
                 133 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.85 A   
                 490 
               
               
                   
               
               
                 134 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.76 A   
                 476 
               
               
                   
               
               
                 135 
                 4-OMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.24 
                 406 
               
               
                   
               
               
                 136 
                 4-OMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.24 
                 406 
               
               
                   
               
               
                 137 
                 7-COOH 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.43 A   
                 420 
               
               
                   
               
               
                 138 
                 4-Fluoro-7- methyl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.37 
                 408 
               
               
                   
               
               
                 139 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.62 A   
                 448 
               
               
                   
               
               
                 140 
                 7-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.74 
                 394 
               
               
                   
               
               
                 141 
                 7-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.74 
                 394 
               
               
                   
               
               
                 142 
                 7-COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.65 A   
                 488 
               
               
                   
               
               
                 143 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.42 A   
                 488 
               
               
                   
               
               
                 144 
                 4-fluoro-7- bromo 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.12 
                 N.D 
               
               
                   
               
               
                 145 
                 4-Fluoro-7- COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.51 
                 452 
               
               
                   
               
               
                 146 
                 4-Fluoro-7- COOMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.39 
                 438 
               
               
                   
               
               
                 147 
                 4-Fluoro-7- OMe 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.31 
                 424 
               
               
                   
               
             
          
         
       
     
     Note in Table 6, and other tables herein, in the HPLC column, numbers with superscript “A”, “B,” or “C” refer to the HPLC method used (i.e. Methods A, B or C, respectively). 
     Preparation of Examples 148 -194 in Table 7 
     Step A.                           
     To substituted indole-3-glyoxylyl chloride V (1 eq) in CH 2 Cl 2  at room temperature was added tert-butyl 1-piperazinecarboxylate (1 eq) and diisopropylethylamine (1.5 eq). The solution was stirred for 2 hr at room temperature after which time LC/MS analysis indicated the completion of the reaction. The solvent was removed in vacuo and the resulting residue was diluted with ethyl acetate (250 ml) and diethylether (250 ml). The organic solution was then washed with water (100 ml×3) and brine (50 ml), dried over MgSO 4 , filtered and concentrated. To the light-yellow solid was then added 30 ml of 20% trifluoroacetic acid in CH 2 Cl 2 . The solution was concentrated and dried in vacuo to give the desired product VII. LC/MS analysis indicated this product was 100% pure and it was used for the next reaction without further purification. 
     Step B.                           
     To piperazine indole-3-glyoxylamide (1 eq) was added resin-bound 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (P-EDC) (7 eq) and carboxylic acid (RCOOH) (2 eq) in dichloroethane (DCE) or DMF(dimethylfornamide) in cases where the carboxylic acids are not soluble in DCE. The reaction was shaken for 12 hr at room temperature. The product XLI was filtered and concentrated. Products with purity less than 70% were diluted in methanol and purified using a Shimadzu automated preparative HPLC System. 
     Preparation of Example 195 in Table 7 
     Step A                           
     To a solution of tert-butyl-1-piperazine carboxylate (601 mg, 3.23 mmol) and 4-acetic acid imidazole (330 mg, 2.94 mmol) in dichloromethane (30 ml), were added DMAP (394 mg, 3.22 mmol) and EDC (616 mg, 3.22 mmol). The reaction mixture was stirred at room temperature for 21.5 hours. Removal of solvent in vacuo afforded a white solid, which was subjected to flash chromatography using a gradient elution (100% EtOAc, to 2% to 5% MeOH/EtOAc, to 1/5/95 NH 3 (sat. aq.)/MeOH/EtOAc) to give XLII as a white solid. 
     Step B                           
     To compound XXLII (130 mg, 0.464 mmol) was added a solution of HCl in dioxane (4 M, 5 ml), and the mixture stirred at room temperature for 3 hours. Removal of the excess reagent in vacuo afforded the hydrochloride salt XLIII as a white solid (100% conversion). 
     Step C                           
     4-Fluoroindole glyoxyl chloride was coupled with XLIII as described previously. 
     
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 7 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 HFLC 
                   
               
               
                   
                   
                   
                 Retention 
               
               
                   
                   
                   
                 Time 
                 MS Data 
               
               
                 Entry 
                 R 
                 Ar 
                 (min) 
                 (M+H) +   
               
               
                   
               
               
                 148 
                 4-Fluoro 
                 3-Thiophenyl 
                 1.74 
                 386 
               
               
                 149 
                 4-Fluoro 
                 1,2,3-Thiadiazolyl 
                 1.52 
                 388 
               
               
                 150 
                 4-Fluoro 
                 2-(4-Methoxy)- 
                 1.78 
                 416 
               
               
                   
                   
                 thiophenyl 
               
               
                 151 
                 4-Fluoro 
                 2-(5-Methylthio)- 
                 2.28 
                 432 
               
               
                   
                   
                 thiophenyl 
               
               
                 152 
                 4-Fluoro 
                 2-(3-Bromo)- 
                 2.22 
                 465 
               
               
                   
                   
                 thiophenyl 
               
               
                 153 
                 4-Fluoro 
                 2-(5-Bromo)- 
                 2.29 
                 465 
               
               
                   
                   
                 thiophenyl 
               
               
                 154 
                 4-Fluoro 
                 2-Pyrazinyl 
                 1.76 
                 382 
               
               
                 155 
                 4-Fluoro 
                 2-(5-Methyl)- 
                 2.24 
                 400 
               
               
                   
                   
                 thiophenyl 
               
               
                 156 
                 4-Fluoro 
                 2-(5-Chloro)- 
                 2.08 
                 421 
               
               
                   
                   
                 thiophenyl 
                   
               
               
                 157 
                 4-Fluoro 
                 2-Indolyl 
                 2.07 
                 419 
               
               
                 158 
                 4-Fluoro 
                 4-(2-Methyl)- 
                 2.00 
                 401 
               
               
                   
                   
                 thiazolyl 
               
               
                 159 
                 4-Fluoro 
                 4-Thiazolyl 
                 1.05 
                 387 
               
               
                 160 
                 4-Fluoro 
                 4-Pyridyl 
                 0.84 
                 381 
               
               
                 161 
                 4-Fluoro 
                 3-(6-Methyl)-pyridyl 
                 0.87 
                 395 
               
               
                 162 
                 4-Fluoro 
                 3-Pyridyl 
                 0.93 
                 381 
               
               
                 163 
                 4-Fluoro 
                 5-Isoxazolyl 
                 1.08 
                 371 
               
               
                 164 
                 4-Fluoro 
                 2-Furanyl 
                 1.17 
                 370 
               
               
                 165 
                 4-Fluoro 
                 3-Pyrazolyl 
                 1.03 
                 370 
               
               
                 166 
                 4-Fluoro 
                 2-Pyridyl 
                 1.08 
                 381 
               
               
                 167 
                 4-Fluoro 
                 3-Furanyl 
                 1.14 
                 370 
               
               
                 168 
                 4-Fluoro 
                 2-Thiophenyl 
                 1.24 
                 386 
               
               
                 169 
                 4-Fluoro 
                 2-Benzofuranyl 
                 1.48 
                 420 
               
               
                 170 
                 4-Fluoro 
                 2-(5-Bromo)-furanyl 
                 1.37 
                 449 
               
               
                 171 
                 4-Fluoro 
                 2-(3-Methyl)-furanyl 
                 1.30 
                 384 
               
               
                 172 
                 4-Fluoro 
                 2-(3-Chloro)- 
                 1.34 
                 420 
               
               
                   
                   
                 thiophenyl 
               
               
                 173 
                 4-Fluoro 
                 3-(5-Chloro-4- 
                 1.45 
                 451 
               
               
                   
                   
                 methoxy)- 
               
               
                   
                   
                 thiophenyl 
               
               
                 174 
                 4-Fluoro 
                 2-(5-Chloro)-furanyl 
                 1.32 
                 404 
               
               
                 175 
                 4-Chloro 
                 3-Thiophenyl 
                 2.02 
                 403 
               
               
                 176 
                 4-Chloro 
                 2-[5-(Pyrid-2-yl)]- 
                 2.07 
                 480 
               
               
                   
                   
                 thiophenyl 
               
               
                 177 
                 4-Chloro 
                 2-Thieno[3,2-B]- 
                 2.33 
                 459 
               
               
                   
                   
                 thiophenyl 
               
               
                 178 
                 4-Chloro 
                 2-(5-Methylthio)- 
                 2.33 
                 449 
               
               
                   
                   
                 thiophenyl 
               
               
                 179 
                 4-Chloro 
                 2-(5-Bromo)- 
                 2.34 
                 481 
               
               
                   
                   
                 thiophenyl 
               
               
                 180 
                 4-Chloro 
                 2-Pyrazinyl 
                 1.91 
                 398 
               
               
                 181 
                 4-Chloro 
                 2-Pyridyl 
                 1.92 
                 397 
               
               
                 182 
                 4-Chloro 
                 2-Benzothiophenyl 
                 2.36 
                 453 
               
               
                 183 
                 4-Chloro 
                 2-(5-Chloro)- 
                 2.33 
                 437 
               
               
                   
                   
                 thiophenyl 
               
               
                 184 
                 4-Chloro 
                 2-(3-Chloro)- 
                 2.27 
                 437 
               
               
                   
                   
                 thiophenyl 
               
               
                 185 
                 4-Chloro 
                 2-Indolyl 
                 2.33 
                 436 
               
               
                 186 
                 4-Chloro 
                 4-(2-Methyl)- 
                 2.22 
                 418 
               
               
                   
                   
                 thiazolyl 
               
               
                 187 
                 4-Chloro 
                 4-Thiazolyl 
                 1.20 
                 404 
               
               
                 188 
                 4,7-Difluoro 
                 2-(5-Chloro)-furanyl 
                 1.39 
                 422 
               
               
                 189 
                 4,7-Difluoro 
                 2-(5-Bromo)-furanyl 
                 1.46 
                 467 
               
               
                 190 
                 4,7-Difluoro 
                 2-furanyl 
                 1.28 
                 388 
               
               
                 191 
                 4,7-Difluoro 
                 2-Pyridyl 
                 1.17 
                 399 
               
               
                 192 
                 4,7-Difluoro 
                 2-(3,4-Dichloro)- 
                 1.47 
                 457 
               
               
                   
                   
                 furanyl 
               
               
                 193 
                 4,7-Difluoro 
                 2-(5- 
                 1.54 
                 456 
               
               
                   
                   
                 Trifluoromethyl)- 
               
               
                   
                   
                 furanyl 
               
               
                 194 
                 4,7-Difluoro 
                 2-(4,5-Dimethyl)- 
                 1.49 
                 416 
               
               
                   
                   
                 furanyl 
               
               
                 195 
                 4-Fluoro 
                 2-Imidazolyl 
                 0.81 
                 370 
               
               
                   
               
             
          
         
       
     
     Synthesis of Examples 195-215 in Table 8 
     Step A                           
     To pentafluorophenol (1.84 g, 10 mmol) in DMF (15 mL) was added picolinic acid (1.23 g, 10 mmol) and EDC (1.91 g, 10 mmol) at room temperature for 4 h. The crude product XLIV was diluted with CH 2 Cl 2  and was washed with water, 0.1 M HCl and brine. The organic phase was dried over MgSO4, filtered and concentrated. The crude material was used without further purification. 
     Step B                           
     To a solution of (R)-methyl pierazine (1.0 g, 10 mmol) in DMF (20 mL) at room temperature was slowly added a solution of picolinic acid pentafluorophenylester XLIV in DMF (20 mL). The reaction mixture was stirred at room temperature for 16 h. The product was diluted with CH2Cl2 and was washed with water and brine, dried over MgSO4, filtered and concentrated. The product XLV was then purified by flash chromatography (100% EtOAc—50% MeOH/EtOAc). 
     Piperazine XLVI was prepared using similar methodology to that outlined in Step A and Step B above.                           
     Step C                           
     To the mixture of indole glyoxylchloride V (1 eq) and 3-(R)-methyl-1-piperazinecarboxylate XLV or XLVI (1 eq) in THF was added diisopropylethylamine (1.5 eq) dropwise at 0° C. The solution was stirred for additional 2 hr at room temperature and the resulting crude compounds were purified by preparative HPLC. 
     
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 8 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 HPLC 
                   
               
               
                   
                   
                   
                 Retention 
               
               
                   
                   
                   
                 Time 
                 MS Data 
               
               
                 Entry 
                 R 
                 Ar 
                 (min) 
                 (M+H) +   
               
               
                   
               
               
                 196 
                 4,7- 
                 2-Pyridyl 
                 1.23 
                 413 
               
               
                   
                 difluoro 
               
               
                 197 
                 4-Fluoro-7- 
                 2-Pyridyl 
                 1.17 
                 409 
               
               
                   
                 methyl 
               
               
                 198 
                 4,7- 
                 2-(5-Bromo)- 
                 1.52 
                 481 
               
               
                   
                 Difluoro 
                 furanyl 
               
               
                 199 
                 4,7- 
                 2-(5-Bromo)- 
                 1.45 
                 506 
               
               
                   
                 Dimethoxy 
                 furanyl 
               
               
                 200 
                 7-COOMe 
                 2-(5-Bromo)- 
                 1.70 
                 504 
               
               
                   
                   
                 furanyl 
               
               
                 201 
                 4,7- 
                 2-Pyridyl 
                 1.23 
                 413 
               
               
                   
                 Difluoro 
               
               
                 202 
                 4-Fluoro 
                 2-Pyridyl 
                 1.07 
                 395 
               
               
                 203 
                 4-Chloro 
                 2-Pyridyl 
                 1.22 
                 411 
               
               
                 204 
                 4-Bromo 
                 2-Pyridyl 
                 1.25 
                 457 
               
               
                 205 
                 5-Fluoro 
                 2-Pyridyl 
                 1.21 
                 395 
               
               
                 206 
                 6-Chloro 
                 2-Pyridyl 
                 1.43 
                 411 
               
               
                 207 
                 7-Fluoro 
                 2-Pyridyl 
                 1.29 
                 395 
               
               
                 208 
                 7-Methoxy 
                 2-Pyridyl 
                 1.26 
                 407 
               
               
                 209 
                 7-Methyl 
                 2-Pyridyl 
                 1.31 
                 391 
               
               
                 210 
                 7-Ethyl 
                 2-Pyridyl 
                 1.46 
                  403* 
               
               
                 211 
                 4-methoxy- 
                 2-Pyridyl 
                 1.22 
                 441 
               
               
                   
                 7-chloro 
               
               
                 212 
                 7-cyano 
                 2-Pyridyl 
                 1.24 
                 402 
               
               
                 213 
                 4-Methoxy 
                 2-Pyridyl 
                 1.09 
                 407 
               
               
                 214 
                 4- 
                 2-Pyridyl 
                 1.28 
                 487 
               
               
                   
                 Methoxy- 
               
               
                   
                 7-Bromo 
               
               
                 215 
                 4-Fluoro-7- 
                 2-Pyridyl 
                 1.16 
                 425 
               
               
                   
                 Methoxy 
               
               
                   
               
               
                 *(M-H) measured in negative ionization mode  
               
             
          
         
       
     
     Additional Analytical Data for Selected Compounds 
     1-(4-Methylbenzoyl)-4-[(1H-indol-3-yl)oxoacetyl]piperazine (Example 15)                           
     MS (ESI): 376 (M+H) + ; IR (KBr): 3150, 3104, 2922, 2868, 1780, 1629, 1519, 1433, 1272, 1158, 1006, 829, 775, 753, 645 cm −1 ;  1 H NMR (CDCl 3 ) δ 2.40 (s, 3H), 3.60-3.79 (m, 8H), 7.23-7.45 (m, 7H), 7.99 (d, J=3.1 Hz, 1H), 8.34 (m, 1H), 9.10 (s, 1H). 
     1-(Benzoyl)-4-[(1H-4-fluoroindol-3-yl)oxoacetyl]piperazine (Example 19)                           
     MS (ESI): 380 (M+H) +  HRMS calcd for C 21 H 18 FN 3 O 3  [(M+H)] + , 380.14105; found, 380.1412.  1 H-NMR (DMF-d7) δ 12.71(s, 1H), 8.02 (s, 1H), 7.46-7.56 (m, 6H), 7.31 (ddd, J=4.71, 7.99 Hz, 1H), 7.03 (dd, J=7.84, 10.98 Hz, 1H), 3.77 (br. s, 4H), 3.57 (br. s, 4H). 
     1-(Benzoyl)-4-[(1H-4-chloroindol-3-yl)oxoacetyl]piperazine (Example 20)                           
     MS (ESI): 396 (M+H) +  HRMS calcd for C 21 H 18 ClN 3 O 3  [(M+H)] + , 396.11150; found, 396.1105. 1H NMR (DMF-d7) δ 12.74 (br. s, 1H), 8.03 (s,1H), 7.57-7.65 (m, 1H), 7.50 (s, 5H), 7.28-7.38 (m, 1H), 3.42-3.83 (m, 8H). 
     1-(Benzoyl)-4-[(1H-6-fluoroindol-3-yl)oxoacetyl]piperazine (Example 28)                           
     MS (ESI): 380 (M+H) +  HRMS calcd for C 21 H 18 FN 3 O 3  [(M+H)] + , 380.14105; found, 380.1414. 1H NMR (DMF-d7) δ 12.09 (s, 1H), 7.81 (dd, J=5.64, 8.46 Hz, 1H), 7.62(s, 1H), 7.08 (s, 5H), 7.01 (dd, J=2.28, 9.61 Hz, 1H), 2.86-3.52 (m, 8H). Anal. Calcd for C 21 H 18 FN 3 O 3 : C, 66.48; H, 4.78, N, 11.08. Found: C, 66.09, H, 4.78, N, 10.94. 
     1-(Benzoyl)-4[(1H-4,6-difluoroindol-3-yl)oxoacetyl]piperazine (Example 42)                           
       1 H NMR (DMSO-d 6 ) δ 3.40 (br s, 4H), 3.65 (br s, 4H), 7.06 (t, 1H), 7.20 (d, J=8.49 Hz, 1H), 8.27 (s, 1H), 12.65 (br s, 1 H). Anal. Calcd for C 21 H 17 F 2 N 3 .O 3 0.322 H 2 O: C, 62.57; H, 4.41; N, 10.42; Found: C, 62.56; H, 4.46; N, 10.11. 
     1-(benzoyl)-4-[(1H-5-fluoro-7-bromoindol-3-yl)oxoacetyl]piperazine (Example 48)                           
       1 H NMR (DMSO-d 6 ) δ 3.40 (br s, 4H), 3.67 (br s, 4H), 7.43 (br s, 5H), 7.54 (dd, J=2.25, 8.97 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 8.29 (s, 1H), 12.79 (br s, 1 H). Anal. Calcd for C 21 H 17 N 3 BrF 3 .1.2 H 2 O: C, 52.56; H, 4.07; N, 8.76. Found: C, 52.33; H, 3.69; N, 8.50. 
     1-(benzoyl)-4-[(1H-4-fluoro-7-trifluoroethoxyindol-3-yl)oxoacetyl]piperazine (Example 51)                           
       1 H NMR (DMSO-d 6 ) δ 3.61 (br m, 4H), 3.80 (br m, 4H), 4.52 (m, 2H), 6.68 (m, 1H), 6.91 (m, 1H), 7.45 (s, 5H), 8.07 (d, J=2.91 Hz, 1H), 9.37 (s 1H). Anal. Calcd for C 23 H 19 F 4 N 3  O 4 .0.59 H 2 O, 0.47 ethyl acetate C, 56.44; H, 4.56; N,=7.94; Found: C, 56.44; H, 4.16; N,=8.19. 
     1-(Benzoyl)-4-[(1H-4-bromo-7-fluoroindol-3-yl)oxoacetyl]piperazine (Example 55)                           
       1 H NMR (CDCl 3 ) δ 3.6-3.9 (br m, 8H), 6.92 (t, 1H), 7.42 (br s, 6H), 8.09 (s, 1H), 9.5 (br s, 1 H). Anal. Calcd for C 21 H 17 BrFN 3 O 3 .0.25 H 2 O, 0.21 ethyl acetate: C, 54.5; H, 4.02; N, 16.6; Found: C, 54.50; H, 4.09; N,  8.44. Example  90                          
       1 H NMR: (DMSO-d 6 ) δ 3.66 (br. s, 4H), 7.27 (t, J=8.31 Hz, 1H), 7.43 (br. s, 7H), 8.01 (m, 1H), 8.14 (s, 1H), 10.14 (s, 1H), 12.42 (br. s, 1H) MS: (M+H) +  480.00, (M−H) 406.02; IR: 1636,1592 cm −1 . 
     N-(Benzoyl)-(R)-3-methyl-N′-[(4-fluoro-indol-3-yl)-oxoacetyl]-piperazine (Example 93)                           
       1 H NMR (300 MHz, CD 3 OD) δ 8.20 (s, 0.5H), 8.15 (s, 0.5H), 7.48-6.90 (m, 8H), 5.00-3.00 (m, 7H), 1.30 (b, 3H). MS m/z: (M+H) +  calcd for C 22 H 21 FN 3 O 3 : 394.16; found 394.23. HPLC retention time: 0.92 minutes (Method B). 
     N-(Benzoyl)-(S)-3-methyl-N′-[(fluoro-indol-3-yl)-oxoacetyl]-piperazine (Example 94)                           
       1 H NMR (300 MHz, CD 3 OD) δ 8.20 (s, 0.5H), 8.13 (s, 0.5H), 7.48-6.90 (m, 8H), 5.00-3.00 (m, 7H), 1.30 (b, 3H). MS m/z: (M+H) +  calcd for C 22 H 21 FN 3 O 3 : 394.16; found 394.25. HPLC retention time: 1.32 minutes (Method A). 
     N-(Benzoyl)-2-methyl-N′-[(4-fluoro-indol-3-yl)-oxoacetyl]-piperazine (Example 95)                           
       1 H NMR (300 MHz, CD 3 OD) δ 8.20 (s, 0.5H), 8.13 (s, 0.5H), 7.48-6.90 (m, 8H), 5.00-3.00 (m, 7H), 1.37 (d, J=6.78 Hz, 1.5H), 1.27 (d, J=6.84 Hz, 1.5H). MS m/z: (M+H) +  calcd for C 22 H 21 FN 3 O 3 : 394.16; found 394.23. HPLC retention time: 1.32 minutes (Method A). 
     N-(Benzoyl)-3-hydroxylmethyl-N′-[(4-fluoro-indol-3-yl)-oxoacetyl]-piperazine (Example 99)                           
       1 H NMR (300 MHz, CD 3 OD) δ 7.50 (b, 5H), 7.39-6.72 (m, 4H), 5.00-2.80 (m, 9H). MS m/z: (M+Na) +  calcd for C 22 H 20 FN 3 NaO 4 : 432.13; found 432.19. HPLC retention time: 1.23 minutes (Method A). 
     N-(benzoyl)-(R)-3-methyl-N′-[(7-methoxycarbonyl-indol-3-yl)-oxoacetyl]-piperazine (Example 102)                           
     1H NMR (300 MHz, CD 3 OD) 8.50 (d, J=6.48 Hz, 1H), 8.15 (s, 0.5H), 8.10 (s, 0.5H), 8.00 (d, J=7.38 Hz, 1H), 7.42 (m, 6H), 5.00-3.00 (m, 7H), 4.02 (s, 3H), 1,34 (b, 3H);  13 C NMR (75 MHz, CD 3 OD); δ 186.2, 166.9, 137.9, 135.3, 130.3, 128.8, 127.2, 126.9, 126.4, 122.7, 114.5, 114.0, 51.6, 50.7, 45.6, 15.4, 14.2. MS m/z: (M+H) +  calcd for C 24 H 24 N 3 O 5 : 434.17; found 434.24. HPLC retention time: 1.41 minutes (Method B). 
     N-(Benzoyl)-3-hydroxylmethyl-N′-[(7-methoxycarbonyl-indol-3-yl)-oxoacetyl]-piperazine (Example 98)                           
       1 H NMR (300 MHz, CD 3 OD) δ 8.54 (b, 1H), 8.24 (s, 0.5H), 8.16 (s, 0.5H), 8.00 (m, 1H), 7.47 (m, 6H), 5.00-3.00 (m, 9H), 4.02 (s, 3H). MS m/z: (M+H) +  calcd for C 24 H 24 N 3 O 6 : 450.17; found 450.24. HPLC retention time: 1.44 minutes (Method A). 
     N-(Benzoyl)-2-methoxycarbonyl-N′-[(7-methoxycarbonyl-indol-3-yl)-oxoacetyl]-tetrahydropyrazine (Example 121)                           
       1 H NMR (500 MHz, CD 3 OD) δ 8.50 (m, 1H), 8.21 (s, 1H), 7.93 (m, 1H), 7.44 (m, 7H), 4.00 (s, 6H), 4.00-3.30 (m, 4H);  13 C NMR (125 MHz, CD 3 OD) δ 184.7, 167.9, 166.1, 165.3, 165.1, 164.9, 140.2, 137.2, 132.5, 129.6, 128.3, 128.2, 127.6, 125.1, 123.9, 116.0, 115.6, 115.0, 52.8, 52.6, 47.0, 43.8. MS m/z: (M+H) +  calcd for C 25 H 22 N 3 O 7 : 476.15; found 476.21. HPLC retention time: 1.62 minutes (Method A). 
     N-(Benzoyl)-2-propyl-N′-[(7-methoxycarbonyl-indol-3-yl)-oxoacetyl]-piperazine (Example 126)                           
       1 H NMR (300 MHz, CD 3 OD) δ 8.50 (d, J=6.93 Hz, 1H), 8.17 (s, 0.5H), 8.08 (s, 0.5H), 7.98 (d, J=6.00 Hz, 1H), 7.45 (m, 6H), 5.00-2.90 (m, 7H), 4.02 (s, 3H), 1.70-0.60 (m, 7H);  13 C NMR (75 MHz, CD 3 OD) 5186.0, 167.6, 166.9, 138.0, 136.1, 135.8, 130.2, 128.9, 127.2, 126.9, 126.4, 122.7, 114.5, 114.1, 51.7, 46.2, 44.0, 41.3, 31.5, 19.2, 13.2, 12.9. MS m/z: (M+H) +  calcd for C 26 H 28 N 3 O 5 : 462.20; found 462.30. HPLC retention time: 1.69 minutes (Method A). 
     N-(Benzoyl)-(R)-3-methyl-N′-[(7-hydroxycarbonyl-indol-3-yl)-oxoacetyl]-piperazine (Example 137)                           
       1 H NMR (300 MHz, CD 3 OD) δ 8.46 (b, 1H), 8.14 (s, 0.5H), 8.09 (s, 0.5H), 8.00 (d, J=7.17 Hz, 1H), 7.43 (m, 6H), 5.00-2.90 (m, 7H), 1.32 (b, 3H);  13 C NMR (75 MHz, CD 3 OD) δ 186.3, 168.2, 167.1, 137.8, 135.3, 130.3, 128.8, 127.1, 126.9, 126.7, 122.7, 115.4, 113.9, 50.7, 45.6, 15.4, 14.2. MS m/z: (M+H) +  calcd for C 27 H 30 N 3 O 5 : 420.16; found 420.16. HPLC retention time: 1.43 minutes (Method A). 
     N-(Benzoyl)-3-trifluoromethyl-N′-[(7-methoxycarbonyl-indol-3-yl)-oxoacetyl]-piperazine (Example 142)                           
       1 H NMR (300 MHz, CD 3 OD) δ 8.52 (b, 1H), 8.03 (s, 1H), 8.02 (d, J=7.56 Hz, 1H), 7.45 (m, 6H), 5.00-3.00 (m, 7H), 4.03 (s, 3H). MS m/z: (M+H) +  calcd for C 24 H 21 F 3 N 3 O 5 : 488.14; found 488.15. HPLC retention time: 1.65 minutes (Method A). 
     N-(Benzoyl)-3-trifluoromethyl-N′-[(4-fluoro-indol-3-yl)-oxoacetyl]-piperazine (Example 143)                           
       1 H NMR (300 MHz, CD 3 OD) δ 8.11 (s, 1H), 7.50-6.90 (m, 9H), 5.00-3.00 (m, 7H). MS m/z: (M+H) +  calcd for C 24 H 21 F 3 N 3 O 5 : 488.14; found 488.12. HPLC retention time: 1.42 minutes (Method A). 
     N-(Benzoyl)-(R)-3-methyl-N′-[(4-fluoro-7-bromoindol-3-yl)-oxoacetyl]-piperazine (Example 144)                           
       1 H NMR (CDCl 3 ) δ 1.31 (br. s, 3H), 3.34 (br. s, 4H), 3.59 (br. s, 3H), 6.90 (t, J=8.7 Hz, 1H), 7.38 (br. s, 6H), 8.05 (br. s, 1H), 9.46 (br. s, 1H); MS: (M+H) +  473.80, (M−H) 470.02; IR: 1634, 1579 cm −1 ; Anal. calcd. for C22H19N3O3BrF. 0.6H2O C, 54.68; H, 4.21; N, 8.7. Found C, 54.46; H, 4.14; N, 8.56. 
     1-[(Pyrid-2-yl)oxo]-4-[(1H-4-fluoro-indol-3-yl)oxoacetyl]piperazine (Example 166)                           
     MS (ESI): 381 (M+H) + ;  1 H NMR (CDCl 3 ) δ 3.56 (m, 2H), 3.66 (m, 2H), 3.82-3.94 (m, 4H), 6.97 (m, 1H), 7.33 (m, 2H), 7.57 (m, 1H), 7.70 (m, 1H), 8.01 (m, 1H), 8.20 (s, 1H), 8.66 (m, 1H). 
     1-[(Pyrid-2-yl)oxo]-4-[(1H-4,7-difluoro-indol-3-yl)oxoacetyl]piperazine (Example 191)                           
     MS (ESI): 413 (M+H) + ;  1 H NMR (CDCl 3 ) δ 3.54-3.65 (m, 4H), 3.76-3.93 (m, 4H), 6.95 (m, 2H), 7.52 (m, 1H), 7.66 (m, 1H), 7.96 (m, 1H), 8.20 (m, 1H), 8.60 (m, 1H). Example 195                          
     MS (ESI): 370 (M+H) +1 H NMR: (CD 3 OD, δ=3.30 ppm) 8.82 (s, 1H), 8.21 (s,1H), 8.00 (s, 1H), 7.37-7.26 (m, 2H), 7.02-6.96 (m, 1H), 3.97(b s, 2H), 3.86 (app dd, J=6.4, 3.3, 4H), 3.64 (app dd, J=6.3, 4.0, 2H); LC/MS: (ES+) m/z (M+H) + =370, Analytical HPLC (R t =0.810 min) purity: 100%. Example 212                          
     MS (ESI): 402 (M+H) +   1 H NMR: (CD 3 OD, δ=3.30 ppm) 8.65-8.51 (m, 2H), 8.24-8.19 (m, 1H), 8.02-7.94 (m, 1H), 7.73-7.68 (m, 2H), 7.56-7.39 (m, 2H), 4.63-3.09 (b m, 7H), 1.35 (m, 3H). 
     Procedures for making compounds of formula I are shown in Schemes 14-22, and further exemplified in Tables 14-18.                           
     Starting indoles 1 (Scheme 14) are known or are readily prepared according to literature procedures, such as those described in Gribble, G. (Ref. 24) or Bartoli et al (Ref. 36). The indoles 1 are treated with oxalyl chloride in either THF (tetrahydrofuran) or ether to afford the desired glyoxyl chlorides 2 according to literature procedures (Lingens, F. et al, Ref. 25). The intermediate glyoxyl chlorides 2 are then coupled with benzoyl piperazine 3 (Desai, M. et al, Ref. 26) under basic conditions to afford 4.                           
     Treatment of indole glyoxamide 4 (Scheme 15) with an alkylating agent (R 40 X) under basic conditions (BEMP or NaH) affords N-alkylated derivatives 5.                           
     N-acyl derivatives 6 are prepared by treatment of indole gyloxamide 4 with an acid chloride (R 40a COCl) in the presence of i-Pr 2 NEt (Scheme 16). Alternatively, bis-acylated products are prepared as shown in Scheme 17.                           
     Treatment of indole-3-glyoxyl chloride 2 (Scheme 17) with tert-butyl 1-piperazinecarboxylate 7 affords the coupled product 8. Removal of the Boc protecting group of 8 is effected with 20% TFA/CH 2 Cl 2  to yield 9. This product is then coupled with acid chloride (R 40c COCl) to afford bis-acyl products 10.                           
     Carbamates 11 are synthesised by reaction of indole glyoxamide 4 with chloroformate (R 40d OCOCl) in the presence of i-Pr 2 NEt or NaH (Scheme 18).                           
     Ureas are prepared by three methods. Direct treatment of indole glyoxamide 4 with carbamoyl chloride (R a R b NCOCl) in the presence of i-Pr 2 NEt affords the desired ureas 12 (Scheme 19).                           
     Alternatively, treatment of 4 (Scheme 20) with p-nitrophenylchloroformate and i-Pr 2 NEt affords p-nitrophenylcarbamate 13 which, on exposure to amine (R a R b NH), affords the desired urea 14.                           
     Finally, reaction of indole glyoxamide 4 with isocyanate (R a NCO) in the presence of i-Pr 2 NEt affords urea 15 (Scheme 21).                           
     Indole sulfonamides 15 (Scheme 22) are readily prepared by treatment of indole glyoxamide 4 with sulfonyl chloride (R a SO 2 Cl) in the presence of i-Pr 2 NEt. 
     
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 9 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 % 
               
               
                   
                   
                   
                 Inhibition 
               
               
                 Example # 
                 R 1   
                 R 40   
                 @ 10 μM 
               
               
                   
               
             
          
           
               
                 1 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 65 
               
               
                   
               
               
                 2 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 98 
               
               
                   
               
               
                 3 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 71 
               
               
                   
               
               
                 4 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 45 
               
               
                   
               
               
                 5 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 83 
               
               
                   
               
               
                 6 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 89 
               
               
                   
               
               
                 7 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 60 
               
               
                   
               
               
                 8 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 89 
               
               
                   
               
               
                 9 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 82 
               
               
                   
               
               
                 10 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 84 
               
               
                   
               
               
                 11 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 84 
               
               
                   
               
               
                 12 
                 2-Methyl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 69 
               
               
                   
               
               
                 13 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 14 
                 4-Chloro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 15 
                 6-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 97 
               
               
                   
               
               
                 16 
                 4,7- Difluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 71 
               
               
                   
               
               
                 17 
                 4,7- Difluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 97 
               
               
                   
               
               
                 18 
                 4,7- Difluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 96 
               
               
                   
               
               
                 19 
                 4,7- Difluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 88 
               
               
                   
               
               
                 20 
                 4,7- Difluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 21 
                 4,7- Difluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 93 
               
               
                   
               
               
                 22 
                 4,7- Difluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 89 
               
               
                   
               
               
                 23 
                 4,7- Difluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 98 
               
               
                   
               
               
                 24 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 91 
               
               
                   
               
               
                 25 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 92 
               
               
                   
               
               
                 26 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 95 
               
               
                   
               
               
                 27 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 98 
               
               
                   
               
               
                 28 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 96 
               
               
                   
               
               
                 29 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 93 
               
               
                   
               
               
                 30 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 92 
               
               
                   
               
               
                 31 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 82 
               
               
                   
               
               
                 32 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 97 
               
               
                   
               
               
                 33 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 80 
               
               
                   
               
               
                 34 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 88 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 10 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 % 
               
               
                   
                   
                   
                   
                 Inhibition 
               
               
                 Example # 
                 R 1   
                 R 40   
                 R 5   
                 @ 10 μM 
               
               
                   
               
             
          
           
               
                 35 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 95 
               
               
                   
               
               
                 36 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 55 
               
               
                   
               
               
                 37 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 50 
               
               
                   
               
               
                 38 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &lt;10 
               
               
                   
               
               
                 39 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 81 
               
               
                   
               
               
                 40 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 82 
               
               
                   
               
               
                 41 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 86 
               
               
                   
               
               
                 42 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 35 
               
               
                   
               
               
                 43 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 86 
               
               
                   
               
               
                 44 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 52 
               
               
                   
               
               
                 45 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 64 
               
               
                   
               
               
                 46 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 46 
               
               
                   
               
               
                 47 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 48 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 93 
               
               
                   
               
               
                 49 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 97 
               
               
                   
               
               
                 50 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 97 
               
               
                   
               
               
                 51 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 96 
               
               
                   
               
               
                 52 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 96 
               
               
                   
               
               
                 53 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 96 
               
               
                   
               
               
                 54 
                 4-Chloro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 55 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 56 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 11 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                 Example 
                   
                   
                 % Inhibition 
               
               
                   
                 # 
                 R 1   
                 R t   
                 @ 10 μM 
               
               
                   
                   
               
             
          
           
               
                   
                 57 
                 4-Choro 
                 Phenyl 
                 &gt;98 
               
               
                   
                 58 
                 H 
                 Phenyl 
                 97 
               
               
                   
                 59 
                 4-Fluoro 
                 Phenyl 
                 &gt;98 
               
               
                   
                 60 
                 4-Fluoro 
                 Benzyl 
                 &gt;98 
               
               
                   
                 61 
                 7-Methyl 
                 t-Butyl 
                 96 
               
               
                   
                 62 
                 4-Fluoro 
                 Methyl 
                 &gt;98 
               
               
                   
                 63 
                 4-Fluoro 
                 Ethyl 
                 &gt;98 
               
               
                   
                 64 
                 4-Fluoro 
                 t-Butyl 
                 &gt;98 
               
               
                   
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
             
               
               
               
             
           
               
                 TABLE 12 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Example 
                   
                 % Inhibition 
               
               
                 # 
                 R m   
                 @ 10 uM 
               
               
                   
               
             
          
           
               
                 65 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 93 
               
               
                   
               
               
                 66 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
               
                 67 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 97 
               
               
                   
               
               
                 68 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 97 
               
               
                   
               
               
                 69 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;98 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
             
           
               
                 TABLE 13 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Example 
                   
                 % Inhibition 
               
               
                 # 
                 R n   
                 @ 10 uM 
               
               
                   
               
               
                 70 
                 Phenyl 
                 90 
               
               
                 71 
                 Methyl 
                 82 
               
               
                   
               
             
          
         
       
     
     EXPERIMENTALS 
     3) General Procedure for Preparation of Examples 1-34 
     Step A.                           
     To a solution of substituted indole IV (1 eq) in dry Et 2 O was dropwise added oxalylchloride (1.2 eq) at 0° C. After 5 min., the reaction mixture was warmed to room temperature, or heated to ˜35° C. overnight if necessary. The intermediate substituted-indole-3-glyoxyl chloride V, which was formed as a solid, was filtered and washed with dry ether (2×1 ml) to remove excessive oxalyl chloride. The product was then dried under vacuum to give desired glyoxyl chlorides V. 
     In cases where reaction in Et 2 O was unsuccessful, the following procedure was adopted: To a solution of substituted indole IV (1 eq) in dry THF (tetrahydrofuran) solvent was dropwise added oxalyl chloride (1.2 eq) at 0° C. After 5 min., the reaction was warmed to room temperature, or heated to ˜70° C. under nitrogen if necessary. After concentration in vacuo, the resulting crude intermediate V was submitted to next step without further treatment. 
     Step B                           
     To a solution of indole glyoxyl chloride V (1 eq) in dry THF was added benzoylpiperazine (1 eq) at room temperature. Then the mixture was cooled down to 0° C., followed by dropwise addition of diisopropylamine (1.3 eq). After 5 min., the reaction mixture was warmed to room temperature and was shaken for 3 hr. The resulting crude products VI were purified by preparative HPLC and characterized as shown in Table 14. 
     Step C                           
     To a predried 5 ml vial was added indoles glyoxamide VIa (0.0416 μM), alkyl or aryl halide R 2 X (0.0478 μM), dry DMF (2 ml) and BEMP (0.0541 μM) at rt. The reaction was shaken at 70˜80° C. in a heating block under nitrogen for 4 hr. After evaporation of the solvent in vacuo, the crude compound was purified by prep HPLC and characterized as shown in Table 14. 
     For examples 33 and 34, the reactions were conducted in NMP and were heated to 80° C. for 16 h before purification by prep. HPLC. 
     Preparation of Example 19 
     
       
                 
         
             
             
         
      
     
     To indole glyoxamide VIId (200 mg, 0.5 mmol) in THF (1 mL) in a sealed tube was added BEMP (0.2 equiv) and t-butylacrylate (0.37 mL, 2.5 mmol). The reaction mixture was heated to 90° C. overnight. The crude product was poured into 1M HCl and was extracted with EtOAc. The organic phase was washed with sat. NaCl and dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (2:1 EtOAc/Hexane) to afford 195 mg of alkylated product 19. 
     Preparation of Example 21 
     
       
                 
         
             
             
         
      
     
     To ester 19 (956 mg) was added CH2Cl2 (4 mL) followed by TFA (4 mL). The reaction mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo and the product was triturated with ether to afford acid 21 (802 mg) as a white solid. 
     Preparation of Example 22 
     
       
                 
         
             
             
         
      
     
     To nitrile 17 (330 mg, 0.76 mmol) in EtOH/H2O (18 mL, 2:1) was added hydroxylamine (189 mg, 2.72 mmol) followed by K2CO3 (209 mg, 1.5 mmol). The reaction mixture was heated to 65° C. overnight. The solvent was then removed in vacuo. The residue was partitioned between water and EtOAc. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The product was then triturated with ether to afford 22 (276 mg) as a white solid. 
     Preparation of Example 23 
     
       
                 
         
             
             
         
      
     
     To glyoxamide 22 (100 mg, 0.21 mmol) was added toluene (1.5 mL) followed by K 2 CO 3  (35 mg, 0.26 mmol) and phosgene in toluene (1.09 mL, 20% solution). The reaction mixture was heated to reflex for 2.5 h. The mixture was then cooled to r.t. and was stirred overnight. The product was filtered, concentrated and triturated with ether to yield 23 (89 mg) as a gold colored solid. 
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 14 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Ex- 
                   
                   
                 HPCL 
                   
               
               
                 am- 
                   
                   
                 Reten- 
                 MS 
               
               
                 ple 
                   
                   
                 tion 
                 Data 
               
               
                 # 
                 R 1   
                 R 2   
                 Time 
                 (M + H) +   
               
               
                   
               
             
          
           
               
                 1 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.62 
                 402.19 
               
               
                   
               
               
                 2 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.99 
                 400.16 
               
               
                   
               
               
                 3 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.92 
                 520.22 
               
               
                   
               
               
                 4 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.87 
                 466.24 
               
               
                   
               
               
                 5 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.75 
                 482.20 
               
               
                   
               
               
                 6 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.52 
                 376.23 
               
               
                   
               
               
                 7 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.82 
                 432.30 
               
               
                   
               
               
                 8 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.91 
                 458.20 
               
               
                   
               
               
                 9 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.77 
                 430.30 
               
               
                   
               
               
                 10 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.73 
                 390.20 
               
               
                   
               
               
                 11 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.74 
                 418.30 
               
               
                   
               
               
                 12 
                 2-Methyl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.36 
                 390.15 
               
               
                   
               
               
                 13 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.24 
                 394.05 
               
               
                   
               
               
                 14 
                 4-Chloro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.39 
                 410.10 
               
               
                   
               
               
                 15 
                 6-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.38 
                 393.79 
               
               
                   
               
               
                 16 
                 4,7- Difluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.16 
                 469 
               
               
                   
               
               
                 17 
                 4,7- Difluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.35 
                 437 
               
               
                   
               
               
                 18 
                 4,7- Difluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.49 
                 511 
               
               
                   
               
               
                 19 
                 4,7- Difluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.68 
                 526 
               
               
                   
               
               
                 20 
                 4,7- Difluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.47 
                 412 
               
               
                   
               
               
                 21 
                 4,7- Difluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.32 
                 470 
               
               
                   
               
               
                 22 
                 4,7- Difluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.18 
                 470 
               
               
                   
               
               
                 23 
                 4,7- Difluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.47 
                 496 
               
               
                   
               
               
                 24 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.09 
                 451 
               
               
                   
               
               
                 25 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.40 
                 442 
               
               
                   
               
               
                 26 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2.08 
                 494 
               
               
                   
               
               
                 27 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2.14 
                 522 
               
               
                   
               
               
                 28 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2.00 
                 466 
               
               
                   
               
               
                 29 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.24 
                 471 
               
               
                   
               
               
                 30 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.09 
                 471 
               
               
                   
               
               
                 31 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.39 
                 471 
               
               
                   
               
               
                 32 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.67 
                 494 
               
               
                   
               
               
                 33 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2.03 
                 528 
               
               
                   
               
               
                 34 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.79 
                 501 
               
               
                   
               
             
          
         
       
     
     General Procedure for Preparation of Examples 35-56 
     Step A                           
     To indole-3-glyoxylyl chloride I (3 gram, 14.45 mmol) in CH 2 Cl 2  at room temperature was added tert-butyl 1-piperazinecarboxylate (2.7 gram, 14.45 mmol) and diisopropylethylamine (2.76 ml, 15.9 mmol). The light-brown color solution was stirred for 2 hr at room temperature after which time LC/MS analysis indicated the completion of the reaction. The solvent was removed in vacuo and the resulting residue was diluted with ethyl acetate (250 ml) and diethylether (250 ml). The organic solution was then washed with water (100 ml×3) and brine (50 ml), dried over MgSO 4 , filtered and concentrated. To the light-yellow solid was then added 30 ml of 20% trifluoroacetic acid in CH 2 Cl 2 . The solution was concentrated and the light-brown solid was dried in vacuo to give 3.5 g (95%) of product II. LC/MS analysis indicated this product was 100% pure and it was used for the next reaction without further purification. 
     Step B                           
     To piperazine glyoxamide II (1 equiv.) in dichloroethane (DCE) was added substituted benzoyl chloride (3 equiv.) followed by i-Pr 2 NEt (4 equiv.). The reaction mixture was stirred at room temperature for 16 h and product III was then purified by prep HPLC. 
     General Procedure for Preparation of Examples 35-56 
     
       
                 
         
             
             
         
      
     
     To indole gloxamide VIb (1 equiv.) in DCE was added substituted acid chloride (3 equiv.) followed by i-Pr 2 NEt (4 equiv.). The reaction mixture was stirred at room temperature for 16 h and product VIIa was then purified by prep HPLC. 
     
       
         
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 15 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 HFLC 
                   
               
               
                   
                   
                   
                   
                 Reten- 
               
               
                   
                   
                   
                   
                 tion 
                 MS 
               
               
                 Exp. # 
                 R 1   
                 R 2   
                 R 3   
                 Time 
                 Data 
               
               
                   
               
               
                 35 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2.20 
                 502 
               
               
                   
               
               
                 36 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2.28 
                 536 
               
               
                   
               
               
                 37 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2.27 
                 624 
               
               
                   
               
               
                 38 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2.19 
                 526 
               
               
                   
               
               
                 39 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2.32 
                 502 
               
               
                   
               
               
                 40 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2.34 
                 534 
               
               
                   
               
               
                 41 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2.37 
                 623 
               
               
                   
               
               
                 42 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2.25 
                 526 
               
               
                   
               
               
                 43 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2.20 
                 502 
               
               
                   
               
               
                 44 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2.33 
                 534 
               
               
                   
               
               
                 45 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2.37 
                 623 
               
               
                   
               
               
                 46 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2.34 
                 526 
               
               
                   
               
               
                 47 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.80 
                 466 
               
               
                   
               
               
                 48 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.58 
                 404 
               
               
                   
               
               
                 49 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.86 
                 484 
               
               
                   
               
               
                 50 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.90 
                 500 
               
               
                   
               
               
                 51 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.91 
                 546 
               
               
                   
               
               
                 52 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.87 
                 496 
               
               
                   
               
               
                 53 
                 H 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.77 
                 496 
               
               
                   
               
               
                 54 
                 4-Chloro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.75 
                 500 
               
               
                   
               
               
                 55 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.64 
                 484 
               
               
                   
               
               
                 56 
                 4-Fluoro 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.73 
                 514 
               
               
                   
               
             
          
         
       
     
     Procedure for Preparation of Examples 57-64 
     
       
                 
         
             
             
         
      
     
     To indole gloxamide VI (1 equiv.) in DCE was added chloroformate R 2 OCOCl (3 equiv.) followed by i-Pr 2 NEt (4 equiv.). The reaction mixture was stirred at room temperature for 16 h and carbamate VIIb was then purified by prep HPLC. 
     
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 16 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 HPLC 
                   
               
               
                 Example 
                   
                   
                 Retention 
                 MS Data 
               
               
                 # 
                 R 1   
                 R 2   
                 Time 
                 (M+H)+ 
               
               
                   
               
               
                 57 
                 4-Choro 
                 Phenyl 
                 1.82 
                 516 
               
               
                 58 
                 H 
                 Phenyl 
                 1.77 
                 482 
               
               
                 59 
                 4-Fluoro 
                 Phenyl 
                 2.22 
                 500 
               
               
                 60 
                 4-Fluoro 
                 Benzyl 
                 2.25 
                 514 
               
               
                 61 
                 7-Methyl 
                 t-Butyl 
                 1.93 
                 476 
               
               
                 62 
                 4-Fluoro 
                 Methyl 
                 1.54 
                 438 
               
               
                 63 
                 4-Fluoro 
                 Ethyl 
                 1.65 
                 452 
               
               
                 64 
                 4-Fluoro 
                 t-Butyl 
                 1.82 
                 480 
               
               
                   
               
             
          
         
       
     
     General Procedure for Preparation of Examples 65-69 
     
       
                 
         
             
             
         
      
     
     To indole gloxamide VIe (1 equiv.) in NMP was added carbamoyl chloride R 1 R 2 NCOCl (2 equiv.) followed by i-Pr 2 NEt (4 equiv.). The reaction mixture was stirred at room temperature for 16 h and urea VIIe was then purified by prep HPLC. 
     General Procedure for Preparation of Examples 65-69 
     Step A                           
     To indole gloxamide VIIe (1 equiv.) in DCE was added p-nitrophenylchloroformate (1.1 equiv.) followed by i-Pr 2 Nt (3 equiv.). The reaction mixture was stirred at room temperature for 3 h and the crude product was used in the following reaction without further work-up or purification. 
     Step B                           
     To crude p-nitrophenylcarbamate VIIe was added secondary amine R 1 R 2 NH. The reaction mixture was stirred for 16 h at room temperature and urea IXe was then purified by prep. HPLC. 
     Preparation of Examples 65-69 in Table 17 
     
       
                 
         
             
             
         
      
     
     To indole glyoxamide VIIe (1 equiv.) in CH 2 Cl 2  at room temperature was added isocyanate (R 1 NCO) (2 equiv.) followed by i-Pr 2 NEt (3 equiv.). The reaction mixture was stirred at room temperature for 18 h and the crude product Xe was purified by prep. HPLC. 
     
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 17 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                 HPLC 
                   
               
               
                 Example 
                   
                 Retention 
                 MS Data 
               
               
                 # 
                 R 
                 Time 
                 (M+H) +   
               
               
                   
               
               
                 65 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.76 
                 513 
               
               
                   
               
               
                 66 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.60 
                 493 
               
               
                   
               
               
                 67 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.58 
                 451 
               
               
                   
               
               
                 68 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.45 
                 506 
               
               
                   
               
               
                 69 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 1.48 
                 451 
               
               
                   
               
             
          
         
       
     
     Preparation of Examples 70-71 in Table 18 
     
       
                 
         
             
             
         
      
     
     To indole gloxamide XIf (1 equiv.) in DCE was added psulfonyl chloride (2 equiv.) followed by i-Pr 2 NEt (3 equiv.). The reaction mixture was stirred at room temperature for 3 h and the crude product XIIf was purified by prep. HPLC. 
     
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 18 
               
             
             
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                   
                   
                   
                 HPLC 
                   
               
               
                   
                 Example 
                   
                 Retention 
                 MS Data 
               
               
                   
                 # 
                 R 
                 Time 
                 (M+H) +   
               
               
                   
                   
               
               
                   
                 70 
                 Phenyl 
                 1.85 
                 502 
               
               
                   
                 71 
                 Methyl 
                 1.69 
                 440 
               
               
                   
                   
               
             
          
         
       
     
     Additional Analytical Data for Selected Compounds 
     
       
                 
         
             
             
         
      
     
       1 H-NMR (300 MHz,DMF-d7): δ 8.30 (s, 1H), 8.22(d, 1H, J=7.26 Hz), 7.84 (d, 1H, J=7.26 Hz), 7.30-7.54 (m, 7H), 4.99 (s, 3H), 3.52-3.92 (m, 8H).                           
       1 H-NMR (300 MHz, CD3OD): δ 8.28 (d, 1H, J=8.37 Hz), 8.22 (s, 1H), 7.64 (d, 1H, J=7.26), 7.27-7.56 (m, 7H), 5.16 (d, 2H, J=2.52 Hz), 3.36-4.02 (m, 8H), 3.02 (t, 1H, J=2.55 Hz).                           
       1 H-NMR (500 MHz, CD3Cl): δ 8.05 (s, 1H), 7.45 (br. s, 5H), 6.88-7.01 (m, 2H), 5.04 (s, 2H), 3.79 (br. m, 4H), 3.59 (br. m, 4H). Anal. Calcd for C 23 H 18 F 2 N 4 O 3 : C 63.30; H 4.16; N 12.84; F 8.71; O 11.00. Found C 62.33; H 4.52; N 12.05. MS 437 (M+H) + .                           
       1 H-NMR (500 MHz, CD3Cl): δ 7.99 (s, 1H), 7.44 (br. s, 5H), 6.74-6.85 (m, 2H), 4.90 (s, 2H), 3.79 (br. m, 4H), 3.57 (br. m, 4H), 3.45 (q, J=11.4 Hz, 4H). 1.35 (t, J=11.4 Hz, 3H), 1.21 (t, J=11.4 Hz, 3H). Anal. Calcd for C 27 H 28 F 2 N 4 O 4 : C 63.52; H 5.54; N 10.97. Found C 62.75; H 5.54; N 10.80.                           
       1 H-NMR (500 MHz, DMSO-d6): δ 8.32 (s, 1H), 7.44 (br. s, 6H), 7.12 (app. t, 1H), 3.87 (s, 3H), 3.2-3.7 (br. m, 8H). MS 412 (M+H) +  Anal. for C 22 H 19 F 2 N 3 O 3 : C 64.23; H 4.65; N 10.1. Found C 64.58 ; H 4.74; N 9.63.                           
       1 H-NMR (500 MHz, DMSO-d6): δ 8.40 (s, 1H), 7.44 (br. s, 6H), 7.14 (app. t, 1H), 5.01 (br. s, 2H), 3.2-3.7 (br. m). MS 470 (M+H) +  Anal. for C 23 H 21 F 2 N 5 O 4 : C 58.85; H 4.51; N 14.92. Found C 58.17; H 5.06; N 13.85.                           
       1 H-NMR (500 MHz, DMSO-d6): δ 8.40 (s, 1H), 7.4-7.55 (m, 6H), 7.16 (app. t, 1H), 5.61 (br. s, 2H), 3.2-3.7 (br. m). MS 496 (M+H) +   
     The compounds of the present invention may be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles. 
     Thus, in accordance with the present invention there is further provided a method of treating and a pharmaceutical composition for treating viral infections such as HIV infection and AIDS. The treatment involves administering to a patient in need of such treatment a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically-effective amount of a compound of the present invention. 
     The pharmaceutical composition may be in the form of orally-administrable suspensions or tablets; nasal sprays, sterile injectable preparations, for example, as sterile injectable aqueous or oleagenous suspensions or suppositories. 
     When administered orally as a suspension, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweetners/flavoring agents known in the art. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art. 
     The injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer&#39;s solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid. 
     The compounds of this invention can be administered orally to humans in a dosage range of 1 to 100 mg/kg body weight in divided doses. One preferred dosage range is 1 to 10 mg/kg body weight orally in divided doses. Another preferred dosage range is 1 to 20 mg/kg body weight orally in divided doses. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. 
     
       
         
               
             
               
               
               
             
           
               
                   
               
               
                 Abbreviations 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 TFA 
                 Trifluoroacetic Acid 
               
               
                   
                 P-EDC 
                 Polymer supported 1-(3-dimethylaminopropyl)-3- 
               
               
                   
                   
                 ethylcarbodiimide 
               
               
                   
                 EDC 
                 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 
               
               
                   
                 DCE 
                 1,2-Dichloroethane 
               
               
                   
                 DMF 
                 N,N-dimethylformamide 
               
               
                   
                 THF 
                 Tetrahydrofuran 
               
               
                   
                 NMP 
                 N-methylpyrrolidone 
               
               
                   
                 BEMP 
                 2-tert-Butylimino-2-diethylamino-1,3-dimethyl- 
               
               
                   
                   
                 perhydro-1,3,2-diazaphosphorine