HK1209129B - 7-deazapurine nucleosides for therapeutic uses - Google Patents

Description

7-Deazapurine nucleosides for therapeutic use

This application is a divisional application based on the patent application with application date of April 19, 2010, application number 201080027802.1 (PCT/CZ2010/000050), and invention name: "New 7-deazapurine nucleosides for therapeutic use".

Background Art

The present invention relates to novel antiproliferative compounds and their therapeutic uses.

Summary of the Invention

The present invention provides anticancer compounds. Accordingly, in one aspect, the present invention provides a compound of the present invention, which is a compound of formula I or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a mixture of optical isomers:

in:

_R1 is hydrogen, monophosphonic acid, diphosphonic acid or triphosphonic acid (mono-, di-, or tri-phosphate);

_R2 is aryl, heteroaryl or alkynyl, wherein the aryl group is optionally substituted with one or two substituents selected from alkoxy, alkylthio or halogen;

_R3 is hydrogen or alkyl.

On the other hand, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a mixture of optical isomers, wherein R ₁ is hydrogen, monophosphono, diphosphono or triphosphono; R ₂ is aryl, which is optionally substituted with a substituent selected from alkoxy, alkylthio or halogen; and R ₃ is hydrogen.

On the other hand, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a mixture of optical isomers, wherein R ₁ is hydrogen, monophosphino, diphosphino or triphosphino; R ₂ is aryl, which is optionally substituted with a substituent selected from alkoxy, alkylthio or halogen; and R ₃ is alkyl.

In another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a mixture of optical isomers thereof, wherein R ₁ is hydrogen, monophosphono, diphosphono or triphosphono; R ₂ is heteroaryl; R ₃ is hydrogen, provided that R ₂ is not 1,3-oxazol-2-yl, furan-2-yl, 1,2,4-triazin-3-yl, 5,6-dimethyl-1,2,4-triazin-3-yl, 5,6-diphenyl-1,2,4-triazin-3-yl, 1,2,4-oxadiazol-3-yl, 4H-1,2,4-triazol-3-yl, 5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl, 4,5-dihydro-1H-imidazol-2-yl, 4-phenylthiazol-2-yl, 1H-tetrazol-5-yl, 1,4,5,6-tetrahydropyrimidin-2-yl or 9-oxo-9H-indeno[1,2-e][1,2,4]triazin-3-yl.

In another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a mixture of optical isomers thereof, wherein R ₁ is hydrogen, monophosphono, diphosphono or triphosphono; R ₂ is heteroaryl; R ₃ is alkyl, provided that R ₂ is not 1,3-oxazol-2-yl, furan-2-yl, 1,2,4-triazin-3-yl, 5,6-dimethyl-1,2,4-triazin-3-yl, 5,6-diphenyl-1,2,4-triazin-3-yl, 1,2,4-oxadiazol-3-yl, 4H-1,2,4-triazol-3-yl, 5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl, 4,5-dihydro-1H-imidazol-2-yl, 4-phenylthiazol-2-yl, 1H-tetrazol-5-yl, 1,4,5,6-tetrahydropyrimidin-2-yl or 9-oxo-9H-indeno[1,2-e][1,2,4]triazin-3-yl.

In another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a mixture of optical isomers, wherein R ₁ is hydrogen, monophosphono, diphosphono or triphosphono; R ₂ is alkynyl; and R ₃ is hydrogen.

The present invention also provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

The present invention also provides a method for inhibiting tumor growth or cell proliferation in tumor/cancer cells in vitro or in vivo, comprising contacting a subject in need of such treatment with a compound of formula I or a pharmaceutically acceptable salt thereof.

The present invention also provides a method for treating cancer in an animal, comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof to the animal.

The present invention also provides a method for inhibiting tumor diseases in animals, which comprises administering a compound of formula I or a pharmaceutically acceptable salt thereof to the animal.

The present invention also provides the use of the compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a drug for inhibiting tumor/cancer cell growth or cell proliferation, slowing down cell cycle progression in tumor/cancer cells, and treating animal cancer.

The present invention also provides use of the compound of formula I or a pharmaceutically acceptable salt thereof in preparing a medicament for inhibiting animal tumor diseases.

The present invention also provides the synthetic method and synthetic intermediates disclosed in the present application for preparing the compound of formula (I) or its salt.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a structural diagram of the compound of formula (I).

DETAILED DESCRIPTION

For the purposes of this specification, the following definitions apply and, wherever appropriate, terms used in the singular shall include the plural and vice versa.

The term "alkyl" as used herein refers to a branched or straight chain hydrocarbon moiety. Preferably, the alkyl comprises 1 to 20 carbon atoms, more preferably 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 7 carbon atoms or 1 to 4 carbon atoms. The representative examples of alkyl include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, the tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl etc. When alkyl comprises one or more unsaturated bonds, it can represent alkenyl (double bond) or alkynyl (triple bond). In addition, when alkyl is connected with aryl (defined below), it can be referred to as "arylalkyl".

The term "alkynyl" as used herein refers to straight-chain and branched-alkyl groups having 2 to 12 carbon atoms and one or more carbon-carbon triple bonds. Preferably, the alkynyl group contains 2 to 8 or 2 to 4 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, propynyl, butynyl, octynyl, decynyl, etc.

The term "alkoxy" as used herein refers to an alkyl-O- group, wherein alkyl is as defined above. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy-, and the like. The term "lower alkoxy" as used herein refers to an alkoxy group having 1-7 carbon atoms, preferably 1-4 carbon atoms.

The term "aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 20 carbon atoms in the ring portion. Preferably, the aryl group is a ( _C6 - _C10 ) aryl group. Non-limiting examples include phenyl, biphenyl, naphthyl or tetrahydronaphthyl, each of which may be optionally substituted with 1 to 4 substituents, such as optionally substituted alkyl, trifluoromethyl, cycloalkyl, halogen, hydroxyl, alkoxy, acyl, alkyl-C (O)-O-, aryl-O-, heteroaryl-O-, optionally substituted amino, sulfhydryl, alkylthio, arylthio, nitro, cyano, carboxyl, alkyl-OC (O)-, carbamoyl, alkylthiocarbonyl, sulfonyl, sulfonamido, heterocycloalkyl, etc.

Additionally, the term "aryl" as used herein also refers to aromatic substituents, which may be aromatic monocyclic rings or aromatic polycyclic rings fused together, covalently linked, or linked to a common group such as a methylene or ethylene moiety. The common linking group may also be the carbonyl in benzophenone, the oxygen in diphenyl ether, or the nitrogen in diphenylamine.

The term "heteroaryl" as used herein refers to a 5-14 membered monocyclic or bicyclic or fused polycyclic ring system having 1-8 heteroatoms selected from N, O, S or Se. Preferably, the heteroaryl is a 5-10 membered ring system. Typical heteroaryl groups include thiophene-2-yl or thiophene-3-yl, furan-2-yl or furan-3-yl, pyrrol-2-yl or pyrrol-3-yl, imidazole-2-yl, imidazole-4-yl or imidazole-5-yl, pyrazol-3-yl, pyrazol-4-yl or pyrazol-5-yl, thiazol-2-yl, thiazol-4-yl or thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl or isothiazol-5-yl, oxazol-2-yl, oxazol-4-yl or oxazol-5-yl, isoxazole -3-yl, isoxazol-4-yl or isoxazol-5-yl, 1,2,4-triazol-3-yl or 1,2,4-triazol-5-yl, 1,2,3-triazol-4-yl or 1,2,3-triazol-5-yl, tetrazolyl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, pyridazin-3-yl or pyridazin-4-yl, pyrazin-3-yl, pyrazin-4-yl or pyrazin-5-yl, pyrazin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl or pyrimidin-5-yl.

The term "heteroaryl" also refers to a group in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocycloalkyl rings, wherein the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include, but are not limited to, indolizin-1-yl, indolizin-2-yl, indolizin-3-yl, indolizin-5-yl, indolizin-6-yl, indolizin-7-yl, or indolizin-8-yl, isoindole-1-yl, isoindole-3-yl, isoindole-4-yl, isoindole-5-yl, isoindole-6-yl, or isoindole-7-yl, indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, or indol-7-yl, indole-2-yl, indole-3-yl, indole-4-yl, indole-5-yl, indole-6-yl, or indole-7-yl, purin-2-yl, purin-4-yl, purin-5-yl, purin-6-yl, purin-7-yl, or purin-8-yl, quinolizin-1-yl, quinolizin-2-yl, quinolizin-3-yl, quinolizin-4-yl, quinolizin-5-yl, quinolizin-6-yl, quinolizin-7-yl, quinoliz ... 1-yl, quinolizin-2-yl, quinolizin-3-yl, quinolizin-4-yl, quinolizin-6-yl, quinolizin-7-yl, quinolizin-8-yl or quinolizin-9-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolizin-7-yl or quinolizin-8-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl or isoquinolin-8-yl, phthalazin-1-yl, phthalazin-4-yl, phthalazin-5-yl, phthalazin-6-yl, phthalazin-7-yl or phthalazin-8-yl, naphthyridine-2-yl, naphthyridine-3-yl, naphthyridine-4-yl, naphthyridine-5-yl or naphthyridine-8-yl naphthazin-6-yl, quinazolin-2-yl, quinazolin-3-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl or quinazolin-8-yl, cinnolin-3-yl, cinnolin-4-yl, cinnolin-5-yl, cinnolin-6-yl, cinnolin-7-yl or cinnolin-8-yl, pteridin-2-yl, pteridin-4-yl, pteridin-6-yl or pteridin-7-yl, 4aHcarbazol-1-yl, 4aHcarbazol-2-yl, 4aHcarbazol-3-yl, 4aHcarbazol-4-yl, 4aHcarbazol-5-yl, 4aHcarbazol-6-yl, 4aHcarbazol-7-yl or 4aHcarbazol-8-yl, carbazol-1-yl, carbazol-2-yl, carbazol-3-yl, carbazol-4-yl, carbazol-5-yl, yl, carbazol-6-yl, carbazol-7-yl or carbazol-8-yl, carboline-1-yl, carboline-3-yl, carboline-4-yl, carboline-5-yl, carboline-6-yl, carboline-7-yl, carboline-8-yl or carboline-9-yl, phenanthridin-1-yl, phenanthridin-2-yl, phenanthridin-3-yl, phenanthridin-4-yl, phenanthridin-6-yl, phenanthridin-7-yl yl, phenanthridin-8-yl, phenanthridin-9-yl or phenanthridin-10-yl, acridin-1-yl, acridin-2-yl, acridin-3-yl, acridin-4-yl, acridin-5-yl, acridin-6-yl, acridin-7-yl, acridin-8-yl or acridin-9-yl, perylene-1-yl, perylene-2-yl, perylene-4-yl -yl, perylene-5-yl, perylene-6-yl, perylene-7-yl, perylene-8-yl or perylene-9-yl, phenanthroline-2-yl, phenanthroline-3-yl, phenanthroline-4-yl, phenanthroline-5-yl, phenanthroline-6-yl, phenanthroline-8-yl, phenanthroline-9-yl or phenanthroline-10-yl, phenazine-1-yl, phenazine-2-yl, phenazine-3-yl, phenazine-4-yl, phenazine-6-yl, phenazine-7-yl, phenazine-8-yl or phenazine-9-yl, phenothiazine-1-yl, phenothiazine-2-yl, phenothiazine-3-yl, phenothiazine-4-yl, phenothiazine-6-yl, phenothiazine-7-yl, phenothiazine-8-yl or phenanthroline-9-yl yl, phenothiazin-9-yl or phenothiazin-10-yl, phenoxazin-1-yl, phenoxazin-2-yl, phenoxazin-3-yl, phenoxazin-4-yl, phenoxazin-6-yl, phenoxazin-7-yl, phenoxazin-8-yl, phenoxazin-9-yl or phenoxazin-10-yl, benzisoquinolin-2-yl, benzisoquinolin-3-yl, benzisoquinolin-4-yl, benzisoquinolin-5-yl, benzisoquinolin-6-yl or benzisoquinolin-1-yl, benzisoquinolin-3-yl, benzisoquinolin-4-yl, benzisoquinolin-5-yl, benzisoquinolin-6-yl, benzisoquinolin-7-yl, benzisoquinolin-8-yl, benzisoquinolin-9-yl or benzisoquinolin-10-yl, thieno[2, 3-b]furan-2-yl, thieno[2,3-b]furan-3-yl, thieno[2,3-b]furan-4-yl or thieno[2,3-b]furan-2-yl, 7H-pyrazino[2,3-c]carbazole-3-yl, 7H-pyrazino[2,3-c]carbazole-5-yl, 7H-pyrazino[2,3-c]carbazole-6-yl, 7H-pyrazino[2,3-c]carbazole-7-yl, 7H-pyrazino[2,3-c]carbazole-8-yl, 7H-pyrazino[2,3-c]carbazole-9-yl, 7H-pyrazino[2,3-c]carbazole-10-yl or 7H-pyrazino[2,3-c]carbazole-11-yl -yl, 2H-furo[3,2-b]-pyran-2-yl, 2H-furo[3,2-b]-pyran-3-yl, 2H-furo[3,2-b]-pyran-5-yl, 2H-furo[3,2-b]-pyran-6-yl or 2H-furo[3,2-b]-pyran-7-yl, 5H-pyrido[2,3-d]-o-oxazin-2-yl, 5H-pyrido[2,3-d]-o-oxazin-3-yl, 5H-pyrido[2,3-d]-o-oxazin-4-yl, 5H-pyrido[2,3-d]-o-oxazin-5-yl, 5H-pyrido[2,3-d]-o-oxazin-7-yl or 5H-pyrido[2,3-d]-o- oxazin-8-yl, 1H-pyrazolo[4,3-d]-oxazol-1-yl, 1H-pyrazolo[4,3-d]-oxazol-3-yl or 1H-pyrazolo[4,3-d]-oxazol-5-yl, 4H-imidazo[4,5-d]thiazol-2-yl, 4H-imidazo[4,5-d]thiazol-4-yl or 4H-imidazo[4,5-d]thiazol-5-yl, pyrazino[2,3-d]pyridazin-3-yl, Pyrazino[2,3-d]pyridazin-5-yl or pyrazino[2,3-d]pyridazin-8-yl, imidazo[2,1-b]thiazol-2-yl, imidazo[2,1-b]thiazol-3-yl, imidazo[2,1-b]thiazol-5-yl or imidazo[2,1-b]thiazol-6-yl, furo[3,4-c]cinnolin-1-yl, furo[3,4-c]cinnolin-3-yl, furo[3,4-c]cinnoline -6-yl, furo[3,4-c]cinnolin-7-yl, furo[3,4-c]cinnolin-8-yl or furo[3,4-c]cinnolin-9-yl, 4H-pyrido[2,3-c]carbazole-1-yl, 4H-pyrido[2,3-c]carbazole-2-yl, 4H-pyrido[2,3-c]carbazole-3-yl, 4H-pyrido[2,3-c]carbazole-4-yl, 4H-pyrido[2,3-c]carbazole-5-yl, 4H-pyrido[2,3-c]carbazole-6-yl, furo[3,4-c]cinnolin-7-yl, furo[3,4-c]cinnolin-8-yl or furo[3,4-c]cinnolin-9-yl, 4H-pyrido[2,3-c]carbazole-1-yl, 4H-pyrido[2,3-c]carbazole-2-yl, 4H-pyrido[2,3-c]carbazole-3-yl, 4H-pyrido[2,3-c]carbazole-4-yl, 4H-pyrido[2,3-c ]carbazol-5-yl, 4H-pyrido[2,3-c]carbazol-6-yl, 4H-pyrido[2,3-c]carbazol-8-yl, 4H-pyrido[2,3-c]carbazol-9-yl, 4H-pyrido[2,3-c]carbazol-10-yl or 4H-pyrido[2,3-c]carbazol-11-yl, imidazo[1,2-b][1,2,4]triazine-2-yl, imidazo[1,2-b][1,2 ,4]triazine-3-yl, imidazo[1,2-b][1,2,4]triazine-6-yl or imidazo[1,2-b][1,2,4]triazine-7-yl, benzo[b]thiophene-7-yl, benzoxazol-2-yl, benzoxazol-4-yl, benzoxazol-5-yl, benzoxazol-6-yl or benzoxazol-7-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl or benzoxazol-7-yl -yl or benzimidazol-7-yl, benzothiazol-2-yl, benzothiazol-4-yl, benzothiazol-4-yl, benzothiazol-5-yl, benzothiazol-6-yl or benzothiazol-7-yl, benzoxepin-1-yl, benzoxepin-2-yl, benzoxepin-4-yl, benzoxepin-5-yl, benzoxepin-6-yl, benzoxepin-7-yl, benzoxepin-8-yl or benzoxepin-9-yl, benzoxazin-2-yl, benzoxepin-1-yl, benzoxepin-2-yl, benzoxepin-4-yl, benzoxepin-5-yl, benzoxepin-6-yl, benzoxepin-7-yl, benzoxepin-8-yl or benzoxepin-9-yl, benzoxazin-2-yl, benzoxepin- benzoxazin-4-yl, benzoxazin-5-yl, benzoxazin-6-yl, benzoxazin-7-yl or benzoxazin-8-yl, 1H-pyrrolo[1,2-b][2]benzazepin-1-yl, 1H-pyrrolo[1,2-b][2]benzazepin-2-yl, 1H-pyrrolo[1,2-b][2]benzazepin-3-yl, 1H-pyrrolo[1,2-b][2]benzazepin-5-yl, 1H-pyrrolo[1,2-b][2]benzazepin ... pyrrolo[1,2-b][2]benzazepin-6-yl, 1H-pyrrolo[1,2-b][2]benzazepin-7-yl, 1H-pyrrolo[1,2-b][2]benzazepin-8-yl, 1H-pyrrolo[1,2-b][2]benzazepin-9-yl, 1H-pyrrolo[1,2-b][2]benzazepin-10-yl or 1H-pyrrolo[1,2-b][2]benzazepin-11-yl. Typical fused heteroaryl groups include, but are not limited to, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, or quinolin-8-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, or isoquinolin-8-yl, indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, or indol-7-yl, benzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl , benzo[b]thiophene-4-yl, benzo[b]thiophene-5-yl, benzo[b]thiophene-6-yl or benzo[b]thiophene-7-yl, benzoxazolyl-2-yl, benzoxazolyl-4-yl, benzoxazolyl-5-yl, benzoxazolyl-6-yl or benzoxazolyl-7-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl or benzimidazol-7-yl, benzothiazol-2-yl, benzothiazol-4-yl, benzothiazol-5-yl, benzothiazol-6-yl or benzothiazol-7-yl. The heteroaryl group may be mono-, di-, tri- or polycyclic, preferably mono-, di- or tricyclic, more preferably mono- or bicyclic.

[0046] The term "halo" or "halogen" as used herein refers to fluorine, chlorine, bromine, and iodine.

As used herein, the term "isomer" refers to different compounds having the same molecular formula. Additionally, the term "optical isomer" refers to any of the different stereoisomeric configurations, including geometric isomers, that exist for a given compound of the present invention. It is understood that substituents may be attached to chiral centers at carbon atoms. Thus, the present invention encompasses enantiomers, diastereomers, or racemic compounds of a compound. "Enantiomers" refers to a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. Where appropriate, the term is used to refer to a racemic mixture. "Diastereomers" refers to stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Lngold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specifically characterized by R or S. Compounds whose absolute configuration after resolution is unknown can be defined as (+) or (-), depending on the direction (dextrose- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers, and therefore may occur as various enantiomers, diastereomers, and other stereoisomeric forms, which can be defined as (R)- or (S)- in terms of absolute stereochemistry. The present invention is intended to include all possible such isomers, including racemic mixtures, optically pure forms, and mixtures of intermediates. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents can be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents can have a cis- or trans-configuration. The present invention also includes all tautomeric forms. The term "pharmaceutically acceptable salts" as used herein refers to salts that retain the biological efficacy and properties of the compounds of the invention and are not biologically or otherwise undesirable. In many cases, the compounds of the present invention can form acid salts and/or base salts due to the presence of amino and/or carboxyl groups or similar groups thereto (e.g., phenol or hydroxyamide acid). Pharmaceutically acceptable acid addition salts can be formed using inorganic acids and organic acids. Inorganic acids that can form inorganic acid salts can include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Organic acids that can form organic acid salts include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Pharmaceutically acceptable base addition salts can be formed using inorganic bases and organic bases. Inorganic bases that can form inorganic base salts can include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc., with ammonium, potassium, sodium, calcium, and magnesium salts being particularly preferred. Organic bases that can form organic base salts include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, alkaline or acidic moieties by conventional chemical methods. In general, the salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg, or K), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. The reaction is typically carried out in water or an organic solvent or a mixture of the two. Non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are generally preferred. Additional suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing Company, Easton, Pa., (1985), which is incorporated herein by reference. The term "pharmaceutical carrier/excipient" as used herein includes any and all solvents, dispersion media, coating agents, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, drugs, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavorings, dyes, similar substances well known to those skilled in the art, and combinations thereof (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329, incorporated herein by reference). As long as there is no incompatibility with the active ingredient, the use of any conventional carrier in the treatment or pharmaceutical composition is contemplated. The term "therapeutically effective amount" of a compound of the present invention refers to an amount of the compound of the present invention that can induce a biological or medical response to a subject, or alleviate symptoms, slow or delay disease progression, or prevent disease, etc. In a preferred embodiment, an "effective amount" refers to an amount that inhibits or reduces cancer cell proliferation, or inhibits or reduces tumor/cancer growth in vitro or in vivo, or inhibits or reduces a neoplastic disease in a subject, such as a mammal. In another preferred embodiment, it also refers to an amount that reduces the size of a primary tumor/cancer, inhibits the infiltration of cancer cells into peripheral organs, slows or stops tumor metastasis, or alleviates one or more symptoms associated with a tumor or cancer, etc. to at least a certain degree. The term "subject" as used herein refers to an animal. Preferably, the animal is a mammal. The subject also refers to, for example, primates (such as humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In a preferred embodiment, the subject is a human. The term "disorder" or "disease" as used herein refers to any functional disorder or abnormality; an unhealthy physical or mental state. See Dorland's Illustrated Medical Dictionary, (W.B.Saunders Co. 27th ed. 1988). The term "inhibit" as used herein refers to alleviating or inhibiting a specified disorder, symptom or disease, or significantly reducing the baseline activity of a physiological activity or process. In one embodiment, it refers to an effect that can cause a reduction in tumor or cancer growth or a reduction in the size of a tumor or cancer. As used herein, the term "treatment" of any disease or condition refers, in one embodiment, to alleviation of the disease or condition (i.e., preventing or alleviating the development of the disease or at least one of its clinical symptoms). In another embodiment, "treatment" refers to alleviation of at least one physical parameter that may not be perceived by the patient. In another embodiment, "treatment" refers to regulating the disease or condition physically (e.g., stabilizing a perceptible symptom) or physiologically (stabilizing a physical parameter), or both physically and physiologically. In another embodiment, "treatment" refers to preventing or delaying the onset, development, or progression of the disease or condition. As used herein, the terms "a," "an," "the," and similar terms used in the context of this invention (particularly in the context of the claims) should be understood to include both the singular and the plural, unless otherwise specified herein or clearly contradicted by the context. The listing of numerical ranges in this application is intended solely as a shorthand method of describing each individual value falling within the range individually. Unless otherwise specified herein, each individual value is incorporated into this specification as if it were individually recited herein. All methods described herein can be performed in any order as appropriate, unless otherwise specified herein or clearly contradicted by the context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended solely to better illustrate the invention and does not limit the scope of the invention as otherwise claimed. No wording in the specification should be construed as indicating any non-required element as essential to the practice of the invention.

The present invention provides anticancer compounds. Accordingly, in one aspect, the present invention provides a compound of the present invention, which is a compound of formula I or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a mixture of optical isomers:

in:

_R1 is hydrogen, monophosphono, diphosphono or triphosphono;

_R2 is aryl, heteroaryl or alkynyl, wherein the aryl group is optionally substituted with one or two substituents selected from alkoxy, alkylthio or halogen;

_R3 is hydrogen or alkyl.

On the other hand, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a mixture of optical isomers, wherein R ₁ is hydrogen, monophosphinocarboxyl, diphosphinocarboxyl or triphosphinocarboxyl; R ₂ is aryl, which is optionally substituted with a substituent selected from alkoxy, alkylthio or halogen; and R ₃ is hydrogen.

Preferably, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a mixture of optical isomers, wherein R ₁ is hydrogen, R ₂ is phenyl, which is optionally substituted with a substituent selected from (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )alkylthio or halogen; and R ₃ is hydrogen.

On the other hand, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a mixture of optical isomers, wherein R ₁ is hydrogen, monophosphino, diphosphino or triphosphino; R ₂ is aryl, which is optionally substituted with a substituent selected from alkoxy, alkylthio or halogen; and R ₃ is alkyl.

Preferably, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a mixture of optical isomers, wherein R ₁ is hydrogen, R ₂ is phenyl, which is optionally substituted with a substituent selected from (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )alkylthio or halogen; and R ₃ is (C ₁ -C ₄ )alkyl.

In another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a mixture of optical isomers thereof, wherein R ₁ is hydrogen, monophosphono, diphosphono or triphosphono; R ₂ is heteroaryl; R ₃ is hydrogen, provided that R ₂ is not 1,3-oxazol-2-yl, furan-2-yl, 1,2,4-triazin-3-yl, 5,6-dimethyl-1,2,4-triazin-3-yl, 5,6-diphenyl-1,2,4-triazin-3-yl, 1,2,4-oxadiazol-3-yl, 4H-1,2,4-triazol-3-yl, 5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl, 4,5-dihydro-1H-imidazol-2-yl, 4-phenylthiazol-2-yl, 1H-tetrazol-5-yl, 1,4,5,6-tetrahydropyrimidin-2-yl or 9-oxo-9H-indeno[1,2-e][1,2,4]triazin-3-yl.

Preferably, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a mixture of optical isomers, wherein R ₁ is hydrogen, R ₂ is a (5-7) membered heteroaryl group; R ₃ is hydrogen, provided that R ₂ is not 1,3-oxazol-2-yl, furan-2-yl, 1,2,4-triazin-3-yl, 5,6-dimethyl-1,2,4-triazin-3-yl, 5,6-diphenyl-1,2,4-triazin-3-yl, 1,2,4-oxadiazol-3-yl, 4H-1,2,4-triazol-3-yl, 5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl, 4,5-dihydro-1H-imidazol-2-yl, 4-phenylthiazol-2-yl, 1H-tetrazol-5-yl, 1,4,5,6-tetrahydropyrimidin-2-yl or 9-oxo-9H-indeno[1,2-e][1,2,4]triazin-3-yl.

In another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a mixture of optical isomers thereof, wherein R ₁ is hydrogen, monophosphono, diphosphono or triphosphono; R ₂ is heteroaryl; R ₃ is alkyl, provided that R ₂ is not 1,3-oxazol-2-yl, furan-2-yl, 1,2,4-triazin-3-yl, 5,6-dimethyl-1,2,4-triazin-3-yl, 5,6-diphenyl-1,2,4-triazin-3-yl, 1,2,4-oxadiazol-3-yl, 4H-1,2,4-triazol-3-yl, 5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl, 4,5-dihydro-1H-imidazol-2-yl, 4-phenylthiazol-2-yl, 1H-tetrazol-5-yl, 1,4,5,6-tetrahydropyrimidin-2-yl or 9-oxo-9H-indeno[1,2-e][1,2,4]triazin-3-yl.

Preferably, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a mixture of optical isomers, wherein R ₁ is hydrogen, R ₂ is a (5-7) membered heteroaryl group; R ₃ is a (C ₁ -C ₄ ) alkyl group, provided that R ₂ is not 1,3-oxazol-2-yl, furan-2-yl, 1,2,4-triazin-3-yl, 5,6-dimethyl-1,2,4-triazin-3-yl, 5,6-diphenyl-1,2,4-triazin-3-yl, 1,2,4-oxadiazol-3-yl, 4H-1,2,4-triazol-3-yl, 5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl, 4,5-dihydro-1H-imidazol-2-yl, 4-phenylthiazol-2-yl, 1H-tetrazol-5-yl, 1,4,5,6-tetrahydropyrimidin-2-yl or 9-oxo-9H-indeno[1,2-e][1,2,4]triazin-3-yl.

In another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a mixture of optical isomers, wherein _R1 is hydrogen, monophosphono, diphosphono, or triphosphono; _R2 is alkynyl; and _R3 is hydrogen. Preferably, _R1 and _R3 are hydrogen, and _R2 is ( _C2 - _C4 )alkynyl. Further preferably, _R1 and _R3 are hydrogen, and _R2 is ethynyl.

In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a mixture of optical isomers, represented by the following structure or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a mixture of optical isomers:

or a pharmaceutically acceptable salt thereof; or an optical isomer thereof; or a mixture of optical isomers.

The present invention provides compounds of formula I, compositions using the compounds (including pharmaceutically acceptable salts thereof) or pharmaceutically acceptable carriers/excipients thereof, and methods of using the compounds.

Any asymmetric carbon atom in the compounds of the present invention may exist in the (R)-, (S)- or (R,S)-configuration, with the (R)- or (S)-configuration being preferred.

Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the components into the pure geometric or optical isomers, diastereomers, racemic compounds, for example, by chromatography and/or fractional crystallization.

Any resulting racemic compound of the final product or intermediate can be resolved into optical antipodes by known methods, for example, by separating their diastereomeric salts, obtaining and releasing the optically active acid or basic compound using an optically active acid or base. In particular, the hydroxyamide or sulfonamide moiety can therefore be used to resolve the compounds of the invention into optical isomers, for example, by fractional crystallization of a metal (e.g., Zn ²⁺ ) complex formed with an optically active co-ligand, such as L- or D-histidine. The racemic product can also be resolved by chiral chromatography, for example, using high performance liquid chromatography (HPLC) using a chiral adsorbent.

It will be appreciated by those skilled in the art that compounds of the present invention having chiral centers can exist and be isolated in optically active and racemic forms. Some compounds may exist in polymorphic forms. It will be understood that the present invention encompasses any racemic, optically active, polymorphic, or stereoisomeric form of the compounds of the present invention, or mixtures thereof, that possess the beneficial properties described herein, and that it is well known in the art how to prepare optically active forms (e.g., by resolution of racemic forms by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by separation by chromatography using a chiral stationary phase).

The compounds of the present invention are useful for inhibiting tumor/cancer cell growth or cell proliferation and slowing cell cycle progression in tumor/cancer cells. Furthermore, the compounds of the present invention have been shown to induce apoptosis. Inducing apoptosis has been used as an important chemotherapeutic approach for treating cancer/tumors. Therefore, the compounds of the present invention possess important pharmaceutical properties and are useful as antiproliferative and antitumor/anticancer agents.

Thus, in one aspect, the compounds of the present invention can be used to inhibit cell proliferation in vitro and in vivo. In one embodiment, the compounds of the present invention can be used to inhibit cell proliferation in tumor/cancer cells by contacting them with an effective amount of a compound of the present invention. In one embodiment, the compounds of the present invention can be used to treat cell proliferative diseases or conditions. Such diseases can include, but are not limited to, cancer, dysplasia, neoplasia, skin or mucosal warts, autoimmune diseases, fungal conditions, arthritis, transplant rejection, inflammatory bowel disease, medical treatments including, but not limited to, surgery, angioplasty-induced cell proliferation, and the like.

On the other hand, the compounds of the present invention can be used to inhibit tumor/cancer growth in vitro and in vivo. In one embodiment, the compounds can be used to inhibit tumor/cancer cell growth by contacting the tumor/cancer cell with an effective amount of the compounds of the present invention. In one embodiment, the present invention provides methods of using the compounds of the present invention to inhibit tumor or cancer growth. According to the methods of the present invention, treatable tumors or cancers include, for example, tumors or cancers located in the breast, lung, thyroid, lymph nodes, urogenital system, kidney, ureter, bladder, ovary, testicle, prostate, musculoskeletal system, bone, skeletal muscle, bone marrow, gastrointestinal tract, stomach, esophagus, small intestine, colon, rectum, pancreas, liver, smooth muscle, central or peripheral nervous system, brain, spinal cord, nerves, head, neck, ear, eye, nasopharynx, oropharynx, salivary glands, cardiovascular system, oral cavity, tongue, larynx, hypopharynx, soft tissue, skin, cervix, anus, retina and/or heart of a mammal.

In one embodiment, the present invention provides a method of treating a neoplastic disease or tumor/cancer using the compounds of the present invention. As used herein, the term "neoplastic disease" refers to any benign (non-cancerous) or malignant (cancerous) abnormal growth of cells or tissues. According to the methods of the present invention, neoplastic diseases that can be treated include, for example, tumors from acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, cutaneous T-lymphocytic tumors, hairy cell leukemia, and non-Hodgkin's lymphoma.

Furthermore, the present invention provides:

- a compound of the invention for use as a medicament;

- Use of the compounds of the present invention in the preparation of a medicament for inhibiting cell proliferation or slowing down cell cycle progression in tumor/cancer cells;

- Use of a compound of the present invention in the preparation of a medicament for treating a cell proliferative disease or disorder;

- Use of the compounds of the present invention in the preparation of medicaments for inhibiting tumor/cancer growth in vitro and in vivo;

- Use of the compounds of the present invention in the preparation of medicaments for treating tumor diseases;

- Use of the compound of the present invention in preparing a medicament for treating tumors or cancers.

Methods for preparing compounds of formula I are provided as further embodiments of the present invention and are illustrated by the following steps, wherein the formula groups have the same meanings as defined above unless otherwise indicated.

Compounds of formula I can be prepared as follows.

Chemical methods

Suzuki-Miyaura cross-coupling reaction of 7-iodotuberculocidin 1 (Scheme 1, Table 1) {for preparation, see Seela, F.; Ming, X. Tetrahedron 2007, 63, 9850-9861} with corresponding aryl and heteroaryl boronic acids under Shaughnessy aqueous conditions afforded the desired 7-substituted-7-deazaadenosines 2a-n.

Solution 1

Table 1. Suzuki cross-coupling reaction

It should be noted that the N-protecting groups in the starting pyrrolylboronic acid were removed under the coupling conditions (Nos. 11 and 12). Due to the low yield of the Suzuki reaction (No. 13), the pyrazol-4-yl derivative 2m was alternatively prepared by Stille reaction of compound 1 with 1-dimethylaminosulfonyl-4-tributylstannylpyrazole {for preparation, see US 2004/0157892 A1}, followed by removal of the dimethylaminosulfonyl group under acidic conditions (1 M aq HCl), with an overall yield of 68% after recrystallization.

The ethynyl derivative 2o was prepared by the Sonogashira reaction of compound 1 with trimethylsilyl acetylene (Scheme 2) and protodesilylation of the TMS-ethynyl derivative 3 under basic conditions. The triazolyl derivative 2p was prepared by a copper-mediated [3+2] cycloaddition reaction of the ethynyl derivative 2o with trimethylsilyl azide {Jin, T.; Kamijo, S.; Yamamoto, Y. Eur. J. Org. Chem. 2004, 3789-3791}.

Option 2

Imidazole and thiazolyl derivatives 2q-s were prepared by Negishi or Stille cross-coupling reactions of per-O-silylated 7-iodotuberculocidin 4 with the corresponding protected organometallic reagents (Scheme 3, Table 2), followed by deprotection under acidic conditions.

reaction

Option 3

Table 2. Cross-coupling and deprotection

Analogs 2'-C-methyl-7-substituted-7-deazapurine inosines were prepared by aqueous Suzuki cross-coupling of 2'-C-methyl-7-iodo-7-deazaadenosine 6 (Scheme 4) with boronic acid to afford products 7a-i.

Option 4

The synthesis of the desired starting material, 2'-C-methylinosine 6, began with acid-promoted glycosylation of 6-chloro-7-iodo-deazapurine 8 (Scheme 5) with per-O-benzoyl-2-C-methyl-β-D-ribofuranose 9 to afford protected 2'-C-methylinosine 10 in 48% yield. Heating compound 10 with aqueous ammonia afforded the desired free nucleoside 6 in 69% yield.

Option 5

To synthesize 7-substituted-7-deazaadenosine 5'-O-triphosphates and 5'-O-monophosphates, 7-iodo-7-deazaadenosine 5'-O-triphosphates 11 and 5'-O-monophosphates 12 were subjected to Suzuki reactions with boronic acids (Scheme 6, Table 3) to afford triphosphates 13a-f and monophosphates 14a-f. The required starting iodotriphosphates and monophosphates 11 and 12 were readily prepared by phosphorylation of 7-iodotuberculocidin 1.

Option 6

Table 3. Cross _- coupling reactions of 11 and 12

Salts and hydrates

The compositions of the present invention optionally include salts of the compounds described herein, particularly pharmaceutically acceptable non-toxic salts containing, for example, Na ⁺ , Li ⁺ , K ⁺ , Ca ⁺² and Mg ⁺² . The salts may include those derived from combinations of suitable cations such as alkali metal and alkaline earth metal ions or ammonium and quaternary ammonium ions with acidic anions (typically carboxylic acids). If a water-soluble salt is desired, a monovalent salt is preferred. Some salts can be used as intermediates for purifying compounds of Formula I or for preparing other salts.

Metal salts are typically prepared by reacting metal hydroxides with the compounds of the present invention. Examples of metal salts that can be prepared in this manner are salts containing Li ⁺ , Na ⁺ , and K ⁺ . Poorly soluble metal salts can be precipitated from more soluble salts by adding a suitable metal compound. In addition, salts can also be formed by the addition of certain organic and inorganic acids, such as HCl, _HBr , _H2SO4 , _H3PO4 , or organic sulfonic acids, to a basic center (usually an amine) or acidic group. Finally, it should be understood that the compositions herein include the compounds _of the present invention in unionized form, in zwitterionic form, and in the form of hydrates formed in combination with a stoichiometric amount of water.

Also included within the scope of the invention are salts of the parent compound with one or more amino acids. Any of the amino acids listed above are suitable, particularly those naturally occurring amino acids found as components of proteins, although the amino acids will typically be those with basic or acidic side chains such as lysine, arginine or glutamic acid, or with neutral groups such as glycine, serine, threonine, alanine, isoleucine or leucine.

pharmaceutical preparations

The compounds of the present invention are formulated with conventional carriers and excipients that can be selected according to conventional practice. Tablets may contain excipients, glidants, fillers, binders, etc. Aqueous formulations are prepared in a sterile form and, when administered by other parenteral administration methods, are generally isotonic. All formulations optionally contain various excipients such as those described in the Handbook of Pharmaceutical Excipients (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrins, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, etc. The pH range of the formulation is from about 3 to about 11, but is typically from about 7 to 10.

When the active ingredient can be administered alone, it is preferably presented in the form of a pharmaceutical formulation. The formulations of the present invention for veterinary and human use comprise at least one of the above-mentioned active ingredients and one or more acceptable carriers and optionally other therapeutic ingredients. The carrier must be "acceptable" in the sense that it must be compatible with the other ingredients in the formulation and physiologically non-toxic to the recipient.

Formulations include those suitable for the aforementioned routes of administration. These formulations can generally be presented in unit dosage form and can be prepared by any method well known in the pharmaceutical art. The techniques and formulations can generally be found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). The method comprises the step of mixing the active ingredient with a carrier that constitutes one or more auxiliary ingredients. The formulation is generally prepared by uniformly and densely mixing the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, molding the product.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, lozenges or tablets containing a predetermined amount of the active ingredient; powders or granules; solutions or suspensions in water or non-aqueous liquids; or oil-in-water liquid emulsions or water-in-oil liquid emulsions. The active ingredient may also be administered as a bolus, electuary or paste.

Tablets are optionally compressed or molded with the aid of one or more auxiliary ingredients. Compressed tablets can be formed by pressing the active ingredient into a free-flowing form such as a powder or granule in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersant. Molded tablets can be formed by molding a mixture of powdered active ingredients moistened with an inert liquid diluent in a suitable machine. Tablets can optionally be coated or scored, and can optionally be formulated to achieve slow or controlled release of the active ingredient.

For administration to the eye or other external tissues, such as the mouth and skin, the formulation is preferably administered as a topical ointment or cream containing the active ingredient in an amount of, for example, 0.075 to 20% w/w (including a range of active ingredient between 0.1% and 20% in increments of 0.1% w/w, such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w, and most preferably 0.5 to 10% w/w. When formulated as an ointment, the active ingredient may be used with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated as an emulsion with an oil-in-water emulsion base.

If desired, the aqueous phase of the emulsion may include, for example, at least 30% w/w of a polyol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG 400), and mixtures thereof. Topical formulations may desirably include compounds that promote the absorption or penetration of the active ingredient into the skin or other affected area. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs.

The oil phase of the emulsion of the present invention can be composed of known ingredients in a known manner. When the oil phase contains only an emulsifier, it is ideally composed of at least one emulsifier and a fat or oil or a mixture of a fat and an oil. Preferably, the oil phase contains a hydrophilic emulsifier with a lipophilic emulsifier as a stabilizer. It is also preferred to contain both oil and fat. The emulsifier, with or without a stabilizer, constitutes a so-called emulsifying wax, which, together with the oil and fat, constitutes a so-called emulsifying ointment base, which forms the oily dispersed phase of the cream.

Suitable purgatives and emulsion stabilizers for use in the formulations of the present invention include cetearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate.

The selection of oil or fat that is applicable to preparation of the present invention is based on realizing desired cosmetic properties.Emulsifier is preferably non-greasy, unpainted and washable product, has suitable denseness to avoid leaking from conduit or other container.Can use propylene glycol diester of straight or branched list or dibasic alkyl ester such as two-isoadipic acid ester, isocetyl stearate, coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or be called Crodamol CAP, the latter three are preferred esters.They can be used alone or in combination, and this depends on desired characteristic.Alternatively, also can use high melting point lipid such as white soft paraffin and/or liquid paraffin or other mineral oil.

The pharmaceutical preparation according to the present invention comprises one or more compounds of the present invention and one or more pharmaceutical carriers or excipients and optional other therapeutic drugs. The pharmaceutical preparation containing the active ingredient can be in any form suitable for the intended method of administration. When used for oral administration, it can be prepared into tablets, lozenges, pastilles, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard capsules or soft capsules, syrups or elixirs. The composition for oral administration can be prepared according to any method of pharmaceutical composition preparation well known in the art, and in order to obtain a palatable product, the composition can contain one or more adjuvants, including sweeteners, flavorings, coloring agents and preservatives. Tablets containing the active ingredient and non-toxic pharmaceutical excipients suitable for preparing tablets are acceptable. The excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate or sodium phosphate; granulating agents and disintegrants such as corn starch or alginic acid; binders such as cellulose, microcrystalline cellulose, starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or coated by known techniques, including microencapsulation to delay disintegration and absorption in the gastrointestinal tract, thereby achieving a sustained action over a longer period of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate, alone or in admixture with paraffin wax, may be used.

Oral preparations may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent such as calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oily base such as peanut oil, liquid paraffin or olive oil.

The aqueous suspensions of the present invention contain the active material mixed with excipients suitable for preparing aqueous suspensions. The excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic, and dispersants or wetting agents such as naturally occurring phospholipids (e.g., lecithin), condensation products of olefin oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain fatty alcohols (e.g., heptadecacyclohexadecanol), condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweeteners such as sucrose or saccharin.

Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. Oral suspensions can contain thickeners such as beeswax, hard paraffin or cetyl alcohol. For example, the above-mentioned sweeteners and flavorings can be added to obtain a palatable oral preparation. These compositions can be preserved by adding antioxidants such as ascorbic acid.

The dispersible powders and granules of the present invention are suitable for preparing aqueous suspensions by mixing the active ingredient with a dispersant or wetting agent, a suspending agent, and one or more preservatives by adding water. Examples of suitable dispersants or wetting agents and suspending agents are as described above. In addition, excipients such as sweeteners, flavorings, and coloring agents may also be present.

The pharmaceutical composition of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil such as olive oil or peanut oil, a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include naturally occurring gums such as gum arabic and tragacanth, naturally occurring phospholipids such as soy lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsion can also contain sweeteners and flavorings. Syrups and elixirs can be formulated using sweeteners such as glycerol, sorbitol, or sucrose. The formulation can also contain a wetting agent, a preservative, a flavoring, or a coloring agent.

The pharmaceutical composition of the present invention may be in the form of a sterile injectable formulation such as sterile water for injection or an oily suspension. The suspension may be prepared according to known techniques using the appropriate dispersants or wetting agents and suspending agents mentioned above. The sterile injectable formulation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent such as 1,3-butanediol or prepared as a lyophilized powder. Acceptable vehicles and solvents that may be used include water, Grignard solution, and isotonic chlorinated vehicles. For these purposes, any mild fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may also be similarly used to prepare injections.

The amount of active ingredient mixed with carrier material to prepare a single dosage form can vary depending on the host to be treated and the specific mode of administration. For example, a delayed-release formulation intended for oral administration to a human can contain about 1-1000 mg of active substance, mixed with a suitable and conventional amount of carrier material, the latter typically accounting for about 5% to about 95% (weight:weight) of the total composition. The pharmaceutical composition can be prepared into a dosage that is convenient for measurement. For example, an aqueous solution intended for intravenous infusion can contain about 3-500 μg of active ingredient per milliliter of solution, so that an appropriate volume can be infused at a rate of about 30 mL/hour.

Formulations suitable for administration to the eye include eye drops in which the active ingredient is dissolved or suspended in a carrier suitable for the active ingredient, particularly an aqueous solvent. The active ingredient is preferably present in the formulation at a concentration of 0.5 to 20%, advantageously 0.5 to 10%, particularly about 1.5% w/w.

Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Formulations for rectal administration may be presented as a suppository with a suitable base containing for example cocoa butter or a salicylate.

Preparations suitable for intrapulmonary or intranasal administration have, for example, a particle size of 0.1-500 microns (including a particle size of 0.1-500 microns, increments such as 0.5, 1, 30 microns, 35 microns, etc.), which are rapidly inhaled through the nasal passages or inhaled by the mouth to reach the alveolar sacs. Suitable preparations include aqueous or oily solutions of the active ingredient. Preparations suitable for aerosol or dry powder administration can be prepared according to conventional methods and can be delivered together with other therapeutic agents such as compounds for the treatment or prevention of cancerous infections described below.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing, in addition to the active ingredient, suitable amounts of carriers known in the art.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats and solutes that render the formulation isotonic with the blood of the recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents.

The preparation can be presented in unit dose or multidose containers such as sealed ampoules and vials and can be stored under freeze-drying (lyophilization) conditions, requiring only the addition of a sterile liquid carrier such as water for injection before use. Extemporaneous injection solutions and suspensions are prepared from the aforementioned sterile powders, granules, and tablets. Preferred unit dose formulations are those containing a daily dose or unit sub-daily dose or an appropriate number of active ingredients thereof.

It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example, formulations suitable for oral administration may include flavoring agents.

The present invention further provides a veterinary composition comprising at least one of the above active ingredients and the aforementioned veterinary carrier.

Veterinary carriers are materials that can be used for the purpose of administering the composition and can be solid, liquid or gaseous, which are inert and acceptable in the field of veterinary medicine and are compatible with the active ingredient. These veterinary compositions can be administered orally, parenterally or by other desired routes.

The compounds of the present invention can also be formulated to control the release of the active ingredient so that it can be administered more frequently, or to improve the pharmacokinetics or toxicity profile of the active ingredient. Therefore, the present invention also provides a composition comprising one or more compounds of the present invention for sustained or controlled release.

The effective dose of active ingredient depends at least on the nature of the condition to be treated, toxicity, whether the compound is used to prevent (low dose) or treat active cancerous infection, delivery method and pharmaceutical formulation, which can be determined by a clinician using conventional dose expansion studies. It can be expected that it is from about 0.0001 to about 100 mg/kg body weight/day. Typically, it is from about 0.01 to about 10 mg/kg body weight/day. More typically, it is from about 0.01 to about 5 mg/kg body weight/day. More typically, it is from about 0.05 to about 0.5 mg/kg body weight/day. For example, for an adult of about 70 kg body weight, its daily candidate dose is 1 mg to 1000 mg, preferably 5 mg to 500 mg, and can take single dose or multiple dose form.

Route of administration

One or more compounds of the present invention (referred to herein as active ingredients) are administered by any route suitable for the condition to be treated. Suitable routes include oral, rectal, intranasal, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural) administration. It will be appreciated that the preferred route depends, for example, on the condition of the recipient. An advantage of the compounds of the present invention is that they are orally bioavailable and can therefore be administered orally.

Combination therapy

The active ingredients of the present invention can also be used in combination with other active ingredients. The combination is selected based on the condition to be treated, the cross-reactivity of the ingredients, and the pharmacological properties of the combination. For example, in the treatment of cancer, the composition of the present invention can be combined with other therapeutic drugs. The second chemotherapeutic drug can be a compound with biological activity against one or more forms of cancer.

Any of the compounds of the present invention can also be combined with one or more other active ingredients in a single dosage form for simultaneous or sequential administration to a cancer patient. The combination therapy can be administered according to a simultaneous or sequential dosing regimen. When administered sequentially, the combination can be administered twice or more. The second and third active ingredients in the combination can have chemotherapeutic activity and include any of the other chemotherapeutic drugs described herein. Exemplary active ingredients that can be administered in combination with the compounds of the present invention are described below.

Suitable other chemotherapeutic drugs include, for example: (a) anthracycline antibiotics (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin, and mitoxantrone); (b) other DNA intercalators (e.g., actinomycin C, D, B, etc.; podophyllotoxin and etoposide (etoposide, teniposide, ctoposide)); (c) alkylating agents (e.g., nitrogen mustard, melphalan, cyclophosphamide, chlorambucil, ifosfamide, carmustine, lomo (d) hormonal agents (e.g., antiestrogen/estrogen antagonists (tamoxifen and other SERMs); LHRH agonists and antagonists (leuprolide acetate, goserelin, abarelix); aromatase inhibitors and antiandrogens); (e) chemopreventive agents (e.g., NSAIDs and cis-retinoids); and (f) cell cycle chemopreventive agents.

Alternatively, the other chemotherapeutic drugs may include, for example, antitumor drugs. Representative antitumor drugs include, for example, adjuvant therapy drugs (e.g., levamisole, gallium nitrate, granisetron, sargramostim strontium chloride-89, filgrastim, pilocarpine, dexrazoxane, and ondansetron); androgen inhibitors (e.g., flutamide and leuprorelin acetate); antibiotic derivatives (e.g., doxorubicin, bleomycin sulfate, daunorubicin, dactinomycin, and idarubicin); antiestrogens (e.g., tamoxifen citrate and its analogs, and nonsteroidal antiestrogens such as toremifene, droloxifene, and raloxifene); antimetabolites (e.g., fludarabine phosphate, recombinant interferon α-2b, methotrexate sodium, plicamycin, mercaptopurine, and thioguanine); cytotoxic agents (e.g., doxorubicin, carmustine [BCNU], lomustine [CCNU], cytarabine USP, cyclophosphamide, estramustine sodium phosphate, altretamine, hydroxyurea, ifosfamide, procarbazine, mitomycin, busulfan, cyclophosphamide, mitoxantrone, carboplatin, cisplatin, recombinant interferon alfa-2a, paclitaxel, teniposide, and streptozocin); hormones (e.g., medroxyprogesterone acetate, estradiol, megestrol acetate, octreotide acetate, diethylstilbestrol diphosphate, testolactone, and goserelin acetate); immunomodulators (e.g., aldesleukin); nitrogen mustard derivatives (e.g., melphalan, chlorambucil, mechlorethamine, and thiotepa); and steroids (betamethasone sodium phosphate and betamethasone acetate).

Suitable other chemotherapeutic drugs include alkylating agents, antimitotic agents, plant alkaloids, biologics, topoisomerase I inhibitors, topoisomerase II inhibitors and synthetics.

Representative alkylating agents include, for example, leucine oncolysin, AZQ, BCNU, busulfan, bisulphan, carboxyplatinum phthalate, CBDCA, CCNU, CHIP, chlorambucil, chlorozotocin, cisplatin, chloroethenol, cyanomorpholinodoxorubicin, ethylene glycol methanesulfonate, cyclophosphamide, dehydrodulcitol, fludopane, hepsulfam, hydantoin, ifosfamide, melphalan, methyl CCNU, mitomycin C, mitozolamide, mechlorethamine, PCNU, piperazine, diketopiperazine, pipobroman, porfiromycin, spiromustine, streptozotocin, tiroxilon, tetraplatin, thiotepa, troxantamide, uracil, and Yoshi-864.

Representative antimitotic agents include, for example, allocolchicine, halichondrin B, colchicine, colchicine derivatives, dolastatin 10, maytansine, rhizoxin, paclitaxel derivatives, paclitaxel, thiocolchicine, tritylcysteine, vinblastine sulfate, and vincristine sulfate.

Representative plant alkaloids include, for example, actinomycin D, bleomycin, L-asparaginase, idarubicin, vinblastine sulfate, vincristine sulfate, chlortetracycline, mitomycin, daunorubicin, VP-16-213, VM-26, vinorelbine, and taxotere.

Representative biologics include, for example, interferon alpha, BCG, G-CSF, GM-CSF, and interleukin-2.

Representative topoisomerase I inhibitors include, for example, camptothecin, camptothecin derivatives, and morpholinodoxorubicin.

Representative topoisomerase II inhibitors include, for example, mitoxantrone, aminafide, m-AMSA, anthrapyrazole derivatives, pyrazoline acridine, bisantrene HCL, daunorubicin, deoxydoxorubicin, menocril, N,N-dibenzyldaunorubicin, thiothrene, daunorubicin phenylhydrazone, VM-26, and VP-16.

Representative synthetic agents include, for example, hydroxyurea, procarbazine, o,p'-DDD, dacarbazine, CCNU, BCNU, cisplatin, mitoxantrone, CBDCA, levamisole, altretinoin, all-trans retinoic acid, carmustine wafers, and porfimer sodium.

Alternatively, the other chemotherapeutic drugs may include, for example, tubulin-binding drugs and drugs that affect tubulin dynamics and function, including various drugs that are chemically unrelated to vinca alkaloids and taxanes (e.g., CP-248 (a derivative of ixesulin) and ILX-651). These drugs have characteristic effects on G2M-phase cells and may therefore have functionally independent effects on cells in G1 and/or S phase.

Alternatively, the other chemotherapeutic drugs may include, for example, selective apoptotic anticancer drugs (SAANDs), including sulindac, sulfamethoxazole, CP-461, CP-248, and related sulindac derivatives that inhibit one or more isozymes of cyclic GMP phosphodiesterase (cGMP PDE) 1, 2, or 5.

Alternatively, the other chemotherapeutic drugs can include, for example, drugs that inhibit proteosomes (bortezomib or Velcade). Proteosomes degrade many ubiquitinated proteins that have been marked as active. Ubiquitinated proteins include many key cell cycle regulatory molecules and molecules that regulate apoptosis at specific stages of the cell cycle. When proteosomes can degrade proteins throughout the cell cycle, the proteins that can be degraded by proteosomes include some of the most critical cell cycle regulatory proteins. The so-called "cell cycle active rationale" can be used to treat various diseases, including cancer, inflammatory/autoimmune diseases, and neurological diseases involving cell cycle disorders and/or apoptosis.

Alternatively, the other chemotherapeutic agents may include, for example, drugs that inhibit heat shock protein 90 (HSP90), a chaperone involved in the degradation of 'visit' proteins in the ubiquitin-mediated proteosome pathway. Several drugs appear to exert their anti-tumor effects by inhibiting the intrinsic ATPase activity of HSP90, leading to degradation of HSP90 'visit' proteins via the ubiquitin proteosome pathway. Specific examples include geldanamycin, 17-allylaminogeldanamycin, 17-demethoxygeldanamycin, and radicicol.

Suitable cell cycle-dependent biological agents or biological agents that rely on a dosing regimen include drugs, proteins or other molecules that block, hinder or otherwise interfere with cell cycle progression in the G1 phase, G1/S critical phase, S phase, G2/M critical phase or M phase of the cell cycle. These drugs rely on the cell cycle or dosing regimen.

Specifically, suitable cell cycle-dependent biologics or biologics that rely on a dosing regimen include:

(1) Uridine analogs, thymidine analogs, and uridine and thymidine analogs. These compounds act on the S phase of tumor cells and possibly neurovascular epithelial cells. These compounds include, for example, 5-fluorodeoxyuridine (fluorouridine, FUDR); 5-fluorouracil (5-FU); prodrugs of 5-FU (e.g., capecitabine, 5'-deoxy-5-fluorouridine, tegafur, flucytosine); bromodeoxyuridine; and iodideoxyuridine.

(2) Fluoropyrimidine modulators. These compounds act on the S phase of tumor cells and possibly neurovascular epithelial cells. These compounds include, for example, leucovorin, methotrexate, and other folates; levamisole; acivicin; phosphonoacetyl-L-aspartate (PALA); brequinar; 5-ethynyluracil; and uracil.

(3) Cytosine analogs and cytidine nucleoside analogs. These compounds act on the S phase of tumor cells and possibly neurovascular epithelial cells. These compounds include, for example, cytarabine (Ara-C, cytarabine); gemcitabine (2',2'-difluorodeoxycytidylic acid); and 5-azacytidine nucleoside.

(4) Purine analogs and purine nucleoside analogs. These compounds act on the S phase of tumor cells and possibly neurovascular epithelial cells. These compounds include, for example, 6-thioguanine; 6-mercaptopurine; azathioprine; vidarabine (Ara-A); 2',2'-difluorodeoxyguanosine; deoxycoformycin (pentostatin); cladribine (2-chlorodeoxyadenosine); and adenosine deaminase inhibitors.

(5) Antifolates. These compounds act on the S phase of tumor cells and possibly neurovascular epithelial cells. These compounds include, for example, methotrexate; aminopterin; trimetrexate; edatrexate; N10-propargyl-5,8-dideazafolate (CB3717); ZD1694, 5,8-dideazaisofolate (IAHQ); 5,10-dideazatetrahydrofolate (DDATHF); 5-deazafolate (an effective substrate for FPGS); PT523 (Nα-(4-amino-4-deoxypteroyl)-Nδ-semiphthaloyl-L-ornithine); 10-ethyl-10- Deazaaminopterin (DDATHF, lometrexol); pirtrexine; 10-EDAM; ZD1694; GW1843; PDX (10-propargyl-10-deazaaminopterin); multi-targeted folate (i.e., LY231514, pemetrexed), any folate-based inhibitor of thymidine nucleotide synthase (TS); any folate-based inhibitor of dihydrofolate reductase (DHFR); any folate-based inhibitor of aglyconamide nucleotide transformylase (GARTF); any inhibitor of folate polyglutamate synthase (FPGS); and any folate-based inhibitor of GAR formyltransferase (AICAR transformylase).

(6) Other antimetabolites. These compounds act on the S phase of tumor cells and possibly neurovascular epithelial cells. These compounds include, for example, hydroxyurea and polyamines.

(7) S-phase specific radioactive toxins (deoxythymidine analogs). These compounds act on the S-phase of all cells undergoing DNA synthesis. They infiltrate chromosomal DNA during the S-phase. These compounds include, for example, [125I]-iododeoxyuridine; [123I]-iododeoxyuridine; [124I]-iododeoxyuridine; [80mBr]-iododeoxyuridine; [131I]-iododeoxyuridine; and [211At]-astatine-deoxyuridine.

(8) Inhibitors of enzymes involved in deoxyribonucleoside/deoxynucleotide metabolism. These compounds act on the S-phase of tumor cells and possibly neurovascular epithelial cells. These compounds include, for example, thymidine synthase (TS) inhibitors; dihydrofolate reductase (DHFR) inhibitors; glucosamine nucleotide transformylase (GARTF) inhibitors; folic acid polyglutamate synthase (FPGS) inhibitors; GAR formyltransferase (AICAR transformylase) inhibitors; DNA polymerase (DNA Pol; for example, aphidomycin) inhibitors; ribonucleotide reductase (RNR) inhibitors; thymidine kinase (TK) inhibitors; and topoisomerase I inhibitors (for example, camptothecin, irinotecan [CPT-11, camptosar], topotecan, NX-211 [lutotecan], rubitecan, etc.).

(9) DNA chain-terminating nucleoside analogs. These compounds act specifically on cells in the S-phase and then infiltrate into chromosomal DNA during the S-phase, terminating the growing DNA chain. These compounds include, for example, acyclovir; abacavir; famciclovir; zidovudine (AZT); didanosine (ddI, dideoxycytidine); zalcitabine (ddC); stavudine (D4T); lamivudine (3TC); any 2',3'-dideoxynucleoside analog; and any 2',3'-dideoxynucleoside analog that terminates DNA synthesis. These compounds include, for example, cell cycle inhibitors of growth factor receptor tyrosine kinases that regulate progression of the cell cycle at the G1-phase, G1/S critical or S-phase (e.g., EGF receptor, HER-2neu/c-erbB2 receptor, PDGF receptor, etc. [e.g., trastuzumab, iressa, erbitux, tarceva]); non-receptor tyrosine kinase inhibitors (e.g., c-src family of tyrosine kinases [e.g., Gleevec]); serine-threonine kinase inhibitors that regulate progression of the cell cycle at the G1-phase, G1/S critical or S-phase (e.g., G1-dependent cyclin kinases, G1/S-dependent cell cycle inhibitors). Cyclin kinases and S-dependent cyclin kinases [e.g., CDK2, CDK4, CDK5, CDK6]; mitogen-activated kinases; MAP kinase signaling pathways); inhibitors of G1-phase, G1/S critical, or S-phase cell cycle proteins [e.g., cyclins D1, D2, D3, E, and A]); inhibitors of G-proteins and cGMP phosphodiesterases that positively regulate progression through the cell cycle at G1-phase, G1/S critical, or S-phase; drugs that inhibit the recruitment of immediate-early response transcription factors (e.g., N-terminal c-jun kinase, c-myc); and drugs that inhibit proteosomes that degrade 'reverse' cell cycle regulatory molecules (e.g., p53, p27/Kip1 [e.g., bortezomib]).

(10) Cytokines, growth factors, anti-angiogenic factors, and other proteins that inhibit cell cycle progression at the G1-phase or G1/S critical phase of the cell cycle. These compounds act at the G1, G1/S, or S-phase of tumor cells and, in some cases, neurovascular epithelial cells. These compounds include, for example, interferons; interleukins; somatostatin and somatostatin analogs (octreotide, sandostatin LAR); and many anti-angiogenic factors that inhibit the proliferation of epithelial cells at the G1-phase or G1/S phase of the cell cycle.

(11) Drugs and compounds that inhibit cell cycle progression at the G2/M critical or M-phase of the cell cycle. These compounds act on tumor cells and, in some cases, neurovascular epithelial cells at the G2/M critical or M-phase. These compounds include, for example, (a) microtubule-targeting drugs - taxanes (e.g., Taxol, Taxotere, epothilones and other taxanes and derivatives); (b) microtubule-targeting drugs - vinca alkaloids (e.g., vinblastine, vincristine, vindesine; vinflunine, vinorelbine, vinblastine, nocodazole and colchicine); (c) microtubule-targeting drugs - others (e.g., estramustine, CP-248 and CP-461); (d) serine-threonine kinase inhibitors that regulate cell cycle G2/M critical or M-phase progression (e.g., G2/M-dependent cyclin kinase (e.g., CDC2) inhibitors; M-phase cyclin (e.g., cyclin B) inhibitors, and any drug that blocks, impedes or otherwise interferes with cell cycle progression at the G2/M critical or M-phase of the cell cycle.

(12) Radiopharmaceuticals that can be used for radiotherapy and/or diagnosis. One class of suitable radioisotopes decays by a nuclear fission process known as the "Auger process" or "Auger cascade." Auger-emitting isotopes emit short-lived electrons that can effectively cleave double-stranded DNA. Suitable Auger-emitting radioisotopes include, for example, 125-iodine, 123-iodine, and 80m-bromide. Suitable corresponding halogenated pyrimidine and purine nucleosides include, for example, 5-125-iodine-2'-deoxyuridine, 5-123-iodine-2'-deoxyuridine, 5-80m-bromide-2'-deoxyuridine, and 8-80m-bromide-2'-guanidine.

Growth factors

Many growth factors and cytokines can stimulate malignant cells to cross specific sites in the cell cycle. For example, G-CSF or GM-CSF can stimulate leukemic blasts in acute myeloid leukemia to cross the G1/S critical point. This increases the sensitivity of cells to cell cycle-specific drugs such as cytarabine. Similar protocols have been tested using EGF and cytotoxic drugs for solid tumors. In order to respond to growth factors, cells must be in a specific phase of the cell cycle, such as the G1/S critical point. The continued presence of growth factors may be beneficial because at any given time, only blast subtypes are located in G1/S. Therefore, growth factors act in a cell-specific manner. Similar logic can be applied to the use of hematopoietic growth factors to treat neutropenia, anemia, and thrombocytopenia.

Thus, peptide/protein growth factors can be used in the present invention to promote the survival of normal non-malignant cell lines. One of the benefits of using such substances is the ability to protect proliferating cells in the bone marrow, skin, oral and gastrointestinal mucosa, and hair follicles.

Examples of substances that fall into the above categories include, for example, hematopoietic growth factors: G-CSF, GM-CSF, erythropoietin, thrombopoietin and physiologically active derivatives of these peptides; keratinocyte growth factor (KGF) for mucositis; B-lymphocyte stimulating peptide (BLys); platelet-derived growth factor (PDGF), epidermal growth factor (EGF), TGF-α and related growth factors; interleukins (e.g., IL-2, IL-6); other cytokines, growth factors and peptides that stimulate the proliferation of non-malignant cells that need protection.

Therapeutic growth factors/cytokines

Some therapeutic growth factors/cytokines can inhibit the proliferation of cancer cells and/or neurovascular cells at specific stages of the cell cycle. For example, interferon, somatostatin, octreotide and its analogs, thrombospondin, and troponin-I inhibit the proliferation of neurovascular epithelial cells by slowing the rate at which cells enter the S-phase. Thus, any one or more of these substances can be used in the present invention.

Combination therapy can provide "synergy" and "synergistic effects," i.e., the effect obtained when the active ingredients are taken together is greater than the sum of the effects of the compounds taken separately. A synergistic effect can be obtained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered in alternating or parallel doses as separate formulations; or (3) by some other dosing regimen. When delivered in alternation therapy, a synergistic effect can be obtained when the compounds are administered or delivered sequentially, for example, as separate tablets, pills, or capsules or as different injections in separate syringes. Generally, in alternation therapy, effective doses of each active ingredient are administered sequentially, i.e., serially, whereas in combination therapy, effective doses of two or more active ingredients are administered simultaneously.

Metabolites of the compounds of the present invention

Also within the scope of the present invention are the in vivo metabolic products of the compounds described herein. These products can be obtained, for example, by oxidation, reduction, hydrolysis, amidation, esterification, phosphorylation, or the like of the administered compound, primarily by enzymatic methods. Thus, the present invention encompasses compounds produced after contacting a compound of the invention with a mammal for a period of time sufficient to produce its metabolites. These products are typically identified by preparing a radiolabeled (e.g., ^C₁₄ or ^H₃ ) compound of the invention, administering it to cultured cells in vitro or injecting it into an animal, such as a rat, mouse, guinea pig, monkey, or human, at a detectable dose (e.g., greater than about 0.5 mg/kg), allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours), and then isolating the conversion products from urine, blood, or other biological samples. These products are readily isolated because they are labeled (other methods include using antibodies capable of binding to antigenic determinants present in the metabolites). Metabolite structures are determined by conventional means, such as MS or NMR analysis. Metabolite analysis is typically performed in the same manner as conventional drug metabolism studies familiar to those skilled in the art. The conversion products, so long as they are not otherwise found in vivo, can be used in diagnostic assays for therapeutic doses of the compounds of the invention, even if they themselves do not possess anticancer activity.

Formulas and methods for determining the stability of a compound in a user's gastrointestinal secretions are known. A compound is considered stable in the gastrointestinal tract if less than about 50 mole percent of the protecting groups are deprotected after incubation in the user's intestinal or gastric fluids at 37°C for one hour. Simply because a compound is stable in the gastrointestinal tract, it does not necessarily mean that it cannot be hydrolyzed in vivo.

In one embodiment of the present invention, the compound is in an isolated and purified form. The term "isolated and purified" generally refers to a compound that is substantially free of biological matter (e.g., blood, tissue, cells, etc.). In a specific embodiment of the present invention, the term refers to a compound of the present invention or a conjugate that is at least about 50 wt.% free of biological matter; in another specific embodiment, the term refers to a compound of the present invention or a conjugate that is at least about 75 wt.% free of biological matter; in another specific embodiment, the term refers to a compound of the present invention or a conjugate that is at least about 90 wt.% free of biological matter; in another specific embodiment, the term refers to a compound of the present invention or a conjugate that is at least about 98 wt.% free of biological matter; and in another embodiment, the term refers to a compound of the present invention or a conjugate that is at least about 99 wt.% free of biological matter. In another specific embodiment, the present invention provides a compound of the present invention or a conjugate that is obtained by synthetic preparation (e.g., in vitro).

The anti-cancer activity of a compound can be determined using pharmacological models well known in the art, for example, using Test A or Test B described below.

Test A: Cell culture assay for cytokine inhibition of solid tumor cell lines ( _CC50 )

This assay is based on the quantification of cell populations by colorimetric detection of cell-associated proteins. It relies on the ability of thiocyanate B (SRB) to bind to protein components of cells fixed on tissue culture plates with trichloroacetic acid (TCA). SRB is a bright pink aminoxanthene dye with two sulfonic acid groups that bind to basic amino acid residues under weakly acidic conditions and dissociate under alkaline conditions. Because SRB binding is stoichiometric, the amount of dye extracted from stained cells is proportional to the cell population.

Cell lines: All cell lines were obtained from ATCC (Manassas, VA). Glutamax-containing culture medium and trypsin were purchased from Invitrogen (Carlsbad, CA). Doxorubicin, tuberculin, clofarabine, TCA, and SRB were from Sigma-Aldrich (St. Louis, MO). Gemcitabine was obtained from Moravek Biochemicals (Brea, CA).

Assay protocol:

1) Cell lines were maintained in the culture medium listed in Table 1. Subconfluent cells were trypsinized, counted, and then the cell concentration was adjusted according to the cell count listed in Table 1.

2) The cells were distributed in 150 μL of culture medium in a 96-well plate and the plate was incubated at 37°C in a humidified _CO2 incubator overnight.

3) Fix one plate of each cell line with TCA. Discard the medium from the plate by quickly flicking, and add 100 μL of cold 10% (v/v) TCA to each well. Incubate the plate in a 4°C refrigerator for 1 hour. Discard the TCA from the plate by quickly flicking. Rinse the plate four times in a basin of tap water. Store the plate at room temperature. This plate represents the cell count on Day 0.

4) Prepare a set of culture medium solutions containing various concentrations of the test compound (prepared by 5-fold serial dilution) in a 96-well plate. Add 50 μL of the diluted compound to each well. This includes controls containing untreated cells and cells treated with doxorubicin, tuberculin, clofarabine, and/or gemcitabine.

5) Incubate the plate at 37°C for 5 days.

6) Fix the plate with TCA. Discard the medium from the plate by quickly flicking it, and add 100 μL of cold 10% (v/v) TCA to each well. Incubate the plate in a 4°C refrigerator for 1 hour. Discard the TCA from the plate by quickly flicking it. Rinse the plate four times in a basin of tap water.

7) Remove excess water by tapping the plate face down on a paper towel. Allow the plate to air dry at room temperature.

8) On day 0 and day 5, add 100 μL of 0.057% SRB in 1% (vol/vol) acetic acid solution to each well of the TCA-fixed culture plate and incubate at room temperature for 30 minutes.

9) Discard the SRB by flicking the plate quickly. Rinse the plate four times with 1% (vol/vol) acetic acid.

10) Store the plate in a 37°C incubator to accelerate drying.

11) Once the plate is completely dry, add 200 μL of 10 mM Tris substrate solution (pH 10.5) to each well and allow to stand at room temperature for 30 minutes to allow the SRB to dissolve.

12) Measure the OD at 500 nm on an automatic quantitative microplate reader.

13) Calculate the percentage of cell growth inhibition using the following formula: Percentage of control cell growth = 100 x (OD _sample - average OD _{day 0} ) / (OD _{negative control} - average OD _{day 0} ).

To determine _CC50 , a dose response curve is plotted between compound concentration and _percent growth inhibition.CC50 values can be obtained by fitting the dose response curve using a sigmoidal dose response equation.

Table 4. Culture conditions of solid tumor cell lines

Test B: Cytokine inhibition cell culture assay ( _CC50 ) for lymphoma cell lines

This test is usually carried out using a cell line derived from a hematological tumor and grown in suspension. An example of the cell line is the human MT-4 T-lymphocyte cell line used to determine the cell growth inhibition activity of the test compound. MT-4 cells are derived from the NIH AIDS Research and Reference Reagents Program and stored in RPMI-1640 culture medium supplemented with 10% FBS and antibiotics. The cells are passaged twice a week in suspension and the density is maintained at 500,000 cells/mL. In order to determine CC ₅₀ , cells are seeded into 384-well plates at 2,000 cells/well in 20 μL culture medium. The compound is serially diluted in culture medium and added in triplicate to make the final assay volume 40 μL/well. The plate is cultured with the test compound for 5 days. After the culture is complete, 40 μL CellTiter Glo reagents are added, followed by fluorescence readings, to determine cell activity.

The _CC50 value was defined as the concentration of each test compound that resulted in a 50% reduction in the cell viability signal.Data analysis and calculation of _CC50 values were performed using GraphPad Prism software (GraphPad Software, San Diego, CA) by applying nonlinear regression.

Representative compounds of the present invention generally have inhibitory activity against one or more of the above-mentioned cell lines with a CC ₅₀ of less than about 20 μM. Certain representative compounds of the present invention have inhibitory activity against one or more of the above-mentioned cell lines with a CC ₅₀ of less than about 1 μM. Still other representative compounds of the present invention have inhibitory activity against one or more of the above-mentioned cell lines with a CC ₅₀ of less than about 0.1 μM.

The data of representative compounds of the present invention in Test A and Test B are shown in Table 5 below.

Table 5

Representative compounds of the present invention have also been found to inhibit adenosine kinase from mycobacteria. Therefore, in one embodiment, the present invention also provides a method for inhibiting adenosine kinase (e.g., adenosine kinase from mycobacteria), comprising contacting adenosine kinase with a compound of Formula I or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention also provides a method for treating a disease associated with adenosine kinase activity in an animal, the method comprising administering to an animal (e.g., a mammal such as a human) in need of such treatment an amount of a compound of Formula I or a pharmaceutically acceptable salt thereof that effectively inhibits adenosine kinase. Diseases associated with adenosine kinase activity may include inflammation, sepsis, arthritis, rheumatoid arthritis, osteoarthritis, autoimmune diseases, burns, adult respiratory distress syndrome, inflammatory bowel syndrome, necrotizing enterocolitis, chronic obstructive pulmonary disease, psoriasis, conjunctivitis, iridocyclitis, ischemia, reperfusion injury, peripheral vascular disease, pancreatitis, atherosclerosis, meningitis, vasculitis, dermatitis, myositis, nephritis, sepsis, septicemia (e.g., endotoxemia), and septic shock (e.g., endotoxic shock).

In another embodiment, the present invention also provides a method for treating tuberculosis in an animal (eg, a mammal such as a human), comprising administering to the animal a compound of formula I or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention also provides use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting adenosine kinase in an animal (eg, a mammal such as a human).

In another embodiment, the present invention also provides use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease associated with adenosine kinase in an animal (eg, a mammal such as a human).

In another embodiment, the present invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating tuberculosis in animals (eg, mammals such as humans).

abbreviation

AcOEt ethyl acetate

Boc tert-Butoxycarbonyl

bd broad doublet

bs broad singlet

Butyl

Bz benzoyl

calcd calculated value

cat. catalyst

d Doublet

dd doublet

ddd double double peak

DMF dimethylformamide

DMSO dimethyl sulfoxide

dt double triplet

Et ethyl

EDTA Ethylenediaminetetraacetic acid

FAB Fast Atom Bombardment

gem pairs

HPFC High Performance Flash Chromatography

HR High Resolution

i different

iPr Isopropyl

IR infrared spectroscopy

m multiplet

m rooms

Me methyl

MeCN Acetonitrile

MeOH methanol

MeONa sodium methoxide

MS

ν wave number

naphth

NMR Nuclear Magnetic Resonance

o Neighbor

p pair

Ph Phenyl

PPh ₃ triphenylphosphine

Py pyridyl

pyrr pyrrole

q quartet

rel. relative

RT Room temperature

s single peak

sat. saturated

sol. solution

t Triplet

TBS tert-Butyldimethylsilyl

td triple doublet

THF Tetrahydrofuran

TFA trifluoroacetic acid

TPPTS triphenylphosphine trisulfonate sodium salt

Tr triphenylmethyl, triphenylmethyl

vic adjacent

The invention is illustrated by the following non-limiting examples.

Example

General method melting point was determined on a Kofler block. Optical rotation was measured at 25 ° C, and [α] _D ²⁰ values were given in 10 ^–1 degrees cm ² g ^–1 . NMR spectra were measured at 400 MHz for ¹ H and 100.6 MHz for ¹³ C nuclei, 500 MHz for ¹ H and 125.8 MHz for ¹³ C nuclei, or 600 MHz for ¹ H and 151 MHz for ¹³ C nuclei in CDCl ₃ (TMS was used as an internal standard), MeOH-d ₄ (referenced to the residual solvent signal), or DMSO-d ₆ (referenced to the residual solvent signal). Chemical shifts are given in ppm (δ-scale), and coupling constants (J) are given in Hz. Complete attribution of all NMR signals was performed using a combination of H, H-COSY, H, H-ROESY, H, C-HSQC, and H, C-HMBC experiments. Mass spectrometry was performed using FAB (Xe ionization, accelerating voltage 8 kV, glycerol + thioglycerol matrix) or ESI (electrospray). Reversed phase chromatography was performed on a Biotage SP1 apparatus equipped with a KP-C18-HS, 25+M, 35-70 mm, or 40+M HPFC system.

Example 1. 4-Amino-5-phenyl-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (2a)

A mixture of 7-iodotuberculocidin 1 (200 mg, 0.51 mmol) {for preparation, see Seela, F.; Ming, X. Tetrahedron 2007, 63, 9850-9861}, phenylboronic acid (93 mg, 0.76 mmol), Na ₂ CO ₃ (502 mg, 4.74 mmol), Pd(OAc) ₂ (6.6 mg, 0.029 mmol), and TPPTS (42 mg, 0.07 mmol) in water/MeCN (2:1, 3.6 ml) was stirred at 80° C. for 1 hour under argon purging. After removal of volatiles in vacuo, the residue was purified by reverse phase chromatography (0→100% MeOH in water) to afford the title compound 2a as a white solid (94 mg, 54%). Mp 119° C. [α] ²⁰ _D −49.8 (c 0.301, MeOH). ¹ H NMR (600MHz, DMSO-d ₆ ): 3.53 (ddd, 1H, J _gem = 11.9, J _{5′b, OH} = 6.1, J _{5′b, 4′} = 3.9, H-5′b); 3.63 (ddd, 1H, J _gem = 11.9, J _{5′a, OH} = 5.2, J _{5′a, 4′} =3.4, H-5′a); 3.90 (ddd, 1H, J _4′,5′ = 3.9, 3.4, J _4′,3′ = 3.5, H-4′); 4.10 (bm, 1H, H-3′); 4.46 (bm, 1H, H-2′); 5.16 (d, 1H, J _{OH, 3′} =3.5, OH-3′); 5.22 (dd, 1H, J _OH,5′ = 6.1, 5.2, OH-5′); 5.36 (d, 1H, J _OH,2′ = 4.8, OH-2′); 6.12 (d, 1H, J _{1′, 2′} =6.3, H-1′); 7.37 (m, 1H, Hp-Ph); 7.47 (m, 2H, Ho-Ph); 7.49 (m, 2H, Hm-Ph); 7.54 (s, 1H, H-6); 8.15 (s, 1H, H-2). ¹³ C NMR (151MHz, DMSO-d ₆ ): 61.93 (CH ₂ -5′);70.89(CH-3′);74.05(CH-2′);85.38(CH-4′);87.27(CH-1′);100.73(C-4a);116.57(C-5);121.41(CH-6);12 7.20(CH-p-Ph); 128.70(CH-o-Ph); 129.28(CH-m-Ph); 134.71(Ci-Ph); 151.10(C-7a); 151.95(CH-2); 157.57(C-4). IR (KBr): 3479, 3391, 1623, 1585, 1566, 1538, 1489, 1466, 1445, 1296, 1216, 1182, 1157, 1147, 1119, 1083, 1047, 1028, 1000, 798, 762, 705, 615 _{, 503.} MS (FAB) m _/ z ₃₄₃ (M+H), 365 (M+Na). HRMS (FAB) calculated for _Ci7H19N4O4 [M+H]: 343.1406; found: 343.1409. Calculated _{for C17H18N4O4-0.8H2O} : C, 57.23; H, 5.54; _N , 15.70. Found: C, 57.44; _H , 5.27; _N , 15.43.

Example 2. 4-Amino-5-(4-methoxyphenyl)-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (2b)

The title compound was prepared according to the method of Example 1. It was freeze-dried to give a pale yellow solid. Yield: 36%. Mp: 121°C. [α] ²⁰ _D -21.2 (c: 0.304, MeOH). ¹ H NMR (600MHz, DMSO-d ₆ ): 3.53 (ddd, 1H, J _gem = 11.9, J _{5′b, OH} = 6.3, J _{5′b, 4′} = 3.8, H-5′b); 3.62 (ddd, 1H, J _gem = 11.9, J _{5′a, OH} = 4.8, J _{5′a, 4′} =3.8, H-5′a); 3.80 (s, 3H, CH ₃ O); 3.90 (td, 1H, J _{4′, 5′} = 3.8, J _{4′, 3′} = 3.1, H-4′); 4.09 (ddd, 1H, J _{3′, 2′} = 5.1, J _{3, OH} = 4.7, J _{3′, 4′} =3.1, H-3′); 4.45 (ddd, 1H, J _{2′, OH} = 6.5, J _{2′, 1′} = 6.3, J _{2′, 3′} = 5.1, H-2′); 5.14 (d, 1H, J _{OH, 3′} = 4.7, OH-3′); 5.22 (dd, 1H, J _{OH, 5′} =6.3, 4.8, OH-5′); 5.33 (d, 1H, J _OH,2′ = 6.5, OH-2′); 6.10 (d, 1H, J _1′,2′ = 6.3, H-1′); 7.05 (m, 2H, HmC ₆ H ₄ OMe); 7.38 (m, 2H, HoC ₆ H ₄ OMe); 7.45 (s, 1H, H-6); 8.13 (s, 1H, H-2). ¹³ C NMR (151MHz, DMSO-d ₆ ): 55.44 (CH ₃ O); 61.94 (CH ₂ -5′); 70.90(CH-3′); 74.01(CH-2′); 85.34(CH-4′); 87.24(CH-1′); 100.96(C-4a); 114.70(CH-mC ₆ H ₄ OMe); 116.20 (C-5); 120.81 (CH-6); 126.85 (CiC ₆ H ₄ OMe); 129.97 (CH-oC ₆ H ₄ OMe); 150.88 (C-7a); 151.86 (CH-2); 157.59 (C-4); 158.68 (CpC ₆ H _4OMe ). IR(KBr): 3470, 3391, 2836, 1630, 1620, 1586, 1565, 1540, 1506, 1466, 1442, 1421 , 1292, 1246, 1216, 1175, 1147, 1117, 1109, 1083, 1055, 1030, 838, 796, 706, 637. MS (FAB) m/z 373 (M+H), 395 (M+Na). HRMS (FAB) calcd for _{C18H21N4O5 [} M+H _] : 373.1512; found: 373.1498; calcd _{for C18H20NaN4O5 [} M+Na]: 395.1331; found: 395.1327. Calcd _{for C18H20N4O5} · _0.95H2O : C, _55.51 ; H, _5.67 ; _N , 14.38. Found: C, 55.59; H _, 5.44; N, 14.04.

Example 3. 4-Amino-5-[4-(methylthio)phenyl]-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (2c)

The title compound was prepared according to the method of Example 1. Recrystallization from MeOH gave white needles. Yield: 48%. Mp: 227-228°C. [α] ²⁰ _D -67.3 (c: 0.237, DMSO). ¹ H NMR (500MHz, DMSO-d ₆ ): 2.52 (s, 3H, CH ₃ S); 3.53 (ddd, 1H, J _gem = 12.0, J _{5′b, OH} = 6.3, J _{5′, 4′} = 3.9, H-5′b); 3.63 (ddd, 1H, J _gem = 12.0, J _{5′a, OH} =5.1, J _5′a,4′ =3.8, H-5′a); 3.90 (ddd, 1H, J _4′,5′ = 3.9, 3.8, J _4′,3′ = 3.1, H-4′); 4.10 (ddd, 1H, J _3′,2′ = 5.1, J _3,OH = 4.8, J _3′,4′ =3.1, H-3′); 4.45 (ddd, 1H, J _{2′, OH} = 6.5, J _{2′, 1′} = 6.2, J _{2′, 3′} = 5.1, H-2′); 5.12 (d, 1H, J _{OH, 3′} = 4.8, OH-3′); 5.20 (dd, 1H, J _{OH, 5′} =6.3, 5.1, OH-5'); 5.32 (d, 1H, J _OH,2' = 6.5, OH-2'); 6.11 (d, 1H, J _{1', 2'} = 6.2, H-1'); 6.16 (bs, 2H, NH ₂ ); 7.37 (m, 2H, HmC ₆ H ₄ SMe); 7.41(m, 2H, HoC ₆ H ₄ SMe); 7.52 (s, 1H, H-6); 8.14 (s, 1H, H-2). ¹³ C NMR (125.7MHz, DMSO-d ₆ ): 14.98 (CH ₃ S); 61.88 (CH ₂ -5′); 70.83(CH-3′); 73.99(CH-2′); 85.32(CH-4′); 87.24(CH-1′); 100.67(C-4a); 116.01(C-5); 121.25(CH-6); 126.72(CH-mC ₆ H ₄ SMe); 129.12 (CH-oC ₆ H ₄ SMe); 131.15 (CiC ₆ H ₄ SMe); 136.90 (CpC ₆ H ₄ SMe); 151.07(C-7a); 151.90(CH-2); 157.55(C-4). IR(KBr): 3476, 3440, 3343, 3318, 3200, 3123, 2693, 1630, 1584, 1570, 1549, 1534, 1492, 1465, 1 430, 1402, 1298, 1269, 1212, 1177, 1147, 1124, 1096, 1080, 1054, 1016, 967, 832, 796, 716, 690. MS(FAB): m/z 389(M+H). HRMS (FAB) calcd for _{C18H21N4O4S [ M} +H _] : 389.1284; found: 389.1282 _{. Calcd for C18H20N4O4S : C} , 55.66; H, 5.19; N, 14.42. Found: C, 55.28; H _, 5.25; N, 14.16.

Example 4. 4-Amino-5-(naphthalen-1-yl)-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (2d)

The title compound was prepared according to the method of Example 1. The crude product was purified by silica gel chromatography (0→20% MeOH in CHCl ₃ ) before final reverse phase chromatography. Freeze-dried to a white solid. Yield 47%. _{M p} 134°C. [α] ²⁰ _D -56.1 (c 0.292, MeOH). ¹ H NMR (500MHz, DMSO-d ₆ , T = 353K): 3.57 (bddd, 1H, J _gem = 12.0, J _{5′b, OH} = 5.1, J _{5′, 4′} = 3.8, H-5′b); 3.67 (bdt, 1H, J _gem = 12.0, J _{5′a, OH} = J _5′a,4′ =4.0,H-5′a);3.96(ddd,1H,J _4′,5′ =4.0,3.8,J _4′,3′ =3.1, H-4′); 4.17 (bm, 1H, H-3′); 4.54 (bm, 1H, H-2′); 4.88 (bs, 1H, OH-3′); 4.95 (bdd, 1H, J _{OH, 5′} =5.1, 4.8, OH-5′); 5.13 (bs, 1H, OH-2′); 5.43 (bs, 2H, NH ₂ ); 6.19 (d, 1H, J _1′,2′ =5.9, H-1′); 7.49-7.53 (m, 3H, H-6 and H-2,7-naphthyl); 7.56 (ddd, 1H, J _6,5 =8.1, J _6,7 =6.9, J _6,8 =1.1, H-6-naphthyl); 7.61 (dd, 1H, J _3,4 =8.2, J _3,2 =7.1, H-3-naphthyl); 7.81 (bd, 1H, J _8,7 =8.4, H-8-naphthyl); 7.99 (bd, 1H, J _4,3 =8.2, H-4-naphthyl); 8.01 (bd, 1H, J _5,6 =8.1, H-5-naphthyl); 8.18 (s, 1H, H-2). ¹³ C NMR (151 MHz, DMSO-d ₆ , T=353K): 61.66 (CH ₂ -5′); 70.53 (CH-3′); 73.90 (CH-2′); 85.06 (CH-4′); 87.75 (CH-1′); 102.65 (C-4a); 113.04 (C-5); 122.03 (CH-6); 125.38 (CH-3-naphthyl); 125.46 (CH-8-naphthyl); 125.99 (CH-6-naphthyl); 126 .38 (CH-7-naphthyl); 127.82 (CH-4-naphthyl); 128.05 (CH-2-naphthyl); 128.10 (CH-5-naphthyl); 131.55 (C-1-naphthyl); 132.10 (C-8a-naphthyl); 133.41 (C-4a-naphthyl); 150.43 (C-7a); 151.66 (CH-2); 157.09 (C-4). IR (KBr): 3478, 3436, 3392, 3240, 3057, 1632, 1621, 1585, 1569, 1535, 1506, 1469, 1398, 1296, 1257, 1108, 1081, 1046, 1016, 946, 849, 805, 797, ₇₉₀ , 779, 740. MS (FAB): m/ _{z 393} (M+H). HRMS calculated for _C21H21N4O4 [M+H] (FAB): 393.1563; found: 393.1564. Calculated _{for C21H20N4O4-0.8H2O} : C, 62.00; H, 5.35; _N , 13.77. Found: C, 62.25; _H , 5.21; _N , 13.52.

Example 5. 4-amino-5-(naphthalen-2-yl)-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (2e)

The title compound was prepared according to the method of Example 1. The crude product was purified by silica gel chromatography (0→10% MeOH in CHCl ₃ ) before final reverse phase chromatography. Freeze-dried to a white solid. Yield: 18%. Mp: 129°C. [α] ²⁰ _D -59.8 (c: 0.246, MeOH). ¹ H NMR (500MHz, DMSO-d ₆ ): 3.55 (ddd, 1H, J _gem = 11.7, J _{5′b, OH} = 6.2, J _{5′, 4′} = 3.5, H-5′b); 3.65 (ddd, 1H, J _gem = 11.7, J _{5′a, OH} = 5.1, J _{5′a, 4′} =3.5, H-5′a); 3.92 (q, 1H, J _4′,5′ = J _4′,3′ = 3.5, H-4′); 4.13 (ddd, 1H, J _3′,2′ = 5.2, J _3,OH = 4.7, J _3′,4′ = 3.5, H-3′); 4.49 (ddd, 1H, J _2′,OH =6.5,J _2′,1′ =6.2, J _2′,3′ =5.2, H-2′); 5.15 (d, 1H, J _OH,3′ = 4.7, OH-3′); 5.22 (dd, 1H, J _OH,5′ = 6.2, 5.1, OH-5′); 5.36 (d, 1H, J _OH,2′ =6.5, OH-2′); 6.15 (d, 1H, J _1′,2′ = 6.2, H-1′); 6.20 (bs, 2H, NH ₂ ); 7.53 (td, 1H, J _6,5 = J _6,7 = 8.2, J _6,8 = 1.4, H-6-naphthyl); 7.56 (td, 1H, J _7,6 ＝J _7,8 ＝8.2，J _7,6 =1.4, H-7-naphthyl); 7.65 (dd, 1H, J _3,4 =8.6, J _3,1 =1.7, H-3-naphthyl); 7.66 (s, 1H, H-6); 7.97-8.00 (m, 3H, H-1,5,8-naphthyl); 8.03 (d, 1H, J _4,3 =8.6, H-4-naphthyl); 8.17 (s, 1H, H-2). ¹³ C NMR (125.7 MHz, DMSO-d ₆ ): 61.86 (CH ₂ -5′); 70.77(CH-3′); 74.00(CH-2′); 85.29(CH-4′); 87.32(CH-1′); 100.83(C-4a) ;116.50(C-5);121.66(CH-6);126.06(CH-6-naphthyl);126.70(CH-7-naphthyl);126.79(CH-1- naphthyl); 127.13 (CH-3-naphthyl); 127.79 and 127.95 (CH-5,8-naphthyl); 128.63 (CH-4-naphthyl); 132.00 and 132.10 (C-1,4a-naphthyl); 133.40 (C-8a-naphthyl); 151.20 (C-7a); 151.90 (CH-2); 157.57 (C-4). IR (KBr): 3475, 3438, 3392 _, 3240, 3054, 1630, 1621, 1584, 1566, 1538, 1505, ₁₄₆₉ , 1376, 1295, 1145, 1119, 1085, 1047, 1020, 861, 824, 796, 768, 750, 624, 478. MS (FAB): m/ _z 393 (M+H). HRMS (FAB) calculated for _C21H21N4O4 [M+H]: 393.1563; found: 393.1571. Calculated for _{C21H20N4O4-0.65H2O} : C, _62.41 ; H, 5.31; _N , 13.86. Found: C, 62.58; _H , 5.18; _N , 13.64.

Example 6. 4-Amino-5-(furan-2-yl)-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (2f)

The title compound was prepared according to the method of Example 1. It was freeze-dried to a tan solid. Yield: 35%. Mp: 118°C. [α] ²⁰ _D -52.5 (c: 0.287, MeOH). ¹ H NMR (500MHz, DMSO-d ₆ ): 3.55 and 3.65 (2×dd, 2H, J _gem = 11.9, J _{5′, 4′} = 3.9, H-5′); 3.91 (td, 1H, J _{4′, 5′} = 3.9, J _{4′, 3′} ＝3.4, H-4′); 4.11(dd, 1H, J _3′,2′ ＝5.2, J _3′,4′ ＝3.4, H-3′); 4.41 (dd, 1H, J _2′,1′ ＝6.1, J _2′,3′ =5.2, H-2′); 5.00-5.50 (bs, 2H, OH-2′, 3′, 5′); 6.09 (d, 1H, J _{1′, 2′ 5} ＝1.9, H-5-furyl); 7.83 ( _{s ,} 1H, H- ₆ ) _{; 8.13} (s, 1H, H- ₂ ). ¹³ C NMR (125.7 MHz, DMSO-d ₆ ): 61.81 (CH ₂ -5′); 70.67 (CH-3′); 74.00 (CH-2′); 85.33 (CH-4′); 87.27 (CH-1′); 99.55 (C-4a); 105.50 (CH-3-furyl); 106.34 (C-5); 112.09 (CH-4-furyl); 120.70 (CH-6); 142.16 (CH-5-furyl); 148.77 (C-2-furyl); 151.04 (C-7a); 152.26 (CH-2); 157.45 (C-4). IR (KBr): 3468, 3391, 3252, 1631, 1577, 1562, 1532, 1497, 1456, 1299, 1145, ₁₁₂₁ , 1083, 1049, ₁₀₁₅ , 892, 794, _{550. MS (FAB): m/z 333 (M+H), 355 (M+Na). HRMS (FAB) calcd for C15H17N4O5 [M+H]: 333.1199; found: 333.1202. calcd for C15H16N4O5 · 1.05H2O : C , 51.30} ; H, 5.19; N, 15.95. Found: C, 51.64; H, 5.01; N, 15.63.

Example 7. 4-amino-7-(β-D-ribofuranosyl)-5-(thien-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (2 g)

The title compound was prepared according to the method of Example 1. Recrystallization from MeOH gave a white solid. Yield: 32%. Mp: 188°C. [α] ²⁰ _D -74.5 (c: 0.235, DMSO). ¹ H NMR (500 MHz, DMSO-d ₆ ): 3.54 (ddd, 1H, J _gem = 12.0, J _5′b,OH = 6.2, J _5′,4′ = 3.8, H-5′b); 3.63 (ddd, 1H, J _gem = 12.0, J _5′a,OH = 5.0, J _5′a,4′ =3.8, H-5′a); 3.91 (td, 1H, J _{4′, 5′} = 3.8, J _{4′, 3′} = 2.9, H-4′); 4.09 (ddd, 1H, J _{3′, 2′} = 5.0, J _{3, OH} = 4.7, J _{3′, 4′} =2.9, H-3′); 4.43(ddd, 1H, J _{2′, OH} =6.4, J _2′,1′ =6.3, J _2′,3′ =5.0, H-2′); 5.13 (d, 1H, J _OH,3′ = 4.7, OH-3′); 5.20 (dd, 1H, J _OH,5′ = 6.2, 5.0, OH-5′); 5.34 (d, 1H, J _OH,2′) =6.4, OH-2′); 6.10 (d, 1H, J _1′,2′ = 6.3, H-1′); 6.32 (bs, 2H, NH ₂ ); 7.15 (dd, 1H, J _3,4 = 3.5, J _3,5 = 1.2, H-3-thienyl); 7.18 (dd, 1H, J _4,5 =5.1, J _4,3 =3.5, H-4-thienyl); 7.57 (dd, 1H, J _5,4 ＝5.1, J _5,3 ＝1.2, H-5-thienyl); 7.62 (s, 1H, H-6); 8.15 (s, 1H, H-2). ¹³ C NMR (125.7 MHz, DMSO-d ₆ ): 61.79 (CH ₂ -5′); 70.78 (CH-3′); 74.06 (CH-2′); 85.40 (CH-4′); 87.17 (CH-1′); 100.84 (C-4a); 108.65 (C-5); 122.26 (CH-6); 126.06 (CH-5-thienyl); 126.58 (CH-3-thienyl); 128.49 (CH-4-thienyl); 135.72 (C-2-thienyl); 150.82 (C-7a); 152.22 (CH-2); 157.49 (C-4). IR (KBr): 3509, 3395, 3322, 3220, 3102, 1620, 1590, 1576, 1555, 1508, 1460, ₁₄₃₄ , ₁₃₄₉ , 1300, 1236, 1144, 1119, 1102, 1086, 1063, 1042, 1038, 852, 832, 793, 703, 562, 453. MS (FAB): m/z ₃₄₉ (M+H). HRMS (FAB) calculated for _C15H17N4O4S [M+H]: 349.0971; found: 349.0965. Calculated for _C15H16N4O4S : C, _51.71 ; H, 4.63; _N , 16.08. Found: C, 51.33; _H , 4.48; N, 15.75.

Example 8. 4-amino-5-(furan-3-yl)-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (2h)

The title compound was prepared according to the method of Example 1. Recrystallization from MeOH gave a pale yellow solid. Yield: 28%. Mp: 190°C. [α] ²⁰ _D -56.9 (c: 0.232, DMSO). ¹ H NMR (600MHz, DMSO-d ₆ ): 3.53 (ddd, 1H, J _gem =12.0, J _5′b,OH =6.2, J _5′,4′ =3.8, H-5′b); 3.62 (ddd, 1H, J _gem =12.0, J _5′a,OH =4.8, J _5′a,4′ =3.9, H-5′a); 3.89 (ddd, 1H, J _4′,5′ = 3.9, 3.8, J _4′,3′ = 3.1, H-4′); 4.04 (bddd, 1H, J _{3′, OH} = 3.8, J _{3′, 2′} = 3.6, J _{3′, 4′} =3.1, H-3′); 4.42(bddd, 1H, J _2′,1′ =6.3, J _2′,OH =5.1, J _2′,3′ =3.6, H-2′); 5.14 (bd, 1H, J _OH,3′ = 3.8, OH-3′); 5.21 (dd, 1H, J _OH,5′ = 6.2, 4.8, OH-5′); 5.33 (bd, 1H, J _OH,2′ =5.1, OH-2′); 6.08 (d, 1H, J _1′,2′ = 6.3, H-1′); 6.27 (bs, 2H, NH ₂ ); 6.70 (dd, 1H, J _4,5 = 1.8, J _4,2 =0.9, H-4-furyl); 7.50 (s, 1H, H-6); 7.81 (dd, 1H, J _δ =1.8, J _5,2 =1.6, H-5-furyl); 7.83 (dd, 1H, J _2,5 =1.6, J _2,4 =0.9, H-2-furyl); 8.12 (s, 1H, H-2). ¹³ C NMR (151 MHz, DMSO-d ₆ ): 61.92 (CH ₂ -5′); 70.84 (CH-3′); 73.96 (CH-2′); 85.31 (CH-4′); 87.14 (CH-1′); 101.22 (C-4a); 106.44 (C-5); 111.75 (CH-4-furyl); 118.77 (C-3-furyl); 121.17 (CH-6); 139.86 (CH-2-furyl); 144.41 (CH-5-furyl); 150.92 (C-7a); 151.97 (CH-2); 157.70 (C-4). IR (KBr): 3512, 3394, 3296 _, 3252, 1623, 1582, 1561, 1504, 1457, 1364, 1306, 1286, 1245, 1152, 1121, 1109, 1067, 1038, 1021, 972, 873, 793, _777. MS (FAB): m _{/ z 333} (M+H). HRMS (FAB) calculated for _C15H17N4O5 [ _M + _H] : 333.1199; found: 333.1204. Calculated for _C15H16N4O5 : C, 54.21; H, 4.85; N, 16.86. Found: C, 53.82; H, 4.85; N, 16.49.

Example 9. 4-Amino-7-(β-D-ribofuranosyl)-5-(thien-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (2i)

The title compound was prepared according to the method of Example 1. Recrystallization from MeOH gave a white-gray solid. Yield: 56%. Mp: 197°C. [α] ²⁰ _D -58.7 (c: 0.237, DMSO). ¹ H NMR (600MHz, DMSO-d ₆ ): 3.53 (ddd, 1H, J _gem = 12.0, J _{5′b, OH} = 6.1, J _{5′, 4′} = 3.8, H-5′b); 3.62 (ddd, 1H, J _gem = 12.0, J _{5′a, OH} = 4.9, J _{5′a, 4′} =3.9, H-5′a); 3.90 (ddd, 1H, J _{4′, 5′} = 3.9, 3.8, J _{4′, 3′} = 3.0, H-4′); 4.09 (bddd, 1H, J _{3′, 2′ =} 4.2, J _{3, OH} = 3.2, J _{3′, 4′} =3.0, H-3′); 4.43(bddd, 1H, J _2′,1′ =6.3, J _2′,OH =5.1, J _2′,3′ =4.2, H-2′); 5.14 (bd, 1H, J _OH,3′ = 3.2, OH-3′); 5.21 (dd, 1H, J _OH,5′ = 6.1, 4.9, OH-5′); 5.34 (bd, 1H, J _OH,2′ =5.1, OH-2′); 6.09 (d, 1H, J _1′,2′ = 6.3, H-1′); 6.21 (bs, 2H, NH ₂ ); 7.27 (dd, 1H, J _4,5 = 4.9, J _4,2 = 1.3, H-4-thienyl); 7.52 (dd, 1H, J _2,5 =2.9, J _2,4 =1.3, H-2-thienyl); 7.55 (s, 1H, H-6); 7.72 (dd, 1H, J _5,4 ＝5.1, J _5,2 ＝2.9, H-5-thienyl); 8.13 (s, 1H, H-2). ¹³ C NMR (151 MHz, DMSO-d ₆ ): 61.90 (CH ₂ -5′); 70.84 (CH-3′); 74.00 (CH-2′); 85.32 (CH-4′); 87.17 (CH-1′); 101.00 (C-4a); 111.19 (C-5); 121.29 (CH-6); 122.24 (CH-2-thienyl); 127.62 (CH-5-thienyl); 128.71 (CH-4-thienyl); 134.94 (C-3-thienyl); 150.79 (C-7a); 151.96 (CH-2); 157.62 (C-4). IR (KBr): 3509, 3396, 3338, 3240, 3106, 1621, 1593, 1576, 1553, 1509, 1460, ₁₄₂₂ , 1351, 1299, ₁₂₁₄ , 1144, 1121, 1101, 1080, 1061, 1036, 856, 796, 775, 713, 562, 456. MS (FAB): m _/z 349 (M+H). HRMS (FAB) calculated for _C15H17N4O4S [M+H]: 349.0971; found: 349.0962. Calculated for _C15H16N4O4S : C, _51.71 ; H, 4.63; _N , 16.08. Found: C, 51.51; _H , 4.63; N, 15.76.

Example 10. 4-Amino-5-(benzofuran-2-yl)-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (2j)

The title compound was prepared according to the method of Example 1. Recrystallization from MeOH/water gave white needles. Yield: 27%. Mp: 177°C. [α] ²⁰ _D -68.8 (c: 0.257, MeOH). ¹ H NMR (500MHz, DMSO-d ₆ ): 3.57 (ddd, 1H, J _gem = 12.0, J _{5′b, OH} = 6.1, J _{5′, 4′} = 3.9, H-5′b); 3.67 (ddd, 1H, J _gem = 12.0, J _{5′a, OH} = 5.1, J _{5′a, 4′} =3.9, H-5′a); 3.93(td, 1H, J _4′,5′ = 3.9, J _4′,3′ = 3.3, H-4′); 4.13 (ddd, 1H, J _3′,2′ = 5.1, J _3,OH = 4.9, J _{3′, 4} ′ ₌ 3.3, H-3′); 4.46 (ddd, 1H, J _{2′, OH} =6.3, J _2′,1′ =6.1, J _2′,3′ =5.1, H-2′); 5.17 (d, 1H, J _OH,3′ =4.9, OH-3′); 5.23 (dd, 1H, J _OH,5′ =6.1, 5.1, OH-5′); 5.40 (d, 1H, J _OH,2′ =6.3, OH-2′); 6.14 (d, 1H, J _1′,2′ =6.1, H-1′); 7.00 (bs, 2H, NH ₂ ); 7.13 (d, 1H, J _3,7 =1.0, H-3-benzofuranyl); 7.28 (td, 1H, J _5,4 =J _5,6 =7.3, J _5,7 ＝1.5, H-5-benzofuranyl); 7.30 (td, 1H, J _6,5 ＝J _6,7 ＝7.3, J _6,4 ＝1.7, H-6-benzofuranyl); 7.62-7.69 (m, 2H, H-4,7-benzofuranyl); 8.11 (s, 1H, H-6); 8.18 (s, 1H, H-2). ¹³ C NMR (125.7 MHz, DMSO-d ₆ ): 61.79 (CH ₂ -5′); 70.70 (CH-3′); 74.12 (CH-2′); 85.46 (CH-4′); 87.35 (CH-1′); 99.62 (C-4a); 101.83 (CH-3-benzofuranyl); 105.72 (C-5); 111.30 (CH-7-benzofuranyl); 120.84 (CH-4-benzofuranyl); 122.94 (CH-6); 123.69 (CH-5-benzofuranyl); 124.07 (CH-6-benzofuranyl); 129.02 (C-3a-benzofuranyl); 151.29 (C-2-benzofuranyl); 151.35 (C-7a); 152.52 (CH-2); 153.99 (C-7a-benzofuranyl); 157.52 (C-4). IR (KBr): 3498, 3473, 3462, 3379, 3328, 3234, 3197, 3118, 2700, 1639, 1628, ₁₆₁₄ , 1576, 1558, 1525, 1483, 1474, 1456, 1303, 1262, 1186, 1145, 1127, 1108, 1085, 1056, 1010, 884, 806, 792, 785, 746. MS (ESI): m/ _{z 383} (M+H). HRMS (ESI) Calcd. for _C19H19N4O5 [M+H]: 383.1350; Found: 383.1348. _{Calculated for C19H18N4O5-0.6H2O :} C, 58.04; H, 4.92; _N , 14.25. Found: C, 57.78; _H , 4.56; N, 14.16.

Example 11. 4-Amino-5-(1H-pyrrol-2-yl)-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (2k)

A mixture of 7-iodotuberculocidin 1 (196 mg, 0.50 mmol), 1-N-(Boc)-pyrrole-2-boronic acid (126 mg, 0.60 mmol), Na ₂ CO ₃ (160 mg, 1.5 mmol), Pd(OAc) ₂ (5.6 mg, 0.025 mmol), and TPPTS (36 _mg , 0.06 mmol) in water/MeCN (2:1, 3 ml) was stirred at 100° C. for 3 hours under argon purge. After cooling, the mixture was neutralized by the addition of aqueous HCl (1 M), the volatiles were removed in vacuo, and the residue was purified by reverse phase chromatography (0→100% MeOH in water) to give the title compound 2k as a green solid (127 mg, 77%). After decolorization with activated charcoal, the compound was recrystallized from MeOH as a white solid. Mp 205-207° C. [α] _D -80.5 (c 0.205, DMSO). ¹ HNMR (500.0MHz, DMSO-d6): 3.54 (ddd, 1H, J _gem = 11.9, J _{5′b, OH} = 6.2, J _{5′b, 4′} = 3.9, H-5′b); 3.62 (dd, 1H, J _gem = 11.9, J _{5′a, OH} = 5.0, J _{5′a, 4′} =3.9, H-5′a); 3.90 (td, 1H, J _{4′, 5′} = 3.9, J _{4′, 3′} = 3.1, H-4′); 4.09 (ddd, 1H, J _{3′, 2′} = 5.1, J _{3′, OH} = 4.8, J _{3′, 4′} =3.1, H-3′); 4.41(ddd, 1H, J _{2′, OH} =6.5, J _2′,1′ =6.3, J _2′,3′ =5.1, H-2′); 5.17 (d, 1H, J _OH,3′ = 4.8, OH-3′); 5.20 (dd, 1H, J _OH,5′ = 6.2, 5.0, OH-5′); 5.33 (d, 1H, J _OH,2′) =6.5, OH-5′); 6.09 (d, 1H, J _1′,2′ = 6.3, H-1′); 6.13 (ddd, 1H, J _3,4 = 3.3, J _3,NH = 2.4, J _3,5 = 1.5, H-3-pyrrolyl); 6.16 (ddd, 1H, J _4,3 = 3.3, J _4,5 =2.7,J _4,NH =2.4, H-4-pyrrolyl); 6.32 (bs, 2H, NH ₂ ); 6.85 (td, 1H, J _5,4 ＝J _5,NH ＝2.7, J _5,3 ＝1.5, H-5-pyrrolyl); 7.43 (s, 1H, H-6); 8.12 (s, 1H, H-2); 11.14 (bs, 1H, NH-pyrrolyl). ¹³ C NMR (125.7 MHz, DMSO-d ₆ ): 62.00 (CH ₂ -5′); 70.92 (CH-3′); 74.11 (CH-2′); 85.30 (CH-4′); 87.20 (CH-1′); 101.09 (C-4a); 107.34 (CH-3-pyrrolyl); 108.68 (C-5); 109.06 (CH-4-pyrrolyl); 118.77 (CH-5-pyrrolyl); 120.55 (CH-6); 124.69 (C-2-pyrrolyl); 150.35 (C-7a); 151.98 (CH-2); 157.62 (C-4). MS (ESI) m/z 332 (M+H), ₃₅₄ ( _M +Na). HRMS (ESI) calculated for _C15H18N5O4 [M+H]: 332.1353; found: 332.1354. Calculated _{for C15H17N5O4} · ₁ / _3H2O : C, 53.41; H, 5.28; N, 20.76. Found: C, 53.32; H, 5.16 _{; N} , 20.57.

Example 12. 4-Amino-5-(1H-pyrrol-3-yl)-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (21)

A mixture of 7-iodotuberculocidin 1 (893 mg, 2.28 mmol), 1-(triisopropylsilyl)-1H-pyrrole-3-boronic acid (126 mg, 0.60 mmol), Na ₂ CO ₃ (724 mg, 6.83 mmol), Pd(OAc) ₂ (26 mg, 0.12 mmol), and TPPTS (162 mg, 0.28 mmol) in water/MeCN (2:1, 18 ml) was stirred at 100° C. for 18 hours under argon purge. After cooling, the mixture was neutralized by adding aqueous HCl (1 M) and desalted by reverse phase chromatography (0→100% MeOH in water) to give a crude product impure with the starting iodide. The title compound 21 was further purified by silica gel column chromatography (6% MeOH in CHCl ₃ ) to give the title compound 21 as a white solid (480 mg, 63%). The compound was recrystallized from MeOH. MP188-190℃. [α] _D -59.8 (c 0.276, DMSO). ¹ H NMR (500.0MHz, DMSO-d ₆ ): 3.52 (ddd, 1H, J _gem = 12.0, J _{5′b, OH} = 6.3, J _{5′b, 4′} = 3.8, H-5′b); 3.61 (dd, 1H, J _gem = 12.0, J _{5′a, OH} = 4.9, J _{5′a, 4′} =3.8, H-5′a); 3.88 (td, 1H, J _{4′, 5′} = 3.8, J _{4′, 3′} = 3.0, H-4′); 4.08 (ddd, 1H, J _{3′, 2′} = 5.1, J _{3′, OH} = 4.7, J _{3′, 4′} =3.0, H-3′); 4.43(ddd, 1H, J _{2′, OH} =6.5, J _2′,1′ =6.4, J _2′,3′ =5.1, H-2′); 5.11 (d, 1H, J _OH,3′ = 4.7, OH-3′); 5.24 (dd, 1H, J _OH,5′ = 6.3, 4.9, OH-5′); 5.30 (d, 1H, J _OH,2′) =6.5, OH-5′); 6.06 (d, 1H, J _1′,2′ = 6.4, H-1′); 6.18 (td, 1H, J _4,5 = J _4,NH = 2.6, J _4,2 = 1.6, H-4-pyrrolyl); 6.26 (bs, 2H, NH ₂ ); 6.88 (dt, 1H, J _2,NH =2.6,J _2,4 ＝J _2,5 ＝1.6, H-2-pyrrolyl); 6.90 (td, 1H, J _5,4 ＝J _5,NH ＝2.6, J _5,2 ＝1.6, H-5-pyrrolyl); 7.27 (s, 1H, H-6); 8.08 (s, 1H, H-2); 11.03 (bs, 1H, NH-pyrrolyl). ¹³ C NMR (125.7 MHz, DMSO-d ₆ ): 62.00 (CH ₂ -5′); 70.94 (CH-3′); 73.89 (CH-2′); 85.23 (CH-4′); 87.12 (CH-1′); 101.65 (C-4a); 108.29 (CH-4-pyrrolyl); 111.17 (C-5); 115.87 (C-3-pyrrolyl); 116.44 (CH-2-pyrrolyl); 119.33 (CH-2-pyrrolyl); 119.65 (CH-6); 150.42 (C-7a); 151.62 (CH-2); 157.77 (C-4). MS (ESI) m/z ₃₃₂ (M+H), ₃₅₄ (M+Na). HRMS (ESI) calculated for _C15H18N5O4 [M+H]: _332.1353 ; found: 332.1354 _. Calculated _{for C15H17N5O4} · _0.8H2O : C, 52.11; _H , 5.42; N, 20.26. Found: C, 52.32; H, 5.32; N, 20.03.

Example 13. 4-Amino-5-(1H-pyrazol-4-yl)-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (2m)

Method A. The title compound was prepared according to the method of Example 1. White solid. Yield 9%. Mp 156°C. ^1H NMR (500 MHz, DMSO- _d6 + DCl): 3.53 and 3.61 (2×dd, 2×1H, _Jgem = 11.9, J _5′,4′ = 3.8, H-5′); 3.93 (td, 1H, J _4′,5′ = 3.8, J _4′,3′ = 3.3, H-4′); 4.10 (dd, 1H, J _3′,2′ = 4.9, J _3′,4′ = 3.3, H-3′); 4.35 (dd, 1H, J 2′,1′ = 6.1, J _2′,3′ = 4.9, H-2′); 6.15 (d, 1H, J _1′,2′ = 4.7, H- _3′ ); =6.1, H-1′); 7.85 (s, 1H, H-6); 8.09 (s, 2H, H-3,5-pyrazole); 8.52 (s, 1H, H-2). ¹³ C NMR (125.7 MHz, DMSO-d ₆ +DCl): 61.52 (CH ₂ -5′); 70.72 (CH-3′); 74.83 (CH-2′); 85.97 (CH-4′); 87.14 (CH-1′); 99.99 (C-4a); 109.14 (C-4-pyrazole); 112.19 (C-5); 124.02 (CH-6); 133.06 (CH-3,5-pyrazole); 142.88 (CH-2); 148.10 (C-7a); 151.41 (C-4). IR (KBr): 3468, 3338, 3239, 3200, 3115, 1740, 1629, 1583, 1559, 1523, 1469, 1306, 1123, 1076, 1044, ₁₀₂₄ , 796. MS (ESI): m/ _z 333 (M+H), ₃₅₅ (M+Na). HRMS (ESI) calculated for _C14H17N6O4 [M+H]: 333.1306; found: 333.1304.

Method B. A mixture of 7-iodotuberculocidin 1 (1.649 g, 4.2 mmol), 1-dimethylaminosulfonyl-4-tributylstannylpyrazole {for preparation, see US 2004/0157892A1} (2.97 g, 6.4 mmol), _Na₂CO₃ (724 _mg , 6.83 mmol), and PdCl₂( _PPh₃ ) _{₂ (} 148 mg, 0.21 mmol) in DMF (15 ml) was stirred at 100° C. for 3 hours under argon purge. The volatiles were removed under reduced pressure, and the residue was co-evaporated with toluene/methanol several times and purified by silica gel column chromatography (0→8% MeOH in _CHCl₃ ) to afford the product (1.459 g, 79%) in which the pyrazole nitrogen atom was protected with a dimethylaminosulfonyl group. This material was directly deprotected by adding aqueous HCl (1 M, 20 ml) and stirring at 100° C. for 3 hours. The volatiles were removed in vacuo, and the residue was co-evaporated with water (10-15×), co-evaporated once with aqueous ammonia (25% w/w), and co-evaporated again with water (6×). Recrystallization from water gave the title compound 2m as white needles (707 mg, 64% yield for the deprotection step). After crystallization from MeOH/water, the mother liquor was purified by reverse phase chromatography (0→100% MeOH in water) to give another portion of the title compound (243 mg, 22% yield for the deprotection step). The overall yield (coupling + deprotection) was 60%.

Example 14. 4-Amino-5-(1H-pyrazol-3-yl)-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (2n)

A mixture of 7-iodotuberculocidin 1 (392 mg, 1 mmol), pyrazole-5-boronic acid (224 mg, 2 mmol), Na ₂ CO ₃ (318 mg, 3 mmol), Pd(OAc) ₂ (11 mg, 0.05 mmol), and TPPTS (71 mg, 0.125 mmol) in water/MeCN (2:1, 5 ml) was stirred at 100° C. for 18 hours under argon purge. After cooling, the mixture was neutralized by adding aqueous HCl (1 M) and desalted by reverse phase chromatography (0→100% MeOH in water). The title compound 2n was purified by silica gel column chromatography (8% MeOH in CHCl ₃ ) to give the title compound 2n as a white glassy solid (273 mg, 82%). Recrystallization from boiling water gave a white solid. Mp 135° C. ¹ H NMR (500MHz, DMSO-d ₆ ): 3.55 (ddd, 1H, J _gem = 12.1, J _{5′b, OH} = 6.4, J _{5′b, 4′} = 4.1, H-5′b); 3.66 (ddd, 1H, J _gem = 12.1, J _{5′a, OH} = 5.0, J _{5′a, 4′} =3.9, H-5′a); 3.90 (ddd, 1H, J _4′,5′ = 4.1, 3.9, J _4′,3′ = 3.2, H-4′); 4.11 (ddd, 1H, J _{3′, 2′} = 5.2, J _{3′, 2′} = 4.8, J _{3′, 4′} =3.2, H-3′); 4.44(ddd, 1H, J _2′,OH =6.4, J _2′,1′ =6.3, J _2′,3′ =5.2, H-2′); 6.04 (d, 1H, J _1′,2′ = 6.1, H-1′); 6.66 (dd, 1H, J _4,5 = 2.4, J _{4, NH} =1.9, H-4-pyrazole); 7.25 (bs, 1H, NH _a H _b ); 7.81 (dd, 1H, J _5,4 = 2.4, J _{5, NH} = 1.5, H-5-pyrazole); 7.86 (s, 1H, H-6); 8.04 (s, 1H, H-2); 9.24 (bs, 1H, NH _a H _b ); 12.88 (bs, 1H, NH). ¹³ C NMR (125.7 MHz, DMSO-d ₆ ): 61.98 (CH ₂ -5′); 70.76 (CH-3′); 73.75 (CH-2′); 85.27 (CH-4′); 87.32 (CH-1′); 100.36 (C-4a); 101.91 (CH-4-pyrazole); 109.76 (C-5); 120.64 (CH-6); 130.20 (CH-5-pyrazole); 146.26 (C-3-pyrazole); 151.02 (C-7a); 152.44 (CH-2); 158.47 (C-4). IR (KBr): 3411, 3290, 3136, 2665, 1633, 1597, 1576, 1550, 1474, 1301, 1138, 1109, 1082, 1050, ₁₀₁₉ , 934, 798, 765, _651. MS (ESI): m/z ₃₃₃ (M+H), ₃₅₅ (M+Na). HRMS (ESI) calculated for C14H17N6O4 [ _{M + H]} : 333.1306; found: 333.1306. Calculated for _C14H16N6O4 · _1.85H2O : C, 45.99; H, 5.43; N, 22.98. Found: C, 46.22; H, 5.44; N, 22.68.

Example 15. 4-Amino-5-ethynyl-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (2o)

Step 1. 4-Amino-7-(β-D-ribofuranosyl)-5-[(trimethylsilyl)ethynyl]-7H-pyrrolo[2,3-d]pyrimidine (3)

A mixture of 7-iodotuberculocidin 1 (1010 mg, 2.57 mmol), _PdCl2 ( _PPh3 ) ₂ (90 mg, 0.13 mmol), CuI (49 mg, 0.26 mmol), trimethylsilylacetylene (3.6 ml, 25.7 mmol), and triethylamine (1 ml) in DMF (4 ml) purged with argon was stirred at room temperature for 16 hours. The volatiles were removed in vacuo, and the residue was co-evaporated twice with EtOH and loaded onto silica gel by co-evaporation from EtOH. Silica gel column chromatography (0→3% MeOH in _CHCl3 ) gave the product 3 as an off-white crystalline solid (962 mg, quantitative). The product was recrystallized from _CHCl3 /MeOH. Mp 167-169°C. [α] _D -77.6 (c 0.313, DMSO). ¹ H NMR (400.0MHz, DMSO-d ₆ ): 0.24 (s, 9H, CH ₃ -TMS); 3.54 (ddd, 1H, J _gem = 12.0, J _{5′b, OH} = 6.2, J _{5′b, 4′} = 3.8, H-5′b); 3.63 (dd, 1H, J _gem = 12.0, J _5′a,OH =5.0, J _5′a,4′ =3.8, H-5′a); 3.90 (td, 1H, J _4′,5′ = 3.8, J _4′,3′ = 3.2, H-4′); 4.08 (ddd, 1H, J _3′,2′ = 5.0, J _3′,OH = 4.8, J _3′,4′ =3.2, H-3′); 4.36 (ddd, 1H, J _{2′, OH} = 6.3, J _{2′, 1′} = 6.0, J _{2′, 3′} = 5.0, H-2′); 5.15 (d, 1H, J _{OH, 3′} = 4.7, OH-3′); 5.20 (dd, 1H, J _{OH, 5′} =6.2, 5.0, OH-5'); 5.35 (d, 1H, J _OH,2' = 6.3, OH-5'); 6.02 (d, 1H, J _{1', 2'} = 6.0, H-1'); 6.64 (bs, 2H, NH ₂ ); 7.84 (s, 1H, H-6); 8.13 (s, 1H, H-2). ¹³ C NMR (100.6MHz, DMSO-d ₆ ): -0.19 (CH ₃ -TMS); 61.47 (CH ₂ -5′); 70.45(CH-3′); 74.06(CH-2′); 85.26(CH-4′); 87.23(CH-1′); 94.60(C-5); 96.78(-C≡CTMS ); 99.14(-C≡CTMS); 102.41(C-4a); 127.38(CH-6); 149.48(C-7a); 152.82(CH-2); 157.58(C-4). MS (ESI) m/z 363 (M+H), 385 (M+Na). HRMS (ESI) Calcd _{for C16H23N4O4Si [} M+H _] : 363.1483; Found: 363.1484 _{. Calcd for C16H22N4O4Si : C} , _53.02 ; H, 6.12; N, 15.46. Found: C, 52.91; H, 6.11; N, 15.30.

Step 2. 4-Amino-5-ethynyl-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (2o)

A mixture of compound 3 (686 mg, 1.89 mmol) obtained in step 1 and _K₂CO₃ (130 mg, 0.94 mmol) in _MeOH (15 ml) was stirred at room temperature for 1 hour and then co-evaporated with silica gel. Silica gel column chromatography (5% MeOH in _CHCl₃ ) afforded the title compound 2o as a white crystalline solid (528 mg, 96%). The compound was recrystallized from MeOH/water as long, tan needles. Mp 215-217°C. [α] _D -88.3 (c 0.524, DMSO). ¹ H NMR (500.0MHz, DMSO-d ₆ ): 3.53 (ddd, 1H, J _gem = 12.0, J _{5′b, OH} = 6.2, J _{5′b, 4′} = 3.8, H-5′b); 3.63 (dd, 1H, J _gem = 12.0, J _{5′a, OH} = 5.0, J _{5′a, 4′} =3.8, H-5′a); 3.89 (td, 1H, J _{4′, 5′} = 3.8, J _{4′, 3′} = 3.2, H-4′); 4.07 (ddd, 1H, J _{3′, 2′} = 5.0, J _{3′, OH} = 4.8, J _{3′, 4′} =3.2, H-3′); 4.29 (s, 1H, HC≡C-); 4.37 (ddd, 1H, J _2′,OH = 6.3, J _2′,1′ = 6.1, J _2′,3′ = 5.0, H-2′); 5.16 (d, 1H, J _OH,3′ =4.8, OH-3′); 5.23 (dd, 1H, J _OH,5′ = 6.2, 5.0, OH-5′); 5.38 (d, 1H, J _OH,2′ = 6.3, OH-5′); 6.01 (d, 1H, J _1′,2′ = 6.1, H-1′); 6.70 (bs, 2H, NH ₂ ); 7.83 (s, 1H, H-6); 8.12 (s, 1H, H-2). ¹³ C NMR (125.7MHz, DMSO-d ₆ ): 61.73 (CH ₂ -5′); 70.74(CH-3′); 74.21(CH-2′); 77.52(-C≡CH); 83.37(-C≡CH); 85.51(CH-4′); 87.42(CH-1′); 94.17(C-5); 102.65(C-4a); 127.74(CH-6); 149.73(C-7a); 153.04(CH-2); 157.78(C-4). MS (ESI) m/z 291 (M+H), 313 (M+Na). HRMS (ESI) Calcd for _{C13H15N4O4 [} M+H _] : 291.1088; Found: 291.1088. Calcd _{for C13H14N4O4} : C, _53.79 ; _H , _4.86 ; N, 18.91. Found: C, 53.34; H, 4.95; N, 18.97.

Example 16. 4-Amino-7-(β-D-ribofuranosyl)-5-(1H-1,2,3-triazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (2p)

A mixture of 7-ethynyltuberculocidin 1 (the compound obtained in Example 15), CuI (6.5 mg, 0.03 mmol), and TMSN ₃ (150 μl, 1.15 mmol) in MeOH (0.2 ml)/DMF (1.8 ml) was stirred at 100° C. for 24 hours under argon purge. The volatiles were evaporated under reduced pressure, and the residue was co-evaporated twice with MeOH. The residue was suspended in MeOH and filtered through Celite. The filtrate was co-evaporated with silica gel and subjected to silica gel column chromatography to afford the title compound 2p as a yellow solid (55 mg, 24%). The product was recrystallized from water. Mp 286-288° C. [α] _D -70 (c 0.217, DMSO). ¹ H NMR (499.8MHz, DMSO-d ₆ , t=60°C): 3.58 (dd, 1H, J _gem =11.9, J _5′b,4′ =4.2, H-5′b); 3.68 (dd, 1H, J _gem =11.9, J _5′a,4′ =3.9, H-5′a); 3.93 (ddd, 1H, J _4′,5′ = 4.2, 3.9, J _4′,3′ = 3.6, H-4′); 4.15 (dd, 1H, J _3′,2′ = 5.3, J _3′,4′ = 3.6, H-3′); 4.45 (dd, 1H, J _2′,1′ =6.0, J _2′,3′ =5.3, H-2′); 4.93, 5.04 and 5.17 (3×bs, 3×1H, OH-2′,3′,5′); 6.08 (d, 1H, J _1′,2′ =6.0, H-1′); 7.85 (bs, 2H, NH2); 7.91 (s, 1H, H-6); 8.09 (s, 1H, H-2); 8.23 (s, 1H, H-5-triazole). ¹³ C NMR (125,7 MHz, DMSO-d ₆ , t=60° C.): 61.83 (CH ₂ -5′); 70.54 (CH-3′); 73.72 (CH-2′); 85.15 (CH-4′); 87.41 (CH-1′); 100.16 (C-4a); 105.83 (C-5); 120.80 (CH-6); 126.16 (CH-5-triazole); 141.51 (C-4-triazole); 151.04 (C-7a); 152.35 (CH-2); 158.04 (C-4). MS (ESI) m/z 334 (M+H), 356 (M+Na). HRMS (ESI) Calcd. for ₁₃ H ₁₆ N ₇ O ₄ [M+H]: 334.1258; Found: 334.1258. Calcd. for C ₁₃ H ₁₅ N ₇ O ₄ : C, 46.85; H, 4.54; N, 29.42. Found: C, 47.12; H, 4.82; N, 27.96.

Example 17. 4-Amino-7-(β-D-ribofuranosyl)-5-(thiazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (2q)

Step 1. 4-Amino-5-iodo-7-[2,3,5-tri-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine (4)

Tert-butyldimethylsilyl chloride (6.78g, 45mmol) is added to a solution of 7-iodotuberculocidin 1 (3.92g, 10mmol) and imidazoles (6.12g, 90mmol) in DMF (20ml), and the mixture is stirred at RT overnight. The mixture is diluted with hexane (100ml) and washed with a NaCl aqueous solution (5%, 100ml). The aqueous layer is extracted again with hexane (2×25ml). The organic phase is washed with a NaCl aqueous solution (5%w/w, 4×50ml). The combined organic extracts are dried over MgSO ₄ , evaporated and chromatographically purified on silica gel (hexane/AcOEt, 50:1→5:1) to obtain title compound 4, which is a colorless foam (3.05g, 41%), and the by-product caused by the silylation of 6-amino acids is quickly removed. The oversilylated byproduct was converted to the title compound 4 (2.96 g, 40%) by allowing its methanolic solution to stand at RT for several days. The overall yield of the title compound 4 was 81%. ¹ H NMR (500.0MHz, CDCl ₃ ): -0.28, -0.08, 0.096, 0.098, 0.17 and 0.18 (6×s, 6×3H, CH ₃ Si); 0.77, 0.93 and 0.99 (3×s, 3×9H, (CH ₃ )C); 3.77 (dd, 1H, J _gem ＝11.4, J _5′b,4′ ＝2.3, H-5′b); 3.95(dd, 1H, J _gem ＝11.4, J _5′a,4′ ＝3.0, H-5′a); 4.08(td, 1H, J _4′,5′ ＝3.0, 2.3, J _4′,3′ =3.0,H-4′);4.22(dd,1H,J _3′,2′ =4.5, J _3′,4′ =3.0, H-3′); 4.39 (dd, 1H, J _2′,1′ = 5.6, J _2′,3′ = 4.5, H-2′); 5.70 (bs, 2H, NH ₂ ); 6.26 (d, 1H, J _1′,2′ =5.6, H-1'); 7.52 (s, 1H, H-6); 8.26 (s, 1H, H-2). ¹³ C NMR (125.7MHz, CDCl ₃ ): -5.33, -5.31, -5.26, -4.76, -4.75 and -4.41 (CH ₃ Si); 17.84, 18.10 and 18.60 (C(CH ₃ ) ₃ ); 25.65, 25.84 and 26.17 ((CH ₃ ) ₃ C); 50.20(C-5); 62.94(CH ₂ -5′); 72.43(CH-3′); 76.78(CH-2′); 85.46(CH-4′); 87.48(CH-1′); 104.26(C-4a); 126.62(CH-6); 150.66(C-7a); 152.19(CH-2); 156.74(C-4). MS (ESI) m/z 735 (M+H), 757 (M+Na).

Step 2. 4-Amino-5-(thiazol-2-yl)-7-[2,3,5-tri-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine (5)

_{A mixture of compound 4 (544 mg, 0.74 mmol) obtained from step 1, 2-(tributylstannyl)thiazole (554 mg, 1.48 mmol) and PdCl2(PPh3)2 ( 22} mg, 0.03 mmol) in DMF (3 ml) purged with argon was stirred at 100°C for 48 hours. The volatiles were evaporated under reduced pressure, and the residue was co-evaporated with water (3×), co-evaporated twice with MeOH, co-evaporated twice with hexane, and then co-evaporated with silica gel in hexane. Purification by silica gel column chromatography (hexane, then hexane/AcOEt, 10:1→6:1) gave the title compound 5 as a foam (454 mg, 89%). ¹ H NMR (500.0MHz, CDCl ₃ ): -0.36, -0.10, 0.11, 0.13, 0.17 and 0.18 (6×s, 6×3H, CH ₃ Si); 0.74, 0.95 and 0.99 (3×s, 3×9H, (CH ₃ )C); 3.79 (dd, 1H, J _gem =11.4, J _5′b,4′ =2.7, H-5′b); 3.96 (dd, 1H, J _gem = 11.4, J _5′a,4′ = 3.2, H-5′a); 4.11 (ddd, 1H, J _4′,5′ = 3.9, 2.7, J _4′,3′ =1.8,H-4′);4.23(dd,1H,J _3′,2′ 5,4 ＝3.4, H-5-thiazolyl); 7.72 (d, _{1H , J 4,5 ＝} 3.4, H-4 _- thiazolyl); 7.74 (s, 1H _, H-6); 8.26 (s, 1H, H- ₂ ); 9.79 ₍ bs, 1H, NH _{a H b} ). ¹³ C NMR (125.7 MHz, CDCl ₃ ): -5.35, -5.33, -5.19, -4.65, -4.61 and -4.47 (CH ₃ Si); 17.82, 18.13 and 18.57 (C(CH ₃ ) ₃ ); 25.61, 25.86 and 26.15 ((CH ₃ ) ₃ C); 63.37 (CH ₂ 141.71 (CH-4-thiazolyl); 151.57 (C-7a); 151.94 (CH-2); 157.52 (C-4); 163.53 (C-2-thiazolyl). MS (ESI) m/z 692 (M+H), 714 (M+Na). HRMS (ESI) calcd _{for C32H58N5O4SSi3} [M+H _{] : 692.3512} ; found: 692.3512.

Step 3. 4-Amino-7-(β-D-ribofuranosyl)-5-(thiazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (2q)

Compound 5 (448 mg, 0.65 mmol) obtained by step 2 was treated with a solution of HCl aqueous solution (1 M, 1 ml) in methanol (1 ml) at RT for 2 hours. Volatiles were removed in vacuo, and the solid residue was co-evaporated with water (6 ×). The crude product was recrystallized in MeOH/water to give the title compound 2q as a long white needle (132 mg, 58%). The mother liquor was purified by silica gel column chromatography (8% MeOH in CHCl ₃ ) to give another portion of the product (61 mg, 27%). Overall yield 85%. Mp 226-228 ° C. [α] _D -81.5 (c 0.254, DMSO). ¹ H NMR (600.1MHz, DMSO-d ₆ ): 3.61 (dd, 1H, J _gem = 12.0, J _{5′b, 4′} = 3.6, H-5′b); 3.72 (dd, 1H, J _gem = 12.0, J _{5′a, 4′} = 3.9, H-5′a); 3.97 (td, 1H, J _4′,5′ =3.9,3.6,J _4′,3′ =3.9,H-4′);4.16(dd,1H,J _3′,2′ =4.9,J _3′,4′ =3.9,H-3′);4.41(dd,1H,J _2′,1′ =5.6,J _2′,3′ =4.9, H-2′); 6.14(d, 1H, J _1′,2′ =5.6, H-1′); 7.80 (d, 1H, J _5,4 =3.3, H-5-thiazolyl); 7.91 (d, 1H, J _4,5 =3.3, H-4-thiazolyl); 8.48 (s, 1H, H-2); 8.62 (s, 1H, H-6); 8.99 and 10.88 (2×bs, 2H, NH ₂ ). ¹³ C NMR (150.9 MHz, DMSO-d ₆ ): 61.12 (CH ₂ -5′); 70.19 (CH-3′); 74.78 (CH-2′); 85.80 (CH-4′); 87.63 (CH-1′); 99.39 (C-4a); 113.09 (C-5); 120.13 (CH-5-thiazolyl); 125.34 (CH-6); 142.09 (CH-4-thiazolyl); 145.00 (CH-2); 148.55 (C-7a); 152.47 (C-4); 162.07 (C-2-thiazolyl). MS (ESI) m/z 350 (M+H), 372 (M+Na). HRMS (ESI _{) calcd for C14H16N5O4S[M+H]: 350.0918; found: 350.0918. Calcd for C14H15N5O4S·1/2H2O·CH3OH : C , 46.15 ; H , 5.16 ;} N, 17.94. Found: C, 46.41; H, 4.96; N, 17.67.

Example 18. 4-Amino-5-(1H-imidazol-4-yl)-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (2r)

To a solution of 4-iodo-1-trityl-1H-imidazole (609 mg, 1.4 mmol) in anhydrous THF (6 ml) was added EtMgBr (1 M in THF, 1.5 ml, 1.5 mmol), and the mixture was stirred at room temperature for 10 minutes. Then, a solution of _ZnCl₂ (1 M in THF, 2.8 ml, 2.8 mmol) was added dropwise, and the mixture was stirred for 2 hours. The resulting viscous slurry was transferred to an argon-purged mixture of 2',3',5'-tri-O-TBS-7-iodotuberculocidin {Compound 4 obtained from Step 1 of Example 17} (515 mg, 0.7 mmol) and Pd( _PPh₃ ) _₄ (40 mg, 0.035 mmol), and the mixture was stirred at 90°C for 16 hours. The mixture was diluted with _CHCl₃ (20 ml) and washed with aqueous EDTA (saturated, 20 ml). The aqueous layer was extracted again with _CHCl₃ (2×5 ml). The collected organic extracts were dried over _MgSO₄ , evaporated and purified by silica gel chromatography (hexane/AcOEt, 4:1→3:1) to give crude TBS. The Tr-protected product contained N-tritylimidazole as an impurity. The crude product was deprotected by stirring in a TFA aqueous solution (90% v/v, 2 ml) at RT for 18 hours. The volatiles were removed in vacuo, and the residue was co-evaporated with MeOH several times and finally loaded onto silica gel by co-evaporation in MeOH. Purification by silica gel column chromatography (0→10% MeOH in _CHCl₃ ) gave the title compound 2r as a white powder (179 mg, 77%). The compound was recrystallized from MeOH/water. Mp 276-278°C. [α] _D -61.4 (c 0.249, DMSO). ¹ H NMR (500.0MHz, DMSO-d ₆ ): 3.53 (ddd, 1H, J _gem = 12.0, J _{5′b, OH} = 6.5, J _{5′b, 4′} = 4.2, H-5′b); 3.64 (dd, 1H, J _gem = 12.0, J _{5′a, OH} = 4.8, J _{5′a, 4′} =4.2, H-5′a); 3.89 (td, 1H, J _{4′, 5′} = 4.2, J _{4′, 3′} = 3.4, H-4′); 4.09 (ddd, 1H, J _{3′, 2′} = 5.0, J _{3′, OH} = 4.8, J _{3′, 4′} =3.4, H-3′); 4.41(ddd, 1H, J _{2′, OH} =6.5, J _2′,1′ =6.3, J _2′,3′ =5.0, H-2′); 5.14 (d, 1H, J _OH,3′ = 4.8, OH-3′); 5.30 (dd, 1H, J _OH,5′ = 6.5, 4.8, OH-5′); 5.34 (d, 1H, J _{OH, 2′} =6.5, OH-5′); 6.03 (d, 1H, J _1′,2′ = 6.3, H-1′); 7.14 (bs, 1H, NH _a H _b ); 7.50 (d, 1H, J _{5, NH} = 2.0, J _5,2 =0.8, H-5-imidazole); 7.68 (s, 1H, H-6); 7.81 (d, 1H, J _2,5 =0.8, H-2-imidazole); 8.01 (s, 1H, H-2); 9.99 (bs, 1H, NH _a H _b ); 12.31 (bs, 1H, NH-imidazole). ¹³ C NMR (125.7 MHz, DMSO-d ₆ ): 62.11 (CH ₂ -5′); 70.87 (CH-3′); 73.76 (CH-2′); 85.23 (CH-4′); 87.30 (CH-1′); 100.77 (C-4a); 110.84 (C-5); 111.81 (CH-5-imidazole); 117.90 (CH-6); 134.95 (CH-2-imidazole); 135.10 (C-4-imidazole); 150.56 (C-7a); 152.08 (CH-2); 158.59 (C-4). MS (ESI) m/z 333 (M+H), 355 (M+Na). HRMS (ESI) Calcd _{for C14H17N6O4 [ M} +H _] : 333.1306; Found: 333.1306. Calcd _{for C14H16N6O4} : C, _50.60 ; H, _4.85 ; N, 25.29. Found: C, 50.55; H, 5.01; N, 24.28.

Example 19. 4-Amino-5-(1H-imidazol-2-yl)-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (2s)

To a stirred solution of 1-(N,N-dimethylaminosulfonyl)-1H-imidazole (875 mg, 5 mmol) in THF (15 ml) was added n-butyllithium (1.6 M in hexane, 3.1 ml, 5 mmol) dropwise at -78°C over 30 minutes. _ZnCl₂ solution (1 M in THF, 10 ml, 10 mmol) was then added dropwise at -78°C, and the mixture was allowed to warm to room temperature over 45 minutes. The resulting orange solution was transferred to an argon-purged mixture of 2',3',5'-tri-O-TBS-7-iodotuberculocidin {Compound 4 obtained from Example 17, Step 1} (735 mg, 1 mmol) and Pd( _PPh₃ ) _₄ (116 mg, 0.1 mmol), and the mixture was stirred at 90°C for 24 hours. The mixture was diluted with AcOEt (20 ml) and washed with an EDTA aqueous solution (saturated, 25 ml). The aqueous layer was extracted again with AcOEt (10 ml). The collected organic extracts were dried over MgSO ₄ , evaporated, and the residue was purified by silica gel chromatography (hexane/AcOEt, 5: 1 → 1: 1; then AcOEt) to give a product containing an inseparable mixture of imidazoles initially protected. The mixture was directly deprotected by stirring in an aqueous HCl solution (1 M, 2 ml) and MeOH (2 ml) at 100 ° C for 24 hours. The volatiles were removed in vacuo, and the residue was co-evaporated with water (5 ×). The residue was treated with MeOH, and the insoluble solid (imidazole) was filtered off and washed with MeOH. The filtrate was evaporated and purified by reverse phase chromatography (0→100% MeOH in water) to give the crude product, which was repurified by silica gel column chromatography (8% MeOH in CHCl ₃ ) to give the title compound 2s as a yellow foam (42 mg, 13%). The compound was recrystallized from MeOH/water. Mp 153-156°C. [α] _D -72.1 (c 0.19, DMSO). ¹ H NMR (499.8MHz, DMSO-d ₆ ): 3.56 (ddd, 1H, J _gem = 11.9, J _{5′b, OH} = 6.5, J _{5′b, 4′} = 4.6, H-5′b); 3.64 (dd, 1H, J _gem = 11.9, J _{5′a, OH} = 5.0, J _{5′a, 4′} =4.1, H-5′a); 3.92 (ddd, 1H, J _4′,5′ = 4.6, 4.1, J _4′,3′ = 3.4, H-4′); 4.10 (ddd, 1H, J _{3′, OH} = 5.2, J _{3′, 2′} = 5.0, J _{3′, 4′} =3.4, H-3′); 4.36 (ddd, 1H, J _2′,OH =6.3, J _2′,1′ =6.0, J _2′,3′ =5.0, H-2′); 5.16 (dd, 1H, J _OH,5′ = 6.5, 5.0, OH-5′); 5.17 (d, 1H, J _OH,3′ = 5.2, OH-3′); 5.39 (d, 1H, J _OH,2′ =6.3, OH-5′); 6.05 (d, 1H, J _1′,2′ = 6.0, H-1′); 7.00 (t, 1H, J _{4,5 =} J _{4, NH} = 1.4, H-4-imidazole); 7.22 (dd, 1H, J _{5, NH} = 2.0, J _5,4 =1.4, H-5-imidazole); 7.24 (bs, 1H, NH _a H _b ); 7.86 (s, 1H, H-6); 8.06 (s, 1H, H-2); 10.23 (bs, 1H, NH _a H _b ); 12.42 (bs, 1H, NH-imidazole). ¹³ C NMR (125.7 MHz, DMSO-d ₆ ): 62.25 (CH ₂ -5′); 70.90 (CH-3′); 73.99 (CH-2′); 85.27 (CH-4′); 87.33 (CH-1′); 100.12 (C-4a); 107.87 (C-5); 116.81 (CH-5-imidazole); 119.44 (CH-6); 127.22 (CH-4-imidazole); 142.49 (C-2-imidazole); 150.82 (C-7a); 152.91 (CH-2); 158.58 (C-4). MS (ESI) m/z 333 (M+H), 355 (M+Na). HRMS (ESI) calculated for _C14H17N6O4 [ _M +H _] : 333.1306; found: 333.1306. _{Calculated for C14H16N6O4} · _1.85H2O · _{0.55CH3OH :} C, 45.60; H, 5.76; N, 21.93. Found: C, 45.67; H, 5.66; _N , 21.86.

Example 20. 4-Amino-7-(2-C-methyl-β-D-ribofuranosyl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidine (7a)

Step 1. 4-Chloro-5-iodo-7-(2-C-methyl-2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (10).

To a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine 8 (903 mg, 3.23 mmol), 2-C-methyl-1,2,3,5-tetra-O-benzoyl-β-D-ribofuranose 9 (1.7 g, 2.93 mmol) and DBU (1.3 ml, 8.69 mmol) in MeCN (20 ml) was added TMSOTf (2.1 ml, 11.62 mmol) dropwise at 0 ° C., and the mixture was stirred at 70 ° C. for 22.5 hours. After cooling, the mixture was diluted with AcOEt (100 ml), washed with NaHCO ₃ aqueous solution (saturated, 25 ml), water (25 ml) and brine (25 ml). The organic layer was dried over MgSO ₄ and evaporated. The residue was purified by silica gel chromatography (hexane/toluene, 1:1; then hexane/toluene/MeCN, 49:49:2→3:3:4) to afford the title compound 10 as a white foam (1.04 g, 48%). The compound was recrystallized from EtOH. Mp 95°C. [α] ²⁰ _D -69.3 (c 0.280, CHCl ₃ ). ¹ H NMR (500MHz, CDCl ₃ ): 1.59 (s, 3H, CH ₃ ); 4.72 (td, 1H, J _{4′, 3′} = J _{4′, 5′b} = 5.8, J _{4′, 5′a} = 3.4, H-4′); 4.85 (dd, 1H, J _gem = 12.2, J _{5′b, 4′} =5.8, H-5′b); 4.95 (dd, 1H, J _gem =12.2, J _5′a,4′ = 3.4, H-5′a); 6.03 (d, 1H, J _3′,4′ =5.8, H-3'); 6.95 (s, 1H, H-1'); 7.34, 7.46 and 7.47 (3 x m, 3 x 2H, Hm-Bz); 7.54, 7.59 and 7.61 (3 x m, 3 x 1H, Hp-Bz); 7.69 (s, 1H, H-6); 7.96, 8.10 and 8.11 (3 x m, 3 x 2H, Ho-Bz); 8.75 (s, 1H, H-2). ¹³ C NMR (125.7 MHz, CDCl ₃ ): 17.92 (CH ₃ ); 52.68 (C-5); 63.33 (CH ₂ -5'); 75.55 (CH-3'); 80.04 (CH-4'); 84.93 (C-2'); 88.95 (CH-1'); 117.71 (C-4a); 128.49, 128.54 and 128.63 (CH-m-Bz); 128.65, 129.50 and 129.61 (Ci-Bz); 129. 78, 129.83 and 129.92 (CH-o-Bz); 132.66 (CH-6); 133.38, 133.66, 133.72 (CH-p-Bz); 150.68 (C-7a); 151.17 (CH-2); 153.15 (C-4); 165.09, 165.33 and 166.32 (CO). IR (CHCl ₃ ): 3092, 3066, 3034, 1727, 1602, 1587, 1577, 1538, 1504, 1493, 1451, 1444, 1339, 1316, 1269, 1248, 1178, 1162, 1141, 1116, 1070, 1027, 1002, 952, 943, 843, 822, 725, 712, 686, 617, 600. MS (FAB): m/z 738 (M+H). HRMS (FAB) calcd for C ₃₃ H ₂₆ ClIN ₃ O ₇ [M+H]: 738.0504; found: 738.0491. Calculated for _C33H25C1N3O7 : C, _53.71 ; H _, 3.41; N, 5.69. Found: _C 53.91; H 3.29; N 5.38.

Step 2. 4-Amino-5-iodo-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (6).

A mixture of compound 10 (200 mg, 0.27 mmol) obtained in step 1 and aqueous ammonia (25% w/w, 3 ml) in dioxane (3 ml) was stirred in a sealed tube at 120°C for 10 hours. After cooling, the volatiles were evaporated, and the crude product was purified by silica gel chromatography ( _CHCl₃ → _CHCl₃ /MeOH, 8:2) and then by reverse phase chromatography (0 → 100% MeOH in water) to afford the title compound 6 as a white solid (76 mg, 69%). The compound was recrystallized from MeOH/MeCN. Mp 207°C. [α] ^₂O _D -39.0 (c 0.274, MeOH). ¹ H NMR (600MHz, DMSO-d ₆ ): 0.67 (s, 3H, CH3); 3.65 (ddd, 1H, J _gem = 12.1, J _{5′b, OH} = 4.8, J _{5′b, 4′} = 2.7, H-5′b); 3.81 (ddd, 1H, J _gem = 12.1, J _{5′a, OH} =4.8, J _5′a,4′ =2.0, H-5′a); 3.79 (ddd, 1H, J _4′,3′ = 9.1, J _4′,5′ = 2.7, 2.0, H-4′); 3.93 (bd, 1H, J _3′,4′ =9.1, H-3′); 5.14 (s, 1H, OH-2′); 5.16 (bs, 1H, OH-3′); 5.22 (t, 1H, J _OH,5′ = 4.8, OH-5′); 6.10 (s, 1H, H-1′); 6.67 (bs, 2H, NH ₂ ); 7.82 (s, 1H, H-6); 8.10 (s, 1H, H-2). ¹³ C NMR (151MHz, DMSO-d ₆ ): 19.89 (CH ₃ ); 51.68 (C-5); 59.46 (CH ₂ -5′); 71.76(CH-3′); 78.87(C-2′); 82.39(CH-4′); 90.71(CH-1′); 103.11(C-4a); 126.81(CH-6); 149.88(C-7a); 152.23(CH-2); 157.43(C-4). IR (KBr): 3474, 3429, 3392, 3366, 1631, 1582, 1553, 1504, 1440, 1343, ₁₂₉₅ , 1147, 1128, 1070, 1045, 789. MS (FAB): m/ _{z 407} (M+H). HRMS ( _FAB ) calculated for _Ci2Hi6In4O4 [M ₊ H]: 407.0216; found: 407.0225. Calculated _{for Ci2Hi5In4O4} : C, 35.48; H, 3.72; N, 13.79. Found: C 35.37; H 3.72; N 13.39.

Step 3. 4-Amino-7-(2-C-methyl-β-D-ribofuranosyl)-5-phenyl-7H-pyrrolo[2,3-d]pyrimidine (7a)

A mixture of compound 6 (49 mg, 0.12 mmol) obtained in step 2, phenylboronic acid (25 mg, 0.20 mmol ₎ , _Na₂CO₃ (144 mg, 1.36 mmol), TPPTS (15.5 mg, 0.027 mmol), and Pd(OAc) _₂ (1.4 mg, 6.2 μmol) in water/MeCN (2:1, 1.8 ml) was stirred at 80°C for 1 hour under argon purging. After cooling, the volatiles were evaporated, and the residue was purified by reverse phase chromatography (0→100% MeOH in water) to provide the title compound 7a as a white solid (30 mg, 70%). Mp 129°C. [α] ^₂O _D -55.7 (c 0.226, MeOH). ¹ H NMR (600MHz, DMSO-d ₆ ): 0.75 (s, 3H, CH ₃ ); 3.65 (bdd, 1H, J _gem = 12.2, J _{5′b, 4′} = 2.9, H-5′b); 3.82 (bdd, 1H, J _gem = 12.2, J _{5′a, 4′} ＝2.1, H-5′a); 3.86(ddd, 1H, J _4′,3′ ＝9.1, J _4′,5′ ＝2.9, 2.1, H-4′); 4.02(d, 1H, J _3′,4′ =9.1, H-3′); 5.15 (bs, 3H, OH-2′, 3′, 5′); 6.10 (bs, 2H, NH ₂ ); 6.23 (s, 1H, H-1′); 7.36 (m, 1H, Hp-Ph); 7.44-7.50 (m, 4H, Ho, m-Ph); 7.70 (s, 1H, H-6); 8.16 (s, 1H, H-2). ¹³ C NMR (151MHz, DMSO-d ₆ ): 20.00 (CH ₃ ); 59.60 (CH ₂ 127 .05(CH-p-Ph); 128.64(CH-o-Ph); 129.23(CH-m-Ph); 134.89(Ci-Ph); 150.67(C-7a); 151.94(CH-2); 157.49(C-4). IR (KBr): 3480, 3431, 3400, 1631, 1622, 1585, 1566, 1537, 1489, 1464, 1445, ₁₂₉₉ , 1178, 1123, 1073, 1058, 1029, 799, 763, 705, 550. MS (FAB) m _{/ z 357} (M+H). HRMS (FAB) calcd for C18H21N4O4: _[ M _{+ H} ]: 357.1563; found: 357.1557. Calcd for _C18H20N4O4 · _1.6H2O : C, 56.13; H, 6.07; N, 14.54. Found: C, 56.52; H, 5.74; N, 14.14.

Example 21. 4-Amino-5-(4-methoxyphenyl)-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (7b)

The title compound was prepared according to the procedure of Example 20, Step 3. White solid. Yield 67%. Mp 127°C. [α] ²⁰ _D -48.4 (c 0.225, MeOH). ¹ H NMR (600MHz, DMSO-d ₆ ): 0.74 (s, 3H, CH ₃ ); 3.64 (bdd, 1H, J _gem = 12.21, J _{5′b, 4′} = 2.9, H-5′b); 3.80 (s, 3H, CH ₃ O); 3.81 (bdd, 1H, J _gem = 12.1, J _5′a,4′ =2.1, H-5′a); 3.85 (ddd, 1H, J _4′,3′ = 9.1, J _4′,5′ = 2.9, 2.1, H-4′); 4.01 (d, 1H, J _3′,4′ =9.1, H-3′); 5.13 (bs, 3H, OH-2′, 3′, 5′); 6.08 (bs, 2H, NH ₂ ); 6.22 (s, 1H, H-1'); 7.04 (m, 2H, HmC ₆ H ₄ OMe); 7.36 (m, 2H, HoC ₆ H ₄ OMe); 7.60 (s, 1H, H-6); 8.14 (s, 1H, H-2). ¹³ C NMR (151MHz, DMSO-d ₆ ): 19.99 (CH ₃ ); 55.39 (CH ₃ O); 59.61 (CH ₂ -5′); 72.03(CH-3′); 78.87(C-2′); 82.34(CH-4′); 90.47(CH-1′); 100.31(C-4a); 114.65(CH-mC ₆ H ₄ OMe); 116.06 (C-5); 120.14 (CH-6); 127.04 (CiC ₆ H ₄ OMe); 129.91 (CH-oC ₆ H ₄ OMe); 150.45 (C-7a); 151.85 (CH-2); 157.51 (C- ₄ ); 158.58 (CpC6H4OMe). IR (KBr): 3435, 2836, 1631, ₁₆₂₂ , 1586, 1565, 1539, 1506, 1464, 1419, 1293, 1247, 1174, 1110, 1072, 1033, 839, 798, ₇₉₁ , 712, 550. MS (FAB) m/ _{z 387} (M+H ₎ . HRMS (FAB) calcd for C19H23N4O5 [M+H]: 387.1668; found: 387.1665. _{Calculated for C19H22N4O5-1.6H2O :} C, 54.96; H, 6.12; _N , 13.49. Found: C, 55.30; _H , 5.91; N, 13.18.

Example 22. 4-Amino-7-(2-C-methyl-β-D-ribofuranosyl)-5-(naphthalen-1-yl)-7H-pyrrolo[2,3-d]pyrimidine (7c)

The title compound was prepared according to the procedure of Example 20, Step 3. The crude product was prepurified by silica gel chromatography (0→20% MeOH in _CHCl₃ ) before final reverse phase chromatography. Tan solid. Yield 41%. Mp 142°C. [α] ^₂O _D -58.6 (c 0.239, MeOH). ¹ H NMR (500MHz, DMSO-d ₆ , T=353K): 0.90 (s, 3H, CH ₃ ); 3.67 (dd, 1H, J _gem = 12.2, J _{5′b, 4′} = 3.5, H-5′b); 3.83 (dd, 1H, J _gem = 12.2, J _{5′a, 4′} ＝2.3, H-5′a); 3.91(ddd, 1H, J _4′,3′ ＝8.9, J _4′,5′ ＝3.5, 2.3, H-4′); 4.04(d, 1H, J _3′,4′ =8.9, H-3′); 4.89 (bs, 3H, OH-2′, 3′, 5′); 5.39 (bs, 2H, NH ₂ ); 6.34 (s, 1H, H-1′); 7.500 (ddd, 1H, J _7,8 ＝8.3, J _7,6 ＝6.9, J _7,5 ＝1.3, H-7-naphthyl); 7.502 (dd, 1H, J _2,3 ＝6.9, J _2,4 ＝1.3, H-2-naphthyl); 7.56 (ddd, 1H, J _6,5 ＝8.1, J _6,7 ＝6.9, J _6,8 ＝1.3, H-6-naphthyl); 7.60 (dd, 1H, J _3,4 ＝8.3, J _3,2 ＝6.9, H-3-naphthyl); 7.63 (s, 1H, H-6); 7.75 (dddd, 1H, J _8,7 ＝8.3, J _8,6 =1.3, J _8,4 =1.0, J _8,5 =0.8, H-8-naphthyl); 7.98 (ddd, 1H, J _4,3 =8.3, J _4,2 =1.3, J _4,8 =1.0, H-4-naphthyl); 8.01 (ddd, 1H, J _5,6 =8.1, J _5,7 =1.3, J _5,8 =0.8, H-5-naphthyl); 8.19 (s, 1H, H-2). ¹³ C NMR (151 MHz, DMSO-d ₆ , T=353K): 19.73 (CH ₃ ); 59.70 (CH ₂ -5'); 72.30 (CH-3'); 78.69 (C-2'); 82.28 (CH-4'); 90.64 (CH-1'); 102.10 (C-4a); 113.02 (C-5); 121.50 (CH-6); 125.27 (CH-8-naphthyl); 125.38 (CH-3-naphthyl); 125.98 (CH-6- naphthyl); 126.42 (CH-7-naphthyl); 127.82 (CH-4-naphthyl); 128.12 (CH-2,5-naphthyl); 131.63 (C-1-naphthyl); 132.13 (C-8a-naphthyl); 133.39 (C-4a-naphthyl); 150.05 (C-7a); 151.61 (CH-2); 156.96 (C-4). IR (KBr): 3478, 3438, 3395, 3058, 2973, 1620, 1583, 1578, 1568, 1533, 1507, 1468, 1398, 1377, 1298, 1256, 1178, 1143, 1117, 1071, 1050, 1035, 1018, ₈₅₂ , 799, 786, 780, 740. MS (ESI) m/ _{z 407 (M+H), 429 (M+Na). HRMS (ESI) calcd for C22H23N4O4 [} M+H]: 407.1714; found: 407.1704. Calculated _{for C22H22N4O4} · _1.5H2O : C, 60.96; H, 5.81; N, 12.93. Found: C, 61.30; H _, 5.72; _N , 13.28.

Example 23. 4-Amino-7-(2-C-methyl-β-D-ribofuranosyl)-5-(naphthalen-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (7d)

The title compound was prepared according to the procedure of Example 20, Step 3. The crude product was prepurified by silica gel chromatography (0→20% MeOH in _CHCl₃ ) before final reverse phase chromatography. Cream solid. Yield 65%. Mp 143°C. [α] ^₂O _D -64.3 (c 0.253, MeOH). ¹ H NMR (500MHz, DMSO-d ₆ ): 0.79 (s, 3H, CH ₃ ); 3.66 (ddd, 1H, J _gem = 12.6, J _{5′b, OH} = 5.0, J _{5′b, 4′} = 2.9, H-5′b); 3.84 (ddd, 1H, J _gem = 12.6, J _{5′a, OH} =5.0, J _5′a,4′ =2.1, H-5′a); 3.88 (ddd, 1H, J _4′,3′ = 9.1, J _4′,5′ = 2.9, 2.1, H-4′); 4.06 (bdd, 1H, J _3′,4′ = 9.1, J _{3′, OH} ＝4.6, H-3′); 5.11-5.17 (bm, 3H, OH-2′,3′,5′); 6.19 (bs, 2H, NH ₂ ); 6.27 (s, 1H, H-1′); 7.52 (m, 1H, H-6-naphthyl); 7.55 (m, 1H, H-7-naphthyl); 7.62 (dd, 1H, J _3,4 ＝8.5, J _3,1 ＝1.8, H-3-naphthyl); 7.81 (s, 1H, H-6); 7.94-7.97 (m, 3H, H-1,5,8-naphthyl); 8.01 (d, 1H, J _4,3 ＝8.5, H-4-naphthyl); 8.18 (s, 1H, H-2). ¹³ C NMR (125.7 MHz, DMSO-d ₆ ): 20.03 (CH ₃ ); 59.66 (CH ₂ -5′); 72.08 (CH-3′); 78.90 (C-2′); 82.41 (CH-4′); 90.57 (CH-1′); 100.24 (C-4a); 116.45 (C-5); 121.14 (CH-6); 126.10 (CH-6-naphthyl); 126.76 (CH-7-naphthyl); 126.82 (CH-1-naphthyl); 127.23 (CH-3-naphthyl); 127.87 and 128.02 (CH-5,8-naphthyl); 128.70 (CH-4-naphthyl); 132.00 (C-4a-naphthyl); 132.35 (C-1-naphthyl); 133.46 (C-8a-naphthyl); 150.82 (C-7a); 152.02 (CH-2); 157.61 (C-4). IR(KBr): 3506, 3481, 3452, 3402, 3325, 3242, 3210, 3110, 3052, 2973, 1645, 1624, 1605, 1587, 1567, 1535, 1503, 1469, 1378, 1298, 1274, 1142, 1128, 1116, 1075, 1057, 1050, 1019, 897, 860, 821, 796, 767, 750, 478. MS (ESI) m/z 407 (M+H), 429 (M+Na). HRMS (ESI) Calcd _{. for C22H23N4O4} [ _M +H _] : 407.1714; Found: 407.1715. Calcd. _{for C22H22N4O4} · _1.3H2O : C, 61.47; H, 5.77; N, 13.03. Found: C, 61.83; H _, 5.51; N, 12.65.

Example 24. 4-Amino-5-(furan-2-yl)-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (7e)

The title compound was prepared according to the procedure of Example 20, Step 3. White solid. Yield 55%. Mp 130°C. [α] ²⁰ _D -53.3 (c 0.250, MeOH). ¹ H NMR (600MHz, DMSO-d ₆ ): 0.72 (s, 3H, CH ₃ ); 3.68 and 3.85 (2×bd, 2H, J _gem = 12.0, H-5′); 3.87 (ddd, 1H, J _{4′, 3′} = 9.1, J _{4′, 5′} =2.9, 2.0, H-4′); 4.00 (bd, 1H, J _{3′, 4′} = 9.1, H-3′); 5.16 (bs, 2H, OH-2′, 3′); 5.25 (bs, 1H, OH-5′); 6.19 (s, 1H, H-1′); 6.58 (dd, 1H, J _3,4 =3.3,J _3,5 =0.8, H-3-furyl); 6.60 (dd, 1H, J _4,3 =3.3, J _4,5 =1.9, H-4-furyl); 6.90 (bs, 2H, NH ₂ ); 7.78 (dd, 1H, J _5,4 =1.9, J _5,3 =0.8, H-5-furyl); 8.01 (s, 1H, H-6); 8.14 (s, 1H, H-2). ¹³ C NMR (151 MHz, DMSO-d ₆ ): 19.91 (CH ₃ ); 59.66 (CH ₂ -5′); 71.92 (CH-3′); 78.85 (C-2′); 82.48 (CH-4′); 90.60 (CH-1′); 99.03 (C-4a); 105.22 (CH-3-furyl); 106.10 (C-5); 112.13 (CH-4-furyl); 120.07 (CH-6); 142.17 (CH-5-furyl); 148.98 (C-2-furyl); 150.60 (C-7a); 152.35 (CH-2); 157.46 (C-4). IR (KBr): 3474, 3385, 3351, 3245, 3200, 1630, 1575, 1560, 1531, 1497, 1472, ₁₄₅₅ , 1379, 1299, 1124, 1072, ₁₀₄₉ , ₁₀₁₆ , 893, 795, _594. MS (ESI) m/z ₃₄₇ (M+H), 369 (M+Na). HRMS (ESI) calcd for C16H19N4O5 _{[ M} +H]: 347.1355; found: 347.1347. Calcd for _C16H18N4O5 · _0.7H2O : C, 53.54; H, 5.45; N, 15.61. Found: C, 53.86; H, 5.48; N, 15.22.

Example 25. 4-Amino-7-(2-C-methyl-β-D-ribofuranosyl)-5-(thien-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (7f)

The title compound was prepared according to the procedure of Example 20, Step 3. White solid. Yield 77%. Mp 131°C. [α] ²⁰ _D -51.4 (c 0.255, MeOH). ¹ H NMR (600MHz, DMSO-d ₆ ): 0.73 (s, 3H, CH ₃ ); 3.65 (dd, 1H, J _gem = 12.3, J _{5′b, 4′} = 2.9, H-5′b); 3.83 (dd, 1H, J _gem = 12.3, J _{5′a, 4′} ＝2.1, H-5′a); 3.86(ddd, 1H, J _4′,3′ ＝9.1, J _4′,5′ ＝2.9, 2.1, H-4′); 4.00 (bd, 1H, J _3′,4′ =9.1, H-3′); 5.20 (bs, 3H, OH-2′, 3′, 5′); 6.19 (s, 1H, H-1′); 6.30 (bs, 2H, NH ₂ ); 7.13 (dd, 1H, J _3,4 ＝3.5, J _3,5 ＝1.2, H-3-thienyl); 7.16 (dd, 1H, J _4,5 ＝5.2, J _4,3 ＝3.5, H-4-thienyl); 7.55 (dd, 1H, J _5,4 ＝5.2, J _5,3 ＝1.1, H-2-thienyl); 7.82 (s, 1H, H-6); 8.16 (s, 1H, H-2). ¹³ C NMR (151 MHz, DMSO-d ₆ ): 19.96 (CH ₃ ); 59.37 (CH ₂ -5′); 71.76 (CH-3′); 78.88 (C-2′); 82.38 (CH-4′); 90.53 (CH-1′); 100.27 (C-4a); 108.51 (C-5); 121.64 (CH-6); 125.93 (CH-5-thienyl); 126.42 (CH-3-thienyl); 128.53 (CH-4-thienyl); 136.04 (C-2-thienyl); 150.40 (C-7a); 152.26 (CH-2); 157.47 (C-4). IR (KBr): 3471, 3380, 3350, 3235, 3195, 1622, 1591, 1575, 1549, 1507, 1460, 1430, 1372, 1349, 1296, 1228, 1122, 1071, 1050, 850, 796, 707, 559. MS (ESI) _{m / z 363} (M+H), 385 (M+Na). HRMS (ESI) calculated for Ci6H19N4O4S [M+H]: 363.1127; found: 363.1121. Calculated _{for C16H18N4O4S} · _0.95H2O : C, 50.64; H, 5.28; _N , 14.76. Found: C, 51.03; H _, 5.06; N, 14.40.

Example 26. 4-amino-5-(furan-3-yl)-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (7 g)

The title compound was prepared according to the procedure of Example 20, Step 3. Retention time: 2.5 hours. White solid. Yield: 59%. Mp: 123°C. [α] ²⁰ _D -54.5 (c: 0.217, MeOH). ¹ HNMR (600MHz, DMSO-d ₆ ): 0.72 (s, 3H, CH ₃ ); 3.65 (dd, 1H, J _gem = 12.2, J _{5′b, 4′} = 3.0, H-5′b); 3.82 (dd, 1H, J _gem = 12.2, J _{5′a, 4′} ＝2.1, H-5′a); 3.85(ddd, 1H, J _4′,3′ ＝9.1, J _4′,5′ ＝3.0, 2.1, H-4′); 3.99 (d, 1H, J _3′,4′ =9.1, H-3′); 5.16 (bs, 3H, OH-2′, 3′, 5′); 6.19 (s, 1H, H-1′); 6.25 (bs, 2H, NH ₂ 5 ＝1.7, J _2,4 ＝0.8, H-2 _- furyl) _; 8.13 _{( s} , _1H , H-2). ¹³ C NMR (151 MHz, DMSO-d ₆ ): 19.99 (CH ₃ ); 59.74 (CH ₂ -5′); 72.08 (CH-3′); 78.87 (C-2′); 82.41 (CH-4′); 90.56 (CH-1′); 100.67 (C-4a); 106.27 (C-5); 111.78 (CH-4-furyl); 119.00 (C-3-furyl); 120.61 (CH-6); 139.79 (CH-2-furyl); 144.43 (CH-5-furyl); 150.52 (C-7a); 152.03 (CH-2); 157.68 (C-4). IR (KBr): 3478, 3337, 3243, 3208, 3150, 1623, 1583, 1561, 1534, 1498, 1455, 1378, 1357, 1350, 1300, 1159, 1120, 1071, 1056, 1026, 874, 793, 602. MS (ESI) _{m / z 347} (M+H). HRMS (ESI) calculated for _Ci6Hi9N4O5 [M _{+ H]} : 347.1350; found: 347.1349. Calculated for _Ci6Hi8N4O5 · _1.7H2O : C, 50.98; H, 5.72; N, 14.86. Found: C, 51.30; H, 5.33; N, 14.46.

Example 27. 4-Amino-7-(2-C-methyl-β-D-ribofuranosyl)-5-(thien-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (7h)

The title compound was prepared according to the procedure of Example 20, Step 3. White solid. Yield 62%. Mp 128°C. [α] ²⁰ _D -60.3 (c 0.222, MeOH). ¹ H NMR (600MHz, DMSO-d ₆ ): 0.74 (s, 3H, CH3); 3.65 (ddd, 1H, J _gem = 12.1, J _{5′b, OH} = 4.8, J _{5′b, 4′} = 2.9, H-5′b); 3.82 (ddd, 1H, J _gem = 12.1, J _{5′a, OH} =4.8, J _5′a,4′ =2.1, H-5′a); 3.85 (ddd, 1H, J _4′,3′ = 9.0, J _4′,5′ = 2.9, 2.1, H-4′); 4.00 (dd, 1H, J _3′,4′ = 9.0, J _{3′, OH} =7.1,H-3′);5.12(d,1H,J _OH,3′ 5,5 ＝4.9, J 4,2 ＝1.4, H-4-thienyl); 7.49 (dd, 1H, _{J 2,5} ＝2.9, J 2,4 ＝1.4, H- _2-thienyl ); 7.698 (dd, 1H, J _5,4 ＝4.9, J _5,2 ＝2.9, H-5-thienyl); 7.70 (s, 1H, H- ₆ ); _8.14 (s, 1H, H _{- 2} ). ¹³ C NMR (151 MHz, DMSO-d ₆ ): 20.01 (CH ₃ ); 59.67 (CH ₂ -5′); 72.04 (CH-3′); 78.89 (C-2′); 82.41 (CH-4′); 90.55 (CH-1′); 100.44 (C-4a); 111.08 (C-5); 120.73 (CH-6); 122.11 (CH-2-thienyl); 127.66 (CH-5-thienyl); 128.72 (CH-4-thienyl); 135.16 (C-3-thienyl); 150.38 (C-7a); 151.96 (CH-2); 157.57 (C-4). IR (KBr): 3475, 3351, 3240 _, 3200, 3120, 3107, 1621, 1594, 1575, 1549, 1510, ₁₄₆₅ , 1409, 1378, 1346, 1297, 1139, 1123, 1072, 1045, 861, 788. MS (ESI) m/ _{z 363} (M+H), 385 (M+Na). HRMS (ESI) calcd for C16H19N4O4S _[ M _{+ H} ]: 363.1122; found: 363.1122. calcd for _C16H18N4O4S · _1.1H2O : C, 50.28; H, 5.33; N, 14.66. Found: C, 50.42; H, 5.20; N, 14.45.

Example 28. 4-Amino-5-(benzofuran-2-yl)-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (7i)

The title compound was prepared according to the procedure of Example 20, Step 3. White solid. Yield 66%. Mp 248°C (dec.). [α] ²⁰ _D -55.0 (c 0.220, MeOH). ¹ H NMR (500MHz, DMSO-d ₆ ): 0.76 (s, 3H, CH ₃ ); 3.72 (ddd, 1H, J _gem = 12.5, J _{5′b, OH} = 5.0, J _{5′b, 4′} = 2.9, H-5′b); 3.88 (ddd, 1H, J _gem = 12.5, J _{5′a, OH} =5.0, J _5′a,4′ =2.0, H-5′a); 3.90 (ddd, 1H, J _4′,3′ = 9.2, J _4′,5′ = 2.9, 2.0, H-4′); 4.04 (dd, 1H, J _3′,4′ = 9.2, J _{3′, OH} =7.0, H-3′); 5.17(d, 1H, J _OH,3′ ＝7.0, OH-3′); 5.19 (s, 1H, OH-2′); 5.28 (t, 1H, J _OH,5′ ＝5.0, OH-5′); 6.23 (s, 1H, H-1′); 6.98 (bs, 2H, NH ₂ ); 7.04 (d, 1H, J _3,7 ＝1.0, H-3-benzofuranyl); 7.27 (td, 1H, J _5,4 ＝J _5,6 ＝7.3, J _5,7 ＝1.4, H-5-benzofuranyl); 7.29 (td, 1H, J _6,5 ＝J _6,7 ＝7.3, J _6,4 =1.7, H-6-benzofuranyl); 7.61-7.67 (m, 2H, H-4,7-benzofuranyl); 8.19 (s, 1H, H-2); 8.26 (s, 1H, H-6). ¹³ C NMR (125.7 MHz, DMSO-d ₆ ): 19.96 (CH ₃ ); 59.72 (CH ₂ -5'); 71.97 (CH-3'); 78.91 (C-2'); 82.59 (CH-4'); 90.74 (CH-1'); 99.19 (C-4a); 101.58 (CH-3-benzofuranyl); 105.47 (C-5); 111.30 (CH-7-benzofuranyl); 120.81 (CH-4-benzofuranyl); 122. 32 (CH-6); 123.73 (CH-5-benzofuranyl); 124.08 (CH-6-benzofuranyl); 129.01 (C-3a-benzofuranyl); 150.94 (C-7a); 151.45 (C-2-benzofuranyl); 152.58 (CH-2); 154.00 (C-7a-benzofuranyl); 157.50 (C-4). MS ₍ ESI, negative ion mode) m/z 395 (MH _{). HRMS (ESI, negative ion mode) calculated for C20H19N4O5 : [} MH]: 395.1350; found: 395.1358. Calculated for _C20H20N4O5 · _{1 / 3H2O} : C, 59.70; H, 5.18; N, 13.92. Found: C, 59.98; _H , 5.13; N, 13.46.

Example 29. 4-Amino-5-phenyl-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine 5'-O-triphosphate sodium salt (13a)

Step 1. 4-Amino-5-iodo-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine 5'-O-triphosphate sodium salt (11)

Phosphorus oxychloride (45 μ l, 0.49 mmol) is added dropwise to a stirred mixture of 7-iodotuberculocidin 1 (150 mg, 0.38 mmol) in trimethyl phosphate (1 ml), and the solution is stirred at 0 ° C for 1.25 hours. A solution of freshly prepared di-(tri-n-butylammonium) pyrophosphate (1.05 g, 1.91 mmol) and tri-n-butylamine (0.4 ml, 1.66 mmol) in anhydrous DMF (4 ml) is stirred at 0 ° C for at least 15 minutes with molecular sieves, then added to the stirred reaction mixture at 0 ° C. Before quenching with a TEBA aqueous solution (2 M, 1.2 ml), the mixture is kept at the same temperature for 1.5 hours. Volatiles are removed in vacuo, and the residue is co-evaporated with water several times. The residue was purified by ion exchange chromatography on DEAE-Sephadex (0→60% TEAB in 2M water) and the triethylammonium salt of the obtained product was converted to the sodium salt by Dowex 50 (Na ⁺ form) column. Freeze drying gave the title compound 11 as a white cotton product (131 mg, 48%). ¹ H NMR (500 MHz, D ₂ O + phosphate buffer solution, pH = 7.1, ref _dioxane = 3.75 ppm): 4.15 (ddd, 1H, J _gem = 11.6, J _{H, P} = 4.9, J _{5′b, 4′} = 3.3, H-5′b); 4.24 (ddd, 1H, J _gem = 11.6, J _{H, P} = 6.6, J _{5′a, 4′} = 3.2, H-5′a); 4.34 (m, 1H, J _{4′, 5′} = 3.3, 3.2, J _{4′, 3′} = 2.9, J _{H, P} = 2.1, H-4′); 4.54 (ddd, 1H, J _{3′, 2′} = 5.3, J _{3′, 4′} = 2.9, J _{H, P =} =0.4, H-3′); 4.65 (dd, 1H, J _2′,1′ = 6.7, J _2′,3′ = 5.3, H-2′); 6.21 (d, 1H, J _1′2′ = 6.7, H-1′); 7.71 (s, 1H, H-8); 8.09 (s, 1H, H-2). ¹³ C NMR (125.7 MHz, D ₂ O + phosphate buffer solution, pH = 7.1, ref _dioxane = 69.3 ppm): 55.01 (C-7); 68.18 (d, J _{C, P} = 6, CH ₂ -5′); 73.21 (CH-3′); 76.51 (CH-2′); 86.33 (d, J _{C, P} = 9, CH-4′); 88.50 (CH-1′); 106.76 (C-4a); 129.78 (CH-6); 152.52 (C-7a); 154.17 (CH-2); 159.72 (C-4). ³¹ P ( ¹ H dec.) NMR (202.4 MHz, D ₂ O + phosphate buffer solution, pH = 7.1, ref _{H 3 PO 4} = 0 ppm): −20.78 (t, J = 19.5, P _β ); −9.66 (d, J = 19.5, P _α ); −7.00 (d, J = 19.5, P _γ ). MS (ESI) m/z 699 (M + H), 721 (M + Na). MS (ESI, negative ion mode) m/z 631 (M - 3 Na + 2 H), 653 (M - 2 Na + H), 675 (M - Na). HRMS (ESI, negative ion mode) calculated for C ₁₁ H ₁₄ IN ₄ NaO ₁₃ P ₃ [M-2Na+H]: 652.8713; found: 652.8731.

Step 2. 4-Amino-5-phenyl-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine 5'-O-triphosphate sodium salt (13a)

An argon-purged mixture of Pd(OAc) ₂ (1.5 mg, 6.7 μmol) and TPPTS (17.3 mg, 30 μmol) in water/MeCN (2:1, 1.2 ml) was sonicated to completely dissolve the mixture, and a quarter of the pre-prepared solution (0.3 ml, 1/4 of the total amount) was added to an argon-purged mixture of compound 11 (20.1 mg, 29 μmol) obtained in step 1, phenylboronic acid (5.2 mg, 42 μmol) and _Cs2CO3 ( ₂₇ mg, 83 μmol) in water/MeCN (2:1, 0.6 ml), and the mixture was stirred at 110°C for 30 min. After cooling, the mixture was filtered through a microfilter and separated by HPLC on a C-18 phase (0→100% MeOH in 0.1 M TEAB in water) and, after ion exchange on Dowex 50 (Na ⁺ form), freeze-dried to give the title compound 13a as a white cotton product (8.6 mg, 46%). ¹ H NMR (500 MHz, D ₂ O + phosphate buffer solution, pH = 7.1, ref _dioxane = 3.75 ppm): 4.14 (ddd, 1H, J _gem = 11.6, J _{H, P} = 4.7, J _{5′b, 4′} = 3.5, H-5′b); 4.25 (ddd, 1H, J _gem = 11.6, J _{H, P} = 6.5, J _{5′a, 4} ′ = 3.3, H-5′a); 4.35 (m, 1H, J _{4′, 5′} = 3.5, 3.3, J _{4′, 3′} = 2.9, J _{H, P} = 1.7, H-4′); 4.57 (dd, 1H, J _{3′, 2′} = 5.4, J _{3′, 4′} =2.9, H-3′); 4.73 (dd, 1H, J _2′,1′ = 6.9, J _2′,3′ = 5.4, H-2′); 6.30 (d, 1H, J _1′2′ =6.9, H-1'); 7.45 (m, 1H, Hp-Ph); 7.49-7.56 (m, 4H, Ho, m-Ph); 7.57 (s, 1H, H-6); 8.16 (s, 1H, H-2). ¹³ C NMR (125.7 MHz, D ₂ O + phosphate buffer solution, pH = 7.1, ref _dioxane = 69.3 ppm): 68.22 (d, J _{C, P} = 5, CH ₂ -5′); 73.26 (CH-3′); 76.24 (CH-2′); 86.31 (d, J _{C, P} =9, CH-4′); 88.34(CH-1′); 103.75(C-4a); 121.56(C-5); 122.86(CH-6); 130.41(CH-p-Ph); 131.59 and 131.94(CH-o,m-Ph); 136.10(Ci-Ph); 153.15(C-7a); 153.67(CH-2); 159.61(C-4). ^31P ( ¹ H dec.) NMR (202.4 MHz, D ₂ O + phosphate buffer, pH = 7.1, refH 3 PO 4 = 0 ppm): −21.32 (dd, J = 19.3, 19.0, P _β ); −10.45 (d, J = 19.3, P _α ); −6.98 (d, J = 19.0, P _γ ). MS (ESI, negative ion mode) m/z 581 (M − 3Na + 2H), 603 (M − 2Na + H), 625 (M − Na). HRMS (ESI, negative ion mode) calculated for C ₁₇ H ₂₀ N ₄ O ₁₃ P ₃ [M − 3Na + 2H]: 581.0240; found: 581.0253.

Example 30. 4-Amino-5-(4-fluorophenyl)-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine 5'-O-triphosphate sodium salt (13b)

The title compound was prepared according to the procedure of Example 29, Step 2. White cotton product. Yield: 25%. ¹ H NMR (500 MHz, D ₂ O + phosphate buffer solution, pH = 7.1, ref _dioxane = 3.75 ppm): 4.13 (dt, 1H, J _gem = 11.4, J _{H, P} = J _{5′b, 4′} = 4.2, H-5′b); 4.25 (ddd, 1H, J _gem = 11.4, J _{H, P} = 6.5, J _{5′a, 4′} = 3.3, H-5′a); 4.35 (bddd, 1H, J _{4′, 5′} = 4.2, 3.3, J _{4′, 3′} = 2.7, H-4′); 4.58 (dd, 1H, J _{3′, 2′} = 5.4, J _{3′, 4′} = 2.7, H-3′); 4.72 (dd, 1H, J _{2′, 1′} = 4. =6.9, J _2′,3′ =5.4, H-2′); 6.31 (d, 1H, J _1′2′ = 6.9, H-1′); 7.24 (m, 2H, HmC ₆ H ₄ F); 7.53 (m, 2H, HoC ₆ H ₄ F); 7.56 (s, 1H, H-6); 8.17 (s, 1H, H-2). ¹³ C NMR (125.7 MHz, D ₂ O + phosphate buffer solution, pH = 7.1, ref _dioxane = 69.3 ppm): 68.19 (d, J _{C, P} = 6, CH ₂ -5′); 73.26 (CH-3′); 76.21 (CH-2′); 86.34 (d, J _{C, P} = 9, CH-4′); 88.26 (CH-1′); 103.93 (C-4a); 118.57 (d, J _{C, F} = 22, CH-mC ₆ H ₄ F); 120.54 (C-5); 122.83 (CH-6); 132.26 (d, J _{C, F} = 3, CiC ₆ H ₄ F); 133.44 (d, J _{C, F} = 8, CH-oC ₆ H ₄ F); 153.24 (C-7a); 154.16 (CH-2); 159.98 (C-4); 164.95 (d, J _C,F = 244, CpC ₆ H ₄ F). ³¹ P ( ¹ H dec.) NMR (202.4 MHz, D ₂ O + phosphate buffer solution, pH = 7.1, ref _{H 3 PO 4} = 0 ppm): -21.04 (dd, J = 18.9, 18.4, P _β ); -10.39 (d, J = 18.9, P _α ); -6.12 (d, J = 18.4, P _γ ). MS (ESI, negative ion mode) m/z 621 (M-2Na+H), 643 (M-Na). HRMS (ESI, _{negative ion} mode) calculated for _{C17H17FN4Na2O13P3} [M _- Na _] : _642.9779 ; found: 642.9789.

Example 31. 4-Amino-5-(furan-2-yl)-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine 5'-O-triphosphate sodium salt (13c)

The title compound was prepared according to the procedure of Example 29, Step 2. After HPLC on C-18, it was repurified by ion exchange HPLC on Poros HQ (TEAB gradient). White cotton product. Yield 27%. ^1H NMR (500 MHz, D ₂ O + phosphate buffer solution, pH = 7.1, ref _dioxane = 3.75 ppm): 4.19 (ddd, 1H, J _gem = 11.7, J _{H, P} = 4.7, J _5′b,4′ = 3.2, H-5′b); 4.28 (ddd, 1H, J _gem = 11.7, J _{H, P} = 6.2, J _5′a,4′ = 2.8, H-5′a); 4.36 (ddd, 1H, J _4′,5′ = 3.2, 2.8, J _4′,3′ = 2.9, H-4′); 4.59 (dd, 1H, J _3′,2′ = 5.2, J _3′,4′ = 2.9, H-3′); 4.71 (dd, 1H, J _{δ 5,4} ＝1.9 ， H _{-5-furyl); 7.84 (s，1H，} H-6）； 8.08 (s，1H，H-2）。 δ 5,4 ＝1.9 ， J _2′,1′ ＝6.6， J 2′,3′ ＝5.2，H-2′); 6.25 (d，1H，J _{1′2 ′} ＝6.6，H-1′); 6.57 (dd，1H，J _4,3 ＝3.4，J _4,5 ＝1.9,H-4-furyl); 6.75 (dd，1H，J _3,4 ＝3.4,J 3,5 ＝0.7,H-3-furyl); 7.57 (dd，1H，J _5,4 ＝1.9,J 5,3 ＝0.7,H-5-furyl); 7.84 (s，1H，H-6); 8.08 (s，1H，H-2). ¹³ C NMR (125.7 MHz, D ₂ O + phosphate buffer solution, pH = 7.1, ref _dioxane = 69.3 ppm): 68.14 (d, J _{C, P} = 5, CH ₂ -5′); 73.28 (CH-3′); 76.60 (CH-2′); 86.40 (d, J _{C, P} =9, CH-4′); 88.60 (CH-1′); 102.45 (C-4a); 108.95 (CH-3-furyl); 111.18 (C-5); 114.80 (CH-4-furyl); 122.05 (CH-6); 144.63 (CH-5-furyl); 150.34 (C-2-furyl); 152.81 (C-7a); 153.46 (CH-2); 159.28 (C-4). ³¹ P ( ¹ H dec.) NMR (202.4 MHz, D ₂ O + phosphate buffer solution, pH = 7.1, ref _{H 3 PO 4} = 0 ppm): -21.09 (dd, J = 19.2, 18.7, P _β ); -10.43 (d, J = 19.2, P _α ); -6.25 (d, J = 18.7, P _γ ). MS (ESI, negative ion mode) m/z 593 (M-2Na+H), 615 (M-Na). HRMS (ESI, negative _ion mode) calculated for _{C15H17N4NaO14P3} [M- _2Na +H _] : 592.9846; found: 592.9868; calculated for _{C15H16N4Na2O14P3} [M-Na] _{: 614.9666} ; found: 614.9686; calculated for _{C15H14N4Na4O14P3} [ _{M - 2H + Na ]} : _658.9310 ; found: _{658.9321 .}

Example 32. 4-Amino-7-(β-D-ribofuranosyl)-5-(thien-2-yl)-7H-pyrrolo[2,3-d]pyrimidine 5'-O-triphosphate sodium salt (13d)

The title compound was prepared according to the procedure of Example 29, Step 2. White solid. Yield 53%. ¹ H NMR (500 MHz, D ₂ O + phosphate buffer solution, pH = 7.1, ref _dioxane = 3.75 ppm): 4.14 (ddd, 1H, J _gem = 11.7, J _{H, P} = 4.9, J _5′b,4′ = 3.6, H-5′b); 4.28 (ddd, 1H, J _gem = 11.7, J _{H, P} = 6.9, J _5′a,4′ = 3.6, H-5′a); 4.35 (td, 1H, J _4′,5′ = 3.6, J _4′,3′ = 2.7, H-4′); 4.58 (dd, 1H, J _3′,2′ = 5.3, J _3′,4′ = 2.7, H-3′); 4.73 (dd, 1H, J _2′,1′ = 3. 5 ＝1.4, H _{-5- thienyl} ); 7.64 ( _s , 1H, H-6) _; 8.18 ₍ s, 1H, H _{- 2 )} . ¹³ C NMR (125.7 MHz, D ₂ O + phosphate buffer solution, pH = 7.1, ref _dioxane = 69.3 ppm): 68.20 (d, J _{C, P} = 5, CH ₂ -5′); 73.22 (CH-3′); 76.21 (CH-2′); 86.40 (d, J _{C, P} =9, CH-4′); 88.28 (CH-1′); 104.13 (C-4a); 113.58 (C-5); 123.93 (CH-6); 129.26 (CH-5-thienyl); 130.14 (CH-3-thienyl); 130.95 (CH-4-thienyl); 137.11 (C-2-thienyl); 153.14 (C-7a); 154.52 (CH-2); 160.04 (C-4). ^31P ( ¹ H dec.) NMR (202.4 MHz, D ₂ O + phosphate buffer, pH = 7.1, ref _{H 3 PO 4} = 0 ppm): −21.12 (bdd, J = 20.5, 19.4, P _β ); −10.41 (d, J = 19.4, P _α ); −6.23 (d, J = 20.5, P _γ ). MS (ESI, negative ion mode) m/z 609 (M-2Na+H), 631 (M-Na). HRMS (ESI, negative ion mode) calculated for C ₁₅ H ₁₇ N ₄ NaO ₁₃ P ₃ S [M-2Na+H]: 608.9618; found: 608.9637.

Example 33. 4-Amino-5-(furan-3-yl)-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine 5'-O-triphosphate sodium salt (13e)

The title compound was prepared according to the procedure of Example 29, Step 2. After HPLC on C-18, it was repurified by ion exchange HPLC on Poros HQ (TEAB gradient). Pale yellow solid. Yield 37%. ¹ H NMR (600 MHz, D ₂ O + phosphate buffer solution, pH = 7.1, ref _dioxane = 3.75 ppm): 4.14 (ddd, 1H, J _gem = 11.2, J _{H, P} = 4.9, J _5′b,4′ = 2.9, H-5′b); 4.25 (ddd, 1H, J _gem = 11.2, J _{H, P} = 6.4, J _5′a,4′ = 3.1, H-5′a); 4.35 (ddd, 1H, J _4′,5′ = 3.2, 2.9, J _4′,3′ = 2.4, H-4′); 4.57 (dd, 1H, J _3′,2′ = 5.4, J _3′,4′ = 2.4, H-3′); 4.73 (dd, 1H, J _5,4 ＝1.9, J 5,2 ＝1.6, _H -5-furyl); 7.75 (dd, 1H _{, J 2,5} ＝1.6, J _2,4 ＝0.9, H-2-furyl _{) ;} 8.16 _{( s} , 1H, H- ₂ ). ¹³ C NMR (151 MHz, D ₂ O + phosphate buffer solution, pH = 7.1, ref _dioxane = 69.3 ppm): 68.22 (d, J _{C, P} = 5, CH ₂ -5′); 73.32 (CH-3′); 76.22 (CH-2′); 86.35 (d, J _{C, P} =9, CH-4′); 88.24 (CH-1′); 104.39 (C-4a); 111.40 (C-5); 114.18 (CH-4-furyl); 120.38 (C-3-furyl); 122.84 (CH-6); 143.14 (CH-2-furyl); 147.03 (CH-5-furyl); 153.22 (C-7a); 154.35 (CH-2); 160.22 (C-4). ³¹ P ( ¹ H dec.) NMR (202.4 MHz, D ₂ O + phosphate buffer, pH = 7.1, ref _{H 3 PO 4} = 0 ppm): −20.54 (bdd, J = 17.8, 15.0, P _β ); −10.35 (d, J = 17.8, P _α ); −5.66 (d, J = 15.0, P _γ ). MS (ESI, negative ion mode) m/z 593 (M-2Na+H), 615 (M-Na). HRMS (ESI, negative ion mode) calculated for C ₁₅ H ₁₆ N ₄ Na ₂ O ₁₄ P ₃ [M-Na]: 614.9666; found: 614.9678.

Example 34. 4-Amino-7-(β-D-ribofuranosyl)-5-(thien-3-yl)-7H-pyrrolo[2,3-d]pyrimidine 5'-O-triphosphate sodium salt (13f)

The title compound was prepared according to the procedure of Example 29, Step 2. White cotton product. Yield: 67%. ¹ H NMR (500 MHz, D ₂ O + phosphate buffer solution, pH = 7.1, ref _dioxane = 3.75 ppm): 4.14 (ddd, 1H, J _gem = 11.6, J H, P = 4.8, J _{5′b, 4′} = 3.5, H-5′b); 4.25 (ddd, 1H, J _gem = 11.6, J _{H, P} = 6.6, J _{5′a, 4′} = 3.2, H-5′a); 4.35 (ddd, 1H, J _{4′, 5′} = 3.5, 3.2, J _{4′, 3′} = 2.7, H-4′); 4.58 (dd, 1H, J _{3′, 2′} = 5.3, J _{3′, 4′} = 2.7, H-3′); 4.74 (dd, 1H, J _{2′, 1′} = 3. 5 ＝5.0, J _{5,2 ＝1.4, H-4-thienyl); 7.52 (dd, 1H, J 2,5 ＝3.0, J 2,4 ＝} 1.4, H-2-thienyl); 7.607 (s, 1H, H- ₆ ); 7.610 (dd, 1H, J _5,4 ＝5.0, J _5,2 ＝ _3.0 , H- ₅ -thienyl); 8.17 (s, 1H, H-2). ¹³ C NMR (125.7 MHz, D ₂ O + phosphate buffer solution, pH = 7.1, ref _dioxane = 69.3 ppm): 68.20 (d, J _{C, P} = 5, CH ₂ -5′); 73.30 (CH-3′); 76.24 (CH-2′); 86.38 (d, J _{C, P} =9, CH-4′); 88.28 (CH-1′); 104.09 (C-4a); 116.08 (C-5); 122.81 (CH-6); 125.88 (CH-2-thienyl); 130.18 (CH-5-thienyl); 131.28 (CH-4-thienyl); 136.31 (C-3-thienyl); 153.09 (C-7a); 154.20 (CH-2); 160.06 (C-4). ^31P ( ^1Hdec .) NMR (202.4 MHz, _D2O + phosphate buffer, pH = 7.1, ref _H3PO4 = 0 ppm): -21.14 (bdd, J = 21.0, 19.3, _Pβ ); -10.39 (d, J = 19.3, _Pα ); -6.45 (d, J = 21.0, _Pγ ). MS (ESI, negative ion _mode ) m/z 609 (M-2Na+H), ₆₃₁ (M-Na). HRMS (ESI, negative _ion mode) calculated for _{C15H17N4NaO13P3S} [M-2Na+H]: _608.9618 ; found: 608.9635.

Example 35. 4-Amino-5-phenyl-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine 5'-O-monophosphate sodium salt (14a)

Step 1. 4-Amino-5-iodo-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine 5'-O-monophosphate sodium salt (12)

Phosphorus oxychloride (70 μl, 0.77 mmol) was added dropwise to a stirred mixture of 7-iodotuberculocidin 1 (250 mg, 0.64 mmol) in trimethyl phosphate (2 ml) at 0 ° C, and the solution was stirred at 0 ° C for 2 hours. The reaction was quenched by adding a TEAB aqueous solution (2 M, 2 ml), and the residue was co-evaporated with water several times after evaporation. The residue was purified by ion exchange chromatography (0 → 60% 2M TEAB solution in water) on DEAE-Sephadex. After ion exchange on Dowex 50 (Na ⁺ type), lyophilization gave the title compound 12 as a white cotton-like substance (229 mg, 73% yield). ¹ H NMR (500MHz, D ₂ O, ref _dioxane = 3.75 ppm): 3.97 (dt, 1H, J _gem = 11.4, J _{H, P} = J _{5'b, 4'} = 4.0, H-5'b); 4.00 (ddd, 1H, J _gem = 11.4, J _{H, P} = 5.3, J _{5'a, 4'} =3.7, H-5′a); 4.30 (m, 1H, J _{4′, 5′} = 4.0, 3.7, J _{4′, 3′} = 3.0, J _{H, P} = 1.0, H-4′); 4.44 (dd, 1H, J _{3′, 2′} = 5.4, J _{3′, 4′} =3.0,H-3′);4.63(dd,1H,J _2′,1′ =6.7, J _2′,3′ =5.4, H-2′); 6.20 (d, 1H, J _1′,2′ = 6.7, H-1′); 7.70 (s, 1H, H-6); 8.08 (s, 1H, H-2). ¹³ C NMR (125.7MHz, D ₂ O, ref _dioxane = 69.3 ppm): 54.97 (C-5); 66.81 (d, J _{C, P} = 5, CH ₂ -5′); 73.50 (CH-3′); 76.59 (CH-2′); 86.74 (d, J _{C, P} =9, CH-4′); 88.52(CH-1′); 106.71(C-4a); 129.72(CH-6); 152.45(C-7a); 154.24(CH-2); 159.74(C-4). ³¹ P ( ¹ H dec.) NMR (202.4 MHz, D ₂ O, ref _H3PO4 = 0 ppm): 3.24. MS (ESI, negative ion mode) m/z 471 (M-Na). HRMS (ESI, negative ion mode) calculated for _{C 11} H ₁₃ N ₄ IO ₇ P: [M-Na]: 470.9561; found: 470.9576.

Step 2. 4-Amino-5-phenyl-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine 5'-[O-monophosphate] sodium salt (14a)

An argon-purged mixture of Pd(OAc) ₂ (1.7 mg, 7.6 μmol) and TPPTS (21.7 mg, 38 μmol) in water/MeCN (2:1, 1.6 ml) was sonicated to completely dissolve, and a quarter of this pre-prepared solution (0.3 ml, 1/4 of the total amount) was added to an argon-purged mixture of compound 12 (17 mg, 34 μmol) obtained in step 1, phenylboronic acid (7.9 mg, 65 μmol) and _Na2CO3 ( ₁₇ mg, 160 μmol) in water/MeCN (2:1, 0.8 ml), and the mixture was stirred at 125°C for 1.5 hours. After cooling, the mixture was filtered through a microfilter and purified by HPLC on C-18 phase (0→100% MeOH in 0.1 M TEAB in water) and, after ion exchange on Dowex 50 (Na ⁺ form), freeze-dried to give the title compound 14a as a white solid (14.4 mg, 94%). ¹ H NMR (500MHz, D ₂ O, ref _dioxane = 3.75 ppm): 3.91 (dt, 1H, J _gem = 11.4, J _{H, P} = J _{5'b, 4'} = 4.4, H-5'b); 3.95 (ddd, 1H, J _gem = 11.4, J _{H, P} = 5.6, J _{5'a, 4'} =4.2, H-5′a); 4.30 (ddd, 1H, J _4′,5′ = 4.4, 4.2, J _4′,3′ = 2.7, H-4′); 4.46 (dd, 1H, J _3′,2′ = 5.4, J _3′,4′ = 2.7, H-3′); 4.75 (dd, 1H, J _2′,1′ =7.1, J _2′,3′ =5.4, H-2'); 6.31 (d, 1H, J _1'2' = 7.1, H-1'); 7.46 (m, 1H, Hp-Ph); 7.54 (m, 2H, Hm-Ph); 7.56 (m, 2H, Ho-Ph); 7.58 (s, 1H, H-6); 8.18 (s, 1H, H-2). ¹³ C NMR (125.7MHz, D ₂ O, ref _dioxane = 69.3 ppm): 66.53 (d, J _{C, P} = 5, CH ₂ -5′); 73.61 (CH-3′); 76.15 (CH-2′); 86.94 (d, J _{C, P} =9, CH-4′); 88.22(CH-1′); 103.97(C-4a); 121.38(C-5); 122.79(CH-6); 130.44(CH-p-Ph); 131 .72(CH-o-Ph); 131.91(CH-m-Ph); 136.31(Ci-Ph); 153.35(C-7a); 154.40(CH-2); 160.15(C-4). ³¹ P ( ¹ H dec.) NMR (202.4 MHz, D ₂ O, ref _{H 3 PO 4} =0 ppm): 4.64. MS (ESI) m/z 445 (M+H), 467 (M+Na). HRMS (ESI) calculated for _{C 17} H ₁₉ N ₄ NaO ₇ P: [M+H]: 445.0884; found: 445.0880.

Example 36. 4-Amino-5-(4-fluorophenyl)-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine 5'-O-monophosphate sodium salt (14b)

The title compound was prepared according to the procedure of Example 35, Step 2. White solid. Yield 47%. ¹ H NMR (500MHz, D ₂ O, ref _dioxane = 3.75 ppm): 3.90 (dt, 1H, J _gem = 11.4, J _{H, P} = J _{5'b, 4'} = 4.1, H-5'b); 3.94 (ddd, 1H, J _gem = 11.4, J _{H, P} = 5.6, J _{5'a, 4'} =4.1, H-5′a); 4.30 (tdd, 1H, J _{4′, 5′} = 4.1, J _{4′, 3′} = 2.7, J _{H, P} = 1.1, H-4′); 4.46 (dd, 1H, J _{3′, 2′} = 5.4, J _{3′, 4′} =2.7,H-3′);4.74(dd,1H,J _2′,1′ =7.2,J _{2′, 3′} = 5.4, H-2′); 6.30 (d, 1H, J _1′2′ = 7.2, H-1′); 7.25 (m, 2H, HmC ₆ H ₄ F); 7.54 (m, 2H, HoC ₆ H ₄ F); 7.57 (s, 1H, H-6); 8.18 (s, 1H, H-2). ¹³ C NMR (125.7MHz, D ₂ O, ref _dioxane = 69.3 ppm): 66.52 (d, J _{C, P} = 4, CH ₂ -5′); 73.61 (CH-3′); 76.17 (CH-2′); 86.97 (d, J _{C, P} =9, CH-4'); 88.20 (CH-1'); 104.07 (C-4a); 118.55 (d, J _{C, F} = 22, CH-mC ₆ H ₄ F); 120.44 (C-5); 122.89 (CH-6); 132.35 (d, J _{C, F} = 3, CiC ₆ H ₄ F); 133.55 (d, J _{C, F} = 8, CH-oC ₆ H ₄ F); 153.31 (C-7a); 154.45 ₍ CH-2); 160.18 (C-4); 165.00 (d, JC, F = 245, CpC6H4F). ^31P ( ^1H dec.) NMR (202.4 MHz, _D2O , ref _H3PO4 = 0 ppm): 4.65. MS (ESI, _{negative ion mode} ) m/z ₄₃₉ (M-Na), 461 (MH). HRMS (ESI, negative ion mode) calculated for _C17H17FN4O7P [M-Na]: _439.0813 ; found: 439.0828; calculated for _{C17H16FN4NaO7P} [MH] _{: 461.0633} ; found: 461.0647.

Example 37. 4-Amino-5-(furan-2-yl)-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine 5'-O-monophosphate sodium salt (14c)

The title compound was prepared by the procedure of Example 35, Step 2. Tan cotton product. Yield: 34%. ¹ HNMR (500MHz, D ₂ O, ref _dioxane = 3.75 ppm): 3.94 (ddd, 1H, J _gem = 11.4, J _{H, P} = 4.0, J _{5′b, 4′} = 2.6, H-5′b); 3.98 (ddd, 1H, J _gem = 11.4, J _{H, P} = 5.2, J _5′a,4′ =3.7,H-5′a);4.31(m,1H,J _4′,5′ =3.7,2.6,J _4′,3′ =2.9,J _H,P =1.1,H-4′);4.47(dd,1H,J _3′,2′ =5.3,J _3′,4′ =2.9, H-3′); 4.73(dd, 1H, J _2′,1′ 5 ＝1.9, H _{-5- furyl} ); 7.87 ( _s , 1H, H-6) _; 8.14 _{( s} , 1H, H- _{2 )} . ¹³ C NMR (125.7 MHz, D ₂ O, ref _dioxane =69.3 ppm): 66.52 (d, J _{C, P} =5, CH ₂ -5′); 73.65 (CH-3′); 76.41 (CH-2′); 87.09 (d, J _{C, P} =9, CH-4'); 88.38 (CH-1'); 102.81 (C-4a); 109.23 (CH-3-furyl); 111.01 (C-5); 114.78 (CH-4-furyl); 122.30 (CH-6); 144.85 (CH-5-furyl); 150.56 (C-2-furyl); 153.34 (C-7a); 154.57 (CH-2); 160.08 (C-4). ³¹ P ( ¹ H dec.) NMR (202.4 MHz, D ₂ O, ref H 3 _{PO 4} = 0 ppm): 4.37. MS (ESI, negative ion mode) m/z 411 (M-Na), 433 (MH). HRMS (ESI, negative _ion mode) calcd for _C15H16N4O8P [M-Na _] : _411.0700 ; found: 411.0702.

Example 38. 4-Amino-7-(β-D-ribofuranosyl)-5-(thien-2-yl)-7H-pyrrolo[2,3-d]pyrimidine 5'-O-monophosphate sodium salt (14d)

The title compound was prepared according to the procedure of Example 35, Step 2. Yield 51%. ¹ H NMR (500MHz, D ₂ O, ref _dioxane = 3.75 ppm): 3.91 (dt, 1H, J _gem = 11.4, J _{H, P} = J _{5'b, 4'} = 3.3, H-5'b); 3.95 (ddd, 1H, J _gem = 11.4, J _{H, P} = 5.4, J _{5'a, 4'} =4.2, H-5′a); 4.30 (ddd, 1H, J _4′,5′ = 4.2, 3.3, J _4′,3′ = 2.8, H-4′); 4.45 (dd, 1H, J _3′,2′ = 5.4, J _3′,4′ = 2.8, H-3′); 4.72 (dd, 1H, J _2′,1′ =7.0, J _{2′,3′ 5} ＝1.5, H-5-thienyl) _; 7.65 _{( s} , 1H, H-6) _; 8.17 _{( s} , 1H, H-2). ¹³ C NMR (125.7 MHz, D ₂ O, ref _dioxane =69.3 ppm): 66.53 (d, J _{C, P} =5, CH ₂ -5′); 73.57 (CH-3′); 76.18 (CH-2′); 86.97 (d, J _{C, P} =9, CH-4'); 88.22 (CH-1'); 104.21 (C-4a); 113.44 (C-5); 124.02 (CH-6); 129.30 (CH-5-thienyl); 130.25 (CH-3-thienyl); 130.93 (CH-4-thienyl); 137.08 (C-2-thienyl); 153.12 (C-7a); 154.63 (CH-2); 160.11 (C-4). ³¹ P ( ¹ H dec.) NMR (202.4 MHz, D ₂ O, ref H 3 _{PO 4} = 0 ppm): 4.57. MS (ESI, negative ion mode) m/z 427 (M-Na), 449 (MH). HRMS (ESI, negative _ion mode) calculated for _C15H16SN4O7P [M-Na _] : _427.0472 ; found: 427.0473.

Example 39. 4-Amino-5-(furan-3-yl)-7-(β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine 5'-O-monophosphate sodium salt (14e)

The title compound was prepared according to the procedure of Example 35, Step 2. White cotton product. Yield 45%. ¹ H NMR (500MHz, D ₂ O, ref _dioxane = 3.75 ppm): 3.91 (dt, 1H, J _gem = 11.3, J _{H, P} = J _{5'b, 4'} = 4.1, H-5'b); 3.95 (ddd, 1H, J _gem = 11.3, J _{H, P} = 5.2, J _{5'a, 4'} =4.1, H-5′a); 4.30(td, 1H, J _4′,5′ = 4.1, J _4′,3′ = 2.7, H-4′); 4.46 (dd, 1H, J _3′,2′ = 5.6, J _3′,4′ = 2.7, H-3′); 4.73 (dd, 1H, J _{2′, 1′} =7.0, J _2′,3′ 5,4 ＝1.8, J 5,2 _{＝1.6, H-5-furyl); 7.75 (dd, 1H, J 2,5 ＝1.6, J 2,4 ＝ 0.9 , H} -2-furyl) _; 8.17 (s, 1H, H- ₂ ). ¹³ C NMR (151 MHz, D ₂ O, ref _dioxane =69.3 ppm): 66.51 (d, J _{C, P} =4, CH ₂ -5′); 73.66 (CH-3′); 76.19 (CH-2′); 87.04 (d, J _{C, P} =9, CH-4'); 88.14 (CH-1'); 104.48 (C-4a); 111.30 (C-5); 114.25 (CH-4-furyl); 120.37 (C-3-furyl); 122.96 (CH-6); 143.22 (CH-2-furyl); 147.02 (CH-5-furyl); 153.24 (C-7a); 154.46 (CH-2); 160.30 (C-4). ³¹ P ( ¹ H dec.) NMR (202.4 MHz, D ₂ O, ref H 3 _{PO 4} = 0 ppm): 4.55. MS (ESI, negative ion mode) m/z 411 (M-Na), 433 (MH). _HRMS (ESI, negative _ion mode) calculated for _C15H16N4O8P [M-Na _] : _411.0700 ; found: 411.0706; calculated for _{C15H15N4O8PNa} [MH _] : _433.0520 ; found: 411.0526.

Example 40. 4-Amino-7-(β-D-ribofuranosyl)-5-(thien-3-yl)-7H-pyrrolo[2,3-d]pyrimidine 5'-O-monophosphate sodium salt (14f)

The title compound was prepared according to the procedure of Example 35, Step 2. Pink solid. Yield 47%. ¹ H NMR (600MHz, D ₂ O, ref _dioxane = 3.75 ppm): 3.91 (dt, 1H, J _gem = 11.4, J _{H, P} = J _{5'b, 4'} = 4.1, H-5'b); 3.95 (ddd, 1H, J _gem = 11.4, J _{H, P} = 5.5, J _{5'a, 4'} =4.0, H-5′a); 4.30 (m, 1H, J _{4′, 5′} = 4.1, 4.0, J _{4′, 3′} = 2.7, J _{H, P} = 1.2, H-4′); 4.46 (dd, 1H, J _{3′, 2′} = 5.4, J _{3′, 4′} =2.7,H-3′);4.74(dd,1H,J _2′,1′ 5 ＝4.9, J _5,2 ＝ _2.9 , H-5-thienyl); 7.612 ( _s , 1H _, H-6) _; 8.16 (s, 1H, H _{- 2 )} . ¹³ C NMR (151 MHz, D ₂ O, ref _dioxane =69.3 ppm): 66.55 (d, J _{C, P} =5, CH ₂ -5′); 73.66 (CH-3′); 76.21 (CH-2′); 87.00 (d, J _{C, P} =9, CH-4'); 88.18 (CH-1'); 104.18 (C-4a); 115.99 (C-5); 122.83 (CH-6); 125.98 (CH-2-thienyl); 130.186 (CH-5-thienyl); 131.33 (CH-4-thienyl); 136.34 (C-3-thienyl); 153.11 (C-7a); 154.39 (CH-2); 160.19 (C-4). ³¹ P ( ¹ H dec.) NMR (202.4 MHz, D ₂ O, ref H 3 _{PO 4} = 0 ppm): 4.46. MS (ESI, negative ion mode) m/z 427 (M-Na), 449 (MH). HRMS (ESI, negative _ion mode) calculated for _C15H16SN4O7P : [M-Na _] : _427.0472 ; found: 427.0474; calculated for _{C15H15SN4O7PNa} : [MH _{] : 449.0291} ; found: 449.0295.

The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many changes and modifications can be made without departing from the spirit and scope of the invention.

The present invention includes the following contents:

1. A compound of formula I or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a mixture of optical isomers thereof:

in:

_R1 is hydrogen, monophosphono, diphosphono or triphosphono;

R ₂ is aryl, heteroaryl or alkynyl, wherein the aryl group is optionally substituted with one or two substituents selected from alkoxy, alkylthio or halogen;

_R3 is hydrogen or alkyl.

2. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a mixture of optical isomers thereof,

wherein R ₁ is hydrogen, monophosphino, diphosphino or triphosphino; R ₂ is aryl, which is optionally substituted by a substituent selected from alkoxy, alkylthio or halogen; and R ₃ is hydrogen.

3. The compound of embodiment 2 or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a mixture of optical isomers, wherein R ₁ is hydrogen, R ₂ is phenyl, and the phenyl group is optionally substituted with a substituent selected from (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )alkylthio or halogen; and R ₃ is hydrogen.

4. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a mixture of optical isomers thereof,

wherein R ₁ is hydrogen, monophosphino, diphosphino or triphosphino; R ₂ is aryl, which is optionally substituted by a substituent selected from alkoxy, alkylthio or halogen; and R ₃ is alkyl.

5. The compound of embodiment 4 or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a mixture of optical isomers, wherein R ₁ is hydrogen, R ₂ is phenyl, and the phenyl group is optionally substituted with a substituent selected from (C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )alkylthio or halogen; and R ₃ is (C ₁ -C ₄ )alkyl.

6. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a mixture of optical isomers thereof,

wherein R ₁ is hydrogen, monophosphino, diphosphino or triphosphino; R ₂ is heteroaryl; R ₃ is hydrogen, provided that R ₂ is not 1,3-oxazol-2-yl, furan-2-yl, 1,2,4-triazin-3-yl, 5,6-dimethyl-1,2,4-triazin-3-yl, 5,6-diphenyl-1,2,4-triazin-3-yl, 1,2,4-oxadiazol-3-yl, 4H-1,2,4-triazol-3-yl, 5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl, 4,5-dihydro-1H-imidazol-2-yl, 4-phenylthiazol-2-yl, 1H-tetrazol-5-yl, 1,4,5,6-tetrahydropyrimidin-2-yl or 9-oxo-9H-indeno[1,2-e][1,2,4]triazin-3-yl.

7. The compound of embodiment 6 or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a mixture of optical isomers, wherein R ₁ is hydrogen, R ₂ is a (5-7) membered heteroaryl group; R ₃ is hydrogen, provided that R ₂ is not 1,3-oxazol-2-yl, furan-2-yl, 1,2,4-triazin-3-yl, 5,6-dimethyl-1,2,4-triazin-3-yl, 5,6-diphenyl-1,2,4-triazin-3-yl, 1,2,4-oxadiazol-3-yl, 4H-1,2,4-triazol-3-yl, 5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl, 4,5-dihydro-1H-imidazol-2-yl, 4-phenylthiazol-2-yl, 1H-tetrazol-5-yl, 1,4,5,6-tetrahydropyrimidin-2-yl or 9-oxo-9H-indeno[1,2-e][1,2,4]triazin-3-yl.

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a mixture of optical isomers thereof,

wherein R ₁ is hydrogen, monophosphino, diphosphino or triphosphino; R ₂ is heteroaryl; R ₃ is alkyl, provided that R ₂ is not 1,3-oxazol-2-yl, furan-2-yl, 1,2,4-triazin-3-yl, 5,6-dimethyl-1,2,4-triazin-3-yl, 5,6-diphenyl-1,2,4-triazin-3-yl, 1,2,4-oxadiazol-3-yl, 4H-1,2,4-triazol-3-yl, 5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl, 4,5-dihydro-1H-imidazol-2-yl, 4-phenylthiazol-2-yl, 1H-tetrazol-5-yl, 1,4,5,6-tetrahydropyrimidin-2-yl or 9-oxo-9H-indeno[1,2-e][1,2,4]triazin-3-yl.

9. The compound of embodiment 8 or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a mixture of optical isomers, wherein R ₁ is hydrogen, R ₂ is a (5-7) membered heteroaryl group; and R ₃ is a (C ₁ -C ₄ ) alkyl group, provided that R ₂ is not 1,3-oxazol-2-yl, furan-2-yl, 1,2,4-triazin-3-yl, 5,6-dimethyl-1,2,4-triazin-3-yl, 5,6-diphenyl-1,2,4-triazin-3-yl, 1,2,4-oxadiazol-3-yl, 4H-1,2,4-triazol-3-yl, 5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl, 4,5-dihydro-1H-imidazol-2-yl, 4-phenylthiazol-2-yl, 1H-tetrazol-5-yl, 1,4,5,6-tetrahydropyrimidin-2-yl or 9-oxo-9H-indeno[1,2-e][1,2,4]triazin-3-yl.

10. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a mixture of optical isomers thereof,

wherein R ₁ is hydrogen, monophosphino, diphosphino or triphosphino; R ₂ is alkynyl; and R ₃ is hydrogen.

11. The compound of embodiment 10, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a mixture of optical isomers thereof, wherein R ₁ and R ₃ are hydrogen, and R ₂ is ethynyl.

12. The compound of embodiment 1 or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, or a mixture of optical isomers thereof, which is selected from the following compounds:

13. A method of inhibiting tumor/cancer growth in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 12.

14. A method of inhibiting cell proliferation in a tumor/cancer cell in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 12.

15. A method of treating a cell proliferative disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 12.

16. A method of treating a neoplastic disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 12.

17. A method of treating a tumor or cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 12.

18. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of embodiments 1 to 12 and one or more pharmaceutically acceptable carriers.

19. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of embodiments 1 to 12, and a second therapeutic agent selected from anthracyclines, DNA intercalators, alkylating agents, hormonal agents, LHRH agonists and antagonists, aromatase inhibitors, antiandrogens, chemopreventive agents, cell cycle chemopreventive agents, antitumor drugs, antimitotic agents, plant alkaloids, topoisomerase I inhibitors, topoisomerase II inhibitors, proteosome inhibitors, nucleoside analogs, cytokines, growth factors, anti-angiogenic factors, and one or more pharmaceutically acceptable carriers.

20. Use of a compound according to any one of embodiments 1 to 12 for the preparation of a medicament for inhibiting tumor/cancer growth in a subject.

21. Use of a compound according to any one of embodiments 1 to 12 for the preparation of a medicament for inhibiting cell proliferation in a tumor/cancer cell in a subject.

22. Use of a compound according to any one of embodiments 1 to 12 for the preparation of a medicament for treating a cell proliferative disease in a subject.

23. Use of a compound according to any one of embodiments 1 to 12 for the preparation of a medicament for treating a neoplastic disease in a subject.

24. Use of a compound according to any one of embodiments 1 to 12 for the preparation of a medicament for treating a tumor or cancer in a subject.

Claims (12)

1. Compounds of formula I or their pharmaceutical salts: in: _R1 is hydrogen, monophosphine carboxyl, diphosphine carboxyl, or triphosphine carboxyl; _R2 is a heteroaryl group; The condition is that _R2 is not 1,3-oxazol-2-yl, furan-2-yl, 1,2,4-triazin-3-yl, 1,2,4-oxadiazol-3-yl, 4H-1,2,4-triazol-3-yl, or 1H-tetrazol-5-yl, and When _R3 is an alkyl group, _R2 is furan-3-yl, thiophene-2-yl, thiophene-3-yl, or benzofuran-2-yl, and _R3 is hydrogen or ( _C1 - _C4 ) alkyl. The heteroaryl group is a 5-14 member monocyclic, bicyclic, or fused polycyclic system having 1-8 heteroatoms selected from N, O, S, or Se. 2. The optical isomer of the compound of claim 1, wherein the optical isomer is β-D-ribofuranosyl. 3. A mixture of optical isomers of the compound of claim 1, wherein at least one optical isomer comprises β-D-ribofuranosylfuranose. 4. The compound of any one of claims 1 to 3 or its pharmaceutical salt, wherein _R2 is furanyl, thiophene, pyrrole, benzofuranyl, pyrazolyl, imidazolyl or triazolyl, provided that _R2 is not 1,3-oxazol-2-yl, furan-2-yl, 1,2,4-triazin-3-yl, 1,2,4-oxadiazol-3-yl, 4H-1,2,4-triazol-3-yl, 1H-tetrazol-5-yl, and when _R3 is an alkyl group, _R2 is furan-3-yl, thiophene-2-yl, thiophene-3-yl or benzofuran-2-yl; _R3 is ( _C1 - _C4 ) alkyl. 5. A compound or a pharmaceutical salt thereof, said compound being selected from the following compounds: 6. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1 to 5 and one or more pharmaceutical carriers. 7. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1 to 5, and a second therapeutic agent selected from anthracycline antibiotics, DNA intercalating agents, alkylating agents, hormonal drugs, LHRH agonists and antagonists, aromatase inhibitors, antiandrogens, chemopreventive agents, cell cycle chemopreventive agents, antitumor drugs, antimitotic agents, plant alkaloids, topoisomerase I inhibitors, topoisomerase II inhibitors, protein body inhibitors, nucleoside analogs, cytokines, growth factors, antiangiogenic factors, and one or more pharmaceutical carriers. 8. Use of the compound of any one of claims 1-5 in the preparation of a medicament for inhibiting tumor/cancer growth in a subject. 9. Use of the compound of any one of claims 1-5 in the preparation of a medicament for inhibiting cell proliferation in a subject's tumor/cancer cells. 10. Use of the compound of any one of claims 1-5 in the preparation of a medicament for treating a proliferative disease of a subject's cells. 11. Use of the compound of any one of claims 1-5 in the preparation of a medicament for treating neoplastic diseases in a subject. 12. Use of the compound of any one of claims 1-5 in the preparation of a medicament for treating a tumor or cancer in a subject.