MXPA00012915A - Adenosine derivatives - Google Patents

Abstract

A compound of formula (I) which is an agonist at the adenosine A1 receptor, wherein Y, Z and W represent heteroatoms, and salts and solvates thereof, in particular, physiologically acceptable solvates and salts thereof for use in therapy.

Description

ADENOSINE DERIVATIVES The present invention relates to novel adenosine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine. r Publications in this area include WO 98/16539 (Novo Nordisk A / S) which describes adenosine derivatives for the treatment of myocardial or cerebral ischemia and epilepsy; WO 98/04126 (Rhone-Poulenc Rorer Pharmaceuticals Inc.) which refers to adenosine derivatives having antihypertension, cardioprotective, anti-ischemic and antilipolytic properties; and WO 98/01459 (Novo Nordisk A / S) which describes the N, 9-disubstituted adenine derivatives which are substituted at the 4 'position by unsubstituted oxazolyl or isoxazolyl and the use of such compounds for the treatment of disorders that involve cytokines in humans. In this manner, the invention provides a compound of the formula (I) which is an agonist at the adenosine Al receptor.

Ref. 125990 , .Í > - Z.-j / Z Jß¡m- * a. ~ & ft .: nde X represents 0 or CH2; R2 represents alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, halogen and hydrogen; R3 represents H, phenyl (optionally substituted by halogen), a 5- or 6-membered heteroaryl group, alkoxy of 1 to 6 carbon atoms, alkyl-6CO (CH2) n where n is 0-6, cycloalkyl of 3 to 7 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, halogen or a straight or branched alkyl group, of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms or alkynyl of 1 to 6 carbon atoms optionally substituted by one or more halogens.

Y and Z represent O, N, CH, N (alkyl of 1 to 6 carbon atoms) ~,.-anftiJ ^ - ^ fan ^, ') - .. - * -' - * ~ W represents CH, O, N, S, N (alkyl of 1 to 6 carbon atoms) and wherein at least one of W and Z represents a heteroatom (and when Y, Z and / or W is N, the presence or absence of an additional H would be apparent to a person skilled in the art) with the proviso that when W represents CH, Z represents N and Y represents 0, R3 can not be H.

R4 and R5 independently represent H or an alkyl group of 1 to 6 carbon atoms, straight or branched chain.

R1 represents hydrogen or a group selected from (1) - (alk) n-cycloalkyl of 3 to 7 carbon atoms, including bridged cycloalkyl, the cycloalkyl group optionally substituted by one or more substituents selected from OH, halogen, -alkoxy of 1 to 3 carbon atoms, wherein (alk) represents alkylene of 1 to 3 carbon atoms and n represents 0 or 1. (2) a 4- to 6-membered, heterocyclic, heterocyclic group containing at least one heteroatom selected from 0, N or S, optionally substituted by one or more substituents selected from the group ^ ¿^ ^ ^ ^ ^ ^ ^ Consisting of -alkyl of 1 to 3 carbon atoms, -C02-alkyl of 1 to 4 carbon atoms, -CO (alkyl of 1 to 3 carbon atoms). -S (= 0) "- (alkyl of 1 to 3 carbon atoms), -C0NRaRb (wherein Ra and Rb independently represent H or alkyl of 1 to 3 carbon atoms) or = 0; where there is a sulfur atom in the heterocyclic ring, the sulfur is optionally substituted by (= 0) n, where n is 1 or 2. (3) C 1 -C 12 straight or branched alkyl, optionally including one or more 0, S (= 0) n groups (where n is 0, 1 or 2) and N substituted within the alkyl chain , the alkyl optionally substituted by one or more of the following groups, phenyl, halogen, hydroxy, cycloalkyl of 3 to 7 carbon atoms or NRaRb wherein Ra and Rb independently represent hydrogen, cycloalkyl of 3 to 7 carbon atoms or an alkyl from 1 to 6 carbon atoms, straight or branched chain, optionally substituted by cycloalkyl of 3 to 7 carbon atoms; (4) an aromatic, bicyclic, fused ring ^^ ^^^^^^ & s¿ ^^ i ^^^^ wherein B represents an aromatic, heterocyclic, 5- or 6-membered group containing 1 or more 0, N or S atoms, wherein the bicyclic ring is attached to the nitrogen atom of the formula (I) by means of an atom of ring of ring A and ring B is optionally substituted by -C02- (alkyl of 1 to 3 carbon atoms). (5) a phenyl group optionally substituted by one or more substituents selected from: -halogen, -S03H, - (alk) nOH, - (alk) n-cyano, - (0) n -alkyl of 1 to 6 carbon atoms (optionally substituted by one or more halogens), - (alk) n - nitro, - (0) m - (alq) n- C02Rc, - (alq ") - C0NRcRd - (alq)" -C0Rc, - (alq) "-C0Re, - (alq)" -S02Re, (alq) n - S02NRcRd, - (alq) nORc, - (alq) n - (C0) m- NHS02Re, - (alk) n- NHC0Rc, - (alq) n-NRcRd, where m and n are 0 ol and alk represents an alkylene group of 1 to 6 carbon atoms or an alkenyl group of 2 to 6 carbon atoms. (6) A phenyl group substituted by an aromatic, heterocyclic, 5- or 6-membered group, the aromatic, heterocyclic group which is optionally substituted by alkyl of 1 to 3 carbon atoms or NRcRd.

Rc and Rd can each independently represent hydrogen or alkyl of 1 to 3 carbon atoms or when part of a group NRcRd, Rc and Rd together with the nitrogen atom R1 where X represents 0 or CH2; R2 represents alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, halogen or hydrogen; R3 represents H, phenyl (optionally substituted by halogen), a 5- or 6-membered heteroaryl group, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, straight or branched optionally substituted by one or more halogens, cycloalkyl of 3 to 7 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms or halogen.

Y and Z represent O, N, CH W represents CH, O, N, S and wherein at least one of W and Z represents a heteroatom (and when Y, Z and / or W is N, the presence or absence of a Additional H would be apparent to a person skilled in the art) with the proviso that when W represents CH, Z represents N and Y represents 0, R3 can not be H.

R4 and R5 independently represent H or an alkyl group of 1 to 6 carbon atoms, straight or branched chain.

R1 represents a group selected from (1) - (alk) n-cycloalkyl of 3 to 7 carbon atoms, including bridged cycloalkyl, the cycloalkyl group optionally substituted by one or more substituents selected from OH, halogen, -alkoxy of 1 to 3 carbon atoms, wherein (alk) represents alkylene of 1 to 3 carbon atoms and n represents 0 or 1. (2) a 4- to 6-membered heterocyclic ring, aliphatic group containing at least one heteroatom selected from 0, N or S, optionally substituted by one or more substituents selected from the group consisting of -alkyl of 1 to 3 carbon atoms; carbon, -C02-alkyl of 1 to 4 carbon atoms, -CO (alkyl of 1 to 3 carbon atoms), -S (= 0) n- (alkyl of 1 to 3 carbon atoms), -C0NRaRb (in which Ra and Rb independently represents H or alkyl of 1 to 3 atoms) ds carbon) or = 0; where there is a sulfur atom in the heterocyclic ring, the sulfur is optionally substituted by (= 0) n, where n is 1 or 2. (3) C 1 -C 12 straight or branched alkyl, optionally including one or more 0, S (= 0) n groups (where n is 0, 1 or 2) and N substituted within the alkyl chain , the alkyl optionally substituted by one or more of the following groups, phenyl, halogen, hydroxy, cycloalkyl of 3 to 7 carbon atoms or NRaRb wherein Ra and Rb independently represent hydrogen, cycloalkyl of 3 to 7 carbon atoms or an alkyl from 1 to 6 carbon atoms, straight or branched chain optionally substituted by cycloalkyl of 3 to 7 carbon atoms; (4) an aromatic, bicyclic, fused ring ^^^^ ¡gH wherein B represents a 5- or 6-membered, heterocyclic, aromatic group containing 1 or more 0, N or S atoms, wherein the bicyclic ring is attached to the nitrogen atom of the formula (I ) by means of a ring atom of ring A and ring B is optionally substituted by -C02- (alkyl of 1 to 3 carbon atoms). (5) a phenyl group optionally substituted by one or more substituents selected from: -halogen, -S03H, - (alk) n0H, - (alk) n-cyano, - (0) n -alkyl of 1 to 6 carbon atoms (optionally substituted by one or more halogens), - (alk) n - nitro, - (0) m - (alq) n- C02Rc, - (alq - C0NRcRd - (alq) n -C0Rc, - (alq) n -SORe, - (alq) n -S02Re, (alq) "- S02NRcRd , - (alq) nORc, - (alq) n - (C0) m- NHS02Re, - (alq) n- NHCORc, - (alq) n-NRcRd, where m and n are 0 ol and alk represents an alkylene group of 1 to 6 carbon atoms or an alkenyl group of 2 to 6 carbon atoms. (6) A phenyl group substituted by an aromatic, heterocyclic, 5- or 6-membered group, the aromatic, heterocyclic group which is optionally substituted by alkyl of 1 to 3 carbon atoms or NRCRC Rc and Rd can each independently represent hydrogen or alkyl of 1 to 3 carbon atoms or when part of a group NRcRd, Rc and Rd together with the nitrogen atom can form a 5 or 6-membered heterocyclic ring optionally containing other heteroatoms , heterocyclic ring which may be optionally further substituted by: one or more alkyl groups of 1 to 3 carbon atoms.

Re represents alkyl of 1 to 3 carbon atoms and salts and solvates thereof, in particular, solvates and physiologically acceptable salts thereof.

The invention further provides pharmaceutical compositions of the formula (I) or (Ia) together with a pharmaceutically acceptable diluent or carrier.

It will be appreciated that certain compounds encompassed by formula (I) are novel per se. A particular group of the compounds can be defined by the formula (Ib). Therefore, the invention further provides compounds of the formula (Ib) which are agonists at the adenosine receptor Al R1 wherein X represents O or CH2; R2 represents alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, halogen or hydrogen; R3 represents H, phenyl (optionally substituted by halogen), a 5- or 6-membered heteroaryl group, alkoxy of 1 to 6 carbon atoms, alkyl-6CO (CH2) n where n is 0-6, cycloalkyl of 3 to 7 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, halogen or an alkyl group of 1 to 6 carbon atoms, straight or branched, alkenyl of 1 to 6 carbon atoms or alkynyl of 1 to 6 carbon atoms optionally substituted by one or more halogens.

Y and Z represent 0, N, CH, N (alkyl of 1 to 5 carbon atoms) 5 W represents CH, 0, N, S, N (alkyl of 1 to 6 carbon atoms) and wherein at least one of W and Z represents a heteroatom (and when Y, Z and / or W is N, the presence or absence of an additional H would be apparent to a person skilled in the art) with the proviso that when W represents CH, Z represents N and Y represents 0, R3 can not be H.

R4 and R5 independently represent H or an alkyl group of 1 to 6 carbon atoms, straight chain or branched chain.

R1 represents hydrogen or a group selected from (1) - (alk) n-cycloalkyl of 3 to 7 carbon atoms, including bridged cycloalkyl, the cycloalkyl group optionally substituted by one or more substituents selected from OH, halogen, -alkoxy of 1 to 3 carbon atoms, wherein (alk) represents alkylene of 1 to 3 carbon atoms and n represents 0 or 1.

S | i ^^^ sy ^^^^^^^ «- ^ fc J ^ j ^ & j (2) a heterocyclic, aliphatic group of 4-6 membered rings containing at least one heteroatom selected from 0, N or S, optionally substituted by one or more substituents selected from the group consisting of -alkyl of 1 to 3 carbon atoms, -C02-alkyl of 1 to 4 carbon atoms, -CO (alkyl of 1 to 3 carbon atoms) carbon), -S (= 0) n- (alkyl of 1 to 3 carbon atoms) ,. -C0NRaRb (wherein Ra and Rb independently represent H or alkyl of 1 to 3 carbon atoms) or = 0; where there is a sulfur atom in the heterocyclic ring, the sulfur is optionally substituted by (= 0) n, where n is 1 or 2. (3) C 1 -C 12 straight or branched alkyl, optionally including one or more 0, S (= 0) n groups (where n is 0, 1 or 2) and N substituted within the chain of alkyl, the alkyl optionally substituted by one or more of The following groups, phenyl, halogen, hydroxy, cycloalkyl of 3 to 7 carbon atoms or NRaRb where Ra and Rb independently represent hydrogen, cycloalkyl of 3 to 7 carbon atoms or an alkyl of 1 to 6 carbon atoms, chain straight or branched optionally substituted by cycloalkyl of 3 to 7 carbon atoms; 4) an aromatic, bicyclic, fused ring wherein B represents an aromatic, heterocyclic, 5- or 6-membered group containing 1 or more 0, N or S atoms, wherein the bicyclic ring is attached to the nitrogen atom of the formula (I) by means of an atom of ring of ring A and ring B is optionally substituted by -C02- (alkyl of 1 to 3 carbon atoms). (5) a phenyl group optionally substituted by one or more substituents selected from: -halogen, -S03H, - (alk) n0H, - (alk) n-cyano, - (0) "- (alkyl of 1 to 6 carbon atoms (optionally substituted by one or more halogens), - (alk) n -nitro, - (0) m - (alq) n- C02Rc, - (alq - C0NRcRd - (alq) n -CORc, - (alq) n -SORe, - (alq) "-S02Re, - (alq) n - S02NRcRd, - (alq) nORc, - (alq) "- (CO) m- NHS02R% 2 »- (alk) n-NHCORc, - (alk) n-NRcRd, wherein y n is 0 or 1 and alk represents an alkylene group of 1 to 6 carbon atoms or an alkenyl group of 2 to 5 carbon atoms. (6) A phenyl group substituted by an aromatic, heterocyclic, 5- or 6-membered group, the aromatic, heterocyclic group which is optionally substituted by alkyl of 1 to 3 carbon atoms or NRcRd.

Rc and Rd can each independently represent hydrogen or alkyl of 1 to 3 carbon atoms or when part of a group NRcRd, Rc and Rd together with the nitrogen atom can form a 5- or 6-membered heterocyclic ring optionally containing other heteroatoms , heterocyclic ring which may optionally be further substituted by one or more alkyl groups of 1 to 3 carbon atoms.

Re represents alkyl of 1 to 3 carbon atoms with the proviso that when R4 and R5 both represent H, R2 represents halogen, R3 can not represent methyl, ethyl, n-propyl, isopropyl, ^ .m, A ^ ií ^? t? ^^. ^ isA.-? cyclopropyl, CH (OH) CH3, alkoxy of 1 to 3 carbon atoms and salts and solvates thereof, in particular, solvates and physiologically acceptable salts thereof.

Preferably, the compound is of the formula (le): R1 wherein X represents O or CH2; R2 represents alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, halogen or hydrogen; R3 represents H, phenyl (optionally substituted by halogen), a heteroaryl group of 5 or 6 members, alkoxy of 1 to 6 carbon atoms, straight or branched alkyl of 1 to 6 carbon atoms optionally substituted by one or more halogens, cycloalkyl of 3 to 7 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms or halogen.

Y and Z represent 0, N, CH W represents CH, 0, N, S and wherein at least one of W and Z represents a heteroatom (and when Y, Z and / or W is N, the presence or absence of a Additional H would be apparent to a person skilled in the art) with the proviso that when W represents CH, Z represents N and Y represents 0, R3 can not be H.

R4 and R5 independently represent H or an alkyl group of 1 to 6 carbon atoms, straight or branched chain.

R1 represents a group selected from (1) - (alk) n-cycloalkyl of 3 to 7 carbon atoms, including bridged cycloalkyl, the cycloalkyl group optionally substituted by one or more substituents selected from OH, halogen, -alkoxy of 1 to 3 carbon atoms, in where (alq) represents alkylene of 1 to 3 carbon atoms and i represents 0 or 1. (2) a 4- to 6-membered heterocyclic, aliphatic ring group containing at least one heteroatom selected from 0, or S, optionally substituted by one or more substituents selected from the group consisting of -alkyl of 1 to 3 carbon atoms , -C02-alkyl of 1 to 4 carbon atoms, -CO (alkyl of 1 to 3 carbon atoms), -S (= 0) n- (alkyl of 1 to 3 carbon atoms), -C0NRaRb (where Ra and Rb independently represent H or alkyl of 1 to 3 carbon atoms) or = 0; where there is a sulfur atom in the heterocyclic ring, the sulfur is optionally substituted by (= 0) n, where n is 1 or 2.(3) C 1 -C 12 straight or branched alkyl, optionally including one or more 0, S (= 0) n groups (where n is 0, 1 or 2) and N substituted within the alkyl chain , the alkyl optionally substituted by one or more of the following groups, phenyl, halogen, hydroxy, cycloalkyl of 3 to 7 carbon atoms or NRaRb wherein Ra and Rb independently represent &numsp &numsp               hydrogen, cycloalkyl of 3 to 7 carbon atoms or straight or branched chain alkyl of 1 to 6 carbon atoms optionally substituted by cycloalkyl of 3 to 7 carbon atoms; 4) an aromatic, bicyclic, fused ring wherein B represents an aromatic, heterocyclic, 5- or 6-membered group containing 1 or more O, N or S atoms, wherein the bicyclic ring is attached to the nitrogen atom of the formula (I) by means of an atom of ring L of ring A and ring B is optionally substituted by -C02- (alkyl of 1 to 3 carbon atoms). (5) a phenyl group optionally substituted by one or more substituents selected from: -halogen, -S03H, - (alk) nOH, - (alk) n-cyano, - (0) n -alkyl of 1 to 6 carbon atoms (optionally substituted by one or more halogens), - (alk) n -nitro, - (0) m - (alq) n- C02Rc, - (alq - CONRcRd - (alq) n -CORc, - (alq) n -SORe, - (alq) n -S02Re, (alq) n- S02NRcRd, - (alq) nORc, - (alq) n - (C0) m- NHS02R% - (alq) n- NHCORc, - (alq) n-NRcRd, where yn is 0 oly alq represents an alkylene group of 1 to 6 carbon atoms or an alkenyl group of 2 to 6 carbon atoms. (6) A phenyl group substituted by an aromatic, heterocyclic, 5- or 6-membered group, the aromatic, heterocyclic group which is optionally substituted by alkyl of 1 to 3 carbon atoms or NRcRd.

Rc and Rd can each independently represent hydrogen or alkyl of 1 to 3 carbon atoms or when part of a group NRcRd, Rc and Rd together with the nitrogen atom can form a 5- or 6-membered heterocyclic ring optionally containing other heteroatoms , heterocyclic ring which may be optionally further substituted by one or more alkyl groups of 1 to 3 carbon atoms.

Re represents alkyl of 1 to 3 carbon atoms with the proviso that when R4 and R5 both represent H, R2 represents halogen, R3 can not . ^ *, * • - * $ & amp; amp; & amp; & amp; ás ^ -, ^ ga ^ ¡g ^ e? represent methyl, ethyl, n-propyl, isopropyl, cyclopropyl, CH (OH) CH3, alkoxy of 1 to 3 carbon atoms and salts and solvates thereof, in particular, solvates and physiologically acceptable salts of L itself.

Suitably, the adenosine Al agonists of the general formula (I) above exhibit greater activity at the adenosine Al receptor than the other subtypes of adenosine receptors, particularly A3. More particularly, the compounds exhibit little or no agonist activity in the A3 receptor. It will be appreciated that where R1 and / or R2 in the compounds of the formula (I) contain one or more asymmetric carbon atoms, the invention includes all diastereomers of the compounds of the formula (I) and mixtures thereof. Otherwise, the stereochemical configuration of the compounds of the invention is as represented in formula (I) above. As used herein, the term "alkyl" means a straight or branched chain alkyl group. Examples of suitable alkyl groups within R1 and R2 include methyl, ethyl, n-propyl, I-propyl, n-butyl, s-butyl, t-butyl and 2,2-dimethylpropyl. As used herein, the term "alkylene" means a straight or branched chain alkylene group containing 1-6 carbon atoms, for example methylene. As used herein, the term "alkenyl of 2 to 6 carbon atoms" means a straight or branched chain alkenyl group containing 2 to 6 carbon atoms. Allyl represents an example of a suitable alkenyl group of 2 to 6 carbon atoms. The term "halogen" means fluorine, chlorine, bromine or iodine. By heterocyclic group, aliphatic, defined for R1 is intended to mean a cyclic group of 4-6 carbon atoms wherein one or more of the carbon atoms is / are replaced by heteroatoms independently selected from hydrogen, oxygen or sulfur. This group may be optionally substituted as defined hereinabove. The term aromatic, heterocyclic group, defined for Rx refers to a mono- or bicyclic ring system comprising from 5 to 10 carbon atoms in where one or more of the carbon atoms is / are replaced by heteroatoms independently selected from nitrogen, oxygen and sulfur, which ring system may be optionally substituted as defined hereinbefore. The pharmaceutically acceptable salts of the compounds of the formula (I) include those derived from pharmaceutically acceptable inorganic and organic acids. Examples of suitable acids include acids hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulphonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic Y benzenesulfonic. A pharmaceutically acceptable salt, particularly suitable of the compounds of the formula (I) is the hydrochloride salt. Other acids such as oxalic, while not, themselves pharmaceutically acceptable, may be useful as intermediates in the Preparation of the compounds of the invention and their pharmaceutically acceptable acid addition salts. The solvates can be, for example, hydrates. Examples of W, Y and Z containing heterocyclic groups include isoxazoles, oxadiazoles, pyrazoles, oxazoles, triazoles and thiadiazoles.

Preferred W, Y and Z containing heterocyclic groups are isoxazoles and 1,2,4- and 1,3,4-oxadiazoles. R 2 preferably represents hydrogen, methyl, methoxy or halogen, more preferably hydrogen or chlorine. Conveniently, R 1 can represent (alk) n-cycloalkyl of 3 to 6 carbon atoms wherein n is 0 or 1 and the cycloalkyl is either substituted by at least one substituent selected from halogen, particularly fluorine, and OH or is unsubstituted . Preferably, n is zero. More preferably, the cycloalkyl group is unsubstituted or monosubstituted with OH and more preferably the cycloalkyl ring has 5 carbon members. More preferably, the cycloalkyl group is hydroxycyclopentyl. Alternatively, R1 may represent a heterocyclic, aliphatic, substituted or unsubstituted group, the substituent selected from the group consisting of -C02-alkyl of 1 to 4 carbon atoms. Conveniently, the heterocyclic, aliphatic group is unsubstituted or when the substituent is -C02-alkyl of 1 to 4 carbon atoms, the heteroatom gg > ^^^^^^ «is N and the substitute is directly attached to the nitrogen atom of the ring. Preferably, the heterocyclic ring is 6-membered and more preferably contains only one heteroatom of 0, N or S. More preferably, when the heterocyclic ring is unsubstituted the heteroatom is 0. Much more preferably when the heterocyclic ring is substituted the hetero atom is N. Alternatively, R 1 may represent a straight or branched alkyl of 1-6 carbon atoms optionally with at least one S (= 0) n and where S (= 0) n is present, optionally substituted with N at a position adjacent to the group S (= 0) n; where there is a group S (= 0) n in the chain, substitution with N in a position adjacent to the group S (= 0) n is preferred; where there is a group S (= 0) n in the chain, preferably n is 1 or 2, more preferably n is 2. The alkyl group may conveniently be unsubstituted or substituted by at least one OH group. Alternatively, R1 may represent a phenyl group which is substituted by one or two substituents selected from OH, alkyl, particularly alkyl of 1 to 4 carbon atoms and halogen. Preferably, the phenyl group is disubstituted in the 2,4-positions. Preferably, both substituents are halogen, more particularly fluorine or chlorine. For example, a particularly preferred combination is 2-fluoro and 4-chloro. Preferably, R4 and R5 represent hydrogen. It should be understood that the present invention covers all combinations of the particular and preferred groups mentioned above. Particular novel compounds include the compounds of Examples 1-165 hereinafter. Preferred compounds include: (2S, 3S, 4R, 5R) -2- (5-tert-Butyl- [1,3,4] oxadiazol-2-yl) -5- [6- (tetrahydro-pyran-4-) ilamino) -purin-9-yl] -tetrahydro-furan-3,4-diol; Ethyl ester of 4- acid. { 9- [5S- (5-tert-butyl- [1, 3, 4] oxadiazol-2-yl) -3R, 4S-dihydroxy-tetrahydrofuran-2R-1] -9H-purin-6-ylamino} -piperidine-1-carboxylic acid; (2S, 3S, R, 5R) -2- (5-Isopropyl- [1,3,4] oxadiazol-2-yl) -5- [6- (tetrahydro-pyran-4-ylamino) -purin-9- il] -tetrahydro-furan-3, 4-diol; Ethyl ester of 4- acid. { 9- [5S- (5-cyclopropyl- [1,3,4] oxadiazol-2-yl) -3R, 4S-dihydroxy-tetrahydro-furan-2R-1] -9H-purin-6-ylamino} -piperidine-1-carboxylic acid;~ ^^ - ^ j ^ ^ E ^^^^^^^^ j ^^^? ^^^^ - (2S, 3S, 4R, 5R) -2- (5-ter-Butyl- [1,3 ,] oxadiazol-2-yl) -5- [6- (4-chloro-2-fluoro-phenylamino) -purin-9-yl] -tetrahydrofuran-3,4-diol; (2S, 3S, 4R, 5R) -2- (5-Ethyl-oxazol-2-yl) -5- [6- (tetrahydro-pyran-4-ylamino) -purin-9-yl] -tetrahydrofuran- 3, 4-diol; (2S, 3S, 4R, 5R) -2- (3-Cyclopropyl- [1,2,4] oxadiazol-5-yl) -5- [6- (2S-hydroxy-cyclopent- (S) -ylamino) - purin-9-yl] - tetrahydro-furan-3,4-diol; (2S, 3S, 4R, 5R) -2- (3-tert-Butyl- [1,2,4] oxadiazol-5-yl) -5- [6- (2S-hydroxy-cyclopent- (S) -ylamino ) -purin-9-yl] -tetrahydro-furan-3,4-diol; (2S, 3S, 4R, 5R) -2- (3-Cyclopropyl- [1,2,] oxadiazol-5-yl) -5- [6- (tetrahydro-pyran-4-ylamino) -purin-9-yl ] -tetrahydro-furan-3, 4-diol; (2S, 3S, 4R, 5R) -2- (3-tert-Butyl-isoxazol-5-yl) -5- [6- (tetrahydro-pyran-4-ylamino) -purin-9-yl] -tetrahydro- furan-3, 4-diol; 4- ( {9- [(2R, 3R, 4S, 5S) -3, -Dihydroxy-5- (3-methyl-1,2,4-oxadiazol-5-yl) tetrahydrofuran-2-yl] - 9H-purin-6-yl.} Amino) piperidine-1-carboxylic acid ethyl ester; (2S, 3S, 4R, 5R) -2- [3- (tert-Butyl) -1,2,4-oxadiazol-5-yl] -5-. { 6- [(cyclopropylmethyl) amino] -9H-purin-9-yl} tetrahydrofuran-3, -diol; , ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ (2S, 3S, 4R, 5R) -2- [3- ( ter-Butyl) -1,2,4-oxadiazol-5-yl] -5-. { 6- (isobutylamino) -9H-purin-9-yl] tetrahydrofuran-3, 4-diol; (2R, 3R, 4S, 5S) -2- [6- (Cyclopropylamino) -9H-purin-9-yl] -5- (3-isopropy1-1,2,4-oxadiazol-5-yl) tetrahydrofuran- 3, 4-diol; 2- ( {9- [(2R, 3R, 4S, 5S) -3,4-Dihydroxy-5- (3-isopropyl-1, 2,4-oxadiazol-5-yl) tetrahydrofuran-2-yl] -9H-purin-6-yl.} Amino) -N-methylethanesulfonamide; 10 (2R, 3R, 4S, 5S) -2- [6- (3,4-difluoroanilino) -9H-purin-9-yl] -5- (3-isopropyl-1,2,4-oxadiazole-5-) il) tetrahydrofuran-3, 4-diol; (2R, 3R, 4S, 5S) -2- [6- (4-Chloro-2-fluoroanilino) -9H-purin-9-yl] -5- (3-cyclopropyl-1,2,4-oxadiazole-5-) 15 il) tetrahydrofuran-3,4-diol; (2R, 3S, 4R, 5R) -2- [5- (tert-Butyl) -4H-1,2,4-triazol-3-yl] -5- [6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] tetrahydrofuran-3,4-diol; (2R, 3R, 4S, 5S) -2- [6- (2-Chloro-4-fluoroanilino) -9H-purin-9- 20 yl] -5- (5-isopropyl-4H-1, 2,4- triazol-3-yl) tetrahydrofuran-3,4-diol; (2S, 3S, 4R, 5R) -2- (5-Cyclopropyl-1,3,4-oxadiazol-2-yl) -5- [6- (tetrahydro-2H-pyran-4-ylamino) -9H-purin -9-yl] tetrahydrofuran-3,4-diol; (2S, 3S, 4R, 5R) -2- [5- (tert-Butyl) -1,3,4-oxadiazol-2-yl] -5- [6- (2-chloro-4-fluoroanilino) -9H -purin-9-yl] tetrahydrofuran-3,4-diol; (2S, 3S, 4R, 5R) -2- [3- (tert-Butyl) isoxazol-5-yl] -5-. { 6 - [(1, 1-dioxidotetrahydro-2H-thiopyran-4-yl) amino] -9H-purin-9-yl} tetrahydrofuran-3,4-diol; 2- [(9- { (2R, 3R, 4S, 5S) -5- [5- (tert-butyl) -1,3,4-oxadiazol-2-yl] -3,4-dihydroxytetrahydrofuran-2 -yl.}. -9H-purin-6-yl) amino] -N-ethylethanesulfonamide; 2- [(9- { (2R, 3R, 4S, 5S) -5- [5- (tert-butyl) -1,3,4-oxadiazol-2-yl] -3,4-dihydroxytetrahydrofuran-2 -yl) -9H-purin-6-yl) amino] -N- (3-methylphenyl) ethanesulfonamide; 2- ( {9- [(2R, 3R, 4S, 5S) -3,4-dihydroxy-5- (5-methyl-l, 3-oxazol-2-yl) tetrahydrofuran-2-yl] -9H -purin-6-yl.}. amino) -N-methylethanesulfonamide; (2R, 3R, 4S, 5S) -2- [6- (Cyclopentylamino) -9H-purin-9-yl] -5- [3- (methoxymethyl) -1,2,4-oxadiazol-5-yl] tetrahydrofuran - 3, 4-diol; (2S, 3S, 4R, 5R) -2- (5-ethyl-1,3,4-oxadiazol-2-yl) -5- [6- (isopropylamino) -9H-purin-9-yl] tetrahydrofuran-3 4-diol; (2R, 3R, 4S, 5S) -2- (6- { [(1S, 2S) -2-hydroxycyclopentyl] amino.}. -9H-purin-9-yl] -5- (5-methyl- 1,3,4-oxadiazol-2-yl) tetrahydrofuran-3,4-diol; ^ - ^^. formate (2R, 3R, 4S, 5S) -2-. { 2-Chloro-6- [(1-ethylpropyl) amino] -9H-purin-9-yl} -5- (3-cyclopropyl-l, 2,4-oxadiazol-5-yl) tetrahydrofuran-3,4-diol (1: 2); diformate of (2R, 3R, 4S, 5S) -2- [2-chloro-6- (1-ethyl-propylamino) -purin-9-yl] -5- (3-cyclopropyl- [1,2,4] oxadiazol-5-yl) -tetrahydrofuran-3, -diol; (2S, 3S, 4R, 5R) -2- (3-Ethylisoxazol-5-yl) -5- [6- (tetrahydro-2H-pyran-4-ylamino) -9H-purin-9-yl] tetrahydrofuran-3 4-diol; (2S, 3S, 4R, 5R) -2- (3-ethylisoxazol-5-yl) -5- (6-. {[[(SS, 2S) -2-hydroxycyclopentyl] amino.}. -9H-purine 9-yl) tetrahydrofuran-3,4-diol; 4- ( {9- [(2R, 3R, 4S, 5S) -5- (3-ethyl-butxazol-5-yl) -3,4-dihydroxytetrahydrofuran-2-yl] -9H-purin-6- ethyl] piperidine-1-carboxylate; (2R, 3S, 4R, 5R) -2- [5- (tert-butyl) -4H-1, 2,4-triazol-3-yl] - 5- [6- (tetrahydro-2H-pyran-4-ylamino) -9H-purin-9-yl] tetrahydrofuran-3,4-diol; (2R, 3S, 4R, 5R) -2- (5-isopropyl- 4H-1, 2,4-triazol-3-yl) -5- [6- (tetrahydro-2H-pyran-4-ylamino) -9H-purin-9-yl] tetrahydrofuran-3,4-diol; , 3R, S, 5S) -2- [2-chloro-6- (2-chloro-4-fluoroanilino) -9H-purin-9-yl] -5- (5-methyl-l, 3-oxazole-2 -yl) tetrahydrofuran-3,4-diol; (2R, 3R, 4S, 5S) -2- [6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] -5- (3-methylisoxazole-5-y1) tetrahydrofuran-3, 4 -diol; '(2R, 3R, 4S, 5S) -2- [6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] -5- (3-propylisoxazol-5-yl) tetrahydrofuran-3, 4-diol; 5 (2R, 3R, 4S, 5S) -2- [2-chloro-6- (tetrahydro-2H-pyran-4-ylamino) -9H-purin-9-yl] -5- (3-ethylisoxazole-5- id) tetrahydrofuran-3,4-diol; 4- (. {2-chloro-9- [(2R, 3R, 4S, 5S) -5- (3-ethylisoxazol-5-yl) -3, 4- dihydroxytetrahydrofuran-2-yl] -9H-purin-6-yl.}. amino) piperidine-1-carboxylic acid ethyl ester; (2R, 3R, 4S, 5S) -2- (2-chloro-6-. {[[(SS, 2S) -2-hydroxycyclopentyl] amino] -9H-purin-9-yl] -5- ( 3- ethylisoxazol-5-yl) tetrahydrofuran-3,4-diol; (2R, 3R, 4S, 5S) -2- (2-chloro-6- { [2- (ethyl-sulfonyl) ethyl] amino}. .9H-purin-9-yl] -5- (3-ethylisoxazol-5-yl) tetrahydrofuran-3,4-diol; - • - (2R, 3R, 4S, 5S) -2- [2-chloro- 6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] -5- (3-ethylisoxazol-5-yl) tetrahydrofuran-3, 4-diol; 20 (2R, 3R, 4S, 5S) -2- [2-chloro-6- (2-chloro-4-fluoroanilino) -9H-purin-9-yl] -5- (3-ethylisoxazol-5-yl) tetrahydrofuran-3, 4-diol; , 3R, 4S, 5S) -2- [2-chloro-6- (2-fluoroanilino) -9H-purin-9-yl] -5- (3-ethylisoxazol-5-yl) tetrahydrofuran-3,4-diol; ^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^ g ^^^^ * ^ * ^ i ^^^^^ ^^^^ - ^^^ (2R, 3R, 4S, 5S) -2- [2-chloro-6- (2-chloroanilino) -9H-purin-9-yl] -5- (3-ethylisoxazol-5-yl) tetrahydrofuran -3,4-diol; (2R, 3R, 4S, 5S) -2- (6- { [(1S, 2S) -2- hydroxycyclopentyl] amino.}. -9H-purin-9-yl] -5- [3-5 ( hydroxymethyl) isoxazol-5-yl] tetrahydrofuran-3,4-diol; 4- [(9-. {(2R, 3R, 4S, 5S) -3,4-dihydroxy-5- [3- (hydroxymethyl) isoxazole] -5-yl] tetrahydrofuran-2-yl.} - 9H-purin-6-yl) amino] piperidine-1-carboxylic acid ethyl ester (2R, 3S, 4R, 5R) -2- [3- (hydroxymethyl) isoxazol-5-yl] -5- [6- (tetrahydro-2H-pyran-4-ylamino) -9H-purin-9-yl] tetrahydrofuran-3,4-diol; (2R, 3R, 4S, 5S) -2- [6- (-chloro-2-fluoroanilino) -9H-purin-9-yl] -5- (3-ethylisoxazol-5-yl) tetrahydrofuran-3,4-diol; (2R, 3R, 4S, 5S) -2- [6- (2-chloro-4-fluoroanilino) -9H-purin-9-yl] -5- (3-ethylisoxazol-5-yl) tetrahydrofuran-3,4-diol; (2S, 3S, 4R, 5R) -2- (3-ethylisoxazol-5-yl) -5- [6- (2-fluoroanilino) -9H-purin-9-yl] tetrahydrofuran-3,4-diol; (2R, 3R , 4S, 5S) -2- [6- (2-chloroanilino) -9H-purin-9-yl] -5- (3-ethylisoxazol-5-yl) tetrahydrofuran-3,4-diol; 20 (2S, 3S , 4R, 5R) -2- [5- (tert-butyl) -1,3,4-oxad iazol-2-yl] -5- [6- (piperidin-4-ylamino) -9H-purin-9-yl] tetrahydrofuran-3,4-diol; formate (2R, 3R, 4S, 5R) -2-. { 2-chloro-6- [(1-ethylpropyl) amino] -9H-purin-9-yl} -5- (5-ethylisoxazol-3-yl) yl) tetrahydrofuran-3, -diol; ^^ - .......... a .. - ........, ZZ. ^ ..., .., aa..a | f ^ - .. ^ flffigffg ^^ , Zl ^, ^ .mmA ^ (2S, 3S, 4R, 5R) -2- (3-bromoisoxazol-5-yl) -5- [6- (4-chloro-2-fluoroanilino) -9H-purin-9 -yl] tetrahydrofuran-3, -diol, (2S, 3S, 4R, 5R) -2- [3-tert-butyl) isoxazol-5-yl] -5- (6- { [1- (methylsulfonyl) piperidin-4-yl] amino.}. -9H-pur? n-9-yl) tetrahydrofuran-3,4-diol; (2S, 3S, 4R, 5R) -2- [3- (tert-butyl) isoxazol-5-yl] -5- (6- { [1- (propylsulfonyl) piperidin-4-yl] amino.} .9H-purin-9-? L) -tetrahydrofuran-3,4-diol; (2S, 3S, 4R, 5R) -2- [3- (tert-butyl) -isoxazol-5-yl] -5- (6-. {[[1- (isopropylsulfonyl) piperidin-4-yl] amino] .) .9H-purin-9-yl) -tetrahydrofuran-3,4-diol; (2S, 3S, 4R, 5R) -2- [3- (tert-butyl) isoxazol-5-yl] -5- (6- { [1- (ethylsulfonyl) piperidin-4-yl] amino.} .9H-purin-9-yl) -tetrahydrofuran-3,4-diol; 15 (2S, 3S, 4R, 5R) -2- [3- (tert-butyl) isoxazol-5-yl] -5- [2-chloro-6- (4-chloro-2-fluoroanilmo) -9H-purin -9-yl] tetrahydrofuran-3,4-diol; (2S, 3S, R, 5R) -2- [3- (tert-butyl) isoxazol-5-yl] -5- [2-chloro-6- (2-chloro-4-fluoroanilino) -9H-purin- 9-yl] tetrahydrofuran-3,4-diol; 2- [(9- ((2R, 3R, 4S, 5S) -5- [3- (tert-butyl) isoxazol-5-yl] -3, 4-dihydroxytetrahydrofuran-2-yl} -2-chloro -9H-purin-6-yl) amino] -N-ethylethanesulfonamide; 2- [(9- ((2R, 3R, S, 5S) -5- [3- (tert-butyl) isoxazol-5-yl] -3,4-dihydroxytetrahydrofuran-2-yl.} -2-chloro -9H-purin-6-yl) amino] -N-isopropyletanesulfonamide; (2S, 3S, 4R, 5R) -2- [3- (tert-butyl) isoxazol-5-yl] -5- [2-chloro-6- (tetrahydro-2H-pyran-4-ylamino) -9H -purin-9-yl] tetrahydrofuran-3, -diol; (2S, 3R, 4S, 5S) -2- [6- (4-Chloro-2-fluoroanilino) -9H-purin-9-yl] -5- (3-pyridin-3-ylisoxazol-5-yl) - tetrahydrofuran-3, 4-diol; IC (2S, 3R, 4S, 5S) -2- [6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] -5- [3- (4-hydroxybutyl) isoxazol-5-yl ) -tetrahydrofuran-3,4-diol; 2- [(9- ((2R, 3R, 4S, 5S) -5- [3- (tert-butyl) isoxazol-5-yl] -3, 4-dihydroxytetrahydrofuran-2-yl}.-9H-purin -6-yl) amino] -N-15-ethylenesulfonamide; (2S, 3R, S, 5S) -2- [6- (cyclopentylamino) -9H-purin-9-yl] -5- [5- (trifluoromethyl) - 1,3-oxadiazol-2-yl] -tetrahydrofuran-3, 4-diol; (2S, 3R, S, 5S) -2- (6- { [(ÍS, 2S) -2-hydroxycyclopentyl] amino ) - 9H-purin-9-yl] -5- [5- (trifluoromethyl) -1,3-oxadiazol-2-yl] -tetrahydrofuran-3,4-diol; ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^ ^ ^ ^ j ^^ gg ^^^^ j ^ ¡j ^^ ^ ^^^^^^^^^ 4- [(9- { (2S, 3R, 4S, 5S) -3,4-dihydroxy-5- [5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl] -tetrahydrofuran-2-yl] -9H-purin-6-yl) amino] ethyl piperidine-1-carboxylate; (2S, 3R, 4S, 5S) -2- [6- (4-chloro-2-fluoroanilino) -9H-purm-9-yl] -5- (5-methyl-1,3,4-oxadiazole-2) -yl) -tetrahydrofuran-3,4-diol; (2S, 3R, 4S, 5S) -2- [6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] -5- (3-cyclopropylisoxazol-5-yl) -tetrahydrofuran-3, 4-diol; (2S, 3R, 4S, 5S) -2- [3- (tert-butyl) isoxazol-5-yl] -5-. { 6- [(1-Butylpiperidin-4-yl) amino] -9H-purin-9-yl} -tetrahydrofuran-3,4-diol; 4- [(9-. {(2S, 3R, S, 5S) -5- [3- (tert-butyl) isoxazol-5-yl] -3, -dihydroxytetrahydrofuran-2-yl}. -9H- purin-6-yl) amino] piperidine-1-carboxylic acid isopropyl ester; (2S, 3R, 4S, 5S) -2- [3- (tert-butyl) isoxazol-5-yl] -5- (6- { [1- (2,2, 2-trifluoroacetyl) piperidin-4 -yl] amino.}. -9H-purin-9-yl) -tetrahydrofuran-3, -diol; 4- [(9-. {(2S, 3R, 4S, 5S) -5- [3- (tert-butyl) isoxazol-5-yl] -3,4-dihydroxytetrahydrofuran-2-yl.} -9H methyl -purin-6-yl) amino] piperidine-1-carboxylate; (2S, 3R, S, 5S) -2- [6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] -5- [hydroxymethyl) isoxazol-5-yl) -tetrahydrofuran-3, 4-diol; (2S, 3R, 4S, 5S) -2- [6- (2-Chloro-4-fluoroanilino) -9H-purin-9-yl] -5- [3- (hydroxymethyl) isoxazol-5-yl) -tetrahydrofuran -3, -diol; (2S, 3R, 4S, 5S) -2- [6- (2-fluoroanilino) -9H-purin-9-yl] -5- [3- (hydroxymethyl) isoxazol-5-yl) -tetrahydrofuran-3, 4 -diol; (2S, 3R, 4S, 5S) -2- (2-chloro-6-. {[[(LS, 2S) -2-hydroxycyclopentyl] amino) -9H-purin-9-yl] -5- [3- (hydroxymethyl)? soxazol-5-yl) -tetrahydrofuran-3,4-diol; (2S, 3R, S, 5S) -2- [2-chloro-6- (tetrahydro-2H-pyran-4-ylamino) -9H-purin-9-yl] -5- [3- (hydroxymethyl) isoxazole- 5-yl] -tetrahydrofuran-3,4-diol; 2- [(2-chloro-9-. {(2R, 3R, 4S, 5S) -3,4-dihydroxy-5- [3- (hydroxymethyl) isoxazol-5-yl] tetrahydrofuran-2-yl} .9H-purin-6-yl) amino] -N-ethylethanesulfonamide; 4- [(2-chloro-9-. {(2R, 3R, 4S, 5S) -3,4-dihydroxy-5- [3- (hydroxymethyl) isoxazol-5-yl] tetrahydrofuran-2-y1.} -9H-purin-6-yl) amino] piperidine-1-carboxylic acid ethyl ester; ^^^^^ * ¡^^^ g ^^^ | ^^^^^ j * ^ gg ^^^ j ^ (2S, 3R, 4S, 5S) -2- [2-chloro-6- (4 -chloro-2-fluoroanilmo) -9H-purin-9-yl] -5- [3- (hydroxymethyl) isoxazol-5-yl] -tetrahydrofuran-3,4-diol; (2S, 3R, 4S, 5S) -2- [2-chloro-6- (2-chloro-4-fluoroanilino) -9H-purin-9-yl] -5- [3- (hydroxymethyl) isoxazole-5- il] - tetrahydrofuran-3,4-diol; (2S, 3R, 4S, 5S) -2- [2-chloro-6- (2-fluoroanilino) -9H-purin-9-yl] -5- [3- (hydroxymethyl) isoxazol-5-yl] -tetrahydrofuran -3, -diol; (2S, 3R, 4S, 5S) -2- (3-Ethylisoxazol-5-yl) -5- [2-methoxy-6- (tetrahydro-2H-pyran-4-ylamino) -9H-purin-9-yl ] - tetrahydrofuran-3,4-diol; 4- ( { 9- [(2S, 3R, 4S, 5S) -5- [3-ethylisoxazol-5-yl] -3, 4-dihydroxytetrahydrofuran-2-yl] -2-methoxy-9H-purin- 6-yl.} Amino] piperidine-1-carboxylic acid ethyl ester; (2S, 3R, 4S, 5S) -2- (3-ethylisoxazol-5-yl) -5- (6-. {[[(LS, 2S) -2- hydroxycyclopentyl] amino.} -2-methoxy- 9H-purin-9-yl) -tetrahydrofuran-3,4-diol; (2S, 3R, 4S, 5S) -2- (3-ethylisoxazol-5-yl) -5- (6- { [2- (ethylsulfonyl) ethyl] amino} -2-methoxy-9H-purin -9-yl) - tetrahydrofuran-3, -diol; (2S, 3R, 4S, 5S) -2- [6- (2-chloro-4-f-luoroanilmo) -2-methoxy-9H-purin-9-yl] -5- (3-ethyl-isoxazol-5-yl) ) tetrahydrofuran-3, -diol; (2S, 3R, S, 5S) -2- (3-et? Lysoxazol-5-yl) -5- [6- (2-fluoroanilmo) -2-methoxy-9H-purin-9-? L) - tetrahydrofuran-3, 4-diol; (2S, 3R, 4S, 5S) -2- [6- (4-Chloro-2-fluoroanilino) -2-methoxy-9H-purin-9-yl] -5- (3-ethylisoxazol-5-yl) - tetrahydrofuran-3, -10-diol; (2S, 3R, S, 5S) -2- [3- (tert-butyl) -l, 2,4-oxad? Azol-5-yl] -5- [6- (cyclopropylamino) -9H-pur? N -9-? L] -tetrahydrofuran-3, 4-d? Ol; (2S, 3R, S, 5S) -2- [5- (tert-butyl) -1, 3, 4-oxad? Azol-2-yl] -5- [2- 15 chloro-6- (4-chloro -2-fluoroanilmo) -9H-purin-9-yl] -tetrah? Drofuran-3, 4-d? Ol; (2S, 3R, 4S, 5S) -2- [6- (4-chloro-2-fluoroanilino) -9H-pur? N-9-yl] -5- (5-? - sopropyl-l, 3, -oxadiazole -2-yl) tetrahydrofuran-3,4-d-ol; The compounds according to the invention have applicability as inhibitors of lipolysis ie, these decrease the concentrations of free fatty acid in the plasma. In this manner, the compounds may be useful in the treatment of hyperlipemia. In addition, as a consequence of their anti-lipolytic activity, the compounds have the ability to decrease the high levels of glucose, insulin and ketone in the blood and therefore can be the value in the therapy of diabetes. Since anti-lipolytic agents have hypolipidemic and hypofibrimogenic activity, the compounds may also exhibit anti-atherosclerotic activity. The anti-lipolytic activity of the compounds of the invention have been demonstrated by their ability to decrease the concentration of non-esterified fatty acids (NEFA) in orally dosed hungry rats according to the method described by P. Strong et al. In Clinical Science (1993), ¡3_4, 663-669. In addition to their anti-lipolytic effect, the compounds of the invention can independently affect cardiac function by reducing the speed and conduction of the heart. In this way, the compounds can be used in the therapy of a number of cardiovascular disorders, for example cardiac arrhythmias, particularly after myocardial infarction, and angina. In addition, the compounds of the invention are useful as cardioprotective agents, which have applicability in the treatment of ischemic heart disease. As used herein, the term "ischemic heart disease" includes the damage associated with both myocardial ischemia and reperfusion, for example, associated with coronary artery bypass graft (CABG), percutaneous, translumenal coronary angioplasty. (PTCA), cardioplegia, acute myocardial infarction, thrombolysis, stable and unstable angina and cardiac surgery that includes in particular cardiac transplantation. The compounds of the invention are additionally useful for the treatment of ischemic damage to other organs. The compounds of the invention may also be valuable in the treatment of other disorders that arise as a result of atheromatous disease spread or spread, for example peripheral vascular disease (PVD) and apoplexy. -. - > «& ati» aiafa «, mJ. imm »S. & i.«. ^ J-ÍSiÉ ^^ Compounds can also inhibit the release of renin and thus can be of use in the therapy of hypertension and heart failure. The compounds may also be useful as CNS agents (for example as hypnotics, sedatives, analgesics and / or anti-consultants, finding use particularly in the treatment of epilepsy). In addition, the compounds of the invention can find use in the treatment of sleep apnea. The compound of the formula (I) and the pharmaceutically acceptable acid addition salts thereof are useful as analgesics. Therefore, they are useful in the treatment or prevention of pain. These can be used to improve the condition of a host, typically of a human being, who suffers from pain. These can be used to relieve pain in a host. In this way, the compound of the formula (I) and its pharmaceutically acceptable acid addition salts can be used as a preventive analgesic for treating acute pain such as musculoskeletal pain, postoperative pain and surgical pain, chronic pain such as inflammatory, chronic pain (for example rheumatoid arthritis (RA) ) and osteoarthritis (OA), neuropathic pain (for example post-herpetic neuralgia (PHN), trigeminal neuralgia, neuropathies associated with diabetes and sympathetically maintained pain) and pain associated with cancer and fibromyalgia The compound of the formula (I) ) can also be used in the treatment or prevention of pain associated with migraine, headache from tension and group headaches and pain associated with Functional Bowel Disorders (for example Irritable Bowel Syndrome), non-cardiac chest pain and non-ulcerative dyspepsia.Additionally, when administered topically, the compounds of the present invention exhibit active Analgesic and anti-inflammatory properties and therefore are useful in a number of inflammatory, chronic pain conditions such as OA, RA and neuropathic conditions such as fibromyalgia and PHN. Accordingly, the invention provides a compound of the formula (I) or a physiologically acceptable salt or solvate thereof for use in therapy, and in particular in the treatment of human or animal subjects suffering from a condition in which there is an advantage in decreasing the concentration of free fatty acids in the plasma, or reducing the speed and conduction of the heart or with which the therapy involves the treatment of ischemic heart disease, vascular disease . ^^. aa a te, .. .. peripheral or apoplexy or that the subject is suffering from a CNS disorder, sleep apnea or pain. In a further aspect, the invention provides a method of treating a human or animal subject suffering from a condition in which there is an advantage in decreasing the concentration of free fatty acids in plasma, or reducing the rate and conduction of the heart, or that the subject is suffering from or is susceptible to ischemic heart disease, peripheral vascular disease or stroke, or that the subject is suffering from a CNS disorder or suffers from sleep apnea or suffers from pain , the method comprising administering to the subject an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof. In a further aspect, the invention provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof for the preparation of a medicament for the treatment of a human or animal suffering from a condition in which there is an advantage in decreasing the concentration of free fatty acids in the plasma, or reducing the speed and conduction of the heart, or that the subject is suffering from or is susceptible to ischemic heart disease. heart, peripheral vascular disease or stroke or that the subject is suffering from a CNS disorder or suffering from sleep apnea or suffering from pain. With respect to the ischemic treatment mentioned above, it has been found that according to a particularly unexpected aspect of the present invention, not only administration of a compound of formula (I) before ischemia provides protection against myocardial infarction, but protection can also be given if The compound of the formula (I) is administered after the ischemic event and before reperfusion. This means that the methods of the present invention are applicable not only where ischemia is planned or expected, for example, in cardiac surgery, but also in cases of sudden or unexpected ischemia, for example heart attack and unstable angina. . It will be appreciated that reference to L treatment includes acute treatment or prophylaxis as well as relief of stable symptoms. The pharmaceutical composition comprises, as an active ingredient, at least one compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof in association with a carrier and / or pharmaceutical excipient for use in therapy, and in particular < i O in the treatment of human or animal subjects suffering from a condition in which there is an advantage in decreasing the concentration of free fatty acids in the plasma, or reducing the speed or conduction of the heart, or that the subject is suffering o Is susceptible to ischemic heart disease, peripheral vascular disease or stroke, or that the subject is suffering from a CNS disorder, sleep apnea or pain. In addition, there is provided by the present invention a method for preparing a pharmaceutical composition, the process comprising mixing at least one compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with a carrier and / or excipient pharmaceutically acceptable. The compositions according to the invention can be formulated for topical, oral, buccal, parenteral or rectal administration or in a form suitable for administration by inhalation or insufflation. Oral administration is preferred. The compositions can be adapted for sustained release. For topical administration, the pharmaceutical composition can be given in the form of a transdermal patch.

/ Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example starch mucilage or polyvinylpyrrolidone; fillers, for example, lactose, microcrystalline cellulose or corn starch; lubricants, for example, magnesium stearate, stearic acid; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycolate; or wetting agents such as sodium lauryl sulfate. The tablets may be coated according to methods well known in the art. The liquid, oral preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, or carboxymethyl cellulose; emulsifying agents, for example, sorbitan mono-oleate; non-aqueous vehicles (which may include edible oils), for example, propylene glycol or ethyl alcohol; and preservatives, for example, methyl or propyl p-hydroxybenzoates or sorbic acid. The preparations may also contain buffer salts, flavors, colorants and sweetening agents (for example mannitol) as appropriate. For buccal administration, the compositions can take the form of tablets or lozenges formulated in a conventional manner. The compounds of the formula (I) can be formulated for parenteral administration by bolus injection or continuous infusion and can be present in unit dose form in ampoules, or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain agents formulators such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, pyrogen-free, sterile water, before use. The compounds of the formula (I) can also be formulated as suppositories, for example containing conventional suppository bases such as cocoa butter or other glycerides. A proposed dose of the compounds of the invention for the administration to man (of ^ '-Í' * J '-' ^ "• * '- - **** ¿~ • * - < * -" - * "- - - • ^^ r ^ a, ^ f | arfl. .1tft (1t ^^ a ^^. ^ A, ^ .-. ^. A. ..- .i ^. ^ Approximately 70 kg of body weight) is 1 mg of 2 g, preferably 1 mg a 100 mg, of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day. It will be appreciated that it may be necessary to make routine variations to the dosage, depending on the age and condition of the patient. The dosage will also depend on the route of administration. In a still further aspect, the invention also provides the use of a compound of the formula (I) or a pharmaceutically acceptable salt or solvate of same for the preparation of a medicament for the treatment of human or animal subjects suffering from a condition in which there is an advantage in the decrease in the concentration of free fatty acids in the plasma, or the reduction in the speed and conduction of the heart, or that the subject is suffering from or is susceptible to ischemic heart disease, peripheral vascular disease (PVD) or Stroke, or that the patient is suffering from a CNS disorder, sleep apnea or pain. The compounds of the formula (I) and the physiologically acceptable salts or solvates thereof can be prepared by the methods described later in the present, the procedures that they constitute a further aspect of the invention. In the following description, the groups R1, R2 and R3 are as defined for the compounds of the formula (I) unless stated otherwise. According to a first general process A, a compound of the formula (I) can be prepared by reacting a compound of the formula (II) wherein L represents a leaving group such as a halogen atom (for example chlorine), or a linker group capable of binding to a solid phase polymer support (for example a polystyrene resin) and for example can be -S02alkylene of 1 to 4 carbon atoms and P1 and P2 represent hydrogen, alkyl of 1 to 6 carbon atoms, straight or branched chain or a suitable protecting group (for example acetyl or a protecting group in which P1 and P2 together form an alkylidema group) with a compound of the formula R1NH2 or a salt thereof under the conditions basic He substituent of the 4'-heterocycle group can be protected ^ x ^ st -. - ¿j- & _. -hw ^ - -j, m? i? Sm ± &? ¡? "É tafs ^. ^. ^^ tMá = e ei ^ '. if it is required, for example, to see the route V described later in the present. The compounds of the formula (II) can be used to produce the compounds of the formula. { I] directly by reaction with the group R1NH2 either in the absence or the presence of a solvent taL such as an alcohol (for example a lower alkanol taL such as isopropanol, t-butanol or 3-pentanol), an ether (for example tetrahydrofuran or dioxane), a substituted amide (for example dimethylformamide), a halogenated hydrocarbon (for example chloroform), an aromatic hydrocarbon (for example toluene), dimethyl sulfoxide (DMSO) or acetonitrile, preferably at an elevated temperature (for example example up to the reflux temperature of the solvent), in the presence of a suitable acid scavenger, for example, inorganic bases such as sodium, cesium or potassium carbonate, or organic bases such as triethylamine, diisopropylethylamine or pyridine, optionally in the presence of a palladium catalyst (for example palladium acetate) and a phosphine ligand (for example R- (+) - 2, 2'-bis (diphenylphosphino) -1,1'-biphenyl). Optionally, where at least one of Y, Z and W is N, the alkylation can be carried out on an atom of N at Y, Z or W at any appropriate stage in D? synthesis, for example, see Route X described later in the present. The above reactions can be preceded or followed, where appropriate, by an in situ removal of the protecting groups P1 and P2. For example, when P1 and P2 represent acetyl, this can be carried out with an amine such as ammonia or tert-butylamine in a solvent such as methanol or when p1 and P2 represent an alkylidine by hydrolysis of acid, for example with trifluoroacetic acid ( TFA). The interconversion of the protecting groups P1 and P2 can occur at any stage in the preparation of the compounds of the formula (II), for example when P1 and P2 represent acetyl, the compounds of the formula (II) can be prepared. of the compounds wherein P1 and P2 together represent an alkylidine protecting group by the acid-catalyzed removal of the alkylidine protecting group, for example with hydrogen chloride in methanol followed by in situ acylation, for example with acetic anhydride in the presence of a base such as pyridine, in a solvent such as dichloromethane. Otherwise, the interconversion of the protecting groups P1 and P2 can occur at any stage during the preparation of the compounds of the formula (II). It will be apparent to those skilled in the art that in the preparation of the compounds of the formula (II) or (I) the 4'-heterocycle can be formed at any stage. For example, heterocycles can be prepared from carboxylic acid or acetylene starting materials prior to the addition of the purine ring (see Schemes 1, la and 2) or the ss heterocycles can form after the addition of the purine ring. (see Schemes 3, 4 and 5 and Route W). The compounds of the formula (II) wherein X = D can be prepared by reacting the compounds of the formula (III) wherein R3 represents a suitable protecting group, for example acetyl, or a substituent such as alkyl of 1 to 3 carbon atoms, and P1, P2 and P3 are as defined above, with the compounds of the formula (IV) where L and R2 are as defined above. The reaction is conveniently carried out in a suitable solvent, such as acetonitrile in the presence of a silylating agent such as trimethylsilyl trifluoromethanesulfonate and a base such as diazabicyclo [5.4.0] undec-7-ene (DBU). Alternatively, the compound of the formula (IV) can first be silylated with a suitable silylating agent for example hexamethyldisilazane followed by the reaction of the silylated intermediate with a compound of the formula (III) and a suitable Lewis acid, for example , trimethylsilyl trifluoromethanesulfonate in a suitable solvent such as acetonitrile. The compounds of the formula (IV) are either known in the art or can be prepared from known compounds using methods analogous to those used to prepare the known compounds of the formula (IV). As described above, the compounds of the formula (III) can be prepared from ^^^ mXS * Z i ^ ... * mm¡m. protected, alternative compounds by replacing the protective groups P1 and P2, alternatively with other groups P1 and P2. These represent an exchange of one protective group by another and will be apparent to those skilled in the art. The compounds of the formula (III) can be made, for example, by the following syntheses: The compounds of the formula (III) can be prepared, for example, when the heterocycle defined by W, Y and Z above in the present represents an isoxazole (optionally substituted) by the following reaction schemes.

Scheme 1 HOOC¿J ° p.ó (Ill Me > ? The general conditions for Steps 1-4 will be known to those skilled in the art. It will also be appreciated that the reagents and conditions set forth in Scheme 1 are conditions of the examples and alternative reagents and conditions for achieving the same chemical transformation may be known to those skilled in the art. P4 and P5 together represent protecting group (s) of alkylidin. P6 represents alkyl of 1 to 4 carbon atoms. R3 is as previously defined. Although scheme 1 shows the preparation of the compounds of the formula (III) wherein the heterocycle portion is an isoxazole, it would be apparent to a person skilled in the art that other normal methods could be employed to produce the compounds of the formula (III ) with other heterocycles from carboxylic acid starting materials, such as a compound of the formula (Illa), for example, see the Q route as described hereinafter. An alternative method for the synthesis of the compounds of the formula (III) is shown in Scheme la.

Outline the nBuLi R3CHO MnO, Stage 2 H2NOH TFA Stage 4 The general conditions for Steps 1-5 in the Scheme will be known to those skilled in the art. R3, P4, P5 and P6 are as previously defined. ^^ ^^ ^^^^^^ g ^ ^^^^ Scheme 2 represents a method for the preparation of the compounds of the formula (III) when Y = N, Z = NH, W = CH and R3 = H or tautomers thereof. P1, P2 and P6 are as previously defined.

Scheme 2 Ph? Etapii 2 N2H4 / H20 An additional process (B) comprises converting a compound of the formula (I) to a different compound of the formula (I) by modifying the groups R1, R2 and / or R3 therein.

All of the compounds of the formulas (III) are novel intermediates and form an additional aspect of the present invention. The compounds of the formula R1NH2 are either known or can be prepared from known compounds using conventional procedures. The optical isomers, specific to a compound of formula (I) can be obtained by conventional methods for example, by synthesis of an asymmetric starting material, appropriate using any of the processes described herein, or where appropriate, by separation of a mixture of isomers of a compound of the formula (I) by conventional means for example by fractional crystallization or chromatography. According to a third process (C), the compounds of the formula (I) can be prepared from the compounds of the formula (V) or (VI): where R1, R2, X, L, P1 and P2 represent groups as ss previously defined. Also, the compounds of the formula (VI) ss can be prepared from the compounds of the formula (V) by methods analogous to those described in the process (A) above. The synthesis of the compounds of the formulas (I) of the corresponding acids of the formulas (V) (VI) will be apparent to a skilled person using synthetic, conventional techniques. As an example, when W = 0, Y = N and Z = ^ in formula 1 above defining a 1,3,4-oxadiazole in this way, the synthesis is according to the reaction scheme 3. J represents a leaving group L as previously defined, or a group NHR1, R2, X, P1 and P2 are as previously defined. ^^^^^^^ fe ^ M ^^^^^^^^^^ W Scheme 3 Method A SOCI2 Stage Method B POCyDMF Continue as described in Procedure A The compounds of the formula (I) wherein Z = 0, Y = N and W = N (thereby defining a 1,2,4-oxadiazole i can be prepared from the compounds of the formula (V) or ( VI) by a first method involving the activation of the carboxyl group in the compound of the formula (V) or (VI) followed by the reaction with an amidoxime of the formula HO-N = C (R3) NH2 in a solvent such as tetrahydrofuran or chloroform, in the presence of a base such as pyridine or di-isopropylethylamine, followed by cyclization at a temperature of 20 ° C-150 ° C in a solvent such as toluene, tetrahydrofuran (THF) or chloroform (see scheme 4) The carboxyl activation methods include the reaction with an acid chloride, such as pivaloyl chloride, or an acid anhydride in the presence of a base such as a tertiary amine, for example di-isopropylethylamine, or with chloride thionyl in dimethylformamide (DMF) Activation agents can also be used used in the chemistry of peptides such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) or 1-hydroxybenzotriazole 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride. The hydroxyl protecting groups can be removed under conditions known to those skilled in the art. For example, the acetonide group can be removed by treatment with an acid (at a temperature of 0 ° C-150 ° C) such as trifluoroacetic acid suitably at 0-20 ° C or acetic acid suitably at 50-150 ° C. In scheme 4, R2, R3, X, J, P1 and P2 are as defined above.

«¡Bg ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ? ^ Scheme 4 Modification of J and other protective groups as required Alternatively, a compound of the formula (II) can be prepared from a compound of the formula (VII), for example, see the U-route as described hereinafter. It would be apparent to those skilled in the art that methods analogous to the U path could be used to prepare the compounds of the formula (I) with other 4'-heterocycle, for example, see the M route as described hereinafter . rfiHT tf? ii-miifii "(Vil) According to the general procedure D, a compound of the formula (I) can be prepared from a compound of the formula (V), as shown in Scheme 5, followed by the removal of the protective groups P1 and P2 as described previously in procedure A. It will be apparent to those skilled in the art that methods analogous to that shown in Scheme 5 could be used to prepare the compounds of formula (I) with other 4'-heterocycles using the syntheses of alternative heterocycles. In Scheme 5, R1, R3, J, P1 and P2 are as previously defined. l- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride / dimethylformamide Stage 2 R'NHj / diisopropylethylamine / dimethyl sulfoxide Modification of protective groups as required The invention is further illustrated by the following intermediates and non-limiting examples. The experimental, complete details are given later for routes A-X and Z; the data for the remaining examples prepared by analogous routes are given in Table 1.

The conditions of the normal CLAP are as follows: column for Preparatory, Automated, Normal CLAP, conditions and eluent Preparative, automated high performance liquid chromatography (CLAP autoprep.) Was carried out using an ABZ + 5 m column, 100 mm x 22 mm i.d. eluted with a mixture of solvents consisting of d) i) 0.1% formic acid in water and ii) 0.05% formic acid in acetonitrile, the eluent being expressed as the percentage of ii) in the solvent mixture, at a rate of flow of 4 ml per minute. Unless stated otherwise, the eluent was used as a gradient of 0-95% of (ii) for 18.5 minutes.

CL / MS system Four systems of Alternative Liquid Chromatography Mass Spectroscopy (LC / MS): If system A: This system used an ABZ + PLUS column, 3.3 cm x 4.6 mm i.d., eluting with solvents: A - 0.1% v / v of formic acid + 0.077% w / v of ammonium acetate in water; and B-95: 5 acetonitrile: water + 0.05% v / v formic acid, at a flow rate of 1 ml per minute. The following gradient protocol was used: 100% A for 0.7 minutes; mixtures of A + B, gradient profile 0-100% of B for 3.5 minutes; keep 100% of B for 3.5 minutes; return to 100% of A for 0.3 minutes.

If system B: This system used an ABZ + PLUS column, 3.3 cm x 2.0 mm i.d., eluting with solvents: A - 0.1% v / v of formic acid + 0.077% w / v of ammonium acetate in water; and B-95: 5 acetonitrile: water + 0.05% v / v formic acid, at a flow rate of 0.8 ml per minute.

The following gradient protocol was used: mixtures of A + B, gradient profile 0-100% B for 3.5 minutes; keep 100% B for 1.5 minutes; return to 100% of A for 0.5 minutes.

'^^^^ ¡¡^ ^ ^ ^ ^^^^^^^^ * ^ I ^^^^^^^^^^^^^^^^^^^^^^ Yes Stema C: This system used an ABZ + PLUS column, 3.3 cm x 4.6 mm id, eluting with solvents: A - 0.1% v / v of formic acid + 0.077% w / v of ammonium acetate in 5 water; and B - 95% acetonitrile: water + 0.05% v / v ds formic acid, at a flow rate of 3 ml per minute. The following gradient protocol was used: 100% A for 0.7 minutes; mixtures of A + B, gradient profile 0-100% B for 3.7 minutes; keep 10 100% of B for 0.9 minutes; return to 100% of A for 0.2 minutes.

If s topic D: This system used an ABZ + PLUS column, 3.3 cm x 4.6 mm i.d., eluting with solvents: A - 0.1% v / v formic acid in water; and B - 95% acetonitrile: water + 0.07% v / v formic acid, at a flow rate of 1.5 ml per minute. The following gradient protocol was used: 100% A for 0.2 minutes; mixtures of A + B, gradient profile 0 - 100% of B for 3.3 minutes; maintain 100% B for 1 minute; return to 100% of A for 0.2 minutes. All the CL / MS systems used a micromassage xplataforma spectrometer, with Electro-dew ionization, positive and negative ion exchange, mass range 80-1000 a.m.u. Flash chromatography was carried out either on Merck silica gel (Merck 9385), or in pre-packaged silica gel cartridges (Biotage).

All temperatures were in ° C.

^ ¡^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^ SÍSC ii | ayZtíMJ &"Aj ^^^ J ^^ ^^^^^^^^^^^^^^^^^^ & ^^^^^^^^^^ H ^ gg ^. --iiitm ^^^^^ ^ mmt? amü ^ í -.

^^^^ ^ ^^^^^^^^^^^^^^ Sg ^^^^^^^^^ ? - ?? iit? - ÜBtYJtíSátMi ^ l ^ itmí 131 a w i; , -f "9» 6 a &»» ^ a it *? m »aj &amp &m; t? < j ¿¡¡eam £ z? BÁX 0 * & amp & B & jt-2. »¿-y & & amp; & &Z 1Ü7 . ^ sÉá "** 3 '' - ' s, - X ^ a - ^ - ^ i- ^ a? -i fe ^^ s? ^ áail ^ t¿ £ ^ * ^^ fe V é B r -? ^ Ajj ^ fe.fafct = a ,. "fib ki-jag. -fe * ^.,?" * + teL ^ aim £ t & t ^ * ^^ Table 1 . Examples Name Details Expt, Data no. (note 1) characterization 164 (2S, 3S, 4R, 5R) -2- (3- Route W CL / MS (Bromoisoxa5-yl) -5- C) Rt = 3.22 [6- (4-chloro-2-min. Fluoroanilino ) -9H-purin- Spectrum of 9-yl] tetrahydrofuran- Masses 3,4-diol M / z 511 [MH +] 165 (2R, 3R, 4S, 5S) -2- [6- (4- Analogue to LC / MS chloro-2-fluoroanilino) - path W (System C) Rt 9H-purin-9-il] -5- [3- 3.55 minutes (3, 5-difluorophenyl) - Spectrum of isoxa-5-Masses m / z 545 il] tetrahydrofuran-3, 4- [MH +]. diol 166 (2S, 3S, 4R, 5R) -2- [3-ter- Analog to LC / MS butyl) isoxa5-yl] -5- path Y (System C) Rt (6- { [ 1- 2.69 minutes (methylsulfonyl) piperidin spectrum of -4-yl] amino.}. -9H-purin-9- Masses m / z 522 il) tetrahydrofuran-3, 4- [MH +]. diol; 167 (2S, 3S, 4R, 5R) -2- [3- (ter- Analog to LC / MS butyl) isoxa5-yl] -5- path Y (System C) Rt (ß- { [ 1- 2.90 minutes (propylsulfonyl) piperidi Spectrum of n-4-yl] amino.}. -9H-purin- Masas m / z 550 9-yl) -tetrahydrofuran- [MH +]. 3,4-diol; 168 (2S, 3S, 4R, 5R) -2- [3- (ter- Analog to LC / MS butyl) -isoxa5-yl] -5- path Y (System C) Rt (6- { [1-87 minutes (isopropylsulfonyl) piper Idin-4-yl] amino] spectrum. -9H-Masses m / z 550 purin-9-yl) - [MH +]. tetrahydrofuran-3, 4-diol; 169 (2S, 3S, 4R, 5R) -2- [3- (ter- Analog to LC / MS butyl) isoxa5-yl] -5- path Y (System C) Rt (6- { [ 1- 2.77 minutes (ethylsulfonyl) piperidin- Spectrum of .............................................................................................................................................................................................. aaa ^ ta ^ a ^ J ^ ^ Za ^ ^ a ^ g • 4-il] amino} -9H-purin-9- Masses m / z 536 il) -tetrahydrofuran-3, 4- [MH +]. diol; 170 (2S, 3S, 4R, 5R) -2- [3- (ter- Analog to L C / MS butyl) isoxa5-yl] -5- path I (System C) Rt [2-chloro-6- (4-chloro-2- 3.60 minutes fluoroanilino) -9H-purin- Spectrum of 9-yl] tetrahydrofuran-Masas m / z 524 3, 4 -diol; [MH +]. 171 (2S, 3S, 4R, 5R) -2- [3- (ter- Analog to L C / MS butyl) isoxa5-yl] -5- path I (System C) Rt [2-chloro-6- (2-chloro-4-350 minutes fluoroanilino) -9H-purin- Spectrum of 9-yl] tetrahydrofuran-Masas m / z 524 3, 4-diol; [MH +]. 172 2 - [(9- { (2R, 3R, 4S, 5S) -5- Analogous to L C / MS [3- (tert-butyl) isoxa- path I (System C) Rt -yl] -3.4- 2.94 minutes dihydroxytetrahydrofuran Spectrum of -2-il} -2-chloro-9H-purin- Masas m / z 530 il) -tetrahydrofuran-3, 4- Masses m / z 510 diol; [MH +]. 176 2R, 3R, 4S, 5S) -2- [6- (4- Analogous to LC / MS chloro-2-fluoroanilino) - pathway W (System C) Rt 9H-purin-9-il] -5- [ 3- (4-3,35 minutes hydroxybutyl) isoxa-5- Spectrum of il) -tetrahydrofuran-3, 4- Masses m / z 505 diol; [MH +]. 177 2- [(9- { (2R, 3R, 4S, 5S) -5- Analogous to L C / MS [3- (tert-butyl) isoxa-path I (System C) Rt -yl] -3,4- 2.65 minutes dihydroxytetrahydrofuran Spectrum of -2-il} -9H-purin-6-Masas m / z 496 il) amino] -N- [MH +]. ethylenesulfonamide; 178 (2R, 3R, 4S, 5S) -2- [6- Analogue to LC / MS (cyclopentylamino) -9H- pathway A (System C) Rt purin-9-yl] -5- [5- 2.80 minutes ( trifluoromethyl) -1, 3, 4- Spectrum of oxadia2-yl] - Masas / z 442 ¿¿¿^ ^ ^ ^^ S? > £? ^ & ^ !;; ^^ = ^ * z tetrahydrofuran-3, 4- [MH +] diol; 179 (2R, 3R, 4S, 5S) -2- (6- Analogue to LC / MS { [(LS, 2S) -2- path A (System C) Rt hydroxycyclopentyl] ammo 2.48 minutes) -9H- pupn-9-? l] -5- [5- Spectrum of (trifluoromethyl) -1, 3, 4- Masses m / z 458 oxadia2-yl] - [MH +]. tetrahydrofuran-3, 4-diol; 180 4- [(9- { (2R, 3R, 4S, 5S) - Analogous to L C / MS 3, -d? Hydroxy-5- [5- path A (System C) Rt (trifluoromethyl) -1, 3, 4- 2.74 minutes oxad? a-2-yl] - Spectrum of tetrahydrofuran-2-yl} - Masses m / z 529 9H-purin-6- [MH +]. il) amino] piperidine-1-ethyl carboxylate; 181 (2R, 3R, 4S, 5S) -2- [6- (4- Analogue to the LC / MS chloro-2-fluoroanilmo) - Ce path (System C) Rt 9H-purin-9-il] -5- (5-77 minutes methyl-1, 3, 4-oxadia-2-spectrum of il) -tetrahydrofuran-3, 4- Masses m / z 44 diol; [MH +]. 182 (2R, 3R, 4S, 5S) -2- [6- (4- Analog to LC / MS chloro-2-fluoroanilino) - path W (System C) Rt 9H-purin-9-il] -5- (3- 3.15 minutes cyclopropylisoxa-5-spectrum of il) -tetrah? Drofuran-3, 4- Masses m / z 473 diol; [MH +]. 183 2S, 3S, 4R, 5R) -2- [3- (ter- Analog to L C / MS butyl) isoxazol-5-yl] -5- path Y (System C) Rt. { 6- [(l-butylpiperidin-4- 2.74 minutes il) amino] -9H-purin-9- Spectrum of il} -tetrah? drofuran-3, 4- Masses m / z 514 diol; [MH +]. 184 4- [(9- { (2R, 3R, 4S, 5S) -5- Analogous to LC / MS [3- (tert-butyl) isoxazole-Y pathway (System C) Rt 5-il] - 3.4- 3.10 minutes dihydroxytetrahydrofuran Spectrum of i * 5 9H-pupn-9-yl] -5- [3- 2.67 minutes (hydroxymethyl) isoxazole- Spectrum of 5- l) -tetrahydrofuran-Masses m / z 463 3, -diol; [MH +]. 188 (2R, 3R, 4S, 5S) -2- [6- (2- Fluoroaniline LC / MS analogue) -9H-pur? N- V route (System C) Rt 9-il] -5- [3 2.56 minutes (hydroxymethyl) isoxazole- Spectrum of 5-yl) -tetrahydrofuran-Masses m / z 463 3, 4-diol; [MH +]. 189 (2R, 3R, 4S, 5S) -2- [6- (2-analogue to LC / MS chloro-4-fluoroanilino) -V path (System C) Rt 9H-purin-9-il] -5 [ 3- 2.40 minutes (hydroxymethyl) isoxazole- Spectrum of 5-yl] tetrahydrofuran-Masas m / z 429 3,4-diol [MH +]. 190 (2R, 3R, 4S, 5S) -2- [6- (2-analogue to LC / MS chloroaniline) -9H-pupn-path V (System C) Rt 9-il] -5- [3- 2.54 minutes (hydroxymethyl) isoxazole- Spectrum of 5-yl] tetrahydrofuran-Masas m / z 445 3,4-diol [MH +]. 191 (2R, 3R, 4S, 5S) -2- (62- Analog to LC / MS chloro-6-. {[[(LS, 2S) -2- path Bb (System C) Rt hydroxycyclopentyl] amino 2.32 minutes ) -9H-purin-9-yl] -5- [3- Spectrum of (hydroxymethyl) isoxazole-Masas m / z 5-yl) -tetrahydrofuran-453/455 [MH +]. 3, -diol; 192 (2R, 3R, 4S, 5S) -2- [2- Analogous to LC / MS chloro-β- (tetrahydro-2H- path Bb (System C) Rt piran-4-ylamino) -9H- 2.32 minutes purin -9-yl] -5- [3- Spectrum of (hydroxymethyl) isoxazole-Masas m / z 5-yl] -tetrahydrofuran-453/455 [MH +]. 3, 4-diol; 193 2- [(2-chloro-9- { (2R, Analogous to L C / MS 3R, 4S, 5S) -3,4-dihydroxy-path Bb (System C) Rt - [3- 2.32 minutes (hydroxymethyl) isoxazole- Spectrum of 5-? L] tetrahydrofuran-2-Masas m / z il} -9H-purin-6- 504/506 [MH +]. ? --- 7 - »?; . t3 & £ (hydroxymethyl) isoxazole-Masas m / z 5-yl] -tetrahydrofuran-497/499 [MH +] 3, 4-diol; 197 (2R, 3R, 4S, 5S) -2- [2- Analogue to the LC / MS chloro-6- (2- path Bb (System C) Rt fluoroanilino) -9H-purin- 2.72 minutes 9-il] - 5- [3- Spectrum of (hydroxymethyl) isoxazole-Masas m / z 463 5-yl] -tetrahydrofuran- [MH +]. 3,4-diol; 198 2S, 3S, 4R, 5R) -2- (3- Analog to the LC / MS ethyl isoxazol-5-yl) -5- [2- path L (System C) Rt methoxy-6- (tetrahydro-2H- 2.57 minutes pyran-4-ylamino) -9H- Spectrum of purin-9-yl] - Masses m / z 447 tetrahydrofuran-3, 4- [MH +]. diol; 199 (4- ( {9- [(2R, 3R, 4S, 5S) -5- Analogous to LC / MS [3-ethylisoxazol-5-yl] - path L (System C) Rt 3,4- 2.75 minutes dihydroxytetrahydrofuran Spectrum of -2-yl] -2-methoxy-9H-masses m / z 51I purin-6- [MH +]. il} amino] piperidine-1-ethyl carboxylate; 200 2S, 3S, 4R, 5R) -2- (3- Analog to the LC / MS ethyl isoxazol-5-yl) -5- (6- path L (System C) Rt { [(LS, 2S) - 2- 2.66 minutes hydroxycyclopentyl] amino Spectrum of.} -2-methoxy-9H-purin-9- Masses m / z 447 il) -tetrahydrofuran-3, 4- [MH +]. diol; 201 (2S, 3S, 4R, 5R) -2- (3- Analog to the LC / MS ethyl-soxazol-5-yl) -5- (6- path L (System C) Rt { [2- 2.42 minutes (ethylsulfonyl) ethyl] amino Spectrum of.} -2-methoxy-9H-purin-9-masses / z 483 yl) -tetrahydrofuran-3, 4- [MH +]. diol; 202 (2R, 3R, 4S, 5S) -2- [6- (2-analogue to LC / MS chloro-4-fluoroanilino) - path L (System C) Rt 2-methoxy-9H-purin-9-il ] - 3.12 minutes 5- (3-Ethylisoxazole-5- Spectrum of Experimental details for the route (A) Intermediary 1 N '- (2,2-dimethyl-propionyl) -hydrazide (3aS, 4S, 6aR) -6-chloro-purin-9-yl) -2,2-dimethyl-tetrahydrofuro [3, d] [ 1,3] dioxol-4-carboxylic acid The acid (3aS, 4S, 6R, 6aR) -6- (6-chloro-purin-9-yl) -2,2-dimethyl-tetrahydro-furo [3, 4-d] [1, 3] dioxol-4 - carboxylic acid (2.5 g) suspended in 1,2-dimethoxymethane (100 ml) was treated with 2,2-dimethylpropionic acid hydrazide (1.1 g) and 2-ethoxy-1-ethoxycarbonyl-l, 2-dihydroquinoline (EEDQ) , and the mixture was heated under reflux for 16 hours. The mixture was poured into aqueous citric acid (250 ml) and extracted with ethyl acetate.; the organic layers were washed with citric acid and brine, dried (MgSO) and evaporated in vacuo to give the crude product. Purification by flash chromatography on silica gel (Biotage Cartridge), eluting with ethyl acetate: cyclohexane 65:35, gave the title compound as a white solid (1.92 g). LC / MS (System B): Rt 2.49 min Mass spectrum m / z 439 [MH +].

Intermediate 2 9- [6S- (5-tert-Butyl- [1,3,4] oxadiazol-2-yl) -2, 2-dimethyl-tetrahydro- (3aR, 6aS) -furo [3, 4-d] [1, 3] dioxol-4R-yl] -6-chloro-9H-purine N '- (2,2-dimethyl-propionyl) -hydrazide (3aS, 4S, 6R, 6aR) -6- (6-chloro-purin-9-yl) -2,2- dimethyl-tetrahydro-furo [3,4-d] [1,3] dioxol-4-carboxylic acid (1.5 g) was dissolved in thionyl chloride (15 ml) and the solution was irradiated in a microwave oven at 150W of power for 7 minutes. The excess thionyl chloride was evaporated in vacuo to give the crude product which was dissolved in dry acetonitrile (6 ml) and heated under reflux for 3 hours. The solvent was evaporated and the residue was purified by flash chromatography on silica gel, eluting with ethyl acetate: cyclohexane 35:65 - 40:60, to give the title compound as a white solid (0.645 g).

LC / MS (System B): Rt 2.86 min Mass spectrum m / z 421 [MH +].

Intermediate 3 (2S, 3S, 4R, 5R) -2- (5-tert-Butyl- [1,3,4] oxadiazol-2-yl) -5- (6-chloro-purin-9-yl) -tetrahydro -furan-3, 4-diol 9- [6S- (5-tert-butyl- [1,3,4] oxadiazol-2-yl) -2,2-dimethyl-tetrahydro- (3aR, 6aS) -furo [3, 4-d] [ 1, 3] dioxol-4R-yl] -6-chloro-9H-purine (0.64 g) was treated with trifluoroacetic acid: water 10: 1 (9 ml) at 0 ° C for 5 hours, and the mixture was allowed to stand in the refrigerator (2nd) during the night. The mixture was evaporated in vacuo at a low volume (approximately 1 ml), emptied in aS-B ^ aqueous sodium bicarbonate, cooled with ice, and extracted with ethyl acetate (3x50 ml). The organic layers were washed with brine, dried (MgSO4) and evaporated in vacuo to give the crude product (371 mg).

LC / MS (System B): Rt 2.42 min Mass spectrum m / z 381 [MH +].

Example 3 (2S, 3S, 4R, 5R) -2- (5-tert-Butyl- [1,3,4] oxadiazol-2-yl) -5- [6- (tetrahydro-pyran-4-ylamino) - purin-9-yl] -tetrahydrofuran-3,4-diol (2S, 3S, 4R, 5R) -2- (5-tert-butyl- [1,3,4] oxadiazol-2-yl) -5- (6-chloro-purin-9-yl) -tetrahydro- furan-3, 4-diol (41 mg) was heated under reflux with 4-art? -tetrahydropyran hydrochloride (59 mg), diisopropylethylamine (0.11 ml), and isopropanol (5 ml) for 15 hours. The solvent was evaporated in vacuo, the residue was purified by chromatography on silica gel, eluting with ethyl acetate: methanol 100: 0-90:10, to give the title compound (37 mg).

LC / MS (System B): Rt 2.31 min Mass spectrum m / z 446 [MH +].

Experimental details for the route (B) Intermediate 4 2-Chloro-N- (tetrahydro-pyran-4-yl) -adenosine A mixture of 4R-acetoxy-5R-acetoxymethyl-2R- (2,6-dichloro-purin-9-yl) -tetrahydro-furan-3R-yl ester of acetic acid (10 g), diisopropylethylamine (5.7 ml) and hydrochloride of 4-amino tetrahydropyran (2.02 g), in isopropanol (200 ml) was heated at 50 ° C for 4 hours. The cold mixture was evaporated in vacuo, the residue re-dissolved in methanol (200 ml) and ammonia gas was bubbled through the solution for 2 hours. The mixture was stirred at 22 ° C overnight, and evaporated in vacuo to give a brown oily solid. Purification by flash chromatography on silica gel (Merck 9385), eluting with DCM: EtOH: 880 NHL 75: 8: 1 to DCM: EtOH: NH3 880 50: 8.1 gave the title compound as an oily solid colored Pale coffee (7.81 g) • LC / MS (System B): Rt 2.24 min Mass spectrum m / z 3.86 [MH +]. - < & Intermediary 5. { 6R- [2-Chloro-6- (tetrahydro-pyran-4-ylamino) -purin-9-yl] -2,2-dimethyl-tetrahydro- (3aR, 6aR) -furo [3, -d] [1, 3] dioxo1- 4R-il} -methanol 5 A solution of 2-chloro-N- (tetrahydro-p? ran-4-yl) -adenosine (7.81 g) in acetone (500 ml) was treated with 2,2-dimethoxypropane (14.7 ml) and p-acid. toluenesulfonic (3.8 g) and the mixture was stirred at 20 ° C overnight. HE formed a white precipitate. The mixture was evaporated in vacuo, and the residue was partitioned between ethyl acetate (700 ml) and aqueous sodium bicarbonate solution (500 ml). The organic layer was washed with aqueous sodium bicarbonate (2x250 ml), dried (Na2SO4) and evaporated in. vacuo to give a pale brown foam (7 g). Purification by flash chromatography on silica gel (Merck 9385), eluting with ethyl acetate: cyclohexane 4: 1, gave the title compound as a pale yellow foam (5.7 g). LC / MS (System B): Rt 2.68 min. Mass spectrum m / z 4.26 [MH +]. ^^ _ ¡^^^^^ ^ ^ ^ ^ ^ ^ i.

Intermediary 6 Acid (3aS, 4S, 6R, 6aR) -6- [2-Chloro-6- (tetrahydro-p-ran-4-ylamino) -purin-9-yl] -2, 2-dimethyl-tetrahydrofide [3,4-d] [1, 3] dioxol-4-carboxylic A solution of. { 6R- [2-chloro-6- (tetrahydro-pyran-4-ylamino) -purin-9-yl] -2, 2-dimethyl-tetrahydro- (3aR, 6aR) -furo [3, 4-d] [1, 3] dioxol-4R-il} -methanol (2.5 g) in ethyl acetate (90 ml) was treated with an aqueous, saturated solution of sodium bicarbonate (60 ml) and the biphasic mixture was stirred rapidly at 0 ° C. After stirring at 0 ° C for 5 minutes, potassium bromide (70 mg) was added followed by 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical (TEMPO) (4.6 ml). A freshly prepared solution of sodium bicarbonate (185 mg) in aqueous sodium hypochlorite (3.2 ml) and water was added dropwise to the stirred mixture, cooled for 15 minutes. The mixture was stirred for an additional 20 minutes at 0 ° C. Two more additional potassium bromide, TEMPO and the aqueous solution of sodium bicarbonate / sodium hypochlorite, freshly prepared in the same amounts as above, were made each followed by stirring at 0 ° C for 15-20 minutes. The mixture was poured into ethyl acetate (400 ml), stirred with sodium sulfite (10 g), diluted with water (300 ml), stirred, and the organic and aqueous layers were separated. The aqueous layer was acidified to pH 1-2 with 2N hydrochloric acid solution and extracted with ethyl acetate (2x 300 ml). The organic layers were combined with those from a second identical reaction, and evaporated in vacuo to give the product as a cream colored foam (4.47 g). LC / MS (System B): Rt 2.81 min Mass spectrum m / z 440 [MH +]. 10 Intermediate 7 N '- (2, 2-Dimethyl-propionyl) -hydrazide acid (3aS, 4S, 6R, 6aR) -6- [2-chloro-6- (tetrahydro-pyran-4-ylamino) -purin-9-yl] -2, 2-dimethyl-tetrahydro-furo [3, 4- 15 d] [1, 3] dioxol-4-carboxylic Diisopropylethylamine (0.487 ml) was added to a stirred solution of acid (3aS, 4S, 6R, 6aR) -6- [2-chloro-6- (tetrahydro-pyran-4-ylamino) -purin-9-yl] -2 , 2- 20 dimethyl-tetrahydro-furo [3,4-d] [1, 3] dioxol-4-carboxylic acid (350 mg) in dry tetrahydrofuran (8 ml) at 0 ° C under nitrogen. After 5 minutes, pivaloyl chloride (0.098 ml) was added and the mixture was stirred at 0 ° C for 2. 5 hours. 2,2-Dimethylpropionic acid hydrazide in tetrahydrofuran (2 ml) was added at 0 ° C and ¿^^^ ¿^ ^ ^^^^^^? JSja. stirring was continued at 0-22 ° C overnight. The mixture was concentrated in vacuo and partitioned between ethyl acetate (2x30 ml) and saturated aqueous sodium bicarbonate (30 ml). The organic layers were washed with brine (50 ml), dried (MgSO 4) and evaporated in vacuo. The residue was made azeotropic with dichloromethane (10 ml) to give the title compound as a cream colored solid (357 mg). LC / MS (System B): Rt 2.76 min Mass spectrum m / z 538 [MH +].

Intermediary 8. { 9- [6S- (5-tert-Butyl- [1,3,4] oxadia o1-2-i1) -2 and 2-dimethyl-tetrahydro- (2aR, 6aS) -furo [3, 4-d] [1 , 3] dioxol-4R-I1] -2-chloro-9H-purin-6-yl} - (tetrahydro-pyran-4-yl) -amine N '- (2, 2-dimethyl-propionyl) -hydrazide (3aS, 4S, 6R, 6aR) -6- [2-chloro-6- (tetrahydro-pyran-4-ylamino) -purin-9- il] -2,2-dimethyl-tetrahydro-furo [3,4-d] [1, 3] dioxol-4-carboxylic acid (150 mg) was dissolved in N, N-dimethylformamide (1.2 ml) and the solution was cooled at 0 ° C under nitrogen. To the stirred, cooled solution was added phosphorus oxychloride (0.039 ml). The solution was stirred at 0 ° C for 1 hour and at 22 ° C for 16 hours. The mixture was cooled to 0 ° C, more phosphorus oxychloride (0.026 ml) was added, and the mixture was stirred at 0 ° C for 1 hour and at 22 ° C for 20 hours. The mixture was partially evaporated in vacuo, and partitioned between ethyl acetate (2x30 ml) and aqueous sodium bicarbonate (30 ml). The organic layers were dried (MgSO4) and concentrated in vacuo to give a yellow oil. Purification by flash chromatography on silica gel, eluting with 30-100% ethyl acetate in cyclohexane, gave the title compound (60 ml). g; LC / MS (System A): Rt 4.41 min Mass spectrum m / z 520 [MH +].

Example 8 Formate of; 2S, 3S, 4R, 5R) -2- (5-tert-buty1- [1, 3, 4] oxadiazol-2-yl) -5- [2-chloro-6- (tetrahydro- pyran-4-ylamino) -purin-9-yl] -tetrahydro-furan-3,4-diol The. { 9- [6S- (5-tert-butyl- [1, 3, 4] oxadiazol-2-yl) -2,2-dimethyl-tetrahydro- (3aR, 6aS) -furo [3, 4-d] [1 , 3] dioxo1-4R-yl] -2-chloro-9H-purin-6-yl} - (tetrahydro-pyran-4-yl) -amine (60 mg) was dissolved in trifluoroacetic acid: water 10: 1 (2 ml) and the mixture was stirred at 0 ° C for 1 hour, and to 22 ° C for 4 hours. The mixture was evaporated in vacuo and a = s. K & amp; amp; amp; 3 & amp; & amp; Jl £ St. it was made azeotropic with toluene (2 x 6 ml). The residue was purified by preparative CLAP (5-90% gradient profile (ii) for 18.5 minutes) to give the title compound as a white solid (37 mg).

LC / MS (System A): Rt 3.86 min Mass spectrum m / z 480 [MH +].

Experimental details for the route (C) Intermediate 9 Acid methyl ester (3aS, 4S, 6R, 6aR) -6- (6-cyclopentylamino-purin-9-yl) -2, 2-dimethyl-tetrahydrofuran [3, 4-d] [1,3 ] dioxo1-4-carboxylic A solution of acid (3aS, 4S, 6R, 6aR) -6- (6-cyclopentylamino-purin-9-yl) -2,2-dimethyl-tetrahydrofuro [3,4-d] [1, 3] dioxol 4-carboxylic acid (3.018 g) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (2.66 g) in methanol (120 ml) was heated under reflux for 17 hours. The resulting mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (150 ml). The solution was washed with an aqueous solution of 0.5M citric acid (3 x 25 ml) and brine (50 ml), dried (magnesium sulfate), and evaporated in vacuo to give 1 a white foam. Purification by column chromatography on silica gel, eluting with ethyl acetate: cyclohexane (1: 1), gave the title compound as a white solid (2.32 g). 5 CCD Si02 (CH2Cl2: MeOH: NH3 880 94: 6: 1) Rf = 0.62 Intermediate 10 Acid hydrazide (3aS, 4S, 6R, 6aR) -6- (6-cyclopentylamino-purin-9-yl) -2, 2-dimethyl-tetrahydro-10 furo [3, 4-d] [1,3 ] dioxol-4-carboxylic acid A mixture of methyl ester of acid (3aS, 4S, 6R, 6aR) -6- (6-cyclopentylamino-purin-9-yl) -2,2-dimethyl-tetrahydro-furo [3,4-d] [1, 3] dioxol-4-carboxylic acid (0.48 g) and hydrazine hydrate (0.29 ml) in methanol (10 ml) was heated to reflux for 28 hours. After cooling to room temperature, the mixture was concentrated in vacuo and the residue was evaporated twice with dichloromethane (2 x 20 ml) to give the title compound. title as a white solid (0.49 g).

NMR (DMSO) 9.4 (H, broad s, NH), 8.32 (H, s, CH) 8.20 (H, s, CH), 7.90 (H, broad d, NH), 6.35 (H, broad s, CH) , 5.28 (2H, broad, 2 x CH), 4.65 (ÍH, s broad, CH), 4.50 (ÍH, broad, CH), 4.20 (2H, broad s, NH2), 2.0-1.5 (11H, 2xm + s, 4 x CH2 + CH3) Intermediate 11 5 Cyclopentyl- [9- (2, 2-dimethyl-6S- [1,3,4] oxadiazol-2-yl-tetrahydro- (3aR, 6aS) -furo [3, 4-d] [1, 3 ] dioxol-4R-yl) -9H-purin-6-yl] -amine A mixture of 10 (3aS, 4S, 6R, 6aR) -6- (6-cyclopentylamino-purin-9-yl) -2,2-dimethyl-tetrahydro-furo [3,4-d] [1] hydrazide 3] dioxol-4-carboxylic acid (0.5 g) and triethyl orthoformate (5 ml, 4.45 g) was heated at reflux for 48 hours; on cooling, the solution was evaporated to give a brown oil. Purification by flash chromatography on silica gel, eluting with ethyl acetate: cyclohexane (3: 1), gave the title compound as a cream foam (0.157 g). CCD SiO2 (ethyl acetate: cyclohexane 3: 1) Rf = 0.17 Example 15 (2R, 3R, 4S, 5S) -2- (6-Cyclopentylamino-purin-9-yl) -5- [1,3,4 ] oxadiazol-2-yl-tetrahydro-furan-3,4-diol Trifluoroacetic acid (1.5 ml) and water (0.15 ml) were added to the cyclopentyl- [9- (2, 2-dimethyl-6S- [1,3,4] oxadiazol-2-i1-tetrahydro- (3aR, 6aR) -furo [3,4-d] [1, 3] dioxol-4R-yl) -9H-purin-6-yl] -amine (0.157 g) at 0 ° C and the mixture was stirred for 2 hours. The resulting solution was emptied into 8% aqueous sodium bicarbonate solution (10 ml) and extracted with ethyl acetate (4 x 20 ml); The organic layers were dried (MgSO 4), filtered and evaporated to dryness to give a pale cream foam (0.148 g). Methanol (20 ml) was added and the solid was filtered to give the title compound as a white solid (0.46 g).

CCD Si02 (Ethyl acetate) R £ = 0.13 Analysis Found: C, 50.77; H, 5.14; N, 25.53% C? 6H? 9N704. 0.2MeOH. 0.1H20 requires: C 50.99; H, 5.3; N, 25.7% Experimental details for the route (D) Intermediate 12 (2-oxo-butyl) -amide of acid (3aS, 4S, 6R, 6aR) -6- (6-chloro-purin-9-yl) -2, 2-dimethyl-tetrahydro-furo [3, 4 - d] [1, 3] dioxol-4-carboxylic A solution of acid (3aS, S, 6R, 6aR) -6- (6-chloro-purin-9-yl) -2,2-dimethyl-tetrahydro-furo [3, 4-d] [1, 3] dioxol 4-carboxylic acid (1.3 g), in dry tetrahydrofuran (30 ml) was cooled to 3 ° C before triethylamine (1.07 ml) was added. After stirring for 15 minutes at 3 ° C, trimethylacetyl chloride (0.56 ml) was added and the suspension was stirred for 40 minutes at 3 ° C. This suspension was added to a stirred mixture of 2-oxybutylamine hydrochloride in acetonitrile (50 ml) containing triethylamine (2.3 ml). The mixture was allowed to warm to room temperature, stirred overnight, and partitioned between ethyl acetate (150 ml) and 10% aqueous sodium chloride (100 ml). The separated aqueous phase was further extracted with ethyl acetate (2 x 100 ml) and the combined organic extracts were washed with brine (70 ml), dried and concentrated in vacuo to give a dark red gum (1.83 g). ). Purification by chromatography on silica gel (Merck 7734), eluting with dichloromethane: ethanol: 880 ammonia (250: 8: 1) gave the title compound as a yellow-brown foam (1.11 g). NMR d (CDC13) 8.68 (lH, s, CH), 8.27 (lH, s, CH), 6.73 (lH, broad t, NH), 6.30 (lH, d, CH), 5.64 (lH, dd, CH) , 5.46 (lH, dd, CH), 4.80 (lH, d, CH), 3.76 (2H, ABX, CH2), a-aAt- ** aS? lMAaaBb &amp? la? b ».í.m ._ .. ^ > _ "^^^^^^^^^^^^^^^^^^^^^^^^ (2H, q, CH2), 1.65 (3H, s, -CH3), 1.42 (3H, s, -CH3 ), 0.99 (3H, t, CH3).

Intermediate 13 5 6-Chloro-9- [6S- (5-ethyl-oxazol-2-yl) -2, 2-dimethyl-tetrahydro- (3aR, 6aS) -furo [3, 4-d] [1, 3 ] dioxol-4R-yl] -9H-purine Phosphorus oxychloride (1.43 g) was added to a stirred solution of (3aS, 4S, 6R, 6aR) -6- (6-chloro-purin-9-yl) -2,2-dimethyl-tetrahydro-furo (2-oxo-butyl) -amide. 3,4-d] [1,3] dioxol-4-carboxylic acid (1.05 g) in acetonitrile (60 ml). The solution was stirred at reflux for 5.5 hours before resting at room temperature. atmosphere during the night. Stirring was continued at reflux for a further 4.5 hours, and the mixture was cooled and partitioned between ethyl acetate (150 ml) and 8% aqueous sodium bicarbonate (100 ml). The separated aqueous phase was further extracted with ethyl acetate (1 x 100 ml) and the combined organic extracts were dried and concentrated in vacuo to give a red gum (1.8 g). Purification by chromatography on silica gel (Merck 7734), eluting with dichloromethane: ethanol: ammonia (250: 8: 1), gave the composed of the title as a yellow gum (0.86 g).

I ^ _ ^ 2mím: S¿Sm¿2Sm ^ Sa! Í ^ iAJ »jáa ^ la ^ aSfej. 1 3 CCD S i02 (CH2Cl2: EtOH: NH3 880 100: 8: 1) Rf = 0. 5 Intermediate 14 (2R, 3R, 4S, 5S) -2- (6-Chloro-purin-9-yl) -5- (5-ethyl-oxazol-2-yl) -tetrahydro-furan-3,4-diol To 6-chloro-9- [6S- (5-ethyl-oxazol-2-yl) -2,2- dimethyl-tetrahydro- (3aR, 6aS) -furo [3, 4-d] [1, 3] dioxol-4R-yl] -9H-purine (0.85 g) cooled (0 ° C) was added a cold mixture (0 ° C) of trifluoroacetic acid (8.2 ml) and water (0.8 ml). The mixture was stirred at 0 ° C for 5 hours before being stored in the refrigerator overnight. The mixture was concentrated in vacuo to give a yellow residue which was azeotroped with Dichloromethane: ethanol: ammonia (75: 8: 1) (3 x 40 ml) to give a yellow liquid (4 ml). This was diluted with ethanol (5 ml) and purified by chromatography on silica gel (Merck 7734), eluting with dichloromethane: ethanol: ammonia (100: 8: 1) to (50: 8: 1) to give the title diol as a pale yellow solid (0.355 g). NMR d (DMSO) 9.00 (1H, s, CH), 8.85 (1H, s, CH), 6.99 (1H, fine t, CH), 6.1-5.9 (2H, 2x broad, 2xOH), 5.05 (1H, d , CH), 4.89 (lH, t, CH), 4.70 (lH, t, CH), 2.7 (2H, dq, CH2), 1.20 (3H, t, CH3). ^^^^^^^^^^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ 2-yl) -5- [6- (tetrahydro-pyran-4-ylamino) -purin-9-yl] -tetrahydro-furan-3,4-diol To a solution of (2R, 3R, 4S, 5S) -2- (6-chloro-purin-9-yl) -5- (5-ethyl-oxazol-2-yl) -tetrahydro-furan-3, 4- diol (0.19 g), in isopropanol (15 ml) was added diisopropylethylamine (0.3 ml) and 4-aminotetrahydropyran hydrochloride (0.135 g). After stirring at reflux for 16 hours, additional diisopropylethylamine (0.2 ml) and 4-aminotetrahydropyran hydrochloride (60 mg) were added. Stirring was continued at reflux for an additional 20 hours before the mixture was cooled and concentrated in vacuo to give a yellow gum (0.8 g). Purification by chromatography on silica gel (Merck 7734) with dichloromethane: ethanol: monic (250: 8: 1) - (100: 8: 1), gave the title compound, as a white foam (0.182 g) • Mass spectrum m / z 417 [MH +] NMR d (CDC13) 8.27 (lH, s, CH), 8.13 (lH, s, CH), 6.72 (1H, S, CH), 6.6-6.2 (lH, broad) , -OH), 6.21 (lH, d, CH), 5.98 (lH, broad d, NH), 5.31 (lH, d, CH), 4.79 (2H, m, 2xCH), 4.40 (H, broad s, CH ), 4.02 (2H, broad d, equatorial 2xCH), 3.57 (2H, t, 2xCH axial), 2.66 (2H, q, CH2), . & amp; -X, < ^ X * &X .. eleven 2. 07 (2H, broad d, equatorial 2xCH), 1.63 (2H, broad q, axial 2xCH), 1.23 (3H, t, CH3).

Experimental details for the route (E) Example 17 (2S, 3S, 4R, 5R) -2- (6-Cyclopentylamino-purin-9-yl) -5- (5-cyclopropyl- [1, 3, 4] thiadiazol-2-yl) -tetrahydro-furan -3, 4-diol N '- [6R- (6-cyclopentylamino-purin-9-yl) -2,2-di ethyl-tetrahydro- (3aS, 6aS) -furo [3,4-d] [1,3] dioxo1-4S -carbonyl] -cyclopropanecarboxylic acid hydrazide (12 mg) was heated at 80 ° C with Lawesson's reagent (19 mg) in acetonitrile (2 ml) for 8 hours. Additional Lawesson's reagent (40 mg) was added, and the mixture was heated at 70 ° C for 16 hours. The solvent was evaporated and the residue was purified by chromatography on silica gel (Varian Bondelut cartridge) eluting with ethyl acetate: cyclohexane 20:80 - 100: 0 and ethyl acetate: methanol 98: 2 - 95: 5, to give the protected product (31 mg). This material was treated with trifluoroacetic acid (1 ml) and water (0.1 ml) and the solution was allowed to stand at 4 ° C overnight (19 h). The mixture was poured into aqueous sodium bicarbonate, cooled with ice (15 ml) and extracted with ethyl acetate (3 x 15 ml). The organic layers were washed with brine, dried (MgSO 4) and evaporated in vacuo to give a colorless gum. Purification by automated CLAP (gradient profile 30-60% of (ii) for 20 minutes) gave the title compound (1.33 mg). LC / MS (System A): Rt 4.0 min Mass spectrum m / z 430 [MH +].

Experimental details for the route (F) Intermediate 15 Acid (3aS, 4S, 6R, 6aR) -6- (6-Isopropylamino-purin-9-yl) -2, 2-dimethyl-tetrahydro-furo [3, 4-d] [1, 3] dioxo1- 4-carboxylic A mixture of acid (3aS, S, 6R, 6aR) -6- (6-chloro-purin-9-yl) -2, 2-dimethyl-tetrahydro-furo [3,4-d [[1, 3] dioxol 4-carboxylic acid (5.82 g) and isopropylane (7.27 ml) in isopropanol (20 ml) was heated under reflux for 40 hours, cooled to room temperature and concentrated in vacuo. The resulting residue was partitioned between ethyl acetate (75 ml) and citric acid (0.5M, 75 ml). The layers were separated, and the organic phase was washed with citric acid solution (2 x 50 ml). The extracts The organic, combined were washed with water (50 ml) and brine (80 ml), dried (MgSO 4), filtered and concentrated in vacuo to give the title compound as a light brown foam (4.49 g). ).

CCD Si02 (ethyl acetate) Rf = 0.35 Intermediate 16 Methyl ester of acid (3aS, 4S, 6R, 6aR) -6- (6- 10-Isopropylamino-purin-9-yl) -2,2-dimethyl-tetrahydrofuro [3,4-d] [1] 3] dioxol-4-carboxylic acid A mixture of acid (3aS, 4S, 6R, 6aR) -6- (6-isopropylamino-purin-9-yl) -2, 2-dimethyl-tetrahydro-15-furo [3, 4-d] [1, 3] dioxol-4-carboxylic acid (4.82 g) and 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ, 3.36 g) in methanol (150 ml) was heated under reflux for 60 hours. After cooling to room temperature, the solution was concentrated in vacuo and the residue The resulting mixture was partitioned between ethyl acetate (100 ml) and citric acid solution (0.5M, 75 ml). The organic layer was extracted with ethyl acetate (4 x 25 ml) and the combined organic extracts were washed with water (50 ml) and brine (75 ml), dried (MgSO4), filtered and concentrated in vacuo. The rest The resulting product was purified by flash chromatography on silica gel, eluting with ethyl acetate: cyclohexane (1: 1) to give the title compound as a white solid (3.76 g). 5 CCD Si02 (ethyl acetate: cyclohexane 1: 1) Rf = 0.20.

Intermediate 17 Acid hydrazide (3aS, 4S, 6R, 6aR) -6- (6-Isopropylamino-purin-9-yl) -2, 2-dimethyl-tetrahydro-furo [3, 4- 10 d] [1, 3 ] dioxol-4-carboxylic acid A mixture of methyl ester of acid (3aS, 4S, 6R, 6aR) -6- (6-isopropylamino-purin-9-yl) -2,2-dimethyl-tetrahydro-furo [3, -d] [1,3 ] dioxol-4-carboxylic acid (3.76 g) and hydrazine hydrate (1.26 ml) in methanol (140 ml) was heated under reflux for 48 hours. After cooling to room temperature, the mixture was concentrated in vacuo and the residue was triturated with ethyl acetate to give the title compound as a white solid (3.3 g). Analysis Found: C 51.5; H, 6.5; N, 23.6% C? 6H23N704. 0.4EtOAc requires: C, 51.0; H, 6.4; N, 23.8% Example 18 (2R, 3R, 4S, 5R) -2- (6-isopropylamino-purin-9-yl) -5- (5-methyl-4H- [1, 2,] triazol-3-yl) trifluoroacetate - tetrahydro-furan-3, 4-diol A mixture of acid hydrazide (3aS, 4S, 6R, 6aR) -6- (6-isopropylamino-purin-9-yl) -2, 2-dimethyl-tetrahydro-furo [3, 4-d] [1,3 ] dioxol-4-carboxylic acid (0.5 g), ethylacetimidate hydrochloride (0.24 g) and triethylamine (0.55 ml) in ethanol (10 ml) was heated under reflux for 72 hours and cooled to room temperature. The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel (Merck 9385), eluting with ethyl acetate methanol (9: 1), to give a white solid (0.37 g), which was treated with trifluoroacetic acid (3.6 ml) and water (0.36 ml); the mixture was stirred at 0 ° C for 6 hours. The resulting solution was evaporated to dryness, toluene was added and the mixture was evaporated again to dryness. The resulting residue was triturated with ethyl acetate to give the title compound as a white solid (0.41 g).

R (DMSO) 8.71 (ÍH, s broad-, NH), 8.40-8.20 (2H, s + s broad 2 x CH), 6.11 (ÍH, d, CH), 5.00 (ÍH, d, CH), 4. 73 (1H, t, CH), 4.44 (2H, t + broad, 2 xCH), 2.42 (3H, s, CH3), 1.27 (6H, d, 2 x CH3) Analysis Found: C 42.9; H, 4.45; N, 23.5% C15H2oNß03 requires: C, 43.0; H, 4.4; N, 23.6% Experimental details for the route (G).

Intermediate 18 6-Chloro-9- [6S- (3-cyclopropyl- [1,2,4] oxadiazol-5-yl) -2,2-dimethyl-tetrahydro- (3aR, 6aS) -furo [3, 4- d] [1, 3] dioxol-4R-yl] -9H-purine An acid suspension (3aS, 4S, 6R, 6aR) -6- (6-chloro-purin-9-yl) -2, 2-dimethyl-tetrahydro-furo [3,4-d] [1, 3] dioxol 4-carboxylic acid (4.17 g) in anhydrous tetrahydrofuran (80 ml) was cooled under nitrogen at 5 ° C. To the suspension was added diisopropylethylamine (4.68 ml). Pivaloyl chloride (1.65 ml) was added after 10 minutes, and the mixture was stirred at 0 ° C for 1 hour, and allowed to warm to room temperature for 1 hour. The mixture was again cooled to 5 ° C, cyclopropylamidoxime (1.47 g) was added dropwise, the bath with cooling was removed and stirring was continued at 22 ° C for 18 hours. The hydrochloride "-fe- **** 8¡mmi-- .m. i.. j & _ t ^ k ^? AßJ? SSSh» ..

Diisopropylethylamine was filtered and washed with tetrahydrofuran (100 ml). The filtrate was heated to reflux for 10 hours, cooled and concentrated in vacuo to give a residue which was purified by chromatography on silica gel (Varian Mega Bondelut cartridge), eluting with ethyl acetate: cyclohexane (3). : 1), to give the title compound as a white solid (1.99 g). LC / MS (System B): Rt 2.91 min Mass spectrum m / z 405 (MH +).

Intermediate 19 (2R, 3R, 4S, 5S) -2- (6-Chloro-purin-9-yl) -5- (3-cyclopropyl- [1, 2,4] oxadiajzol-5-yl) -tetrahydro-furan -3, -diol A solution of 6-chloro-9- [6S- (3-cyclopropyl- [1,2,4] oxadia zol-5-yl) -2, 2-dimethyl-tetrahydro- (3aR, 6aS) -furo- [3 , 4-d] [1, 3] dioxol-4R-yl] -9H-purine (1.99 g) in a cold mixture of trifluoroacetic acid: water (9: 1, 25 ml) was kept at 4 ° C for 20 hours . The resulting solution was basified in an ice bath with a saturated solution of sodium bicarbonate (200 ml), extracted with ethyl acetate (3 x 70 ml) and the extracts were dried (MgSO 4) and concentrated in vacuo. The resulting brown oil was purified by chromatography on silica gel (Varian Mega Bondelut cartridge), eluting with dichloromethane: methanol (10: 1) to give the title compound (1.29 g) as a white solid. LC / MS (System B): Rt 2.42 min Mass spectrum m / z 365 (MH +) Example 19 (2S, 3S, 4R, 5R; -2- (3-Cyclopropyl- [1,2,4] oxadiazol-5-yl) -5- [6- (2S-hydroxy-cyclopent- (S) -ylamino ) -purin-9-yl] -tetrahydro-furan-3, 4-diol A solution of (2R, 3R, 4S, 5S) -2- (6-chloro-purin-9-yl) -5- (3-cyclopropyl- [1, 2, 4] oxadiazol-5-yl) -tetrahydro -furan-3, 4-diol (50 mg) in isopropanol (5 ml) was added diisopropylethylamine (0.072 ml) and hydrochloride ie trans- (2S, 2S) -2-aminocyclopentanol (37.8 mg). The mixture was heated to reflux for 48 hours, cooled to room temperature and concentrated to dryness in vacuo to give a residue which was purified by solid phase extraction (Varian Mega Bondelut cartridge, 5 g. , bound aminopropyl phase, eluting with (i) CHC13, (ii) ethyl acetate: cyclohexane (1: 1), (iii) ethyl acetate, (iv) dichloromethane, (v) dichloromethane: methanol (20: 1) , (saw) J & b? Zr "imsaÉS - '' s? ¡J" - & * á taw .ñ * & 'm dichloromethane methanol (10: 1) and (vii) methanol to give the compound of title (47.3 mg) LC / MS (System B): Rt = 2.37 min Mass spectrum m / z 430 (MH +) Experimental details for the route (H) Intermediary 20 Ethyl ester of 4- [9- (6S-carboxy-2, 2-dimethyl-tetrahydro- (3aR, 6aS) -furo [3,4-d] [1, 3] dioxol-4R-I1) - 9H-purin-6-ilam.i | no] -piperidin-1-carboxylic acid A mixture of ethyl 4-amino-piperidinecarboxylate (1.80 ml), acid (3aS, 4S, 6R, 6aR) -6- (6-chloro-purin-9-yl) -2, 2-di ethyl-tetrahydro-furo [3,4-d] [1,3] dioxol-4-carboxylic acid [2.0 g] and diisopropylethylamine (2.74 ml) was heated to reflux in isopropanol (100 ml) for 70 hours. After cooling to room temperature, the mixture was concentrated in vacuo. Water (100 ml) was added to the residue and the mixture was acidified to pH 4 (citric acid) mixture was extracted rapidly with dichloromethane (3 x 50 ml) and the extracts were dried (MgSO4) and concentrated in vacuo to give the title compound as a yellow solid (2.56 g! LC / MS (System B): Rt = 2.62 min. - ¿& i ^? SÉ ^ á ^ imíí ^ Mass spectrum m / z 477 Intermediate 21 Ethyl ester of 4- [9- (6S-carbamoyl-2, 2-dimethyl-5-tetrahydro- (3aR, 6aS) -furo [3,4-d] [1,3] d? Oxol-4R- acid il) -9H-purin-6-ylamino] -piperidine-1-carboxylic acid A cold solution (0 ° C) of 4- [9- (6S-carboxy-2, 2-dimethyl-tetrahydro- (3aR, 6aS) -10 furo [3, 4-d] [1, 3] ethyl ester. ] dioxol-4R-yl) -9H-purin-6-ylamino] -piperidine-1-carboxylic acid (2.56 g) in anhydrous dichloromethane (50 ml) was treated with triethylamine (0.82 ml) and pivaloyl chloride (0.73 ml). Ammonia was bubbled into the solution for 70 minutes. The mixture was evaporated to Dryness in vacuo to give a crude product, which was dissolved in ethyl acetate and washed with water (3 x 70 ml). The extracts were dried (MgSO 4) and concentrated in vacuo to give the title compound as a pale orange solide (1.97 g). 20 LC / MS (System B): Rt = 2.54 min Mass spectrum m / z 476 (MH +) i i-- Intermediary 22 Ethyl ester of 4- [9- (6R-cyano-2, 2-dimethyl- (3aR, 6aR) -tetrahydro-furo [3,4-d] [1, 3] dioxol-4R-yl) - 9H- purin-6-ylamino] -piperidine-1-carboxylic acid A solution of 4- [9- (6S-carbamoyl-2, 2-dimethyl-tetrahydro- (3aR, 6aS) -furo [3,4- d] [1,3] dioxo1-4R-Ü) ethyl ester -9H-purin-6-ylamino] -piperidine-1-carboxylic acid (1.97 g) in anhydrous acetonitrile (40 ml) was treated with 4-dimethylaminopyridine (1.01 g). The mixture was cooled to 0 ° C and phosphorus oxychloride (1.93 ml) was added dropwise. The mixture was allowed to warm to room temperature and stirred at this temperature for 1 hour, then heated to reflux for 7 hours. After cooling, the mixture was evaporated to dryness in vacuo to give the crude product which was dissolved in water (50 ml) and extracted with ethyl acetate (3 x 70 ml). The extracts were concentrated in vacuo to give the title compound as a pale orange solid (1.91 g). LC / MS (System A): Rt = 4.09 min Mass spectrum m / z 458 (MH +) Intermediary 23 Ethyl ester of 4- acid. { 9- [6R- (N-hydroxycarbamimidoyl) -2,2-dimethyl-1-tetrahydro- (3aR, 6aR) -furo [3,4-d] [1,3] dioxo 1-4R-yl] - -9H -purin-6-ylamino} piperidine-1-carboxylic Ethyl 4- [9- (6R-cyano-2, 2-dimethyl- (3aR, 6aR) -tetrahydro-furo [3,4-d] [1,3] dioxol-4R-yl) -9H ethyl ester -purin-6-ylamino] -piperidine-1-carboxylic acid (1.0 g) and hydroxylamine (50%, 0.29 ml) were heated to reflux in ethanol (25 ml) for 9 hours. After cooling, the mixture was concentrated in vacuo and the residue was co-evaporated in toluene (50 ml) to give the title compound as a yellow solid (1.25 g). LC / MS (System A): Rt = 3.82 min Mass spectrum m / z 490 (MH +) Intermediary 24 Ethyl ester of 4- acid. { 9- [6R- (5-tert-butyl- [1,2,4] oxadiazol-3-yl) -2,2-dimethyl-tetrahydro- (3aR, 6aR) -furo [3, 4-d] [1 , 3] dioxol-4R-I1] -9H-purin-6-ylamino} -piperidine-1-carboxylic acid The ethyl ester of 4- acid. { 9- [6R- (N-hydroxycarbamimidoyl) -2, 2-dimethyl-tetrahydro- (3aR, 6aR) -furo [3, 4-d] [1,3] dioxo1-4R-Í1] -9H-purin-6 -Imino} - piperidine-1-carboxylic acid (1.0 g) was stirred with pivalic acid (15 ml) and pivalic anhydride (0.49 ml) at room temperature for 2 hours, then heated to reflux for 9 hours. After cooling, the residue was treated with a saturated solution of sodium bicarbonate (100 ml) and extracted with ethyl acetate (4 x 100 ml). The extracts were dried (MgSO4) and concentrated in vacuo. To the residue was added diethyl ether (100 ml). A brown precipitate formed and filtered, and the filtrate was concentrated in vacuo to give a crude product. Purification by chromatography on silica gel (Varian Mega Bondelut cartridge) eluting with ethyl acetate gave the title compound as a pale orange oil (0.360 g). LC / MS (System B): Rt = 3.13 min Mass spectrum m / z 557 (MH +) Example 26 Ethyl ester of 4- acid. { 9- [5R- (5-tert-butyl- [1, 2,4] oxadiazol-3-yl) -3R, 4S-dihydroxy-tetrahydro-furan-2R-1] -9H-purin-6-ylamino} -piperidine-1-carboxylic acid A solution of ethyl ester of 4- acid. { 9- [6R- (5-tert-butyl- [1,2,4] oxadiazol-3-yl) -2,2-dimethyl-tetrahydro- (3aR, 6aR) -furo [3, 4-d] [1 , 3] dioxol-4R-i1] -9H-purin-6-ylamino} -piperidine-1-carboxylic acid (360 mg) in a cold mixture of trifluoroacetic acid: water (9: 1, 5 ml) was cooled to 0 ° C for 20 hours. The resulting solution was neutralized with a saturated solution cooled with ice of sodium bicarbonate (70 ml), extracted with ethyl acetate (3 x 50 ml) and the extracts were dried (MgSO 4) and concentrated in vacuo. The preparative clap was carried out on a Supelcosil LC-ABZ column (size 21.2 mm x 10 cm) operating at 8 ml / min (the eluents were A: 0.1% trifluoroacetic acid / water, B: 0.01% trifluoroacetic acid in acetonitrile / water 95: 5) (gradient profile 15-95% B over 25 minutes) to give the title compound as a blancc solid (6.9 mg). LC / MS (System B): Rt = 2.76 min Mass spectrum m / z 517 (MH +) Experimental details for the route (I) Intermediate 25 (3aS, 4S, 6R, 6aR) -6-methoxy-2, 2-dimethyl-tetrahydro-furo [3,4-d] [1,3] dioxol-4-carboxylic acid methoxy-methyl-amide áfS Mj í S-Si »-. Xf3ütamj .'- and &? ¿, MCi,.

The acid (3aS, 4S, 6R, 6aR) -methoxy-2, 2-dimethyl-tetrahydro-furo- [3,4-d] [1,3] dioxol-4-carboxylic acid (11 g) was dissolved in dichloromethane ( 100 ml) and carbonyldiimidazole (8.47 g) was added dropwise over 10 minutes at 22 ° C and the solution was stirred at 22 ° C for 0.5 hour. The N, 0-dimethylhydroxylamine hydrochloride (12.5 g) in water (50 ml) was added and ION sodium hydroxide (20 ml) was added, and the solution was extracted with dichloromethane (3 x 50 ml). The extracts Dichloromethane was dried (Na 2 SO 4) and filtered, and the solution was added to the previous solution. After stirring for 3 days, the solution was washed with 0.5M citric acid (200 ml), 8% sodium bicarbonate (200 ml), dried (Na2SO4) and evaporated in vacuo to give Give the title compound as a colorless oil (14.2 g). CCD: Si02 (ether) Rf = 0.33.

Intermediate 26 20 1- (6R-Methoxy-2, 2-dimethyl-tetrahydro- (3aS, 6aR) -furo [3,4- d] [1,3] dioxol-4S-yl) -4,4-dimethyl- pent-2-in-l-one The 3, 3-dimethyl-l-butine (10 g) in THF (90 ml) was added slowly to a 0.3M solution of sodium chloride.

Methylmagnesium in THF (50 ml) under nitrogen at 0-5 ° C, and was stirred at 0-5 ° C for 5 hours. The methoxy-methyl-amide of (3aS, 4S, 6R, 6aR) -6-methoxy-2,2-dimethyl-tetrahydro-furo [3,4-d] [1,3] dioxol-4-carboxylic acid (14.17 g) was added in THF (20 ml) for 20 minutes at 0-5 ° C, and the solution was stirred at 0-5 ° C for 2 hours. The reaction mixture was quenched with 30% ammonium chloride (150 ml) and 2M hydrochloric acid (15 ml) and extracted with ethyl acetate (2 x 150 ml). The combined organic phases were dried (Na2SO4) and evaporated in vacuo, and the residue was purified by flash chromatography on silica (150 g) eluting with cyclohexane-diethyl ether (2: 1) to give the title compound as a colorless solid (4.01 g). CCD: Si02 (ether) Rf = 0.55 Intermediate 27 1- (6R-Methoxy-2, 2-dimethyl-tetrahydro- (3as, 6aR) -furo [3,4- d] [1,3] dioxol-4S-yl) -4,4-dimethyl-pentane -l, 3-dione-3-oxime 1- (6R-methoxy-2,2-dimethyl-tetrahydro- (3aS, 6aR) -furo [3,4-d] [1,3] dioxol-4S-yl) -4,4-dimethyl-pent- 2-in-l-one (573 mg) was dissolved in methanol (6 ml) and 50% aqueous hydroxylamine (0.19 ml) was added.

After standing at 23 ° C for 5 hours, the solution was concentrated in vacuo, diluted with water (10 ml) and extracted with ethyl acetate (2 x 15 ml). The extracts were dried (Na2SO4) and evaporated in vacuo to give the title compound as a colorless oil (0.635 g). CCD: Si02 (cyclohexane-Et20 3: 2) Rf = 0.16 Intermediate 28 Ester 4R-acetoxy-2S- (3-tert-butyl-isoxazol-5-yl) -5- 10-methoxy-tetrahydro-furan-3R-yl acetic acid The 3-oxime of 1- (6R-methoxy-2,2-dimethyl-tetrahydro- (3aS, 6aR) -furo [3,4-d] [1, 3] dioxol-4S-yl) -4, 4- dimethyl-pentane-1,3-dione (632 mg) was dissolved in Methanol (15 ml) and concentrated hydrochloric acid (1 ml) was added. The resulting solution was heated under reflux under nitrogen for 20 hours, cooled and evaporated in vacuo. The residue was dissolved in pyridine (10 ml) and 4-dimethylaminopyridine (1 mg) and added acetic anhydride (2 ml). The solution was allowed to stand at 22 ° C / 3h, and the solvents were removed in vacuo. The residue was dissolved in ethyl acetate (100 ml), washed with 8% sodium bicarbonate (50 ml), dried (Na 2 SO 4) and evaporated in vacuo to give the title compound as a pale yellow gum (575 mg). Mass spectrum m / z 342 (MH +) Intermediate 29 Ester 4R-acetoxy-5S- (3-tert-butyl-isoxazol-5-yl) -2R- (6-chloro-purin-9-yl) -tetrahydro-furan-3R-yl acetic acid 6-Chloropurine (1.36 g), toluene (20 ml) and hexamethyldisilazane (10 ml) were heated under reflux under nitrogen for 2 hours, cooled and evaporated in vacuo. The residue was co-evaporated with dry toluene (12 ml) and taken up in acetonitrile (20 ml) and 4R-acetoxy-2S- (3-tert-butyl-isoxazol-5-yl) -5-methoxy-tetrahydrofuran- ester. 3R-Acetic acid (1.01 g) and trimethylsilyl trifluoromethanesulfonate (1.8 ml) was added., and the solution was heated under reflux under nitrogen for 5 hours. The solution was cooled and poured into 8% sodium bicarbonate (150 ml) and extracted with ethyl acetate (2 x 100 ml). The extracts were combined, dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica (200 g) eluting with cyclohexane-ether (1: 1-1: 4) to give the title compound as a colorless foam (0.953 g). LC / MS (system A) Rt = 4.35 minutes.

Example 27 (2S, 3S, 4R, 5R) -2- (3-tert-Butyl-isoxazol-5-yl) -5- [6- (2S-hydroxy-cyclopent- (S) -ylamine) -purin-9 -yl] -tetrahydro-furan-3, 4-diol The 4R-acetoxy-5S- (3-tert-butyl-isoxazol-5-yl) -2R- (6-chloro-purin-9-yl) -tetarhydro-furan-3R-acetic acid acetic acid ester (70 mg) and trans- (SS, 2S) -2-aminocyclopentanol hydrochloride (62 mg) were dissolved in isopropanol (10 ml) and diisopropylethylamine (0.16 ml) was added, and the solution was heated under reflux for 17 hours. The solvent was evaporated in vacuo and the residue was dissolved in saturated methanolic ammonia (7 ml) and allowed to stand for 3 hours. The solvent was removed in vacuo and the residue was purified by chromatography on silica (5 g) eluting with ethyl acetate-methanol (10: 1). Further purification by selfpreparative CLAP gave the compound of the tint as a colorless gum (40 mg). LC / MS (system A): Rt = 3.81 min. Mass spectrum: m / z 445 (MH +) Example 28 (2S, 3S, 4R, 5R) -2- (3-tert-Butyl-isoxazol-5-yl) -5- [6- (tetrahydro-pyran-4 -amino) -purin-9-yl] -tetrahydrofuran-3,4-diol 5-4R-acetoxy-5S- (3-tert-butyl-isoxazol-5-yl) -2R- (6-chloro- purin-9-yl) -tetrahydro-furan-3R-yl acetic acid (70 mg) and the 4- to inotetrahydropyran hydrochloride (62 mg) were dissolved in isopropanol (10 ml) and di-isopropylethylamine (0.16 ml) was added, and the solution was heated under reflux for 17 hours. The solvent was removed in vacuo and the residue was dissolved in saturated methanolic ammonia (7 ml) and allowed to stand for 3 hours. The solvent was removed in. Vacuum and the residue was purified by solid phase extraction (Varian Bondelut aminopropyl bonded silica gel cartridge), eluting with ethyl acetate-methanol (10: 1). The additional purification using the selfprep CLAP. gave the title compound as a colorless gum (31 mg). LC / MS (system A): Rt = 3.78 min. Mass spectrum: m / z 445 (MH +) Experimental details for the route (J) 25 .mmjz ,; '*, 3U * .Í * .-. - & w-.mttÉmt & aa amtt? a ~ *. • < »». ... .ft., μ! '-? --- »^ i ^: ^ aa - ^^ áifeis? - • > »&« * »» ... . .WASZ ... .

Intermediate 30 (E) -3-Dimethylamino-1- (6R-methoxy-2,2-dimethyl-tetrahydro- (3aS, 6aR) -furo [3,4-d] [1,3] dioxol-4S-I1) -propenone 1- (6R-methoxy-2,2-dimethyl-tetrahydro- (3aS, 6aR) -furo [3,4-d] [1, 3] diox-4S-yl) -ethanone (0.62 g) was dissolved in toluene (25 ml) and dimethylformamide dimethyl acetal (5 ml) was added and the solution was heated under reflux under nitrogen for 17 hours. The solvents were removed in vacuo and the residue was purified by flash chromatography on silica (30 g) eluting with ethyl acetate to give the title compound as a yellow gum (0.102 g). Mass spectrum: m / z 272 (MH +) Intermediate 31 5- (6R-Methoxy-2, 2-dimethyl-tetrahydro- (3aR, 6aR) -furo [3,4- d] [1, 3] dioxol-4R-yl) -lH-pyrazole (E) -3-dimethylamino-1- (6R-methoxy-2, 2-dimethyl-tetrahydro- (3aR, 6aR) -furo [3,4-d] [1,3] dioxol-S-il) - Propenone (102 mg) was dissolved in methanol (15 ml) and hydrazine hydrate (0.5 ml) was added and the solution was heated under reflux for 1.5 hours. The solvents were removed in vacuo and the residue was purified by flash chromatography on silica gel, eluting with diethyl ether to give the title compound as a colorless gum (47 mg). • 5 Mass spectrum: m / z 241 (MH +) Intermediary 32 Ester 4R-acetoxy-2R- (l-acetyl-lH-pyrazol-3-yl) -5R-methoxy-tetrahydro-furan-3R-yl acetic acid The 5- (6R-methoxy-2,2-dimethyl-tetrahydro- (3aR, 6aR) -furo [3,4-d] [1,3] dioxol-4R-yl) -lH-pyrazole (1.66 g) was dissolved in methanol (120 ml), treated with concentrated hydrochloric acid (1 ml), heated under reflux for 22 hours, it was cooled and evaporated in vacuo. The residue was dissolved in pyridine (80 ml), acetic anhydride (4 ml) was added and the solution was allowed to stand for 3 hours. The solvents were removed in vacuo and the residue taken up in ethyl acetate (200 ml) and washed successively with 0.5M citric acid (100 ml), 8% sodium bicarbonate (100 ml) and brine (100 ml). The organic phase was dried (Na2SO4), evaporated in vacuo and the residue was purified by flash chromatography on silica gel, eluting with cyclohexane-diethyl ether (2: 1-1: 1) to give the title compound as a colorless gum (646 mg). Mass spectrum: m / z 327 (MH +), 344 (MNH4 +) Intermediate 33 Ester 4R-acetoxy-5R- (l-acetyl-lH-pyrazol-3-yl) -2R- (6-chloro-purin-9-yl) tetrahydro-furan-3R-yl acetic acid 6-Chloropurine (1 g) was suspended in toluene (40 ml), hexamethyldisilazane (10 ml) was added, and the mixture was heated under reflux for 1 hour. After cooling, the solvents were evaporated in vacuo followed by co-evaporation with toluene (10 ml). The residue was dissolved in dry acetonitrile (40 ml), the 4R-acetoxy-2R- (1-acetyl-1H-pyrazol-3-yl) -5R-methoxy-tetrahydro-furan-3R-yl ester of acetic acid was added. (645 mg), DBU (1 ml) and trimethylsilyl trifluoromethanesulfonate (1 ml), and the resulting solution was heated under reflux under nitrogen for 3 hours. The cold solution was emptied in 8% sodium bicarbonate (150 ml) and extracted with ethyl acetate (2 x 100 ml).

The combined extracts were dried (Na 2 SO) and evaporated in vacuo to give a mixture which was purified by evaporation chromatography.

Flash over silica gel, eluting with ether-cyclohexane (3: 1) to give the title compound (42 mg). Mass spectrum: m / z 449/451 (MH +) Intermediate 34 (2R, 3R, 4S, 5R) -2- (6-Chloro-purin-9-yl) -5- (2H-pyrazol-3-yl) -tetrahydro-furan-3,4-diol The 4R-acetoxy-5- (l-acetyl-lH-pyrazol-3-yl) -2R- (6-chloro-purin-9-yl) -tetrahydro-furan-3R-yl acetic acid ester (42 mg ) was dissolved in methanol (3 ml) and cooled to 0 ° C. Tert-butylamine (0.2 ml) was added and the solution was allowed to stand for 25 minutes at 0 ° C. The Solvents were removed in vacuo to provide the title compound (35 mg). Mass spectrum: m / z 323/325 (MH +) Example 29 (2R, 3R, 4S, 5R) -2- (2H-Pyrazol-3-yl) -5- (6-tetrahydro-pyran-4-ylamino-purin-9-yl) -tetrahydro-furan-3 4-diol (2R, 3R, 4S, 5R) -2- (6-chloro-purin-9-yl) -5- (2H-pyrazol-3-yl) -tetrahydro-furan-3,4-diol (35 mg ) HE dissolved in isopropanol (3 ml), the N, N- were added. di-isopropylethylamine (0.12 ml) and tetrahydro-pyran-4-ylamine hydrochloride (46 mg), and the resulting solution was heated under reflux under nitrogen for 17 hours. The solvent was removed in vacuo, the residue was dissolved in methanol (10 ml), and 8% sodium bicarbonate (3 ml) was added, followed by silica gel (3 g). The solvents were removed in vacuo and the residue was added to a column with flash silica gel packed in dichloromethane. Elution with dichloromethane-methanol (4: 1) gave the title compound as a clear, viscous gum (5.2 mg). LC / MS (system A): Rt = 3.34 min. Mass spectrum: m / z 388 (MH +) 15 Experimental details for the route (K) Intermediate 35 Methoxy-methyl-amide acid (3aS, 4S, 6R, 6aR) -6- (6- 20 chloropurin-9-yl) -2, 2-dimethyl-tetrahydro-furo [3, 4- d] [1 , 3] dioxol-4-carboxylic acid The acid (3aS, 4S, 6R, 6aR) -6- (6-chloro-purin-9-yl) -2, 2-dimethyl-tetrahydro-furo [3, 4-d] [1, 3] dioxol-4 - 25 carboxylic acid (35.88 g) was dissolved in dichloromethane (300 ml) and treated with 1,1 '-carbonyldiimidazole (20.5 g) with ice-cooling. The solution was stirred at 22 ° C for 1 hour, N, 0-dimethylhydroxylamine hydrochloride (12.3 g) and pyridine (15 ml) were added, and stirring was continued at 22 ° C for 24 hours. The solution was washed with 0.5M citric acid (250 ml) and 8% sodium bicarbonate (200 ml), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with ethyl acetate to give the title compound as a colorless solid (26.4 g). LC / MS (system A): Rt = 3.77 min. Mass spectrum: m / z 384/386 (MH +) Intermediate 36 (3aS, 4S, 6R, 6aR) -2, 2-dimethyl-6- (6-thioxo-1,6-dihydro-purin-9-yl) -tetrahydro-furo acid [3aS, 4S, 6R, 6aR) , 4-d] [1, 3] dioxol-4-carboxylic acid Methoxy-methyl-amide acid (3aS, S, 6R, 6aR) -6- (6-Chloro-purin-9-yl) -2, 2-dimethyl-1-tetrahydro-furo [3,4-d] [1,3] dioxide-4-carboxylic acid (23.3 g) was suspended in ethanol (250 ml) and treated with sodium acid sulfide (10 g). The mixture was stirred under reflux under nitrogen for 3 hours, cooled and evaporated in vacuo. The residue in water (250 ml) was acidified with 0.5M citric acid (approximately 40 ml), filtered and the filtered solid was washed with water (250 ml) and isopropanol (100 ml) and dried in vacuo to give the title compound as a yellow solid. (16.3 g). LC / MS (system A): Rt = 3.53 min. Mass spectrum: m / z 382 (MH +) Intermediary 37. { 9- [6R- (5-tert-Butyl-2H-pyrazol-3-yl) -2,2-dimethyl-tetrahydro- (3aR, 6aR) -furo [3,4-d] [1, 3] dioxol- 4R-yl] -9H-purin-6-yl} -cyclopentylamine Methoxy-methyl-amide acid (3aS, 4S, 6R, 6aR) -2, 2-dimethyl-1-6- (6-thioxo-l, 6-dihydro-purin-9-yl) -tetrahydro-furo [3, 4-d] [1,3 ] dioxol-4-carboxylic acid (1 g) was dissolved in N, N-dimethylformamide (DMF) (25 ml) with heating and filtered while heating. The filtrate was treated with diisopropylethylamine (0.5 ml) and Merrifield resin (chloromethyl form, 2 g, 0.8 mmol / g, 1% crosslinked) and the mixture was stirred for 24 hours. The mixture was filtered and the filtered resin was washed with DMF (2 x 15 ml), dichloromethane (2 x 15 ml) and ether (3 x 15 ml). The resin ia, z ^, «j» ^ < tte < "Above was added to a solution of 3,3-dimethyl-1-butynylmagnesium chloride (prepared by treating 3, 3-dimethyl-l-butyne [2 ml] with methyl magnesium chloride 3. OM in tetrahydrofuran (THF) ) [4 ml] in THF [25 ml] at 22 ° for 17 hours) in THF at 0-5 ° C, and the mixture was stirred at 0-5 ° for 6 hours. 2M hydrochloric acid (6 ml) and THF (12 ml) were added, and after 10 minutes of stirring, the resin was filtered and washed with THF (2 x 15 ml) and ether (2 x 15 ml). The resin was resuspended in DMF (25 ml), hydrazine hydrate (2 ml) was added, and the mixture was stirred for 17 hours. The mixture was filtered, washed with DMF (30 ml), dichloromethane (2 x 10 ml) and ether (3 x 10 ml), suspended again in dichloromethane (15 ml), treated with 3-chloroperoxybenzoic acid (57-). 81%, 0.50 g) and shaken at 22 ° C for 17 hours. The resin was filtered and washed with dichloromethane (3 x 10 ml) and ether (2 x 10 ml). The residue in THF (10 ml) was treated with cyclopentylamine (88 1) and diisopropylethylamine (0.16 ml), and the mixture was stirred at 22 ° C for 17 hours. The mixture was filtered, washed with THF-methanol (3: 1, 2 x 10 ml) and the filtrate and washings were evaporated in vacuo. Purification by preparative, automated CLAP gave the title compound (20 mg). LC / MS (system A): Rt = 4.48 min.

- Mass spectrum: m / z 468 (MH +) Example 30 (2R, 3R, 4S, 5S) -2- (5-tert-Butyl-2H-pyrazol-3-yl) -5- (6-cyclopentylamino-purin-9-yl) -tetrahydro-furan-3, 4-diol The . { 9- [6R- (5-tert-butyl-2H-pyrazol-3-yl) -2,2- dimethyl-tetrahydro- (3aR, 6aR) -furo [3,4-d] [1,3] dioxo1- 4R-il] -9H-purin-6-yl} -cyclopentylamine (20 mg) was dissolved in trifluoroacetic acid-water (9: 1, 4 ml) and the mixture was allowed to stand at 0-5 ° C for 17 hours. The solution was evaporated in vacuo (bath temperature <30 ° C) and quenched with 2M sodium carbonate (15 ml). The mixture was extracted with ethyl acetate (2 x 15 ml), the combined extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by chromatography on silica gel (Varian Bondelut cartridge), eluting with ethyl acetate-methanol (9: 1), to give the title compound as a clear gum (19 mg). LC / MS (system A): Rt = 4.0 min. Mass spectrum: m / z 428 (MH +) Experimental details for the route (L) Intermediate 38 3-Ethyl-5- (6R-methoxy-2,2-dimethyl-tetrahydro- (3aR, 6aR) -furo [3,4-d] [1,3] dioxol-4S-yl) -isoxazole To a stirring mixture of 4R-ethynyl-6R-methoxy-2,2-dimethyl-tetrahydro- (3aR, 6aR) -furo [3,4-d] [1, 3] dioxol [lit. co pd.; ref: Hel v. Chim. Ac ta 1980, 63 1181-1189] (0.271 g) and phenyl isocyanate (0.328 ml) in dry toluene (1.5 ml) under nitrogen, a mixture of 1-nitropropane (0.134 ml) and triethylamine was added. (0.038 ml) in dry toluene (1 ml) for 5 minutes. A precipitate formed slowly during the addition. The resulting mixture was heated between 73 ° C to 82 ° C during 18 hours. The cold reaction mixture was filtered through silica gel, washed well with ether and then 40% ethyl acetate-cyclohexane. Removal of the solvent in vacuo gave a light brown solid (0.487 g) which was subjected to flash chromatography on silica gel, eluting with ethyl acetate: cyclohexane 20: 80-30: 70, to give the compound of the title as a clear oil (0.329 g).

CCD (cyclohexane-ethyl acetate 3: 2) Rf = 0.49.

Intermediate 39a Ester 4R, 5S-diace: toxi-2S- (3-ethyl-isoxazol-5-yl) -tetrahydro-furan -3R-alkyl acetic acid and Intermediate 39b Ester 4R, 5R-diacetoxy-2S- (3-ethyl-isoxazol-5-yl) -tet: acetic acid rahydro-furan-3R-yl A solution of 3-ethyl-5- (6R-methoxy-2, 2-dimethyl-tetrahydro- (3aR, 6aR) -furo [3,4-d] [1, 3] dioxol-4S-yl) isoxazole (0.355) g) in a mixture of trifluoroacetic acid (5 ml) and water (0.05 ml) was stirred at room temperature for 27 hours and then evaporated in vacuo. The residue was azeotroped with toluene (x3), dissolved in dry dichloromethane (10 ml) under nitrogen, and cooled to 0 ° C. 4- (N, N-dimethylamino) pyridine (0.048 g), triethylamine (8.3 ml) followed by acetic anhydride (2.49 ml) were added. The mixture was stirred at 0 ° C at room temperature overnight. The resulting mixture was evaporated in vacuo to give a brown liquid (1.34 g). Purification by flash chromatography on silica gel, eluting with ethyl acetate: cyclohexane 20: 80-40:60, gave the ester 4R, 5S-diacetoxy-2S- (3-ethyl-isoxazol-5-yl) -tetrahydro-furan-3R-ethyl acetic acid (0.192 g) as a light brown oil, followed by ester 4R, 5R-diacetoxy-2R- (3-ethyl-isoxazol-5-yl) -tetrahydro- Furan-3R-ethyl acetic acid (0.16 g) as a light brown oil.

Intermediary 39a Si02 CCD (Cyclohexane-ethyl acetate 5 3: 2), Rf = 0.28 Intermediary 39b Si02 CCD (Cyclohexane-ethyl acetate 3: 2), R £ = 0.22 Intermediate 40 Ester 4R-Acetoxy-2R- (2,6-dichloro-purin-9-yl) -5S- (3-ethyl-isoxazol-5-yl) -tetrahydro-furan-3R-yl-acetic acid ester To a mixture of 4R, 5S-diacetoxy-2S- (3-ethyl-isoxazol-5-yl) -tetrahydro-furan-3R-yl ester of acetic acid and 4R, 5R-diacetoxy-2S- (3-ethyl) ester -isoxazol-5-yl) -tetrahydro-furan-3R-yl of acetic acid (0.909 g) in dry acetonitrile (5 ml) at room temperature under Nitrogen was added 2,6-dichloropurine (0.779 g), DBU (0.692 ml) followed by trimethylsilyl triflate (0.99 ml). The reaction was stirred at room temperature for 20 hours and quenched with aqueous, saturated sodium bicarbonate solution (30 ml). The removal with ethyl acetate (3 x 40 ml) gave a colored liquid coffee (3.54 g). Purification by flash chromatography on silica gel, eluting with ethyl acetate: cyclohexane 40: 60-50: 50, gave the title compound as a white, creamy foam (0.798 g).

CCD SiO2 (Cyclohexane-ethyl acetate 2: 3), Rf = 0.25.

Intermediate 41 Ester 4R-acetoxy-2R- [2-chloro-6- (lS-hydroxymethyl-2-phenyl-ethylamino) -purin-9-yl] -5S- (3-ethyl-isoxazol-5-yl) -tetrahydro -furan-3R-acetic acid The 4R-acetoxy-2R- (2,6-dichloro-purin-9-yl) -5S- (3-ethyl-isoxazol-5-yl) -tetrahydro-furan-3R-yl ester of acetic acid (151 mg) , (S) -phenylalaninol (53 mg) and diisopropylethylamine (67 1) were dissolved in isopropanol (2 ml) and heated at 50 ° C for 7.5 hours. The solvent was removed in vacuo to give the crude title compound as a clear gum (260 mg). LC / MS (system): Rt = 4.63 mm. Mass spectrum: m / z 585/587 Example 31 (2R, 3R, 4S, 5R) -2- [6- (lS-hydroxymethyl-2-phenyl-ethylamino) -2-methoxy-purin-9-yl) -5- (3-ethyl-isoxazole- 5-yl) -tetrahydrofuran-3,4-diol The ester 4R-acetoxy-2R- [2-chloro-6- (1S-hydroxymethyl-2-phenyl-ethylamino) -purin-9-yl] -5S- (3 3-ethylhexyl-5-yl) -tetrahydro-furan-3R-yl acetic acid (259 mg) was added to 25% sodium methoxide 5 in methanol (4 ml) and the mixture was stirred at 22 ° C. 8 hours. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel, eluting with ethyl acetate-methanol (10: 1) to give the title compound 10 as a pale yellow gum (101 mg ). LC / MS (system A): Rt = 4.04 min. Mass spectrum: m / z 497 (MH +) Experimental details for route (M) Intermediate 42 15 (3aS, 4S, 6R, 6aR) -2, 2-dimethyl-6- (6-oxo-l, 6-dihydro- purin-9-yl) cyclopenta [ 1,3] dioxol-4-carboxylic acid The potassium permanganate (3.0 g) and the potassium hydroxide (1.0 g) in water (60 ml) were stirred together at room temperature overnight and the solution was then cooled to 0 ° C. [3aS- (3a, 4, 6, 6a)] 1, 9-dihydro-9- [tetrahydro-6- (hydroxymethyl) -2, 2-dimethyl-4H-cyclopenta-l, 3-dioxol-4- il] -6H-purin-6-one ft j-atfc .- * - Jt? aSu * »!» ». , S 'Mlmm' £ tl ^ ^^^ IMMS Isias & ii. Í.i'lí ^ ^ lm * a, £% ^ Ka? T ^^ it ^ -i¿S "& &. ^ Áji¡ fc ^? ¿-t ^^ Z ". V », m-" - bind "to £ ¡? . ia t JH-fej &S. < (2.92 g) was added slowly such that the temperature of the reaction mixture was kept below 5 ° C. The mixture was stirred at room temperature for 5 hours, then cooled to 0 ° C and treated with sodium metabisulfite (4.2 g). Hydrochloric acid (5M) was cautiously added to adjust the pH to about 3.5. The solution was stored at 4 ° C overnight and the resulting precipitate was collected, washed with cold water and dried in vacuo. The title compound was obtained as a white solid (1.82 g).

Mass spectrum: m / z 321 (MH +) Intermediate 43 15 6-Chloro-9- [2, 2-dimeth? L-6S- (3-cyclopropyl- [l, 2,4] oxadiazol-5-yl) -tetrahydro (3aS, 6aR) cyclopenta [ 1, 3] dioxol-4R-I1] -9H-pu ina (3aS, 4S, 6R, 6aR) -2, 2-dimethyl-6- (6-oxo-1, 6-dihydro-purin-9-yl) -cyclopenta [1,3] dioxo-1-4-carboxylic acid (118 mg) in anhydrous chloroform (4.5 ml) was heated to reflux with dimethylformamide (291) and thionyl chloride (108 1) for 4 hours. After cooling to room temperature, the solvent and the excess reactants were removed by evaporation and the The residue was taken in anhydrous chloroform (1.5 ml). The mixture was added to a cold (0 ° C) solution of cyclopropylamidoxime (110 mg) and pyridine (41 1) in chloroform (2.5 ml). The mixture was heated to reflux for 24 hours. After cooling, the mixture was evaporated to dryness and the residue was purified by flash chromatography on silica gel), eluting with ethyl acetate / cyclohexane (40:60). On evaporation, the title compound was obtained as a colorless gum (56 mg).

Mass spectrum: m / z 403 (MH +) Intermediate 44 (IR, 2S, 3R, 5S) -3- (6-Chloro-purin-9-yl) -5- (3-cyclopropyl- [1,2,4] -oxadiazol-5-yl) -cyclopentane- 1,2-diol 6-Chloro-9- [2, 2-dimethyl-6S- (3-cyclopropyl- [1,2,4] oxadiazol-5-yl) -tetrahydro (3aS, 6aR) - cyclopenta [1, 3] dioxol -4R-yl] -9H-purine (50 mg) is treated with cold trifluoroacetic acid-water 0 ° C (2 ml, 9: 1). The mixture was stored at 4 ° C overnight and evaporated to dryness. The title compound was obtained as a colorless gum (60 mg).

Mass spectrum m / z 363 (MH +) Example 32 (SS, 2R, 3S, 5R) -3- (3-cyclopropyl- [1, 2, 4] oxadiazol-5-yl) -5- [2S-hydroxy-cyclopent- (S) -lamino-purin- 9-yl] - cyclopentane-1,2-diol The (IR, 2S, 3R, 5S) -3- (6-chloro-purin-9-yl) -5- (3-cyclopropyl- [1,2,4] oxadiazol-5-yl) -cyclopentan-1, 2-diol (57 mg) in isopropanol (5 ml) was treated with hydrochloride trans- (iS, 2S) -2-aminocyclopentanol (34 mg) and diisopropylethylamine (85 .mu.l) at reflux temperature overnight. The excess solvent was evaporated and the residue was purified by preparative, automated clap. The title compound was obtained as an almost colorless glass (15 mg).

LC / MS (system C): Rt = 2.4 min.

Mass spectrum m / z 428 (MH +) Experimental details for the route (N) Intermediary 45. { 9-. { (3aR, 4R, 6S, 6aR) -6- [3- (tert-butyl) -1,2,4-oxadiazol-5-yl] -2,2-dimethyl-tetrahydrofuro [3,4-d] [1, 3 ] dioxol-4-il} -6- (1H-1,2, 3-benzotriazol-l-yloxy) -9H-purine To a solution of acid (3aS, 4S, 6R, 6aR) -6- (6-chloro-purin-9-yl) -2, 2-dimethyl-tetrahydro-furo [3,4-d] [1, 3] dioxol-4-carboxylic acid (10 g) in dimethylformamide (200 ml) was added 1-hydroxybenzotriazole (3.96 g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (5.62 g). T-butylacetamidoxime (3.40 g) was added in dimethylformamide (30 ml) and the mixture was stirred at 20 ° C for 24 hours under nitrogen. The mixture was then heated at 70 ° C for an additional 36 hours. The resulting mixture was then cooled to 20 ° C, basified with a saturated solution of sodium bicarbonate (200 ml) and extracted with ethyl acetate (2 x 150 ml). The organic layers were washed with brine (300 ml), dried (MgSO 4), evaporated to dryness in vacuo and triturated with ether to give a yellow solid (11.08 g). Purification by chromatography on silica gel, eluting with ethyl acetate: cyclohexane (3: 7), gave the title compound (4.75 g) as a white solid.

LC / MS (System C): Rt = 3.46 min. Mass spectrum: m / z 520 [MH +] Intermediary 46: 9-. { (3aR, 4R, 6S, 6aR) -6- [3- (tert-butyl) -1,2,4-oxadiazol-5-yl] -2,2-dimethyltetrahydrofuro [3,4-d] [1, 3 ] dioxol-4-il} -N-isobutyl-9H-purin-6-amine To a solution of 9-. { (3aR, 4R, 6S, 6aR) -6- [3- (tert-butyl) -1,2,4-oxadiazol-5-yl] -2,2-dimethyltetrahydrofuro [3, 4-d] [1, 3 ] dioxol-4-il} -6- (1H-1, 2, 3-benzotriazol-1-yloxy) -9H-purine (50 mg) in dimethyl sulfoxide (0.4 ml) was added diisopropylethylamine (0.1 ml) and isobutylamine (0.038 ml). The mixture was stirred at 20 ° C for 16 hours under nitrogen. The mixture was then evaporated to dryness in vacuo to give a residue which was purified by preparative CLAP, automated to give the title compound (14 mg) as a white compound. LC / MS (system C): Rt = 3.38 Mass spectrum: m / z 458 [MH +] Example 45 (2S, 3S, 4R, 5R) -2- [3- (tert-butyl) -1,2,4-oxadiazol-5-yl] -5- [6- (isobutylamino) -9H-purin-9 -yl] tetrahydrofuran-3,4-diol to a solution of 9-. { (3aR, 4R, 6S, 6aR) -6- [3- (tert-butyl) -1,2,4-oxadiazol-5-yl] -2,2-dimethyltetrahydrofuro [3, 4-d] [1, 3 ] dioxol-4-il} -N-isobutyl-9H-purin-6-amine (14 mg) in a cold mixture of trifluoroacetic acid: water (9: 1, 1 ml) was kept at 4 ° C for 18 hours. The resulting solution was basified in an ice bath with saturated aqueous sodium bicarbonate (20 ml), extracted with ethyl acetate (2 x 20 ml), the extracts were dried (MgSO 4) and evaporated to dryness in vacuo give the title compound (7.66 mg) as a white solid.

LC / MS (System C): Rt = 2.85 min. Mass spectrum: / z 418 [MH +] Experimental details for the route (O) Intermediary 47: 9-. { (3aR, 4R, 6S, 6aR) -6- [3- (tert-butyl) -1,2,4-oxadiazol-5-yl] -2,2-dimethyltetrahydrofuro [3, 4-d] [1, 3 ] dioxol-4-il} -N- (2,4-difluorophenyl) -9H-purin-6-amine The 9-. { (3aR, 4R, 6S, 6aR) -6- [3- (tert-Butyl) -1,2,4-oxadiazol-5-yl] -2,2-dimethyltetrahydrofuro [3,4- d] [1, 3 ] dioxol-4-il} -6- (1H-1,2, 3-benzotriazol-l-yloxy) - ,? 9H-purine (50 mg) was dissolved in 2,4-difluoroaniline (0.4 ml) and the mixture was heated at 80 ° C for 96 hours. The mixture was then cooled to 20 ° C and partitioned between dichloromethane (25 ml) and 1 M hydrochloric acid (15 ml). The separated aqueous phase was further extracted with dichloromethane (1 x 25 ml) and the combined organic extracts were evaporated to dryness in vacuo. Purification by preparative, automated CLAP gave the title compound (18.3 mg) as a dark purple gum.

LC / MS (System C): Rt = 2.85 min. Mass spectrum: m / z 418 [MH +] Example 49 (2S, 3S, 4R, 5R) -2- [3- (tert-butyl) -1,2,4-oxadiazol-5-yl] -5- [6- (2,4-difluoroanilyl) -9H -purin-9-yl] tetrahydrofuran-3,4-diol A solution of 9-. { (3aR, 4R, 6S, 6aR) -6- [3- (tert-butyl) -1,2,4-oxadiazol-5-yl] -2,2-dimethyltetrahydrofuro [3, 4-d] [1,3 ] dioxol-4-il} -N- (2,4-difluorophenyl) -9H-purin-6-amine (18.3 mg) in a cold mixture of trifluoroacetic acid: water (9: 1, 1 ml) was kept at 4 ° C for 18 hours. The resulting solution basified in an ice bath with a saturated solution of sodium bicarbonate (20 ml), extracted with ethyl acetate (2 x 20 ml), the extracts were dried (MgSO4) and evaporated to dryness in vacuo to give the title compound (14.3 ing) as a purple solid.

LC / MS (System C): Rt = 3.03 min. Mass spectrum: Í? / Z 474 [MH +] Experimental details for the route (P) Intermediate 48: (3aR, 4S, 6R, 6aR) -6- (6-chloro-9H-purin-9-yl) -N- (2-hydroxypropyl) -2, 2-dimethyltetrahydrofuro [3,4-d] [ 1, 3] dioxol-4-carboxamide Thionyl chloride (4.3 ml) was added to a stirred solution of acid (3aS, 4S, 6R, 6aR) -6- (6-chloro-purin-9-yl) -2,2-dimethyl-tetrahydro-furo [3 , 4-d] [1, 3] dioxol-4-carboxylic acid (10.0 g), in chloroform (100 ml). The mixture was heated to reflux temperature under nitrogen for 60 minutes. After cooling to 20 ° C the solvent was removed in vacuo and the residue azeotroped with toluene (2 x 50 ml). A suspension of the residue in chloroform (50 ml) was added dropwise at an equal rate with a solution of 1-amino-2-propanol (2.3 ml) and diisopropylethylamine (5.1 ml) in chloroform (50 ml) for 10 minutes at chloroform (50 ml) at 0 ° C. The mixture was stirred at 20 ° C for 18 hours. The phosphate buffer (pH 6.5100 ml) was added and the phases were separated. The aqueous phase was extracted with chloroform (50 ml). The combined chloroform layers were dried with sodium sulfate and the solvent was removed in vacuo to give the title compound as a white foam (6.63 g).

Mass spectrum: m / z 398 [MH +] Intermediate 49: (3aR, 4S, 6R, 6aR) -6- (6-chloro-9H-purin-9-yl) -2, 2-dimethyl-N- (2-oxopropyl) tetrahydrofuro [3, 4-d] [l, 3] dioxol-4-carboxamide To a mixture of (3aR, 4S, 6R, 6aR) -6- (6-chloro-9H-purin-9-yl) -N- (2-hydroxypropyl) -2, 2-dimethyltetrahydrofuro [3, 4-d] [1,3] dioxol-4-carboxamide (6.60 g) and molecular sieves 4Á powder (10 g) in dichloromethane (165 ml) at 0 ° C, acetic acid (3.0 ml) was added followed by the addition portion by portion from pyridinium dichromate (9.36 g). The mixture was stirred at 0 ° C for 15 minutes and then at 20 ° C for 2 hours. Isopropanol (10 ml) was added and the mixture was stirred for 15 minutes. Silica gel (Merck 9385, 9.9 g) and ethyl acetate (165 ml) were added and the reaction was stirred for an additional 15 minutes. The mixture was filtered through celite and the filter cake was washed with ethyl acetate (300 ml). The filtrate was evaporated in vacuo to give a brown solid. Purification by flash chromatography on silica gel, eluting with dichloromethane: methanol (100: 3) gave a light brown foam. Further purification by chromatography on silica gel (Merck 9385), eluting with ethyl acetate followed by ethyl acetate-methanol (100: 2) gave the title compound as a white foam (4.6 g). CCD SiO2 (ethyl acetate: methanol 100: 20) Rf = 0.4.

Experimental details for the route (Q) Intermediate 50: (3aR, 4S, 6R, 6aR) -N- (2-hydroxybutyl) -6-methoxy-2,2-di-ethyl-tetrahydrofuro [3,4-d] [1,3] dioxo-1-4-carboxamide A furo acid solution [3,4-d] -1,3-dioxol-β-D ribofuranose (5.0 g) in dichloromethane (50 ml) was added carbonyl diimidazole (4.83 g), the mixture was stirred for 20 minutes at 20 ° C and 1-amino-2-butanol (2.45 g) was added and the mixture was stirred under nitrogen at 20 ° C for 18 hours. The mixture was diluted with ether (50 ml) and washed with a solution of saturated citric acid (100 ml) and saturated aqueous sodium bicarbonate (100 ml). The layers were separated and the organic layers were concentrated in vacuo; The resulting residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate: cyclohexane 1: 1, to give the title compound as a clear gum (3.81 g).

Mass spectrum: m / z 290 [MH +] Intermediate 51 (3aR, 4S, 6R, 6aR) -6-methoxy-2, 2-dimethyl-N- (2-oxobutyl) tetrahydrofuro [3,4-d] [1,3] dioxol-4-carboxamide To a solution of (3aR, 4S, 6R, 6aR) -N- (2-hydroxybutyl) -6-methoxy-2,2-dimethyltetrahydrofuro [3,4-] [1,3] dioxol-4-carboxamide (3.81) g) in anhydrous dichloromethane (115 ml), containing 4A molecular sieves in powder (5.7 g) at 0 ° C, under nitrogen, acetic acid (2.59 ml) and potassium dichromate (7.93 g) were added, portion by portion. The reaction mixture was stirred at 0 ° C for 15 minutes and at 20 ° C for an additional 2 hours. The mixture was quenched with isopropanol (40 ml) and stirred for 30 minutes, silica gel (Merck 9385) (40 g) and ethyl acetate (100 ml) were added, and the mixture was stirred for a further 30 minutes. This mixture was filtered through a harborlite® filtration aid and the filtrate was concentrated in vacuo to give a crude product which was purified by flash column chromatography on silica gel, eluting with ethyl acetate: cyclohexane 2: 1 to give the title compound (1.91 g) rmn aH d 7.405 (HH, broad t, -NH), 5.125 (HH, broad, CH), 5.095 (HH, dd, CH), 4.655 (HH) , broad s, CH), 4.565 (ΔH, d, CH), 4.155 (2H, m, CH2), 3.555 (3H, s, OMe), 2.505 (2H, q, CH2), 1.505 (3H, s, - Me), 1.355 (3H, s, -Me), 1.105 (3H, t, -CH3) Intermediate 52: 2- [(3aR, S, 6R, 6aR) -6-methoxy-2,2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl] -5-ethyl-1, 3-oxazole _ ^ e ^^ 'J & ^^ ß! ß? ^^ ?? ^ Í-sA & to m.?r&,,.

To a solution of (3aR, 4S, 6R, 6aR) -6-methox-2, 2-dimethyl-N- (2-oxobutyl) tetrahydrofuro [3,4-d] [1, 3] dioxol-4-carboxamide (740 mg) in a dry toluene (10 ml), phosphorus oxychloride (1.44 ml) was added under nitrogen and the mixture was heated under reflux for 3.5 hours. The reaction mixture was cooled to 0 ° C, quenched with saturated aqueous sodium bicarbonate (30 ml), stirred vigorously for 30 minutes and extracted with ethyl acetate (4 x 5 ml).; the organic layers were combined, washed with brine (30 ml), dried (MgSO 4) and concentrated in vacuo to give a crude product, which was purified by flash column chromatography on silica gel, eluting with a mixture of cyclohexane: ethyl acetate 5: 1 to 7: 2, to give the title compound as a yellow oil (0.83 g).

Mass spectrum: m / z 270 [MH +] Intermediate 53: Acetate of (2R, 3R, 4R, 5S) -2,4-bis (acetyloxy) -5- (5-ethyl-1, 3-oxazol-2-yl) tetrahydrofuran-3-yl Al 2- [ (3aR, 4S, 6R, 6aR) -6-methoxy-2, 2-di-ethyl-tetrahydrofuro [3,4-d] [1,3] dioxol-4-yl] -5-ethyl-1,3-oxazole (0.83) g) trifluoroacetic acid: water 9: 1 (3.56 ml) was added, and the mixture was stirred at 20 ° C for 3.5 hours. The solvents were removed in vacuo to give an orange / brown oil. This material was dissolved in pyridine (7 ml) under nitrogen, acetic anhydride (2.76 ml) was added and the mixture was stirred at 22 ° C for 18 hours. The mixture was concentrated in vacuo, diluted with ethyl acetate (50 ml) and washed with IM HCl (50 ml), saturated aqueous sodium bicarbonate (3 x 50 ml) and brine (50 ml); the organic layer was dried (MgSO4) and the solvent was evaporated to dryness to give the title compound as a brown / orange oil (0.854 g).

Mass spectrum: m / z 342 [MI?] Intermediate 54: Acetate of (2R, 3R, R, 5S) -4- (acetyloxy) -2- (6-chloro-9H-purin-9-yl) -5- (5-ethyl-l, 3-oxazole- 2-yl) tetrahydrofuran-3-yl To 6-chloropurine (0.854 g) was added 1, 1, 1, 3, 3, 3-hexamethyldisilazane (4 ml) and toluene (15 ml) and the mixture was heated under reflux for 2 hours. The solvent was removed in vacuo, the residue was azeotroped with toluene (1 x 8 ml) and the mixture was evaporated to dryness. To this residue was added 5 (2R, 3R, 4R, 5S) -2,4-bis (acetyloxy) -5- (5-ethyl-l, 3-oxazol-2-yl) tetrahydrofuran-3-yl acetate ( 0.854 g) in acetonitrile (20 ml), trimethylsilyl triflate (0.624 ml) and 1,8-diazabicyclo [5.4.0] undec-7-ene (0.374 ml). The reaction mixture was stirred at 20 ° C for 18 hours and at 80 ° C for 3 hours and then allowed to cool. The mixture was poured into saturated aqueous bicarbonate (40 ml) and extracted with dichloromethane (4 x 40 ml); the organic layers were combined, dried (MgSO4) and the solvent removed in vacuo to give a crude product which was purified by flash chromatography on silica gel, eluting with cyclohexane: ethyl acetate 4: 1 then 3: 2, to provide the title compound as a colorless gum (355 mg). 0 Mass spectrum: m / z 346 [MU *] EXAMPLE 84 2- (. {9- [(2R, 3R, 4S, 5S) -5- (5-ethyl-l, 3-oxazol-2-yl) -3,4-hydroxytetrahydrofuran-2-yl] - 9H-purin-6-yl.}. Amino) -N, N- di-ethylenesulfonamide To a solution of (2R, 3R, 4R, 5S) -4- (cetyloxy) -2- (6-chloro-9H-purin-9-yl) -5- (5-ethyl-l, 3-oxazole acetate -2-yl) tetrahydrofuran-3-yl (50 mg) in isopropanol (5 ml), N, N-diisopropylethylamine (0.120 ral) and N, N-dimethyl-2-aminoethanesulfonamide hydrochloride were added. (86 mg). The mixture was stirred at reflux temperature, under nitrogen, for 48 hours and then cooled. A methanol / ammonia solution (4 ml) was added, the mixture was stirred and allowed to stand for 24 hours. The solvent was evaporated and the resulting residue was purified by preparative CLAP, automated to give the title compound (8.6 mg).

Mass spectrum: m / z 468 [MH +] Experimental details for the route (R) Intermediary 55 N-. { 9- [(3aR, 4R, 6S, 6aR) -2, 2-dimethyl-6- (3-methyl-1, 2,4-oxadiazol-5-yl) tetrahydrofuro [3, 4-d] [1, 3 ] dioxol-4-yl] -9H-purin-6-yl} -N-cyclopentylamine A mixture of acid (3aR, 4R, 6S, 6aR) -6- (6-cyclopentylamino-purin-9-yl) -2,2-dimethyl-tetrahydro-furo [3,4-d] [1, 3] dioxol -4-carboxylic acid (0.2 g), 2-ethoxy-l- " ethoxycarbonyl-1,2-dihydroquinoline (146 mg), acetaldoxime (76 mg) and dimethoxyethane (DME, 25 ml) was heated under reflux for 4 days and then cooled to 22 ° C. The mixture was concentrated in vacuo and ethyl acetate (40 ml) was added to the residue. The resulting suspension was washed with 0.5M citric acid solution (3 x 20 ml) and the aqueous washings were extracted with ethyl acetate (2 x 20 ml). The combined organic extracts were washed with water (20 ml) and brine (30 ml) and dried (MgSO 4). After concentration in vacuo, the residue was purified by chromatography on silica gel, eluting with ethyl acetate: cyclohexane (1: 1), to give the title compound (63 mg).

NMR (CDC13) d 8.03 (1H, broad s, heterocyclic CH); 7.84 (1H, s, heterocyclic CH); 6.29 (ÍH, broad s, CH), 5.84 (1H, dd, CH); 5.64 (ÍH, d, CH); 5.48 (ÍH, d, CH); 4.56 (ÍH, broad s, CH); 2.19 (3H, s, Me); 1.85-1.5 (9H, m + x, 6x 1 / 2CH2 + Me); 1.45 (3H, s, Me); 1.25-0.85 (2H, m, 2xl / 2CH2).

Example 39 (2R, 3R, 4S, 5S) -2- [6- (Cyclopentylamino) -9H-purin-9-yl] -5- (3-methyl-1,2,4-oxadiazol-5-yl) tetrahydrofuran -3, -diol A mixture of N-. { 9- [(3aR, 4R, 6S, 6aR) -2, 2-dimethyl-6- (3-methyl-1,2,4-oxadiazol-5-yl) tetrahydrofuro [3, 4-d] [1, 3 ] dioxol-4-yl] -9H-purin-6-yl} -N-cyclopentylamine (63 mg), trifluoroacetic acid (1 ml) and water (0.1 ml) was stirred at 0 ° C for 6 hours and then diluted with ethyl acetate (20 ml). The mixture was neutralized with sodium bicarbonate solution and the aqueous phase was extracted with ethyl acetate (2 x 10 ml). The combined organic extracts were washed with water (8 ml) and brine (10 ml) and dried (MgSO 4). After in vacuo concentration, the residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate: methanol (19: 1) to give the title compound as a white foam (42 mg ).

CCD SiO 2 (ethyl acetate methanol 19: 1) Rf 0.30 NMR (DMSO) d 8.43 (HH, s, CH); 8.20 (ÍH, broad s, CH); 7.79 (1H, broad d, NH); 6.45 (2H, broad v.s, 2x OH); 6.16 (lH, d, CH), 5.24 (lH, d, CH); 4.89 (1H, t, CH); 4.73 (ÍH, t, CH); 4.58 (lH, broad m, CH); 2.42 (3H, s, Me); 2.10- 1.50 (8H, m, 4xCH2) Experimental details for the route (S) -.

Intermediate 56: 1- [(3aR, 4R, 6R, 6aR) -6-methoxy-2, 2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl] pent-1-in- 3 -ol 5 A solution of 4R-ethynyl-6R-methoxy-2, 2-dimethyl-tetrahydro- (3aR, 6aR) -furo [3,4-d] [1,3] dioxol (1.5 g) in tetrahydrofuran (20 ml) was cooled to -78 ° C for 15 minutes under nitrogen. A solution of propionaldehyde (1.09 ml) in tetrahydrofuran (0.5 ml) was added by means of a syringe and the stirring was continued for 5 hours. The mixture was allowed to warm to 22 ° C and was stirred for an additional 16 hours. The solvents were removed and the resulting orange oil was partitioned between ether and aqueous ammonium chloride. The organic layers were washed with additional aqueous ammonium chloride, dried (MgSO 4), and concentrated in vacuo to give a yellow oil. Purification by chromatography on silica gel (Varian Bondelut cartridge), eluting with (i) cyclohexane, (ii) dichloromethane, (iii) ether, (iv) ethyl acetate gave the title compound as a colorless oil (1.33). g). CCD Si02 (ether: cyclohexane 1: 1) Rf = 0.39 25 GIVES*. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Intermediate 57 1- [(3aR, 4R, 6R, 6aR) -6-methoxy-2, 2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxo1-4-yl] pent-1-in- 3- ona 5 A solution of 1- [(3aR, 4R, 6R, 6aR) -6-methoxy? -2,2-dimethyltetrahydrofuro [3,4-d] [1, 3] dioxol-4-yl] pent-1 in-3-ol (1.3 g) in dichloromethane (100 ml) was added to a stirred suspension of manganese dioxide (60 g) in dichloromethane at 0 ° C. The mixture was stirred at 0 ° C for 3 hours, filtered through magnesium sulfate (50 g) and the solvent was removed in vacuo to give the title compound as a colorless oil (550 mg). d NMR (CDC13) 5.07 (lH, s, CH); 4.97 (lH, d, CH); 4.93 (ÍH, s, CH); 4.68 (ÍH, d, CH); 3.41 (3H, s, OMe); 2.58 (2H, q, CH2); 1.47 (3H, s, Me), 1.31 (3H, s, Me); 1.14 (3H, t, Me).

Intermediate 58: 1-oxime of 1- [(3aR, 4R, 6R, 6aR) -6-methoxy-2, 2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl] pentan- 1, 3- diona 25 z? A mixture of 1- [(3aR, 4R, 6R, 6aR) -6-methoxy-2,2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl] pent-1-in-3 -one (550 mg) and hydroxylamine (50% water solution) (0.2 ml) in ethanol (10 ml) was stirred overnight at 22 ° C. The mixture was concentrated in vacuo to give the title compound as a yellow oil (554 mg). NMR d (CDC13) 5.36, 5.31 (1H, 2x d, CH); 5.00 (lH, d, CH); 4.92 (ÍH, d, CH); 4.65 (LH, 2x d, CH); 3.40, 3.35 (3H, 2x s, OMe); 3.03-2.85 (2H, 2x AB, CH2); 1.92 (2H, m, CH2); 1.50, 1.34 (6H, 2x s, 2x Me); 1.03 (3H, 2x t, Me).

Intermediate 59: (3R, 4S, 5R) -5- (5-Ethylisoxazol-3-yl) tetrahydrofuran-2,3,4-triol The 1-oxime of 1- [(3aR, 4R, 6R, 6aR) -6-methoxy-2,2-dimethyl-tetrahydrofuro [3,4-d] [1,3] dioxol-4-yl] pentan-1, 3 -dione (0.5 g) was dissolved in aqueous acetic acid (18 mg) and the mixture was heated at 100 ° C for 2 hours. The solution was cooled and concentrated in vacuo to give a brown oil which was azeotroped with toluene. Purification by chromatography on silica gel (Varian Bondelut silica gel cartridge), eluting with (i) dichloromethane, (ii) ether, (iii) acetate X ^^^^^^^^^^^ of ethyl, (iv) methanol, gave the title compound (150 mg). CCD Si02 (ether) Rf = 0.17 Intermediary 60: Acetate of (2R, 3R, 4R) -4,5-bis (acetyloxy) -2- (5-ethylisoxazol-3-yl) tetrahydrofuran-3-yl Isomer 1 of (3R, 4S, 5R) -5- (5-ethylisoxazol-3-yl) tetrahydrofuran-2,3,4-triol (150 mg) was dissolved in pyridine (4 ml) and the mixture was treated with acetic anhydride (0.983 ml). The resulting solution was stirred at 22 ° C for 18 hours. The mixture was concentrated in vacuo to give a brown oil. Purification by chromatography on silica gel (Si02 Varian Bondelut cartridge), eluting with (i) dichloromethane, (ii) ether, (iii) ethyl acetate, gave the title compound as a pale yellow solid (142 mg ).

CCD Si02 (ether) Rf = 0.53 Intermediary 61: Acetate of (2R, 3R, 4R, 5S) -4- (acetyloxy) -2- (2,6-dichloro-9H-purin-9-yl) -5- (5-ethylsoxazol-3-yl) tetrahydrofuran-3-yl Isomer 1 of (2R, 3R, 4R) -4,5-bis (acetyloxy) -2- (5-ethylisoxazol-3-yl) tetrahydrofuran-3-yl acetate (193 mg) was dissolved in acetonitrile (5 ml) and treated sequentially with 2,6-dichloropurine (231 mg), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) (0.186 ml) and trimethylsilyl trifluoromethanesulfonate (TMSOTf) (0.255 ml) by means of a syringe for 5 minutes. The light yellow solution was stirred at 22 ° C for 40 hours, at 60 ° C for 21 hours, and at 80 ° C for 6 hours. The mixture was cooled to room temperature and more DBU (0.186 ml) and TMSOTf (0.225 ml) were added. After stirring at 22 ° C for 36 hours, the yellow mixture was heated at 60 ° C overnight and at 80 ° C for 6 hours. The solvents were removed in vacuo and the resulting brown, oily solid was taken up in ethyl acetate and washed with water (20 ml, 3: 1). The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried (MgSO4) and evaporated in vacuo to give a brown oil solid. The residue was triturated with dichloromethane and a white solid was removed by filtration. Evaporation of the filtrate gave a tan solid. Purification by chromatography on silica gel eluting with ether: cyclohexane (1: 1) gave the title compound as a white solid (161 mg).

LC / MS (System C) Rf = 3.34 min. Mass spectrum: m / z 470, 472 [MH +], [MH + 2 +] Intermediary 62: Acetate of (2R, 3R, 4R, 5R) -4- (acetyloxy) -2-. { 2-chloro-6- [(1-ethylpropyl) amino] -9H-purin-9-yl} -5- (5-Ethylisoxazol-3-yl) tetrahydofuran-3-yl (2R, 3R, 4R, 5R) -4- (Acetyloxy) -2- (2,6-dichloro-9H-purin-9-yl.). -5- (5-Ethylisoxazole-3-yl) acetate Tetrahydofuran-3-yl (125 mg) was dissolved in isopropanol (5 ml) and the solution was treated with diisopropylethylamine (0.06 ml) followed by 1-ethylpropylamine (0.044 ml) The mixture was heated at 50 ° C under nitrogen for 16 hours. The solvent was removed in vacuo and the mixture was partitioned between ethyl acetate and hydrochloric acid, M. The organic layers were washed with saturated sodium bicarbonate solution and brine, dried (MgSO.sub.4) and evaporated in vacuo. by chromatography on silica gel (Varian Bondelut cartridge), eluting with (i) dichloromethane, (ii) ether and (iii) ethyl acetate, gave the title compound as a colorless oil (108 mg) CCD SiO2 (ether) ) Rf = 0.26.

- Example 163 Formate of (2R, 3R, 4S, 5R) -2-. { 2-chloro- [(6- [(1-ethylpropyl) amino] -9H-purin-9-yl}. -5- (5-ethylisoxazol-3-yl) tetrahydrofuran-3,4-diol A mixture of (2R, 3R, 4R, 5R) -4- (acetyloxy) -2- acetate. { 2-chloro-6- [(1-ethylpropi1) amino] -9H-purin-9-yl} -5- (5-Ethylisoxazol-3-yl) tetrahydrofuran-3-yl (30 mg) and 2-morpholinoethylamine (0.037 ml) was heated at 90 ° C for 24 hours in dimethyl sulfoxide (0.5 ml). Heating was continued for 60 hours at 90 ° C. Purification by preparative CLAP (gradient profile 5-95% of (ii) for 18.25 minutes) gave the title compound as a white solid (6 mg). LC / MS (System C) Rt = 3.41 min. Mass spectrum m / z 437 [MH +] Experimental details for the route (T) Intermediary 63: 9-. { (3aR, 4R, 6S, 6aR) -6- [5- (tert-butyl-1,3,4-oxadiazol-2-yl] -2,2-dimethyl-tetrahydrofuro [3,4-d] [1,3] dioxol-4-yl.}. -N- (4-chloro-2-fluorophenyl) -9H-purin-6-amine The 9- [6S- (5-tert-butyl- [1,3,4] oxadiazole- 2-yl) -2,2-dimethyl-tetrahydro- (3aR, 6aS) -furo [3,4-d] [1, 3] dioxol-4R-1] -6-chloro-9H-purine (2.8 g) was treated with 4-chloro-2-fluoroaniline (4.48 ml), palladium acetate (146 mg) and (R) -2, 2'-bis (diphenylphosphino) -1,1-biphenyl (620 mg) in dry toluene (34 ml) and the mixture was stirred at room temperature for 5 minutes (the reaction was carried out in seven portions), cesium carbonate (3.08 g, in seven portions) was added, and the mixtures were heated to 86 g. -96 ° C for 16 hours The mixtures were combined and partitioned between water (200 ml) and dichloromethane (3 x 120 ml) The organic layers were washed with brine, dried (MgSO4) and evaporated in vacuo to give a brown oil (8.7 g). Purification by chromatography on silica gel, eluting with ethyl acetate: cyclohexane 30:70 gave an off-white solid (2.35 g). LC / MS (System C) Rt = 3.41 min. Mass spectrum m / z 530 [MH +] Example 14 (2R, 3R, 4S, 5R) -2- (5-tert-Butyl- [1,3,4] oxadiazol-2-yl) -5- [6- (4-chloro-2-fluoro-phenylamino ) -purin-9-yl] tetrahydrofuran-3,4-diol The 9-. { (3aR, 4R, 6S, 6aR) -6- [5- (tert-butyl) -1,3,4-oxadiazol-2-yl] -2,2-dimethyltetrahydrofuro [3,4-d] [1, 3 ] dioxol-4-il} -N- (4-chloro-2-fluorophenyl) -9H-purin-6-amine (2.35 g) was dissolved in trifluoroacetic acid (20 ml) and water (2 ml) with ice-bath cooling, and the mixture was let stand at 4 ° C for 17 hours. The mixture was slowly poured into saturated aqueous sodium bicarbonate, cooled with ice (400 ml) and extracted with ethyl acetate (3 x 200 ml). The organic layers were washed with brine, dried (MgSO 4) and evaporated in vacuo to give the title compound as a buff colored or light yellow solid (2.30 g). LC / MS (System C) Rt = 3.04 min. Mass spectrum m / z 490 [MH +] Experimental details for the route (U) Intermediate 64 9- [6S- (5-tert-Butyl- [1,3,4] oxadiazol-2-yl) -2,2-dimethyl-tetrahydro- (3aR, 6aS) -furo [3, 4-d] [1, 3] dioxol-4R-yl] -6-chloro-9H-purine The 1-deoxy-l- (1,6-dihydro-6-oxo-9H-purin-9-yl) -2, 3-0- (1-methylethylidene) -β-D-ribofuranonic acid 1 (0.4 g) dissolved in tetrahydrofuran (10 ml), diisopropylethylamine (0.075 ml) was added and the reaction mixture was stirred at 0 ° C for 10 minutes. Then pivaloyl chloride (0.016 ml) was added to the mixture and the reaction was stirred at 0 ° C for 3 hours. The t-butylhydrazide trifluoroacetate (0.36 g) was dissolved in tetrahydrofuran, cooled to 0 ° C and treated with diisopropylethylamine (0.24 ml); this solution was then added to the reaction mixture. The mixture was allowed to warm to 20 ° C and was stirred for 20 hours. The solvent was removed in vacuo and the resulting residue was purified by flash chromatography (silica gel, eluting with 5% methanol in dichloromethane) to give the corresponding diazyl hydrazide (0.41 g). The diacylhydrazide intermediate (30 mg) was dissolved in dimethylformamide (3 ml) and cooled to 0 ° C. Phosphorus oxychloride (45 mg) was added, and the reaction mixture was stirred at room temperature for 18 hours, and at 90 ° C for 2 hours. The solvent was removed in vacuo, and the resulting residue was purified by preparative, automated CLAP to give the title compound (20 mg). x "R.A. Olsson et al., J. Med. Chem., 1986, 29, 1683- Experimental details for the route (V) Intermediary 65 Acetate of; 2R, 3R, 4R, 5S) -4- (acetyloxy) -5-. { 3- [(acetyloxy) methyl] isoxazol-5-yl} -2- (6-chloro-9H-purin-9-yl) tetrahydrofuran-3-yl To 6-chloropurine (1.08 g) was added 1, 1, 1, 3, 3, 3-hexamethyldisilazane (20 ml) and the mixture was heated at 100 ° C, under nitrogen for 2.5 hours. The reaction was allowed to cool, the solvent was removed in vacuo, the residue was azeotroped with anhydrous toluene. (2 x 2.5 ml) and the mixture was evaporated to dryness to give an off white solid. To this solid was added 4R-acetoxy-2R- (3-acetoxymethyl-isoxazol-5-yl) -5R-methoxy-tetrahydro-furan-3R-yl ester of acetic acid (450 mg) in anhydrous acetonitrile (15 ml) under nitrogen, the mixture was cooled to 0 ° C and trimethylsilyl trifluoromethanesulfonate (1.4 ml) was added. The mixture was allowed to warm to 20 ° C for 20 minutes, then heated at 80 ° C for 16 hours. After cooling, the mixture was poured into saturated aqueous sodium bicarbonate (40 ml) and extracted with ethyl acetate (3 x 70 ml); the organic layers were combined, washed with brine (50 ml), dried (MgSO4) and concentrated to dryness '-a Z - - * to give a crude product which was purified by flash column chromatography on silica gel, eluting with ethyl acetate: cyclohexane 1: 1 to give the title compound as a clear oil ( 310 mg).

LC / MS (System C) Rt = 2.76 min. Mass spectrum m / z 480/482 [MH +] / [MH + 2 +] Example 155 (2R, 3R, 4S, 5S) -2- (6-. {[[(LS, S2) -2-hydroxycyclopentyl] amino]} -9H-purin-9-yl) -5- [3- (hydroxymethyl) isoxazol-5-yl] tetrahydrofuran-3,4-diol To a solution of (2R, 3R, R, 5S) -4- (acetyl i) -5- acetate. { 3- [(acetyloxy) methyl] isoxazol-5-yl} -2- (6-chloro-9H-purin-9-yl) tetrahydrofuran-3-yl (20 mg) in isopropyl alcohol (2 ml) was added N, N-diisopropylethylamine (0.043 ml) and 2-hydroxycyclopentylamine hydrochloride ( 11.4 mg). The mixture was stirred 50 ° C, under nitrogen for 18 hours, cooled and evaporated to dryness in vacuo. The resulting residue was purified by preparative, automated CLAP (gradient profile 5% -90% of (ii) for 20 minutes) to give the protected product with the intermediary of ^^. J ^ S ^^ M ^ tl ^ sJX, triacetoxi. To this residue was added methanol (1 ml) and t-butylamine (0.013 ml) and the mixture was stirred at 0 ° C for 3 hours. The solvent was evaporated in vacuo to yield the title compound as a white solid (5 mg).

LC / MS (System C) Rt = 2.25 min. Mass spectrum m / z 419 [MH +] Experimental details for the route (W) Intermediary 66: Acetate of (2R, 3R, 4R, 5R) -4- (acetyloxy) -2-ethynyl-5-methoxytetrahydrofuran-3-yl The 4R-ethynyl-6R-methoxy-2,2-dimethyl-tetrahydro- (3aR, 6aR) -furo [3,4-d] [1, 3] dioxol (0.965 g) was heated under reflux with concentrated hydrochloric acid ( 1.0 ml) in methanol (30 ml) for 6 hours. The methanol was evaporated in vacuo, more methanol was added and heating under reflux continued for 16 hours. Pyridine (1.6 ml) was added, the methanol was evaporated to leave vacuo, more methanol was added, and the mixture was evaporated to dryness in va cuo. Dry toluene (10 ml) was added and the mixture was evaporated again to dryness. The residue is' , i, Ks9.CZ > . dissolved in dry dichloromethane and treated with pyridine (1.6 ml), 4-dimethylaminopyridine (25 mg), and acetic anhydride (1.37 mg), and the mixture was stirred at 22 ° C under nitrogen for 18 hours. The mixture was evaporated to dryness in vacuo and the residue was partitioned between aqueous citric acid, saturated (100 ml) and dichloromethane (2x75 ml). The organic layers were washed with saturated aqueous sodium bicarbonate, dried (MgSO 4) and evaporated in vacuo to give a pale yellow oil (1.19 g). Purification by chromatography on silica gel (10 g Varian Bondelut cartridge), eluting with ethyl acetate: cyclohexane 5: 95-30: 70) gave the title compound as a colorless oil (724 mg). CCD Si02 (Ethyl acetate: cyclohexane 25:75) Rf = 0.3 Intermediate 67: Acetate of (2R, 3R, 4R, 5R) -4- (acetyloxy) -2- (6-chloro-9H-purin-9-yl) -5-ethynyltetrahydrofuran-3-yl The 6-chloropurine (250 mg) was heated at 130 ° C (oil bath) with hexamethyldisilazane (6 ml) with stirring under nitrogen for 2 hours. The excess reagent was evaporated in vacuo and the residue was dried. azeotrope with dry toluene (3 x 5 ml) to give a pale yellow solid. The (2R, 3R, 4R, 5R) -4- (acetyloxy) -2-ethynyl-5-methoxytetrahydrofuran-3-yl acetate (121 mg) was made azeotroped with dry toluene (2 x 5 ml), dissolved in dry acetonitrile, and added to the silylated purine, followed by trimethylsilyl trifluoromethanesulfonate (0.334 ml). The mixture was heated at 73-74 ° for 2 hours. The mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3 x 60 ml). The organic layers were washed with brine, dried (MgSO 4) and evaporated in vacuo to give a yellow oil (203 mg). Purification by chromatography on silica gel (Varian Bondelut cartridge), eluting with ethyl acetate: cyclohexane 10: 90-60: 40, gave the title compound as a colorless gum (84 mg). CCD Si02 (Ethyl acetate: cyclohexane 50:50) Rf = 0.25 Intermediate 68 Acetate of (2R, 3R, 4R, 5R) -4- (acetyloxy) -2- [6- (1H-1, 2, 3-benzotriazol-1-yloxy) -9H-purin-9-yl] - 5-ethynyltetrahydrofuran-3-yl (2R, 3R, 4R, 5R) -4- (Acetyloxy) -2- (6-chloro-9H-purin-9-yl) -5-ethynyltetrahydrofuran-3-yl acetate g: .ji -i- (104 mg) was treated with 1-hydroxybenzotriazole (136 mg) in dry DMF (3 ml) for 45 hours at 22 ° C. The mixture was emptied into cold iM hydrochloric acid (50 ml) and extracted with dichloromethane (3 x 25 ml); The organic layers were washed with water (20 ml) and saturated aqueous sodium bicarbonate (20 ml), dried (MgSO 4) and evaporated to a vacuo to give a colorless gum (148 mg).

LC / MS (System C) Rt = 3.19 min. Mass spectrum m / z 464 [MH +] Intermediate 69: Acetate of (2R, 3R, 4R, 5R) -4- (acetyloxy) -2- [6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] -5-ethynyltetrahydrofuran-3 -ilo (2R, 3R, 4R, 5R) -4- (Acetyloxy) -2- [6- (1H-1, 2,3-benzotriazol-1-yloxy) -9H-purin-9-yl] -5 acetate -etinyltetrahydrofuran-3-yl was treated with 2-fluoro-4-chloroaniline (0.63 ml), and the mixture was heated at 60 ° C for 22.5 hours. The mixture was purified by chromatography on silica gel (Varian Bondelut cartridge), eluting with ethyl acetate: cyclohexane 10: 90-60: 40, to give the title compound (55 mg). ? & V V? - - * CCD Yes02 (Ethyl acetate: cyclohexane 50:50) Rf = 0.3 Intermediate 70 Acetate of (2R, 3R, 4R, 5S) -4- (acetyloxy) -5- (3-bromoisoxazol-5-i1-2- [6- (4-chloro-2-fluoroanilino) -9H- purin- 9-yl] tetrahydrofuran-3-yl (2R, 3R, 4R, 5R) -4- (Acetyloxy) -2- [6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] -5-ethynyltetrahydrofuran-3-yl acetate (20 mg) was stirred at 22 ° C with dibromoformaldoxime (12.5 mg), sodium bicarbonate (39 mg), water (0.075 ml) and ethyl acetate (1.5 ml) for 88 hours. The mixture was partitioned between water (20 ml) and ethyl acetate (3 x 10 ml), the organic layers were washed with brine and evaporated in vacuo to give a brown gum (19 mg). Purification by chromatography on silica gel (Varian Bondelut cartridge), eluting with ethyl acetate: cyclohexane 20: 80-80: 20), gave the title compound as a colorless gum (16.8 mg). LC / MS (System C) Rt = 3.6 min. Mass spectrum m / z 595, 597 [MH +], [MH + 2 +] f W ^ Example 164 (2S, 3S, 4R, 5R) -2- (3-bromoisoxazol-5-yl) -5- [6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] tetrahydrofuran-3,4-diol (2R, 3R, 4R, 5S) -4- (Acetyloxy) -5- (3-bromoisoxazol-5-yl) -2- [6- (4-chloro-2-fluoroanilino) -9H-purin acetate -9-yl] tetrahydrofuran-3-yl (16.8 mg) was treated with t-butylamine (0.08 ml) in methanol (0.8 ml) at 0 ° C for 1.5 hours, and the mixture was evaporated to dryness to give the title compound (16 mg).

LC / MS (System C) Rt = 3.22 min. Mass spectrum m / z 511 [MH +] Experimental details for the route (Wb) Example 144 (2R, 3R, 4S, 5S) -2- [6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] -5- (3-methylisoxazol-5-yl) tetrahydrofuran-3 , 4-diol 20 (2R, 3R, 4R, 5R) -4- (Acetyloxy) -2- (6-chloro-9H-purin-9-yl) -5-ethynyltetrahydrofuran-3-yl acetate (20 mg ) was dissolved in anhydrous toluene (0.5 ml) and treated with triethylamine (0.006 ml), nitroethane (0.004 ml) and phenyl isocyanate (0.012 ml). The reaction heated at 100 ° C for 24 hours, cooled to room temperature and concentrated in vacuo. The resulting residue was purified by preparative, automated CLAP to produce an intermediate which was then dissolved in anhydrous methanol, cooled to 0 ° C and treated with t-butylamine (0.02 ml) for 1 hour. The reaction mixture was concentrated in vacuo to give the title compound as a white solid (143 mg).

LC / MS (System C) Rt = 2.95 min. Mass spectrum m / z 447 [MH +] Experimental details for the route (X) EXAMPLE 130 (2R, 3R, 4S, 5R) -2- [6- (Cyclopentylamino) -9H-purin-9-yl] -5- (1,5-dimethyl-lH-1, 2,4-triazole) trifluoroacetate -3-yl) tetrahydrofuran-3,4-diol [9- [2,2-Dimethyl-6R- (5-methyl-4H- [1, 2,4] triazol-3-yl) -tetrahydro (3aR, 6aR) -furo [3,4-d] [ 1,3] dioxo1-4R-I1] -9H-purin-6-yl} -cyclopropyl-amine (250 mg) was dissolved in anhydrous toluene (10 ml) and treated with dimethylformamide dimethyl acetal (0.47 ml). The mixture was heated to reflux temperature for 7 hours. '3Jaa'¿-fcfc afc, t. hours and then cooled to 20 ° C and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel, eluting with ethyl acetate: ethanol 19: 1. The resulting intermediates were treated with a mixture of trifluoroacetic acid / water (9: 1) at 0 ° C for 6 hours. The reaction mixture was then concentrated in vacuo, to give, after trituration with ethyl acetate, the title compound as a white solid (143 mg).

Analysis: Found (%): C 44.4; H, 4.8; N, 20.4 Required for d8H24N80. CF3C02H.1.5H20: C, 44.4; H, 5.2; N, 20.7 Experimental details for the route (Z) Intermediate 71 Acetate (2R, 3R, 4S, 5R) -4- (acetyloxy) -2- [(acetyloxy) methyl] -5- [2-chloro-6- (4-chloro-2-fluoroanilino) -9H- purin-9-yl] tetrahydrofuran-3-yl To a stirred solution of 2,6-dichloro-9- (2, 3, 5-tri-O-acetyl-β-D-ribofuranosyl) -9H-purine2 (1.0 g) in toluene (25 ml) was added ethyl acetate. palladium (50 mg), 4-chloro-2-fluoroaniline (0.5 ml) and bis [2-] ether (diphenylphosphino) phenyl] 3 (120 mg) and the reaction was stirred at 20 ° C for 15 minutes. Cesium carbonate (872 mg) was added and the mixture was heated at 90 ° C for 16 hours. The reaction mixture was cooled to 20 ° C and partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was washed with brine (100 ml), dried with magnesium sulfate and the solvent removed in vacuo. Purification by flash chromatography on silica gel, eluting with ethyl acetate: cyclohexane (1: 1) gave the title compound (400 mg).

Mass spectrum m / z 556 [MH +] 2 'M. J. Robins and B. Uznanski Cañad. J. Chem., 1981, 59 (17), 2608 3- J.P. Sadighi, M.C. Harris and S.L. Buchwald Tett. Lett. 1998, 5327-5330 Intermediary 72:. { (3aR, 4R, 6R, 6aR) -6- [2-chloro-6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] -2,2-dimethyltetrahydrofuro [3,4-d] [1,3] dioxol-4-yl} methanol To a suspension of (2R, 3R, 4R, 5R) -4- (acetyloxy) -2- [(acetyloxy) methyl] -5- [2-chloro-6- (4-chloro-2-fluoroanilino) acetate) -9H-purin-9-yl] tetrahydrofuran-3-yl (400 mg) in methanol (7 ml) was added sodium methoxide, 25% in methanol, (3 drops). On stirring for 15 minutes at 20 ° C, the reaction mixture was clear. In the stirring at 20 ° C for an additional 90 minutes a precipitate formed. The precipitate was collected by filtration and dried in vacuo for 16 hours. This was dissolved in a mixture of acetone (15 ml) and 2-2-dimethoxypropane (3 ml), and para-toluene sulfonic acid (193 mg) was added. The mixture was stirred at 20 ° C for 3 hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (50 ml), washed with water (50 ml) and brine (30 ml), dried (MgSO 4) and the solvent removed in vacuo. Purification by chromatography on silica gel (Varian Bondelut cartridge), eluting with cyclohexane: ethyl acetate (1: 1) gave the title compound as a white foam (240 mg).

Mass spectrum m / z 470 [MH +] Experimental details for the route (Y) Intermediate 73 4- [(9- { (2R, 3R, 4R, 5S) -3, -bis (acetyloxy) -5- [3- (tert-butyl) isoxazol-5-yl] tetrahydrofuran-2-yl .}. -9H-purin-6-yl) ammo] piperidine-1-tert-butyl carboxylate To a solution of acetic acid 4R-acetoxy-5S- (3-tert-butyl-isoxazol-5-yl) -2R- (6-chloro-purin-9-yl) -tetrahydro-furan-3R-yl ester (455 mg) in isopropanol (20 mL) was added tert-butyl-4-amino-1-piperidinecarboxylate (785 mg) and disopropylethylamine (1.03 mL). The mixture was heated at 95 ° C for 60 hours. The resulting mixture was then cooled and evaporated to dryness in vacuo. The resulting residue was dissolved in pipdma (20 mL) and acetic anhydride (19 mL) was added. The mixture was stirred at room temperature for 16 hours, evaporated to dryness in vacuo and redissolved in ethyl acetate (50 mL). Citric acid (2 x 50 mL) was added to the mixture and the separated layers. The aqueous layers were extracted with ethyl acetate ((100 mL) The combined ethyl acetate layers were dried (MgSO4), filtered and evaporated to dryness in vacuo to give the title product (500 mg) as a yellow solid.

LC / MS (System C): Rt = 3.59 min Mass spectrum m / z 628 [MH +] Intermediary 74 Acetate (2R, 3R, 4R, 5s) -4- (acetyloxy) -5- [3- (tert-butyl) isoxazol-5-yl] -2- [6-piperidin-4-ylamino) -9H-purin -9- il] tetrahydrofuran-3-yl 4- [(9-. {(2R, 3R, 4R, 5S) -3,4-bis (acetyloxy) -5- [3- (tert-butyl) isoxazol-5-yl] tetrahydrofuran-2-yl} -9H-purin-6-yl) ammo] piperidma-1-carboxylate of tert-butyl (500 mg) was dissolved in trifluoroacetic acid: dichloromethane (1: 9, 2C mL) and the mixture was kept at 3 ° C for 16 hours. The mixture was then removed with a solution of sodium bicarbonate (100 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with a solution of saturated sodium bicarbonate (100 mL) and evaporated by dryness in vacuo to give . . the title compound (407 mg) as a crystalline solid, LC / MS (system C): Rt = 2.45 min Mass spectrum m / z 528 [MH +] 5 Intermediary 75: Acetate (2R, 3R, 4R, 5s) -4- (acetyloxy) -5- [3- (tert-butyl) isoxazol-5-yl] -2- [6-. { [1- (methylsulfonyl) piperidin-4-yl] amino]} -9H-purin-9-yl] tetrahydrofuran-3-yl To a solution of (2R, 3R, 4R, 5S) -4- (acetyloxy) -5- [3- (tert-butyl) isoxazol-5-yl] -2- [6- (piperidin-4-ylamino ) -9H- pur? N-9-yl] tetrahydrofuran-3-yl (40 mg) in tetrahydrofuran (4 mL) was added methanesulfonyl chloride (0.0088 mL) and triethylamine (0.01212 mL). The reaction mixture was stirred for 16 hours at 20 ° C, and partitioned between ethyl acetate (2 x 100 mL) and water (100 mL). The organic layers were washed with water (100 mL), dried (MgSO4), and evaporated in vacuo to give the title compound (36.7 mg) as a colorless gum.

LC / MS (System C): Rt = 3.20 min Mass spectrum m / z 606 [MH +] Example 167 5 (2S, 3S, 4R, 5R) -2- [3- (tert-butyl) isoxazol-5-yl] -5- (6- { [1- (methylsulfonyl) piperidin-4-yl] amino.}. -9H-purin-9-yl) tetrahydrofuran-3,4-diol Acetate (2R, 3R, 4R, 5S) -4- (acetyloxy) -5- [3- (tert-10-butyl) -soxazole-5-? L] -2- (6- { [1- ( methylsulfonyl) piperidn-4-yl] ammono.) -9H-purm-9-? l) tetrahydrofuran-3-yl (36.7 mg) was dissolved in cold methanol (2 mL) and) was added. Butylene (0.038 mL) at 0 ° C. The mixture was kept at 3 ° C for 1.5 hours, and evaporated in vacuo to give the compound of title as a white solid (30.8 mg).

LC / MS (System C): Rt = 2.69 mm Mass spectrum m / z 522 [MH +] Experimental details for the route (Bb) Intermediary 76: - Acetate of (2R, 3R, 4R, 5R) -4- (acetyloxy) -5-. { 3- [(acetyloxy) methyl] isoxzol-5-yl} -2- [2-chloro-6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] tetrahydrofuran-3-yl 5 A ester of 4R-acetoxy-5S- (3-acetoxymethyl-isoxazole- 5-yl) -2R- (2,6-dichloro-purin-9-yl) -tetrahydro-furan-3R-yl acetic acid (50 mg) in toluene (2 mL), palladium (II) acetate was added (2.2 mg), 2, 2'-bis (diphenylphosphino) -1, 1'-10 binaphthyl (6 mg) and 4-chloro-2-fluoroaniline (28.5 mg). the mixture was stirred under nitrogen for 20 minutes, cesium carbonate (38 mg) was added, and stirring was continued at 80 ° C for 24 hours. The mixture was cooled, diluted with ethyl acetate (25 mL), washed with water (25 mL) and Brine (25 mL) and evaporated in vacuo. Purification was performed by automatic HPLC preparative (5-90% profile gradient (ii) for 18.5 minutes) to give the title compound as a white solid (3.02 mg).

LI / MS (System C) Rt = 3.52 min Mass spectrum m / z = 623 [MH +] Intermediate 77: (2R, 3R, 4R, 5R) -2- [2-chloro-6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] -5- [3- (hydroxymethyl) isoxazole -5-yl] tetrahydrofuran-3,4-diol 5 A (2R, 3R, 4R, 5R) -4- (acetyloxy) -5- acetate. { 3- [(acetyloxy) methyl] isoxazol-5-yl] -2- [2-chloro-6- (4-chloro-2-fluoroanilino) -9 H -purin-9-yl] tetrahydrofuran-3-yl (4.0 mg ) n methanol (2 mL) at 0 ° C was added tert-butylamine (0.012 mL), and the mixture was allowed to stand at 0 ° C for 3 hours. The solvent was evaporated in vacuo to obtain the title compound as a yellow gum (2.48 mg).

LC / MS (System C) Rt = 3.10 min 15 Mass spectrum m / z = 497 [MH +] Experimental details for the route Ce 20 Intermediary 78 (2aR, 4S, 6R, 6aR) -N '-acetyl-6- [6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] -2,2-dimethyltetrahydrofuro [3, 4-d] ] [1,3] dioxol-4-carbohydrazide To a solution of (3aR, 4S, 6R, 6aR) -6- [6- (-chloro-2-fluoroanilino) -9H-purin-9-yl] -2,2-dimethyltetrahydrofuro [3, 4-d] [ 1,3] dioxol-4-carbohydrazide (50 mg) in N, N'-dimethylformamide (2 mL) at 0 ° C for 5 hours. The mixture was partitioned between ethyl acetate (20 mL) and water (20 mL). The organic layer was washed with brine (20 mL), dried (MgSO) and the solvent was removed in vacuo. The residue was purified by automatic preparative HPLC (profile gradient 5-95% (ii) for 18.5 minutes) to give the title compound (25 mg).

LC / MS (System C): Rt = 3.59 min Mass spectrum m / z 628 [MH +] Experiments with Genes Reporters - The agonist activity was measured in Chinese hamster ovary cells (CHO) containing the reporter gene elements CRE / SPAP / HYG (CRE = cyclic AMP response element, HYG = hygromycin resistance, SPAP = alkaline phosphatase, placental , secreted), which with the stimulation of cAMP levels produced SPAP. A cell line was used, which was transfected stably with either the human Al adenosine receptor or the human A3 adenosine receptor in the addition to the above elements. The cells were placed in 96-well plates in culture medium and incubated at 37 ° C for 1 hour. For the measurement of potency, agonists were added to the appropriate wells in a range of concentrations of approximately 10"10 - 10" 5 M. 15 minutes later, cAMP levels were stimulated by the addition of a maximum concentration of forskolin. . All the cells were then incubated for an additional 5 hours at 37 ° C, and cooled to room temperature, after which a substrate for the phosphatase (para-nitrophenol phosphate, pNPP) was then added, which is converted to the SPAP to a colored reagent) and the 96-well plates were read in a plate reader. From these readings, one can calculate the dependence to the concentration of the inhibition by ¿I i? ' * lí¡mJÍ -. the agonist for SPAP production stimulated with Forskolin. One of the agonists analyzed in each of the 96-well plates was the normal non-selective agonist, N-ethylcarboxamidoadenosine (ÑECA), and the potency of all test agonists is expressed in relation to that of normal ÑECA.

(ECR = the ratio of the equipotent concentration relative to ÑECA = 1) Table 2: Potencies in the reporter gene assay * ECR = the relation of the equipotent concentration relative to the ECA = 1 (see description in the Essay with Genes Reporters). DECLARATION THAT INCLUDES PROCESS It is stated that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property. • ^ y »- r» '- - £ út ... "* ~ J &frCs. * ..

Claims (24)

to CLAIMS

1. A compound of the formula (I) which is onist at the adenosine Al receptor R1 characterized in that X represents O or CH2; R2 represents alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, halogen or hydrogen; R3 represents H, phenyl (optionally substituted by halogen), a 5- or 6-membered heteroaryl group, alkoxy of 1 to 6 carbon atoms, alkyl-6CO (CH2) n where n is 0-6, cycloalkyl of 3 to 7 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, halogen or a straight or branched alkyl group, of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms or alkynyl of ^ # e "1 to 6 carbon atoms optionally substituted by one or more halogens. Y and Z represent 0, N, CH, N (alkyl of 1 to 6 carbon atoms) 5 W represents CH, 0, N, S, N (alkyl of 1 to 6 carbon atoms) and wherein at least one of W and Z represents a heteroatom (and when Y, Z and / or W is N, the presence or absence of an additional H would be apparent to a person skilled in the art) with the proviso that when W represents CH, Z represents N and Y represents 0, R3 can not be H. R4 and R5 independently represent H or an alkyl group of 1 to 6 carbon atoms, straight chain or branched chain. R1 represents hydrogen or a group selected from (1) - (alk) n-cycloalkyl of 3 to 7 carbon atoms, including bridged cycloalkyl, the cycloalkyl group optionally substituted by one or more substituents selected from OH, halogen, -alkoxy of 1 to 3 carbon atoms, where ** * & mm- £ * '? .. a j Z ^ Za ^ -j ^ é "». (alk) represents alkylene of 1 to 3 carbon atoms and n represents 0 or 1. (2) a heterocyclic, aliphatic group of d '4 to 6-membered rings containing at least one heteroatom selected from 0, N or S, optionally substituted by one or more substituents selected from the group consisting of -alkyl of 1 to 3 atoms of carbon, -C02-alkyl of 1 to 4 carbon atoms, -CO (alkyl of 1 to 3 carbon atoms), -S (= 0) n- (alkyl of 1 to 3 carbon atoms), -C0NRaRb ( wherein Ra and Rb independently represent H or alkyl of 1 to 3 carbon atoms) or = 0; where there is a sulfur atom in the heterocyclic ring, the sulfur is optionally substituted by (= 0) n, where n is 1 or 2. (3) C 1 -C 12 straight or branched alkyl, optionally including one or more 0, S (= 0) n groups (where n is 0, 1 or 2) and N substituted within the alkyl chain , the alkyl optionally substituted by one or more of the following groups, phenyl, halogen, hydroxy, cycloalkyl of 3 to 7 carbon atoms or NRaRb wherein Ra and Rb independently represent hydrogen, cycloalkyl of 3 to 7 carbon atoms or an alkyl from 1 to 6 carbon atoms, straight or branched chain, optionally substituted by cycloalkyl of 3 to 7 carbon atoms; (4) an aromatic, bicyclic, fused ring wherein B represents an aromatic, heterocyclic, 5- or 6-membered group containing 1 or more O, N or S atoms, wherein the bicyclic ring is attached to the nitrogen atom of the formula (I) by means of an atom of ring of ring A and ring B is optionally substituted by -C02- (alkyl of 1 to 3 carbon atoms). (5) a phenyl group optionally substituted by one or more substituents selected from: -halogen, -S03H, - (alk) nOH, - (alk) n-cyano, - (0) n -alkyl of 1 to 6 carbon atoms (optionally substituted by one or more halogens), - (alq) n -nitro, - (0) m - (alq) "-C02Rc, - (alqn) -C0NRcRd- (alq) n -C0Rc, - (alk) n -S0Re, - (alq) n -S02Re, (alq) "- S02NRcRd, - (alq) n0Rc, - (alq) n - (C0) m- NHS02R% - (alq)" - NHC0Rc, - (alq) " - NRcRd, where m and n are 0 or 1 and alk represents an alkylene group of 1 to 6 carbon atoms or an alkenyl group of 2 to 6 carbon atoms. (6) A phenyl group substituted by an aromatic, heterocyclic, 5- or 6-membered group, the aromatic, heterocyclic group which is optionally substituted by alkyl of 1 to 3 carbon atoms or NRcR. Rc and Rd can each independently represent hydrogen or alkyl of 1 to 3 carbon atoms or when part of a group NRcRd, Rc and Rd together with the nitrogen atom can form a 5- or 6-membered heterocyclic ring optionally containing other heteroatoms , heterocyclic ring which may be optionally substituted by one or more alkyl groups of 1 to 3 carbon atoms. Re represents alkyl of 1 to 3 carbon atoms and salts and solvates thereof, in particular, solvates and physiologically acceptable salts thereof for use in therapy.

2. A compound of formula (la) which is an agonist at the adenosine Al receptor characterized in that X represents O or CH2; R2 represents alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, halogen or hydrogen; Jz R3 represents H, phenyl (optionally substituted by halogen), a 5- or 6-membered heteroaryl group, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, straight or branched optionally substituted by one or more halogens, cycloalkyl of 3 to 7 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms or halogen. Y and Z represent 0, N, CH W represents CH, 0, N, S and wherein at least one of W and Z represents a heteroatom (and when Y, Z and / or W is N, the presence or absence of a Additional H would be apparent to a person skilled in the art) with the proviso that when W represents CH, Z represents N and Y represents 0, R3 can not be H. R4 and R5 independently represent H or an alkyl group of 1 to 6 carbon atoms, straight or branched chain. R1 represents a group selected from (1) - (alk) n-cycloalkyl of 3 to 7 carbon atoms, including bridged cycloalkyl, the cycloalkyl group optionally substituted by one or more substituents selected from OH, halogen, -alkoxy of 1 to 3 carbon atoms, in where (alk) represents alkylene of 1 to 3 carbon atoms and n represents 0 or 1. (2) a 4- to 6-membered heterocyclic ring, aliphatic group containing at least one heteroatom selected from 0, N or S, optionally substituted by one or more substituents selected from the group consisting of -alkyl of 1 to 3 carbon atoms; carbon, -C02-alkyl of 1 to 4 carbon atoms, -CO (alkyl of 1 to 3 carbon atoms), -S (= 0) n- (alkyl of 1 to 3 carbon atoms), -C0NRaRb (in where Ra and Rb independently represent H or alkyl of 1 to 3 carbon atoms) or = 0; where there is a sulfur atom in the heterocyclic ring, the sulfur is optionally substituted by (= 0) n, where n is 1 or 2. (3) C 1 -C 12 straight or branched alkyl, optionally including one or more 0, S (= 0) n groups (where n is 0, 1 or 2) and N substituted within the alkyl chain , the alkyl optionally substituted by one or more t &Ja. ' Amxa-¿jím t l > , »-" l tA £? ^? A ^ JÍ ^ I ^? ¿? »T &? S ^ .. ^^ J ': SáÜl?,. -jüa, ", iffl. - ~ l &M * .S of the following groups, phenyl, halogen, hydroxy, cycloalkyl of 3 to 7 carbon atoms or NRaRb where Ra and Rb independently represent hydrogen, cycloalkyl of 3 to 7 carbon atoms or an alkyl of 1 to 6 carbon atoms, straight or branched chain optionally substituted by cycloalkyl of 3 to 7 carbon atoms. (4) an aromatic, bicyclic, fused ring wherein B represents an aromatic, heterocyclic, 5- or 6-membered group containing 1 or more O-atoms, or S, wherein the bicyclic ring is attached to the nitrogen atom of the formula (I) by means of a hydrogen atom. ring of ring A and ring B is optionally! substituted by -C02- (alkyl of 1 to 3 carbon atoms). (5) a phenyl group optionally substituted by one or more substituents selected from: £! J £ £ £ £ ^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ tlbAiJmji ^ -í ^ ^ e ^ fi? a ^ mSm .. * '^ £ &SÜfa á¡ * J! a 3 -halogen, -S03H, * - (alq) nOH, - (alq) n -ciano, - (0) n -alkyl of 1 to 6 carbon atoms (optionally substituted by one or more halogens), - (alk) ^ Tnitro, - (0) m - (alk) n- C02Rc, - (alqn ) - C0NRcRd - (alq) n -C0Rc, - (alq) n -S0Re, - (alq) n -S02Re, (alq) "- S02NRcRd, - (alq) n0Rc, - (alq) n - (C0) m - NHS02Re, - (alk) "- NHC0Rc, - (alk) n ~ NRcRd, where m and n are 0 or 1 and alk represents an alkylene group of 1 to 6 carbon atoms or an alkenyl group of 2 to 6 carbon atoms . (6) A phenyl group substituted by an aromatic, heterocyclic, 5- or 6-membered group, the aromatic, heterocyclic group which is optionally substituted by alkyl of 1 to 3 carbon atoms or NRcRd. Rc and Rd can each independently represent hydrogen or alkyl of 1 to 3 carbon atoms or when part of a group NRcRd, Rc and Rd together with the nitrogen atom can form a 5- or 6-membered heterocyclic ring optionally containing other heteroatoms , heterocyclic ring which may be optionally substituted / 4D additionally by one or more alkyl groups of 1 to 3 carbon atoms. Re represents alkyl of 1 to 3 carbon atoms and salts and solvates thereof, in particular, solvates and physiologically acceptable salts thereof for use in therapy.

3. A compound of the formula (Ib) which is an agonist at the adenosine Al receptor 10 Characterized in that X represents O or CH2; R2 represents alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, halogen or hydrogen; R3 represents H, phenyl (optionally substituted by halogen), a 5- or 6-membered heteroaryl group, alkoxy of 1 to 6 carbon atoms, alkyl-eCO (CH2) n where n is 0-6, cycloalkyl of 3 to 7 atoms carbon, hydroxyalkyl of 1 to 6 carbon atoms, halogen or an alkyl group of 1 to 6 carbon atoms, straight or branched, alkenyl of 1 to 6 carbon atoms or alkynyl of 1 to 6 carbon atoms optionally substituted by one or more halogens. Y and Z represent 0, N, CH, N (alkyl of 1 to 6 carbon atoms) W represents CH, O, N, S, N (alkyl of 1 to 6 carbon atoms) and wherein at least one of W and Z represents a heteroatom (and when Y, Z and / or W is N, the presence or absence of an additional H would be apparent to a person skilled in the art) with the proviso that when W represents CH, Z represents N and Y represent 0, R3 can not be H. R4 and R5 independently represent H or an alkyl group of 1 to 6 carbon atoms, straight or branched chain. R1 represents hydrogen or a group selected from (1) - (alk) n ~ cycloalkyl of 3 to 7 carbon atoms, including bridged cycloalkyl, the cycloalkyl group optionally substituted by one or more substituents selected from OH, halogen, -alkoxy of 1 to 3 carbon atoms, in where (alk) represents alkylene of 1 to 3 carbon atoms and n represents 0 or 1. (2) a 4- to 6-membered heterocyclic ring, aliphatic group containing at least one heteroatom selected from O, N or S, optionally substituted by one or more substituents selected from the group consisting of -alkyl of 1 to 3 carbon atoms; 'carbon, -C02-alkyl of 1 to 4 carbon atoms, -CO (alkyl of 1 to 3 carbon atoms), -S (= 0) n- (alkyl of 1 to 3 carbon atoms), - C0NRaRb (wherein Ra and Rb independently represent H or alkyl of 1 to 3 carbon atoms) or = 0; where there is a 'sulfur atom in the heterocyclic ring, the sulfur' is optionally substituted by (= 0) n, where n is 1 or 2. (3) C 1 -C 12 straight or branched alkyl, optionally including one or more 0, S (= 0) n groups (where n is 0, 1 or 2) and N substituted within the alkyl chain , he Alkyl optionally substituted by one or more of the following groups, phenyl, halogen, hydroxy, cycloalkyl of 3 to 7 carbon atoms or NRaRb wherein Ra and Rb independently represent hydrogen, cycloalkyl of 3 to 7 carbon atoms or an alkyl from 1 to 6 carbon atoms, straight or branched chain optionally substituted by cycloalkyl of 3 to 7 carbon atoms; (4) an aromatic, bicyclic, fused ring fifteen wherein B represents an aromatic, heterocyclic, 5- or 6-membered group containing 1 or more 0, N or S atoms, wherein the bicyclic ring joins the nitrogen atom of the formula (I) by means of a ring atom ring A and ring B is optionally substituted by -C02- (alkyl of 1 to 3 carbon atoms). (5) a phenyl group optionally substituted by one or more substituents selected from: -halogen, -S03H, - (alk) nOH, - (alk) n-cyano, - (0) n -alkyl of 1 to 6 carbon atoms (optionally substituted by one or more halogens), - (alk) n - nitro, - (O) rr - (alq ") - CONRcRd - (alq)" -CORc, - (alq) n ~ SORe, - (alq) n -S02Re, - (alq) "- S02NRcRd, - (alq) nORc, - (alk) n - (CO) m- NHS02Re, - (alk) n-NHCORc, - (alk) n-NRcRd, where m and n are 0 or 1 and alk represents an alkylene group of 1 to 6 carbon atoms carbon or an alkenyl group of 2 to 6 carbon atoms. (6) A phenyl group substituted by an aromatic, heterocyclic, 5- or 6-membered group, the aromatic, heterocyclic group which is optionally substituted by alkyl of 1 to 3 carbon atoms or NRcRd. Rc and Rd can each independently represent hydrogen or alkyl of 1 to 3 carbon atoms or when part of a group NRcRd, Rc and Rd together with the nitrogen atom can form a 5- or 6-membered heterocyclic ring optionally containing other heteroatoms , heterocyclic ring which may optionally be further substituted by one or more alkyl groups of 1 to 3 carbon atoms. Re represents alkyl of 1 to 3 carbon atoms with the proviso that when R 4 and R 5 both represent H, R 3 represents halogen, R 3 can not represent methyl, ethyl, n-propyl, isopropyl, cyclopropyl, CH (OH) CH 3, alkoxy 1 to 3 carbon atoms. and salts and solvates thereof, in particular, solvates and physiologically acceptable salts thereof.

4. A compound of the formula (le) which is ta at the adenosine Al receptor characterized in that X represents O or CH2; R2 represents alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, halogen or hydrogen; R3 represents H, phenyl (optionally substituted by halogen), a 5- or 6-membered heteroaryl group, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, straight or branched optionally substituted by one or more halogens, cycloalkyl of 3 to 7 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms or halogen. Y and Z represent O, N, CH W represents CH, O, N, S '** - i £ bU¿íc "nfj A ÜS, a and wherein at least one of W and Z represents a heteroatom (and when Y, Z and / or W is N, the presence or absence of an additional H would be apparent to a person skilled in the art) with the proviso that when W Represent CH, Z represent N and Y represent 0, R3 can not be H. R4 and R5 independently represent H or an alkyl group of 1 to 6 carbon atoms, straight or branched chain. R1 represents a group selected from (1) - (alk) n-cycloalkyl of 3 to 7 carbon atoms, including bridged cycloalkyl, the cycloalkyl group optionally substituted by one or more substituents selected from OH, halogen, -alkoxy of 1 to 3 carbon atoms, in where (alk) represents alkylene of 1 to 3 carbon atoms and n represents 0 or 1. (2) a heterocyclic, aliphatic group of rings. 4 to 6 members containing at least one heteroatom selected from O, N or S, optionally substituted by one or more substituents selected from the group consisting of: -alkyl of 1 to 3 carbon atoms, -C02-alkyl of 1 to 4 carbon atoms, -CO (alkyl of 1 to 3 carbon atoms), -S (= 0) n- (alkyl of 1 to 3 carbon atoms), -CONRaRb (wherein Ra and Rb independently represent H or alkyl of 1 to 3 carbon atoms) or = 0; where there is a sulfur atom in the heterocyclic ring, the sulfur is optionally substituted by (= 0) n, where n is 1 or 2. (3) C 1 -C 12 straight or branched alkyl, optionally including one or more 0, S (= 0) n groups (where n is 0, 1 or 2) and N substituted within the alkyl chain , the alkyl optionally substituted by one or more of the following groups, phenyl, halogen, hydroxy, cycloalkyl of 3 to 7 carbon atoms or NRaRb wherein Ra and Rb independently represent hydrogen, cycloalkyl of 3 to 7 carbon atoms or an alkyl from 1 to 6 carbon atoms, straight or branched chain optionally substituted by cycloalkyl of 3 to 7 carbon atoms; (4) an aromatic, bicyclic ring, fused zo wherein B represents an aromatic, heterocyclic, 5- or 6-membered group containing 1 or more 0, N or S atoms, wherein the bicyclic ring is attached to the nitrogen atom of the formula (I) by means of an atom of ring of ring A and ring B is optionally substituted by -C02- (alkyl of 1 to 3 carbon atoms). (5) a phenyl group optionally substituted by one or more substituents selected from: -halogen, -S03H, - (alk) n0H, - (alk) n -ciano, - (0) n -alkyl of 1 to 6 carbon atoms (optionally substituted by one or more halogens), - (alk) n -nitro, - (O) m - (alk) n- C02Rc, - (alq - C0NRcRd - (alq) "-C0Rc, - (alq) n -S0Re, - (alq) n -S02Re, (alq) n- S02NRcRd, - (alq) n0Rc, - (alq) n - (CO) m- NHS02Re, - (alq) n- NHCORc, - (alk) n-NRcRd, wherein m and n are 0 or 1 and alq represents an alkylene group of 1 to 6 carbon atoms or an alkenyl group of 2 to 6 carbon atoms. (6) A phenyl group substituted by an aromatic, heterocyclic, 5- or 6-membered group, 5 aromatic, heterocyclic group which is optionally substituted by alkyl of 1 to 3 carbon atoms or NRcRd. Rc and Rd can each independently represent hydrogen or alkyl of 1 to 3 10 carbon atoms or when part of a group NRcRd, Rc and Rd together with the nitrogen atom can form a 5- or 6-membered heterocyclic ring optionally containing other heteroatoms, heterocyclic ring the Which may also be optionally further substituted by one or more alkyl groups of 1 to 3 carbon atoms. Re represents alkyl of 1 to 3 carbon atoms with the proviso that when R4 and R5 both represent H, R3 can not represent methyl, ethyl, n-propyl, isopropyl, cyclopropyl, CH (OH) CH3, alkoxy of 1 to 3. carbon atoms. and salts and solvatof-T thereof, in particular, solvates and physiologically acceptable salts thereof.

5. A compound according to claims 1-4, characterized in that it exhibits little or no agonist activity in the A3 receptor.

6. A compound according to claims 1-5, characterized in that the heterocyclic groups containing W, Y and X include isoxazoles, oxadiazoles, pyrazoles, oxazoles, triazoles, thiadiazoles.

7. A compound according to claims 1-6, characterized in that the heterocyclic groups containing W, Y and X are isoxazoles, and 1,2,4- and 1,3,4-oxadiazoles.

8. A compound according to claims 1-7, characterized in that R 2 represents hydrogen, methyl, methoxy or halogen, more preferably hydrogen or chlorine.

9. A compound according to claims 1-8, characterized in that R1 can represent (alk) n-cycloalkyl of 3 to 6 carbon atoms wherein n is 0 or 1 and the cycloalkyl is substituted by at least one substituent selected from halogen, particularly fluorine, and OH or is unsubstituted and n is zero.

10. A compound according to claim 9, characterized in that the cycloalkyl group is unsubstituted or monosubstituted with OH.

11. A compound according to claim 10, characterized in that the cycloalkyl group is 5 members.

12. A compound according to claims 1-8, characterized in that R1 can represent a heterocyclic group, aliphatic, substituted or unsubstituted, the substituent is selected from the group consisting of -C02-alkyl of 1 to 4 carbon atoms.

13. A compound according to claim 12, characterized in that the heterocyclic, aliphatic group is unsubstituted or when the substituent is -C02-alkyl of 1 to 4 carbon atoms, the heteroatom is N and the substituent is directly attached to the nitrogen atom From the ring.

14. A compound according to claim 12-13, characterized in that the heterocyclic ring is 6 members.

15. A compound according to claim 14, characterized in that the heterocyclic ring contains only one heteroatom of O, N or S.

16. A compound according to claims 1-8, characterized in that R1 can represent a straight or branched alkyl of 1-6 carbon atoms optionally with at least one S (= 0) n and / or N substituted on the chain; where there is an S (= 0) n in the The chain, preferably n is 1 or 2 and is unsubstituted or substituted by at least one OH group.

17. A compound according to claims 1-8, characterized in that R1 can 25 represent a phenyl group which is substituted by «G.t a > a .. j ~.? - J - it -a .. ^ JgSStÉ lh *** ¿¡¡i? S¡. one or two substituents selected from OH, alkyl, particularly alkyl of 1 to 4 carbon atoms and halogen.

18. A compound according to claim 17, characterized in that the phenyl is substituted in the 2,4-positions.

19. A compound according to claims 16 and 17, characterized in that both substituents are halogen.

20. A compound according to any of the preceding claims, characterized in that R4 and R5 both represent hydrogen.

21. A compound selected from: (2S, 3S, 4R, 5R) -2- (5-tert-Butyl- [1,3,4] oxadiazol-2-yl) -5- [6- (tetrahydro-pyran-4-) ilamino) -purin-9-yl] -tetrahydrofuran-3,4-diol; Ethyl ester of 4- acid. { 9- [5S- (5-tert-butyl- [1,3,4] oxadiazol-2-yl) -3R, 4S-dihydroxy-tetrahydro-furan-2R-1] -9H-purin-6-ylamino} -piperidine-1-carboxylic acid; (2S, 3S, 4R, 5R) -2- (5- I sopropi lt [1, 3, 4] oxadiazol-2-yl) -5- [6- (tetrahydro-pyran-4-ylphino) -purin-9- -yl] - tetrahydro-furan-3,4-diol; Ethyl ester of 4- acid. { 9- [5S- (5-cyclopropyl- [1,3,4] oxadiazol-2-yl) -3R, 4S-dihydroxy-tetrahydro-furan-2R-yl] -9H-purin-6-ylamino} -piperidine-1-carboxylic acid; (2S, 3S, 4R, 5R) -2- (5-tert-Butyl- [1,3,] oxadiazol-2-yl) -5- [6- (4-chloro-2-fluoro-phenylamino) -purin -9-yl] -tetrahydro-furan-3, 4-diol; (2S, 3S, 4R, 5R) -2- (5-Ethyl-oxazol-2-yl) -5- [6- (tetrahydro-pyran-4-ylamino) -purin-9-yl] -tetrahydro-furan- 3, 4-diol; (2S, 3S, 4R, 5R) -2- (3-Cyclopropyl- [1,2,4] oxadiazol-5-yl) -5- [6- (2S-hydroxy-cyclopent- (S) -ylamino) - purin-9-yl] -tetrahydro-furan-3, -diol; (2S, 3S, 4R, 5R) -2- (3-tert-Butyl- [1,2,4] oxadiazol-5-yl) -5- [6- (2S-hydroxy-cyclopent- (S) -ylamino ) -purin-9-yl] -tetrahydro-furan-3, -diol; (2S, 3S, 4R, 5R) -2- (3-Cyclopropyl- [1,2,4] oxadiazol-5-yl) -5- [6- (tetrahydro-pyran-4-ylamino) -purin-9- il] -tetrahydro-furan-3, 4-diol; (2S, 3S, 4R, 5R) -2- (3-tert-Butyl-isoxazol-5-yl) -5- [6- (tetrahydro-pyran-4-ylamino) -purin-9-yl] -tetrahydro- furan-3, 4-diol; -? r, 4- ( {9- [(2R, 3R, 4S, 5S) -3,4-Dihydroxy-5- (3-methyl-1,2,4-oxadiazol-5-yl) tetrahydrofuran- 2-yl] -9H-purin-6-yl.} Amino) piperidine-1-carboxylic acid ethyl ester; (2S, 3S, 4R, 5R) -2- [3- (tert-Butyl) -1,2,4-oxadiazol-5-yl] -5-. { 6- [(cyclopropylmethyl) amino] -9H-purin-9-yl} tetrahydrofuran-3,4-diol; (2S, 3S, 4R, 5R) -2- [3- (tert-Butyl) -1,2,4-oxadiazol-5-yl] -5-. { 6- (isobutylamino) -9H-purin-9-yl] tetrahydrofuran-3, 4-diol; (2R, 3R, 4S, 5S) -2- [6- (Cyclopropylamino) -9H-purin-9-yl] -5- (3-isopropyl-l, 2,4-oxadiazol-5-yl) tetrahydrofuran-3 , 4-diol; 2- ( {9- [(2R, 3R, 4S, 5S) -3,4-Dihydroxy-5- (3-isopropyl-l, 2,4-oxadiazol-5-yl) tetrahydrofuran-2-yl] -9H-purin-6-yl.} Ammo) -N-methylethanesulfonamide; (2R, 3R, 4S, 5S) -2- [6- (3,4-difluoroanilino) -9H-purin-9-yl] -5- (3-isopropyl-1,2,4-oxadiazol-5-yl) ) tetrahydrofuran-3, 4-diol; (2R, 3R, 4S, 5S) -2- [6- (4-Chloro-2-fluoroanilino) -9H-purin-9-yl] -5- (3-cyclopropyl-1,2,4-oxadiazole-5) - il) tetrahydrofuran-3,4-diol; (2S, 3S, 4R, 5R) -2- [5- (tert-butyl) -4H-1,2,4-triazol-3-yl] -5- [6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] tetrahydrofuran-3,4-diol; (2R, 3R, 4S, 5S) -2- [6- (2-Chloro-4-fluoroanilino) -9H-purin-9-yl] -5- (5-isopropyl-4H-1, 2,4-triazole -3-yl) tetrahydrofuran-3,4-diol; (2S, 3S, 4R, 5R) -2- (5-cyclopropyl-1,3,4-oxadiazol-2-yl) -5- [6- (tetrahydro-2H-pyran-4-ylamino) -9H-purin -9-yl] tetrahydrofuran-3,4-diol; (2S, 3S, 4R, 5R) -2- [5- (tert-butyl) -1,3,4-oxadiazol-2-yl] -5- [6- (2-chloro-4-fluoroanilino) -9H -purin-9-yl] tetrahydrofuran-3,4-diol; (2S, 3S, 4R, 5R) -2- [3- (tert-butyl) isoxazol-5-yl] -5-. { 6- [(1,1-dioxidotetrahydro-2H-thiopyran-4-yl) amino] -9H-purin-9-yl} tetrahydrofuran-3,4-diol; 2- [(9- { (2R, 3R, 4S, 5S) -5- [5- (tert-butyl) -1,3,4-oxadiazol-2-yl] -3,4-dihydroxytetrahydrofuran-2 -yl.}. -9H-purin-6-yl) amino] -N-ethylethanesulfonamide; 2- [(9- { (2R, 3R, 4S, 5S) -5- [5- (tert-butyl) -1,3,4-oxadiazol-2-yl] -3,4-dihydroxytetrahydrofuran-2 -yl.}. -9H-purin-6-yl) amino] -N- (3-methylphenyl) ethanesulfonamide; 2- ( {9- [(2R, 3R, 4S, 5S) -3,4-dihydroxy-5- (5-methyl-l, 3-oxazol-2-yl) tetrahydrofuran-2-yl] -9H -purin-6-yl.}. amino) -N-methylethanesulfonamide; (2R, 3R, 4S, 5S) -2- [6- (Cyclopentylamino) -9H-purin-9-yl] -5- [3- (methoxymethyl) -1,2,4-oxadiazol-5-yl] tetrahydrofuran - 3, 4-diol; (2S, 3S, 4R, 5R) -2- (5-ethyl-1,3,4-oxadiazol-2-yl) -5- [6- (isopropylamino) -9H-purin-9-yl] tetrahydrofuran-3 4-diol; (2R, 3R, 4S, 5S) -2- (6-. {[[(1S, 2S) -2-hydroxycyclopentyl] amino] -9H-purin-9-yl] -5- (5-methyl-) 1,3,4-oxadiazol-2-yl) tetrahydrofuran-3,4-diol; (2R, 3R, 4S, 5S) -2-. {2-chloro-6- [(1-ethylpropyl) amino) formate ] -9H-purin-9-yl.}. -5- (3-cyclopropyl-l, 2,4-oxadiazol-5-yl) tetrahydrofuran-3,4-diol (1: 2); diformate of (2R, 3R, 4S, 5S) -2- [2-chloro-6- (1-ethyl-propylamino) -purin-9-yl] -5- (3-cyclopropyl- [1,2,4] oxadiazol-5-yl) ) -tetrahydro-furan-3, 4-diol; (2S, 3S, 4R, 5R) -2- (3-ethylisoxazol-5-yl) -5- [6- (tetrahydro-2H-pyran-4-ylamino) -9H-purin-9-yl] tetrahydrofuran-3,4-diol; (2S, 3S, 4R, 5R) -2- (3-ethylisoxazol-5-yl) -5- (6- { [(LS , 2S) -2-hydroxycyclopentyl] amino.}. -9H-purin-9-yl) tetrahydrofuran-3,4-diol; 4- (. {9- [(2R, 3R, 4S, 5S) -5- (3-Ethylisoxazol-5-yl) -3,4-dihydroxytetrahydrofuran-2-yl] -9H-purin-6-yl} amino] piperidine-1-carboxylic acid ethyl ester (2R, 3S, 4R, 5R) -2- [5- (tert-butyl) -4H-1, 2,4-triazol-3-yl] -5- [6- (tetrahydro-2H-pi ran-4-ylamino) -9H-purin-9-yl] tetrahydrofuran-3,4-diol; .t sC sjba: ^ ¡^ jpfr ^ .z (2R, 3S, 4R, 5R) -2- (5-isopropyl-4H-1,2,4-triazol-3-yl) -5- [6- ( tetrahydro-2H-pyran-4-ylamino) -9H-purin-9-yl] tetrahydrofuran-3,4-diol; (2R, 3R, 4S, 5S) -2- [2-chloro-6- (2-chloro-4-fluoroanilino) -9H-purin-9-yl] -5- (5-methyl-l, 3-oxazole -2-yl) tetrahydrofuran-3,4-diol; (2R, 3R, 4S, 5S) -2- [6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] -5- (3-methylisoxazol-5-yl) tetrahydrofuran-3, 4 -diol; (2R, 3R, 4S, 5S) -2- [6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] -5- (3-propylisoxazol-5-yl) tetrahydrofuran-3, 4 -diol; (2R, 3R, 4S, 5S) -2- [2-chloro-6- (tetrahydro-2H-pyran-4-ylamino) -9H-purin-9-yl] -5- (3-ethylisoxazole-5-yl) ) tetrahydrofuran-3, -diol; 4- ( { 2-chloro-9- [(2R, 3R, 4S, 5S) -5- (3-ethylisoxazol-5-yl) -3,4-dihydroxytetrahydrofuran-2-yl] -9H-purin- 6-yl.} Amino) piperidine-1-carboxylic acid ethyl ester; (2R, 3R, 4S, 5S) -2- (2-chloro-6-. {[[(1S, 2S) -2-hydroxycyclopentyl] amino] -9H-purin-9-yl] -5- ( 3- ethylisoxazol-5-yl) tetrahydrofuran-3,4-diol; (2R, 3R, 4S, 5S) -2- (2-chloro-6- { [2- (ethylsulfonyl) ethyl] amino}. -9H-purin-9-yl] -5- (3-ethylisoxazol-5-yl) tetrahydrofuran-3,4-diol; (2R, 3R, 4S, 5S) -2- [2-chloro-6- (4 -chloro-2-fluoroanilino) -9H-purin-9-yl] -5- (3-ethylisoxazol-5-yl) tetrahydrofuran-3, 4-diol; (2R, 3R, S, 5S) -2- [2-chloro-6- (2-chloro-4-fluoroanilino) -9H-purin-9-yl] -5- (3-ethylisoxazol-5-yl) tetrahydrofuran -3, -diol; (2R, 3R, 4S, 5S) -2- [2-chloro-6- (2-fluoroanilino) -9H-purin-9-yl] -5- (3-ethylisoxazol-5-yl) tetrahydrofuran-3, 4 -diol; (2R, 3R, 4S, 5S) -2- [2-chloro-6- (2-chloroanilino) -9H-purin-9-yl] -5- (3-ethylisoxazol-5-yl) tetrahydrofuran-3, 4 -diol; (2R, 3R, 4S, 5S) -2- (6-. {[[(SS, 2S) -2- hydroxycyclopentyl] amino] -9H-purin-9-yl] -5- [3- (hydroxymethyl) isoxazol-5-yl] tetrahydrofuran-3, -diol; 4- [(9-. {(2R, 3R, 4S, 5S) -3,4-dihydroxy-5- [3- (hydroxylaethyl) isoxazole-5 -yl] tetrahydrofuran-2-yl.} - 9H-purin-6-yl) amino] piperidine-1-carboxylic acid ethyl ester (2R, 3S, 4R, 5R) -2- [3- (hydroxymethyl) isoxazole- 5-yl] -5- [6- (tetrahydro-2H-pyran-4-ylamino) -9H-purin-9-yl] tetrahydrofuran-3,4-diol; (2R, 3R, 4S, 5S) -2- [6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] -5- (3-ethylisoxazol-5-yl) tetrahydrofuran-3,4-diol; (2R, 3R, 4S, 5S) -2- [6- (2-C-gold-4-fluoroanilino) -9H-purin-9-yl] -5- (3-ethylisoxazol-5-yl) tetrahydrofuran-3,4-diol; (2S, 3S, 4R, 5R) -2- (3-ethylisoxazol-5-yl) -5- [6- (2-fluoroanilino) -9H-purin-9-yl] tetrahydrofuran-3,4-diol; (2R, 3R, 4S , 5S) -2- [6- (2-chloroanilino) -9H-purin-9-yl] -5- (3-ethylisoxazol-5-yl) tetrahydrofuran-3,4-diol; (2S, 3S, 4R, 5R) -2- [5-tert-butyl] -l 3f 4-oxadiazol-2-yl] -5- [6- (piperidin-4-ylamino) -9H4frarin-9-yl] tetrahydrofuran- 3, 4-diol; formate (2R, 3R, 4S, 5R) -2-. { 2-chloro-6- [(1-ethylpropi1) amino] -9H-purin-9-yl} -5- (5-ethylisoxazole-3-11) tetrahydrofuran-3,4-diol; (2S, 3S, 4R, 5R) -2- (3-bromoisoxazol-5-yl) -5- [6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] tetrahydrofuran-3, diol . (2S, 3S, 4R, 5R) -2- (3-bromoisoxazol-5-yl) -5- [6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] tetrahydrofuran-3, 4 -diol, (2S, 3S, 4R, 5R) -2- [3-tert-butyl) isoxazol-5-yl] -5- (6-. {[[(1-propylsulfonyl) piperidin-4-yl] amino}. -9H-purin-9-yl) tetrahydrofuran-3,4-diol; (2S, 3S, 4R, 5R) -2- [3-tert-butyl) isoxazol-5-yl] -5- (6- { [(1- (isopropylsulfoniyl) piperidin-4-yl] amino.} .9H-purin-9-yl) tetrahydrofuran-3,4-diol; (2S, 3S, 4R, 5R) -2- [3-tert-butyl) isoxazol-5-yl] -5- (6- { [(1- (ethylsulfonyl) piperidin-4-yl] amino.} -9H-pupn-9-? L) -tetrahydrofuran-3,4-diol; (2S, 3S, 4R, 5R) -2- [3-tert-butyl) isoxazol-5-yl] -5- (2-chloro-6- (4-chloro-2-fluoroanilino) -9H-purin-9 -yl) tetrahydrofuran-3,4-diol; 2S, 3S, 4R, 5R) -2- [3-tert-butyl) isoxazol-5-yl] -5- (2-chloro-6- (2-chloro-4-fluoroanilino) -9H-purin-9- il) tetrahydrofuran-3, -d? ol; 2- [(9- ((2R, 3R, 4S, 5S) -5- [3-tert-butyl] isoxazol-5-yl] -3,4-dihydroxytetrahydrofuran-2-y1.} -2-chloro- 9H-purin-6-yl) ammo] -N-ethyletansulkfonamide; - > ASZJ sr * 5 * "-. 2- [(9- ((2R, 3R, 4S, 5S) -5- [3- (tert-butyl) isoxazol-5-yl] -3,4-dihydroxytetrahydrofuran-2-yl} -2-chloro -9H-purin-6-yl) amino] -N-isopropyletanesulfonamide; (2S, 3S, 4R, 5R) -2- [3- (tert-butyl) isoxazol-5-yl] -5- [2-chloro- 6- (tetrahydro-2H-pyran-4-ylamino) -9H-purin-9-yl] tetrahydrofuran-3, -diol; (2S, 3R, 4S, 5S) -2- [6- (4-chloro-2 -fluoroanilino) -9H-purin-9-yl] -5- (3-pyridin-3-ylisoxazol-5-yl) -tetrahydrofuran-3,4-diol; (2S, 3R, 4S, 5S) -2- [ 6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] -5- [3- (4-hydroxybutyl) isoxazol-5-yl) -tetrahydrofuran-3,4-diol; 2- [(9- ((2R, 3R, 4S, 5S) -5- [3- (tert-butyl) isoxazol-5-yl] -3, -dihydroxytetrahydrofuran-2-yl.} -9H-purin- 6-yl) amino] -N-ethylethanesulfonamide; (2S, 3R, 4S, 5S) -2- [6- (cyclopentylamino) -9H-purin-9-yl] -5- [5- (trifluoromethyl) -1, 3, 4-oxadiazol-2-yl] -tetrahydrofuran-3,4-diol; (2S, 3R, 4S, 5S) -2- (6- { [(1S, 2S) -2-hydroxycyclopentyl] amino) -9H-purin-9-yl] -5- [5- (trifluoromethyl) -1,4,4-oxadiazol-2-yl] -tetrahydrofuran-3,4-diol; ^^^^^^ tój ^^^^^^^^^^^^^^^^^^^^^. ^^ g ^ ^ 4- [(9- { (2S, 3R, 4S, 5S) -3,4-dihydroxy-5- [5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl] -tetrahydrofuran-2-yl.}. -TH-purin-d-yl) amino] piperidine-1-carboxylic acid ethyl ester; (2S, 3R, 4S, 5S) -2- [6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] -5- (5-methyl-1,3,4-oxadiazole-2) -yl) -tetrahydrofuran-3,4-diol; (2S, 3R, 4S, 5S) -2- [6- (4-chloro-2-fluoroanilino) -9H-purm-9-yl] -5- (3-cyclopropylisoxazol-5-yl) -tetrahydrofuran-3, 4-diol; (2S, 3R, 4S, 5S) -2- [3- (tert-butyl) isoxazol-5-yl] -5-. { 6- [(1-Butylpiperidin-4-yl) amino] -9H-purin-9-yl} -tetrahydrofuran-3,4-diol; 4- [(9-. {(2S, 3R, 4S, 5S) -5- [3- (tert-butyl) isoxazol-5-yl] -3,4-dihydroxytetrahydrofuran-2-yl.} -9H -purin-6-yl) amino] piperidine-1-carboxylic acid isopropyl ester; (2S, 3R, 4S, 5S) -2- [3- (tert-butyl) isoxazol-5-yl] -5- (6- { [1- (2,2, 2-trifluoroacetyl) piperidin-4 -yl] amino.}. -9H-purin-9-yl) -tetrahydrofuran-3,4-diol; 4- [(9-. {(2S, 3R, 4S, 5S) -5- [3- (tert-butyl) isoxazol-5-yl] -3,4-dihydroxytetrahydrofuran-2-yl.} -9H methyl -purin-6-yl) amino] piperidine-1-carboxylate; (2S, 3R, 4S, 5S) -2- [6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] -5- [hydroxymethyl) isoxazol-5-yl) -tetrahydrofuran-3, 4-diol; 5 (2S, 3R, 4S, 5S) -2- [6- (2-Chloro-4-fluoroanilino) -9H-purin-9-yl] -5- [3- (hydroxymethyl) isoxazol-5-yl) - tetrahydrofuran-3, 4-diol; (2S, 3R, 4S, 5S) -2- [6- (2-fluoroanilino) -9H-purin-9-yl] -5- [3- (hydroxymethyl) isoxazol-5-yl) -tetrahydrofuran-3, 4 -diol; 10 (2S, 3R, 4S, 5S) -2- (2-chloro-6-. {[[(LS, 2S) -2- hydroxycyclopentyl] amino) -9H-purin-9-yl] -5- [3 - (hydroxymethyl) isoxazol-5-yl) -tetrahydrofuran-3,4-diol; (2S, 3R, 4S, 5S) -2- [2-chloro-6- (tetrahydro-2H-pyran-4-ylamino) -9H-purin-9-yl] -5- [3- (hydroxymethyl) isoxazole- 5-yl] -15-tetrahydrofuran-3,4-diol; 2- [(2-chloro-9-. {(2R, 3R, 4S, 5S) -3,4-dihydroxy-5- [3- (hydroxymethyl) isoxazol-5-yl] tetrahydrofuran-2-yl} .9H-purin-6-yl) amino] -N-ethylethanesulfonamide; 20 4- [(2-chloro-9-. {(2R, 3R, 4S, 5S) -3,4-dihydroxy-5- [3- (hydroxymethyl) isoxazol-5-yl] tetrahydrofuran-2-yl} -9H-purin-6-yl) amino] piperidine-1-carboxylic acid ethyl ester; ^^ tot ^^^^^ ^^ ia ^^^^^ & ^ i (2S, 3R, 4S, 5S) -2- [2-chloro-6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] -5- [3- (hydroxymethyl) isoxazol-5-yl] -tetrahydrofuran-3,4-diol; (2S, 3R, 4S, 5S) -2- [2-chloro-6- (2-chloro-4-fluoroanilino) -9H-purin-9-yl] -5- [3- (hydroxymethyl) isoxazole-5- il] -tetrahydrofuran-3,4-diol; (2S, 3R, 4S, 5S) -2- [2-chloro-6- (2-fluoroanilino) -9H-purin-9-yl] -5- [3- (hydroxymethyl) isoxazol-5-yl] -tetrahydrofuran -3,4-diol; (2S, 3R, S, 5S) -2- (3-Ethylisoxazol-5-yl) -5- [2-methoxy-6- (tetrahydro-2H-pyran-4-ylamino) -9H-purin-9-yl ] -tetrahydrofuran-3,4-diol; 4- ( {9- [(2S, 3R, 4S, 5S) -5- [3-ethylisoxazol-5-yl] -3,4-dihydroxytetrahydrofuran-2-yl] -2-methoxy-9H-purin- 6-yl.} Amino] piperidine-1-carboxylic acid ethyl ester; (2S, 3R, 4S, 5S) -2- (3-ethylisoxazol-5-yl) -5- (6- { [(SS, 2S) -2-hydroxycyclopentyl] amino.} -2-methoxy- 9H-purin-9-yl) -tetrahydrofuran-3,4-diol; (2S, 3R, 4S, 5S) -2- (3-ethylisoxazol-5-yl) -5- (6- { [2- (ethylsulfonyl) ethyl] amino.} -2-methoxy-9H-purin -9-yl) -tetrahydrofuran-3,4-diol; (2S, 3R, 4S, 5S) -2- [6- (2-Chloro-4-fluoroanilino) -2-methoxy-9H-purin-9-yl] -5- (3-ethylisoxazol-5-yl) tetrahydrofuran -3,4-diol; (2S, 3R, 4S, 5S) -2- (3-Ethylisoxazol-5-yl) -5- [6- (2-fluoroanilino) -2-methoxy-9H-purin-9-yl) -tetrahydrofuran-3, 4-diol; (2S, 3R, 4S, 5S) -2- [6- (4-Chloro-2-fluoroanilino) -2-methoxy-9H-purin-9-yl] -5- (3-ethylisoxazol-5-yl) - tetrahydrofuran-3,4-diol; (2S, 3R, 4S, 5S) -2- [3- (tert-butyl) -1,2,4-oxadiazol-5-yl] -5- [6- (cyclopropylamino) -9H-purin-9-yl ] -tetrahydrofuran-3,4-diol; (2S, 3R, 4S, 5S) -2- [5- (tert-butyl) -1, 3, 4-oxadiazol-2-yl] -5- [2-chloro-6- (4-chloro-2- fluoroanilino) -9H-purin-9-yl] -tetrahydrofuran-3,4-diol; (2S, 3R, 4S, 5S) -2- [6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] -5- (5-isopropyl-1,3,4-oxadiazole-2) -yl) tetrahydrofuran-3,4-diol; ^^? ^^^. ^^^^^^^^^^^. ^ ftBá,

22. a pharmaceutical composition characterized in that it comprises the compounds of claims 1-21 in conjunction with a pharmaceutically-acceptable diluent or carrier > tabl < = -

23. Use of a compound according to claims 1-21 for the preparation of a medicament for the patient suffering from a condition where there is an advantage in decreasing the concentration of free fatty acids in the plasma, or reducing the rate or that the subject is suffering from or is susceptible to ischemic heart disease, peripheral vascular disease or stroke or that the subject is suffering from pain, a CNS disorder or sleep apnea.

24. A method for treating a patient suffering from a condition where there is an advantage in 1 decreasing the concentration of free fatty acids in the plasma, or reducing the cardiac rate or that the subject is suffering from or is susceptible to ischemic disease of the heart, peripheral vascular disease or stroke or that the subject is suffering from pain, CNS disorder or sleep apnea, characterized in that it comprises the administration of an effective therapeutic amount of a splinter in accordance with claims 1-21 . ¡^ ^ ^ ^ ^ ^ ^ ^^^^^. ^ ^ ^ ^ ^. & * ¡¡¡¡¡¡¡¡¡= ítiai A compound of the formula (I which is an agonist at the adenosine Al receptor R1 where Y, Z and W represent heteroatoria, And salts and solvates thereof, in particular, solvates and physiologically acceptable salts thereof for use in therapy.