WO2009006089A2 - A2 adenosine receptor agonists - Google Patents

Abstract

Disclosed are AZB adenosine receptor (AR) agonists of formula (I), in which R1, R2, R3, R4, Z, and n are defined herein. The invention also provides compositions comprising at least one compound of formula I and methods of use thereof, for example, in the treatment of septic shock, cystic fibrosis, restenosis, erectile dysfunction, inflammation, myocardial ischemia, and reperfusion injury.

Description

A2 ADENOSINE RECEPTOR AGONISTS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of United States Provisional Patent Application Nos. 60/947,066, filed June 29, 2007 and 60/950,250, filed July 17, 2007, the disclosures of which are incorporated by reference.

BACKGROUND OF THE INVENTION

[0002] There are four subtypes of adenosine receptors (ARs): A₁, A_2A, A_2B, and A₃ (Fredholm et al. Pharmacol. Rev. 2001, 53, 527-552). Activation or blocking one or more of these ARs leads to useful therapeutic applications. For example, activation of the A₂βAR can induce angiogenesis, reduce vascular permeabilization, increase production of the anti- inflammatory cytokine IL-10, increase chloride secretion in epithelial cells, or increase release of inflammatory mediators from human and canine mast cells. Accordingly, there is a desire for A₂βAR agonists for use in therapeutic applications.

BRIEF SUMMARY OF THE INVENTION

[0003] The invention provides A_2B adenosine receptor (AR) agonists of formula I. Exemplary compounds of formula I have enhanced potency at the A₂βAR and reduced potency at other AR subtypes, wherein R¹ -R⁴, Z, and n are described below in detail.

(I)

It is contemplated that some compounds of formula I are agonists for both A_2A and A_2B adenosine receptors.

[0004] The invention also provides compositions comprising at least one compound of formula I and methods of use thereof, for example, in a method of treating a disease based on the modulation of the adenosine system, e.g., septic shock, cystic fibrosis, restenosis, erectile dysfunction, inflammation, myocardial ischemia, and reperfusion injury.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0005] Figure 1 depicts chemical structures of exemplary compounds of formula I (8 and

17-40), in accordance with an embodiment of the invention.

[0006] Figure 2 depicts a reaction scheme to prepare intermediates for the 2-ether component of compounds of formula I in accordance with an embodiment of the invention.

Step (a): TsCl, NaH, THF, 0 ⁰C - room temperature; step (b): NaI, DMF, 60 ⁰C; step (c) (i):

TsOH-H₂O, MeOH, 60 ⁰C; (ii): LAH, THF, 4 ⁰C - room temperature; step (d): EtOH, reflux; step (e): oxalyl chloride, Et₂O; step (f): LAH, THF, reflux; and step (g): I₂, PPh₃, imidazole, benzene.

[0007] Figure 3 depicts another reaction scheme to prepare intermediates for the 2-ether component of compounds of formula I in accordance with an embodiment of the invention.

Step (a) (i): TsCl, pyridine, CH₂Cl₂; (ii): 3-butyn-l-ol, Pd(PPh₃)₂Cl₂, CuI, Et₃N, DMF, 70 ⁰C; step (b): I₂, PPh₃, imidazole, Et₂O-MeCN, room temperature; and step (c): LAH, THF, 0 ⁰C - room temperature.

[0008] Figure 4 depicts a reaction scheme to prepare compounds 8, 17-36, and 119-127 in accordance with an embodiment of the invention. Step (a): R¹CH₂CH₂-I (47 - 49, 59-61,

74-77, 85, 86, l-iodo-3-phenylpropane, 89, 94, 95 and 99, respectively), Cs₂CO₃, DMF, room temperature; step (b): saturated NH₃ in EtOH, 120 ⁰C; and step (c): deprotection of tosyl group of 18, 119-121, 26, 32, 122-126, 21 and 127; KOH, MeOH 70 - 90 ⁰C.

[0009] Figure 5 depicts a reaction scheme to prepare compound 39 in accordance with an embodiment of the invention. Step (a): guanidine solution (Jacobson et al., Chem. Biol. 2005,

12, 237-247), DABCO, EtOH, 110 ⁰C; and step (b) (i): EtNH₂ HCl, DIPEA, DMF, 140 ⁰C;

(ii): KOH, MeOH, 80 ⁰C.

[0010] Figure 6 depicts a reaction scheme to prepare compound 40 in accordance with an embodiment of the invention. Step (a): 2,2-dimethoxypropane, p-TsOH-H₂O, DMF; step

(b): KMnO₄, KOH, H₂O; step (c): PyBop, DIPEA, EtNH₂ HCl, DMF; step (d): f-butyl nitrite,

2-PrOH/H₂O (1:1); step (e): iodide 47, Cs₂CO₃, DMF, room temperature; step (f): saturated

NH₃, EtOH, 120 ⁰C; step (g): 80% AcOH, 80 ⁰C; and step (h): KOH, MeOH, 70 ⁰C. [0011] Figure 7A depicts activation curves (log [Agonist] versus percent agonist efficacy) for 28 (^) in comparison to 2 (■) at the Ai adenosine receptors.

[0012] Figure 7B depicts activation curves (log [Agonist] versus percent agonist efficacy) for 28 (^) in comparison to 2 (■) at the A_2A adenosine receptors.

[0013] Figure 7C depicts activation curves (log [Agonist] versus percent agonist efficacy) for 28 (^A) in comparison to 2 (■) at the A_2B adenosine receptors.

[0014] Figure 7D depicts activation curves (log [Agonist] versus percent agonist efficacy) for 28 (^) in comparison to 2 (■) at the A₃ adenosine receptors.

[0015] Figure 8 depicts the percent of risk zone infracted in an isolated rabbit heart for a control group and a group that had been administered 200 nM of 28 in accordance with an embodiment of the invention.

[0016] Figure 9 depicts the infarct size (cm ) as a function of risk size (cm ) in accordance with an embodiment of the invention. The symbol • represents the control group, whereas O represents 28.

DETAILED DESCRIPTION OF THE INVENTION

[0017] The present invention provides a compound of formula I or pharmaceutically acceptable salt thereof:

(I) wherein

R¹ is selected from the group consisting of aryl, cycloalkylaryl, heterocycloalkylaryl, heteroaryl, heterocycloalkyl, and arylheterocycloalkyl, each of which is optionally substituted with 1 to 3 substituents selected from the group consisting of C_M2 alkyl, hydroxyl, Ci_-I2 alkoxy, halo, tosyl (Ts), CN, -C(O)OH, aminocarbonyl, amino, C₁-_J2 dialkylamino, and Ci_-J2 alkylamino;

Z is a bond or -CH₂-;

n is an integer of 1 to 4;

R² is selected from the group consisting Of-CH₂OH, aminocarbonyl, Cj_-J2 alkylaminocarbonyl, and di-Cj.j_∑ alkylaminocarbonyl; and

R³ and R⁴ are the same or different and each is selected from the group consisting of hydrogen, C_J-CJ₂ alkyl, C₃-C₈ cycloalkyl, C₆-C₃₀ aryl, and imidamido;

provided that when R² is -CH₂OH, and R³ and R⁴ are hydrogen, then -0-(CH₂)_H-Z-R¹ is not benzyloxy, phenylalkoxy or a substituted phenylalkoxy, thiophenylalkoxy or a substituted thiophenylalkoxy, pyridylalkoxy, indolylalkoxy, naphthylalkoxy, biphenylalkoxy, or indolylalkoxy.

[0018] In preferred embodiments, R¹ is selected from the group consisting Of C_6-3O aryl, heteroaryl, heterocycloalkyl, C_5-7 cycloalkyl-C_6-3o aryl, heterocycloalkyl-Ce^o aryl, C_6-30 aryl- heteroaryl, and C_6-30 aryl-heterocycloalkyl. For example, R¹ is selected from the group consisting of

C_6-3O aryl (e.g., phenyl, biphenyl, naphthyl, anthracenyl, pyrenyl), a heteroaryl consisting of one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom (e.g., pyridinyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)- and (l,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thiophenyl, isothiazolyl, thiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, pyrrolo[3,2-d]pyrimidinyl, and pyrrolo[2,3- d]pyrimidinyl), a heterocycloalkyl consisting of a 5 or 6-membered monocyclic ring that contains one, two, or three heteroatoms selected from nitrogen, oxygen, and/or sulfur (e.g., pyrrolinyl, pyranyl, piperidyl, tetrahydrofuranyl, tetrahydrothiopheneyl, and moφholinyl), C_5-7 cycloalkyl-fused phenyl (e.g., 5-, 6-, 7-, or 8-1,2,3,4-tetrahydronaphthalenyl and 4-, 5-, 6-, or 7-2,3-dihydro-lH-indenyl), heterocycloalkyl-fused phenyl, wherein the heterocycloalkyl consists of a 5 or 6- membered monocyclic ring that contains one, two, or three heteroatoms selected from nitrogen, oxygen, and/or sulfur (e.g., 5-, 6-, 7-, or 8-1,2,3,4- tetrahydroquinolinyl, 5-, 6-, 7-, or 8-1,2,3,4-tetrahydroquinoxalinyl, and 5-, 6-, 7-, or 8-2,3-dihydrobenzo[b][l,4]dioxinyl), a benzo-fused heteroaryl, wherein the heteroaryl consists of one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom (e.g., benzimidazolyl, indolyl, indazolyl, benzo-1,2,3- triazolyl, 2-benzo[d]oxazolyl, 2-benzo[d]thiazolyl, 1,- 3-,or 4-isoquinolinyl, 2-, 3-, or 4-quinolinyl, and 2- or 3-quinoxalinyl), and a benzo-fused heterocycloalkyl, wherein the heterocycloalkyl consists of a 5 or 6- membered monocyclic ring that contains one, two, or three heteroatoms selected from N, O, and/or S (e.g., 2,3-dihydrobenzo[b][l,4]dioxinyl, 2- indolinyl, and 3-indolinyl). [0019] In particularly preferred embodiments, R¹ is selected from the group consisting of

wherein

R⁵ and R⁵ are the same or different and each is hydrogen or 1 to 3 substituents individually selected from the group consisting of Ci_-I2 alkyl, hydroxyl, Ci_-I2 alkoxy, halo, tosyl (Ts), CN, -C(O)OH, aminocarbonyl, amino, Ci_-I2 dialkylamino, and Ci_-I2 alkylamino; and

R⁶ is selected from the group consisting of hydrogen, Ci_-I2 alkyl, C_3-8 cycloalkyl, and C_6-30 aryl.

[0020] For example, R¹ is selected from the group consisting of

Specific embodiments of these compounds include wherein R¹ is selected from the group consisting of

and

[0021] In any of the foregoing embodiments, R⁵ and R⁵ are the same or different and each can be hydrogen, Ci_-I2 alkyl, hydroxyl, C_1-I2 alkoxy, halo, or tosyl. For instance, in preferred compounds, R¹ is selected from the group consisting of

[0022] In an embodiment of the invention, in the compound of formula I, n is 1, 2, or 3, particularly n is 2 or 3. In especially preferred compounds, n is 2.

[0023] In another embodiment of the invention, R² is -CH₂OH or C_M2 alkylaminocarbonyl (e.g., N-methylcarboxaminocarbonyl, N-ethylcarboxaminocarbonyl, N- propylcarboxaminocarbonyl) .

[0024] In preferred embodiments of the invention, R³ and R⁴ are the same or different and each is selected from the group consisting of hydrogen, Ci-Ci₂ alkyl, and imidamido.

Compounds in which R³ is hydrogen and R⁴ is hydrogen, Ci_-I2 alkyl, or imidamido are especially preferred. Figure 1 depicts the chemical structures of exemplary compounds of formula I.

[0025] Referring now to terminology used generically herein, the term "alkyl" implies a straight or branched alkyl moiety containing from, for example, 1 to 12 carbon atoms, preferably from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms. Examples of such moieties include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isoamyl, hexyl, octyl, dodecanyl, and the like.

[0026] The term "cycloalkyl," as used herein, means a cyclic moiety containing from, for example, 1-3 rings (i.e., monocyclic, bicyclic, tricyclic, or spiro), 3 to 8 carbon atoms per ring, preferably from 5 to 8 carbon atoms, more preferably from 5 to 6 carbon atoms. Examples of such moieties include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0027] The term "aryl" refers to an unsubstituted or substituted aromatic carbocyclic moiety, as commonly understood in the art, and includes monocyclic and polycyclic aromatics such as, for example, phenyl, biphenyl, naphthyl, anthracenyl, pyrenyl, and the like. An aryl moiety generally contains from, for example, 6 to 30 carbon atoms, preferably from 6 to 18 carbon atoms, more preferably from 6 to 14 carbon atoms and most preferably from 6 to 10 carbon atoms. It is understood that the term aryl includes carbocyclic moieties that are planar and comprise 4n+2 π electrons, according to Hϋckel's Rule, wherein n = 1, 2, or 3.

[0028] The term "heterocycloalkyl" means a cycloalkyl moiety having one or more heteroatoms selected from nitrogen, sulfur, and/or oxygen. Preferably, a heterocycloalkyl is a 5 or 6-membered monocyclic ring and contains one, two, or three heteroatoms selected from nitrogen, oxygen, and/or sulfur. The heterocycloalkyl can be attached to the parent structure through a carbon atom or through any heteroatom of the heterocycloalkyl that results in a stable structure. Examples of such heterocyclic rings are pyrrolinyl, pyranyl, piperidyl, tetrahydrofuranyl, tetrahydrothiopheneyl, and morpholinyl.

[0029] The term "arylheterocycloalkyl" refers to a heterocycloalkyl, as defined herein, that is substituted with an aryl group, as defined herein, as a fused ring, e.g., benzo. Examples include 2,3-dihydrobenzo[b][l,4]dioxinyl, 2-indolinyl, and 3-indolinyl. [0030] The terms "cycloalkylaryl" and "heterocycloalkylaryl" refer to an aryl, as defined herein, that is substituted with a cycloalkyl group or a heterocycloalkyl group, respectively, as defined herein, or as a fused ring, e.g., benzo. Examples of cycloalkylaryl groups include 5-, 6-, 7-, or 8-1,2,3,4-tetrahydronaphthalenyl and 4-, 5-, 6-, or 7-2,3-dihydro-lH-indenyl. Examples of heterocycloalkylaryl include 5-, 6-, 7-, or 8-1,2,3,4-tetrahydroquinolinyl, 5-, 6-, 7-, or 8-1,2,3,4-tetrahydroquinoxalinyl, and 5-, 6-, 7-, or 8-2,3-dihydrobenzo[b][l,4]dioxinyl. [0031] The term "heteroaryl" refers to aromatic 4, 5, or 6 membered monocyclic groups, 9 or 10 membered bicyclic groups, and 11 to 14 membered tricyclic aryl groups having one or more heteroatoms (O, S, or N). Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. The nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atoms may optionally be quaternized. The heteroaryl group can be attached at any available nitrogen or carbon atom of any ring. Illustrative examples of heteroaryl groups are pyridinyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl,

(1,2,3,)- and (l,2,4)-triazolyl, pyrimidinyl, tetrazolyl, furyl, thiophenyl, isothiazolyl, thiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, pyrrolo[3,2-d]pyrimidinyl, and pyrrolo[2,3- d]pyrimidinyl.

[0032] The term "arylheteroaryl" refers to heteroaryl, as defined herein, that is substituted with an aryl group, as defined herein, as a fused ring, e.g., benzo. Examples of arylheteroaryl groups include benzimidazolyl, indolyl, indazolyl, benzo-l,2,3-triazolyl, 2-benzo[d] oxazolyl,

2-benzo[d]thiazolyl, 1,- 3-,or 4-isoquinolinyl, 2-, 3-, or 4-quinolinyl, and 2- or 3- quinoxalinyl.

[0033] The term "alkoxy" embraces linear or branched alkyl groups that are attached to a an ether oxygen. The alkyl group is the same as described herein. Examples of such substituents include methoxy, ethoxy, t-butoxy, and the like.

[0034] The term "alkylamino" refers to a group with one hydrogen and one alkyl group directly attached to a trivalent nitrogen atom. The term "dialkylamino" refers to a group with two of the same or different alkyl groups directly attached to a trivalent nitrogen atom.

[0035] The term "aminocarbonyl" refers to the group -C(O)NH₂. The terms

"alkylaminocarbonyl" and "dialkylaminocarbonly" refer to the group -C(O)NRR', in which

R is hydrogen or an alkyl group and R' is the same or different alkyl group as described herein.

[0036] The term "imidamido," also known as guanidino, refers to the group

-C(=NH)NH₂.

[0037] The term "halo" as used herein, means a substituent selected from Group VIIA, such as, for example, fluorine, bromine, chlorine, and iodine.

[0038] For the purpose of the present invention, the term "fused" includes a polycyclic compound in which one ring contains one or more atoms preferably one, two, or three atoms in common with one or more other rings.

[0039] Whenever a range of the number of atoms in a structure is indicated (e.g., a Ci_-I2,

Ci_-8, Ci_-6, or CM alkyl, alkylamino, etc.), it is specifically contemplated that any sub-range or individual number of carbon atoms falling within the indicated range also can be used. Thus, for instance, the recitation of a range of 1-8 carbon atoms (e.g., Cj-Cg), 1-6 carbon atoms (e.g., C_I-C_O), 1-4 carbon atoms (e.g., Ci-C₄), 1-3 carbon atoms (e.g., C1-C3), or 2-8 carbon atoms (e.g., C₂-C₈) as used with respect to any chemical group (e.g., alkyl, alkylamino, etc.) referenced herein encompasses and specifically describes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and/or 12 carbon atoms, as appropriate, as well as any sub-range thereof (e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms, 1-9 carbon atoms, 1-10 carbon atoms, 1-11 carbon atoms, 1-12 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 2-7 carbon atoms, 2-8 carbon atoms, 2-9 carbon atoms, 2-10 carbon atoms, 2-11 carbon atoms, 2- 12 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3-6 carbon atoms, 3-7 carbon atoms, 3-8 carbon atoms, 3-9 carbon atoms, 3-10 carbon atoms, 3-11 carbon atoms, 3-12 carbon atoms, 4-5 carbon atoms, 4-6 carbon atoms, 4-7 carbon atoms, 4-8 carbon atoms, 4-9 carbon atoms, 4-10 carbon atoms, 4-11 carbon atoms, and/or 4-12 carbon atoms, etc., as appropriate).

[0040] The compounds of formula I can be prepared by any suitable method. For example, 2', 3', 5'-triacetyl-6-chloroguanosine can be synthetically modified to prepare 2- ether-substituted 2', 3', 5'-triacetyl-6-chloroadenosine derivatives. To make a nucleophilic substitution of the 6-chloro group, a suitable amine (e.g., ammonia, ethylamine hydrochloride, guanidine hydrochloride) can be added. In case of deprotection of a protecting group (e.g., tosyl), the adenosine derivative is treated with a suitable strong acid or base (e.g., KOH) to form the compounds of formula I. Specific embodiments of the preparation of compounds of formula I and intermediates thereof are described in the Examples and in Figures 2-6.

[0041] Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick-layer chromatography, preparative low or high-pressure liquid chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the Examples described herein. However, other equivalent separation or isolation procedures can also be used. [0042] The present invention further provides a pharmaceutical composition comprising at least one compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier can be any of those conventionally used and is limited only by chemico-physical considerations, such as solubility and lack of reactivity with the compound, and by the route of administration. It will be appreciated by one of skill in the art that, in addition to the following described pharmaceutical compositions; the compounds of the present invention can be formulated as inclusion complexes, such as cyclodextrin inclusion complexes or liposomes. [0043] The pharmaceutically acceptable carriers described herein, for example, vehicles, adjuvants, excipients, or diluents, are well known to those who are skilled in the art and are readily available to the public. It is preferred that the pharmaceutically acceptable carrier be one which is chemically inert to the active compounds and one which has no detrimental side effects or toxicity under the conditions of use.

[0044] The choice of carrier will be determined in part by the particular active agent, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present invention. The following formulations for oral, aerosol, parenteral, subcutaneous, intravenous, intraarterial, intramuscular, interperitoneal, intrathecal, rectal, and vaginal administration are merely exemplary and are in no way limiting.

[0045] Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions. Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and cornstarch. Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers. Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.

[0046] The compounds of the present invention, alone or in combination with other suitable components, can be made into aerosol formulations to be administered via inhalation. These aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also may be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer. [0047] Formulations suitable for parenteral administration include aqueous and nonaqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The compound can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, glycerol ketals, such as 2,2-dimethyl-l,3-dioxolane- 4-methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants. [0048] Oils, which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters. Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts, and suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene-polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-beta-aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (3) mixtures thereof.

[0049] The parenteral formulations will typically contain from about 0.5 to about 25% by weight of the active ingredient in solution. Suitable preservatives and buffers can be used in such formulations. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile-Iipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations ranges from about 5 to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol. The parenteral formulations can be presented in unit-dose or multi- dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.

[0050] The compounds of the present invention may be made into injectable formulations. The requirements for effective pharmaceutical carriers for injectable compositions are well known to those of ordinary skill in the art. See Pharmaceutics and Pharmacy Practice, J. B. Lippincott Co., Philadelphia, Pa., Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630 (1986).

[0051] Additionally, the compounds of the present invention may be made into suppositories by mixing with a variety of bases, such as emulsifying bases or water-soluble bases. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.

[0052] Suitable carriers and their formulations are further described in A.R. Gennaro, ed., Remington: The Science and Practice of Pharmacy (19th ed.), Mack Publishing Company, Easton, PA (1995).

[0053] The compound of the invention or a composition thereof can potentially be administered as a pharmaceutically acceptable acid-addition, base neutralized or addition salt, formed by reaction with inorganic acids, such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid, or by reaction with an inorganic base, such as sodium hydroxide, ammonium hydroxide, potassium hydroxide, and organic bases, such as mono-, di-, trialkyl, and aryl amines and substituted ethanolamines. The conversion to a salt is accomplished by treatment of the base compound with at least a stoichiometric amount of an appropriate acid. Typically, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol, methanol, and the like, and the acid is added in a similar solvent. The mixture is maintained at a suitable temperature (e.g., between 0 ⁰C and 50 ⁰C). The resulting salt precipitates spontaneously or can be brought out of solution with a less polar solvent.

[0054] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention. [0055] The present invention provides a method for activating an A_2B adenosine receptor in a mammal comprising administering to the mammal an effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof. The method can further comprise activating an A_2A adenosine receptor upon administration of the compound of formula I. The effective amount can be a therapeutically effective amount or a prophylactically effective amount. In addition, the compound can be administered acutely or chronically.

[0056] The present invention also provides a method for activating an A_2B adenosine receptor in a cell comprising contacting the cell with a compound or pharmaceutically acceptable salt of formula I. The method can further comprise activating an A_2A adenosine receptor upon contacting the cell with a compound of formula I. The method includes contacting the cell and the compound or salt of formula I is carried out in vitro, in vivo, or ex vivo. As used herein, the term "in vitro" means that the cell is not in a living organism. As used herein, the term "in vivo" means that the cell is a part of a living organism or is the living organism. The term "ex vivo" as used herein refers to the administration of a compound to a cell or a population of cells in vitro, followed by administration of the cell or population of cells to a host. [0057] Preferably the cell is in or from a host. Hosts include, for example, bacteria, yeast, fungi, plants, and mammals. Preferably, the host is a mammal. For purposes of the present invention, mammals include, but are not limited to, the order Rodentia, such as mice, and the order Logomorpha, such as rabbits. It is preferred that the mammals are from the order Carnivora, including Felines (cats) and Canines (dogs). It is more preferred that the mammals are from the order Artiodactyla, including Bovines (cows) and Swines (pigs) or of the order Perssodactyla, including Equines (horses). It is most preferred that the mammals are of the order Primates, Ceboids, or Simioids (monkeys) or of the order Anthropoids (humans and apes). An especially preferred mammal is the human. Furthermore, the host can be the unborn offspring of any of the forgoing hosts, especially mammals (e.g., humans), in which case any screening of the host or cells of the host, or administration of compounds to the host or cells of the host, can be performed in utero.

[0058] The amount or dose of a compound of formula I, a salt thereof, or a composition thereof should be sufficient to affect a therapeutic or prophylactic response in the host over a reasonable time frame. The appropriate dose will depend upon the nature and severity of the disease or affliction to be treated or prevented, as well as by other factors. For instance, the dose also will be determined by the existence, nature and extent of any adverse side effects that might accompany the administration of a particular compound or salt. Ultimately, the attending physician will decide the dosage of the compound of the present invention with which to treat each individual patient, taking into consideration a variety of factors, such as age, body weight, general health, diet, sex, compound or salt to be administered, route of administration, and the severity of the condition being treated. Typical doses might be, for example, 0.1 mg to 1 g daily, such as 5 mg to 500 mg daily.

[0059] Moreover, since the compound of formula I or pharmaceutically salt thereof acts as an agonist of an A_2B adenosine receptor, the inventive compounds are contemplated to be useful for treating disorders in which therapeutic treatment is effected by activating the A_2B adenosine receptor. The method can further comprise treating disorders in which therapeutic treatment is effected by activating both the A_2A and A_2B adenosine receptors. More specifically, the present invention contemplates a method of treating or preventing a disorder in a mammal comprising administering a therapeutically effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof to the mammal, whereupon the disorder is treated or prevented. The disorder is any disorder in which activation of the A_2B or both the A_2B and A_2A adenosine receptors is beneficial in its treatment or prevention. Such disorders include, for example, septic shock, cystic fibrosis, restenosis, erectile dysfunction, inflammation, and cardiac ischemia. The compounds or pharmaceutically acceptable salts of the invention find use in the preparation of a medicament for activating A_2B adenosine receptors in a mammal. [0060] The present invention also provides a method of treating or preventing (a) myocardial ischemia or (b) myocardial ischemia/reperfusion injury in a mammal comprising administering a therapeutically effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof to the mammal, whereupon the (a) myocardial ischemia or (b) myocardial ischemia/reperfusion injury is treated or prevented. A period of myocardial ischemia followed by reperfusion produces damage to the myocardium. In a particularly preferred embodiment, the compound of formula I or a salt thereof is administered for at least the first 24 hrs following reperfusion. In this method, the compound of formula I or a salt thereof can limit infarct size when administered at the time of reperfusion. If desired, the compound of formula I or a salt thereof can be administered prior to reperfusion. In a particularly preferred embodiment of this method, the compound administered is 2-(3"-(6"-bromo-indolyl)ethyloxy)adenosine (i.e., compound 28) or a pharmaceutically acceptable salt thereof. The compounds or pharmaceutically acceptable salts of the invention find use in the preparation of a medicament for treating or preventing myocardial ischemia or myocardial ischemia/reperfusion injury.

[0061] Ischemic preconditioning protects a reperfused heart by inhibiting the formation of permeability transition pores that normally form in many of the heart's mitochondria in the first minutes of reperfusion. These large conductance pores span both the inner and outer membrane and depolarize the matrix which uncouples the mitochondria and halts the oxidative phosphorylation of ADP to ATP. Energy production is thus inhibited at a time when the ischemic cells need it the most. If enough of the cell's mitochondria experience pore formation, then the cell will swell uncontrollably because it lacks the energy required to run the membrane ion pumps that maintain volume control. Those cells suffer lethal membrane rupture and die.

[0062] Ischemic preconditioning causes activation of ERK and PB -kinase at reperfusion, which ultimately act to inhibit transition pore formation at reperfusion. The signal transduction pathway responsible for the kinase activation in the preconditioned heart includes the A_2B receptor (Kuno et al., J. MoI. Cell. Cardiol, in press (2007)). When the untreated heart is reperfused, there are 3 populations of cells present. The first population is killed by the ischemia itself and represents that volume of necrotic tissue seen in the drug- treated groups in Figure 8. The second population includes those cells that have experienced a sub-lethal injury and will recover spontaneously with no treatment. That population represents the surviving tissue seen in the control hearts in Figure 8. The third population represents cells that are still viable at reperfusion but will soon be killed by transition pore formation. It is that population that is salvaged by a drug of formula I (necrotic tissue in the control group minus that in the drug-treated groups in Figure 8).

[0063] There is a second wave of killing that is not detected by either of the models used in this study. In the blood-perfused heart, ischemically injured tissue that is still alive can become pro-inflammatory. Leukocytes and particularly lymphocytes can attack these cells and kill some of them over the first 24 hr of reperfusion (Yang et al., Circulation, 111: 2190- 2197 (2005)). A_2A-selective agonists attenuate this process, and thus induce salvage by a mechanism unrelated to that from A_2B agonists (Glover et al., Am. J. Physiol., 288: H1851- H1858 (2005)). Thus, some of those cells that survive the first several hours of reperfusion will be targeted 6-8 hr later by a second wave of cell death due to inflammation. Compounds of formula I that are agonists for both A_2A and A_2B (e.g., compound 28) should protect against myocardial ischemia/reperfusion injury.

[0064] The mammal is a patient prone to reperfusion injury, for example, a patient with coronary artery diseases in general or a patient about to have occluded arteries opened (reperfused) by one or more various interventions (e.g., coronary artery bypass grafts, angioplasty, or thrombolytic therapy).

[0065] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.

Materials and instrumentation

[0066] 2-Amino-6-chloropurine-9-riboside, tryptophol, l-iodo-3-phenylpropane, 5- bromoindole-3 -acetic acid, 5-methoxyindole-3-acetic acid and other reagents and solvents are purchased from Sigma-Aldrich (St. Louis, MO), and 5-fluoroindole-3-acetic acid is purchased from Wako Chemicals USA, Inc. (Richmond, VA). Compound 69 is prepared as reported (Chou et al., Heterocycles 2003, 60, 1095-1110).

[0067] ¹H NMR spectra are obtained with a Varian Gemini 300 spectrometer using

CDCl₃, CD₃OD as solvents. Chemical shifts are expressed in δ values (ppm) with tetramethylsilane (50.00) for CDCl₃ and (53.30) for CD₃OD. [0068] Purity of the nucleosides submitted for biological testing is checked using a Hewlett-Packard 1100 HPLC equipped with a Luna 5μ RP-C 18(2) analytical column (250 X 4.6 mm; Agilent Technologies, Santa Clara, CA). System A: linear gradient solvent system: CH₃CN/H₂O from 20/80 to 40/60 in 20 min; the flow rate is 1 mL/min., System B: linear gradient solvent system: CH₃CNZH₂O from 20/80 to 60/40 in 20 min; the flow rate is 1 mL/min., System C: linear gradient solvent system: CH₃CN/5mM TBAP from 20/80 to 60/40 in 20 min.; the flow rate is 1 mL/min., System D: linear gradient solvent system: CH₃CN/5mM TBAP from 5/95 to 80/20 in 20 min.; the flow rate is 1 mL/min. Peaks are detected by UV absorption with a diode array detector. All derivatives tested for biological activity show >98% purity in the HPLC systems.

[0069] TLC analysis is carried out on aluminum sheets pre-coated with silica gel F₂₅₄ (0.2 mm) from Aldrich. Low-resolution mass spectrometry is performed with a JEOL SXl 02 spectrometer with 6-kV Xe atoms following desorption from a glycerol matrix or on an Agilent LC/MS 1100 MSD, with a Waters (Milford, MA) Atlantis Cl 8 column. High resolution mass spectroscopic (HRMS) measurements are performed on a proteomics optimized Q-TOF-2 (Micromass- Waters) using external calibration using polyalanine. Observed mass accuracies are those expected based on known performance of the instrument as well as trends in masses of standard compounds observed at intervals during the series of measurements. Reported masses are observed masses uncorrected for this time-dependent drift in mass accuracy.

[0070] In the pharmacological methods, [¹²⁵I]N⁵-(4-amino-3-iodobenzyl)adenosine-5'-N- methyluronamide (I-AB-MECA; 2000 Ci/mmol), [³H]CCPA (2-chloro-N⁶- cyclopentyladenosine, 42.6 Ci/mmol), [³H]CGS21680 (2-[p-(2- carboxyethy^phenylethylaminol-S'-N-ethylcarboxaminocarbonyl-adenosine, 47 Ci/mmol), and [³H]cyclic AMP (40 Ci/mmol) are from Amersham Pharmacia Biotech (Buckinghamshire, UK).

[0071] For the statistical analysis, binding and functional parameters are calculated using Prism 4.0 software (GraphPAD, San Diego, CA, USA). IC₅₀ values obtained from competition curves are converted to K; values using the Cheng-Prusoff equation (Cheng et al., Biochem. Pharmacol. 1973, 22, 3099-3108). Data are expressed as mean + standard error. EXAMPLE 1

[0072] This example demonstrates a general tosylation procedure for the synthesis of 3- iodoethylindole derivatives, 44-46, 56-58, 71-73 and 84 used in the preparation of compounds in accordance with an embodiment of the invention. See Figure 2. [0073] To a solution of the alcohol in THF (tetrahydrofuran) is added sodium hydride (60 %, 3 eq) at 0 ⁰C, and the reaction mixture is stirred at 0 ⁰C for 1 h. Tosyl chloride (3 eq) is added to the suspension at 0 °C, and the reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with ethyl acetate and washed with water, dried over MgSO₄, and filtered. The filtrate is evaporated to give a crude oil, which is subjected to column chromatography on silica gel. Elution with a mixture of toluene and acetone (40: 1) gives the desired tosylated derivative.

EXAMPLE 2

[0074] This example demonstrates a general iodination procedure for the synthesis of compounds 47-49, 59-61, 74-77, and 85 used in the preparation of compounds in accordance with an embodiment of the invention. See Figure 2.

[0075] A solution of the tosylate and sodium iodide (3.5 eq) in N, N-dimethylformamide is stirred overnight at 60 ⁰C. The reaction mixture is diluted with ethyl acetate and washed with water, dried over MgSO₄, and filtered. The filtrate is evaporated to give a crude oil, which is subjected to column chromatography on silica gel. Elution with a mixture of hexanes and ethyl acetate (4:1) gives the iodide.

3-(p-Toluenesulfonyloxyethyl)-l-(p-toluenesulfonyl)indole (44)

[0076] The yield is 62%: ¹H ΝMR (CDCl₃) δ 7.93 (IH, d with small coupling, J = 8.0

Hz), 7.74 (2H, d, J= 8.2 Hz), 7.56 (2H, d, J= 8.5 Hz), 7.12 - 7.34 (7H, m), 4.24 (2H, t, J= 6.6 Hz), 3.01 (2H, t, J= 6.6 Hz), 2.38 (3H, s), 2.32 (3H, s); HRMS (ESI-MS m/z) calcd for C₂₄H₂₃NO₅S₂Na (M+Na)⁺ 492.0915, found 492.0914.

5-Methoxy-3-(p-toluenesulfonyloxyethyl)-l-(p-toluenesulfonyl)indole (45)

[0077] The yield is 56 %. ¹H NMR (CDCl₃) δ 7.82 (IH, d, J= 9.1 Hz), 7.71 (2H, d with small coupling, J= 8.5 Hz), 7.53 (2H, d with small coupling, J= 8.2 Hz), 7.27 (IH, s), 7.21 (2H, dd, J= 0.6 and 8.8 Hz), 7.15 (2H, dd, J= 0.6 and 8.5 Hz), 6.89 (IH, dd, J= 2.5 and 9.1 Hz), 6.71 (IH, d, J = 2.2 Hz), 4.23 (2H, t, J= 6.6 Hz), 3.77 (3H, s), 2.97 (2H, dt, J= 0.8 and 6.6 Hz), 2.39 (3H, s), 2.32 (3H, s); HRMS (ESI-MS m/z) calcd for C₂₅H₂₆NO₆S₂ 500.1202 (M+H)⁺, found 500.1207.

l-(p-Toluenesulfonyl)-3-(p-toluenesulfonyloxyethyl)-5-(p-toluenesulfonyloxy) indole (46) [0078] The yield is 57%: ¹H NMR (CDCl₃) δ 7.80 (IH, d, J= 9.1 Hz), 7.71 (2H, d with small coupling, J= 8.5 Hz), 7.82 (2H, d with small coupling, J= 8.5 Hz), 7.58 (2H, d, with small coupling, J= 8.2 Hz), 7.36 (IH, s), 7.31 (2H, dd, J= 0.6 and 8.5 Hz), 7.25 (2H, d, J= 8.4 Hz), 7.19 (2H, d, J= 8.2 Hz), 6.97 (IH, d, J= 2.2 Hz), 6.84 (IH, dd, J= 2.3 and 8.9 Hz), 4.18 (2H, t, J= 6.5 Hz), 2.90 (2H, t, J= 6.5 Hz), 2.46 (3H, s), 2.40 (3H, s), 2.35 (3H, s); HRMS (ESI-MS m/z) calcd for C₃iH₃₀NO₈S₃ (M+H)⁺ 640.1134 found 640.1099.

3-Iodoethyl-l-(p-toluenesufonyl)mdole (47)

[0079] The yield is 70%: ¹H NMR (CDCl₃) δ 7.98 (IH, d with small coupling, J = 8.2

Hz), 7.76 (2H, dt, J= 1.9 and 8.5 Hz), 7.45 (2H, m), 7.32 (IH, ddd, J= 1.3, 7.1, and 8.4 Hz), 7.23 - 7.28 (2H, m), 7.20 (2H, d with small coupling, J= 8.0 Hz), 3.41 (2H, t with small coupling, J= 7.1 Hz), 3.24 (2H, t with small coupling, J= 7.3 Hz), 2.33 (3H, s); HRMS (ESI- MS m/z) calcd for Ci₇Hi₇NO₂SI (M+H)⁺ 426.0025, found 426.0016.

3-Iodoethyl-5-methoxy-l-(p-toluenesulfonyl)indole (48)

[0080] The yield is 74 %. ¹H NMR (CDCl₃) δ 7.74 (IH, d with small coupling, J= 9.1

Hz), 7.73 (2H, d with small coupling, J= 8.2 Hz), 7.40 (IH, s), 7.20 (2H, dd, J= 0.7 and 8.7 Hz), 6.92 (IH, dd, J= 2.5 and 9.2 Hz), 6.85 (IH, d, J= 2.5 Hz), 3.82 (3H, s), 3.40 (2H, dt, J = 0.7 and 7.6 Hz), 3.20 (2H, t, J= 7.3 Hz), 2.33 (3H, s); HRMS (ESI-MS m/z) calcd for Ci₈Hi₉NO₃SI (M+H)⁺ 456.0130, found 456.0135.

3-Iodoethyl-l-(p-toluenesulfonyl)-5-(p-toluenesulfonyloxy) indole (49)

[0081] The yield is 83%. ¹H NMR (CDCl₃) δ 7.85 (IH, d, J= 9.1 Hz), 7.73 (2H, d with small coupling, J= 8.5 Hz), 7.68 (2H, d with small coupling, J= 8.2 Hz), 7.47 (IH, s), 7.30 (2H, d, J= 8.3 Hz), 7.23 (2H, d, J= 8.3 Hz), 7.02 (IH, d, J= 2.5 Hz), 6.91 (IH, dd, J= 2.3 and 8.9 Hz), 3.26 (2H, t with small coupling, J =7.4 Hz), 3.12 (2H, t with small coupling, J= 7.1 Hz), 2.46 (3H, s), 2.36 (3H, s); APCI-MS (m/z) 596.0 (M+H)⁺. EXAMPLE 3

[0082] This example demonstrates a general procedure for the synthesis of 3- hydroxyethylindole derivatives 53-55 used in the preparation of compounds in accordance with an embodiment of the invention. See Figure 2.

[0083] To a solution of a 2- and/or 5-substituted-indole-3-acetic acid in methanol is added />-toluenesulfonic acid monohydrate (3 eq), and the reaction mixture is stirred at 60⁰C overnight. After neutralization with IN aqueous NaOH, the solvent is evaporated leaving an oily residue, which is dissolved in ethyl acetate. The solution is washed with water, dried over MgSO₄, and filtered. The filtrate is evaporated leaving an oily residue, which is subjected to column flush chromatography on silica gel. Elution with a mixture of toluene and acetone (5:1) gives the corresponding ester.

[0084] To a solution of the ester in THF is added lithium aluminum hydride (2.8 eq) at 0 ⁰C, and the reaction mixture is stirred at 0 ⁰C for 1 h and at room temperature for 1 h. After addition of ethyl acetate, the reaction mixture is stirred at room temperature for 30 min. The reaction mixture is diluted with ethyl acetate and washed with water, dried over MgSO₄, and filtered. The filtrate is evaporated leaving an oily residue, which is subjected to column chromatography on silica gel. Elution with a mixture of toluene and acetone (3:1) gives the pure alcohol.

5-Fluoro-tryptopho] (53)

[0085] Compound 53 is identical to the known compound reported by Mewshaw et al. (J.

Med. Chem. 2004, 47, 3823-3842).

5-Bromo-tryptophol (54)

[0086] Compound 54 is identical to the commercially available compound.

3-Hydroxyethyl-5-methoxy-2-methylindole (55)

[0087] The yield is 81%. ¹H NMR (CDCl₃) δ 7.27 (IH, br s), 7.16 (IH, d, J= 8.8 Hz),

6.97 (IH, d, J= 2.2 Hz), 6.78 (IH, dd, J= 2.5 and 8.5 Hz), 3.78 - 3.88 (2H, m overlapped with OCH₃), 3.85 (3H, s), 2.94 (2H, t, J= 6.5 Hz), 2.39 (3H, s); HRMS (ESI-MS m/z) calcd for Ci₂Hi₆NO₂206.1181 , found 206.1190. S-Fluoro-l-Cp-toluenesulfonylJ-S-Cp-toluenesulfonyloxyethy^indoIe CSδ)

[0088] The yield is 58 %. ¹H NMR (CDCl₃) δ 7.87 (IH, dd, J= 4.1 and 9.1 Hz), 7.72

(2H, d with small couplings, J= 8.5 Hz), 7.55 (2H, d with small coupling, J= 8.2 Hz), 7.36 (IH, S), 7.24 (2H, d with small coupling, J= 8.0 Hz), 7.16 (2H, dd, J= 0.7 and 8.7 Hz), 7.00 (IH, dt, J= 2.4 and 9.0 Hz), 6.89 (IH, dd, J= 2.2 and 8.5 Hz), 4.22 (3H, t, J= 6.5 Hz), 2.95 (3H, t, J= 6.5 Hz), 2.39 (3H, s), 2.34 (3H, s); HRMS (ESI-MS m/z) calcd for C₂₄H₂₃NO₅S₂F (M+H)⁺ 488.1002, found 488.0995.

5-Bromo-3-(p-toluenesulfonyIoxyethyI)-l-(p-toIuenesulfonyl)indoIe (57)

[0089] The yield is 63%. ¹H NMR (CDCl₃) δ 7.80 (IH, d with small coupling, J= 9.6

Hz), 7.73 (2H, d with small coupling, J= 8.2 Hz), 7.52 (2H, d with small coupling, J= 8.5 Hz), 7.32-7.39 (3H, m), 7.25 (2H, d, J= 8.0 Hz), 7.13 (2H, d, J= 8.0 Hz), 4.23 (2H, t, J= 6.3 Hz), 2.95 (2H, dt, J= 0.8 and 6.5 Hz), 2.39 (3H, s), 2.34 (3H, s); HRMS (ESI-MS m/z) calcd for C₂₄H₂₂NO₅S₂BrLi (M+Li)⁺ 554.0283, found 554.0292.

5-Methoxy-2-methyl-3-(p-toluenesulfonyIoxyethyl)-l-(p-toluenesulfonyI)indole (58) [0090] The yield was 30%. ¹H NMR (CDCl₃) δ 8.02 (IH, d, J = 9.1 Hz), 7.58 (2H, d with small coupling, J= 8.2Hz), 7.48 (2H, d with small coupling, J= 8.2 Hz), 7.18 (2H, dd, J = 0.7 and 8.7 Hz), 7.13 (2H, dd, J= 0.6 and 8.5 Hz), 6.84 (IH, dd, J= 2.8 and 9.1 Hz), 6.64 (IH, d, J= 2.5 Hz), 4.11 (2H, t, J= 6.7 Hz), 3.79 (3H, s), 2.90 (2H, t, J= 6.7 Hz), 2.43 (3H, s), 2.39 (3H, s), 2.33 (3H, s); HRMS (ESI-MS m/z) calcd for C₂₆H₂₇NO₆S₂Na (M+Na)⁺ 536.1178, found 536.1186.

3-Iodoethyl-5-fluoro-l-(p-toluenesulfonyl)indole (59)

[0091] Yield 70 %. ¹H NMR (CDCl₃) δ 7.92 (IH, ddd, J= 0.6, 4.3 and 9.1 Hz), 7.74

(2H, dt, J= 1.9 and 8.5 Hz), 7.48 (IH, s), 7.22 (2H, d, J= 8.0 Hz), 7.09 (IH, dd, J= 2.5 and 8.5 Hz), 7.04 (IH, dt, J= 2.5 and 9.1 Hz), 3.39 (2H, dt, J= 0.7 and 6.8 Hz), 3.19 (2H, t, J= 7.3 Hz), 2.35 (3H, s); HRMS (ESI-MS m/z) calcd for Ci₇Hi₅NO₂FS 316.0808, found 316.0810.

5-Bromo-3-Iodoethyl-l-(p-toluenesufonyl)indole (60)

[0092] The yield is 65 %. ¹H NMR (CDCl₃) δ 7.85 (IH, d, J= 8.8 Hz), 7.74 (2H, d with small coupling, J= 8.2 Hz), 7.57 (IH, d, J= 1.9 Hz), 7.45 (IH, s), 7.41 (IH, dd, J= 1.9 and 8.8 Hz), 7.22 (2H, d, J= 8.2 Hz), 3.88 (2H, t, J= 7.0 Hz), 3.19 (2H, t, J= 7.3 Hz), 2.35 (3H, s); HRMS (ESI-MS m/z) calcd for C_nHi₅NO₂SBrI (M+H)⁺ 502.9025, found 502.9036.

3-Iodoethyl-5-methoxy-2-methyl-l-(p-toluenesufonyl)indole (61)

[0093] The yield is 85%. ¹H NMR (CDCl₃) δ 8.07 (IH, d, J= 9.1 Hz), 7.58 (2H, dt, J =

1.8 and 8.5 Hz), 7.17 (2H, d, J= 8.2 Hz), 6.87 (IH, dd, J= 2.5 and 9.1 Hz), 6.79 (IH, d, J = 2.5 Hz), 3.84 (3H, s), 3.26 (2H, m), 3.14 (2H, m), 2.52 (3H, s), 2.33 (3H, s); HRMS (ESI-MS m/z) calcd for Ci₉H_2INO₃IS (M+H)⁺ 470.0287, found 470.0294.

EXAMPLE 4

[0094] This example demonstrates a general synthetic procedure for 3- hydroxyethylindole derivatives (67-70) via Fischer indole ring preparation used in the preparation of compounds in accordance with an embodiment of the invention. See Figure 2. [0095] A solution of substituted phenylhydrazine hydrochloride and ethoxytetrahydrofuran (1.5 eq) in 95 % ethanol is refluxed overnight. The reaction mixture is filtered through celite. The filtrate is evaporated to give a crude solid. The solid is dissolved in ethyl acetate, and the solution is washed with water, dried over MgSO₄, and filtered. The filtrate is evaporated to give a crude oil, which is subjected to column chromatography on silica gel. Elution with a mixture of toluene and acetone (2:1) gives the alcohol.

6-Chloro-tryptophol (67), 6-Bromo-tryptophol (68), and 5-ChIoro-tryptophol (69) [0096] These compounds are identical to the known compounds. 67: WO 2001/049679;

68: Fuchs et al. (J Am. Chem. Soc. 2004, 126, 5068-5069); and 69 Chou {Heterocycles 2003, 60, 1095-1110).

5-Iodo-tryptophol (70)

[0097] The yield is 32 %. ¹H NMR (CDCl₃) δ 8.07 (IH, br s), 7.95 (IH, m), 7.45 (IH, dd, J= 1.7 and 8.5 Hz), 7.16 (IH, d, J= 8.5 Hz), 7.06 (IH, d, J = 2.2 Hz), 3.89 (2H, br s), 2.98 (2H, dt, J= 0.8 and 6.3 Hz), 1.45 (IH, br s); APCI-MS (m/z) 288.0 (M+H)⁺.

6-ChIoro-3-(p-toluenesulfonyloxyethyl)-l-(p-toluenesulfonyI)indole (71)

[0098] The yield is 32%. ¹H NMR (CDCl₃) δ 7.94 (IH, d, J= 1.7 Hz), 7.74 (2H, d with small coupling, J= 8.5 Hz), 7.51 (2H, d with small coupling, J= 8.2 Hz), 7.29 (2H, d, J= 8.5 Hz), 7.25 (IH, s), 7.19 (IH, d, J= 8.2 Hz), 7.10-7.16 (3H, m), 4.27 (2H, t, J= 6.3 Hz), 2.97 (2H, t, J= 6.3 Hz), 2.40 (3H, s), 2.35 (3H, s); APCI-MS (m/z) 504.1 (M+H)⁺.

6-Bromo-3-(p-toluenesulfonyloxyethyl)-l-(p-toluenesulfonyl)indoIe (72)

[0099] The yield is 30 %. ¹H NMR (CDCl₃) δ 8.10 (IH, d, J= 1.4Hz), 7.74 (2H, d with small coupling, J= 8.2 Hz), 7.51 (2H, d with small coupling, J= 8.2 Hz), 7.23-7.30 (5H, m), 7.13 (2H, dd, J= 1.7 and 8.2 Hz), 4.23 (2H, t, J= 6.3 Hz), 2.97 (2H, t, J= 6.3 Hz), 2.40 (3H, s), 2.35 (3H, s); APCI-MS (m/z) found 548.0 (M+H)⁺.

5-Chloro-3-(p-toIuenesulfonyloxyethyl)-l-(p-toluenesulfonyl)indole (73)

[00100] The yield is 30 %. ¹H NMR (CDCl₃) δ 7.85 (IH, dd, J= 0.6 and 8.8 Hz), 7.73

(2H, dt, J= 2.1 and 8.7 Hz), 7.53 (2H, dt, J= 1.8 and 8.5 Hz), 7.36 (IH, s), 7.21 - 7.26 (3H, m), 7.19 (IH, dd, J= 0.6 and 1.9 Hz), 7.14 (2H, dd, J= 0.5 and 8.5 Hz), 4.23 (2H, t, J= 6.5 Hz), 2.95 (2H, dt, J= 0.8 and 6.5 Hz), 2.39 (3H, s), 2.34 (3H, s); HRMS (ESI-MS m/z) calcd for C₂₄H₂₂NO₅NaS₂Cl 526.0526, found 526.0535.

6-Chloro-3-iodoethyl-l-(p-toluenesulfonyl)indole (74)

[0100] The yield is 67 %. ¹H NMR (CDCl₃) d 8.00 (IH, d, J = 1.7 Hz), 7.76 (2H, d with small coupling, J= 8.5 Hz), 7.43 (IH, s), 7.36 (IH, d, J= 8.5 Hz), 7.25 ~ 7.28 (2H overlapped with CHCl₃), 7.22 (IH, dd, J= 1.8 and 8.4 Hz), 3.39 (2H, t with small coupling, J = 7.3 Hz), 3.21 (2H, t, Jwith small coupling, J= 7.3 Hz), APCI-MS (m/z) 460.0 (M+H)⁺.

6-Bromo-3-iodoethyl-l-(p-toluenesulfonyl)indole (75)

[0101] The yield is 67 %. ¹H NMR (CDCl₃) δ 8.16 (IH, d, J= 1.7 Hz), 7.76 (2H, dd, J =

1.9 and 8.5 Hz), 7.42 (IH, br s), 7.36 (IH, dd, J= 1.7 and 8.5 Hz), 7.30 (IH, d, J= 8.2 Hz), 7.25 (2H, d, J= 8.5 Hz), 3.38 (2H, t with small coupling, J= 7.4 Hz), 3.21 (2H, t with small coupling, J= 7.3 Hz), 2.36 (3H, s); HRMS (ESI-MS m/z) calcd for C_nHi₅BrINO₂S (M)⁺ 502.9052, found 502.9066.

5-Chloro-3-iodoethyl-l-(p-toluenesulfonyl)indole (76)

[0102] The yield is 60 %. ¹H NMR (CDCl₃) δ 7.90 (IH, dd, J= 0.6 and 8.8 Hz), 7.74

(2H, d with small coupling, J= 8.2 Hz), 7.47 (IH, s), 7.41 (IH, dd, J= 0.6 and 1.9 Hz), 7.24- 7.29 (IH overlaped with CHCl₃), 7.22 (2H, d, J= 8.3 Hz), 3.39 (2H, dt, J= 0.8 and 7.3 Hz), 3.20 (2H, t, J= 7.3 Hz), 2.35 (3H, s); HRMS (ESI-MS m/z) calcd for C_I7H_I6NO₂ICIS (M+H)⁺ 459.9635, found 459.9625.

5-Iodo-3-iodoethyl-l-(p-toluenesuIfonyl)indole (77)

[0103] The yield is 68 %. ¹H NMR (CDCl₃) δ 7.77 (IH, d, J= 1.6 Hz), 7.74 (IH, d, J =

8.8 Hz), 7.73 (2H, d with small coupling, J= 8.5 Hz), 7.58 (IH, dd, J= 1.7 and 8.5 Hz), 7.41 (IH, s), 7.22 (2H, d, J= 8.2 Hz), 3.83 (2H, t, J= 7.2 Hz), 3.19 (2H, t, J= 7.3 Hz), 2.35 (3H, s); APCI-MS (m/z) 551.9 (M+H)⁺.

EXAMPLE 5

[0104] This example demonstrates a synthesis of ethyl 4-bromo-3-indolylglyoxylate (80) used in the preparation of compounds in accordance with an embodiment of the invention. See Figure 2.

[0105] To a solution of 78 (2.94 g, 15.0 mmol) in diethyl ether (60 mL) is added oxalyl chloride (3.01 ml, 34.5 mmol) at 0 ⁰C, and the reaction mixture is stirred at room temperature for 1O h. After evaporation, ethanol (30 mL) is added to the solids, and the solution is stirred at room temperarure overnight. The solvent is evaporated to give a solid. This residue is dissolved in ethyl acetate, washed with water, dried over MgSO₄, and filtered. The filtrate is evaporated to give a crude solid, which is subjected to column chromatography on silica gel. Elution with a mixture of hexanes and ethyl acetate (1:1) gives 80 (2.3g, 52 %). ¹H NMR (CDCl₃) δ 9.55 (IH, br s), 8.24 (IH, d, J= 3.3 Hz), 7.50 (IH, dd, J= 0.8 and 7.7 Hz), 7.42 (IH, dd, J= 0.8 and 8.3 Hz), 7.13 (IH, t, J= 8.0 Hz), 4.41 (2H, q, J= 7.1 Hz), 1.40 (3H, t, J = 7.1 Hz); APCI-MS (m/z) 296.0 (M+H)⁺.

EXAMPLE 6

[0106] This example demonstrates a synthesis of ethyl 7-bromo-3-indolylglyoxylate (81) in an embodiment of the invention. See Figure 2.

[0107] Compound 81 is obtained from 79 by the similar procedure for the preparation of 80 (yield 70 %). ¹H NMR (CDCl₃) δ 8.96 (IH, br s), 8.55 (IH, d, J= 3.3 Hz), 8.39 (IH, dd, J = 0.6 and 8.0 Hz), 7.48 (IH, dd, J= 0.8 and 8.0 Hz), 7.23 (IH, t, J= 7.8 Hz), 4.43 (2H, q, J= 7.1 Hz), 1.44 (3H, t, J= 7.1 Hz), APCI-MS (m/z) 296.0 (M+H)⁺. EXAMPLE 7

[0108] This example demonstrates a synthesis of 4-bromo-tryptophol (82) used in the preparation of compounds in accordance with an embodiment of the invention. See Figure 2. [0109] To a solution of 80 (20 mg, 0.0675 mmol) in THF (1.4 mL) is added lithium aluminum hydride (17.4 mg, 0.459 mmol), and the reaction mixture is refluxed for 2 h. The mixture is diluted with ethyl acetate and washed with water, dried over MgSO₄, and filtered. The filtrate is evaporated to give a crude oil, which is subjected to preparative TLC developed with a mixture of hexanes and ethyl acetate (1 : 1) to give 82 (10 mg, 63 % yield). ¹H NMR (CDCl₃) δ 8.12 (IH, br s), 7.32 (IH, dd, J= 0.8 and 7.7 Hz), 7.28 (IH, dd, J= 0.8 and 7.7 Hz), 7.14 (IH, d, J= 2.5 Hz), 7.02 (IH, t, J= 7.8 Hz), 3.97 (2H, q, J= 6.1 Hz), 3.29 (2H, dt, J= 0.6 and 6.5 Hz), 1.46 (IH, t, J= 5.6 Hz); HRMS (ESI-MS m/z) calcd for Ci₀Hi₁BrNO (M+H)⁺ 240.0024, found 240.0028.

EXAMPLE 8

[0110] This example demonstrates a synthesis of 83-86 used in the preparation of compounds in accordance with an embodiment of the invention. See Figure 2. [0111] Compounds 83-86 are obtained from 81 by the similar procedure for the preparation of 82.

7-Bromo-tryptophol (83)

[0112] The yield is 52 %. IH NMR (CDCl₃) δ 8.82 (IH, br s), 7.57 (IH, d, J = 8.0 Hz),

7.36 (IH, d, J = 8.0 Hz), 7.16 (IH, d, J = 2.2 Hz), 7.02 (IH, t, J = 7.8 Hz), 3.91 (2H, q, J = 6.2 Hz), 3.02 (2H, dt, J = 0.5 and 6.3 Hz), 1.46 (IH, t, J = 6.0 Hz); HRMS (ESI-MS m/z) calcd for Ci₀HnNOBr (M+H)+ 240.0024, found 240.0031.

4-Bromo-3-(p-toluenesulfonyloxyethyl)-l-(p-toluenesulfonyl)indole (84)

[0113] The yield is 41 %. IH NMR (CDCl₃) δ 7.91 (IH, dd, J = 0.8 and 8.2 Hz), 7.75

(2H, d with small coupling, J = 8.5 Hz), 7.55 (2H, d with small coupling, J = 8.2 Hz), 7.41 (IH, s), 7.28 (IH, dd, J = 1.0 and 7.8 Hz), 7.25 (2H, d, J = 8.2 Hz), 7.11 (2H, d, J = 8.0 Hz), 7.09 (IH, t, J = 8.0 Hz), 4.32 (2H, t, J = 6.5 Hz), 3.25 (2H, t, J = 6.3 Hz), 2.34 (6H, s); APCI- MS (m/z) 548.0 (M+H)+.

4-Bromo-3-iodoethyI-l-(p-toluenesulfonyl)-indole (85) [0114] The yield is 67 %. ¹H NMR (CDCl₃) δ 7.96 (IH, dd, J= 0.8 and 8.2 Hz), 7.76 (2H, d with small coupling, J= 8.5 Hz), 7.52 (IH, s), 7.38 (IH, dd, J= 0.8 and 8.0 Hz), 7.23 (2H, dd, J= 0.6 and 8.5 Hz), 7.13 (IH, t, J= 8.1 Hz), 3.45 (4H, s), 2.35 (2H, s); HRMS (ESI- MS m/z) calcd for Ci₇Hi₆NO₂IBrS (M+H)⁺ 509.9130, found 509.9114.

7-Bromo-3-iodoethylindole (86)

[0115] The yield is 88 %. IH NMR (CDCl₃) δ 8.21 (IH, br s), 7.52 (IH, dd, J = 0.8 and

8.0 Hz), 7.36 (IH, d, J = 7.7 Hz), 7.16 (IH, d, J = 2.2 Hz), 7.02 (IH, t, J = 7.7 Hz), 3.39-3.46 (2H, m), 3.29-3.37 (2H, m); HRMS (ESI-MS m/z) calcd for Ci₀Hi₀NBrI (M+H)+ 349.9041, found 349.9036.

EXAMPLE 9

[0116] This example demonstrates a synthesis of 2-hydroxyethyl-l-(p-toluenesulfonyl)- indole (88) used in the preparation of compounds in accordance with an embodiment of the invention. See Figure 3.

[0117] To a solution of N-tosyl-2-iodoanilide (1.172g. 3.14 mmol) in DMF are added 3- butyn-1-ol (1.42 ml, 18.8 mmol), copper iodide (119 mg, 0.628 mmol), triethyl amine (13.56 mL, 97.3 mmol) and Pd(PPh₃)₂Cl₂ (220.3 mg, 0.314 mmol). The reaction mixture is stirred at 70 ⁰C overnight. The reaction mixture is diluted with ethyl acetate. The solution is washed with water, dried over MgSO₄, and filtered. The filtrate is evaporated to give an oil, which is subjected to column chromatography on silica gel. Elution with a mixture of hexanes and ethyl acetate (1:1) gives 88 (820 mg, 83%). ¹H ΝMR (CDCl₃) δ 8.16 (IH, d, J = 8.2 Hz), 7.61 (2H, d with small coupling, J= 8.2 Hz), 7.42 (IH, dd, J= 1.7 and 7.4 Hz), 7.28 (IH, dt, J= 2.2 and 7.6 Hz), 7.23 (IH overlapped with Ph), 7.18 (2H, d, J= 8.5 Hz), 6.50 (IH, s), 4.01 (2H, t, J= 6.1 Hz), 3.29 (2H, t, J= 6.2 Hz), 2.33 (3H, s); APCI-MS (m/z) 316.0 (M+H)⁺.

EXAMPLE 10

[0118] This example demonstrates a synthesis of 2-iodoethyl-l-(p-toluenesulfonyl)- indole (89) used in the preparation of compounds in an embodiment of the invention. See Figure 3.

[0119] To a solution of 88 (638 mg, 2.02 mmol) in a mixture of diethylether (24 mL) and acetnitrile (8 mL) are added triphenylphosphine (1.589 g, 6.06 mmol), imidazole (439 mg, 6.46 mmol), and iodine (1.639 g, 6.46 mmol). The reaction mixture is stirred at 0 ⁰C for 1 h. The reaction mixture is diluted with ethyl acetate. The solution is washed with water, dried over MgSO₄, and filtered. The filtrate is evaporated to give an oil, which is subjected to column chromatography on silica gel. Elution with a mixture of hexanes and ethyl acetate (4: 1) gives 89 (847 mg, 98 %). ¹H NMR (CDCl₃) δ 8.14 (IH, d with small coupling, J= 8.2 Hz), 7.60 (2H, dt, J= 2.0 and 8.6 Hz), 7.45 (IH, dd, J= 1.0 and 6.7 Hz), 7.30 (IH, dt, J= 1.5 and 8.0 Hz), 7.23 (IH, dd, J= 1.2 and 7.6 Hz), 7.18 (2H, d with small coupling, J= 8.0 Hz), 6.50 (IH, s), 3.46 - 3.60 (4H, m), 2.33 (3H, s); HRMS (ESI-MS m/z) calcd for Ci₇Hi₇NO₂IS (M+H)⁺ 426,0025 found 426.0035.

EXAMPLE I l

[0120] This example demonstrates a synthesis of benzoimidazol-1-yl-ethanol (92) used in the preparation of compounds in an embodiment of the invention. See Figure 3. [0121] To a solution of benzoimidazol-1-yl-acetic acid (893 mg, 5.06 mmol) in THF (20 mL) is added lithium aluminum hydride (672 mg, 17.7 mmol) at 0 ⁰C, and the reaction mixture is stirred at room temperature for 5 h. After dilution with ethyl acetate the solution is washed with water, dried over MgSO₄, and filtered. The filtrate is evaporated to give a crude oil, which is subjected to column chromatography on silica gel. Elution with a mixture of chloroform and methanol (8: 1) gives 92 (620 mg, 76 %). ¹H NMR (CDCl₃) δ 7.63 (IH, s), 7.38 (IH, dt, J= 1.0 and 8.2 Hz), 7.31 (IH, dt, J= 1.0 and 8.0 Hz), 7.17 (IH, ddd, J= 1.0, 7.1, and 8.1 Hz), 7.06 (IH, ddd, J= 1.1, 7.1, and 8.1 Hz), 4.22 (2H, t, J = 4.9 Hz), 3.99 (2H, t, J= 4.8 Hz); HRMS (ESI-MS m/z) calcd for C₉HnN₂O (M+H)⁺ 163.0871, found 163.0880.

EXAMPLE 12

[0122] This example demonstrates a synthesis of benzotriazol-1-yl-ethanol (93) used in the preparation of compounds in an embodiment of the invention. See Figure 3. [0123] Procedure used for the preparation of 93 from 91 is similar to those used for the preparation of 92 from 90; amorphous solid, the yield is 59 %. ¹H NMR (CDCl₃) δ (IH, d with small coupling, J= 8.5 Hz), 7.61 (IH, d with small coupling, J= 8.2 Hz), 7.50 (IH, ddd, J= 1.1, 7.0 and 8.1 Hz), 7.36 (IH, ddd, J= 1.2, 6.9 and 8.1 Hz), 4.75 (2H, t, J= 5.1 Hz), 4.25 (2H, dd, J= 5.9 and 10.3 Hz), 2.55 (IH, t, J= 6.0 Hz); HRMS (ESI-MS m/z) calcd for C₈Hi₀N₃O 164.0824 found 164.0812. EXAMPLE 13

[0124] This example demonstrates a synthesis of benzoimidazol-1-yl-ethyliodide (94) used in the preparation of compounds in an embodiment of the invention. See Figure 3. [0125] To a solution of 92 (22 mg, 0.134 mmol) in a mixture of acetonitrile (0.3 mL) and diethylether (0.9 mL) are added triphenylphosphine (105 mg, 0.402 mmol), imidazole (29 mg, 0.428 mmol), and iodine (108 mg, 0.428 mmol) at 0 ⁰C. The reaction mixture is stirred for 2 h. The mixture is diluted with ethyl acetate, washed with water, dried over MgSO₄, and filtered. The filtrate is evaporated to give a crude oil, which is subjected to preparative TLC developed with a mixture of toluene and acetone (2: 1) to give 94 (32.3 mg, 88 %). ¹H NMR (CDCl₃) δ 7.97 (IH, s), 7.80-7.87 (IH, m), 7.28-7.42 (3H, m), 4.58 (2H, t, J= 7.0 Hz), 3.51 (2H, t, J= 7.1 Hz); APCI-MS (m/z) 273.0 (M+H)⁺.

EXAMPLE 14

[0126] This example demonstrates a synthesis of benzotriazol-1-yl-ethyliodide (95) used in the preparation of compounds in an embodiment of the invention. See Figure 3. [0127] The procedure used for the preparation of 95 from 93 is similar to that used for the preparation of 94 from 92; amorphous solid, the yield is 88 %. ¹H NMR (CDCl₃) δ 8.09 (IH, dt, J= 1.0 and 8.3 Hz), 7.50 - 7.60 (2H, m), 7.40 (IH, ddd, J= 1.8, 6.3, and 8.1 Hz), 5.02 (2H, t, J= 7.3 Hz), 3.67 (2H, t, J= 7.3 Hz); HRMS (ESI- MS m/z) calcd for C₈H₉N₃I (M+H)⁺ 273.9841, found 273.9833.

EXAMPLE 15

[0128] This example demonstrates a synthesis of 3-hydroxyethyl- 1 -(p- toluenesulfonyl)pyrrole (98) used in the preparation of compounds in an embodiment of the invention. See Figure 3.

[0129] To a solution of 97 (1.24 g, 4.21 mmol) in THF (20 mL) is added lithium aluminum hydride (340 mg, 6.32 mmol) at 0 ⁰C. The reaction mixture is stirred for 2 h. After addition of ethyl acetate, the mixture is stirred for 30 min. The mixture is diluted with ethyl acetate, washed with water, dried over MgSO₄, and filtered. The filtrate is evaporated to give a crude oil, which is subjected to column chromatography on silica gel. Elution with a mixture of chloroform and methanol (20:1) gives 98 (692 mg, 62 %). ¹H NMR δ 7.74 (2H, d, J= 8.4 Hz), 7.28 (2H, d, J= 8.7 Hz), 7.10 (IH, t, J= 2.7 Hz), 6.99 (IH, m), 6.19 (IH, dd, J = 1.5 and 3.3 Hz), 3.74 (2H, t, J= 6.5 Hz), 2.64 (2H, t, J= 6.5 Hz), 2.40 (3H, s); HRMS (ESI-MS m/z) calcd for Ci₃Hi₆NO₃S (M+H)⁺ 266.0851, found 266.0837.

EXAMPLE 16

[0130] This example demonstrates a synthesis of 3-iodoethyl-l-(p- toluenesulfonyl)pyrrole (99) used in the preparation of compounds in an embodiment of the invention. See Figure 3.

[0131] The procedure used for preparation of 99 from 98 is similar to that used for the preparation of 89 from 88; the yield was 62 %. ¹H NMR (CDCl₃) δ 7.73 (2H, d, J= 8.2 Hz), 7.29 (2H, d, J= 8.5 Hz), 7.08 (IH, t, J= 2.8 Hz), 6.99 (IH, m), 6.16 (IH, dd, J= 1.6 and 3.3 Hz), 3.24 (2H, t, J= 7.3 Hz), 2.96 (2H, t, J=7.6 Hz), 2.40 (3H, s); HRMS (ESI-MS m/z) calcd for Ci₃Hi₅NO₂SI (M+H)⁺ 375.9868, found 375.9857.

EXAMPLE 17

[0132] This example demonstrates a general synthetic procedure for 2-substituted adenosine derivatives in an embodiment of the invention. See Figure 4. [0133] To a solution of 2', 3', 5'-triacetyl-6-chloroguanosine in N,N-dimethylformamide are added iodide (1.8 eq) and Cs₂CO₃ (2.7 eq) at room temperature, and the reaction mixture is stirred overnight. After dilution with ethyl acetate, the solution is washed with water twice, dried over MgSO₄, and filtered. The filtrate is evaporated to give a crude oil, which is purified by column chromatography or preparative TLC on silica gel. Elution or developing with a mixture of toluene and acetone (4:1) gives the 2-substituted 2', 3', 5'-triacetyl-6- chloroadenosine derivative.

[0134] A solution of 2-substituted 2', 3', 5'-triacetyl-6-chloroadenosine derivative in saturated ammonia ethanol solution is stirred in sealed tube overnight at 110 - 120 ⁰C. The solvent is evaporated to give an oil, which is subjected to preparative TLC developed with a mixture of chloroform and methanol (8:1) to give the 2-substituted adenosine derivative. [0135] In case of deprotection of the tosyl group as a 2-substituent, tosylated adenosine derivative is treated with KOH (20 eq) in methanol overnight at 70 ⁰C in sealed tube. The reaction mixture is concentrated to a small amount of solution, which is subjected to preparative TLC developed with a mixture of chloroform and methanol (5:1) to give the final product. 6-Chloro-2-(3"-(l "-(p-toluenesuIfonyl)indolyl)ethyloxy)-3', 4', 5'-triacetyladenosine

(102)

[0136] The yield is 86 %. ¹H NMR (CDCl₃) δ 8.09 (IH, s), 7.98 (IH, d with small coupling, J= 6.6 Hz), 7.76 (2H, d with small coupling, J= 8.2 Hz), 7.61 (IH, d with small coupling, J= 7.1 Hz), 7.53 (IH, s), 7.14 - 7.36 (6H, m), 6.13 (IH, d, J= 4.7 Hz), 5.93 (IH, t, J= 5.1 Hz), 5.65 (IH, t, J = 5.5 Hz), 4.71 (2H, m), 4.39 - 4.49 (2H, m), 4.32 (IH, dd, J= 4.7 and 12.6 Hz), 3.24 (2H, t, J= 7.0 Hz), 2.32 (3H, s), 2.14 (3H, s), 2.09 (3H, s), 2.05 (3H, s); HRMS (ESI-MS m/z) calcd for C₃₃H₃₂N₅Oi₀ClSNa (M+Na)⁺ 748.1456, found 748.1455.

6-Chloro-2-(3"-(5"-methoxy-l"-(p-toluenesulfonyl)indolyl)ethyloxy)- 3', 4', 5'- triacetyladenosine (103)

[0137] The yield is 72 %. ¹H NMR (CDCl₃) δ 8.09 (IH, s), 7.86 (IH, dd, J= 9.1 Hz),

7.73 (2H, d, J= 8.5 Hz), 7.48 (IH, s), 7.20 (2H, d, J= 8.2 Hz), 7.03 (IH, d, J= 2.5 Hz), 6.92 (IH, dd, J= 2.3 and 8.9 Hz), 6.12 (IH, d, J= 4.7 Hz), 5.93 (IH, t, J= 5.1 Hz), 5.66 (IH, t, J = 5.6 Hz), 4.69 (2H, ddd, J= 3.8, 7.4, and 14.3 Hz), 4.40 - 4.49 (2H, m), 4.31 (IH, dd, J = 4.4 and 12.6 Hz), 3.85 (3H, s), 3.19 (2H, t, J= 6.7 Hz), 2.32 (3H, s), 2.14 (3H, s), 2.09 (3H, s), 2.05 (3H, s); HRMS (ESI-MS m/z) calcd for C₃₄H₃₅N₅O_nSCl (M+H)⁺ 756.1742, found 756.1735.

6-Chloro-2-(3"-(5"-(p-toluenesulfonyIoxy) -l"-(p-toluenesulfonyl)indolyl)ethyloxy)- 3',

4', 5'-triacetyladenosme (104)

[0138] The yield is 51 %. ¹H NMR (CDCl₃) δ 8.09 (IH, s), 7.83 (IH, d, J= 8.5 Hz), 7.72

(2H, d with small coupling, J= 8.5 Hz), 7.68 (2H, d with small coupling, J= 8.2 Hz), 7.57 (IH, s), 7.25-7.31 (3H, m), 7.22 (2H, d, J = 8.0 Hz), 6.83 (IH, dd, J= 2.3 and 8.9 Hz), 6.12 (IH, d, J= 4.4 Hz), 5.94 (IH, dd, J= 4.7 and 5.5 Hz), 5.67 (IH, t, J= 5.4 Hz), 4.64 (2H, m), 4.40-4.50 (2H, m), 4.31 (IH, dd, J= 5.1 and 12.8 Hz), 3.13 (2H, t, J= 6.7 Hz), 2.42 (3H, s), 2.34 (3H, s), 2.15 (3H, s), 2.08 (3H, s), 2.03 (3H, s); HRMS (ESI-MS m/z) calcd for C₄₀H₃₉ClN₅Oi₃S₂ (M+H)⁺ 896.1674 found 896.1638.

6-Chloro-2-(3"-(5"-fluoro-l"-(p-toluenesulfonyl)indolyl)ethyloxy)-3', 4', 5'- triacetyladenosine (105)

[0139] The yield is 59 %. ¹H NMR (CDCl₃) δ 8.09 (IH, s), 7.91 (IH, dd, J= 4.4 and 9.1

Hz), 7.74 (2H, d with small coupling, J = 8.5 Hz), 7.57 (IH, s), 7.25-7.31 (IH overlapped with CHCl₃), 7.22 (2H, d, J= 8.0 Hz), 7.04 (IH, dt, J = 2.6 and 9.0 Hz), 6.11 (IH, d, J= 4.7 Hz), 5.94 (IH, t, J= 4.9 Hz), 5.67 (IH, t, J= 5.5 Hz), 4.69 (2H, m), 4.40-4.50 (2H, m), 4.31 (IH, dd, J = 4.9 and 12.9 Hz), 3.18 (2H, t, J= 6.9 Hz), 2.33 (3H, s), 2.15 (3H, s), 2.09 (3H, s), 2.04 (3H, s); HRMS (ESI-MS m/z) calcd for C₃₂H₂₃NSO ioSFCl (M+H)⁺ 744.1542, found 744.1522.

2-(3"-(5"-Bromo-l"-(p-toluenesulfonyl)indolyl)ethyloxy)-6-chloro-3', 4', 5'- triacetyladenosine (106)

[0140] The yield is 47 %. ¹H NMR (CDCl₃) δ 8.09 (IH, s), 7.84 (IH, d, J= 8.8 Hz), 7.75

(IH, s), 7.73 (2H, d with small coupling, J= 6.6 Hz), 7.54 (IH, s), 7.40 (IH, dd, J= 1.8 and 8.9 Hz), 7.22 (2H, d, J= 8.5 Hz), 6.13 (IH, d, J = 4.7 Hz), 5.94 (IH, t, J = 4.9 Hz), 5.67 (IH, t, J = 5.4 Hz), 4.69 (2H, t, J= 6.6 Hz), 4.40-4.50 (2H, m), 4.31 (IH, dd, J= 5.2 Hz), 3.19 (2H, t, J= 6.7 Hz), 2.33 (3H,s), 2.15 (3H, s), 2.09 (3H, s), 2.03 (3H, s); HRMS (ESI-MS m/z) calcd for C₃₃H₃₂N₅Oi₀BSClBr (M+H)⁺ 804.0742, found 804.0752.

6-ChIoro-2-(3"-(5"-methoxy-2"-methyl-l"-0>-toluenesulfonyl)indolyl)ethyloxy)- 3',4',5'- triacetyladenosine (107)

[0141] The yield is 72 %. ¹H NMR (CDCl₃) δ 8.08 (IH, s), 8.07 (IH, d, J= 9.6 Hz), 7.60

(2H, d with small coupling, J= 8.5 Hz), 7.17 (2H, d, J= 8.0 Hz), 6.98 (IH, d, J= 2.5 Hz), 6.87 (IH, dd, J= 2.8 and 9.1 Hz), 6.12 (IH, d, J= 5.0 Hz), 5.83 (IH, t, J= 5.2 Hz), 4.36 - 4.54 (5H, m), 4.31 (IH, dd, J= 4.1 and 12.4 Hz), 3.86 (3H, s), 3.13 (2H, t, J= 7.8 Hz), 2.61 (3H, s), 2.32 (3H, s), 2.13 (3H,s), 2.06 (3H,s), 2.05 (3H, s); HRMS (ESI-MS m/z) calcd for C₃₅H₃₇N₅OnSCl (M+H)⁺ 770.1899, found 770.1895.

6-Chloro-2-(3"-(6"-chIoro-l"-(p-toIuenesuIfonyI)indoIyI)ethyIoxy)-3', 4', 5'- triacetyladenosine (108)

[0142] The yield is 70 %. ¹H NMR (CDCl₃) d 8.09 (IH, s), 7.99 (IH, d, J= 1.9 Hz), 7.76

(2H, d with small coupling, J= 8.5 Hz), 7.53 (IH, d, J= 8.5 Hz), 7.52 (IH, s), 7.20 - 7.28 (3H, m), 6.11 (IH, d, J = 4.7 Hz), 5.95 (IH, t, J= 4.9 Hz), 5.66 (IH, t, J = 5.5 Hz), 4.68 (2H, m), 4.38-4.50 (2H, m), 4.31 (IH, dd, J= 4.5 and 12.2 Hz), 3.20 (2H, t, J= 6.9 Hz), 2.35 (3H, s), 2.14 (3H, s), 2.09 (3H, s), 2.06 (3H, s); APCI-MS (m/z) 760.1 (M+H)⁺.

2-(3"-(6"-Bromo-l "-(p-toluenesulfonyl)indolyl)ethyloxy)-6-chloro-3^f, 4', 5'- triacetyladenosine (109)

[0143] The yield is 45 %. ¹HNMR (CDCl₃) δ 8.15 (IH, d, J= 1.6 Hz), 8.09 (IH, s), 7.76

(2H, d with small coupling, J= 8.2 Hz), 7.50 (IH, s), 7.49 (IH, d, J= 9.1 Hz), 7.38 (IH, dd, J = 1.7 and 8.5 Hz), 7.25 (2H, d, J= 8.2 Hz), 6.11 (IH, d, J= 4.7 Hz), 5.95 (IH, t, J= 4.9 Hz), 5.66 (IH, t, J= 5.5 Hz), 4.68 (2H, m), 4.18-4.50 (2H, m), 4.31 (IH, dd, J= 4.5 and 12.5 Hz), 3.20 (2H, t, J= 7.0 Hz), 2.35 (3H, s), 2.14 (3H, s), 2.09 (3H, s), 2.06 (3H, s); HRMS (ESI- MS m/z) calcd for C₃₃H₃₂N₅Oi₀SCl Br(M+H)⁺ 804.0742, found 804.0760.

6-Chloro-2-(3"-(5"-cMoro-l"-(p-toluenesulfonyl)indolyl)ethyloxy)- 3', 4', 5'- triacetyladenosine (110)

[0144] The yield is 46 %. ¹H NMR (CDCl₃) δ 8.09 (IH, s), 7.89 (IH, d, J= 9.1 Hz), 7.73

(2H, d with small coupling, J= 8.2 Hz), 7.59 (IH, d, J= 2.2 Hz), 7.24-7.30 (IH, m), 7.22 (2H, d, J= 8.0 Hz), 6.12 (IH, d, J= 4.4 Hz), 5.94 (IH, t, J= 5.1 Hz), 5.67 (IH, t, J= 5.4 Hz), 4.69 (2H, m), 4.40-4.49 (2H, m), 4.31 (IH, dd, J= 4.9 and 13.2 Hz), 3.18 (2H, t, J= 6.7 Hz), 2.33 (3H, s), 2.15 (3H, s), 2.09 (3H, s), 2.04 (3H, s); HRMS (ESI-MS m/z) calcd for C₃₃H_3IN₅Oi₀SCl₂Na (M+Na)⁺ 782.1066, found 782.1071.

6-Chloro-2-(3"-(5"-iodo-l"-(p-tolueiiesuIfoiiyI)indoIyl)ethyloxy)- 3', 4', 5'- triacetyladenosine (111)

[0145] The yield is 45 %. ¹H NMR (CDCl₃) δ 8.09 (IH, s), 7.93 (IH, d, J= 1.7 Hz), 7.73

(3H, m), 7.57 (IH, dd, J= 1.8 and 8.7 Hz), 7.50 (IH, s), 7.22 (2H, d, J = 8.0 Hz), 6.13 (IH, d, J= 4.7 Hz), 5.94 (IH, t, J= 5.1 Hz), 5.67 (IH, t, J= 5.4 Hz), 4.68 (2H, t, J= 7.0 Hz), 4.40- 4.48 (2H, m), 4.31 (IH, dd, J= 5.1 and 13.3 Hz), 3.18 (2H, t, J= 6.9 Hz), 2.33 (3H, s), 2.15 (3H, s), 2.09 (3H, s), 2.04 (3H, s); HRMS (ESI-MS m/z) calcd for C₃₃H₃₂N₅Oi₀SClI (M+H)⁺ 852.0603, found 852.0566.

6-ChIoro-2-(3"-(4"-broino-l"-(p-toIuenesulfonyl)indolyl)ethyloxy)- 3', 4', 5'- triacetyladenosine (112)

[0146] The yield is 40 %. ¹H NMR (CDCl₃) δ 8.09 (IH, s), 7.95 (IH, dd, J= 0.8 and 8.2

Hz), 7.75 (2H, d with small coupling, J= 8.5 Hz), 7.59 (IH, s), 7.39 (IH, dd, J= 0.8 and 8.0 Hz), 7.23 (2H, d, J= 8.5 Hz), 7.12 (IH, t, J= 8.1 Hz), 6.13 (IH, d, J= 5.0 Hz), 5.92 (IH, t, J = 5.1 Hz), 5.64 (IH, t, J= 5.4 Hz), 4.75 (2H, m), 4.38-4.50 (2H, m), 4.33 (IH, dd, J= 4.7 and 12.9 Hz), 3.53 (2H, t, J= 7.0 Hz), 2.34 (3H, s), 2.13 (3H, s), 2.09 (3H, s), 2.05 (3H, s); APCI- MS (m/z) 806.1 (M+H)⁺. 6-Chloro-2-(3"-(7"-bromoindolyl)ethyloxy)- 3', 4', 5'-triacetyIadenosine (113)

[0147] The yield is 10 %. ¹H NMR (CDCl₃) δ 8.06 (IH, s), 7.66 (IH, d, J= 8.0 Hz), 7.35 (IH, d, J= 7.7 Hz), 7.27 (IH overlapped with CHC13), 7.03 (IH, t, J= 7.7 Hz), 6.11 (IH, d, J = 5.0 Hz), 5.91 (IH, t, J= 5.2 Hz), 5.64 (IH, t, J= 5.2 Hz), 4.70 (2H, m), 4.37-4.46 (2H, m), 4.32 (IH, dd, J= 5.4 and 13.1 Hz), 3.30 (2H, t,J= 7.1 Hz), 2.13 (3H, s), 2.07 (3H, s), 2.07 (3H, s); APCI-MS (m/z) 672.1 (M+Na)⁺.

6-Chloro-2-phenypropoxy-3', 4', 5'-triacetyladenosine (114)

[0148] The yield is 63 %. ¹H NMR (CDCl₃) δ 8.08 (IH, s), 7.16-7.34 (5H, m), 6.14 (IH, d, J= 4.9 Hz), 5.91 (IH, t, J= 5.4 Hz), 5.63 (IH, t, J= 5.2 Hz), 4.38 - 4.52 (5H, m), 4.31 (IH, dd, J= 3.8 and 11.8 Hz), 2.85 (2H, dd, J= 7.4 and 8.0 Hz), 2.12 - 2.24 (2H, m), 2.15 (3H, s), 2.10 (3H, s), 2.09 (3H, s); HRMS (ESI-MS m/z) calcd for C₂₅H₂₇N₄O₈ClLi (M+Li)⁺ 553.1677, found 553.1661.

6-Chloro-2-(2"-(l"-(p-toluenesulfonyl)indolyl)ethyloxy)- 3', 4', 5'-triacetyladenosine

(115)

[0149] The yield is 40 %. ¹H NMR (CDCl₃) δ 8.16 (IH, d, J= 8.2 Hz), 8.09 (IH, s), 7.63

(2H, d, J= 8.5 Hz), 7.42 (2H, d, J= 7.1 Hz), 7.15 - 7.32 (5H, m), 6.59 (IH, s), 6.16 (IH, d, J = 5.0 Hz), 5.87 (IH, t, J= 5.2 Hz), 5.61 (IH, t, J= 5.2 Hz), 4.83 (2H, m), 4.40 - 4.48 (2H, m), 4.34 (IH, dd, J= 4.9 and 13.2 Hz), 3.58 (2H, t, J= 6.6 Hz), 2.33 (3H, s), 2.12 (3H, s), 2.08 (3H,s), 2.07 (3H,s); HRMS (ESI-MS m/z) calcd for C₃₃H₃₃N₅Oi₀ClS (M+H)⁺ 726.1637, found 726.1640.

6-Chloro-2-(3"-(benzoimidazoI-l"-yl)ethyloxy)- 3', 4', 5'-triacetyladenosine (116)

[0150] The yield is 51 %. ¹H NMR (CD₃OD) δ 8.09 (2H, d, J= 8.0 Hz), 7.79 (IH, dd, J =

1.4 and 7.1 Hz), 7.55 (IH, dd, J= 1.1 and 7.1 Hz), 7.34 (IH, dt, J= 1.4 and 7.4 Hz), 7.28 (IH, dt, J = 1.4 and 7.5 Hz), 6.05 (IH, d, J= 4.7 Hz), 5.92 (IH, t, J= 4.9 Hz), 5.67 (IH, t, J = 5.4 Hz), 4.82 (2H, m), 4.66 (2H, t, J= 5.4 Hz), 4.39 - 4.48 (2H, m), 4.27 (IH, dd, J= 5.2 and 13.2 Hz), 2.16 (3H, s), 2.09 (3H, s), 2.02 (3H, s); HRMS (ESI-MS m/z) calcd for C₂₅H₂₆N₆O₈Cl (M+H)⁺ 573.1501, found 573.1503.

6-Chloro-2-(3"-(benzotriazol-l"-yl)ethoxy)- 3', 4', 5'-triacetyladenosine (117) [0151] The yield is 53 %. ¹H NMR (CDCl₃) δ 8.08 (IH, s), 8.03 (IH, dt, J= 0.8 and 8.5 Hz), 7.72 (IH, dt, J= 0.8 and 8.5 Hz), 7.52 (IH, ddd, J= 1.0, 7.1 and 8.1 Hz), 7.36 (IH, ddd, J= 1.1, 7.1 and 8.2 Hz), 6.07 (IH, d, J= 4.4 Hz), 5.89 (IH, dd, J= 4.7 and 5.5 Hz), 5.62 (IH, t, J= 5.4 Hz), 5.11 (2H, m), 5.00 (2H, m), 4.40-4.48 (2H, m), 4.26-4.34 (IH, m), 2.15, 2.10 and 2.05 (each 3H, s); HRMS (ESI-MS m/z) calcd for C₂₄H₂₅N₇O₈Cl (M+H)⁺ 574.1453, found 574.1456.

6-Chloro-2-(3"-(l"-/»-toluenesulfonyl)pyrrolyl)ethyloxy)- 3', 4', 5'-triacetyladenosine

(118)

[0152] The yield is 61%. ¹H NMR (CDCl₃) δ 8.08 (IH, s), 7.73 (IH, d, J= 8.5 Hz), 7.27

(2H, d overlapped with CHCl₃), 7.08 (2H, m), 6.28 (IH, dd, J= 1.9 and 3.0 Hz), 6.13 (IH, d, J= 5.0 Hz), 5.91 (IH, t, J= 5.1 Hz), 5.63 (IH, t, J= 5.4 Hz), 4.57 (IH, dd, J= 2.8 and 7.4 Hz), 4.53 (IH, dd, J= 3.0 and 7.7 Hz), 4.38 - 4.45 (2H, m), 4.32 (IH, dd, J= 4.3 and 12.2 Hz), 2.95 (2H, t, J= 7.0 Hz), 2.40(3H, s), 2.15(3H, s), 2.09 (3H, s), 2.07 (3H, s); HRMS (ESI-MS m/z) calcd for C₂₉H₃₁N₅O₁₀SCI (M+H)⁺ 676.1480, found 676.1450.

2-(3"-(5"-Methoxy-l"-(p-toluenesulfonyl)indolyI)ethyloxy)adenosine (119)

[0153] The yield is 56 %. ¹H NMR (CD₃OD) δ 8.14 (IH, s), 7.81 (IH, d, J= 9.3 Hz),

7.67 (2H, dt, J =1.9 and 8.5 Hz), 7.52 (IH, s), 7.15 (2H, dd, J= 0.6 and 8.5 Hz), 7.02 (IH, d, J=2.5 Hz), 6.89 (IH, dd, J= 2.8 and 8.8 Hz), 5.89 (IH, d, J= 6.0 Hz), 4.72 (IH, t, J= 5.6 Hz), 4.55 (2H, dt, J= 1.1 and 6.3 Hz), 4.33 (IH, dd, J= 3.3 and 5.0 Hz), 4.12 (IH, q, J= 3.0 Hz), 3.88 (IH, dd, J= 2.7 and 12.4 Hz), 3.78 (3H, s), 3.74 (IH, dd, J=3.2 and 12.5 Hz), 3.11 (2H, t, J= 6.3 Hz), 2.25 (3H, s); HRMS (ESI-MS m/z) calcd for C₂₈H₃ iN₆O₈S (M+H)⁺ 611.1924, found 611.1899.

2-(3"-(5"-(p-toluenesulfonyloxy) -l"-(p-toluenesulfonyl)indolyl)ethyloxy)adenosine (120) [0154] The yield is 63 %. ¹H NMR (CD₃OD) δ 8.15 (IH, s), 7.86 (IH, d, J= 8.8 Hz),

7.71 (2H, d with small coupling, J= 8.5 Hz), 7.64 (IH, s), 7.60 (2H, d with small coupling, J = 8.2 Hz), 7.28 (2H, d, J= 8.5 Hz), 7.21 (2H, d, J= 8.0 Hz), 7.08 (IH, d, J= 2.5 Hz), 6.93 (IH, dd, J= 2.2 and 9.1 Hz), 5.90 (IH, d, J= 6.1 Hz), 4.71 (IH, t, J= 5.6 Hz), 4.42 (2H, t, J = 6.6 Hz), 4.33 (2H, t, J= 6.6 Hz), 4.33 (IH, dd, J= 3.2 and 5.1 Hz), 4.14 (IH, q, J= 3.0 Hz), 3.90 (IH, dd, J= 2.8 and 12.6 Hz), 3.74 (IH, dd, J= 3.2 and 12.5 Hz), 3.00 (2H, t, J = 6.6 Hz), 2.34 (3H, s), 2.29 (3H, s); HRMS (ESI-MS m/z) calcd for C₃₄H₃₅N₆Oi₀S₂ (M+H)⁺ 751.1856, found 751.1819.

2-(3"-(5"-FIuoro-l"-(p-toluenesulfonyl)indolyl)ethyloxy)adenosine (121)

[0155] The yield is 55 %. ¹H NMR (CD₃OD) δ 8.13 (IH, s), 7.91 (IH, dd, J= 4.4 and

9.1 Hz), 7.70 (2H, d with small coupling, J= 8.5 Hz), 7.64 (IH, s), 7.29 (IH, dd, J= 2.5 and 8.8 Hz), 7.16 (2H, d, J= 8.0 Hz), 7.05 (IH, dt, J= 2.5 and 9.1 Hz), 5.89 (IH, d, J= 6.0 Hz), 4.73 (IH, t, J= 5.5 Hz), 4.54 (2H, t, J= 6.2 Hz), 4.33 (IH, dd, J= 3.3 and 5.2 Hz), 4.12 (IH, q, J= 3.0 Hz), 3.89 (IH, dd, J= 2.7 and 12.4 Hz), 3.74 (IH, dd, J = 3.2 and 12.5 Hz), 3.10 (2H, t, J= 6.3 Hz), 2.26 (3 H, s); HRMS (ESI-MS m/z) calcd for C₂₇H₂₈N₆O₇SF (M+H)⁺ 599.1724, found 599.1714.

2-(3"-(6"-Chloro-l"-(/7-toluenesulfonyl)indolyl)ethyloxy)adenosine (122)

[0156] The yield is 51 %. ¹H NMR (CD₃OD) δ 8.13 (1 H, s), 7.92 (1 H, d, J = 1.7 Hz),

7.72 (2H, d with small coupling, J= 8.2 Hz), 7.61 (IH, s), 7.58 (IH, d, J= 8.5 Hz), 7.25 (IH, dd, J= 1.9 and 8.5 Hz), 7.21 (2H, dd, J= 0.7 and 8.7 Hz), 5.89 (IH, d, J= 6.1 Hz), 4.72 (IH, t, J= 5.5 Hz), 4.55 (2H, m), 4.33 (IH, dd, J= 3.3 and 5.2 Hz), 4.12 (IH, q, J= 2.9 Hz), 3.88 (IH, dd, J= 2.8 and 12.4 Hz), 3.74 (IH, dd, J= 3.3 and 12.4 Hz), 3.12 (2H, t, J= 6.5 Hz), 2.28 (3H, s); HRMS (ESI-MS m/z) calcd for C₂₇H₂₈N₆O₇SCl (M+H)⁺ 615.1429, found 615.1413.

2-(3"-(6"-Bromo-l"-(p-toluenesu]fonyl)indolyl)ethyloxy)adenosine (123)

[0157] The yield is 50 %. ¹H NMR (CD₃OD) δ 8.13 (IH, s), 8.08 (IH, d, J= 1.7 Hz),

7.71 (2H, dt, J= 2.1 and 8.5 Hz), 7.60 (IH, s), 7.53 (IH, d, J= 8.2 Hz), 7.38 (IH, dd, J= 1.7 and 8.2 Hz), 7.21 (2H, d with small coupling, J= 8.2 Hz), 5.89 (IH, d, J= 6.1 Hz), 4.72 (IH, t, J= 5.5 Hz), 4.54 (2H, m), 4.33 (IH, dd, J= 3.3 and 5.2 Hz), 4.12 (IH, q, J= 3.0 Hz), 3.88 (IH, dd, J= 2.7 and 12.4 Hz), 3.74 (IH, dd, J= 3.3 and 12.4 Hz), 3.12 (2H, t, J= 6.5 Hz), 2.28 (3H, s); HRMS (ESI-MS m/z) calcd for C₂₇H₂₈N₆O₇BrS (M+H)⁺ 659.0924, found 659.0910.

2-(3"-(5"-Chloro-l"-(/?-toIuenesulfonyl)indolyl)ethyloxy)adenosine (124) [0158] The yield is 62 %. ¹H NMR (CD₃OD) 8 8.13 (IH, s), 7.90 (IH, d, J= 8.8), 7.71 (2H, d with small coupling, J= 8.8 Hz), 7.64 (IH, s), 7.57 (IH, d, J= 1.9 Hz), 7.27 (IH, dd, J = 1.9 and 8.8 Hz), 7.18 (2H, d, J= 8.2 Hz), 5.89 (IH, d, J= 5.8 Hz), 4.73 (IH, t, J= 5.6 Hz), 4.55 (2H, t, J= 6.5 Hz), 4.33 (IH, dd, J= 3.3 and 5.2 Hz), 4.12 (IH, q, J= 3.1 Hz), 3.89 (IH, dd, J= 2.7 and 12.6 Hz), 3.74 (IH, dd, J= 3.2 and 12.5 Hz), 3.11 (2H, t, J= 6.3 Hz), HRMS (ESI-MS m/z) calcd for C₂₇H₂₈N₆O₇SCl (M+H)⁺ 615.1429, found 615.1401.

2-(3"-(5"-Iodo-l"-(p-toluenesulfonyl)indolyl)ethyloxy)adenosine (125)

[0159] The yield is 71 %. ¹H NMR (CD₃OD) δ 8.14 (IH, s), 7.89 (IH, d, J= 1.7 Hz),

7.73 (IH, d, J= 9.1 Hz), 7.71 (2H, d with small coupling, J= 8.5 Hz), 7.58 (IH, s), 7.57 (IH, dd, J= 1.8 and 8.7 Hz), 7.18 (2H, d, J= 8.2 Hz), 5.89 (IH, d, J= 5.8 Hz), 4.73 (IH, t, J= 5.5 Hz), 4.54 (2H, t, J= 6.3 Hz), 4.34 (IH, dd, J= 3.3 and 5.2 Hz), 4.12 (IH, q, J= 3.0 Hz), 3.89 (IH, dd, J= 2.9 and 12.5 Hz), 3.75 (IH, dd, J= 3.3 and 12.4 Hz), 3.10 (2H, t, J= 6.3 Hz), 3.27 (3H, s); APCI-MS (m/z) 707.0 (M+H)⁺.

2-(3"-(4"-Bromo-l"-(p-toluenesulfonyl)indolyl)ethyloxy)adeiiosine (126)

[0160] The yield is 43 %. ¹H NMR (CD₃OD) 8 8.13 (IH, s), 7.95 (IH, dd, J= 0.7 and

8.4 Hz), 7.73 (2H, d with small coupling, J = 8.5 Hz), 7.69 (IH, s), 7.39 (IH, dd, J= 0.8 and 7.7 Hz), 7.19 (2H, dd, J= 0.6 and 8.5 Hz), 7.15 (IH, t, J= 8.1 Hz), 5.89 (IH, d, J= 6.1 Hz),

4.74 (IH, t, J= 5.5 Hz), 4.61 (2H, m), 4.33 (IH, dd, J= 3.3 and 5.2 Hz), 4.12 (IH, q, J= 3.1 Hz), 3.89 (IH, dd, J= 2.8 and 12.4 Hz), 3.75 (IH, dd, J= 3.3 and 12.4 Hz), 3.44 (2H, m), 2.27 (3H, s); APCI-MS (m/z) 659.1 (M+H)⁺.

2-(3"-(l"-(^-toluenesulfonyl)pyrrolyl)ethyloxy)-adenosine (127)

[0161] The yield is 69 %. IH NMR (CD3OD) D 8.12 (IH, s), 7.72 (2H, d with small coupling, J = 8.5 H), 7.29 (2H, d, J = 8.5Hz), 7.08-7.14 (2H, m), 6.30 (IH, dd, J = 1.7 and 3.2 Hz), 5.88 (IH, d, J = 6.0 Hz), 4.71 (IH, t, J = 5.5 Hz), 4.41 (2H, t, J = 6.7 Hz), 4.32 (IH, dd, J = 3.4 and 5.1 Hz), 4.11 (IH, q, J = 3.2 Hz), 3.86 (IH, dd, J = 2.6 and 12.5 Hz), 3.73 (IH, dd, J = 3.3 and 12.7 Hz), 2.85 (2H, t, J = 6.5 Hz), 2.36 (3H, s); HRMS (ESI-MS m/z) calcd for C₂₃H₂₇N6O7S (M+H)⁺ 531.1662, found 531.1667. EXAMPLE 18

[0162] This example demonstrates a synthesis of (2R, 3S, 4S, 5R)-2-(2'-amino-6'- chloropurin-9'-yl)-5-hydroxymethyl-3, 4-<9-isopropylidene-tetrahydrofuran (128) used in the preparation of compounds in an embodiment of the invention. See Figure 6. [0163] To a solution of 2-amino-6-chloropurine-9-riboside (100 mg, 0.331 mmol) in N₅N- dimethylformamide (2 mL) are added 2,2-dimethoxypropane (0.242 ml, 1.97 mmol) andp- toluenesulfonic acid monohydrate (188 mg, 0.993 mmol). The reaction mixture is stirred overnight at room temperature. The reaction is diluted with ethyl acetate, washed with water, dried over MgSO₄, and filtered. The filtrate is evaporated to give an oil, which is subjected to preparative TLC developed with a mixture of toluene and acetone (1:1) to give 128 (56 mg, 50 %). ¹H ΝMR (CDCl₃) δ 7.81 (IH, s), 5.79 (IH, d, J = 4.9 Hz), 5.68 (IH, dd, J= 1.4 and 11.3 Hz), 5.14 - 5.24 (3H, m), 5.08 (IH, dd, J= 1.4 and 6.0 Hz), 4.51 (IH, d, J= 1.7 Hz), 3.97 (IH, d with small coupling, J= 12.6 Hz), 3.78 (IH, ddd, J= 1.9, 11.3 and 13.2 Hz), 1.64 (3H, s), 1.38 (3H, s); HRMS (ESI-MS m/z) calcd for C₁₃H]₇N₅O₄Cl (M+H)⁺ 342.0969, found 342.0979.

EXAMPLE 19

[0164] This example demonstrates a synthesis of (2R, 3S, 4S, 5R)-2-(2'-amino-6'- chloropurin-9'-yl)-5-carboxy-3, 4-<9-isopropylidene-tetrahydrofuran (129) used in the preparation of compounds in an embodiment of the invention. See Figure 6. [0165] To a solution of 128 (16.9 mg, 0.0494 mmol) in water (4.5 mL) are added potassium permanganate (70.3 mg, 0.445 mmol) and potassium hydroxide (25 mg, 0.444 mmol), and the reaction mixture is stirred for 1 h. After addition of isopropanol the reaction mixture is filtered. The filtrate is neutralized with 0.1N hydrochloric acid aqueous solution and evaporated to give a crude solid, which is subjected to preparative TLC developed with a mixture of chloroform, methanol, and saturated aqueous ammonia (2: 1 : 0.3) to give 129 (9 mg, 51 %). ¹H NMR (CD₃OD) δ 8.29 (IH, s), 6.18 (IH, d, J= 1.2 Hz), 5.52 (IH, dd, J= 1.7 and 6.2 Hz), 5.37 (IH, d, J= 6.0 Hz), 4.59 (IH, d, J= 1.7 Hz), 1.55 (3H, s), 1.39 (3H, S); HRMS (ESI-MS m/z) calcd for Ci₃H₁₃N₅O₅Cl (M-H)- 354.0605, found 354.0622. EXAMPLE 20

[0166] This example demonstrates a synthesis of (2R, 3 S, 4S, 5R)-2-(2'-amino-6'- chloropurin-9'-yl)-5-ethoxycarboxyamide-3, 4-isopropylidene-tetrahydrofuran (130) used in the preparation of compounds in an embodiment of the invention. See Figure 6. [0167] To a solution of 129 (11.9 mg, 0.0334 mmol) in N, N-dimethylformamide (0.8 mL) are added ethylamine hydrochloride (8.1 mg, 0.100 mmol), N, N-diisopropylethylamine (0.035 ml, 0.200 mmol), and (benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate (22.5 mg, 0.0434 mmol). The reaction mixture is stirred overnight. The mixture is diluted with ethyl acetate, washed with water, dried over MgSO₄, and filtered. The filtrate is evaporated to give a crude oil, which is subjected to preparative TLC developed with a mixture of chloroform and methanol (10:1) to give 130 (10 mg, 78 %). ¹H ΝMR (CD₃OD) δ 8.16(1H, s), 6.27 (IH, s), 5.73 (IH, dd, J= 1.9 and 6.3 Hz), 5.43 (IH, d, J = 6.3 Hz), 4.62 (IH, d, J= 1.7 Hz), 2.91 (IH, dt, J= 6.0 and 13.3 Hz), 2.80 (IH, dt, J= 6.0 and 13.3 Hz), 1.55 (3H, s), 1.40 (3H,s), 0.61 (3H, t, J= 7.3 Hz); HRMS (ESI- MS m/z) calcd for Ci₅H₂₀N₆O₄Cl (M+H)⁺383.1235, found 383.1229.

EXAMPLE 21

[0168] This example demonstrates a synthesis of (2R, 3S, 4S, 5R)-5- ethoxycarboxyamide-2-(2'-hydroxy-6'-chloropurin-9'-yl)-3, 4-O-isopropylidene- tetrahydrofuran (131) used in the preparation of compounds in an embodiment of the invention. See Figure 6.

[0169] To a solution of 130 (10 mg, 0.026 mmol) in a mixture of 2-propanol (0.4 mL) and water (0.4 mL) is added ^-butylnitrite (13.3 μl, 0.115 mmol) at 4 ⁰C. The reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with ethyl acetate, washed with water, dried over MgSO₄, and filtered. The filtrate is evaporated to give a crude oil, which is subjected to preparative TLC developed with a mixture of chloroform and methanol (10:1) to give 131 (5 mg, 50 %). ¹H NMR (CDCl₃) δ 7.99 (IH, s), 6.37 (IH, br t, J = 6.1Hz), 6.11 (IH, d, J = 1.6 Hz), 5.72 (IH, dd, J = 1.7 and 6.1 Hz), 5.36 (IH, dd, J = 1.7 and 6.0 Hz), 4.75 (IH, s), 3.05 (2H, m), 1.61 (3H, s), 1.41 (3H, s), 0.77 (3H, t, J = 7.3 Hz); APCI-MS (m/z) 384.1 (M+H)⁺. EXAMPLE 22

[0170] This example demonstrates a synthesis of (2R, 3 S, 4S, 5R)-5-ethylcarboxyamide- 2-2'-(3"-(l"-(p-toluenesufonyl)indolyl)ethyloxy)-6'-chloropurin-9'-yl)-3, 4-isopropylidene- tetrahydrofuran (132) used in the preparation of compounds in an embodiment of the invention. See Figure 6.

[0171] To a solution of 131 (19.4 mg, 0.0505 mmol) in N, N-dimethylformamide (0.8 mL) is added iodide 47 (43 mg, 0.101 mmol) and cesium carbonate (49.3 mg, 0.151 mmol), and the reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with ethyl acetate, washed with water, dried over MgSO₄, and filtered. The filtrate is evaporated to give a crude oil, which is subjected to preparative TLC developed with a mixture of toluene and acetone (4:1) to give 132 (24 mg, 70 %). ¹H ΝMR (CDCl₃) δ 7.99 (IH, s), 7.98 (IH, d, J= 8.2 Hz), 7.77 (2H, d with small coupling, J= 8.5 Hz), 7.61 (IH, d with small coupling, J= 7.7 Hz), 7.56 (IH, s), 7.24-7.35 (2H, m), 7.21 (2H, d, J= 8.5 Hz), 6.27 (IH, t, J= 6.0 Hz), 6.14 (IH, d, J= 2.2 Hz), 5.52 (IH, dd, J= 1.9 and 6.1 Hz), 5.39 (IH, dd, J= 2.1 and 6.2 Hz), 4.60-4.80 (3H, m), 3.27 (2H, t, J= 6.7 Hz), 2.97 (2H, m), 2.32 (3H, s), 1.61 (3H, s), 1.35 (3H, s), 0.69 (3H, t, J = 7.3Hz); HRMS (ESI-MS m/z) calcd for C₃₂H₃₃N₆O₇SCl Na (M+Na)⁺ 703.1718, found 703.1732.

EXAMPLE 23

[0172] This example demonstrates a synthesis of (2R, 3S, 4S, 5R)-5-ethylcarboxyamide- 2-(6'-amino -2'-(3"-(I "-(p-toluenesufonyl)indolyl)ethyloxy)-purin-9'-yl)-3, 4-0- isopropylidene-tetrahydrofuran (133) used in the preparation of compounds in an embodiment of the invention. See Figure 6.

[0173] A solution of 132 in saturated ammonia ethanol solution was stirred at 120 ⁰C overnight. The solvent is evaporated to give an oil, which is subjected to preparative TLC developed with a mixture of chloroform and methanol (10:1) to give 133 (17 mg, 88 % yield). ¹H NMR (CDCl₃) δ 7.96 (IH, d, J= 7.7 Hz), 7.77 (2H, d, J= 8.2 Hz), 7.68 (IH, s), 7.54-7.60 (2H, m), 7.30 (IH, dt, J= 1.6 and 7.7 Hz), 7.24 (IH, overlapped with CHCl₃), 7.19 (2H, d, J= 8.5 Hz), 6.44 (IH, t, J= 5.9 Hz), 6.07 (IH, d, J= 1.9 Hz), 5.59 (IH, br s), 5.51 (IH, dd, J= 1.9 and 6.0 Hz), 5.43 (IH, dd, J= 1.8 and 6.2 Hz), 4.70 (IH, d, J= 1.9 Hz), 4.61 (2H, m), 3.18 (2H, t, J= 6.7 Hz), 2.96 (2H, m), 2.31 (3H, s), 1.64 (3H, s), 1.31 (3H, s), 0.69 (3H, t, J= 7.3 Hz); HRMS (ESI-MS m/z) calcd for C₃₂H₃₆N₇O₇S (M+H)⁺ 662.2397, found 662.2374.

EXAMPLE 24

[0174] This example demonstrates a synthesis of (2R, 3S, 4S, 5R)-5-ethylcarboxyamide- 2-(6'-amino -2'-(3 "-( 1 " -(p-toluenesufonyl)mdolyl)ethyloxy)-purin-9'-yl)-tetrahydrofuran (134) in an embodiment of the invention. See Figure 6.

[0175] A solution of 133 (13.4 mg, 0.0202 mmol) in 80 % acetic acid aqueous solution is stirred at 80 ⁰C for 63 h and evaporated to give an oil, which is subjected to preparative TLC developed with a mixture of chloroform and methanol (8:1) to give 134 (9 mg, recovery yield 85 %). ¹H NMR (CD₃OD) δ 8.09 (IH, s), 7.94 (IH, d, J= 7.7 Hz), 7.69 (2H, d with small coupling, J= 8.5 Hz), 7.56 (IH, d with small coupling, J= 1.1 Hz), 7.52 (IH, s), 7.30 (IH, dt, J= 1.3 and 7.7 Hz), 7.16-7.26 (3H, m), 5.93 (IH, d, J= 7.4 Hz), 4.54-4.76 (2H, m), 4.42 (IH, d, J= 1.9 Hz), 4.31 (IH, dd, J= 1.8 and 4.8 Hz), 3.00-3.18 (4H, m), 2.28 (3H, s), 0.83 (3H, t, J= 7.1 Hz); HRMS (ESI-MS m/z) calcd for C₂₉H₃₂N₇O₇S (M+H)⁺ 622.2084, found 622.2095.

2-Phenylpropoxyadenosine (8)

[0176] The yield is 66 %. ¹H NMR (CD₃OD) 5 8.11 (IH, s), 7.10 - 7.28 (5H, m), 5.88

(IH, d, J= 6.1 Hz), 4.72 (IH, t, J= 5.5 Hz), 4.30 -4.34 (IH overlaped with CH₂), 4.29 (2H, t, J= 6.6 Hz), 4.10 (IH, q, J= 3.2 Hz), 3.85 (IH, dd, J= 2.9 and 12.5 Hz), 3.72 (IH, dd, J = 3.3 and 12.4 Hz), 2.78 (2H, t, J= 7.7 Hz), 2.06 (2H, dt, J= 6.4 and 15.3 Hz); HRMS (ESI- MS m/z) calcd for Ci₉H₂₄N₅O₅(M+H)⁺ 402.1777, found 402.1771; HPLC (system A) 14.1 min (99%), (system C) 10.7 min (99%).

2-(3"-Indolylethyloxy)adenosine (17)

[0177] The yield is 72 %. ¹H NMR (CD₃OD) δ 8.12 (IH, s), 7.60 (IH, d with small coupling, J= 7.7 Hz), 7.32 (IH, d with small coupling, J= 7.7 Hz), 7.15 (IH, s), 7.07 (IH, dt, J= 1.2 and 7.5 Hz), 7.01 (IH, dt, J= 1.2 and 7.3 Hz), 5.90 (IH, d, J = 5.5 Hz), 4.71 (IH, t, J= 5.5 Hz), 4.58 (2H, m), 4.31 (IH, dd, J= 3.6 and 5.2 Hz), 4.11 (IH, q, J= 3.2 Hz), 3.85 (IH, dd, J= 2.8 and 12.4 Hz), 3.73 (IH, dd, J= 3.4 and 12.2 Hz), 3.24 (2H, t, J= 7.3 Hz); HRMS (ESI-MS m/z) calcd for C₂₀H₂₃N₆O₅ (M+H)⁺ 427.1730, found 427.17¹11; HPLC (system A) 11.4 min (99 %), (system C) 9.3 min (99 %). 2-(3"-(l"-(p-Toluenesulfonyl)indolyl)ethyloxy)adenosine (18)

[0178] The yield is 60 %. ¹H NMR (CD₃OD) δ 8.14 (IH, s), 7.93 (IH, d with small coupling, J= 7.4 Hz), 7.70 (2H, d with small coupling, J= 8.2 Hz), 7.59 (2H, m), 7.29 (IH, dt, J= 1.7 and 8.1 Hz), 7.23 (IH, dt, J= 1.5 and 8.1 Hz), 7.17 (2H, d, J= 8.0 Hz), 5.90 (IH, d, J= 6.0 Hz), 4.73 (IH, t, J= 5.6 Hz), 4.57 (2H, m), 4.33 (IH, dd, J= 3.2 and 5.1 Hz), 4.12 (IH, q, J= 3.0 Hz), 3.88 (IH, dd, J= 2.8 and 12.4 Hz), 3.74 (IH, dd, J= 3.3 and 12.4 Hz), 3.14 (2H, t, J= 6.3 Hz); HRMS (ESI-MS m/z) calcd for C₂₇H₂₉N₆O₇S (M+H)⁺ 581.1818, found 581.1797; HPLC (system B) 16.5 min (99%), (system C) 16.7 min(99%).

2-(3"-Pyrrolylethyloxy)adenosine (19)

[0179] The yield is 57 %. ¹H NMR (CD₃OD) δ 8.11(1H, s), 6.63(2H, d, J= 2.2 Hz), 6.04

(IH, t, J= 2.1 Hz), 5.88 (IH, d, J= 5.8 Hz), 4.72 (IH, t, J= 5.5 Hz), 4.42 (2H, t, J= 7.4 Hz), 4.31 (IH, dd, J= 3.4 and 5.1 Hz), 4.10 (IH, q, J=3.2 Hz). 3.85 (IH, dd, J= 3.0 and 12.4 Hz), 3.73 (IH, dd, J = 3.6 and 12.4 Hz), 2.91 (2H, t, J= 7.3 Hz); HRMS (ESI-MS m/z) calcd for C₁₆H₂IN₆O₅ (M+H)⁺ 377.1573, found 377.1577; HPLC (system A) 4.5 min (99%), (system C) 4.7 min (99%).

2-(2"-Indolylethyloxy)adenosine (20)

[0180] The yield is 32 %. ¹H NMR (CD₃OD) δ 8.08 (IH, s), 7.37 (IH, d with small couplings, J= 7.4 Hz), 7.25 (IH, d with small coupling, J= 8.0 Hz), 6.97 (IH, dt, J= 1.4 and 7.1 Hz), 6.88 (IH, dt, J= 1.1 and 7.2 Hz), 6.21 (IH, d, J= 0.8 Hz), 5.86 (IH, d, J= 5.8 Hz), 4.69 (IH, t, J= 5.5 Hz), 4.57 (2H, t, J= 6.6 Hz), 4.30 (IH, dd, J= 3.3 and 5.2 Hz), 4.08 (IH, q, J= 3.3 Hz), 3.83 (IH, dd, J= 2.9 and 12.2 Hz), 3.72 (IH, dd, J= 3.3 and 12.4 Hz), 3.18 (2H, t, J= 6.7 Hz); HRMS (ESI-MS m/z) calcd for C₂₀H₂₃N₆O₅ (M+H)⁺ 427.1730, found 427.1735; HPLC (system A) 14.6 min (99 %), (system C) 10.9 min (99 %).

2-(2"-(l "-fø-Tøluenesulfonyl)indolyl)ethyloxy)adenosine (21)

[0181] The yield is 55 %. ¹H NMR (CDCl₃) δ 8.10 (IH, d, J= 8.2 Hz), 7.57-7.64 (3H, m), 7.37 (IH, d, J= 7.7 Hz), 7.11-7.26 (4H, m), 6.52 (IH, s), 5.71 (IH, d, J= 6.9 Hz), 5.66 (2H, br s), 5.03 (IH, t, J= 6.9 Hz), 4.62 (IH, m), 4.62 (IH, m), 4.46 (2H, m), 4.27 (IH, s), 3.89 (IH, d,J= 11.5 Hz), 3.74 (IH, d, J= 11.5 Hz), 3.43 (2H, m), 3.19 (IH, br s), 2.30 (3H, s); HRMS (ESI-MS m/z) calcd for C₂₇H₂₉N₆O₇S (M+H)⁺ 581.1818, found 581.1802; HPLC (system A) 23.0 min (99%), (system C) 16.7 min (99%).

2-(3"-(5"-Fluoro-indolyl)ethyloxy)adenosine (22)

[0182] The yield is 80 %. ¹H NMR (CD₃OD) δ 8.12 (IH, s), 7.20 ~ 7.30 (3H, m), 6.83

(IH, dt, J= 2.5 and 9.1 Hz), 5.89 (IH, d, J= 5.8 Hz), 4.72 (IH, t, J= 5.5 Hz), 4.55 (2H, t, J= 7.0 Hz), 4.31 (IH, dd, J= 3.3 and 5.2 Hz), 4.11 (IH, q, J= 3.3 Hz), 3.86 (IH, dd, J= 2.8 and 12.4 Hz), 3.73 (IH, dd, J= 3.6 and 12.4 Hz), 3.16 (2H, t, J= 7.1 Hz); HRMS (ESI-MS m/z) calcd for C₂₀H₂IN₆O₅FNa (M+Na)⁺ 467.1455, found 467.1479; HPLC (system A) 13.1 min (99%), (system C) 10.2 min (99 %).

2-(3"-(6"-Chloro-indolyl)ethyloxy)adenosine (23)

[0183] The yield is 54 %. ¹H NMR (CD₃OD) δ 8.08 (IH, s), 7.52 (IH, d, J= 8.5 Hz),

7.27 (IH, d, J= 1.7 Hz), 7.13 (IH, s), 6.95 (IH, dd, J= 1.9 and 8.5 Hz), 5.86 (IH, d, J= 6.0 Hz), 4.67 (IH, t, J= 5.5 Hz), 4.51 (2H, m), 4.28 (IH, dd, J= 3.4 and 5.1 Hz), 4.07 (IH, q, J=

3.2 Hz), 3.81 (IH, dd, J= 2.8 and 12.4 Hz), 3.69 (IH, dd, J= 3.3 and 12.4 Hz), 3.14 (2H, t, J = 7.0 Hz); HRMS (ESI-MS m/z) calcd for C₂₀H₂₂N₆O₅Cl (M+H)⁺ 461.1340, found 461.1339; HPLC (system A) 15.7 min (99 %), (system C) 11.9 min (99 %).

2-(3"-(5"-Bromo-indolyl)ethyloxy)adenosine (24)

[0184] The yield is 70 %. ¹H NMR (CD₃OD) δ 8.12 (IH, s), 7.70 (IH, d, J= 1.9 Hz),

7.24 (IH, d, J= 8.8 Hz), 7.20 (IH, s), 7.15 (IH, dd, J= 1.8 and 8.7 Hz), 5.89 (IH, d, J= 5.8 Hz), 4.71 (IH, t, J= 5.5 Hz), 4.56 (2H, t, J= 7.0 Hz), 4.32 (IH, dd, J= 3.6 and 5.2 Hz), 4.11 (IH, q, J= 3.2 Hz), 3.86 (IH, dd, J= 2.8 and 12.4 Hz), 3.73 (IH, dd, J= 3.6 and 12.4 Hz), 3.17 (2H, t, J= 6.9 Hz); HRMS (ESI-MS m/z) calcd for C₂₀H₂₂N₆O₅Br (M+H)⁺ 505.0835, found 505.0822; HPLC (system A) 15.2 min(98 %), (system C) 12.2 min (98%).

2-(3"-(5"-Iodo-indolyl)ethyloxy)adenosine (25)

[0185] The yield is 56 %. ¹H NMR (CD₃OD) δ 8.12 (IH, s) 7.89 (IH, dd, J= 0.6 and 1.7

Hz), 7.32 (IH, dd, J= 1.7 and 8.5 Hz), 7.16 (IH, s), 7.15 (IH, dd, J= 0.6 and 8.5 Hz), 5.89 (IH, d, J= 5.8 Hz), 4.71 (IH, t, J= 5.5 Hz), 4.55 (2H, t, J= 7.0 Hz), 4.32 (IH, dd, J= 3.6 and 5.2 Hz), 4.11 (IH, q, J= 3.2 Hz), 3.86 (IH, dd, J= 2.8 and 12.4 Hz), 3.73 (IH, dd, J-

3.3 and 12.4 Hz), 3.16 (2H, t, J= 6.9 Hz); HRMS (ESI-MS m/z) calcd for C₂₀H₂₂N₆O₅I (M+H)⁺ 553.0696, found 553.0681; HPLC (system A) 19.0 min (98 %), (system C) 13.1 min (98 %).

2-(3"-(5"-Bromo-l"-(/>-toluenesulfonyl)indolyl)ethyloxy)adenosine (26)

[0186] The yield is 68 %. ¹H NMR (CD₃OD) δ 8.14 (IH, s), 7.86 (IH, dd, J= 0.6 and

8.8 Hz), 7.68 - 7.74 (3H, m), 7.63 (IH, s), 7.40 (IH, dd, J= 1.8 and 8.8 Hz), 7.18 (2H, d with small coupling, J= 8.5 Hz), 5.89 (IH, d, J= 6.0 Hz), 4.73 (IH, t, J= 5.6 Hz), 4.55 (2H, t, J = 6.3 Hz), 4.33 (IH, dd, J= 3.3 and 5.2 Hz), 4.12 (IH, q, J= 3.0 Hz), 3.89 (IH, dd, J= 2.9 and 12.5 Hz), 3.74 (IH, dd, J= 3.3 and 12.4 Hz), 3.11 (2H, t, J= 6.2 Hz), 2.27 (3H, s); HRMS (ESI MS m/z) calcd for C₂₇H₂₈N₆O₇BrS (M+H)⁺ 659.0924, found 659.0921.

2-(3"-(5"-Chloro-indolyl)ethyloxy)adenosine (27)

[0187] The yield is 54 %. ¹H NMR (CD₃OD) δ 8.12 (IH, s), 7.55 (IH, d, J= 1.9 Hz),

7.28 (IH, dd, J= 0.5 and 8.5 Hz), 7.22 (IH, s), 7.03 (IH, dd, J= 1.9 and 8.5 Hz), 5.89 (IH, d, J= 6.0 Hz), 4.71 (IH, t, J= 5.5 Hz), 4.56 (2H, t, J= 7.0 Hz), 4.31 (IH, dd, J= 3.6 and 5.2 Hz), 4.11 (IH, q, J= 3.2 Hz), 3.86 (IH, dd, J= 2.9 and 12.5 Hz), 3.73 (IH, dd, J= 3.3 and 12.4 Hz), 3.17 (2H, t, J= 7.0 Hz); HRMS (ESI-MS m/z) calcd for C₂₀H₂₂N₆O₅Cl (M+H)⁺ 461.1340, found 461.1332; HPLC (system A) 16.6 min (99 %), (system C) 11.8 min (99 %).

2-(3"-(6"-Bromo-indolyl)ethyloxy)adenosine (28)

[0188] The yield is 71 %. ¹H NMR (CD₃OD) δ 8.12 (IH, s), 7.52 (IH, d, J= 8.5 Hz),

7.48 (IH, d, J= 1.7 Hz), 7.17 (IH, s), 7.12 (IH, dd,J= 1.7 and 8.5 Hz), 5.90 (IH, d, J= 5.8 Hz), 4.71 (IH, t, J= 5.5 Hz), 4.56 (2H, m), 4.31 (IH, dd, J= 3.3 and 5.2 Hz), 4.11 (IH, q, J= 3.2 Hz), 3.85 (IH, dd, J= 3.4 and 12.2 Hz), 3.73 (IH, dd, J =3.4 and 12.2 Hz), 3.21 (2H, t, J = 7.2 Hz); HRMS (ESI-MS m/z) calcd for C₂₀H₂₂N₆O₅Br (M+H)⁺ 505.0835 found 505.0840; HPLC (system A) 18.1 min (98 %), (system C) 12.6 min (98 %).

2-(3"-(4"-Bromo-indo]yl)ethyloxy)adenosine (29)

[0189] The yield is 44 %. ¹H NMR (CD₃OD) δ 8.11 (IH, s), 7.31 (IH, dd, J= 0.8 and

8.0 Hz), 7.24 (IH, s), 7.16 (IH, dd, J= 0.8 and 7.4 Hz), 6.93 (IH, t, J= 7.8 Hz), 5.89 (IH, d, J= 6.0 Hz), 4.71 (IH, t, J= 5.5 Hz), 4.60 (2H, m), 4.31 (IH, dd, J= 3.6 and 5.0 Hz), 4.10 (IH, q, J= 3.2 Hz), 3.85 (IH, dd, J= 2.9 and 12.5 Hz), 3.73 (IH, dd, J= 3.4 and 12.5 Hz), 3.47 (IH, t, J= 7.1 Hz); HRMS (ESI-MS m/z) calcd for C₂₀H₂₂N₆O₅Br (M+H)⁺ 505.0835, found 505.0843; HPLC (system A) 15.3 min (99 %), (system C) 11.7 min (99 %).

2-(3"-(7"-Bromo-indolyl)ethyloxy)adenosine (30)

[0190] The yield is 27 %. ¹H NMR (CD₃OD) δ 8.12 (IH, s), 7.60 (IH, d, J= 8.0 Hz),

7.25 (IH, d, J= IA Hz), 7.24 (IH, s), 6.95 (IH, t, J= 7.8 Hz), 5.90 (IH, d, J= 5.8 Hz), 4.71 (IH, t, J = 5.6 Hz), 4.58 (2H, m), 4.31 (IH, dd, J= 3.6 and 4.9 Hz), 4.11 (IH, q, J= 3.2 Hz), 3.85 (IH, dd, J= 2.9 and 12.2 Hz), 3.73 (IH, dd, J= 3.3 and 12.4 Hz), 3.20 (2H, t, J= 6.9 Hz); HRMS (ESI-MS m/z) calcd for C₂₀H₂₂N₆O₅Br (M+H)+ 505.0835, found 505.0837; HPLC (system A) 15.9 min (99 %), (system C) 12.1 min (99 %).

2-(3"-(5"-Methoxy-2"-methylindolyl)ethyloxy)adenosine (31)

[0191] The yield is 29 %. ¹H NMR (CD₃OD) δ 8.13 (IH, s), 7.10 (IH, dd, J= 0.6 and 8.8

Hz), 6.96 (IH, d, J= 2.2 Hz), 6.65 (IH, dd, J= 2.3 and 8.7 Hz), 5.90 (IH, d, J= 5.8 Hz), 4.68 (IH, t, J= 5.5 Hz), 4.47 (2H, m), 4.30 (IH, dd,J= 3.6 and 5.2 Hz), 4.10 (IH, q,J= 3.2 and 6.5 Hz), 3.84 (IH, dd, J= 2.9 and 12.2 Hz), 3.72 (IH, dd, J= 3.3 and 12.4 Hz), 3.13 (2H, t, J= 7.3 Hz), 2.37 (3H, s); HRMS (ESI-MS m/z) calcd for C₂₂H₂₆N₆O₈Na (M+Na)⁺ 493.1812, found 493.1792; HPLC (system A) 11.8 min (98%), (system C) 9.4 min (98 %).

2-(3"-(5"-Methoxy-2"-methyl-l"-(p-toluenesulfonyl)indolyl)ethyloxy)adenosine (32) [0192] The yield is 71 %. ¹H NMR (CD₃OD) δ 8.12 (lH,s), 7.96 (IH, d, J= 9.1 Hz),

7.52 (2H, d, J= 8.5 Hz), 7.11 (2H, d, J= 8.5 Hz), 6.92 (IH, d, J= 2.5 Hz), 6.82 (IH, dd, J= 2.5 and 9.1 Hz), 5.87 (IH, d, J= 6.0 Hz), 4.66 (IH, t, J= 5.6 Hz), 4.41 (2H, m), 4.29 (IH, dd, J= 3.2 and 5.1 Hz), 4.10 (IH, q, J=2.9 Hz), 3.82 (IH, dd, J= 2.8 and 12.4 Hz), 3.77 (3H, s), 3.70 (IH, dd, J= 3.2 and 12.5 Hz), 3.06 (2H, t, J= 6.6 Hz), 2.56 (3H, s), 2.21 (3H, s); HRMS (ESI-MS m/z) calcd for C₂₉H₃₃N₆O₈S (M+H)⁺ 625.2081, found 625.2079; HPLC (system B) 17.3 min (99 %), (system C) 17.6 min (99 %).

2-(3"-(5"-Methoxy-indoIyI)ethyIoxy)adenosine (33)

[0193] The yield is 54 %. ¹H NMR (CD₃OD) δ 8.12 (IH, s), 7.20 (IH, d, J= 8.8 Hz),

7.12 (IH, s), 7.05 (IH, d, J= 2.5 Hz), 6.73 (IH, dd,J= 2.5 and 8.8 Hz), 5.89 (IH, d,J= 5.8 Hz), 4.71 (IH, t, J= 5.5 Hz), 4.56 (2H, t, J=7.1 Hz), 4.31 (IH, dd, J=3.3 and 5.2 Hz), 4.10 (IH₅ q, J= 3.2 Hz), 3.84 (IH, dd, J= 2.8 and 12.4 Hz), 3.72 (IH, dd, J= 3.3 and 12.4 Hz), 3.18 (2H, t, J= 7.1 Hz), HRMS (ESI-MS m/z) calcd for C₂iH₂₅N₆O₆ (M+H)⁺ 457.1836, found 457.1815; HPLC (system A) 10.7 min (98 %), (system C) 8.8 min (98%).

2-(3"-(5"-Hydroxyindolyl)ethyloxy)adenosine (34)

[0194] The yield is 31 %. ¹H NMR (CD₃OD) δ 8.12 (IH, s), 7.15 (IH, dd, J= 0.6 and

8.8 Hz), 7.09 (IH, s), 7.01 (IH, dd, J= 0.5 and 2.5 Hz), 6.65 (IH, dd, J= 2.3 and 8.4 Hz), 5.90 (IH, d, J= 5.8 Hz), 4.72 (IH, t, J= 5.6 Hz), 4.54 (2H, t, J= 7.4 Hz), 4.31 (IH, dd, J = 3.3 and 5.2 Hz), 4.11 (IH, q, J= 3.2 Hz), 3.86 (IH, dd, J= 2.7 and 12.4 Hz), 3.74 (IH, dd, J = 3.3 and 12.4 Hz), 3.13 (2H, t, J= 7.3 Hz); HRMS (ESI-MS m/z) calcd for C₂₀H₂₂N₆O₆Na (M+Na)⁺ 465.1499, found 465.1471; HPLC (system A) 5.5 min (98%), (system C) 5.3 min (98 %).

2-(3"-(Benzoimidazole-l"-yl)ethyloxy)adenosine (35)

[0195] The yield is 57 %. ¹H NMR (CD₃OD) δ 8.22 (IH, s), 8.10 (IH, s), 7.62 (2H, d with small coupling, J= 8.2 Hz), 7.31 (IH, dt, J= 1.2 and 7.6 Hz), 7.24 (IH, dt, J= 1.3 and 7.6 Hz), 5.84 (IH, d, J= 5.8 Hz), 4.63 - 4.74 (5H, m), 4.31 (IH, dd, J= 3.2 and 5.1 Hz), 4.11 (IH, q, J= 3.0 Hz), 3.86 (IH, dd, J= 2.8 and 12.4 Hz), 3.73 (IH, dd, J= 3.0 and 12.4 Hz); HRMS (ESI-MS m/z) calcd for Ci₉H₂₂N₇O₅ (M+H)⁺ 428.1682, found 428.1691; HPLC (system A) 4.9 min (99%), (system D) 8.3 min (99 %).

2-(3"-(Benzotriazole-l"-yI)ethyloxy)adenosine (36)

[0196] The yield is 40 %. ¹H NMR (CD₃OD) δ 8.10 (IH, s), 7.93(1H, dt, J=LO and 7.4

Hz), 7.80 (IH, dt, J=0.8 and 8.2 Hz), 7.52 (IH, ddd, J= 1.0, 7.1 and 8.1 Hz), 7.38 (IH, ddd, J=LO, 7.1 and 8.1 Hz), 5.83 (IH, d, J= 5.8 Hz), 5.13 (2H, m), 4.82-4.92 (2H, m, overlapped with HDO), 4.64 (IH, t, J= 5.6 Hz), 4.31 (IH, dd, J= 3.3 and 5.2 Hz), 4.10 (IH, q, J= 3.1 Hz), 3.83 (IH, dd, J= 2.8 and 12.6 Hz), 3.72 (IH, dd, J= 3.3 and 12.4 Hz); HRMS (ESI- MS m/z) calcd for Ci₈H₂iN₈O₅ (M+H)⁺ 429.1635, found 429.1642; HPLC (system A) 4.7 min (99 %), (system C) 4.8 min (99 %).

EXAMPLE 25

[0197] This example demonstrates a synthesis of 6-guanidino-2-(3"- indolylethyloxy)adenosine (37) and 6-guanidino-2-(3"-(l"-(p- toluenesulfonyl)indolyl)ethyloxy)adenosine (38) in an embodiment of the invention. See Figure 5.

[0198] To a solution of guanidine hydrochloride (98 mg, 1.02 mmol) in acetonitrile (2.2 mL) and N, N-dimethylformamide (1.1 mL) is added sodium hydride (60 %) (41.2 mg, 1.02 mmol) at room temperature, and the reaction mixture is stirred overnight. This guanidine solution is added to a mixture of compound 102 (46 mg, 0.0633 mmol) and 1,4- diazabicyclo[2.2.2]octane (14 mg, 0.0126 mmol), and the resulting mixture is stirred overnight at 110 ⁰C and filtered. The filtrate is evaporated to give a crude oil, which is subjected to preparative TLC developed with a mixture of chloroform, methanol and saturated aqueous ammonia (2:1:0.3) to give 37 (2.3 mg, 8 %) and 38 (9 mg, 23 %) as an amorphous solid.

[0199] Compound 37: ¹B ΝMR (CD₃OD) £8.09 (IH, s), 7.60 (IH, d with small coupling, J= 7.7 Hz), 7.32 (IH, d with small coupling, J= 7.2 Hz), 7.16 (IH, s), 7.08 (IH, dt, J= 1.3 and 7.6 Hz), 7.01 (IH, dt, J = 1.2 and 7.3 Hz), 5.90 (IH, d, J= 6.0 Hz), 4.73 (IH, X, J = 5.5 Hz), 4.54 (2H, t, J= 7.1 Hz), 4.32 (IH, dd, J= 3.3 and 4.9 Hz), 4.12 (IH₅ q, J= 3.0 Hz), 3.87 (IH, dd, J= 2.8 and 12.6 Hz), 3.73 (IH, dd, J= 3.3 and 12.4 Hz), 3.24 (2H, t, J =

7.4 Hz); HRMS (ESI-MS m/z) calcd for C_2IH₂₅N₈O₅ (M+H)⁺ 469.1948, found 469.1952; HPLC (system B) 8.9 min (97 %), (system D) 7.5 min (97 %).

[0200] Compound 38: ¹H NMR (CD₃OD) δ 8.25 (IH, s), 7.93 (IH, dd, J= 1.4 and 7.4 Hz), 7.71 (2H, d with small coupling, J= 8.5 Hz), 7.61 (IH, dd, J= 1.4 and 7.1 Hz), 7.59 (IH, s), 7.30 (IH, dt, J= 1.2 and 7.6 Hz), 7.24 (IH, dt, J= 1.2 and 7.6 Hz), 7.18 (2H, d with small coupling, J= 8.5 Hz), 5.96 (IH, d, J= 6.0 Hz), 4.74 (IH, t, J= 5.5 Hz), 4.59 (2H, t, J =

6.5 Hz), 4.35 (IH, dd, J= 3.4 and 5.1 Hz), 4.13 (IH, q, J= 3.2 Hz), 3.89 (IH, dd, J= 2.9 and 12.5 Hz), 3.76 (IH, dd, J= 3.6 and 12.4 Hz), 3.18 (2H, t, J= 6.5 Hz), 3.26 (3H, s); HRMS (ESI-MS m/z) calcd for C₂₈H₃₁N₈O₇S (M+H)⁺ 623.2036, found 623.2045; HPLC (system A) 16.3 min (97 %), (system C) 8.7 min (97 %).

EXAMPLE 26

[0201] This example demonstrates a synthesis of 6-ethylamino-2-(3"- indolyl)ethyloxy)adenosine (39) in an embodiment of the invention. See Figure 5. [0202] To a solution of 102 (28.3 mg, 0.0389 mmol) in DMF (1.4 mL) in sealed tube are added ethylamine hydrochloride (63.5 mg, 0.779 mmol) and N, N-diisopropylethylamine (0.271 niL), and the reaction mixture is stirred at 140 ⁰C overnight and evaporated to give an oil. The oil is dissolved in methanol (1 mL), KOH (14.6 mg, 0.261 mmol) is added, and the reaction mixture is stirred for 42 h at 80 ⁰C. The solvent is evaporated to give a crude solid which is subjected to preparative TLC developed with a mixture of chloroform and methanol (5:1) to give 39 (2.2 mg, 28 % yield in two steps). ¹B NMR (CD₃OD) £8.05 (IH, s), 7.60 (IH, d with small coupling, J= 7.1 Hz), 7.32 (IH, d with small coupling, J= 7.7 Hz), 7.14 (IH, s), 7.07 (IH, dt, J= 1.3 and 7.6 Hz), 7.00 (IH, dt, J= 1.1 and 7.4 Hz), 5.87 (IH, d, J = 6.0 Hz), 4.71 (IH, t, J= 5.6 Hz), 4.60 (2H, t, J= 7.0 Hz), 4.30 (IH, dd, J= 3.2 and 5.1 Hz), 4.11 (IH, q, J= 3.0 Hz), 3.86 (IH, dd, J= 2.6 and 12.5 Hz), 3.73 (IH, dd, J= 3.2 and 12.5 Hz), 3.50-3.66 (2H, br m), 3.22 (2H, t, J= 7.1 Hz), 1.26 (3H, t, J= 7.3 Hz); HRMS (ESI-MS m/z) calcd for C₂₂H₂₇N₆O₅ (M+H)⁺ 455.2043, found 455.2063; HPLC (system A) 19.5 min (99 %), (system C) 13.5 min (99 %).

EXAMPLE 27

[0203] This example demonstrates a synthesis of (2R, 3S, 4S, 5R)-6-amino-5- ethylcarboxyamide-2-(3"-indolyl)ethyloxy)-purin-9-yl)-tetrahydrofuran (40) in an embodiment of the invention. See Figure 6.

[0204] Potassium hydroxide (12.6 mg, 0.025 mmol) is added to a solution of 134 (7.0 mg, 0.0112 mmol) in methanol (1.5 mL), and the reaction mixture is stirred at 70 °C overnight. The mixture is evaporated to a small amount of solution, which is subjected to preparative TLC developed with a mixture of chloroform and methanol (5:1) to give 40 (1.7 mg, 33% yield). ¹H NMR (CD₃OD) δ 8.06 (IH, s), 7.56 (IH, d with small coupling, J= 8.0 Hz), 7.32 (IH, d with small coupling, J= 8.0 Hz), 7.11 (IH, s), 7.08 (IH, dt, J= 1.2 and 8.1 Hz), 7.00 (IH, dt, J = Ll and 8.1 Hz), 5.91 (IH, d, J= 7.4 Hz), 4.74 (IH, dd, J= 4.8 and 7.3 Hz), 4.61 (2H, m), 4.41 (IH, d, J= 1.9 Hz), 4.30 (IH, dd, J= 1.7 and 4.9 Hz), 3.15-3.26 (4H, m), 0.99 (3H, t, J= 7.2 Hz); HRMS (ESI MS m/z) calcd for C₂₂H₂₆N₇O₅(M+H)⁺ 468.1995, found 468.2015; HPLC (system A) 15.7 min (98 %), (system C) 11.4 min (98 %).

EXAMPLE 28

[0205] This example demonstrates cell culture and membrane preparation used in the testing of compounds in accordance with an embodiment of the invention. [0206] CHO (Chinese hamster ovary) cells expressing the recombinant human ARs (Gao et al., Biochem. Pharmacol. 2004, 68, 1985-1993) are cultured in DMEM supplemented with 10% fetal bovine serum, 100 units/mL penicillin, 100 μg/mL streptomycin, 2 μmol/mL glutamine, and 800 μg/mL geneticin. Cells are harvested by trypsinization. After homogenization and suspension, cells are centrifuged at 500 g for 10 min, and the pellet is re- suspended in 50 mM Tris-HCl buffer (pH 8.0) containing 10 mM MgCl₂, 1 mM EDTA, and 0.1 mg/mL CHAPS. The suspension is homogenized with an electric homogenizer for 10 sec, and is then re-centrifuged at 20,000 g for 20 min at 4 ⁰C. The resultant pellets are re- suspended in buffer in the presence of 3 Units/ml adenosine deaminase, and the suspension is stored at -80 ⁰C until the binding experiments. The protein concentration is measured using the Bradford assay (Bradford et al., Anal. Biochem. 1976, 72, 248-254).

EXAMPLE 29

[0207] This example illustrates binding assays that can be carried out on compounds in accordance with an embodiment of the invention.

Human Ai and A_2A Receptors

[0208] For binding to human A₁ receptors, [³H]CCPA (1 nM) is incubated with membranes (40 μg/tube) from CHO cells stably expressing human Aj receptors at 25 ⁰C for 60 min in 50 mM Tris-HCl buffer (pH 7.4; MgCl₂, 10 mM) in a total assay volume of 200 μL. Nonspecific binding is determined using 10 μM of CPA. For human A_2A receptor binding, membranes (20 μg/tube) from HEK-293 cells stably expressing human A_2A receptors are incubated with 15 nM [³H]CGS21680 at 25 ⁰C for 60 min in 200 μl 50 mM Tris-HCl, pH 7.4, containing 10 mM MgCl₂. NECA (10 μM) is used to define nonspecific binding. The reaction is terminated by filtration with GF/B filters.

Human A₃ Receptor

[0209] For competitive binding assay, each tube contains 100 μL membrane suspension (20 μg protein), 50 μL of [¹²⁵I]I-AB-MECA (0.5 nM), and 50 μL of increasing concentrations of the nucleoside derivative in Tris-HCl buffer (50 mM, pH 7.4) containing 10 mM MgCl₂, 1 mM EDTA. Nonspecific binding is determined using 10 μM of Cl-IB-MECA in the buffer. The mixtures are incubated at 25 ⁰C for 60 min. Binding reactions are terminated by filtration through Whatman GF/B filters under reduced pressure using a MT-24 cell harvester (Brandell, Gaithersburgh, MD, USA). Filters are washed three times with 9 mL ice-cold buffer. Radioactivity is determined in a Beckman 5500B γ-counter. [0210] The adenosine receptor (AR) binding affinities of compounds 8 and 17 - 40 are investigated in comparison to compounds 1-7 and 9-16 (Table 1).

Table l^a

H, R² = CH₂OH, unless noted

EC_so at K₁ at

Ki at A₁AR K₁ at A₃AR Efficacy,

A₂₈AR (nM) A_2AAR

Compound Name/Substitution (nM) or % (nM) or % A₃AR or (% _κ (nM) or % inhibition" ,_. inhibition" % aaccttiivvaattiioonn)) inhibition

Reference

Agonists

R-Λ^-φhenylisopropyl)

1 1680±500 2.0±0.3 884±188 8.7±0.9 102±6 adenosine (R-PIA)

5'-JV-

2 ethylcarboxamido- 140+19 6.8±2.4 2.2+0.6 16.0±5.4 100 adenosine (NECA) 6-guanidino-NECA 54.5±13.3 7.0+1.0 628+39 5.1+1.3 100

(S)-2-(3-hydroxy-3- phenyl- 1 -propyn- 1 -

220 2.1 2.0 0.75 yl)NECA (OS)-PHP-NECA) -Ethers

5^e (-1%) 2640±540 360+139 568+205 99±4

(36%) (36%) 579±250 578±182 52±3

3490±1490 221±57 9.3±2.9 54.2±14.3 71±3

(29%) 960±95 500±50 66 ± 3 42±8

%) 2060 ± 630 519 ± 41 352 ± 66 37±8

10^e (13%) 1560 ± 250 413 ± 37 312 ± 47 18±8

ll^e (12%) 331+22 58.1+24.9 77.8+13.5 45±5

12^e (64%) 312±24 69.3 ±4.7 119±8 50±7

13^e (11%) 467±100 56.8+16.3 112+16 74±5

14^e 1440±70 141±51 16.1±7.0 130+8 45±9

15^e -O 1780±260 174±20 10.9+4.8 93.3±16.8 80±5

16^e 280±72 13.3±4.1 101+34 62±15

17° 299±45 148±19 45.0±11.6 232±54 17±3

31 (48%) 579±88 (64*2%) 599±3 13*4

32 (24%) 20±2% (26*4%) (66*5%) 3±2

33 1250 1820±330 1400±300 360±50 -3*3

34 896 310 ± 90 450±8 120 ± 20 24±3

35 (18*4%) 3870±497 2070 ± 700 3±2

36 (41*5%) (46*2%) 1920 ± 470 13*4

37 (40%) 73.6 ± 8.0 277 ± 74 90 ± 10 58±8

R⁴ = C(NH)NH₂

38 (42%) 52±2% 344 ± 72 457 ± 40 24±7

R⁴ = C(NH)NH₂

39 3270 640±110 40±4% 30±10 54±12

R⁴ = Et

40 989 190±20 250±30 110*20 102±2

R² = CONHEt aPotency of various adenosine derivatives in activation of the human A₂₈AR expressed in CHO cells, with values expressed either the EC₅₀ (nM) or the percent stimulation at 10 μM (in parentheses). For comparison, binding affinities of the adenosine derivatives at human Ai , A_2A, and A₃ ARs expressed in CHO cells (expressed as Kj value or percent displacement at 10 μM) and maximal agonist effects at 10 μM at the A₃AR. Values for compounds 5 - 7 and 9 - 16 are from Gao et al., Biochem. Pharmacol. 2004, 68, 1985-1993; ^bAll experiments are performed using adherent CHO cells stably transfected with cDNA encoding a human AR. Percent activation of the human A_2B or A₃AR is determined at 10 μM. Binding at A₁, A_2A and A₃ARs was carried out as described in Experimental Procedures. The A₃ receptor activation results were from three separate experiments. The K₁ and EC₅₀ values from the present study are expressed as mean±s.e.m., N = 3-5; ^cCompounds 3, MRS3218; 17, MRS3534; 24, MRS3854; 28, MRS3997; ^dData from references Volpini et al., J. Med. Chem. 2002, 45, 3271-3279 and Vittori et al., Nucleosides Nucleotides Nucleic Acids 2004, 23, 471-481; and ^eData from Gao et al., Biochem. Pharmacol. 2004, 68, 1985-1993.

[0211] For several decades NECA (S'-N-ethylcarboxaminocarbonyladenosine) 2 was considered to be the most potent known agonist at the A_2B AR, with an EC₅₀ of 140 nM (Hide et al., MoI. Pharmacol. 1992, 41, 352-359; Gao et al., Biochem. Pharmacol. 2004, 68, 1985- 1993; and Klotz et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 1998, 357, 1-9).

The functional effects of compound 28 compared to compound 2 on adenylate cyclase in CHO cells stably expressing the human ARs are depicted in Figure 7. Compound 28 is a full agonist at the A_2A and A_2B adenosine receptors. In the curves shown, the EC₅₀ values for 2 are 21.9 nM (A₂A, Figure 7B) and 110 nM (A_2B, Figure 7C). The EC₅₀ values of compound 28 are 39.7 nM (A_2A, Figure 7B) and 109 nM (A_2B, Figure 7C) are obtained. The relative maximal efficacy of 28 at the Ai and A₃ adenosine receptors is 31.8% and 20.2±1.0% of the full agonist 2, respectively. Compound 28 is more selective to A_2B adeonosine receptors than compound 2.

EXAMPLE 30

[0212] This example illustrates an anti-infarct effect of compound 28 in an isolated rabbit heart model of ischemia/reperfusion injury in accordance with an embodiment of the invention.

[0213] New Zealand White rabbits are anesthetized with pentobarbital sodium (30 mg/kg i.v.) and ventilated with 100% oxygen. A suture is passed around a coronary arterial branch.

The excised heart is perfused on a Langendorff apparatus with Krebs-Henseleit bicarbonate buffer bubbled with 95% O₂/5% CO₂ to a pH of 7.35 - 7.45 at 38 ⁰C. A fluid-filled latex balloon measures pressure in the left ventricle as the heart spontaneously beats in an isometric fashion on the balloon.

[0214] A prominent branch of the left coronary artery is occluded (regional ischemia) for

30 min and reperfused for 2 hr in both the control and the treated groups. In the control group no other treatment is given. In the drug-treated group, 200 nM of compound 28 is given for one hour starting 10 min prior to reperfusion. Figure 8 shows the infarct sizes for the 3 groups. Both of the treated groups were protected.

[0215] The percentage of the ischemic region that infarcts in a rabbit heart is a function of the absolute size of the risk zone. Therefore, infarct size is examined by plotting it against the risk zone to make sure that the apparent salvage seen in the drug is not an artifact resulting from smaller risk zones in the treatment group. As shown in Figure 9, a line is fit to the control data with an intercept at about 0.35 cm³. This result means that no infarction would occur in an untreated heart with a 30-minute insult if the risk zone is less than 0.35 cm³. Figure 9 shows that all of the drug-treated hearts fell well below the line. Thus for any given risk zone volume, the infarcts are clearly smaller in the treated groups. In addition, a single high dose (e.g., 160 μg/kg) bolus plus a continued administration (e.g., 1920 μg/kg/hr) of compound 28 provides a reduction in the size of the infarcted area. [0216] The foregoing shows that compound 28 provides treatment/prevention of myocardial ischemia and/or myocardial ischemia/reperfusion injury.

[0217] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0218] The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to,") unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. AU methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0219] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

CLAIM(S):

1. A compound of formula I or pharmaceutically acceptable salt thereof

(I) wherein

R¹ is selected from the group consisting of aryl, heteroaryl, heterocycloalkyl, cycloalkylaryl, heterocycloalkylaryl, arylheteroaryl, and arylheterocycloalkyl, each of which is optionally substituted with 1 to 3 substituents selected from the group consisting of Ci_-I2 alkyl, hydroxyl, CM₂ alkoxy, halo, tosyl (Ts), CN, -C(O)OH, aminocarbonyl, amino, Ci_-I2 dialkylamino, and Ci_-I2 alkylamino;

Z is a bond or -CH₂-;

n is an integer of 1 to 4;

R² is selected from the group consisting Of -CH₂OH, aminocarbonyl, Ci_-I2 alkylaminocarbonyl, and di-Ci-i₂ alkylaminocarbonyl; and

R³ and R⁴ are the same or different and each is selected from the group consisting of hydrogen, CM₂ alkyl, C_3-8 cycloalkyl, C_ό-3o aryl, and imidamido;

provided that when R² is -CH₂OH, and R³ and R⁴ are hydrogen, then -0-(CH₂)_H-Z-R¹ is not benzyloxy, phenylalkoxy or a substituted phenylalkoxy, thiophenylalkoxy or a substituted thiophenylalkoxy, pyridylalkoxy, indolylalkoxy, naphthylalkoxy, biphenylalkoxy, or indolylalkoxy.

2. The compound or pharmaceutically acceptable salt of claim 1, wherein R¹ is selected from the group consisting of

C_6-30 aryl, a heteroaryl consisting of one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom, a heterocycloalkyl consisting of a 5 or 6- membered monocyclic ring that contains one, two, or three heteroatoms selected from nitrogen, oxygen, and/or sulfur, Cs_-7 cycloalkyl-fused phenyl, heterocycloalkyl-fused phenyl, wherein the heterocycloalkyl consists of a 5 or 6-membered monocyclic ring that contains one, two, or three heteroatoms selected from nitrogen, oxygen, and/or sulfur, a benzo-fused heteroaryl, wherein the heteroaryl consists of one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom, and a benzo-fused heterocycloalkyl, wherein the heterocycloalkyl consists of a 5 or 6-membered monocyclic ring that contains one, two, or three heteroatoms selected from N, O, and/or S.

3. The compound or pharmaceutically acceptable salt of claim 1 or 2, wherein R¹ is selected from the group consisting of phenyl, biphenyl, naphthyl, anthracenyl, pyrenyl, pyridinyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)- and (l,2,4)-triazolyl, pyrimidinyl, tetrazolyl, furyl, thiophenyl, isothiazolyl, thiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, pyrrolo[3,2-d]pyrimidinyl, pyrrolo[2,3- d]pyrimidinyl), pyrrolinyl, pyranyl, piperidyl, tetrahydrofuranyl, tetrahydrothiopheneyl, morpholinyl), 5-, 6-, 7-, or 8-1,2,3,4-tetrahydronaphthalenyl, 4-, 5-, 6-, or 7-2,3-dihydro-lH- indenyl), 5-, 6-, 7-, or 8-1,2,3,4-tetrahydroquinolinyl, 5-, 6-, 7-, or 8-1,2,3,4- tetrahydroquinoxalinyl, 5-, 6-, 7-, or 8-2,3-dihydrobenzo[b][l,4]dioxinyl), benzimidazolyl, indolyl, indazolyl, benzo-l,2,3-triazolyl, 2-benzo[d]oxazolyl, 2-benzo[d]thiazolyl, 1,- 3-,or 4- isoquinolinyl, 2-, 3-, or 4-quinolinyl, 2- or 3-quinoxalinyl, 2,3-dihydrobenzo[b][l,4]dioxinyl, 2-indolinyl, and 3-indolinyl.

4. The compound or pharmaceutically acceptable salt of any of claims 1 -3, wherein R¹ is selected from the group consisting of

wherein

R and R are the same or different and are selected from the group consisting of hydrogen, Ci_-I2 alkyl, hydroxyl, Ci_-I2 alkoxy, halo, tosyl, CN, -C(O)OH, aminocarbonyl, amino, Ci_-I2 dialkylamino, and Ci_-I2 alkylamino, and

R⁶ is selected from the group consisting of hydrogen, CM₂ alkyl, C_3-8 cycloalkyl, and C_6-3o aryl.

5. The compound or pharmaceutically acceptable salt of claim 4, wherein R¹ is selected from the group consisting of

6. The compound or pharmaceutically acceptable salt of claim 5, wherein R¹ is selected from the group consisting of

7. The compound or pharmaceutically acceptable salt of any of claims 4-6, wherein R⁵ and R⁵ are the same or different and each is selected from the group consisting of hydrogen, Ci-Cj₂ alkyl, hydroxyl, Cj-Ci₂ alkoxy, halo, and tosyl.

8. The compound or pharmaceutically acceptable salt of any of claims 1 -5, wherein R¹ is selected from the group consisting of

9. The compound or pharmaceutically acceptable salt of any of claims 1 -8, wherein n is 2 or 3.

10. The compound or pharmaceutically acceptable salt of any of claims 1 -9, wherein n is 2.

11. The compound or pharmaceutically acceptable salt of any of claims 1-10, wherein R² is selected from the group consisting Of -CH₂OH and Ci_-I2 alkylaminocarbonyl.

12. The compound or pharmaceutically acceptable salt of any of claims 1-11, wherein R² is -CH₂OH.

13. The compound or pharmaceutically acceptable salt of any of claims 1-11, wherein R² is N-ethylcarboxaminocarbonyl.

14. The compound or pharmaceutically acceptable salt of any of claims 1-13, wherein R³ and R⁴ are the same or different and each is selected from the group consisting of hydrogen, Ci_-I2 alkyl, and imidamido.

15. The compound or pharmaceutically acceptable salt of any of claims 1-14, wherein R³ and R⁴ are hydrogen.

16. The compound or pharmaceutically acceptable salt of any of claims 1-14, wherein R³ is hydrogen and R⁴ is Ci_-I2 alkyl or imidamido.

17. The compound or pharmaceutically acceptable salt of claim 16, wherein R⁴ is C_M2 alkyl.

18. The compound or pharmaceutically acceptable salt of claim 16, wherein R⁴ is imidamido.

19. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any of claims 1-18 and a pharmaceutically acceptable carrier.

20. A method for activating an A_2B adenosine receptor in a mammal comprising administering to the mammal an effective amount of a compound or pharmaceutically acceptable salt of any of claims 1-18.

21. A method for activating an A_2B adenosine receptor in a cell comprising contacting the cell with a compound or pharmaceutically acceptable salt of any of claims 1- 18.

22. The method of claim 21 , wherein said contacting is carried out in vivo.

23. The method of claim 21, wherein said contacting is carried out in vitro.

24. The method of any of claims 20-23, further comprising activating an A_2A adenosine receptor.

25. A method of treating or preventing (a) myocardial ischemia or (b) myocardial ischemia/reperfusion injury in a mammal comprising administering a therapeutically effective amount of a compound or pharmaceutically acceptable salt of any of claims 1-18 to the mammal, whereupon the (a) myocardial ischemia or (b) myocardial ischemia/reperfusion injury is treated or prevented.

26. The method of claim 25, wherein the compound or pharmaceutically acceptable salt thereof is administered for at least the first 24 hrs following reperfusion.

27. The method of claim 25 or 26, wherein the compound or pharmaceutically acceptable salt thereof is administered during reperfusion.

28. The method of any of claims 25-27, wherein the compound is 2-(3"-(6"- bromo-indolyl)ethyloxy)adenosine or a pharmaceutically acceptable salt thereof.

29. Use of a compound or pharmaceutically acceptable salt of any of claims 1-18 in the preparation of a medicament for activating A₂B adenosine receptors of a mammal.

30. Use of a compound or pharmaceutically acceptable salt of any of claims 1-18 in the preparation of a medicament for treating or preventing myocardial ischemia or myocardial ischemia/reperfusion injury in a mammal.