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US 20100.009970A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0009970 A1 Johansen et al. (43) Pub. Date: Jan. 14, 2010

(54) COMPOSITIONS AND METHODS FOR Publication Classification TREATMENT OF VRAL DISEASES (51) Int. Cl. (75) Inventors: Lisa M. Johansen, Belmont, MA A63L/36 (2006.01) (US); Christopher M. Owens, A63L/404 (2006.01) Cambridge, MA (US); Christina A63L/366 (2006.01) Mawhinney, Jamaica Plain, MA A 6LX 3L/505 (2006.01) (US); Todd W. Chappell, Boston, A63/495 (2006.01) MA (US); Alexander T. Brown, CD7C 2 II/33 (2006.01) Watertown, MA (US); Michael G. C07C 21 7/56 (2006.01) Frank, Boston, MA (US); Michael A6IP 25/00 (2006.01) A. Foley, Chestnut hill, MA (US); A6II 3/445 (2006.01) Ralf Altmeyer, Singapore (SG); Yu A6II 3/55 (2006.01) Chen, Singapore (SG) A 6LX 3/5.375 (2006.01) A63/4965 (2006.01) Correspondence Address: (52) U.S. Cl...... 514/218: 514/647: 514/419:514/460; Gearhart Law LLC 514/275: 514/255.04:564/367: 514/603; 4 Femdale Avenue 514/655; 564/384: 514/331; 514/239.5: 514/255.03 Chatham, NJ 07928 (US) (73) Assignee: Combinatorx (Singapore) Pte. (57) ABSTRACT Ltd., Singapore (SG) The present invention features compositions, methods, and kits useful in the treatment of viral diseases. In certain (21) Appl. No.: 12/406,626 embodiments, the viral disease is caused by a single stranded RNA virus, a flaviviridae virus, or a hepatic virus. In particu (22) Filed: Mar. 18, 2009 lar embodiments, the viral disease is viral hepatitis (e.g., hepatitis A, hepatitis B, hepatitis C, hepatitis D. hepatitis E) Related U.S. Application Data and the agent or combination of agents includes , a (60) Provisional application No. 61/070,047, filed on Mar. Sertraline analog. UK-416244, or a UK-416244 analog. Also 19, 2008, provisional application No. 61/089,850, featured are screening methods for identification of novel filed on Aug. 18, 2008. compounds that may be used to treat a viral disease. Patent Application Publication Jan. 14, 2010 Sheet 1 of 2 US 2010/0009970 A1

80

---- Vehicle 0.5% HPMC E. - - - Sertraline-30mg/kg/day - A - 60 Sertraline-100mg/kg/day/kg/day E. - V-- Oseltamivir-30mg/kg/day --- is a Oseltamivir-100mg/kg/day CRX-165 (Sertraline 30mg/Kg+ -0. ------40 0.1 mg/Kg)

Figure 1 Patent Application Publication Jan. 14, 2010 Sheet 2 of 2 US 2010/0009970 A1

OO 58 OO

4 O

2 O

Wehicle Seitaline 10ng. Kg Sertaline 30mg Kg Sentraline 100mg Kg

Figure 2 US 2010/0009970 A1 Jan. 14, 2010

COMPOSITIONS AND METHODS FOR and the currently recommended therapy, a combination of TREATMENT OF VIRAL DISEASES pegylated interferon and ribavirin, is effective in only about 50% of those infected with HCV genotype 1. Further, both CROSS-REFERENCE TO RELATED interferon and ribavirin have potentially serious side effects, APPLICATIONS which include seizures, acute heart or kidney failure, and 0001. This application claims the benefit of U.S. Provi anemia. sional Application No. 61/070,047, filed Mar. 19, 2008 and 0005 Given the lack of safe, efficacious treatments for U.S. Provisional Application No. 61/089,850, filed Aug. 18, many viral diseases, there exists a need for improved thera 2008, each of which is hereby incorporated by reference. p1es. BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION 0002. The invention relates to the treatment of diseases 0006 Based on the results of our screen identifying com caused by a virus. pounds and combinations of compounds having antiviral 0003 Diseases caused by viruses are major health prob activity, the present invention features compositions, meth lems worldwide, and include many potentially fatal or dis ods, and kits for the treatment of viral disease (e.g., caused by abilitating illnesses. Viral diseases include diseases caused by the viruses described herein). In certain embodiments, the single stranded RNA viruses, flaviviridae viruses, and hepatic viral disease may be caused by a virus which is a member of viruses. In one example, viral hepatitis (e.g., hepatitis A, one or more of the following groups: single Stranded RNA hepatitis B, hepatitis C, hepatitis D, and hepatitis E) can result viruses, flaviviridae viruses (e.g., a hepacivirus Such as HCV. in chronic or acute hepatitis. While vaccines protective flavivirus, pestivirus, or hepatitis G Virus), and hepatic against hepatitis A and hepatitis B exist, no cures for many viruses. HCV, for example, is a single stranded RNA virus, a viruses, including hepatitis B, C, D, or E, are available. flaviviridae virus, and a hepatic virus. In certain embodi 0004. With regard to the hepatitis C virus (HCV), the ments, the viral disease is caused by the hepatitis C virus. Center for Disease Control estimates that 4.1 million Ameri Additional exemplary viruses are described herein. cans (1.6%) have been infected with this virus. Of those 0007 Accordingly in a first aspect, the invention features infected, 3.2 million are chronically infected, and HCV is the a composition including a first agent selected from the agents leading cause of death from disease in the United States. of Table 1, Table 2, and Table 3, or an analog thereof, and a Hepatitis C is a major risk factor for developing liver cirrhosis second agent selected from the agents of Table 1, Table 2, and hepatocellular carcinoma, and the World Health Organi Table 3, Table 4, and Table 5, or an analog thereof (e.g., Table zation indicates that hepatitis C is responsible for two thirds 4 and Table 5, or excluding the combinations of Table 6). In of liver transplants. Worldwide, an estimated 180 million certain embodiments, the first agent is sertraline, a sertraline people, or about 3% of the world's population, are infected analog, UK-416244, or a UK-4162244 analog (e.g., any of with HCV. No vaccine for hepatitis C is presently available, those described herein).

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 (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 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 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 US 2010/0009970 A1 Jan. 14, 2010

TABLE 1-continued

Compound C50% Compound IC50: Bifonazole 6.15 Oxfendazole 7.30 Bismuth Subsalicylate 8.09 Oxibendazole O.300 Bromhexine 4.25 Oxyphenbutazone (e.g., hydrate) 4.17 (e.g., meSylate) 3.38 O.O092 Budesonide S.66 Padimate O 5.44 Bufexamac 8.29 P-Aminosalicylic acid 1316 Camptothecin O.O26 2.69 1.72 3.60 Carbaryl 9.65 Phenazopyridine (e.g., hydrochloride) 7.85 CAY10433 7.88 Piceatannol 547 O449 Picotamide 28.78 6.21 PKR inhibitor 1.75 Chlorophyllin 1.30 Pramoxine (e.g., hydrochloride) 5.17% (e.g., hydrochloride) 6.2O (e.g., hydrochloride) 16.12 (e.g., hydrobromide) 27.30 Propidium (e.g., iodide) 9.38 Cladribine O. 112 Quinacrine 4.17 Clomiphene (e.g., citrate) 1.19 5.43 Cobamamide O.410 R(+)-Verapamil (e.g., hydrochloride) 15.67 Cyclocytidine (e.g., hydrochloride) O.183 (e.g., hydrochloride) 3.74 Cycloheximide O.184 Repaglinide 12.21 (e.g., hydrochloride) 17.97 Rescinnamine 7.88 1119 25.29 (e.g., citrate) 11.14 Rifabutin 17.25 Desoratadine 6.07 19.36 Desoxycorticosterone (e.g., acetate) 14.65 361.62 (e.g., sodium) S.OO Satraplatin 4.8O Dibucaine (e.g., hydrochloride) 6.68 SB-2021.90 S.18 Dicyclomine (e.g., hydrochloride) 25.01 Sertraline (e.g., hydrochloride) 5.39 16.49 Shikonin 26.4% 12.18 SiguaZodan 2.20 (e.g., meSylate) 22.75 Silver sulfadiazine 2.20 Dilazep (e.g., dihydrochloride) 13.87 0.005* Diphenidol (e.g., hydrochloride) 25.45 Fusidic acid (e.g., sodium fusidate) 7.72 Disulfiram 5.50 7.21 DNA-PK inhibitor II 6.52 15.18 (e.g., hydrochloride) 29.29 Suberohydroxamic acid 4.02 (e.g., hydrochloride) 1488 (e.g., citrate) 3.13 2.75 2.55 Erbstatin 7.63 8.11 Mesylates 15.25 Thapsigargin O.O113 Evans Blue 1.94 Thiostrepton 3.84 29.04 Thiram 3.64 4.2O Tioxolone 6.24 Fascaplysin 0.444 Tirapazamine 1.83 O419 Tiratricol 5.56 Fenretinide 2.26 (e.g., tartrate) 27.23 Fenvalerate 18.95 Topotecan (e.g., hydrochloride) O.095 Flubendazole O.173 5.86 Fludarabine 4.47 Trequinsin (e.g., hydrochloride) 2.93 Fluorouracil 18.66 (e.g., hydrochloride) 4.97 (e.g., dihydrochloride) 3.60 7.8O (e.g., hydrochloride) 3.35 (e.g., maleate) S.62 (e.g., maleate) 23.79 Tyrphostin 23 4.61 FR122047 23.01 Tyrphostin 25 6.O1 3.05 Tyrphostin 46 21.22 Gefitinib (Base) 3.17 Tyrphostin 47 8.3% Gramicidin O.O17 Tyrphostin Ag 1478 3.41 (e.g., microcrystalline) 11.53 U18666A O.O2O GW 5074 2.36 UCH-L1 inhibitor 7.18 Halcinonide 17.40 UCH-L3 inhibitor 9.7% Hydroquinone 13.99 (e.g., acetate) 3.73 Hydroxocobalamin 1.33 Vinorelbine O.O81 (e.g., hydrochloride) 10.93 Vitamin B12 8.28 (e.g., tartrate) 4.68 Vitamin K5 9.59 (e.g., hydrochloride) 16.93 4.66 Indocyanine Green 8.13 Wortmannin 3.16 Iophenoxic acid 10.63 8.49 LY 2940O2 3.40 Zimelidine (e.g., dihydrochloride) 5.14 (S,S)-N-Desmethylsertraline (e.g., 4.94 3',3'-(Pentamethylenedioxy)diacetanilide 9.35% hydrochloride) US 2010/0009970 A1 Jan. 14, 2010

TABLE 1-continued Compound IC50* Compound IC50: 1.5-Bis(4-aminophenoxy)pentane 1.70 rac-cis-N-Desmethyl Sertraline, (e.g., hydrochloride) 6.03 Emetime (e.g., dihydrochloride hydrate) 0.03 2,2'-(Pentamethylenedioxy)dianiline 0.27 Irinotecan (e.g., hydrochloride) 1.56 UK-416244 1.41 *Values noted with an asterisk (*) are IC25 values

TABLE 2

Compound IC50 Compound IC50

Efavirenz 15.45 Cytarabine O.117 Nelfinavir (e.g., meSylate) 4.25 Floxuridine O.OO45 Vidarabine 26.71 Edoxudine 1.95 14.91 Cepharanthine 1948 Aphidicolin 1.71 Tunicamycin O.107 Andrographis 8.39 Triciribine 2.14 Saquinavir (e.g., mesylate) 10.04 8.68 Trifluridine 0.380 Vincristine (e.g., Sulfate) O.O2 Arbidol 12.2O

where R and R are independently selected from the group TABLE 3 consisting of H, optionally substituted C. (CH) COOH, or CHCHOH(CH), (CH), N(CH), wherex is 1, Compound IC50* Compound IC50: 2, 3, 4, or 5, and optionally substituted C, heteroalkyl; R. R. Rs, and R are independently H or optionally Substituted 1.41 4.45 Artemether Dihydroartemisinin 3.87 C. alkyl; X and Y are each selected from the group consist Artesunate 3.73 Nitazoxanide 14.04 ing of H. F. Cl, Br, CF, Ce alkoxy, and cyano; and W is Cyclosporine 0.379 Chloroquine 4.78 NHCOPh. NHSOPh. NHCOcyclopentyl, (e.g., phosphate) NHSO cyclopropyl, NHCOH, CONHPh. Ribavirin 42.95 Mevastatin 3.45 hydroxy acid, 13.40 TOFA 5.53 ammonium salt Mycophenolic Acid 0.751 2'-C-Methylcytidine 1.63 35.60 Adefovir (e.g., dipivoxil) O.319 (e.g., sodium) 22.20 Telaprevir (VX-950) O.S29 Celgosivir 6.25* Valopicitabine (NM-283) 11.2 Merimepodib (VX-497) O.47S HCV-796 O.O.192 Boceprevir (SCH 5.03034) 0.259 Gemcitabine O.O6 (e.g., hydrochloride) Interferon Alfa-2a. 2.35 Simvastatin 21.34 CONHcyclopropyl, *Values noted with an asterisk (*) are IC25 values O011 0008. In another aspect, the invention features a composi tion including (a) sertraline, a sertraline analog, UK-416244. or a UK-416244 analog; and (b) an HMG-CoA reductase inhibitor. The HMG-CoA reductase inhibitor may be fluvas tatin, simvastatin, lovastatin, or . 0009. In another aspect, the invention features a composi tion including (a) sertraline, a sertraline analog, UK-416244. or a UK-416244 analog; and (b) an . The anti may be hydroxy Zine. C(S)NH2, NHC(S)CH, CHS(O),R, where n is 0, 1, or 2 0010. In another aspect, the invention features structural and R is phenyl, Cheterocyclyl, Cas unsubstituted alkyl, analogs of Sertraline and UK-416244 (e.g., those described or Cs substituted alkyl. The compound may have a structure herein). In certain embodiments, the invention features a selected from the group consisting of those listed in Table 9. compound having the formula: or the compound may have the formula: US 2010/0009970 A1 Jan. 14, 2010

CONHcylopropyl, NHC(S)CH, CONHCHCOOCH, CONHCHCOOH, NH CONHCH cyclopropyl, CONCCH)cyclopropyl, CONHcy clobutyl, N(CH)COCH, and CHS(O),R, where n is 0, 1, or 2 and R is phenyl, C. heterocyclyl, or optionally Sub stituted Cls alkyl (e.g., Cls unsubstituted alkyl such as Bu or C.s substituted alkyl), wherein said compound is not sertra line or an isomer thereof. In other embodiments, the com pound has formula set forth herein (e.g., in the Examples). 0013 The compound may have a formula selected from the group consisting of

C where n is 0, 1, or 2; and R is phenyl, Cheterocyclyl, Cas N unsubstituted alkyl, or Cs substituted alkyl. The compound ? N may be part of a composition along with a pharmaceutically N N acceptable carrier. 0012. In another aspect, the invention features a com pound having the formula:

R

NN1

C

C r and N N where R is C alkyl and R is CH-CH(OH)Rs, or CHCH (Rs)NRRo, where Rs, Ro, and Ro are independently H or C. alkyl; R. R. Rs, and R are independently H or option ally substituted Calkyl: XandYare each selected from the group consisting of H. F. Cl, Br, CF, Calkoxy, and cyano: and W is selected from the group consisting of H. F. Cl, Br, CF, C alkoxy, COOH, CHCH-OH, NHCOH, C NHCOCH, CH-NH, CHS(O)CH, CONH, CHOH, NHCOPh, CHNHS(O)CH, NHS(O), Ph, N(CH), S(O) C NH, NHCOBu, NHS(O)CH, NHCOcyclopropyl, NHCOcyclopentyl, CN, NHS(O)cyclopropyl, NH, NO, I, r NRoR10, SON(CH), SONHMe, SONHCHCH-OH, CO.Me, NHSOBu, CONHCH, CH-NHCOCH CONHPh. N N

ls N o s N O.N O. H 1. NHS(O)

N N 1SN N, C

C CHS(O) US 2010/0009970 A1 Jan. 14, 2010

or have the formula: where R is H or Ce alkyl and R is C alkyl Substituted with OHoris CHXR or CHCH-XR, where X is N, O, or S, and R is H. C. alkyl, optionally Substituted C. het Rs -*. eroalkyl, or (CH2)(C. cycloalkyl) where q is 0, 1, 2, or 3, and R is independently H, I, Br, F, Cl, C. alkyl, CF, CN, R OCF.C. alkylthio, Calkoxy, aryloxy, or CONRR, n is R4 O 1, 2, or 3; and R and Rs are independently A-X, where A is 21 —CH=CH or -(CH2), where p is 0, 1, or 2: X is H. F. Cl, Br, I, CONRR, SONRR, SONHC(=O)R, OH, B Calkoxy, NRSOR, NO, NRR, CN, COR, CHO, SX SRio, S(O)R, or SORo: R. R. Rs, and Ro are indepen dently H or Ce alkyl, Caryl optionally Substituted inde pendently by one or more R, or C. alkyl-aryl optionally Substituted; R is C alkyl optionally Substituted indepen where R and Rare independently H, C alkyl, CHCHN dently by one or more R, R is H. C. alkyl optionally (CH), (CH2)(C. cycloalkyl) where m is 0, 1, 2, or 3, or R substituted independently by one or more R2, C(O)R. and R together with the to which they are attached form an aZetidine ring; each R is independently H, I, Br, F. COR, C(O)NHR, or SONRR: R is F (preferably up to Cl, Ce alkyl, CF, CN, OCF. C. alkylthio, Calkoxy, 3), OH, CO.H. C. cycloalkyl, NH, CONH, C alkoxy, aryloxy, or CONRR, n is 1, 2, or 3; where one of R and Rs Calkoxycarbonyl or a 5- or 6-membered heterocyclic ring is A-X, where A is CH=CH or (CH), wherep is 0, containing 1, 2, or 3 heteroatoms selected from N. S., and O 1, or 2: X is H, F, Cl, Br, I, CONRR, SONRR, SONHC optionally substituted independently by one or more R, or (=O)R, OH, C alkoxy, NRSOR, NO, NRR, CN, Re and R-7, together with the nitrogen to which they are COR CHO, SR S(O)R or SORo: R. R. Rs and Rio attached, form a 4-, 5-, or 6-membered heterocyclic ring independently are H. C. alkyl, Caryl optionally substi optionally substituted independently by one or more R, or a tuted independently by one or more R, or C. alkyl-aryl 5- or 6-membered heterocyclic ring containing 1, 2, or 3 optionally substituted, and the other of R and Rs is SNHPh. heteroatoms selected from N. S., and O optionally substituted SONHPh, or SONHPh, where the phenyl is optionally sub stituted by one or more R. R. is C alkyl optionally sub independently by one or more R; where R is hydroxy, Ca stituted independently by one or more R, R is H. C. alkoxy, F. C. alkyl, haloalkyl, haloalkoxy, —NH, -NH alkyl optionally substituted independently by one or more (C. alkyl) or —N(C. alkyl). In certain embodiments, R R. C(O)R COR, C(O)NHR, or SONRR: R is F is H, CH, or CHCH and R is CHCH-OH, CH(OH)CH, (preferably up to 3), Br, OH, OCH CO.H. C. cycloalkyl, CHCHCH-OH, CH(CH,)CHOH, and NH, CONH, C alkoxy, Calkoxycarbonyl, or a 5- or CHCHCHCH-OH, CH(OH)CHCHCH, CHCH(OH) 6-membered heterocyclic ring containing 1, 2, or 3 heteroa CHCH, and CHCH-CH(OH)CH. In particular embodi toms selected from N. S. and O optionally substituted inde ments, the compound has the structure: pendently by one or more R, or R and R-7, together with the nitrogen to which they are attached, form a 4-, 5-, or 6-mem bered heterocyclic ring optionally substituted independently by one or more Rs, or a 5- or 6-membered heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N. S., and O HNOS optionally Substituted independently by one or more Rs: where R is hydroxy, C alkoxy, F. C. alkyl, haloalkyl, haloalkoxy, —NH2, —NH(C. alkyl), or —N(C. alkyl) —. The UK-416244 analog may have a structure listed in Table 10 or Table 11 or described in the Examples. 0014. In another aspect, the invention features a com pound having the structure:

SMe Rs n

R O

21 where R is H or C. alkyl and R is C alkyl substituted with OH (e.g., where R is H, CH, or CHCH and R is CHCH-OH, CH(OH)CH, CHCHCH-OH, CH(CH.) CHOH, CHCHCHCH-OH, CH(OH)CHCHCH, CHCH(OH)CHCH, or CHCH-CH(OH)CH. The com pound may have the structure US 2010/0009970 A1 Jan. 14, 2010

-continued F (Compound 1) HNOS OH 2Lyu2 1N1 O C H N / O -O-2) O -O-O.\ / SMe (Compound 2) HNOS2Lyu2 1N1 OH. -O-O- N O

-o N N C

SMe )-( N / 0015. In other embodiments, the UK-416244 analog has \ / \ . l) "N the structure: N o ( N -" N -NO N

(R3), where R. RandRs areas defined above and Zis CHNRR where R and R are as defined above, NH, optionally sub -O -( stituted optional hetero Cls alkyl (e.g., with hydroxyl, NH2, NHC alkyl), or is selected from the group consisting of O H

“oH

In certain embodiments, Z is CN, CHCH(CH), CHOCH, CHN(CH)CHCH-OH, N(CH), CHN(CH), COOH, CH-NHCH, CH-OH, CH-NHCOCH, CONHCH, CH-NH(CH)N(CH), CH-NH(CH)N(CH), CHC (CH), CHN(CH)(CH)N(CH), CHN(CH)(CH)N (CH), or CHCHCCH). 0016. In yet another aspect, the invention features a com position including a pair of agents selected from the group consisting of amorolfine and Sertraline; fluvastatin and Ser traline; rosuvastatin and Sertraline; fulvestrant and satrapl US 2010/0009970 A1 Jan. 14, 2010

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 VX-950; triciribine and VX-950; suberohydroxamic acid and ethyl sertraline and simvastatin; artemisinin and SB-202190: VX-950; HCV-796 and suberohydroxamic acid; sirolimus interferon alfa-2a and sirolimus; amorolfine and indocyanine and VX-950; melphalan and SCH 5.03034; SCH503034 and green; TOFA and triciribine; 3,3'-(pentamethylenedioxy)di wortmannin; SCH503034 and tolterodine; ritonavir and SCH and artemisinin; artemisinin and wortmannin; 3.3"- 503034; ezetimibe and VX-950; HCV-796 and VX-497; (pentamethylenedioxy)diacetanilide and artemisinin; amo chlorophyllin and VX-497; HCV-796 and melphalan; capsai rolfine and benzamil: artemisinin and triciribine; 2,2'- cin and NM-283: SCH503034 and sirolimus; LY294.002 and (pentamethylenedioxy)dianiline and amorolfine; (S,S)-n- SCH 5.03034; adefovir dipivoxil and SCH503034; interferon desmethyl sertraline and simvastatin; levothyroxine and alfa-2a and trifluridine: HCV-796 and trifluridine; GW 5074 wedelolactone; 1.5-bis(4-aminophenoxy)pentane and arte and NM-283; mosapride and VX-950; interferon alfa-2a and misinin; benzamil and dextrothyroxine; amorolfine and trif VX-497; NM-283 and trequinsin; cytarabine and HCV-796: luperidol; artemisinin and indocyanine green; dihydroarte adefoviridipivoxil and VX-950; cytarabine and VX-950:SCH misinin and wortmannin; flupentiXol and Sertraline; benzamil 503034 and saquinavir; VX-950 and wortmannin; capsaicin and levothyroxine; amorolfine and meclizine; and and VX-950: 2-hydroxyflavanone and NM-283; bromhexine Sertraline; 1.5-bis(4-aminophenoxy)pentane and indocya and VX-950; HCV-796 and wortmannin; artemisinin and rib nine green, 2-hydroxyflavanone and amorolfine; ritonavir avirin; VX-950 and verapamil: SCH 5.03034 and verapamil: and Vinorelbine; benoximate and dehydroepiandrosterone; SCH 5.03034 and topotecan; HCV-796 and topotecan; triflu ifenprodil and indocyanine green; amorolfine and arbidol; peridol and VX-950; irinotecan and SCH 5.03034; artesunate 3.3'-(pentamethylenedioxy)dianiline and indocyanine green; and SCH 5.03034; repaglinide and SCH 5.03034; topotecan fulvestrant and vinorelbine; amorolfine and eZetimibe; amo and VX-950; tepaglinide and VX-950; arbidol and VX-950: rolfine and Evans blue; amorolfine and gefitinib; amorolfine chlorophyllin and HCV-796; benzydamine and VX-950: and topotecan; 2,2'-(pentamethylenedioxy)diacetanilide NM-283 and trifluperidol; capsaicin and HCV-796; NM-283 and artemisinin; amorolfine and Wedelolactone; 3,3'-(pen and phenazopyridine; NM-283 and trifluridine; and adefovir tamethylenedioxy)dianiline and amorolfine; simvastatin and dipivoxil and HCV-796. In any of the pairs of agents above, rac-cis-n-desmethyl sertraline; adefovir dipivoxil and tricir the agent may be substituted with an analog of that agent (e.g., ibine; cytarabine and Evans blue; artemisinin and Evans blue; any analog described herein). In particular embodiments, fluphenazine and sertraline; benzamil and SB-202190: arte misinin and rifabutin, fluiphenazine and tolterodine; inter sertraline is substituted with a sertraline analog. UK-416244, feron alfa-2a and melphalan; amorolfine and melphalan; arte or a UK-416244 analog. misinin and fulvestrant; ifenprodil and quinacrine; 0017. In certain embodiments, the combination is selected simvastatin and rac-cis-n-desmethyl sertraline; flupentixol from group consisting of simvastatin and Sertraline, a Sertra and tolterodine; triciribine and wortmannin; loratadine and line analog. UK-416244, or a UK-416244 analog; fluvastatin vinorelbine; meclizine and sertraline; budesonide and and Sertraline, a Sertraline analog, UK-416244, or a Vinorelbine; 2-hydroxyflavanone and indocyanine green; UK-416244 analog; fluphenazine and Sertraline, a Sertraline hydroxy Zine and Sertraline: 2,2'-(pentamethylenedioxy)di analog, UK-416244, or a UK-416244 analog; artesunate and aniline and artemisinin; amorolfine and flupentiXol; artemisi simvastatin; artesunate and wortmannin; artemisinin and nin and chlorophyllin: ezetimibe and fluphenazine; benzamil chlorophyllin; artemisinin and 3,3'-(pentamethylenedioxy) and fluphenazine; artemisinin and Wedelolactone; cytarabine dianiline; amorolfine and meclizine; amorolfine and Sertra and dydrogesterone; artemisinin and benzamil: 3,3'-(pentam line, a sertraline analog, UK-416244, or a UK-416244 ana )dianiline and artemether, tolterodine and trif log; amorolfine and trifluridine; amorolfine and luperidol; artesunate and fluvastatin; artemisinin and trifluri 2-hydroxyflavanone; amorolfine and ezetimibe; amorolfine dine; adefovir dipivoxil and amorolfine; interferon alfa-2a and benzamil: amorolfine and trifluperidol; and octyl meth and trifluridine; fulvestrant and triciribine; artesunate and oxycinnamate and Suberohydroxamic acid. dydrogesterone; artesunate and LY 294.002; mosapride cit 0018. In any of the above aspects, the two agents may be rate and TOFA: bromocriptine and wedelolactone; artemisi present in amounts that, when administered to a patient hav nin and sodium fusidate; celgosivir and interferon alfa-2a: ing a viral disease (e.g., any viral disease described herein), amorolfine and dextrothyroxine; andrographis and fulves are effective to treat the patient. The composition may further trant; 2'-c-methylcytidine and artemisinin; amorolfine and include one or more (e.g., two, three, four, five, or six) addi gemcitabine; OXeladin and Sertraline; artemisinin and par tional agents selected from the agents of Table 1, Table 2, thenolide; artemisinin and ribavirin; dehydroepiandrosterone Table 3, Table 4, and Table 5 (e.g., where the agents are not a and tyrphostin AG 1478; sertraline and toremifene; dihy combination of agents selected from Table 7). The composi droartemisinin and fulvestrant, 2-hydroxyflavanone and tion may be formulated, for example, for oral, systemic, TOFA; artesunate and repaglinide; mofebutaZone and parenteral, topical (e.g., ophthalmic, dermatologic), intrave wedelolactone; artesunate and simvastatin; 2,2'-(pentameth nous, or intramuscular administration. ylenedioxy)dianiline and artesunate; artemisinin and gemcit 0019. In another aspect, the invention features a method abine; dihydroartemisinin and ezetimibe; chlorophyllin and for treating a patient having a viral disease. The method cytarabine; interferon alfa-2a and sirolimus; Suberohydrox includes administering to the patient an agent selected from US 2010/0009970 A1 Jan. 14, 2010

the agents of Table 1, or an analog thereof, in an amount levothyroxine and Wedelolactone; 1.5-bis(4-aminophenoxy) effective to treat the patient. In certain embodiments, the pentane and artemisinin; benzamil and dextrothyroxine; agent is Sertraline, a Sertraline analog, UK-416244, or a amorolfine and trifluperidol; artemisinin and indocyanine UK-416244 analog (e.g., any of those described herein). green; dihydroartemisinin and wortmannin; flupentiXol and 0020. In another aspect, the invention features a method sertraline, a sertraline analog, UK-416244, or a UK-416244 for treating a patient having hepatitis C. The method includes analog; benzamil and levothyroxine; amorolfine and mecliz administering to the patient an agent selected from the agents ine; pravastatin and Sertraline, a Sertraline analog, of Table 1 and Table 2, or an analog thereof, in an amount UK-416244, or a UK-416244 analog: 1.5-bis(4-aminophe effective to treat the patient. In certain embodiments, the noxy)pentane and indocyanine green; 2-hydroxyflavanone agent is Sertraline, a Sertraline analog, UK-416244, or a and amorolfine; ritonavir and vinorelbine; benoximate and UK-416244 analog (e.g., any of those described herein). dehydroepiandrosterone; ifenprodil and indocyanine green; 0021. 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 a plurality of agents ineandezetimibe; amorolfine and Evans blue; amorolfine and where the first agent is selected from the agents of Table 1, gefitinib, amorolfine and topotecan; 2.2"-(pentamethylene Table 2, and Table 3, or an analog thereof, and the second dioxy)diacetanilide and artemisinin; amorolfine and agent is selected from the agents of Table 1, Table 2, Table 3, wedelolactone; 3,3'-(pentamethylenedioxy)dianiline and Table 4, and Table 5 (e.g., Table 4 and Table 5), or an analog amorolfine; simvastatin and rac-cis-n-desmethyl sertraline; thereof, where the agents are administered within 28 days adefovir dipivoxil and triciribine; cytarabine and Evans blue; (e.g., within 21, 14, 10, 7, 5, 4, 3, 2, or 1 days) or within 24 artemisinin and Evans blue; fluphenazine and Sertraline, a hours (e.g., 12, 6, 3, 2, or 1 hours; or concomitantly) of each sertraline analog, UK-416244, or a UK-416244 analog; ben otherinamounts that together are effective to treat the patient. Zamil and SB-202190: artemisinin and rifabutin; fluphena 0022. 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 Sertraline, a sertraline and quinacrine; simvastatin and rac-cis-n-desmethyl sertra analog, UK-416244, or a UK-416244 analog, and an HMG line; flupentixol and tolterodine; triciribine and wortmannin: CoA reductase inhibitor, where the two agents are adminis loratadine and vinorelbine; meclizine and Sertraline, a Sertra tered within 28 days of each otherinamounts that together are line analog. UK-416244, or a UK-416244 analog: budes effective to treat the patient. The HMG-CoA reductase inhibi onide and vinorelbine: 2-hydroxyflavanone and indocyanine tor may be fluvastatin, simvastatin, lovastatin, or rosuvastatin. green; hydroxy Zine and Sertraline: 2,2'-(pentamethylene 0023. In another aspect, the invention features a method dioxy)dianiline and artemisinin; amorolfine and flupentixol; for treating a patient having a viral disease. The method artemisinin and chlorophyllin; eZetimibe and fluphenazine; includes administering to the patient Sertraline, a sertraline benzamil and fluphenazine; artemisinin and Wedelolactone; analog, UK-416244, or a UK-416244 analog, and an antihis cytarabine and dydrogesterone; artemisinin and benzamil; tamine where the two agents are administered within 28 days 3,3'-(pentamethylenedioxy)dianiline and artemether; toltero of each other in amounts that together are effective to treat the dine and trifluperidol; artesunate and fluvastatin; artemisinin patient. The antihistamine may be hydroxy Zine. and trifluridine; adefovir dipivoxil and amorolfine; interferon 0024. In yet another aspect, the invention features a alfa-2a and trifluridine; fulvestrant and triciribine; artesunate method for treating a patient having a viral disease. The and dydrogesterone; artesunate and LY 294.002; mosapride method includes administering to the patient a pair of agents citrate and TOFA; bromocriptine and wedelolactone; arte selected from the group consisting of amorolfine and Sertra misinin and sodium fusidate; celgosivir and interferon alfa line, a sertraline analog, UK-416244, or a UK-416244 ana 2a; amorolfine and dextrothyroxine; andrographis and fulves log; fluvastatin and Sertraline, a Sertraline analog, trant; 2'-c-methylcytidine and artemisinin; amorolfine and UK-416244, or a UK-416244 analog: rosuvastatin and ser gemcitabine; oxeladin and Sertraline, a Sertraline analog, traline, a sertraline analog. UK-416244, or a UK-416244 UK-416244, or a UK-416244 analog: artemisinin and par analog; fulvestrant and satraplatin; amorolfine and mebever thenolide; artemisinin and ribavirin; dehydroepiandrosterone ine; amorolfine and satraplatin; ifenprodil and Sertraline; and tyrphostin AG 1478; Sertraline, a Sertraline analog, amorolfine and tolterodine; atorvastatin and Sertraline; amo UK-416244, or a UK-416244 analog and toremifene; dihy rolfine and irinotecan; lovastatin and Sertraline, a sertraline droartemisinin and fulvestrant, 2-hydroxyflavanone and analog, UK-416244, or a UK-416244 analog: cytarabine and TOFA; artesunate and repaglinide; mofebutaZone and triciribine; artesunate and wortmannin; Sertraline, a sertraline wedelolactone; artesunate and simvastatin; 2,2'-(pentameth analog, UK-416244, or a UK-416244 analog and simvastatin ylenedioxy)dianiline and artesunate; artemisinin and gemcit hydroxy acid, ammonium salt; amorolfine and cytarabine; abine; dihydroartemisinin and ezetimibe; chlorophyllin and sertraline, a sertraline analog, UK-416244, or a UK-416244 cytarabine; interferon alfa-2a and sirolimus; Suberohydrox analog and simvastatin; octyl methoxycinnamate and Subero amic acid and VX-497; artemisinin and VX-497; artesunate hydroxamic acid; 1.5-bis(4-aminophenoxy)pentane and and VX-497; tolterodine and VX-950; artemisinin and HCV amorolfine; (S,S) N-desmethyl sertraline and simvastatin: 796; artemisinin and NM-283; NM-283 and wedelolactone; artemisinin and SB-202190: interferon alfa-2a and sirolimus: artemisinin and SCH 503034; cytarabine and SCH 5.03034; amorolfine and indocyanine green; TOFA and triciribine; SCH 5.03034 and triciribine; interferon alfa-2a and mel 3.3'-(pentamethylenedioxy)dianiline and artemisinin; arte phalan; benoximate and VX-950; HCV-796 and sirolimus: misinin and wortmannin; 3.3"-(pentamethylenedioxy)diac benoximate and SCH 503034; melphalan and VX-950: etanilide and artemisinin; amorolfine and benzamil; artemisi ritonavir and VX-950; VX-950 and VX-497; artemisinin and nin and triciribine; 2,2'-(pentamethylenedioxy)dianiline and VX-950; triciribine and VX-950; suberohydroxamic acid and amorolfine; (S,S)-n-desmethyl sertraline and simvastatin: VX-950; HCV-796 and suberohydroxamic acid; sirolimus US 2010/0009970 A1 Jan. 14, 2010

and VX-950; melphalan and SCH 5.03034; SCH503034 and diagnosed with or does not suffer from hypercholestera wortmannin; SCH503034 and tolterodine; ritonavir and SCH olemia, primary familial hypercholesterolemia (heterozy 503034; ezetimibe and VX-950; HCV-796 and VX-497; gous variant), mixed hyperlipidaemia (corresponding to type chlorophyllin and VX-497; HCV-796 and melphalan; capsai IIa and IIb of the Fredrickson classification), or coronary cin and NM-283: SCH503034 and sirolimus; LY 294.002 and disease, or has not had a myocardial infarction, a cere SCH 5.03034; adefovir dipivoxil and SCH503034; interferon brovascular event, an coronary bypass Surgery, or a translu alfa-2a and trifluridine: HCV-796 and trifluridine; GW 5074 men percutaneous coronary angioplasty. and NM-283; mosapride and VX-950; interferon alfa-2a and 0028. In another aspect, the invention features a kit includ VX-497; NM-283 and trequinsin; cytarabine and HCV-796: ing an agent selected from any of the agents of Table 1, or an adefoviridipivoxil and VX-950: cytarabine and VX-950:SCH analog thereof, and instructions for administering the agent to 503034 and saquinavir; VX-950 and wortmannin; capsaicin a patient having a viral disease. and VX-950: 2-hydroxyflavanone and NM-283; bromhexine 0029. In another aspect, the invention features a kit includ and VX-950; HCV-796 and wortmannin; artemisinin and rib ing an agent selected from any of the agents of Table 1 and avirin; VX-950 and verapamil: SCH 5.03034 and verapamil: Table 2, or an analog thereof, and instructions for adminis SCH 5.03034 and topotecan; HCV-796 and topotecan; triflu tering the agent to a patient having hepatitis C. peridol and VX-950; irinotecan and SCH 5.03034; artesunate 0030. In another aspect, the invention features a kit includ and SCH 5.03034; repaglinide and SCH 5.03034; topotecan ing a composition including two or more (e.g., 3, 4, 5, 6, or 7) and VX-950; tepaglinide and VX-950; arbidol and VX-950: agents selected from any of the agents of Table 1, oran analog chlorophyllin and HCV-796; benzydamine and VX-950: thereof, Table 2, and Table 3; and instructions for administer NM-283 and trifluperidol; capsaicin and HCV-796; NM-283 ing the composition to a patient having a viral disease. and phenazopyridine; NM-283 and trifluridine; and adefovir 0031. In another aspect, the invention features a kit includ dipivoxil and HCV-796, where the agents are administered ing a first agent selected from any of the agents of Table 1, within 28 days of each other in amounts that together are Table 2, and Table 3, or an analog thereof; a second, different effective to treat the patient. agent selected from any of the agents of Table 1, Table 2, and 0025. In another aspect, the invention features a method Table 3, or an analog thereof, and instructions for adminis for treating a patient having a viral disease. The method tering the first and second agents to a patient having a viral includes administering to the patient a pair of agents selected disease. from the group consisting of simvastatin and Sertraline, a 0032. In another aspect, the invention features a kit includ sertraline analog, UK-416244, or a UK-416244 analog; flu ing an agent selected from any one of the agents of Table 1. vastatin and Sertraline, a sertraline analog. UK-416244, or a Table 2, and Table 3, oran analog thereof; and instructions for UK-416244 analog; fluphenazine and Sertraline, a sertraline administering the agent with a second, different agent analog, UK-416244, or a UK-416244 analog; artesunate and selected from any of the agents of Table 1, Table 2, and Table simvastatin; artesunate and wortmannin; artemisinin and 3, or an analog thereof to a patient having a viral disease. chlorophyllin; artemisinin and 3,3'-(pentamethylenedioxy) 0033. In another aspect, the invention features a kit includ dianiline; amorolfine and meclizine; amorolfine and Sertra ing a composition including (i) a first agent selected from any line, a sertraline analog, UK-416244, or a UK-416244 ana one of the agents of Table 1, Table 2, and Table 3, or an analog log; amorolfine and trifluridine; amorolfine and thereof, and (ii) one or more agents of Table 4 and Table 5, or 2-hydroxyflavanone; amorolfine and ezetimibe; amorolfine an analog thereof, and instructions for administering the com and benzamil; amorolfine and trifluperidol; and octyl meth position to a patient having a viral disease. oxycinnamate and Suberohydroxamic acid, where the two 0034. In another aspect, the invention features a kit includ agents are administered within 28 days of each other in ing (a) a first agent selected from any of the agents of Table 1, amounts that together are effective to treat the patient. Table 2, and Table 3, or an analog thereof; (b) one or more 0026. The methods of any of the above aspects may be agents of Table 4 and Table 5, or an analog thereof, and (c) performed in conjunction with administering to the patient an instructions for administering (a) and (b) to a patient having a additional treatment (e.g., an antiviral therapy such as those viral disease. agents listed in Table 4 and Table 5, or an analog thereof) for 0035. In another aspect, the invention features a kit includ a viral disease, where the method and the additional treatment ing an agent selected from any of the agents of Table 1, or an (e.g., not a combination of agents selected from Table 6 and analog thereof, and instructions for administering the agent Table 7) are administered within 6 months (e.g., within 3, 2, or and one or more agents of Table 4 or Table 5, or an analog 1 months; within 28, 21, 14, 10, 7, 5, 4, 3, 2, or 1 days; within thereof, to a patient having a viral disease. 24, 12, 6, 3, 2, or 1 hours; or concomitantly) of each other. The 0036. In another aspect, the invention features a kit includ agents may be administered to the patient by intravenous, ing an agent selected from any of the agents of Table 1 and intramuscular, inhalation, topical (e.g., ophthalmic, determa Table 2, or an analog thereof, and instructions for adminis tologic), or oral administration. tering the agent and one or more agents of Table 4 or Table 5. 0027. In certain embodiments of any of the above methods or an analog thereof, to a patient having hepatitis C. (e.g., methods including administration of an 0037. In another aspect, the invention features a kit includ agent such as an SSRI or a antidepressant), the ing (a) one or more agents of Table 4 and Table 5, oran analog patient being treated has not been diagnosed with or does not thereof, and (b) instructions for administering the agent from Suffer from depression, major depressive disorder, obsessive (a) with any agent of Table 1, Table 2, and Table 3, or an compulsive disorder, panic disorder, posttraumatic stress dis analog thereof, to a patient having a viral disease. order, Social anxiety disorder, generalized anxiety disorder, or 0038. In another aspect, the invention features a kit includ premenstrual dysphoric disorder. In other embodiments, ing a agent selected from the group consisting of sertraline, a (e.g., methods including administration of an HMG-CoA Sertraline analog, UK-416244, and a UK-416244 analog; an reductase inhibitor), the patient being treated has not been HMG-CoA reductase inhibitor (e.g., fluvastatin, simvastatin, US 2010/0009970 A1 Jan. 14, 2010

lovastatin, or rosuvastatin); and instructions for administer and indocyanine green; hydroxy Zine and Sertraline; 2,2'- ing the agent and the HMG-CoA reductase inhibitor to a (pentamethylenedioxy)dianiline and artemisinin; amorolfine patient having a viral disease. and flupentixol; artemisinin and chlorophyllin; eZetimibe and 0039. In another aspect, the invention features a kit includ fluphenazine; benzamil and fluiphenazine; artemisinin and ing a composition including Sertraline, a Sertraline analog, wedelolactone; cytarabine and dydrogesterone; artemisinin UK-416244, or a UK-416244 analog, and an HMG-CoA and benzamil: 3,3'-(pentamethylenedioxy)dianiline and arte reductase inhibitor (e.g., fluvastatin, simvastatin, lovastatin, mether; tolterodine and trifluperidol; artesunate and fluvasta or rosuvastatin); and instructions for administering the com tin; artemisinin and trifluridine: adefovir dipivoxil and amo position to a patient having a viral disease. rolfine; interferon alfa-2a and trifluridine; fulvestrant and 0040. In another aspect, the invention features a kit includ triciribine; artesunate and dydrogesterone; artesunate and LY ing Sertraline, a sertraline analog, UK-416244, or a 294,002; mosapride citrate and TOFA; bromocriptine and UK-416244 analog; an antihistamine (e.g., hydroxy Zine); wedelolactone; artemisinin and sodium fusidate; celgosivir and instructions for administering the Sertraline or Sertraline and interferon alfa-2a, amorolfine and dextrothyroxine; analog and the antihistamine to a patient having a viral dis andrographis and fulvestrant; 2'-c-methylcytidine and arte CaSC. misinin; amorolfine and gemcitabine; oxeladin and Sertraline; 0041. In another aspect, the invention features a kit includ artemisinin and parthenolide; artemisinin and ribavirin; ing a composition including Sertraline or UK-416244, and an dehydroepiandrosterone and tyrphostin ag 1478; Sertraline antihistamine (e.g., hydroxy Zine); and instructions for and toremifene; dihydroartemisinin and fulvestrant, 2-hy administering the composition to a patient having a viral droxyflavanone and TOFA; artesunate and repaglinide; disease. mofebutaZone and Wedelolactone; artesunate and simvasta 0042. 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 and Wedelolactone; 1.5-bis(4- 503034; adefovir dipivoxil and SCH503034; 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. In tin; fluphenazine and tolterodine; interferon alfa-2a and mel certain embodiments of the kit, sertraline is substituted for a phalan; amorolfine and melphalan; artemisinin and fulves Sertraline analog, UK-416244, or a UK-416244 analog. trant; ifenprodil and quinacrine; simvastatin and rac-cis-n- 0043. In another aspect, the invention features a kit includ desmethyl sertraline; flupentixol and tolterodine: triciribine ing (a) a pair of agents selected from the group consisting of and wortmannin; loratadine and vinorelbine; meclizine and simvastatin and Sertraline; fluvastatin and Sertraline; sertraline; budesonide and vinorelbine: 2-hydroxyflavanone fluphenazine and Sertraline; artesunate and simvastatin; arte US 2010/0009970 A1 Jan. 14, 2010

Sunate and wortmannin; artemisinin and chlorophyllin; arte of the invention, the compositions and kits of the invention, misinin and 3,3'-(pentamethylenedioxy)dianiline; amorolf and methods of the invention for identifying combinations ine and meclizine; amorolfine and Sertraline; amorolfine and may be caused by a single stranded RNA virus, a flaviviridae trifluridine; amorolfine and 2-hydroxyflavanone; amorolfine virus (e.g., a hepacivirus such as HCV, flavivirus, pestivirus, and eZetimibe; amorolfine and benzamil; amorolfine and tri or hepatitis G. virus), or a hepatic virus (e.g., any hepatic virus fluperidol; and octyl methoxycinnamate and Suberohydrox described herein such as hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E, non-ABCDE hepatitis, or hepatitis amic acid; and (b) instructions for administering the pair of G). In certain embodiments, the viral disease is caused by a agents to a patient having a viral disease. The kit may include flavivirus which include without limitation Absettarov, Alfuy, a composition including the pair of agents. In certain embodi Apoi, Aroa, Bagaza, Banzi, Bouboui, BuSSuquara, Cacipa ments of the kit, sertraline is substituted for a sertraline ana core, Carey Island, Dakar bat, Dengue 1, Dengue 2, Dengue log, UK-416244, or a UK-416244 analog. 3, Dengue 4, Edge Hill, Entebbe bat, Gadgets Gully, Hanza 0044. In another aspect, the invention features a method of lova, Hypr, Ilheus, Israel turkey meningoencephalitis, Japa identifying a combination that may be useful for the treatment nese encephalitis, Jugra, Jutiapa, Kadam, Karshi, Kedougou, of a patient having a viral disease, or the prevention or reduc Kokobera, Koutango, Kumlinge, Kunjin, Kyasanur Forest tion of the viral disease. The method includes the steps of disease, Langat, Louping ill. Meaban, Modoc, Montana myo contacting cells including at least a portion of the genome of tis leukoencephalitis, Murray Valley encephalitis, Naranjal, a virus with an agent selected from any one the agents of Table Negishi, Ntaya, Omsk hemorrhagic fever, Phnom-Penh bat, 1, Table 2, and Table 3 and a candidate compound, wherein Powassan, Rio Bravo, Rocio, royal farm, Russian spring the portion of the genome (e.g., of any virus described herein) Summer encephalitis, Saboya, St. Louis encephalitis, Sal is capable of replication in the cells; and determining whether Vieja, San Perlita, Saumarez Reef, Sepik, Sokuluk, Spond the combination of the agent and the candidate compound weni, Stratford, Tembusu, Tyuleniy, Uganda S. Usutu, Wes inhibits the replication of the portion of the genome relative to selsbron, west Nile, Yaounde, yellow fever, and Zika viruses, cells contacted with the agent but not contacted with the or any of the viruses described in Chapter 31 of Fields Virol candidate compound, where a reduction in replication iden ogy, Fields, B. N., Knipe, D. M., and Howley, P. M., eds. tifies the combination as a combination useful for the treat Lippincott-Raven Publishers, Philadelphia, Pa., 1996. In ment of a patient having a viral disease, or the prevention or other embodiments, the viral disease is caused by a pestivirus, reduction of a viral disease. The reduction in replication may which include bovine viral diarrhea virus (“BVDV), classi be the result of a decreased rate of DNA or RNA replication, cal Swine fever virus (“CSFV, also called hog cholera virus), a decreased rate of RNA translation, or inhibition of a protein border disease virus (“BDV) and any of those discussed in required for viral replication (e.g., a protein coded for by the Chapter 33 of Fields Virology, supra. In other embodiments, viral genome or the host organism). If the at least portion of a the viral disease is caused by a virus Such as hepatitis A, genome is from the hepatitis C genome, the reduction in hepatitis B. hepatitis C (e.g., genotype 1 such as 1a or 1b; replication may also be due to a decreased rate of polyprotein genotype 2 Such as 2a, 2b, or ; genotype 3; genotype 4: processing. The cells may be mammalian cells (e.g., hepatic genotype 5: genotype 6); hepatitis D; or hepatitis E. The viral cells, for example, any of those described herein) such as hepatitis may further be a non-ABCDE viral hepatitis (e.g., human cells. hepatitis G). 0045. The viral disease referred to in any of the above 0046 Additional viral therapies are described in Table 4 aspects of the invention, including the methods of treatment and Table 5.

TABLE 4 (+)-Calanolide A (+)-Dihydrocalanolide A 2-Nor-cyclic GMP 3,4-Dicaffeoylquinic acid 3-Hydroxymethyl 3-Hydroxyphthaloyl-beta 3-Nitrosobenzamide dicamphanoyl khellactone lactoglobulin 4-Azidothymidine 4-Methyl dicamphanoyl 524C79 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 Aciclovir (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 Alovudine 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 US 2010/0009970 A1 Jan. 14, 2010 12

TABLE 4-continued 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 95214 ARB 9726S ARB 97268 ARQ 323 AS 101 AT 61 Atazanavir Ateviridine AV 1101 AV 2921 AV 2923 AV 2925 AV 2927 Avarol AXD 455 AZidodideoxyguanosine AZodicarbonamide Bafilomycin A1 BAY 414109 BAY 43969S BAY SO4798 BAYZ 430S 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 BILR 355 BIRMECA 10-142 BL 1743 BMS10836 BMS 181167-O2 BMS 181184 BMS 1821.93 BMS 1863.18 BMS 187071 BMS 488043 BMS 806 BMY 27709 Brecanavir Brefeldin A Brequinar Brivudine BRL 47923DP BSL 4 BST SOO1 BTA 188 BTA 798 C 1605 C 2507 C31G spirulan Canventol Capravirine Carbendazim Carbocyclic deazaadenosine Carbopol polymer gel Carbovir CC 3052 CD4 fusion toxin CD4 IgG CD4-ricin chain A Cellulose sulfate CF 1743 CFY 196 CGA 137053 CGP35269 CGP 4.9689 CGP 53437 CGP 53820 CGP 57813 CGP 61.783 CGP 64222 CGP 70726 CGP 751.36 CGP 751.76 CGP 75355 CI1012 CI1013 Cidofovir Civamide CL 190O38 CL 387626 Clevudine CMV 423 CMXOO1 CNBA-Na. Cobra venom Conocurvone Cosalane Costatolide CP 1018161. CP38 CP51 CPFDD CRL 1072 Crofelemer CS 8958 CS 92 CT 2576 CTC96 Curdlan sulfate Cyanovirin-N CYT 99007 Cytomegalovirus immune globulin DAB486interleukin-2 DABO 1220 Dacopafant DAP 30 DAP 32 Dapivirine Darunavir D-aspartic-beta-hydroxamate DB340 DDCDP-DG DDGA Deazaadenosine DeaZaneplanocin A DEB O2S Delavirdine Delimitide Denileukin diftitox Deoxyfluoroguanosine DES 6 Dexelvucitabine Dextran sulfate Dextrin 2-sulfate DG 3S Didanosine Dideoxyadenosine Dideoxyguanosine Dideoxythymidine Didox Dihydrocostatolide Dinitrochlorobenzene DL110 DMP 323 DMP 850 DMP 851 DmTr-ODN12 Docosanol DP 107 DPC 082 DPC 083 DPC 681 DPC 684 DPC 961 DPC 963 Droximavir DUP 925 913 B-Foscarnet E-EPSEU EGS 21 HT 899 vucitabine

EM 1421 EM2487 ivirine 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 Famciclovir asudil Fattiviracin A1 FEAU Feglymycin elvizumab GI 345 Fiacitabine Fialuridine utimide Fomivirsen Fosalvudine tidoxil Osamprenavir Foscarnet Sodium Fozivudine FP 21.399 -PBT FPMPA FPMPDAP FR 191512 R 198248 alactan Sulfate Ganciclovir 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 US 2010/0009970 A1 Jan. 14, 2010 13

TABLE 4-continued Hepatitis B immune globulin HEPT HGS-HIA27 HI 236 HI 240 HI 244 HI 28O HI346 HI443 HI445 HIV DNA vaccine (Antigen Thiovir Express, Inc.) HIV immune globulin HIV immune plasma HOE BAY 793 HRG 214 HSO58 Hydroxycarbamide Hydroxychloroquine 152 AZT doxuridine M28 mmStat mmuDyn mmunocal mreg 1 incadronic acid NCB 94.71 nfliximab influenza matrix protein Zn2+ ngenol Triacetate nophyllum B nosine pranobex finger peptide interferon-tau interleukin-1 receptor 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 Lamivudine? 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 Lobucavir 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 LY3554.55 LY 366094 LY3664OS LY 368.177 LY 73497 Lysozyme Madu Mannan sulfate MAP 30 Maraviroc Maribavir 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- 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 Moroxydine 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 Nitric oxide (e.g., ProStrakan) Nitrodeazauridine NMO1 NM 49 NM 55 NNY-RANTES Nonakine 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 Oseltamivir Oxetanocin Oxothiazolidine carboxylate PA 344, PA 34.4B Palinavir PaliwiZumab PAMBAEEG Papuamide A PBS 119 PC 1250 PC 515 PCL O16 PDOO84430 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 Penciclovir Pentosan polysulfate Pentoxifylline Peptide T Peramivir PETT 4 PG 36 Phellodendrine Phosphatidyllamivudine Phosphatidylzalcitabine Phosphatidylzidovudine Phosphazid Phosphinic cyclocreatine Pinosylvin Pirodawir US 2010/0009970 A1 Jan. 14, 2010 14

TABLE 4-continued

PL 2500 Pleconaril Plerixafor M 104 PM 19 PM 523 PM921.31 C M94116 PMEDAP PMS 601 PMTG MTI PN355 PNU 103657 PNU 142721 podophyllotoxin Poly ICLC Polyadenylic polyuridylic acid Polysaccharide K P 29 PPB 2. PPL 100 Pradefovir Pradimicin A PRO 140 PRO 2000 RO 367 PRO S42 (Vyrex Corp.) Propagermanium Prostratin Pseudohypericin PSI SOO4 PTPR TX111 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 R87366 R91767 R944 R95288 Raluridine Ramatroban Ranpirinase RB 2121 RBC CD4 RD 30O28 RD 42024 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 Rolipram RP 70034 RP 71955 RPI312 PI856 RPR 103611 RPR 106868 RPR111423 S 654 RS 980 RSV 604 Rubitecan upintrivir S 1360 S 2720 A. 1 O 42 SA8443 SB 180922 B 2.05700 B2O6343 SB 73 SC 49.483 C 55099 CH3SO 634 SD 894 S-DABO DF 1 DZ, 282870 SDZ, 28.3053 SDZ, 2834.71 DZPRIOS3 SEO63 Semapimod F 950 SF 953 Siamycin 1 ICAM-1 Sifuwirtide SIGA246 3366 SKO34 KF 108.922 SKI 1695 O 3 2 4 Sodium laurilsulfate olutein orivudine (e.g., topical) P 10 SP 1093V. parfosic acid PC3 PD 756 SpecifEx-Hep B PI 119 PL 2992 PL 7013 SPV 30 R 10204 R 10208 R11335 SR 3745A R3773 R3775 R3784 SR 3785 R. 41476 RL 172 RRSB3 ST 135647 achyflin stallimycin ampidine Statolon avudine Stepronin S uksdorfin Sulfated maltoheptaose Superoxide dismutase (e.g., sodium) S y 801 T 1100 T 118 T 22 T 30.695 T 611 T 705 acrine TAK 220 TAK 652 TAK779 alviraline TAP 29 TASP Teceleukin ecogalan (e.g., Sodium) TEI 2306 Telbivudine Telinavir emacrazine Tenidap Tenofovir Tenofovir disoproxil fumarate TGG II 23A TH94O7 TH 9411 hiophosphonoformic acid Thymoctonian fraction 5 Thymotrinan ICAM-1 Tifuwirtide Tillarginine Tipranavir iviciclovir Tivirapine TJ 41 TL3024 TMC 126 TNF-alpha inhibitor TNK 6123 TNX355 odoxin Tomeglovir Transforming growth factor TraT recovirsen alpha Tremacamra Trichosanthin Triconal rimidox Trodusquemine Tromantadine Trovirdine uvirumab U103017 U 75875 U 78036 U 80493 U 81749 U88204E U 96988 U 98.43 UA926 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 Valaciclovir Valganciclovir Valomaciclovir Valtorcitabine Varicella Zoster immune 9. lobulin 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 US 2010/0009970 A1 Jan. 14, 2010 15

TABLE 4-continued

Y-ART-3 YHI1 YKFH312 Z 100 Z 15 Zalcitabine Zanamivir Zidovudine (e.g., phosphate didanosine dimer) Zidovudine triphosphate mimics ZXO610 ZXO62O ZXO791 ZXO792 ZX O793 ZXO851 ZY II

0047. Additional hepatitis C therapies are described in Table 5.

TABLE 5 Albuferon JTKOO3 R7128 2'-C-methyl-7-deaza-adenosine HCV AB 68 JTK 109 Residuimod A-837.093 HCVSM KPE OOOO1113 RosiglitaZone AG-021541 HE 2000 KPEO2OO3OO2 Sargramostim 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 Taribavirin BIVN4O1 CN 17261 Milk thistle BLX 833 (e.g., controlled DN 6556 Mitoquinone Thymalfasin (e.g., Zadaxin) release) miquimod NIM 811 Thymus extract CellCept LiceOil N-nonyl-DNJ TT 9 Ceplene interferon alfa-2b (e.g., NOV 205 Tucaresol inhalation) Ciluprevir (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 interferon alpha-n3 PEGylated interferon VP 504O6 EHC 18 interferon beta-1a Pegylated thymalfasin VRT 21493 EMZ 702 interferon beta-1b PF-03491390 Fas- inhibitor interferon gamma-1b PG 3.01029 WF 10 Ginseng Lnterferon 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 7 Peginterferon-alpha ribavirin/EMZ 702 TABLE 6 Efavirenziemtricitabinetenofovir disoproxil fumarate Interferon alpha-2biribavirin 0048 Analogs of any of the compounds listed in Tables 1, 2, or 3 may be used in any of the compositions, methods, and Lopinavirritonavir kits of the invention. Such analogs include any agent from the Peginterferon alfa-2biribavirin same therapeutic class, having the same or related molecular targets, or from the same mechanistic class as those listed in Table 8. Exemplary analogs of these compounds are described throughout the specification. US 2010/0009970 A1 Jan. 14, 2010 16

8HT8IVIL US 2010/0009970 A1 Jan. 14, 2010 17 US 2010/0009970 A1 Jan. 14, 2010 18 US 2010/0009970 A1 Jan. 14, 2010 19

6TW US 2010/0009970 A1 Jan. 14, 2010 20 US 2010/0009970 A1 Jan. 14, 2010 21

TRISS

QUITEN US 2010/0009970 A1 Jan. 14, 2010 22 US 2010/0009970 A1 Jan. 14, 2010 23 US 2010/0009970 A1 Jan. 14, 2010 24 US 2010/0009970 A1 Jan. 14, 2010 25 US 2010/0009970 A1 Jan. 14, 2010 26 US 2010/0009970 A1 Jan. 14, 2010 27 US 2010/0009970 A1 Jan. 14, 2010 28

Joideo?IVOIWN

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0049 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 0056 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, , nitrogen, , phosphorous, pound for treatment of any human disease or condition. fluorine, and chlorine, (e.g., H, H, C, C, N, O, '70, 0057 By “hypercholesterolemia' is meantan total choles 'P 'P, S, F, and Cl). Isotopically-labeled compounds terol level of at least 200 mg/dl. High risk groups include can be prepared by Synthesizing a compound using a readily those with at least 240 mg/dl. Normal levels are available isotopically-labeled reagent in place of a non-iso below 200 mg/dl. Hypercholesterolemia may also be defined topically-labeled reagent. by low density lipoprotein (LDL) levels. Less than 100 mg/dl is considered optimal; 100 to 129 mg/dl is considered near 0050. By “patient' is meant any animal (e.g., a mammal optimal/above optimal: 130 to 159 mg/dl borderline high; 160 Such as a human). Any animal can be treated using the meth to 189 mg/dl high; and 190 mg/dl and above is considered ods, compositions, and kits of the invention. very high. 0051) To “treat’ is meant to administer one or more agents 0.058 By a “candidate compound is meant a chemical, be to measurably slow or stop the replication of a virus in vitro or it naturally-occurring or artificially-derived. Candidate com in vivo, to measurably decrease the load of a virus (e.g., any pounds may include, for example, , polypeptides, virus described herein including a hepatitis virus Such as synthetic organic molecules, naturally occurring organic hepatitis A, B, C, D, or E) in a cell in vitro or in vivo, or to molecules, nucleic acid molecules, peptide nucleic acid mol reduce at least one symptom (e.g., those described herein) ecules, and components or derivatives thereof. associated with having a viral disease in a patient. Desirably, 0059. In the generic descriptions of compounds of this the slowing in replication or the decrease in viral load is at invention, the number of atoms of a particular type in a least 20%, 30%, 50%, 70%, 80%, 90%, 95%, or 99%, as Substituent group is generally given as a range, e.g., an alkyl determined using a suitable assay (e.g., a replication assay group containing from 1 to 4 carbon atoms or C alkyl. described herein). Typically, a decrease in viral replication is Reference to such a range is intended to include specific accomplished by reducing the rate of DNA or RNA polymer references to groups having each of the integer number of ization, RNA translation, polyprotein processing, or by atoms within the specified range. For example, an alkyl group reducing the activity of a protein involved in any step of viral from 1 to 4 carbon atoms includes each of C, C, C, and C. replication (e.g., proteins coded by the genome of the virus or AC. heteroalkyl, for example, includes from 1 to 12 car host protein important for viral replication). bon atoms in addition to one or more heteroatoms. Other 0052 By “an effective amount' is meant the amount of a numbers of atoms and other types of atoms may be indicated compound, alone or in combination with another therapeutic in a similar manner. regimen, required to treat a patient with a viral disease (e.g., 0060. As used herein, the terms “alkyl and the prefix any virus described herein including a hepatitis virus Such as “alk- are inclusive of both straight chain and branched chain hepatitis A, B, C, D, or E) in a clinically relevant manner. A groups and of cyclic groups, i.e., cycloalkyl. Cyclic groups Sufficient amount of an active compound used to practice the can be monocyclic or polycyclic and preferably have from 3 present invention for therapeutic treatment of conditions to 12 ring carbon atoms, inclusive. Exemplary cyclic groups caused by a virus varies depending upon the manner of include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl administration, the age, body weight, and general health of groups. the patient. Ultimately, the prescribers will decide the appro 0061. By "C. alkyl is meant a branched or unbranched priate amount and dosage regimen. Additionally, an effective hydrocarbon group having from 1 to 4 carbon atoms. A Ca amount may be an amount of compound in the combination of alkyl group may be substituted or unsubstituted. Exemplary the invention that is safe and efficacious in the treatment of a Substituents include alkoxy, aryloxy, Sulfhydryl, alkylthio. patient having a viral disease over each agent alone as deter arylthio, halide, hydroxyl, fluoroalkyl, perfluoralkyl, amino, mined and approved by a regulatory authority (Such as the aminoalkyl, disubstituted amino, quaternary amino, U.S. Food and Drug Administration). hydroxyalkyl, carboxyalkyl, and carboxyl groups. Calkyls 0053. By “more effective' is meant that a treatment exhib include, without limitation, methyl, ethyl, n-propyl, isopro its greater efficacy, or is less toxic, safer, more convenient, or pyl, cyclopropyl, cyclopropylmethyl, n-butyl, iso-butyl, sec less expensive than another treatment with which it is being butyl, tert-butyl, and cyclobutyl. compared. Efficacy may be measured by a skilled practitioner 0062 By “C. alkenyl is meant a branched or using any standard method that is appropriate for a given unbranched hydrocarbon group containing one or more indication. double bonds and having from 2 to 4 carbon atoms. A Ca 0054 By “hepatic virus' is meant a virus that can cause alkenyl may optionally include monocyclic or polycyclic hepatitis. Such viruses include hepatitis A, hepatitis B, hepa rings, in which each ring desirably has from three to six titis C, hepatitis D, hepatitis E, non-ABCDE hepatitis, and members. The C alkenyl group may be substituted or hepatitis G. unsubstituted. Exemplary Substituents include alkoxy, ary 0055. By a “low dosage” is meant at least 5% less (e.g., at loxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoro least 10%, 20%, 50%, 80%, 90%, or even 95%) than the alkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, lowest standard recommended dosage of a particular com quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl pound formulated for a given route of administration for groups. Calkenyls include, without limitation, vinyl, allyl, treatment of any human disease or condition. For example, a 2-cyclopropyl-1-ethenyl, 1-propenyl, 1-butenyl, 2-butenyl, low dosage of an agent that inhibits viral replication and that 3-butenyl, 2-methyl-1-propenyl, and 2-methyl-2-propenyl. US 2010/0009970 A1 Jan. 14, 2010 37

0063. By “C. alkynyl is meant a branched or pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, unbranched hydrocarbon group containing one or more triple pyrrolyl pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetra bonds and having from 2 to 4 carbon atoms. A C- alkynyl Zolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimida may optionally include monocyclic, bicyclic, or tricyclic Zolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotria rings, in which each ring desirably has five or six members. Zolyl, benzisoxazolyl, OXindolylbenzoxazolinyl, quinolinyl, The C- alkynyl group may be substituted or unsubstituted. and isoquinolinyl. Preferred 5 to 6 membered heterocycles Exemplary Substituents include alkoxy, aryloxy, Sulfhydryl, include, without limitation, pyridinyl, pyrimidinyl, triazinyl, alkylthio, arylthio, halide, hydroxy, fluoroalkyl, perfluo furanyl, thienyl, thiazolyl pyrrolyl, piperazinyl, piperidinyl, ralkyl, amino, aminoalkyl, disubstituted amino, quaternary pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl. amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups. 0065. By "Caryl' is meant an aromatic group having a C. alkynyls include, without limitation, ethynyl, 1-propy ring system comprised of carbon atoms with conjugated at nyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl. electrons (e.g., phenyl). The aryl group has from 6 to 12 0064. By "C. heterocyclyl” is meant a stable 5- to carbon atoms. Aryl groups may optionally include monocy 7-membered monocyclic or 7- to 14-membered bicyclic het clic, bicyclic, or tricyclic rings, in which each ring desirably erocyclic ring which is saturated, partially unsaturated, or has five or six members. The aryl group may be substituted or unsaturated (aromatic), and which consists of 2 to 6 carbon unsubstituted. Exemplary substituents include alkyl, atoms and 1, 2, 3, or 4 heteroatoms independently selected hydroxy, alkoxy, aryloxy, Sulfhydryl, alkylthio, arylthio. from N, O, and S and including any bicyclic group in which halide, fluoroalkyl, carboxyl, hydroxyalkyl, carboxyalkyl, any of the above-defined heterocyclic rings is fused to a amino, aminoalkyl, monosubstituted amino, disubstituted ring. The heterocyclyl group may be substituted or amino, and quaternary amino groups. unsubstituted. Exemplary Substituents include alkoxy, ary 0.066 By “C, alkaryl is meant an alkyl substituted by loxy, sulfhydryl, alkylthio, arylthio, halide, hydroxy, fluoro an aryl group (e.g., benzyl, phenethyl, or 3,4-dichlorophen alkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, ethyl) having from 7 to 14 carbon atoms. quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl 0067 By “Coalkheterocyclyl is meant an alkyl substi groups. The nitrogen and heteroatoms may optionally tuted heterocyclic group having from 3 to 10 carbon atoms in be oxidized. The heterocyclic ring may be covalently attached addition to one or more heteroatoms (e.g., 3-furanylmethyl, via any heteroatom or carbon atom which results in a stable 2-furanylmethyl, 3-tetrahydrofuranylmethyl, or 2-tetrahy structure, e.g., an imidazolinyl ring may be linked at either of drofuranylmethyl). the ring-carbon atom positions or at the nitrogen atom. A 0068. 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 , tation, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1.5.2-dithiazi secondary amines, , thioethers, , thioamides, nyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, , thiocarbamates, , , phosphodi 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, , phosphoramidates, Sulfonamides, and . 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, heteroalkyls furanyl, isochromanyl, isolindazolyl, isoindolinyl, isoindolyl, include, without limitation, methoxymethyl and ethoxyethyl. isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naph 0069. 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 Zolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, 0070. By “fluoroalkyl is meant an alkyl group that is phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, substituted with a fluorine atom. phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, 0071. By “perfluoroalkyl is meant an alkyl group consist piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperido ing of only carbon and fluorine atoms. nyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, 0072 By “carboxyalkyl is meanta chemical moiety with pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyri the formula—(R)-COOH, wherein R is selected from C, doimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, alkyl, C2-7 alkenyl, C2-7 alkynyl, C-heterocyclyl, C-2 aryl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, C- alkaryl, Coalkheterocyclyl, or C, heteroalkyl. 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tet 0073. By “hydroxyalkyl is meant a chemical moiety with rahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinoli the formula —(R) —OH, wherein R is selected from C, nyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadia alkyl, C2-7 alkenyl, C2-7 alkynyl, C-heterocyclyl, C-2 aryl, Zolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, C- alkaryl, Coalkheterocyclyl, or C, heteroalkyl. thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimi 0074 By “alkoxy” is meant a chemical substituent of the dazolyl, thiophenyl, triazinyl, 1.2.3-triazolyl, 1,2,4-triazolyl, formula —OR, wherein R is selected from C, alkyl, C-7 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Preferred 5 to alkenyl, C2-7 alkynyl, C2-a heterocyclyl, C-2 aryl, C7-14 10 membered heterocycles include, but are not limited to, alkaryl, Coalkheterocyclyl, or C-7 heteroalkyl. US 2010/0009970 A1 Jan. 14, 2010

0075. By “aryloxy' is meant a chemical substituent of the other therapeutic regimen is lowered to achieve the same formula —OR, wherein R is a C-2 aryl group. therapeutic benefit, thereby moderating any unwanted side 0076. By “alkylthio’ is meant a chemical substituent of effects. the formula—SR, wherein R is selected from C, alkyl, C-7 I0083. In one particular example, the patient being treated alkenyl, C2-7 alkynyl, C2-a heterocyclyl, C-2 aryl, C7-14 is administered two agents listed in Table 1, Table 2 and/or alkaryl, Coalkheterocyclyl, or C-7 heteroalkyl. Table 3 within 28 days of each other in amounts that together 0077. By “arylthio” is meant a chemical substituent of the are sufficient to treat a patient having a viral disease. The two formula—SR, wherein R is a Caryl group. agents can be administered within 14 days of each other, 0078. By “quaternary amino” is meant a chemical sub within seven days of each other, within twenty-four hours of stituent of the formula—(R) N(R')(R") (R")", wherein R, each other, or even simultaneously (i.e., concomitantly). If R", R", and R" are each independently an alkyl, alkenyl, desired, either one of the two agents may be administered in alkynyl, or aryl group. R may be an alkyl group linking the low dosage. quaternary amino nitrogen atom, as a Substituent, to another moiety. The nitrogen atom, N, is covalently attached to four Viral Diseases carbon atoms of alkyl, heteroalkyl, heteroaryl, and/or aryl groups, resulting in a positive charge at the nitrogen atom. 0084. The invention relates to the treatment of viral dis 0079. Other features and advantages of the invention will ease, which can becaused by any virus. Viruses include single be apparent from the following Detailed Description and the stranded RNA viruses, flaviviridae viruses, and hepatic viruses. In particular, the flaviviridae family of viruses claims. include hepacivirus (e.g., HCV); flaviviruses; pestiviruses, and hepatitis G. virus. BRIEF DESCRIPTION OF THE DRAWINGS I0085 Flaviviruses generally are discussed in Chapter 31 of Fields Virology, supra. Exemplary flaviviruses include 0080 FIG. 1 is a graph showing survival data for sertraline Absettarov, Alfuy, Apoi, Aroa, Bagaza, Banzi, Bouboui, Bus and oseltamivir in the lethal infection of influenza A/PR/8/34 Suquara, Cacipacore, Carey Island, Dakar bat, Dengue 1. induced in C57/BL6 mice. Dengue 2, Dengue 3, Dengue 4, Edge Hill, Entebbe bat, 0081 FIG. 2 is a graph showing dose dependant increase Gadgets Gully, Hanzalova, Hypr, Ilheus, Israel turkey men in Survival rate of Sertraline-treated groups as compared to ingoencephalitis, Japanese encephalitis, Jugra, Jutiapa, vehicle-treated groups. 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 0082 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 Uganda S. Usutu, Wesselsbron, west Nile, Yaounde, yellow flaviviridae virus, or a hepatic virus (e.g., described herein). fever, and Zika viruses. In certain embodiments, the viral disease is viral hepatitis I0086 Pestiviruses generally are discussed in Chapter 33 (e.g., hepatitis A, hepatitis B, hepatitis C, hepatitis D, and of Fields Virology, supra. Specific pestiviruses include, with hepatitis E). The invention also features screening methods out limitation: bovine viral diarrhea virus, classical Swine useful for the identification of novel compounds for the treat fever virus (also called hog cholera virus), and border disease ment of viral diseases. Compositions of the invention can W1US. include one or more agents selected from the agents of Table 1, Table 2, Table 3, Table 4, and Table 5. Treatment methods Hepatitis Viruses of the invention include administration of one or more agents selected from the agents of Table 1, Table 2, and Table 3, I0087 Viruses that can cause viral hepatitis include hepa optionally along with an additional antiviral therapy (e.g., titis A, hepatitis B, hepatitis C, hepatitis D, and hepatitis E. In administration of one or more agents of Table 4 or Table 5) to addition, non-ABCDE cases of viral hepatitis have also been a patient (e.g., a mammal Such as a human). Optionally, reported (see, for example, Rochling et al., Hepatology functional or structural analogs (e.g., those described herein) 25:478-483, 1997). Within each type of viral hepatitis, several of these agents or agents of the same therapeutic or mecha Subgroupings have been identified. Hepatitis C, for example, nistic class as those described herein (see, e.g., Table 8) may has at least six distinct genotypes (1, 2, 3, 4, 5, and 6), which be employed in the compositions, methods, and kits of the have been further categorized into Subtypes (e.g., 1a, 1b, 2a, invention. The ability of a composition to reduce replication 2b, 2c, 3a, 4a) (Simmonds, J. Gen. Virol. 85:3173-3188, of a virus may be due to a decrease in RNA or DNA polymer 2004). ization, RNA translation, RNA or DNA transcription, a I0088. In the case of hepatitis C, acute symptoms can decrease in posttranslational protein processing (e.g., include jaundice, abdominal pain, fatigue, loss of appetite, polyprotein processing in hepatitis C), or a decrease in activ nausea, vomiting, low-grade fever, pale or clay-colored ity of a protein involved in viral replication (e.g., a protein stools, dark urine, generalized itching, ascites, and bleeding coded for by the viral genome or a host protein required for Varices (dilated veins in the esophagus). Hepatitis C can viral replication). The compounds or combinations of com become a chronic infection, which can lead to liver infection pounds may also enhance the efficacy of the other therapeutic and Scarring of the liver, which can, in turn, require the patient regimens such that the dosage, frequency, or duration of the to undergo a liver transplant. US 2010/0009970 A1 Jan. 14, 2010 39

0089 Hepatitis C is an RNA virus taken up specifically by maleate, carphenazine maleate, carvotroline hepatic cells. Once inside the cells, the RNA is translated into hydrochloride, , chlorpromazine hydrochlo a polyprotein of about 3,000 amino acids. The protein is then ride, , cinperene: cintriamide, clomacran processed into three structural and several non-structural pro phosphate, , , clopipazan mesylate, teins necessary for viral replication. Accordingly, HCV may cloroperone hydrochloride, clothiapine, clothixamide male be treated by reducing the rate any of the steps required for its ate, cyclophenazine hydrochloride, , replication or inhibiting any molecule involved in replication, hydrochloride, fenimide, , , fluphena including but not limited to, entry into a target cell, viral Zine decanoate, fluphenazine enanthate, fluphenazine hydro genome replication, translation of viral RNA, protolytic pro chloride, fluspiperone, , flutroline, cessing, and assembly and release from the target cell (e.g., hydrochloride, halopemide, , haloperidol using the agents described herein). decanoate, illoperidone, imidoline hydrochloride, , Succinate, mesoridazine, mesoridazine besylate, Compounds , milemperone, millipertine, hydrochlo ride, hydrochloride, neflumozidehydrochloride, oca 0090 Certain compounds that may be employed in the peridone, , oxiperomide, , pentiapine methods, compositions, and kits of the present invention are maleate, , , hydrochloride, discussed in greater detail below. It will be understood that , , palmitate, piquin analogs of any compound of Table 1, Table 2, or Table 3 can done hydrochloride, edisylate, prochlor be used instead of the compound of Table 1, Table 2, or Table maleate, promazine hydrochloride, , 3 in the methods, compositions, and kits of the present inven remoxipride hydrochloride, hydrochloride, seperi tion. dol hydrochloride, , , spiperone, thior idazine, hydrochloride, thiothixene, thiothixene HMG-CoA Reductase Inhibitors hydrochloride, tioperidone hydrochloride, hydro 0091. 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- (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, 0093 Trifluperidol , rosuvastatin, fluindostatin, Velostatin, compac 0094. In certain embodiments, trifluperidol or an analog tin, dihydrocompactin, rivastatin, dalvastatin, , thereof can be used in the compositions, methods, and kits of BAY 102987, BAY X 2678, BB476, bervastatin, BMY21950, 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 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 5,273,995; 5,276,021; 5,369,123: 5,385,932; 5,502,199; 5,763,414; 5,877.208; and 6,541,511; and U.S. Pat. Applica Air 4 Ox" tion Publication Nos. 2002/0013334 A1: 2002/0028826A1; (Cf.)N(C1, CH,) 2002/0061901 A1; and 2002/0094977 A1. Air Clozapine where Arand Arare monocyclic aryl rings, is 2 to 4, n is 1 or 0092. In certain embodiments, clozapine or a clozapine 2, m is 0, 1, or 2, and X is a hydrogen or a . Arand analog can be used in the compositions, methods, and kits of Ar' can 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, butaperazine, butylphenyl; and a trifluoromethylphenyl radical. (CH2), can US 2010/0009970 A1 Jan. 14, 2010 40 represent a lower alkylene group, e.g., 2 to 4 carbon atoms dinium bases (see, e.g., U.S. Pat. No. 2,135,293). Heterocy Such as , trimethylene, propylene, butylene, methyl clic azo derivatives and N-substituted diaminopyridines have propylene, and tetramethylene. also been described (U.S. Pat. Nos. 2,145,579 and 3,647, 808). Paclitaxel

0095. In certain embodiments, paclitaxel or a paclitaxel E-1 analog can be used in the compositions, methods, and kits of N the invention. Paclitaxel is described in U.S. Pat. No. 4,814, 470. Paclitaxel analogs include isoserine, taxol, taxotere, s cephalomannine, 10-deacetylbaccatine III and those com 2 pounds described in U.S. Pat. Nos. 4,814,470, 4,857,653, 4,876,399, 4,924.011, 4,924.012, 4,942,184, 4,960,790, NH2 5,015,744, 5,059,699, 5,136,060, 5,157,049, 5,192,796, 4-aminopyridine 5,227,400, 5,243,045, 5,248,796, 5,250,683, 5,254,580, E-2 5,271,268, 5,272,171, 5,283,253, 5,284.864, 5,290,957, N 5,292,921, 5,294,637, 5,319,112, 5,336,684, 5,338,872, n 5,350,866, 5,380,751, 5,380,916, 5,399,726, 5,430,160, 5,438,072, 5,470,866, 5,489,601, 5,508.447, 5,539,103, 2 NH2 5,547,981, 5,556,878, 5,574,156, 5,580,899, 5,580,998, 5,587,489, 5,587,493, 5,606,083, 5,622,986, 5,635,531, NH2 5,646,176, 5,654,447, 5,677,470, 5,688,977, 5,693,666, 5,703,117, 5,710,287, 5,714,512, 5,714.513, 5,717,115, 3,4-diaminopyridine E-3 5,721,268, 5,728,725, 5,728,850, 5,739,362, 5,750,562, N NH2 5,760,219, 5,773,464, 5,807,888, 5,821,363, 5,840,748, n 5,840,929, 5,840,930, 5,854,278, 5,912,264, 5,919,815, 5,902,822, 5,965,739, 5,977,386, 5,990.325, 5,994,576, HN 2 5,998,656, 6,011,056, 6,017,935, 6,018,073, 6,028,205, 6,051,724, 6,066,747, 6,080,877, 6,107,332, 6,118,011, CH 6,124,481, 6,136,961, 6,147,234, 6,177,456, 6,307,064, 6,310,201, 6,350,886, 6,362,217, 6,455,575, 6,462,208, 2,5-diamino-4-methylpyridine 6,482,963, 6,495,704, 6,515,151, 6,545,168, 6,710,191, E-4 6,762,309, 6,794,523, 6,797,833, 6,878,834, 6,911,549, and HN N NH2 7,019,150. s Estrogenic Compounds 2 NH2 0096. In certain embodiments, an estrogenic compound 2,3,6-triaminopyridine can be used in the compositions, methods, and kits of the E-5 invention. Estrogenic compounds include (e.g., HN N NH2 estradiol Valerate, estradiol cypionate), colpormon, 2-methy oxyestradiol, conjugated estrogenic hormones, , 21s , dienestrol, ethinyl estradiol, , , mox estrol, quinestradiol, quinestrol, , estrone Sulfate, equilin, diethylstilbestrol, broparoestrol, chlorotrianisine, NH2 , , , and . Estrogenic 2,4,6-triaminopyridine compounds are also described in U.S. Pat. Nos. 2,096,744, E-6 2,465,505, 2,464,203, and 3,159,543. HN N NH2 Aminopyridines 21s 0097. In certain embodiments, an aminopyridine can be used in the composition, methods, and kits of the invention. 2,6-diaminopyridine By “aminopyridine' is meant any ring-containing compound in which the pyridine has one, two, or three amino group Substituents. Other substituents may optionally be present. Exemplary aminopyridines include phenazopyri 0098. In certain embodiments, an can be used dine, 4-aminopyridine, 3,4-diaminopyridine, 2,5-diamino-4- in the methods, compositions, and kits of the invention. Anti methylpyridine, 2.3.6-triaminopyridine, 2,4,6-triaminopyri include tamoxifen, 4-hydroxy tamoxifen, clo dine, and 2,6-diaminopyridine, the structures of which are mifene, raloxifene, faslodex, , fulvestrant, CI-680, depicted below. Phenazopyridine and derivatives thereof CI-628, CN-55,956-27, MER-25, U-11,555A, U-11100A, have been disclosed in U.S. Pat. Nos. 1,680,108 through ICI-46,669, ICI-46,474, diphenolhydrochrysene, erythro 1,680,111. Modifications of di-amino(phenylazo) MEA, Parke Davis CN-35.945, allenolic acid, , have been performed to improve in water by react , and and those compounds ing these compounds with alkylating agents (e.g., alkyl described in U.S. Pat. Nos. 5,384.332, 4,894,373, 4,536,516, halides and alkyl Sulphates) to produce quaternary pyri 4,418,068, and 2,914,563. US 2010/0009970 A1 Jan. 14, 2010 41

Calcium Channel Inhibitors

0099. In certain embodiments, a calcium channel inhibitor (I) can be used in the compositions, methods, and kits of the X X invention. Calcium channel inhibitors include thapsigargin, X Y. X Verapamil, anipamil, bepridil, gallopamil, devapamil, falli pamil, tiapamil, , , daZodipine, felo dipine, isradipine, lanicardipine, , , , , ryosidie, diltiazem, , X f X X A X , BAY-m 4786, and diperdipine. n Verapamil N(B) 01.00 (II) 0101. In certain embodiments, Verapamil or an analog X X thereof can be used in the compositions, methods, and kits of X Y. X the invention. The structure of Verapamil is:

X X

(III)

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

Rs X OCO X R R =ly R. X X Rs6– R N-(CH), \ { X A SN(B),X x / (CH2) R7 wherein each X is, independently, H, Cl, F, Br, I, CH, CF, ir OH, OCH, CHCH, or OCHCH;Y is CH, O, NH, S(O) N o, (CH), (CH), CHO, CHNH, CHN, or CHS; Z is C or S; A is a branched or unbranched, Saturated or monounsat urated hydrocarbon chain having between 3 and 6 , inclusive; each B is, independently, H., Cl, F, Br, I, CX, CHCH, OCX, or OCXCX; and D is CH, O, NH, or where R is a lower aliphatic hydrocarbon radical; R is hydro S(O). In preferred embodiments, each X is, independently, H, Cl, or F: Y is (CH), Z is C; A is (CH); and each B is, gen, a lower alkyl radical, a saturated or unsaturated cyclic or independently, H., Cl, or F. Other tricyclic compounds are bicyclic hydrocarbon radical, the benzyl radical, or the phenyl described below. Tricyclic compounds include tricyclic anti radical; R. R. R. R. R. and R-7 are hydrogen, halogen, depressants such as , 8-hydroxyamoxapine, 7-hy lower alkyl radicals, lower alkoxy groups, or two of said droxyamoxapine, (e.g., loxapine Succinate, loxap Substituents togetherforming the methylene dioxy group; n is ine hydrochloride), 8-hydroxyloxapine, , an integer between 2 and 4; and m is an integer between 1 and , doxepin, imipramine, trimipramine, 3. , , and , although com pounds need not have antidepressant activities to be consid Tricyclic Compounds ered tricyclic compounds of the invention. 0103 Tricyclic compounds that can be used in connection 0102. In certain embodiments, a tricyclic compound can with the invention include amitriptyline, amoxapine, clomi be used in the compositions, methods, and kits of the inven pramine, desipramine, dothiepin, doxepin, imipramine, tion. By “tricyclic compound is meant a compound having , maprotiline, mianserin, , nortrip one the formulas (I), (II), (III), or (IV): tyline, , , protriptyline, trimipramine, US 2010/0009970 A1 Jan. 14, 2010 42

10-(4-methylpiperazin-1-yl)pyrido(4.3-b)(1,4)benzothiaz 01.05 Structural analogs of Sertraline are those having the epine; 11-(4-methyl-1-piperazinyl)-5H-dibenzo(b.e)(1,4)di formula: azepine; 5,10-dihydro-7-chloro-10-(2-(morpholino)ethyl)- 11H-dibenzo(b.e)(1,4)diazepin-1 1-one: 2-(2-(7-hydroxy-4- dibenzo(b.f)(1,4)thiazepine-11-yl-1-piperazinyl)ethoxy) R R ethanol: 2-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo NN1 (b.e)(1,4)diazepine; 4-(11H-dibenz(b.e)azepin-6-yl) ; 8-chloro-11-(4-methyl-1-piperazinyl)-5H dibenzo(b.e)(1,4)diazepin-2-ol; 8-chloro-11-(4-methyl-1- piperazinyl)-5H-dibenzo(b.e)(1,4)diazepine monohydrochloride: (Z)-2-butenedioate 5H-dibenzo(b.e)(1, 4)diazepine; adinazolam; ; ; ; clothiapine; clozapine; ; 11-(4- methyl-1-piperazinyl)-dibenz(b.f)(1,4)oxazepine; 11-(4-me thyl-1-piperazinyl)-2-nitro-dibenZ(b.f)(1,4)oxazepine; 2-chloro-11-(4-methyl-1-piperazinyl)-dibenz(b.f)(1,4)ox azepine monohydrochloride: ; 11-(4-methyl-1- piperazinyl)-dibenzo(b,f) (14)thiazepine; ; flua where R and R2 are independently selected from the group cizine; ; imipramine N-oxide; ; consisting of H, optionally Substituted C. alkyl (e.g., CH, lofepramine; ; ; metiapine; metralin dole; mianserin; mirtazapine; 8-chloro-6-(4-methyl-1-piper (CH),OH, cyclopropyl, (CH),COOH, or CHCHOH(CH) azinyl)-morphanthridine, N-acetylamoxapine; nomifensine; (CH), N(CfI), where X is 1, 2, 3, 4, or 5), and optionally ; norclozapine; noxiptilin; ; substituted C, heteroalkyl (e.g., CHCHN(CH)) or R oxaprotiline; ; pizotyline; ; ; and R together form a Cs cycloalkyl optionally heterocy ; ; tomoxetine; flupenthixol; clo clic, optionally substituted (e.g., forming a morpholine ring), penthixol; piflutixol; chlorprothixene; and thiothixene. Other R. R. Rs, and R are independently H, Cl, F, Br, OH, or tricyclic compounds are described in U.S. Pat. Nos. 2,554, optionally substituted C. alkyl; X and Y are each selected 736, 3,046,283, 3,058,979, 3,310,553, 3,177.209, 3,194,733, from the group consisting of H. F. Cl, Br, CF, Calkoxy 3,205.264, 3,244,748, 3,271,451, 3,272,826, 3,282,930, (e.g., OPhand OCH), and cyano; and W is selected from the 3,282,942, 3,299,139, 3,312,689, 3,389,139, 3,399,201, group consisting of H, F, Cl, Br, CF, C alkoxy, COOH, 3,409,640, 3,419,547, 3,438,981, 3,454,554, 3,467,650, 3,505,321, 3,527,766, 3,534,041, 3,539,573, 3,574,852, CHCH-OH, NHCOH, NHCOCH, CHS(O)CH, 3,622,565, 3,637,660, 3,663,696, 3,758,528, 3,922,305, CH-NH CONH, CHOH, NHCOPh, CHNHS(O)CH, 3,963,778, 3,978,121, 3,981,917, 4,017,542, 4,017,621, NHS(O), Ph, N(CH), S(O)NH, NHCOBu, NHS(O)CH, 4,020,096, 4,045,560, 4,045,580, 4,048,223, 4,062,848, NHCOcyclopentyl, CN, NHS(O)cyclopropyl, NH, NO, I, 4,088,647, 4,128,641, 4,148,919, 4,153,629, 4,224,321, SON(CH), SONHMe, SONHCHCH-OH, CO.Me, 4,224,344, 4,250,094, 4,284,559, 4,333,935, 4,358,620, NHSOBu, CONHCH, CH-NHCOCH CONHPh. 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 O 21 N2\ 6,600,065, and compounds that fit Formula (I) of U.S. patent application Ser. Nos. 10/617,424 (published as us N s s 1. Ns us/ s U.S. 2004/0116407) or 60/504,310. (O), Sertraline and Analogs thereof. N

0104. In certain embodiments, sertraline or an analog H \ s thereof can be used in the compositions, methods, and kits of M the invention. Sertraline has the structure: -N-1s (O)

HN1 CONHcylopropyl, C(S)NH, NHC(S)CH, CONHCHCOOCH, CONHCHCOOH, CONHCH cyclopropyl, CONCCH)cyclopropyl, CONHcy clobutyl, NHCOcyclopropyl, NH(CH)COCH, N(CH) COCH, and CHS(O),R, where n is 0, 1, or 2 and R is phenyl, C. heterocyclyl, optionally Substituted Cls alkyl (e.g., C.s unsubstituted alkyl Such as Bu or Cs substituted alkyl). In certain embodiments, R is CH and R is CH, CHCH-OH, cyclopropyl, CHCOOH, CHCH-NH. CHCH(OH)Rs, or CHCH(Rs.)NRRo, where n is 0, 1, or 2 and Rs. Ro, and Rio are independently H or C. alkyl. In C certain embodiments, X is H and Y is p-OPh, p-OCF, o-OCH m-OCH or p-OCH. In certain embodiments of the above structure, the Sertraline analog has the formula: US 2010/0009970 A1 Jan. 14, 2010 43

-continued NRR 2 HN O A-X Cl, and C Other sertraline analogs have the formula:

R7 HN R3

W 1N R4 N4 Rs R6

C. r C Sás-X X Y 0106 Other sertraline analogs have the formula: where R. R. R. R. W, X, and Y are as defined above, and R R2 R R2

R, is independently H, NH(CH), CH, O(CH2)CH, OH, NN1 N1 O(CH2)CH =O, C-alkyl (e.g., isopropyl), or Ce alky oxy, where m is 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, R. R. Rs, and R are H; X and Y are each C1 at the 3 and 4 positions of the benzyl ring. Exemplary analogs include:

where R. R. R. R. R. R. X and Y are as defined above, and R, is H or C optionally substituted alkyl. Other sertraline analogs are described by the formula:

Cl, C s C N N r N N r rH O O O O

C C Cl, C C C US 2010/0009970 A1 Jan. 14, 2010 44 wherein Rs. Ro, and Ro are independently H, optionally Substituted C. alkyl (e.g., CH (CH), OH, cyclopropyl. TABLE 9-continued (CH),COOH, or CHCHOH(CH), (CH), N(CfFH), where X is 1, 2, 3, 4, or 5), and optionally substituted C-7 heteroalkyl (e.g., CHCHN(CH)) 0107. In certain embodiments, sertraline analogs are in the cis-isomeric configuration. The term “cis-isomeric' refers to the relative orientation of the NRR and phenyl moieties on C the cyclohexene ring (i.e., they are both oriented on the same oHCI side of the ring). Because both the 1- and 4-carbons are asymmetrically Substituted, each cis-compound has two opti cally active enantiomeric forms denoted (with reference to the 1-carbon) as the cis-(1R) and cis-(1S) enantiomers. Ser C traline analogs are also described in U.S. Pat. No. 4,536,518. C Other related compounds include (S.S) N-desmethylsertra (1S, 4R) Sertraline Hydrochloride line, rac-cis-N-desmethylsertraline, (1S,4S)-desmethyl ser traline, 1-des (methylamine)-1-oxo-2-(R.S)-hydroxy sertra HN1 line, (1R,4R)-desmethyl sertraline, sertraline sulfonamide, sertraline (reverse) methanesulfonamide, 1 R,4R sertraline enantiomer, N,N-dimethyl sertraline, nitro sertraline, sertra line aniline, sertraline iodide, sertraline sulfonamide NH sertraline sulfonamide ethanol, sertraline , sertraline CME, dimethyl sertraline reverse sulfonamide, sertraline reverse sulfonamide (CH linker), sertraline B-ring ortho methoxy, Sertraline A-ring methyl , Sertraline A-ring ethanol, sertraline N,N-dimethylsulfonamide, sertraline A-ring , sertraline B-ring para-phenoxy, ser traline B-ring para-trifluoromethane, N,N-dimethyl sertra line B-Ring para-trifluoromethane, Sertraline A-ring methyl . (CH2 linker), Sertraline A-ring carboxamide, Sertra line A-ring reverse carboxamide, Sertraline A-ring metha Sertraline B-Ring Para-Phenoxy namine, Sertraline A-ring Sulfonylmethane (CH2 linker), Ser traline (reverse) methanesulfonamide, Sertraline A-ring thiophene, reduced sulfur sertraline A-ring methyl sulfoxide HN1 (CH linker), and hetrocyclic substituted stertraline (reverse) methanesulfonamide. Structures of these analogs and others are shown in Table 9 below. Analogs are also described in Tables 19-24 below. OMe TABLE 9

Sertraline B-Ring Ortho-Methoxy

N N H

oHCI

C C C (1R, 4S) Sertraline Hydrochloride C 1R, 4R Sertraline. Enantiomer US 2010/0009970 A1 Jan. 14, 2010 45

TABLE 9-continued TABLE 9-continued HN1 O2 S N1H

Cl Cl Cl Cl Sertraline Sulfonamide (1R, R4)-Desmethyl. Sertraline YNH NHMe MeOC ON

Cl C C Cl Sertraline A-Ring Methyl Ester Nitro Sertraline NH NH, HCI HN

Cl Cl Cl C rac-cis-N-Desmethyl Sertraline, Sertraline Aniline Hydrochloride

O HN1 N N1 NA O H /N \-N O H 1 \,\

C Cl

Cl Cl Sertraline Reverse Sulfonamide (CH2 linker) Dimethyl Sertraline Reverse Sulfonamide US 2010/0009970 A1 Jan. 14, 2010 46

TABLE 9-continued TABLE 9-continued YNH HN1 I O2 N1 S

Cl CI Cl Cl Sertraline Iodide

Sertraline N,N-Dimethylsulfonamide O &OH OH NHMe

CI

CI C 1-Des(methylamine)-1-oxo-2-(R.S)-hydroxy Sertraline C Sertraline A-Ring Ethanol NH NC 1) OH O

Cl

Cl O Sertraline Nitrile Cl N 1. Cl N Sertraline-CME

CI N HN

C

CF CI N,N-Dimethyl Sertraline B-Ring Para (1S, 4S)-Desmethyl Sertraline, Hydrochloride Trifluoromethane US 2010/0009970 A1 Jan. 14, 2010 47

TABLE 9-continued TABLE 9-continued

NHMe N NH O2 HN1 S

C

C CF Sertraline Sulfonamide NH 2 Sertraline B-Ring Para-Trifluoromethane HN1 N1 Os1 O

C C

C C Sertraline (Reverse) Methanesulfonamide N,N-Dimethyl Sertraline YNH NHMe HOOC Ns

O

C C C C Sertraline A-ring Methyl Sulfoxide (CH Sertraline A-Ring Carboxylic Acid Linker)

NHMe NHMe O HOS-1a -S HNOC H

C C

C C Sertraline Sulfonamide Ethanol Sertraline A-ring carboxamide US 2010/0009970 A1 Jan. 14, 2010 48

TABLE 9-continued TABLE 9-continued

NHMe NHMe rH S O

C C C C Sertraline A-ring Thiophene Sertraline A-ring reverse carboxamide

NHMe YNH N S HN

C C C C Sertraline A-ring Methylsulfide Sertraline A-Ring methanamine

NHMe N NHMe Ns so O

C

C Sertraline A-Ring Sulfonylmethane (CH2 Linker) Sertraline A-ring Methylimidazole Reverse Sulfonamide

NHMe NHMe MeOSHN H 1. N O

C C

C C Sertraline (Reverse) Methanesulfonamide Sertraline A-ring reverse formamide US 2010/0009970 A1 Jan. 14, 2010 49

TABLE 9-continued TABLE 9-continued NMe2 H N O HN1 Ph N 2 N N O H

C C C N,N-Dimethyl Sertraline A-ring Reverse C Sertraline A-ring Pyridine Carboxamide

1. O HN O HN1

H N ". ^loH C C C C Sertraline A-ring Methylcarboxamide Setraline cyclopropyl carboxamide O NHMe ul S NHMe N HN

C C C Sertraline A-ring Reverse Carobxamide C (CH2 linker) Sertraline A-Ring Thiocarboxamide

O HN1 NHMe

N H S

C C

C C Sertraline A-ring Benzamide Sertraline A-Ring Reverse Thiocarboxamide US 2010/0009970 A1 Jan. 14, 2010 50

TABLE 9-continued TABLE 9-continued A N

NN r

CI

C N-cyclopropyl Sertraline C

Cl NH N-methyl,N-CH2CH2N(CH3)2 Sertraline

YNH

OMe Sertraline B-Ring p-methoxy S N O N 1. Sertraline B-ring 2-thiophene

HO YNH

C Sertraline without B-ring CI N,N-dimethyl Sertraline A-ring Carboxylic N 1N1 OH Acid YNH

Cl OMe N-ethanol Sertraline Sertraline B-ring m-Methoxy US 2010/0009970 A1 Jan. 14, 2010 51

TABLE 9-continued TABLE 9-continued O N1 OH

HN

C C C C Sertraline N,N-Dimethyl Sertraline A-Ring Carboxamide NH O

C C C C Sertraline A-ring Cycloproprane Reverse 4S-Sertraline Ketone Sulfonamide

N NH YNH OsS1 N

N-1- O

C C

C C Sertraline A-Ring Reverse Sertraline A-ring Benzene Reverse Sulfonamide Sulfonamide

N NH YNH H ~ N O

C C

C C Sertraline A-ring Reverse Pentanamide Sertraline A-Ring Reverse Benzamide US 2010/0009970 A1 Jan. 14, 2010 52

TABLE 9-continued TABLE 9-continued NH -N HN1 OisNo

C

C Sertraline A-Ring N,N- Dimethylamine C

C OMe Sertraline A-Ring Phenylsulfone (CH2 linker)

N HN O C1 ? -Y 1. 2 C N s Methoxy 4S-Sertraline O so

NHMe H N O O C C Sertraline A-Ring Methyltriazolesulfone (CH2 linker)

C

C Sertralinecyclopetanecarboxamide A-Ring Reverse / NHMe f s HN Né S Ns O

C C C C Sertraline A-Ring Methyltriazolesulfoxide Sertraline A-Ring Methylsulfide (CH2 linker) US 2010/0009970 A1 Jan. 14, 2010 53

TABLE 9-continued TABLE 9-continued

N1S-1 OH rH OC C

C Isopropyl Sertraline C

C H Y N N-ethanol Sertralinecarboxamide A-ring reverse O

OH C N1\- C Ns Isopropyl Sertraline reverse carboxamide O

O

HN C

C N-ethanol Sertraline A-ring Sulfoxide (CH2 linker)

C

C Isopropyl Sertraline carboxamide N-N-NMes

HN

C C C C N-(N,N-dimethyl)ethyl Sertraline Isopropyl Sertraline methanamine US 2010/0009970 A1 Jan. 14, 2010 54

TABLE 9-continued TABLE 9-continued O N1

N H O

N

C

C N,N dimethyl Sertraline cyclopropyl carboxamide

O N1 C Ph C NN N-morpholine Sertraline H

O NH C C v- N O N,N-demethyl Sertraline phenylcarboxamide YNH H N

O C

C Sertraline cyclopropyl (CH2 linker) carboxamide

C

C Sertraline reverse cyclopropyl carboxamide

CA - H YNH Ph N O

C C Sertraline cyclobutyl carboxamide Sertraline reverse phenylcarboxamide US 2010/0009970 A1 Jan. 14, 2010 55

TABLE 9-continued TABLE 9-continued O HN1

-" H O

Cl

Cl Cl Cl No-N Sertraine Sertraline A-Ring Methyl Acetate Carboxamide O N1 O HN1 H HO r NH O --- .

Cl

C C N,N Dimethyl Sertraline A-Ring Reverse Cl Carboxamide (CH2 linker) Sertraline A-Ring Acetic Acid Carboxamide N1 O N1 r H O

Cl CI Cl Cl Sertraline A-ring N-methyl reverse N.N. Dimethyl Sertraline A-Ring carboxamide Cyclopropylmethyl Carboxamide N1 O N1 A N

Cl Cl Cl Cl N,N-Dimethyl Sertraline A-Ring N-Methyl N, N Dimethyl Sertraline A-Ring Cyclobutyl Cyclpropane Carboxamide Carboxamide US 2010/0009970 A1 Jan. 14, 2010 56

UK-416244 TABLE 9-continued 0109 UK-416244 is an SSRI that is phenoxybenzylamine derivative. UK-416244 has the structure:

N1 HNOS HN O

C

C SN Isoproyl Sertraline A-Ring carboxamide 0110 Structural analogs of UK-416244 are compounds having the formula:

Rs N1 R HN1 R ro R4 O Y

Z

C where R and R, independently, are H.C. alkyl (e.g., CH) C or substituted heteroalkyl (e.g., CHCHN(CH) and Sertraline A ring N-methyl reverse CHOCH), or (CH) (C. cycloalkyl) where d is 0, 1, 2, or carboxamide 3; or R and R together with the nitrogen to which they are attached form an azetidine ring; ZorY is —S(O)R and the other Z or Y is halogen or —R; where R is independently Calkyl optionally Substituted with fluorine (e.g., where R. is or is not CF) andnis 0, 1, or 2; or ZandYare linked so that, together with the interconnecting atoms, ZandY form a fused 0108 Particularly useful are the following compounds, in 5 to 7-membered carbocyclic or heterocyclic ring which may be saturated, unsaturated, or aromatic, and where when Zand either the (1S)-enantiomeric or (1S)(1R) racemic forms, and Y form a heterocyclic ring, in addition to carbon atoms, the their pharmaceutically acceptable salts: cis-N-methyl-4-(3,4- linkage contains one or two heteroatoms independently dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine, cis selected from O, S, and N: (e.g., with the proviso that when Rs N-methyl-4-(4-bromophenyl)-1,2,3,4-tetrahydro-1-naphtha is F and R is methyl then the fused ring is not 1,3- lenamine; cis-N-methyl-4-(4-chlorophenyl)-1,2,3,4- and ZandY together do not form a fused phenyl ring); R and tetrahydro-1-naphthalenamine; cis-N-methyl-4-(3- Rs are, independently, A-X, where A is —CH=CH- or trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-1- -(CH2), wherep is 0, 1, or 2; X is H, F, Cl, Br, I, NH, OH, naphthalenamine; cis-N-methyl-4-(3-trifluoromethyl-4- CONRR, SONRR, SONHC(=O)R. C. alkoxy, chlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine, cis-N. NRSOR, NO, NRR (e.g., N(CH), CN, COR (e.g., N-dimethyl-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-1- COOH), CHO, SR S(O)R or SOR: R. R. Rs and Rio independently are H. C. alkyl (e.g., CH (CH2)CH or naphthalenamine: cis-N,N-dimethyl-4-(3-trifluoromethyl cyclopropyl), Caryl (e.g., phenyl) optionally Substituted phenyl)-1,2,3,4-tetrahydro-1-naphthalenamine; and cis-N- independently by one or more R, or C. alkyl-aryl option methyl-4-(4-chlorophenyl)-7-chloro-1,2,3,4-tetrahydro-1- ally Substituted (e.g., CHPh); R is C alkyl optionally naphthalenamine. Of interest also is the (1R)-enantiomer of Substituted independently by one or more R, R is H. C. cis-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1- alkyl optionally substituted independently by one or more naphthalenamine. R. C(O)R COR, C(O)NHR, or SONRR,; R is F US 2010/0009970 A1 Jan. 14, 2010 57

(preferably up to 3), Br, OCH, OH, CO.H. C. cycloalkyl, SONHCOCH, CH-NHSOCH, NH, ORNO, benzyl NH, CONH, C alkoxy, Calkoxycarbonyl, or a 5- or , acylsulfonamide, reverse sulfonamide, NHCH 6-membered heterocyclic ring containing 1, 2, or 3 heteroa N(CH), SONH, CHOH, NHSOCH, toms selected from N. S. and O optionally substituted inde SONHCHCCH CH-NH. SONHBu, and pendently by one or more R, or RandR, together with the SONHcyclopropyl. UK-416244 structural analogs are nitrogen to which they are attached, form a 4-, 5-, or 6-mem described in U.S. Pat. Nos. 6,448,293 and 6,610,747. bered heterocyclic ring optionally substituted independently UK-416244 analogs are described below. by one or more Rs, or a 5- or 6-membered heterocyclic ring 0112. Other analogs of UK-416244 can be described by containing 1, 2, or 3 heteroatoms selected from N. S., and O the formula: optionally substituted independently by one or more R: where R is hydroxy, C alkoxy, F. C. alkyl, haloalkyl, haloalkoxy, —NH2, —NH(C. alkyl), or —N(C. alkyl) Rs Z 2 , 0111 or compounds having the formula: R4 O

R R 21 5 N1 2 B R SX R O (R3),

21 where are R. R. and Rs are as defined above and Z is B CHNRR, where R and R are as defined above, NH, SX optionally substituted optionally hetero Cls alkyl (e.g., Sub (R3), stituted with hydroxyl, NH, NHC alkyl), or is selected from the group consisting of where R and R2 are independently H. C. alkyl (e.g., CH) or substituted heteroalkyl, (CH2)(C. cycloalkyl) where m is 0, 1, 2, or 3, or RandR together with the nitrogen to which they are attached form an azetidine ring; each R is indepen dently H, I, Br, F, Cl, C. alkyl (e.g., CH). CF, CN, OCF, Calkylthio (e.g., SCH), Calkoxy (e.g., OCH), aryloxy (e.g., OPh), or CONRR,; n is 1, 2, or 3; and Ra and Rs are independently A-X, where A is CH=CH-or-(CH2) where p is 0, 1, or 2: X is H, F, Cl, Br, I, CONRR, SONRR, SONHC(=O)ROH, Calkoxy, NRSOR, NO, NRR, CN, COR (e.g., COOH), CHO, SR, S(O) R, or SOR. R. R. Rs, and Ro are independently H or C. alkyl (e.g., (CH2)3CH3 or cyclopropyl), C-12 aryl (e.g., phenyl) optionally substituted independently by one or more R, or Ce alkyl-aryl optionally Substituted; R is C alkyl optionally Substituted independently by one or more R. R. is H. C. alkyl optionally substituted independently by one or more RC(O)R CORC(O)NHR, or SONRR,; R is F (preferably up to 3), OH, COH, C, cycloalkyl, NH, CONH2, Calkoxy, Calkoxycarbonyl or a 5- or 6-mem bered heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N. S., and O optionally substituted indepen dently by one or more Rs, or R and R-7, together with the nitrogen to which they are attached, form a 4-, 5-, or 6-mem bered heterocyclic ring optionally substituted independently by one or more R, or a 5- or 6-membered heterocyclic ring -N N O containing 1, 2, or 3 heteroatoms selected from N. S., and O \ / optionally Substituted independently by one or more Rs: where R is hydroxy, C alkoxy, F. C. alkyl, haloalkyl, -N N N haloalkoxy, —NH2, —NH(C. alkyl) or —N(C. alkyl) (e.g., where when R and Rare methyl, R and Rs are hydro gen and n is 1, R is not a —SMe group para to the linkage linking ringSA and B). In certain embodiments, n is 1 or 2, and the R group(s) is/are at positions 3 and/or 4 of the B ring, for example, are CH SCH, OCH, Br, or CF. For -N N C either of the above structures, R or Rs can be SONHPh. SONHCH, CN, H, Br, CONH COOH, SONHCHPh. US 2010/0009970 A1 Jan. 14, 2010 58

selected from N. S., and O optionally substituted indepen -continued dently by one or more Rs, or R and R, together with the nitrogen to which they are attached, form a 4-, 5-, or 6-mem N bered heterocyclic ring optionally substituted independently by one or more Rs; or a 5- or 6-membered heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N. S., and O N N optionally Substituted independently by one or more Rs: where Rs is hydroxy, C alkoxy, F. C. alkyl, haloalkyl, \-on O-(\ haloalkoxy, NH, -NH(C. alkyl) or—N(Calkyl). In certain embodiments, where R is Br. OMe, NO, COMe, or N N CN. R. may be at the ortho, meta, or para position) N . 0114. Still other UK-416244 analogs are described by the C) formula: N --> N RX l C) O N1 OH HNOS

N O N K 'OH

N NH

SMe In certain embodiments, Z is CN, CHCH (CH), CHOCH, CHN(CH)CHCH-OH, N(CH), CHN(CH), COOH, CH-NHCH, CHOH, CH-NHCOCH, CONHCH, CH-NH(CH)N(CH), CH-NH(CH)N(CH), CHC where X is N, O, or S, and R is H. C. alkyl or substituted (CH), CHN(CH)(CH)N(CH), CHN(CH)(CH)N heteroalkyl, (CH), (C. cycloalkyl) where m is 0, 1, 2, or 3. (CH), or CHCHCCH). 0115 Additional compounds have the structure: 0113. Other UK-416244 analogs are described by the for mula. R R N 21 . N1 S. 1 R N R O O 21B S X

SMe where R is H or Ce alkyl (e.g., CH, CHCH) and R is where R is H, I, Br, F, Cl, C. alkyl (e.g., CH). CF, CN, C. alkyl substituted with OH, such as CH-OH, OCF, Calkylthio (e.g., SCH), C alkoxy (e.g., OCH), CHCH-OH, CH(OH)CH, CHCHCH-OH, CH(CH.) aryloxy, or CONRR: n is 1, 2, or 3; R and R are indepen CHOH, and CHCHCHCH-OH, CH(OH)CHCHCH dently Hor Calkyl (e.g., (CH2)CH or cyclopropyl), C-2 CHCH(OH)CHCH, and CHCH-CH(OH)CH) or is aryl (e.g., phenyl) optionally Substituted independently by CHXR or CHCH-XR, where X is N, O, or S, and R is one or more R or Calkyl-aryl optionally Substituted; R is H, C, alkyl or substituted heteroalkyl, (CH2)(Cs. F (preferably up to 3), OH, COH, C cycloalkyl, NH, cycloalkyl) where q is 0, 1, 2, or 3, and where R. R. and Rs CONH2, Calkoxy, Calkoxycarbonyl or a 5- or 6-mem are as defined above. In certain embodiments, the compound bered heterocyclic ring containing 1, 2, or 3 heteroatoms has the structure, US 2010/0009970 A1 Jan. 14, 2010 59

TABLE 10-continued HNOS Compound 2 HNOS OC OH

SMe oSMe where R is H or C. alkyl (e.g., CH, CHCH) and R is C. alkyl substituted with OH, e.g., CH-OH, CHCH-OH, CH(OH)CH, CHCH(OH)CH, CHCHCH-OH, CH(CH,)CHOH, and CHCHCHCH-OH, CH(OH) CHCHCH, CHCH(OH)CHCH, and CHCH-CH(OH) CH). In particular embodiments, the compound is: Compound 3 ric N 1. O HNOS2Lyu2 1S-1 OH or H

O

Compound 4 Phy SMe HNOS HNOS OH 2 2 ~ O

oSMe SMe

0116. In any of the UK-416244 analogs, the bridge between the A and Brings may be replaced with an —NH Compound 5 HNOS 1. bridge (e.g., Compound 108). N 0117 Particular UK-416244 analogs include those of Table 10:

TABLE 10

Compound 1 HNOS21yu2 N 1N1 OH H O ClS 4. N

SMe 0118. Other UK-416244 analogs include those of Table 11. US 2010/0009970 A1 Jan. 14, 2010 60

TABLE 11 TABLE 11-continued

Compound 6 O Compound 10

SMe

Compound 7 Compound 11

SMe Compound 8 Compound 12

SMe

SMe

Compound 9 Compound 13

SMe US 2010/0009970 A1 Jan. 14, 2010 61

TABLE 11-continued TABLE 11-continued

Compound 14 O Compound 18 leo N1 S N1 2 H HN O O

SMe OO n Compound 15 Ph Compound 19

2 1. HN

O

Compound 16 OCN Compound 20

2 1. HN

O

Compound 17 S. Compound 21 HNOS O 1.

O

ClS 1. US 2010/0009970 A1 Jan. 14, 2010 62

TABLE 11-continued TABLE 11-continued Compound 26 HNOS COOH Compound 22

SMe Compound 27

Compound 23 NMe2

SMe Compound 28

ClSMe

Compound 24

NMe2

Compound 29

SMe

Compound 25 SMe Compound 30

SMe US 2010/0009970 A1 Jan. 14, 2010 63

TABLE 11-continued TABLE 11-continued Compound 31 Br NHMe Compound 363 Br NHMe O O

SMe Compound 32 OMe NHMe Compound 37 Br O orsO

Br OMe Compound 33 Compound 38 NHMe Br NMe2 O O

OMe SMe Compound 39 Compound 34 Br NHMe NHMe

O

CF SMe Compound 35 Compound 40 OC NMe2 NMe2 OO OO US 2010/0009970 A1 Jan. 14, 2010 64

TABLE 11-continued TABLE 11-continued

Compound 41 Compound 45 Br O NMe2 HNOS NHMe O

n SMe SMe

Compound 42 Compound 46 Br HNOS

orsO orsO

O OSMe Compound 43 HNOS NHMe Compound 47 HNO2S OH O

O

SMe

SMe

Compound 44 Compound 48 HNOS HNO2S or NHMe O O

O SMe US 2010/0009970 A1 Jan. 14, 2010 65

TABLE 11-continued TABLE 11-continued

Compound 49 Ph Compound 53 HNOS HN o NMe2 orsO

SMe oSMe

Compound 50 Compound 54 ON ON NHMe o NMe2

oSMe oSMe

Compound 51 Compound 55 H NNNoS NMe2 Crs O o OO Compound 52 Compound 56 HNOS 21yu2 N ls Crs O

SMe SMe US 2010/0009970 A1 Jan. 14, 2010 66

TABLE 11-continued TABLE 11-continued

Compound 57 Compound 61 Br

H.N/S 1.

H N1 or forO O

ClBr SN Compound 62 Compound 58 O O H.N/ VW S NH

O O Cl SN Compound 63 Compound 59

Compound 64 Compound 60 US 2010/0009970 A1 Jan. 14, 2010 67

TABLE 11-continued TABLE 11-continued

Compound 65 Compound 69

S

forO

Compound 66

Compound 70

Compound 67

Compound 71

Compound 68

Compound 72 US 2010/0009970 A1 Jan. 14, 2010 68

TABLE 11-continued TABLE 11-continued

Compound 73 Compound 77 O H2NN SM O M orco

Compound 74 Compound 78 Br CC- N1

S N

Compound 75 Compound 79 O H2NN M MS N 1N1 a N1 O H

oS N Compound 76 Compound 80

S 1. / ors

NO co US 2010/0009970 A1 Jan. 14, 2010 69

TABLE 11-continued TABLE 11-continued

Compound 81 Compound 85 1. HN O HN H.N/S 2 n 4 M N M O F O O

Sn

Compound 82 Compound 86 H2NN 4.O H2NN 4. M -> O o c N- / o S N Sn

Compound 83 Compound 87 O O H2NN 4. CN H.N./ ?o O f GOOuO N- r

S N 1. S

Compound 84 Compound 88 HN1 HN/ H.N/ 7 N / O \ O O US 2010/0009970 A1 Jan. 14, 2010 70

TABLE 11-continued TABLE 11-continued

Compound 89 Compound 93 HN/ OM r oN O Sn

Compound 90 Compound 94 H.N./O / r

N oSN

Compound 91 Compound 95 H.N/O HN/

O N N O N N for)O N forO to N1 No Cl C Sn 1S

Compound 92 Compound 96 O O H2NN M M 1N-1 N O H

ClSN US 2010/0009970 A1 Jan. 14, 2010 71

TABLE 11-continued TABLE 11-continued

Compound 97 Compound 101 O H2NN 4. N HN/ / o r- N O o O Sn SN

Compound 98 Compound 102 N N1 O OH

Br HN/ O C fortO

SN Sn

Compound 99 Compound 103 O 1. O -OH H2NN 4. H.N/ s / O O

SN Sn Compound 104 Compound 100 O O -OMe H2NN M H.N./ s /

N US 2010/0009970 A1 Jan. 14, 2010 72

TABLE 11-continued TABLE 11-continued

Compound 105 Compound 109

ss -C) O N H2NN / S H2NN 4. / M CC) O

Cl oS N Compound 106 H2NN 4. Compound 110 M r O OH O N N H2NN M o r 1. S

Compound 107 H2NN 4. / J 1. N Compound 111

SN Compound 108 O N N1 H2NN 4. / NH 0119. In certain embodiments, a can be used in the compositions, methods, and kits of the invention. If desired, one or more corticosteroid may be administered in a method of the invention or may be formulated with a tricy clic compound in a composition of the invention. Suitable SN corticosteroids include 11-alpha,17-alpha,21-trihydrox ypregn-4-ene-320-dione; 11-beta, 16-alpha,17.21-tetrahy droxypregn-4-ene-320-dione; 11-beta, 16-alpha, 17.21-tet US 2010/0009970 A1 Jan. 14, 2010 rahydroxypregn-1,4-diene-3,20-dione; 11-beta, 17-alpha,21 lon; ; medroxyprogesterone; medrysone; trihydroxy-6-alpha-methylpregn-4-ene-320-dione; megestrol; ; melengestrol; meprednisone; 11-dehydrocorticosterone; 11-deoxycortisol; 11-hydroxy-1, methandrostenolone; ; methylpredniso 4-androstadiene-3,17-dione; 11-ketotestosterone; 14-hy lone aceponate; methylprednisolone acetate; methylpred droxyandrost-4-ene-3,6,17-trione; 15,17-dihydroxyprogest nisolone hemisuccinate; methylprednisolone sodium Succi erone; 16-methylhydrocortisone; 17,21-dihydroxy-16 nate; methyltestosterone; ; mometasone (analogs alpha-methylpregna-1,4,9(11)-triene-320-dione; 17-alpha described in 4,472.393); mometasone furoate; mometasone hydroxypregn-4-ene-320-dione; 17-alpha furoate monohydrate; nisone; ; norgestomet; hydroxypregnenolone; 17-hydroxy-16-beta-methyl-5-beta pregn-9(11)-ene-320-dione; 17-hydroxy-4,6,8(14)- ; ; paramethasone; parametha pregnatriene-320-dione; 17-hydroxypregna-4.9(11)-diene Sone acetate; ponasterone; ; ; 3.20-dione; 18-hydroxycorticosterone: prednisolone; prednisolone 21-diethylaminoacetate; pred 18-hydroxycortisone; 18-oxocortisol; 21-acetoxypreg nisolone 21-hemisuccinate; prednisolone acetate; predniso nenolone; 21-deoxyaldosterone; 21-deoxycortisone; lone farnesylate; prednisolone hemisuccinate; prednisolone 2-deoxyecdysone; 2-methylcortisone; 3-dehydroecdysone; 21 (beta-D-glucuronide); prednisolone metasulphobenzoate; 4-pregnene-17-alpha,20-beta,21-triol-3,11-dione: 6,17.20 prednisolone sodium phosphate; prednisolone steaglate; trihydroxypregn-4-ene-3-one; 6-alpha-hydroxycortisol; prednisolone tebutate; prednisolone tetrahydrophthalate: 6-alpha-fluoroprednisolone, 6-alpha-methylprednisolone, ; prednival; prednylidene; ; procino 6-alpha-methylprednisolone 21-acetate, 6-alpha-methyl nide; tralonide; ; ; rhapontister prednisolone 21-hemisuccinate Sodium salt, 6-beta-hydroxy one; ; roXibolone; rubrosterone; stizophyllin; , 6-alpha,9-alpha-difluoroprednisolone 21'-acetate 17-butyrate, 6-hydroxycorticosterone: 6-hydroxydexam tiXocortol; ; ; triamcinolone ethasone; 6-hydroxyprednisolone; 9-fluorocortisone; acetonide; triamcinolone acetonide 21-palmitate; triamcino alclomethasone dipropionate; ; algestone; alpha lone benetonide; triamcinolone diacetate; triamcinolone derm; amadinone; amcinonide; anagestone; androstenedi hexacetonide; ; turkesterone; and wortmannin one; anecortave acetate; beclomethasone; beclomethasone or derivatives thereof (see, e.g., U.S. Pat. No. 7,081,475). dipropionate; betamethasone 17-Valerate; betamethasone 0120 Receptor Modulators Sodium acetate; betamethasone sodium phosphate: 0121 Steroid receptor modulators (e.g., antagonists and betamethasone valerate; ; budesonide (analogs ) may be used as a Substitute for or in addition to a described in U.S. Pat. No. 3,929,768); ; chlorma dinone; chloroprednisone; chloroprednisone acetate; choles corticosteroid in the compositions, methods, and kits of the terol, ciclesonide; clobetasol, clobetasol propionate; clobeta invention. Sone; clocortolone; clocortolone pivalate; clogestone; 0.122 receptor modulators that may used cloprednol; ; cortisol; cortisol acetate; cortisol in the compositions, methods, and kits of the invention butyrate; cortisol cypionate; cortisol octanoate; cortisol include compounds described in U.S. Pat. Nos. 6,380.207, Sodium phosphate; cortisol Sodium Succinate; cortisol Valer 6,380,223, 6,448,405, 6,506,766, and 6,570,020, U.S. Pat. ate; ; ; cortivaZol; cortodoxone; Application Publication Nos. 2003/0176478, 2003/0171585, daturaolone; deflazacort, 21-deoxycortisol, dehydroepi ; delmadinone; deoxycorticosterone; depro 2003/0120081, 2003/0073703, 2002/015631, 2002/ done; descinolone; desonide; desoximethasone; dexafen; 0147336, 2002/0107235, 2002/0103217, and 2001/0041802, ; dexamethasone 21-acetate; dexamethasone and PCT Publication No. WO00/66522, each of which is acetate; dexamethasone sodium phosphate; dichlorisone; hereby incorporated by reference. Other steroid receptor diflorasone; diflorasone diacetate; diflucortolone; diflupred modulators may also be used in the methods, compositions, nate; dihydroelatericina; domoprednate, doxibetasol, ecdys and kits of the invention are described in U.S. Pat. Nos. one; ecdysterone; emoXolone; endrysone; enoXolone; fluaza 6,093,821, 6,121,450, 5,994,544, 5,696,133, 5,696,127, cort, flucinolone; flucloronide; ; 5,693,647, 5,693,646, 5,688,810, 5,688,808, and 5,696,130, fludrocortisone acetate; flugestone; flumethasone; flumetha each of which is hereby incorporated by reference. sone pivalate; flumoxonide; flunisolide; fluocinolone; fluoci nolone acetonide; fluocinonide; fluocortin butyl; 9-fluorocor tisone; fluocortolone; fluorohydroxyandrostenedione; Bufexamac ; fluorometholone acetate; : (0123. In certain embodiments, bufexamac or a bufexamac fluperolone acetate; fluprednidene; fluprednisolone; fluran analog can be used in the compositions, methods, and kits of drenolide; fluticasone; fluticaSone propionate; ; ; formocortal: gestonorone; glyderinine; halcino the invention. By "bufexamac analog is meant a compound nide; halobetasol propionate; halometaSone; halopredone; having the formula (VI): haloprogesterone; ; hydrocortiosone cypi onate; ; hydrocortisone 21-butyrate; hydro cortisone aceponate; hydrocortisone acetate; hydrocortisone buteprate; hydrocortisone butyrate; hydrocortisone cypi onate; hydrocortisone hemisuccinate; hydrocortisone probu tate; hydrocortisone sodium phosphate; hydrocortisone Sodium Succinate; hydrocortisone Valerate; hydroxyprogest erone; inokosterone; isoflupredone; isoflupredone acetate; isoprednidene; loteprednoletabonate; meclorisone; mecorto US 2010/0009970 A1 Jan. 14, 2010 74 wherein R' is 0127 Ritonavir 0.128 Ritonavir is an antiviral used in treatment of HIV and has the structure:

RIB wherein R'' is and R' is H, halo, CFs, optionally substituted Calkyl, optionally Substituted Coalkenyl, optionally Sub stituted C- alkynyl, optionally substituted Cls cycloalkyl, optionally substituted C. alkoxy, or optionally Substituted C, thioalkoxy; each of RandR is, independently, H, C, alkyl, or CF; and R is optionally substituted C. alkyl or optionally Substituted Cls cycloalkyl. Ritonavir analogs are described, for example, in U.S. Pat. No. Antiviral Agents 5,541.206 and have the general structure: 0124. In certain embodiments, an antiviral agent can be R4a used in the compositions, methods, and kits of the invention. R O R3 X O R6 Suitable antiviral agents include, without limitation, abacavir, acemannan, acyclovir, adefovir, amantadine, amidinomycin, -suls-s-sN ls ampligen, amprenavir, aphidicolin, atevirdine, capravirine cidofovir, cytarabine, delavirdine, didanosine, dideoxyad O Y enosine, n-docosanol, edoxudine, , emitricitabine, R4 famciclovir, floxuridine, fomivirsen, foscamet sodium, gan ciclovir, idoxuridine, imiquimod, indinavir, inosine pra where R is monosubstituted thiazolyl, monosubstituted nobex, interferon-C. interferon-B, kethoxal, lamivudine, lopi oxazolyl, monosubstituted isoxazolyl or monosubstituted navir, lysozyme, madu, methisaZone, moroxydine, nelfinavir, isothiazolyl wherein the substituent is selected from (i) low nevirapine, nitaZoxanide, oseltamivir, palivizumab, penciclo eralkyl, (ii) loweralkenyl, (iii) cycloalkyl, (iv) cycloalkyla vir, enfuvirtide, pleconaril, podophyllotoxin, ribavirin, lkyl, (v) cycloalkenyl, (vi) cycloalkenylalkyl, (vii) heterocy clic wherein the heterocyclic is selected from aziridinyl, rimantadine, ritonavir, saquinavir, Sorivudine, stallimycin, aZetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholi statolon, stavudine, tenofovir, tremacamra, triciribine, triflu nyl, thiomorpholinyl, thiazolyl, oxazolyl, isoxazolyl, isothia ridine, tromantadine, tunicamycin, Valacyclovir, Valganciclo Zolyl, pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl and Vir, Vidarabine, Zalcitabine, Zanamivir, Zidovudine, residui wherein the heterocyclic is unsubstituted or substituted with mod, atazanavir, tipranavir, entecavir, fosamprenavir, a substituent selected from halo, loweralkyl, hydroxy, alkoxy merimepodlib, docosanol, VX-950, and peg interferon. Addi and thioalkoxy, (viii) (heterocyclic)alkyl wherein heterocy tional antiviral agents are listed in Table 4 and Table 5. clic is defined as above, (ix) alkoxyalkyl, (X) thioalkoxyalkyl, 0.125 Structural analogs of antiviral agents which may be (xi) alkylamino, (xii) dialkylamino, (xiii) phenyl wherein the used in the combinations of the invention include 9-((2-ami phenyl ring is unsubstituted or substituted with a substituent noethoxy)methyl)guanine, 8-hydroxyacyclovir. 2'-O-glycyl selected from halo, loweralkyl, hydroxy, alkoxy and thio acyclovir, ganciclovir, PD 116124, Valacyclovir, omaciclovir, alkoxy, (xiv) phenylalkyl wherein the phenyl ring is unsub Valganciclovir, buciclovir, penciclovir, Valmaciclovir, carbo stituted or substituted as defined above, (XV) dialkylami Vir, theophylline, Xanthine, 3-methylguanine, enprofylline, noalkyl, (Xvi) alkoxy and (Xvii) thioalkoxy; n is 1, 2 or 3: R. cafaminol, 7-methylxanthine, L 653180, BMS 181164, valo is hydrogen or loweralkyl; R is loweralkyl; R and Ra, are maciclovir Stearate, deriphyllin, acyclovir monophosphate, independently selected from phenyl, thiazolyl and oxazolyl acyclovir diphosphate dimyristoylglycerol, and etofylline. wherein the phenyl, thiazolylor oxazolyl ring is unsubstituted or substituted with a substituent selected from (i) halo, (ii) 0126 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 387. Cytarabine analogs are described in U.S. Pat. No. 3,116, proviso that X is hydrogen and Y is —OH when R is methyl 282. Triciribine analogs, including triciribine 5'-phosphate and R, is unsubstituted; and Z is absent, —O— —S—, and triciribine-dimethylformamide, are described in U.S. Pat. —CH2—or—N(Rs)— wherein Rs is loweralkyl, cycloalkyl, No. 5,633.235. Nitazoxanide analogs are described in U.S. —OH or—NHRs, wherein Rs is hydrogen, loweralkyl oran Pat. No. 3,950,391. N-protecting group. US 2010/0009970 A1 Jan. 14, 2010

0129. Saquinavir 0130. 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 specific for the HIV-1 and HIV-2 proteases. The structure of saquinavir is:

RCH(R)-OCHP-OH OH HN O 21 wherein R is a hydrogenatom, an alkyl group containing one N Sn to three carbon atoms, or a hydroxymethyl group, and R is a N methylene, ethylene, propylene, ethylidene, methoxyethyl ene, benzyloxyethylene, tetrahydropyran-2-yloxyethylene, (1-ethoxyethoxy)ethylene, or 1.2-O-isopropylidene-1,2-di hydroxypropylene group. (0.133 Celgosivir 0.134. 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 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:

H OH OH

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

RO

RO OH OR

where R, R and R2 are independently hydrogen, Ca alkanoyl, C- alkenoyl, cyclohexanecarbonyl, Cs alkoxy acetyl, where R is benzyloxycarbonyl or 2-quinolylcarbonyl, and pharmaceutically acceptable acid addition salts thereof. 0131) Adefovir Dipivoxil s— 0.132. In certain embodiments, adefovir dipivoxil or its analogs can be used in the compositions, methods, and kits of Yix / 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 2010/0009970 A1 Jan. 14, 2010 76 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, 0141 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 0.142 Pimecrolimus 0135) In certain embodiments, a nonsteroidal immunophi 0.143 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), 0144. Rapamycin , and pimecrolimus. 0145 Rapamycin structural and functional analogs 0.136 Cyclosporines include mono- and diacylated rapamycin derivatives (U.S. 0.137 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); (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 of proinflammatory cytokines, such as IL-2. Peptide Moieties 0.138. Many different cyclosporines (e.g., cyclosporine A, B, C, D, E, F, G, H, and I) are produced by fungi. Cyclospo 0146 Peptides, peptide mimetics, peptide fragments, rine A is a commercially available under the trade name either natural, synthetic or chemically modified, that impair NEORAL from Novartis. Cyclosporine A structural and the calcineurin-mediated dephosphorylation and nuclear functional analogs include cyclosporines having one or more translocation of NFAT are suitable for use in practicing the fluorinated amino acids (described, e.g., in U.S. Pat. No. invention. Examples of peptides that act as calcineurin inhibi 5.227.467); cyclosporines having modified amino acids (de tors by inhibiting the NFAT activation and the NFAT tran scribed, e.g., in U.S. Pat. Nos. 5,122,511 and 4.798,823); and Scription factor are described, e.g., by Aramburu et al., Sci deuterated cyclosporines, such as ISAtx247 (described in ence 285:2129-2133, 1999) and Aramburu et al., Mol. Cell. U.S. Pat. Application Publication No. 2002/0132763 A1). 1:627-637, 1998). As a class of calcineurin inhibitors, these Additional cyclosporine analogs are described in U.S. Pat. agents are useful in the methods of the invention. Nos. 6,136,357, 4,384,996, 5,284.826, and 5,709,797. Cyclosporine analogs include, but are not limited to, D-Sar (C-SMe) Val-DH Cs (209-825), Allo-Thr-2-Cs, Norval 0.147. In certain embodiments, an antihistamine oran anti ine-2-Cs, D-Ala(3-acetylamino)-8-Cs. Thr-2-Cs, and histamine analog can be used in the compositions, methods, D-MeSer-3-Cs, D-Ser(O CHCH-OH)-8-Cs, and and kits of the invention. Antihistamines are compounds that D-Ser-8-Cs, which are described in Cruz et al. (Antimicrob. block the action of histamine. Classes of antihistamines Agents Chemother. 44:143-149, 2000). include: 0139 Tacrolimus 0140 Tacrolimus and tacrolimus analogs are described by 0148 (1) Ethanolamines (e.g., bromodiphenhydramine, Tanaka et al., (J. Am. Chem. Soc., 109:5031, 1987) and in , , , diphenhy U.S. Pat. Nos. 4,894,366, 4,929,611, and 4,956,352. FK506 dramine, , and ); related compounds, including FR-900520, FR-900523, and 0149 (2) (e.g., , pyril FR-900525, are described in U.S. Pat. No. 5.254.562; O-aryl, , , and ); O-alkyl, O-alkenyl, and O-alkynylmacrollides are described 0150 (3) (e.g., diethazine, ethopropazine, in U.S. Pat. Nos. 5,250,678, 532,248, 5,693,648; amino , , , and trimepra O-aryl macrollides are described in U.S. Pat. No. 5,262,533; Zine); alkylidene macrollides are described in U.S. Pat. No. 5.284, 0151 (4) Alkylamines (e.g., , bromphe 840; N-heteroaryl, N-alkylheteroaryl, N-alkenylheteroaryl, niramine, chlorpheniramine, desbrompheniramine, dexchlo and N-alkynylheteroaryl macrollides are described in U.S. rpheniramine, , and triprolidine); US 2010/0009970 A1 Jan. 14, 2010 77

0152 (5) (e.g., , , chlorcy pyl)-2-methylthio-phenothiazine: 4-(dibenzo(b.e)thiepin-6 clizine, , meclizine, hydroxy Zine); (11H)-ylidene)-1-methyl-piperidine hydrochloride; prochlo 0153 (6) Piperidines (e.g., , , cypro rperazine; promazine; (e.g., propiomazine heptadine, , , loratadine, , hydrochloride); rotoxamine; : SCH 37370; SCH , , and ); 434, tecastemizole; thiazinamium; ; thior 0154 (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. 0155. In the compositions, methods, and kits of the inven 0158 Other compounds that are suitable for use in the tion, both non-sedating and sedating antihistamines may be invention are AD-0261; AHR-5333; allinastine; arpromidine: employed. Non-sedating antihistamines include loratadine ATI-19000; bermastine; bilastin; Bron-12; carebastine; chlo and desloratadine. Sedating antihistamines include azata 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: KAA-276; KY-234; lamiakast, LAS-36509; LAS-36674; Zine; and tripelennamine. ; levoprotiline; : NIP-531; 0156. Other antihistamines suitable for use in the compo 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 0159. Still other compounds that are suitable for use in the (e.g., cetirizine hydrochloride); cetoxime; chlorocyclizine; invention are described in U.S. Pat. Nos. 2,595,405, 2,709, ; ; chlorphenoxamine; cinnariz 169, 2,785,202, 2,899,436, 3,014,911, 3,813,384, 3,956,296, ine; clemastine (e.g., clemastine fumarate); , 4,254,129, 4,254,130, 4,282,833, 4,283,408, 4.362,736, ; ; cyclizine (e.g., cyclizine hydro 4,394,508, 4,285,957, 4,285,958, 4,440,933, 4,510,309, chloride; cyclizine lactate); deptropine; dexchlorphe 4,550,116, 4,659,716, 4,692,456, 4,742,175, 4,833,138, niramine; maleate; diphenylpyraline; 4,908,372, 5,204.249, 5,375,693, 5,578,610, 5,581,011, doxepin; ; ; (e.g., emedastine 5,589.487, 5,663,412, 5,994,549, 6,201,124, and 6,458,958. difumarate); ; hydrochloride; fex (0160 Hydroxyzine ofenadine (e.g., fexofenadine hydrochloride); histapyrrod 0.161 In certain embodiments, hydroxy Zine or an analog ine; hydroxy Zine (e.g., hydroxy Zine hydrochloride; hydrox thereof can be used in the compositions, methods, and kits of yZine pamoate); ; ; the invention. The structure of hydroxyzine is: (e.g., levocabastine hydrochloride); mebhy droline; meduitazine; methafurylene; methapyrilene; met ron; , olapatadine (e.g., olopatadine hydrochlo ride); ; phenindamine (e.g., phenindamine tartrate); pheniramine; ; p-methyldiphen hydramine; pyrrobutamine; ; ; terfenadine; Nu ; thiazinamium (e.g., thiazinamium methylsul fate); hydrochloride; ; triproli dine; and . 0157 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- 0162 Analogs of hydroxyzine are described, for example, (4-methyl-1-piperazinyl)propyl)-10H-phenothiazin-2-yl)- in U.S. Pat. No. 2,899,436 and have the general structure: (9CI) 1-propanone; 3-methoxycyproheptadine: 4-(3-(2- Chloro-1 OH-phenothiazin-10-yl)propyl)piperazine-1- ethanol hydrochloride: 10,11-dihydro-5-(3-(4- CH2) ethoxycarbonyl-4-phenylpiperidino)propylidene)-5H N r 's-R dibenzo(a,d)cycloheptene; ; acetophenazine; R alimemazin (e.g., alimemazin hydrochloride); aminopro Nu mazine; ; butaperazine; ; chlor ; 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 wherein R and R" are a hydrogen atom, a halogen atom, an nyl)propyl)phenothiazin-2-yl ketone; ; medry alkyl group, or an , R' and R" being in ortho, lamine; mesoridazine; methylpromazine: N-desmethyl meta, or para positions; R contains 2 to 11 carbon atoms and promethazine; nilprazole; northioridazine; perphenazine is alkyl, phenyl, alkyl Substituted phenyl, aralkyl, cycloalkyl, (e.g., perphenazine enanthate); 10-(3-dimethylaminopro hydroxyalkyl, hydroxycycloalkyl or —CH2—CH2—O— US 2010/0009970 A1 Jan. 14, 2010

CH2—CH2—OH, and n is an integer from 1 to 6, inclusive. alkylaminoC2-galkyl, Co alkyamino-C2-alkyl, C2-6 ami The compound may be in the form of a mineral acid salt oran noalkyl, or a 3-7 member unsubstituted or substituted car organic acid salt. bocyclic ring; and when R is —N—R(R), the R and R groups may be combined together to form a ring. Irinotecan Camptothecins 0163. In certain embodiments, irinotecan, topotecan, or their analogs can be used in the compositions, methods, and 0164. In certain embodiments, the anti-infective therapeu kits of the invention. Analogs ofirinotecan are described, for tic agent is camptothecin, or an analogue or derivative example, in U.S. Pat. No. 4,604,463 and have the general thereof. Camptothecins have the following general structure. Structure:

0.165. 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. . R is typically Horan amino con where R is a hydrogenatom, a halogenatom, or a C alkyl, taining group Such as (CH)NHCH, but may be other and X is a chlorine or —NRR, wherein R and R are the groups e.g., NO, NH, halogen (as disclosed in, e.g., U.S. same or different and each represents a hydrogenatom, a Ca Pat. No. 5,552,156) or a short alkane containing these groups. alkyl, or a substituted or unsubstituted carbocyclic or hetero R is typically Hora short alkyl Such as CHs. R is typically cyclic group, with the proviso that when both R- and R are Hbut may be other groups, e.g., a group with the Substituted or unsubstituted alkyl groups, they may be R. combined together with the nitrogen atom, to which they are 0166 Exemplary camptothecin compounds include topo bonded, to form a heterocyclic ring which may be interrupted tecan, irinotecan (CPT-11), 9-aminocamptothecin, 21-lac with —O— —S—, and/or >N-R in which R is a hydro tam-20(S)-camptothecin, 10, 11-methylenedioxycamptoth gen atom, a Substituted or unsubstituted C. alkyl, or a Sub ecin, SN-38, 9-nitrocamptothecin, 10-hydroxycamptothecin. stituted or unsubstituted and where the group Exemplary compounds have the structures: 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. Analogs oftopotecan are described, for example, in European Patent No. 321122 and include compounds with the general formula:

R R2 R Camptothecin: H H H Topotecan: OH (CH)NHCH2 H SN-38: OH H C2H5 X: O for most analogs, NH for 21-lactam analogs 0.167 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. 0168 Camptothecins are believed to function as topoi where X is hydroxy, hydrogen, cyano, —CHNH2 or formyl; Somerase I inhibitors and/or DNA cleavage agents. R is hydrogen when X is cyano, CH-NH or formyl or R is —CHO or —CHR when X is hydrogen or hydroxy: R is Disulfuram —O-R-S-R. —N-R(R); or—N' R (R)(R). (0169 Disulfuram is used in the treatment of alcoholism; R. R. and R are the same or different and are selected from its mechanism of action is inhibition of alcohol dehydroge H. C. alkyl, C. hydroxyalkyl, Ce dialkyamino, Co-di nase. The structure of disulfuram is: US 2010/0009970 A1 Jan. 14, 2010 79

-continued H3C S H3C N1 N S Ns ls 1NCH3 S s RO ZR

where R represents acetylor, when Z is oxygen, hydrogen; R. Analogs of disulfuram are described in, for example, U.S. represents a C alkyl. A represents a C- alkylene chain, Pat. No. 1,796,977 and have the general structure: straight or branched; Y represents oxygen or Sulfur, and Z represents oxygen or —NH-. 0173 Auronfin is a white, odorless, crystalline powder S and is insoluble in water. It is administered orally in tablet form. N S ul R R1 Ns NSAIDS S R 0.174. In certain embodiments, an NSAID can be used in the compositions, methods, and kits of the invention. Suitable NSAIDs include A183827, ABT963, aceclofenac, acemeta cin, acetyl salicylic acid, AHR10037, alclofenac, alminopro fen, ampiroXicam, amtolimetinguacil, apaZone, aspirin, atlip wherein the R groups represent same of dissimilar organic rofen methyl ester, AU8001, azelastine, benoxaprofen, groups (e.g., C ). benzydamine, benzydamine flufenamate, benzydamine 0170 Analogs include thiram. Disulfuram is a crystal, hydrochloride, bermoprofen, bezpiperylon, BF388, BF389, barely soluble in water, and is soluble in solvents such as BIRL790, BMS347070, bromfenac, bucloxic acid, buti alcohol, ether, , and benzene. Disulfuram is available bufen, BW755C, C53, C73, C85, carprofen, CBS1108, cele in tablet form, and is typically administered orally. coxib, CHF2003, chlorobiphenyl, trisali cylate, CHX108, cimicoxib, cinnoxicam, clidanac, Auranofin CLX1205, CP331, CS502, CS706, D1367, curcumin, dar 0171 Auranofin is an anti-inflammatory agent and an anti bufelone, deracoxib, dexibuprofen, dexibuprofen , rheumatic. The structure of auranofin is: dexketoprofen, DFP. DFU, diclofenac (e.g., diclofenac potas sium, diclofenac sodium), diflunisal, DPI 55, DRF4367, E5110, E6087, eltenac, ER34122, esflurbiprofen, etoricoxib, RO F025, felbinac ethyl, fenbufen, fenclofenac, fenclozic acid, S Au=P(CHs), fenclozine, fenoprofen, fentiazac, feprazone, filenadol, O flobufen, florifenine, flosulide, flubichin methanesulfonate, RO OR , fluprofen, flurbiprofen, FPL62064. FR122047, FR123826, FR140423, FR188582, FS205397, H furofenac, GR253035, GW406381, HAI 105, HAI 106, OR HCT2035, HCT6015, HGP12, HN3392, HP977, HX0835. R = COCH HYAL AT2101, ibufenac, ibuprofen, ibuproxam-beta-cyclo dextrin, icodulinum, IDEA070, iguratimod, imrecoxib, indomethacin, indoprofen, IP751, isoxepac, isoxicam, KC764, ketoprofen, L652343, L745337, L748731, L752860, L761066, L768277, L776967, L783003, L784520, L791456, L804600, L818571, LAS33815, LAS34475, licofelone, LM 0172 Analogs of auranofin are described, for example, in 4108, lobuprofen, lomoxicam, lumiracoxib, mabuprofen, U.S. Pat. No. 3,635,945, and can be represented by the gen , meclofenamate sodium, , eral formulas: meloxicam, mercaptoethylguanidine, mesoporphyrin, metoxibutropate, miroprofen, mofebutaZone, mofeZolac,

MX1094, nabumetone, naproxen Sodium, naproxen-sodium/ metoclopramide, NCX1101, NCX284, NCX285, NCX4016, NCX4215, NCX530, , nitric oxide-based COX-2 inhibitors and NSAIDs (NitroMed), nitrofenac, nitroflurbiprofen, nitronaproxen, NS398, Ocimum sanctum and oil, ONO3144, orpanoxin, oxaprozin, OXindanac, oXpinac, /ibuprofen, oxyphenbutazone, P10294, P54, P8892, pamicogrel, parcetasal, parecoxib, PD138387, PD145246, PD164387, pelubiprofen, pemedolac, phenylb utaZone, piraZolac, piroXicam, piroXicam beta-cyclodextrin, US 2010/0009970 A1 Jan. 14, 2010 piroXicam pivalate, pirprofen, pranoprofen, , wherein R is selected from the class consisting of hydrogen R-ketoprofen, R-ketorolac, rofecoxib, RP66364, RU43526, and chlorine; R' is selected from the class consisting of lower RU54808, RWJ63556, S19812, S2474, S33516, salicylsali alkyland phenyl groups which latter may be substituted or not cylic acid, satigrel, SC236, SC57666, SC58125, SC58451, in their phenyl nucleus by halogen atoms or lower alkyl or SFPP. SKF 105809, SKF86002, sodium salicylate, sudoxi lower alkoxy groups; R" is a member selected from the class cam, sulfasalazine, sulindac, suprofen, SVT2016, T3788, consisting of hydrogen and lower alkyl groups; R", which TA60, talmetacin, talniflumate, tazofelone, tebufelone, may be like or unlike, are lower alkyl residues; n is selected tenidap, tenoxican, tepoxalin, tiaprofenic acid, tilmacoxib, from the group consisting of 1 and 2. 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, 0179. In certain embodiments, an such as tester Zidometacin, and Zomepirac. one or a testosterone analog can be used in the compositions, (0175 Other NSAIDs are described in U.S. Pat. Nos. methods, and kits of the invention. Androgens such as andros 2,745,783, 3,318,905, 5,344,991, 5,380,738, 5,393,790, tenols include 14-hydroxyandrost-4-ene-3,6,17-trione, 5,401,765, 5,418,254, 5,420,287, 5,434,178, 5,466,823, 16-acetoxy-17-acetoxymethyl-11,17-dihydroxy-D-homoan 5,475,018, 5,474,995, 5,486,534, 5,504,215, 5,508,426, drosta-1,4-diene-3,17-dione, 17beta-((1R)-1-hydroxy-2- 5,510,368, 5,510,496, 5,516,907, 5,521,193, 5,521,207, propynyl)androst-4-en-3-one, 17beta-amino-3beta-meth 5,534,521, 5,565,482, 5,596,008, 5,616,601, 5,633,272, oxy-5-androstene, 17beta-hydroxy-17-(2-methylallyl)- 5,639,777, 5,663,180, 5,668,161, 5,670,510, 5,672,626, 9beta, 10alpha-androst-4-en-3-one, 17-(cyclopropylamino) 5,672,627 5,736,579, 5,739,166, 5,760,068, 5,756,529, androst-5-en-3-ol, 17-acetamido-5-androsten-3-ol-4-bis(2- 5,859,257, 5,886,016, 5,908,852, 5,916,905, 6,294,558, chloroethyl)aminophenylacetate, 17-beta-hydroxy-7alpha 6,476,042, 6,486,203, 6,492,411, 6,608.095, 6,649,645, methyl-androst-5-en-3-one, 17-ethynyl-(5a)-androst-2-ene 6,673,818, 6,689,805, 6,696,477, 6,727,268, 6,699,884, 17-ol-17-nicotinate, 17-ethynylandrost-2-ene-17-ol-17 6,727,238, 6,777,434, 6,846,818, 6,849,652, 6,949,536, acetate, 17-hydroxy-17-methyl-3-oxospiro (androst-5-ene-4, 6,967,213, 7,019,144, and 7,041,694, PCT Publication Nos. 1'-)-2-carbonitrile, 17-methyl-17 WO94/13635, WO94/15932, WO94/20480, WO94/26731, hydroxyandrosta-1,4,6-trien-3-one, 19-ethynyl-19 WO96/03387, WO96/03388, WO96/09293, WO97/16435, hydroxyandrost-4-en-17-one, 2,3,17, 19 WO98/03484, WO98/47890, WO96/06840, WO96/25405, tetrahydroxyandrost-4-ene, 2-beta-hydroxy-19-oxo-4- WO95/15316, WO94/15932, WO94/27980, WO95/00501, androstene-3,17-dione, 3beta-methoxy-5-androsten-17-one, and WO94/2673, and GB 839,057, GB 2,294.879, and EP 3’-azido-3'-deoxy-5'-O-((11-hydroxy-3-oxo-17-androst-4- O745596. enyl)carbonyl)thymidine, 3,15, 17-trihydroxy-5-androstene, Benzydamine 3.16, 19-trihydroxy-5-androsten-17-one, 3,17-dihydroxy-7- (0176) (4-methoxyphenyl)-androst-5-ene 3,17-diacetate, 3-hy 0177. In certain embodiments, an NSAID such as benzy droxy-17-methyl-18-norandrost-13(17)-ene-16-one, damine oran analog thereof can be used in the compositions, 3-methoxy-17-aza-homoandrost-5-ene-17-one, 5alpha-an methods, and kits of the invention. The structure of benzy drost-16-en-3beta-ol, 5-androstene-3,16,17-triol, 9-fluoro damine is: 11,16,17-trihydroxy-17-hydroxymethyl-D-homoandrosta-1, 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 17beta-ol, androsta-5,16-dien-3beta-ol, Androstenediols (e.g., 17-cyano-9,17-dihydroxyandrost-4-ene-3-one, 2-car bamoyl-4,5-epoxyandrost-2-ene-3,17-diol. 3beta, 17 beta-di hydroxyandrost-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-3beta, 17beta-diol dicyclopentylpropionate, androst-4- ene-3beta, 17 beta-diol dienanthate, , cortienic acid, delta (2,16)-5alpha-androstadiene-3,17-diol-3,17-diac 0.178 Analogs of benzydamine are described, for etate, Fluoxymesterone, formyldienolone, , and example, in U.S. Pat. No. 3,318.905 and have the general viridiol), azastene, cyanoketone (e.g., Win 19578), Dehy Structure: droepiandrosterone (e.g., 1-hydroxydehydroepiandroster one, 15beta-carboxyethylmercaptodehydroepiandrosterone, 15-hydroxydehydroisoandrosterone, 16-hydroxydehydroe piandrosterone, 16-hydroxydehydroepiandrosterone Sulfate, 1N O N-(CH3).-NM 7-hydroxydehydroepiandrosterone, 7-oxodehydroepi R-i Y. androsterone, androst-5-en-17-one, dehydroepiandrosterone 21 N1 N acetate, dehydroepiandrosterone enanthate, dehydroepi androsterone sulfate, dehydroepiandrosterone-3-O-meth R ylthiophosphonate, fluasterone, gonasterone, gynodian, OH 8356, and testosterone ), epostane, etiocholenic acid, methyl 14-hydroxy-17, 17-trioxoandrost-8-ene-19-oate, US 2010/0009970 A1 Jan. 14, 2010

mexrenoate potassium, , ratibol, RS 21314, RS 17-triol, -3,7,17-triol, androstane-3,7-diol disul 85095, , , testosterone, and thi fate), androsterone or its derivatives (e.g., 11beta OneSterOne. hydroxyandrosterone, 11-ketoandrosterone, 16beta 0180 Testosterone derivatives include 11-ketotestoster hydroxyandrosterone, 16-bromoepiandrosterone, one, 11-oxatestosterone, 15beta-carboxyethylmercaptotest 17-hydroxy-6,6-ethylene-4-androsten-3-one, 19-hydroxy-4- osterone, 15-carboxymethyltestosterone, 17beta-aminocar androsten-17-one, 3-bromoacetoxyandrostan-17-one, 3-hy bonyloxy-4-androsten-3-one, 17-bromoacetoxy-4- droxy-4-androsten-17-one, androsterone 3-benzoate, andros androsten-3-one, 17-ethinyl-11-Oxa-testosterone, 19-O- terone 3-palmitate, androsterone glucuronide, and carboxymethoxytestosterone, 4-(carboxymethylmercapto) androsterone sulfate), BOMT, CCI 22277, dihydrotestoster testosterone, 6-dehydrotestosterone, one or its derivatives (e.g., 11-fluoro-19-nor-dihydro-test 6-methylenetestosterone acetate, ablacton, androsta-3,5-di osterone, 11-fluoro-dihydro-testosterone, 16-iodostanolone, ene-3,17-diol diacetate, bolasterone, unde 17-(2-iodoethenyl)androsta-4,6-dien-17-ol-3-one, 17-(2-io cylenate, climacterone, , D-4-chloro-17beta-hy doethynyl)androsta-4,6-dien-17-ol-3-one, 17-(2-iodovinyl) droxy-3-oxo-17alpha-methylandrosta-1,4-diene, , 17-hydroxyandrostan-19-ol-3-one, dehydrotestosterone, deladumone, dimeric testosterone, epit 17-hydroxyandrostan-3-one 17-sulfate, 17-ketotrilostane, estosterone, estandron prolongatum, ethynodiol testosterone 17-N,N-diethylcarbamoyl-4-methyl-4-azaandrostane-3-one, ester, gonasterone, hydroxytestosterones, metharmon F. 17-N,N-diisopropylcarbamoyl-4-azaandrostan-3-one, methenolone, methyltestosterone, nichlotest, synovex-H, tes 18-hydroxy-18-methyl-16, 17-methylene-D-homoandros tosterone 17beta-carboxylic acid, testosterone 17beta-cypi tane-3-one, 2,17-dimethyldihydrotestosterone, 2-bromo-5- onate, testosterone 17-cyclohexanecarboxylate, testosterone dihydrotestosterone, 2-chloroethylnitrosocarbamoylalanine 17-enanthate 3-benzilic acid , testosterone 3-(O- 17-dihydrotestosterone ester, 3-hydroxyandrostan-1 6-one, dimethylaminopropyl), 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, dihydrotestosterone 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 androstane-3,17-dione), , , mepitios pot, topterone, trofodermin, and turinabol. tane, N-cyano-2-aza-A-norandrostan-17-ol acetate, nister ime acetate, ORG 9943, ORG 9991, Org NA 13, oxan 0181 Androstanols include 1.2-seco-A-bis(noran drolone, or its derivatives (e.g., 17-hydroxy drostan-17-ol)acetate, 1,3,5,6-tetrahydroxyandrostan-17 2-(hydroxymethylene)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, 3alpha,17beta-dibutyry androsta-1,4,6-triene-3-one, 16,17-epoxyandrostan-3-ol, loxy-2beta, 16beta-dipiperidino-5alpha-androstane dimetho 17beta-(3-furyl)-5beta, 14beta-androstane-3beta, 14beta , 3-(deacetoxy)pancuronium, diol, 17-(3'-thiophenyl)androstane-3,14-diol 3-glucopyrano 3-desacetylpancuronium, dacuronium, and Org 6368), RU side, 17-acetamido-5-androstan-3-ol-4-bis(2-chloroethyl) 26988, rubrosterone, Samanine, spiro-3-oxiranylandrostan aminophenylacetate, 17-ethyl-17-hydroxyandrostane, 17-ol, stanozolol or its derivatives (e.g., 16-hydroxyStano 17-hydroxy-2,3-cyclopropanoandrostane, 17-methyl-17a Zolol and 4,16-dihydroxystanozolol), or chloro-D-homoandrostan-3-ol, 2-(2-(3-hydroxy-12-(2-me its derivatives (e.g., (dideacetoxy)Vecuronium, thyl-1-oxobutoxy)-5-androstan-17-yl)ethyl)tetrahydro-4- 17-deacetylvecuronium, 3,17-bis-deacetylvecuronium, hydroxy-2H-pyran-6-one, 3beta-acetoxy-5.6beta 3-(deacetoxy)vecuronium,3-deacetylvecuronium, Org 7617, dichloromethylene-5beta-androstan-17-one, 3,3- Org 7678, Org 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) 0182 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- Tyrphostins dihydroxyandrostan-17-one-3-acetate, amafolone, androsol acetate, androstan-17-ol, androstan-3-ol, androstane-3,17 0183 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 US 2010/0009970 A1 Jan. 14, 2010

AG 1478, tyrphostin AG 555, tyrphostin AG 568, tyrphostin tion. In general, Suitable platinum complexes may be of Pt(II) AG-490, tyrphostin AG17, tyrphostin AG879, and tyrphostin or Pt(IV) and have this basic structure: AG957. Tyrphostins are described in U.S. Pat. Nos. 5,728, 868 and 5,854,285. Vitamin B 0184 Vitamin B and B analogs can be used in the compositions, methods, and kits of the invention. Vitamin B, its derivatives, and its analogs are cofactors in folate and synthase. 5-Deoxyadenosylcobal amin is a cofactor required by the that converts L-me wherein X and Y are anionic leaving groups such as Sulfate, thylmalonyl-CoA to Succinyl-CoA. Other vitamin Bana phosphate, carboxylate, and halogen; R and R are alkyl, logs include 1.N(6)-ethenoadenosylcobalamin, 2',5'- amine, amino alkyl any may be further substituted, and are dideoxyadenosylcobalamin, 2-methyl-2-aminopropanol basically inert or bridging groups. For Pt(II) complexes Z. B12. adeninylethylcobalamin, ambene, and Z are non-existent. For Pt(IV) Z and Z may be anionic aminopropylcobalamin, aquacobalamin, biofer, Co-(car groups such as halogen, hydroxy, carboxylate, ester, Sulfate boxymethyl)cobalamin, cob(II) alamin, cobamides (e.g., or phosphate. See, e.g., U.S. Pat. Nos. 4,588,831 and 4.250, (2-amino-5,6-dimethylbenzimidazolyl)cobamide, (2-hy 189. droxy-5,6-dimethylbenzimidazolyl)cobamide, 2-methyl 0187 Suitable platinum complexes may contain multiple sulfinyladenylcobamide, 2-methylsulfonyladenylcobamide, Pt atoms. See, e.g., U.S. Pat. Nos. 5,409,915 and 5,380,897. 4-cresolylcobamide, adenosylcobinamide methylphosphate, For example bisplatinum and triplatinum complexes of the coalpha-(alpha-5,6-dimethylbenzimidazolyl)-cobeta-cyano type: cobamide, cobamamide, cobamamide 5'-phosphate, cobina mide, phenolylcobamide, thiobanzyme), cobyric acid, coby Z1 Z rinic acid, cobyrinic acid hexamethyl ester f-nitrile, 2 compound 102804, cyanocobalamin-b-monocarboxylic XS-R, XSL-R acid, cyanocobalamin-e-monocarboxylic acid, cysteinylco y1 N-1 Ny balamin, factor A, factor III, ferribalamin, formylmethylco balamin, FV 82, glutathionylcobalamin, hepavis, hydroxoco Z1 4. A Z1 Z1 Z 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 0185. Histone deacetylase inhibitors and their analogs may be used in the compositions, methods, and kits of the 0188 Exemplary platinum compounds are cisplatin, car invention. Exemplary HDACs include CAY10433 and sub boplatin, oxaliplatin, and miboplatin having the structures: erohydroxamic acid. Histone deacetylase inhibitors are used, for example, in therapy, and in the treatment of inflam mation and are a group of compounds that include, for O O example, cyclic peptides (e.g., depsipeptides such as FK228), t short chain fatty acids (e.g., phenylbutyrate and Valproic t Sh acid), (e.g., CI-994 and MS-27-275), and CI-Pt-NH. O YNH, hydroxamic acids (e.g., Suberoylanilide hydroxamic acid C (SAHA)) as described in Richon and O’Brien ((2002) Clin. Cisplatin O Canc. Res. 8, 662-664). Cyclic peptides and analogs useful in Carboplatin the invention are described, for example, in U.S. Pat. No. O O H. H. 6,403,555. Short chain fatty acid HDAC inhibitors are O NH O Y described in, for example, U.S. Pat. Nos. 6,888,027 and V / 2 MSW 5,369,108. Benzamides analogs are described, for example, in U.S. Pat. No. 5,137,918. Analogs of SAHA are described, C /v NH' O/". 2. N H for example, in U.S. Pat. No. 6.511,990. Other HDACs M include anacardic acid, apicidin, histone deacetylase inhibitor O O H I, histone deacetylase inhibitor II, histone deacetylase inhibi Oxaliplatin Milboplatin tor III, ITSA1, oxamflatin, SBHA, scriptaid, sirtinol, splito micin, trichostatin A, and valproic acid (e.g., sodium salt). Any of these compounds or other HDAC inhibitors may be 0189 Other representative platinum compounds include used in the compositions, methods, or kits of the invention. (CPA),Pt(DOLYM) and (DACH)Pt(DOLYM) cisplatin (Choi et al., Arch. Pharmacal Res. 22(2):151-156, 1999), Platinum Complexes Cis-(PtCl(4.7-H-5-methyl-7-oxo)1.2.4(triazolo (1.5-a)pyri 0186. In certain embodiments, a platinum compound can midine)) (Navarro et al., J. Med. Chem. 41(3):332-338, be used in the compositions, methods, and kits of the inven 1998), (Pt(cis-1,4-DACH)(trans-Cl)(CBDCA))./2MeOH US 2010/0009970 A1 Jan. 14, 2010

cisplatin (Shamsuddin et al., Inorg. Chem. 36(25):5969 (Harstricket al., Int. J. Androl. 10(1): 139-45, 1987), (NPr") 5971, 1997), 4-pyridoxate diammine hydroxy platinum ((PtCL).cis-(PtCl2 (NHMe))) (Brammer et al., J. (Tokunaga et al., Pharm. Sci. 3(7):353–356, 1997), Pt(II) ... Chem. Soc., Chem. Commun. 6:443-5, 1987), aliphatic tricar Pt(II) (Pt(NHCHN(C(CH2)(CH)))) (Navarro et al., Inorg. boxylic acid platinum complexes (EPA 185225), and cis Chem. 35(26):7829-7835, 1996), 254-S cisplatin analogue dichloro() (tert-butylamine)platinum(II) com (Koga et al., Neurol. Res. 18(3):244-247, 1996), o-phenylene plexes (Pasini & Bersanetti, Inorg. Chim. Acta 107(4): 259 diamine ligand bearing cisplatin analogues (Koeckerbauer & 67, 1985). Oxaliplatin analogs are described in U.S. Pat. Nos. Bednarski, J. Inorg. Biochem. 62(4):281-298, 1996), trans, 4,169,846, 5,290,961, 5,298,642, and 6,153,646. Satraplatin cis-(Pt(OAc). I(en)) (Kratochwil et al., J. Med. Chem. is described in Choy, Expert Rev. Anticancer Ther. 6(7):973 39(13):2499-2507, 1996), estrogenic 1,2-diarylethylenedi 982, 2006). These compounds are thought to function by amine ligand (with Sulfur-containing amino acids and glu binding to DNA, i.e., acting as alkylating agents of DNA. tathione) bearing cisplatin analogues (Bednarski, J. Inorg. Flavanones Biochem. 62(1):75, 1996), cis-1,4-diaminocyclohexane cis platin analogues (Shamsuddin et al., J. Inorg. Biochem. 61(4): 0190. In certain embodiments, a flavanone can be used in 29.1-301, 1996), 5' orientational isomer of cis-(Pt(NH)(4- the compositions, methods, and kits of the invention. Exem aminoTEMP-O){d(GpG)}) (Dunham & Lippard, J. Am. plary flavanones include 2-hydroxyflavanone, 137 L, 2',3,5, 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), ()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: (0191 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 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) dichloro(ethylenediamine)platinum(II) (Eastman, Anal. Bio chem. 197(2):311-15, 1991), trans-diamminedichloroplati num(II) and cis-(Pt(NH)-(N-cytosine)Cl) (Bellon & Lippard, Biophys. Chem. 35(2-3): 179-88, 1990), 3H-cis-1,2- diaminocyclohexanedichloroplatinum(II) and 3H-cis-1,2-di aminocyclohexane-malonatoplatinum (II) (Oswald et al., Analogs of amorolfine are described, for example, in U.S. Res. Commun. Chem. Pathol. Pharmacol. 64(1):41-58, Pat. No. 4,202,894 and have the general structure: 1989), diaminocarboxylatoplatinum (EPA 296321), trans (D, 1)-1,2-diaminocyclohexane carrier ligand-bearing plati R4 Rs num analogues (Wyrick & Chaney, J. Labelled Compa. R Radiopharm. 25(4): 349-57, 1988), aminoalkylaminoan R2 XY X thraquinone-derived cisplatin analogues (Kitov et al., Eur: J. Med. Chem. 23(4): 381-3, 1988), spiroplatin, carboplatin, iproplatin and JM40 platinum analogues (Schroyen et al., Eur: J. Cancer Clin. Oncol. 24(8): 1309-12, 1988), bidentate tertiary diamine-containing cisplatinum derivatives (Orbellet al., Inorg. Chim. Acta 152(2):125-34, 1988), platinum(II), platinum(IV) (Liu & Wang, Shandong Yike Daxue Xuebao 24(1):35-41, 1986), cis-diammine(1,1-cyclobutanedicar boxylato-)platinum(II) (carboplatin, JM8) and ethylenediam wherein R is alkyl of 4 to 12 carbon atoms, cycloalkyl of 3 to mine-malonatoplatinum(II) (JM40) (Begg et al., Radiother: 7 carbon atoms, mono(lower alkyl)-substituted cycloalkyl of Oncol. 9(2): 157-65, 1987), JM8 and JM9 cisplatin analogues 4 to 7 carbon atoms, cycloalkylalkyl of 4 to 12 carbon atoms, US 2010/0009970 A1 Jan. 14, 2010 phenyl or aryl-(lower alkyl) of 7 to 12 carbon atoms; R. R. atrienoyl)morpholine, 4-amino-5-chloro-2-ethoxy-N-((2- and R, independently, are hydrogen or alkyl of 1 to 8 carbon morpholinyl)methyl)benzamide, 4-amino-N-(4-benzyl-2- atoms; R Rs, and R, independently, are hydrogen or alkyl morpholinyl)methyl)-5-chloro-2-ethoxybenzamide, of 1 to 8 carbonatoms, and two of R. Rs, and R can each be 4-amino-N-(4-benzyl-2-morpholinyl)methyl)-5-chloro-2- bonded to the same carbon atom or together can form a fused methoxybenzamide, 4-benzylphenoxy-N-ethylmorpholine, alicyclic or aromatic 6-membered ring; provided that when R 4-cyclododecyl-2,6-dimethylmorpholine acetate, 4-methox is tert-butyl, at least one of R and R is alkyl of 2 to 8 carbon yphenyl-(5-methyl-6-(2-(4-morpholinyl)ethyl)-6H-thieno atoms or R is hydrogen or alkyl of 2 to 8 carbon atoms or at (2,3-b)pyrrol-4-yl)phenylmethanone, 4-methylmorpholine, least one of R. Rs, and R is alkyl of 5 to 8 carbon atoms: X 4-methylmorpholine N-oxide, 4-morpholinedithiocarbam is methylene oran oxygen atom; Z is Zero or 1 and the dotted ate, 4-morpholinocarbonitrile, 5-pentyl-N-nitrosomorpho bonds can be hydrogenated, and acid addition salts of those compounds of formula I which are basic, where the term line. A 74273, AH 19437, , AWD 140076, befol. “lower alkyl denotes a straight-chain or branched-chain BIBW 22, bis(3,5-dimethyl-5-hydroxymethyl-2-oxomor hydrocarbon group of 1 to 4 carbon atoms, such as, methyl, pholin-3-yl), BW 175, cetethyl morpholinium, CGP 53437, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl. Alkyl C11033, ciclosidomine, CNK 6001, CNK 6004, CP80794, groups of4 to 12 carbonatoms are straight-chain or branched CP 84364, CS 722, delmopinol, detensitral, Dextromora chain hydrocarbon groups, for example, butyl, isobutyl, tert.- mide, di-beta-(morpholinoethyl)selenide, dimethomorph, butyl, neopentyl, 1,1-dimethylpropyl, 1,1-dimethylpentyl, dimethyl morpholinophosphoramidate, dimorpholamine, ES 1,1-diethylpropyl, 1,1-dimethylbutyl, 1-isopropyl-3-methyl but-1-yl, 1-ethyl-1-methylbutyl, dodecyl, and the like. 6864, ES 8891, fempropimorph, filenadol, FK 906, fomi Cycloalkylalkyls include, in particular, those groups in which noben, FR 76830, Go 8288, GYKI 11679, indeloxazine, L the alkyl moiety is branched. The term “aryl-(lower alkyl) 689502, L 742694, L 760735, , lateritin, M&B includes not only groups which are mono- or di(lower alkyl)- 16573, MDL 101146, MF 268, mofarotene, Molsidomine, Substituted in the aryl ring but also groups which are mono- or morfolep. Moricizine, morlincain, moroxybrate, moroxy di(lower alkyl)-substituted in the lower alkyl moiety. Exem dine, morpholine, morpholineoethylamino-3-benzocyclo plary of aryl(lower alkyl) groups are benzyl, phenylethyl, hepta(5.6-c)pyridazine, morpholinoamidine, morpholino (lower alkyl)-benzyl, for example, methylbenzyl and dimeth phosphordichloridite, morpholinopropane , ylbenzyl, naphthylmethyl 2-phenyl-propan-2-yl, 1-phenyl morpholinosulfonic acid, morpholinylethoxy-3-methyl-4- 1-ethyl, or the like. (2-naphthyl)-6-pyridazine, mosapride, N,N'-dicyclohexyl 0.192 Amorolfine is a member of the morpholines, which 4-morpholinecarboxamidine, N-(4-benzyl-2-morpholinyl) include ((2-azido-4-benzyl)phenoxy)-N-ethylmorpholine, methyl)-5-chloro-4-(dimethylamino)-2-methoxybenzamide, (+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid, (morpholi N-(3.N'-morpholinopropyl)-2-(3-nitropyrrolo-(2,3-b)pyri nyl-2-methoxy)-8-tetrahydro-1,2,3,4-, 1,1'-hexam ethylenebis(3-cyclohexyl-3-((cyclohexylimino)(4-mor dine-1-yl)ethanoic acid amide, N-(3-nitro-4-quinoline)mor pholinyl)methyl)), 1,4-bis(3'-morpholinopropyl-1-yl pholino-4-carboxamidine, N-dodecylmorpholine, N-ethyl 1)benzene, 1,4-thiomorpholine-3,5-dicarboxylic acid, 1,4- morpholine, N-hexylmorpholine-2',5'-oligoadenylate, thiomorpholine-3-carboxylic acid, 1-(morpholinomethyl)-4- N-nitromorpholine, N-oxydiethylene-2- sulfe phthalimidopiperidine-2,6-dione, 1-deoxy-1-morpholino namide, O-(N-morpholinocarbonyl)-3-phenyllacetic acid, psicose, 1-deoxy-1-morpholinofructose, 1-phenyl-2,3- , oxymorphindole, P 1487, P34081, PD 132002, dimethyl-4-naphthalanmorpholinomethylpyrazolin-5-one, phendimetrazine, Phenmetrazine, phenyl 2-(2-N-morpholi 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol. 2.6- noethoxy)phenyl ether, , phosphorodiamidate bis(carboxymethyl)-4,4-dimethylmorpholinium, 2,6-dim morpholino oligomer, pinaverium, pramoxine, proctofoam ethylmorpholine, 2,6-dioxo-N-(carboxymethyl)morpholine, HC, promolate, RE 102, , Ro 12-5637, Ro 2-(((3-(morpholinylmethyl)-2H-chromen-8-yl)oxy)methyl) 12-8095, RS 1893, RV 538, S 12024, S 14001, S-anisylfor morpholine, 2-(3-trifluoromethyl)phenyltetrahydro-1,4-ox mamidino-4-(N-methylisothioamide)morpholine, S-phen azine, 2-(4-morpholino)ethyl-1-phenylcyclohexane-1-car boxylate, 2-(4-morpholino-6-propyl-1,3,5-triazin-2-yl) ethylformamidino-4-(N-ethylisothioamide)morpholine, SC aminoethanol. 2-(4-morpholinyl)-4H-1-benzopyran-4-one, 46944, Seda-Miroton, silatiemonium iodide, SIN 1C, SR 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one, 2-(4- 121463A, Stymulen, sufoxazine, teomorfolin, theniloxazine, nitrophenyl)-4-isopropylmorpholine, 2-(morpholin-4-yl) thiamorpholine, , tiemonium methylsul benzohchromen-4-one, 2-(N-methylmorpholinium)ethyl fate, tridemorph, trifenmorph, trimetozine, trimorfamid, acetate, 2-(N-morpholino)ethanesulfonic acid, 2-benzylmor trithiozine, TVX 2656, U 37883A, U 84569, U 86983, UP pholine, 2-hydroxy-4,4-dimethyl-2-(4-tolyl)morpholinium, 614-04, Viloxazine, Win 55212-2, and YM21095. 2-methyl-3-(2-methyl-2,3-diphenyl-4-morpholinyl)-1-phe nyl-1-propanone, 2-morpholinomethyl-2',3',4'-trimethoxy Andrographis acrylophenone, 2-n-pentyloxy-2-phenyl-4-methylmorpho line, 2-phenyl-5,5-dimethyltetrahydro-1,4-oxazine, 0193 In certain embodiments, andrographis, or an extract 2-thiomorpholinoethylacrylamide, 3.5.5-trimethyl-2-mor or component thereof, can be used in the compositions, meth pholinon-3-yl radical dimer, 3-((benzyloxy)methyl)morpho ods, and kits of the invention. Andographis paniculata is line, 3-(beta-morpholinoethoxy)-1H-indazole, 3-cyano-2- medicinal herb, which has been used as an antipyretic, an morpholino-5-(pyrid-4-yl)pyridine, anti-inflammatory agent, and a liver protectant. It also is 3-thiomorpholinopropylacrylamide, 4,4'-dithiodimorpho reported to have anticancer and antiviral (e.g., anti-HCV and line, 4.4-methylenedimorpholine, 4-(2-morpholinoethoxy) anti-HIV) properties. The primary active agent in androgra benzophenone, 4-(3,7,11,15-tetramethyl-6,10,14-hexadec phis is andrographolide. The structure of andrographolide is: US 2010/0009970 A1 Jan. 14, 2010 85

targeting moiety or oxygen radical through a spacer group; or alternatively, R. R. R. R. R. R. R-7, Rs. R. Rio, R. R. Ris. R14, R1s. R16, R17, R1s. Ris, R19, R20. R2, R22, R2s, R24. R2s, R26, R27, R2s, R29, Rao, Rs 1 and Rs2 can individually come together to form a bridged compound comprising of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalky nyl, aryl, alkaryl, aryl alkyl, heterocyclic, heteroaromatic, acyl, carbamide, alkoxy, amino, halogen, silyl, , Sulfinyl, Sulfamoyl, ester, amide, phosphonyl, phosphinyl, phospho ryl, , , ether, oXime, carbamate, thioether, resi due of a natural or synthetic amino acid or a carbohydrate, any of which can be optionally attached to the targeting moiety or oxygen radical through a spacer group; and each carbonatom cannot be covalently bound to more than two heteroatoms; and wherein each B, W and X cannot be all heteroatom Andrographolide analogs are described, for example, in U.S. moieties unless B, W and X are all nitrogen based or Band X Pat. Application Publication No. 2006/0223785 and have the are independently O or N and W is PR, POR PO, S(Y), general structure: 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. 0194 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, CRC, C(Ys), O, or a covalent bond; and X, X and X are independently hydro gen, CR sRoRo CER2, R22, C=R2s. 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 X1,X2, and X is hydrogen. 0.195. In another embodiment of the above formula, at least one R, R2, Rs. R4 Rs. Rs. R-7, Rs. Ro, Rio, R1, R12R1s. R14, R1s. R16, R17, Ris, R19, R20. R2, R22, R2s, R24. R2s, R26. R7, R-2s, RoRo R, and R 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. 0196. In one embodiment of the above formula, at least or its cis isomer, or its pharmaceutically acceptable salt, ester, One R, R2, Rs. R4 Rs. R. R-7, Rs. Ro, Rio. R11, R12, R1s. R4, salt of an ester or prodrug, wherein: B, B and B are inde R1s. R16, R17, Ris, R19, R20. R2, R22, R23, R24. R2s, R26, R27. pendently CRR, C(Y), O, NR, PRs, P(=Y)R P(=Y) Rs. R. Ro R and R is selected from a carbonyl con S(=Y), a spacer group or a covalent bond; and k can be taining groups, including, but not limited to, , 0, 1 or 2; and W. W. and W are independently CR,Rs, CR ketone, carboxylic acid, ester, amide, enone, acyl chloride or C,C(Y.), O, NRio, PR, P(=Y)R, P(=Y), S(=Ys), or anhydride. a covalent bond; and f can be 0, 1 or 2; or B. W. B. W. 0.197 In one embodiment of the above formula, at least and/or B. W. are independently CR=CR or C=C; and X1, X2 and X are independently hydrogen, CRs RoRo One R, R2, Rs. R4 Rs. R. R-7, Rs. Ro, Rio. R11, R12, R1s. R4, C=RR, C=Rs, C=N, C(=Y)R, ORs, NR-R-7, R1s. R16, R17, Ris, R19, R20. R2, R22, R23, R24. R2s, R26, R27. N=NRs, P(=Yo),(R)V. S(=Y) (Rao), or NO, and d Rs. Rao, Ro R and R is selected from an alkyl, aryl, can be 0, 1 or 2; and V can be 0, 1 or 2; and i can be heteroaryl or heteroaromatic ring. independently 0 or 1; and Y.Y.Y. Ya, Ys, Y, Y, Ys, Y, 0.198. In one embodiment of the above formula, at least Yo, and Y are independently O, S, or NZ; and Z can be One R, R2, Rs. R4 Rs. R. R-7, Rs. Ro, Rio. R11, R12, R1s. R4, independently hydrogen, R, OR, SRs or NRR, and Rs. R16. R17. R1s. R19. R20. R21. R22. R2s. R24. R2s. R26. R27. R1, R2, R. R. Rs. Rs. R-7, Rs. Ro, Rio, R1, R12, R1s. R4, R2s, Rao, Rao, Rs and R-2 is independently selected from R1s. R16, R17, R1s. Ris, R19, R20. R2, R22, R2s, R24. R2s, R26. alkyl, nitro, a phosphate, a Sulfate, a thiol, and an amine. R27, R-2s, Rao, Rao, Rs and R-2 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalky Arbidol nyl, aryl, alkaryl, arylalkyl, heterocyclic, heteroaromatic, acyl, aldehyde, carbamide, alkoxy, amino, halogen, silyl, 0199. In certain embodiments, arbidol or an analog thiol, Sulfoxy, Sulfinyl, Sulfamoyl, hydroxyl, ester, carboxylic thereof can be used in the compositions, methods, and kits of acid, amide, nitro, cyano, phosphonyl, phosphinyl, phospho the invention. Arbidol is an antiviral that has anti-influenza ryl, imide, thioester, ether, acid halide, oxime, carbamate, activity and functions by inhibition of the fusion of influenza thioether, residue of a natural or synthetic amino acid or a A and B viruses within endosomes. The structure of arbidol carbohydrate, any of which can be optionally attached to the is: US 2010/0009970 A1 Jan. 14, 2010

artemisin, artemisinin B, artemisinine, artemisitene, artesu nate, artesunic acid, deoxoartemisinin, deoxyartemisinin, and dihydroquinghaosu. The active metabolite of artemisi nins is dihydroartemisinin.

Benoximate 0203. In certain embodiments, procaine or a derivative thereof Such as benoxiante can be used in the compositions, methods, and kits of the invention. Benoximate is an anes thetic agent. The structure of benoximate is: Arbidol is typically administered orally. 0200. In certain embodiments, artemisinin or an analog N O thereof can be used in the compositions, methods, and kits of the invention. The artemeisins area family of compounds that include antimalarials such as artemisinin and artemether, a semi-synthetic derivative of artemisinin. The structure of N-N-1-CrNH2 artemisinin is:

Benoximate is a procaine derivative. Other procaine deriva H tives include 4-bromoacetamidoprocaine, analgesin, aslavi tal, benoximate, bivelin, Cardioplegin, celnovocaine, chloro procaine, efatin, Fluress, Impletol, impletol depot Bayer, N,N-diethylaminoethyl(2-N-methyl)benzoate, N-acetylp rocaine, nicotinoylprocaine, novdimal, G, Procaine, procaine acryloyl polymer, procaine azide, procaine , Renovaine, Sulfocamphocaine, Tar domyocel compound, and turigeran.

0201 The structure of artemether is: 0204. In certain embodiments, amiloride or an analog thereof Such as benzamil can be used in the compositions, y methods, and kits of the invention. Amiloride is a diuretic agent. The structure of amiloride is:

O NH C N ls n N NH2 OCH H 2 0202 The structure of artesunate is: HN N NH2

0205 The structure of benzamil is:

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

Other artemisinins include 3-hydroxydeoxyartemisinin, Amiloride derivatives are described, for example, in U.S. Pat. C-propoxycarbonyldihydroartemisine, arteannuin B, No. 3,313,813 and can be represented by the following for arteether, arteflene, artelinic acid, artemether, artemisic acid, mula: US 2010/0009970 A1 Jan. 14, 2010 87

unsubstituted as described above for R or R and R can be lower alkyl groups linked directly together or through a het O NR ero atom, especially through oxygen or nitrogen to produce a 5 to 8 membered cyclic structure, thus forming with the X Nn N l -R nitrogen atom to which they are attached a 1-pyrrolidinyl, H piperidino. 1-piperazinyl, especially a 4-lower alkyl-1-piper 2 R3 azinyl or morpholino, and the like radicals; and when R and Y N Amino R (or Ra) each represents a lower alkyl, they can be linked together to form a cyclic structure with the nitrogenatoms to where X represents hydrogen, a halogen or halogen-like radi which they are attached, particularly to form a 2-(2-imida cal. Such as, chloro, bromo, iodo or trifluoromethyl, or a Zolinyl) radical. The 3-position amino group can be an unsub lower-alkyl, lower-cycloalkyl, mononuclear aryl, either stituted amino as well as mono- or di-Substituted amino unsubstituted or Substituted, advantageously with a halogen groups, the Substituent(s) advantageously being lower alkyl especially a chloro or bromo Substituent, amino, Z-thio or and lower alkanoyland also where the substituents are linked Z-sulfonyl wherein Z is lower alkyl or phenyl-lower alkyl: Y to form a heterocyclic structure with the amino nitrogen to represents hydrogen, hydroxyl or mercapto, lower alkoxy or which they are attached. lower alkyl-thio, halogen, especially chlorine, lower-alkyl, 0206 Amiloride derivatives include 2',4'-dichloroben lower-cycloalkyl, mononuclear aryl, especially phenyl or Zamil amiloride, 2',4'-dimethylbenzamil, 2'-methoxy-5'-ni amino, advantageously having the structure NRR, wherein R trobenzamil, 2-chlorobenzylamiloride, 3',4'-dichloroben and R1 can be similar or dissimilar radicals and respectively Zamil, 3.5-diamino-6-fluoro-2-pyrazinoylguanidine, 3.5- represent hydrogen, amino or mono- or di-lower-alkylamino, (advantageously forming a hydrazino group at the 5-position diamino-N-(aminoiminomethyl)-6-bromopyrazine-N- carbon), lower alkoxy, Y represents Substituted amino, methylcarboxamide, 4-(((((3,5-diamino-6-chloropyrazinyl) —NRR, where RandR represent lower alkyl either straight carbonyl)amino)iminomethyl)amino)-2.2.6.6-tetramethyl or branched chain or cyclic (3- to 6-membered rings) and 1-piperidinyloxy, 5,6-dichloroamiloride, 5-(ethylpropyl) either unsubstituted or containing one or more Substituents amiloride, 5-(N.N-hexamethylene)amiloride, 5-(N-2'-(4"- Such as hydroxyl, halogen (chlorine, bromine, fluorine and azidosalicylamidino)ethyl-N'-isopropyl)amiloride, 5-(N-2'- the like), a cycloalkyl substituent having 3 to 6 carbons in the aminoethyl-N'-isopropyl)amiloride-N-(4"- cycloalkyl structure, an aryl substituent preferably phenyl or azidosalicylamide), 5-(N-4-chlorobenzyl)-N-(2',4'- Substituted phenyl Such as lower-alkyl-phenyl and halophe dimethyl)benzamil, 5-(N-butyl-N-methyl)amiloride, 5-(N- nyl as chlorophenyl, bromophenyl, fluorophenyl, and the like, ethyl-(2-methoxy-5'-nitrobenzyl)amiloride, 5-(N-methyl or a heterocyclic Substituent especially furyl, pyridyl, and N-isobutyl)amiloride, 5-(N-methyl-N-propyl)amiloride, (CH),N- wherein n is one of the numerals 4 through 6, or 5-(N-propyl-N-butyl)-2',4'-dichlorobenzamil amiloride, an amino Substituent as the unsubstituted amino, or mono- or 5-(N-tert-butyl)amiloride, 5-diethylamiloride, 5-dimethy di4ower-alkyl amino, and when R and Reach represents a lamiloride, 5-N-(3-aminophenyl)amiloride, 5H-amiloride, lower alkyl, the lower alkyl groups can be linked together to 6-bromoamiloride, 6-bromobenzamil, 6-chloro-3,5-diami form a cyclic structure with the nitrogen atom to which they nopyrazine-3-carboxamide, 6-iodoamiloride, alpha',2'-ben are attached, particularly a 5- to 8-membered ring, advanta Zobenzamil, amiloride caproate, benzamil, co-amilozide, geously forming with the nitrogen atom a 1-pyrrolidinyl, Esmalorid, ethylisopropylamiloride, frumil, kalten, methyl piperidino, hexahydro-1-azepinyl, or octahydro-1-azocinyl isopropylamiloride, moducirin, N(5)-piperazine-amiloride, radical and the like, Y represents substituted amino, NRR, where RandR represent lower alkenyl, aryl, advantageously N(5)-piperidine-amiloride, phenylamil, and uranidil A. an unsubstituted or substituted phenyl, wherein the substitu ent(s) are preferably halogen (chlorine, bromine, fluorine) or lower alkyl (methyl, ethyl, propyl, iso-propyl) and the like, 0207. In certain embodiments, ergotamine alkaloids such amidino or substituted amidino, especially an N,N-di-lower alkyl-imidino, such as N,N-dimethylamidino: X and Y, in as bromocriptine, can be used in the compositions, methods, addition, can be linked together to form a 4-membered carbon and kits of the invention. Bromocriptin analogs are described, chain that can be either unsaturated or Saturated and that can for example, in U.S. Pat. No. 4,145.549. Ergotamine alka be unsubstituted or substituted, and if substituted the substitu liods include 1-methylergotamine, 9,10-dihydroergosine, ent advantageously is a halogen, especially a chloro-atom. R bellataminal, Bellergal, beta-ergoptine, Bromocriptine, dihy represents hydrogen and lower alkyl, R represents hydrogen, droergocornine, dihydroergocristine, , lower alkyl, either saturated or unsaturated and substituted or dihydroergotamine, dihydroergotoxine, ergosine, ergota unsubstituted, the Substituent group(s) preferably being mine, ergovaline, and neo-Secatropin. hydroxyl, aryl, either mono- or di-nuclear aryl, as phenyl or naphthyl, and either unsubstituted or containing one or more Chlorophyllin substituents, especially selected from lower alkyl, definition of substituents, continued Substituents on aryl moiety of aryl 0208. In certain embodiments, a chlorophyllide oranana alkyl group halogen, lower alkyl, lower alkoxy, or any com log thereof can be used in the compositions, methods, and kits bination of these Substituent groups, mono- or di-lower-alky of the invention. Chlorophyllin is a derivative of chlorophyl, lamino, wherein the alkyl groups may be linked to form a and a member of the chlorophyllides. Other chlorophyllides hetero structure with the aminonitrogen to which they are include chlorophyllide a, chlorophyllide b, methylchloro attached Such as to form an azacycloalkyl group, heterocy phyllide A, and methylchlorophyllide B. clic, and especially the pyridyl group, halogen, aryl or Sub stituted aryl, the Substituent group(s) preferably being halo Cytarabine gen, and lower alkyl, heterocyclic, advantageously a pyridyl radical, alkylideneamino, and acyl: R represents hydrogen, 0209. In certain embodiments, cytarabine or an analog lower alkyl, either saturated or unsaturated and substituted or thereof can be used in the compositions, methods, and kits of US 2010/0009970 A1 Jan. 14, 2010

the invention. Cytarabine is an antimetabolic and an antiviral melengestrol acetate, nivaZol, oxyma, pregnadienediols, agent. Cytarabine analogs are described in U.S. Pat. No. pregnadienetriols, rimexolone, Ro 12-2503, Ro 14-9012, Ro 3,116,282. 6-1963, and triamcinolone. Thyroxines Evans Blue 0213. In certain embodiments, a azo dye such as Evans 0210. In certain embodiments, a thyroxine or derivative blue can be used in the compositions, methods, and kits of the thereof can be used in the compositions, methods, and kits of invention. Evans blue is used in blood volume and cardiac the invention. Thyroxines are thyroid hormones and include output measurement by the dye dilution method. It is very levo thyroxine and dextrothyroxine, which has been used as soluble, strongly bound to plasma albumin. The structure of antihyperlipidemic. The formula for dextrathyroxine is: Evans blue is:

4 Na"

OSEO

O

AZetidines 0214. In certain embodiments, an azetidine or derivative thereof Such as eZitamibe can be used in the compositions, methods, and kits of the invention. The structure of eZitamibe I O is: HO

I

0211 Dextrathyroxine can be administered orally and is typically provided in 2 mg or 4 mg tablets. Levothyroxine is used to increase the metabolic rate of cells.

Pregnadienes Analogs of eZitamibe are described, for example, in U.S. Pat. 0212. In certain embodiments, a pregnadiene or an analog No. 5,767,115 and are described by the formula: or derivative thereof Such as dydrogesterone can be used in the compositions, methods, and kits of the invention. Dydrogesterone is a progesterone and used thus to treat X Y Z Arg progesterone deficiency. Pregnadienes include 12-hydroxy Ari 1" N,g 1 n N1g P 3-oxo-1,4-pregnadiene-20-carboxylic acid, 17-benzoyloxy 11-hydroxy-320-dioxo-1,4-pregnadien-21-al hemiacetal, R R3 N 20-carboxy-14-pregnadien-3-one, 20-Succinamylpregna-1, O Ar2 4-dien-3-one, 21-hydroxypregna-1,4-diene-3,11,20-trione, 3alpha-hydroxy-5alpha-pregna-9(11), 16-diene-20-one, where Ar and Ar, are independently selected from the group 3-hydroxy-5.7-pregnadien-20-one, canrenoate potassium, consisting of aryl and Ra-Substituted aryl; Ars is aryl or , , cymegesolate, cyproter Rs-substituted aryl; X, Y and Z are independently selected one, , domoprednate, , GR from the group consisting of —CH2—, —CH(lower alkyl)- 2-1159, icometasone enbutate, medrogestone, megestrol, and —C(dillower alkyl)-; RandR are independently selected US 2010/0009970 A1 Jan. 14, 2010

from the group consisting of —OR —O(CO)R —O(CO) 2-, 3-carboxy-thioxanthone-10,10-dioxide, OR and —O(CO)NRR,; R. and R are independently 4-(beta-diethylaminoethylamino)-1,2-cyclohexenothiaxan selected from the group consisting of hydrogen, lower alkyl thone, 4-(bis(2-chloroethyl)amino)propylamino-1,2-cyclo and aryl; q is 0 or 1, r is 0 or 1; m, n and pare independently hexenothioxanthone, 7-oxo-7-thiomethoxyxanthone-2-car 0, 1, 2, 3 or 4: provided that at least one of q and r is 1, and the boxylic acid, BW 616U76, chlorprothixene, clopenthixol, Sum of m, n, p, q and r is 1, 2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1, the sum of m, q and n is 1, 2, 3, 4 or 5: doxantrazole, flupenthixol, hycanthone, lucanthone, methix R is 1-5 substituents independently selected from the group ene, piflutiXol, , prothixene, quantacure QTX, consisting of lower alkyl, —OR —O(CO)R —O(CO) spasmocanulase, teflutixol, thiothixene, and WIN 33377. OR —O(CH2)5OR —O(CO)NRR-7, NRR-7, NR (CO)R - NR(CO)OR - NR (CO)NRRs, NR Gemcitabine SOR, COOR —CONRR-7, COR. —SONRR, S(O)o-Ro. —O(CH). COOR, —O(CH). 0217. In certain embodiments, gemcitabine or an analog 10CONRR, -(lower alkylene)COOR -CH=CH thereof can be used in the compositions, methods, and kits of COOR —CF, —CN, NO, and halogen; Rs is 1-5 sub the invention. Gemcitabine is a nucleoside with antineoplas stituents independently selected from the group consisting of tic activity. —OR —O(CO)R —O(CO)OR —O(CH2)5OR, 0218. Analogs of gemcitabine are described, for example, –O(CO)NRR, NRR, NR(CO)R, NR(CO) in U.S. Pat. No. 4,808.614 and have the general structure: OR —NR(CO)NR7Rs —NRSOR. - COOR, —CONRR, COR.—SONRR-7, S(O).R.—O(CH) COOR —O(CH2)CONRR-7, -(lower alkylene) COOR and —CH=CH-COOR. R. R., and Rs are inde HO R pendently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; and R is lower alkyl, aryl or aryl-substituted lower alkyl. R is prefer OH F ably 1-3 independently selected substituents, and Rs is pref erably 1-3 independently selected substituents. Preferred are compounds of formula I wherein Ar is phenyl or R-substi wherein R is a base of one of the formulae: tuted phenyl, especially (4-R)-substituted phenyl. Ar is preferably phenyl or R-substituted phenyl, especially (4-R)-substituted phenyl. Ars is preferably Rs-substituted O O phenyl, especially (4-Rs)-substituted phenyl. When Ar is (4-R)-substituted phenyl, P4 is preferably a halogen. When R1, N. : Ar and Ars are Ra- and Rs-Substituted phenyl, respectively, R is preferably halogen or —OR and Rs is preferably O JJ HN J-2s —OR, wherein R is lower alkyl or hydrogen. Especially preferred are compounds wherein each of Ar and Ar is 4-fluorophenyl and Ars is 4-hydroxyphenyl or 4-methox NH2 NH2 yphenyl. R1, N s and 0215. Other azetidines include 1,4-bis(4-methoxyphe nyl)-3-(3-phenylpropyl)-2-azetidinone, 1-(N-(3-ammonio propyl)-N-(n-propyl)amino)diaZen-1-ium-1,2-diolate, O Jr cy4. 1-methyl-2-(3-pyridyl)azetidine, 2-oxo-3-phenyl-1,3-oxaze tidine, 2-tetradecylglycidyl-coenzyme A, 3-(2-oxopropy lidene)aZetidin-2-one, 3-aminonocardicinic acid, 3-phenyl R2 2-methylazetidine-3-ol, 4-(4-carboxyphenyl)oxy)-3.3- diethyl-1-(((phenylmethyl)amino)carbonyl)-2-aZetidinone, N21 SCHR, 4-(3-amino-2-oxoaZetidinonyl-1)methylbenzoic acid, 4-(3- amino-2-oxoaZetidinonyl-1)methylcyclohexanecarboxylic acid, AHR 11748, azetidine, azetidine platinum(II), azetidi 1s. necarboxylic acid, azetidyl-2-carboxylic acid, azetirelin, BDF 91.48, BMS-262084, E 4695, fluzinamide, L 652117, L 684248, N-(2-chloromethylphenyl)-3,3-difluoroazetidin-2- wherein R is hydrogen, methyl, bromo, fluoro, chloro, or one, SCH 60663, SF 2185, tabtoxinine beta-lactam, tazad iodo; R is hydroxy oramino; R is hydrogen, bromo, chloro, olene Succinate, and Ximelagatran. or iodo. Thioxanthanes GW 5074 0216. In certain embodiments, thioxanthanes such as flu pentiXol can be used in the compositions, methods, and kits of 0219. In certain embodiments, GW 5074 or an analog the invention. FlupentiXol is a that acts as a thereof can be used in the compositions, methods, and kits of (D2 receptor) antagonist. Thioxanthane analogs the invention. GW 5074 is a benzylidene-1,3-dihydro-indol are described, for example, in U.S. Pat. No.3,951,961. Thiox 2-one derivative which acts as a receptor kinase anthane analogs include 2-(beta-diethylaminoethylamino)-3, inhibitor (e.g., raf such as cKaf1). The structure of GW 5074 4-cyclohexenothia-Xanthone, 2-chlorothioxanthen-9-one, 1S US 2010/0009970 A1 Jan. 14, 2010 90

Caliphatic, aryl or HET is optionally substituted by one to three of halo, another HET, aryl, CN, —SR —OR, —N(R), —S(O)R. —SOR, —SON(R), —NRCOR —NRCOR —NRCONCR), —NR (NR)NHR, —COR2, —CONCR), —NRSO.R. —OCON(R), where HET and Rare as defined below; R is H or Ro: R2 is H. Caliphatic or HET, said Caliphatic optionally substituted by one to three of halogen or OH where HET is as defined below; and HET is a five to ten-membered saturated or unsaturated het erocyclic ring selected from the group consisting of benzo Analogs of GW 5074 are described, for example, in U.S. Pat. furan, benzoxazole, dioxin, dioxane, dioxolane, dithiane, No. 6,268.391 and have the general structure: dithiazine, dithiazole, dithiolane, furan, , , indazole, morpholine, oxazole, oxadiazole, Oxathiazole, R6 Oxathiazolidine, oxazine, oxiadiazine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyr R R rolidine, quinoline, quinazoline, tetrahydrofuran, tetrazine, tetrazole, thiophene, thiadiazine, thiadiazole, thiatriazole, R "-(f ) thiazine, thiazole, thiomorpholine, thianaphthalene, thiopy O R8 ran, triazine, and triazole; and the pharmaceutically accept able salts, biohydrolyzable esters, biohydrolyzable amides, R3 N biohydrolyzable carbamates, biohydrolyzable , biohydrolyzable ureides, Solvates, hydrates, or prodrugs of the as defined above. wherein R is H or optionally joined with R to form a fused Melphalan ring selected from the group consisting of five to ten mem bered aryl, heteroaryl or heterocyclyl rings, said heteroaryl or 0220. In certain embodiments, melphalan or an analog said heterocyclyl rings having one to three heteroatoms where thereof can be used in the compositions, methods, and kits of Zero to three of said heteroatoms are N and Zero to 1 of said the invention. Melphalan is an alkylating nitrogen mustard heteroatoms are O or Sand where said fused ring is optionally used as an antineoplastic in the form of the levo isomer, substituted by one to three of Ro, where R and R are as melphalan. The racemic mixture is merphalan, and the dextro defined below; R and Rs are independently H, HET, aryl, isomer is medphalan. Melphalan analogs are described, for Caliphatic, CN, NO, halogen, Rio —OR —SRio, example, in U.S. Pat. No. 3,032.584. —S(O)Ro, —SOR, —NRoR, —NRR, —NRCOR. - NRCOR. - NRCONRR, Mosapride —NRSOR, NRC(NR)NHR, —COR, 0221. In certain embodiments, mosapride or an analog —COR, —CONRR, —SONRR, thereof can be used in the compositions, methods, and kits of —OCONRR, C(NR)NRR where said C. ali the invention. Mosapride is a benzamide that acts as a selec phatic optionally bears one or two insertions of one to two tive 5-HT, receptoragonist and is used as a gastroprokinetic. groups selected from C(O), O, S, S(O), SO or NR; with said HET, aryl or Caliphatic being optionally Substituted The structure of mosparide is: by one to three of Rio; and where R is optionally joined with F NH2 R to form a fused ring selected from the group consisting of N-1 five to ten membered aryl, heteroaryl or heterocyclyl rings, H said heteroaryl or said heterocyclyl rings having Zero to three Null C heteroatoms where Zero to three of said heteroatoms are N and Zero to one of said heteroatoms are O or Sand where said O fused ring is optionally substituted by one to three of Rs. where HET, R. R. R. and R2 are as defined below; R is Analogs of mosparide are described, for example, in U.S. Pat. H, halogen, NO or CN; Rs is H or Caliphatic optionally No. 4,870,074 and have the general structure: substituted by one to three of halo, hydroxyl, heteroaryl, or R aryl; R and R, are independently halogen, CN, NO, (R5) in —CONRR, -SO2NRR, —NRR, or —OR, 1n R R3 where RandR areas defined below: Rs is OH, NHSOR (CH2) A.O or NHCOCF, Ro is each independently halogen, Cali phatic, CN, -NO, Rio —OR, —SR, —S(O)Ro, R1 Nullsx1 R4 —SO-Ro. —NRoR —NR, —NRCOR, —NRCOR. - NRCONRR - NRSOR, O —NRC(NR)NHR, —COR, —CONRR, —SONRR, —OCONR,R or C(NR)NRR, wherein R is hydrogen, a C-C alkoxycarbonyl, benzyloxy where Rio, R and R2 are as defined below; Rio is each carbonyl, a heteroaryl(C-C)alkyl in which the heteroaryl is independently H, halogen, Caliphatic, aryl or HET, where furyl, thienyl, pyridyl, or 1.2-benzisoxazolyl, a phenyl (C- said Caliphatic optionally bears an inserted one to two Cs)alkenyl, or -T-(Y), R (wherein T is a single bond or a groups selected from O, S, S(O), SO or NR, where said C-C alkylene, Y is oxygen, Sulfur or carbonyl, R is phenyl,

US 2010/0009970 A1 Jan. 14, 2010 92 carboxylic acid, , nitromide, norcisapride, NP 4-hydroxy-3-methoxycinnamylpiperidine, 4-hydroxycin 101A, pancopride, parsalmide, Pellit, penfluoron, picoben namic acid (1-phenylalanine methyl ester) amide, 4-meth Zide, picobenzide N-oxide, Procainamide, Procarbazine, oxycinnamate methyl ester, 4-methoxycinnamic acid, 5-(2- pronamide, , rebemide, Remoxipride, , (methyl(2-phenethyl)amino)-2-oxoethyl)-2-(benzyloxy) RG-4, RG-7, riparin, Ro 12-5637, Ro 12-8095, Ro 16-3177, cinnamic acid. A 25794, adamon, alpha-cyanocinnamate, Ro 16-6491, roflumilast, S 1688, SC 53116, sirtinol, SNC alpha-methyl-2-hydroxy-4-diethylaminocinnamic acid, 121, spectramide, SR 48968, , T 0070907, tefluben alpha-phenylcinnamate, aminocinnamonitrile, antithiamine Zuron, tegalide, , tonabersat, triflumuron, tri factor, asarumin C, BM 42304, caffeic acids (e.g., 1,1-dim methobenzamide, WAY 100289, YM-08050, Z 338, and ethylallyl caffeic acid ester, 2-S-glutathionylcaffeic acid, 3,4- . dihydroxyphenylpropionic acid, 7-caffeoylloganin, caffeic Octyl Methoxycinnamate acid, caffeic acid phenethyl ester, calceolarioside A, chicoric acid, crenatoside, dehydrodicaffeic acid dilactone, ethyl caf 0223) In certain embodiments, telaprevir or an analog feate, ethyl ferulate, , fukinolic acid, methyl caffeate, thereof can be used in the compositions, methods, and kits of myriceron caffeoyl ester, N-(3,4-diacetoxycinnamoyl)-2- the invention. Octyl methoxycinnamate absorbs ultraviolet pyrrolidone, N-caffeoyl-4-aminobutyric acid, octyl caffeate, (UV) light and is used in Sunscreens and other topical appli petasiphenol, phenylethyl 3-methylcaffeate, Salvianolic acid cations where UV protection is desired. The structure of octyl A, Suspensaside, and Swertiamacroside), caracasanamide, methoxycinnamte is: chlorogenic acid, cinametic acid, or derivatives thereof (e.g., SQ 10631 and SQ 11447), cinnamic acid, cin namic anhydride, cinnamoyl chloride, cinnamyl isobutyrate, cinromide, CKA 1303, clocinnamox, coniferin, coumaric acids (e.g., (3,4-disinapoyl)fructofuranosyl-(6-sinapoyl)glu copyranoside, (3-Sinapoyl)fructofuranosyl-(6-sinapoyl)glu copyranoside, 1-(4-coumaroyl)alpha-rhamnopyranose, 2-hydroxycinnamic acid, 3-coumaric acid, 4-coumaric acid, 4-coumaric acid methyl ester, 4-hydroxycinnamoylmethane, 5-hydroxyferulic acid, 5-O-feruloylarabinose, alpha-cyano Cinnamic acid derivatives are described, for example, in U.S. 3-hydroxycinnamate, alpha-cyano-4-hydroxycinnamate, Pat. No. 5,457.226 and have the general structure: angoroside C, asprelic acid A, coniferyl ferulate, cycloartenol ferulic acid ester, dihydro-3-coumaric acid, ferulic acid, feruloylputrescine, feruloyltyramine, karenin, RO methyl 5-O-feruloylarabinofuranoside, and sinapinic acid), cyclamen aldehyde, cyclamen aldehyde methyl anthranilate, diacetylcymarol, dimethylaminoethyl-alpha-phenylcin namate, Dolo-Adamon, ethyl 2,5-dihydroxycinnamate, ethyl cinnamate, fagaramide, gagaminine, hordatine M, hygromy cin A, , isoferulic acid, kutkin, linusitamarin, maxa wherein R signifies hydrogen or Cs-alkyl and R2 signifies fil, methyl 2,5-dihydroxycinnamate, methyl 3-phenyl-2,3- hydrogen, Co-alkyl, Co-hydroxyalkyl or C-alkoxy epoxypropanoate, methyl 4-(dimethylamino)cinnamate, Co-alkyl. Cinnamic acid derivative include Other cin methyl cinnamate, N,N-dimethylhydrocinnamide, N-hy inmates include (4-(dimethylamino)cinnamoyl)imidazole, droxy-N-methyl-3-(2-(methylthio)phenyl)-2-propenamide, (N-(3,5-dimethoxy-4-n-octyloxycinnamoyl)-N'-(3,4-dim O-(alpha-(benzoylamino)-4-(phenylazo)cinnamoyl)-beta ethylphenyl)piperazine), 1,1-dimethylallyl-3',4'-dihydroxy phenylactate, O-(alpha-(benzoylamino)cinnamoyl)-beta cinnamic acid ester, 2.3-dihydroxycinnamic acid, 2-(4-amyl phenylactate, octylmethoxycinnamate, ONO 8713, penupo cinnamoyl)amino-4-chlorobenzoic acid, 2-chlorocinnamic genin, picroside I, picroside II, or derivative acid, 2-ethylhexyl-4-methoxycinnamate, 2-fluoro-p-hy thereof (e.g. 2'-deoxypuromycin, 4-azidopuromycin, car droxycinnamate, 2-fluorocinnamic acid, 3,4,5-trimethoxy bocyclic puromycin, cyclohexylpuromycin, cytidine-2(3)- cinnamic acid, 3,4-di(OH)-cinnamate, 3,4-dihydroxyhy P-5'-puromycin, methionylpuromycin, N-(2-nitro-4-azido drocinammic acid (1- dibenzyl ester) amide, 3.5- benzoyl)puromycin, N-acetylphenylalanylpuromycin, dihydroxycinnamic acid, 3,5-dimethoxycinnamic acid, 3.7- N-iodoacetylpuromycin, O-demethylpuromycin, puromycin dimethyl-1,6-octadien-3-yl cinnamtae, 3-(3,4- aminonucleoside, and sparsopuromycin), Ro 03-6037, ros dimethoxyphenyl)propenoic acid, 3-(4-hydroxy-3- marinic acid, S8932, SC 1001A, sibirate, SQ10624, ST 638, adamantylbiphenyl-4-yl)acrylic acid, 3-(4-(1,2-diphenylbut SU 1498, tolibut, trans-3-(2-methylphenyl)-2-propene-1- 1-enyl)phenyl)acrylic acid, 3-(4-methoxyphenyl)-2- carboxamide, Vanicoside A, and Vanicoside B. propenoic acid 3-methylbutyl ester, 3-(trifluoromethyl) cinnamide, 3-bromocinnamamide, 3-bromocinnamic acid, Oxeladin 3-fluorocinnamic acid, 4-(3.3-dimethyl-1-triaZeno)cinnamic acid, 4-(3-(1-adamantyl)-4-hydroxyphenyl)-3-chlorocin 0224. In certain embodiments, oxeladin or an analog namic acid, 4-amidinophenyl 2-methylcinnamate, 4-amidi thereof can be used in the compositions, methods, and kits of nophenyl cinnamate, 4-amylcinnamoylanthranilic acid, the invention. Oxeladin is a used as an antitussive agent. The 4-dimethylaminocinnamaldehyde, 4-fluorocinnamic acid, structure of oxeladin is: US 2010/0009970 A1 Jan. 14, 2010 93

N N-1-1-N-N-1 wherein RandR may be the same or different; R is selected from hydrogen, alkyl, Substituted alkyl, cycloalkyl, Substi Oxeladin derivates are described, for example, in U.S. Pat. tuted cycloalkyl, hydroxyalkyl, alkenyl, Substituted alkenyl, No. 2,885.404 and have the general structure: alkynyl. Substituted alkynyl, aryl. Substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, aryla lkenyl, Substituted arylalkenyl, arylalkynyl, Substituted ary lalkynyl, heterocyclic, substituted heterocyclic, trifluorom ethyl, perfluoroalkyl, cyano, cyanomethyl, carboxyl, carbamate, Sulfonyl, Sulfonamide and aryloxyalkyl, or OR, wherein, O is an oxygen; R is selected from hydrogen, alkyl, R substituted alkyl, cycloalkyl, substituted cycloalkyl, hydroxyalkyl, alkenyl, Substituted alkenyl, alkynyl, Substi O N tuted alkynyl, aryl, substituted aryl, alkylaryl, substituted N-1N1-1 YR, alkylaryl, arylalkyl, Substituted arylalkyl, arylalkenyl, Substi tuted arylalkenyl, arylalkynyl, Substituted arylalkynyl, het erocyclic, substituted heterocyclic, trifluoromethyl, perfluo roalkyl, cyano, cyanomethyl, carboxyl, carbamate, Sulfonyl, in which R and R2 are alkyl groups containing together not Sulfonamide and aryloxyalkyl. In certain embodiments, R is more than 12 carbonatoms, or togetherform a cyclic structure hydrogen or optionally substituted lower alkyl; and R is wherein—NRR represents pyrrolidino, piperideino or pip optionally substituted lower alkyl. R and R can be each eridino. The groups R and R may be the same or different. —CH, or each —CH2CH. R can be —CH2CH and R can Particular derivatives include 2-(B-diethylaminoethoxy)ethyl be —CH. R can be —CHCHCH and R can be —CH. diethylphenylacetate, 2-(B-N-pyrrolidinoethoxy)ethyl dieth R can be —CH(CH), and R can be —CH. R. and R2 also ylphenylacetate, 2-(B-N-piperidinoethoxy)ethyl diethylphe can combine with N to form a ring system. Examples of Such combination include —CH2(CH2)CH2—, where n is nylacetate, 2-(B-N-A-piperideinoethoxy)ethyl diethylphe selected from 0 to 5. These ring systems can also have one or nylacetate, 2-(B-N-ethylmethylaminoethoxy)ethyl more substituents selected from alkyl, substituted alkyl, diethylphenylacetate, 2-(B-N-ethylpropylaminoethoxy)ethyl cycloalkyl, Substituted cycloalkyl, hydroxyalkyl, alkenyl, diethylphenylacetate, 2-(B-N-di-n-butylaminoethoxy)ethyl Substituted alkenyl, alkynyl. Substituted alkynyl, aryl, Substi diethylphenylacetate and 2-(B-di-n-hexylaminoethoxy)ethyl tuted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substi diethylphenylacetate. tuted arylalkyl, arylalkenyl, Substituted arylalkenyl, arylalky nyl, substituted arylalkynyl, heterocyclic, substituted Parthenolide heterocyclic, trifluoromethyl, perfluoroalkyl, cyano, cya nomethyl, carboxyl, carbamate, Sulfonyl, Sulfonamide, ary 0225. In certain embodiments, parthenolide or an analog loxyalkyl and halogenas set forth above. This ring system can thereof can be used in the compositions, methods, and kits of also be —CH(CH),CHZ-; where Z is O, S, Se, Si, P. the invention. Parthenolide is a sesquiterpene lactone found in CO . —SO —SO —PO—; and —CH2(CH) plants such as feverfew and Chrysanthemum parthenium. It CH2— are the groups as set forth above. Alternatively, this has anti NFKB activity. The structure of parthenolide is: 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, Si, P. —CO . —SO , —SO or —PO . This ring sys tem can also be a uracil ring and its derivatives with one or more substituents. These ring systems can also have one or more Substituents connected to the carbon atom(s) and/or Z. The substituent is selected from alkyl, substituted alkyl, 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 heterocyclic, trifluoromethyl, perfluoroalkyl, cyano, cya Analogs of parthenolide are described, for example, in U.S. nomethyl, carboxyl, carbamate, Sulfonyl, Sulfonamide, ary Pat. Application Publication No. 2005/0032886 and have the loxyalkyl and halogen as set forth above. These ring systems following structure. can also be aromatic, such as pyrrole, imidazole, purine, and US 2010/0009970 A1 Jan. 14, 2010 94 pyrazole and substituted derivative of these heterocyclics wherein R stands for hydrogen oralkyl, at least one R for the listed above with one or more substituents selected from nitro group and another R for a basic residue, the remaining alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, R representing hydrogen, halogen, or a nitro-, alkyl- or hydroxyalkyl, alkenyl, Substituted alkenyl, alkynyl, Substi alkoxy group, where a “basic residue' is By the term “basic tuted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, Substituted arylalkyl, arylalkenyl, Substi residue' is to be understood in the sense of the foregoing tuted arylalkenyl, arylalkynyl, Substituted arylalkynyl, het formula Such groups contain at least one aliphatically bound erocyclic, substituted heterocyclic, trifluoromethyl, perfluo N-atom and which may be linked to the ring for roalkyl, cyano, cyanomethyl, carboxyl, carboxylate, instance through the medium of oxygen (in the manner of an carboxaldehyde, carboxamide, carbamate, hydroxy, alkoxy, ether), of nitrogen (in the manner of an amine), or of carbon , isothiocyanate, nitro, , , Sulfate, Sul (in the manner of a C-C linkage). Derivatives of quinacrine fonyl, Sulfonamide, thiol, thioalkyl, aryloxyalkyland halogen include acrisuXine, collagenan, dimethylguinacrine, Prepara as set forth above. Any of the above ring systems comprising tion ABP, quinacrine half mustard, and quinacrine mustard. NRR may optionally be fused with another ring to form an optionally substituted bicyclic or tricyclic ring system, each 0227 Quinacrine is an aminoacridine. Other ami of the rings optionally comprising one or more heteroatoms. noacridines include (((amino-2-ethyl)-2-aminomethyl)-2- Preferred ring systems include aziridin-1-yl, azetidin-1-yl, pyridine-6-carboxylhistidyl-gamma-(2-amino-2-deoxyglu pyrrolidin-1-yl, piperidin-1-yl, homopiperidyn-1-yland hep cosyl)glutamylglycylamino)-4-phenyl-1-aminoacridine, (N- tamethyleneimin-1-yl, each being optionally Substituted with (2-((4-((2-((4-(9-acridinylamino)phenyl)amino)-2- one or more Substituents as set forth above. Exemplary par oxoethyl)amino)-4-oxobutyl)amino)-1-(1H-imidazol-4- thenolide derivatives include 11 BH, 13-Dimethylaminopar ylmethyl)-1-oxoethyl)-6-(((-2-aminoethyl)amino)methyl)- thenolide; 113H, 13-Diethylaminoparthenolide; 11 BH,13 2-pyridinecarboxamidato) iron(1 +), 1,2,3,4-tetrahydro-N- (tert-Butylamino)parthenolide; 11 BH, 13-(Pyrrolidin-1-yl) (3-iodophenyl-methyl)-9-acridinamine, 1,2,3,4-tetrahydro parthenolide; 11 BH, 13-(Piperidin-1-yl)parthenolide; 11 BH, N-(phenyl-methyl)-9-acridinamine, 1-nitro-9- 13-(Morpholin-1-yl)parthenolide; 11 BH, 13-(4- (dimethylamino)acridine, 10-N-nonylacridinium orange, Methylpiperidin-1-yl)parthenolide; 11 BH, 13-(4- Methylpiperazin-1-yl)parthenolide; 11 BH,13 2-(3,6-bis(dimethylamino)-10-acridinyl)ethyl-(2,3-di-O- (Homopiperidin-1-yl)parthenolide; 11 BH,13 palmitoylglycero)phosphate, 2-aminoacridone, 3,6-diamino (Heptamethyleneimin-1-yl)parthenolide; 11 BH,13 10-methylacridinium, 3,6-diamino-9-(4-(methylsulfonyl) (AZetidin-1-yl)parthenolide; and 11 BH,13 aminophenyl)aminoacridine, 3-amino-6-methoxy-9-(2- Diallylaminoparthenolide. hydroxyethylamino)acridine, 3-amino-6-methoxyacridine, 3-amino-7-methoxyacridine, 3-amino-9-(diethylaminoeth Quinacrine ylthio)acridine, 3-aminothioacridone, 3-dimethylamino-6- 0226. In certain embodiments, quinacrine or an analog methoxyacridine, 4-(9-acridinylamino)-N-(4-(((4-amino-1- thereof can be used in the compositions, methods, and kits of methylpyrrol-2-yl)carbonyl)amino)-1-methylpyrrol-2- the invention. Quinacrine is an antiparasitic and an antipro carbonyl)glycylaniline, 4-(9-acridinylamino)-N-(glycyl toZoal (e.g., antimalarial) agent. The structure of quinacrine histidyl-lysyl-glycyl)aniline, 9-((6-(4-nitrobenzoyloxy) 1S hexyl)amino)acridine, 9-(2-(2-nitro-1-imidazolyl) ethylamino)acridine, 9-(5-carboxypentylamino)acridine, 9-(6-(2-diazocyclopentadienylcarbonyloxy)hexylamino) acridine, 9-(6-(4-azidobenzamido)hexylamino)acridine, 9-amino-2-hydroxyacridine, 9-amino-3-azido-7-methoxy N acridine, 9-amino-6-chloro-2-methoxyacridine, 9-amino-6- chloroacridine-2-phosphate, 9-aminoacridine-4-carboxam OCH ide, acridine mustard, , acridine yellow, , aminacrine, , C 1310, C 1311, C325, C 2 829, coriphosphine, ethacridine, euchrysine, fluoroquina C N r crine, N-((2-dimethylamino)ethyl)-9-aminoacridine-4-car boxamide, N-((4-dimethylamino)butyl)-9-aminoacridine-4- Analogs of quincrine are described, for example, in U.S. Pat. carboxamide, N-(6-azido-2-methoxy-9-acridinyl)-N'-(9- No. 1,782.272 and have the following structure: acridinyl)octane-1,8-diamine, N-(9-acridinyl) bromoacetamide, Nitracrine, NLA 1, NSC 210733, R , pyracrine phosphate, SDM, Suronacrine, and R, HN1 R, tacrine. R N R Repaglinide 0228. In certain embodiments, repaglinide or an analog R N 2 O R2 thereof can be used in the compositions, methods, and kits of R R the invention. Repaglinide is an antidiabetic agent which lowers levels by closing potassium channels in the b-cell membrane. The structure of repaglinide is: US 2010/0009970 A1 Jan. 14, 2010 95

OH N

Analogs of repaglinide are described, for example, in U.S. Pat. No. 5.312,924 and can be represented as follows:

OR4 Rifabutin analogs are described, for example, in U.S. Pat. No. N 4.219.478, and have the general structure:

wherein R represents an unbranched alkyleneimino group 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 ; R represents a hydrogen atom, an alkyl group with 1 to 7 carbon atoms, a phenyl group optionally substituted by a halogen atom or a methyl or methoxy group, an alkyl group with 1 or 2 carbon atoms Substituted by a hydroxy, alkoxy, alkanoyloxy, tetrahy drofuranyl, tetrahydropyranyl, cycloalkyl orphenyl group, in which the alkoxy part can contain from 1 to 3 carbon atoms, the alkanoyloxy part can contain 2 to 3 carbon atoms and the cycloalkyl part can contain 3 to 7 carbon atoms, an alkenyl group with 3 to 6 carbon atoms, an alkynyl group with 3 to 5 carbon atoms, a carboxy group or an alkoxycarbonyl group with a total of 2 to 5 carbon atoms; R represents a hydrogen atom, a methyl, ethyl or ; and W represents a methyl, hydroxymethyl, formyl, carboxyl, alkoxycarbonyl, where R is selected from the group consisting of linear alkyl cyanomethyl, 2-cyano-ethyl, 2-cyano-ethenyl, carboxym having 4 to 8 carbon atoms, branched alkyl having 4 to 8 ethyl, 2-carboxyethyl, 2-carboxyethenyl, alkoxycarbonylm carbonatoms, alkenyl having 3 or 4 carbon atoms, cycloalkyl ethyl, 2-alkoxycarbonyl-ethyl or 2-alkoxycarbonylethenyl having 3 to 6 carbon atoms, alkoxyalkyl having 3 to 7 carbon atoms, alkyl-furyl having 5 or 6 carbon atoms, alkyl tetrahy group, in which each alkoxy part can contain from 1 to 4 drofuryl having 5 or 6 carbon atoms, alkanoyl having 5 or 6 carbon atoms and can be substituted by a phenyl group; and carbon atoms, and monohaloalkanoyl having 2 to 6 carbon when R is other then hydrogen and/or the radical R contains atoms, and Y is —H or COCH. Other rifamycins include an optically active carbon atom, the enantiomeres and the 16,17-dihydro-17-hydroxyrifamycin S, 16,17-dihydrorifa diastereomeres thereofortheir mixtures; when W is carboxyl, mycin S, 25-deacetoxy-25-hydroxyrifamycin S, 3-((dimeth a non-toxic salt thereof formed with an inorganic or organic ylhydrazono)methyl)rifamycin SV. 3-carbomethoxy rifamy base; or a non-toxic acid addition salt thereof formed by an cin S, 3-formyl-25-desacetylrifamycin, 3-formylrifamycin inorganic or organic acid with the amino function in the SV, 31-homorifamycin W. 4-deoxy-3'-bromopyrido(1.2-1. R-position. 2)imidazo[5.4-crifamycin S, AF 013, benzothiazole-rifamy cin, C 27, CGP 27557, CGP 29861, CGP 4832, CGP 7040, Rifamycins FCE 22250, FCE 22807, halomicin B, kanglemycin A, KRM 1648, KRM 1657, KRM 1668, KRM 1671, protorifamycin I, 0229. In certain embodiments, a rifamycin such as rifabu R 761, reprimun, rifabutin derivatives (e.g., 17-(allylamino)- tin or an analog thereof can be used in the compositions, 17-demethoxygeldanamycin, 25-desacetylrifabutin, and methods, and kits of the invention. Rifamycins are streptovaricin), rifamdin, rifamexil, rifamide, Rifampin or compounds. The structure of rifabutin, an exemplary rifamy derivatives thereof (e.g., 18,19-dihydrorifampicin, C1n, 1S. 25-deacetylrifampicin, 25-desacetylrifapentine, CGP 43371, US 2010/0009970 A1 Jan. 14, 2010 96

CGS 24565, dehydrorifampicin, DMB-, rifampi cin N-oxide, rifapentine, Rifaprim, Rifater, and rivicycline), rifamycin B, rifamycin L, rifamycin O, rifamycin P. rifamy cin Q, rifamycin S. rifamycin SV, rifamycin Verde, rifaximin, rifazone-82, SPA-S 565, streptovaricin derivatives (e.g., damavaricin C, damavaricin Fc pentyl ether, protostreptova (—NCN)—NRR —(C(R)),NRC(O)C(O) NRR, ricin, Streptoval C. Streptovaricin C, and streptovarone), toly —(C(R))NRC(O)C(O)—OR —(C(R)),C pomycin Y, and tolypomycinone. (=NRo)—NRRo, -(C(Ro)), C(=NRo)-ZR —(C (Ro)), OC(Z)-NRRo. —(C(Ro))NRoS(O)CF, SB-2021.90 —(C(Ro))NRC(O)CRio; t is an integer having a value of 0, 1, 2, or 3; Xa is independently —(C(Ro)), —NRs , 0230. In certain embodiments, SB-202190 or an analog —O— or—S-; Z is oxygen or Sulfur, m' is an integer having thereof can be used in the compositions, methods, and kits of a value of 1 or 2; n is an integer having a value of 0 to 10; Rs the invention. SB-202190 is a pyridyl substituted imidazole is hydrogen, C alkyl, C. alkenyl, C. alkynyl, C-7 with selective p38 MAP Kinase (MAPK) inhibitory activity. cycloalkyl, Cs, cycloalkenyl, aryl, or N(R-7), provided that SB-202190 binds to the ATP binding site on active p38 when m is 1 or 2 then Rs is not hydrogen. Reis hydrogen, C. MAPK. The structure of SB-202190 is: alkyl, halo Substituted C. alkyl, Calkenyl, C- alkynyl, C-7 cycloalkyl, Cs, cycloalkenyl, or aryl; R is hydrogen, C. alkyl, C. alkenyl, C. alkynyl, aryl, or may form a F heterocyclic ring of 5 to 7 members together with the nitro gen, said ring optionally containing an additional heteroatom N 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 hydrogen, Clio alkyl, C2-io alkenyl, C2-io alkynyl, C-7 cycloalkyl, Cs, cycloalkenyl, heterocyclic, heterocyclic rN alkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl; R is Nn 2 hydrogen, Clio alkyl, C2-io alkenyl, C2-io alkynyl, C-7 cycloalkyl, Cs, cycloalkenyl, aryl, arylalkyl, heteroaryl, het eroarylalkyl or Rs and R may together form a heterocyclic Analogs of SB-202190 are described, for example, in U.S. ring of 5 to 7 members together with the nitrogen, said ring Pat. No. 6,008,235 and have the structure: optionally containing an additional heteroatom selected from the group consisting of oxygen, Sulfur or nitrogen; Rio is hydrogen, or Calkyl, R is Coalkyl, Coalkenyl, Co R3 N alkynyl, C-7 cycloalkyl, Cs, cycloalkenyl, aryl, aryl alkyl, heteroaryl, heteroarylalkyl; R is hydrogen, Calkyl, aryl. D X-R, or may form a heterocyclic ring of 5 to 7 members together R N with the nitrogen; R is hydrogen, Co alkyl, cycloalkyl, R heterocylic, aryl, aryl alkyl, heteroaryl, or heteroarylalkyl. wherein R is a mono- or di-substituted 4-quinolyl, 4-pyridyl, Fusidic Acid 1-imidazolyl, 1-benzimidazolyl, 4-pyrimidinyl wherein the Substituent is independently selected from the group consist 0231. In certain embodiments, fusidic acid or a derivative ing of hydrogen, C alkyl, halo, O—C alkyl, S Cla thereof (e.g., sodium fusidate) can be used in the composi alkyl, or N(R), R is hydrogen, C alkyl, or R together tions, methods, and kits of the invention. The structure of with the nitrogen, may form a heterocyclic ring of 5 to 7 fusidic acid is: members, said ring optionally containing an additional het eroatom selected from the group consisting of oxygen, Sulfur or nitrogen; R is mono- or di-substituted phenyl wherein the Substituents are independently selected from the group con sisting of hydrogen, halo, S(O).Rs, OR, halo Substituted Calkyl, Calkyl, or N(R), R is hydrogen, Co alkyl, Coalkenyl, Co alkynyl, C-7 cycloalkyl, CS-7 cycloalk enyl, heterocyclic, heterocyclicalkyl, aryl, aryl alkyl, het eroaryl, heteroarylalkyl, R is (X),-(Q)-(Y), X is hydrogen, —(C(Ro)), —NR —O—, or S(O), r is a number hav ing a value of 0 or 1; m is a number having a value of 0, 1 or 2; Q is alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocy clic, heterocyclicalkyl, aryl, arylalkyl, heteroaryl, or het eroarylalkyl; s is a number having a value of 0 or 1; Y is a Substituent selected from the group consisting of hydrogen, Co alkyl, halo-substituted Co alkyl, halogen, —(C(Ro) Fusidic acid derivatives are described in U.S. Pat. Nos. 3,352, 2), ORs, —(C(R).)NO —(C(R)), S(O).R. —(C 854, 3,385,869, 3,376,324, 4,004,004, 4,060,606, 4,162,259, (Ro)), SRs —(C(R)), S(O), ORs, —(C(R)), S(O) 4,315,004, 4,119,717, 6,103,884, and 6,593,319. Derivative NRRo. —X P(Z)-(X,R), —(C(Ro)),NRRo. —(C include 11-monoketofusidic acid, 16-O-deacetylfusidic acid, US 2010/0009970 A1 Jan. 14, 2010 97

16-O-deacetylfusidic acid lactone, 3,11-diketofusidic acid, diethanolamine fusidate, helvolic acid, and tauro-24,25-dihy drofusidate. OH

TOFA H 0232. In certain embodiments, 5-(tetradecyloxy)-2-furan r 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:

Analogs of tolterodine are described, for example, in U.S. Pat. No. 5,382,600 and have the general structure: N-1a1a1a1a1a1a10 O \ W OH

Analogs of TOFA are described, for example, in U.S. Pat. No. 4.382,143 and have the general structure:

x1 A nN.1 Y. Z H O wherein X is selected from the group consisting of hydrogen, wherein R signifies hydrogen or methyl, R. R. and R. C-Cs cycloalkyl, and Substituted or unsubstituted aryl; A is a independently signify hydrogen, methyl, methoxy, hydroxy, divalent radical selected from the group consisting of carbamoyl, Sulphanoylorhalogen, and X represents a tertiary branched or unbranched C-C alkylene, alkenylene, and amino group (-NRR) wherein Rs and R signify non alkynylene;Y is a 5- or 6-membered heteroaryl ring contain aromatic hydrocarbol groups, which may be the same or ing one or more nitrogen, Sulfur, or oxygenatoms and option different and which together contain at least three carbon ally unsubstituted or substituted with one fluoro; and Z is atoms, preferably at least four or five carbon atoms, and selected from the group consisting of hydrogen, hydroxy, where Rs and R may form a ring together with the amine loweralkoxy, loweralkoxyloweralkoxy, diloweralkylami nitrogen, said ring preferably having no other hetero atom noloweralkoxy, (mono- or polyhydroxy)loweralkoxy, that the amine nitrogen. (mono- or polycarboxy)loweralkoxy, (mono- or polycar boxy)hydroxyloweralkoxy, allyloxy, 2,3-epoxypropoxy, Sub Toremifene stituted or unsubstituted-(phenoxy, benzyloxy, or 3-pyridy loxy), pyridylmethoxy, tetrahydropyranyloxy, (mono- or 0234. In certain embodiments, toremifene or an analog polyhydroxy)alkylamino, allylamino, propargylamino, thereof can be used in the compositions, methods, and kits of 2-sulfoethylamino, (mono- or polycarboxyl)loweralky the invention. Toremifene is antiestrogen and antineoplastic lamino, loweralkanoylamino, (Substituted or unsubstituted) agent. The structure of toremifene is: 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.

Tolterodine N-1-1

0233. In certain embodiments, tolterodine or an analog C N 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