PYRIMIDINE COMPOUNDS AND METHODS USING THE SAME

Abstract

The present invention relates to 2-amino-4-arylpyrimidine and 2-amino-4-aryltriazine compounds as inhibitors of heat shock protein 90 family of chaperone proteins. The invention also features pharmaceutical compositions and kits that include the compounds and compositions of the invention. The invention further relates to the medical use of these compounds and compositions for the treatment of a disorder hi a subject. For example, the disorder is a neurodegenerative disease.

Claims

1-17. (canceled)

18. A compound having the formula: ##STR00406## or a pharmaceutically acceptable salt thereof.

19. A compound having the formula: ##STR00407## or a pharmaceutically acceptable salt thereof.

20. A compound having the formula: ##STR00408## or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising the compound of claim 18, or a pharmaceutically acceptable salt thereof, and one or more of pharmaceutically acceptable carriers or excipients.

22-23. (canceled)

24. A method of treating a disorder in a mammal caused by the action of heat shock protein 90 (Hsp90), said method comprising administering an effective amount of the compound of claim 18 or a pharmaceutically acceptable salt thereof to said mammal.

25-26. (canceled)

27. The method of claim 24, wherein said disorder is a neurodegenerative disorder selected from Alzheimer's disease, Huntington's disease, progressive supranuclear palsy, Parkinson's disease, Pick's disease, corticobasal degeneration, chronic traumatic encephalopathy, traumatic brain injury, and frontotemporal dementia.

28. The method of claim 27, wherein said neurodegenerative disorder is Alzheimer's disease.

29-43. (canceled)

44. A method of inhibiting Hsp90, said method comprising contacting a cell with the compound of claim 18 or a pharmaceutically acceptable salt thereof.

45. (canceled)

46. A kit comprising: (i) the pharmaceutical composition of claim 21; and (ii) instructions for use of the pharmaceutical compositions of (i) to treat a disorder in a mammal caused by the action of Hsp90.

47. A pharmaceutical composition comprising the compound of claim 19, or a pharmaceutically acceptable salt thereof, and one or more of pharmaceutically acceptable carriers or excipients.

48. A method of treating a disorder in a mammal caused by the action of Hsp90, said method comprising administering an effective amount of the compound of claim 19 or a pharmaceutically acceptable salt thereof to said mammal.

49. The method of claim 48, wherein said disorder is a neurodegenerative disorder selected from Alzheimer's disease, Huntington's disease, progressive supranuclear palsy, Parkinson's disease, Pick's disease, corticobasal degeneration, chronic traumatic encephalopathy, traumatic brain injury, and frontotemporal dementia.

50. The method of claim 49, wherein said neurodegenerative disorder is Alzheimer's disease.

51. A method of inhibiting Hsp90, said method comprising contacting a cell with the compound of claim 19 or a pharmaceutically acceptable salt thereof.

52. A kit comprising: (i) the pharmaceutical composition of claim 47; and (ii) instructions for use of the pharmaceutical compositions of (i) to treat a disorder in a mammal caused by the action of Hsp90.

53. A pharmaceutical composition comprising the compound of claim 20, or a pharmaceutically acceptable salt thereof, and one or more of pharmaceutically acceptable carriers or excipients.

54. A method of treating a disorder in a mammal caused by the action of Hsp90, said method comprising administering an effective amount of the compound of claim 20 or a pharmaceutically acceptable salt thereof to said mammal.

55. The method of claim 54, wherein said disorder is a neurodegenerative disorder selected from Alzheimer's disease, Huntington's disease, progressive supranuclear palsy, Parkinson's disease, Pick's disease, corticobasal degeneration, chronic traumatic encephalopathy, traumatic brain injury, and frontotemporal dementia.

56. The method of claim 55, wherein said neurodegenerative disorder is Alzheimer's disease.

57. A method of inhibiting Hsp90, said method comprising contacting a cell with the compound of claim 20 or a pharmaceutically acceptable salt thereof.

58. A kit comprising: (i) the pharmaceutical composition of claim 53; and (ii) instructions for use of the pharmaceutical compositions of (i) to treat a disorder in a mammal caused by the action of Hsp90.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0687] FIG. 1 shows a 500 MHz .sup.1H NMR spectrum of compound 20 in CDCl.sub.3.

[0688] FIG. 2 shows a 500 MHz .sup.1H NMR spectrum of compound 34 in CDCl.sub.3.

[0689] FIG. 3 shows a 500 MHz .sup.1H NMR spectrum of compound 36 in CDCl.sub.3.

[0690] FIG. 4 shows five graphs providing IC.sub.50 data for compounds 20, 36, 37, and 39 and for a known Hsp90 inhibitor, as measured using a fluorescence polarization assay described in Example 2.

[0691] FIG. 5A shows a graph comparing relative association/dissociation rates to the concentration of compound 20.

[0692] FIG. 5B is a photograph of a gel demonstrating increase of the expression of Hsp70 at higher concentrations of compound 20 in a cell based functional assay. Further, FIG. 5B shows that expression of Hsp90 remains unchanged relative to variation in the concentration of compound 20.

[0693] FIG. 6A shows a histogram comparing % cell viability in viable cells (VC), cells contacted with compound 20, and cells contacted with a control compound (JNK inhibitor).

[0694] FIG. 6B shows a graph comparing pTau231 levels in viable cells (VC), cells contacted with compound 20, and cells contacted with a control compound (JNK inhibitor).

[0695] FIG. 6C shows a graph comparing pTau396 levels in viable cells (VC), cells contacted with compound 20, and cells contacted with a control compound (JNK inhibitor).

[0696] FIG. 7 shows a graph of the concentration of compound 20 in mouse plasma. The data in this graph excludes the plasma level of compound 20 in animal IRN 12.

[0697] FIG. 8 shows a graph of the concentration of compound 20 in mouse plasma. The data in this graph includes all mouse plasma data points.

[0698] FIG. 9 shows a graph of the concentration of compound 20 in mouse brain tissue. The data in this graph excludes the plasma level of compound 20 in animal IRN 12.

[0699] FIG. 10 shows a graph of the concentration of compound 20 in mouse brain tissue. The data in this graph includes all mouse brain tissue data points.

DETAILED DESCRIPTION

[0700] The invention features novel aminopyrimidines and related compounds having Hsp90 inhibitory activity, pharmaceutical compositions containing them, and their medical use (e.g., treatment of a proliferative disease (e.g., cancer) or a neurodegenerative disease (e.g., a tauopathy)). In particular, the compounds of the invention are capable to penetrate blood-brain-barrier. Therefore, medical use of these compounds encompasses diseases and conditions afflicting mammalian (e.g., human) brain.

[0701] Compounds of the Invention

[0702] Exemplary compounds of the invention are shown in Table 2.

TABLE-US-00002 TABLE 2 [00147] 1 [00148] 2 [00149] 3 [00150] 4 [00151] 5 [00152] 6 [00153] 7 [00154] 8 [00155] 9 [00156] 10 [00157] 11 [00158] 12 [00159] 13 [00160] 14 [00161] 15 [00162] 16 [00163] 17 [00164] 18 [00165] 19 [00166] 20 [00167] 21 [00168] 22 [00169] 23 [00170] 24 [00171] 25 [00172] 26 [00173] 27 [00174] 28 [00175] 29 [00176] 30 [00177] 31 [00178] 32 [00179] 33 [00180] 34 [00181] 35 [00182] 36 [00183] 37 [00184] 40 [00185] 41 [00186] 42 [00187] 43 [00188] 44 [00189] 45 [00190] 46 [00191] 47 [00192] 48 [00193] 49 [00194] 50 [00195] 51 [00196] 52 [00197] 53 [00198] 54 [00199] 55 [00200] 56 [00201] 57 [00202] 58 [00203] 59 [00204] 60 [00205] 61 [00206] 62 [00207] 63 [00208] 64 [00209] 65 [00210] 66 [00211] 67 [00212] 68 [00213] 69 [00214] 70 [00215] 71 [00216] 72 [00217] 73 [00218] 74 [00219] 75 [00220] 76 [00221] 77 [00222] 78 [00223] 79
or a pharmaceutically acceptable salt thereof.

[0703] A non-limiting example of a pharmaceutically acceptable salt of a compound of the invention is:

##STR00224##

[0704] Exemplary methods for synthesizing compounds of the invention are described herein.

[0705] Methods of Preparing Compounds of the Invention

[0706] The compounds of the invention can be prepared by processes analogous to those established in the art, for example, by the reaction sequence shown in Scheme 1. The numbering system used for the general schemes does not necessarily correspond to that employed elsewhere in the description or in the claims.

[0707] As shown in Scheme 1, one strategy to access compounds of the invention (C) is to utilize standard cross-coupling reactions (e.g., Suzuki coupling, Hiyama coupling, Stille coupling, Negishi coupling, Tamao-Kumada coupling, or Murahashi coupling), where a nucleophile A and an electrophile B are coupled in the presence of a metal salt, e.g., a palladium, copper, iron, or nickel salt (e.g., PdCl.sub.2, Pd(OAc).sub.2, CuBr, Cul, (CuOTf).sub.2 toluene complex, Fe(OTf).sub.3, FeCl.sub.3, FeBr.sub.3, NiCl.sub.2, or NiBr.sub.2). Optionally ligands, e.g., a phosphine (e.g., PPh.sub.3, P(2-furyl).sub.3, P(f-Bu).sub.3, dppf, dppb, or BINAP), an N-heterocyclic carbene (e.g., SIMes or SIPr), or di-pyridine (e.g., 2,2′-bipyridyl or 1,10-phenanthroline), may be added to promote the reaction. Alternatively, an organometallic complex, e.g., Pd(PPh.sub.3).sub.4 or (dppf)PdCl.sub.2, may be employed directly with or without additional ligands. Additives, e.g., tetrabutylammonium fluoride, LiCl, KOAc, or AgOTf, may be added to minimize dehalogenation or to facilitate the cross-coupling reaction. One of skill in the art would be able to determine an appropriate solvent for the reaction through standard screening. Non-limiting examples of solvents used in cross-coupling reactions are water, ethanol, acetone, tetrahydrofuran, toluene, 1,4-dioxane, and mixtures thereof. For non-limiting examples of conditions and catalysts that can be used to prepare a compound of the invention according to formula C using cross-coupling chemistry, see Miyaura et al., “Cross-Coupling Reactions: A Practical Guide” in Topics in Current Chemistry, Springer, 2002, and Nicolaou et al., Angew. Chem. Int. Ed., 44:4442-4489, 2005, which are incorporated herein by reference. Alternatively, a compound of formula A may be an electrophile and have a leaving group X instead of M, while compound of formula B may be a nucleophile and have a metal or metalloid group M instead of X.

##STR00225##

[0708] A compound of formula A may be prepared according any method known in the art, e.g., metal-halogen (e.g., lithium-halogen) exchange (with or without a subsequent addition of boron-based, silicon-based, tin-based, zinc-based, or magnesium-based agents), preparation of Grignard reagent, Sandmeyer reaction, or cross-coupling with di-metalloid agent (e.g., Miyaura borylation reaction). Non-limiting examples of preparation of A (Sandmeyer reaction and lithium halogen exchange to prepare E, and Miyaura borylation reaction to prepare G) are shown in Scheme 2.

##STR00226##

[0709] A compound of formula B may be prepared according to any method known in the art, e.g., Biginelli reaction followed by oxidation of the resulting 2-aminodihydropyrimidine derivative. Alternatively, a synthetic approach outlines in Scheme 3 can be used to access a compound of formula B.

##STR00227##

[0710] As shown in Scheme 3, a compound of formula H may undergo condensation with a compound of formula I to give a compound of formula J. The amino group of 2-aminopyrimidine derivative J may then be protected (P=a divalent N-protecting group, two monovalent N-protecting groups, or one monovalent N-protecting group and one hydrogen) to furnish a compound of formula K. The hydroxyl group in the compound of formula K may then be converted to a halogen in the compound of formula L according to any method known in the art, e.g., using dehydrating-halogenating reagents (e.g., POCl.sub.3, PCl.sub.5, SOCl.sub.2, SO.sub.2Cl.sub.2, and brominating or iodinating variants thereof). Alternatively, the hydroxyl group of the compound of formula K may be converted into a pseudohalogen in the compound of formula L using reagents, e.g., Tf.sub.2O, PhNTf.sub.2, PhNNf.sub.2, or P(O)(OR).sub.2Cl, and, optionally, a base (e.g., Et.sub.3N, (iPr).sub.2NEt, or pyridine) and/or catalyst (e.g., 4-dimethylaminopyridine). N-protecting group P may be removed from the compound L before or after the cross coupling shown in Scheme 1 according to methods known in the art (see, e.g., Greene, Protective Groups in Organic Synthesis, 3.sup.rd Edition (John Wiley & Sons, New York, 1999)).

[0711] In the reactions described above, it may be necessary to protect reactive functional groups (e.g., hydroxy, amino, thio, or carboxy groups) to avoid their unwanted participation in the reactions. The incorporation of such groups, and the methods required to introduce and remove them are known to those skilled in the art (for example, Greene, supra). The deprotection step may be the final step in the synthesis such that the removal of protecting groups affords compounds of formula (Ia) as disclosed herein. Starting materials used in any of the schemes above can be purchased or prepared by methods described in the chemical literature, or by adaptations thereof, using methods known by those skilled in the art. The order in which the steps are performed can vary depending on the groups introduced and the reagents used, but would be apparent to those skilled in the art.

[0712] Compounds of any of formula (I), (Ia), (Ib), (Va), or (Vb), or any of the intermediates described in the schemes above, can be further derivatized by using one or more standard synthetic methods known to those skilled in the art. Such methods can involve substitution, oxidation or reduction reactions. These methods can also be used to obtain or modify compounds of formula (I), (Ia), (Ib), (Va), or (Vb), or any preceding intermediates by modifying, introducing or removing appropriate functional groups. Particular substitution approaches include alkylation, arylation, heteroarylation, acylation, thioacylation, halogenation, sulphonylation, nitration, formylation, hydrolysis, and coupling procedures. These procedures can be used to introduce a functional group onto the parent molecule (e.g., the nitration or sulphonylation of aromatic rings) or to couple two molecules together (for example to couple an amine to a carboxylic acid to afford an amide; or to form a carbon-carbon bond between two heterocycles). For example, alcohol or phenol groups can be converted to ether groups by coupling a phenol with an alcohol in a solvent, e.g., tetrahydrofuran in the presence of a phosphine (e.g., triphenylphosphine) and a dehydrating agent (e.g., diethyl-, diisopropyl-, ordimethylazodicarboxylate). Alternatively, ether groups can be prepared by deprotonation of an alcohol, using a suitable base (e.g., sodium hydride) followed by the addition of an alkylating agent (e.g., an alkyl halide or an alkylsulphonate).

[0713] In another example, a primary or secondary amine can be alkylated using a reductive alkylation process. For example, the amine can be treated with an aldehyde and a borohydride (e.g., sodium triacetoxyborohydride, or sodium cyanoborohydride) in a solvent (e.g., a halogenated hydrocarbon, for example, dichloromethane, or an alcohol, for example, ethanol) and, where necessary, in the presence of an acid (e.g., acetic acid).

[0714] In another example, —OH groups may be generated from the corresponding ester, acid, acid chloride or aldehyde by reduction with a suitable reducing agent, e.g., a complex metal hydride, e.g., lithium aluminium hydride in a solvent (e.g., tetrahydrofuran).

[0715] In another example, hydroxy groups (including phenolic OH groups) can be converted into leaving groups, e.g., halogen atoms or sulphonyloxy groups (e.g., alkylsulphonyloxy, e.g., trifluoromethylsulphonyloxy, or arylsuphonyl, e.g., p-toluenesulphonyloxy) using conditions known to those skilled in the art. For example, an aliphatic alcohol can be reacted with thionyl chloride in a halogenated hydrocarbon (e.g., dichloromethane) to afford the corresponding alkylchloride. A base (e.g., triethylamine) can also be used in the reaction.

[0716] In another example, ester groups can be converted to the corresponding carboxylic acid by acid- or base-catalysed hydrolysis depending on the nature of the ester group. Acid catalysed hydrolysis can be achieved by treatment with an organic or inorganic acid (e.g., trifluoroacetic acid in an aqueous solvent, or a mineral acid, e.g., hydrochloric acid in a solvent, e.g., dioxan). Base catalysed hydrolysis can be achieved by treatment with an alkali metal hydroxide (e.g., lithium hydroxide in an aqueous alcohol, e.g., methanol).

[0717] In another example, aromatic halogen substituents in the compounds may be subjected to halogen-metal exchange by treatment with a base (e.g., a lithium base, e.g., n-butyl or t-butyl lithium) optionally at a low temperature (e.g., −78° C.) in a solvent (e.g., tetrahydrofuran) and the mixture may then quenched with an electrophile to introduce a desired substituent. Thus, for example, a formyl group can be introduced by using dimethylformamide as the electrophile. Aromatic halogen substituents can also be subjected to palladium catalysed reactions to introduce groups, e.g., carboxylic acids, esters, cyano, or amino substituents.

[0718] In another example, aromatic halogen substituents in the compounds may participate in a range of metal catalysed reactions to introduce alternative functional groups, e.g., amines, amides, ethers, thiols, aryl groups, or heteroaryl groups.

[0719] Particular oxidation approaches include dehydrogenations and aromatisation, and the addition of oxygen to certain functional groups. For example, aldehyde groups can be prepared by oxidation of the corresponding alcohol using conditions well known to those skilled in the art. For example, an alcohol can be treated with an oxidising agent (e.g., the Dess-Martin reagent) in a solvent (e.g., a halogenated hydrocarbon, for example dichloromethane). Alternative oxidising conditions can be used, e.g., treatment with oxalyl chloride and an activating amount of dimethylsulphoxide and subsequent quenching by the addition of an amine (e.g., triethylamine). Such a reaction can be carried out in an appropriate solvent (e.g., a halogenated hydrocarbon, for example dichloromethane) and under appropriate conditions (e.g., cooling below room temperature, e.g., to −78° C. followed by warming to room temperature). In another example, sulphur atoms can be oxidised to the corresponding sulphoxide or sulphone using an oxidising agent (e.g., a peroxy acid, e.g., 3-chloroperoxybenzoic acid) in an inert solvent (e.g., a halogenated hydrocarbon, e.g., dichloromethane) at around ambient temperature.

[0720] Particular reduction approaches include the removal of oxygen atoms from particular functional groups, saturation (or partial saturation) of unsaturated compounds including aromatic rings. For example, primary alcohols can be generated from the corresponding ester or aldehyde by reduction, using a metal hydride (e.g., lithium aluminium hydride or sodium borohydride in a solvent, e.g., methanol). Alternatively, —OH groups can be generated from the corresponding carboxylic acid by reduction, using a metal hydride (e.g., lithium aluminium hydride in a solvent, e.g., tetrahydrofuran). In another example, a nitro group may be reduced to an amine by catalytic hydrogenation in the presence of a metal catalyst (e.g., palladium on a solid support, e.g., carbon) in a solvent (e.g., an ether, e.g., tetrahydrofuran, or an alcohol, e.g., methanol), or by chemical reduction using a metal (e.g., tin or iron) in the presence of an acid (e.g., hydrochloric acid). In a further example an amine can be obtained by reduction of a nitrile, e.g., by catalytic hydrogenation in the presence of a metal catalyst (e.g., palladium on a solid support, e.g., carbon), or Raney nickel in a solvent (e.g., tetrahydrofuran) and under suitable conditions (e.g., cooling to below room temperature, e.g., to −78° C., or heating, e.g., to reflux).

[0721] Pharmaceutical Compositions

[0722] The compounds used in the methods described herein are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for administration in vivo. Pharmaceutical compositions typically include a compound as described herein and a pharmaceutically acceptable excipient.

[0723] The compounds described herein can also be used in the form of the free base, in the form of salts, zwitterions, solvates, or as prodrugs, or pharmaceutical compositions thereof. All forms are within the scope of the invention. The compounds, salts, zwitterions, solvates, prodrugs, or pharmaceutical compositions thereof, may be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. The compounds used in the methods described herein may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump, or transdermal administration, and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0724] For human use, a compound of the invention can be administered alone or in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions for use in accordance with the present invention thus can be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries that facilitate processing of compounds of Formula (I), (Ia), (Ib), (Va), or (Vb) into preparations which can be used pharmaceutically.

[0725] This invention also includes pharmaceutical compositions which can contain one or more pharmaceutically acceptable carriers. In making the pharmaceutical compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semisolid, or liquid material (e.g., normal saline), which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, and soft and hard gelatin capsules. As is known in the art, the type of diluent can vary depending upon the intended route of administration. The resulting compositions can include additional agents, e.g., preservatives.

[0726] The excipient or carrier is selected on the basis of the mode and route of administration. Suitable pharmaceutical carriers, as well as pharmaceutical necessities for use in pharmaceutical formulations, are described in Remington: The Science and Practice of Pharmacy, 21.sup.st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005), a well-known reference text in this field, and in the USP/NF (United States Pharmacopeia and the National Formulary). Examples of suitable excipients are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents, e.g., talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents, e.g., methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. Other exemplary excipients are described in Handbook of Pharmaceutical Excipients, 6.sup.th Edition, Rowe et al., Eds., Pharmaceutical Press (2009).

[0727] These pharmaceutical compositions can be manufactured in a conventional manner, e.g., by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Methods well known in the art for making formulations are found, for example, in Remington: The Science and Practice of Pharmacy, 21.sup.st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005), and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York. Proper formulation is dependent upon the route of administration chosen. The formulation and preparation of such compositions is well-known to those skilled in the art of pharmaceutical formulation. In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh.

[0728] Dosages

[0729] The dosage of the compound used in the methods described herein, or pharmaceutically acceptable salts or prodrugs thereof, or pharmaceutical compositions thereof, can vary depending on many factors, e.g., the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and extent of the symptoms; the frequency of the treatment, and the type of concurrent treatment, if any; and the clearance rate of the compound in the animal to be treated.

[0730] One of skill in the art can determine the appropriate dosage based on the above factors. The compounds used in the methods described herein may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. In general, a suitable daily dose of a compound of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0731] A compound of the invention may be administered to the patient in a single dose or in multiple doses. When multiple doses are administered, the doses may be separated from one another by, for example, 1-24 hours, 1-7 days, 1-4 weeks, or 1-12 months. The compound may be administered according to a schedule or the compound may be administered without a predetermined schedule. An active compound may be administered, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times per day, every 2.sup.nd, 3.sup.rd, 4.sup.th, 5.sup.th, or 6.sup.th day, 1, 2, 3, 4, 5, 6, or 7 times per week, 1, 2, 3, 4, 5, or 6 times per month, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times per year. It is to be understood that, for any particular subject, specific dosage regimes should be adjusted overtime according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.

[0732] While the attending physician ultimately will decide the appropriate amount and dosage regimen, an effective amount of a compound of the invention may be, for example, a total daily dosage of, e.g., between 0.05 mg and 3000 mg of any of the compounds described herein. Alternatively, the dosage amount can be calculated using the body weight of the patient. Such dose ranges may include, for example, between 10-1000 mg (e.g., 50-800 mg). In some embodiments, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of the compound is administered.

[0733] In the methods of the invention, the time period during which multiple doses of a compound of the invention are administered to a patient can vary. For example, in some embodiments doses of the compounds of the invention are administered to a patient over a time period that is 1-7 days; 1-12 weeks; or 1-3 months. In other embodiments, the compounds are administered to the patient over a time period that is, for example, 4-11 months or 1-30 years. In other embodiments, the compounds are administered to a patient at the onset of symptoms. In any of these embodiments, the amount of compound that is administered may vary during the time period of administration. When a compound is administered daily, administration may occur, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times per day.

[0734] Formulations

[0735] A compound identified as capable of treating any of the conditions described herein, using any of the methods described herein, may be administered to patients or animals with a pharmaceutically-acceptable diluent, carrier, or excipient, in unit dosage form. The chemical compounds for use in such therapies may be produced and isolated by any standard technique known to those in the field of medicinal chemistry. Conventional pharmaceutical practice may be employed to provide suitable formulations or compositions to administer the identified compound to patients suffering from a disease in which necrosis occurs. Administration may begin before the patient is symptomatic.

[0736] Exemplary routes of administration of the compounds (e.g., the compounds having Formula (I), (Ia), (Ib), (Va) or (Vb)), or pharmaceutical compositions thereof, used in the present invention include oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intra-arterial, intracranial, subcutaneous, intraorbital, intraventricular, intraspinal, intraperitoneal, intranasal, inhalation, and topical administration. The compounds desirably are administered with a pharmaceutically acceptable carrier. Pharmaceutical formulations of the compounds described herein formulated for treatment of the disorders described herein are also part of the present invention.

[0737] Formulations for Oral Administration

[0738] The pharmaceutical compositions contemplated by the invention include those formulated for oral administration (“oral dosage forms”). Oral dosage forms can be, for example, in the form of tablets, capsules, a liquid solution or suspension, a powder, or liquid or solid crystals, which contain the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.

[0739] Formulations for oral administration may also be presented as chewable tablets, as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.

[0740] Controlled release compositions for oral use may be constructed to release the active drug by controlling the dissolution and/or the diffusion of the active drug substance. Any of a number of strategies can be pursued in order to obtain controlled release and the targeted plasma concentration versus time profile. In one example, controlled release is obtained by appropriate selection of various formulation parameters and ingredients, including, e.g., various types of controlled release compositions and coatings. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes. In certain embodiments, compositions include biodegradable, pH, and/or temperature-sensitive polymer coatings.

[0741] Dissolution or diffusion controlled release can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of compounds, or by incorporating the compound into an appropriate matrix. A controlled release coating may include one or more of the coating substances mentioned above and/or, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2-hydroxymethacrylate, methacrylate hydrogels, 1,3 butylene glycol, ethylene glycol methacrylate, and/or polyethylene glycols. In a controlled release matrix formulation, the matrix material may also include, e.g., hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and/or halogenated fluorocarbon.

[0742] The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils, e.g., cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0743] Formulations for Buccal Administration

[0744] Dosages for buccal or sublingual administration typically are 0.1 to 500 mg per single dose as required. In practice, the physician determines the actual dosing regimen which is most suitable for an individual patient, and the dosage varies with the age, weight, and response of the particular patient. The above dosages are exemplary of the average case, but individual instances exist wherein higher or lower dosages are merited, and such are within the scope of this invention.

[0745] For buccal administration, the compositions may take the form of tablets, lozenges, etc. formulated in a conventional manner. Liquid drug formulations suitable for use with nebulizers and liquid spray devices and electrohydrodynamic (EHD) aerosol devices will typically include a compound of the invention with a pharmaceutically acceptable carrier. Preferably, the pharmaceutically acceptable carrier is a liquid, e.g., alcohol, water, polyethylene glycol, or a perfluorocarbon. Optionally, another material may be added to alter the aerosol properties of the solution or suspension of compounds of the invention. Desirably, this material is liquid, e.g., an alcohol, glycol, polyglycol, or a fatty acid. Other methods of formulating liquid drug solutions or suspension suitable for use in aerosol devices are known to those of skill in the art (see, e.g., Biesalski, U.S. Pat. No. 5,112,598 and Biesalski, U.S. Pat. No. 5,556,611, each of which is herein incorporated by reference).

[0746] Formulations for Nasal or Inhalation Administration

[0747] The compounds may also be formulated for nasal administration. Compositions for nasal administration also may conveniently be formulated as aerosols, drops, gels, and powders. The formulations may be provided in a single or multidose form. In the case of a dropper or pipette, dosing may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved, for example, by means of a metering atomizing spray pump.

[0748] The compounds may further be formulated for aerosol administration, particularly to the respiratory tract by inhalation and including intranasal administration. The compound will generally have a small particle size for example on the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant, e.g., a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide, or other suitable gas. The aerosol may conveniently also contain a surfactant, e.g., lecithin. The dose of drug may be controlled by a metered valve. Alternatively, the active ingredients may be provided in a form of a dry powder, e.g., a powder mix of the compound in a suitable powder base, e.g., lactose, starch, and starch derivatives, e.g., hydroxypropylmethyl cellulose, and polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatin or blister packs from which the powder may be administered by means of an inhaler.

[0749] Aerosol formulations typically include a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a unitary dispensing device, e.g., a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant, which can be a compressed gas, e.g., compressed air or an organic propellant, e.g., fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomizer.

[0750] Formulations for Parenteral Administration

[0751] The compounds described herein for use in the methods of the invention can be administered in a pharmaceutically acceptable parenteral (e.g., intravenous or intramuscular) formulation as described herein. The pharmaceutical formulation may also be administered parenterally (intravenous, intramuscular, subcutaneous or the like) in dosage forms or formulations containing conventional, non-toxic pharmaceutically acceptable carriers and adjuvants. In particular, formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. For example, to prepare such a composition, the compounds of the invention may be dissolved or suspended in a parenterally acceptable liquid vehicle. Among acceptable vehicles and solvents that may be employed are water, water adjusted to a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1,3-butanediol, Ringer's solution and isotonic sodium chloride solution. The aqueous formulation may also contain one or more preservatives, for example, methyl, ethyl or n-propyl p-hydroxybenzoate. Additional information regarding parenteral formulations can be found, for example, in the United States Pharmacopeia-National Formulary (USP—NF), herein incorporated by reference.

[0752] The parenteral formulation can be any of the five general types of preparations identified by the USP-NF as suitable for parenteral administration: [0753] (1) “Drug Injection:” a liquid preparation that is a drug substance (e.g., a compound of Formula (I), (Ia), (Ib), (Va) or (Vb)), or a solution thereof; [0754] (2) “Drug for Injection:” the drug substance (e.g., a compound of Formula (I), (Ia), (Ib), (Va) or (Vb)) as a dry solid that will be combined with the appropriate sterile vehicle for parenteral administration as a drug injection; [0755] (3) “Drug Injectable Emulsion:” a liquid preparation of the drug substance (e.g., a compound of Formula (I), (Ia), (Ib), (Va) or (Vb)) that is dissolved or dispersed in a suitable emulsion medium; [0756] (4) “Drug Injectable Suspension:” a liquid preparation of the drug substance (e.g., a compound of Formula (I), (Ia), (Ib), (Va) or (Vb)) suspended in a suitable liquid medium; and [0757] (5) “Drug for Injectable Suspension:” the drug substance (e.g., a compound of Formula (I), (Ia), (Ib), (Va) or (Vb)) as a dry solid that will be combined with the appropriate sterile vehicle for parenteral administration as a drug injectable suspension.

[0758] Exemplary formulations for parenteral administration include solutions of the compound prepared in water suitably mixed with a surfactant, e.g., hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21.sup.st Ed., Gennaro, Ed., Lippencott Williams & Wlkins (2005) and in The United States Pharmacopeia: The National Formulary (USP 36 NF31), published in 2013.

[0759] Formulations for parenteral administration may, for example, contain excipients, sterile water, or saline, polyalkylene glycols, e.g., polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes. Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds. Other potentially useful parenteral delivery systems for compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.

[0760] The parenteral formulation can be formulated for prompt release or for sustained/extended release of the compound. Exemplary formulations for parenteral release of the compound include: aqueous solutions, powders for reconstitution, cosolvent solutions, oil/water emulsions, suspensions, oil-based solutions, liposomes, microspheres, and polymeric gels.

[0761] Methods of Treatment

[0762] The compounds and compositions described herein can be used in the treatment of conditions and disorders in which Hsp90 has been implicated, e.g., cell proliferative disorders, e.g., cancers, neurodegenerative diseases, e.g., tauopathies (e.g., Alzheimer's disease), and infectious diseases.

[0763] Cell Proliferative Disorders

[0764] Hsp90 has emerged as a key therapeutic target for cancer therapy due to the involvement of this multichaperone complex in various pathogenic cellular processes. Hsp90 client proteins include those implicated in: acute myeloid leukemia (Flt-3), breast cancer (HER2), chronic lymphoid leukemia (Zap70), chronic myeloid leukemia (Bcr-Abl or mBcr-Abl), gastrointestinal stromal tumor (c-Kit), gastric cancer (c-Met), glioblastoma (mutant EGFR orc-Met), lung cancer (c-Met), lymphoma (NMP-ALK), melanoma (Raf-1/mutant BRAF), myeloma (IGF-1R/Akt), non-small cell lung cancer (mutant EGFR), renal cancer, (HIF-1α), and small cell lung cancer (Akt). The compounds of the invention are particularly useful in the treatment of brain tumors due to their blood-brain-barrier penetrant properties. Brain tumors that may be treated using compounds of the invention include glioma or meningioma, in particular, glioma (e.g., glioblastoma) or neuroblastoma. The brain tumors (e.g., brain cancers) that may be treated using compounds of the invention according to the methods of the invention may include primary tumors (those tumors that originated in the brain) and metastatic tumors (those tumors that originated in tissues other than brain tissues and spread to the brain). Still other cell proliferative disorders that may be treated by the inhibition of Hsp90 include: blast-phase chronic myelogenous leukemia, leukemia, lymphoproliferative disorder, metastatic melanoma, multiple myeloma (e.g., relapsed or refractory multiple myeloma), myeloproliferative disorders, pancreatic cancer, small intestine cancer, and solid tumor. Moreover, cancer cells have been shown to be more sensitive to Hsp90 inhibition than non-pathogenic cells. Accordingly, the compounds described herein may be useful treatments for cell proliferative disorders.

[0765] Neurodegenerative Diseases

[0766] Increased levels of Hsp90 have been implicated in neurodegenerative disorders. For example, aberrant Hsp90 activity has been shown in tauopathies, which are conditions characterized by accumulation of abnormal Tauproteins (e.g., hyperphosphorylated and aggregated Tau). Accordingly, compounds and compositions described herein can be useful for the treatment of neurodegenerative diseases and tauopathies that include Alzheimer's disease (AD), argyrophilic grain disease, amyotrophic lateral sclerosis, corticobasal degeneration, dementia pugislistica, Down's syndrome, familial British dementia, frontal lobe degeneration (dementia lacking distinctive histopathological features), chronic traumatic encephalopathy, traumatic brain injury, frontotemporal dementia (FTD; e.g., fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP-17)), hippocampal tauopathy in cerebral aging, myotonic dystrophy of type I, Niemann-Pick disease of type C, Parkinson's disease (e.g., parkinsonism-dementia complex of Guam, Parkinsonism with dementia of Guadeloupe, or postencephalitic parkinsonism), Pick's disease (PiD), and progressive supranuclear palsy. Accordingly, the compounds described herein may be useful in treating a neurodegenerative disorder, e.g., tauopathy (e.g., Alzheimer's disease).

[0767] Infectious Diseases

[0768] Hsp90 has emerged as a therapeutic target for treating infectious diseases, e.g., viral infections, fungal infections, and bacterial infections. Many pathogens (e.g., viruses, fungi, and bacteria) rely on Hsp90-dependent processes (see, e.g., Geller et al., Biochim. Biophys. Acta-Mol. Cell Res., 1823:698-706, 2012; the disclosure of which is incorporate herein in its entirety). Thus, inhibition of Hsp90 provides a therapeutic benefit to a patient afflicted with an infection that relies on the activity of Hsp90. For example, an Hsp90 inhibitor (geldanamycin) was shown to delay the growth of influenza virus in cell culture. Other viruses that rely on Hsp90 dependent processes include those belonging to the families: Herpesviridae (e.g., herpes simplex virus-1, herpes simplex virus-2, herpes herpesvirus-5, Kaposi's sarcoma-associated herpesvirus, varicella zoster virus, or Epstein-Barr virus), Polyomaviridae (e.g., SV40), Poxviridae (e.g., vaccinia virus), Reoviridae (e.g., rotavirus), Birnaviridae (e.g., infectious bursal disease virus), Picornaviridae (e.g., poliovirus, rhinovirus, or coxsackievirus), Flaviviridae (e.g., hepatitis C virus or dengue virus), Arenaviridae (e.g., lymphocytic choriomeningitis virus), Hepeviridae (e.g., Hepatitis E virus), Rhabdoviridae (e.g., vesicular stomatitis virus), Paramoxyviridae (e.g., human parainfluenza virus 2, human parainfluenza virus 3, SV5, SV41, measles virus, or Sendai virus), Bunyaviridae (e.g., La Crosse virus), Orthomoxyviridae (e.g., influenza A virus), Filoviridae (e.g., Ebola virus), Retroviridae (e.g., HTLV1 or HIV1), and Hepadnaviridae (e.g., hepatitis B virus). Hsp90 inhibitors have also been used in vivo for the treatment of fungal infectious diseases, e.g., treatment of Candida albicans, Aspergillus fumigates, or Pneumocystis jiroveci. Moreover, Hsp90 inhibitors are also useful in the treatment of bacterial infections, e.g., mycobacteria, anthrax, or bacterial pneumonia. A discussion of the diseases that may be treated with Hsp90 inhibitors is provided in the U.S. Patent Application Publication 2011/0201587, the disclosure of which is incorporated herein by reference in its entirety. Therefore, the compounds of the invention may be used according to the method of the invention to treat infectious diseases, e.g., viral infections, fungal infections, or bacterial infections.

[0769] Inflammatory and Autoimmune Diseases, Allergy

[0770] Hsp90 has been shown to play a role in antigen presentation, activation of lymphocytes, macrophages, maturation of dendritic cells, and in the enhanceosome mediated induction of inflammation. Hsp90 inhibition is associated with blockage of components of inflammation, e.g., reduction of cytokine and NO production, as well as blockage of NFκB nuclear translocation. Further, considerable body of work indicates that chaperones, such as Hsp90, may be capable of inducing the production of proinflammatory cytokines by the monocyte-macrophage system and the activation and maturation of dendritic cells via the TLR2- and 4-signal transduction pathways. Thus, Hsp90 apparently can function as a potent activator of the innate immune system. Indeed, elevated levels of Hsp90 were detected in the serum of systemic lupus erythematosus patients. Autoantibodies and cells reactive to Hsp have been detected in patients with rheumatoid arthritis. Antiinflammatory effect of inhibiting Hsp90 was also observed to reduce airway inflammation in murine model of asthma. The compounds of the invention may be applicable to the treatment of inflammatory or autoimmune diseases in a patient. Moreover, anti-inflammatory effect of Hsp90 inhibition can have therapeutic application in the treatment of allergies. Thus, the compounds of the invention may be used in the treatment of allergy.

[0771] Cardiovascular Diseases

[0772] Hsp90 has recently been implicated in etiology of cardiovascular disorders, such as atherosclerosis and cardiomyopathy. Thus, the compounds of the present invention may be applicable to the treatment of cardiovascular diseases (e.g., atherosclerosis or cardiomyopathy).

[0773] Kits of the Invention

[0774] The present invention also provides kits containing (i) a pharmaceutical composition of the invention, and (ii) instructions for use of the pharmaceutical composition to treat a disorder in a mammal caused by the action of Hsp90, e.g., a neurodegenerative disorder, a proliferative disorder, or an infectious disease, as described herein. Kits of the invention may include instructions explaining how a practitioner (e.g., a physician, a nurse, a care-giver, or a patient) may administer the composition contained therein. The pharmaceutical composition within the kit of the invention may be provided in a container (e.g., a bottle, an ampule, a tube, or a blister pack). Furthermore, the kits may also include additional components, e.g., instructions or administration schedules for a patient suffering from a neurodegenerative disease or a proliferative disease, and optionally, a device(s) for administering the pharmaceutical composition (e.g., a syringe).

[0775] The following examples are meant to illustrate the invention. They are not meant to limit the invention in any way.

EXAMPLES

Example 1. Synthesis of the Compounds of the Invention

[0776] ##STR00228##

4-(5,7-Dichloro-2,3-dihydrobenzofuran-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (20). A mixture of

[0777] 5,7-dichloro-2,3-dihydro-1-benzofuran-4-yl boronic acid (233 mg, 1.0 mmol), 4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine (219 mg, 1.3 mmol), sodium carbonate (318 mg, 3.0 mmol), palladium tetrakis(triphenylphosphine), and dioxane/water (9/5, 14 ml) was stirred at 90° C. under argon for 20 h, then cooled down to room temperature, quenched with brine (25 ml), and extracted with ethyl acetate (30 ml×2). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel using cyclohexane/ethyl acetate (100/0 to 30/70, 15 min) to give a product as a white solid (230 mg, 72%). .sup.1H NMR (500 MHz, CDCl.sub.3): δ 8.01 (s, 1H), 7.45 (t, J=3 Hz, 1H), 7.34 (s, 1H), 6.46 (m, 1H), 4.83 (s, 2H), 4.71 (m, 2H), 3.60 (m, 1H), 2.94 (m, 1H); LCMS [M+H].sup.+: 321.0 (calcd for [C.sub.14H.sub.10Cl.sub.2N.sub.4O+H].sup.+: 321.0).

[0778] The following compounds of the invention have been prepared according to the procedure described herein.

##STR00229##

[0779] 4-(5,7-Dichloro-2,3-dihydrobenzofuran-4-yl)-N,6-dimethylpyrimidin-2-amine(3). .sup.1H NMR (500 MHz, CDCl.sub.3): δ 7.25 (s, 1H), 6.57 (s, 1H), 5.07 (d, J=10 Hz, 1H), 4.68 (t, J=9 Hz, 2H), 3.29 (t, J=9 Hz, 2H), 3.02 (d, J=10 Hz, 3H), 2.40 (s, 3H).

##STR00230##

[0780] 4-(5,7-Dichloro-2,3-dihydrobenzofuran-4-yl)-N,N,6-trimethylpyrimidin-2-amine(4). .sup.1H NMR (500 MHz, CDCl.sub.3): δ 7.25 (s, 1H), 6.51 (s, 1H), 4.67 (t, J=9 Hz, 2H), 3.30 (t, J=9 Hz, 2H), 3.20 (s, 6H), 2.40 (s, 3H).

##STR00231##

[0781] 4-(5,7-Dichloro-2,3-dihydrobenzofuran-4-yl)-6-methylpyrimidin-2-amine(5). .sup.1H NMR (500 MHz, CDCl.sub.3): δ 7.27 (s, 1H), 6.64 (s, 1H), 5.04 (s, 2H), 4.68 (t, J=9 Hz, 2H), 3.25 (t, J=9 Hz, 2H), 2.42 (s, 3H).

##STR00232##

[0782] 4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-6-ethylpyrimidin-2-amine (6). .sup.1H NMR (500 MHz, CDCl.sub.3): δ 7.27 (s, 1H), 6.65 (s, 1H), 5.05 (s, 2H), 4.68 (t, J=9 Hz, 2H), 3.26 (t, J=8.5 Hz, 2H), 2.68 (q, J=8 Hz, 2H), 1.29 (t, J=7.5 Hz, 3H); LCMS [M+H].sup.+: 310.1 (calcd for [C14H13Cl2N3O+H].sup.+: 310.04).

##STR00233##

[0783] 4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-6-isopropylpyrimidin-2-amine (7). .sup.1H NMR (500 MHz, CDCl.sub.3): δ 7.28 (s, 1H), 6.66 (s, 1H), 5.04 (s, 2H), 4.69 (t, J=9 Hz, 2H), 3.27 (t, J=9 Hz, 2H), 2.87 (m, 1H), 1.28 (d, J=7 Hz, 6H); LCMS [M+H].sup.+: 324.02 (calcd for [C15H15Cl2N3O+H].sup.+: 324.06).

##STR00234##

[0784] 4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-6-methoxypyrimidin-2-amine (8). .sup.1H NMR (500 MHz, CDCl.sub.3): δ 7.28 (s, 1H), 6.19 (s, 1H), 4.98 (s, 2H), 4.68 (t, J=8.5 Hz, 2H), 3.94 (s, 3H), 3.25 (t, J=9 Hz, 2H); LCMS [M+H].sup.+: 311.87 (calcd for [C13H11Cl2N3O2+H].sup.+: 312.02).

##STR00235##

[0785] 4-(2,4-Dichloro-5-methoxyphenyl)-5,6-dimethylpyrimidin-2-amine(9). .sup.1H NMR (500 MHz, CDCl.sub.3): δ 7.47 (s, 1H), 6.83 (s, 1H), 4.88 (s, 2H), 3.90 (s, 3H), 2.42 (s, 3H), 1.95 (s, 3H).

##STR00236##

[0786] 4-(5,7-Dichloro-2,3-dihydrobenzofuran-4-yl)-5,6-dimethylpyrimidin-2-amine(10). .sup.1H NMR (500 MHz, CDCl.sub.3): δ 7.25 (s, 1H), 4.89 (s, 2H), 4.69 (t, J=9 Hz, 2H), 3.25 (m, 1H), 2.88 (m, 1H), 2.42 (s, 3H), 1.93 (s, 3H).

##STR00237##

[0787] 4-(2-chloro-4-fluoro-5-methoxyphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (11). .sup.1H NMR (500 MHz, CDCl.sub.3): δ 7.20 (d, J=10.5 Hz, 1H), 6.94 (d, J=9 Hz, 1H), 4.99 (s, 2H), 3.90 (s, 3H), 2.91 (t, J=8 Hz, 2H), 2.72 (t, J=7.5 Hz, 2H), 2.08 (m, 2H); LCMS [M+H].sup.+: 294.2 (calcd for [C14H13ClFN3O+H].sup.+: 294.07).

##STR00238##

[0788] 4-(2,4-Dichloro-5-methoxyphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(12). .sup.1H NMR (500 MHz, CDCl.sub.3): δ 7.47 (s, 1H), 6.90 (s, 1H), 4.98 (s, 2H), 3.91 (s, 3H), 2.92 (t, J=7.5 Hz, 2H), 2.72 (t, J=7.5 Hz, 2H), 2.08 (m, 2H).

##STR00239##

[0789] 4-(5,7-Dichloro-2,3-dihydrobenzofuran-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine(13). .sup.1H NMR (500 MHz, CDCl.sub.3): δ 7.25 (s, 1H), 4.69 (m, 2H), 3.38 (m, 1H), 2.99-2.81 (m, 4H), 2.49 (m, 1H), 2.17-2.00 (m, 2H).

##STR00240##

[0790] 4-(2,4-dichloro-5-(2-(dimethylamino)ethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (14). .sup.1H NMR (500 MHz, CDCl.sub.3): δ 7.46 (s, 1H), 6.90 (s, 1H), 4.97 (s, 2H), 4.13 (t, J=6 Hz, 2H), 2.91 (t, J=8 Hz, 2H), 2.80 (t, J=6 Hz, 2H), 2.71 (t, J=7.5 Hz, 2H), 2.36 (s, 6H), 2.08 (m, 2H); LCMS [M+H].sup.+: 367.1 (calcd for [C17H20Cl2N4O+H].sup.+: 367.10).

##STR00241##

[0791] 4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-5,6,7,8-tetrahydroquinazolin-2-amine (15). .sup.1H NMR (500 MHz, CDCl.sub.3): δ 7.28 (s, 1H), 4.88 (s, 2H), 4.69 (t, J=9 Hz, 2H), 3.21 (m, 1H), 2.89 (m, 1H), 2.78 (m, 2H), 2.44 (m, 1H), 2.15 (m, 1H), 1.86 (m, 2H), 1.72 (m, 2H); LCMS [M+H].sup.+: 336.1 (calcd for [C16H15Cl2N3O+H].sup.+: 336.06).

##STR00242##

[0792] 4-(2,4-Dichloro-5-methoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (19). .sup.1H NMR (500 MHz, CDCl.sub.3): δ 8.15 (s, 1H), 7.54 (s, 1H), 7.46 (m, 1H), 7.15 (s, 1H), 6.45 (m, 1H), 4.86 (s, 2H), 3.94 (s, 3H).

##STR00243##

[0793] 4-(5,7-Dichloro-2,3-dihydrobenzofuran-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (20). .sup.1H NMR (500 MHz, CDCl.sub.3): δ 8.01 (s, 1H), 7.45 (t, J=3 Hz, 1H), 7.34 (s, 1H), 6.46 (m, 1H), 4.83 (s, 2H), 4.71 (m, 2H), 3.60 (m, 1H), 2.94 (m, 1H); LCMS [M+H].sup.+: 321.0 (calcd for [C.sub.14H.sub.10Cl.sub.2N.sub.4O+H].sup.+: 321.0). The .sup.1H NMR spectrum is shown in FIG. 1.

##STR00244##

[0794] 4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-2-amine (21). .sup.1H NMR (500 MHz, CDCl.sub.3): δ 7.32 (s, 1H), 7.22 (d, J=3 Hz, 1H), 6.36 (d, J=3 Hz, 1H), 4.81 (s, 2H), 4.72 (m, 2H), 3.40 (s, 3H), 3.34 (m, 1H), 2.91 (m, 1H); LCMS [M+H].sup.+: 335.0 (calcd for [C15H12Cl2N4O+H].sup.+: 335.04).

##STR00245##

[0795] 4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-5-ethyl-5H-pyrrolo[3,2-d]pyrimidin-2-amine (22). .sup.1H NMR (500 MHz, CDCl.sub.3): δ 7.33 (m, 2H), 6.40 (d, J=2.5 Hz, 1H), 4.80 (s, 2H), 4.70 (m, 2H), 3.72 (d, J=7 Hz, 2H), 3.33 (m, 1H), 2.91 (m, 1H), 1.14 (t, J=7.5 Hz, 3H); LCMS [M+H].sup.+: 349.1 (calcd for [C16H14Cl2N4O+H].sup.+: 349.05).

##STR00246##

[0796] Ethyl-2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxylate (23). .sup.1H NMR (500 MHz, CDCl.sub.3): δ 7.54 (s, 1H), 7.35 (s, 1H), 5.32 (s, 2H), 4.70 (m, 2H), 4.37 (m, 2H), 3.35 (m, 1H), 2.92 (m, 1H), 1.38 (t, J=7 Hz, 3H); LCMS [M+H].sup.+: 410.0 (calcd for [C17H13Cl2N3O3S+H].sup.+: 410.01).

##STR00247##

[0797] 2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N-ethylthieno[2,3-d]pyrimidine-6-carboxamide (24). .sup.1H NMR (500 MHz, CDCl.sub.3): δ 7.34 (s, 1H), 7.21 (s, 1H), 5.91 (s, 1H), 5.28 (s, 2H), 4.70 (m, 2H), 4.48 (m, 2H), 3.36 (m, 1H), 2.91 (m, 1H), 1.26 (t, J=3.5 Hz, 3H); LCMS [M+H].sup.+: 409.0 (calcd for [C17H14Cl2N4O2S+H].sup.+: 409.02).

[0798] Compounds 34 and 36 were prepared according to methods known in the art, e.g., those described herein. The .sup.1H NMR spectra (CDCl.sub.3) for compounds 34 and 36 are provided in FIGS. 2 and 3, respectively.

[0799] Compounds 40-48 can be prepared according to methods known in the art, e.g., those described herein.

##STR00248##

[0800] 4-chloro-6-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)pyrimidin-2-amine (49). .sup.1H NMR (400 MHz, DMSO-d6): δ=7.48 (s, 1H), 7.30 (s, 2H), 6.78 (s, 1H), 4.64 (t, J=8.8 Hz, 2H), 3.20 (t, J=8.8 Hz, 2H). LCMS: m/z calcd for C.sub.12H.sub.8Cl.sub.3N.sub.3O [M+H].sup.+: 316.0; found: 316.0.

##STR00249##

[0801] 4-trifluoromethyl-6-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)pyrimidin-2-amine (50). .sup.1H NMR (400 MHz, DMSO-d6): δ 7.520 (brs, 2H, NH.sub.2), 7.093 (s, 1H), 4.655 (t, 2H, J=8.8 Hz), 3.547 (s, 1H), 3.221 (t, 2H, J=8.8 Hz). LCMS: m/z calcd for C.sub.13H.sub.8Cl.sub.2F.sub.3N.sub.3O [M+H].sup.+: 350.1; found: 350.0.

##STR00250##

[0802] 4-thiomethyl-6-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)pyrimidin-2-amine (51). .sup.1H NMR (400 MHz, DMSO-d6): δ 7.438 (s, 1H), 6.815 (brs, 2H, NH.sub.2), 6.549 (s, 1H), 4.633 (t, 2H, J=8.8 Hz), 3.178 (t, 2H, J=8.8 Hz), 2.453 (s, 3H). LCMS: m/z calcd for C.sub.13H.sub.11Cl.sub.2N.sub.3OS [M+H].sup.+: 328.2; found: 328.1.

##STR00251##

[0803] 4-chloro-6-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)pyrimidine-2,5-diamine (52). .sup.1H NMR (400 MHz, DMSO-d6): δ=7.46 (s, 1H), 6.25 (s, 2H), 4.67 (t, J=8.8 Hz, 2H), 4.30 (s, 2H), 3.15-3.07 m, 2H). HPLC/MS: m/z calcd for C.sub.12H.sub.9Cl.sub.3N.sub.4O [M+H].sup.+: 331.0; found: 331.1.

##STR00252##

[0804] 2-amino-6-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)pyrimidin-4-ol (53). To a flask containing dioxane:1 N NaOH aq. (50:50; 1 mL:1 mL) were added 4-chloro-6-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)pyrimidin-2-amine (49) (20 mg, 0.063 mmol), and DABCO (8 mg, 0.069 mmol), at rt. The reaction was subsequently heated at 80° C. The reaction was cooled down, acidified by addition of 1 N HCl aq. (2 mL), taken up in ethyl acetate (5 mL) and washed with brine (3×5 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered, and volatiles were evaporated. The residue was purified by silica gel chromatography using a gradient of DCM:MeOH (100:0 to 90:10). The product was obtained in 77% yield as a white solid.

[0805] .sup.1H NMR (400 MHz, DMSO-d6): δ=7.39 (s, 1H), 5.57 (s, 1H), 4.62 (t, J=8.8 Hz, 2H), 3.20 (t, J=8.8 Hz, 2H). HPLC/MS: m/z calcd for C.sub.12H.sub.9Cl.sub.2N.sub.3O.sub.2 [M+H].sup.+: 298.0; found: 298.1.

##STR00253##

[0806] Methyl 2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-5-carboxylate (54). To a flask containing 4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (20) (20 mg, 0.062 mmol) in DCM (1 mL) were added dry K.sub.2CO.sub.2>3 (30 mg, 0.22 mmol), and methyl chloroformate (0.014 mL, 0.186 mmol), at 0° C. The reaction was allowed to stir for 8 h at rt. Afterwards, the reaction was quenched by addition of 1 N NaOH aq. (1 mL) and stirred at rt for 1 h. The reaction was taken up in DCM (10 mL) and washed with sat. NaHCO.sub.3 aq. (10 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered, and volatiles were evaporated. The residue was purified by silica gel chromatography using a gradient of DCM:MeOH (100:0 to 90:10). The product was obtained in 66% yield as a yellow solid.

[0807] .sup.1H NMR (400 MHz, CDCl3): δ=7.61 (s, 1H), 7.23 (s, 1H), 6.51 (s, 1H), 4.63 (brs, 2H), 3.77 (s, 3H), 3.65 (br s, 1H), 2.85 (br s, 1H). HPLC/MS: m/z calcd for C.sub.16H.sub.12Cl.sub.2N.sub.4O.sub.3 [M+H].sup.+: 379.0; found: 379.1.

##STR00254##

[0808] 1-(2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethan-1-one (55). To a flask containing 4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (20 mg, 0.062 mmol) in DCM (1 mL) were added dry K.sub.2CO.sub.3 (30 mg, 0.22 mmol), and acetyl chloride (0.006 mL, 0.074 mmol), at 0° C. The reaction was allowed to stir for 8 h at rt. Afterwards, the reaction was quenched by addition of 1 N NaOH aq. (1 mL) and stirred at rt for 1 h. The reaction was taken up in DCM (10 mL) and washed with sat. NaHCO.sub.3 aq. (10 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered, and volatiles were evaporated. The residue was purified by silica gel chromatography using a gradient of DCM:MeOH (100:0 to 90:10). The product was obtained in 81% yield as a yellow solid.

[0809] .sup.1H NMR (400 MHz, CDCl.sub.3): δ=7.57 (s, 1H), 7.23 (s, 1H), 6.55 (s, 1H), 4.63 (brs, 2H), 3.45 (brs, 1H), 3.35 (s, 3H), 2.85 (br s, 1H). HPLC/MS: m/z calcd for C.sub.16H.sub.12Cl.sub.2N.sub.4O.sub.2 [M+H].sup.+: 363.0; found: 363.1.

##STR00255##

[0810] 2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carbaldehyde (56). To a flask containing dry THF (2 mL), were added dry DMF (0.1 mL) and POCl.sub.3 (0.015 mL, 0.16 mmol), at 0° C. Reaction was stirred at 0° C. for 30 min, under argon, upon which 4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (20 mg, 0.062 mmol) in THF (1 mL) was added dropwise. The reaction was allowed to stir for 8 h warming to rt. To the reaction was then added 1 N NaOH aq. (2 mL) and heated to 80° C. for 1 h. The reaction was cooled to rt and taken up in EtOAc (20 mL) and washed with sat. NaHCO.sub.3 aq. (20 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered, and volatiles were evaporated. The residue was purified by silica gel chromatography using a gradient of DCM:MeOH (100:0 to 90:10). The product was obtained in 58% yield as a white solid.

[0811] .sup.1H NMR (400 MHz, CDCl3): δ=10.05 (s, 1H), 7.96 (s, 1H), 7.24 (s, 1H), 4.63 (brs, 2H), 3.31 (brs, 1H), 2.85 (brs, 1H). HPLC/MS: m/z calcd for C.sub.15H.sub.10Cl.sub.2N.sub.4O.sub.2 [M+H].sup.+: 349.0; found: 349.1.

##STR00256##

[0812] 7-bromo-4-(2,4-dichloro-5-methoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (57). To a flask containing 4-(2,4-dichloro-5-methoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (20 mg, 0.065 mmol) in AcOH:tBuOH (50:50, 0.5 mL:0.5 mL) were added LiBr (18 mg, 0.22 mmol), and Br.sub.2 (0.011 mL, 0.22 mmol), at 0° C. The reaction was allowed to stir for 8 h at rt. Afterwards, the reaction was taken up in EtOAc (20 mL) and washed with sat. NaHCO.sub.3 aq. (3×20 mL), and Na.sub.2S.sub.2O.sub.3 (10% wt. aq., 20 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered, and volatiles were evaporated. The residue was purified by silica gel chromatography using a gradient of DCM:MeOH (100:0 to 90:10). The product was obtained in 56% yield as a yellow solid.

[0813] .sup.1H NMR (400 MHz, DMSO-d6): δ=7.75 (s, 1H), 7.72 (s, 1H), 7.26 (s, 1H), 6.24 (s, 2H), 3.86 (s, 3H). HPLC/MS: m/z calcd for C.sub.13H.sub.9BrCl.sub.2N.sub.4O [M+H].sup.+: 386.9; found: 387.0.

General Procedure for Synthesis of 2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxamides

[0814] ##STR00257##

[0815] Step 1: Synthesis of precursor 2,5-dioxopyrrolidin-1-yl 2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxylate. To a flask containing degassed DMF:H.sub.2O (50:50; 2 mL:2 mL) were added ethyl 2-amino-4-chlorothieno[2,3-d]pyrimidine-6-carboxylate (100 mg, 0.39 mmol), (5,7-dichloro-2,3-dihydrobenzofuran-4-yl)boronic acid (91 mg, 0.39 mmol), NaHCO.sub.3 (82 mg, 0.98 mmol), and Pd(PPh.sub.3).sub.4 (22 mg, 0.02 mmol), at rt. The reaction was subsequently heated at 80° C. for 8 h under argon. The reaction was cooled down, taken up in ethyl acetate (20 mL) and washed with brine (3×20 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered, and volatiles were evaporated. The residue was purified by silica gel chromatography using a gradient of DCM:MeOH (100:0 to 90:10). The product ethyl 2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxylate was obtained in 38% yield as a yellow solid.

[0816] Ethyl 2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxylate (60 mg, 0.15 mmol) was dissolved in THF (1 mL) and to the flask was added 1 N NaOH aq. (1 mL). The reaction was stirred for 8 h at rt. Subsequently, the solution was cooled to 0° C. and acidified by addition of 1 N HCl aq. (2 mL), resulting in formation of white precipitate, which was filtered and dried, affording 2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxylic acid in quantitative yield, without further purification. The filtrand (57 mg, 0.15 mmol) was dissolved in dry DMF (1 mL), cooled to 0° C., and to the reaction vessel were added N-hydroxysuccinimide (23 mg, 0.2 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl (38 mg, 0.2 mmol). The reaction was left to stir warming to rt over 8 h. The solution was taken up into DCM (20 mL) and washed with sat. NH.sub.4Cl aq. (3×20 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered, and volatiles were evaporated. The residue was purified by silica gel chromatography using a gradient of DCM:MeOH (100:0 to 90:10). The product 2,5-dioxopyrrolidin-1-yl 2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxylate was obtained as a white solid in 88% yield.

[0817] Step 2: General Procedure for Formation of Amides:

##STR00258##

[0818] To a flask containing the 2,5-dioxopyrrolidin-1-yl 2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxylate (10 mg, 0.02 mmol) was added dry DMF (0.5 mL), followed by addition of an amine (3 eq., 0.06 mmol), (e.g. ammonia, primary amine, or secondary amine). The reaction was allowed to stir at rt for 12 h, upon which it was taken up in DCM (5 mL) and washed with sat. NH.sub.4Cl aq. (3×5 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered, and volatiles were evaporated. The residue was purified by silica gel chromatography using a gradient of DCM:MeOH (100:0 to 90:10). The resulting amides were obtained in good to excellent yields.

##STR00259##

[0819] 2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N-(2-(pyrrolidin-1-yl)ethyl)thieno[2,3-d]pyrimidine-6-carboxamide (58). .sup.1H NMR (400 MHz, DMSO-d6): δ=8.79 (s, 1H), 7.61 (s, 1H), 7.58 (s, 1H), 7.28 (s, 2H), 4.67 (t, J=8.8 Hz, 2H), 3.44-3.11 (m, 6H), 2.90-2.75 (m, 4H), 1.77-1.73 (m, 4H). HPLC/MS: m/z calcd for C.sub.21H.sub.21Cl.sub.2N.sub.5O.sub.2S [M+H].sup.+: 478.1; found: 478.1.

##STR00260##

[0820] 2-amino-N-(2-cyanoethyl)-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxamide (59). .sup.1H NMR (400 MHz, DMSO-d6): δ=8.94 (t, J=5.6 Hz, 1H), 7.63 (s, 1H), 7.60 (s, 1H), 7.34 (s, 2H), 4.69 (t, J=8.8 Hz, 2H), 3.46-3.41 (m, 2H), 3.23-3.15 (m, 1H), 3.03-2.97 (m, 1H), 2.76 (t, J=6.4 Hz, 2H). HPLC/MS: m/z calcd for C.sub.18H.sub.13Cl.sub.2N.sub.5O.sub.2S [M+H].sup.+: 434.0; found: 434.1.

##STR00261##

[0821] 2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N-(2-hydroxyethyl)thieno[2,3-d]pyrimidine-6-carboxamide (60). .sup.1H NMR (400 MHz, DMSO-d6): δ=8.57 (t, J=5.6 Hz, 1H), 7.59 (s, 2H), 7.26 (s, 2H), 4.73 (t, J=5.6 Hz, 1H), 4.67 (t, J=8.8 Hz, 2H), 3.46-3.41 (m, 2H), 3.26-3.12 (m, 3H), 3.03-2.94 (m, 1H). HPLC/MS: m/z calcd for C.sub.17H.sub.14Cl.sub.2N.sub.4O.sub.3S [M+H].sup.+: 425.0; found: 425.1.

##STR00262##

[0822] 2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine-6-carboxamide (61). .sup.1H NMR (400 MHz, DMSO-d6): δ=9.18 (t, J=6.0 Hz, 1H), 7.72 (s, 1H), 7.63 (s, 1H), 7.38 (s, 2H), 4.69 (t, J=8.8 Hz, 2H), 4.12-4.03 (m, 2H), 3.26-3.18 (m, 1H), 3.03-2.94 (m, 1H). HPLC/MS: m/z calcd for C.sub.17H.sub.11Cl.sub.2F.sub.3N.sub.4O.sub.2S [M+H].sup.+: 463.0; found: 463.1.

##STR00263##

[0823] 2-amino-N-cyclopropyl-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxamide (62). .sup.1H NMR (400 MHz, DMSO-d6): δ=8.54 (s, 1H), 7.61 (s, 1H), 7.53 (s, 1H), 7.29 (s, 2H), 4.68 (t, J=8.8 Hz, 2H), 3.26-3.18 (m, 1H), 3.03-2.94 (m, 1H), 2.81-2.71 (m, 1H), 0.75-0.61 (m, 2H), 0.55-0.40 (m, 2H). HPLC/MS: m/z calcd for C.sub.18H.sub.14Cl.sub.2N.sub.4O.sub.2S [M+H].sup.+: 421.0; found: 421.1.

##STR00264##

[0824] 2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N-methylthieno[2,3-d]pyrimidine-6-carboxamide (63). .sup.1H NMR (400 MHz, DMSO-d6): δ=8.62-8.59 (m, 1H), 7.61 (s, 2H), 7.27 (s, 2H), 4.64 (t, J=8.8 Hz, 2H), 3.24 (s, 3H), 3.23-3.18 (m, 1H), 3.03-2.91 (m, 1H). HPLC/MS: m/z calcd for C.sub.16H.sub.12Cl.sub.2N.sub.4O.sub.2S [M+H].sup.+: 395.0; found: 395.1.

##STR00265##

[0825] 2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N-(2-methoxyethyl)thieno[2,3-d]pyrimidine-6-carboxamide (64). .sup.1H NMR (400 MHz, DMSO-d6): δ=8.51-8.41 (m, 1H), 7.59 (s, 1H), 7.50 (s, 1H), 7.26 (s, 2H), 4.67 (t, J=8.8 Hz, 2H), 3.23-3.10 (m, 4H), 3.03-2.91 (m, 2H), 2.72-2.67 (m, 3H). HPLC/MS: m/z calcd for C.sub.18H.sub.16Cl.sub.2N.sub.4O.sub.3S [M+H].sup.+: 439.0; found: 439.1.

##STR00266##

[0826] 2-amino-N-cyclobutyl-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxamide (65). .sup.1H NMR (400 MHz, DMSO-d6): δ=8.68 (d, J=6.8 Hz, 1H), 7.61 (s, 1H), 7.56 (s, 1H), 7.26 (s, 2H), 4.67 (t, J=8.8 Hz, 2H), 4.33-4.26 (m, 1H), 3.23-3.18 (m, 1H), 3.03-2.91 (m, 1H), 2.16-1.92 (m, 2H), 1.70-1.60 (m, 1H), 1.33-1.20 (m, 2H), 0.90-0.78 (m, 1H). HPLC/MS: m/z calcd for C.sub.19H.sub.16Cl.sub.2N.sub.4O.sub.2S [M+H].sup.+: 435.0; found: 435.1.

##STR00267##

[0827] 2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N,N-dimethylthieno[2,3-d]pyrimidine-6-carboxamide (66). .sup.1H NMR (400 MHz, DMSO-d6): δ=7.54 (s, 1H), 7.23 (s, 2H), 7.15 (s, 1H), 4.66 (t, J=8.8 Hz, 2H), 3.31 (s, 3H), 3.23-2.90 (m, 5H). HPLC/MS: m/z calcd for C.sub.17H.sub.14Cl.sub.2N.sub.4O.sub.2S [M+H].sup.+: 409.0; found: 409.1.

##STR00268##

[0828] 2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N-(oxetan-3-yl)thieno[2,3-d]pyrimidine-6-carboxamide (67). .sup.1H NMR (400 MHz, DMSO-d6): δ=9.17 (d, J=6.8 Hz, 1H), 7.64 (s, 1H), 7.62 (s, 1H), 7.31 (s, 2H), 4.97-4.90 (m, 1H), 4.75-4.65 (m, 4H), 4.55-4.45 (m, 2H), 3.20-3.11 (m, 1H), 3.02-2.92 (m, 1H). HPLC/MS: m/z calcd for C.sub.18H.sub.14Cl.sub.2N.sub.4O.sub.3S [M+H].sup.+: 437.0; found: 437.1.

##STR00269##

[0829] (2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidin-6-yl)(morpholino)methanone (68). .sup.1H NMR (400 MHz, DMSO-d6): δ=7.54 (s, 1H), 7.23 (s, 2H), 7.12 (s, 1H), 4.66 (t, J=8.8 Hz, 2H), 3.59 (brs, 8H), 3.26-3.21 (m, 1H), 3.02-2.92 (m, 1H). HPLC/MS: m/z calcd for C.sub.19H.sub.16Cl.sub.2N.sub.4O.sub.3S [M+H].sup.+: 451.0; found: 451.1.

##STR00270##

[0830] (2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidin-6-yl)(pyrrolidin-1-yl)methanone (69). .sup.1H NMR (400 MHz, DMSO-d6): δ=7.54 (s, 1H), 7.23 (s, 2H), 7.21 (s, 1H), 4.66 (t, J=8.8 Hz, 2H), 3.68-3.64 (m, 2H), 3.44 (brs, 2H), 3.26-3.16 (m, 1H), 3.02-2.92 (m, 1H), 1.91-1.76 (m, 4H). HPLC/MS: m/z calcd for C.sub.19H.sub.16Cl.sub.2N.sub.4O.sub.2S [M+H].sup.+: 435.0; found: 435.1.

##STR00271##

[0831] 2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N-methyl-N-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine-6-carboxamide (70). .sup.1H NMR (400 MHz, DMSO-d6): δ=7.54 (s, 1H), 7.33 (s, 3H), 4.66 (t, J=8.8 Hz, 2H), 4.41-4.28 (m, 2H), 3.27 (s, 3H), 3.26-3.16 (m, 1H), 3.02-2.92 (m, 1H). HPLC/MS: m/z calcd for C.sub.18H.sub.13Cl.sub.2F.sub.3N.sub.4O.sub.2S [M+H].sup.+: 477.0; found: 477.1.

##STR00272##

[0832] 2-amino-N-(2-cyanoethyl)-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N-methylthieno[2,3-d]pyrimidine-6-carboxamide (71). .sup.1H NMR (400 MHz, DMSO-d6): δ=7.54 (s, 1H), 7.28 (s, 2H), 7.20 (s, 1H), 4.66 (t, J=8.8 Hz, 2H), 3.69 (brs, 2H), 3.26-3.16 (m, 4H), 3.02-2.92 (m, 1H), 2.82-2.70 (m, 2H). HPLC/MS: m/z calcd for C.sub.19H.sub.15Cl.sub.2N.sub.5O.sub.2S [M+H].sup.+: 448.0; found: 448.1.

##STR00273##

[0833] 2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N-methyl-N-(oxetan-3-yl)thieno[2,3-d]pyrimidine-6-carboxamide (72). .sup.1H NMR (400 MHz, DMSO-d6): δ=7.55 (s, 1H), 7.26 (s, 2H), 7.16 (s, 1H), 5.21-5.16 (m, 1H), 4.69-4.60 (m, 6H), 3.26-3.14 (m, 4H), 3.02-2.92 (m, 1H). HPLC/MS: m/z calcd for C.sub.19H.sub.16Cl.sub.2N.sub.4O.sub.3S [M+H].sup.+: 451.0; found: 451.1.

##STR00274##

[0834] 2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N-(2-hydroxy-2-methylpropyl)thieno[2,3-d]pyrimidine-6-carboxamide (73). .sup.1H NMR (400 MHz, DMSO-d6): δ=8.44 (s, 1H), 7.69 (s, 1H), 7.59 (s, 1H), 7.23 (s, 2H), 4.67 (t, J=8.8 Hz, 2H), 4.45 (s, 1H), 3.21-3.12 (m, 3H), 3.02-2.92 (m, 1H), 1.04 (s, 6H). HPLC/MS: m/z calcd for C.sub.19H.sub.18Cl.sub.2N.sub.4O.sub.3S [M+H].sup.+: 453.0; found: 453.1.

##STR00275##

[0835] 2-amino-N-cyclopropyl-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N-methylthieno[2,3-d]pyrimidine-6-carboxamide (74). .sup.1H NMR (400 MHz, DMSO-d6): δ=7.55 (s, 1H), 7.36 (s, 1H), 7.28 (s, 2H), 4.70-4.62 (m, 2H), 3.13-3.06 (m, 1H), 3.00-2.91 (m, 4H), 0.80-0.72 (m, 2H), 0.68-0.63 (m, 2H). HPLC/MS: m/z calcd for C.sub.19H.sub.16Cl.sub.2N.sub.4O.sub.2S [M+H].sup.+: 435.0; found: 435.1.

##STR00276##

[0836] 2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N-methoxy-N-methylthieno[2,3-d]pyrimidine-6-carboxamide (75). .sup.1H NMR (400 MHz, DMSO-d6): δ=7.57 (s, 1H), 7.47 (s, 1H), 7.37 (s, 2H), 4.70-4.62 (m, 2H), 3.74 (s, 3H), 3.27-3.19 (m, 4H), 3.00-2.91 (m, 1H). HPLC/MS: m/z calcd for C.sub.17H.sub.14Cl.sub.2N.sub.4O.sub.3S [M+H].sup.+: 425.0; found: 425.1.

##STR00277##

[0837] 1-(2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidin-6-yl)propan-1-one (76). To a flask containing 2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)-N-methoxy-N-methylthieno[2,3-d]pyrimidine-6-carboxamide (20 mg, 0.048 mmol) in dry THF (1 mL), was added EtMgBr (2.0 M in THF; 0.029 mL, 0.057 mmol), at 0° C. The reaction was stirred for 8 h, upon which it was quenched by addition of sat. NH.sub.4Cl aq (1 mL). The aqueous layer was extracted with EtOAc (3×2 mL), dried over Na.sub.2SO.sub.4, filtered, and volatiles were evaporated. The residue was purified by silica gel chromatography using a gradient of DCM:MeOH (100:0 to 90:10). The product was obtained in 91% yield as a white solid.

[0838] .sup.1H NMR (400 MHz, CDCl.sub.3): δ=7.41 (s, 1H), 7.34 (s, 1H), 5.84 (br s, 2H), 4.74-4.64 (m, 2H), 3.87-3.76 (m, 1H), 3.30-3.10 (m, 3H), 1.50-1.41 (m, 3H). HPLC/MS: m/z calcd for C.sub.17H.sub.13Cl.sub.2N.sub.3O.sub.2S [M+H].sup.+: 394.0; found: 394.1.

##STR00278##

2-(2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidin-6-yl)propan-2-ol (77)

[0839] To a flask containing ethyl 2-amino-4-(5,7-dichloro-2,3-dihydrobenzofuran-4-yl)thieno[2,3-d]pyrimidine-6-carboxylate (20 mg, 0.048 mmol) in dry THF (1 mL), was added MeMgBr (2.0 M in THF; 0.072 mL, 0.144 mmol), at 0° C. The reaction was stirred for 8 h, upon which it was quenched by addition of sat. NH.sub.4Cl aq (1 mL). The aqueous layer was extracted with EtOAc (3×2 mL), dried over Na.sub.2SO.sub.4, filtered, and volatiles were evaporated. The residue was purified by silica gel chromatography using a gradient of DCM:MeOH (100:0 to 90:10). The product was obtained in 78% yield as a white solid.

[0840] .sup.1H NMR (400 MHz, DMSO-d6): δ=7.53 (s, 1H), 6.85 (s, 2H), 6.54 (s, 1H), 5.95 (s, 1H), 4.64 (t, J=8.8 Hz, 2H), 3.20-3.12 (m, 1H), 3.00-2.90 (m, 1H), 1.46 (s, 3H), 1.44 (s, 3H). HPLC/MS: m/z calcd for C.sub.17H.sub.15Cl.sub.2N.sub.3O.sub.2S [M+H].sup.+: 396.0; found: 396.1.

Example 2. In Vitro Assays of the Compounds of the Invention

[0841] Hsp90 Biochemical Assay (Fluorescence Polarization)

[0842] Hsp90 inhibitory activity of the compounds of the invention was assessed using a fluorescence polarization (FP) assay using FITC-labeled geldanamycin and truncated alpha-Hsp90 protein. Measurement of binding activity was performed on BMG CLARIOstar® reader (BMG Labtech, Ortenberg, Germany). This assay is homogeneous and is performed in 384-well plates performing consistently with known standards. The assay was validated with known Hsp90 inhibitors, e.g., PU-H71 (IC.sub.50=60 nM), which is in agreement with the reported IC.sub.50 (Luo et al., supra). The results of this assay for compounds 20, 36, 37, and 39 and for the known Hsp90 inhibitor are shown in FIG. 4.

[0843] Hsp90 Biochemical Assay (AlphaLISA)

[0844] Hsp90 inhibitory activity of the compounds of the invention was assessed using a robust and reproducible assay based on the AlphaLISA format was developed (PerkinElmer, Inc., Waltham, Mass.; the format of the assay is described in, e.g., ELISA to AlphaLISA Conversion Guide, PerkinElmer, Inc., published in August, 2012). This assay employs biotinylated geldanamycin, His-tagged-Hsp90, and Ni.sup.+2 coated beads. This assay is homogenous and miniaturized to 384-well plates. Measurement of binding activity was performed on an Envision reader. The assay was validated with known Hsp90 inhibitors, including PU-H71 (IC.sub.50=60 nM) which is in agreement with the reported IC.sub.50 (Luo et al., supra). This assay is the primary assay for evaluating compounds of the invention. In this assay, compound 20 showed Hsp90 inhibitory activity (IC.sub.50 of 0.74±0.1 μM; see FIG. 5A).

[0845] Hsp90 Cell Based Functional Assays

[0846] Cells were treated with compounds of the invention for 24 h and then lysed in a buffer containing NP-40, orthovanadate, and protease inhibitors. Western blots were performed with antibodies specific to Hsp70, Hsp90, or actin (as control). Tau phosphorylation was assayed using, e.g., a method of Liu et al., Biochemistry, 49:4921-4929, 2010, with SHSY5Y-hTau441V337M/R406W cell line (Loeffler et al., J. Mol. Neurosci., 47:192-203, 2012). This cell line represents stable transfected cell line that has been shown to have hyper-phosphorylated tau by over-express the longest human tau isoform, hTAU441 with two mutations: V337M and R406W. The functional assay described herein provides an in vitro model of tauopathy and can be used to evaluate the effect of Hsp90 inhibitors on phosphorylated tau protein (p-Tau). In these assays, compound 20 showed increase in the expression of Hsp70 (see FIG. 5B), significant decreases in the levels of pTau231 at 0.1 and 0.5 μM (see FIG. 6B), and significant decreases in the levels of pTau396 at 0.05, 0.1, and 0.5 μM (see FIG. 6C).

[0847] Cytotoxicity Assays

[0848] SH-SY5Y-hTAU441 cell viability was determined using the MTT assay. As shown in FIG. 6A, compound 20 did not affect cell viability of SH-SY5Y-hTAU441 cells. SH-SY5Y cell viability may also be measured after 24 and 48 h with the CellTiter-Glo® assay that measures ATP-levels. In addition, cytotoxicity may be assessed using the Celigo® with live cell microscopic imaging and a GE InCell Analyzer 2000 to measure multiple outcomes including apoptosis markers, membrane permeability, and mitochondrial activity.

[0849] Mouse Liver Microsomal Stability

[0850] Metabolic stability of the compounds of the invention was assessed by monitoring their degradation in mouse liver microsomes. Compound 20 demonstrated good microsomal stability (T.sub.1/2=26 min).

[0851] Solubility

[0852] Compound solubility was determined in pH 7.4 buffer. Aqueous solubility of greater than or equal to about 0.5 μM (e.g., greater than or equal to about 1 μM, greater than or equal to about 2 μM, greater than or equal to about 5 μM, greater than or equal to about 10 μM, greater than or equal to about 20 μM, or greater than or equal to about 30 μM) may indicate a compound having acceptable solubility for medical use, e.g., for treatment of a neurodegenerative disorder. At pH of 7.4, compound 20 exhibits an aqueous solubility of 30 μM.

[0853] Cell Permeability

[0854] Compounds may be assessed in MDR1-MDCK permeability assay or Caco-2 permeability assay to determine their permeability. Apical (A) to basal (B) permeability >3×10.sup.−6 cm/sec and B.fwdarw.A/A.fwdarw.B asymmetry <3 for a compound are considered acceptable predictors of brain penetration, and compounds having such properties are unlikely to be P-glycoprotein (P-gp) substrates. Compound 20 has shown excellent permeability in MDR1-MDCK assay (A−B=28×10.sup.−6 cm/s) with low asymmetry (B.fwdarw.A/A.fwdarw.B asymmetry=0.9).

[0855] Results of the above-described assays for certain compounds of the invention are summarized in Table 3.

TABLE-US-00003 TABLE 3 Hsp90 Hsp 70 inhibitory agonist Compound MW cLogP PSA activity activity 1 [00279] 317 4 60 − 2 [00280] 311 4.3 60 ++ 3 [00281] 309 3.9 46 − 4 [00282] 323 4.7 37 − 5 [00283] 295 3.6 60 +++ >2 fold at 0.4- 1.0 μM 6 [00284] 310 4.1 60 +++ ≥10 μM 7 [00285] 324 4.5 60 +++(1) — 8 [00286] 312 3.5 69 +++(2) — 9 [00287] 298 3.5 60 +++(3) 1.5-fold at 1 μM 10 [00288] 310 3.9 60 +++(4) >2-fold at 0.4 μM 11 [00289] 293 3.7 60 + 12 [00290] 310 3.9 60 +++(5) >2-fold at ≥10 μM 13 [00291] 322 4.2 60 +++(6) — 14 [00292] 367 4.1 63 +++ 2-fold at 10 μM 15 [00293] 336 4.5 60 + 16 [00294] 323 17 [00295] 394 − 18 [00296] 333 19 [00297] 309 3.8 72 +++ >2-fold at 0.4- 1 μM 20 [00298] 321 4.1 72 +++ — 21 [00299] 335 3.1 63 ++ — 22 [00300] 349 3.4 63 + — 23 [00301] 410 4.8 86 +(7) 3.3 μM 24 [00302] 409 4.1 89 +++ 0.4 μM 25 [00303] 292.70 2.5 72 +(8) 1.5 fold, or no observable effect 26 [00304] 306.73 2.7 63 ++(9) 2 fold at 3.3 μM, or no observable effect 27 [00305] 366.25 2.9 75 ++ 10 μM 28 [00306] 324.21 4.5 60 − 29 [00307] 381.23 3.6 103 +++ 0.4 μM 30 [00308] 335.19 3.4 63 − 31 [00309] 406.27 2.3 92 − 32 [00310] 406.27 2.6 92 − 33 [00311] 311.17 3.1 72 + 34 [00312] 317.19 4.5 72 +++ 3.3 μM; 10 μM 35 [00313] 316.20 4.0 60 +++ 3.3 μM; 10 μM 36 [00314] 301.13 3.9 82 +++ >10 μM 37 [00315] 446.11 7.0 82 − 38 [00316] 284.14 3.6 60 ++ 39 [00317] 304.56 3.8 60 +++ 0.4 μM 49 [00318] 316.6 3.8 60 +++ 50 [00319] 350.1 4.0 60 ++ 51 [00320] 328.2 4.0 60 +++ 52 [00321] 331.6 3.0 86 +++ 53 [00322] 298.1 3.2 80 − 54 [00323] 379.2 3.4 90 − 55 [00324] 363.2 2.8 80 − 56 [00325] 348.0 2.6 89 − 57 [00326] 388.1 3.7 72 − 58 [00327] 478.4 4.1 9.2 +++ 59 [00328] 434.3 3.8 113 +++ 60 [00329] 425.3 3.3 109 +++ 61 [00330] 463.3 4.8 89 +++ 62 [00331] 421.3 4.1 89 +++ 63 [00332] 395.3 3.8 89 +++ 64 [00333] 439.3 3.6 98 +++ 65 [00334] 435.3 4.5 89 +++ 66 [00335] 409.3 4.0 80 +++ 67 [00336] 437.3 3.4 98 +++ 68 [00337] 451.3 3.6 89 ++ 69 [00338] 435.3 4.3 80 ++ 70 [00339] 477.3 5.0 89 + 71 [00340] 448.3 4.1 104 +++ 72 [00341] 451.3 3.6 89 ++ 73 [00342] 453.3 3.8 109 +++ 74 [00343] 435.3 4.3 80 ++ 75 [00344] 425.3 89 +++ 76 [00345] 394.3 4.6 77 +++ 77 [00346] 396.3 4.6 80 ++ 78 [00347] 269.01 ++ 79 [00348] 269.01 +++ In Table 3, “Hsp90 inhibitory activity” provides an assessment of exemplary compounds for their ability to inhibit Hsp90. In particular, “−” indicates that the compound has IC.sub.50 of greater than about 10 μM, “+” indicates that the compound has IC.sub.50 in the range of about 4 μM to about 10 μM; “++”indicates that the compound has IC.sub.50 in the range of about 1 μM to about 4 μM; “+++” indicates that the compound has IC.sub.50 of less than about 1 μM. “Hsp 70 agonist activity” indicates EC.sub.50 (μM) of the exemplary compound at which Hsp70 is increased two-fold unless otherwise noted; “—” designates lack of observable effect at concentrations exceeding 10 μM. (1)Data according to AlphaLISA assay, FP assay result: >10 μM. (2)Data according to AlphaLISA assay, FP assay result: 5.5 and 6.2 μM. (3)Data according to AlphaLISA assay, FP assay result: 1 and 1.4 μM. (4)Data according to AlphaLISA assay, FP assay result: 2.3 and 2.4 μM. (5)Data according to AlphaLISA assay, FP assay result: 1.7 μM. (6)Data according to AlphaLISA assay, FP assay result: 1.8 μM. (7)Data according to AlphaLISA assay, FP assay result: 11.1 μM. (8)Data according to AlphaLISA assay, FP assay result: 12.1 and 19.3 μM. (9)Data according to AlphaLISA assay, FP assay result: 8.5 and 11.2 μM.

Example 3. Pharmacokinetic Properties of the Compounds of the Invention

[0856] The pre-clinical study included 85 mice, distributed over 6 groups; a summary of treatment groups is given in Table 4.

TABLE-US-00004 TABLE 4 Group n Sacrificed at Sample reference A 5 Pre-dose A_0 B 3 15 minutes B_0.25 C 3 30 minutes C_0.5 D 3 1 hour D_1 E 3 2 hours E_2 F 3 8 hours F_8

[0857] Plasma and brain samples were taken pre-dose and at post dose time points of pre-dose, 15 and 30 minutes, 1, 2, and 8 hours. The pre-dose group was represented by 5 animals, whereas the post-dose groups were represented by 3 animals.

[0858] Bioanalysis Methods

[0859] Bioanalysis of mouse plasma samples for compound 20 was conducted by protein precipitation and LC-MS/MS with compound 22 as the internal standard. The method was based on a ‘generic assay’ and some method development was conducted to tailor that assay to the particular compound and internal standard. The eventual non-GLP assay was first tested by analyzing a bioanalytical run with spiked mouse plasma samples. The qualification run passed by the run acceptance criteria (see below).

[0860] Bioanalysis was then conducted of plasma sample extracts and of brain sample homogenate extracts, using a calibration and quality control samples spiked in mouse plasma. The assay is described below.

[0861] Assay of Mouse Plasma Levels of Compound 20

[0862] Sample Treatment

[0863] Compound 20 and compound 22 were extracted from the mouse plasma matrix by protein precipitation. To 20.0 μL of sample was added 10.0 μL of internal standard working solution (1000 ng/mL in MeOH) and 200 μL of MeCN. The mixture was vortexed (˜5 sec) and centrifuged (14000 rpm, 5 min). The supernatant was then recovered and evaporated to dryness. The residue was redissolved in 100 μL of redissolving solution (80:20 v:v of mobile phases A:B). For analysis, 20.0 μL was injected in to the LC-MS/MS system.

[0864] Chromatography

[0865] All chromatography was done with a type 1100 liquid chromatograph (Agilent), equipped with an auto-injector. The analytical column was an Xbridge C18 3.5 μm 2.1×50 mm (Waters), employed at 50° C. The mobile phase was a gradient, composed of solvent A: 1 g/L ammonium acetate in Milli-Q water, and solvent B: MeCN. The gradient was as shown in Table 5.

TABLE-US-00005 TABLE 5 Flow rate Step Total time (min) (μL/min) A (%) B (%) 0 0.00 700 80 20 1 0.20 700 80 20 2 1.00 700 0 100 3 2.00 700 0 100 4 2.10 700 80 20 5 5.00 700 80 20

[0866] Mass Spectrometry

[0867] All experiments were done on an API 3000 triple quadrupole instrument (AB Sciex), operated in positive turbo-ionspray mode (‘TIS+’). The instrument parameters had been optimized during method development. The MS/MS transitions employed were as shown in Table 6.

TABLE-US-00006 TABLE 6 Q1, [M + H] + (35Cl2) Q3 [M + H—HCl] + (35Cl2) Compound (Da) (Da) Compound 20 321.1 285.0 Compound 22 349.2 318.9

[0868] Description of Bioanalytical Experiment and Acceptance Criteria

[0869] The calibration range for compound 20 was set up to cover concentrations between 0.988 and 20000 ng/mL. Two sets of calibration samples were used, one set placed before and the other placed after the study samples. In addition, QC samples at 5 levels (two samples at each level) were included in the run, as performance indicators and for run acceptance.

[0870] Acceptance criteria for calibration and QC samples were applied, as follows: [0871] The absolute % RE (% RE) relative to the nominal concentration for individual calibration and QC samples should be within 20% (or 25% at LLOQ); [0872] A calibration level was considered valid when at least one of the calibration samples at that concentration level was accepted by the above |% RE| criterion; [0873] A QC level was considered valid when at least one of the QC samples at that concentration level was accepted by the above % RE criterion.

[0874] The lowest and highest accepted calibration concentration levels were adopted as the lower and upper limit of quantification, LLOQ and HLOQ, respectively.

[0875] Bioanalytical Results

[0876] For compound 20, the highest calibration level (STD L, 20000 ng/mL) did not pass acceptance criteria as both calibration samples displayed too high a bias (see Table 7). All other calibration levels of compound 20, STD A through STD K, were accepted with single samples at STD C and STD G displaying too high bias. As a consequence, the lowest level (STD A, 0.988 ng/mL) was adopted as the LLOQ and the next higher level (STD K, 8000 ng/mL) was adopted as the HLOQ. One of the QC LLOQ and one of the QC Med sample results had too high a bias. The overall method performance in the bioanalytical run was accepted for compound 20.

[0877] Calibration and QC concentration levels employed are shown in Table 7:

TABLE-US-00007 TABLE 7 Compound 20 concentration Sample indicator (ng/mL) STD A 0.988 STD B 2.37 STD C 5.93 STD D 14.8 STD E 35.6 STD F 88.9 STD G 222 STD H 533 STD I 1333 STD J 3333 STD K 8000 STD L 20000 QCLLQ 2.37 QCLow 14.8 QCMed 88.9 QCHigh 1333 QCOC 8000

[0878] The bioanalysis results for plasma and brain samples are presented in Tables 8 and 9.

TABLE-US-00008 TABLE 8 Concentration compound 20 Group IRN (ng/mL) A_0 2 .sup.     0.00 .sup.a A_0 4    2.16 A_0 6 .sup.     0.00 .sup.a A_0 8 .sup.     0.00 .sup.a A_0 10 .sup.     0.00 .sup.a B_0.25 12    2.66 B_0.25 14 .sup. 17,900 .sup.b B_0.25 16 .sup. 12,000 .sup.b C_0.5 18 .sup. 11,500 .sup.b C_0.5 20 .sup. 10,500 .sup.b C_0.5 22 .sup. 11,100 .sup.b D_1 24 6,890 D_1 26 7,130 D_1 28 7,470 E_2 30 4,150 E_2 32 4,180 E_2 34 4,440 F_8 36   99.3 F_8 38   22.5 F_8 40   21.9 .sup.a “0.00” represents ‘below limit of quantification’ (LLOQ; the LLOQ was 0.988 ng/mL). .sup.b Value is out of range (0.988-8000 ng/mL); two calibrators at 20000 ng/mL were rejected but showed an average response of 14000 ng/mL.

TABLE-US-00009 TABLE 9 Homogenate Brain concentration concentration Brain weight of compound 20 Group IRN (ng/mL) (g) (ng/g) A_0 2    .sup. 0.00 .sup.a 0.453     0.00 .sup.a A_0 4    .sup. 0.00 .sup.a 0.483     0.00 .sup.a A_0 6    .sup. 0.00 .sup.a 0.451     0.00 .sup.a A_0 8    .sup. 0.00 .sup.a 0.487     0.00 .sup.a A_0 10    .sup. 0.00 .sup.a 0.472     0.00 .sup.a B_0.25 12    .sup. 0.00 .sup.a 0.463     0.00 .sup.a B_0.25 14 2300  0.445 20674  B_0.25 16 1250  0.460 10870  C_0.5 18 1400  0.482 11618  C_0.5 20 844 0.458 7371 C_0.5 22 1200  0.458 10480  D_1 24 888 0.474 7494 D_1 26 859 0.459 7486 D_1 28 789 0.461 6846 E_2 30 410 0.455 3604 E_2 32 385 0.461 3341 E_2 34 294 0.467 2518 F_8 36    7.53 0.478    63.0 F_8 38    1.83 0.489    15.0 F_8 40    1.53 0.476    12.9 .sup.a “0.00” represents “below limit of quantification” (LLOQ; the LLOQ was 0.988 ng/mL).

[0879] In the plasma samples, the following observations were made: [0880] There was one minor response in a pre-dose sample (one A_0 sample; found at 2.16 ng/mL). This response may have come from a minor contamination or from assay interference. Although selectivity of LC-MS/MS methods is generally high, selectivity for compound 20 in plasma was not tested. Conclusions can only be drawn after more elaborate method qualification or even method validation. At less than 3 times LLOQ, this pre-dose response is considered negligible here. [0881] Results for most measurements in time point B_0.25 and all measurements in time point C_0.5 are above the upper limit of quantification (ULOQ, at 8000 ng/mL). For obtaining more reliable results, these samples would have to be diluted prior to analysis. It is noted that a highest calibrator at 20000 ng/mL was included in the run but failed on bias. The mean back-calculated concentration of 20000 ng/mL was 14000 ng/mL, indicating a bias of −30% at that level. The above ULOQ results were included in this Example as indicative values, in support of PK evaluation. However, the results from B_0.25 and C_0.5 time points should be treated with caution. [0882] Results from the first subject in the time point B_0.25 (IRN 12) are unlikely to be near the observed 2.66 ng/mL, as that does not match with the relatively high concentrations observed in the other two subjects at this first post-dose time point (IRN 14 and 16). Provisionally, PK evaluation for this time point was conducted for both cases: (1) mean of 3 and (2) mean of two with exclusion of this BLOQ result.

[0883] In the brain (homogenate) samples one result appear different from expectation: [0884] results from the first subject in the time point B_0.25 (IRN 12) are unlikely to be below LLOQ, as that does not match with the relatively high concentrations observed in the other two subjects at this first post-dose time point (IRN 14 and 16). Please note that this parallels the findings for plasma from this subject (IRN 12). Provisionally, PK evaluation for this time point was conducted for both cases: (1) mean of 3 and (2) mean of two with exclusion of this BLOQ result.

[0885] Pharmacokinetic Evaluation

[0886] Evaluation of pharmacokinetic parameters was conducted by calculation from the mean concentration (n=5 pre-dose, n=3 post-dose) at each time point. The pharmacokinetic results are summarized below.

[0887] Mouse Plasma

[0888] Results for pharmacokinetic evaluation are given in Tables 10-12 and FIGS. 7 and 8. No corrections were made for results above the ULOQ or for the inclusion of the result for animal IRN12 in group B_0.25.

TABLE-US-00010 TABLE 10 Mean Group Concentration Group Time Point (h) (ng/mL) A_0 0.00     0.432 B_0.25 0.25  .sup. 9968 .sup.a C_0.5 0.50 11033  D_1 1.00 7163 E_2 2.00 4257 F_8 8.00    47.9 .sup.a Excluding IRN 12 result: 14950 ng/mL

[0889] Tables 11 and 12 provide plasma pharmacokinetic profile of compound 20.

TABLE-US-00011 TABLE 11 .sup.(a) Parameter Value Unit C.sub.max 11033 ng/mL T.sub.max 0.50 hours (h) K.sub.elimination 0.725 per hour (h.sup.−1) Half life (t.sub.1/2) 0.96 hours (h) AUC(0-8 h) 27044 ng/mL .Math. h AUC(0-inf) 27055 ng/mL .Math. h .sup.(a) excluding IRN12 result.

TABLE-US-00012 TABLE 12 .sup.(a){ Parameter Value Unit C.sub.max 14950 ng/mL T.sub.max 0.25 hours (h) K.sub.elimination 0.730 per hour (h.sup.−1) Half life (t.sub.1/2) 0.95 hours (h) AUC(0-8 h) 28290 ng/mL .Math. h AUC(0-inf) 28301 ng/mL .Math. h .sup.(a){ including IRN12 result.

[0890] Mouse Brain Tissue

[0891] Results for brain tissue pharmacokinetic evaluation are given in FIGS. 9 and 10 and Tables 13-15. No corrections were made for the inclusion of the odd result for animal IRN 12 in group B_0.25.

TABLE-US-00013 TABLE 13 Mean Group Concentration Group Time Point (h) Homogenate (ng/mL) Tissue (ng/g) A_0 0.00 0.00     0.00 B_0.25 0.25 1183 .sup. 10515 .sup.a C_0.5 0.50 1148 9823 D_1 1.00 845 7275 E_2 2.00 363 3154 F_8 8.00 3.63    30.0 .sup.(a) excluding IRN 12 result: 15772 ng/g.

[0892] Tables 14 and 15 provide brain tissue pharmacokinetic profile of compound 20.

TABLE-US-00014 TABLE 14 .sup.(a) Parameter Value Unit C.sub.max 10515 ng/mL T.sub.max 0.25 hours (h) K.sub.elimination 0.769 per hour (h.sup.−1) Half life (t.sub.1/2) 0.90 hours (h) AUC(0-8 h) 22898 ng/mL .Math. h AUC(0-inf) 22908 ng/mL .Math. h .sup.(a) excluding IRN 12 result.

TABLE-US-00015 TABLE 15 .sup.(a) Parameter Value Unit C.sub.max 15772 ng/mL T.sub.max 0.25 hours (h) K.sub.elimination 0.789 per hour (h.sup.−1) Half life (t.sub.1/2) 0.88 hours (h) AUC(0-8 h) 24212 ng/mL .Math. h AUC(0-inf) 22908 ng/mL .Math. h .sup.(a) including IRN 12 result.

Example 4. Effect of the Compounds of the Invention on the Total Level of Tau and Level of p-Tau in Cerebrospinal Fluid (CSF) and Brain in the Tau Transgenic Mouse Model (hTAU441)

[0893] To assess the effect of the compounds of the invention on p-tau accumulation, age-matched (e.g., 5 month old) transgenic mice humanized for the tau gene (hTAU mice) may be treated with low- or high-dose of a compound of the invention or vehicle by intraperitoneal administration for 7 days (N=6 per arm). Dose of the compound of the invention may be calculated based on the PK results. hTAU transgenic mice (C.sub.57BL/6 background) over-express TAU441 bearing the missense mutations V337M and R406W under the control of the brain specific murine Thy-1 promoter. This human mutated tau isoform is expressed in high levels and the tau pathology and is visible at an early age starting at four months. Severity of the brain pathology correlates with increasing age and behavioral deficits, whereas no motor deficits occur. All animals may be sacrificed and quantified for soluble and insoluble tau and p-tau brain (hippocampus and cortex) using MSD multiarray p-tau (ThR.sup.211) immunosorbent assay (Meso Scale Discovery, Rockville, Md.) to establish total tau and p-tau levels in CSF and Hsp70 levels in brain extracts. Specifically, the animals may be anaesthetized with ketamine/xylazin mix (note: isoflurane is known to influence p-tau levels), kept warm and in a horizontal position, prior to and during the collection of CSF followed by blood. The volume of CSF collected in hTAU441 is only 2-6 μL/mouse compared to some strains (2-15 μL/mouse). p-Tau (ThR.sup.211) and total tau levels may be assessed using phospho-PHF-Tau pThR.sup.211 (MSD duplex kit, Meso Scale Discovery, Rockville, Md.).

[0894] Administration of a compound of the invention may lead to a decrease in p-tau levels in mice treated with a compound of the invention relative to p-tau levels in mice administered a vehicle.

Example 5. Effect of the Compounds of the Invention on Memory and Learning in the hTAU441 Transgenic Mouse Model

[0895] Five month old transgenic hTAU mice described in Example 3 may be administered intraperitoneally a low- or high-dose of a compound of the invention groups or a vehicle daily for 12 weeks (N=15 per arm). A corresponding untreated group of mice will be analyzed as baseline. Behavioral testing, e.g., Probe Trial, Nose Poke Curiosity and Activity Test, and the Morris Water Maze task may be performed. Upon completion of the study, CSF may be collected and brain tissue may be harvested from these animals. Total tau levels and p-tau levels may be assessed in the CSF and brain. Additionally, immunohistochemical determination of tau pathology may be conducted. Tau depositions may be determined using the monoclonal antibodies AT180 (Thermo Scientific Pierce Antibodies, Rockford, Ill.) and HT7 (Thermo Scientific Pierce Antibodies, Rockford, Ill.). Sodium selenate, a PP2A phosphatase activator that dephosphorylates tau and reverses memory deficits, is effective in the TMHT tau model (Corcoran et al., J. Clin. Neuroscience, 17:1025-1033, 2010).

[0896] If chronic treatment with a compound of the invention is associated with a general improvement in memory function as measured by the Morris Maze, reduced levels of p-tau in the brain may be observed.

OTHER EMBODIMENTS

[0897] The invention is also described by the following numbered embodiments:

[0898] 1. A compound according to formula (I):

##STR00349##

or a pharmaceutically acceptable salt thereof,
where [0899] Z.sup.1 is —OR.sup.7, —N(R.sup.10)R.sup.7, —SR.sup.7, or —C(R.sup.10)(R.sup.11)R.sup.7; [0900] Z.sup.2 is —N═ or —C(R.sup.3)═; [0901] each R.sup.1 and R.sup.2 is, independently, H or optionally substituted C.sub.1-3 alkyl; [0902] R.sup.3 is H, halogen, cyano, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.1-3 alkoxy, or optionally substituted amino, and R.sup.4 is halogen, cyano, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.1-3 alkoxy, optionally substituted amino, optionally substituted C.sub.1-6 thioalkoxy, or optionally substituted C.sub.6-10 aryl, or R.sup.3 and R.sup.4, together with the atoms to which each is attached, join to form an optionally substituted five- or six-membered ring optionally including one nitrogen, one oxygen, or one sulfur, where the nitrogen is optionally substituted with R.sup.9; [0903] each R.sup.5 and R.sup.6 is, independently, H, optionally substituted C.sub.1-3 alkyl, optionally substituted C.sub.1-3 alkoxy, halogen, or CN; [0904] R.sup.7 is optionally substituted C.sub.1-3 alkyl, optionally substituted C.sub.1-3 alkcycloalkyl, optionally substituted C.sub.1-3 alkheterocyclyl, or optionally substituted C.sub.1-3 alkaryl, and R.sup.8 is H; or R.sup.7 and R.sup.8, together with the atoms to which each is attached, join to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur; [0905] R.sup.9 is H, optionally substituted C.sub.1-3 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted C.sub.6-10 aryl, optionally substituted C.sub.2-9 heteroaryl, optionally substituted C.sub.2-9 heterocyclyl, optionally substituted C.sub.1-3 alkcycloalkyl, optionally substituted C.sub.1-3 alkheterocyclyl, or optionally substituted C.sub.1-3 alkaryl; [0906] R.sup.10 is H, optionally substituted C.sub.1-3 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted C.sub.6-10 aryl, optionally substituted C.sub.2-9 heteroaryl, optionally substituted C.sub.2-9 heterocyclyl, optionally substituted C.sub.1-3 alkcycloalkyl, optionally substituted C.sub.1-3 alkheterocyclyl, or optionally substituted C.sub.1-3 alkaryl, and R.sup.11 is H, optionally substituted C.sub.1-3 alkyl, or R.sup.10 and R.sup.11 combine to form ═O or ═S; [0907] R.sup.m is H, halogen, optionally substituted C.sub.1-4 alkyl, or optionally substituted C.sub.1-3 alkoxy; where, [0908] when Z.sup.2 is CR.sup.3, each of R.sup.1 and R.sup.2 is H, R.sup.3 is H, R.sup.4 is methyl or chloro, and each of R.sup.5 and R.sup.6 is chloro, [0909] Z.sup.1 is not methoxy; [0910] when Z.sup.2 is N, each of R.sup.5 and R.sup.6 is chloro, R.sup.3 is H, R.sup.4 is substituted C.sub.1-6 thioalkoxy, [0911] Z.sup.1 is not cyanomethoxy or aminomethoxy; [0912] when Z.sup.2 is CR.sup.3, each of R.sup.5 and R.sup.6 is chloro, R.sup.3 is H, and R.sup.4 is halogen, [0913] Z.sup.1 is not 2-amino-2-oxoethoxy, 2-(N,N-diethylamino)ethoxy, methoxy, or benzyloxy; [0914] when R.sup.5 is chloro, R.sup.6 is bromo, Z.sup.1 is —OR.sup.7, and R.sup.3 and R.sup.4 combine to form a group according to formula (IIa):

##STR00350## [0915] R.sup.7 is not methyl, ethyl, n-propyl, 2-(N-pyrazolyl)ethyl, 2-(N-imidazolyl)ethyl, 3-hydroxypropyl, cyanomethyl, 2-chloroethyl, 2-hydroxyethyl, 2-oxo-propyl, 2-(N,N-dimethylamino)ethyl, difluoromethyl, or 2-(t-butylamino)ethyl; [0916] when each R.sup.5 and R.sup.6 is bromo, Z.sup.1 is —OR.sup.7, and R.sup.3 and R.sup.4 combine to form a group according to formula (IIa), [0917] R.sup.7 is not methyl; [0918] when each R.sup.5 and R.sup.6 is chloro, Z.sup.1 is —OR.sup.7, and R.sup.3 and R.sup.4 combine to form a group according to formula (IIa), [0919] R.sup.7 is not methyl, 2-(N-imidazolyl)ethyl, methoxymethyl, 2-(N-pyrazolyl)ethyl, 2-(3-methylpyrazol-1-yl)ethyl, 2-pyridyl-methyl, 1,3-dimethyl-1H-1,2,4-triazol-5-yl-methyl, 2-pyrimidinylmethyl, imidazol-2-yl-methyl, 5-methyl-isoxazol-3-yl-methyl, 4-methyl-imidazol-5-yl-methyl, or 3-methyl-1,2,4-oxadiazol-5-yl-methyl; [0920] when each R.sup.5 and R.sup.6 is chloro, Z.sup.1 is —OR.sup.7, R.sup.7 and R.sup.8 combine to form —CH.sub.2—CH.sub.2—, and R.sup.3 and R.sup.4 combine to form a group according to formula (IIa), [0921] R.sup.9 is not ethoxycarbonyl, cyclobutylaminocarbonyl, or cyclobutadienylaminocarbonyl [0922] when R.sup.5 is methoxy, R.sup.6 is methyl, Z.sup.1 is —OR.sup.7, and R.sup.3 and R.sup.4 combine to form a group according to formula (IIa), [0923] R.sup.7 is not methyl; [0924] when R.sup.5 is chloro, R.sup.6 is ethyl, Z.sup.1 is —OR.sup.7, and R.sup.3 and R.sup.4 combine to form a group according to formula (IIa), [0925] R.sup.7 is not methyl; [0926] when each R.sup.5 and R.sup.6 is chloro, Z.sup.1 is —OR.sup.7, and R.sup.3 and R.sup.4 combine to form a group according to formula (IIb) or (IIc),

##STR00351## [0927] R.sup.7 is not methyl or 2-(N,N-diethylamino)ethyl; [0928] when R.sup.7 is methyl, R.sup.5 is chloro, Z.sup.1 is —OR.sup.7, and R.sup.3 and R.sup.4 combine to form a group according to formula (IIIa),

##STR00352## [0929] R.sup.6 is not bromo; [0930] when R.sup.5 is chloro, R.sup.6 is methoxy, Z.sup.1 is —OR.sup.7, and R.sup.3 and R.sup.4 combine to form a group according to formula (IIIb):

##STR00353## [0931] neither R.sup.1 nor R.sup.2 is 2-(N,N-diethylamino)ethyl; [0932] when each R.sup.5 and R.sup.6 is chloro, Z.sup.1 is —OR.sup.7, and R.sup.3 and R.sup.4 combine to form a group according to formula (IVa):

##STR00354## [0933] R.sup.7 is not 3-(N-morpholinyl)propyl, benzyl, 1-ethyl-pyrrolydin-3-yl, 1-methyl-piperidin-4-yl, 2-(1-methyl-pyrrolidin-2-yl)ethyl, or 3-(N,N-diethylamino)propyl; [0934] when each R.sup.5 and R.sup.6 is chloro, Z.sup.1 is —OR.sup.7, and R.sup.3 and R.sup.4 combine to form a group according to formula (IVb):

##STR00355## [0935] R.sup.7 is not 2-methoxyethyl or benzyl; [0936] when each R.sup.5 and R.sup.6 is chloro, Z.sup.1 is —OR.sup.7, and R.sup.3 and R.sup.4 combine to form a group according to formula (IVc):

##STR00356## [0937] R.sup.7 is not 2-(N,N-diethylamino)ethyl or 3-(N,N-dimethylamino)propyl; [0938] when each R.sup.5 and R.sup.6 is chloro, Z.sup.1 is —OR.sup.7, and R.sup.3 and R.sup.4 combine to form a group according to formula (IVd):

##STR00357## [0939] R.sup.7 is not 2-(pyrrolidin-1-yl)ethyl or 2-hydroxyethyl; [0940] when each R.sup.5 and R.sup.6 is chloro, Z.sup.1 is —OR.sup.7, and R.sup.3 and R.sup.4 combine to form a group according to formula (IVe) or (IVf):

##STR00358## [0941] R.sup.7 is not benzyl; [0942] when R.sup.5 is chloro, R.sup.6 is bromo, Z.sup.1 is —OR.sup.7, and R.sup.3 and R.sup.4 combine to form a group according to formula (IVg), (IVh), (IVi), (IVj), or (IVk):

##STR00359## [0943] R.sup.7 is not methyl; [0944] when R.sup.6 is methyl, [0945] each R.sup.1 and R.sup.2 is H; and [0946] when R.sup.3 is H, Z.sup.1 is —OR.sup.7, and each R.sup.5 and R.sup.6 is chloro, [0947] R.sup.7 is not methyl.

[0948] 2. The compound of embodiment 1, where R.sup.m is H.

[0949] 3. A compound according to formula (Ia):

##STR00360##

or a pharmaceutically acceptable salt thereof,
where [0950] each R.sup.1 and R.sup.2 is, independently, H or optionally substituted C.sub.1-3 alkyl; [0951] R.sup.3 is H, halogen, cyano, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.1-3 alkoxy, or optionally substituted amino, and R.sup.4 is halogen, cyano, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.1-3 alkoxy, optionally substituted amino, optionally substituted C.sub.1-6 thioalkyl, or optionally substituted C.sub.6-10 aryl, or R.sup.3 and R.sup.4, together with the atoms to which each is attached, join to form an optionally substituted five- or six-membered ring optionally including one nitrogen, one oxygen, or one sulfur, where the nitrogen is optionally substituted with R.sup.9; [0952] each R.sup.5 and R.sup.6 is, independently, H, optionally substituted C.sub.1-3 alkyl, optionally substituted C.sub.1-3 alkoxy, halogen, or CN; [0953] R.sup.7 is optionally substituted C.sub.1-3 alkyl, optionally substituted C.sub.1-3 alkcycloalkyl, optionally substituted C.sub.1-3 alkheterocyclyl, or optionally substituted C.sub.1-3 alkaryl, and R.sup.8 is H; or R.sup.7 and R.sup.8, together with the atoms to which each is attached, join to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur; [0954] R.sup.9 is H, optionally substituted C.sub.1-3 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted C.sub.6-10 aryl, optionally substituted C.sub.2-9 heteroaryl, optionally substituted C.sub.2-9 heterocyclyl, optionally substituted C.sub.1-3 alkcycloalkyl, optionally substituted C.sub.1-3 alkheterocyclyl, or optionally substituted C.sub.1-3 alkaryl; [0955] Z.sup.1 is —OR.sup.7, —N(R.sup.10)R.sup.7, —SR.sup.7, or —C(R.sup.10)(R.sup.11)R.sup.7; and [0956] R.sup.10 is H, optionally substituted C.sub.1-3 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted C.sub.6-10 aryl, optionally substituted C.sub.2-9 heteroaryl, optionally substituted C.sub.2-9 heterocyclyl, optionally substituted C.sub.1-3 alkcycloalkyl, optionally substituted C.sub.1-3 alkheterocyclyl, or optionally substituted C.sub.1-3 alkaryl, and R.sup.11 is H, optionally substituted C.sub.1-3 alkyl, or R.sup.10 and R.sup.11 combine to form ═O or ═S;
where, [0957] when each of R.sup.1 and R.sup.2 is H, R.sup.3 is H, R.sup.4 is methyl or chloro, and each of R.sup.5 and R.sup.6 is chloro, [0958] Z.sup.1 is not methoxy; [0959] when each of R.sup.5 and R.sup.6 is chloro, R.sup.3 is H, and R.sup.4 is halogen, [0960] Z.sup.1 is not 2-amino-2-oxoethoxy, 2-(N,N-diethylamino)ethoxy, methoxy, or benzyloxy; [0961] when R.sup.5 is chloro, R.sup.6 is bromo, Z.sup.1 is —OR.sup.7, and R.sup.3 and R.sup.4 combine to form a group according to formula (IIa):

##STR00361## [0962] R.sup.7 is not methyl, ethyl, n-propyl, 2-(N-pyrazolyl)ethyl, 2-(N-imidazolyl)ethyl, 3-hydroxypropyl, cyanomethyl, 2-chloroethyl, 2-hydroxyethyl, 2-oxo-propyl, 2-(N,N-dimethylamino)ethyl, difluoromethyl, or 2-(t-butylamino)ethyl; [0963] when each R.sup.5 and R.sup.6 is bromo, Z.sup.1 is —OR.sup.7, and R.sup.3 and R.sup.4 combine to form a group according to formula (IIa), [0964] R.sup.7 is not methyl; [0965] when each R.sup.5 and R.sup.6 is chloro, Z.sup.1 is —OR.sup.7, and R.sup.3 and R.sup.4 combine to form a group according to formula (IIa), [0966] R.sup.7 is not methyl, 2-(N-imidazolyl)ethyl, methoxymethyl, 2-(N-pyrazolyl)ethyl, 2-(3-methylpyrazol-1-yl)ethyl, 2-pyridyl-methyl, 1,3-dimethyl-1H-1,2,4-triazol-5-yl-methyl, 2-pyrimidinylmethyl, imidazol-2-yl-methyl, 5-methyl-isoxazol-3-yl-methyl, 4-methyl-imidazol-5-yl-methyl, or 3-methyl-1,2,4-oxadiazol-5-yl-methyl; [0967] when each R.sup.5 and R.sup.6 is chloro, Z.sup.1 is —OR.sup.7, R.sup.7 and R.sup.8 combine to form —CH.sub.2—CH.sub.2—, and R.sup.3 and R.sup.4 combine to form a group according to formula (IIa), [0968] R.sup.9 is not ethoxycarbonyl, cyclobutylaminocarbonyl, or cyclobutadienylaminocarbonyl [0969] when R.sup.5 is methoxy, R.sup.6 is methyl, Z.sup.1 is —OR.sup.7, and R.sup.3 and R.sup.4 combine to form a group according to formula (IIa), [0970] R.sup.7 is not methyl; [0971] when R.sup.5 is chloro, R.sup.6 is ethyl, Z.sup.1 is —OR.sup.7, and R.sup.3 and R.sup.4 combine to form a group according to formula (IIa), [0972] R.sup.7 is not methyl; [0973] when each R.sup.5 and R.sup.6 is chloro, Z.sup.1 is —OR.sup.7, and R.sup.3 and R.sup.4 combine to form a group according to formula (IIb) or (IIc),

##STR00362## [0974] R.sup.7 is not methyl or 2-(N,N-diethylamino)ethyl; [0975] when R.sup.7 is methyl, R.sup.5 is chloro, Z.sup.1 is —OR.sup.7, and R.sup.3 and R.sup.4 combine to form a group according to formula (IIIa),

##STR00363## [0976] R.sup.6 is not bromo; [0977] when R.sup.5 is chloro, R.sup.6 is methoxy, Z.sup.1 is —OR.sup.7, and R.sup.3 and R.sup.4 combine to form a group according to formula (IIIb):

##STR00364## [0978] neither R.sup.1 nor R.sup.2 is 2-(N,N-diethylamino)ethyl; [0979] when each R.sup.5 and R.sup.6 is chloro, Z.sup.1 is —OR.sup.7, and R.sup.3 and R.sup.4 combine to form a group according to formula (IVa):

##STR00365## [0980] R.sup.7 is not 3-(N-morpholinyl)propyl, benzyl, 1-ethyl-pyrrolydin-3-yl, 1-methyl-piperidin-4-yl, 2-(1-methyl-pyrrolidin-2-yl)ethyl, or 3-(N,N-diethylamino)propyl; [0981] when each R.sup.5 and R.sup.6 is chloro, Z.sup.1 is —OR.sup.7, and R.sup.3 and R.sup.4 combine to form a group according to formula (IVb):

##STR00366## [0982] R.sup.7 is not 2-methoxyethyl or benzyl; [0983] when each R.sup.5 and R.sup.6 is chloro, Z.sup.1 is —OR.sup.7, and R.sup.3 and R.sup.4 combine to form a group according to formula (IVc):

##STR00367## [0984] R.sup.7 is not 2-(N,N-diethylamino)ethyl or 3-(N,N-dimethylamino)propyl; [0985] when each R.sup.5 and R.sup.6 is chloro, Z.sup.1 is —OR.sup.7, and R.sup.3 and R.sup.4 combine to form a group according to formula (IVd):

##STR00368## [0986] R.sup.7 is not 2-(pyrrolidin-1-yl)ethyl or 2-hydroxyethyl; [0987] when each R.sup.5 and R.sup.6 is chloro, Z.sup.1 is —OR.sup.7, and R.sup.3 and R.sup.4 combine to form a group according to formula (IVe) or (IVf):

##STR00369## [0988] R.sup.7 is not benzyl; [0989] when R.sup.5 is chloro, R.sup.6 is bromo, Z.sup.1 is —OR.sup.7, and R.sup.3 and R.sup.4 combine to form a group according to formula (IVg), (IVh), (IVi), (IVj), or (IVk):

##STR00370## [0990] R.sup.7 is not methyl; [0991] when R.sup.6 is methyl, [0992] each R.sup.1 and R.sup.2 is H; and [0993] when R.sup.3 is H, Z.sup.1 is —OR.sup.7, and each R.sup.5 and R.sup.6 is chloro, [0994] R.sup.7 is not methyl.

[0995] 4. A compound according to formula (Ib):

##STR00371##

or a pharmaceutically acceptable salt thereof, [0996] where [0997] each of R.sup.1 and R.sup.2 is, independently, H or optionally substituted C.sub.1-3 alkyl; [0998] R.sup.3 is H, halogen, cyano, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.1-3 alkoxy, or optionally substituted amino, and R.sup.4 is halogen, cyano, optionally substituted C.sub.1-6 alkyl, optionally substituted C.sub.1-3 alkoxy, optionally substituted amino, optionally substituted C.sub.1-6 thioalkoxy, or optionally substituted C.sub.6-10 aryl, or R.sup.3 and R.sup.4, together with the atoms to which each is attached, join to form an optionally substituted five- or six-membered ring optionally including one nitrogen, one sulfur, or one oxygen, where the nitrogen is optionally substituted with R.sup.9; [0999] each of R.sup.5 and R.sup.6 is, independently, H, optionally substituted C.sub.1-3 alkyl, optionally substituted C.sub.1-3 alkoxy, halogen, or CN; [1000] R.sup.7 is optionally substituted C.sub.1-3 alkyl, optionally substituted C.sub.1-3 alkcycloalkyl, optionally substituted C.sub.1-3 alkheterocyclyl, or optionally substituted C.sub.1-3 alkaryl, and R.sup.8 is H; or R.sup.7 and R.sup.8, together with the atoms to which each is attached, join to form an optionally substituted five- or six-membered ring; and [1001] R.sup.9 is H, optionally substituted C.sub.1-3 alkyl, optionally substituted C.sub.3-8 cycloalkyl, optionally substituted C.sub.6-10 aryl, optionally substituted C.sub.2-9 heteroaryl, optionally substituted C.sub.2-9 heterocyclyl, optionally substituted C.sub.1-3 alkcycloalkyl, optionally substituted C.sub.1-3 alkheterocyclyl, or optionally substituted C.sub.1-3 alkaryl;
where, [1002] when each of R.sup.1 and R.sup.2 is H, R.sup.3 is H, R.sup.4 is methyl or chloro, and each of R.sup.5 and R.sup.6 is chloro, [1003] R.sup.7 is not methyl; [1004] when each of R.sup.5 and R.sup.6 is chloro, R.sup.3 is H, and R.sup.4 is halogen, [1005] R.sup.7 is not 2-amino-2-oxoethyl, 2-(N,N-diethylamino)ethyl, methyl, or benzyl; [1006] when R.sup.5 is chloro, R.sup.6 is bromo, and R.sup.3 and R.sup.4 combine to form a group according to formula (IIa):

##STR00372## [1007] R.sup.7 is not methyl, ethyl, n-propyl, 2-(N-pyrazolyl)ethyl, 2-(N-imidazolyl)ethyl, 3-hydroxypropyl, cyanomethyl, 2-chloroethyl, 2-hydroxyethyl, 2-oxo-propyl, 2-(N,N-dimethylamino)-ethyl, difluoromethyl, or 2-(t-butylamino)ethyl; [1008] when each R.sup.5 and R.sup.6 is bromo, and R.sup.3 and R.sup.4 combine to form a group according to formula (IIa), [1009] R.sup.7 is not methyl; [1010] when each R.sup.5 and R.sup.6 is chloro, R.sup.8 is H, and R.sup.3 and R.sup.4 combine to form a group according to formula (IIa), [1011] R.sup.7 is not methyl, 2-(N-imidazolyl)ethyl, methoxymethyl, 2-(N-pyrazolyl)ethyl, 2-(3-methylpyrazol-1-yl)ethyl, 2-pyridyl-methyl, 1,3-dimethyl-1H-1,2,4-triazol-5-yl-methyl, 2-pyrimidinylmethyl, imidazol-2-yl-methyl, 5-methyl-isoxazol-3-yl-methyl, 4-methyl-imidazol-5-yl-methyl, or 3-methyl-1,2,4-oxadiazol-5-yl-methyl; [1012] when each R.sup.5 and R.sup.6 is chloro, R.sup.7 and R.sup.8 combine to form —CH.sub.2—CH.sub.2—, and R.sup.3 and R.sup.4 combine to form a group according to formula (IIa), [1013] R.sup.9 is not ethoxycarbonyl, cyclobutylaminocarbonyl, or cyclobutadienylaminocarbonyl; [1014] when R.sup.5 is methoxy, R.sup.6 is methyl, and R.sup.3 and R.sup.4 combine to form a group according to formula (IIa), [1015] R.sup.7 is not methyl; [1016] when R.sup.5 is chloro, R.sup.6 is ethyl, and R.sup.3 and R.sup.4 combine to form a group according to formula (IIa), [1017] R.sup.7 is not methyl; [1018] when each R.sup.5 and R.sup.6 is chloro, and R.sup.3 and R.sup.4 combine to form a group according to formula (IIb) or (IIc),

##STR00373## [1019] R.sup.7 is not methyl or 2-(N,N-diethylamino)ethyl; [1020] when R.sup.7 is methyl, R.sup.5 is chloro, and R.sup.3 and R.sup.4 combine to form a group according to formula (IIIa),

##STR00374## [1021] R.sup.6 is not bromo; [1022] when R.sup.5 is chloro, R.sup.6 is methoxy, and R.sup.3 and R.sup.4 combine to form a group according to formula (IIIb):

##STR00375## [1023] neither R.sup.1 nor R.sup.2 is 2-(N,N-diethylamino)ethyl; [1024] when each R.sup.5 and R.sup.6 is chloro, and R.sup.3 and R.sup.4 combine to form a group according to formula (IVa):

##STR00376## [1025] R.sup.7 is not 3-(N-morpholinyl)propyl, benzyl, 1-ethyl-pyrrolydin-3-yl, 1-methyl-piperidin-4-yl, 2-(1-methyl-pyrrolidin-2-yl)ethyl, or 3-(N,N-diethylamino)propyl; [1026] when each R.sup.5 and R.sup.6 is chloro, and R.sup.3 and R.sup.4 combine to form a group according to formula (IVb):

##STR00377## [1027] R.sup.7 is not 2-methoxyethyl or benzyl; [1028] when each R.sup.5 and R.sup.6 is chloro, and R.sup.3 and R.sup.4 combine to form a group according to formula (IVc):

##STR00378## [1029] R.sup.7 is not 2-(N,N-diethylamino)ethyl or 3-(N,N-dimethylamino)propyl; [1030] when each R.sup.5 and R.sup.6 is chloro, and R.sup.3 and R.sup.4 combine to form a group according to formula (IVd):

##STR00379## [1031] R.sup.7 is not 2-(pyrrolidin-1-yl)ethyl or 2-hydroxyethyl; [1032] when each R.sup.5 and R.sup.6 is chloro, and R.sup.3 and R.sup.4 combine to form a group according to formula (IVe) or (IVf):

##STR00380## [1033] R.sup.7 is not benzyl; [1034] when R.sup.5 is chloro, R.sup.6 is bromo, and R.sup.3 and R.sup.4 combine to form a group according to formula (IVg), (IVh), (IVi), (IVj), or (IVk):

##STR00381## [1035] R.sup.7 is not methyl; [1036] when R.sup.6 is methyl, [1037] each R.sup.1 and R.sup.2 is H; and [1038] when R.sup.3 is H, and each R.sup.5 and R.sup.6 is chloro, [1039] R.sup.7 is not methyl.

[1040] 5. The compound of any one of embodiments 1 to 4, where R.sup.3 is H, halogen, optionally substituted C.sub.1-3 alkyl, or optionally substituted C.sub.1-3 alkoxy, and R.sup.4 is halogen, optionally substituted C.sub.1-3 alkyl, optionally substituted C.sub.1-3 alkoxy, optionally substituted amino, optionally substituted C.sub.1-6 thioalkyl, or optionally substituted C.sub.6-10 aryl, or R.sup.3 and R.sup.4, together with the atoms to which each is attached, join to form an optionally substituted five- or six-membered ring optionally including one nitrogen, one oxygen, or one sulfur, where the nitrogen is optionally substituted with R.sup.9.

[1041] 6. The compound of any one of embodiments 1 to 5, where R.sup.3 and R.sup.4, together with the atoms to which each is attached, join to form an optionally substituted five-membered ring.

[1042] 7. The compound of any one of embodiments 1 to 5, where R.sup.3 and R.sup.4 combine to form —CH.sub.2CH.sub.2CH.sub.2— group.

[1043] 8. The compound of any one of embodiments 1 to 5, where R.sup.3 and R.sup.4, together with the atoms to which each is attached, join to form an optionally substituted five-membered ring including one nitrogen.

[1044] 9. The compound of embodiment 8, where R.sup.3 and R.sup.4 combine to form —N(R.sup.9)—CH═CH— group.

[1045] 10. The compound of embodiment 9, where R.sup.9 is H.

[1046] 11. The compounds of any one of embodiments 1 to 5, where R.sup.3 and R.sup.4, together with the atoms to which each is attached, join to form an optionally substituted five-membered ring including one sulfur.

[1047] 12. The compound of any one of embodiments 1 to 5, where R.sup.3 and R.sup.4 combine to form —C(R.sup.13A)═C(R.sup.13B)—S— group, where R.sup.13A is H, and R.sup.13B is H or optionally substituted C.sub.1-3 alkyl.

[1048] 13. The compound of embodiment 12, where R.sup.13B is optionally substituted C.sub.1-3 alkyl.

[1049] 14. The compound of embodiment 13, where R.sup.13B is —C(O)—R.sup.13C, where R.sup.13C is optionally substituted C.sub.1-3 alkoxy or optionally substituted amino.

[1050] 15. The compound of any one of embodiments 1 to 5, where R.sup.3 and R.sup.4 combine to form —C(R.sup.13A)═C(R.sup.13B)—S— group, where R.sup.13A is H, and R.sup.13B is H or —C(O)—R.sup.13C, where R.sup.13C is optionally substituted C.sub.1-3 alkyl, optionally substituted C.sub.1-3 alkoxy, optionally substituted amino, or optionally substituted C.sub.2-9 heterocyclyl.

[1051] 16. The compound of any one of embodiments 1 to 5, where R.sup.4 is C.sub.1-3 alkyl.

[1052] 17. The compound of embodiment 16, where R.sup.4 is methyl, ethyl, or isopropyl.

[1053] 18. The compound of any one of embodiments 1 to 5, where R.sup.4 is C.sub.1-3 alkoxy.

[1054] 19. The compound of embodiment 18, where R.sup.4 is methoxy.

[1055] 20. The compound of any one of embodiments 1 to 5, where R.sup.4 is optionally substituted C.sub.1-6 thioalkoxy.

[1056] 21. The compound of embodiment 20, where R.sup.4 is 4-amino-4-oxobutyl.

[1057] 22. The compound of any one of embodiments 1 to 5, where R.sup.4 is optionally substituted amino.

[1058] 23. The compound of embodiment 22, where R.sup.4 is methylamino.

[1059] 24. The compound of any one of embodiments 1 to 5, where R.sup.4 is halogen.

[1060] 25. The compound of embodiment 24, where R.sup.4 is chloro.

[1061] 26. The compound of any one of embodiments 1-5 and 15-25, where R.sup.3 is hydrogen or C.sub.1-3 alkyl.

[1062] 27. The compound of embodiment 26, where R.sup.3 is hydrogen, methyl, or ethyl.

[1063] 28. The compound of any one of embodiments 1 to 5, where R.sup.3 and R.sup.4 combine to form —X.sup.1—X.sup.2—X.sup.3—, where [1064] X.sup.1 is —S—, —O—, —(CR.sup.14R.sup.15)—, —C(R.sup.16)═, —N(R.sup.9)—, —N═, H, or optionally substituted C.sub.1-3 alkyl; X.sup.2 is absent,—(CR.sup.17R.sup.18).sub.n—, —S—, —O—, —N═, —N(R.sup.9)—, —C(R.sup.19)═, ═N—, ═C(R.sup.20)—, or ═C(R.sup.21)—C(R.sup.22)═; [1065] X.sup.3 is —(CR.sup.14R.sup.15)—, —S—, —O—, —N(R.sup.9)—, ═N—, ═C(R.sup.23)—, halogen, optionally substituted C.sub.1-3 alkyl, optionally substituted C.sub.1-6 thioalkoxy, optionally substituted C.sub.1-3 alkoxy, or optionally substituted C.sub.6-10 aryl; [1066] each R.sup.14 and R.sup.15 is, independently, H or optionally substituted C.sub.1-3 alkyl, or R.sup.14 and R.sup.15 combine to form ═O or ═S; [1067] each R.sup.17 and R.sup.18 is, independently, H or optionally substituted C.sub.1-3 alkyl, or R.sup.17 and R.sup.18 combine to form ═O or ═S; [1068] each R.sup.16, R.sup.19, R.sup.20, R.sup.21, R.sup.22, and R.sup.23 is, independently, H, or optionally substituted C.sub.1-3 alkyl; and [1069] n is 1 or 2; and
where, when X.sup.2 is not absent, [1070] the chain of atoms —X.sup.1—X.sup.2—X.sup.3— includes no more than one heteroatom, the heteroatom being selected from the group consisting of nitrogen, oxygen, and sulfur.

[1071] 29. The compound of embodiment 28, where X.sup.1 is —(CR.sup.14R.sup.15)—, —C(R.sup.16)═, —N(R.sup.9)—, —N═, or optionally substituted C.sub.1-3 alkyl.

[1072] 30. The compound of embodiment 29, where X.sup.1 is —(CR.sup.14R.sup.15)—.

[1073] 31. The compound of embodiment 30, where each R.sup.14 and R.sup.15 is H.

[1074] 32. The compound of embodiment 29, where X.sup.1 is —C(R.sup.16)═.

[1075] 33. The compound of embodiment 32, where R.sup.16 is H.

[1076] 34. The compound of embodiment 29, where X.sup.1 is —N(R.sup.9)—.

[1077] 35. The compound of embodiment 34, where R.sup.9 is H or optionally substituted C.sub.1-3 alkyl.

[1078] 36. The compound of embodiment 35, where R.sup.9 is hydrogen, methyl, or ethyl.

[1079] 37. The compound of embodiment 29, where X.sup.1 is-N═.

[1080] 38. The compound of embodiment 29, where X.sup.1 is optionally substituted C.sub.1-3 alkyl.

[1081] 39. The compound of any one of embodiments 28 to 37, where X.sup.2 is absent, —(CH.sub.2).sub.n—, —N(R.sup.9)—, —C(H)═, ═C(R.sup.20)—, or ═C(H)—C(H)═.

[1082] 40. The compound of embodiment 39, where X.sup.2 is —C(H)═.

[1083] 41. The compound of embodiment 39, where X.sup.2 is —N(R.sup.9)—.

[1084] 42. The compound of embodiment 41, where R.sup.9 is H.

[1085] 43. The compound of embodiment 41, where R.sup.9 is optionally substituted C.sub.1-3 alkyl.

[1086] 44. The compound of embodiment 43, where R.sup.9 is —C(O)—N(H)-Et.

[1087] 45. The compound of embodiment 39, where X.sup.2 is ═C(R.sup.20)—.

[1088] 46. The compound of embodiment 45, where R.sup.20 is optionally substituted C.sub.1-3 alkyl.

[1089] 47. The compound of embodiment 39, where X.sup.2 is absent.

[1090] 48. The compound of any one of embodiments 28-37 and 39-47, where X.sup.3 is —CH.sub.2—, —S—, ═C(H)—, —N(R.sup.9)—, halogen, optionally substituted C.sub.1-3 alkyl, optionally substituted C.sub.1-3 alkoxy, optionally substituted C.sub.1-6 thioalkoxy, optionally substituted C.sub.6-10 aryl.

[1091] 49. The compound of embodiment 48, where X.sup.3 is —CH.sub.2—.

[1092] 50. The compound of embodiment 48, where X.sup.3 is —S—.

[1093] 51. The compound of embodiment 48, where X.sup.3 is ═C(H)—.

[1094] 52. The compound of embodiment 48, where X.sup.3 is —N(R.sup.9)—.

[1095] 53. The compound of embodiment 48, where X.sup.3 is halogen, optionally substituted C.sub.1-3 alkyl, optionally substituted C.sub.1-3 alkoxy, optionally substituted C.sub.1-6 thioalkoxy, or optionally substituted C.sub.6-10 aryl.

[1096] 54. The compound of any one of embodiments 1 to 53, where each R.sup.5 and R.sup.6 is, independently, halo or optionally substituted C.sub.1-3 alkyl.

[1097] 55. The compound of embodiment 54, where each R.sup.5 and R.sup.6 is halo.

[1098] 56. The compound of embodiment 55, where each R.sup.5 and R.sup.6 is chloro.

[1099] 57. The compound of any one of embodiments 1 to 56, where R.sup.7 and R.sup.8, together with the atoms to which each is attached, join to form an optionally substituted five- or six-membered ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

[1100] 58. The compound of any one of embodiments 1 to 56, where R.sup.7 and R.sup.8, together with the atoms to which each is attached, join to form an optionally substituted five- or six-membered saturated ring optionally including one or two heteroatoms selected from nitrogen, oxygen, and sulfur.

[1101] 59. The compound of any one of embodiments 1 to 56, where R.sup.7 and R.sup.8, together with the atoms to which each is attached, join to form an optionally substituted five- of six-membered ring optionally including one or two heteroatoms selected from nitrogen and oxygen.

[1102] 60. The compound of any one of embodiments 1 to 56, where R.sup.7 and R.sup.8, together with the atoms to which each is attached, join to form an optionally substituted five-membered ring.

[1103] 61. The compound of any one of embodiments 1 to 56, where the R.sup.7 and R.sup.8, together with the atoms to which each is attached, join to form an optionally substituted saturated five-membered ring.

[1104] 62. The compound of any one of embodiments 1 to 56, where the R.sup.7 and R.sup.8 combine to form a —CH.sub.2CH.sub.2— group.

[1105] 63. The compound of any one of embodiments 1 to 56, where R.sup.7 is optionally substituted C.sub.1-3 alkyl.

[1106] 64. The compound of embodiment 63, where R.sup.7 is methyl.

[1107] 65. The compound of embodiment 63, where R.sup.7 is —(CH.sub.2).sub.k—N(R.sup.24)R.sup.25, where k is 2 or 3, and where each R.sup.24 and R.sup.25 is, independently, H or optionally substituted C.sub.1-3 alkyl.

[1108] 66. The compound of embodiment 65, where k is 2.

[1109] 67. The compound of embodiment 65 or 66, where each R.sup.24 and R.sup.25 is, independently, optionally substituted C.sub.1-3 alkyl.

[1110] 68. The compound of any one of embodiments 65 to 67, where each R.sup.24 and R.sup.25 is methyl.

[1111] 69. The compound of any one of embodiments 1 to 56, where R.sup.7 and R.sup.8 form a group —Y.sup.1—Y.sup.2—, where: [1112] Y.sup.1 is —(CR.sup.26R.sup.27).sub.m— or optionally substituted C.sub.1-3 alkyl, optionally substituted C.sub.1-3 alkheterocyclyl, optionally substituted C.sub.1-3 alkcycloalkyl, or optionally substituted C.sub.1-3 alkaryl; and [1113] Y.sup.2 is —(CR.sup.26R.sup.27)— or H; where each R.sup.26 and R.sup.27 is, independently, H or optionally substituted C.sub.1-3 alkyl; and [1114] m is 1 or 2.

[1115] 70. The compound of any one of embodiments 1 to 5, where Z.sup.1 and R.sup.8 combine to form —Z.sup.3—Y.sup.1—Y.sup.2—, where [1116] Z.sup.3 is —O—, —N(R.sup.10)—, —N═, —S—, or —(CR.sup.14R.sup.15)—; [1117] Y.sup.1 is —O—, —N(R.sup.10)—, —S—, —(CR.sup.26R.sup.27).sub.m—, —C(R.sup.20)═, ═C(R.sup.20)—, ═C(R.sup.21)—C(R.sup.22)═, optionally substituted C.sub.1-3 alkyl, optionally substituted C.sub.1-3 alkheterocyclyl, optionally substituted C.sub.1-3 alkcycloalkyl, or optionally substituted C.sub.1-3 alkaryl; and [1118] Y.sup.2 is —O—, —S—, —N(R.sup.10)—, —(CR.sup.26R.sup.27)—, ═C(R.sup.20)—, ═N—, or H; [1119] where [1120] each R.sup.20, R.sup.21, and R.sup.22 is, independently, H or optionally substituted C.sub.1-3 alkyl; and [1121] each R.sup.26 and R.sup.27 is, independently, H or optionally substituted C.sub.1-3 alkyl, or R.sup.26 and R.sup.27 combine to form ═O or ═S; [1122] m is 1 or 2; and
where, when Y.sup.2 is H, [1123] the chain of atoms —Z.sup.3—Y.sup.1—Y.sup.2— includes no more than two heteroatoms, the heteroatom selected from nitrogen, oxygen, and sulfur.

[1124] 71. The compound of embodiment 70, where Z.sup.3 is —O—.

[1125] 72. The compound of embodiment 69 or 71, where Y.sup.1 is —(CR.sup.26R.sup.27).sub.m— or optionally substituted C.sub.1-3 alkyl, optionally substituted C.sub.1-3 alkheterocyclyl, optionally substituted C.sub.1-3 alkcycloalkyl, or optionally substituted C.sub.1-3 alkaryl.

[1126] 73. The compound of any one of embodiments 69 to 72, where Y.sup.1 is —(CR.sup.26R.sup.27).sub.m— or optionally substituted C.sub.1-3 alkyl.

[1127] 74. The compound of any one of embodiments 69 to 73, where Y.sup.2 is —(CR.sup.26R.sup.27)— or H.

[1128] 75. The compound of any one of embodiments 69 to 74, where Y.sup.2 is —(CR.sup.26R.sup.27)—.

[1129] 76. The compound of any one of embodiments 69 to 75, where R.sup.26 is H.

[1130] 77. The compound of any one of embodiments 69 to 76, where R.sup.27 is H.

[1131] 78. The compound of any one of embodiments 69 to 77, where m is 1.

[1132] 79. The compound of any one of embodiments 69 to 78, where Y.sup.1 is optionally substituted C.sub.1-3 alkyl.

[1133] 80. The compound of embodiment 79, where Y.sup.1 is methyl.

[1134] 81. The compound of embodiment 80, where Y.sup.1 is —(CH.sub.2).sub.k—N(R.sup.24)R.sup.25, where k is 2 or 3, and where each R.sup.24 and R.sup.25 is, independently, H or optionally substituted C.sub.1-3 alkyl.

[1135] 82. The compound of embodiment 81, where k is 2.

[1136] 83. The compound of embodiment 81 or 82, where each R.sup.24 and R.sup.25 is, independently, optionally substituted C.sub.1-3 alkyl.

[1137] 84. The compound of any one of embodiments 81 to 83, where each R.sup.24 and R.sup.25 is methyl.

[1138] 85. The compound of any one of embodiments 1 to 84, where each R.sup.1 and R.sup.2 is H.

[1139] 86. A compound:

##STR00382## ##STR00383## ##STR00384## ##STR00385## ##STR00386## ##STR00387## ##STR00388## ##STR00389## ##STR00390## ##STR00391## ##STR00392## ##STR00393## ##STR00394## ##STR00395##

or a pharmaceutically acceptable salt thereof.

[1140] 87. The compound of embodiment 84 having the formula:

##STR00396## ##STR00397## ##STR00398## ##STR00399## ##STR00400## ##STR00401## ##STR00402## ##STR00403## ##STR00404## ##STR00405##

or a pharmaceutically acceptable salt thereof.

[1141] 88. A pharmaceutical composition including the compound of any one of embodiments 1 to 87, or a pharmaceutically acceptable salt thereof, and one or more of pharmaceutically acceptable carriers or excipients.

[1142] 89. The pharmaceutical composition of embodiment 88, where the composition is formulated for administration orally, sublingually, buccally, transdermally, intradermally, intramuscularly, parenterally, intravenously, intra-arterially, intracranially, subcutaneously, intraorbitally, intraventricularly, intraspinally, intraperitoneally, intranasally, by inhalation, and topically.

[1143] 90. The pharmaceutical composition of embodiment 89, where the composition is formulated for oral administration.

[1144] 91. A method of treating a disorder in a mammal caused by the action of heat shock protein 90 (Hsp90), the method including administering an effective amount of the compound of any one of embodiments 1 to 87 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of embodiment 88 to the mammal.

[1145] 92. The method of embodiment 91, where the disorder is a neurodegenerative disorder.

[1146] 93. The method of embodiment 92, where the neurodegenerative disorder is a tauopathy.

[1147] 94. The method of embodiment 92 or 93, where the neurodegenerative disorder is Alzheimer's disease, Huntington's disease, progressive supranuclear palsy, Parkinson's disease, Pick's disease, corticobasal degeneration, chronic traumatic encephalopathy, traumatic brain injury, or frontotemporal dementia.

[1148] 95. The method of embodiment 94, where the neurodegenerative disorder is Alzheimer's disease.

[1149] 96. The method of embodiment 91, where the disorder is a proliferative disorder.

[1150] 97. The method of embodiment 96, where the proliferative disorder is a cancer.

[1151] 98. The method of embodiment 97, where the cancer is acute myeloid leukemia, gastrointestinal stromal tumor, gastric cancer, glioma, neuroblastoma, glioblastoma, lung cancer, lymphoma, melanoma, myeloma, non-small cell lung cancer, renal cancer, small cell lung cancer, blast-phase chronic myelogenous leukemia, leukemia, lymphoproliferative disorder, metastatic melanoma, relapsed multiple myeloma, refractory multiple myeloma, myeloproliferative disorders, pancreatic cancer, small intestine cancer, or solid tumor.

[1152] 99. A method of treating an infectious disease in a mammal, the method including administering an effective amount of the compound of any one of embodiments 1 to 87 or a pharmaceutically acceptable salt or the pharmaceutical composition of embodiment 88 thereof to the mammal.

[1153] 100. The method of embodiment 99, where the infectious disease is a viral infection.

[1154] 101. The method of embodiment 100, where the viral infection is an infection by a virus of a family selected from the group consisting of Herpesviridae, Polyomaviridae, Poxviridae, Reoviridae, Birnaviridae, Picornaviridae, Flaviviridae, Arenaviridae, Hepeviridae, Rhabdoviridae, Paramoxyviridae, Bunyaviridae, Orthomoxyviridae, Filoviridae, Retroviridae, and Hepadnaviridae.

[1155] 102. The method of embodiment 101, where the virus of a family Herpesviridae is herpes simplex virus-1, herpes simplex virus-2, herpes herpesvirus-5, Kaposi's sarcoma-associated herpesvirus, varicella zoster virus, or Epstein-Barr virus.

[1156] 103. The method of embodiment 101, where the virus of Polyomaviridae family is SV40.

[1157] 104. The method of embodiment 101, where the virus of Poxviridae family is vaccinia virus.

[1158] 105. The method of embodiment 101, where the virus of Reoviridae family is rotavirus.

[1159] 106. The method of embodiment 101, where the virus of Birnaviridae family is infectious bursal disease virus.

[1160] 107. The method of embodiment 101, where the virus of Picornaviridae family is poliovirus, rhinovirus, or coxsackievirus.

[1161] 108. The method of embodiment 101, where the virus of Flaviviridae family is hepatitis C virus or dengue virus.

[1162] 109. The method of embodiment 101, where the virus of Arenaviridae family is lymphocytic choriomeningitis virus.

[1163] 110. The method of embodiment 101, where the virus of Hepeviridae family is Hepatitis E virus.

[1164] 111. The method of embodiment 101, where the virus of Rhabdoviridae family is vesicular stomatitis virus.

[1165] 112. The method of embodiment 101, where the virus of Paramoxyviridae family is human parainfluenza virus 2, human parainfluenza virus 3, SV5, SV41, measles virus, or Sendai virus.

[1166] 113. The method of embodiment 101, where the virus of Bunyaviridae family is La Crosse virus.

[1167] 114. The method of embodiment 101, where the virus of Orthomoxyviridae family is influenza A virus.

[1168] 115. The method of embodiment 101, where the virus of Filoviridae family is Ebola virus.

[1169] 116. The method of embodiment 101, where the virus of Retroviridae family is HTLV1 or HIV1.

[1170] 117. The method of embodiment 101, where the virus of Hepadnaviridae family is hepatitis B virus.

[1171] 118. The method of embodiment 99, where the infectious disease is a fungal infection.

[1172] 119. The method of embodiment 118, where the fungal infection is a Candida albicans infection, an Aspergillus fumigates infection, or Pneumocystis jiroveci infection.

[1173] 120. The method of embodiment 99, where the infectious disease is a bacterial infection.

[1174] 121. The method of embodiment 120, where the bacterial infection is a mycobacteria infection or anthrax infection.

[1175] 122. The method of embodiment 120, where the bacterial infection is a bacterial pneumonia.

[1176] 123. The method of embodiment 91, where the disorder an inflammatory or autoimmune disease.

[1177] 124. The method of embodiment 123, where the inflammatory or autoimmune disease is rheumatoid arthritis, systemic lupus erythermatosus, or asthma.

[1178] 125. The method of embodiment 91, where the disorder is a cardiovascular disease.

[1179] 126. The method of embodiment 125, where the cardiovascular disease is atherosclerosis or cardiomyopathy.

[1180] 127. The method of embodiment 91, where the disorder is an allergy.

[1181] 128. The method of any one of embodiments 91 to 127, where the compound is administered orally, sublingually, buccally, transdermally, intradermally, intramuscularly, parenterally, intravenously, intra-arterially, intracranially, subcutaneously, intraorbitally, intraventricularly, intraspinally, intraperitoneally, intranasally, by inhalation, and topically.

[1182] 129. The method of embodiment 128, where the compound is administered orally.

[1183] 130. The method of any one of embodiments 91 to 129, where the mammal is human.

[1184] 131. The method of any one of embodiments 91 to 130, where the compound is administered orally, sublingually, buccally, transdermally, intradermally, intramuscularly, parenterally, intravenously, intra-arterially, intracranially, subcutaneously, intraorbitally, intraventricularly, intraspinally, intraperitoneally, intranasally, by inhalation, and topically.

[1185] 132. The method of embodiment 131, where the compound is administered orally.

[1186] 133. The method of any one of embodiments 91 to 132, where the mammal is human.

[1187] 134. A compound for use in treating a disorder in a mammal caused by the action of heat shock protein 90 (Hsp90), where the compound is the compound of any one of embodiments 1 to 87 or a pharmaceutically acceptable salt thereof.

[1188] 135. The compound of embodiment 134, where the disorder is a neurodegenerative disorder.

[1189] 136. The compound of embodiment 135, where the neurodegenerative disorder is a tauopathy.

[1190] 137. The compound of embodiment 134 or 135, where the neurodegenerative disorder is Alzheimer's disease, Huntington's disease, progressive supranuclear palsy, Parkinson's disease, Pick's disease, corticobasal degeneration, chronic traumatic encephalopathy, traumatic brain injury, or frontotemporal dementia.

[1191] 138. The compound of embodiment 137, where the neurodegenerative disorder is Alzheimer's disease.

[1192] 139. The compound of embodiment 134, where the disorder is a proliferative disorder.

[1193] 140. The compound of embodiment 139, where the proliferative disorder is a cancer.

[1194] 141. The compound of embodiment 140, where the cancer is acute myeloid leukemia, gastrointestinal stromal tumor, gastric cancer, glioblastoma, lung cancer, lymphoma, melanoma, myeloma, non-small cell lung cancer, renal cancer, small cell lung cancer, blast-phase chronic myelogenous leukemia, leukemia, lymphoproliferative disorder, metastatic melanoma, relapsed multiple myeloma, refractory multiple myeloma, myeloproliferative disorders, pancreatic cancer, small intestine cancer, or solid tumor.

[1195] 142. The compound of embodiment 134, where the disorder is an infectious disease.

[1196] 143. The compound of embodiment 142, where the infectious disease is a viral infection.

[1197] 144. The compound of embodiment 143, where the viral infection is an infection by a virus of a family selected from the group consisting of Herpesviridae, Polyomaviridae, Poxviridae, Reoviridae, Birnaviridae, Picornaviridae, Flaviviridae, Arenaviridae, Hepeviridae, Rhabdoviridae, Paramoxyviridae, Bunyaviridae, Orthomoxyviridae, Filoviridae, Retroviridae, and Hepadnaviridae.

[1198] 145. The compound of embodiment 144, where the virus of a family Herpesviridae is herpes simplex virus-1, herpes simplex virus-2, herpes herpesvirus-5, Kaposi's sarcoma-associated herpesvirus, varicella zoster virus, or Epstein-Barr virus.

[1199] 146. The compound of embodiment 144, where the virus of Polyomaviridae family is SV40.

[1200] 147. The compound of embodiment 144, where the virus of Poxviridae family is vaccinia virus.

[1201] 148. The compound of embodiment 144, where the virus of Reoviridae family is rotavirus.

[1202] 149. The compound of embodiment 144, where the virus of Birnaviridae family is infectious bursal disease virus.

[1203] 150. The compound of embodiment 144, where the virus of Picornaviridae family is poliovirus, rhinovirus, or coxsackievirus.

[1204] 141. The compound of embodiment 144, where the virus of Flaviviridae family is hepatitis C virus or dengue virus.

[1205] 152. The compound of embodiment 144, where the virus of Arenaviridae family is lymphocytic choriomeningitis virus.

[1206] 153. The compound of embodiment 144, where the virus of Hepeviridae family is Hepatitis E virus.

[1207] 154. The compound of embodiment 144, where the virus of Rhabdoviridae family is vesicular stomatitis virus.

[1208] 155. The compound of embodiment 144, where the virus of Paramoxyviridae family is human parainfluenza virus 2, human parainfluenza virus 3, SV5, SV41, measles virus, or Sendai virus.

[1209] 156. The compound of embodiment 144, where the virus of Bunyaviridae family is La Crosse virus.

[1210] 157. The compound of embodiment 144, where the virus of Orthomoxyviridae family is influenza A virus.

[1211] 158. The compound of embodiment 144, where the virus of Filoviridae family is Ebola virus.

[1212] 159. The compound of embodiment 144, where the virus of Retroviridae family is HTLV1 or HIV1.

[1213] 160. The compound of embodiment 144, where the virus of Hepadnaviridae family is hepatitis B virus.

[1214] 161. The compound of embodiment 134, where the infectious disease is a fungal infection.

[1215] 162. The compound of embodiment 161, where the fungal infection is a Candida albicans infection, an Aspergillus fumigates infection, or Pneumocystis jiroveci infection.

[1216] 163. The compound of embodiment 134, where the infectious disease is a bacterial infection.

[1217] 165. The compound of embodiment 163, where the bacterial infection is a mycobacteria infection or anthrax infection.

[1218] 166. The compound of embodiment 163, where the bacterial infection is a bacterial pneumonia.

[1219] 167. The compound of embodiment 134, where the disorder an inflammatory or autoimmune disease.

[1220] 168. The compound of embodiment 167, where the inflammatory or autoimmune disease is rheumatoid arthritis, systemic lupus erythermatosus, or asthma.

[1221] 169. The compound of embodiment 134, where the disorder is a cardiovascular disease.

[1222] 170. The compound of embodiment 169, where the cardiovascular disease is atherosclerosis or cardiomyopathy.

[1223] 171. The compound of embodiment 170, where the disorder is an allergy.

[1224] 172. Use of a compound in the manufacture of a medicament for treating a disorder in a mammal caused by the action of heat shock protein 90 (Hsp90), where the compound is the compound of any one of embodiments 1 to 87 or a pharmaceutically acceptable salt thereof.

[1225] 173. Use of a compound for treating a disorder in a mammal caused by the action of heat shock protein 90 (Hsp90), where the compound is the compound of any one of embodiments 1 to 87 or a pharmaceutically acceptable salt thereof.

[1226] 174. The use of embodiment 172 or 173, where the disorder is a neurodegenerative disorder.

[1227] 175. The use of embodiment 174, where the neurodegenerative disorder is a tauopathy.

[1228] 176. The use of embodiment 174 or 175, where the neurodegenerative disorder is Alzheimer's disease, Huntington's disease, progressive supranuclear palsy, Parkinson's disease, Pick's disease, corticobasal degeneration, chronic traumatic encephalopathy, traumatic brain injury, or frontotemporal dementia.

[1229] 177. The use of embodiment 176, where the neurodegenerative disorder is Alzheimer's disease.

[1230] 178. The use of embodiment 172 or 173, where the disorder is a proliferative disorder.

[1231] 179. The use of embodiment 178, where the proliferative disorder is a cancer.

[1232] 180. The use of embodiment 179, where the cancer is acute myeloid leukemia, gastrointestinal stromal tumor, gastric cancer, glioblastoma, lung cancer, lymphoma, melanoma, myeloma, non-small cell lung cancer, renal cancer, small cell lung cancer, blast-phase chronic myelogenous leukemia, leukemia, lymphoproliferative disorder, metastatic melanoma, relapsed multiple myeloma, refractory multiple myeloma, myeloproliferative disorders, pancreatic cancer, small intestine cancer, or solid tumor.

[1233] 181. Use of a compound for treating, or in the manufacture of a medicament for treating, an infectious disease, where the compound is the compound of any one of embodiments 1 to 87.

[1234] 182. The use of embodiment 181, where the infectious disease is a viral infection.

[1235] 183. The use of embodiment 182, where the viral infection is an infection by a virus of a family selected from the group consisting of Herpesviridae, Polyomaviridae, Poxviridae, Reoviridae, Birnaviridae, Picornaviridae, Flaviviridae, Arenaviridae, Hepeviridae, Rhabdoviridae, Paramoxyviridae, Bunyaviridae, Orthomoxyviridae, Filoviridae, Retroviridae, and Hepadnaviridae.

[1236] 184. The use of embodiment 183, where the virus of a family Herpesviridae is herpes simplex virus-1, herpes simplex virus-2, herpes herpesvirus-5, Kaposi's sarcoma-associated herpesvirus, varicella zoster virus, or Epstein-Barr virus.

[1237] 185. The use of embodiment 183, where the virus of Polyomaviridae family is SV40.

[1238] 186. The use of embodiment 183, where the virus of Poxviridae family is vaccinia virus.

[1239] 187. The use of embodiment 183, where the virus of Reoviridae family is rotavirus.

[1240] 188. The use of embodiment 183, where the virus of Birnaviridae family is infectious bursal disease virus.

[1241] 189. The use of embodiment 183, where the virus of Picornaviridae family is poliovirus, rhinovirus, or coxsackievirus.

[1242] 190. The use of embodiment 183, where the virus of Flaviviridae family is hepatitis C virus or dengue virus.

[1243] 191. The use of embodiment 183, where the virus of Arenaviridae family is lymphocytic choriomeningitis virus.

[1244] 192. The use of embodiment 183, where the virus of Hepeviridae family is Hepatitis E virus.

[1245] 193. The use of embodiment 183, where the virus of Rhabdoviridae family is vesicular stomatitis virus.

[1246] 194. The use of embodiment 183, where the virus of Paramoxyviridae family is human parainfluenza virus 2, human parainfluenza virus 3, SV5, SV41, measles virus, or Sendai virus.

[1247] 195. The use of embodiment 183, where the virus of Bunyaviridae family is La Crosse virus.

[1248] 196. The use of embodiment 183, where the virus of Orthomoxyviridae family is influenza A virus.

[1249] 197. The use of embodiment 183, where the virus of Filoviridae family is Ebola virus.

[1250] 198. The use of embodiment 183, where the virus of Retroviridae family is HTLV1 or HIV1.

[1251] 199. The use of embodiment 183, where the virus of Hepadnaviridae family is hepatitis B virus.

[1252] 200. The use of embodiment 172 or 173, where the infectious disease is a fungal infection.

[1253] 201. The use of embodiment 200, where the fungal infection is a Candida albicans infection, an Aspergillus fumigates infection, or Pneumocystis jiroveci infection.

[1254] 202. The use of embodiment 172 or 173, where the infectious disease is a bacterial infection.

[1255] 203. The use of embodiment 202, where the bacterial infection is a mycobacteria infection or anthrax infection.

[1256] 204. The use of embodiment 203, where the bacterial infection is a bacterial pneumonia.

[1257] 205. The use of embodiment 172 or 173, where the disorder an inflammatory or autoimmune disease.

[1258] 206. The use of embodiment 205, where the inflammatory or autoimmune disease is rheumatoid arthritis, systemic lupus erythermatosus, or asthma.

[1259] 207. The use of embodiment 172 or 173, where the disorder is a cardiovascular disease.

[1260] 208. The use of embodiment 207, where the cardiovascular disease is atherosclerosis cardiomyopathy.

[1261] 209. The use of embodiment 172 or 173, where the disorder is an allergy.

[1262] 210. The compound of any one of embodiments 134 to 171 or the use of any one of embodiments 172 to

[1263] 209, where the compound is formulated for administration by a route selected from the group consisting of oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intra-arterial, intracranial, subcutaneous, intraorbital, intraventricular, intraspinal, intraperitoneal, intranasal, by inhalation, and topical.

[1264] 211. The compound or the use of embodiment 128, where the compound is formulated for oral administration.

[1265] 212. A method of inhibiting Hsp90, the method including contacting a cell with the compound of any one of embodiments 1 to 87 or a pharmaceutically acceptable salt thereof.

[1266] 213. The method of embodiment 212, where the cell is in vitro.

[1267] 214. A compound for use in inhibiting Hsp90, where the compound is the compound of any one of embodiments 1 to 87 or a pharmaceutically acceptable salt thereof.

[1268] 215. Use of a compound for inhibiting Hsp90, where the compound is the compound of any one of embodiments 1 to 87 or a pharmaceutically acceptable salt thereof.

[1269] 216. A kit including: [1270] (i) the pharmaceutical composition of any one of embodiments 88 to 90; and [1271] (ii) instructions for use of the pharmaceutical compositions of (i) to treat a disorder in a mammal caused by the action of Hsp90.

[1272] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each independent publication or patent application was specifically and individually indicated to be incorporated by reference.

[1273] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims.

[1274] Other embodiments are in the claims