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US 2008O161324A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0161324 A1 Johansen et al. (43) Pub. Date: Jul. 3, 2008

(54) COMPOSITIONS AND METHODS FOR Publication Classification TREATMENT OF VRAL DISEASES (51) Int. Cl. (76) Inventors: Lisa M. Johansen, Belmont, MA A63/495 (2006.01) (US); Christopher M. Owens, A63L/35 (2006.01) Cambridge, MA (US); Christina CI2O I/68 (2006.01) Mawhinney, Jamaica Plain, MA A63L/404 (2006.01) (US); Todd W. Chappell, Boston, A63L/35 (2006.01) MA (US); Alexander T. Brown, A63/4965 (2006.01) Watertown, MA (US); Michael G. A6II 3L/21 (2006.01) Frank, Boston, MA (US); Ralf A6IP3L/20 (2006.01) Altmeyer, Singapore (SG) (52) U.S. Cl...... 514/255.03: 514/647; 435/6: 514/415; Correspondence Address: 514/460, 514/275: 514/529 CLARK & ELBNG LLP 101 FEDERAL STREET BOSTON, MA 02110 (57) ABSTRACT (21) Appl. No.: 11/900,893 The present invention features compositions, methods, and kits useful in the treatment of viral diseases. In certain (22) Filed: Sep. 13, 2007 embodiments, the viral disease is caused by a single stranded RNA virus, a flaviviridae virus, or a hepatic virus. In particu Related U.S. Application Data lar embodiments, the viral disease is viral hepatitis (e.g., (60) Provisional application No. 60/844,463, filed on Sep. hepatitis A, , , , hepatitis E). 14, 2006, provisional application No. 60/874.061, Also featured are screening methods for identification of filed on Dec. 11, 2006. novel compounds that may be used to treat a viral disease. US 2008/O161324 A1 Jul. 3, 2008

COMPOSITIONS AND METHODS FOR people, or about 3% of the world's population, are infected TREATMENT OF VIRAL DISEASES with HCV. No vaccine for hepatitis C is presently available, and the currently recommended therapy, a combination of CROSS-REFERENCE TO RELATED pegylated and , is effective in only about APPLICATIONS 50% of those infected with HCV genotype 1. Further, both interferon and ribavirin have potentially serious side effects, 0001. This application claims benefit of U.S. Provisional which include seizures, acute heart or kidney failure, and Application No. 60/844,463, filed Sep. 14, 2006, and U.S. anemia. Provisional Application No. 60/874,061, filed Dec. 11, 2006, 0005 Given the lack of safe, efficacious treatments for each of which is hereby incorporated by reference. many viral diseases, there exists a need for improved thera p1es. BACKGROUND OF THE INVENTION 0002. The invention relates to the treatment of diseases SUMMARY OF THE INVENTION caused by a virus. 0006 Based on the results of our screen identifying com 0003 Diseases caused by viruses are major health prob pounds and combinations of compounds having antiviral lems worldwide, and include many potentially fatal or dis activity, the present invention features compositions, meth abilitating illnesses. Viral diseases include diseases caused by ods, and kits for the treatment of viral disease (e.g., caused by single stranded RNA viruses, flaviviridae viruses, and hepatic the viruses described herein). In certain embodiments, the viruses. In one example, viral hepatitis (e.g., hepatitis A, viral disease may be caused by a virus which is a member of hepatitis B, hepatitis C, hepatitis D, and hepatitis E) can result one or more of the following groups: single Stranded RNA in chronic or acute hepatitis. While vaccines protective viruses, flaviviridae viruses (e.g., a hepacivirus Such as HCV. against hepatitis A and hepatitis B exist, no cures for many flavivirus, pestivirus, or hepatitis G Virus), and hepatic viruses, including hepatitis B, C, D, or E, are available. viruses. HCV, for example, is a single stranded RNA virus, a 0004. With regard to the hepatitis C virus (HCV), the flaviviridae virus, and a hepatic virus. In certain embodi Center for Disease Control estimates that 4.1 million Ameri ments, the viral disease is caused by the hepatitis C virus. cans (1.6%) have been infected with this virus. Of those Additional exemplary viruses are described herein. infected, 3.2 million are chronically infected, and HCV is the 0007 Accordingly in a first aspect, the invention features leading cause of death from disease in the United States. a composition including a first agent selected from the agents Hepatitis C is a major risk factor for developing liver cirrhosis of Table 1, Table 2, and Table 3; and a second agent selected and hepatocellular carcinoma, and the World Health Organi from the agents of Table 1, Table 2, Table 3, Table 4, and Table zation indicates that hepatitis C is responsible for two thirds 5 (e.g., Table 4 and Table 5, or excluding the combinations of of liver transplants. Worldwide, an estimated 180 million Table 6).

TABLE 1 Compound IC50* Compound IC50: 1.2-Bis-(2-aminophenoxy)ethane N.N.N.N.- 14.50 Isosulfan Blue 24.86 tetreacetic acid 1,5-Isoquinolinediol 25.88 JSH-23 2.55 10-Deacetylbaccatine Ii 10.34 Levothyroxine (e.g., sodium) 3.79 2,2'-(Pentamethylenedioxy)diacetanilide 3.14 8.16 2-Hydroxyflavanone 2.48 Manganese gluconate 24.71 2-Methoxyestradiol 7.91 (e.g., hydrochloride) 7.18 3,3'-(Pentamethylenedioxy)dianiline 1.63 (e.g., hydrochloride) 4.88 6-Nitroquipazine 16.41 Mechlorethamine (e.g., hydrochloride) 4.15 AG-490 5.03 4.62 AG-494 3.45 Mecobalamin O.179 Albendazole 0.324 Melphalan 5.94 26.4 Mequinol 8.6S Amitrole 14.62 (e.g., Besylate) 9.00 Amorolfine (e.g., hydrochloride) 1.62 S.18 Anisomycin 0.608 Methylglyoxal bis(guanylhydrazone) dihydrochloride O.80 hydrate Auranofin 1.07 9.11 6.22 (e.g., hydrochloride) 3.72 Bay 11-7082 15.01 Mitotane 28.1% Bay 41-2272 O.754 ML 9 4.44 Benoximate (e.g., hydrochloride) 3.02 Mofebutazone 4.6O Benzamil (e.g., HCI) 4.73 (e.g., furoate) 1.35 Benzocaine 13.91 Monobenzone 1.59 Benztropine (e.g., mesylate) 5.70 (e.g., citrate) O.91 (e.g., hydrochloride) 9.00 Narasin O.176 Beta Escin 4.27 Noscapine 5.83 Beta-Caroteine 18.50 NSC 663284 O.614 Beta-Ionol 21.00 N-Tosyl-L- chloromethyl 6.67 (e.g., hydrochloride) 29.4 Octyl Methoxycinnamate 1.24 BHQ 23.28 Oxeladin 8.72 Bifonazole 6.15 Oxfendazole 7.30 Bismuth Subsalicylate 18.09 Oxibendazole O.300 US 2008/O161324 A1 Jul. 3, 2008

TABLE 1-continued

Compound IC50: Compound Bromhexine 14.25 Oxyphenbutazone (e.g., hydrate) (e.g., meSylate) 3.38 15.66 Padimate O Bufexamac 8.29 P-Aminosalicylic acid Camptothecin O.O26 Parthenolide 11.72 Carbaryl 9.65 Phenazopyridine (e.g., hydrochloride) CAY10433 7.88 Piceatannol Celastrol O449 Picotamide Cerulenin 16.21 PKR inhibitor Chlorophyllin 1.30 Pramoxine (e.g., hydrochloride) (e.g., hydrochloride) 16.20 (e.g., hydrochloride) Citalopram (e.g., hydrobromide) 27.30 Propidium (e.g., iodide) Cladribine O. 112 Quinacrine Clomiphene (e.g., citrate) 1.19 Cobamamide O.410 R(+)-Verapamil (e.g., hydrochloride) Cyclocytidine (e.g., hydrochloride) O.183 (e.g., hydrochloride) Cycloheximide O.184 Repaglinide (e.g., hydrochloride) 17.97 Rescinnamine 1119 (e.g., citrate) 11.14 Rifabutin Desoratadine 6.07 Desoxycorticosterone (e.g., acetate) 14.65 Saponin Dextrothyroxine (e.g., sodium) S.OO Satraplatin Dibucaine (e.g., hydrochloride) 6.68 SB-2021.90 Dicyclomine (e.g., hydrochloride) 25.01 (e.g., hydrochloride) 16.49 Shikonin 12.18 SiguaZodan (e.g., meSylate) 22.75 Dilazep (e.g., dihydrochloride) 13.87 Sirolimus Diphenidol (e.g., hydrochloride) 25.45 (e.g., sodium fusidate) Disulfiram 5.50 DNA-PK inhibitor II 6.52 Donepezil (e.g., hydrochloride) 29.29 Suberohydroxamic acid (e.g., hydrochloride) 1488 (e.g., citrate) 2.75 Terconazole Erbstatin 7.63 Mesylates 15.25 Thapsigargin Evans Blue 1.94 Thiostrepton 29.04 Thiram Ezetimibe 4.2O Tioxolone Fascaplysin 0.444 Tirapazamine Fenbendazole O419 Tiratricol Fenretinide 2.26 (e.g., tartrate) Fenvalerate 18.95 Topotecan (e.g., hydrochloride) Flubendazole O.173 Fludarabine 4.47 Trequinsin (e.g., hydrochloride) Fluorouracil 18.66 (e.g., hydrochloride) (e.g., dihydrochloride) 3.60 (e.g., hydrochloride) 3.35 (e.g., maleate) Fluvoxamine (e.g., maleate) 23.79 Tyrphostin 23 FR122047 23.01 Tyrphostin 25 3.05 Tyrphostin 46 (Base) 3.17 Tyrphostin 47 Gramicidin O.O17 Tyrphostin Ag 1478 Griseofulvin (e.g., microcrystalline) 11.53 U18666A GW 5074 2.36 UCH-L1 inhibitor 17.40 UCH-L3 inhibitor Hydroquinone 13.99 (e.g., acetate) Hydroxocobalamin 1.33 Vinorelbine (e.g., hydrochloride) 10.93 Vitamin B12 Ifenprodil (e.g., tartrate) 4.68 Vitamin K5 (e.g., hydrochloride) 16.93 Indocyanine Green 8.13 Iophenoxic acid 10.63 Zafirlukast LY 2940O2 3.40 Zimelidine (e.g., dihydrochloride) (S,S)-N-DeSmethyl sertraline (e.g., 4.94 3',3'-(Pentamethylenedioxy)diacetanilide hydrochloride) 1.5-Bis(4-aminophenoxy)pentane 1.70 rac-cis-N-Desmethyl Sertraline, (e.g., hydrochloride) Emetime (e.g., dihydrochloride hydrate) O.O3 2,2'-(Pentamethylenedioxy)dianiline Irinotecan (e.g., hydrochloride) 1.56 *Values noted with an asterisk (*) are IC25 values US 2008/O161324 A1 Jul. 3, 2008

Sertraline; 1.5-bis(4-aminophenoxy)pentane and indocya TABLE 2 nine green, 2-hydroxyflavanone and amorolfine; and Vinorelbine; benoximate and dehydroepiandrosterone; Compound IC50 Compound IC50 ifenprodil and indocyanine green; amorolfine and arbidol; 15.45 O.117 3.3'-(pentamethylenedioxy)dianiline and indocyanine green; Nelfinavir (e.g., meSylate) 4.25 Floxuridine O.OO45 26.71 1.95 fulvestrant and vinorelbine; amorolfine and eZetimibe; amo Ritonavir 14.91 Cepharanthine 1948 rolfine and Evans blue; amorolfine and gefitinib; amorolfine Aphidicolin 1.71 Tunicamycin O.107 and topotecan; 2.2"-(pentamethylenedioxy)diacetanilide Andrographis 8.39 Triciribine 2.14 Saquinavir (e.g., mesylate) 10.04 8.68 and artemisinin; amorolfine and Wedelolactone; 3,3'-(pen 0.380 Vincristine (e.g., Sulfate) O.O2 tamethylenedioxy)dianiline and amorolfine; simvastatin and Arbidol 12.2O rac-cis-n-desmethyl sertraline; dipivoxil and tricir ibine; cytarabine and Evans blue; artemisinin and Evans blue; fluphenazine and sertraline; benzamil and SB-202190: arte misinin and rifabutin, fluiphenazine and tolterodine; inter TABLE 3 feron alfa-2a and melphalan; amorolfine and melphalan; arte Compound IC50* Compound IC50: misinin and fulvestrant; ifenprodil and quinacrine; simvastatin and rac-cis-n-desmethyl sertraline; flupentiXol Lovastatin 1.41 Artemisinin 4.45 Artemether Dihydroartemisinin 3.87 and tolterodine; triciribine and wortmannin; loratadine and Artesunate 3.73 Nitazoxanide 14.04 vinorelbine; meclizine and sertraline; budesonide and Cyclosporine 0.379 Chloroquine 4.78 Vinorelbine; 2-hydroxyflavanone and indocyanine green; (e.g., phosphate) hydroxy Zine and Sertraline: 2,2'-(pentamethylenedioxy)di Ribavirin 42.95 Mevastatin 3.45 Simvastatin hydroxy acid, 13.40 TOFA 5.53 aniline and artemisinin; amorolfine and flupentiXol; artemisi ammonium salt nin and chlorophyllin: ezetimibe and fluphenazine; benzamil Mycophenolic Acid 0.751 2'-C-Methylcytidine 1.63 and fluphenazine; artemisinin and Wedelolactone; cytarabine Atorvastatin 35.60 Adefovir (e.g., dipivoxil) O.319 and dydrogesterone; artemisinin and benzamil: 3,3'-(pentam Fluvastatin (e.g., sodium) 22.20 (VX-950) O.S29 Celgosivir 6.25* (NM-283) 11.2 ethylenedioxy)dianiline and artemether; tolterodine and trif (VX-497) O.47S HCV-796 O.O.192 luperidol; artesunate and fluvastatin; artemisinin and trifluri 0.259 Gemcitabine O.O6 dine; adefovir dipivoxil and amorolfine; interferon alfa-2a (SCH 5.03034) (e.g., hydrochloride) and trifluridine; fulvestrant and triciribine; artesunate and Interferon Alfa-2a. 2.35 Simvastatin 21.34 dydrogesterone; artesunate and LY 294.002; mosapride cit *Values noted with an asterisk (*) are IC25 values rate and TOFA: bromocriptine and wedelolactone; artemisi nin and sodium fusidate; celgosivir and interferon alfa-2a: 0008. In another aspect, the invention features a composi amorolfine and dextrothyroxine; andrographis and fulves tion including sertraline and an HMG-CoA reductase inhibi trant; 2'-c-methylcytidine and artemisinin; amorolfine and tor. The HMG-CoA reductase inhibitor may be fluvastatin, gemcitabine; oxeladin and Sertraline; artemisinin and par simvastatin, lovastatin, or rosuvastatin. thenolide; artemisinin and ribavirin; dehydroepiandrosterone 0009. In another aspect, the invention features a composi and tyrphostin AG 1478; sertraline and toremifene; dihy tion including Sertraline and an . The antihista droartemisinin and fulvestrant, 2-hydroxyflavanone and mine may be hydroxy Zine. TOFA; artesunate and repaglinide; mofebutaZone and 0010. In yet another aspect, the invention features a com wedelolactone; artesunate and simvastatin; 2,2'-(pentameth position including a pair of agents selected from the group ylenedioxy)dianiline and artesunate; artemisinin and gemcit consisting of amorolfine and Sertraline; fluvastatin and Ser abine; dihydroartemisinin and ezetimibe; chlorophyllin and traline; rosuvastatin and Sertraline; fulvestrant and satrapl cytarabine; interferon alfa-2a and sirolimus; Suberohydrox atin; amorolfine and mebeverine; amorolfine and satraplatin: amic acid and VX-497; artemisinin and VX-497; artesunate ifenprodil and sertraline; amorolfine and tolterodine; atorv and VX-497; tolterodine and VX-950; artemisinin and HCV astatin and Sertraline; amorolfine and irinotecan; lovastatin 796; artemisinin and NM-283; NM-283 and wedelolactone; and Sertraline; cytarabine and triciribine; artesunate and wort artemisinin and SCH 503034; cytarabine and SCH 5.03034; mannin; Sertraline and simvastatin hydroxy acid, ammonium SCH 5.03034 and triciribine; interferon alfa-2a and mel salt; amorolfine and cytarabine; Sertraline and simvastatin: phalan; benoximate and VX-950; HCV-796 and sirolimus: octyl methoxycinnamate and Suberohydroxamic acid; 1.5-bis benoximate and SCH 503034; melphalan and VX-950: (4-aminophenoxy)pentane and amorolfine; (S,S) N-desm ritonavir and VX-950; VX-950 and VX-497; artemisinin and ethyl sertraline and simvastatin; artemisinin and SB-202190: VX-950; triciribine and VX-950; suberohydroxamic acid and interferon alfa-2a and sirolimus; amorolfine and indocyanine VX-950; HCV-796 and suberohydroxamic acid; sirolimus green; TOFA and triciribine; 3,3'-(pentamethylenedioxy)di and VX-950; melphalan and SCH 5.03034; SCH503034 and aniline and artemisinin; artemisinin and wortmannin; 3.3"- wortmannin; SCH503034 and tolterodine; ritonavir and SCH (pentamethylenedioxy)diacetanilide and artemisinin; amo 503034; ezetimibe and VX-950; HCV-796 and VX-497; rolfine and benzamil: artemisinin and triciribine; 2,2'- chlorophyllin and VX-497; HCV-796 and melphalan; capsai (pentamethylenedioxy)dianiline and amorolfine; (S,S)-n- cin and NM-283: SCH503034 and sirolimus; LY294.002 and desmethyl sertraline and simvastatin; levothyroxine and SCH 5.03034; adefovir dipivoxil and SCH503034; interferon wedelolactone; 1.5-bis(4-aminophenoxy)pentane and arte alfa-2a and trifluridine: HCV-796 and trifluridine; GW 5074 misinin; benzamil and dextrothyroxine; amorolfine and trif and NM-283; mosapride and VX-950; interferon alfa-2a and luperidol; artemisinin and indocyanine green; dihydroarte VX-497; NM-283 and trequinsin; cytarabine and HCV-796: misinin and wortmannin; flupentiXol and Sertraline; benzamil adefoviridipivoxil and VX-950; cytarabine and VX-950:SCH and levothyroxine; amorolfine and meclizine; pravastatin and 503034 and saquinavir; VX-950 and wortmannin; capsaicin US 2008/O161324 A1 Jul. 3, 2008

and VX-950: 2-hydroxyflavanone and NM-283; bronihexine days of each other in amounts that together are effective to and VX-950; HCV-796 and wortmannin; artemisinin and rib treat the patient. The antihistamine may be hydroxy Zine. avirin; VX-950 and verapamil: SCH 5.03034 and verapamil: 0018. In yet another aspect, the invention features a SCH 5.03034 and topotecan; HCV-796 and topotecan; triflu method for treating a patient having a viral disease. The peridol and VX-950; irinotecan and SCH 5.03034; artesunate method includes administering to the patient a pair of agents and SCH 5.03034; repaglinide and SCH 5.03034; topotecan selected from the group consisting of amorolfine and Sertra and VX-950; tepaglinide and VX-950; arbidol and VX-950: line; fluvastatin and Sertraline; rosuvastatin and Sertraline; chlorophyllin and HCV-796; benzydamine and VX-950: fulvestrant and satraplatin; amorolfine and mebeverine; amo NM-283 and trifluperidol; capsaicin and HCV-796; NM-283 rolfine and satraplatin; ifenprodil and Sertraline; amorolfine and phenazopyridine; NM-283 and trifluridine; and adefovir and tolterodine; atorvastatin and Sertraline; amorolfine and dipivoxil and HCV-796. irinotecan; lovastatin and Sertraline; cytarabine and tricirib 0011. In certain embodiments, the combination is selected ine; artesunate and wortmannin; Sertraline and simvastatin from group consisting of simvastatin and Sertraline; fluvasta hydroxy acid, ammonium salt; amorolfine and cytarabine; tin and Sertraline; fluiphenazine and Sertraline; artesunate and Sertraline and simvastatin; octyl methoxycinnamate and Sub simvastatin; artesunate and wortmannin; artemisinin and erohydroxamic acid; 1.5-bis(4-aminophenoxy)pentane and chlorophyllin; artemisinin and 3,3'-(pentamethylenedioxy) amorolfine; (S,S) N-desmethyl sertraline and simvastatin: dianiline; amorolfine and meclizine; amorolfine and Sertra artemisinin and SB-202190: interferon alfa-2a and sirolimus: line; amorolfine and trifluridine; amorolfine and 2-hydroxy amorolfine and indocyanine green; TOFA and triciribine; flavanone; amorolfine and eZetimibe; amorolfine and 3.3'-(pentamethylenedioxy)dianiline and artemisinin; arte benzamil; amorolfine and trifluperidol; and octyl methoxy misinin and wortmannin; 3.3"-(pentamethylenedioxy)diac cinnamate and Suberohydroxamic acid. etanilide and artemisinin; amorolfine and benzamil; artemisi 0012. In any of the above aspects, the two agents may be nin and triciribine; 2,2'-(pentamethylenedioxy)dianiline and present in amounts that, when administered to a patient hav amorolfine; (S,S)-n-desmethyl sertraline and simvastatin: ing a viral disease (e.g., any viral disease described herein), levothyroxine and Wedelolactone; 1.5-bis(4-aminophenoxy) are effective to treat the patient. The composition may further pentane and artemisinin; benzamil and dextrothyroxine; include one or more (e.g., two, three, four, five, or six) addi amorolfine and trifluperidol; artemisinin and indocyanine tional agents selected from the agents of Table 1, Table 2, green; dihydroartemisinin and wortmannin; flupentiXol and Table 3, Table 4, and Table 5 (e.g., where the agents are not a Sertraline; benzamil and levothyroxine; amorolfine and combination of agents selected from Table 7). The composi meclizine; pravastatin and sertraline; 1.5-bis(4-aminophe tion may be formulated, for example, for oral, systemic, noxy)pentane and indocyanine green; 2-hydroxyflavanone parenteral, topical (e.g., ophthalmic, dermatologic), intrave and amorolfine; ritonavir and vinorelbine; benoximate and nous, or intramuscular administration. dehydroepiandrosterone; ifenprodil and indocyanine green; 0013. In another aspect, the invention features a method amorolfine and arbidol: 3,3'-(pentamethylenedioxy)dianiline for treating a patient having a viral disease. The method and indocyanine green; fulvestrant and vinorelbine; amorolf includes administering to the patient an agent selected from ineandezetimibe; amorolfine and Evans blue; amorolfine and the agents of Table 1 in an amount effective to treat the patient. gefitinib, amorolfine and topotecan; 2.2"-(pentamethylene 0014. In another aspect, the invention features a method dioxy)diacetanilide and artemisinin; amorolfine and for treating a patient having hepatitis C. The method includes wedelolactone; 3,3'-(pentamethylenedioxy)dianiline and administering to the patient an agent selected from the agents amorolfine; simvastatin and rac-cis-n-desmethyl sertraline; of Table 1 and Table 2 in an amount effective to treat the adefovir dipivoxil and triciribine; cytarabine and Evans blue; patient. artemisinin and Evans blue; fluphenazine and Sertraline; ben Zamil and SB-202190: artemisinin and rifabutin; fluphena 0015. In another aspect, the invention features a method Zine and tolterodine; interferon alfa-2a and melphalan; amo for treating a patient having a viral disease. The method rolfine and melphalan; artemisinin and fulvestrant; ifenprodil includes administering to the patient a plurality of agents and quinacrine; simvastatin and rac-cis-n-desmethyl sertra where the first agent is selected from the agents of Table 1, line; flupentixol and tolterodine; triciribine and wortmannin: Table 2, and Table 3 and the second agent is selected from the loratadine and vinorelbine; meclizine and sertraline; budes agents of Table 1, Table 2, Table 3, Table 4, and Table 5 (e.g., onide and vinorelbine, 2-hydroxyflavanone and indocyanine Table 4 and Table 5), where the agents are administered green; hydroxy Zine and Sertraline: 2,2'-(pentamethylene within 28 days (e.g., within 21, 14, 10, 7, 5, 4, 3, 2, or 1 days) dioxy)dianiline and artemisinin; amorolfine and flupentixol; or within 24 hours (e.g., 12, 6, 3, 2, or 1 hours; or concomi artemisinin and chlorophyllin; eZetimibe and fluphenazine; tantly) of each other in amounts that together are effective to benzamil and fluphenazine; artemisinin and Wedelolactone; treat the patient. cytarabine and dydrogesterone; artemisinin and benzamil; 0016. In another aspect, the invention features a method 3,3'-(pentamethylenedioxy)dianiline and artemether; toltero for treating a patient having a viral disease. The method dine and trifluperidol; artesunate and fluvastatin; artemisinin includes administering to the patient sertraline and an HMG and trifluridine; adefovir dipivoxil and amorolfine; interferon CoA reductase inhibitor, where the two agents are adminis alfa-2a and trifluridine; fulvestrant and triciribine; artesunate tered within 28 days of each otherinamounts that together are and dydrogesterone; artesunate and LY 294.002; mosapride effective to treat the patient. The HMG-CoA reductase inhibi citrate and TOFA; bromocriptine and wedelolactone; arte tor may be fluvastatin, simvastatin, lovastatin, or rosuvastatin. misinin and sodium fusidate; celgosivir and interferon alfa 0017. In another aspect, the invention features a method 2a; amorolfine and dextrothyroxine; andrographis and fulves for treating a patient having a viral disease. The method trant; 2'-c-methylcytidine and artemisinin; amorolfine and includes administering to the patient Sertraline and an anti gemcitabine; oxeladin and Sertraline; artemisinin and par where the two agents are administered within 28 thenolide; artemisinin and ribavirin; dehydroepiandrosterone US 2008/O161324 A1 Jul. 3, 2008

and tyrphostin AG 1478; sertraline and toremifene; dihy administered to the patient by intravenous, intramuscular, droartemisinin and fulvestrant, 2-hydroxyflavanone and inhalation, topical (e.g., ophthalmic, determatologic), or oral TOFA; artesunate and repaglinide; mofebutaZone and administration. wedelolactone; artesunate and simvastatin; 2,2'-(pentameth 0021. In another aspect, the invention features a includ ylenedioxy)dianiline and artesunate; artemisinin and gemcit ing an agent selected from any of the agents of Table 1; and abine; dihydroartemisinin and ezetimibe; chlorophyllin and instructions for administering the agent to a patient having a cytarabine; interferon alfa-2a and sirolimus; Suberohydrox viral disease. amic acid and VX-497; artemisinin and VX-497; artesunate 0022. In another aspect, the invention features a kit includ and VX-497; tolterodine and VX-950; artemisinin and HCV ing an agent selected from any of the agents of Table 1 and 796; artemisinin and NM-283; NM-283 and wedelolactone; Table 2; and instructions for administering the agent to a artemisinin and SCH 503034; cytarabine and SCH 5.03034; patient having hepatitis C. SCH 5.03034 and triciribine; interferon alfa-2a and mel 0023. In another aspect, the invention features a kit includ phalan; benoximate and VX-950; HCV-796 and sirolimus: ing a composition including two or more (e.g., 3, 4, 5, 6, or 7) benoximate and SCH 503034; melphalan and VX-950: agents selected from any of the agents of Table 1, Table 2, and ritonavir and VX-950; VX-950 and VX-497; artemisinin and Table 3; and instructions for administering the composition to VX-950; triciribine and VX-950; suberohydroxamic acid and a patient having a viral disease. VX-950; HCV-796 and suberohydroxamic acid; sirolimus 0024. In another aspect, the invention features a kit includ and VX-950; melphalan and SCH 5.03034; SCH503034 and ing a first agent selected from any of the agents of Table 1, wortmannin; SCH503034 and tolterodine; ritonavir and SCH Table 2, and Table 3: a second, different agent selected from 503034; ezetimibe and VX-950; HCV-796 and VX-497; any of the agents of Table 1, Table 2, and Table 3; and instruc chlorophyllin and VX-497; HCV-796 and melphalan; capsai tions for administering the first and second agents to a patient cin and NM-283: SCH503034 and sirolimus; LY 294.002 and having a viral disease. SCH 5.03034; adefovir dipivoxil and SCH503034; interferon 0025 Inanother aspect, the invention features a kit includ alfa-2a and trifluridine: HCV-796 and trifluridine; GW 5074 ing an agent selected from any one of the agents of Table 1, and NM-283; mosapride and VX-950; interferon alfa-2a and Table 2, and Table 3; and instructions for administering the VX-497; NM-283 and trequinsin; cytarabine and HCV-796: agent with a second, different agent selected from any of the adefoviridipivoxil and VX-950: cytarabine and VX-950:SCH agents of Table 1, Table 2, and Table 3 to a patient having a 503034 and saquinavir; VX-950 and wortmannin; capsaicin viral disease. and VX-950; 2-hydroxyflavanone and NM-283; bromhexine and VX-950; HCV-796 and wortmannin; artemisinin and rib 0026. In another aspect, the invention features a kit includ avirin; VX-950 and verapamil: SCH 5.03034 and verapamil: ing a composition including (i) a first agent selected from any SCH 5.03034 and topotecan; HCV-796 and topotecan; triflu one of the agents of Table 1, Table 2, and Table 3, and (ii) one peridol and VX-950; irinotecan and SCH 5.03034; artesunate or more agents of Table 4 and Table 5; and instructions for and SCH 5.03034; repaglinide and SCH 5.03034; topotecan administering the composition to a patient having a viral and VX-950; tepaglinide and VX-950; arbidol and VX-950: disease. chlorophyllin and HCV-796; benzydamine and VX-950: 0027. In another aspect, the invention features a kit includ NM-283 and trifluperidol; capsaicin and HCV-796; NM-283 ing (a) a first agent selected from any of the agents of Table 1, and phenazopyridine; NM-283 and trifluridine; and adefovir Table 2, and Table 3; (b) one or more agents of Table 4 and dipivoxil and HCV-796, where the agents are administered Table 5; and (c) instructions for administering (a) and (b) to a within 28 days of each other in amounts that together are patient having a viral disease. effective to treat the patient. 0028. In another aspect, the invention features a kit includ 0019. In another aspect, the invention features a method ing an agent selected from any of the agents of Table 1; and for treating a patient having a viral disease. The method instructions for administering the agent and one or more includes administering to the patient a pair of agents selected agents of Table 4 or Table 5 to a patient having a viral disease. from the group consisting of simvastatin and Sertraline; flu 0029. In another aspect, the invention features a kit includ vastatin and Sertraline; fluiphenazine and Sertraline; artesu ing an agent selected from any of the agents of Table 1 and nate and simvastatin; artesunate and wortmannin; artemisinin Table 2; and instructions for administering the agent and one and chlorophyllin; artemisinin and 3,3'-(pentamethylene or more agents of Table 4 or Table 5 to a patient having dioxy)dianiline; amorolfine and meclizine; amorolfine and hepatitis C. sertraline; amorolfine and trifluridine; amorolfine and 2-hy 0030. In another aspect, the invention features a kit includ droxyflavanone; amorolfine and eZetimibe; amorolfine and ing (a) one or more agents of Table 4 and Table 5; and (b) benzamil; amorolfine and trifluperidol; and octyl methoxy instructions for administering the agent from (a) with any cinnamate and Suberohydroxamic acid, where the two agents agent of Table 1, Table 2, and Table 3 to a patient having a viral are administered within 28 days of each other in amounts that disease. together are effective to treat the patient. 0031. In another aspect, the invention features a kit includ 0020. The methods of any of the above aspects may be ing sertraline; an HMG-CoA reductase inhibitor (e.g., fluv performed in conjunction with administering to the patient an astatin, simvastatin, lovastatin, or rosuvastatin); and instruc additional treatment (e.g., an antiviral therapy such as those tions for administering the sertraline and the HMG-CoA agents listed in Table 4 and Table 5) for a viral disease, where reductase inhibitor to a patient having a viral disease. the method and the additional treatment (e.g., not a combina 0032. In another aspect, the invention features a kit includ tion of agents selected from Table 6 and Table 7) are admin ing a composition including Sertraline and an HMG-CoA istered within 6 months (e.g., within 3, 2, or 1 months; within reductase inhibitor (e.g., fluvastatin, simvastatin, lovastatin, 28, 21, 14, 10, 7, 5, 4, 3, 2, or 1 days; within 24, 12, 6, 3, 2, or or rosuvastatin); and instructions for administering the com 1 hours; or concomitantly) of each other. The agents may be position to a patient having a viral disease. US 2008/O161324 A1 Jul. 3, 2008

0033. In another aspect, the invention features a kit includ wedelolactone; artemisinin and sodium fusidate; celgosivir ing Sertraline; an antihistamine and interferon alfa-2a, amorolfine and dextrothyroxine; 0034 (e.g., hydroxyzine); and instructions for administer andrographis and fulvestrant; 2'-c-methylcytidine and arte ing the Sertraline and the antihistamine to a patient having a misinin; amorolfine and gemcitabine; oxeladin and Sertraline; viral disease. artemisinin and parthenolide; artemisinin and ribavirin; 0035. In another aspect, the invention features a kit includ dehydroepiandrosterone and tyrphostin ag 1478; Sertraline ing a composition including Sertraline and an antihistamine and toremifene; dihydroartemisinin and fulvestrant, 2-hy (e.g., hydroxy Zine); and instructions for administering the droxyflavanone and TOFA; artesunate and repaglinide; composition to a patient having a viral disease. mofebutaZone and Wedelolactone; artesunate and simvasta 0036. In another aspect, the invention features a kit includ tin; 2,2'-(pentamethylenedioxy)dianiline and artesunate; ing (a) a pair of agents selected from the group consisting of artemisinin and gemcitabine, dihydroartemisinin and amorolfine and Sertraline; fluvastatin and Sertraline; rosuvas eZetimibe; chlorophyllin and cytarabine; interferon alfa-2a tatin and Sertraline; fulvestrant and satraplatin; amorolfine and sirolimus; suberohydroxamic acid and VX-497; artemisi and mebeverine; amorolfine and satraplatin; ifenprodil and nin and VX-497; artesunate and VX-497; tolterodine and Sertraline; amorolfine and tolterodine, atorvastatin and Sertra VX-950; artemisinin and HCV-796; artemisinin and line; amorolfine and irinotecan; lovastatin and Sertraline; cyt NM-283; NM-283 and wedelolactone; artemisinin and SCH arabine and triciribine; artesunate and wortmannin; Sertraline 503034; cytarabine and SCH503034; SCH503034 and tricir and simvastatin hydroxy acid, ammonium salt; amorolfine ibine; interferon alfa-2a and melphalan; benoximate and and cytarabine; Sertraline and simvastatin; octyl methoxycin VX-950; HCV-796 and sirolimus; benoximate and SCH namate and Suberohydroxamic acid; 1.5-bis(4-aminophe 503034; melphalan and VX-950; ritonavir and VX-950: noxy)pentane and amorolfine; (S,S)—N-desmethyl Sertra VX-950 and VX-497; artemisinin and VX-950; triciribine line and simvastatin; artemisinin and SB-202190: interferon and VX-950; suberohydroxamic acid and VX-950; HCV-796 alfa-2a and sirolimus; amorolfine and indocyanine green; and suberohydroxamic acid; sirolimus and VX-950; mel TOFA and triciribine; 3,3'-(pentamethylenedioxy)dianiline phalanand SCH503034; SCH503034 and wortmannin; SCH and artemisinin; artemisinin and wortmannin; 3.3"-(pentam 503034 and tolterodine; ritonavir and SCH 5.03034; ethylenedioxy)diacetanilide and artemisinin; amorolfine and ezetimibe and VX-950; HCV-796 and VX-497; chlorophyllin benzamil: artemisinin and triciribine; 2,2'-(pentamethylene and VX-497; HCV-796 and melphalan; capsaicin and dioxy)dianiline and amorolfine; (S,S)-n-desmethyl sertraline NM-283: SCH 5.03034 and sirolimus: LY 294.002 and SCH and simvastatin; levothyroxine andwedelolactone; 1.5-bis(4- 503034; adefovir dipivoxil and SCH 5.03034; interferon alfa aminophenoxy)pentane and artemisinin; benzamil and dex 2a and trifluridine: HCV-796 and trifluridine; GW 5074 and trothyroxine; amorolfine and trifluperidol; artemisinin and NM-283; mosapride and VX-950; interferon alfa-2a and indocyanine green; dihydroartemisinin and wortmannin; flu VX-497; NM-283 and trequinsin; cytarabine and HCV-796: pentiXol and Sertraline; benzamil and levothyroxine; amo adefoviridipivoxil and VX-950; cytarabine and VX-950:SCH rolfine and meclizine; pravastatin and Sertraline; 1.5-bis(4- 503034 and saquinavir; VX-950 and wortmannin; capsaicin aminophenoxy)pentane and indocyanine green; and VX-950: 2-hydroxyflavanone and NM-283; bromhexine 2-hydroxyflavanone and amorolfine; ritonavir and vinorel and VX-950; HCV-796 and wortmannin; artemisinin and rib bine; benoximate and dehydroepiandrosterone; ifenprodiland avirin; VX-950 and verapamil: SCH 5.03034 and verapamil: indocyanine green; amorolfine and arbidol: 3,3'-(pentameth SCH 5.03034 and topotecan; HCV-796 and topotecan; triflu ylenedioxy)dianiline and indocyanine green; fulvestrant and peridol and VX-950; irinotecan and SCH 5.03034; artesunate vinorelbine; amorolfine and ezetimibe; amorolfine and Evans and SCH 5.03034; repaglinide and SCH 5.03034; topotecan blue; amorolfine and gefitinib; amorolfine and topotecan; and VX-950; repaglinide and VX-950; arbidol and VX-950: 2.2"-(pentamethylenedioxy)diacetanilide and artemisinin; chlorophyllin and HCV-796; benzydamine and VX-950: amorolfine and wedelolactone; 3,3'-(pentamethylenedioxy) NM-283 and trifluperidol; capsaicin and HCV-796; NM-283 dianiline and amorolfine; simvastatin and rac-cis-n-desm and phenazopyridine; NM-283 and trifluridine; and adefovir ethyl sertraline; adefovir dipivoxil and triciribine; cytarabine dipivoxil and HCV-796; and (b) instructions for administer and Evans blue; artemisinin and Evans blue; fluiphenazine and ing the pair of agents to a patient having a viral disease. The sertraline; benzamil and SB-202190: artemisinin and rifabu kit may include a composition including the pair of agents. tin; fluphenazine and tolterodine; interferon alfa-2a and mel 0037. In another aspect, the invention features a kit includ phalan; amorolfine and melphalan; artemisinin and fulves ing (a) a pair of agents selected from the group consisting of trant; ifenprodil and quinacrine; simvastatin and rac-cis-n- simvastatin and Sertraline; fluvastatin and Sertraline; desmethyl sertraline; flupentixol and tolterodine: triciribine fluphenazine and Sertraline; artesunate and simvastatin; arte and wortmannin; loratadine and vinorelbine; meclizine and Sunate and wortmannin; artemisinin and chlorophyllin; arte sertraline; budesonide and vinorelbine: 2-hydroxyflavanone misinin and 3,3'-(pentamethylenedioxy)dianiline; amorolf and indocyanine green; hydroxy Zine and Sertraline; 2,2'- ine and meclizine; amorolfine and Sertraline; amorolfine and (pentamethylenedioxy)dianiline and artemisinin; amorolfine trifluridine; amorolfine and 2-hydroxyflavanone; amorolfine and flupentixol; artemisinin and chlorophyllin; eZetimibe and and eZetimibe; amorolfine and benzamil; amorolfine and tri fluiphenazine; benzamil and fluphenazine; artemisinin and fluperidol; and octyl methoxycinnamate and Suberohydrox wedelolactone; cytarabine and dydrogesterone; artemisinin amic acid; and (b) instructions for administering the pair of and benzamil: 3,3'-(pentamethylenedioxy)dianiline and arte agents to a patient having a viral disease. The kit may include mether, tolterodine and trifluperidol; artesunate and fluvasta a composition including the pair of agents. tin; artemisinin and trifluridine; adefovir dipivoxil and amo 0038. In another aspect, the invention features a method of rolfine; interferon alfa-2a and trifluridine; fulvestrant and identifying a combination that may be useful for the treatment triciribine; artesunate and dydrogesterone; artesunate and LY of a patient having a viral disease, or the prevention or reduc 294.002; mosapride citrate and TOFA; bromocriptine and tion of the viral disease. The method includes the steps of US 2008/O161324 A1 Jul. 3, 2008

contacting cells including at least a portion of the genome of flavivirus which include without limitation Absettarov, Alfuy, a virus with an agent selected from any one the agents of Table Apoi, Aroa, Bagaza, Banzi, Bouboui, BuSSuquara, Cacipa 1, Table 2, and Table 3 and a candidate compound, wherein core, Carey Island, Dakar bat, Dengue 1, Dengue 2, Dengue the portion of the genome (e.g., of any virus described herein) 3, Dengue 4, Edge Hill, Entebbe bat, Gadgets Gully, Hanza is capable of replication in the cells; and determining whether lova, Hypr, Ilheus, Israel turkey meningoencephalitis, Japa the combination of the agent and the candidate compound nese encephalitis, Jugra, Jutiapa, Kadam, Karshi, Kedougou, inhibits the replication of the portion of the genome relative to Kokobera, Koutango, Kumlinge, Kunjin, Kyasanur Forest cells contacted with the agent but not contacted with the disease, Langat, Louping ill. Meaban, Modoc, Montana myo candidate compound, where a reduction in replication iden tis leukoencephalitis, Murray Valley encephalitis, Naranjal, tifies the combination as a combination useful for the treat Negishi, Ntaya, Omsk hemorrhagic fever, Phnom-Penh bat, ment of a patient having a viral disease, or the prevention or Powassan, RiO Bravo, Rocio, royal farm, Russian spring reduction of a viral disease. The reduction in replication may Summer encephalitis, Saboya, St. Louis encephalitis, Sal be the result of a decreased rate of DNA or RNA replication, Vieja, San Perlita, Saumarez Reef, Sepik, Sokuluk, Spond a decreased rate of RNA translation, or inhibition of a protein weni, Stratford, Tembusu, Tyuleniy, Uganda S. Usutu, Wes required for viral replication (e.g., a protein coded for by the selsbron, west Nile, Yaounde, yellow fever, and Zika viruses, viral genome or the host organism). If the at least portion of a or any of the viruses described in Chapter 31 of Fields Virol genome is from the hepatitis C genome, the reduction in ogy, Fields, B. N., Knipe, D. M., and Howley, P. M., eds. replication may also be due to a decreased rate of polyprotein Lippincott-Raven Publishers, Philadelphia, Pa., 1996. In processing. The cells may be mammalian cells (e.g., hepatic other embodiments, the viral disease is caused by a pestivirus, cells, for example, any of those described herein) such as which include bovine viral diarrhea virus (“BVDV), classi human cells. cal Swine fever virus (“CSFV, also called hog cholera virus), 0039. The viral disease referred to in any of the above border disease virus (“BDV) and any of those discussed in aspects of the invention, including the methods of treatment Chapter 33 of Fields Virology, supra. In other embodiments, of the invention, the compositions and kits of the invention, the viral disease is caused by a virus Such as hepatitis A, and methods of the invention for identifying combinations hepatitis B, hepatitis C (e.g., genotype 1 such as 1a or 1b; may be caused by a single stranded RNA virus, a flaviviridae genotype 2 Such as 2a, 2b, or ; genotype 3; genotype 4: virus (e.g., a hepacivirus Such as HCV flavivirus, pestivirus, genotype 5: genotype 6); hepatitis D; or hepatitis E. The viral or hepatitis G. virus), or a hepatic virus (e.g., any hepatic virus hepatitis may further be a non-ABCDE viral hepatitis (e.g., described herein such as hepatitis A, hepatitis B, hepatitis C, hepatitis G). hepatitis D, hepatitis E, non-ABCDE hepatitis, or hepatitis 0040. Additional viral therapies are described in Table 4 G). In certain embodiments, the viral disease is caused by a and Table 5.

TABLE 4 (+)-Calanolide A (+)-Dihydrocalanolide A 14SU87 2-Nor-cyclic GMP 3,4-Dicaffeoylquinic acid 3-Hydroxymethyl 3-Hydroxyphthaloyl-beta- 3-Nitrosobenzamide dicamphanoyl khellactone lactoglobulin 4-Azidothymidine 4-Methyl dicamphanoyl 524C79 739W94 khellactone A 160621 A 315675 A 315677 A SO21 A 74259 A 74704 A 77003 A 8073S A 80987 A 91883A A9888.1 Abacavir AC 2 Acemannan Acetylcysteine-Zambon ACH 126445 ACH 126447 (e.g., extended Aciclovir-PMPA ACPHIP release, controlled release, topical patch) Actinohivin AD 439 ADS 19 Adamantylamide dipeptide ADSJ1 Afovirsen AG 1284 AG 1350 AG 1478 AG 1859 AG SSS AG 6840 AG 6863 AGT-1 AHAO08 Aidfarel AL 721 Alamiifovir Albumin interferon-alpha ALNRSVO1 Alpha HGA Alpha-1 PDX Alpha-antitrypsin Alvirceptsudotox Alvocidib ALXOO19 ALX404C AM285 AM365 AMD O70 AMD 3329 AMD 3465 AMD 8664 Amdoxovir Amidinomycin Aminopeptidase Amitivir Ampligen Amprenavir AMZOO26 Ancriviroc Anti-CCR5 monoclonal antibody Anti-CCR5/CXCR4 sheep Anti-CD3 monoclonal Anti-CD4 monoclonal Anti-CD7 monoclonal monoclonal antibody antibody CD4IgG conjugate antibody antibody Anti-CD8 monoclonal antibody Anti-CMV monoclonal Anti-hepatitis B ribozyme Anti-HIV catalytic antibody antibody Anti-HIV immunotoxin (IVAX) Anti-HIV-1 human Anti-HIV-1 human Anti-HIV-1 human monoclonal antibody 2F5 monoclonal antibody 2G12 monoclonal antibody 4E10 Antineoplaston AS21 (e.g., oral) Anti-RSV antibody (Intracel, Antisense oligonucleotide PB2 Aop-RANTES Corp.) AUG AplaViroc Apricitabine AQ 148 AR 132 AR.177 ARB 952.14 ARB9726S ARB 97268 ARQ 323 AS 101 AT 61 Atazanavir Ateviridine AV 11 O1 AV 2921 US 2008/O161324 A1 Jul. 3, 2008

TABLE 4-continued

AV 2923 AV 2925 AV 2927 Avarol AXD 455 AZidodideoxyguanosine AZodicarbonamide Bafilomycin A1 BAY 414109 BAY 43969S BAY SO4798 BAYZ 430S BB 1OO10 BB 2116 BCH 10652 BCH371 BCH 527 BCTP BCX 140 BCX 1591 BCX 1827 BCX 1898 BCX 1923 BEA BEA OOS Bellenamine Benanomicin A Benzalkonium (e.g., chloride) Benzalkonium Beta-D-FDOC Beta-L-iddC chloridefoctoxynol 9 (e.g., vaginal gel) Beta-L-FddC Bevirimat BG 777 BGP 15 BILA 2185 BS LR355 BIRMECA 10-142 BL 1743 BMS10836 MS 181167–02 BMS 181184 BMS 1821.93 BMS 1863.18 MS 187071 BMS 488043 BMS 806 BMY 27709 recanavir Brefeldin A Brequinar RL 47923DP BSL 4 BST SOO1 BTA 188 TA798 C 1605 C 2507 C31G alcium spirulan Canventol Capravirine Carbendazim arbocyclic deazaadenosine Carbopol polymer gel Carbovir CC 3052 D4 fusion toxin CD4 IgG CD4-ricin chain A Cellulose sulfate F 1743 CFY 196 CGA 137053 CGP35269 GP 49689 CGP 53437 CGP 53820 CGP 57813 GP 61.783 CGP 64222 CGP 70726 CGP 751.36 GP 751.76 CGP 75355 CI1012 CI1013 Civamide CL 190O38 CL 387626 evudine CMV 423 CMXOO1 CNBA-Na. NIO2 Cobra venom peptide Conocurvone Cosalane ostatolide CP 1018161. CP38 CP51 PFDD CRL 1072 Crofelemer CS 8958 CS 92 CT 2576 CTC96 Curdlan sulfate Cyanovirin-N CYT 99007 Cytomegalovirus immune globulin DAB486interleukin-2 DABO 1220 acopafant DAP 30 DAP 32 Dapivirine arunavir D-aspartic-beta-hydroxamate DB340 DDCDP-DG DGA Deazaadenosine DeaZaneplanocin A DEB O2S elavirdine Delimitide Denileukin diftitox Deoxyfluoroguanosine ES 6 Dexelvucitabine Dextran sulfate Dextrin 2-sulfate G35 Didanosine Dideoxyadenosine Dideoxyguanosine ideoxythymidine Didox Dihydrocostatolide Dinitrochlorobenzene L110 DMP 323 DMP 850 DMP 851 mTr-ODN12 Docosanol DP 107 DPC 082 PC 083 DPC 681 DPC 684 DPC 961 PC 963 Droximavir DUP 925 DYE 913 B- E-EPSEU EGS 21 HT 899 vucitabine EM 1421 EM2487 mivirine mtricitabine Emtricitabinetenofovir Enfuwirtide ntecavir sinophil-derived disoproxil fumarate neutralizing agent Episiastatin B ET 007 E anercept her lipid analogue Etoviram Etravirine 105 36 F 50003 asudil ttiviracin A1 FEAU Feglymycin elvizumab GI 345 Fiacitabine Fialuridine utimide Fosalvudine tidoxil Osamprenavir Oscarnet Sodium Fozivudine FP 21.399 -PBT PMPA FPMPDAP FR 191512 R 198248 alactan Sulfate GAP 31 GCA 186 CPK GE 20372A GE 20372B GEM 122 EM132 GEM 144 GEM 92 GEM 93 amolec Glutathionarsenoxide Glycovir GMDP O 6976 GO 7716 GO 7775 Gossypol PG-NH2 GPI 1485 GPI 2A GPS O193 R 137615 GR92938X GS 2838 GS 2992 S3333 GS 3435 GS4O71 GS 438 S 7340 GS 900S GS 916O GS 930 W 275175 GW 595OX HB 19 HBY 946 E317 Hepatitis B immune globulin HEPT HGS-HIFA27 236 HI 240 HI 244 HI 280 346 HI443 HI445 HIV DNA vaccine (Antigen Thi Ow r Express, Inc.) HIV immune globulin HIV immune plasma HL 9 HOE BAY 793 HRG 214 HSO58 Hydroxycarbamide Hydroxychloroquine I 152 LAZT IM28 ImmStat ImmuCyn Immunocal Imreg 1 Incadronic acid INCB 94.71 Indinavir Infliximab US 2008/O161324 A1 Jul. 3, 2008

TABLE 4-continued matrix protein Zn2+ ngenol Triacetate nophyllum B nosine pranobex finger peptide interferon-tau -1 type I interleukin-13 interleukin-15 interleukin-16 interleukin-2 interleukin-4 PR pilimumab SIS 13312 so doA TIOO2 TIO11 BP 485 CA 304 E2147 M 1596 M2763 TK303 K 12 K37 Kamizol kethoxal Kiimicin Kistamicin KKKI 538 KMO43 KNI 102 KNI 241 KNI 272 KNI 413 KNI 684 Kootikuppala KP 1461 KRH 1120 L 6895O2 L 693549 L 696,229 L 696474 L 696661 L 697639 L 697661 L 708,906 L 731988 L 7328O1 L 734OOS L 735882 L 738372 L 738684 L 738872 L 739594 L 748496 L 754394 L 75.6423 L 87.08.10 LHSAara AMP Lamivudinejabacavir ? zidovudine Lasinavir LB 71116 LB 71148 LB 71262 LB 71350 LB 8038O L-chicoric acid Lecithinized Superoxide Leflunomide Lentinan Leukocyte interleukin injection dismutase (CEL-SCI Corp.) Leukotriene B4-LTB4 Levcycloserine Lexithromycin Liposomal ODG-PFA-OMe Lithium Succinate Lodenosine Lopinavir Loviride Luftronil LY 18O299 LY214624 LY 253963 LY 28961.2 LY 296,242 LY 296416 LY 309391 LY30984O LY311912 LY314163 LY314177 LY316683 LY 326.188 LY 326594 LY 32662O LY 338387 LY 343814 LY3S4400 LY3554.55 LY 366094 LY3664OS LY 368.177 LY 73497 M4O401 Madu Mannan sulfate MAP 30 Maraviroc Masoprocol MB-Foscarnet MC 207044 MC2O7685 MC 867 CDS71 MDI-P MDL 101028 MDL 2061O MDL 273.93 MDL 73669 MDL 74428 MDL 74.695 MDL 74968 MDX 240 ME 609 MEDI488 MEN 10690 MEN 10979 MERNSO7SA Met-enkephalin Methisazone MGN 3 Michellamine B Miglustat MIV 150 MIV 210 Mivotilate MKOS18 MK 94.4A MM1 MMS 1 MOL O275 Monoclonal antibody 1F7 Monoclonal antibody 2F5 Monoclonal antibody 3F12 Monoclonal antibody 447-52D Monoclonal antibody 50-61A Monoclonal antibody B4 Monoclonal antibody HNK20 Monoclonal antibody NMO1 Mopyridone Motavizumab Motexafin gadolinium Mozenavir MPC 531 MRK1 MS 1060 MS 1126 MS 8209 MS 888 MSC 127 MSH 143 MTCH 24 MTP-PE Murabutide MV O26048 MX 1313 Mycophenolate mofetil Nawuridine NBOO1 B- conjugate Neotripterifordin Nevirapine Nitric oxide (e.g., ProStrakan) Nitrodeazauridine NMO1 NM 49 NM 55 NNY-RANTES Nonakine NPO6 NP 77A NPC 15437 NSC 158393 NSC 20625 NSC 28.7474 NSC 4493 NSC 615985 NSC 62OOSS NSC 6241.51 NSC 624321 NSC 627708 NSC 651O16 NSC 667952 NSC 708199 Octoxynol 9 OCXO191 OKU 40 OKU 41 Oltipraz Omaciclovir Opaviraline OPTTL3 Oragen ORI902O Oxetanocin Oxothiazolidine carboxylate PA 344, PA 34.4B Palinavir PaliwiZumab PAMBAEEG Papuamide A PBS 119 PC 1250 PC 515 PCL O16 PD OO84430 PD 144795 PD 153103 PD 157945 PD 169277 PD 171277 PD 171791 PD 173606 PD 173638 PD 177298 PD 178390 PD 178392 PD 190497 Pegaldesleukin Peldesine PEN2O3 Pentosan polysulfate Pentoxifylline Peptide T PETT 4 PG 36 Phellodendrine Phosphatidyllamivudine Phosphatidylzalcitabine Phosphatidylzidovudine Phosphazid Phosphinic cyclocreatine Pinosylvin Pirodavir PL 2500 Plerixafor PM 104 PM 19 PM 523 PM921.31 PM 94116 PMEDAP PMS 601 PMTG PMTI PN355 PNU 103657 PNU 142721 Poly ICLC Polyadenylic polyuridylic acid Polysaccharide K PP 29 PPB 2. PPL 100 Pradefovir Pradimicin A PRO 140 PRO 2000 PRO 367 PRO S42 Probucol (Vyrex Corp.) Propagermanium Prostratin Pseudohypericin PSI SOO4 PTPR PTX111 US 2008/O161324 A1 Jul. 3, 2008 10

TABLE 4-continued Pyriferone Q 8045 QM 96521 QM 96639 QR 435 Quinobene Quinoxapeptin A Quinoxapeptin B QYL 438 QYL 609 QYL 685 QYL 769 R 170591 R 18893 R 61837 R71762 R 821SO R 82.913 R 851 R 87366 R91767 R944 R95288 Raluridine Ramatroban Ranpirinase RB 2121 RBC CD4 RD 30O28 RD 42O24 RD 42138 RD 42217 RD 42227 RD 621.98 RD 65071 RD6Y664 Regavirumab Resobene Respiratory syncytial virus Retrogen immune globulin REV 123 RFI 641 Rilpivirine RKS 1443 RO O334649 RO 247429 RO 2SO236 RO 316840 RO 53335 Robustaflavone Rollipram RP 70034 RP 71955 RPI312 PI856 RPR 103611 RPR 106868 RPR111423 S 654 RS 980 RSV 604 ubitecan upintrivir 1360 S 2720 A 1042 SA8443 SB 180922 B 2.05700 B2O6343 S B 73 SC 49.483 C 55099 CH3SO 634 S D 894 S-DABO DF 1 DZ, 282870 S DZ, 28.3053 SDZ, 2834.71 DZPRIOS3 S EO63 Semapimod F 950 S F953 Siamycin 1 SICAM-1 Sifuwirtide GA246 3366 KO34 KF 108.922 KI 1695 O 324 odium laurilsulfate olutein orivudine (e.g., topical) P 10 P 1093V. parfosic acid PC3 PD 756 pecifEx-Hep B PI 119 PL 2992 PL 7013 PV 30 R 10204 R 10208 R11335 R 3745A R3773 R3775 R3784 R3785 R. 41476 RL 172 RRSB3 T 135647 achyflin stallimycin ampidine atolon avudine Stepronin Suksdorfin Sulfated maltoheptaose Superoxide dismutase Suramin (e.g., sodium) Sy 801 T 1100 T 118 T 22 T 30.695 T 611 T 705 Tacrine TAK 220 TAK 652 TAK779 Talviraline TAP 29 TASP Teceleukin Tecogalan (e.g., Sodium) TEI 2306 Telinavir Temacrazine Tenidap Tenofovir fumarate TGG II 23A TH94O7 TH 9411 Thiophosphonoformic acid Thymoctonian Thymosin fraction 5 Thymotrinan ICAM-1 Tifuwirtide Tillarginine Tipranavir Tiviciclovir Tivirapine TJ 41 TL3024 TMC 126 TNF-alpha inhibitor TNK 6123 TNX355 Todoxin Tomeglovir Transforming TraT Trecovirsen alpha Tremacamra Trichosanthin Triconal Trimidox Trodusquemine Trovirdine Tuvirumab U103017 U 75875 U 78036 U 80493 U 81749 U88204E U 96988 U 98.43 UA926 Ubenimex UC 10 UC 16 UC 38 UC 42 UC 68 UC 70 UC 781 UC 81 UC 82 UIC 94.003 Ukrain UL36ANTI UMD 828 Valomaciclovir Valtorcitabine Varicella Zoster immune globulin VB 19038 Vesnarinone WF 1634 VGV 1 Vicriviroc VIR 101 Viraprexin Virodene Viscum album extract WRX 496 VX 10166 VX 10217 VX 10493 VX 11106 WHIO5 WHIO7 WIN 49569 WIN 496.11 WM 5 WR 151327 XK234 XN 482 XP 951 XQ 9302 XR835 XU 348 XU 430 Y-ART-3 YHI1 YKFH312 Z 100 Z 15 Zalcitabine Zidovudine (e.g., phosphate didanosine dimer) Zidovudine triphosphate mimics ZXO791 ZXO792 ZY II US 2008/O161324 A1 Jul. 3, 2008 11

0041 Additional hepatitis C therapies are described in Table 5.

TABLE 5

Albuferon JTKOO3 R7128 2'-C-methyl-7-deaza-adenosine HCVAB 68 JTK 109 Residuimod A-837.093 HCVSM KPE OOOO1113 RosiglitaZone AG-021541 HE 2000 KPEO2OO3OO2 Aldesleukin Hepatitis C immune globulin Lactoferrin ANA 971 Hepex C Lamivudine SCH6 ANA 975 Heptazyme LB 844-51 Schisandra AVI406S Histamine Licorice root SCVO7 AVR 118 Histamine dihydrochloride ME 3.738 SCY635 (e.g., injection, oral) Bavituximab HuMax-HepC Medusa Interferon Silipide BILN 303 SE Hypericin BIVN4O1 CN 17261 Milk thistle BLX 833 (e.g., controlled DN 6556 Mitoquinone Thymalfasin (e.g., Zadaxin) release) miquimod NIM 811 Thymus extract CellCept interferon N-nonyl-DNJ TT 9 Ceplene interferon alfa-2b (e.g., NOV 205 Tucaresol inhalation) (BILN 2061) interferon alfacon-1 NV-08 Ursodeoxycholic acid Civacir interferon alpha (e.g., P 56 UT 231B Sustained release, intranasal, Omniferon) Colloidal silver Peginterferon alfa-2a. Valopicitabine (NM 283) CpG 10101 interferon alpha-2b (e.g., Peginterferon alfa-2b VGX410 controlled release or transdermal) DEBIO-O2S interferon alpha-2b gene PEGinterferon alfacon-1 Virostat herapy Edodekin alfa erferon alpha-n3 PEGylated interferon VP 504O6 EHC 18 erferon beta-1a Pegylated thymalfasin VRT 21493 EMZ 702 erferon beta-1b PF-03491390 Fas-ligand inhibitor erferon gamma-1b PG 3.01029 WF 10 Ginseng erferon omega PSI-6130 XTL 2125 interleukin 10 (e.g., human R 1518 XTL 6865 recombinant) GS 91.32 satoribine R 1626 HCVO86 SIS 14803 R 803 HCV 371 TMN-191 R-1626

TABLE 6 Interferon alpha-2biribavirin Lopinavirritonavir Peginterferon alfa-2biribavirin

TABLE 7 Peginterferon-alpha ribavirin/EMZ 702 Efavirenziemtricitabinetenofovir disoproxil fumarate

0042 Analogs of any of the compounds listed in Tables 1. 2, or 3 may be used in any of the compositions, methods, and kits of the invention. Such analogs include any agent from the same therapeutic class, having the same or related molecular targets, or from the same mechanistic class as those listed in Table 8. US 2008/O161324 A1 Jul. 3, 2008 12 US 2008/O161324 A1 Jul. 3, 2008 13 US 2008/O161324 A1 Jul. 3, 2008 14 US 2008/O161324 A1 Jul. 3, 2008 15 US 2008/O161324 A1 Jul. 3, 2008 16 US 2008/O161324 A1 Jul. 3, 2008 17 US 2008/O161324 A1 Jul. 3, 2008 18

Joideo3.J.Op US 2008/O161324 A1 Jul. 3, 2008 19 US 2008/O161324 A1 Jul. 3, 2008 20

queInseA?nq US 2008/O161324 A1 Jul. 3, 2008 21 US 2008/O161324 A1 Jul. 3, 2008 22

US 2008/O161324 A1 Jul. 3, 2008 24 US 2008/O161324 A1 Jul. 3, 2008 25

US 2008/O161324 A1 Jul. 3, 2008 27 US 2008/O161324 A1 Jul. 3, 2008 28

„BO US 2008/O161324 A1 Jul. 3, 2008 29 US 2008/O161324 A1 Jul. 3, 2008 30

UIOJI

5 555

u?enstAroly VAIOL US 2008/O161324 A1 Jul. 3, 2008 31 US 2008/O161324 A1 Jul. 3, 2008 32

0043 Compounds useful in the invention include those is formulated for administration by intravenous injection will described herein in any of their pharmaceutically acceptable differ from a low dosage of the same agentformulated for oral forms, including isomers such as diastereomers and enanti administration. omers, salts, Solvates, and polymorphs thereof, as well as 0050. By a “high dosage' is meant at least 5% (e.g., at least racemic mixtures. Compounds useful in the invention may 10%, 20%, 50%, 100%, 200%, or even 300%) more than the also be isotopically labeled compounds. Useful isotopes highest standard recommended dosage of a particular com include hydrogen, carbon, nitrogen, oxygen, phosphorous, pound for treatment of any human disease or condition. fluorine, and chlorine, (e.g., H, H, C, C, N, O, '70, 0051. By a “candidate compound is meant a chemical, be 'P 'P, S, F, and Cl). Isotopically-labeled compounds it naturally-occurring or artificially-derived. Candidate com can be prepared by Synthesizing a compound using a readily pounds may include, for example, peptides, polypeptides, available isotopically-labeled reagent in place of a non-iso synthetic organic molecules, naturally occurring organic topically-labeled reagent. molecules, nucleic acid molecules, peptide nucleic acid mol ecules, and components or derivatives thereof. 0044 By "patient' is meant any animal (e.g., a mammal 0052. In the generic descriptions of compounds of this Such as a human). Any animal can be treated using the meth invention, the number of atoms of a particular type in a ods, compositions, and kits of the invention. Substituent group is generally given as a range, e.g., an alkyl 0045. To “treat’ is meant to administer one or more agents group containing from 1 to 4 carbon atoms or Calkyl. to measurably slow or stop the replication of a virus in vitro or Reference to such a range is intended to include specific in vivo, to measurably decrease the load of a virus (e.g., any references to groups having each of the integer number of virus described herein including a hepatitis virus Such as atoms within the specified range. For example, an alkyl group hepatitis A, B, C, D, or E) in a cell in vitro or in vivo, or to from 1 to 4 carbon atoms includes each of C, C, C, and C. reduce at least one symptom (e.g., those described herein) A C-2 heteroalkyl, for example, includes from 1 to 12 car associated with having a viral disease in a patient. Desirably, bon atoms in addition to one or more heteroatoms. Other the slowing in replication or the decrease in viral load is at numbers of atoms and other types of atoms may be indicated least 20%, 30%, 50%, 70%, 80%, 90%, 95%, or 99%, as in a similar manner. determined using a suitable assay (e.g., a replication assay 0053 As used herein, the terms “alkyl and the prefix described herein). Typically, a decrease in viral replication is “alk- are inclusive of both straight chain and branched chain accomplished by reducing the rate of DNA or RNA polymer groups and of cyclic groups, i.e., cycloalkyl. Cyclic groups ization, RNA translation, polyprotein processing, or by can be monocyclic or polycyclic and preferably have from 3 reducing the activity of a protein involved in any step of viral to 12 ring carbon atoms, inclusive. Exemplary cyclic groups replication (e.g., proteins coded by the genome of the virus or include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl host protein important for viral replication). groups. 0046 By “an effective amount' is meant the amount of a 0054 By “Calkyl is meant a branched or unbranched compound, alone or in combination with another therapeutic hydrocarbon group having from 1 to 4 carbon atoms. A regimen, required to treat a patient with a viral disease (e.g., Calkyl group may be substituted or unsubstituted. Exem any virus described herein including a hepatitis virus Such as plary Substituents include alkoxy, aryloxy, Sulfhydryl, alky hepatitis A, B, C, D, or E) in a clinically relevant manner. A lthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoralkyl, Sufficient amount of an active compound used to practice the amino, aminoalkyl, disubstituted amino, quaternary amino, present invention for therapeutic treatment of conditions hydroxyalkyl, carboxyalkyl, and carboxyl groups. Calkyls caused by a virus varies depending upon the manner of include, without limitation, methyl, ethyl, n-propyl, isopro administration, the age, body weight, and general health of pyl, cyclopropyl, cyclopropylmethyl, n-butyl, iso-butyl, sec the patient. Ultimately, the prescribers will decide the appro butyl, tert-butyl, and cyclobutyl. priate amount and dosage regimen. Additionally, an effective 0055. By “C. alkenyl is meant a branched or amount may be an amount of compound in the combination of unbranched hydrocarbon group containing one or more the invention that is safe and efficacious in the treatment of a double bonds and having from 2 to 4 carbon atoms. A Ca patient having a viral disease over each agent alone as deter alkenyl may optionally include monocyclic or polycyclic mined and approved by a regulatory authority (Such as the rings, in which each ring desirably has from three to six U.S. Food and Administration). members. The C alkenyl group may be substituted or 0047. By “more effective' is meant that a treatment exhib unsubstituted. Exemplary Substituents include alkoxy, ary its greater efficacy, or is less toxic, safer, more convenient, or loxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoro less expensive than another treatment with which it is being alkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, compared. Efficacy may be measured by a skilled practitioner quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl using any standard method that is appropriate for a given groups. Calkenyls include, without limitation, vinyl, allyl, indication. 2-cyclopropyl-1-ethenyl, 1-propenyl, 1-butenyl, 2-butenyl, 0048. By “hepatic virus' is meant a virus that can cause 3-butenyl, 2-methyl-1-propenyl, and 2-methyl-2-propenyl. hepatitis. Such viruses include hepatitis A, hepatitis B, hepa 0056 By “C. alkynyl is meant a branched or titis C, hepatitis D, hepatitis E, non-ABCDE hepatitis, and unbranched hydrocarbon group containing one or more triple hepatitis G. bonds and having from 2 to 4 carbon atoms. A C alkynyl 0049. By a “low dosage” is meant at least 5% less (e.g., at may optionally include monocyclic, bicyclic, or least 10%, 20%, 50%, 80%, 90%, or even 95%) than the rings, in which each ring desirably has five or six members. lowest standard recommended dosage of a particular com The C- alkynyl group may be substituted or unsubstituted. pound formulated for a given route of administration for Exemplary Substituents include alkoxy, aryloxy, Sulfhydryl, treatment of any human disease or condition. For example, a alkylthio, arylthio, halide, hydroxy, fluoroalkyl, perfluo low dosage of an agent that inhibits viral replication and that ralkyl, amino, aminoalkyl, disubstituted amino, quaternary US 2008/O161324 A1 Jul. 3, 2008 amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups. 0.058 By “Caryl' is meant an aromatic group having a Calkynyls include, without limitation, ethynyl, 1-propynyl, ring system comprised of carbon atoms with conjugated 71 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl. electrons (e.g., phenyl). The aryl group has from 6 to 12 carbon atoms. Aryl groups may optionally include monocy 0057. By “C. heterocyclyl is meant a stable 5- to clic, bicyclic, or tricyclic rings, in which each ring desirably 7-membered monocyclic or 7- to 14-membered bicyclic het has five or six members. The aryl group may be substituted or erocyclic ring which is saturated, partially unsaturated, or unsubstituted. Exemplary substituents include alkyl, unsaturated (aromatic), and which consists of 2 to 6 carbon hydroxy, alkoxy, aryloxy, Sulfhydryl, alkylthio, arylthio. atoms and 1, 2, 3, or 4 heteroatoms independently selected halide, fluoroalkyl, carboxyl, hydroxyalkyl, carboxyalkyl, from N, O, and S and including any bicyclic group in which amino, aminoalkyl, monosubstituted amino, disubstituted any of the above-defined heterocyclic rings is fused to a amino, and quaternary amino groups. benzene ring. The heterocyclyl group may be substituted or 0059 By “C, alkaryl is meant an alkyl substituted by unsubstituted. Exemplary Substituents include alkoxy, ary an aryl group (e.g., benzyl, phenethyl, or 3,4-dichlorophen loxy, sulfhydryl, alkylthio, arylthio, halide, hydroxy, fluoro ethyl) having from 7 to 14 carbon atoms. alkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, 0060. By “Coalkheterocyclyl is meant an alkyl substi quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl tuted heterocyclic group having from 3 to 10 carbon atoms in groups. The nitrogen and Sulfur heteroatoms may optionally addition to one or more heteroatoms (e.g., 3-furanylmethyl, be oxidized. The heterocyclic ring may be covalently attached 2-furanylmethyl, 3-tetrahydrofuranylmethyl, or 2-tetrahy via any heteroatom or carbon atom which results in a stable drofuranylmethyl). structure, e.g., an imidazolinyl ring may be linked at either of the ring-carbon atom positions or at the nitrogen atom. A 0061. By “C, heteroalkyl is meant a branched or nitrogen atom in the heterocycle may optionally be quater unbranched alkyl, alkenyl, or alkynyl group having from 1 to nized. Preferably when the total number of S and O atoms in 7 carbon atoms in addition to 1, 2, 3, or 4 heteroatoms inde the heterocycle exceeds 1, then these heteroatoms are not pendently selected from the group consisting of N, O, S, and adjacent to one another. Heterocycles include, without limi P. Heteroalkyls include, without limitation, tertiary amines, tation, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1.5.2-dithiazi secondary amines, ethers, thioethers, amides, thioamides, nyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, , thiocarbamates, hydrazones, imines, phosphodi 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, esters, phosphoramidates, Sulfonamides, and disulfides. A benzimidazolyl, benzofuranyl, benzothiofuranyl, ben heteroalkyl may optionally include monocyclic, bicyclic, or Zothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, tricyclic rings, in which each ring desirably has three to six benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimi members. The heteroalkyl group may be substituted or daZalonyl, carbazolyl, 4aH-carbazolyl b-carbolinyl, chroma unsubstituted. Exemplary Substituents include alkoxy, ary nyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H.6H-1.5. loxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoro 2-dithiazinyl, dihydrofuroI2,3-btetrahydrofuran, furanyl, alkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-in quaternary amino, hydroxyalkyl, hydroxyalkyl, carboxy dazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzo alkyl, and carboxyl groups. Examples of C, heteroalkyl furanyl, isochromanyl, isolindazolyl, isoindolinyl, isoindolyl, include, without limitation, methoxymethyl and ethoxyethyl. isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naph 0062 By “halide' or “halogen' is meant bromine, chlo thyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1.2.3-oxa rine, iodine, or fluorine. diazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadia 0063. By “fluoroalkyl is meant an alkyl group that is Zolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, substituted with a fluorine atom. phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, 0064. By “perfluoroalkyl is meant an alkyl group consist phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, ing of only carbon and fluorine atoms. piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperido 0065. By “carboxyalkyl is meanta chemical moiety with nyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, the formula—(R) COOH, wherein R is selected from C, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyri alkyl, C-7 alkenyl, C-7 alkynyl, Cheterocyclyl, Caryl, doimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, C- alkaryl, Coalkheterocyclyl, or C, heteroalkyl. pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 0.066 By “hydroxyalkyl is meant a chemical moiety with 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tet the formula —(R)—OH, wherein R is selected from C, rahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinoli alkyl, C2-7 alkenyl, C2-7 alkynyl, C2-heterocyclyl, C-2 aryl, nyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadia Cz- alkaryl, Coalkheterocyclyl, or C, heteroalkyl. Zolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, 0067 By “alkoxy” is meant a chemical substituent of the thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimi formula —OR, wherein R is selected from C, alkyl, C-7 dazolyl, thiophenyl, triazinyl, 1.2.3-triazolyl, 1,2,4-triazolyl, alkenyl, C2-7 alkynyl, C2-heterocyclyl, C-2 aryl, C7-14 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Preferred 5 to alkaryl, Coalkheterocyclyl, or C-7 heteroalkyl. 10 membered heterocycles include, but are not limited to, 0068. By “aryloxy' is meant a chemical substituent of the pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, formula —OR, wherein R is a C-2 aryl group. pyrrolyl pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetra 0069. By “alkylthio’ is meant a chemical substituent of Zolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimida the formula—SR, wherein R is selected from C, alkyl, C-7 Zolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotria alkenyl, C2-7 alkynyl, C2-heterocyclyl, C-2 aryl, C7-14 Zolyl, benzisoxazolyl, OXindolylbenzoxazolinyl, quinolinyl, alkaryl, Coalkheterocyclyl, or C, heteroalkyl. and isoquinolinyl. Preferred 5 to 6 membered heterocycles 0070. By “arylthio’ is meant a chemical substituent of the include, without limitation, pyridinyl, pyrimidinyl, triazinyl, formula—SR, wherein R is a Caryl group. furanyl, thienyl, thiazolyl pyrrolyl, piperazinyl, piperidinyl, 0071. By “quaternary amino” is meant a chemical sub pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl. stituent of the formula—(R) N(R')(R") (R")", wherein R, US 2008/O161324 A1 Jul. 3, 2008 34

R", R", and R" are each independently an alkyl, alkenyl, 007.6 Flaviviruses generally are discussed in Chapter 31 alkynyl, or aryl group. R may be an alkyl group linking the of Fields Virology, supra. Exemplary flaviviruses include quaternary amino nitrogen atom, as a Substituent, to another Absettarov, Alfuy, Apoi, Aroa, Bagaza, Banzi, Bouboui, Bus moiety. The nitrogen atom, N, is covalently attached to four Suquara, Cacipacore, Carey Island, Dakar bat, Dengue 1. carbon atoms of alkyl, heteroalkyl, heteroaryl, and/or aryl groups, resulting in a positive charge at the nitrogen atom. Dengue 2, Dengue 3, Dengue 4, Edge Hill, Entebbe bat, 0072 Other features and advantages of the invention will Gadgets Gully, Hanzalova, Hypr, Ilheus, Israel turkey men be apparent from the following Detailed Description and the ingoencephalitis, Japanese encephalitis, Jugra, Jutiapa, claims. Kadam, Karshi, Kedougou, Kokobera, Koutango, Kumlinge, Kunjin, Kyasanur Forest disease, Langat, Louping ill. Mea DETAILED DESCRIPTION ban, Modoc, Montana myotis leukoencephalitis, Murray val ley encephalitis, Naranjal, Negishi, Ntaya, Omsk hemor 0073. We have identified compounds that decrease repli rhagic fever, Phnom-Penh bat, Powassan, RiO Bravo, Rocio, cation of a hepatitis C(HCV) replicon in mammalian cells. royal farm, Russian spring-Summerencephalitis, Saboya, St. Accordingly, the present invention provides compositions, Louis encephalitis, Sal Vieja, San Perlita, Saumarez Reef, methods, and kits useful in the treatment of viral diseases, Sepik, Sokuluk, Spondweni, Stratford, Tembusu, Tyuleniy, which may be caused by a single stranded RNA virus, a flaviviridae virus, or a hepatic virus (e.g., described herein). Uganda S. Usutu, Wesselsbron, west Nile, Yaounde, yellow In certain embodiments, the viral disease is viral hepatitis fever, and Zika viruses. (e.g., hepatitis A, hepatitis B, hepatitis C, hepatitis D, and 0077 Pestiviruses generally are discussed in Chapter 33 hepatitis E). The invention also features screening methods of Fields Virology, supra. Specific pestiviruses include, with useful for the identification of novel compounds for the treat out limitation: bovine viral diarrhea virus, classical Swine ment of viral diseases. Compositions of the invention can fever virus (also called hog cholera virus), and border disease include one or more agents selected from the agents of Table W1US. 1, Table 2, Table 3, Table 4, and Table 5. Treatment methods of the invention include administration of one or more agents Hepatitis Viruses selected from the agents of Table 1, Table 2, and Table 3, optionally along with an additional antiviral therapy (e.g., 0078 Viruses that can cause viral hepatitis include hepa administration of one or more agents of Table 4 or Table 5) to titis A, hepatitis B, hepatitis C, hepatitis D, and hepatitis E. In a patient (e.g., a mammal Such as a human). Optionally, addition, non-ABCDE cases of viral hepatitis have also been functional or structural analogs (e.g., those described herein) reported (see, for example, Rochling et al., Hepatology of these agents or agents of the same therapeutic or mecha 25:478-483, 1997). Within each type of viral hepatitis, several nistic class as those described herein (see, e.g., Table 8) may Subgroupings have been identified. Hepatitis C, for example, be employed in the compositions, methods, and kits of the has at least six distinct genotypes (1, 2, 3, 4, 5, and 6), which invention. The ability of a composition to reduce replication have been further categorized into Subtypes (e.g., 1a, 1b, 2a, of a virus may be due to a decrease in RNA or DNA polymer 2b, 2c, 3a, 4a) (Simmonds, J. Gen. Virol. 85:3173-3188, ization, RNA translation, RNA or DNA transcription, a decrease in posttranslational protein processing (e.g., 2004). polyprotein processing in hepatitis C), or a decrease in activ 0079. In the case of hepatitis C, acute symptoms can ity of a protein involved in viral replication (e.g., a protein include jaundice, abdominal pain, fatigue, loss of appetite, coded for by the viral genome or a host protein required for nausea, vomiting, low-grade fever, pale or clay-colored viral replication). The compounds or combinations of com stools, dark urine, generalized itching, ascites, and bleeding pounds may also enhance the efficacy of the other therapeutic Varices (dilated veins in the esophagus). Hepatitis C can regimens such that the dosage, frequency, or duration of the become a chronic , which can lead to liver infection other therapeutic regimen is lowered to achieve the same and Scarring of the liver, which can, in turn, require the patient therapeutic benefit, thereby moderating any unwanted side to undergo a liver transplant. effects. 0080 Hepatitis C is an RNA virus taken up specifically by 0074. In one particular example, the patient being treated hepatic cells. Once inside the cells, the RNA is translated into is administered two agents listed in Table 1, Table 2 and/or a polyprotein of about 3,000 amino acids. The protein is then Table 3 within 28 days of each other in amounts that together processed into three structural and several non-structural pro are sufficient to treat a patient having a viral disease. The two teins necessary for viral replication. Accordingly, HCV may agents can be administered within 14 days of each other, be treated by reducing the rate any of the steps required for its within seven days of each other, within twenty-four hours of replication or inhibiting any molecule involved in replication, each other, or even simultaneously (i.e., concomitantly). If including but not limited to, entry into a target cell, viral desired, either one of the two agents may be administered in genome replication, translation of viral RNA, protolytic pro low dosage. cessing, and assembly and release from the target cell (e.g., Viral Diseases using the agents described herein). 0075. The invention relates to the treatment of viral dis Compounds ease, which can becaused by any virus. Viruses include single stranded RNA viruses, flaviviridae viruses, and hepatic I0081 Certain compounds that may be employed in the viruses. In particular, the flaviviridae family of viruses methods, compositions, and kits of the present invention are include hepacivirus (e.g., HCV); flaviviruses; pestiviruses, discussed in greater detail below. It will be understood that and hepatitis G. virus. analogs of any compound of Table 1, Table 2, or Table 3 can US 2008/O161324 A1 Jul. 3, 2008

be used instead of the compound of Table 1, Table 2, or Table done hydrochloride, edisylate, prochlor 3 in the methods, compositions, and kits of the present inven maleate, promazine hydrochloride, , tion. remoxipride hydrochloride, rimcazole hydrochloride, seperi dol hydrochloride, , , spiperone, thior HMG-CoA Reductase Inhibitors idazine, hydrochloride, thiothixene, thiothixene hydrochloride, tioperidone hydrochloride, hydro 0082 In certain embodiments, an HMG-CoA reductase chloride, trifluoperazine hydrochloride, trifluperidol, triflu inhibitor can be used in the compositions, methods, and kits promazine, hydrochloride, and of the invention. By an “HMG-CoA reductase inhibitor is a hydrochloride. Additional analogs are described in compound that inhibits the enzymatic activity of 3-hydroxy U.S. Pat. Nos. 2,519,886; 2,921,069, 3,084,161, 3,155,669, 3-methylglutaryl-coenzyme A (HMG-CoA) reductase by at 3,155,670, 3,438,991, 3,161,644, 4,045,445, 4,308,207, least about 10%. HMG-CoA reductase inhibitors include but 4,459,232, 4,460,508, 4,460,587, 4,507,311, 4,595.535, are not limited to simvastatin, lovastatin, mevastatin, pravas 4,192,803, 5,955,459, and 6,197,764. tatin, monacolin M, monacolin X, fluvastatin, atorvastatin, I0084 Trifluperidol cerivastatin, rosuvastatin, fluindostatin, Velostatin, compac I0085. In certain embodiments, trifluperidol or an analog tin, dihydrocompactin, rivastatin, dalvastatin, pitavastatin, thereof can be used in the compositions, methods, and kits of BAY 102987, BAY X 2678, BB476, bervastatin, BM21950, the invention. The structure of trifluperidol is: BMY22089, colestolone, CP83101, crilvastatin, DMP565, glenvastatin, L659699, L669262, P882222, P882284, PD134965, PD135022, RP61969, S2468, SC37.111, SC45355, SQ33600, SR 12813, SR45023A, U20685, and U88156, as well as pharmaceutically acceptable salts thereof (e.g., simvastatin Sodium, lovastatin Sodium, fluvastatin CF sodium, etc.). Additional HMG-CoA reductase inhibitors and OH analogs thereofuseful in the methods and compositions of the present invention are described in U.S. Pat. Nos. 3,983,140; 4,231,938; 4,282,155; 4,293,496; 4,294,926; 4,319,039; 4,343,814; 4,346,227; 4,351,844; 4,361,515; 4,376,863; 4,444,784; 4,448,784; 4,448,979; 4,450,171; 4,503,072: 4,517,373; 4,661,483; 4,668,699; 4,681,893; 4,719,229: Analogs of trifluperidol are described for example in U.S. Pat. 4,738,982; 4,739,073; 4,766,145; 4,782,084; 4,804,770; No. 3,438,991 and have the general structure: 4,841,074; 4,847,306; 4,857,546; 4,857,547: 4,940,727: 4,946,864; 5,001,148; 5,006,530; 5,075,311; 5,112,857; 5,116,870; 5,120,848; 5,166.364; 5,173,487; 5,177,080: O OH 5,273,995; 5,276,021; 5,369,123: 5,385,932; 5,502,199; N 5,763,414; 5,877.208; and 6,541,511; and U.S. Pat. Applica Air (Cf. NC?. CH3), tion Publication Nos. 2002/0013334 A1: 2002/0028826A1; 2002/0061901 A1; and 2002/0094977 A1. Air Clozapine where Arand Ar" are monocyclic aryl rings, p is 2 to 4, n is 1 0083. In certain embodiments, clozapine or a clozapine or 2, m is 0, 1, or 2, and X is a hydrogen or a methyl group. Ar analog can be used in the compositions, methods, and kits of and Arcan represent halophenyls such as fluorophenyl, chlo the invention. Suitable clozapine analogs include rophenyl, bromophenyl, and iodophenyl; alkoxyphenyls such maleate, hydrobromide, alpertine, as methoxyphenyl, ethoxyphenyl, dimethoxyphenyl, and tri , maleate, , benzindopyrine methoxyphenyl: monocyclic aromatic hydrocarbon radicals hydrochloride, brofoxine, , bromperidol Such as phenyl, tolyl. Xylyl, isopropylphenyl, and tertiary decanoate, hydrochloride, , butyl phenyl; and a trifiuoromethylphenyl radical. (CH), can butaperazine maleate, carphenazine maleate, carvotroline represent a lower alkylene group, e.g., 2 to 4 carbon atoms hydrochloride, , chlorpromazine hydrochlo Such as ethylene, trimethylene, propylene, butylene, methyl ride, , cinperene: cintriamide, clomacran propylene, and tetramethylene. phosphate, , , clopipazan mesylate, cloroperone hydrochloride, clothiapine, clothixamide male Paclitaxel ate, cyclophenazine hydrochloride, , I0086. In certain embodiments, paclitaxel or a paclitaxel hydrochloride, fenimide, , , fluphena analog can be used in the compositions, methods, and kits of Zine decanoate, fluphenazine enanthate, fluiphenazine hydro the invention. Paclitaxel is described in U.S. Pat. No. 4,814, chloride, fluspiperone, , flutroline, 470. Paclitaxel analogs include isoserine, taxol, taxotere, hydrochloride, halopemide, , haloperidol cephalomannine, 10-deacetylbaccatine III and those com decanoate, illoperidone, imidoline hydrochloride, , pounds described in U.S. Pat. Nos. 4,814,470, 4,857,653, Succinate, mesoridazine, mesoridazine besylate, 4,876,399, 4,924.011, 4,924.012, 4,942,184, 4,960,790, , milemperone, millipertine, hydrochlo 5,015,744, 5,059,699, 5,136,060, 5,157,049, 5,192,796, ride, hydrochloride, neflumozidehydrochloride, oca 5,227,400, 5,243,045, 5,248,796, 5,250,683, 5,254,580, peridone, , oxiperomide, , pentiapine 5,271,268, 5,272,171, 5,283,253, 5,284,864, 5,290,957, maleate, , , hydrochloride, 5,292,921, 5,294,637, 5,319,112, 5,336,684, 5,338,872, , , palmitate, piquin 5,350,866, 5,380,751, 5,380,916, 5,399,726, 5,430,160, US 2008/O161324 A1 Jul. 3, 2008 36

5,438,072, 5,470,866, 5,489,601, 5,508.447, 5,539,103, 5,547,981, 5,556,878, 5,574,156, 5,580,899, 5,580,998, -continued E-2 5,587,489, 5,587,493, 5,606,083, 5,622,986, 5,635,531, N 5,646,176, 5,654,447, 5,677,470, 5,688,977, 5,693,666, n 5,703,117, 5,710,287, 5,714,512, 5,714.513, 5,717,115, 5,721,268, 5,728,725, 5,728,850, 5,739,362, 5,750,562, 21 NH2 5,760,219, 5,773,464, 5,807,888, 5,821,363, 5,840,748, 5,840,929, 5,840,930, 5,854.278, 5,912,264, 5,919,815, NH2 5,902,822, 5,965,739, 5,977,386, 5,990.325, 5,994,576, 3,4-diaminopyridine 5,998,656, 6,011,056, 6,017,935, 6,018,073, 6,028,205, E-3 6,051,724, 6,066,747, 6,080,877, 6,107,332, 6,118,011, N NH2 6,124,481, 6,136,961, 6,147,234, 6,177,456, 6,307,064, n 6,310,201, 6,350,886, 6,362,217, 6,455,575, 6,462,208, 6,482,963, 6,495,704, 6,515,151, 6,545,168, 6,710,191, HN 2 6,762,309, 6,794,523, 6,797,833, 6,878,834, 6,911,549, and 7,019,150. CH3 2,5-diamino-4-methylpyridine E-4 Estrogenic Compounds HN N NH2 0087. In certain embodiments, an estrogenic compound can be used in the compositions, methods, and kits of the s invention. Estrogenic compounds include (e.g., 21 NH2 , ), colpormon, 2-methy 2,3,6-triaminopyridine oxyestradiol, conjugated estrogenic hormones, , E-5 , dienestrol, ethinyl estradiol, , , mox HN N NH2 estrol, quinestradiol, quinestrol, , , equilin, diethylstilbestrol, broparoestrol, chlorotrianisine, 2 , , , and . Estrogenic compounds are also described in U.S. Pat. Nos. 2,096,744, NH2 2,465,505, 2,464,203, 3,159,543. 2,4,6-triaminopyridine E-6 Aminopyridines HN N NH2 0088. In certain embodiments, an aminopyridine can be used in the composition, methods, and kits of the invention. 2s By “aminopyridine' is meant any pyridine ring-containing compound in which the pyridine has one, two, or three amino 2,6-diaminopyridine group Substituents. Other substituents may optionally be present. Exemplary aminopyridines include phenazopyri dine, 4-aminopyridine, 3,4-diaminopyridine, 2,5-diamino-4- methylpyridine, 2.3.6-triaminopyridine, 2,4,6-triaminopyri dine, and 2,6-diaminopyridine, the structures of which are I0089. In certain embodiments, an can be used depicted below. Phenazopyridine and derivatives thereof in the methods, compositions, and kits of the invention. Anti have been disclosed in U.S. Pat. Nos. 1,680,108 through include tamoxifen, 4-hydroxy tamoxifen, clo 1,680,111. Modifications of di-amino(phenylazo)pyridines mifene, raloxifene, faslodex, , fulvestrant, CI-680, have been performed to improve solubility in water by react CI-628, CN-55,956-27, MER-25, U-11,555A, U-11100A, ing these compounds with alkylating agents (e.g., alkyl ICI-46,669, ICI-46,474, diphenolhydrochrysene, erythro halides and alkyl Sulphates) to produce quaternary pyri MEA, Parke Davis CN-35.945, allenolic acid, , dinium bases (see, e.g., U.S. Pat. No. 2,135,293). Heterocy , and triparanol and those compounds clic azo derivatives and N-substituted diaminopyridines have described in U.S. Pat. Nos. 5,384.332, 4,894,373, 4,536,516, also been described (U.S. Pat. Nos. 2,145,579 and 3,647, 808). 4,418,068, and 2,914,563. Channel Inhibitors E-1 N 0090. In certain embodiments, a calcium channel inhibitor n can be used in the compositions, methods, and kits of the invention. Calcium channel inhibitors include thapsigargin, 2 Verapamil, anipamil, bepridil, gallopamil, devapamil, falli pamil, tiapamil, , , daZodipine, felo NH2 dipine, isradipine, lanicardipine, , , 4-aminopyridine nisoldipine, , ryosidie, diltiazem, , , BAY-m 4786, and diperdipine. US 2008/O161324 A1 Jul. 3, 2008 37

0091 Verapamil 0092. In certain embodiments, Verapamil or an analog -continued (III) thereof can be used in the compositions, methods, and kits of X X the invention. The structure of Verapamil is: X X D X

X N2 X X ( N V B (IV) N X X Verapamil analogs are described, for example, in U.S. Pat. No. 3,261,859 and have the general formula: Rs X (CO X X X

X A X n Re-I-V N-(CH) \ 5* N(B) x / (CH2) 7 or wherein each X is, independently, H, Cl, F, Br, I, CH, CF, N OH, OCH, CHCH, or OCHCH;Y is CH, O, NH, S(O) o, (CH), (CH), CHO, CH-NH, CHN, or CHS: Z is C or S: A is a branched or unbranched, Saturated or monounsat where R is a lower aliphatic hydrocarbon radical; R is hydro urated hydrocarbon chain having between 3 and 6 carbons, gen, a lower alkyl radical, a saturated or unsaturated cyclic or inclusive; each B is, independently, H, Cl, F, Br, I, CX, bicyclic hydrocarbon radical, the benzyl radical, or the phenyl CHCH, OCX, or OCXCX; and D is CH, O, NH, or radical; R2, R. R. Rs. R. and R-7 are hydrogen, halogen, S(O). In preferred embodiments, each X is, independently, lower alkyl radicals, lower alkoxy groups, or two of said H, Cl, or F: Y is (CH), Z is C; A is (CH); and each B is, Substituents togetherforming the methylene dioxy group; n is independently, H., Cl, or F. Other tricyclic compounds are an integer between 2 and 4; and m is an integer between 1 and described below. Tricyclic compounds include tricyclic anti 3. depressants such as , 8-hydroxyamoxapine, 7-hy droxyamoxapine, (e.g., loxapine Succinate, loxap Tricyclic Compounds ine hydrochloride), 8-hydroxyloxapine, , 0093. In certain embodiments, a tricyclic compound can , doxepin, imipramine, trimipramine, be used in the compositions, methods, and kits of the inven , , and , although com tion. By “tricyclic compound is meant a compound having pounds need not have activities to be consid one the formulas (I), (II), (III), or (IV): ered tricyclic compounds of the invention. 0094 Tricyclic compounds that can be used in connection with the invention include amitriptyline, amoxapine, clomi (I) pramine, desipramine, dothiepin, doxepin, imipramine, X X , maprotiline, mianserin, , nortrip tyline, , , protriptyline, trimipramine, X Y. X 10-(4-methylpiperazin-1-yl)pyrido(4.3-b)(1,4)benzothiaz epine; 11-(4-methyl-1-piperazinyl)-5H-dibenzo(b.e)(1,4)di azepine; 5,10-dihydro-7-chloro-10-(2-(morpholino)ethyl)- X f X 11H-dibenzo(b.e)(1,4)diazepin-1 1-one: 2-(2-(7-hydroxy-4- X A X dibenzo(b.f)(14)thiazepine-11-yl-1-piperazinyl)ethoxy) N N(B) ethanol: 2-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo (II) (b.e)(1,4)diazepine; 4-(11H-dibenz(b.e)azepin-6-yl) X X ; 8-chloro-11-(4-methyl-1-piperazinyl)-5H dibenzo(b.e)(1,4)diazepin-2-ol; 8-chloro-11-(4-methyl-1- X Y. X piperazinyl)-5H-dibenzo(b.e)(1,4)diazepine monohydrochloride: (Z)-2-butenedioate 5H-dibenzo(b.e)(1, 4)diazepine; adinazolam; ; ; X X ; clothiapine; clozapine; ; 11-(4- X A X n methyl-1-piperazinyl)-dibenZ(b.f)(1,4)oxazepine; 11-(4-me N(B) thyl-1-piperazinyl)-2-nitro-dibenZ(b.f)(1,4)oxazepine; 2-chloro-11-(4-methyl-1-piperazinyl)-dibenz(b.f)(1,4)ox US 2008/O161324 A1 Jul. 3, 2008 azepine monohydrochloride: ; 11-(4-methyl-1- as well as pharmaceutically acceptable salts thereof, wherein piperazinyl)-dibenzo(b,f) (14)thiazepine; ; flua R is a C-C alkyl and R is H or C. alkyl, R is H. C. cizine; ; imipramine N-oxide; ; alkyl, Calkenyl, phenylalkyl or cycloalkylalkyl with 3 to 6 lofepramine; ; ; metiapine; metralin cyclic carbon atoms, alkanoyl phenylalkanoyl or cycloalky dole; mianserin; mirtazapine; 8-chloro-6-(4-methyl-1-piper lcarbonyl having 3 to 6 cyclic carbon atoms, or R and R azinyl)-morphanthridine, N-acetylamoxapine; nomifensine; form, together with the nitrogen atom to which they are ; norclozapine; noxiptilin; ; linked, a heterocycle saturated with 5 to 7 chain links which oxaprotiline; ; pizotyline; ; ; can have, as the second heteroatom not directly connected to ; ; tomoxetine; flupenthixol; clo the nitrogen atom, an oxygen, a Sulphur or a nitrogen, the penthixol; piflutixol; chlorprothixene; and thiothixene. Other latter nitrogen heteroatom possibly carrying a C- alkyl. tricyclic compounds are described in U.S. Pat. Nos. 2,554, 0.098 Exemplary cericlamine structural analogs are 2-me 736, 3,046,283, 3,058,979, 3,310,553, 3,177.209, 3,194,733, thyl-2-amino-3-(3,4-dichlorophenyl)-propanol, 2-pentyl-2- 3,205.264, 3,244,748, 3,271,451, 3,272,826, 3,282,930, amino-3-(3,4-dichlorophenyl)-propanol, 2-methyl-2-methy 3,282,942, 3,299,139, 3,312,689, 3,389,139, 3,399,201, lamino-3-(3,4-dichlorophenyl)-propanol, 2-methyl-2- 3,409,640, 3,419,547, 3,438,981, 3,454,554, 3,467,650, dimethylamino-3-(3,4-dichlorophenyl)-propanol, and 3,505,321, 3,527,766, 3,534,041, 3,539,573, 3,574,852, pharmaceutically acceptable salts of any thereof. 3,622,565, 3,637,660, 3,663,696, 3,758,528, 3,922,305, 0099 Structural analogs of citalopram are those having 3,963,778, 3,978,121, 3,981,917, 4,017,542, 4,017,621, the formula: 4,020,096, 4,045,560, 4,045,580, 4,048,223, 4,062,848, 4,088,647, 4,128,641, 4,148,919, 4,153,629, 4,224,321, 4,224,344, 4,250,094, 4,284,559, 4,333,935, 4,358,620, R 4,548,933, 4,691,040, 4,879,288, 5,238,959, 5,266,570, 5,399,568, 5,464,840, 5,455,246, 5,512,575, 5,550,136, 5,574,173, 5,681,840, 5,688,805, 5,916,889, 6,545,057, and 6,600,065, and compounds that fit Formula (I) of U.S. patent application Ser. Nos. 10/617,424 (published as U.S. 2004/0116407) or 60/504,310. O Selective Reuptake Inhibitors R 0.095. In certain embodiments, a selective serotonin reuptake inhibitor can be used in the compositions, methods, and kits of the invention. By “selective serotonin reuptake as well as pharmaceutically acceptable salts thereof, wherein inhibitor or “SSRI is meant any member of the class of each of R and R is independently selected from the group compounds that (i) inhibit the uptake of serotonin by neurons consisting of bromo, chloro, fluoro, trifluoromethyl, cyano of the central nervous system, (ii) have an inhibition constant and R CO , wherein R is C alkyl. (Ki) of 10 nM or less, and (iii) a selectivity for serotonin over 0100 Exemplary citalopram structural analogs (which are (i.e., the ratio of K, (norepinephrine) over thus SSRI structural analogs according to the invention) are 1-(4-fluorophenyl)-1-(3-dimethylaminopropyl)-5-bro K(serotonin)) of greater than 100. mophthalane: 1-(4-chlorophenyl)-1-(3-dimethylaminopro 0096. SSRIs may be used in connection with the invention pyl)-5-chlorophthalane: 1-(4-bromophenyl)-1-(3-dimethy include cericlamine (e.g., cericlamine hydrochloride); citalo laminopropyl)-5-chlorophthalane: 1-(4'-fluorophenyl)-1-(3- pram (e.g., citalopram hydrobromide); ; cyan dimethylaminopropyl)-5-chlorophthalane; 1-(4'- odothiepin; dapoxetine; escitalopram (escitalopram oxalate); chlorophenyl)-1-(3-dimethylaminopropyl)-5- (e.g., femoxetine hydrochloride); (e.g., trifluoromethyl-phthalane; 1-(4-bromophenyl)-1-(3- fluoxetine hydrochloride); fluvoxamine (e.g., fluvoxamine dimethylaminopropyl)-5-trifluoromethyl-phthalane: 1-(4'- maleate); ifoxetine; indalpine (e.g., indalpine hydrochloride); fluorophenyl)-1-(3-dimethylaminopropyl)-5- indeloxazine (e.g., indeloxazine hydrochloride); ; trifluoromethyl-phthalane; 1-(4'-fluorophenyl)-1-(3- milnacipran (e.g., minlacipran hydrochloride); 6-nitroqui dimethylaminopropyl)-5-fluorophthalane; 1-(4'- pazine; (e.g., paroxetine hydrochloride hemihy chlorophenyl)-1-(3-dimethylaminopropyl)-5- drate; paroxetine maleate; paroxetine mesylate); Sertraline fluorophthalane; 1-(4-chlorophenyl)-1-(3- (e.g., Sertraline hydrochloride); tametraline hydrochloride; dimethylaminopropyl)-5-phthalancarbonitrile; 1-(4'- Vicqualine; and Zimeldine (e.g., Zimeldine hydrochloride). fluorophenyl)-1-(3-dimethylaminopropyl)-5- 0097 Structural analogs of cericlamine are those having phthalancarbonitrile; 1-(4-cyanophenyl)-1-(3- the formula: dimethylaminopropyl)-5-phthalancarbonitrile; 1-(4'- cyanophenyl)-1-(3-dimethylaminopropyl)-5- chlorophthalane; 1-(4-cyanophenyl)-1-(3- C dimethylaminopropyl)-5-trifluoromethylphthalane: 1-(4'- fluorophenyl)-1-(3-dimethylaminopropyl)-5- phthalancarbonitrile; 1-(4-chlorophenyl)-1-(3- C dimethylaminopropyl)-5-ionylphthalane; 1-(4- (chlorophenyl)-1-(3-dimethylaminopropyl)-5- propionylphthalane; and pharmaceutically acceptable salts of any thereof. Citalopram analogs are also described in U.S. Pat. No. 4,136,193. US 2008/O161324 A1 Jul. 3, 2008 39

0101 Structural analogs of clovoxamine are those having as well as pharmaceutically acceptable salts thereof, wherein the formula: each R is independently hydrogen or methyl; R is naphthyl or

- y-(R), \ X

wherein each of R and R is, independently, bromo, chloro, N fluoro, trifluoromethyl, C. alkyl, C. alkoxy or C. alk enyl; and each of n and m is, independently, 0, 1 or 2. When Hal v R is naphthyl, it can be either C.-naphthyl or f3-naphthyl. (CH2)4-R 0106 Exemplary fluoxetine structural analogs are 3-(p- isopropoxyphenoxy)-3-phenylpropylamine methane sulfonate, N,N-dimethyl 3-(3',4'-dimethoxyphenoxy)-3-phe as well as pharmaceutically acceptable salts thereof, wherein nylpropylamine p-hydroxybenzoate, N,N-dimethyl 3-(o- Hal is a chloro, bromo, or fluoro group and R is a cyano, naphthoxy)-3-phenylpropylamine , N,N-dimethyl methoxy, ethoxy, methoxymethyl, ethoxymethyl, methoxy 3-(B-naphthoxy)-3-phenyl-1-methylpropylamine iodide, ethoxy, or cyanomethyl group. 3-(2-methyl-4,5'-dichlorophenoxy)-3-phenylpropylamine 0102) Exemplary clovoxamine structural analogs are nitrate, 3-(p-t-butylphenoxy)-3-phenylpropylamine glut 4'-chloro-5-ethoxyvalerophenone O-(2-aminoethyl)oxime; arate, N-methyl 3-(2-chloro-p-tolyloxy)-3-phenyl-1-meth 4'-chloro-5-(2-methoxyethoxy)Valerophenone O-(2-amino ylpropylamine lactate, 3-(2',4'-dichlorophenoxy)-3-phenyl ethyl)oxime; 4'-chloro-6-methoxycaprophenone O-(2-ami 2-methylpropylamine citrate, N,N-dimethyl 3-(m- noethyl)oxime; 4'-chloro-6-ethoxycaprophenone O-(2-ami anisyloxy)-3-phenyl-1-methylpropylamine maleate, noethyl)oxime; 4'-bromo-5-(2-methoxyethoxy) N-methyl 3-(p-tolyloxy)-3-phenylpropylamine sulfate, N.N- Valerophenone O-(2-aminoethyl)oxime; 4'-bromo-5- dimethyl 3-(2',4'-difluorophenoxy)-3-phenylpropylamine methoxyvalerophenone O-(2-aminoethyl)oxime; 4'-chloro 2,4-dinitrobenzoate, 3-(o-ethylphenoxy)-3-phenylpropy 6-cyanocaprophenone O-(2-aminoethyl)oxime; 4'-chloro-5- lamine dihydrogen phosphate, N-methyl 3-(2-chloro-4-iso cyanovalerophenone O-(2-aminoethyl)oxime; 4'-bromo-5- propylphenoxy)-3-phenyl-2-methylpropylamine maleate, cyanovalerophenone O-(2-aminoethyl)oxime; and N,N-dimethyl 3-(2-alkyl-4-fluorophenoxy)-3-phenyl-pro pylamine Succinate, N,N-dimethyl 3-(o-isopropoxyphe pharmaceutically acceptable salts of any thereof. noxy)-3-phenyl-propylamine phenylacetate, N,N-dimethyl 0103 Structural analogs of femoxetine are those having 3-(o-bromophenoxy)-3-phenyl-propylamine B-phenylpropi the formula: onate, N-methyl 3-(p-iodophenoxy)-3-phenyl-propylamine propiolate, and N-methyl 3-(3-n-propylphenoxy)-3-phenyl propylamine decanoate. 0107 Structural analogs of fluvoxamine are those having R-N the formula:

CHOR wherein R represents a C alkyl or C. alkynyl group, or a phenyl group optionally Substituted by C. alkyl, C. alky lthio, Calkoxy, bromo, chloro, fluoro, nitro, acylamino, methylsulfonyl, methylenedioxy, or tetrahydronaphthyl, R represents a C alkyl or C. alkynyl group, and R repre N sents hydrogen, C alkyl, Calkoxy, trifluoroalkyl, hydroxy, bromo, chloro, fluoro, methylthio, or aralkyloxy. -() {(CH)-R 0104 Exemplary femoxetine structural analogs are dis closed in Examples 7-67 of U.S. Pat. No. 3,912,743, hereby as well as pharmaceutically acceptable salts thereof, wherein incorporated by reference. R is cyano, cyanomethyl, methoxymethyl, or ethoxymethyl. 0105 Structural analogs of fluoxetine are those com Analogs of fluvoxamine are also described in U.S. Pat. No. pounds having the formula: 4,085,225. 0.108 Structural analogs of indalpine are those having the formula:

RO

NH US 2008/O161324 A1 Jul. 3, 2008 40 or pharmaceutically acceptable salts thereof, wherein R is a 0112 Structural analogs of milnacipram are those having hydrogen atom, a C-C alkyl group, or an aralkyl group of the formula: which the alkyl has 1 or 2 carbon atoms, R is hydrogen, Ca alkyl, C. alkoxy or C. alkylthio, chloro, bromo, fluoro, trifluoromethyl, nitro, hydroxy, oramino, the latter optionally N Substituted by one or two Calkyl groups, an acyl group or X a Calkylsulfonyl group; A represents —CO or —CH2— R-f 2 R4 group; and n is 0, 1 or 2. I 0109 Exemplary indalpine structural analogs are N indolyl-3 (piperidyl-4 methyl) ketone; (methoxy-5-indolyl O N-R2 R3 3) (piperidyl-4 methyl) ketone; (chloro-5-indolyl-3) (pip I eridyl-4 methyl) ketone; (indolyl-3)-1 (piperidyl-4)-3 pro R panone, indolyl-3 piperidyl-4, ketone; (methyl-1 indolyl-3) as well as pharmaceutically acceptable salts thereof, wherein (piperidyl-4 methyl) ketone, (benzyl-1 indolyl-3) (pip each R, independently, represents hydrogen, bromo, chloro, eridyl-4 methyl) ketone; (methoxy-5 indolyl-3)-2 ethyl-pi fluoro, Calkyl, Calkoxy, hydroxy, nitro or amino; each peridine, (methyl-1 indolyl-3)-2 ethyl-4-piperidine; (in of R and R2, independently, represents hydrogen, Calkyl, dolyl-3)-2 ethyl-4 piperidine; (indolyl-3 methyl)-4 Caryl or Cz-alkylaryl, optionally substituted, preferably in para position, by bromo, chloro, or fluoro, or R and R piperidine, (chloro-5 indolyl-3)-2 ethyl-4 piperidine; (in together form a heterocycle having 5 or 6 members with the dolyl-b 3)-3 propyl-4 piperidine; (benzyl-1 indolyl-3)-2 adjacent nitrogen atoms; R and R represent hydrogen or a ethyl-4 piperidine; and pharmaceutically acceptable salts of C, alkyl group or R and R form with the adjacent nitrogen any thereof. atom a heterocycle having 5 or 6 members, optionally con taining an additional heteroatom selected from nitrogen, Sul 0110 Structural analogs of indeloxazine are those having phur, and oxygen. the formula: 0113 Exemplary milnacipram structural analogs are 1-phenyl 1-aminocarbonyl 2-dimethylaminomethyl cyclo propane, 1-phenyl 1-dimethylaminocarbonyl 2-dimethy laminomethylcyclopropane; 1-phenyl 1-ethylaminocarbonyl 2-dimethylaminomethyl : 1-phenyl 1-diethy laminocarbonyl 2-aminomethyl cyclopropane: 1-phenyl 2-dimethylaminomethyl N-(4-chlorophenyl)cyclopropane carboxamide: 1-phenyl 2-dimethylaminomethyl N-(4-chlo robenzyl)cyclopropane carboxamide: 1-phenyl 2-dimethy laminomethyl N-(2-phenylethyl)cyclopropane carboxamide; (3,4-dichloro-1-phenyl) 2-dimethylaminomethyl N,N-dim ethylcyclopropane carboxamide: 1-phenyl 1-pyrrolidinocar bonyl 2-morpholinomethyl cyclopropane; 1-p-chlorophenyl 1-aminocarbonyl 2-aminomethyl cyclopropane: 1-or thochlorophenyl 1-aminocarbonyl 2-dimethylaminomethyl and pharmaceutically acceptable salts thereof, wherein R cyclopropane: 1-p-hydroxypheny 1-aminocarbonyl 2-dim and Rs each represents hydrogen, C alkyl, or phenyl; R. ethylaminomethyl cyclopropane, 1-p-nitrophenyl 1-dim represents hydrogen, C alkyl, Cal, cycloalkyl, phenyl or ethylaminocarbonyl 2-dimethylaminomethyl cyclopropane; benzyl, one of the dotted lines means a single bond and the 1-p-aminophenyl 1-dimethylaminocarbonyl 2-dimethylami nomethyl cyclopropane: 1-p-tolyl 1-methylaminocarbonyl other means a double bond, or the tautomeric mixtures 2-dimethylaminomethyl cyclopropane: 1-p-methoxyphenyl thereof. 1-aminomethylcarbonyl 2-aminomethyl cyclopropane; and 0111 Exemplary indeloxazine structural analogs are 2-(7- pharmaceutically acceptable salts of any thereof. indenyloxymethyl)-4-isopropylmorpholine, 4-butyl-2-(7-in 0114 Structural analogs of paroxetine are those having denyloxymethyl)morpholine: 2-(7-indenyloxymethyl)-4- the formula: methylmorpholine; 4-ethyl-2-(7-indenyloxymethyl) morpholine, 2-(7-indenyloxymethyl)-morpholine: 2-(7- indenyloxymethyl)-4-propylmorpholine: 4-cyclohexyl-2-(7- indenyloxymethyl)morpholine; 4-benzyl-2-(7- indenyloxymethyl)-morpholine: 2-(7-indenyloxymethyl)-4- phenylmorpholine; 2-(4-indenyloxymethyl)morpholine; 2-(3-methyl-7-indenyloxymethyl)-morpholine: 4-isopropyl 2-(3-methyl-7-indenyloxymethyl)morpholine: 4-isopropyl O 2-(3-methyl-4-indenyloxymethyl)morpholine: 4-isopropyl 2-(3-methyl-5-indenyloxymethyl)morpholine: 4-isopropyl R-N 2-(1-methyl-3-phenyl-6-indenyloxymethyl)morpholine; 2-(5-indenyloxymethyl)-4-isopropyl-morpholine, 2-(6-inde nyloxymethyl)-4-isopropylmorpholine; and 4-isopropyl-2- and pharmaceutically acceptable salts thereof, wherein R (3-phenyl-6-indenyloxymethyl)morpholine; as well as phar represents hydrogen or a C alkyl group, and the fluorine maceutically acceptable salts of any thereof. atom may be in any of the available positions. US 2008/O161324 A1 Jul. 3, 2008 41

0115 Structural analogs of Sertraline are those having the and pharmaceutically acceptable salts thereof, wherein the formula: pyridine nucleus is bound in ortho-, meta- or para-position to the adjacent carbon atom and where R is selected from the group consisting of H. chloro, fluoro, and bromo. NRR 0118 Exemplary Zimeldine analogs are (e)- and (Z)-3-(4- bromophenyl-3-(2"-pyridyl)-dimethylallylamine: 3-(4-bro mophenyl)-3-(3'-pyridyl)-dimethylallylamine: 3-(4-bro mophenyl)-3-(4"-pyridyl)-dimethylallylamine; and pharmaceutically acceptable salts of any thereof. Zimelidine analogs are also described in U.S. Pat. No. 3,928,369. 0119 Structural analogs of any of the above SSRIs are 21 considered herein to be SSRI analogs and thus may be employed in any of the methods, compositions, and kits of the invention. A-X 0120 Metabolites I0121 Pharmacologically active metabolites of any of the foregoing SSRIs can also be used in the methods, composi wherein R is selected from the group consisting of hydrogen tions, and kits of the invention. Exemplary metabolites are and Calkyl, R is hydrogen, or Calkyl; X and Y are each , desmethylcitalopram, desmethylser selected from the group consisting of hydrogen, fluoro, traline, and norfluoxetine. chloro, bromo, trifluoromethyl, Calkoxy, and cyano; and 0.122 Analogs W is selected from the group consisting of hydrogen, fluoro, I0123 Functional analogs of SSRIs can also be used in the chloro, bromo, trifluoromethyl and C alkoxy. Preferred methods, compositions, and kits of the invention. Exemplary Sertraline analogs are in the cis-isomeric configuration. The SSRI functional analogs are provided below. One class of term “cis-isomeric' refers to the relative orientation of the SSRI analogs includes SNRIs (selective serotonin norepi NRR and phenyl moieties on the cyclohexenering (i.e. they nephrine reuptake inhibitors), which include Venlafaxine, are both oriented on the same side of the ring). Because both dulloxetine, and 4-(2-fluorophenyl)-6-methyl-2-piperazi the 1- and 4-carbons are asymmetrically Substituted, each nothieno 2,3-dipyrimidine. cis-compound has two optically active enantiomeric forms 0.124 Structural analogs of Venlafaxine are those com denoted (with reference to the 1-carbon) as the cis-(1R) and pounds having the formula: cis-(1S) enantiomers. Sertraline analogs are also described in U.S. Pat. No. 4,536,518. Other related compounds include (S,S) N-desmethylsetraline and rac-cis-N-desmethylser R traline. 0116 Particularly useful are the following compounds, in N 2 either the (1S)-enantiomeric or (1S)(1R) racemic forms, and A their pharmaceutically acceptable salts: cis-N-methyl-4-(3,4- dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine, cis 1N N-methyl-4-(4-bromophenyl)-1,2,3,4-tetrahydro-1-naphtha Rs U R3 lenamine; cis-N-methyl-4-(4-chlorophenyl)-1,2,3,4- 2 tetrahydro-1-naphthalenamine; cis-N-methyl-4-(3- trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-1- naphthalenamine; cis-N-methyl-4-(3-trifluoromethyl-4- as well as pharmaceutically acceptable salts thereof, wherein chlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine, cis-N. N-dimethyl-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-1- A is a moiety of the formula: naphthalenamine: cis-N,N-dimethyl-4-(3-trifluoromethyl phenyl)-1,2,3,4-tetrahydro-1-naphthalenamine; and cis-N- methyl-4-(4-chlorophenyl)-7-chloro-1,2,3,4-tetrahydro-1- naphthalenamine. Of interest also is the (1R)-enantiomer of cis-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1- naphthalenamine. (CH2) or (CH2) 0117 Structural analogs of Zimeldine are those com pounds having the formula: where the dotted line represents optional unsaturation; R is hydrogen oralkyl, R is Calkyl; R is hydrogen, Calkyl, Hal formyl or alkanoyl; R is hydrogen or C. alkyl; Rs and R. are, independently, hydrogen, hydroxyl, Calkyl, Calkoxy, Calkanoyloxy, cyano, nitro, alkylmercapto, amino, C alkylamino, dialkylamino, C alkanamido, halo, trifluoromethyl or, taken together, methylenedioxy; and n is 0, 1, 2, 3 or 4. 0.125 Structural analogs of dulloxetine are those com pounds described by the formula disclosed in U.S. Pat. No. 4.956,388, hereby incorporated by reference. Other SSRI analogs are 4-(2-fluorophenyl)-6-methyl-2-piperazinothieno US 2008/O161324 A1 Jul. 3, 2008 42

2,3-dipyrimidine, 1,2,3,4-tetrahydro-N-methyl-4-phenyl-1- tisone; ; fluorohydroxyandrostenedione; naphthylamine hydrochloride; 1,2,3,4-tetrahydro-N-methyl ; ; : 4-phenyl-(E)-1-naphthylamine hydrochloride: N,N-dim acetate; ; ; fluran ethyl-1-phenyl-1-phthalanpropylamine hydrochloride: drenolide; ; ; ; gamma-(4-(trifluoromethyl)phenoxy)-benzenepropanamine ; : gestonorone; glyderinine; halcino nide; halobetasol propionate; ; ; hydrochloride: BP 554; CP 53261; O-desmethylvenlafaxine: haloprogesterone; ; hydrocortiosone cypi WY 45,818: WY 45,881; N-(3-fluoropropyl)paroxetine: Lu onate; ; hydrocortisone 21-butyrate; hydro 19005; and SNRIs described in PCT Publication No. WO aceponate; ; hydrocortisone 04/004734. buteprate; ; hydrocortisone cypi onate; hydrocortisone hemisuccinate; hydrocortisone probu tate; hydrocortisone sodium phosphate; hydrocortisone 0126. In certain embodiments, a can be Sodium Succinate; ; hydroxyprogest used in the compositions, methods, and kits of the invention. erone; inokosterone; ; isoflupredone acetate; If desired, one or more corticosteroid may be administered in ; loteprednoletabonate; ; mecorto a method of the invention or may be formulated with a tricy lon; ; medroxyprogesterone; ; clic compound in a composition of the invention. Suitable megestrol; ; melengestrol; ; corticosteroids include 11-alpha, 17-alpha, 21-trihydrox methandrostenolone; ; methylpredniso ypregn-4-ene-320-dione; 11-beta, 16-alpha, 17.21-tetrahy lone aceponate; methylprednisolone acetate; methylpred droxypregn-4-ene-320-dione; 11-beta, 16-alpha, 17.21-tet nisolone hemisuccinate; methylprednisolone sodium Succi rahydroxypregn-1,4-diene-3,20-dione; 11-beta, 17-alpha, nate; methyltestosterone; ; mometasone (analogs 21-trihydroxy-6-alpha-methylpregn-4-ene-320-dione; described in U.S. Pat. No. 4,472.393); mometasone furoate: 11-dehydrocorticosterone; 11-deoxycortisol; 11-hydroxy-1, mometasone furoate monohydrate; nisone; ; 4-androstadiene-3,17-dione; 11-ketotestosterone; 14-hy ; ; ; ; droxyandrost-4-ene-3,6,17-trione; 15,17-dihydroxyprogest ; ponasterone; ; pred erone; 16-methylhydrocortisone; 17,21-dihydroxy-16 nisolamate; ; prednisolone 21-diethylaminoac alpha-methylpregna-1,4,9(11)-triene-320-dione; 17-alpha hydroxypregn-4-ene-320-dione; 17-alpha etate; prednisolone 21-hemisuccinate; ; hydroxypregnenolone; 17-hydroxy-16-beta-methyl-5-beta prednisolone farnesylate; prednisolone hemisuccinate; pred pregn-9(11)-ene-320-dione; 17-hydroxy-4,6,8(14)- nisolone-21 (beta-D-glucuronide); prednisolone metasul pregnatriene-320-dione; 17-hydroxypregna-4.9(11)-diene phobenzoate; prednisolone sodium phosphate; prednisolone 3.20-dione; 18-hydroxycorticosterone: Steaglate; ; prednisolone tetrahydro 18-hydroxycortisone; 18-oxocortisol; 21-acetoxypreg ; ; prednival; ; preg nenolone; 21-deoxyaldosterone; 21-deoxycortisone; nenolone; ; ; ; promege 2-deoxyecdysone; 2-methylcortisone; 3-dehydroecdysone; Stone; rhapontisterone; ; roxibolone; 4-pregnene-17-alpha, 20-beta, 21-triol-3,11-dione; 6, 17.20 rubrosterone; stizophyllin; ; ; triamcino trihydroxypregn-4-ene-3-one; 6-alpha-hydroxycortisol; lone; acetonide; 6-alpha-fluoroprednisolone, 6-alpha-methylprednisolone, 21-palmitate; triamcinolone benetonide; triamcinolone diac 6-alpha-methylprednisolone 21-acetate, 6-alpha-methyl etate; triamcinolone hexacetonide; ; turkester prednisolone 21-hemisuccinate Sodium salt, 6-beta-hydroxy one; and wortmannin or derivatives thereof (see, e.g., U.S. , 6-alpha, 9-alpha-difluoroprednisolone 21-acetate Pat. No. 7,081.475). 17-butyrate, 6-hydroxycorticosterone: 6-hydroxydexam (O127 Receptor Modulators ethasone; 6-hydroxyprednisolone; 9-fluorocortisone; 0128 Steroid receptor modulators (e.g., antagonists and alclomethasone dipropionate; ; algestone; alpha ) may be used as a Substitute for or in addition to a derm; amadinone; ; anagestone; androstenedi corticosteroid in the compositions, methods, and kits of the one; anecortave acetate; beclomethasone; beclomethasone invention. dipropionate; 17-Valerate; betamethasone Sodium acetate; betamethasone sodium phosphate: I0129. receptor modulators that may used ; ; budesonide (analogs in the compositions, methods, and kits of the invention described in U.S. Pat. No. 3,929,768); ; chlorma include compounds described in U.S. Pat. Nos. 6,380.207, dinone; ; chloroprednisone acetate; choles 6,380,223, 6,448,405, 6,506,766, and 6,570,020, U.S. Pat. terol, ; , ; clobeta Application Publication Nos. 2003/0176478, 2003/0171585, Sone; ; ; clogestone; 2003/0120081, 2003/0073703, 2002/015631, 2002/ ; ; cortisol; cortisol acetate; cortisol 0147336, 2002/0107235, 2002/0103217, and 2001/0041802, butyrate; cortisol cypionate; cortisol octanoate; cortisol and PCT Publication No. WO00/66522, each of which is Sodium phosphate; cortisol Sodium Succinate; cortisol Valer hereby incorporated by reference. Other steroid receptor ate; cortisone; ; ; cortodoxone; daturaolone; , 21-deoxycortisol, dehydroepi modulators may also be used in the methods, compositions, ; delmadinone; deoxycorticosterone; depro and kits of the invention are described in U.S. Pat. Nos. done; ; ; desoximethasone; dexafen; 6,093,821, 6,121,450, 5,994,544, 5,696,133, 5,696,127, ; dexamethasone 21-acetate; dexamethasone 5,693,647, 5,693,646, 5,688,810, 5,688,808, and 5,696,130, acetate; dexamethasone sodium phosphate; ; each of which is hereby incorporated by reference. ; ; ; diflupred nate; dihydroelatericina; , , ecdys Bufexamac one; ecdysterone; emoXolone; endrysone; ; fluaza cort, flucinolone; flucloronide; ; 0.130. In certain embodiments, bufexamac or a bufexamac fludrocortisone acetate; ; flumethasone; flumetha analog can be used in the compositions, methods, and kits of sone pivalate; ; ; ; fluoci the invention. By "bufexamac analog is meant a compound nolone acetonide; ; butyl; 9-fluorocor having the formula (VI): US 2008/O161324 A1 Jul. 3, 2008 43

387. Cytarabine analogs are described in U.S. Pat. No. 3,116, 282. Triciribine analogs, including triciribine 5'-phosphate O OH M and triciribine-dimethylformamide, are described in U.S. Pat. N No. 5,633,235. Nitazoxanide analogs are described in U.S. V Pat. No. 3,950,391. RI R*, 0.134 Ritonavir R2 R3 0.135 Ritonavir is an antiviral used in treatment of HIV and has the structure: wherein R' is Ne”S O - N-N-N-sul RIB N. N. N O wherein R'' is and R' is H, halo, CFs, optionally substituted X Calkyl, optionally substituted Calkenyl, optionally sub N stituted C- alkynyl, optionally Substituted Css cycloalkyl, optionally substituted C. alkoxy, or optionally substituted C, thioalkoxy; each of R° and R is, independently, H, C, Ritonavir analogs are described, for example, in U.S. Pat. No. alkyl, or CF; and R is optionally substituted C. alkyl or 5,541.206 and have the general structure: optionally Substituted Cls cycloalkyl.

Antiviral Agents R O R3 0131. In certain embodiments, an antiviral agent can be N used in the compositions, methods, and kits of the invention. R le'sin Z. ls N H Suitable antiviral agents include, without limitation, abacavir, H acemannan, acyclovir, adefovir, amantadine, amidinomycin, O ampligen, amprenavir, aphidicolin, atevirdine, capravirine R cidofovir, cytarabine, delavirdine, didanosine, dideoxyad enosine, n-docosanol, edoxudine, efavirenz, emitricitabine, where R is monosubstituted thiazolyl, monosubstituted famciclovir, floXuridine, fomivirsen, foScamet Sodium, gan oxazolyl, monosubstituted isoxazolyl or monosubstituted ciclovir, idoxuridine, , indinavir, pra isothiazolyl wherein the substituent is selected from (i) low nobex, interferon-C. interferon-B, kethoxal, lamivudine, lopi eralkyl, (ii) loweralkenyl, (iii) cycloalkyl, (iv) cycloalkyla navir, lysozyme, madu, methisaZone, moroxydine, nelfinavir, lkyl, (v) cycloalkenyl, (vi) cycloalkenylalkyl, (vii) heterocy nevirapine, nitaZoxanide, oseltamivir, palivizumab, penciclo clic wherein the heterocyclic is selected from aziridinyl, vir, enfuvirtide, pleconaril, podophyllotoxin, ribavirin, aZetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholi rimantadine, ritonavir, saquinavir, , stallimycin, nyl, thiomorpholinyl, thiazolyl, oxazolyl, isoxazolyl, isothia statolon, stavudine, tenofovir, tremacamra, triciribine, triflu Zolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl and ridine, tromantadine, tunicamycin, Valacyclovir, Valganciclo wherein the heterocyclic is unsubstituted or substituted with Vir, Vidarabine, Zalcitabine, Zanamivir, Zidovudine, residui a substituent selected from halo, loweralkyl, hydroxy, alkoxy mod, atazanavir, tipranavir, , fosamprenavir, and thioalkoxy, (viii) (heterocyclic)alkyl wherein heterocy merimepodlib, docosanol, VX-950, and peg interferon. Addi clic is defined as above, (ix) alkoxyalkyl, (X) thioalkoxyalkyl, tional antiviral agents are listed in Table 4 and Table 5. (xi) alkylamino, (xii) dialkylamino, (xiii) phenyl wherein the 0132 Structural analogs of antiviral agents which may be phenyl ring is unsubstituted or substituted with a substituent used in the combinations of the invention include 9-((2-ami selected from halo, loweralkyl, hydroxy, alkoxy and thio noethoxy)methyl), 8-hydroxyacyclovir. 2'-O-glycyl alkoxy, (xiv) phenylalkyl wherein the phenyl ring is unsub acyclovir, ganciclovir, PD 116124, Valacyclovir, omaciclovir, stituted or substituted as defined above, (XV) dialkylami Valganciclovir, buciclovir, penciclovir, Valmaciclovir, carbo noalkyl, (xvi) alkoxy and (xvii) thioalkoxy; n is 1, 2 or 3: R. Vir, theophylline, Xanthine, 3-methylguanine, enprofylline, is hydrogen or loweralkyl; R is loweralkyl; R and Ra, are cafaminol, 7-methylxanthine, L 653180, BMS 181164, valo independently selected from phenyl, thiazolyl and oxazolyl maciclovir Stearate, deriphyllin, acyclovir monophosphate, wherein the phenyl, thiazolylor oxazolyl ring is unsubstituted acyclovir diphosphate dimyristoylglycerol, and etofylline. or substituted with a substituent selected from (i) halo, (ii) 0.133 Edoxudine analogs are described in U.S. Pat. No. loweralkyl, (iii) hydroxy, (iv) alkoxy and (v) thioalkoxy; R is 3,553,192. Efavirenz analogs are described in European hydrogen or loweralkyl; R, is thiazolyl, oxazolyl, isoxazolyl Patent 582,455 and U.S. Pat. No. 5,519,021. Floxuridine or isothiazolyl wherein the thiazolyl, oxazolyl, isoxazolyl or analogs are described in U.S. Pat. Nos. 2,970,139 and 2,949, isothiazolyl ring is unsubstituted or substituted with lower 451. Nelfinavir analogs are described in U.S. Pat. No. 5,484. alkyl; X is hydrogen and Y is —OH or X is —OH and Y is 926. Aphidicolin analogs are described in U.S. Pat. No. 3,761, hydrogen, with the proviso that X is hydrogen and Y is —OH 512. Trifluridine analogs are described in U.S. Pat. No. 3,201, when Z is —N(Rs)— and R, is unsubstituted and with the US 2008/O161324 A1 Jul. 3, 2008 44 proviso that X is hydrogen and Y is —OH when R is methyl and R, is unsubstituted; and Z is absent, —O— —S . —CH2— or—N(Rs)—wherein Rs is loweralkyl, cycloalkyl, NH2 —OH or—NHRs, wherein Rs is hydrogen, loweralkyl oran N-protecting group. 0136 Saquinavir y 0.137 In certain embodiments, saquinavir or its analogs - can be used in the compositions, methods, and kits of the invention. Saquinavir is a protease inhibitor that is highly RCH(R)-OCHP-OH specific for the HIV-1 and HIV-2 proteases. The structure of OH saquinavir is: wherein R is a hydrogenatom, an alkyl group containing one to three carbonatoms, or a hydroxymethyl group, and R is a 21 methylene, ethylene, propylene, ethylidene, methoxyethyl ene, benzyloxyethylene, tetrahydropyran-2-yloxyethylene, Sa (1-ethoxyethoxy)ethylene, or 1.2-O-isopropylidene-1,2-di hydroxypropylene group.

(O140 Celgosivir 0.141. In certain embodiments, celgosivir or an analog thereof can be used in the compositions, methods, and kits of the invention. Celgosivir is a of castanospermine, a natural product derived from the Australian Black Bean chestnut tree. It has antiviral (e.g., anti-HCV) activity, and acts as an inhibitor of C- and B-glucosidase. The structure of celgosivir is:

Saquinavir analogs are described, for example, in U.S. Pat. No. 5,196.438 and have the general structure:

HN OH OH

Analogs of celgosivir are described, for example, in PCT Publication No. WO 2006/096285 and have the general struc ture:

RO

RO OR

where R, R and R2 are independently hydrogen, Ca alkanoyl, Calkenoyl cyclohexanecarbonyl, Cs alkoxy acetyl, where R is benzyloxycarbonyl or 2-quinolylcarbonyl, and pharmaceutically acceptable acid addition salts thereof. 0138 Adefovir Dipivoxil 0.139. In certain embodiments, adefovir dipivoxil or its analogs can be used in the compositions, methods, and kits of the invention. Analogs of adefovir dipivoxil are described, for example, in U.S. Pat. No. 4,808,716 and include compounds naphthalenecarbonyl optionally substituted by methyl or with the general structure: halogen; phenyl(C. alkanoyl) wherein the phenyl is option US 2008/O161324 A1 Jul. 3, 2008

ally Substituted by methyl or halogen; cinnamoyl; pyridin Pat. No. 5,208,241; aminomacrollides and derivatives thereof ecarbonyl optionally substituted by methyl or halogen; dihy are described in U.S. Pat. No. 5,208,228; fluoromacrollides dropyridine carbonyl optionally substituted by Co alkyl; are described in U.S. Pat. No. 5,189,042; amino O-alkyl, thiophenecarbonyl optionally substituted by methyl or halo O-alkenyl, and O-alkynylmacrollides are described in U.S. gen; or furancarbonyl optionally Substituted by methyl or Pat. No. 5,162.334; and halomacrollides are described in U.S. halogen: Y is hydrogen, C alkyl, C. alkoxy, halogen, Pat. No. 5,143,918. trifluoromethyl, C. alkylsulphonyl, C. alkylmercapto, 0148 Tacrolimus is extensively metabolized by the cyano or dimethylamino: Y" is hydrogen, C alkyl, Ca mixed-function oxidase system, in particular, by the cyto alkoxy, halogen or it is combined with Y to give 3.4-methyl chrome P-450 system. The primary mechanism of metabo enedioxy;Y" is hydrogen, Calkyl, Calkoxy or halogen; lism is demethylation and hydroxylation. While various tac and pharmaceutically acceptable salts thereof. rolimus metabolites are likely to exhibit immunosuppressive biological activity, the 13-demethyl metabolite is reported to Immunophilin-Dependent Immunosuppres have the same activity as tacrolimus. SantS 0149 Pimecrolimus 0142. In certain embodiments, a nonsteroidal immunophi (O150 Pimecrolimus is the 33-epi-chloro derivative of the lin-dependent immunosuppressant can be used in the compo macrolactam ascomyin. Pimecrolimus structural and func sitions, methods, and kits of the invention. Suitable Ns|DIs tional analogs are described in U.S. Pat. No. 6,384,073. include cyclosporine, tacrolimus, rapamycin (sirolimus), 0151. Rapamycin everolimus, and pimecrolimus. 0152 Rapamycin structural and functional analogs 0143 Cyclosporines include mono- and diacylated rapamycin derivatives (U.S. 0144. The cyclosporines are fungal metabolites that com Pat. No. 4.316,885); rapamycin water-soluble (U.S. prise a class of cyclic oligopeptides that act as immunosup Pat. No. 4,650,803); carboxylic acid esters (PCT Publication pressants. Cyclosporine A is a hydrophobic cyclic polypep No. WO92/05179); carbamates (U.S. Pat. No. 5,118,678); tide consisting of eleven amino acids. It binds and forms a amide esters (U.S. Pat. No. 5,118,678); biotin esters (U.S. complex with the intracellular receptor cyclophilin. The Pat. No. 5,504,091); fluorinated esters (U.S. Pat. No. 5,100, cyclosporine/cyclophilin complex binds to and inhibits cal 883); acetals (U.S. Pat. No. 5,151,413); silyl ethers (U.S. Pat. cineurin, a Ca"-calmodulin-dependent serine- No. 5,120,842); bicyclic derivatives (U.S. Pat. No. 5,120, specific protein phosphatase. Calcineurin mediates signal 725); rapamycin dimers (U.S. Pat. No. 5,120,727); O-aryl, transduction events required for T-cell activation (reviewed in O-alkyl, O-alkyenyland O-alkynyl derivatives (U.S. Pat. No. Schreiber et al., Cell 70:365-368, 1991). Cyclosporines and 5,258,389); and deuterated rapamycin (U.S. Pat. No. 6,503, their functional and structural analogs Suppress the T cell 921). Additional rapamycin analogs are described in U.S. Pat. dependent immune response by inhibiting antigen-triggered Nos. 5,202,332 and 5,169,851. signal transduction. This inhibition decreases the expression 0153. Peptide Moieties of proinflammatory cytokines, such as IL-2. 0154 Peptides, peptide mimetics, peptide fragments, 0145 Many different cyclosporines (e.g., cyclosporine A, either natural, synthetic or chemically modified, that impair B, C, D, E, F, G, H, and I) are produced by fungi. Cyclospo the calcineurin-mediated dephosphorylation and nuclear rine A is a commercially available under the trade name translocation of NFAT are suitable for use in practicing the NEORAL from Novartis. Cyclosporine A structural and invention. Examples of peptides that act as calcineurin inhibi functional analogs include cyclosporines having one or more tors by inhibiting the NFAT activation and the NFAT tran fluorinated amino acids (described, e.g., in U.S. Pat. No. Scription factor are described, e.g., by Aramburu et al., Sci 5.227.467); cyclosporines having modified amino acids (de ence 285:2129-2133, 1999) and Aramburu et al., Mol. Cell scribed, e.g., in U.S. Pat. Nos. 5,122,511 and 4.798,823); and 1:627-637, 1998). As a class of calcineurin inhibitors, these deuterated cyclosporines, such as ISAtx247 (described in agents are useful in the methods of the invention. U.S. Pat. Application Publication No. 2002/0132763 A1). Additional cyclosporine analogs are described in U.S. Pat. Nos. 6,136,357, 4,384,996, 5,284.826, and 5,709,797. Cyclosporine analogs include, but are not limited to, D-Sar 0.155. In certain embodiments, an antihistamine oran anti (C-SMe) Val-DH-Cs (209-825), Allo-Thr-2-Cs, Norvaline histamine analog can be used in the compositions, methods, 2-Cs, D-Ala(3-acetylamino)-8-Cs. Thr-2-Cs, and D-MeSer and kits of the invention. Antihistamines are compounds that 3-Cs, D-Ser(O CHCH-OH)-8-Cs, and D-Ser-8-Cs. block the action of histamine. Classes of antihistamines which are described in Cruz et al. (Antimicrob. Agents include: Chemother. 44:143-149, 2000). 0156 (1) Ethanolamines (e.g., bromodiphenhydramine, 0146 Tacrolimus , , , diphenhy 0147 Tacrolimus and tacrolimus analogs are described by dramine, , and ); Tanaka et al., (J. Am. Chem. Soc., 109:5031, 1987) and in 0157 (2) Ethylenediamines (e.g., , pyril U.S. Pat. Nos. 4,894,366, 4,929,611, and 4,956,352. FK506 amine, , and ); related compounds, including FR-900520, FR-900523, and 0158 (3) (e.g., diethazine, ethopropazine, FR-900525, are described in U.S. Pat. No. 5.254.562; O-aryl, , , , and trimepra O-alkyl, O-alkenyl, and O-alkynylmacrollides are described Zine); in U.S. Pat. Nos. 5,250,678, 532,248, 5,693,648; amino 0159 (4) Alkylamines (e.g., , bromphe O-aryl macrollides are described in U.S. Pat. No. 5,262,533; niramine, chlorpheniramine, desbrompheniramine, dexchlo alkylidene macrollides are described in U.S. Pat. No. 5.284, rpheniramine, , and triprolidine); 840; N-heteroaryl, N-alkylheteroaryl, N-alkenylheteroaryl, 0160 (5) (e.g., , , chlorcy and N-alkynylheteroaryl macrollides are described in U.S. clizine, , meclizine, hydroxyZine); US 2008/O161324 A1 Jul. 3, 2008 46

0161 (6) Piperidines (e.g., , , cypro rperazine; promazine; (e.g., propiomazine heptadine, , , loratadine, , hydrochloride); rotoxamine; : SCH 37370; SCH , , and ); 434, tecastemizole; thiazinamium; ; thior 0162 (7) Atypical antihistamines (e.g., azelastine, levo idazine (e.g., thioridazine hydrochloride); and 3-(10,11-dihy cabastine, , and phenyltoxamine). dro-5H-dibenzo(a,d)cyclohepten-5-ylidene)-tropane. 0163. In the compositions, methods, and kits of the inven tion, both non-sedating and sedating antihistamines may be 0166 Other compounds that are suitable for use in the employed. Non-sedating antihistamines include loratadine invention are AD-0261; AHR-5333; allinastine; arpromidine: and desloratadine. Sedating antihistamines include azata ATI-19000; bermastine; bilastin; Bron-12; carebastine; chlo dine, bromodiphenhydramine; chlorpheniramine; ; rphenamine; clofurenadine; corsym: DF-1 105501; cyproheptadine; dimenhydrinate; : doxy DF-1 1062: DF-111 1301; EL-301; elbanizine; F-7946T: lamine; meclizine; promethazine; pyrilamine; thiethylpera F-9505; HE-90481; HE-90512; hivenyl; HSR-609; icotidine: Zine; and tripelennamine. KAA-276; KY-234; lamiakast, LAS-36509; LAS-36674; 0164. Other antihistamines suitable for use in the compo ; levoprotiline; : NIP-531; sitions, methods, and kits of the invention are acrivastine; noberastine; : PR-881-884A; quisultazine; rocas ahistan; ; astemizole; azelastine (e.g., azelsatine tine; selenotifen; SK&F-94461; SODAS-HC; tagorizine; hydrochloride); ; ; benztropine, biet TAK-427; temelastine; UCB-34742; UCB-35440; VUF-K- anautine; (e.g., brompheniramine male 8707; Wy-49051; and ZCR-2060. ate); carbinoxamine (e.g., carbinoxamine maleate); cetirizine (e.g., cetirizine hydrochloride); cetoxime; chlorocyclizine; 0.167 Still other compounds that are suitable for use in the ; ; chlorphenoxamine; cinnariz invention are described in U.S. Pat. Nos. 2,595,405, 2,709, ine; clemastine (e.g., clemastine fumarate); , 169, 2,785,202, 2,899,436, 3,014,911, 3,813,384, 3,956,296, ; ; cyclizine (e.g., cyclizine hydro 4,254,129, 4,254,130, 4,282,833, 4,283,408, 4.362,736, chloride; cyclizine lactate); deptropine; dexchlorphe 4,394,508, 4,285,957, 4,285,958, 4,440,933, 4,510,309, niramine; maleate; diphenylpyraline; 4,550,116, 4,659,716, 4,692,456, 4,742,175, 4,833,138, doxepin; ; ; (e.g., emedastine 4,908,372, 5,204.249, 5,375,693, 5,578,610, 5,581,011, difumarate); ; hydrochloride; fex 5,589.487, 5,663,412, 5,994,549, 6,201,124, and 6,458,958. ofenadine (e.g., fexofenadine hydrochloride); histapyrrod Hydroxyzine ine; hydroxyzine (e.g., hydroxyzine hydrochloride; hydrox (0168 yZine pamoate); ; ; 0169. In certain embodiments, hydroxyzine or an analog (e.g., levocabastine hydrochloride); mebhy thereof can be used in the compositions, methods, and kits of droline; meduitazine; methafurylene; methapyrilene; met the invention. The structure of hydroxyzine is: ron; , olapatadine (e.g., olopatadine hydrochlo ride); ; phenindamine (e.g., phenindamine tartrate); pheniramine; ; p-methyldiphen C hydramine; pyrrobutamine; ; ; terfenadine; ; thiazinamium (e.g., thiazinamium methylsul r^-r fate); hydrochloride; ; triproli dine; and tritoqualine. 0.165 Antihistamine analogs may also be used in accord ing to the invention. Antihistamine analogs include 10-piper azinylpropylphenothiazine: 4-(3-(2-chlorophenothiazin-10 yl)propyl)-1-piperazineethanol dihydrochloride: 1-(10-(3- (4-methyl-1-piperazinyl)propyl)-10H-phenothiazin-2-yl)- (9CI) 1-propanone; 3-methoxycyproheptadine: 4-(3-(2- 0170 Analogs of hydroxyzine are described, for example, Chloro-1 OH-phenothiazin-10-yl)propyl)piperazine-1- in U.S. Pat. No. 2,899,436 and have the general structure: ethanol hydrochloride: 10,11-dihydro-5-(3-(4- ethoxycarbonyl-4-phenylpiperidino)propylidene)-5H dibenzo(a,d)cycloheptene; ; acetophenazine; CH2) alimemazin (e.g., alimemazin hydrochloride); aminopro N r S-R mazine; benzimidazole; butaperazine; ; chlor R- - ; chlormidazole; cinprazole; desmethylastemi Zole; desmethylcyproheptadine; diethazine (e.g., diethazine hydrochloride); ethopropazine (e.g., ethopropazine hydro chloride); 2-(p-bromophenyl-(p'-tolyl)methoxy)-N,N-dim ethyl-ethylamine hydrochloride: N,N-dimethyl-2-(diphenyl methoxy)-ethylamine methylbromide: EX-10-542A; fenethazine; fuprazole; methyl 10-(3-(4-methyl-1-piperazi nyl)propyl)phenothiazin-2-yl ketone; ; medry lamine; mesoridazine; methylpromazine: N-desmethyl wherein R and R" are a hydrogen atom, a halogen atom, an promethazine; nilprazole; northioridazine; perphenazine alkyl group, or an alkoxy group, R' and R" being in ortho, (e.g., perphenazine enanthate); 10-(3-dimethylaminopro meta, or para positions; R contains 2 to 11 carbon atoms and pyl)-2-methylthio-phenothiazine: 4-(dibenzo(b.e)thiepin-6 is alkyl, phenyl, alkyl Substituted phenyl, aralkyl, cycloalkyl, (11H)-ylidene)-1-methyl-piperidine hydrochloride; prochlo hydroxyalkyl, hydroxycycloalkyl or —CH2—CH2—O— US 2008/O161324 A1 Jul. 3, 2008 47

CH2—CH2—OH, and n is an integer from 1 to 6, inclusive.

The compound may be in the form of a mineral acid salt oran organic acid salt. Irinotecan 0171 In certain embodiments, irinotecan, topotecan, or their analogs can be used in the compositions, methods, and kits of the invention. Analogs ofirinotecan are described, for example, in U.S. Pat. No. 4,604,463 and have the general Structure:

0.174. In this structure, X is typically O, but can be other groups, e.g., NH in the case of 21-lactam derivatives. R is typically H or OH, but may be other groups, e.g., a terminally hydroxylated C. alkane. R is typically Horan amino con taining group such as (CH)NHCH, but may be other groups e.g., NO, NH, halogen (as disclosed in, e.g., U.S. Pat. No. 5,552,156) or a short alkane containing these groups. R is typically Hora short alkyl such as CHs. R is typically Hbut may be other groups, e.g., a methylenedioxy group with R. 0.175 Exemplary camptothecin compounds include topo where R is a hydrogenatom, a halogenatom, or a C alkyl, tecan, irinotecan (CPT-11), 9-aminocamptothecin, 21-lac and X is a chlorine or —NRR, wherein R and Rs are the tam-20(S)-camptothecin, 10, 11-methylenedioxycamptoth same or different and each represents a hydrogenatom, a Ca alkyl, or a substituted or unsubstituted carbocyclic or hetero ecin, SN-38, 9-nitrocamptothecin, 10-hydroxycamptothecin. cyclic group, with the proviso that when both R- and R are Exemplary compounds have the structures: the Substituted or unsubstituted alkyl groups, they may be combined together with the nitrogen atom, to which they are bonded, to form a heterocyclic ring which may be interrupted with —O— —S , and/or >N-R in which R is a hydro gen atom, a Substituted or unsubstituted C. alkyl, or a Sub stituted or unsubstituted phenyl group and where the group ing—O—CO—X is bonded to a carbon atom located in any of the 9-, 10-, and 11-positions in the ring A of camptothecin. 0172 Analogs of topotecan are described, for example, in European Patent No. 321122 and include compounds with the general formula: R R2 R3 Camptothecin: H H H Topotecan: OH (CH3)NHCH. H. SN-38: OH. H. CH5 X: O for most analogs, NH for 21-lactam analogs

0176 Camptothecins have the five rings shown here. The ring labeled E must be intact (the lactone rather than carboxy late form) for maximum activity and minimum toxicity. 0177 Camptothecins are believed to function as topoi Somerase I inhibitors and/or DNA cleavage agents.

Disulfuram where X is hydroxy, hydrogen, cyano. —CH-NH2 or formyl; R is hydrogen when X is cyano, CH-NH or formyl or R is 0.178 Disulfuram is used in the treatment of alcoholism; —CHO or —CHR, when X is hydrogen or hydroxy: R is its mechanism of action is inhibition of dehydroge —O-R-S-R. —N-R(R); or—N' R (R)(R). nase. The structure of disulfuram is: R. R. and R are the same or different and are selected from H. C. alkyl, C. hydroxyalkyl, Ce dialkyamino, Co-di alkylaminoC2-galkyl, Co alkyamino-C2-alkyl, C2-6 ami HC noalkyl, or a 3-7 member unsubstituted or substituted car S bocyclic ring; and when R is —N—R(R), the R and R HC N S ul groups may be combined together to form a ring. in 1 r Ns N1 NCH, Camptothecins S ls 0173. In certain embodiments, the anti-infective therapeu CH tic agent is camptothecin, or an analogue or derivative thereof. Camptothecins have the following general structure. US 2008/O161324 A1 Jul. 3, 2008 48

0179 Analogs of disulfuram are described in, for NSAIDS example, U.S. Pat. No. 1,796,977 and have the general struc 0184. In certain embodiments, an NSAID can be used in ture: the compositions, methods, and kits of the invention. Suitable NSAIDs include A183827, ABT963, aceclofenac, acemeta cin, acetyl salicylic acid, AHR10037, alclofenac, alminopro S fen, ampiroXicam, amtolimetinguacil, apaZone, aspirin, atlip N S ul R rofen methyl ester, AU8001, azelastine, benoxaprofen, R1 r Ns benzydamine, benzydamine flufenamate, benzydamine S R hydrochloride, bermoprofen, bezpiperylon, BF388, BF389, BIRL790, BMS347070, bromfenac, bucloxic acid, buti bufen, BW755C, C53, C73, C85, carprofen, CBS1108, cele wherein the R groups represent same of dissimilar organic coxib, CHF2003, chlorobiphenyl, trisali groups (e.g., C alkyls). cylate, CHX108, cimicoxib, cinnoxicam, clidanac, 0180 Analogs include thiram. Disulfuram is a crystal, CLX1205, CP331, CS502, CS706, D1367, curcumin, dar barely soluble in water, and is soluble in solvents such as bufelone, deracoxib, dexibuprofen, dexibuprofen , alcohol, ether, , and benzene. Disulfuram is available dexketoprofen, DFP. DFU, diclofenac (e.g., diclofenac potas in tablet form, and is typically administered orally. sium, diclofenac sodium), diflunisal, DP155, DRF4367, E5110, E6087, eltenac, ER34122, esflurbiprofen, etoricoxib, Auranofin F025, felbinac ethyl, fenbufen, fenclofenac, fenclozic acid, 0181 Auranofin is an anti-inflammatory agent and an anti fenclozine, fenoprofen, fentiazac, feprazone, filenadol, rheumatic. The structure of auranofin is: flobufen, florifenine, flosulide, flubichin methanesulfonate, , fluprofen, flurbiprofen, FPL62064. FR122047, FR123826, FR140423, FR188582, FS205397, RO furofenac, GR253035, GW406381, HAI 105, HAI 106, HCT2035, HCT6015, HGP12, HN3392, HP977, H0835. O - All-PCH), HYAL AT2101, ibufenac, ibuprofen, ibuproxam-beta-cyclo dextrin, icodulinum, IDEA070, iguratimod, imrecoxib, RO OR indomethacin, indoprofen, IP751, isoxepac, isoxicam, KC764, ketoprofen, L652343, L745337, L748731, L752860, H L761066, L768277, L776967, L783003, L784520, L791456, OR L804600, L818571, LAS33815, LAS34475, licofelone, LM R = COCH 4108, lobuprofen, lornoxicam, lumiracoxib, mabuprofen, , meclofenamate sodium, , meloxicam, mercaptoethylguanidine, mesoporphyrin, 0182 Analogs of auranofin are described, for example, in metoxibutropate, miroprofen, mofebutaZone, mofeZolac, U.S. Pat. No. 3,635,945, and can be represented by the gen MX1094, nabumetone, naproxen Sodium, naproxen-sodium/ eral formulas: metoclopramide, NCX1101, NCX284, NCX285, NCX4016, NCX4215, NCX530, , nitric oxide-based

COX-2 inhibitors and NSAIDs (NitroMed), nitrofenac, nitroflurbiprofen, nitronaproxen, NS398, Ocimum sanctum oil, ONO3144, orpanoxin, oxaprozin, OXindanac, oXpinac, oxycodone/ibuprofen, oxyphenbutazone, P10294, P54, P8892, pamicogrel, parcetasal, parecoxib, PD138387, PD145246, PD164387, pelubiprofen, pemedolac, phenylb utaZone, piraZolac, piroXicam, piroXicam beta-cyclodextrin, piroXicam pivalate, pirprofen, pranoprofen, , R-ketoprofen, R-ketorolac, rofecoxib, RP66364, RU43526, RU54808, RWJ63556, S19812, S2474, S33516, salicylsali cylic acid, satigrel, SC236, SC57666, SC58125, SC58451, SFPP. SKF 105809, SKF86002, sodium salicylate, sudoxi cam, sulfasalazine, sulindac, suprofen, SVT2016, T3788, TA60, talmetacin, talniflumate, tazofelone, tebufelone, tenidap, tenoxican, tepoxalin, tiaprofenic acid, tilmacoxib, tilnoprofen arbamel, tinoridine, tiopinac, tioxaprofen, tolfe namic acid, tolmetin, triflusal, tropesin, TY10222. TY10246, TY10474, UR8962, ursolic acid, valdecoxib, WAY 120739, WY28342, WY41770, Ximoprofen, YS134, Zaltoprofen, where R represents acetylor, when Z is oxygen, hydrogen; R. Zidometacin, and Zomepirac. represents a C alkyl. A represents a C-s alkylene chain, 0185. Other NSAIDs are described in U.S. Pat. Nos. straight or branched; Y represents oxygen or Sulfur, and Z 2,745,783, 3,318,905, 5,344,991, 5,380,738, 5,393,790, represents oxygen or —NH-. 5,401,765, 5,418,254, 5,420,287, 5,434,178, 5,466,823, 0183 Auronfin is a white, odorless, crystalline powder 5,475,018, 5,474,995, 5,486,534, 5,504,215, 5,508,426, and is insoluble in water. It is administered orally in tablet 5,510,368, 5,510,496, 5,516,907, 5,521,193, 5,521,207, form. 5,534,521, 5,565,482, 5,596,008, 5,616,601, 5,633,272, US 2008/O161324 A1 Jul. 3, 2008 49

5,639,777, 5,663,180, 5,668,161, 5,670,510, 5,672,626, chloroethyl)aminophenylacetate, 17-beta-hydroxy-7 alpha 5,672,627 5,736,579, 5,739,166, 5,760,068, 5,756,529, methyl-androst-5-en-3-one, 17-ethynyl-(5a)-androst-2-ene 5,859,257, 5,886,016, 5,908,852, 5,916,905, 6,294,558, 17-ol-17-nicotinate, 17-ethynylandrost-2-ene-17-ol-17 6,476,042, 6,486,203, 6,492,411, 6,608.095, 6,649,645, acetate, 17-hydroxy-17-methyl-3-oxospiro (androst-5-ene-4, 6,673,818, 6,689,805, 6,696,477, 6,727,268, 6,699,884, 1'-cyclopropane)-2-carbonitrile, 17-methyl-17 6,727,238, 6,777,434, 6,846,818, 6,849,652, 6,949,536, hydroxyandrosta-1,4,6-trien-3-one, 19-ethynyl-19 6,967,213, 7,019,144, and 7,041,694, PCT Publication Nos. hydroxyandrost-4-en-17-one, 2,3,17, 19 WO94/13635, WO94/15932, WO94/20480, WO94/26731, tetrahydroxyandrost-4-ene, 2-beta-hydroxy-19-oxo-4- WO96/03387, WO96/03388, WO96/09293, WO97/16435, androstene-3,17-dione, 3 beta-methoxy-5-androsten-17-one, WO98/03484, WO98/47890, WO96/06840, WO96/25405, 3’-azido-3'-deoxy-5'-O-((11-hydroxy-3-oxo-17-androst-4- WO95/15316, WO94/15932, WO94/27980, WO95/00501, enyl)carbonyl), 3,15, 17-trihydroxy-5-androstene, and WO94/2673, and GB 839,057, GB 2,294.879, and EP 3.16, 19-trihydroxy-5-androsten-17-one, 3,17-dihydroxy-7- O745596. (4-methoxyphenyl)-androst-5-ene 3,17-diacetate, 3-hy 0186 Benzydamine droxy-17-methyl-18-norandrost-13(17)-ene-16-one, 0187. In certain embodiments, an NSAID such as benzy 3-methoxy-17-aza-homoandrost-5-ene-17-one, 5 alpha-an damine oran analog thereof can be used in the compositions, drost-16-en-3 beta-ol, 5-androstene-3,16,17-triol, 9-fluoro methods, and kits of the invention. The structure of benzy 11,16,17-trihydroxy-17-hydroxymethyl-D-homoandrosta-1, damine is: 4-diene-3,17-dione, 9-fluoro-16-methyl-6,11,16-trihydroxy 1,4-androstadiene-3,17-dione, abiraterone, androst-16-en-3- ol, androst-16-en-3-ol Sulfoconjugate, androst-5-en-3-ol, androst-5-ene-3,16,17-triol-3-sulfate, androsta-2,4-diene-17 beta-ol, androsta-5,16-dien-3 beta-ol. Androstenediols (e.g., 17-cyano-9,17-dihydroxyandrost-4-ene-3-one, 2-carbam oyl-4,5-epoxyandrost-2-ene-3,17-diol, 3 beta, 17 beta-dihy droxyandrost-5-en-16-one, 3,16-dihydroxyandrost-5-ene 17, 19-dione, 4-androstene-3,17-diol, 4a,17-dimethyl-A- homo-B, 19-dinor-3,4-secoandrost-9-ene-3,17-diol, androst 4-ene-3 beta, 17 beta-diol dicyclopentylpropionate, androst 4-ene-3 beta, 17-beta-diol dienanthate, , cortienic acid, delta (2,16)-5alpha-androstadiene-3,17-diol 3,17-diacetate, Fluoxymesterone, formyldienolone, Meth 0188 Analogs of benzydamine are described, for andriol, and viridiol), azastene, cyanoketone (e.g., Win example, in U.S. Pat. No. 3,318.905 and have the general 19578), Dehydroepiandrosterone (e.g., 1-hydroxydehydroe Structure: piandrosterone, 15 beta-carboxyethylmercaptodehydroe piandrosterone, 15-hydroxydehydroisoandrosterone, 16-hy droxydehydroepiandrosterone, 16-hydroxydehydroepiandrosterone sulfate, 7-hydroxydehy droepiandrosterone, 7-oxodehydroepiandrosterone, androst 5-en-17-one, dehydroepiandrosterone acetate, dehydroepi androsterone enanthate, dehydroepiandrosterone sulfate, dehydroepiandrosterone-3-O-methylthiophosphonate, fluias terone, gonasterone, gynodian, OH 8356, and testosterone ), epostane, etiocholenic acid, methyl 14-hydroxy-1, wherein R is selected from the class consisting of hydrogen 7, 17-trioxoandrost-8-ene-19-oate, mexrenoate potassium, and chlorine; R' is selected from the class consisting of lower , ratibol, RS 21314, RS 85095, , sten alkyland phenyl groups which latter may be substituted or not bolone acetate, testosterone, and thiomesterone. 0.190 Testosterone derivatives include 11-ketotestoster in their phenyl nucleus by halogen atoms or lower alkyl or one, 11-oxatestosterone, 15 beta-carboxyethylmercaptotest lower alkoxy groups; R" is a member selected from the class osterone, 15-carboxymethyltestosterone, 17 beta-aminocar consisting of hydrogen and lower alkyl groups; R", which bonyloxy-4-androsten-3-one, 17-bromoacetoxy-4- may be like or unlike, are lower alkyl residues; n is selected androsten-3-one, 17-ethinyl-11-Oxa-testosterone, 19-O- from the group consisting of 1 and 2. carboxymethoxytestosterone, 4-(carboxymethylmercapto) testosterone, 6-dehydrotestosterone, 6-methylenetestosterone acetate, ablacton, androsta-3,5-di 0189 In certain embodiments, an such as tester ene-3,17-diol diacetate, bolasterone, unde one or a testosterone analog can be used in the compositions, cylenate, climacterone, , D-4-chloro-17 beta-hy methods, and kits of the invention. Androgens such as andros droxy-3-oxo-17 alpha-methylandrosta-1,4-diene, tenols include 14-hydroxyandrost-4-ene-3,6,17-trione, dehydrotestosterone, deladumone, dimeric testosterone, epit 16-acetoxy-17-acetoxymethyl-11,17-dihydroxy-D-homoan estosterone, estandron prolongatum, ethynodiol testosterone drosta-1,4-diene-3,17-dione, 17 beta-((1R)-1-hydroxy-2- ester, gonasterone, hydroxytestosterones, metharmon F. propynyl)androst-4-en-3-one, 17 beta-amino-3 beta-meth methenolone, methyltestosterone, nichlotest, synovex-H, tes oxy-5-androstene, 17 beta-hydroxy-17-(2-methylallyl)-9 tosterone 17 beta-carboxylic acid, testosterone 17 beta-cypi beta, 10 alpha-androst-4-en-3-one, 17-(cyclopropylamino) onate, testosterone 17-cyclohexanecarboxylate, testosterone androst-5-en-3-ol, 17-acetamido-5-androsten-3-ol-4-bis(2- 17-enanthate 3-benzilic acid hydrazone, testosterone 3-(O- US 2008/O161324 A1 Jul. 3, 2008 50 dimethylaminopropyl)oxime, testosterone 4-n-butylcyclo 4,17-dimethyltrilostane, 4.5-secodihydrotestosterone, 5-di hexylcarboxylic acid, , testosterone hydrotestosterone 3,17-bromoacetate, androstan-3,17-diol decanoate, , , tes 11-one, androstan-3-one, demalon, tosterone glucuronate, , testosterone 17-bromoacetate, dihydrotestosterone glucuronide, dihy isocaproate, , testosterone pivalate, tes drotestosterone heptanoate, dihydrotestosterone propionate, tosterone propionate, , testosterone dihydrotestosterone-17-N-bis(2-chloroethyl), 17-succinate, testosterone-17-sulfate, testosterone-19 , mesterolone, nitrostanolone, stanolone ben hemisuccinate, testosterone-3-(n-hexyl)cyclobutane Zoate, testiphenon, and ), dromostanolone, dromo carboxylate, testosterone-3-oxime, testosterone-4-n-pentyl stanolone propionate, , etiocholanolone or its cyclohexyl carboxylate, testosterone-cysteamine-DANS, derivatives (e.g., 11-ketoetiocholanolone, 3,7-dihydroxyan testosterone-DAH-fluorescein, testosterone-DAP-fluores drostan-17-one, 3-hydroxyandrostane-7,17-dione, and cein, testosteronyl 4-dimethylaminobutyrate, testoviron-de -3,17-dione), , , mepitios pot, topterone, trofodermin, and turinabol. tane, N-cyano-2-aza-A-norandrostan-17-ol acetate, nister ime acetate, ORG9943, ORG9991, OrgNA13, , 0191 Androstanols include 1.2-seco-A-bis(noran or its derivatives (e.g., 17-hydroxy-2-(hy drostan-17-ol)acetate, 1,3,5,6-tetrahydroxyandrostan-17 droxymethylene)androstan-3-one), Pancuronium or its One, 1,3-trimethylene-2,5-epoxyandrostane-3,17-diol derivative (e.g., (dideacetoxy)pancuronium, 2.16-dipiperidi 17-propionate, 11,17-dihydroxy-6-methyl-17-(1-propynyl) noandrostane-3,17-diol dipivalate, 3 alpha, 17 beta-dibutyry androsta-1,4,6-triene-3-one, 16,17-epoxyandrostan-3-ol, 17 loxy-2 beta, 16 beta-dipiperidino-5 alpha-androstane beta-(3-furyl)-5beta, 14 beta-androstane-3beta, 14 beta-diol, dimethobromide, 3-(deacetoxy)pancuronium, 3-de 17-(3'-thiophenyl)androstane-3,14-diol 3-glucopyranoside, sacetylpancuronium, dacuronium, and Org 6368), RU 26988, 17-acetamido-5-androstan-3-ol-4-bis(2-chloroethyl)ami rubrosterone, Samanine, spiro-3-oxiranylandrostan-17-ol. nophenylacetate, 17-ethyl-17-hydroxyandrostane, 17-hy stanozolol or its derivatives (e.g., 16-hydroxyStanozolol and droxy-2,3-cyclopropanoandrostane, 17-methyl-17a-chloro 4, 16-dihydroxystanozolol), or its D-homoandrostan-3-ol, 2-(2-(3-hydroxy-12-(2-methyl-1- derivatives (e.g., (dideacetoxy)Vecuronium, 17-deacetylve oxobutoxy)-5-androstan-17-yl)ethyl)tetrahydro-4-hydroxy curonium, 3,17-bis-deacetylvecuronium, 3-(deacetoxy)Ve 2H-pyran-6-one, 3 beta-acetoxy-5.6 beta curonium, 3-deacetylvecuronium, Org 7617, Org 7678, Org dichloromethylene-5 beta-androstan-17-one, 3,3- 7684, Org9273, and Org 9616). difluoroandrostane-17-ol acetate, 3-acetoxy-7, 15-oxido-16 oxaandrostan-17-one, 3-hydroxy-17-(1H-1,2,3-triazol-1-yl) (0192 Stanozolol analogs are described in U.S. Pat. No. androsta-5,16-diene, 3-hydroxy-5-androstane-17 3,030,358. Mesterolone analogs are described in U.S. Pat. carbonitrile, 3-hydroxyetianic acid, 3-keto-5,10-epoxy-nor No. 3,361,773. Methyltestosterone analogs are described in 19-methylandrostane-17-acetate, 4.5-epoxy-17-hydroxy-2- U.S. Pat. No. 2,374,370. methylsulfonyl-3-androstanone, 5-bromo-3,6- dihydroxyandrostan-17-one-3-acetate, amafolone, androsol Tyrphostins acetate, androstan-17-ol, androstan-3-ol, androstane-3,17 0193 In certain embodiments, a tyrophostin can be used in diol or derivatives thereof (e.g., 17-hydroxyandrostane-3- the compositions, methods, and kits of the invention. The glucuronide, 17-methyl-D-homoandrostane-3,17-diol. 2,4- tyrphostins are family of synthetic kinase inhibitors. Exem cycloandrostane-3,17-diol diacetate, plary tyrphostins include 6,7-dimethoxy-2-phenylduinoxa 3-desacetylpipecuronium, 4-ethenylideneandrostane-3,17 line, AG 127, AG 183, AG30, AG 494, AG 556, AG 879, RG diol, 4-ethenylideneandrostane-3,17-dione, androstane-2.3, 13022, RG 14620, RG 50810, RG 50864, tyrphostin 11, 17-triol, androstane-3,14-diol, androstane-3,16,17-triol, tyrphostin 23, tyrphostin 25, tyrphostin 8, tyrophostin 47. androstane-3,17-diol 17-sulfate, androstane-3,17-diol dipro tyrphostin A46, tyrphostin A51, tyrphostin A9, tyrphostin AG pionate, androstane-3,17-diol glucuronide, androstane-3,6, 1024, tyrphostin AG 1112, tyrphostin AG 1296, tyrphostin 17-triol, androstane-3,7,17-triol, androstane-3,7-diol disul AG 1478, tyrphostin AG 555, tyrphostin AG 568, tyrphostin fate), androsterone or its derivatives (e.g., 11 beta AG-490, tyrphostin AG17, tyrphostin AG879, and tyrphostin hydroxyandrosterone, 1-ketoandrosterone, 16 beta hydroxyandrosterone, 16-bromoepiandrosterone, AG957. Tyrphostins are described in U.S. Pat. Nos. 5,728, 17-hydroxy-6,6-ethylene-4-androsten-3-one, 19-hydroxy-4- 868 and 5,854,285. androsten-17-one, 3-bromoacetoxyandrostan-17-one, 3-hy droxy-4-androsten-17-one, androsterone 3-benzoate, andros Vitamin B terone 3-palmitate, androsterone glucuronide, and (0194 Vitamin B and B analogs can be used in the androsterone sulfate), BOMT, CCI 22277, dihydrotestoster compositions, methods, and kits of the invention. Vitamin one or its derviatives (e.g., 11-fluoro-19-nor-dihydro-test B, its derivatives, and its analogs are cofactors in folate osterone, 11-fluoro-dihydro-testosterone, 16-iodostanolone, enzymes and methionine synthase. 5-Deoxyadenosylcobal 17-(2-iodoethenyl)androsta-4,6-dien-17-ol-3-one, 17-(2-io amin is a cofactor required by the enzyme that converts L-me doethynyl)androsta-4,6-dien-17-ol-3-one, 17-(2-iodovinyl) thylmalonyl-CoA to Succinyl-CoA. Other vitamin Bana dihydrotestosterone, 17-hydroxyandrostan-19-ol-3-one, logs include 1.N(6)-ethenoadenosylcobalamin, 2',5'- 17-hydroxyandrostan-3-one 17-sulfate, 17-ketotrilostane, dideoxyadenosylcobalamin, 2-methyl-2-aminopropanol 17-N,N-diethylcarbamoyl-4-methyl-4-azaandrostane-3-one, B12. adeninylethylcobalamin, ambene, 17-N,N-diisopropylcarbamoyl-4-azaandrostan-3-one, aminopropylcobalamin, aquacobalamin, biofer, Co-(car 18-hydroxy-18-methyl-16, 17-methylene-D-homoandros boxymethyl)cobalamin, cob(II)alamin, cobamides (e.g., tane-3-one, 2,17-dimethyldihydrotestosterone, 2-bromo-5- (2-amino-5,6-dimethylbenzimidazolyl)cobamide, (2-hy dihydrotestosterone, 2-chloroethylnitrosocarbamoylalanine droxy-5,6-dimethylbenzimidazolyl)cobamide, 2-methyl 17-dihydrotestosterone ester, 3-hydroxyandrostan-1 6-one, sulfinyladenylcobamide, 2-methylsulfonyladenylcobamide, US 2008/O161324 A1 Jul. 3, 2008

4-cresolylcobamide, adenosylcobinamide methylphosphate, 0.197 Suitable platinum complexes may contain multiple coalpha-(alpha-5,6-dimethylbenzimidazolyl)-cobeta-cyano Pt atoms. See, e.g., U.S. Pat. Nos. 5,409,915 and 5,380,897. cobamide, cobamamide, cobamamide 5'-phosphate, cobina For example bisplatinum and triplatinum complexes of the mide, phenolylcobamide, thiobanzyme), cobyric acid, coby type: rinic acid, cobyrinic acid hexamethyl ester f-nitrile, compound 102804, cyanocobalamin-b-monocarboxylic acid, cyanocobalamin-e-monocarboxylic acid, cysteinylco balamin, factor A, factor III, ferribalamin, formylmethylco balamin, FV 82, glutathionylcobalamin, hepavis, hydroxoco balamin (e.g., nitrosocobalamin and acetatocobalamin), Jectofer compound, mecobalamin, methylcobalamine chlor palladate, nitritocobalamin, nitrosylcobalamin, proheparum, pseudovitamin B2, Sulfitocobalamin, Transcobalamins, triredisol, and vitamin B factor B. Cobamamide analogs are described in U.S. Pat. No. 3,461,114. Histone Deacetylase (HDAC) Inhibitors 0.195 Histone deacetylase inhibitors and their analogs may be used in the compositions, methods, and kits of the invention. Exemplary HDACs include CAY10433 and sub erohydroxamic acid. Histone deacetylase inhibitors are used, 0198 Exemplary platinum compounds are cisplatin, car for example, in cancer therapy, and in the treatment of inflam boplatin, oxaliplatin, and miboplatin having the structures: mation and are a group of compounds that include, for example, cyclic peptides (e.g., depsipeptides such as FK228), short chain fatty acids (e.g., phenylbutyrate and Valproic NH acid), (e.g., CI-994 and MS-27-275), and O O hydroxamic acids (e.g., Suberoylanilide hydroxamic acid NH NH (SAHA)) as described in Richon and O’Brien ((2002) Clin. O Canc. Res. 8, 662-664). Cyclic peptides and analogs useful in the invention are described, for example, in U.S. Pat. No. c-i-Nil 6,403,555. Short chain fatty acid HDAC inhibitors are C O described in, for example, U.S. Pat. Nos. 6,888,027 and Cisplatin Carboplatin 5,369,108. Benzamides analogs are described, for example, O H. H. in U.S. Pat. No. 5,137,918. Analogs of SAHA are described, O o \ for example, in U.S. Pat. No. 6.511,990. Other HDACs O.M /NH2 VsP include anacardic acid, apicidin, histone deacetylase inhibitor /N / 2 H I, histone deacetylase inhibitor II, histone deacetylase inhibi of YH O tor III, ITSA1, oxamflatin, SBHA, scriptaid, sirtinol, splito H micin, trichostatin A, and valproic acid (e.g., sodium salt). O O Any of these compounds or other HDAC inhibitors may be Oxaliplatin Milboplatin used in the compositions, methods, or kits of the invention. 0199. Other representative platinum compounds include Platinum Complexes (CPA),Pt(DOLYM) and (DACH)Pt(DOLYM) cisplatin 0196. In certain embodiments, a platinum compound can (Choi et al., Arch. Pharmacal Res. 22(2):151-156, 1999), be used in the compositions, methods, and kits of the inven Cis-(PtCl(4.7-H-5-methyl-7-oxo)1.2.4(triazolo(1.5-a)pyri tion. In general, Suitable platinum complexes may be of Pt(II) midine)) (Navarro et al., J. Med. Chem. 41(3):332-338, or Pt(IV) and have this basic structure: 1998), (Pt(cis-1,4-DACH)(trans-Cl)(CBDCA))./2MeOH cisplatin (Shamsuddin et al., Inorg. Chem. 36(25):5969 5971, 1997), 4-pyridoxate diammine hydroxy platinum (Tokunaga et al., Pharm. Sci. 3(7):353–356, 1997), Pt(II) ... Pt(II) (Pt(NHCHN(C(CH2)(CH)))) (Navarro et al., Inorg. Chem. 35(26):7829-7835, 1996), 254-S cisplatin analogue (Koga et al., Neurol. Res. 18(3):244-247, 1996), o-phenylene diamine ligand bearing cisplatin analogues (Koeckerbauer & Bednarski, J. Inorg. Biochem. 62(4):281-298, 1996), trans, wherein X and Y are anionic leaving groups such as Sulfate, cis-(Pt(OAc)(en)) (Kratochwil et al., J. Med. Chem. phosphate, carboxylate, and halogen; R and R are alkyl, 39(13):2499-2507, 1996), estrogenic 1,2-diarylethylenedi amine, amino alkyl any may be further substituted, and are amine ligand (with Sulfur-containing amino acids and glu basically inert or bridging groups. For Pt(II) complexes Z. tathione) bearing cisplatin analogues (Bednarski, J. Inorg. and Z are non-existent. For Pt(IV) Z and Z may be anionic Biochem. 62(1):75, 1996), cis-1,4-diaminocyclohexane cis groups such as halogen, hydroxy, carboxylate, ester, Sulfate platin analogues (Shamsuddin et al., J. Inorg. Biochem. 61 (4): or phosphate. See, e.g., U.S. Pat. Nos. 4,588,831 and 4.250, 291-301, 1996), 5' orientational isomer of cis-(Pt(NH)(4- 189. aminoTEMP-O) {d(GpG)}) (Dunham & Lippard, J. Am. US 2008/O161324 A1 Jul. 3, 2008 52

Chem. Soc. 117(43): 10702-12, 1995), chelating diamine 7-tetrahydroxyflavanone, 3'-prenylmaringenin, 6-(1,1-dim bearing cisplatin analogues (Koeckerbauer & Bednarski, J. ethylallyl)maringenin, 7-hydroxyflavanone, 7-O- Pharm. Sci. 84(7):819-23, 1995), 1,2-diarylethyleneamine methyleriodictyol, 8-prenylmaringenin, , BE ligand-bearing cisplatin analogues (Otto et al., J. Cancer Res. 14348D, carthamidin, desimal, eriodictyol, eriodictyol 7-glu Clin. Oncol. 121 (1): 31-8, 1995), (ethylenediamine)platinum curonide, flavanone, flemiphilippinin D, Hesperidin (e.g., (II) complexes (Pasini et al., J. Chem. Soc., Dalton Trans. Cirkan N. D., dehydro-sanol-tri, essaven, fleboplex, hespere 4:579-85, 1995), CI-973 cisplatin analogue (Yang et al., Int. J. tin, hesperetin 5-O-glucoside, hesperetin 7-O-lauryl ether, Oncol. 5(3):597-602, 1994), cis-diaminedichloroplatinum hesperidin methylchalcone, methyl hesperidin, neohesperi (II) and its analogues cis-1,1-cyclobutanedicarbosylato(2R)- din dihydrochalcone, and S5682), , maringenin, 2-methyl-1,4-butanediamineplatinum(II) and cis-diammine -6-C-glucoside, naringin, pinobanksin, pinocem (glycolato)platinum (Claycamp & Zimbrick, J. Inorg. brin, plantagoside, Scuteamoenin, Scuteamoenoside, shinfla Biochem. 26(4):257-67, 1986; Fanet al., Cancer Res. 48(11): vanone, uralenin, vexibinol, wogonin, and WS 7528. 3135-9, 1988; Heiger-Bernays et al., Biochemistry 29(36): 8461-6, 1990; Kikkawa et al., J. Exp. Clin. Cancer Res. Amorolfine 12(4):233-40, 1993; Murray et al., Biochemistry 31 (47): 11812-17, 1992: Takahashi et al., Cancer Chemother: 0201 In certain embodiments, amorolfine or an amorolf Pharmacol. 33(1): 31-5, 1993), cis-amine-cyclohexylamine ine derivative Such as benzamil can be used in the composi dichloroplatinum(II) (Yoshida et al., Biochem. Pharmacol. tions, methods, and kits of the invention. Amorolfine is an 48(4):793-9, 1994), gem-diphosphonate cisplatin analogues antifungal agent that is typically administered topically. The (FR 2683529), (meso-1,2-bis(2,6-dichloro-4-hydroxyple structure of amorolfine is: nyl)ethylenediamine) dichloroplatinum(II) (Bednarski et al., J. Med. Chem. 35(23):4479-85, 1992), cisplatin analogues containing a tethered dansyl group (Hartwig et al., J. Am. Chem. Soc. 114(21):8292-3, 1992), platinum(II) polyamines (Siegmann et al., Inorg. Met.-Containing Polym. Mater. (Proc. Am. Chem. Soc. Int. Symp.), 335-61, 1990), cis-(3H) r dichloro(ethylenediamine)platinum(II) (Eastman, Anal. Bio N chem. 197(2):311-15, 1991), trans-diamminedichloroplati num(II) and cis-(Pt(NH)-(N-)Cl) (Bellon & Lippard, Biophys. Chem. 35(2-3): 179-88, 1990), 3H-cis-1,2- Analogs of amorolfine are described, for example, in U.S. diaminocyclohexanedichloroplatinum(II) and 3H-cis-1,2-di Pat. No. 4,202,894 and have the general structure: aminocyclohexanemalonatoplatinum (II) (Oswald et al., Res. Commun. Chem. Pathol. Pharmacol. 64(1): 41-58, 1989), diaminocarboxylatoplatinum (EPA 296321), trans-(D, 1)-1, R4 Rs 2-diaminocyclohexane carrier ligand-bearing platinum ana R Xy. logues (Wyrick & Chaney, J. Labelled Compa. Radiopharm. 25(4): 349-57, 1988), aminoalkylaminoanthraquinone-de rived cisplatin analogues (Kitov et al., Eur: J. Med. Chem. 23(4): 381-3, 1988), spiroplatin, carboplatin, iproplatin and R R3 JM40 platinum analogues (Schroyen et al., Eur: J. Cancer Clin. Oncol. 24(8): 1309-12, 1988), bidentate tertiary diamine-containing cisplatinum derivatives (Orbell et al., wherein R is alkyl of 4 to 12 carbon atoms, cycloalkyl of 3 to Inorg. Chim. Acta 152(2):125-34, 1988), platinum(II), plati 7 carbon atoms, mono(lower alkyl)-substituted cycloalkyl of num(IV) (Liu & Wang, Shandong Yike Daxue Xuebao 24(1): 4 to 7 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, 35-41, 1986), cis-diammine(1,1-cyclobutanedicarboxylato-) phenyl or aryl-(lower alkyl) of 7 to 12 carbon atoms; R. R. platinum(II) (carboplatin, JM8) and ethylenediammine and R, independently, are hydrogen or alkyl of 1 to 8 carbon malonatoplatinum(II) (JM40) (Begg et al., Radiother. Oncol. atoms; R. Rs, and R, independently, are hydrogen or alkyl 9(2): 157-65, 1987), JM8 and JM9 cisplatin analogues (Har of 1 to 8 carbonatoms, and two of R. Rs, and R can each be strick et al., Int. J. Androl. 10(1): 139-45, 1987), (NPr"), bonded to the same carbon atom or together can form a fused ((PtCL).cis-(PtCl2 (NHMe))) (Brammer et al., J. Chem. alicyclic or aromatic 6-membered ring; provided that when R Soc., Chem. Commun. 6:443-5, 1987), aliphatic tricarboxylic is tert-butyl, at least one of R and R is alkyl of 2 to 8 carbon acid platinum complexes (EPA 185225), and cis-dichloro atoms or R is hydrogen or alkyl of 2 to 8 carbon atoms or at (amino acid) (tert-butylamine)platinum(II) complexes least one of R. Rs, and R is alkyl of 5 to 8 carbon atoms: X (Pasini & Bersanetti, Inorg. Chim. Acta 107(4):259-67, is methylene oran oxygen atom; Z is Zero or 1 and the dotted 1985). Oxaliplatin analogs are described in U.S. Pat. Nos. bonds can be hydrogenated, and acid addition salts of those 4,169,846, 5,290,961, 5,298,642, and 6,153,646. Satraplatin compounds of formula I which are basic, where the term is described in Choy, Expert Rev. Anticancer Ther. 6(7):973 “lower alkyl denotes a straight-chain or branched-chain 982, 2006). These compounds are thought to function by hydrocarbon group of 1 to 4 carbon atoms, such as, methyl, binding to DNA, i.e., acting as alkylating agents of DNA. ethyl, propyl, isopropyl, butyl, isobutyl and tert.-butyl. Alkyl groups of4 to 12 carbonatoms are straight-chain or branched chain hydrocarbon groups, for example, butyl, isobutyl, tert.- Flavanones butyl, neopentyl, 1,1-dimethylpropyl, 1,1-dimethylpentyl, 0200. In certain embodiments, a flavanone can be used in 1,1-diethylpropyl, 1,1-dimethylbutyl, 1-isopropyl-3-methyl the compositions, methods, and kits of the invention. Exem but-1-yl, 1-ethyl-1-methylbutyl, dodecyl, and the like. plary flavanones include 2-hydroxyflavanone, 137 L, 2',3,5, Cycloalkylalkyls include, in particular, those groups in which US 2008/O161324 A1 Jul. 3, 2008 the alkyl moiety is branched. The term “aryl-(lower alkyl) (2-naphthyl)-6-pyridazine, mosapride, N,N'-dicyclohexyl 4-mo NAREIGine N-(4-benzyl-2-morpholinyl) includes not only groups which are mono- or di(lower alkyl)- methyl)-5-chloro-4-(dimethylamino)-2-methoxybenzamide, Substituted in the aryl ring but also groups which are mono- or N-(3.N'-morpholinopropyl)-2-(3-nitropyrrolo-(2,3-b)pyri di(lower alkyl)-substituted in the lower alkyl moiety. Exem dine-1-yl)ethanoic acid amide, N-(3-nitro-4-quinoline)mor plary of aryl(lower alkyl) groups are benzyl, phenylethyl, pholino-4-carboxamidine, N-dodecylmorpholine, N-ethyl morpholine, N-hexylmorpholine-2',5'-oligoadenylate, (lower alkyl)-benzyl, for example, methylbenzyl and dimeth N-nitromorpholine, N-oxydiethylene-2- Sulfe ylbenzyl, naphthylmethyl 2-phenyl-propan-2-yl, 1-phenyl namide, O-(N-morpholinocarbonyl)-3-phenyllacetic acid, 1-ethyl, or the like. , oxymorphindole, P 1487, P34081, PD 132002, phendimetrazine, Phenmetrazine, phenyl 2-(2-N-morpholi 0202 Amorolfine is a member of the morpholines, which noethoxy)phenyl ether, pholcodine, phosphorodiamidate include ((2-azido-4-benzyl)phenoxy)-N-ethylmorpholine, morpholino oligomer, pinaverium, pramoxine, proctofoam (+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid, (morpholi HC, promolate, RE 102, , Ro 12-5637, Ro nyl-2-methoxy)-8-tetrahydro-1,2,3,4-quinoline, 1,1'-hexam 12-8095, RS 1893, RV 538, S 12024, S 14001, S-anisylfor ethylenebis(3-cyclohexyl-3-((cyclohexylimino)(4-mor mamidino-4-(N-methylisothioamide)morpholine, S-phen pholinyl)methyl)urea), 1,4-bis(3'-morpholinopropyl-1-yl ethylformamidino-4-(N-ethylisothioamide)morpholine, SC 1)benzene, 1,4-thiomorpholine-3,5-dicarboxylic acid, 1,4- 46944, Seda-Miroton, silatiemonium iodide, SIN IC, SR thiomorpholine-3-carboxylic acid, 1-(morpholinomethyl)-4- 121463A, Stymulen, sufoxazine, teomorfolin, theniloxazine, phthalimidopiperidine-2,6-dione, 1-deoxy-1-morpholino thiamorpholine, , tiemonium methylsul psicose, 1-deoxy-1-morpholinofructose, 1-phenyl-2,3- fate, tridemorph, trifenmorph, trimetozine, trimorfamid, dimethyl-4-naphthalanmorpholinomethylpyrazolin-5-one, trithiozine, TVX 2656, U 37883A, U 84569, U 86983, UP 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol. 2.6- 614-04, , Win 55212-2, and YM21095. bis(carboxymethyl)-4,4-dimethylmorpholinium, 2,6-dim Andrographis ethylmorpholine, 2,6-dioxo-N-(carboxymethyl)morpholine, 2-(((3-(morpholinylmethyl)-2H-chromen-8-yl)oxy)methyl) 0203. In certain embodiments, andrographis, or an extract morpholine, 2-(3-trifluoromethyl)phenyltetrahydro-1,4-ox or component thereof, can be used in the compositions, meth azine, 2-(4-morpholino)ethyl-1-phenylcyclohexane-1-car ods, and kits of the invention. Andographis paniculata is boxylate, 2-(4-morpholino-6-propyl-1,3,5-triazin-2-yl) medicinal herb, which has been used as an antipyretic, an aminoethanol. 2-(4-morpholinyl)-4H-1-benzopyran-4-one, anti-inflammatory agent, and a liver protectant. It also is 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one, 2-(4- reported to have anticancer and antiviral (e.g., anti-HCV and nitrophenyl)-4-isopropylmorpholine, 2-(morpholin-4-yl) anti-HIV) properties. The primary active agent in androgra benzo(h)chromen-4-one, 2-(N-methylmorpholinium)ethyl phis is andrographolide. The structure of andrographolide is: acetate, 2-(N-morpholino)ethanesulfonic acid, 2-benzylmor pholine, 2-hydroxy-4,4-dimethyl-2-(4-tolyl)morpholinium, O 2-methyl-3-(2-methyl-2,3-diphenyl-4-morpholinyl)-1-phe nyl-1-propanone, 2-morpholinomethyl-2',3',4'-trimethoxy acrylophenone, 2-n-pentyloxy-2-phenyl-4-methylmorpho line, 2-phenyl-5,5-dimethyltetrahydro-1,4-oxazine, 2-thiomorpholinoethylacrylamide, 3.5.5-trimethyl-2-mor

pholinon-3-yl radical dimer, 3-((benzyloxy)methyl)morpho line, 3-(beta-morpholinoethoxy)-1H-indazole, 3-cyano-2- morpholino-5-(pyrid-4-yl)pyridine, 3-thiomorpholinopropylacrylamide, 4,4'-dithiodimorpho line, 4.4-methylenedimorpholine, 4-(2-morpholinoethoxy) HO benzophenone, 4-(3,7,11,15-tetramethyl-6,10,14-hexadec atrienoyl)morpholine, 4-amino-5-chloro-2-ethoxy-N-((2- OH morpholinyl)methyl), 4-amino-N-(4-benzyl-2- Andrographolide analogs are described, for example, in U.S. morpholinyl)-methyl)-5-chloro-2-ethoxybenzamide, 4-amino-N-(4-benzyl-2-morpholinyl)methyl)-5-chloro-2- Pat. Application Publication No. 2006/0223785 and have the methoxybenzamide, 4-benzylphenoxy-N-ethylmorpholine, general structure: 4-cyclododecyl-2,6-dimethylmorpholine acetate, 4-methox yphenyl-(5-methyl-6-(2-(4-morpholinyl)ethyl)-6H-thieno (2,3-b)pyrrol-4-yl)phenylmethanone, 4-methylmorpholine, O 4-methylmorpholine N-oxide, 4-morpholinedithiocarbam W ate, 4-morpholinocarbonitrile, 5-pentyl-N-nitrosomorpho x1"'YB, N O line. A 74273, AH 19437, aprepitant, AWD 140076, befol. BIBW 22, bis(3,5-dimethyl-5-hydroxymethyl-2-oxomor pholin-3-yl), BW 175, cetethyl morpholinium, CGP 53437, CI1033, ciclosidomine, CNK 6001, CNK 6004, CP80794, CP 84364, CS 722, delmopinol, detensitral, Dextromora mide, di-beta-(morpholinoethyl)selenide, dimethomorph, dimethyl morpholinophosphoramidate, dimorpholamine, ES W 6864, ES 8891, fempropimorph, filenadol, FK 906, fomi x1 B noben, FR 76830, Go 8288, GYKI 11679, indeloxazine, L 689502, L 742694, L 760735, , lateritin, M&B 16573, MDL 101146, MF 268, mofarotene, Molsidomine, B morfolep. Moricizine, morlincain, moroxybrate, moroxy w2 dine, morpholine, morpholineoethylamino-3-benzocyclo / hepta(5.6-c)pyridazine, morpholinoamidine, morpholino X2 phosphordichloridite, morpholinopropane Sulfonic acid, morpholinosulfonic acid, morpholinylethoxy-3-methyl-4- US 2008/O161324 A1 Jul. 3, 2008 54 or its cis isomer, or its pharmaceutically acceptable salt, ester, 0207. In one embodiment of the above formula, at least salt of an ester or prodrug, wherein: B, B and B are inde One R, R2, Rs. R4 Rs. R. R-7, Rs. Ro, Rio. R11, R12, R1s. R4, pendently CRR, C(Y), O, NR, PRs. P(=Y)R. P(—Y.) R1s. R16. R17, R1s. R19. R20. R21. R22. R2s. R24. R2s. R26. R27. S(=Y), a spacer group or a covalent bond; and k can be R2s, Rao, Rao, Rs and R-2 is selected from an alkyl, aryl, 0, 1 or 2; and W. W. and W are independently CRRs. CR heteroaryl or heteroaromatic ring. C,C(Y5), O, NRio, PR, P(=Y)R2, P(=Y), S(=Ys), or 0208. In one embodiment of the above formula, at least a covalent bond; and f can be 0, 1 or 2; or B. W. B. W. One R, R2, Rs. R4 Rs. R. R-7, Rs. Ro, Rio. R11, R12, R1s. R4, and/or B. W. are independently CR =CR or C=C; and R1s. R16. R17, R1s. R19. R20. R21. R22. R2s. R24. R2s. R26. R27. X, X and X are independently hydrogen, CRRoRo R2s, Rao, Rao, Rs and R-2 is independently selected from C=RR, C=Rs, C=N, C(=Y)R, ORs, NR-R-7, alkyl, nitro, a phosphate, a Sulfate, a thiol, and an amine. N=NRs, P(=Y),(R)V. S(=Y) (R), or NO; and d can be 0, 1 or 2; and V can be 0, 1 or 2; and i can be Arbidol independently 0 or 1; and Y.Y.Y. Ya, Ys, Y, Y, Ys, Y, 0209. In certain embodiments, arbidol or an analog Yo, and Y are independently O, S, or NZ; and Z can be thereof can be used in the compositions, methods, and kits of independently hydrogen, R, OR, SRs or NRR, and the invention. Aribdol is an antiviral that has anti-influenza R. R2, Rs. R4, Rs. R6. . Rs. R9. Rio. R11, R12. R1s. R14. activity and functions by inhibition of the fusion of influenza R1s. R16, R17, Ris, Ris, R19, R20 R2, R22, R23, R24. R2s, R26. A and B viruses within endosomes. The structure of arbidol R27, R-2s, Rao, Rao, Rs and R-2 are independently hydrogen, is: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalky nyl, aryl, alkaryl, arylalkyl, heterocyclic, heteroaromatic, acyl, , carbamide, alkoxy, amino, halogen, silyl, thiol, Sulfoxy, Sulfinyl, Sulfamoyl, hydroxyl, ester, carboxylic acid, amide, nitro, cyano, phosphonyl, phosphinyl, phospho ryl, imide, thioester, ether, acid halide, oxime, carbamate, thioether, residue of a natural or synthetic amino acid or a OH carbohydrate, any of which can be optionally attached to the targeting moiety or oxygen radical through a spacer group; or alternatively, R, R2, R. R. Rs. R. R-7, Rs. Ro, Rio R, R2, R13, R14, R1s. R16, R17, Ris. Ris, R19, R20. R2, R22, R23, R24. R2s, R26, R27, R2s, R29, Rao, Rs 1 and R32 can individually come together to form a bridged compound comprising of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalky Arbidol is typically administered orally. nyl, aryl, alkaryl, aryl alkyl, heterocyclic, heteroaromatic, Artemisinins acyl, carbamide, alkoxy, amino, halogen, silyl, thiol, Sulfinyl, 0210. In certain embodiments, artemisinin or an analog Sulfamoyl, ester, amide, phosphonyl, phosphinyl, phospho thereof can be used in the compositions, methods, and kits of ryl, imide, thioester, ether, oXime, carbamate, thioether, resi the invention. The artemeisins are a family of compounds that due of a natural or synthetic amino acidora carbohydrate, any include antimalarials such as artemisinin and artemether, a of which can be optionally attached to the targeting moiety or semi-synthetic derivative of artemisinin. The structure of oxygen radical through a spacer group; and each carbonatom artemisinin is: cannot be covalently bound to more than two heteroatoms; and wherein each B, W and X cannot be all heteroatom moieties unless B, W and X are all nitrogen based or Band X are independently O or N and W is PR, POR POS(Y), H and m is 1 or 2; and wherein each Band WorW and X cannot both be of the general formula C(Y), POR PO, S(=Y), and t is 1 or 2. 0204. In one Subembodiment of formula I, B, B, and B. are independently CRR, C(Y), O, or a covalent bond; W. W, and W are independently CRRs, CR. C. C(Ys), O, or a covalent bond; and X, X and X are independently hydro gen, CRRoRo CERR-. C=R. In one Subembodi ment of formula I, at least one of B. B., and B and at least one W. W., and W is a covalent bond and at least one X, X and X is hydrogen. 0211. The structure of artemether is: 0205. In another embodiment of the above formula, at least one R. R2, Rs. R4, Rs. R6. R7. Rs. R9. Rio. R ls R12. Ris. R14 Ris, R16, R17, Ris, R19, R20 R2, R22, R23, R24. R2s, R26. R27, R-2s, Rao, Rao, Rs 1, and R-2 is selected from an aliphatic, saturated or unsaturated alkyl, alkenyl or alkynyl. In one Subembodiment, the alkyl, alkenyl or alkynyl groups are Sub stituted, and can be halogen Substituted. 0206. In one embodiment of the above formula, at least One R, R2, R. R. Rs. R. R-7, Rs. Ro, Rio R, R2, R. R. R1s. R16. R17, R1s. R19. R20. R21. R22. R2s. R24. R2sm R26. R7, Rs. Ro Ro R and R is selected from a carbonyl containing groups, including, but not limited to, aldehyde, OCH ketone, carboxylic acid, ester, amide, enone, acyl chloride or anhydride. US 2008/O161324 A1 Jul. 3, 2008 55

0212 The structure of artesunate is: 0215. The structure of benzamil is:

O NH C N ls n N N H H 2 HN N NH2

Amiloride derivatives are described, for example, in U.S. Pat. No. 3,313,813 and can be represented by the following for OH mula:

O NR Other artemisinins include 3-hydroxydeoxyartemisinin, C-propoxycarbonyldihydroartemisine, arteannuin B, X Nn N l -R, arteether, arteflene, artelinic acid, artemether, artemisic acid, H artemisin, artemisinin B, artemisinine, artemisitene, artesu 2 R3 nate, artesunic acid, deoxoartemisinin, deoxyartemisinin, Y N Amino and dihydroquinghaosu. The active metabolite of artemisi nins is dihydroartemisinin. where X represents hydrogen, a halogen or halogen-like radi cal. Such as, chloro, bromo, iodo or trifluoromethyl, or a Benoximate lower-alkyl, lower-cycloalkyl, mononuclear aryl, either 0213. In certain embodiments, procaine or a derivative unsubstituted or Substituted, advantageously with a halogen thereof Such as benoxiante can be used in the compositions, especially a chloro or bromo Substituent, animo, Z-thio or methods, and kits of the invention. Benoximate is an anes Z-sulfonyl wherein Z is lower alkyl or phenyl-lower alkyl: Y thetic agent. The structure of benoximate is: represents hydrogen, hydroxyl or mercapto, lower alkoxy or lower alkyl-thio, halogen, especially chlorine, lower-alkyl, lower-cycloalkyl, mononuclear aryl, especially phenyl or amino, advantageously having the structure NRR, wherein R O and R1 can be similar or dissimilar radicals and respectively represent hydrogen, amino or mono-ordi-lower-alkylamino, (advantageously forming a hydrazino group at the 5-position carbon), lower alkoxy, Y represents Substituted amino, -- coNH2 —NRR, where RandR represent lower alkyl either straight or branched chain or cyclic (3- to 6-membered rings) and either unsubstituted or containing one or more Substituents Benoximate is a procaine derivative. Other procaine deriva Such as hydroxyl, halogen (chlorine, bromine, fluorine and tives include 4-bromoacetamidoprocaine, analgesin, aslavi the like), a cycloalkyl substituent having 3 to 6 carbons in the tal, benoximate, bivelin, Cardioplegin, celnovocaine, chloro cycloalkyl structure, an aryl substituent preferably phenyl or procaine, efatin, Fluress, Impletol, impletol depot Bayer, Substituted phenyl such as lower-alkyl-phenyl and halophe N,N-diethylaminoethyl(2-N-methyl)benzoate, N-acetylp nyl as chlorophenyl, bromophenyl, fluorophenyl, and the like, rocaine, nicotinoylprocaine, novdimal, G, or a heterocyclic Substituent especially furyl, pyridyl, and Procaine, procaine acryloyl polymer, procaine azide, (CH),N- wherein n is one of the numerals 4 through 6, or procaine , Renovaine, Sulfocamphocaine, Tar an amino Substituent as the unsubstituted amino, or mono- or domyocel compound, and turigeran. dillower-alkyl amino, and when R and R each represents a lower alkyl, the lower alkyl groups can be linked together to form a cyclic structure with the nitrogen atom to which they are attached, particularly a 5- to 8-membered ring, advanta 0214. In certain embodiments, amiloride or an analog geously forming with the nitrogen atom a 1-pyrrolidinyl, thereof Such as benzamil can be used in the compositions, piperidino, hexahydro-1-azepinyl, or octahydro-1-azocinyl methods, and kits of the invention. Amiloride is a diuretic radical and the like, Y represents substituted amino, —NRR, agent. The structure of amiloride is: where RandR represent lower alkenyl, aryl, advantageously an unsubstituted or substituted phenyl, wherein the substitu O NH ent(s) are preferably halogen (chlorine, bromine, fluorine) or lower alkyl (methyl, ethyl, propyl, iso-propyl) and the like, C N ls amidino or substituted amidino, especially an N,N-di-lower n N NH2 H alkyl-imidino, such as N,N-dimethylamidino: X and Y, in 2 addition, can be linked together to form a 4-membered carbon HN N NH2 chain that can be either unsaturated or Saturated and that can be unsubstituted or substituted, and if substituted the substitu ent advantageously is a halogen, especially a chloro-atom. R US 2008/O161324 A1 Jul. 3, 2008 56 represents hydrogen and lower alkyl, R represents hydrogen, bellataminal, Bellergal, beta-ergoptine, Bromocriptine, dihy lower alkyl, either saturated or unsaturated and substituted or droergocornine, dihydroergocristine, , unsubstituted, the Substituent group(s) preferably being dihydroergotamine, dihydroergotoxine, ergosine, ergota hydroxyl, aryl, either mono- or di-nuclear aryl, as phenyl or mine, ergovaline, and neo-Secatropin. naphthyl, and either unsubstituted or containing one or more Chlorophyllin substituents, especially selected from lower alkyl, definition 0218. In certain embodiments, a chlorophyllide oranana of substituents, continued Substituents on aryl moiety of aryl log thereof can be used in the compositions, methods, and kits alkyl group halogen, lower alkyl, lower alkoxy, or any com of the invention. Chlorophyllin is a derivative of chlorophyl, bination of these Substituent groups, mono- or di-lower-alky and a member of the chlorophyllides. Other chlorophyllides lamino, wherein the alkyl groups may be linked to form a include chlorophyllide a, chlorophyllide b, methylchloro hetero structure with the aminonitrogen to which they are phyllide A, and methylchlorophyllide B. attached Such as to form an azacycloalkyl group, heterocy clic, and especially the pyridyl group, halogen, aryl or Sub Cytarabine stituted aryl, the Substituent group(s) preferably being halo 0219. In certain embodiments, cytarabine or an analog gen, and lower alkyl, heterocyclic, advantageously a pyridyl thereof can be used in the compositions, methods, and kits of radical, alkylideneamino, and acyl: R represents hydrogen, the invention. Cytarabine is an antimetabolic and an antiviral lower alkyl, either saturated or unsaturated and substituted or agent. Cytarabine analogs are described in U.S. Pat. No. unsubstituted as described above for R or R and R can be 3,116,282. lower alkyl groups linked directly together or through a het Thyroxines ero atom, especially through oxygen or nitrogen to produce a 5 to 8 membered cyclic structure, thus forming with the 0220. In certain embodiments, a thyroxine or derivative nitrogen atom to which they are attached a 1-pyrrolidinyl, thereof can be used in the compositions, methods, and kits of piperidino. 1-piperazinyl, especially a 4-lower alkyl-1-piper the invention. Thyroxines are thyroid horomones and include azinyl or morpholino, and the like radicals; and when R and levo thyroxine and dextrothyroxine, which has been used as R (or Ra) each represents a lower alkyl, they can be linked antihyperlipidemic. The formula for dextrthyroxine is: together to form a cyclic structure with the nitrogen atoms to which they are attached, particularly to form a 2-(2-imida Zolinyl) radical. The 3-position amino group can be an unsub stituted amino as well as mono- or di-Substituted amino HO groups, the Substituent(s) advantageously being lower alkyl and lower alkanoyland also where the substituents are linked to form a heterocyclic structure with the amino nitrogen to which they are attached. 0216 Amiloride derivatives include 2',4'-dichloroben Zamil amiloride, 2',4'-dimethylbenzamil, 2-methoxy-5'-ni trobenzamil, 2-chlorobenzylamiloride, 3',4'-dichloroben Dextrathyroxine can be administered orally and is typically Zamil, 3,5-diamino-6-fluoro-2-pyrazinoylguanidine, 3.5- provided in 2 mg or 4 mg tablets. Levothyroxine is used to diamino-N-(aminoiminomethyl)-6-bromopyrazine-N- increase the metabolic rate of cells. methylcarboxamide, 4-(((((3,5-diamino-6-chloropyrazinyl) carbonyl)amino)iminomethyl)amino)-2.2.6.6-tetramethyl Pregnadienes 1-piperidinyloxy, 5,6-dichloroamiloride, 5-(ethylpropyl) 0221. In certain embodiments, a pregnadiene or an analog amiloride, 5-(N.N-hexamethylene)amiloride, 5-(N-2'-(4"- or derivative thereof Such as dydrogesterone can be used in azidosalicylamidino)ethyl-N'-isopropyl)amiloride, S (N- the compositions, methods, and kits of the invention. 2'-aminoethyl-N'-isopropyl)amiloride-N-(4"- Dydrogesterone is a progesterone and used thus to treat azidosalicylamide), 5-(N-4-chlorobenzyl)-N-(2',4'- progesterone deficiency. Pregnadienes include 12-hydroxy dimethyl)benzamil, 5-(N-butyl-N-methyl)amiloride, 5-(N- 3-oxo-1,4-pregnadiene-20-carboxylic acid, 17-benzoyloxy ethyl-(2-methoxy-5'-nitrobenzyl))amiloride, 5-(N-methyl 11-hydroxy-320-dioxo-1,4-pregnadien-21-al hemiacetal, N-isobutyl)amiloride, 5-(N-methyl-N-propyl)amiloride, 20-carboxy-14-pregnadien-3-one, 20-Succinamylpregna-1, 5-(N-propyl-N-butyl)-2',4'-dichlorobenzamil amiloride, 4-dien-3-one, 21-hydroxypregna-1,4-diene-3,11,20-trione, 3 5-(N-tert-butyl)amiloride, 5-diethylamiloride, 5-dimethy alpha-hydroxy-5 alpha-pregna-9(11), 16-diene-20-one, lamiloride, 5-N-(3-aminophenyl)amiloride, 5H-amiloride, 3-hydroxy-5.7-pregnadien-20-one, canrenoate potassium, 6-bromoamiloride, 6-bromobenzamil, 6-chloro-3,5-diami , , cymegesolate, cyproter nopyrazine-3-carboxamide, 6-iodoamiloride, alpha'.2'-ben one, , domoprednate, , GR Zobenzamil, amiloride caproate, benzamil, co-amilozide, 2-1159, icometasone enbutate, medrogestone, megestrol, Esmalorid, ethylisopropylamiloride, frumil, kalten, methyl melengestrol acetate, nivaZol, oxyma, pregnadienediols, isopropylamiloride, moducrin, N(5)-piperazine-amiloride, pregnadienetriols, rimexolone, Ro 12-2503, Ro 14-9012, Ro N(5)-piperidine-amiloride, phenylamil, and uranidil A. 6-1963, and triamcinolone. Evans Blue Alkaloids 0222. In certain embodiments, a azo dye such as Evans 0217. In certain embodiments, ergotamine alkaloids such blue can be used in the compositions, methods, and kits of the as bromocriptine, can be used in the compositions, methods, invention. Evans blue is used in blood volume and cardiac and kits of the invention. Bromocriptin analogs are described, output measurement by the dye dilution method. It is very for example, in U.S. Pat. No. 4,145.549. Ergotamine alka soluble, strongly bound to plasma albumin. The structure of liods include 1-methylergotamine, 9,10-dihydroergosine, Evans blue is: US 2008/O161324 A1 Jul. 3, 2008 57

O. NH2 Q OQ M /S 21 N NN 4 Na"

o==oO

AZetidines OR —O(CH), OR —O(CO)NRR, NRR, NR 0223. In certain embodiments, an azetidine or derivative (CO)R - NR(CO)OR - NR (CO)NRRs, NR thereof Such as eZitamibe can be used in the compositions, SOR, COOR —CONRR-7, COR. —SONRR, methods, and kits of the invention. The structure of eZitamibe S(O)o-Ro. —O(CH). COOR, —O(CH). is: 10CONRR, -(lower alkylene)COOR, -CH=CH COOR —CF, —CN, NO, and halogen; Rs is 1-5 sub stituents independently selected from the group consisting of

—O(CH) COOR —O(CH) CONRR, -(lower alkylene)COOR, and CH=CH-COOR. R. R., and Rs are independently selected from the group consisting of hydrogen, lower alkyl, aryland aryl-substituted lower alkyl; and R is lower alkyl, aryl or aryl-substituted lower alkyl. R. is preferably 1-3 independently selected substituents, and Rs is preferably 1-3 independently selected substituents. Pre Analogs of eZitamibe are described, for example, in U.S. Pat. ferred are compounds of formula I wherein Ar is phenyl or No. 5,767,115 and are described by the formula: R-substituted phenyl, especially (4-R)-substituted phenyl. Ar, is preferably phenyl or R-substituted phenyl, especially (4-R)-substituted phenyl. Ars is preferably Rs-substituted X R Air 1 m n 1n N - Ap 3 phenyl, especially (4-Rs)-substituted phenyl. When Art is Ar '' g (4-R)-substituted phenyl, R is preferably a halogen. When R R3 N Ar, and Ars are Ra- and Rs-substituted phenyl, respectively, N R, is preferably halogen or OR and Rs is preferably O Ar2 —OR, wherein R is lower alkyl or hydrogen. Especially preferred are compounds wherein each of Ar and Ar is where Ar and Arare independently selected from the group 4-fluorophenyl and Ars is 4-hydroxyphenyl or 4-methox consisting of aryl and R-substituted aryl; A is aryl or yphenyl. R-substituted aryl; X, Y and Z are independently selected 0224. Other azetidines include 1,4-bis(4-methoxyphe from the group consisting of —CH2—, —CH(lower alkyl)- nyl)-3-(3-phenylpropyl)-2-azetidinone, 1-(N-(3-ammonio and —C(dillower alkyl)-; RandR are independently selected propyl)-N-(n-propyl)amino)diazen-1-ium-1,2-diolate, from the group consisting of —OR —O(CO)R —O(CO) 1-methyl-2-(3-pyridyl)azetidine, 2-oxo-3-phenyl-1,3-oxaze OR and —O(CO)NR, R.; R and R are independently tidine, 2-tetradecylglycidyl-coenzyme A, 3-(2-oxopropy selected from the group consisting of hydrogen, lower alkyl lidene)aZetidin-2-one, 3-aminonocardicinic acid, 3-phenyl and aryl; q is 0 or 1, r is 0 or 1; m, n and pare independently 2-methylazetidine-3-ol, 4-((4-carboxyphenyl)oxy)-3.3- 0, 1, 2, 3 or 4: provided that at least one of q and r is 1, and the diethyl-1-(((phenylmethyl)amino)carbonyl)-2-aZetidinone, Sum of m, n, p, q and r is 1, 2, 3, 4, 5 or 6; and provided that 4-(3-amino-2-oxoaZetidinonyl-1)methylbenzoic acid, 4-(3- when p is 0 and r is 1, the sum of m, q and n is 1, 2, 3, 4 or 5: amino-2-oxoaZetidinonyl-1)methylcyclohexanecarboxylic R is 1-5 substituents independently selected from the group acid, AHR 11748, azetidine, azetidine platinum(II), azetidi consisting of lower alkyl, —OR —O(CO)R —O(CO) necarboxylic acid, aZetidyl-2-carboxylic acid, azetirelin, US 2008/O161324 A1 Jul. 3, 2008

BDF 91.48, BMS-262084, E 4695, fluzinamide, L 652117, L GW 5074 684248, N-(2-chloromethylphenyl)-3,3-difluoroazetidin-2- 0228. In certain embodiments, GW 5074 or an analog one, SCH 60663, SF 2185, tabtoxinine beta-lactam, tazad thereof can be used in the compositions, methods, and kits of olene Succinate, and Ximelagatran. the invention. GW 5074 is a benzylidene-1,3-dihydro-indol 2-one derivative which acts as a receptor kinase Thioxanthanes inhibitor (e.g., raf, such as cRafi). The structure of GW 5074 0225. In certain embodiments, thioxanthanes such as flu 1S pentiXol can be used in the compositions, methods, and kits of the invention. FlupentiXol is a that acts as a (D2 receptor) antagonist. Thioxanthane analogs are described, for example, in U.S. Pat. No.3,951,961. Thiox anthane analogs include 2-(beta-diethylaminoethylamino)-3, 4-cyclohexenothia-Xanthone, 2-chlorothioxanthen-9-one, 2-, 3-carboxy-thioxanthone-10,10-dioxide, 4-(beta-diethylaminoethylamino)-1,2-cyclohexenothiaxan thone, 4-(bis(2-chloroethyl)amino)propylamino-1,2-cyclo hexenothioxanthone, 7-oxo-7-thiomethoxyxanthone-2-car boxylic acid, BW 616U76, chlorprothixene, clopenthixol, doxantrazole, flupenthixol, hycanthone, lucanthone, methix ene, piflutiXol, , prothixene, quantacure QTX, spasmocanulase, teflutixol, thiothixene, and WIN 33377. Analogs of GW 5074 are described, for example, in U.S. Pat. Gemcitabine No. 6,268.391 and have the general structure:

0226. In certain embodiments, gemcitabine or an analog thereof can be used in the compositions, methods, and kits of the invention. Gemcitabine is a with antineoplas tic activity. 0227 Analogs of gemcitabine are described, for example, in U.S. Pat. No. 4,808.614 and have the general structure:

HO R.

OH F wherein R is H or optionally joined with R to form a fused ring selected from the group consisting of five to ten mem bered aryl, heteroaryl or heterocyclyl rings, said heteroaryl or wherein R is a base of one of the formulae: said heterocyclyl rings having one to three heteroatoms where Zero to three of said heteroatoms are N and Zero to 1 of said heteroatoms are O or Sand where said fused ring is optionally substituted by one to three of Ro, where R and R are as defined below; RandR are independently H, HET, aryl, C. aliphatic, CN, NO, halogen, Rio —OR —SRio —S(O) Ro. —SO-Ro. —NRoR = NR, R2, —NRCOR, —NRCOR. - NRCONRR - NRSOR, —NRC(NR)NHR, —COR, COR — NRRCONR,2R, where -SO2NR2R said Caliphatic - OCONRR, optionally bears C(NR) one or NH2 NH2 two insertions of one to two groups selected from C(O), O, S, S(O), SO, or NR; with said HET, aryl or Caliphatic HN R1, N N and being optionally substituted by one to three of Rio; and where R is optionally joined with R to form a fused ring selected ly from the group consisting of five to ten membered aryl, het 1s, 4. eroaryl or heterocyclyl rings, said heteroaryl or said hetero cyclyl rings having Zero to three heteroatoms where Zero to l three of said heteroatoms are N and Zero to one of said heteroatoms are O or Sand where said fused ring is optionally substituted by one to three of R, where HET, R. R. R. and N21 ScHR, Rare as defined below; R is H, halogen, NO or CN; Rs is H or Caliphatic optionally substituted by one to three of halo, hydroxyl, heteroaryl, or aryl; R and R, are indepen dently halogen, CN, NO. —CONRR, SO, NRoR, —NRoR, or —OR, where Ro and R are as defined below: R is OH, NHSOR or NHCOCF. R is each inde wherein R is hydrogen, methyl, bromo, fluoro, chloro, or pendently halogen, Caliphatic, CN, —NO, Rio —OR, iodo; R is hydroxy oramino; R is hydrogen, bromo, chloro, —SR —S(O)R. —SOR —NRR, —NR, or iodo. —NRCOR. - NRCOR. - NRCONRR, US 2008/O161324 A1 Jul. 3, 2008 59

—NRSOR NRC(NR)NHR, —COR, wherein R is hydrogen, a C-C alkoxycarbonyl, benzyloxy —CONRR, —SONRR, —OCONRR or carbonyl, a heteroaryl(C-C)alkyl in which the heteroaryl is C(NR)NRR, where R. R. and R are as defined furyl, thienyl, pyridyl, or 1,2-benzisoxazolyl, a phenyl (C- below; Rio is each independently H, halogen, Caliphatic, Cs)alkenyl, or -T-(Y), R (wherein T is a single bond or a aryl or HET, where said Caliphatic optionally bears an C-C alkylene, Y is oxygen, sulfur or carbonyl, R is phenyl, inserted one to two groups selected from O, S, S(O), SO or a phenyl substituted by one to five members each indepen NR, where said Caliphatic, aryl or HET is optionally dently selected from the group consisting of a halogen, a substituted by one to three of halo, another HET, aryl, CN, C-C alkyl trifluoromethyl, a C-C alkoxy, nitro, cyano and —SR, —OR, —N(R), —S(O)R. —SOR, amino, naphthyl, or diphenylmethyl, and p is 0 or 1, provided —SON(R), —NR COR —NR COR. - NR that when T is a single bond, p is 0), R is a halogen, hydroxy, CONCR), —NR(NR)NHR, —COR —CON a C-C alkoxy, a C-C cycloalkyloxy, a C-C alkenyloxy, (R), —NRSOR - OCON(R), where HET and a C-C alkynyloxy, a C-C alkoxy interrupted by one or two Rare as defined below; R is H or Ro: R2 is H. C. oxygens or carbonyls, a C-C alkylthio, amino, a monosub aliphatic or HET, said Caliphatic optionally substituted stituted amino in which the Substituted is a C-C alkyl, a by one to three of halogen or OH where HET is as defined phenyl(C-C)alkyl or a C-C cycloalkyl, a C-C alkoxy in below; and HET is a five to ten-membered saturated or unsat which the carbon atom at any position other than the 1-posi urated heterocyclic ring selected from the group consisting of tion is substituted by one hydroxy or amino, or a substituted C-C alkoxy in which the Substituent is a halogen, cyano, a benzofuran, benzoxazole, dioxin, dioxane, , C-C alkoxycarbonyl, phthalimido, a C-C cycloalkyl, a dithiane, dithiazine, dithiaZoie, dithiolane, furan, , phenyl optionally Substituted by one halogen, a phenoxy indole, indazole, morpholine, oxazole, oxadiazole, oxathiaz optionally Substituted by one halogen, or a benzoyl optionally ole, oxathiazolidine, oxazine, oxiadiazine, piperazine, piperi Substituted by one halogen, R is hydrogen, R is hydrogen, a dine, pyran, pyrazine, pyrazole, pyridine, pyrimidine, pyr halogen, amino, a C-C alkylamino, a di(C-C alkyl)amino, role, pyrrolidine, quinoline, quinazoline, tetrahydrofuran, a C-C alkanoylamino, or nitro, R is hydrogen, a halogen, tetrazine, tetrazole, thiophene, thiadiazine, thiadiazole, thia nitro, Sulfamoyl, a C-C alkylsulfamoyl, or a di(C-C alkyl) triazole, thiazine, thiazole, thiomorpholine, thianaphthalene, Sulfamoyl, or any two adjacent groups of the R. R. R. and thiopyran, triazine, and triazole; and the pharmaceutically R, combine to form a C-C alkylenedioxy, and the remaining acceptable salts, biohydrolyzable esters, biohydrolyzable two groups are each hydrogen, Rs is hydrogen or a C-C, amides, biohydrolyzable carbamates, biohydrolyzable car alkyl, X is a C-C alkylene, and m and n are each 1 or 2, bonates, biohydrolyzable ureides, Solvates, hydrates, or pro provided that at least one of the groups R. R. and R is not of the as defined above. hydrogen. Melphalan 0231. Mosapride is a benzamide. Other benzamides 0229. In certain embodiments, melphalan or an analog include 1-((4-fluorobenzoylamino)ethyl)-4-(7-methoxy-1- thereof can be used in the compositions, methods, and kits of naphthyl)piperazine hydrochloride, 1-(3,4-dihydroxyphe the invention. Melphalan is an alkylating nitrogen mustard nyl)-2-(3-(4-carbamylphenyl)-1-methylpropylamino)etha used as an antineoplastic in the form of the levo isomer, nol, 1-nitrohydroxyphenyl-N-benzoylalanine, 2,2'-dithiobis melphalan. The racemic mixture is merphalan, and the dextro (N-2-hydroxypropylbenzamide), 2,3-dimethoxy-5-iodo-N- isomer is medphalan. Melphalan analogs are described, for ((1-(4'-fluorobenzyl)-2-pyrrolidinyl)methyl)benzamide, 2,3- dimethoxy-N-(1-(4-fluorobenzyl)piperidin-4-yl)benzamide, example, in U.S. Pat. No. 3,032.584. 2,3-dimethoxy-N-(9-(4-fluorobenzyl)-9-azabicyclo(3.3.1) Mosapride nonan-3-yl)benzamide, 2,4-dichloro-6-nitrophenolamide, 0230. In certain embodiments, mosapride or an analog 2,6-dichlorobenzamide, 2,6-difluorobenzamide, 2-(2- thereof can be used in the compositions, methods, and kits of chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-di the invention. Mosapride is a benzamide that acts as a selec fluoro-5-bromobenzamide, 2-chlorobenzamide, 2-hexyloxy tive 5-HT receptoragonist and is used as a gastroprokinetic. benzamide, 2-methoxy-4-fluoro-3-amino-N-((2- The structure of mosparide is: methylcyclopropylamino)ethyl)benzamide, 264 CP 3,4,5- trimethoxybenzamide, 3,4-dichloro-N,N-di-sec butylbenzamide, 3-(3-(dimethylamino)propyl)-4-hydroxy N-(4-(4-pyridinyl)phenyl)benzamide, 3-(cyclopentyloxy)- N-19 NH2 N-(3,5-dichloro-4-pyridyl)-4-methoxybenzamide, 3-(N- butyrylamino)benzamide, 3-acetamidobenzamide, 3-aminobenzamide, 3-carbamyl-(3'-picolyl)-4-methoxy-1- benzamide, 3-chloro-N-(4,6-dimethyl-2-pyridiny)benza mide, 3-iodo-2-hydroxy-6-methoxy-N-(1-ethyl-2-pyrro lidinyl)methyl)benzamide, 3-methoxybenzamide, 3-nitrosobenzamide, 4-(methylsulfonyl)amino)-N-(4-phe Analogs of mosparide are described, for example, in U.S. Pat. nylpiperazin-2-yl)methyl)benzamide, 4-(1H-tetrazol-5-yl)- No. 4,870,074 and have the general structure: N-(4-(1H-tetrazol-5-yl)phenyl)benzamide, 4-(3-(2-hydroxy 2-phenyl)ethylamino-3-methylbutyl)benzamide, 4-(5-benzo (1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl) R benzamide, 4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3- sy R 5)m R R3 methoxybenzyl)-N,N-diethylbenzamide, 4-(trifluoromethyl) (CH2) / O benzamide, 4-amino-5-chloro-2-ethoxy-N-((2-morpholinyl) methyl)benzamide, 4-amino-N-(4-benzyl-2-morpholinyl)- methyl)-5-chloro-2-ethoxybenzamide, 4-amino-N-(4- R1 Sullsx1 R4 benzyl-2-morpholinyl)methyl)-5-chloro-2- O methoxybenzamide, 4-aminobenzamidopyridine, 4-azido-5- iodoclebopride, 4-chloro-N-(hydroxymethyl)benzamide, 4-diethoxyphosphorylmethyl-N-(4-bromo-2-cyanophenyl) US 2008/O161324 A1 Jul. 3, 2008 60 benzamide, 4-dimethylamino-N-(4-(2- Zamide, N-propionylbenzamide, N-pyrimidinobenzamide-2- hydroxycarbamoylvinyl)benzyl)benzamide, carboxylic acid, , nitromide, norcisapride, NP 4-fluorobenzamide, 4-fluorobenzylamine, 4-hydroxybenza 101A, pancopride, parsalmide, Pellit, penfluoron, picoben mide, 4-iodo-N-(2-(4-morpholinyl)ethyl)benzamide, 4-iodo Zide, picobenzide N-oxide, Procainamide, Procarbazine, N-piperidinoethylbenzamide, 5-(aziridin-1-yl)-2-nitro-4-ni pronamide, , rebemide, Remoxipride, , troSobenzamide, 5-bromo-2,3-dimethoxy-N-(1-(4- RG-4, RG-7, riparin, Ro 12-5637, Ro 12-8095, Ro 16-3177, fluorobenzyl)-2-pyrrolidinyl)methyl)benzamide, 5-bromo Ro 16-6491, roflumilast, S 1688, SC 53116, sirtinol, SNC 2-ethoxybenzamide, 5-fluoropropylepidepride, 7-(3-(2- 121, spectramide, SR 48968, , T0070907, tefluben (cyclopropylmethyl)-3-methoxy-4-(methylamino) Zuron, tegalide, , tonabersat, triflumuron, tri carbonyl)phenoxy)propoxy)-3,4-dihydro-8-propyl-2H-1- methobenzamide, WAY 100289, YM-08050, Z 338, and benzopyran-2-propanoic acid, A22700, AH 7921, aklomide, . alloclamide, ameltolide, azapride, BA 74, befol, benodanil, Octyl Methoxycinnamate benzamide, benzamide nucleotide, benzcoprine, benzotripte, bis(2-(N-phenylcarboxamido)phenyl)dis 0232. In certain embodiments, telaprevir or an analog elenide, BRL 24682, BRL 32872, BRL 34778, bromadoline, thereof can be used in the compositions, methods, and kits of bromtianide, brovanexine, BW 373U86, BWA 466C, BWA the invention. Octyl methoxycinnamate absorbs ultraviolet 728C. Card-Instenon, , , , (UV) light and is used in Sunscreens and other topical appli cloxacepride, , DEET, dehydroxymethylepoxyqui cations where UV protection is desired. The structure of octyl nomicin, desbenzylclebopride, Diethyltoluamide-20, dimet methoxycinnamte is: pramid, Dinitolmide, dobupride, ecabapide, EL 494, epide pride, ethamivan, ethyl 2-(4-carboxybenzamido)-4- aminobenzoate, ethyl 2-(4-carboxybenzamido)-4- propionamidobenzoate, FLA 981, flatoril, FLB 524, fluoroclebopride, fluphenacur, flurfamide, fomesafen, genti samide, GGTI 297, GGTI 298, GRI 11665, GW 300, GW 532, GW 575, hexafluoron, Hippurates, HMR 1098, , Instenon, iodopride, iofratol, isoxaben, , L 1215, L7063, LY 135114, LY 188544, LY 201409, megli tinide, Metoclopramide, Moclobemide, N(1)-(4-chloroben Cinnamic acid derivatives are described, for example, in U.S. Zoyl)-N(2)-(1-(1-naphthyl)ethyl)-1,2-diaminocyclohexane, Pat. No. 5,457.226 and have the general structure: N,N-dimethylbenzamide, N-(4-benzyl-2-morpholinyl)me thyl)-5-chloro-4-(dimethylamino)-2-methoxybenzamide, N-(4-methylphenyl)sulfonyl)-3-(2-quinolinylmethoxy)ben RO Zamide, N-(1'-benzyl-4-piperidyl-N-oxide)-4-amino-5- chloro-2-methoxybenzamide, N-(2,6-dimethylphenyl)-4- (((diethylamino)acetyl)amino)benzamide, N-(2- (diethylamino)ethyl)-4-, N-(2- (diethylamino)ethyl)benzamide, N-(2-aminocyclohexyl)-3, O 4-dichlorobenzamide, N-(2-aminoethyl)-2-anisamide, N-(2- aminophenyl)-4-(N-(pyridin-3-ylmethoxycarbonyl) wherein R signifies hydrogen or Cs-alkyl and R2 signifies aminomethyl)benzamide, N-(2-dimethylaminoethyl)-2- hydrogen, Co-alkyl, Co-hydroxyalkyl or C-alkoxy anisamide, N-(2-methylaminocyclohexyl)-3,4- Co-alkyl. Cinnamic acid derivative include Other cin dichlorobenzamide, N-(2-picolyl)-3,5-dimethylbenzamide, inmates include (4-(dimethylamino)cinnamoyl)imidazole, N-(3,4,5-trimethoxybenzoyloxy)-3,4,5-trimethoxybenza (N-(3,5-dimethoxy-4-n-octyloxycinnamoyl)-N'-(3,4-dim mide, N-(3-picolyl)-3,5-dimethylbenzamide, N-(4-(delta-1'- ethylphenyl)piperazine), 1,1-dimethylallyl-3',4'-dihydroxy piperidyl-N-oxide))-4-amino-5-chloro-2-methoxybenza cinnamic acid ester, 2.3-dihydroxycinnamic acid, 2-(4-amyl mide, N-(4-(N-hydroxypiperidyl)-4-amino-5-chloro-2- cinnamoyl)amino-4-chlorobenzoic acid, 2-chlorocinnamic methoxybenzamide, N-(4,6-dimethyl-2-pyridinyl) acid, 2-ethylhexyl-4-methoxycinnamate, 2-fluoro-p-hy benzamide, N-(4-(2-(dimethylamino)ethoxy)benzyl)-3,4- droxycinnamate, 2-fluorocinnamic acid, 3,4,5-trimethoxy dimethoxybenzmide, N-(4-(5-bromo-2-pyrimidinyloxy)-3- cinnamic acid, 3,4-di(OH)-cinnamate, 3,4-dihydroxyhy chlorophenyl)-N'-(2-nitrobenzoyl)urea, N-(4-acetyl-1- drocinammic acid (1-aspartic acid dibenzyl ester) amide, 3.5- piperazinyl)-4-fluorobenzamide monohydrate, N-(4-amino dihydroxycinnamic acid, 3,5-dimethoxycinnamic acid, 3.7- 1-butyl)-N-nitrosobenzamide, N-(4-chlorobenzoyl)-N- dimethyl-1,6-octadien-3-yl cinnamtae, 3-(3,4- methyl-4-(4-dimethylaminomethylphenyl) dimethoxyphenyl)propenoic acid, 3-(4-hydroxy-3- cyclohexylamine, N-(acetoxymethyl)-4-chlorobenzamide, adamantylbiphenyl-4-yl)acrylic acid, 3-(4-(1,2-diphenylbut N-(exo-(hexahydro-1H-pyrrolizine-1-yl)methyl)-2-meth 1-enyl)phenyl)acrylic acid, 3-(4-methoxyphenyl)-2- oxy-4-amino-5-chlorobenzamide, N-(N-benzylpiperidin-4- propenoic acid 3-methylbutyl ester, 3-(trifluoromethyl) yl)-4-iodobenzamide, N-2-fluorenylbenzamide, N-acetyl cinnamide, 3-bromocinnamamide, 3-bromocinnamic acid, benzamide, N-butyrylbenzamide, N-demethylbromadoline, 3-fluorocinnamic acid, 4-(3.3-dimethyl-1-triaZeno)cinnamic N-didemethylbromadoline, N-ethylbenzamide, N-formyl acid, 4-(3-(1-adamantyl)-4-hydroxyphenyl)-3-chlorocin benzamide, N-hydroxymethyl-N-methylbenzamide, N-hy namic acid, 4-amidinophenyl 2-methylcinnamate, 4-amidi droxymethylbenzamide, N-isopropyl-4-hydroxymethylben nophenyl cinnamate, 4-amylcinnamoylanthranilic acid, Zamide, N-methyl-2,3-dihydroxybenzamide, 4-dimethylaminocinnamaldehyde, 4-fluorocinnamic acid, N-methylbenzamide, N-octyl-3-nitro-2,4,6-trihydroxyben 4-hydroxy-3-methoxycinnamylpiperidine, 4-hydroxycin US 2008/O161324 A1 Jul. 3, 2008

namic acid (1-phenylalanine methyl ester) amide, 4-meth Oxeladin deriviativates are described, for example, in U.S. oxycinnamate methyl ester, 4-methoxycinnamic acid, 5-(2- Pat. No. 2,885.404 and have the general structure: (methyl(2-phenethyl)amino)-2-oxoethyl)-2-(benzyloxy) cinnamic acid. A 25794, adamon, alpha-cyanocinnamate, alpha-methyl-2-hydroxy-4-diethylaminocinnamic acid, alpha-phenylcinnamate, aminocinnamonitrile, antithiamine factor, asarumin C, BM 42304, caffeic acids (e.g., 1,1-dim ethylallyl caffeic acid ester, 2-S-glutathionylcaffeic acid, 3,4- dihydroxyphenylpropionic acid, 7-caffeoylloganin, caffeic R acid, caffeic acid phenethyl ester, calceolarioside A, chicoric O N acid, crenatoside, dehydrodicaffeic acid dilactone, ethyl caf N-1 no-1N1 YR, feate, ethyl ferulate, , fukinolic acid, methyl caffeate, myriceron caffeoyl ester, N-(3,4-diacetoxycinnamoyl)-2- O pyrrolidone, N-caffeoyl-4-aminobutyric acid, octyl caffeate, petasiphenol, phenylethyl 3-methylcaffeate, Salvianolic acid in which R and R2 are alkyl groups containing together not A, Suspensaside, and Swertiamacroside), caracasanamide, more than 12 carbonatoms, or togetherform a cyclic structure chlorogenic acid, cinametic acid, or derivatives wherein—NRR represents pyrrolidino, piperideino or pip thereof (e.g., SQ 10631 and SQ 11447), cinnamic acid, cin eridino. The groups R and R may be the same or different. namic anhydride, cinnamoyl chloride, cinnamyl isobutyrate, Particular derivatives include 2-(P-diethylaminoethoxy)ethyl cinromide, CKA 1303, clocinnamox, coniferin, coumaric diethylphenylacetate, 2-(P N-pyrrolidinoethoxy) ethyl acids (e.g., (3,4-disinapoyl)fructofuranosyl-(6-sinapoyl)glu diethylphenylacetate, 2-(B-N-piperidinoethoxy)ethyl dieth copyranoside, (3-sinapoyl)fructofuranosyl-(6-sinapoyl)glu ylphenylacetate, 2-(B-N-A-piperideinoethoxy) ethyl dieth copyranoside, 1-(4-coumaroyl)alpha-rhamnopyranose, ylphenylacetate, 2-(B-N-ethylmethylaminoethoxy) ethyl 2-hydroxycinnamic acid, 3-coumaric acid, 4-coumaric acid, 4-coumaric acid methyl ester, 4-hydroxycinnamoylmethane, diethylphenylacetate, 2-(B-N-ethylpropylaminoethoxy)ethyl 5-hydroxyferulic acid, 5-O-feruloylarabinose, alpha-cyano diethylphenylacetate, 2-(B-N-di-n-butylaminoethoxy)ethyl 3-hydroxycinnamate, alpha-cyano-4-hydroxycinnamate, diethylphenylacetate and 2-(B-di-n-hexylaminoethoxy)ethyl angoroside C, asprelic acid A, coniferyl ferulate, diethylphenylacetate. cycloartenol ferulic acid ester, dihydro-3-coumaric acid, Parthenolide ferulic acid, feruloylputrescine, feruloyltyramine, karenin, 0234. In certain embodiments, parthenolide or an analog methyl 5-O-feruloylarabinofuranoside, and sinapinic acid), thereof can be used in the compositions, methods, and kits of cyclamen aldehyde, cyclamen aldehyde methyl anthranilate, the invention. Parthenolide is a sesquiterpene lactone found in diacetylcymarol, dimethylaminoethyl-alpha-phenylcin plants such as feverfew and Chrysanthemum parthenium. It namate, Dolo-Adamon, ethyl 2,5-dihydroxycinnamate, ethyl has anti NFKB activity. The structure of parthenolide is: cinnamate, fagaramide, gagaminine, hordatine M, hygromy cin A, igmesine, isoferulic acid, kutkin, linusitamarin, maxa fil, methyl 2,5-dihydroxycinnamate, methyl 3-phenyl-2,3- epoxypropanoate, methyl 4-(dimethylamino)cinnamate, methyl cinnamate, N,N-dimethylhydrocinnamide, N-hy droxy-N-methyl-3-(2-(methylthio)phenyl)-2-propenamide, O-(alpha-(benzoylamino)-4-(phenylazo)cinnamoyl)-beta phenylactate, O-(alpha-(benzoylamino)cinnamoyl)-beta phenylactate, octylmethoxycinnamate, ONO 8713, penupo genin, picroside I, picroside II, puromycin or derivative thereof (e.g. 2'-deoxypuromycin, 4-azidopuromycin, car bocyclic puromycin, cyclohexylpuromycin, cytidine-2(3')— Analogs of parthenolide are described, for example, in U.S. P-5'-puromycin, methionylpuromycin, N-(2-nitro-4-azido Pat. Application Publication No. 2005/0032886 and have the benzoyl)puromycin, N-acetylphenylalanylpuromycin, following structure. N-iodoacetylpuromycin, O-demethylpuromycin, puromycin

aminonucleoside, and sparsopuromycin), Ro 03-6037, ros marinic acid, S8932, SC 1001A, sibirate, SQ10624, ST 638, SU 1498, tolibut, trans-3-(2-methylphenyl)-2-propene-1- carboxamide, Vanicoside A, and Vanicoside B. Oxeladin 0233. In certain embodiments, oxeladin or an analog thereof can be used in the compositions, methods, and kits of the invention. Oxeladin is a used as an antitussive agent. The structure of oxeladin is: wherein RandR may be the same or different; R is selected from hydrogen, alkyl, Substituted alkyl, cycloalkyl, Substi tuted cycloalkyl, hydroxyalkyl, alkenyl, Substituted alkenyl, alkynyl. Substituted alkynyl, aryl. Substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, aryla lkenyl, Substituted arylalkenyl, arylalkynyl, Substituted ary lalkynyl, heterocyclic, substituted heterocyclic, trifluorom N ethyl, perfluoroalkyl, cyano, cyanomethyl, carboxyl, N-1-1-N-N-1 carbamate, Sulfonyl, and aryloxyalkyl, or OR, wherein, O is an oxygen; R is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, hydroxyalkyl, alkenyl, Substituted alkenyl, alkynyl, Substi tuted alkynyl, aryl, substituted aryl, alkylaryl, substituted US 2008/O161324 A1 Jul. 3, 2008 62 alkylaryl, arylalkyl, Substituted arylalkyl, arylalkenyl, Substi parthenolide; 11 BH, 13-(Piperidin-1-yl)parthenolide; 11 BH, tuted arylalkenyl, arylalkynyl, Substituted arylalkynyl, het 13-(Morpholin-1-yl)parthenolide; 113H, 13-(4-Methylpip erocyclic, substituted heterocyclic, trifluoromethyl, perfluo eridin-1-yl)parthenolide; 11 BH, 13-(4-Methylpiperazin-1- roalkyl, cyano, cyanomethyl, carboxyl, carbamate, Sulfonyl, yl)parthenolide; 11 BH, 13-(Homopiperidin-1-yl)partheno Sulfonamide and aryloxyalkyl. In certain embodiments, R is lide; 11 BH, 13-(Heptamethyleneimin-1-yl)parthenolide; hydrogen or optionally Substituted lower alkyl, and R is 11 BH, 13-(AZetidin-1-yl)parthenolide; and 11BH, 13-Dially optionally substituted lower alkyl. R and R can be each laminoparthenolide. —CH, or each —CH2CH. R can be —CH2CH and R can be —CH. R can be —CH2CHCH and R can be —CH. Quinacrine R, can be -CH(CH4), and R can be —CHs. RandR, also 0235. In certain embodiments, quinacrine or an analog can combine with N to form a ring system. Examples of Such thereof can be used in the compositions, methods, and kits of combination include —CH2(CH2)CH2—, where n is the invention. Quinacrine is an antiparasitic and an antipro selected from 0 to 5. These ring systems can also have one or toZoal (e.g., antimalarial) agent. The structure of quinacrine more substituents selected from alkyl, substituted alkyl, 1S cycloalkyl, Substituted cycloalkyl, hydroxyalkyl, alkenyl, Substituted alkenyl, alkynyl. Substituted alkynyl, aryl, Substi tuted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substi tuted arylalkyl, arylalkenyl, Substituted arylalkenyl, arylalky nyl, substituted arylalkynyl, heterocyclic, substituted N heterocyclic, trifluoromethyl, perfluoroalkyl, cyano, cya nomethyl, carboxyl, carbamate, Sulfonyl, Sulfonamide, ary loxyalkyl and halogenas set forth above. This ring system can OCH also be —CH2(CH2)CHZ-; where Z is O, S, Se, Si, P. CO— —SO —SO —PO—; and —CH2(CH) 2 CH- are the groups as set forth above. Alternatively, this C N r ring system can be —(CH2)-Z-(CH2) : where a and b are the same or different and are from 1 to 4; and Z is O, N, S, Se, Analogs of quincrine are described, for example, in U.S. Pat. Si, P. —CO —SO —SO - or —PO—. This ring sys No. 1,782.272 and have the following structure: tem can also be a uracil ring and its derivatives with one or more substituents. These ring systems can also have one or R more Substituents connected to the carbon atom(s) and/or Z. R; HN1 R, The substituent is selected from alkyl, substituted alkyl, cycloalkyl, Substituted cycloalkyl, hydroxyalkyl, alkenyl, R N R Substituted alkenyl, alkynyl. Substituted alkynyl, aryl, Substi tuted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substi 2 O tuted arylalkyl, arylalkenyl, Substituted arylalkenyl, arylalky R N R2 nyl, substituted arylalkynyl, heterocyclic, substituted R R heterocyclic, trifluoromethyl, perfluoroalkyl, cyano, cya nomethyl, carboxyl, carbamate, Sulfonyl, Sulfonamide, ary wherein R stands for hydrogen oralkyl, at least one R for the loxyalkyl and halogen as set forth above. These ring systems nitro group and another R for a basic residue, the remaining can also be aromatic, such as pyrrole, imidazole, purine, and R representing hydrogen, halogen, or a nitro-, alkyl- or pyrazole and substituted derivative of these heterocyclics alkoxy group, where a “basic residue' is By the term “basic listed above with one or more substituents selected from residue' is to be understood in the sense of the foregoing alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, formula Such groups contain at least one aliphatically bound hydroxyalkyl, alkenyl, Substituted alkenyl, alkynyl, Substi N-atom and which may be linked to the ring for tuted alkynyl, aryl, substituted aryl, alkylaryl, substituted instance through the medium of oxygen (in the manner of an alkylaryl, arylalkyl, Substituted arylalkyl, arylalkenyl, Substi ether), of nitrogen (in the manner of an amine), or of carbon tuted arylalkenyl, arylalkynyl, Substituted arylalkynyl, het (in the manner of a C-C linkage). Derivatives of quinacrine erocyclic, substituted heterocyclic, trifluoromethyl, perfluo include acrisuXine, collagenan, dimethylguinacrine, Prepara roalkyl, cyano, cyanomethyl, carboxyl, carboxylate, tion ABP, quinacrine half mustard, and quinacrine mustard. carboxaldehyde, carboxamide, carbamate, hydroxy, alkoxy, 0236 Quinacrine is an aminoacridine. Other ami isocyanate, isothiocyanate, nitro, nitroso, nitrate, Sulfate, Sul noacridines include (((amino-2-ethyl)-2-aminomethyl)-2- fonyl, Sulfonamide, thiol, thioalkyl, aryloxyalkyland halogen pyridine-6-carboxylhistidyl-gamma-(2-amino-2-deoxyglu as set forth above. Any of the above ring systems comprising cosyl)glutamylglycylamino)-4-phenyl-1-aminoacridine, (N- (2-((4-((2-((4-(9-acridinylamino)phenyl)amino)-2- NRR may optionally be fused with another ring to form an oxoethyl)amino)-4-oxobutyl)amino)-1-(1H-imidazol-4- optionally substituted bicyclic or tricyclic ring system, each ylmethyl)-1-oxoethyl)-6-(((-2-aminoethyl)amino)methyl)- of the rings optionally comprising one or more heteroatoms. 2-pyridinecarboxamidato) iron(1 +), 1,2,3,4-tetrahydro-N- Preferred ring systems include aziridin-1-yl, azetidin-1-yl, (3-iodophenyl-methyl)-9-acridinamine, 1,2,3,4-tetrahydro pyrrolidin-1-yl, piperidin-1-yl, homopiperidyn-1-yland hep N-(phenyl-methyl)-9-acridinamine, 1-nitro-9- tamethyleneimin-1-yl, each being optionally Substituted with (dimethylamino)acridine, 10-N-nonylacridinium orange, one or more Substituents as set forth above. Exemplary par 2-(3,6-bis(dimethylamino)-10-acridinyl)ethyl-(2,3-di-O- thenolide derivatives include 113H, 13-Dimethylaminopar palmitoylglycero)phosphate, 2-aminoacridone, 3,6-diamino thenolide; 11 BH, 13-Diethylaminoparthenolide; 113H, 13 10-methylacridinium, 3,6-diamino-9-(4-(methylsulfonyl) (tert-Butylamino)parthenolide; 11 BH, 13-(Pyrrolidin-1-yl) aminophenyl)aminoacridine, 3-amino-6-methoxy-9-(2- US 2008/O161324 A1 Jul. 3, 2008 hydroxyethylamino)acridine, 3-amino-6-methoxyacridine, cycloalkyl part can contain 3 to 7 carbon atoms, an alkenyl 3-amino-7-methoxyacridine, 3-amino-9-(diethylaminoeth group with 3 to 6 carbon atoms, an alkynyl group with 3 to 5 ylthio)acridine, 3-aminothioacridone, 3-dimethylamino-6- carbon atoms, a carboxy group or an alkoxycarbonyl group methoxyacridine, 4-(9-acridinylamino)-N-(4-(((4-amino-1- with a total of 2 to 5 carbon atoms; R represents a hydrogen methylpyrrol-2-yl)carbonyl)amino)-1-methylpyrrol-2- atom, a methyl, ethyl or allyl group; and W represents a carbonyl)glycylaniline, 4-(9-acridinylamino)-N-(glycyl methyl, hydroxymethyl, formyl, carboxyl, alkoxycarbonyl, histidyl-lysyl-glycyl)aniline, 9-((6-(4-nitrobenzoyloxy) cyanomethyl, 2-cyano-ethyl, 2-cyano-ethenyl, carboxym hexyl)amino)acridine, 9-(2-(2-nitro-1-imidazolyl) ethyl, 2-carboxyethyl, 2-carboxyethenyl, alkoxycarbonylm ethylamino)acridine, 9-(5-carboxypentylamino)acridine, ethyl, 2-alkoxycarbonyl-ethyl or 2-alkoxycarbonylethenyl 9-(6-(2-diazocyclopentadienylcarbonyloxy)hexylamino) group, in which each alkoxy part can contain from 1 to 4 acridine, 9-(6-(4-azidobenzamido)hexylamino)acridine, carbon atoms and can be substituted by a phenyl group; and 9-amino-2-hydroxyacridine, 9-amino-3-azido-7-methoxy when R is other then hydrogen and/or the radical R contains acridine, 9-amino-6-chloro-2-methoxyacridine, 9-amino-6- an optically active carbon atom, the enantiomeres and the chloroacridine-2-phosphate, 9-aminoacridine-4-carboxam diastereomeres thereofortheir mixtures; when W is carboxyl, ide, acridine mustard, acridine orange, acridine yellow, a non-toxic salt thereof formed with an inorganic or organic acriflavine, aminacrine, Amsacrine, C 1310, C 1311, C325, C base; or a non-toxic acid addition salt thereof formed by an 829, coriphosphine, ethacridine, euchrysine, fluoroquina inorganic or organic acid with the amino function in the crine, N-((2-dimethylamino)ethyl)-9-aminoacridine-4-car R-position. boxamide, N-((4-dimethylamino)butyl)-9-aminoacridine-4- carboxamide, N-(6-azido-2-methoxy-9-acridinyl)-N'-(9- 0238. In certain embodiments, a such as rifabu acridinyl)octane-1,8-diamine, N-(9-acridinyl) tin or an analog thereof can be used in the compositions, bromoacetamide, Nitracrine, NLA 1, NSC 210733, methods, and kits of the invention. Rifamycins are proflavine, pyracrine phosphate, SDM, Suronacrine, and compounds. The structure of rifabutin, an exemplary rifamy tacrine. C1n, 1S. Repaglinide 0237. In certain embodiments, repaglinide or an analog thereof can be used in the compositions, methods, and kits of the invention. Repaglinide is an antidiabetic agent which lowers levels by closing potassium channels in the b-cell membrane. The structure of repaglinide is:

Analogs of repaglinide are described, for example, in U.S. Pat. No. 5.312,924 and can be represented as follows: Ribabutin analogs are described, for example, in U.S. Pat. No. 4.219.478, and have the general structure:

N OR4 wherein R represents an unbranched alkyleneimino group H3CO NH with 4 to 6 carbonatoms optionally mono- or di-(alkyl of 1 to 3 carbon atoms)-substituted; R represents a hydrogen or halogen atom or a methyl or methoxy group; R represents a / O \ NH hydrogen atom, an alkyl group with 1 to 7 carbon atoms, a phenyl group optionally substituted by a halogen atom or a O N methyl or methoxy group, an alkyl group with 1 or 2 carbon O atoms Substituted by a hydroxy, alkoxy, alkanoyloxy, tetrahy N drofuranyl, tetrahydropyranyl, cycloalkyl orphenyl group, in V which the alkoxy part can contain from 1 to 3 carbon atoms, the alkanoyloxy part can contain 2 to 3 carbon atoms and the US 2008/O161324 A1 Jul. 3, 2008 64 where R is selected from the group consisting of linear alkyl ing of hydrogen, C alkyl, halo, O—C alkyl, S Cla having 4 to 8 carbon atoms, branched alkyl having 4 to 8 alkyl, or N(R), R is hydrogen, Ce alkyl, or R, together carbonatoms, alkenyl having 3 or 4 carbon atoms, cycloalkyl with the nitrogen, may form a heterocyclic ring of 5 to 7 having 3 to 6 carbonatoms, alkoxyalkyl having 3 to 7 carbon members, said ring optionally containing an additional het atoms, alkyl-furyl having 5 or 6 carbon atoms, alkyl tetrahy eroatom selected from the group consisting of oxygen, Sulfur drofuryl having 5 or 6 carbon atoms, alkanoyl having 5 or 6 or nitrogen; R is mono- or di-substituted phenyl wherein the carbon atoms, and monohaloalkanoyl having 2 to 6 carbon Substituents are independently selected from the group con sisting of hydrogen, halo, S(O).Rs, OR, halo Substituted atoms, and Y is —H or COCH. Other rifamycins include Calkyl, Cia alkyl, or N(R12): R is hydrogen, Clio alkyl, 16,17-dihydro-17-hydroxyrifamycin S, 16,17-dihydrorifa Coalkenyl, Co alkynyl, C-7 cycloalkyl, CS-7 cycloalk mycin S, 25-deacetoxy-25-hydroxyrifamycin S, 3-((dimeth enyl, heterocyclic, heterocyclicalkyl, aryl, aryl alkyl, het ylhydrazono)methyl)rifamycin SV. 3-carbomethoxy rifamy eroaryl, heteroarylalkyl, R is (X), (Q)-(Y), X is hydrogen, cin S, 3-formyl-25-desacetylrifamycin, 3-formylrifamycin —(C(Ro)), NR - O—, or S(O), r is a number having SV, 31-homorifamycin W. 4-deoxy-3'-bromopyrido(1.2-1. a value of 0 or 1; m is a number having a value of 0, 1 or 2: Q 2)imidazo[5.4-crifamycin S, AF 013, benzothiazole-rifamy is alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic, cin, C 27, CGP 27557, CGP 29861, CGP 4832, CGP 7040, heterocyclicalkyl, aryl, arylalkyl, heteroaryl, or heteroaryla FCE 22250, FCE 22807, halomicin B, kanglemycin A, KRM lkyl; s is a number having a value of 0 or 1; Y is a substituent 1648, KRM 1657, KRM 1668, KRM 1671, protorifamycin I, selected from the group consisting of hydrogen, Co alkyl, R 761, reprimun, rifabutin derivatives (e.g., 17-(allylamino)- halo-substituted Co alkyl, halogen, —(C(R)), ORs, 17-demethoxygeldanamycin, 25-desacetylrifabutin, and —(C(Ro)), NO. —(C(Ro)), S(O), R. —(C(Ro)) streptovaricin), rifamdin, rifamexil, rifamide, Rifampin or SRs, —(C(R)), S(O), ORs, —(C(Ro)), S(O)NRRo, derivatives thereof (e.g., 18,19-dihydrorifampicin, —X P(Z)-(X,R) —(C(R).)NRRo, -(C(Ro)) 25-deacetylrifampicin, 25-desacetylrifapentine, CGP 43371, CORs —(C(Ro)), OC(O)—Rs —(C(R)),CN. —(C CGS 24565, dehydrorifampicin, DMB-, rifampi (Ro)), CONRRo. —(C(R)),C(S)NRs, Ro, —(C(Ro)) cin N-oxide, rifapentine, Rifaprim, Rifater, and rivicycline), NRC(O)Rs —(C(R).)NRC(S)Rs —(C(R).) rifamycin B, rifamycin L, rifamycin O, rifamycin P. rifamy NRC(Z)NRRo. —(C(Ro))NRoS(O).R. —(C(Ro) cin Q, rifamycin S. rifamycin SV, rifamycin Verde, rifaximin, ..)NRC(=NCN)—S R. —(C(R).)NRC rifazone-82, SPA-S 565, streptovaricin derivatives (e.g., (—NCN)—NRR —(C(R)),NRC(O)C(O) NRR, damavaricin C, damavaricin Fc pentyl ether, protostreptova (C(R)), NRC(O)C(O) OR —(C(Ro)),C (=NR)—NRRo, -(C(Ro)), C(=NRo)-ZR —(C ricin, Streptoval C. Streptovaricin C, and streptovarone), toly (R)), OC(Z)-NRR, -(C(R).)NRS(O)CF, pomycin Y, and tolypomycinone. —(C(Ro))NRC(O)CRio; t is an integer having a value of 0, 1, 2, or 3: Xa is independently —(C(R)) —NRs . SB-2021.90 —O— or—S-; Z is oxygen or Sulfur, m' is an integer having a value of 1 or 2; n is an integer having a value of 0 to 10; Rs 0239. In certain embodiments, SB-202190 or an analog is hydrogen, C. alkyl, C2a alkenyl, C2a alkynyl, C-7 thereof can be used in the compositions, methods, and kits of cycloalkyl, Cs, cycloalkenyl, aryl, or N(R), provided that the invention. SB-202190 is a pyridyl substituted imidazole when m is 1 or 2 then Rs is not hydrogen. Reis hydrogen, C. with selective p38 MAP Kinase (MAPK) inhibitory activity. alkyl, halo Substituted CIA alkyl, Calkenyl, C. alkynyl, SB-202190 binds to the ATP binding site on active p38 C., cycloalkyl, C-7 cycloalkenyl, or aryl; R, is hydrogen, MAPK. The structure of SB-202190 is: C, alkyl, C. alkenyl, C. alkynyl, aryl, or may form a heterocyclic ring of 5 to 7 members together with the nitro gen, said ring optionally containing an additional heteroatom F selected from the group consisting of oxygen, Sulfur or nitro gen; provided that when Rs is N(R-7) then m is 1 or 2: Rs is N hydrogen, Clio alkyl, C2-io alkenyl, C2-io alkynyl, C-7 cycloalkyl, Cs, cycloalkenyl, heterocyclic, heterocyclic alkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl; R is hydrogen, Clio alkyl, C2-io alkenyl, C2-io alkynyl, C-7 rN cycloalkyl, Cs, cycloalkenyl, aryl, arylalkyl, heteroaryl, het Na2 eroarylalkyl or Rs and R may together form a heterocyclic ring of 5 to 7 members together with the nitrogen, said ring optionally containing an additional heteroatom selected from Analogs of SB-202190 are described, for example, in U.S. the group consisting of oxygen, Sulfur or nitrogen; Rio is Pat. No. 6,008,235 and have the structure: hydrogen, or CIA alkyl, R, is Coalkyl, Coalkenyl, C, alkynyl, C-7 cycloalkyl, Cs, cycloalkenyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl; R is hydrogen, Ca R3 N alkyl, aryl, or may form a heterocyclic ring of 5 to 7 members together with the nitrogen; R is hydrogen, Co alkyl, cycloalkyl, heterocylic, aryl, aryl alkyl, heteroaryl, or het R4D NX-R, eroarylalkyl. R Fusidic Acid 0240. In certain embodiments, fusidic acid or a derivative wherein R is a mono- or di-substituted 4-quinolyl, 4-pyridyl, thereof (e.g., sodium fusidate) can be used in the composi 1-imidazolyl, 1-benzimidazolyl, 4-pyrimidinyl wherein the tions, methods, and kits of the invention. The structure of Substituent is independently selected from the group consist fusidic acid is: US 2008/O161324 A1 Jul. 3, 2008 65

Tolterodine 0242. In certain embodiments, tolterodine or an analog thereof can be used in the compositions, methods, and kits of the invention. Tolterodine is a competitive muscarinic recep tor antagonist. The pharmacologically active agent is the 5-hydroxymethyl derivative. Cholinergic muscarinic recep tors mediate urinary bladder contraction. Tolterodine is thus used to treaturinary incontinence. The structure of tolterod 11S

OH

Fusidic acid derivatives are described in U.S. Pat. Nos. 3,352, 854, 3,385,869, 3,376,324, 4,004,004, 4,060,606, 4,162,259, 4,315,004, 4,119,717, 6,103,884, and 6,593,319. Derivative include 11-monoketofusidic acid, 16-O-deacetylfusidic acid, 16-O-deacetylfusidic acid lactone, 3,11-diketofusidic acid, diethanolamine fusidate, helvolic acid, and tauro-24,25-dihy Analogs of tolterodine are described, for example, in U.S. drofusidate. Pat. No. 5,382,600 and have the general structure: TOFA

0241. In certain embodiments, 5-(tetradecyloxy)-2-furan carboxylic acid (TOFA) or an analog thereof can be used in the compositions, methods, and kits of the invention. TOFA is an inhibitor of acetyl-CoA carboxylase. The structure of TOFA is:

O O OH R

Analogs of TOFA are described, for example, in U.S. Pat. No. wherein R signifies hydrogen or methyl, R. R. and R. 4.382,143 and have the general structure: independently signify hydrogen, methyl, methoxy, hydroxy, carbamoyl, Sulphanoylorhalogen, and X represents a tertiary amino group (-NRR) wherein Rs and R signify non A Y. Z aromatic hydrocarbol groups, which may be the same or x1 nN.1 r different and which together contain at least three carbon H atoms, preferably at least four or five carbon atoms, and O where Rs and R may form a ring together with the amine nitrogen, said ring preferably having no other hetero atom wherein X is selected from the group consisting of hydrogen, that the amine nitrogen. C-Cs cycloalkyl, and Substituted or unsubstituted aryl; A is a divalent radical selected from the group consisting of Toremifene branched or unbranched Co-Co alkylene, alkenylene, and 0243 In certain embodiments, toremifene or an analog alkynylene;Y is a 5- or 6-membered heteroaryl ring contain thereof can be used in the compositions, methods, and kits of ing one or more nitrogen, Sulfur, or oxygenatoms and option the invention. Toremifene is antiestrogen and antineoplastic ally unsubstituted or substituted with one fluoro; and Z is agent. The structure of toremifene is: selected from the group consisting of hydrogen, hydroxy, loweralkoxy, loweralkoxyloweralkoxy, diloweralkylami noloweralkoxy, (mono- or polyhydroxy)loweralkoxy, (mono- or polycarboxy)loweralkoxy, (mono- or polycar boxy)hydroxyloweralkoxy, allyloxy, 2,3-epoxypropoxy, Sub stituted or unsubstituted-(phenoxy, benzyloxy, or 3-pyridy N-11 loxy), pyridylmethoxy, tetrahydropyranyloxy, (mono- or polyhydroxy)alkylamino, allylamino, propargylamino, C N 2-sulfoethylamino, (mono- or polycarboxyl)loweralky lamino, loweralkanoylamino, (Substituted or unsubstituted) aroylamino, loweralkanesulfonylamino, (Substituted or unsubstituted)arenesulfonylamino, loweralkanylhydrazino, hydroxylamino, polymethyleneimino, and (4-carboxy- or 4-carboethoxy)thiazolidino; and the pharmaceutically acceptable acid-addition and cationic salts thereof. US 2008/O161324 A1 Jul. 3, 2008 66

Analogs of toremifene are described, for example, in U.S. Trequinsin analogs are described, for example, in U.S. Pat. Pat. No. 4,696,949 have the general structure: No. 5,141.936 and have the general structure: R3 RsX4, R4

R

() (CH2) O in which R, R and Rs, which may be identical or different, (R4 may be hydrogen, hydroxyl, lower alkoxy, dialkylphosphiny lalkoxy, acyloxy or halogen, where two adjacent groups together may denote a methylenedioxy or ethylenedioxy or the structure: group, and R and R, which may be identical or different, may be hydrogen, hydroxyl, lower alkoxy, amino, alky lamino, dialkylamino, arylamino, alkyl, amino or alkyl Sub stituted by a 5- or 6-membered carbon ring which may con tain up to 3 heteroatoms from the group comprising N, O or S. cycloalkyl, hydroxyalkyl, alkoxyalkyl, dialkoxyalkyl, haloalkyl, dialkylaminoalkyl, aralkyl, acyl and, optionally Substituted, aryl, where aryl is in each case taken to mean an aromatic hydrocarbon having up to 10 carbon atoms, and R denotes an electron pair if R denotes one of the radicals indicated below and R and R together with the nitrogen atom to which they are bonded may denote a part of an optionally Substituted nitrogen heterocycle which may con tain a further nitrogenatom or an oxygenatom, and R stands for hydrogen, alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, wherein n is 0 to 4, R and R, which can be the same or dialkoxyalkyl, haloalkyl, dialkylaminoalkyl, aralkyl, hetero different are H, OH, an alkoxy group of 1 to 4 carbon atoms, cyclic-substituted alkyl, dialkylphosphinylalkyl, acyl and benzyloxy or methoxymethoxy; R is H, OH, halogen, alkoxy optionally substituted aryl, and also stands for an electron pair of 1 to 4 carbon atoms, benzyloxy, methoxymethoxy, 2.3- if R denotes one of the radicals indicated above, and their dihydroxypropoxy or —O(CH), CHNRR, wherein m is 1 acid salts and quaternary ammonium salts. or 2, R and R-7, which can be the same or different, are H or an alkyl group of 1 to 4 carbon atoms, or —NRR, can form Vinorelbine an N-containing three-, four-, five- or six-membered hetero cyclic ring; R is OH. F. Cl, Br, I, mesyloxy, tosyloxy, alkyl 0245. In certain embodiments, vinorelbine or an analog carbonyloxy of 1 to 4 carbon atoms, formyloxy or CHR is thereof can be used in the compositions, methods, and kits of replaced by CHO: Rs is H or OH: or R and Rs together form the invention. Vinorelbine is an antineoplastic agent that func an—O—bridge between the carbon atoms to which they are tions by binding microtubular proteins of the mitotic spindle, attached. thereby inhibiting mitosis. The structure of vinorelbine is: Trequinsin 0244. In certain embodiments, trequinsin or an analog thereof can be used in the compositions, methods, and kits of the invention. Trequinsin is a platelet aggreation inhibitor. The structure of trequinsin is: US 2008/O161324 A1 Jul. 3, 2008 67

Analogs of vinorelbine are described, for example, in U.S. Wedelolactone is a member of the coumarins. Other cou Pat. No. 4.307,100 and have the general structure: marins include 11,12-dihydroxy-5-methylcoumestan, 11-de sacetoxywortmannin, 2',3'-dihydrogeiparvarin, 2-amino-3-

(7-methoxy-4-coumaryl)propionic acid, 2-nitro-6H-dibenzo (b.d)pyran-6-one, 3'-angeloyloxy-4-acetoxy-3',4'- dihydroseselin, 3,4-dichloroisocoumarin, 3,4-dihydro-3,4- dibromo-6-bromomethylcoumarin, 3,4-dihydro-3-benzyl-6- chloromethylcoumarin, 3,4-dihydrocoumarin, 3.8- dihydroxy-6H-dibenzo(b.d)pyran-6-one, 3-(2-(N,N-diethyl N-methylammonium)ethyl)-7-methoxy-4-methylcoumarin, 3-acetylcoumarin, 3-carbethoxypyranocoumarin, 3-carboxy lic acid-picumast, 3-cyano-7-ethoxycoumarin, 3-cyano-7- hydroxycoumarin, 3-hydroxy-(28-4-coumaroyloxy)lup-20 (29)-en-27-oic acid, 3-hydroxymethyl-picumast, 3-nitro-6H dibenzo(b.d)pyran-6-one, 3-phenyl-5,6-benzocoumarin, 3H-naphtho(2,1-b)pyran-3-one, 4'-hydroxyasperentin, 4-(diazomethyl)-7-(diethylamino)coumarin, 4-acetylisocou marin, 4-bromomethyl-6,7-dimethoxycoumarin, 4-bromom ethyl-6,7-methylenedioxycoumarin, 4-bromomethyl-7-ac wherein R' represents a hydrogen atom or an alkoxy, acyl, etoxycoumarin, 4-chloro-3-ethoxy-7- formyl or haloacyl radical, R' represents a hydrogenatom or guanidinoisocoumarin, 4-methyl-7-diethylaminocoumarin, an alkyl radical; R's and R' which may be the same or differ 4-methyl-7-ethoxycoumarin, 4-methyl-N-ethyl pyrrolo3.2- ent each represents a hydrogen atom or a hydroxyl radical or gcoumarin, 4-nitro-6H-dibenzo(b.d)pyran-6-one, 4-phenyl an alkanoyloxyl radical or together represent a carbonyl 3-isocoumarinic acid, 4-phenyl-3-isocoumarinic acid allyla group, or R's and R's together represent an epoxy bridge or a mide, 4-trifluoromethylcoumarin phosphate, 5,6- double bond; R represent a hydrogen atom or an alkyloxy benzocoumarin-3-carboxylic acid ethyl ester, 5,7-dihydroxy carbonyl, hydroxymethyl, alkanoyloxymethyl or acetamido 4-imino-2-oxochroman, 5,7-dimethoxycoumarin, 5-iodo-6- radical; R's and R's which may be the same or different each amino-1,2-benzopyrone, 5-methyl-8-hydroxycoumarin, represents a hydrogen atom or a hydroxyl, alkanoyloxyl, ethyl or 2-hydroxyethyl radical; R's represents a hydrogen 5-methylcoumarin-4-cellobioside, 5-methylcoumarin-4- atom or an ethyl, 2-hydroxyethyl or acetyl radical; R repre gentiobioside, 5H-(2)benzopyrano(3,4-g)(1,4)benzodioxin sents a hydrogen atom or an alkyl, formyl, or acyl radical; R. 5-one, 6'-feruloylnodakenin, 6.7-(4-methyl)coumaro-(2.2.2) represents a hydrogen atom or an alkoxy radical; R repre cryptand, 6,8-dimethoxy-3-methyl-3,4-, sents a hydrogenatom or a hydroxyl or alkanoyloxyl radical, 6-(7-beta-galactosylcoumarin-3-carboxamido)hexylamine, or R and R together represent an epoxy bridge or a double 6-amino-1,2-benzopyrone, 6-amino-4,4,5,7,8-pentameth bond; R represents a hydrogen atom or a hydroxyl or yldihydrocoumarin, 6-chloro-3,4-dihydroxy-2H-1-benzopy alkanoyloxyl radical, or R and Rs together represent an ran-2-one, 6-cyano-7-hydroxy-4,8-dimethylcoumarin, 6-hy epoxy bridge; R represents an alkyloxycarbonyl, hydrazido, droxymellein, 6-methoxy-8-hydroxy-3-methyl-3,4- acetamido, hydroxymethyl or alkanyloxymethyl radical; and Rs and R7 represent a hydrogen atom or a hydroxyl or dihydroisocoumarin, 6-methylcoumarin, alkanoyloxyl radical. Vinorelbine is a member of the vinblas 6-methylthionecoumarin, 6-nitroso-1,2-benzopyrone, 7.8- tine compounds, which include 16-O-acetylvindoline, 3',4'- dimethoxycoumarin, 7-(N-tosylphenylalanyl)amino)-4- anhydrovinblastine, 4'-deoxyvinblastine, 4-desacetylvin chloro-3-methoxyisocoumarin, 7-(alpha-glutamyl)-4-meth blastine, 4-desacetylvinblastine hydrazide, 4-O- ylcoumarylamide, 7-(gamma-glutamyl)-4- deacetylvinblastine-3-oic acid, bis(N-ethylidene vindesine) methylcoumarylamide, 7-(N-benzyloxycarbonyl-beta disulfide, catharanthamine, catharinine, desacetylnavelbine, benzylaspartyl-prolyl-leucyl)amino-4-methylcoumarin, KAR 2, LY 266070, NAPAVIN, ViFuP protocol, vincathi 7-(N-benzyloxycarbonylglycyl-glycyl-leucyl)amino-4-me cine, Vindoline, Vindolinine, Vinepidine, Vinflunine, Vinleuci thylcoumarin, 7-amino-3-(2-bromoethoxy)-4-chloroisocou nol, vinorelbine, vintriptol, and vintriptol acid. marin, 7-amino-4-chloro-3-(3-isothiureidopropoxy)isocou Wedelolactone marin, 7-amino-4-methylcoumarin, 7-amino-4- 0246. In certain embodiments, Wedelolactone oran analog methylcoumarin-3-acetic acid, 7-amino-4- thereof can be used in the compositions, methods, and kits of trifluoromethylcoumarin, 7-aminocoumarin, the invention. Wedelolactone is IKKC. and IKKB kinase 7-aminocoumarin-4-methanesulfonic acid, 7-anilino-4-me inhibitor and a IkB-C kinase inhibitor. The structure of thylcoumarin-3-acetic acid, 7-anilinocoumarin-4-acetic acid, wedelolactone is: 7-benzylcysteinyl-4-methylcoumarinylamide, 7-benzyloxy 4-trifluoromethylcoumarin, 7-beta-galactopyranosyl-oxy coumarin-4-acetic acid methyl ester, 7-beta-galactopyrano CH Syloxycoumarin-4-acetic acid, 7-diethylamino-3-(4- isothiocyanatophenyl)-4-methylcoumarin, HO 7-diethylaminocoumarin-3-carbohydrazide, 7-diethylami nocoumarin-3-carboxylic acid, 7-dimethylamino-4-methyl coumarin, 7-ethenyloxycoumarin, 7-ethoxy-4-trifluorometh HO ylcoumarin, 7-ethoxycoumarin, 7-glycidoxycoumarin, 7-hydroxy-4-phenyl-3-(4-hydroxyphenyl)coumarin, 7-hy HO OCH droxy-4-trifluoromethylcoumarin, 7-hydroxycoumarin-4- acetic acid, 7-leucylamido-4-methylcoumarin, 7-lysylalanyl 4-methylcoumarinamide, 7-Succinylglycyl-prolyl-4- US 2008/O161324 A1 Jul. 3, 2008 methylcoumaryl-7-amide, 8-(3-(4-phenyl-1-piperazinyl) maryl-7-amide, Suksdorfin, Sulfo Succinimidyl 7-amino-4- propoxy)-7-methoxycoumarin, 8-hydroxy-4-methyl-3,4-di methylcoumarin-3-acetate, Surangin B, tert-butyloxycarbo hydroxycoumarin, 8-hydroxycoumarin, 9-(3- nyl-leucyl-glycyl-arginine-4-trifluoromethylcoumarin-7- diethylaminopropyloxy)-3H-naphtho(2,1-b)pyran-3-one. A amide, tert-butyloxycarbonyl-norleucyl-glutaminyl-leucyl 1062, Ac-aspartyl-glutamyl-Valyl-aspartyl-aminomethyl glycyl-arginine-7-amino-4-methylcoumarin, tertiary coumarin, acetyl-aspartyl-glutamyl-Valyl-aspartyl-amino-4- butyloxycarbonylvalyl-leucyl-lysinyl-4-methylcoumarin-7- methylcoumarin, agrimonolide-6-O-glucopyranoside, AI amide, tertiary-butyloxycarbonyl-isoleucyl-glutamyl-gly 77B, alanyl-alanyl-phenylalanyl-7-amino-4-methylcou cyl-arginyl-7-amino-4-methylcoumarin, tertiary-butyloxy carbonyl-phenylalanyl-seryl-arginyl-4-methylcoumarin-7- marin, amicoumacin A, anomalin, arginine 4-methyl-7-cou amide, tertiary-butyloxycarbonyl-Valyl-prolyl-arginyl-7- marylamide, arnottin I, aspartyl-glutamyl-Valyl-aspartyl-7- amino-4-methylcoumarin, theo-esberiven, thunberginol A, amino-4-trifluoromethylcoumarin, aurapten, baciphelacin, thunberginol B, thunberginol D, tioclomarol, toddalolactone, benzyloxycarbonyl-phenylalanylarginine-4-methylcou tosyl-glycyl-prolyl-arginyl-4-methylcoumaryl-7-amide, maryl-7-amide, benzyloxycarbonylarginyl-arginine 4-meth ubiquitin C-terminal 7-amido-4-methylcoumarin, Umbellif ylcoumarin-7-ylamide, bergaptol-O-glucopyranoside, Boc erones, Valyl-leucyl-lysyl-4-aminomethylcoumarin, Valyl leucyl-seryl-threonyl-arginine-4-methylcoumaryl-7-amide, leucyl-lysyl-7-amino-4-methylcoumarin, Venalot, byakangelicol, calanolide A, calanolide B, calophyllolid, car bobenzoxycoumarin, Cassella 7657, CGP 13143, chlorobio W10294A, WS-5995 A, xanthalin, and xanthyletine. cic acid, Chromonar, CI-923, cladosporin, clausarin, clausin Telaprevir dine, clausmarin, columbianadin, cordatolide A, coumachlor, coumarin, coumarin 3.4-epoxide, coumarin-3-carboxylic 0247. In certain embodiments, telaprevir or an analog acid, coumarin-3-carboxylic acid Succinimidyl ester, thereof can be used in the compositions, methods, and kits of coumermycins, , coumetarol, crenulatin, cytoge the invention. Telaprevir (VX-950) is a hepatitis C therapy. nin, daphnoretin, dehydroindicolactone, demethyl The structure of telaprevir is: wedelolactone, dicurin, erythrocentaurin, Esculin, esuprone,

F 1375, ferujol, ferulenol, folescutol, fraxetin, fraxin, gal banic acid, geiparvarin, gerberinside, glaupadiol, glisofla vone, glutaryl-alanyl-alanyl-phenylalanyl-amidomethylcou marin, glutaryl-glycyl-arginine-4-methylcoumaryl-7-amide, glycyl-7-amino-4-methylcounarin-3-acetic acid, glycylpro lyl-4-methylcoumaryl-7-amide, GU 7, GUT-70, 4-hydroxy coumarins, hymecromone O.O-diethyl phosphorothioate, ili parcil, inophyllum B, isobyakangelicin angelate, isofraxidin, isorhamnetin 3-O-beta-(4"-4-coumaroyl-alpha-rhamnosyl (1-6)galactoside), -2,4-dicoumaroyl-3-O-gluco side, licopyranocoumarin, LL-N 313, mammein, mammei Analogs of telaprevir are described, for example, in U.S. Pat. sin, maoyancaosu, marmesin, mannin, melilot, Application Publication No. 2005/01972.99 and can be rep moellendorffiline, morocromen, moxicoumone, murayalac resented as follows: tone, N-(2-(1-maleimidyl)ethyl)-7-(diethylamino)coumarin 3-carboxamide, N-(4-(7-(diethylamino)-4-methylcoumarin 3-yl)maleimide, N-(4-(7-diethylamino 4-methylcoumarin R6 O O 3-yl)phenyl)iodoacetamide, N-(4-(7-diethylamino-4- - L. R l R. R. - * methylcoumarin-3-yl)phenyl)maleimide, N-acetyl-alanyl R9 N1 NR51 N. N1 alanyl-prolyl-alanyl-amidomethylcoumarin, R2 N-benzyloxycarbonylalanyl-arginyl-arginyl-4-trifluorom R8 O R4 O O ethyl-7-coumarylamide, N-benzyloxycarbonylglycyl-gly cyl-arginine-4-methylcoumarinyl-7-amide, N-carbobenzox wherein R is a bond or difluoromethylene; R is hydrogen, yglycyl-prolyl-4-methylcoumarinyl amide, N-Salicylidene optionally Substituted aliphatic group, optionally Substituted 3-aminocoumarin, N-succinimidyl-7- cyclic group or optionally substituted aromatic group; R and dimethylaminocoumarin-4-acetate, necatorin, neoglycyrol, Rare each independently optionally substituted aliphatic nitrofarin, nordentatin, notopterol, Ochratoxins, oosponol, group, optionally Substituted cyclic group or optionally Sub oroselol, osthenol, osthol, oXamarine, pargyropyranone, PD stituted aromatic group; R. R. and R7 are each indepen 118717, peuarenine, peujaponiside, phebalosin, phellopterin, dently (optionally Substituted aliphatic group, optionally Sub , picumast, ponfolin, praeruptorin C, praerup stituted cyclic group or optionally substituted aromatic torin E, Psoralens, , pterybinthinone, pteryxin, group)(optionally Substituted methylene or optionally Substi pyranocoumarins, qianhucoumarin A, qianhucoumarin B, tuted ethylene), optionally substituted (1,1- or 1.2-)cy qianhucoumarin C, reticulol, Ro7-AMCA, rubradiric acid A. cloalkylene or optionally substituted (1,1- or 1.2-)heterocy rubradiric acid B, rubricauloside, Sclerin, scoparone, Scopo clylene; R. R. RandR'' are each independently hydrogen lin, serine-7-amino-4-methylcoumarin carbamate, shijiaoca or optionally Substituted aliphatic group; olactone A, soulattrollide, SP500263, succinyl-isoleucyl-iso leucyl-tryptophyl-methylcoumarinamide, Succinyl-leucyl leucyl-Valyl-tyrosyl-methylcoumarinamide, Succinyl-leucyl tyrosyl-4-methyl-7-coumarylamide. Succinylalanylalanyl prolyl-phenylalanine-4-methylcoumaryl-7-amide, O Succinylglycyl-prolyl-leucyl-glycyl-prolyl-4-methylcou US 2008/O161324 A1 Jul. 3, 2008 69 is Substituted monocyclic azaheterocyclyl or optionally Sub wherein R represents a radical selected from the group con stituted multicyclic azaheterocyclyl, or optionally substituted sisting of hydrogen, alkyl, halogen, and cyano; R represents multicyclic azaheterocyclenyl wherein the unsaturatation is a radical selected from the group consisting of hydrogen, a in the ring distal to the ring bearing the R-L-N(R) R7— substituted or unsubstituted alkyl radical, a substituted or C(O) ),N(R)-R C(O)N moiety and to which the unsubstituted alkoxy group, hydroxy, cycloalkyl, cycloalky —C(O) N(R) R. C(O) C(O)NR'R' moiety is loxy, polyfluoroalkyl, polyfluoroalkoxy, halogen, amino, attached; L is —C(O)— —OC(O)—, NR'C(O) , monoalkylamino, dialkylamino, cyano, a Substituted or —S(O) , or NR'S(O) ; and n is 0 or 1, or a pharma unsubstituted benzyloxy group, and a substituted or unsub ceutically acceptable salt or prodrug thereof, or a Solvate of stituted heterocyclic radical; R represents a radical selected Such a compound, its salt or its prodrug, provided when from the group consisting of hydrogen, a Substituted or unsubstituted alkyl radical, a substituted or unsubstituted alkoxy group, alkenyl, halogen, hydroxy, polyfluoroalkyl, polyfluoroalkoxy, formyl, carboxyl, alkylcarbonyl, alkoxy 'O carbonyl, hydroxyalkylcarbonyl, amino, a Substituted or unsubstituted monoalkylamino, dialkylamino, cyano, amido, is substituted alkoxyamido, a Substituted or unsubstituted heteroarylamino, acetylsulfonylamino, ureido, carboxamide, Sulfonamide, a substituted sulfonamide, a substituted or unsubstituted het erocyclosulfonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonic acid, a substituted or unsubstituted heterocyclic radical, and —O(CH2)—C(=O)—R, R represents a radi cal selected from the group consisting of hydrogen, alkyl, ( halogen, and alkoxy. Rs represents a radical selected from the group consisting of an alkyl (C-C) group, cycloalkyl, and then L is —OC(O)— and R is optionally substituted ali cycloalkylalkyl; R represents a radical selected from the phatic, or at least one of R, R and R7 is (optionally substi group consisting of a substituted or unsubstituted aryl group tuted aliphatic group, optionally Substituted cyclic group or and a substituted or unsubstituted heteroaryl group; R, rep optionally Substituted aromatic group)(optionally Substituted resents a radical selected from the group consisting of dialkyl ethanediyl), or R is optionally substituted aliphatic. amino, a substituted or unsubstituted arylamino, a substituted or unsubstituted heteroarylamino, and a Substituted or unsub HCV-796 stituted aryl group, said monoalkylamino Substituents being one or more radical(s) independently selected from the group 0248. In certain embodiments, HCV-796 or an analog consisting of cycloalkyl, hydroxy, alkoxy, and a Substituted or thereof can be used in the compositions, methods, and kits of unsubstituted heterocyclic radical; said arylamino Substitu the invention. HCV-796 is a non-nucleoside polymerase ents and said heteroarylamino Substituents being one or more inhibitor. The structure of HCV-796 is: radical(s) independently selected from an alkyl group and an alkoxycarbonyl, said Sulfonamide Substituents being one or

more radical(s) independently selected from the group con sisting of alkenyl, cycloalkyl, alkoxy, hydroxy, halogen, poly fluoroalkyl, polyfluoroalkoxy, carboxyl, alkylcarbonyl, alkoxycarbonyl, carboxamide, a Substituted or unsubstituted aryl group, and a substituted or unsubstituted heterocyclic radical; said heterocycloSulfonyl Substituents being one or more radical(s) independently selected from the group con sisting of alkoxy and hydroxy, said alkyl radical Substituents and said alkoxy group Substituents being one or more radical (s) independently selected from the group consisting of alk enyl, amino, monoalkylamino, dialkyl amino, alkoxy, cycloalkyl, hydroxy, carboxyl, halogen, cyano, polyfluoro alkyl, polyfluoroalkoxy, Sulfonamide, carboxamide, alkylsul 0249 Analogs of HCV-796 are described for example, in fonyl, alkylcarbonyl, alkoxycarbonyl, mercapto, 2,2-dim U.S. Pat. No. 7,265,152 and have the general structure: ethyl-4-oxo-4H-benzo. 1.3dioxinyl, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heterocyclic radical, said heterocyclic radical Substituents O Rs R A being one or more radical(s) independently selected from the NH group consisting of alkyl, amino, amido, monoalkylamino, cycloalkyl-alkylamino, dialkylamino, alkoxy, alkoxyalkyl, R hydroxy, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, car boxyl, carboxamide, halogen, haloalkyl, cyano, polyfluoro alkyl, polyfluoroalkoxy, alkylsulfonyl, alkylcarbonyl, R O cycloalkylcarbonyl, alkoxycarbonyl, mercapto, oxo, a Substi R4 tuted or unsubstituted aryl group, arylalkyl, and a Substituted or unsubstituted heteroaryl group; said heteroaryl group Sub stituents being one or more radical(s) independently selected US 2008/O161324 A1 Jul. 3, 2008 70 from the group consisting of alkyl, amino, alkoxy, alkoxy alkyl, hydroxy, hydroxyalkyl, cycloalkyl, carboxyl, carboxa -continued mide, halogen, polyfluoroalkyl, polyfluoroalkoxy, alkylsul X X fonyl, mercapto, and oxo; said benzyloxy group Substituents being one or more radical(s) independently selected from the group consisting of alkyl, alkoxy, polyfluoroalkyl, polyfluo roalkoxy, hydroxy, carboxyl, alkoxycarbonyl, halogen, cyano, alkylsulfonyl, and phenyl; said aryl group Substituents X X being one or more radical(s) independently selected from the group consisting of alkyl, acetylenyl, alkoxy, hydroxy, halo gen, polyfluoroalkyl, polyfluoroalkoxy, cyano, amino, wherein each X is the number of hydrogenatoms necessary to monoalkylamino, dialkylamino, aminoalkyl, alkoxyalkoxy, complete proper Valence; and B optionally comprises up to 3 amido, amidoalkyl, carboxyl, alkylsulfonyl, alkylcarbonyl, substituents, wherein: the first of said substituents, if present, is selected from R', R, R or R, the second of said substitu alkoxycarbonyl, mercapto, and a heterocyclic radical; and ents, if present, is selected from R' or R', and the third of said pharmaceutically acceptable salts thereof; substituents, if present, is R'; and D is selected from C(O), C(S), or S(O); wherein each R" is independently selected Merimepodib (VX-497) from 1.2-methylenedioxy, 1.2-ethylenedioxy, R or (CH.) 0250 In certain embodiments, merimepodibor an analog Y; wherein n is 0, 1 or 2; and Y is selected from halogen, thereof can be used in the compositions, methods, and kits of CN, NO, CF, OCF, OH, SR, S(O)R°, SOR, NH, the invention. Merimepodib is an inhibitor of inosine-5'- NHR, N(R), NRR, COOH, COOR or OR; each R is monophosphate dehydrogenase (IMPDH) and is used to treat independently selected from (C-C)-straight or branched HCV. The structure of merimepodib is: alkyl, or (C-C)-straight or branched alkenyl or alkynyl; and each R optionally comprises up to 2 substituents, wherein the first of said substituents, if present, is selected from R', R' and R, and the second of said substituents, if present, is R'; R is selected from a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, O, or S, and wherein a CH adjacent to any of said N. O, or Sheteroatoms is optionally substituted with C(O); and & circle each R optionally comprises up to 3 substituents, wherein the first of said substituents, if present, is selected from R', R. R' or R, the second of said substituents, if present, is Analogs of merimepodib are described for example, in U.S. selected from R' or R', and the third of said substituents, if Pat. No. 6,541.496 and have the general structure: present, is R'; each R is independently selected from OR, OC(O)R, OC(O)R, OC(O)OR, OC(O)OR, OC(O)N(R) A N. -DS - B OP(O)(OR), SR, SR, S(O)R, S(O)R, SOR, SOR, N N SON(R), SONRR, SOR, C(O)R, C(O)CR, C(O) H H R°, C(O)OR, NC(O)C(O)R, NC(O)C(O)R, NC(O)C(O) OR, NC(O)C(O)N(R), C(O)N(R), C(O)N(OR)R, wherein A is selected from (C-C)-straight or branched C(O)N(OR)R, C(NOR)R, C(NOR)R, N(R), NRC alkyl, or (C-C)-straight or branched alkenyl or alkynyl; and (O)R', NRC(O)R, NRC(O)R, NRC(O)OR, NRC(O) A optionally comprises up to 2 Substituents, wherein the first OR, NRC(O)N(R), NRC(O)NRR, NRSOR, of said substituents, if present, is selected from R' or R, and NRSOR, NRSON(R), NRSONRR, N(OR)R, the second of said substituents, if present, is R'; B is a satu N(OR)R, P(O)(OR)N(R), and P(O)(OR); each R is a rated, unsaturated or partially saturated monocyclic or bicy monocyclic or a bicyclic ring system consisting of 5 to 6 clic ring system optionally comprising up to 4 heteroatoms members per ring, wherein said ring system optionally com selected from N, O, or S and selected from the formulae: prises up to 4 heteroatoms selected from N, O, or S, and wherein a CH adjacent to said N, O or S maybe substituted with C(O); and each Roptionally comprises up to 3 substitu ents, each of which, if present, is R'; each Risindependently selected from H., (C-C)-straight or branched alkyl, or (C- C.) straight or branched alkenyl; and each Roptionally com prises a substituent that is R'; R is a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, O, or S, and wherein a CH adjacent to said N, O or S maybe substituted with C(O); and each Roption ally comprises up to 2 substituents independently chosen from H. (C-C)-straight or branched alkyl, (C-C) straight or branched alkenyl, 1.2-methylenedioxy, 1.2-ethylenedioxy, --O--O) or (CH)-Z; wherein n is 0, 1 or 2; and Z is selected from halogen, CN, NO, CF. OCF, OH, S(C-C)-alkyl, SO(C- US 2008/O161324 A1 Jul. 3, 2008

C)-alkyl, SO(C-C)-alkyl, NH, NH(C-C)-alkyl, N((C- wherein Y is selected from the group consisting of the fol Cl)-alkyl), N(C-C)-alkyl)R, COOH, C(O)O(C-C)- lowing moieties: alkyl, alkyl-aryl, heteroalkyl, heteroaryl, alkyl or O(C-C)-alkyl; and R is an aminoprotecting group; aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl and wherein any carbonatom in any A, R or R is optionally aryloxy, aryloxy, heteroaryloxy, heterocycloalkyloxy, replaced by O, S, SO, SO, NH, or N(C-C)-alkyl. cycloalkyloxy, alkylamino, arylamino, alkyl-arylamino, ary Valopicitabine lamino, heteroarylamino, cycloalkylamino and heterocy 0251. In certain embodiments, valopicitabine (NM-283) cloalkylamino, with the proviso that Y may be optionally or an analog thereof can be used in the compositions, meth Substituted with X or X; X is alkyl, alkenyl, alkynyl, ods, and kits of the invention. Valopicitabine is a hepatitis C cycloalkyl, cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, therapy that acts as a polymerase inhibitor. Valopicitabine is aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or het an orally available prodrug of 2'-C-methylcytidine. The struc eroarylalkyl, with the proviso that X may be additionally ture of valopicitabine is: optionally Substituted with X, X is hydroxy, alkoxy, ary loxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfona mido, carboxy, carbalkoxy, carboxamido, alkoxycarbony NN lamino, alkoxycarbonyloxy, alkylureido, arylureido, halo gen, cyano, or nitro, with the proviso that said alkyl, alkoxy, and aryl may be additionally optionally substituted with moi eties independently selected from X; R is CORs or B(OR) wherein Rs is H, OH, ORs, NRoRo CF, CFs, CF, CF, R or COR, wherein R, is H, OH, ORs, CHRR, or NRRo, wherein R. R. R. and Ro are independently selected from the group consisting of H, alkyl, aryl, het eroalkyl, heteroaryl, cycloalkyl, cycloalkyl, arylalkyl, het eroarylalkyl, ICH(R')COOR, ICH(R')CONR,R, ICH(R')SO.R. [CH(R')COR, ICH(R')CH(OH) Analogs of valopicitabine are described, for example, in U.S. R. CH(R')CONHCH(R')COO R. CH(R')CONHCH Pat. Application Publication No. 2007/0015905, which is (R')CON RR CH(R')CONHCH(R)R CH(R') hereby incorporated by reference. CONHCH(R')CONHCH(R')COOR, CH(R')CONHCH Boceprevir (SCH 5.03034) (R')CONHCH(R')CONRR, CH(R')CONHCH(R') 0252) In certain embodiments, boceprevir (SCH 503034) CONHCH(R)CONHCH(R)COO RCH(R')CONHCH or an analog thereof can be used in the compositions, meth (R')CONHCH(R')CONHCH(R)CONRR.-sup. 13, ods, and kits of the invention. Boceprevir is a hepatitis C CH(R')CONHCH(R)CONHCH(R)CONHCH(R) therapy that acts as a inhibitor of the NS3-serine protease. The CONHCH (R')COO R and CH(R')CONHCH(R') structure of boceprevir is: CONHCH(R')CON HCH(R)CONHCH(R') CONRR, wherein R. R. R. R. R. R. R. R. and R" are independently selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkyl-heteroaryl, aryl-alkyl and heteroaralkyl; Z is selected from O, N, CH or CR; W may be present or absent, and if W is present, W is selected from C—O, C-S, C(=N-CN), or SO, Q may be present or absent, and when Q is present, Q is CH, N, P. (CH,), (CHR), (CRR), O, NR, S, or SO.; and when Q is absent, M may be present or absent; when Q and M are absent, A is directly linked to L: A is O, CH, (CHR), (CHR-CHR), (CRR), NR, S, SO, or a bond; E is CH, N, CR, or a double bond towards A. L or G: G may be present or absent, and when G is present, G is (CH2), (CHR), or Analogs of boceprivir are described, for example, in U.S. Pat. (CRR), and when G is absent, J is present and E is directly Application Publication No. 2004/0254117 and have the gen connected to the carbon atom in Formula I as G is linked to: eral structure: J maybe present or absent, and when J is present, J is (CH2). (CHR), or (CRR), SO, NH, NRor O; and when Jis absent, G is present and E is directly linked to N shown in Formula I /NA as linked to J. L. may be present or absent, and when L is present, L is CH, CR. O.S or NR; and when L is absent, then Y. 1. E M may be present or absent; and if M is present with L being Yw O / Y. absent, then M is directly and independently linked to E, and y \ N. R. J is directly and independently linked to E:M may be present R1 N or absent, and when Mis present, Mis O, NR, S, SO, (CH.), (CHR)(CHR CHR), or (CRR); p is a number from 0 to R3 O R 6; and R. R. R. R. and Ra are independently selected from the group consisting of H; C-Co alkyl, C-Co alkenyl: C-Cs cycloalkyl: Cs-Cs heterocycloalkyl, alkoxy, aryloxy, US 2008/O161324 A1 Jul. 3, 2008 72 alkylthio, arylthio, amino, amido, ester, carboxylic acid, car 455. Ifenprodil analogs are described in U.S. Pat. No. 3,509, bamate, urea, ketone, aldehyde, cyano, nitro, halogen; (cy 164. Indocyanine green analogs are described in U.S. Pat. No. cloalkyl)alkyl and (heterocycloalkyl)alkyl, wherein said 2.895,955. Lophenoxic acid analogs are described in British cycloalkyl is made of three to eight carbonatoms, and Zero to patent GB726987. Isosulfan blue analogs include sulfan blue. six oxygen, nitrogen, Sulfur, or phosphorus atoms, and said Mycophenolic acid analogs are described in U.S. Pat. Nos. 3,705,894, 3,903,071, 4,686,234, 4,725,622, 4,727,069, alkyl is of one to six carbon atoms: aryl; heteroaryl; alkyl 4,753,935, 4,786,637, 4,808,592, 4,861,776, 4,868,153, aryl; and alkyl-heteroaryl; wherein said alkyl, heteroalkyl, 4,948,793, 4,952,579, 4,959,387, 4,992,467, 5,247,083, alkenyl, heteroalkenyl, aryl, heteroaryl, cycloalkyl and het 5,380,879, 5,441,953, 5,444,072, 5,493,030, 5,538,969, erocycloalkyl moieties may be optionally and chemically 5,512,568, 5,525,602, 5,554,612, 5,633.279, 6,399,773, suitably substituted, with said term “substituted” referring to 6,420,403, 6,624,184, 6,916,809, 6,919,335, 7,053,111, and optional and chemically-suitable substitution with one or U.S. patent application Ser. No. 07/927,260. Narasin analogs more moieties selected from the group consisting of alkyl, are described in U.S. Pat. Nos. 4,035,481, 4,038,384, 4,141, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclic, halo 907, 4,174.404, 4,204,039, and 5,541,224. Oxeladin analogs gen, hydroxy, thio, alkoxy, aryloxy, alkylthio, arylthio. are described in U.S. Pat. No. 2,885,404. Oxfendazole ana amino, amido, ester, carboxylic acid, carbamate, urea, logs are described in U.S. Pat. No. 3,929,821. Oxibendazole ketone, aldehyde, cyano, nitro, Sulfonamido, Sulfoxide, Sul analogs are described in U.S. Pat. No. 3,574,845. Perospirone fone, Sulfonyl urea, hydrazide, and hydroxamate; further analogs are described in U.S. Pat. No. 4,745,117. Picotamide analogs are described in French patent FR2100850. Pramox wherein said unit N-C-G-E-L-J-N represents a five-mem ine analogs are described in U.S. Pat. No. 2,870,151. Quina bered or six-membered cyclic ring structure with the proviso crine analogs are described in U.S. Pat. Nos. 2,113,357, that when said unit N-C-G-E-L-J-N represents a five-mem 1782,727, and 1,889,704. Repaglinide analogs are described bered cyclic ring structure, or when the bicyclic ring structure in International Application Publication No. WO 93/00337. in Formula I comprising N. C. G. E. L. J. N., A, Q, and M Rifaximin analogs are described in U.S. Pat. No. 4.341,785. represents a five-membered cyclic ring structure, then said Silver sulfadiazine analogs are described in U.S. Pat. Nos. five-membered cyclic ring structure lacks a as 2,407,966 2.410,793. Terconazole analogs are described in part of the cyclic ring. U.S. Pat. Nos. 4,144.346 and 4.223,036. Tioxolone analogs are described in U.S. Pat. Nos. 2,332,418 and 2,886,488. Tirapazamine analogs are described in U.S. Pat. No. 3,868, 371. Tiratricol analogs are described in British patent Nos. 0253) In certain embodiments, an interferon or an analog GB803149 GB805761. Toremifene analogs are described in thereof can be used in the compositions, methods, and kits of U.S. Pat. No. 4,696,949. Vincristine analogs are described in the invention. Intefereons includes interferon-C, interferon U.S. Pat. No. 4,144.237. Zafirlukast analogs are described in alfa-2a, interferon alfa-2b, interfereon alfa-2c, interferon U.S. Pat. No. 4,859,692. alfacon-1, interferon alfa-n1, interferon alfa-n3, intefereon-?3. interferon B-1a, interferon B-1b, interferon-Y, interferon Y-1a, Conjugates interferon Y-1b, and pegylated forms thereof. 0255 If desired, the agents used in any of the combina tions described herein may be covalently attached to one Miscellaneous Agents another to form a conjugate of formula I. 0254 Albendazole analogs are described in U.S. Pat. Nos. (A)-(L)-(B) (I) 5,468,765, 5,432,187, 4,299,837, 4,156,006, and 4,136,174. Amitraz, analogs are described in U.S. Pat. No. 3,781,355. 0256 Informula I, (A) is a drug listed on Table 1, Table 2, Betaxolol analogs are described in U.S. Pat. No. 4,252.984. or Table 3 covalently tethered via a linker (L) to (B), a second Bromhexine analogs are described in U.S. Pat. Nos. 3,408, drug listed on Table 1, Table 2, Table 3, Table 4, or Table 5. 446 and 4,191,780 and Belgian patent BE625002. Bro 0257 Conjugates of the invention can be administered to a mocriptine analogs are described in U.S. Pat. No. 4,145.549. subject by any route and for the treatment of viral hepatitis Capsaicin analogs are described in U.S. Pat. No. 4,812,446. (e.g., those described herein). Carbaryl analogs are described in U.S. Pat. No. 2.903,478. 0258. The conjugates of the invention can be prodrugs, Chloroquine analogs are described in U.S. Pat. No. 2.233, 970. Cladribine (2-chloro-2'-deoxyadenosine) analogs are releasing drug (A) and drug (B) upon, for example, cleavage described in U.S. Pat. Nos. 4,760,137, 5,208,327, 6,252,061, of the conjugate by intracellular and extracellular enzymes 6,596,858, and 6,884,880. Clomiphene analogs are described (e.g., amidases, esterases, and phosphatases). The conjugates in U.S. Pat. No. 2.914,563. Cyclocytidine analogs are of the invention can also be designed to largely remain intact described in U.S. Pat. No. 3,463,850. Dibucaine analogs are in vivo, resisting cleavage by intracellular and extracellular described in U.S. Pat. No. 1,825,623. Dicyclomine analogs enzymes. The degradation of the conjugate in Vivo can be are described in U.S. Pat. No. 2,474,796. Dilazep analogs are controlled by the design of linker (L) and the covalent bonds described in U.S. Pat. No. 3.532,685. Diphenidol analogs are formed with drug (A) and drug (B) during the synthesis of the described in U.S. Pat. No. 2,411,664. Donepezil analogs are conjugate. described in U.S. Pat. No. 4,895.841. Emetine analogs are 0259 Conjugates can be prepared using techniques famil described in U.S. Pat. No. 3,102,118. Exemestane analogs are iar to those skilled in the art. For example, the conjugates can described in U.S. Pat. No. 4,808,616. Ezetimibe analogs are described in U.S. Pat. No. 5,767,115. Fenbendazole analogs be prepared using the methods disclosed in G. Hermanson, are described in U.S. Pat. No. 3.954,791. Fenretinide analogs Bioconjugate Techniques, Academic Press, Inc., 1996. The are described in U.S. Pat. No. 4,190,594. Fenvalerate analogs synthesis of conjugates may involve the selective protection are described in U.S. Pat. No. 3,996,244. Flubendazole ana and deprotection of , amines, , sulfhydryls or logs are described in U.S. Pat. No. 3,657.267 and German carboxyl functional groups of drug (A), the linker, and/or patent DE2029637. Fludarabine analogs are described in drug (B). For example, commonly used protecting groups for U.S. Pat. No. 5,034,518. Fluorouracil analogs are described amines include carbamates, such as tert-butyl, benzyl, 2.2.2- in U.S. Pat. Nos. 2,802,005, 2,885,396, 4,092,313, and 4,080, trichloroethyl 2-trimethylsilylethyl, 9-fluorenylmethyl, US 2008/O161324 A1 Jul. 3, 2008 allyl, and m-nitrophenyl. Other commonly used protecting group, may be considered as Sulfhydryl reagents if linking groups for amines include amides, such as formamides, occurs through the formation of disulfide bridges. acetamides, trifluoroacetamides, Sulfonamides, trifluo 0264. Examples of reactive moieties capable of reaction romethanesulfonyl amides, trimethylsilylethanesulfona with amino groups include, for example, alkylating and acy mides, and tert-butylsulfonyl amides. Examples of com lating agents. Representative alkylating agents include: monly used protecting groups for carboxyls include esters, 0265 (i) C-haloacetyl compounds, which show specificity such as methyl, ethyl, tert-butyl, 9-fluorenylmethyl 2-(trim towards amino groups in the absence of reactive thiol groups ethylsilyl)ethoxy methyl, benzyl, diphenylmethyl, O-ni and are of the type XCH-CO (where X—Br, Cl, or I), for trobenzyl, ortho-esters, and halo-esters. Examples of com example, as described by Wong Biochemistry 24:5337 monly used protecting groups for alcohols include ethers, (1979); Such as methyl, methoxymethyl, methoxyethoxymethyl, 0266 (ii) N-maleimide derivatives, which may react with methylthiomethyl, benzyloxymethyl, tetrahydropyranyl, amino groups either through a Michael type reaction or ethoxyethyl, benzyl, 2-napthylmethyl, O-nitrobenzyl, P-ni through acylation by addition to the ring carbonyl group, for trobenzyl, P-methoxybenzyl, 9-phenylxanthyl, trityl (includ example, as described by Smyth et al., J. Am. Chem. Soc. ing methoxy-trityls), and silyl ethers. Examples of commonly 82:4600 (1960) and Biochem. J. 91:589 (1964); used protecting groups for sulfhydryls include many of the 0267 (iii) aryl halides such as reactive nitrohaloaromatic same protecting groups used for hydroxyls. In addition, Sulf compounds; hydryls can be protected in a reduced form (e.g., as disulfides) 0268 (iv) alkyl halides, as described, for example, by oran oxidized form (e.g., as Sulfonic acids, Sulfonic esters, or McKenzie et al., J. Protein Chem. 7:581 (1988); Sulfonic amides). Protecting groups can be chosen Such that 0269 (v) and ketones capable of Schiff's base selective conditions (e.g., acidic conditions, basic conditions, formation with amino groups, the adducts formed usually catalysis by a nucleophile, catalysis by a lewis acid, or hydro being stabilized through reduction to give a stable amine; genation) are required to remove each, exclusive of other 0270 (vi) epoxide derivatives such as epichlorohydrin and protecting groups in a molecule. The conditions required for bisoxiranes, which may react with amino, Sulfhydryl, or phe the addition of protecting groups to amine, alcohol, Sulfhy nolic hydroxyl groups; dryl, and carboxyl functionalities and the conditions required 0271 (vii) chlorine-containing derivatives of s-triazines, for their removal are provided in detail in T. W. Green and P. which are very reactive towards nucleophiles such as amino, G. M. Wuts, Protective Groups in Organic Synthesis (2" Sufhydryl, and hydroxyl groups; Ed.), John Wiley & Sons, 1991 and P.J. Kocienski, Protecting 0272 (viii) aziridines based on s-triazine compounds Groups, Georg Thieme Verlag, 1994. Additional synthetic detailed above, e.g., as described by Ross, J. Adv. Cancer Res. details are provided below. 2:1 (1954), which react with nucleophiles such as amino groups by ring opening: Linkers 0273 (ix) squaric acid diethyl esters as described by Tietze, Chem. Ber: 124:1215 (1991); and 0260 The linker component of the invention is, at its sim 0274 (x) O-haloalkyl ethers, which are more reactive plest, a bond between drug (A) and drug (B), but typically alkylating agents than normal alkyl halides because of the provides a linear, cyclic, or branched molecular skeleton hav activation caused by the ether oxygen atom, as described by ing pendant groups covalently linking drug (A) to drug (B). Benneche et al., Eur: J. Med. Chem. 28:463 (1993). 0261 Thus, linking of drug (A) to drug (B) is achieved by 0275 Representative amino-reactive acylating agents covalent means, involving bond formation with one or more include: functional groups located on drug (A) and drug (B). 0276 (i) isocyanates and , particularly Examples of chemically reactive functional groups which aromatic derivatives, which form stable urea and thiourea may be employed for this purpose include, without limitation, derivatives respectively; amino, hydroxyl, Sulfhydryl, carboxyl, carbonyl, carbohy 0277 (ii) sulfonyl chlorides, which have been described drate groups, vicinal diols, thioethers, 2-aminoalcohols, by Herzig et al., Biopolymers 2:349 (1964); 2-aminothiols, guanidinyl, imidazolyl, and phenolic groups. (0278 (iii) acid halides; 0262 The covalent linking of drug (A) and drug (B) may 0279 (iv) active esters such as nitrophenylesters or N-hy be effected using a linker which contains reactive moieties droxysuccinimidyl esters; capable of reaction with Such functional groups present in 0280 (v) acid anhydrides such as mixed, symmetrical, or drug (A) and drug (B). For example, an amine group of drug N-carboxyanhydrides; (A) may react with a carboxyl group of the linker, or an 0281 (vi) other useful reagents foramide bond formation, activated derivative thereof, resulting in the formation of an for example, as described by M. Bodansky, Principles of amide linking the two. Peptide Synthesis, Springer-Verlag, 1984; 0263. Examples of moieties capable of reaction with sulf 0282 (vii) acylazides, e.g., wherein the azide group is hydryl groups include O.-haloacetyl compounds of the type generated from a preformed hydrazide derivative using XCHCO— (where X—Br, Cl, or I), which show particular sodium nitrite, as described by Wetz et al., Anal. Biochem. reactivity for sulfhydryl groups, but which can also be used to 58:347 (1974); and modify imidazolyl, thioether, , and amino groups as 0283 (viii) imidoesters, which form stable amidines on described by Gurd, Methods Enzymol. 11:532 (1967). N-Ma reaction with amino groups, for example, as described by leimide derivatives are also considered selective towards Sulf Hunter and Ludwig, J. Am. Chem. Soc. 84:3491 (1962). hydryl groups, but may additionally be useful in coupling to 0284 Aldehydes and ketones may be reacted with amines amino groups under certain conditions. Reagents such as to form Schiff's bases, which may advantageously be stabi 2-iminothiolane (Traut et al., Biochemistry 12:3266 (1973)), lized through reductive amination. Alkoxylamino moieties which introduce a thiol group through conversion of an amino readily react with ketones and aldehydes to produce stable US 2008/O161324 A1 Jul. 3, 2008 74 alkoxamines, for example, as described by Webb et al., in 0292 Examples of homobifunctional linkers useful in the Bioconjugate Chem. 1:96 (1990). preparation of conjugates of the invention include, without 0285 Examples of reactive moieties capable of reaction limitation, diamines and diols selected from ethylenedi with carboxyl groups include diazo compounds such as dia amine, propylenediamine and hexamethylenediamine, ethyl Zoacetate esters and diazoacetamides, which react with high ene glycol, diethylene glycol, , 1,4-butane specificity to generate ester groups, for example, as described diol, 1.6-hexanediol, cyclohexanediol, and polycaprolactone by Herriot, Adv. Protein Chem. 3:169 (1947). Carboxyl modi diol. fying reagents such as carbodiimides, which react through Formulation of Pharmaceutical Compositions O-acylurea formation followed by amide bond formation, may also be employed. 0293. The compositions, methods, and kits of the inven 0286. It will be appreciated that functional groups in drug tion can include formulation(s) of compound(s) that, upon (A) and/or drug (B) may, if desired, be converted to other administration to a subject, result in a concentration of the functional groups prior to reaction, for example, to confer compound(s) that treats a viral hepatitis infection. The com additional reactivity or selectivity. Examples of methods use pound(s) may be contained in any appropriate amount in any ful for this purpose include conversion of amines to carboxyls Suitable carrier Substance, and are generally present in an using reagents such as dicarboxylic anhydrides; conversion amount of 1-95% by weight of the total weight of the com of amines to thiols using reagents such as N-acetylhomocys position. The composition may be provided in a dosage form teine thiolactone, S-acetylmercaptosuccinic anhydride, that is Suitable for the oral, parenteral (e.g., intravenously or 2-iminothiolane, or thiol-containing Succinimidyl deriva intramuscularly), rectal, determatological, cutaneous, nasal, tives; conversion of thiols to carboxyls using reagents such as vaginal, inhalant, skin (patch), ocular, intrathecal, or intrac C-haloacetates; conversion of thiols to amines using reagents ranial administration route. Thus, the composition may be in Such as ethylenimine or 2-bromoethylamine; conversion of the form of, e.g., tablets, capsules, pills, powders, granulates, carboxyls to amines using reagents such as carbodiimides Suspensions, emulsions, Solutions, gels including hydrogels, followed by diamines; and conversion of alcohols to thiols pastes, ointments, creams, plasters, drenches, osmotic deliv using reagents such as tosyl chloride followed by transesteri ery devices, Suppositories, enemas, injectables, implants, fication with thioacetate and hydrolysis to the thiol with sprays, or aerosols. The pharmaceutical compositions may be Sodium acetate. formulated according to conventional pharmaceutical prac tice (see, e.g., Remington: The Science and Practice of Phar 0287 So-called Zero-length linkers, involving direct cova macy, 20th edition, 2000, ed. A. R. Gennaro, Lippincott Wil lent joining of a reactive chemical group of drug (A) with a liams & Wilkins, Philadelphia, and Encyclopedia of reactive chemical group of drug (B) without introducing addi Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boy tional linking material may, if desired, be used in accordance lan, 1988-1999, Marcel Dekker, New York). with the invention. 0294 Pharmaceutical compositions according to the 0288 More commonly, however, the linker will include invention or used in the methods of the invention may be two or more reactive moieties, as described above, connected formulated to release the active compound immediately upon by a spacer element. The presence of Such a spacer permits administration or at any predetermined time or time period bifunctional linkers to react with specific functional groups after administration. The latter types of compositions are within drug (A) and drug (B), resulting in a covalent linkage generally known as controlled release formulations, which between the two. The reactive moieties in a linker may be the include (i) formulations that create Substantially constant same (homobifunctional linker) or different (heterobifunc concentrations of the agent(s) of the invention within the tional linker, or, where several dissimilar reactive moieties are body over an extended period of time; (ii) formulations that present, heteromultifunctional linker), providing a diversity after a predetermined lag time create Substantially constant of potential reagents that may bring about covalent attach concentrations of the agent(s) of the invention within the ment between drug (A) and drug (B). body over an extended period of time; (iii) formulations that 0289 Spacer elements in the linker typically consist of Sustain the agent(s) action during a predetermined time linear or branched chains and may include a Coalkyl, Co period by maintaining a relatively constant, effective level of alkenyl, Co alkynyl, C2-a heterocyclyl, C-2 aryl, C7-14 the agent(s) in the body with concomitant minimization of alkaryl, Coalkheterocyclyl, or Coheteroalkyl. undesirable side effects associated with fluctuations in the 0290. In some instances, the linker is described by formula plasma level of the agent(s) (sawtooth kinetic pattern); (iv) (II): formulations that localize action of agent(s), e.g., spatial placement of a controlled release composition adjacent to or G'-(Z)-(Y)-(Z)-(Ro)-(Z)-(Y?)-(Z)-G’ (II) in the diseased tissue or organ, (v) formulations that achieve 0291. In formula (II), G is a bond between drug (A) and convenience of dosing, e.g., administering the composition the linker; G is a bond between the linker and drug (B): Z', once per week or once every two weeks; and (vi) formulations Z, Z, and Zeach, independently, is selected from O, S, and that target the action of the agent(s) by using carriers or NR-1, R-1 is hydrogen, Calkyl, C2-alkenyl, C2-alkynyl, chemical derivatives to deliver the combination to a particular C2-6 heterocyclyl, C-2 aryl, C7-14 alkaryl, Cao alkhetero target cell type. Administration of compound(s) in the form of cyclyl, or C, heteroalkyl:Y' and Y are each, independently, a controlled release formulation is especially preferred for selected from carbonyl, thiocarbonyl, Sulphonyl, orphospho compounds having a narrow absorption window in the gastro ryl: o, p, s, t, u, and V are each, independently, 0 or 1; and Ro intestinal tract or a relatively short biological half-life. is a Co alkyl, Coalkenyl, C2-io alkynyl, C2-6 heterocy 0295) Any of a number of strategies can be pursued in clyl, C-2 aryl, C7-14 alkaryl, Cao alkheterocyclyl, or Co order to obtain controlled release in which the rate of release heteroalkyl, or a chemical bond linking G-(Z') -(Y)-(Z) outweighs the rate of of the compound in ques T tO -(Z)-(Y)-(Z)-G’. tion. In one example, controlled release is obtained by appro US 2008/O161324 A1 Jul. 3, 2008

priate selection of various formulation parameters and ingre After a suitable time, viral replication or load of these cells is dients, including, e.g., various types of controlled release examined. A decrease in viral replication or viral load iden compositions and coatings. Thus, the compound(s) are for tifies a candidate compound or combination of agents as an mulated with appropriate excipients into a pharmaceutical effective agent for treating a viral disease. composition that, upon administration, releases the com 0301 The agents of the invention are also useful tools in pound(s) in a controlled manner. Examples include single or elucidating mechanistic information about the biological multiple unit tablet or capsule compositions, oil solutions, pathways involved in viral diseases. Such information can Suspensions, emulsions, microcapsules, molecular com lead to the development of new combinations or single agents plexes, microspheres, nanoparticles, patches, and liposomes. for treating, preventing, or reducing a viral disease. Methods known in the art to determine biological pathways can be used Delivery of Compound(s) to determine the pathway, or network of pathways affected by 0296. It is not intended that administration of compounds contacting cells (e.g., hepatic cells) infected with a virus with be limited to a single formulation and delivery method for all the compounds of the invention. Such methods can include, compounds of a combination. The combination can be analyzing cellular constituents that are expressed or repressed administered using separate formulations and/or delivery after contact with the compounds of the invention as com methods for each compound of the combination using, for pared to untreated, positive or negative control compounds, example, any of the above-described formulations and meth and/or new single agents and combinations, or analyzing ods. In one example, a first agent is delivered orally, and a Some other activity of the cell or virus Such as an enzymatic second agent is delivered intravenously. activity, nutrient uptake, and proliferation. Cellular compo nents analyzed can include gene transcripts, and protein Dosages expression. Suitable methods can include standard biochem istry techniques, radiolabeling the compounds of the inven 0297. The dosage of a compound or a combination of tion (e.g., C or Hlabeling), and observing the compounds compounds depends on several factors, including: the admin binding to proteins, e.g., using 2D gels, gene expression pro istration method, the type of viral hepatitis to be treated, the filing. Once identified, such compounds can be used in in vivo severity of the infection, whether dosage is designed to treat models (e.g., knockout or transgenic mice) to further validate or prevent a viral hepatitis infection, and the age, weight, and the tool or develop new agents or strategies to treat viral health of the patient to be treated. disease. 0298 For combinations that include an anti-viral agent in addition to a compound identified herein (e.g., a compound of Exemplary Candidate Compounds Table 1, Table 2, or Table 3), the recommended dosage for the anti-viral agent is can be less than or equal to the recom 0302) Peptide Moieties mended dose as given in the Physician's Desk Reference, 60' 0303 Peptides, peptide mimetics, and peptide fragments Edition (2006). (whether natural, synthetic or chemically modified) are suit 0299. As described above, the compound in question may able for use in the methods of the invention. Exemplary be administered orally in the form of tablets, capsules, elixirs inhibitors include compounds that reduce the amount of a or syrups, or rectally in the form of suppositories. Parenteral target protein or RNA levels (e.g., antisense compounds, administration of a compound is Suitably performed, for dsRNA, ribozymes) and compounds that compete with viral example, in the form of saline solutions or with the compound reproduction machinery (e.g., dominant negative proteins or incorporated into liposomes. In cases where the compound in polynucleotides encoding the same). itself is not sufficiently soluble to be dissolved, a solubilizer 0304 Antisense Compounds Such as ethanol can be applied. The correct dosage of a com 0305 The biological activity of any protein that increases pound can be determined by examining the efficacy of the viral replication, viral RNA or DNA replication, viral RNA compound in viral replication assays, as well as its toxicity in translation, viral protein processing or activity, or viral pack humans. An antiviral agent is usually given by the same route aging can be reduced through the use of an antisense com of administration that is known to be effective for delivering pound directed to RNA encoding the target protein. Antisense it as a monotherapy. For example, when used in combination compounds can be identified using standard techniques. For therapy with a compound of Table 1, Table 2, or Table 3 example, accessible regions of the target the mRNA of the according to the methods of this invention, an agent of Table target enzyme can be predicted using an RNA secondary 4 or Table 5 is dosed in amounts and frequencies equivalent to structure folding program such as MFOLD (M. Zuker, D. H. or less than those that result in its effective monotherapeutic Mathews & D. H. Turner, Algorithms and Thermodynamics SC. for RNA Secondary Structure Prediction: A Practical Guide. Additional Applications In: RNA Biochemistry and Biotechnology, J. Barciszewski & B. F. C. Clark, eds., NATO ASI Series, Kluwer Academic 0300. If desired, the compounds of the invention may be Publishers, (1999)). Sub-optimal folds with a free energy employed in mechanistic assays to determine whether other value within 5% of the predicted most stable fold of the combinations, or single agents, are as effective as the combi mRNA are predicted using a window of 200 bases within nations of the invention in inhibiting a viral disease (e.g., which a residue can find a complimentary base to form a base those described herein) using assays generally known in the pair bond. Open regions that do not form a base pair are art. For example, candidate compounds may be tested, alone Summed together with each Suboptimal fold and areas that are or in combination (e.g., with an agent that inhibits viral rep predicted as open are considered more accessible to the bind lication, such as those described herein) and applied to cells ing to antisense nucleobase oligomers. Other methods for (e.g., hepatic cells such as Huh?, Huh2, Huh 8, Sk-Hep-1, antisense design are described, for example, in U.S. Pat. No. Huh? lunet, HepG2, WRL-68, FCA-1, LX-1, and LX-2). 6,472,521, Antisense Nucleic Acid Drug Dev. 1997 7:439 US 2008/O161324 A1 Jul. 3, 2008 76

444, Nucleic Acids Res. 28:2597-2604, 2000, and Nucleic tion and not an increase in cell death, a counter Screen is run Acids Res. 31:4989-4994, 2003. in tandem. Huh? parental cells which do not express HCV 0306 RNA Interference replicon RNA are treated similarly to the above replicon cells; 0307 The biological activity of a molecule involved in a briefly, seed cells on a 384-well plate at 4,000 cells/well as viral infection or viral replication can be reduced through the described above. Compounds are added the following day use of RNA interference (RNAi), employing, e.g., a double and, after a subsequent 48-hour incubation at 37°C., 5% CO, stranded RNA (dsRNA) or small interfering RNA (siRNA) 15ul/well of ATPlite (PerkinElmer) is added after plates have directed to the signaling molecule in question (see, e.g., been equilibrated at room temperature. The ATPlite assay Miyamoto et al., Prog. Cell Cycle Res. 5:349-360, 2003: U.S. provides a quantitative measure of the levels of ATP in the cell Pat. Application Publication No. 20030157030). Methods for designing such interfering RNAS are known in the art. For cultures in each well, where higher levels of ATP correlate example, Software for designing interfering RNA is available with greater cellular viability. Thus, a compound with antivi from Oligoengine (Seattle, Wash.). ral activity is expected to inhibit the levels of luciferase mea 0308 Dominant Negative Proteins sured by the Steady Lite assay without any or minimal effect 0309. One skilled in the art would know how to make on the ATP levels measured by the ATPlite assay. dominant negative proteins to the molecules involved in a 0313 Using the screen described above or a similar viral infection or viral replication. Such dominant negative screen, we identified the agents listed in Tables 1, 2, and 3 and proteins are described, for example, in Gupta et al., J. Exp. the combinations of agents listed in Table 9. For screens Med., 186:473–478, 1997: Maegawa et al., J. Biol. Chem. involving a combination of compounds, a synergy score was 274:30236-30243, 1999; Woodford-Thomas et al., J. Cell calculated by the formula S-log flog f>I (I-I). Biol. 1 17:401–414, 1992). Summed over all non-single-agent concentration pairs, and 0310. The following example is intended to illustrate where log frare the natural logarithm of the dilution factors rather than limit the invention. used for each single agent. This effectively calculates a Vol ume between the measured and Loewe additive response EXAMPLE surfaces, weighted towards high inhibition and corrected for HCV Replicon Assay varying dilution factors. The synergy score indicates that the combination of the two agents provides greater antiviral 0311. The HCV replicon assay enables screening of com activity than would be expected based on the protection pro pounds with antiviral activity against HCV viral RNA repli vided by each agent of the combination individually. The cation. Huh? cells expressing a subgenomic RNA replicon of following ranges of concentrations of agents were used to Con1 (genotype 1b) sequence origin and expressing the generate the synergy scores in Table 9: Sertraline (0.105-13 reporter enzyme luciferase were obtained from ReBLikon, uM); simvastatin (0.175-22 uM); fluvastatin (0.22-28 uM); GmBH. In order to perform the assay, seed replicon cells on lovastatin (0.06-7.9 uM); rosuvastatin (0.19-24 LM); and a 384-well plate at 4,000 cells/well in a total volume of 30 hydroxyzine (0.21-27 LM). uL/well. The plated cells are incubated at 37° C., 5% CO. Pre-diluted compounds are added at a 10x concentration to TABLE 9 each well to achieve the desired final concentration. Plates are centrifuged at 900xg, 1 minute following the addition of Combinations of compounds compounds. Incubate cells an additional 48 hours at 37°C., 5% CO. Remove plates from the incubator 30 minutes to 1 Compound 1 Compound 2 Synergy Score hour prior to the addition of 25 LL/well of Steady Lite Sertraline hydrochloride Fluvastatin 4.73OS luciferase assay reagent from PerkinElmer in order to equili Sertraline hydrochloride Lovastatin 3.6093 brate plates to room temperature. Following the addition of Sertraline hydrochloride Rosuvastatin calcium 4.4640 Steady Lite reagent, allow cells to incubate for 10 minutes Sertraline hydrochloride Simvastatin 3.0251 prior to collecting data with a luminometer. Antiviral activity Sertraline hydrochloride Hydroxyzine hydrochloride 1.4113 is quantified by the inhibition of luciferase activity. 0312. In order to confirm that a decrease in luciferase 0314. Synergy scores were also identified for the follow activity correlates with inhibition of HCV replicon replica ing combination of compounds (Tables 10 and 11).

TABLE 10 Compound A Compound B Synergy Score Amorolfine Hydrochloride Sertraline Hydrochloride S.2O2 Fluvastatin Sertraline Hydrochloride 4.729 Rosuvastatin calcium Sertraline Hydrochloride 4.481 Fulvestrant Satraplatin 3.562 Amorolfine Hydrochloride Mebeverine Hydrochloride 3.527 Amorolfine Hydrochloride Satraplatin 3.414 Ifenprodil tartrate Sertraline Hydrochloride 3.344 Amorolfine Hydrochloride Tolterodine Tartrate 3.156 Atorvastatin Sertraline Hydrochloride 3.136 Amorolfine Hydrochloride Irinotecan Hydrochloride 3.059 Lovastatin Sertraline Hydrochloride 3.022 Cytarabine Triciribine 2.970 Artesunate Wortmannin 2.964 US 2008/O161324 A1 Jul. 3, 2008 77

TABLE 10-continued Compound A Compound B Synergy Score Sertraline Hydrochloride Simvastatin Hydroxy Acid, 2.955 Ammonium Salt Amorolfine Hydrochloride Cytarabine 2.944 Sertraline Hydrochloride Simvastatin 2.930 Octyl Methoxycinnamate Suberohydroxamic Acid 2.840 1.5-Bis(4-aminophenoxy)pentane Amorolfine Hydrochloride 2.756 (S,S)-N-Desmethyl Sertraline, Simvastatin 2.737 Hydrochloride Artemisinin SB-2021.90 2.689 Interferon Alfa-2a. Sirolimus 2.678 Amorolfine Hydrochloride Indocyanine Green 2.623 TOFA Triciribine 2.606 3,3'-(Pentamethylenedioxy)dianiline Artemisinin 2.6O2 Artemisinin Wortmannin 2.599 3,3'- Artemisinin 2.SS4 (Pentamethylenedioxy)diacetanilide Amorolfine Hydrochloride Benzamil HCL 2.549 Artemisinin Triciribine 2.495 2,2'-(Pentamethylenedioxy)dianiline Amorolfine Hydrochloride 2.494 (S,S)-N-Desmethyl Sertraline, Simvastatin Hydroxy Acid, 2.475 Hydrochloride Ammonium Salt Levothyroxine Sodium Wedelolactone 2.417 5-Bis(4-aminophenoxy)pentane Artemisinin 2.390 Benzami HCL Dextrothyroxine Sodium 2.353 Amorolfine Hydrochloride Trifluperidol 2.321 Artemisinin (ndocyanine Green 2.311 Dihydroartemisinin Wortmannin 2.243 Flupentixol Dihydrochloride Sertraline Hydrochloride 2.185 Benzami HCL Levothyroxine Sodium 2.131 Amorolfine Hydrochloride Meclizine 2.093 Pravastatin Sodium Sertraline Hydrochloride 2.033 5-Bis(4-aminophenoxy)pentane (ndocyanine Green 2.030 2-Hydroxyflavanone Amorolfine Hydrochloride 990 Ritonavir Vinorelbine 989 Benoximate Hydrochloride Dehydroepiandrosterone 975 fenprodil tartrate (ndocyanine Green 930 Amorolfine Hydrochloride Arbidol 911 3,3'-(Pentamethylenedioxy)dianiline (ndocyanine Green 90S Fulvestrant Vinorelbine .902 Amorolfine Hydrochloride Ezetimibe 890 Amorolfine Hydrochloride Evans Blue .885 Amorolfine Hydrochloride Gefitinib (Base) 838 Amorolfine Hydrochloride Topotecan Hydrochloride 810 2'2"- Artemisinin 798 (Pentamethylenedioxy)diacetanilide Amorolfine Hydrochloride Wedelolactone 770 3,3'-(Pentamethylenedioxy)dianiline Amorolfine Hydrochloride 746 Simvastatin rac-cis-N-Desmethyl Sertraline, 744 Hydrochloride Adefovir Dipivoxi Triciribine 741 Cytarabine Evans Blue 714 Artemisinin Evans Blue 664 Fluphenazine Hydrochloride Sertraline Hydrochloride 647 Benzami HCL SB-2021.90 643 Artemisinin Rifabutin 627 Fluphenazine Hydrochloride Tolterodine Tartrate 603 interferon Alfa-2a. Melphalan 537 Amorolfine Hydrochloride Melphalan 535 Artemisinin Fulvestrant 477 fenprodil tartrate Quinacrine 466 Simvastatin Hydroxy Acid, rac-cis-N-Desmethyl Sertraline, 456 Ammonium Salt Hydrochloride Flupentixol Dihydrochloride Tolterodine Tartrate 440 Triciribine Wortmannin 439 Loratadine Vinorelbine 423 Meclizine Sertraline Hydrochloride 358 Budesonide Vinorelbine 356 2-Hydroxyflavanone Indocyanine Green 3O8 Hydroxyzine Hydrochloride Sertraline Hydrochloride .293 2,2'-(Pentamethylenedioxy)dianiline Artemisinin 281 Amorolfine Hydrochloride Flupentixol Dihydrochloride 259 Artemisinin Chlorophyllin .256 Ezetimibe Fluphenazine Hydrochloride 240 Benzami HCL Fluphenazine Hydrochloride 237 US 2008/O161324 A1 Jul. 3, 2008 78

TABLE 10-continued Compound A Compound B Synergy Score Artemisinin Wedelolactone 1228 Cytarabine Dydrogesterone 1.215 Artemisinin Benzamil HCL 1.205 3,3'-(Pentamethylenedioxy)dianiline Artemether 1.169 Tolterodine Tartrate Trifluperidol 1.146 Artesunate Fluvastatin 1.102 Artemisinin Trifluridine 1.095 Adefovir Dipivoxil Amorolfine Hydrochloride 1069 Interferon Alfa-2a. Trifluridine 1.066 Fulvestrant Triciribine 1.032 Artesunate Dydrogesterone 1.032 Artesunate LY 294.002 1.OO6 Mosapride Citrate TOFA O.986 Bromocriptine Mesylate Wedelolactone O.978 Artemisinin Sodium Fusidate O.968 Celgosivir interferon Alfa-2a. O966 Amorolfine Hydrochloride Dextrothyroxine Sodium O.960 Andrographis Fulvestrant O.944 2'-C-Methylcytidine Artemisinin O.937 Amorolfine Hydrochloride Gemcitabine Hydrochloride O.923 Oxeladin Sertraline Hydrochloride O.909 Artemisinin Parthenolide O.903 Artemisinin Ribavirin O.899 Dehydroepiandrosterone Tyrphostin Ag 1478 O.88O Sertraline Hydrochloride Toremifene O.879 Dihydroartemisinin Fulvestrant O.863 2-Hydroxyflavanone TOFA O.860 Artesunate Repaglinide O.854 Mofebutazone Wedelolactone O.842 Artesunate Simvastatin O.841 2,2'-(Pentamethylenedioxy)dianiline Artesunate O.821 Artemisinin Gemcitabine Hydrochloride O.82O Dihydroartemisinin Ezetimibe O.812 Chlorophyllin Cytarabine O811

TABLE 11 TABLE 11-continued Compound A Compound B Synergy Score Compound A Compound B Synergy Score Interferon Alfa-2a. Sirolimus 2.678 Capsaicin NM-283 1112 Suberohydroxamic Acid VX-497 2.113 SCHSO3O34 Sirolimus 1.1OS Artemisinin VX-497 2.103 LY 2940O2 SCHSO3O34 1.073 Artesunate VX-497 692 Adefovir Dipivoxil SCHSO3O34 1.072 Tolterodine Tartrate VX-950 689 Interferon Alfa-2a. Trifluridine 1.066 Artemisinin HCV-796 683 HCV-796 Trifluridine 1.06S Artemisinin NM-283 681 GW 5074 NM-283 1.061 NM-283 Wedelolactone 667 Mosapride Citrate VX-950 1.057 Artemisinin SCHSO3O34 .654 Interferon Alfa-2a. VX-497 1.017 Cytarabine SCHSO3O34 S62 NM-283 Trequinsin Hydrochloride O.990 SCHSO3O34 Triciribine S49 Cytarabine HCV-796 O.989 Interferon Alfa-2a. Melphalan 537 Adefovir Dipivoxil VX-950 O.961 Benoximate Hydrochloride VX-950 432 Cytarabine VX-950 O.956 HCV-796 Sirolimus 412 SCHSO3O34 Saquinavir Mesylate O.948 Benoximate Hydrochloride SCH 5.03034 4O1 VX-950 Wortmannin O.941 Melphalan VX-950 397 Capsaicin VX-950 O.938 Ritonavir VX-950 388 2-Hydroxyflavanone NM-283 O.935 VX-950 VX-497 3S4 Bromhexine VX-950 O.935 Artemisinin VX-950 343 HCV-796 Wortmannin O.915 Triciribine VX-950 3OS Artemisinin Ribavirin O.899 Suberohydroxamic Acid VX-950 277 VX-950 Verapamil O.895 HCV-796 Suberohydroxamic Acid 259 SCHSO3O34 Verapamil O.88O Sirolimus VX-950 245 SCHSO3O34 Topotecan Hydrochloride O.879 Melphalan SCHSO3O34 .224 HCV-796 Topotecan Hydrochloride 0.875 SCHSO3O34 Wortmannin 212 Trifluperidol VX-950 O.866 SCHSO3O34 Tolterodine Tartrate 188 Irinotecan Hydrochloride SCHSO3O34 O.864 Ritonavir SCHSO3O34 160 Artesunate SCHSO3O34 O.849 Ezetimibe VX-950 160 Repaglinide SCHSO3O34 O.845 HCV-796 VX-497 .146 Topotecan Hydrochloride VX-950 O.839 Chlorophyllin VX-497 .144 Repaglinide VX-950 O.82S HCV-796 Melphalan 143 Arbidol VX-950 O.821 US 2008/O161324 A1 Jul. 3, 2008 79

7. The composition of claim 3, wherein said hepatic virus TABLE 11-continued is hepatitis A, hepatitis B, hepatitis C, hepatitis D, or hepatitis E. Compound A Compound B Synergy Score 8. The composition of claim 2, wherein said viral disease is Chlorophyllin HCV-796 0.813 hepatitis A, hepatitis B, hepatitis C, hepatitis D, or hepatitis E. Benzydamine hydrochloride VX-950 O.800 9. The composition of claim 1, further comprising one or NM-283 Trifluperidol O.798 Capsaicin HCV-796 0.755 more additional agents selected the agents of Table 4 and NM-283 Hydrochloride Phenazopyridine O.692 Table 5. NM-283 Trifluridine O.688 10. The composition of claim 1, wherein said composition Adefovir Dipivoxil HCV-796 O.672 is formulated for oral administration. 11. The composition of claim 1, wherein said composition is formulated for systemic administration. Other Embodiments 12. The composition of claim 1, wherein said composition is formulated for parenteral administration. 0315 All publications, patent applications, and patents 13. A composition comprising Sertraline and an HMG mentioned in this specification are herein incorporated by CoA reductase inhibitor. reference. 0316 Various modifications and variations of the 14. The composition of claim 13, wherein said HMG-CoA described method and system of the invention will be appar reductase inhibitor is fluvastatin, simvastatin, lovastatin, or ent to those skilled in the art without departing from the scope rosuvastatin. and spirit of the invention. Although the invention has been 15. A composition comprising Sertraline and an antihista described in connection with specific desired embodiments, it 1C. should be understood that the invention as claimed should not 16. The composition of claim 15, wherein said antihista be unduly limited to such specific embodiments. Indeed, vari mine is hydroxy Zine. ous modifications of the described modes for carrying out the 17. A composition comprising a pair of agents selected invention that are obvious to those skilled in the fields of from the group consisting of amorolfine and Sertraline; fluv molecular biology, medicine, immunology, pharmacology, astatin and Sertraline; rosuvastatin and Sertraline; fulvestrant Virology, or related fields are intended to be within the scope and satraplatin; amorolfine and mebeverine; amorolfine and of the invention. satraplatin; ifenprodil and Sertraline; amorolfine and toltero dine; atorvastatin and sertraline; amorolfine and irinotecan; What is claimed is: lovastatin and Sertraline; cytarabine and triciribine; artesu 1. A composition comprising: nate and wortmannin; Sertraline and simvastatin hydroxy (a) a first agent selected from the agents of Table 1, Table 2, acid, ammonium salt; amorolfine and cytarabine; Sertraline and Table 3; and and simvastatin; octyl methoxycinnamate and Suberohydrox (b) a second agent selected from the agents of Table 4 and amic acid; 1,5-bis(4-aminophenoxy) pentane and amorolfine; Table 5. (S,S) N-desmethyl sertraline and simvastatin; artemisinin 2. The composition of claim 1, wherein said first agent and and SB-202190: interferon alfa-2a and sirolimus; amorolfine said second agent are present in amounts that, when admin and indocyanine green; TOFA and triciribine; 3,3'-(pentam istered to a patient with a viral disease, are effective to treat ethylenedioxy)dianiline and artemisinin; artemisinin and said patient. wortmannin; 3.3"-(pentamethylenedioxy)diacetanilide and 3. The composition of claim 2, wherein said viral disease is artemisinin; amorolfine and benzamil, artemisinin and tricir caused by a single stranded RNA virus, a flaviviridae virus, or ibine; 2,2'-(pentamethylenedioxy)dianiline and amorolfine; a hepatic virus. (S,S)-n-desmethyl sertraline and simvastatin; levothyroxine 4. The composition of claim 3, wherein said flaviviridae and Wedelolactone; 1.5-bis(4-aminophenoxy)pentane and virus is a hepacivirus, a flavivirus, a pestivirus, or a hepatitis artemisinin; benzamil and dextrothyroxine; amorolfine and G virus. trifluperidol; artemisinin and indocyanine green; dihydroar 5. The composition of claim 4, wherein said flavivirus is temisinin and wortmannin; flupentiXol and Sertraline; ben selected from the group consisting of Absettarov, Alfuy, Apoi, Zamil and levothyroxine; amorolfine and meclizine; pravas Aroa, Bagaza, Banzi, Bouboui, BuSSuquara, Cacipacore, tatin and Sertraline; 1.5-bis(4-aminophenoxy)pentane and Carey Island, Dakar bat, Dengue 1, Dengue 2, Dengue 3, indocyanine green; 2-hydroxyflavanone and amorolfine; Dengue 4, Edge Hill, Entebbe bat, Gadgets Gully, Hanzalova, ritonavir and vinorelbine; benoximate and dehydroepiandros Hypr, Ilheus, Israel turkey meningoencephalitis, Japanese terone; ifenprodil and indocyanine green; amorolfine and encephalitis, Jugra, Jutiapa, Kadam, Karshi, Kedougou, arbidol: 3,3'-(pentamethylenedioxy)dianiline and indocya Kokobera, Koutango, Kumlinge, Kunjin, Kyasanur Forest nine green; fulvestrant and vinorelbine; amorolfine and disease, Langat, Louping ill. Meaban, Modoc, Montanamyo eZetimibe; amorolfine and Evans blue; amorolfine and gefi tis leukoencephalitis, Murray Valley encephalitis, Naranjal, tinib; amorolfine and topotecan; 2.2"-(pentamethylene Negishi, Ntaya, Omsk hemorrhagic fever, Phnom-Penh bat, dioxy)diacetanilide and artemisinin; amorolfine and Powassan, Rio Bravo, Rocio, royal farm, Russian spring wedelolactone; 3,3'-(pentamethylenedioxy)dianiline and Summer encephalitis, Saboya, St. Louis encephalitis, Sal amorolfine; simvastatin and rac-cis-n-desmethyl sertraline; Vieja, San Perlita, Saumarez Reef, Sepik, Sokuluk, Spond adefovir dipivoxil and triciribine; cytarabine and Evans blue; weni, Stratford, Tembusu, Tyuleniy, Uganda S. Usutu, Wes artemisinin and Evans blue; fluphenazine and Sertraline; ben selsbron, west Nile, Yaounde, yellow fever, and Zika. Zamil and SB-202190: artemisinin and rifabutin; fluphena 6. The composition of claim 4, wherein said pestivirus is Zine and tolterodine; interferon alfa-2a and melphalan; amo selected from the group consisting of bovine viral diarrhea rolfine and melphalan; artemisinin and fulvestrant; ifenprodil virus, classical Swine fever virus, and border disease virus. and quinacrine; simvastatin and rac-cis-n-desmethyl sertra US 2008/O161324 A1 Jul. 3, 2008

line; flupentixol and tolterodine; triciribine and wortmannin: sertraline; amorolfine and trifluridine; amorolfine and 2-hy loratadine and vinorelbine; meclizine and sertraline; budes droxyflavanone; amorolfine and eZetimibe; amorolfine and onide and vinorelbine, 2-hydroxyflavanone and indocyanine benzamil; amorolfine and trifluperidol; and octyl methoxy green; hydroxy Zine and Sertraline: 2,2'-(pentamethylene cinnamate and Suberohydroxamic acid. dioxy)dianiline and artemisinin; amorolfine and flupentixol; 19. A method for treating a patient having a viral disease, artemisinin and chlorophyllin; eZetimibe and fluphenazine; said method comprising administering to said patient an benzamil and fluphenazine; artemisinin and Wedelolactone; agent selected from the agents of Table 1 in an amount effec cytarabine and dydrogesterone; artemisinin and benzamil; tive to treat said patient. 3,3'-(pentamethylenedioxy)dianiline and artemether; toltero 20. A method for treating a patient having hepatitis C, said dine and trifluperidol; artesunate and fluvastatin; artemisinin method comprising administering to said patient an agent and trifluridine; adefovir dipivoxil and amorolfine; interferon selected from the agents of Table 1 and Table 2 in an amount alfa-2a and trifluridine; fulvestrant and triciribine; artesunate effective to treat said patient. and dydrogesterone; artesunate and LY 294.002; mosapride 21. A method for treating a patient having a viral disease, citrate and TOFA; bromocriptine and wedelolactone; arte said method comprising administering to said patient a plu misinin and sodium fusidate; celgosivir and interferon alfa rality of agents where the first agent is selected from the 2a; amorolfine and dextrothyroxine; andrographis and fulves agents of Table 1, Table 2, and Table 3 and the second agent is trant; 2'-c-methylcytidine and artemisinin; amorolfine and selected from the agents of Table 4 and Table 5, wherein said gemcitabine; OXeladin and Sertraline; artemisinin and par agents are administered within 28 days of each other in thenolide; artemisinin and ribavirin; dehydroepiandrosterone amounts that together are effective to treat said patient, and tyrphostin AG 1478; sertraline and toremifene; dihy wherein said plurality is not a combination of agents listed in droartemisinin and fulvestrant, 2-hydroxyflavanone and Table 6 or Table 7. TOFA; artesunate and repaglinide; mofebutaZone and 22. The method of claim 21, wherein said agents are wedelolactone; artesunate and simvastatin; 2,2'-(pentameth administered within ten days of each other. ylenedioxy)dianiline and artesunate; artemisinin and gemcit 23. The method of claim 22, wherein said agents are abine; dihydroartemisinin and ezetimibe; chlorophyllin and administered within five days of each other. cytarabine; interferon alfa-2a and sirolimus; Suberohydrox 24. The method of claim 23, wherein said agents are amic acid and VX-497; artemisinin and VX-497; artesunate administered within twenty-four hours of each other. and VX-497; tolterodine and VX-950; artemisinin and HCV 25. The method of claim 19 or 21, wherein said viral 796; artemisinin and NM-283, NM-283 and wedelolactone; disease is caused by a single stranded RNA virus, a flaviviri artemisinin and SCH 503034; cytarabine and SCH 5.03034; dae virus, or a hepatic virus. SCH 5.03034 and triciribine; interferon alfa-2a and mel 26. The method of claim 25, wherein said flaviviridae virus phalan; benoximate and VX-950; HCV-796 and sirolimus: is a hepacivirus, a flavivirus, a pestivirus, or hepatitis G. virus. benoximate and SCH 503034; melphalan and VX-950: 27. The method of claim 26, wherein said flavivirus is ritonavir and VX-950; VX-950 and VX-497; artemisinin and selected from the group consisting of Absettarov, Alfuy, Apoi, VX-950; triciribine and VX-950; suberohydroxamic acid and Aroa, Bagaza, Banzi, Bouboui, BuSSuquara, Cacipacore, VX-950; HCV-796 and suberohydroxamic acid; sirolimus Carey Island, Dakar bat, Dengue 1, Dengue 2, Dengue 3, and VX-950; melphalan and SCH 5.03034; SCH503034 and Dengue 4, Edge Hill, Entebbe bat, Gadgets Gully, Hanzalova, wortmannin; SCH503034 and tolterodine; ritonavir and SCH Hypr, Ilheus, Israel turkey meningoencephalitis, Japanese 503034; ezetimibe and VX-950; HCV-796 and VX-497; encephalitis, Jugra, Jutiapa, Kadam, Karshi, Kedougou, chlorophyllin and VX-497; HCV-796 and melphalan; capsai Kokobera, Koutango, Kumlinge, Kunjin, Kyasanur Forest cin and NM-283: SCH503034 and sirolimus; LY 294.002 and disease, Langat, Louping ill. Meaban, Modoc, Montana myo SCH 5.03034; adefovir dipivoxil and SCH503034; interferon tis leukoencephalitis, Murray Valley encephalitis, Naranjal, alfa-2a and trifluridine: HCV-796 and trifluridine; GW 5074 Negishi, Ntaya, Omsk hemorrhagic fever, Phnom-Penh bat, and NM-283; mosapride and VX-950; interferon alfa-2a and Powassan, Rio Bravo, Rocio, royal farm, Russian spring VX-497; NM-283 and trequinsin; cytarabine and HCV-796: Summer encephalitis, Saboya, St. Louis encephalitis, Sal adefoviridipivoxil and VX-950: cytarabine and VX-950:SCH Vieja, San Perlita, Saumarez Reef, Sepik, Sokuluk, Spond 503034 and saquinavir; VX-950 and wortmannin; capsaicin weni, Stratford, Tembusu, Tyuleniy, Uganda S. Usutu, Wes and VX-950: 2-hydroxyflavanone and NM-283; bromhexine selsbron, west Nile, Yaounde, yellow fever, and Zika. and VX-950; HCV-796 and wortmannin; artemisinin and rib 28. The method of claim 26, wherein said pestivirus is avirin; VX-950 and verapamil: SCH 5.03034 and verapamil: selected from the group consisting of bovine viral diarrhea SCH 5.03034 and topotecan; HCV-796 and topotecan; triflu virus, classical Swine fever viru, and border disease virus. peridol and VX-950; irinotecan and SCH 5.03034; artesunate 29. The method of claim 19 or 21, wherein said viral and SCH 5.03034; repaglinide and SCH 5.03034; topotecan disease is viral hepatitis. and VX-950; tepaglinide and VX-950; arbidol and VX-950: 30. The method of claim 29, wherein said viral hepatitis is chlorophyllin and HCV-796; benzydamine and VX-950: caused by hepatitis A, hepatitis B, hepatitis C, hepatitis D, or NM-283 and trifluperidol; capsaicin and HCV-796; NM-283 hepatitis E. and phenazopyridine; NM-283 and trifluridine; and adefovir 31. The method of claim 25, wherein said hepatic virus is dipivoxil and HCV-796. hepatitis A, hepatitis B, hepatitis C, hepatitis D, or hepatitis E. 18. A composition comprising a pair of agents selected 32. The method of claim 31, wherein said hepatitis C is from the group consisting of simvastatin and Sertraline; flu hepatitis C genotype 1, 2, 3, 4, 5, or 6. vastatin and Sertraline; fluiphenazine and Sertraline; artesu 33. The method of claim 32, wherein said hepatitis C nate and simvastatin; artesunate and wortmannin; artemisinin genotype 1 is genotype 1a or 1b. and chlorophyllin; artemisinin and 3,3'-(pentamethylene 34. The method of claim 19, 20, or 21, wherein said method dioxy)dianiline; amorolfine and meclizine; amorolfine and is performed in conjunction with administering to said patient US 2008/O161324 A1 Jul. 3, 2008

an additional antiviral treatment, wherein said method is per ineandezetimibe; amorolfine and Evans blue; amorolfine and formed and said additional treatment is administered within 6 gefitinib, amorolfine and topotecan; 2.2"-(pentamethylene months of each other. dioxy)diacetanilide and artemisinin; amorolfine and 35. The method of claim 34, wherein said additional anti wedelolactone; 3,3'-(pentamethylenedioxy)dianiline and viral treatment is administered and said method is performed amorolfine; simvastatin and rac-cis-n-desmethyl sertraline; within fourteen days of each other. adefovir dipivoxil and triciribine; cytarabine and Evans blue; 36. The method of claim 34, wherein said additional anti artemisinin and Evans blue; fluphenazine and Sertraline; ben viral treatment is administered and said method is performed Zamil and SB-202190: artemisinin and rifabutin; fluphena within five days of each other. Zine and tolterodine; interferon alfa-2a and melphalan; amo 37. The method of claim 34, wherein said additional anti rolfine and melphalan; artemisinin and fulvestrant; ifenprodil viral treatment is administered and said method is performed and quinacrine; simvastatin and rac-cis-n-desmethyl sertra within twenty-four hours of each other. line; flupentixol and tolterodine; triciribine and wortmannin: 38. The method of claim 34, said additional antiviral treat loratadine and vinorelbine; meclizine and sertraline; budes ment comprising administration of one or more agents onide and vinorelbine, 2-hydroxyflavanone and indocyanine selected from Table 4 and Table 5. green; hydroxy Zine and Sertraline: 2,2'-(pentamethylene 39. The method of claim 19, 20, or 21, wherein said agent dioxy)dianiline and artemisinin; amorolfine and flupentixol; or agents are administered to said patient by intravenous, artemisinin and chlorophyllin; eZetimibe and fluphenazine; intramuscular, inhalation, topical, or oral administration. benzamil and fluphenazine; artemisinin and Wedelolactone; 40. A method for treating a patient having a viral disease, cytarabine and dydrogesterone; artemisinin and benzamil; said method comprising administering to said patient Sertra 3,3'-(pentamethylenedioxy)dianiline and artemether; toltero line and an HMG-CoA reductase inhibitor, wherein said two dine and trifluperidol; artesunate and fluvastatin; artemisinin agents are administered within 28 days of each other in and trifluridine; adefovir dipivoxil and amorolfine; interferon amounts that together are effective to treat said patient. alfa-2a and trifluridine; fulvestrant and triciribine; artesunate 41. The method of claim 40, wherein said HMG-CoA and dydrogesterone; artesunate and LY 294.002; mosapride reductase inhibitor is fluvastatin, simvastatin, lovastatin, or citrate and TOFA; bromocriptine and wedelolactone; arte rosuvastatin. misinin and sodium fusidate; celgosivir and interferon alfa 42. A method for treating a patient having a viral disease, 2a; amorolfine and dextrothyroxine; andrographis and fulves said method comprising administering to said patient Sertra trant; 2'-c-methylcytidine and artemisinin; amorolfine and line and an antihistamine wherein said two agents are admin gemcitabine; oxeladin and sertraline; artemisinin and par istered within 28 days of each other in amounts that together thenolide; artemisinin and ribavirin; dehydroepiandrosterone are effective to treat said patient. and tyrphostin AG 1478; sertraline and toremifene; dihy 43. The method of claim 42, wherein said antihistamine is droartemisinin and fulvestrant, 2-hydroxyflavanone and hydroxy Zine. TOFA; artesunate and repaglinide; mofebutaZone and 44. A method for treating a patient having a viral disease, wedelolactone; artesunate and simvastatin; 2,2'-(pentameth said method comprising administering to said patient a pair of ylenedioxy)dianiline and artesunate; artemisinin and gemcit agents selected from the group consisting of amorolfine and abine; dihydroartemisinin and ezetimibe; chlorophyllin and Sertraline; fluvastatin and Sertraline; rosuvastatin and Sertra cytarabine; interferon alfa-2a and sirolimus; Suberohydrox line; fulvestrant and satraplatin; amorolfine and mebeverine; amic acid and VX-497; artemisinin and VX-497; artesunate amorolfine and satraplatin; ifenprodil and Sertraline; amorolf and VX-497; tolterodine and VX-950; artemisinin and HCV ine and tolterodine; atorvastatin and Sertraline; amorolfine 796; artemisinin and NM-283; NM-283 and wedelolactone; and irinotecan; lovastatin and Sertraline; cytarabine and tricir artemisinin and SCH 503034; cytarabine and SCH 5.03034; ibine; artesunate and wortmannin; Sertraline and simvastatin SCH 5.03034 and triciribine; interferon alfa-2a and mel hydroxy acid, ammonium salt; amorolfine and cytarabine; phalan; benoximate and VX-950; HCV-796 and sirolimus: Sertraline and simvastatin; octyl methoxycinnamate and Sub benoximate and SCH 503034; melphalan and VX-950: erohydroxamic acid; 1.5-bis(4-aminophenoxy)pentane and ritonavir and VX-950; VX-950 and VX-497; artemisinin and amorolfine; (S,S) N-desmethyl sertraline and simvastatin: VX-950; triciribine and VX-950; suberohydroxamic acid and artemisinin and SB-202190: interferon alfa-2a and sirolimus: VX-950; HCV-796 and suberohydroxamic acid; sirolimus amorolfine and indocyanine green; TOFA and triciribine; and VX-950; melphalan and SCH 5.03034; SCH503034 and 3.3'-(pentamethylenedioxy)dianiline and artemisinin; arte wortmannin; SCH503034 and tolterodine; ritonavir and SCH misinin and wortmannin; 3.3"-(pentamethylenedioxy)diac 503034; ezetimibe and VX-950; HCV-796 and VX-497; etanilide and artemisinin; amorolfine and benzamil; artemisi chlorophyllin and VX-497; HCV-796 and melphalan; capsai nin and triciribine; 2,2'-(pentamethylenedioxy)dianiline and cin and NM-283: SCH503034 and sirolimus; LY294.002 and amorolfine; (S,S)-n-desmethyl sertraline and simvastatin: SCH 5.03034; adefovir dipivoxil and SCH503034; interferon levothyroxine and Wedelolactone; 1.5-bis(4-aminophenoxy) alfa-2a and trifluridine: HCV-796 and trifluridine; GW 5074 pentane and artemisinin; benzamil and dextrothyroxine; and NM-283; mosapride and VX-950; interferon alfa-2a and amorolfine and trifluperidol; artemisinin and indocyanine VX-497; NM-283 and trequinsin; cytarabine and HCV-796: green; dihydroartemisinin and wortmannin; flupentiXol and adefoviridipivoxil and VX-950; cytarabine and VX-950:SCH Sertraline; benzamil and levothyroxine; amorolfine and 503034 and saquinavir; VX-950 and wortmannin; capsaicin meclizine; pravastatin and Sertraline; 1.5-bis(4-aminophe and VX-950: 2-hydroxyflavanone and NM-283; bromhexine noxy)pentane and indocyanine green; 2-hydroxyflavanone and VX-950; HCV-796 and wortmannin; artemisinin and rib and amorolfine; ritonavir and vinorelbine; benoximate and avirin; VX-950 and verapamil: SCH 5.03034 and verapamil: dehydroepiandrosterone; ifenprodil and indocyanine green; SCH 5.03034 and topotecan; HCV-796 and topotecan; triflu amorolfine and arbidol: 3,3'-(pentamethylenedioxy)dianiline peridol and VX-950; irinotecan and SCH 5.03034; artesunate and indocyanine green; fulvestrant and vinorelbine; amorolf and SCH 5.03034; repaglinide and SCH 5.03034; topotecan US 2008/O161324 A1 Jul. 3, 2008 82 and VX-950; tepaglinide and VX-950; arbidol and VX-950: (c) instructions for administering (a) and (b) to a patient chlorophyllin and HCV-796; benzydamine and VX-950: having a viral disease. NM-283 and trifluperidol; capsaicin and HCV-796; NM-283 54. A kit comprising: and phenazopyridine; NM-283 and trifluridine; and adefovir (a) a composition comprising Sertraline and an HMG-CoA dipivoxil and HCV-796, wherein said agents are administered reductase inhibitor; and within 28 days of each other in amounts that together are (b) instructions for administering said composition to a effective to treat said patient. patient having a viral disease. 45. A method for treating a patient having a viral disease, 55. The kit of claim 53 or 54, wherein said HMG-CoA said method comprising administering to said patient a pair of reductase inhibitor is fluvastatin, simvastatin, lovastatin, or agents selected from the group consisting of simvastatin and rosuvastatin. Sertraline; fluvastatin and Sertraline; fluiphenazine and Sertra 56. A kit comprising: line; artesunate and simvastatin; artesunate and wortmannin; (a) sertraline; artemisinin and chlorophyllin; artemisinin and 3,3'-(pentam (b) an antihistamine; and ethylenedioxy)dianiline; amorolfine and meclizine; amorolf (c) instructions for administering (a) and (b) to a patient ine and sertraline; amorolfine and trifluridine; amorolfine and having a viral disease. 2-hydroxyflavanone; amorolfine and ezetimibe; amorolfine 57. A kit comprising: and benzamil; amorolfine and trifluperidol; and octyl meth (a) a composition comprising Sertraline and an antihista oxycinnamate and Suberohydroxamic acid, wherein said two mine; and agents are administered within 28 days of each other in (b) instructions for administering said composition to a amounts that together are effective to treat said patient. patient having a viral disease. 46. A kit comprising: 58. The kit of claim 56 or 57, wherein said antihistamine is (a) an agent selected from any of the agents of Table 1; and hydroxy Zine. (b) instructions for administering said agent to a patient 59. A kit comprising: having a viral disease. (a) a pair of agents selected from the group consisting of 47. A kit comprising: amorolfine and Sertraline; fluvastatin and Sertraline; (a) an agent selected from any of the agents of Table 1 and rosuvastatin and Sertraline; fulvestrant and satraplatin; Table 2; and amorolfine and mebeverine; amorolfine and satraplatin: (b) instructions for administering said agent to a patient ifenprodil and sertraline; amorolfine and tolterodine: having hepatitis C. atorvastatin and sertraline; amorolfine and irinotecan; 48. A kit comprising: lovastatin and Sertraline; cytarabine and triciribine; arte (a) a composition comprising: Sunate and wortmannin; Sertraline and simvastatin (i) a first agent selected from any one of the agents of hydroxy acid, ammonium salt; amorolfine and cytara Table 1, Table 2, and Table 3; and bine; Sertraline and simvastatin; octyl methoxycin (ii) one or more agents of Table 4 or Table 5; and namate and Suberohydroxamic acid; 1.5-bis(4-ami (b) instructions for administering said composition to a nophenoxy)pentane and amorolfine; (S,S)—N- patient having a viral disease. desmethyl sertraline and simvastatin; artemisinin and 49. A kit comprising: SB-202190: interferon alfa-2a and sirolimus; amorolf (a) a first agent selected from any of the agents of Table 1, ine and indocyanine green; TOFA and triciribine; 3,3'- Table 2, and Table 3: (pentamethylenedioxy)dianiline and artemisining arte (b) one or more agents of Table 4 or Table 5; and misinin and wortmannin; 3.3"-(pentamethylenedioxy) (c) instructions for administering (a) and (b) to a patient diacetanilide and artemisinin; amorolfine and benzamil; having a viral disease. artemisinin and triciribine; 2,2'-(pentamethylenedioxy) 50. A kit comprising: dianiline and amorolfine; (S,S)-n-desmethyl sertraline (a) an agent selected from any one of the agents of Table 1: and simvastatin; levothyroxine and Wedelolactone; 1.5- and bis(4-aminophenoxy)pentane and artemisinin; ben (b) instructions for administering said agent and one or Zamil and dextrothyroxine; amorolfine and trifluperidol; more agents selected from any of the agents of Table 4 artemisinin and indocyanine green; dihydroartemisinin and Table 5 to a patient having a viral disease. and wortmannin; flupentiXol and Sertraline; benzamil and levothyroxine; amorolfine and meclizine; pravasta 51. A kit comprising: tin and Sertraline; 1.5-bis(4-aminophenoxy)pentane and (a) an agent selected from any of the agents of Table 1 and indocyanine green; 2-hydroxyflavanone and amorolf Table 2; and ine; ritonavir and vinorelbine; benoximate and dehydroe (b) instructions for administering the agent and one or piandrosterone; ifenprodil and indocyanine green; amo more agents of Table 4 or Table 5 to a patient having rolfine and arbidol: 3,3'-(pentamethylenedioxy) hepatitis C. dianiline and indocyanine green; fulvestrant and 52. A kit comprising: vinorelbine; amorolfine and ezetimibe; amorolfine and (a) one or more agents selected from any of the agents of Evans blue; amorolfine and gefitinib; amorolfine and Table 4 and Table 5; and topotecan; 2.2"-(pentamethylenedioxy)diacetanilide (b) instructions for administering said agent from (a) with and artemisinin; amorolfine and wedelolactone; 3,3'- any agent of Table 1, Table 2, and Table 3 to a patient (pentamethylenedioxy)dianiline and amorolfine; simv having a viral disease. astatin and rac-cis-n-desmethyl sertraline; adefovir 53. A kit comprising: dipivoxil and triciribine; cytarabine and Evans blue; (a) Sertraline; artemisinin and Evans blue; fluphenazine and Sertraline; (b) an HMG-CoA reductase inhibitor; and benzamil and SB-202190: artemisinin and rifabutin; US 2008/O161324 A1 Jul. 3, 2008 83

fluphenazine and tolterodine; interferon alfa-2a and 796; benzydamine and VX-950; NM-283 and trifluperi melphalan; amorolfine and melphalan; artemisinin and dol; capsaicin and HCV-796; NM-283 and phenazopy fulvestrant; ifenprodil and quinacrine; simvastatin and ridine: NM-283 and trifluridine; and adefovir dipivoxil rac-cis-n-desmethylsertraline; flupentiXol and tolterod and HCV-796; and ine; triciribine and wortmannin; loratadine and vinorel (b) instructions for administering said pair of agents to a bine; meclizine and sertraline; budesonide and vinorel patient having a viral disease. bine; 2-hydroxyflavanone and indocyanine green; 60. The kit of claim 59, wherein said kit comprises a hydroxy Zine and Sertraline; 2,2'-(pentamethylenedioxy) composition comprising said pair of agents. dianiline and artemisinin; amorolfine and flupentiXol; 61. A kit comprising: artemisinin and chlorophyllin; eZetimibe and fluphena (a) a pair of agents selected from the group consisting of Zine; benzamil and fluphenazine; artemisinin and simvastatin and Sertraline; fluvastatin and Sertraline; wedelolactone; cytarabine and dydrogesterone; arte fluphenazine and Sertraline; artesunate and simvastatin: misinin and benzamil: 3,3'-(pentamethylenedioxy)di artesunate and wortmannin; artemisinin and chlorophyl aniline and artemether; tolterodine and trifluperidol; lin; artemisinin and 3,3'-(pentamethylenedioxy)di artesunate and fluvastatin; artemisinin and trifluridine; aniline; amorolfine and meclizine; amorolfine and Ser adefovir dipivoxil and amorolfine; interferonalfa-2a and traline; amorolfine and trifluridine; amorolfine and trifluridine; fulvestrant and triciribine; artesunate and 2-hydroxyflavanone; amorolfine and eZetimibe; amo dydrogesterone; artesunate and LY 294.002; mosapride rolfine and benzamil; amorolfine and trifluperidol; and citrate and TOFA: bromocriptine and wedelolactone: octyl methoxycinnamate and Suberohydroxamic acid; artemisinin and sodium fusidate; celgosivir and inter and feron alfa-2a, amorolfine and dextrothyroxine; androg (b) instructions for administering said pair of agents to a raphis and fulvestrant; 2'-c-methylcytidine and artemisi patient having a viral disease. nin; amorolfine and gemcitabine; oxeladin and 62. The kit of claim 61, wherein said kit comprises a Sertraline; artemisinin and parthenolide; artemisinin and composition comprising said pair of agents. ribavirin; dehydroepiandrosterone and tyrphostin ag 63. A method for identifying a combination that may be 1478; sertraline and toremifene; dihydroartemisinin and useful for the treatment of a patient having a viral disease, or fulvestrant; 2-hydroxyflavanone and TOFA; artesunate the prevention or reduction of said viral disease, said method and repaglinide; mofebutaZone and Wedelolactone; arte comprising the steps of Sunate and simvastatin: 2,2'-(pentamethylenedioxy)di (a) contacting cells comprising at least a portion of the aniline and artesunate; artemisinin and gemcitabine; genome of a virus with an agent selected from any one dihydroartemisinin and ezetimibe; chlorophyllin and the agents of Table 1, Table 2, and Table 3 and a candi cytarabine; interferon alfa-2a and sirolimus; Suberohy date compound, wherein said portion of the genome is droxamic acid and VX-497; artemisinin and VX-497; capable of replication in said cells; and artesunate and VX-497; tolterodine and VX-950; arte misinin and HCV-796; artemisinin and NM-283; (b) determining whether the combination of said agent and NM-283 and wedelolactone; artemisinin and SCH said candidate compound inhibits the replication of said 503034; cytarabine and SCH 503034; SCH 503034 and portion of the genome relative to cells contacted with triciribine; interferonalfa-2a and melphalan; benoximate said agent but not contacted with the candidate com and VX-950; HCV-796 and sirolimus; benoximate and pound, wherein a reduction in replication identifies the SCH 5.03034; melphalan and VX-950; ritonavir and combination as a combination useful for the treatment of VX-950; VX-950 and VX-497; artemisinin and a patient having a viral disease, or the prevention or VX-950; triciribine and VX-950; suberohydroxamic reduction of a viral disease. acid and VX-950; HCV-796 and suberohydroxamic 64. The method of claim 53, wherein said viral disease is acid; sirolimus and VX-950; melphalan and SCH caused by a single stranded RNA virus, a flaviviridae virus, or 503034; SCH 503034 and wortmannin; SCH 5.03034 a hepatic virus. and tolterodine; ritonavir and SCH 503034; eZetimibe 65. The method of claim 64, wherein said flaviviridae virus and VX-950; HCV-796 and VX-497; chlorophyllin and is a hepacivirus, a flavivirus, a pestivirus, or a hepatitis G VX-497; HCV-796 and melphalan; capsaicin and virus. NM-283: SCH 5.03034 and sirolimus: LY 294.002 and 66. The method of claim 65, wherein said flavivirus is SCH503034; adefoviridipivoxil and SCH503034; inter selected from the group consisting of Absettarov, Alfuy, Apoi, feron alfa-2a and trifluridine: HCV-796 and trifluridine; Aroa, Bagaza, Banzi, Bouboui, BuSSuquara, Cacipacore, GW 5074 and NM-283; mosapride and VX-950; inter Carey Island, Dakar bat, Dengue 1, Dengue 2, Dengue 3, feron alfa-2a and VX-497; NM-283 and trequinsin; cyt Dengue 4, Edge Hill, Entebbe bat, Gadgets Gully, Hanzalova, arabine and HCV-796; adefovir dipivoxil and VX-950: Hypr, Ilheus, Israel turkey meningoencephalitis, Japanese cytarabine and VX-950; SCH 5.03034 and saquinavir; encephalitis, Jugra, Jutiapa, Kadam, Karshi, Kedougou, VX-950 and wortmannin; capsaicin and VX-950: 2-hy Kokobera, Koutango, Kumlinge, Kunjin, Kyasanur Forest droxyflavanone and NM-283; bromhexine and VX-950: disease, Langat, Louping ill. Meaban, Modoc, Montana myo HCV-796 and wortmannin; artemisinin and ribavirin; tis leukoencephalitis, Murray Valley encephalitis, Naranjal, VX-950 and verapamil: SCH 5.03034 and verapamil: Negishi, Ntaya, Omsk hemorrhagic fever, Phnom-Penh bat, SCH 5.03034 and topotecan; HCV-796 and topotecan; Powassan, Rio Bravo, Rocio, royal farm, Russian spring trifluperidol and VX-950; irinotecan and SCH 5.03034; Summer encephalitis, Saboya, St. Louis encephalitis, Sal artesunate and SCH 5.03034; repaglinide and SCH Vieja, San Perlita, Saumarez Reef, Sepik, Sokuluk, Spond 503034; topotecan and VX-950; tepaglinide and weni, Stratford, Tembusu, Tyuleniy, Uganda S. Usutu, Wes VX-950; arbidol and VX-950: chlorophyllin and HCV selsbron, west Nile, Yaounde, yellow fever, and Zika. US 2008/O161324 A1 Jul. 3, 2008

67. The method of claim 65, wherein said pestivirus is tion, decreased RNA transcription, decreased protein trans selected from the group consisting of bovine viral diarrhea lation, or inhibition of a protein required for viral replication. virus, classical Swine fever virus, and border disease virus. 72. The method of claim 70 or 71, wherein said protein 68. The method of claim 53, wherein said viral disease is required for viral replication is a protein coded for by the viral hepatitis A, hepatitis B, hepatitis C, hepatitis D, or hepatitis E. genome or by the host cell. 69. The method of claim 64, wherein said hepatic virus is hepatitis A, hepatitis B, hepatitis C, hepatitis D, or hepatitis E. 73. The method of claim 53, wherein said cells are mam 70. The method of claim 69, wherein said reduction in malian cells. replication is due to decreased polyprotein processing, 74. The method of claim 73, wherein said cells are human decreased RNA replication, decreased RNA transcription, cells. decreased protein translation, or inhibition of a protein 75. The method of claim 73, wherein said cells are hepatic required for viral replication. cells. 71. The method of claim 53, wherein said reduction in replication is the result of decreased DNA or RNA replica