AU2002323990B2 - Adenosine derivatives - Google Patents

Description

AUSTRALIA

PATENTS ACT 1990 DIVISIONAL APPLICATION NAME OF APPLICANT: Glaxo Group Limited ADDRESS FOR SERVICE: DAVIES COLLISON CAVE Patent Attorneys 1 Little Collins Street Melbourne, 3000.

INVENTION TITLE: "Adenosine derivatives" The following statement is a full description of this invention, including the best method of performing it known to us: ADENOSINE DERIVATIVES This is a divisional of Australian patent application No. 45146/99, the entire contents of which are incorporated herein by reference.

The present invention relates to novel adenosine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.

Publications in this area include WO 98/16539 (Novo Nordisk A/S) which describes adenosine derivatives for the treatment of myocardial and cerebral ischaemia and epilepsy; WO 98/04126 (Rhone-Poulenc Rorer Pharmaceuticals Inc.) which relates to adenosine derivatives possessing antihypertensive, cardioprotective, anti-ischaemic and antilipolytic properties; and WO 98/01459 (Novo Nordisk A/S) which describes N,9-disubstituted adenine derivatives which are substituted in the 4' position by unsubstituted oxazolyl or isoxazolyl and the use of such compounds for the treatment of disorders involving cytokines in humans.

Thus the invention provides a compound of formula which is an agonist at the adenosine Al receptor

R

1

NH

N N

(I)

z R3 RW

OR

wherein X represents 0 or CH 2

R

2 represents C 1 .alkyl, Cl.

3 alkoxy, halogen or hydrogen; 2

R

3 represents H, phenyl (optionally substituted by halogen), a 5 or 6 membered heteroaryl group, CI- alkoxy, Ci-6 alkylO(CH 2 )n where n is 0-6, C-7 cycloalkyl, CI-6 hydroxyalkyl, halogen or a CI- straight or branched alkyl, C 1 .e alkenyl or C1.

6alkynyl group optionally substituted by one or more halogens.

Y and Z represent O, N, CH, N(C.e 6 alkyl) W represents CH, O, N, S, N(Ci.

6 alkyl) 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, R 3 cannot be H.

R

4 and R 5 independently represent H or a -Ci- straight chain or branched alkyl group.

R' represents hydrogen or a group selected from -(alk)n (C3-7) cycloalkyl, including bridged cycloalkyl, said cycloalkyl group optionally substituted by one or more substituents selected from OH, halogen, (C1-3) alkoxy, wherein (alk) represents C1-3 alkylene and n represents 0 or 1.

an aliphatic heterocyclic group of 4 to 6 membered rings containing at least one heteroatom selected from O, N or S, optionally substituted by one or more substituents selected from the group consisting of -(C 1 3 )alkyl, -C0 2 -(Ci4)alkyl,

CO(C

1 3 alkyl), 1 .3alkyl), -CONRaRb (wherein Ra and Rb independently represent H or C 1 3 alkyl) or where there is a sulfur atom in the heterocyclic ring, said sulfur is optionally substituted by where n is 1 or 2.

Straight or branched C1.12 alkyl, optionally including one or more O, S(=O)n (where n is 0, 1 or 2) and N groups substituted within the alkyl chain, said alkyl optionally substituted by one or more of the following groups, phenyl, halogen, hydroxy, C3-7 cycloalkyl or NRaRb wherein Ra and Rb independently represent hydrogen, C3.7 cycloalkyl or a C1.e straight chain or branched alkyl optionally substituted by C3.7 cycloalkyl; a fused bicyclic aromatic ring AI B wherein B represents a 5 or 6 membered heterocyclic aromatic group containing 1 or more O, N or S atoms, wherein the bicyclic ring is attached to the nitrogen atom of formula via a ring atom of ring A and ring B is optionally substituted by -C02 3 alkyl).

a phenyl group optionally substituted by one or more substituents selected from: -halogen, -SO 3 H, -(alk)nOH, -(alk)n -cyano, -(C1.

6 )alkyl (optionally substituted by one or more halogens), (alk)n -nitro, -(alk)n- CO 2

RC,

-(alkn)- CONRCR d -(alk)n -COR c -(alk)n -SORe, -(alk)n -S02R e -(alk)n-

SO

2

NRCR

d -(alk)nORc, -(alk)n NHSO 2

R

e -(alk)n- NHCORc, -(alk)n- NRCRd wherein m and n are 0 or 1 and alk represents a C-.

6 alkylene group or C2.

6 alkenyl group.

116) A phenyl group substituted by a 5 or 6 membered heterocyclic aromatic group, said heterocyclic aromatic group optionally being substituted by C1.

3 alkyl or NRRd.

RC and Rd may each independently represent hydrogen, or C1.3 alkyl or when part of a group NRCR d Rc and Rd together with the nitrogen atom may form a or 6 membered heterocyclic ring optionally containing other heteroatoms, which heterocyclic ring may optionally be substituted further by one or more C1-3 alkyl groups.

Re represents Cl.

3 alkyl and salts and solvates thereof, in particular, physiologically acceptable solvates and salts thereof for use in therapy.

Preferably the compound is of formula (la)

R

I

NH

R

3 "W R'O OR' wherein X represents O or CH2;

R

2 represents C13alkyl, C1.

3 alkoxy, halogen'or hydrogen;

R

3 represents H, phenyl (optionally substituted by halogen), a 5 or 6 membered heteroaryl group, C1-6 alkoxy, CI- straight or branched alkyl optionally substituted by one or more halogens, C3- 7 cycloalkyl, C1.6 hydroxyalkyl 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 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, R 3 cannot be H.

R

4 and R 5 independently represent H or a Ci-6 straight chain or branched alkyl group.

R

1 represents a group selected from -(alk)n (C3- 7 cycloalkyl, including bridged cycloalkyl, said cycloalkyl group optionally substituted by one or more substituents selected from OH, halogen,

(CI.

3 alkoxy, wherein (alk) represents C1.3 alkylene and n represents 0 or 1.

an aliphatic heterocyclic group of 4 to 6 membered rings containing at least one heteroatom selected from O, N or S, optionally substituted by one or more substituents selected from the group consisting of -(Cl.

3 )alkyl, -C0 2 -(C.4)alkyl, CO(Ci.

3 alkyl), 1 3 alkyl), -CONRaRb (wherein Ra and Rb independently represent H or C1.3alkyl) or where there is a sulfur atom in the heterocyclic ring, said sulfur is optionally substituted by where n is 1 or 2.

1(3) Straight or branched C1-12 alkyl, optionally including one or more O, S(=O)n (where n is 0, 1 or 2) and N groups substituted within the alkyl chain, said alkyl optionally substituted by one or more of the following groups, phenyl, halogen, hydroxy, C3.7 cycloalkyl or NRaRb wherein R a and Rb independently represent hydrogen, C 3 7 cycloalkyl or a Cl. straight chain or branched alkyl optionally substituted by C3.7 cycloalkyl; a fused bicyclic aromatic ring wherein B represents a 5 or 6 membered heterocyclic aromatic group containing 1 or more O, N or S atoms, wherein the bicyclic ring is attached to the nitrogen atom of formula via a ring atom of ring A and ring B is optionally substituted by -CO 2

-(C

1 3 alkyl).

a phenyl group optionally substituted by one or more substituents selected from: -halogen, -SO 3 H, -(alk)nOH, -(alk)n -cyano, -(C 1 l 6 )alkyl (optionally substituted by one or more halogens), (alk)n -nitro, -(alk)n- CO 2 Rc, -(alkn)- CONRcRd -(alk)n -COR c -(alk)n -SOR e -(alk)n -SO2R e -(alk)n-

SO

2 NRCRd, -(alk)nOR. -(alk)n NHSO 2 Re, -(alk)n- NHCORc, -(alk)n-

NRCR

d wherein m and n are 0 or 1 and alk represents a C 16 alkylene group or C2.

6 alkenyl group.

A phenyl group substituted by a 5 or 6 membered heterocyclic aromatic group, said heterocyclic aromatic group optionally being substituted by Cv.3alkyl or NRCRd Re and Rd may each independently represent hydrogen, or CI-. alkyl or when part of a group NRCRd, RC and Rd together with the nitrogen atom may form a or 6 membered heterocyclic ring optionally containing other heteroatoms, which heterocyclic ring may optionally be substituted further by one or more C 1 -3 alkyl groups.

Re represents C 1 .3alkyl and salts and solvates thereof, in particular, physiologically acceptable solvates and salts thereof.

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

It will be appreciated that certain compounds embraced by formula are novel per se. A particular group of compounds may be defined by formula (Ib).

Therefore, the invention further provides compounds of formula (Ib) which are agonists at the adenosine Al receptor R1

NH

N N R2 (Ib) R W

R

4 0 OR wherein X represents O or CH2

R

2 represents C1.

3 alkyl, C 1 3 alkoxy, halogen or hydrogen;

R

3 represents H, phenyl (optionally substituted by halogen), a 5 or 6 membered heteroaryl group, Ci.e alkoxy, C1. alkylO(CH 2 )n where n is 0-6, C3-7 cycloalkyl, C.6 hydroxyalkyl, halogen or a C-6 straight or branched alkyl, C-.6 alkenyl or C1.

6 alkynyl group optionally substituted by one or more halogens.

Y and Z represent O, N, CH, N(Ci.

6 alkyl) W represents CH, O, N, S, N(C1 6 alkyl) 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, R 3 cannot be H.

R

4 and R 5 independently represent H or a C1.6 straight chain or branched alkyl group.

R

1 represents hydrogen or a group selected from -(alk)n (C3-7) cycloalkyl, including bridged cycloalkyl, said cycloalkyl group optionally substituted by one or more substituents selected from OH, halogen, alkoxy, wherein (alk) represents C1-3 alkylene and n represents 0 or 1.

an aliphatic heterocyclic group of 4 to 6 membered rings containing at least one heteroatom selected from O, N or S, optionally substituted by one or more substituents selected from the group consisting of -(Cl.

3 )alkyl, -CO 2 -(C-4)alkyl, CO(Ci.

3 alkyl), 1 -3alkyl), -CONRaRb (wherein Ra and Rb independently represent H or C 1 3 alkyl) or where there is a sulfur atom in the heterocyclic ring, said sulfur is optionally substituted by where n is 1 or 2.

3Q3) Straight or branched C1-12 alkyl, optionally including one or more O, S(=O)n (where n is 0, 1 or 2) and N groups substituted within the alkyl chain, said alkyl optionally substituted by one or more of the following groups, phenyl, halogen, hydroxy, C3-.7 cycloalkyl or NRaRb wherein Ra and Rb independently represent hydrogen, C3.7 cycloalkyl or a C 1 6 straight chain or branched alkyl optionally substituted by C 3 7 cycloalkyl; a fused bicyclic aromatic ring wherein B represents a 5 or 6 membered heterocyclic aromatic group containing 1 or more O, N or S atoms, wherein the bicyclic ring is attached to the nitrogen atom of formula via a ring atom of ring A and ring B is optionally substituted by -CO 2 3 alkyl).

10(5) a phenyl group optionally substituted by one or more substituents selected from: -halogen, -SO 3 H, -(alk)nOH, -(alk)n -cyano, -(C 16 )alkyl (optionally substituted by one or more halogens), (alk)n -nitro, -(alk)n- CO 2

R,

-(alkn)- CONRcR d -(alk)n -COR c -(alk)n -SOR e -(alk)n -SO2R e -(alk)n-

SO

2

NRCR

d -(alk)nORc, -(alk)n NHSO 2 Re, -(alk)n- NHCORc, -(alk)n-

NRCR

d wherein m and n are 0 or 1 and alk represents a C 1 6 alkylene group or C2- 6 alkenyl group.

A phenyl group substituted by a 5 or 6 membered heterocyclic aromatic group, said heterocyclic aromatic group optionally being substituted by Ci.

3 alkyl or

NRR

d Rc and R d may each independently represent hydrogen, or C1.3 alkyl or when part of a group NRCRd, Rc and Rd together with the nitrogen atom may form a or 6 membered heterocyclic ring optionally containing other heteroatoms, which heterocyclic ring may optionally be substituted further by one or more Ci-3 alkyl groups.

Re represents C.3alkyl with the proviso that when R 4 and R 5 both represent H, R 2 represents halogen,

R

3 cannot represent methyl, ethyl, n-propyl, isopropyl, cyclopropyl, CH(OH)CH 3 Ci.

3 alkoxy and salts and solvates thereof, in particular, physiologically acceptable solvates and salts thereof.

Preferably, the compound is of formula (Ic):

R

I

NH

N N Y o-z-

R

4 0 OR wherein X represents O or CH 2

R

2 represents C1-3alkyl, C 13 alkoxy, halogen or hydrogen;

R

3 represents H, phenyl (optionally substituted by halogen), a 5 or 6 membered heteroaryl group, C1-6 alkoxy, C1.e straight or branched alkyl optionally substituted by one or more halogens, C 3 -7 cycloalkyl, C.16 hydroxyalkyl or halogen.

Y and Z represent 0, 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 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, R 3 cannot be H.

R

4 and R s independently represent H or a Cil- straight chain or branched alkyl group.

R

1 represents a group selected from -(alk)n (C3-7) cycloalkyl, including bridged cycloalkyl, said cycloalkyl group optionally substituted by one or more substituents selected from OH, halogen,

(C

1 3 alkoxy, wherein (alk) represents Ci.3 alkylene and n represents 0 or 1.

an aliphatic heterocyclic group of 4 to 6 membered rings containing at least one heteroatom selected from O, N or S, optionally substituted by one or more substituents selected from the group consisting of -(Ci.

3 )alkyl, -C0 2 -(C.-4)alkyl, CO(Cl.

3 alkyl), 3 alkyl), -CONRaRb (wherein Ra and Rb independently represent H or C.3alkyl) or where there is a sulfur atom in the heterocyclic ring, said sulfur is optionally substituted by where n is 1 or 2.

1(3) Straight or branched C1-12 alkyl, optionally including one or more O, S(=O)n (where n is 0, 1 or 2) and N groups substituted within the alkyl chain, said alkyl optionally substituted by one or more of the following groups, phenyl, halogen, hydroxy, C3-7 cycloalkyl or NRaRb wherein Ra and R b independently represent hydrogen, C3-7 cycloalkyl or a C.-6 straight chain or branched alkyl optionally substituted by C3.7 cycloalkyl; a fused bicyclic aromatic ring Aj B wherein B represents a 5 or 6 membered heterocyclic aromatic group containing 1 or more O, N or S atoms, wherein the bicyclic ring is attached to the nitrogen atom of formula via a ring atom of ring A and ring B is optionally substituted by -CO2 3 alkyl).

a phenyl group optionally substituted by one or more substituents selected from: -halogen, -SO 3 H, -(alk)nOH, -(alk)n -cyano, -(Cl.

6 )alkyl (optionally substituted by one or more halogens), (alk)n -nitro, -(alk)n- CO 2

R

C

-(alkn)- CONRcR -(alk)n -COR c -(alk)n -SOR e -(alk)n -S02R e -(alk)n-

SO

2 NRCRd, -(alk)nORc, -(alk)n NHSO2R e -(alk)n- NHC'OR, -(alk)n- NRCRd wherein m and n are 0 or 1 and alk represents a C 1 6alkylene group or C 2 6 alkenyl group.

A phenyl group substituted by a 5 or 6 membered heterocyclic aromatic group, said heterocyclic aromatic group optionally being substituted by CI.3alkyl or NRCRd.

Rc and Rd may each independently represent hydrogen, or C.-3 alkyl or when part of a group NRCRd, Rc and R" together with the nitrogen atom may form a or 6 membered heterocyclic ring optionally containing other heteroatoms, which heterocyclic ring may optionally be substituted further by one or more C1- 3 alkyl groups.

Re represents Cl.

3 alkyl with the proviso that when R 4 and R 5 both represent H, R 2 represents halogen,

R

3 cannot represent methyl, ethyl, n-propyl, isopropyl, cyclopropyl, CH(OH)CH 3

C

13 alkoxy and salts and solvates thereof, in particular, physiologically acceptable solvates and salts thereof.

Conveniently the adenosine Al agonists of the general formula above exhibit greater activity at the adenosine Al receptor than the other adenosine receptor subtypes, particularly A3. More particularly the compounds exhibit little or no agonist activity at the the A3 receptor.

It will be appreciated that wherein R' and/or R 2 in compounds of formula (I) contain one or more asymmetric carbon atoms the invention includes all diastereoisomers of compounds of formula and mixtures thereof. Otherwise the stereochemical configuration of compounds of the invention is as depicted in formula above.

As used herein, the term "alkyl" means a straight or branched chain alkyl group.

Examples of suitable alkyl groups within R 1 and R 2 include methyl, ethyl, npropyl, 1-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, e.g. methylene.

As used herein, the term "C2-6alkenyl" means a straight or branched chain alkenyl group containing 2 to 6 carbon atoms. Allyl represents an example of a suitable C 2 6 alkenyl group.

The term "halogen" means fluorine, chlorine, bromine or iodine.

By aliphatic heterocyclic group defined for R' is meant a cyclic group of 4-6 carbon atoms wherein one or more of the carbon atoms is/are replaced by heteroatoms independently selected from nitrogen, oxygen or sulfur. This group may optionally be substituted as defined hereinabove.

The term heterocyclic aromatic group defined for R' refers to an aromatic mono or bicyclic ring system comprising from 5 to 10 carbon atoms wherein one or more of the carbon atoms is/are replaced by heteroatoms independently selected from nitrogen, oxygen and sulfur, which ring system may optionally be substituted as defined hereinabove.

Pharmaceutically acceptable salts of the compounds of formula include those derived from pharmaceutically acceptable inorganic and organic acids.

Examples of suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toluene-p-sulphonic, tartaric, acetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic and benzenesulphonic acids. A particularly suitable pharmaceutically acceptable salt of the compounds of formula is the hydrochloride salt. Other acids such as oxalic, while not, in themselves pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. The solvates may 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 1,2,4and 1,3,4- oxadiazoles.

R

2 preferably represents hydrogen, methyl, methoxy or halogen, more preferably hydrogen or chlorine.

Conveniently, R 1 may represent (alk)n- C3-6 cycloalkyl wherein n is 0 or 1 and the said 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. Most preferably, the cycloalkyl group is hydroxycyclopentyl.

Alternatively R 1 may represent a substituted or unsubstituted aliphatic heterocyclic group, the substitutent being selected from the group consisting of

-CO

2 -(CI.4)alkyl.

Conveniently, the aliphatic heterocyclic group is unsubstituted or when the substituent is -C0 2

(C

14 )alkyl, the heteroatom is N and the substituent is directly attached to said ring nitrogen atom.

Preferably the heterocyclic ring is 6 membered and more preferably contains only one 0, N or S heteroatom. Most preferably when the heterocyclic ring is unsubstituted the heteroatom is O. Most preferably when the heterocyclic ring is substituted the heteroatom is N.

Alternatively, R 1 may represent a straight or branched alkyl of 1-6 carbon atoms optionally with at least one S(=O)n and where S(=O)n is present, optionally substituted with N at a position adjacent to the S(=O)n group; where there is an S(=O)n in the chain, substitution with N at a position adjacent to the S(=O)n group is Preferred; where there is an S(=O)n in the chain, preferably n is 1 or 2, more preferably n is 2. The alkyl group conveniently may be uns'ubstituted 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 C1-4 alkyl and halogen.

Preferably the phenyl is disubstituted in the 2,4 positions. Preferably both substituents are halogen more particularly, fluorine and chlorine. For example, a particularly preferred combination is 2-fluoro and 4-chloro.

Preferably R 4 and R 5 represent hydrogen.

It is to be understood that the present invention covers all combinations of particular and preferred groups mentioned above.

Particular novel compounds include compounds of Examples 1-207 herein below.

Preferred compounds include: (2S ,3S ,4 R,5R}-2-(5-tert-B utyl-[1.3 ,4]oxad iazol-2-yl )-5-[6-(tetrahydro-pyra n4ylamino)-pu rin-9-yl]-tetrahydro-furan-3 ,4-d 101; 4-{g-[5S-(5-tert-Butyl-[ 1 3,4]oxad iazoI-2-yl )-3R,4 S-d i hyd roxy-tetra hyd ro-fu ran- 2R-yIj-9H-purin-6-ylamino}-pipendine~ I-carboxylic-acid ethyl ester; (2S ,3S,4R,5R)-2-(5-sopropy-[1 ,3 .4]oxadiazol-2-yl )-5-[6-(tetrahydro-pyran-4ylamino)-purin-9-yl]-tetrahyd ro-fura n-3 ,4-d 101; 4-{9-[5S-(5-Cyclopropyl-[1 ,3,4loxad iazol-2-yl R,4S-dihyd roxy-tetrahyd ro-furan- 2R-yl]-9H-purin-6-ylamino}-piperidine-1 -carboxylic acid ethyl ester; (2S,3S,4R,5R)-2-(5-tert-Butyl-[1 ,3,4Joxadiazol-2-yI)-5-[6-(4-chloro-2-fluorophenylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol; ,3S ,4R,5R)-2-(5-Ethyl-oxazol-2-y )5-[6-(tetra hydro-pyran-4-ylamino)-purin-9yiJ-tetrahydro-furan-3,4-dioli (2S .3S,4R.5R)-2-(3-Cyclopropyl-[ 1,2 ,4]oxadiazol-5-yI)-5-[6-(2S-hydroxycyclopent-(S )-ylamino)-pu rin-9-yI]-tetrahydro-fu ran-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.4 R,5R)-2-(3-Cyclopropyf ,2,4joxadiazol-5-yI)-5-[6-(tetrahydro-pyra n-4ylamino)-purin-9-ylJ-tetrahydro-furan-3,4-diol; (2S ,3S ,4R, 5R)-2-(3-tert-Butyl-isoxazol-5-yI)-5-[6-(tetrahydro-pyran-4-ylamino)punn-9-yIj-tetrahydro-furan-3,4-diol; ethyl 4-({9-[(2R,3R,4S ,5S )3,4-dihydroxy-5-(3-methyl-1 ,2,4-oxadiazol-5yt)tetrahydrofuran-2-yl]-9H-purin-6-yl~amino)pipendine-1 -carboxylate; (2S,3S.4 R,5R)-2-[3-(tert-butyl)- 1,2,4-oxadiazol-5-yfl-5-{6- [(cyclopropylmethy)amino-9H-purin-9-yl~tetrahydrofuran-3,4-diol; (2S, ,3S,4 R. 5R)-2-[3-(tert-butyl)- 1, 2 4-oxad iazof -5-yIj-5-I[6-(isobutyla min o)-9H purin-9-ylltetrahydrofuran-3,4-diol; (2R,3R,4S,5S-2-[6-(cyclopropylamino)-9H-purin-9-yJ-5-(3-isopropyl- 1,2,4- )tetrahyd rofuran -3 .4-diol: R,3R,4S ,5S )3 ,4-dihyd roxy-5-(3-isopropyl- 1,2 .4-oxad jazof yl)tetrahyd rofu ran-2-yI]-9H-purin-6-yl~amino).N-methylethanesulfonamide; (2R,3R,4S,5S-2-[6-(3,4-difluoroaniino)-9H-puin-9-y]-5-(3-isopropyl-1 .2,4ran-3 .4-diol; (2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroanilino9H-pun-9-y]-5-(3-cycIopropyl- 1,2 ,4-oxadiazol-5-yI)tetrahydrofuran-3 .4-diol; (2R,3S ,4R,5R)-2-[5-(tert-butyl H- 1,2 ,4-tnazol-3-yJ-5-[6-(4-choro-2fluoroanilino)-9H-purin-9-yI]tetrahydrofuran-3,4-diol; (2 R,3R,4S, 5R2[-2clr--lu o i o9 -ur 1,2 ,4-triazol-3-yI )tetrahyd rofuran-3 .4-diol; (2S ,3S ,4R,5R)-2-(5-cyclopropyl- 1,3 ,4-oxadiazol-2-yI)-5-[6-(tetrahyd ro-2H-pyran- 4-ylamino)-9H-puin-9-yI]tetrahyd rofuran-3,4-diot; (2S ,3S ,4R,5R)-2-[5-(tert-butyl 1,3 ,4-oxadiazo-2-yJ-5-[6-(2-chloro-4fluoroanilino)-9H-purin-9-yI]tetrahyd rofuran-3,4-diol; (2S ,3S.4 R,5R)-2-[3-(tert-butyl )isoxazol-5-yl]-5-{6-[( 1,1 -dioxidotetrahyd ro-2 Hthiopyran-4-yI )aminoj-9H-pu rin-9-yItetrahydrofuran-3 ,4-diol; 2-[(9-{(2R,3R,4S ,5S)-5-[5-(tert-butyl)-1.3 ,4-oxadiazol-2-yt]-3,4dihyd roxytetrahydrofuran-2-yi}-9H-pu nn-6-yl)amino]-N-ethylethaflesulfdfla mid e; 2-[(9-{(2R,3R,4S ,5S)-5-f 5-(tert-butyl)- 1,3 ,4-oxadiazol-2-yl]-3,4d ihyd roxytetrahydrofu ran-2-yt}-9H-pu rin-6-yt)amino]-N-(3methytphenyl)ethanesulfonamide;.

2-({9-((2R,3R,4S,5S)-3 ,4-dihydroxy-5-(5-methyl-1 ,3-oxazol-2-yI )tetrahydrofuran- 2-yI]-9H-purin-6-yi~amino )-N-methylethanesulfonamide: (2R,3R,4S S)- 2 6 -(cyclopentylamino)-9H-purin-9yI.5[3.(methoxymethyl.

1 2 4 -oxadiazol-5-yltetrahydrofuran.34-dijol; (2S .35 4R,5R)-2-(5-ethyl- 1,3 4 -oxadiazol-2-y)-5-[6-(isopropylamno..H-pun.9 yljtetrahydrofuran-3 .4-diol; (2R,3R,4S iS 2S)-2-hydroxycyclopentylJaminoj-9H-puin-9-yf..s(5.

methyl- l.

3 4 -oxadiazol-2-yI)tetrahydrofuran-3,4.diol; (2R ,3R,4S ,5S)-2-{2-chloro-6-[( 1 -ethyfpropy)amino-9H-purin-9-yl}..s-(3cyclopropyl-1 2 ,4-oxadiazol-5-yI)tetrahydrofuran.3,4-dial formate (2R.,3R ,4S, 5S)-2-[2-Chloro-6-( 1 -ethyl-propylamino)-purin-9-yj...(3cyclopropyl 1, 4 oxad iazol-5-yl)-tetrah yd rofu ran 3 4-diol diformate; (2S ,3S .4 RR)- 2 3 -ethylisoxazoi5yl)5[6-(tetrahydro-2H.pyran-4ylamino)-9Hpu ri n-9-ylj tetra hyd rofu ra'n-3,4.d iol; (2S, 35,4 R,5R)-2-(3-ethylisoxazol-5-yl)-5-(6{[( 1 S ,2S hydroxycyclopentyl~amino}-9H-.puin-9yl)tetrahydrofuran.3,4-iol; ethyl R,3R ,4S ,5S )-5-(3-ethylisoxazol-5-yl)-3,4-dihyd roxytetra hyd rofuran- 2 -yI]- 9 H-purin-6-ylamino)piperidine-1 -carboxylate; (2R, 3S ,4R, 5R)-2-[5-(tert-butyl )-4H-1 .2,4-triazol-3-yl]-5-[6-(tetra hydro-2H-pyran- 4-yla mino)-9H-purin-g-ylltetrahydrofuran.3 ,4-d jol; (2R,3S.4 R, 5R)-2-(5-isopropyl-4H- .2 ,4-triazol-3-yl )-5-[6-(tetrahyd ro-2H-pyran-4ylam ino 9 H-purin-9-yl]tetrahydrofuran-3 .4-diol; (2R,3R,4S .SS)-2-[2-chloro-6-(2-chloroA4-fluoroanilino)-9H-purin-9-yi]-5-(5methyl-i ,3-oxazol-2-yl )tetrahyd rofuran-3,4-diol; (2 R,3R,4S .SS)- 2 6 -(4-chloro-2-fluoroanilino9Hpurin9-y]-5-.(3-.methylisoxazol.

5-yl)tetrahydrofuran-3,4-diol; (2R,3R,4S .SS)-2-[6-(4-chloro-2-fluoroanilino-9H..purin.9-yl]-5.(3.propylisoxazol- )tetrahyd rofu ra n-3 .4-diol; (2R,3R,4S ,5S 2 -[2-chtoro-6-(tetrahydro-2H-pyranA-ylamino)-9H-puin-9-y]-5- )tetrahyd rofu ran-3 .4-diol; ethyl 4-({2-chloro-9-[(2R,3 R,4S ,5S)-5-(3-ethylisoxazol-5-y .4d ihyd roxytetra hyd rofu ra n-2-yl-9 Hpu rin-6-y~a mino)pi pe rid ine- 1 -carboxylate; (2R ,3R,4S ,5S 15,25 )-2-hydroxycyclopentyl]amino-9H-purin-9yl 3 -ethylisoxazol-5-yl)tetrahydrofuran-34-~iol.

(2R,3R,4S .55)- 2 -(2-chloro-6-{[2-(ethylsulfony)ethyl]amino-9H-purin-9-y)-5(3- )tetrahyd rofuran-3,4-d iol, (2R, 3R,4S ,5S )-2-[2-chloro-6-(4-chloro-2-fluoroanilino-9H-puril-9-y]-5-(3ethyl isoxazol-5-yI)tetrahyd rofura n-3,4-diol; (2R, 3R,4S ,5S )-2-[2-chloro-6-(2-chloro-4-fiuoroaniino)-9H-pulf-9-yl-5-(3ethylisoxazol-5-yI)tetrahydrofuran-3,4-diol; (2R,3R ,4S ,5S)-2-[2-chloro-6-(2-fluoroanino)-9H-purn-9-yI-5-(3-ethylisoxazol-5yl)t etrahydrofuran-3,4-diol; (2R, 3R,4S, 5S )-2-[2-chloro-6-(2-chloroanilino)-9H-purin-9-yll-5-(3-ethylisoxazol- 5-yI)tetrahydrofuran-3,4-diol; (2R.3 R,4S ,5S I S ,2S)-2-hydroxycyclopentyllamino)-9H-purin-9-yl)-5-[3- (hydroxymethyl )isoxazol-5-yljtetrahydrofuran-3 ,4-d jol; ethyl R,3R,4S ,5S ,4-dihydroxy-5-[3-(hyd roxymethyl yljtetrahydrofu ran-2-yl}-9H-purin-6-ylaminojpiperidine-1-ca rboxylate; (2S,35,4R,5R)-2-[3-(hyd roxymethyl)isoxazol-5-ylJ-5-[6-(tetra hydro-2 H-pyran-4ylamino)-9H-purin-9-yljtetrahydrofuran-3,4-diol; (2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroanlino)-9H-purin-9-y]-5-(3-ethylisoxazol-5yl)tetrahydrofuran-3 ,4-diol; (2R,3R,4S ,5S )-2-[6-(2-chloro-4-fluoroanilino)-9H-pu rin-9-yI]-5-(3-ethylisoxazol-5yI)tetrahydrofuran-3 ,4-diol; (2S,35 ,4R,5R)-2-(3-ethylisoxazol-5-y)-5-[6-(2-fluoroanilino)-9H-puril-9yI]tetrahydrofuran-3,4-diol; (2R,3R,4S ,55 )-2-[6-(2-chloroanilino)-9H-purin-9-yII-5-(3-ethyl yI)tetrahydrofuran-3,4-diol; ,3S ,4R,5R)-2-[5-(tert-butyl)-1,3,4-oxadiazol-2-y]-5-[6-(piperidin-4-yanfo)- 9H-purin-9-yl]tetrahydrofuran-3,4-diot; (2R,3R,4S ,5R)-2-{2-chloro-6-[( I -ethyipropyl)amino]-9H-pu rin-9-yI}-5-(5ethyl isoxazol -3-yI )tetra hyd rofu ran-3,4-diol formate; (2S .33,4R ,5R)-2-(3-bromoisoxazol-5-yI )5-[6-(4-chloro-2-fl uoroanil ino)-9H-punn-.

9-yI]tetrahydrofuran-3 ,4-diol ,3S ,4 R,5R)-2-[3-(tert-butyl )isoxazo-5-y]-5-(6-{[ 1 -(methylsulfonyt )piperid in-4yIla mino}-9H-punn-9-yI )tetrahydrofuran-3,'4-diol .3 S,4 R.5 rt-butyl)isoxazol-5-yJ-5-(6-{[ 1 -(pro pyl su Ifonyl )piperdin-4yI~amino}-9H-punn-9-yI )tetrahydrofuran-3,4-diol (25,35 ,4R,5R)-2-13-(tert-butyl)isoxazol-5-yI-5-(6-{[1 -(isopropylsulfonyl)pipeddin- 4-ylJamino)-9H-pu rin-9-yI )tetrahydrofuran-3 ,4-dioI (2S ,3S ,4R, 5R)-2-[3-(tert-butyl)isoxazoI5yj-5(6.{[1 -(ethylsulfonyf)piperidinA4 yllamino)- 9 H-purin.9-y1)tetrahydrofuran-3,4dioI (2S ,3S,4R, SR)- 2 -f3-(tert-butyI)isoxazoI.5]5[2choro,..6.(4chloro-2 flu oroanilino) 9H-purin-9gyujtetrahydrofuran..3,4.dio (2S,3S4,R--3(etbt ioaol5yj5[-hoo6(-hoo4 fluoroanilino)-9H-purin-.9..yfjtetrahydrofuran-34-ioI ,4S ,5S )5-[3-(tert-butyl)isoxazol-5-yf]-3 4 -dihydroxytetrahydrofuran.

2-yI}-2-chloro-9H-pu rn-6-yl)aminoj-N-ethyletha nesulfonamide 24(9-{(2R.3R ,4S ;5S )-5-[3-(tert-butyl)isoxazol-5-ylj-3 1 4-dihydroxytetrahydrofuran.

2 -yI)- 2 -chloro-9H-purin-6-y)amino-N-isopropylethanesulfonamide (2S ,3S ,4R, SR)- 2 3 -(tert-butyI)isoxazolI5.yj5[2.choro6(tetrahydro-2H-pyra n- 4-yla mino)-9H-pu rin-9-yI]tetrahyd rofuran-3 .4-diol (2R, 3R,4S ,5S 2 -[6-(4-chloro-2-fluoroanilino).9H-pu rin-9-ylJ-5-(3-pyndin-3rofu ra n-3 ,4-dioI 2 R,3R,4S,5S)-2-[6-(4-chloro.2-fluoroaniino)..9H-purin.9I]-5{3(4hyd roxybutyl )isoxazol-5-yIjtetrahyd rofuran-3 ,4-d 101 2-[(9-{(2R,3R,4S ,5S)-5-[3-(tert-butyl )isoxazol-5-yl]-3 ,4-d ihydroxytetrahyd rofuran- 2 -yI}- 9 H-purin-6-yf)amino]-N..ethylethanesulfonamide (2R, 3R,4S ,5S 2 6 -(cyclopentylamino)-9H-punn-9-y1-5-[5-(tnfluoromethyl 1 3 4 -oxadiazol-2-yI]tetrahydrofuran-34.dioI (2R,3R,4S S .2S)-2-hydroxycyclopentyllamino}-9H-punn-9-yi)-5-(s- (trifluoromethyl)-1,3 ,4-oxad iazol-2-yI jtetrahydrofu ran-3 ,4-d 101 ethyl 4 9 -{(2R,3R,4S,5S)-3,4-dihydroxy-5-[5-(trifluoromethyl. I,3,4-oxadiazol-2yljtetra hyd rofuran-2-yl}-9H-pu rin-6-yI)amino]pipendine- 1 -carboxylate 2

R,

3 R,4S,5S)-2-[6-(4-chloro-2-fluoroanilino)9Hpurin9.yl]..s(5methyl13,4oxad iazol-2-yI )tetrahydrofu ran-3,4-d 101 (2R,3R,4S ,5S )-2-[6-(4-chloro-2-fluoroanilno)-9H-purin-9y].5(3.

)tetrahydrofuran-3,4-diol (2S .35.4R,5R)-2-[3-(tert-butyl)isoxazol-5-yI]-5-{6-[( I -butyrylpipenddin-4-yl )amino]- 9 H-purin-9-yl~tetrahydrofuran-3,4.cioI isopropyl .45,5S )-5-[3-(tert-butyl )isoxazol-5-yll-3,4d ihyd roxytetrahyd rofu ra n-2-yl}-9H-purin-6-yl)aminojpipendine- I-carboxylate ,3S,4 R,5R)-2-[3-(tert-butyl )isoxazol-5-yI-5-(6-{[1 trifluoroacetyl )piperidin-4-yllamino)-9H-purin-9-yI )tetrahydrofuran-3,4-diol methyl 4-[(9-{(2R,3R.4S ,5S)-5-[3-(tert-butyl)isoxazol-5-ylJ-3 ,4dihydroxytetrahydrofura n-2-yf }9H-purin-6-yl)aminojpiperidine- 1 -ca rboxylate (2R, 3R ,4S ,5S)-2-[6-(4-chloro-2-fluoroanilino-9H-purin-9-y]-5-[3- (hydroxymethyl)isoxazol-5-yljtetrahydrofuran-3, 4-diol (2R,3R,4S,5S)-2-[6-(2-chloro-4-fluoroanilino)-gH-purn-9-yl-5-[3- (hydroxymethyl)isoxazol-5-yfjtetrahydrofuran-3,4-dio (2R, 3R 1 4S ,5S)-2-(6-(2-fluoroaniino-9H-purin-9-ylj-5-[3-(hydroxymethyl )isoxazol- 5-yl]tetrahydrofuran-3,4-diol (2R,3R,4S,5S)-2-[6-(2-chloroaniino)-9H-puin-9-yl-5-[3- (hydroxymethyl)isoxazol-5-yljtetrahydrofura n-3 ,4-diol (2R,3R,4S,5S-2-(2-choro-6-[( 1 S,2S)-2-hydroxycyclopentyljamino}-9H-purin-9yd roxym eth yl)isoxazol-5-yl]tetra hyd rofu ran -3,4-d iol (2R,3R.4S ,5S)-24[2-chloro-6-(tetrahydro-2 H-pyran-4-ylamino)-9H-purin-9-yl]-5- [3-(hydroxymethyl )isoxazol-5-yljtetrahydrofuran-3 ,4-diol 2-[(2-chloro-9-{(2R,3R,4S ,5S ,4-dihyd roxy-5-[3-(hydroxymethyl yfltetrahyd rofuran-2-yl}-9H-purin-6-y )amino]-N-ethylethanesulfonamide ethyl 4-[(2-chloro-9-{(2R,3R,4S ,5S )3 ,4-dihydroxy-5-[3-(hydroxymethyl)isoxazol- 5-yl]tetrahydrofuran-2-y)-9H-purin-6-yl)amino]pipeidine-1 -carboxylate (2R,3R,4S ,5S )2-[2-chloro-6-(4-chloro-2-fluoroanilino-9H-punn-9-y]-5-[3- (hyd roxymethyl)isoxazol-5-yl~tetrahydrofuran-3 ,4-diol (2R,3R,4S ,5S)-2-[2-chloro-6-(2-chloro-4-fluoroanilino-9H-purin-9-y]-5-[3- (hydroxymethyl )isoxazol-5-yI~tetrahydrofuran-3,4-dioI (2R,3R,4S,5S)-2-[2-chloro-6-(2-fluoroanilino)-9H-purin-9-yJ-5-[3- (hydroxymethyl)isoxazol-5-yl~tetrahydrofuran-3 ,4-diol (2S ,3S ,4R,5R)-2-(3-ethylisoxazol-5-yl )-5-[2-methoxy-6-(tetrahydro-2H-pyrafl-4ylamino)-9H-purin-9-yl~tetrahydrofuran-3 ,4-d jol ethyl R, 3 R,4S, 5S )-5-(3-ethyl isoxazol-5-yl -3 ,4-d ihyd roxytetra hyd rofu ran 2-ytJ-2-methoxy-9H-pu rn-6-yl~amino)piperidine- 1 -carboxylate (2S ,3S ,4R,5R)-2-(3-ethylisoxazol-5-yl)-5-(6-[( I S ,2S)-2hydroxycyclopentylamino}-2-methoxy-9H-purin-9 y)tetrahydrofuran-34-diol (2S .35,4R,5R )-2-(3-ethyl isoxazol-5-yl )-5-(6-{[2-(ethylsulfonyl )ethyljamino}-2methoxy-9H-purin-9-yl )tetrahydrofuran-3 ,4-diol (2R,3R,4S,5S)-2-[6-(2-chloro-4-fluoroanilino)-2-methoxy-9H-pun-9-yJ-5-(3ethyl isoxazol-5-yI )tetrahydrofu ran-3 .4-diol (2S,3S,4R, SR)-2-(3-ethyisoxazol-5-y)-5-[6-(2-fluoroanilino)-2-methoxy-9Hpurin-9-yljtetrahydrofuran-3,4-diol (2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroanilino)-2-methoxy-9H-puin-9-ylj-5-(3ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol (2S,3S,4R,5R)-2-[3-(tert-butyl)- ,2,4-oxadiazol-5-yl]-5-[6-(cyclopropylamino)-9Hpurin-9-ylltetrahydrofuran-3,4-diol (2S,3S,4R,5R)-2-15-(tert-butyl-1 ,3,4-oxadiazol-2-ylJ-5-[2-chloro-6-(4-chloro-2fluoroanilino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol (2R,3R,4S, 5S)-2-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-ylj-5-(5-isopropyl-1,3,4oxadiazol-2-yl)tetrahydrofuran-3,4-diol.

Compounds according to the invention have applicability as inhibitors of lipolysis i.e. they decrease plasma free fatty acid concentrations. The compounds may thus be used in the treatment of hyperlipidaemias. Furthermore, as a consequence of their anti-lipolytic activity, the compounds have the ability to lower elevated blood glucose, insulin and ketone body levels and therefore may be of value in the therapy of diabetes. Since anti-lipolytic agents have hypolipidaemic and hypofibrinogenaemic activity, the compounds may also show anti-atherosclerotic activity. The anti-lipolytic activity of compounds of the invention has been demonstrated by their ability to lower the concentration of non-esterified fatty acids (NEFA) in starved rats dosed orally according to the method described by P. Strong et al. In Clinical Science (1993), 4, 663-669.

In addition to their anti-lipolytic effect, the compounds of the invention may independently affect cardiac function by reducing heart rate and conduction.

The compounds may thus be used in the therapy of a number of cardiovascular disorders, for example cardiac arrythmias, particularly following myocardial infarction, and angina.

Furthermore, the compounds of the invention are useful as cardioprotective agents, having applicability in the treatment of ischaemic heart disease. As used herein the term "ischaemic heart disease" includes damage associated with both myocardial ischaemia and reperfusion, for example, associated with coronary artery bypass grafting (CABG), percutaneous translumenal coronary angioplasty (PTCA), cardioplegia, acute myocardial infarction, thrombolysis, stable and unstable angina and cardiac surgery including in particular cardiac transplantation. The compounds of the invention additionally are useful for treating ischaemic damage to other organs. The compounds of the invention may also be valuable in the treatment of other disorders arising as a result of widespread atheromatous disease, for example, peripheral vascular disease (PVD) and stroke.

The compounds may also inhibit renin release and thus be of use in the therapy of hypertension and heart failure. The compounds may also be useful as CNS agents as hypnotics, sedatives, analgesics and/or anti-convulsants particularly finding use in the treatment of epilepsy).

In addition, the compounds of the invention may find use in the treatment of sleep apnoea.

The compound of formula and pharmaceutically acceptable acid addition salts thereof are useful as analgesics. They are therefore useful in treating or preventing pain. They may be used to improve the condition of a host, typically of a human being, suffering from pain. They may be employed to alleviate pain in a host. Thus, the compound of formula and its pharmaceutically acceptable acid addition salts may be used as a preemptive analgesic to treat acute pain such as musculoskeletal pain, post operative pain and surgical pain, chronic pain such as chronic inflammatory pain rheumatoid arthritis (RA) and osteoarthritis neuropathic pain post herpetic neuralgia (PHN), trigeminal neuralgia, neuropathiesassociated with diabetes and sympathetically maintained pain) and pain associated with cancer and fibromyalgia. The compound of formula may also be used in the treatment or prevention of pain associated with migraine, tension headache and cluster headaches and pain associated with Functional Bowel Disorders Irritable Bowel Syndrome), non cardiac chest pain and non ulcer dyspepsia. Additionally, when topically administered, the compounds of the present invention exhibit analgesic and anti-inflammatory activity and are therefore useful in a number of chronic inflammatory pain conditions such as OA, RA and neuropathic conditions such as fibomyalgia and PHN.

Accordingly, the invention provides a compound of formula 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 plasma free fatty acid concentration, or reducing heart rate and conduction, or whereby the therapy involves the treatment of ischaemic heart disease, peripheral vascular disease or stroke or which subject is suffering from a CNS disorder, sleep apnoea or pain.

In a further aspect, the invention provides a method of treatment of a human or animal subject suffering from a condition in which there is an advantage in decreasing plasma free fatty acid concentration, or reducing heart rate and conduction, or which subject is suffering from or susceptible to ischaemic heart disease, peripheral vascular disease or stroke, or which subject is suffering a CNS disorder or suffering from sleep apnoea or suffering pain, which method comprises administering to the subject an effective amount of a compound of formula or a pharmaceutically acceptable salt or solvate thereof.

In a further aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of a human or animal suffering from a condition in which there is an advantage in decreasing plasma free fatty acid concentration, or reducing heart rate and conduction, or which subject is suffering from or susceptible to ishaemic heart disease, peripheral vascular disease or stroke, or which subject is suffering a CNS disorder or suffering from sleep apnoea or suffering pain.

In respect of the above mentioned ischaemic treatment, it has been found that according to a particularly unexpected aspect of the present invention, not only does administration of a compound of formula prior to ischaemia provide protection against myocardial infarction, but protection is also afforded if the compound of formula is administered after the ischaemic event and before reperfusion. This means that the methods of the present invention are applicable not only where ischaemia is planned or expected, for example in cardiac surgery, but also in cases of sudden or unexpected ischaemia, for example in heart attack and unstable angina.

It will be appreciated that reference to treatment includes acute treatment or prophylaxis as well as the alleviation of established symptoms.

The pharmaceutical composition comprises, as active ingredient, at least one compound of formula or a pharmaceutically acceptable salt or solvate thereof in association with a pharmaceutical carrier and/or excipient 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 plasma free fatty acid concentration, or reducing heart rate and conduction, or which subject is suffering from or susceptible to ischaemic heart disease, peripheral vascular disease or stroke, or which subject is suffering from a CNS disorder, sleep apnoea or pain.

There is further provided by the present invention a process of preparing a pharmaceutical composition, which process comprises mixing at least one compound of formula or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable carrier and/or excipient.

Compositions according to the invention may 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 may be adapted for sustained release.

For topical administration, the pharmaceutical composition may 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 mucilage of starch or polyvinylpyrrolidone; fillers, for example, lactose, microcrystalline cellulose or maize-starch; lubricants, for example, magnesium stearate or stearic acid; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or 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, flavouring, colouring and sweetening agents mannitol) as appropriate.

For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.

The compounds of formula may be formulated for parenteral administration by bolus injection or continuous infusion and may be presented 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 formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g.

sterile pyrogen-free water, before use.

The compounds of formula may also be formulated as suppositories, e.g.

containing conventional suppository bases such as cocoa butter or other glycerides.

A proposed dose of the compounds of the invention for administration to man (of approximately 70kg body weight) is 1mg to 2g, preferably img to 100mg, of the active ingredient per unit dose which could be administered, for exarmple, 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 yet further aspect the invention also provides for the use of a compound of formula or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of human or animal subjects suffering from a condition in which there is an advantage in decreasing plasma free fatty acid concentration, or reducing heart rate and conduction, or which subject is suffering from or susceptible to ischaemic heart disease, peripheral vascular disease (PVD) or stroke, or which patient is suffering from a CNS disorder, sleep apnoea or pain.

The compounds of formula and physiologically acceptable salts or solvates thereof may be prepared by the processes described hereinafter, said processes constituting a further aspect of the invention. In the following description, the groups R 1

R

2 and R 3 are as defined for compounds of formula unless otherwise stated.

According to a first general process A, a compound of formula may be prepared by reacting a compound of formula (II)

L

R Z N (II) P'O Op 2 wherein L represents a leaving group such as a halogen atom chlorine), or a linker group capable of binding to a solid phase polymeric support a polystyrene resin) and for example may be -SO 2 Cl4alkylene and P' and -,P2: represent hydrogen, Ci.

6 straight chain or branched alkyl or a suitable protecting group acetyl or a protecting group wherein P 1 and P 2 together form an alkylidine group) with a compound of formula R'NH 2 or a salt thereof under basic conditions. The 4'-heterocycle group substituent may be protected if required, for example, see route Bb and V described hereinbelow.

Compounds of formula (II) may be used to produce compounds of formula (I) directly by reaction with the group R 1

NH

2 either in the absence or presence of a solvent such as an alcohol a lower alkanol such as isopropanol, t-butanol or 3-pentanol), an ether tetrahydrofuran or dioxan), a substituted amide dimethylformamide), a halogenated hydrocarbon chloroform), an aromatic hydrocarbon toluene), dimethyl sulfoxide (DMSO) or acetonitrile, preferably at an elevated temperature up to the reflux temperature of the solvent), in the presence of a suitable acid scavanger, 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 palladium acetate) and phosphine ligand 2,2'-bis(diphenylphosphino)- 1-1' binaphthyl).

Optionally, where at least one of Y, Z and W is N, alkylation may be carried out on a N atom at Y, Z or W at any appropriate stage in the synthesis, for example, see Route X described hereinbelow.

The above reactions may be preceded or followed where appropriate by in situ removal of the P' and P 2 protecting groups. For example when P1 and p 2 represent acetyl, this may be effected with an amine such as ammonia or tertbutylamine in a solvent such as methanol or when P' and P2 represent an alkylidine by acid hydrolysis, e.g. with trifluoroacetic acid (TFA). Interconversion of P 1 and P 2 protecting groups may occur at any stage in the preparation of the compounds of formula for example when P' and P 2 represent acetyl, compounds of formula (II) may be prepared from compounds wherein P' and P together represent an alkylidine protecting group by acid catalysed removal of the alkylidine protecting group, e.g. 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, interconversion of P' and P 2 protecting groups may occur at any stage during the preparation of compounds of formula (II).

It will be apparent to persons skilled in the art that in the preparation of compounds of formula (II) or the 4'-heterocycle may be formed at any stage.

For example, heterocycles may be prepared from carboxylic acid or acetylene starting materials before the addition of the purine ring (see Schemes 1, la and 2) or heterocycles may be formed after the addition of the purine ring (see Schemes 3, 4 and 5 and Route W).

Compounds of formula (II) where X O may be prepared by reacting compounds of formula (111) RYP (Il

R

3 P'o"

OP

2 wherein P 3 represents a suitable protecting group, for example acetyl, or a substituent such as C1-3 alkyl, and P 2 and R 3 are as defined above, with compounds of formula (IV)

L

NZ N I (IV) 2 R N wherein L and R 2 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 trifluoromethane sulfonate and a base such as diazabicyclo[5.4.0]undec-7-ene

(DBU).

Altematively the compound of formula (IV) may first be silylated with a suitable silylating agent e.g. hexamethyldisilazane followed by reaction of the silylated intermediate with a compound of formula (111) and a suitable Lewis acid, e.g.

trimethylsilyl trifluoromethanesulfonate in a suitable solvent such as acetonitrile.

Compounds of formula (IV) are either known in the art or may be prepared from known compounds using methods analogous to those used to prepare the known compounds of formula (IV).

As described above, the compounds of formula (Ill) may be prepared from alternative protected compounds by replacement of the alternate P' and P 2 protecting groups with other P 1 and P 2 groups. These represent an exchanging of one protecting group for another and will be apparent to those skilled in the art. Compounds of formula (III) may be made for example by the following syntheses: Compounds of formula (111) may be prepared, for example when the heterocycle defined by W, Y and Z hereinabove represents an isoxazole (optionally substituted) by the following reaction schemes.

Scheme 1 0 HOO 0 OP Stage 1 MeN- O P C4111 P O OP5 MeNHOMe.HCI/ Me o

PO

CDI/pyridine/ CH,CIl (Illa) 0 Stage 2 Ra 3

O

THF

-MgCI 4 P OP Stage 3 NH 2

OH

MeOH

N-O

R

3 0 OP 6 AcO OAc Stage 4 1. MeOH/HCI 2. Ac20/ 0

,OH

NO 0 P0 OP H'p'O O 6 Me2N-\ N General conditions for Stages 1-4 will be known to persons skilled in the art. It will also be appreciated that the reagents and conditions set out in Scheme 1 are example conditions and alternative reagents and conditions for achieving the same chemical transformation may be known to persons skilled in the art. P 4 and P5 together represent alkylidine protecting group(s). P6 represents C 14 alkyl. R 3 is as previously defined.

Although scheme 1 shows the preparation of compounds of formula (III) where the heterocycle moiety is an isoxazole it would be apparent to a person skilled in the art that other standard methods could be employed to produce compounds of formula (III) with other heterocycles from carboxylic acid starting materials, such a compound of formula (Ilia), for example, see route Q as described hereinbelow.

An alternative method for synthesis of compounds of formula (III) is shown in Scheme la.

Scheme la 0 OP 6 P 0 OP5 Stage 1 nBuLi

R

3

CHO

HO

R 3 OP 6 p4 0 b S MnO 2 Stage 2

HO

0 N 0 OP6 4 5 Po 0 OP 0 R 3

OP

8 6 p 4 0

PS

Stage 3

H

2

NOH

TFA I Stage 4 -N OH Stage 5 ROAc Ac 2 OAc O Ac HO

OH

General conditions for Stages 1-5 in Scheme la will be known to persons skilled in the art. P4, P 5 and P6 are as previously defined.

Scheme 2 represents a method of preparing compounds of formula (111) when Y N, Z NH, W CH and R 3 H or tautomers thereof. P 1

P

2 and P 6 are as previously defined.

Scheme 2 0 Me 6 p 2 P' op, Stage 1 OMe Me N-- OMe PhMe 0 0

OP

6 MeN O P 6 P'S OP2 Stage 2 N2H4/H 2 0

H

N OP 6 P bOP 2 A further process comprises converting a compound of formula into a different compound of formula by modifying the R 2 and/or R 3 groups therein.

All compounds of formulae (III) are novel intermediates and form a further aspect of the present invention.

Compounds of the formula R'NH 2 are either known compounds or may be prepared from known compounds using conventional procedures.

Specific optical isomers of a compound of formula may be obtained by conventional methods for example, by synthesis from an appropriate asymmetric starting material using any of the processes described herein, or where appropriate by separation of a mixture of isomers of a compound of formula by conventional means e.g by fractional crystallisation or chromatography.

According to a third process compounds of from compounds of formula or (VI):

L

N HOOC

HOOC*.

formula may be prepared

NHR'

R

2 N N HOOC Xj P'O bOP P'O Op 2

(VI)

where R 1 R 2X, L, P1 and P2 represent groups as previously defined.

Also compounds of formula (VI) may be prepared from compounds of formula by analogous methods to those described. in process above.

Synthesis of the compounds of formulae from the corresponding acids of formulae and (VI) will be apparent to a skilled person using conventional synthetic techniques.

33 As an example, when W O, Y N and Z N in formula 1 above thus defining a 1,3,4 oxadiazole, the synthesis is according to reaction scheme 3. J represents a leaving group L as previously defined, or a NHR' group. R 2 X, P 1 and P2 are as previously defined.

Scheme 3 RN N HOOC XJ P'O O 2 Stage 1 Method A

EEDQ/R

3

CONHNH)/DME

Method B

R

3

CONHNH

2 /tBuCOCI/ iPr 2 NEt/THF O R 2 R .NN

HH

Method A SOC2 Method B

POCI

3

DMF

Stage 2 Continue as described in Process A

J

N/ N N-N X P'O

OP

2 Compounds of formula where Z=0, Y=N and W=N (thus defining a 1,2,4oxadiazole) may be prepared from compounds of formula or (VI) by a first process involving activation of the carboxyl group on the compound of formula or (VI) followed by reaction with an amidoxime of formula HO-N=C(R 3

)NH

2 in a solvent such as tetrahydrofuran or chloroform, in the presence of a base such as pyridine or di-isopropylethylamine, followed by cyclisation at a temperature of 20*C-150*C in a solvent such as toluene, tetrahydrofuran (THF) or chloroform (see scheme Methods of carboxyl activation include 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 thionyl chloride in dimethylformamide (DMF). Activating agents used in peptide chemistry such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) or 1 -hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, may also be used. Hydroxyl protecting groups may be removed under conditions known to those practising in the art. For example, the acetonide group may be removed by treatment with an acid (at a temperature of 0°C-150C) such as trifluoroacetic acid suitably at 0-200C or acetic acid suitably at 50-150°C.

In scheme 4 R 2

R

3 X, J, P1 and P2 and are as defined above.

Scheme 4 see text

N.OH

R 3-N H, Modification of J and other protecting groups as required Alternatively, a compound of formula (II) may be prepared from a compound of formula (VII), for example, see route U as described hereinbelow. It would be apparent to persons skilled in the art that analagous methods to route U could be used to prepare compounds of formula with other 4'-heterocycles, for example, see route M as described hereinbelow.

0 o N N HOOC* Xj P'52 PO Op 2

(VII)

According to an general process D, a compound of formula may be prepared from a compound of formula as shown in Scheme 5, followed by removal of the P1 and P2 protecting groups as described previously in process A. It will be apparent to persons skilled in the art that analagous methods to that shown in Scheme 5 could be used to prepare compounds of formula with other 4'heterocycles using alternative heterocycle syntheses. In Scheme 5, R 1

R

3 J, P 1 and P2 are as previously defined.

Scheme

HO~

P

1 0"'"Op 2 Stage 1

IR

3 NH 2

N

N-O N N R 3 0 p 1 0 OP 2 /1 -hydroxybenzotriazole/ 1 -(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride/ dimethylformnamride Stage 2

R

1

NH

2

I

diisopropyleth dimnethylsulfox ylamine/ ide Modification of protecting groups as required N~

N

N-O N N 1 3 2- P 10

"OP

The invention is further illustrated by the following non limiting interm~diates and Examples.

Full experimental details are given below for routes A-Z, Bb and Cc; data for remaining examples prepared by analogous routes are given in Table 1.

Standard HPLC conditions are as follows: Standard Automated Preparative HPLC column, conditions eluent Automated preparative high performance liquid chromatography (autoprep.

HPLC) was carried out using a Supelco ABZ+ 5 m 100mmx22mm i.d. column eluted with a mixture of solvents consisting of 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 flow rate of 4ml per minute. Unless otherwise stated the eluent was used as a gradient of 0-95 (ii) over 18.5 minutes.

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

System B: This system used an ABZ+PLUS, 3.3cm x 2.0mm i.d. column, eluting with solvents: A 0.1%v/v formic acid 0.077%w/v ammonium acetate in water; and B 95:5 acetonitrile:water 0.05%v/v formic acid, at a flow rate of 0.8ml per minute. The following gradient protocol was used: A+B mixtures, gradient profile 0 100% B over 3.5mins; hold at 100% B for 1.5mins; return to 100% A over System C: This system used an ABZ+PLUS, 3.3cm x 4.6mm i.d. column, eluting with solvents: A 0.1%v/v formic acid 0.077%w/v ammonium acetate in water; and B 95% acetonitnle:water 0.05%v/v formic acid, at a flow rate of 3m1 per minute. The following gradient protocol was used: 100% A for 0.7 mins; A+B mixtures, gradient profile 0 100% B over 3.7mins; hold at 100% B for 0.9mins; return to 100% A over 0.2mins.

System D: This system used an ABZ+PLUS, 3.3cm x 4.6mm i.d. column, 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 .5mi per minute. The following gradient protocol was used: 100% A for 0.2 mins; A+B mixtures, gradient profile 0 100% B over 3.3mins; hold at 100% B for 1min; return to 100% A over 0.2mins.

All LC/MS systems used a micromass 'platform' spectrometer, with electrospray ionisation mode, positive and negative ion switching, mass range 80-1000 a.m.u.

Flash chromatography was carried out either on Merck silica gel (Merck 9385), or on pre-packed silica gel cartridges (Biotage).

All temperatures were in OC.

Examples Table.

Table 1. Ex Name Expt. Details Characterising data No 1 (2R,3R,4S,5S)-2-[6-(2R- Analogous TLC SiO 2

(CH

2

CI

2 :MeOH: Hydroxy-cyclopent-(R)- method to 880NH 3 90:10:1) Rf 0.39 yiamino)-purin-9-yl]-5-(5- route A isopropyl-[1.3 ,4]oxadiazol- Microanalysis Found: C,52.9; 2-yl)-tetrahydro-furan-3,4- H, 5.9; N, 22.7.

diol

C

19

H

23

N

7 0 5 requires C, 52.9; H, 5.8; N, 22.7.

Table 1. Examples Ex Name Expt. Details Characterising data No II(note 1) 1 2 (2R,3R,4S,5S)-2-(6- Analogous TLC Si0 2

(CH

2

CI

2 :MeOH: Cyclopentylamino-purin-9- method to 880NH 3 94:6:1) Rf 0.10 route A [1 ,3,4joxadiazol-2-yl)- Microanalysis Found: 0,57. 1; tetra hyd ro-fu ran-3,4-d iol H, 5.3; N, 21.0.

C

22

H

23

N

7 0 4 requires C, 57.2;- H, 5.3; N, 21.2.

3 (2S,3S,4R,5R)-2-(5-tert- See below See below (route A) B utyl-[1 ,3,4]oxad iazol-2-yI (route A) 5-[6-(tetrahydro-pyra n-4yfamino)-purin-9-yl]terahd -ur o-furan-,ddi l_ 4 4-{9-[5S-(5-tert-Butyl- Analogous LC/MS (System B) [1 ,3,4]oxadiazol-2-yl)- method to Rt 2.55 min.

3R,4S-dihydroxy- route A Mass Spectrum m/z 517 tetra hyd ro-fu ran-2 R-yIJ-9 H- IM H-1.

purin-6-ylamino}piperidine-1 -carboxylic acid ethyl ester (2S,3S,4R,5R)-2-(5-tert- Analogous LC/MS (System B) Butyi-[1 ,3,4]oxadiazol-2-y)- method to Rt 2.35 min.

5-[6-(2S-hydroxy- route A Mass Spectrum m/z 446 cyclopent-(S)ytamino)- purin-9-Al-tetrahydrofuran-3 ,4-diol 6 (2S,3S,4R,5R)-2-(5- Analogous LC/MS (System B1) Isopropyl-[1I,3,4]oxadiazol- method to R, 2.24 min.

2-yI)-5-[6-(tetrahydro- route A Mass Spectrum m/z 432 pyran-4-ytamino)-purin-9- IMH-].

yi]-tetrahydro-furan-3 ,4-dil I Table 1. Examples Ex jName No I Expt.

(note Details 1) (2S,3S,4R,5R)-2-(5-tert- Butyl-[1 ,3,4Joxadiazol-2-yl)- 5-(6-cyclopentylaminopurin-9-A9-tetrahydrofuran-3,4-diol Analogous method to route A Characterising data LC/MS (System B) R, 2.61 min.

Mass Spectrum mnz 430 [MH 8 (2S,3S,4R,5R)-2-(5-tert- See below See below (route B) Butyl-[1 ,3,4]oxadiazol-2-yl)- (route B) 5-[2-chloro-6-(tetrahyd ropyran-4-yiamino)-purin-9yl]-tetrahydro-fuiran-3,4-diol formate 9 (2S,3S.4R,5R)-2-(5-tert- Analogous LCIMS (System A) Butyl-[1 ,3,4]oxadiazol-2-yl)- method to Rt 4.35 min.

5-(2-chloro-6- route B Mass Spectrum m/z 464 cyclopentylamino-purin-9- yl)-tetrahydro-furan-3 ,4-dioI formate,_______ (2S,3S,4R,5R}-2-(5- Analogous LCIMS (System D) Cyclopropyl- method to Rt 2.32 min.

[1 ,3,4]oxadiazol-2-yl)-5-[6- route A Mass Spectrum m/z 430 (2S-hydroxy-cyclopent-(S)- IIMH+].

ylamino)-purin-9-yl]tetra hydro-furan-3 ,4-d iol 11 (2R,3R,4S,5S)-2-(6- Analogous LCIMS (System D) Cyclopentylamino-purin-9- method to Rt 2.44 min. route A Mass Spectrum rhz 414 [1,3,4]oxadiazol-2-y}- [MH]I.

tetra hydro-furan-3 ,4-d iol Table 1. Examples Ex Name Expt. Details Characterising data No I note'l 1I 12 4-{9-[5S-(5-Cyclopropyl- Analogous LC/MS (System D) [1 .3,4Joxadiazol-2-yl)- method to Rt 2.57 min.

3R,4S-dihydroxy- route A Mass Spectrum m/z 501 tetra hyd ro-fura n-2R-ylJ-9H- prin-6-ylamino}ieridine- 1-carboxylic acid ethyl ester 13 (2R,3R,4S,5S)-2-(6- Analogous LCIMS (System D) Cyclopentylamino-purin-9- method to Rt 2.74 min.

route A Mass Spectrum m/z 442 [1 ,3,4loxadiazol-2-yl)- tetra hyd ro-fu ran-3 ,4-d iol 14 (2S,3S,4R,5R)-2-(5-tert- Analogous LCIMS (System B) Butyl-[1l 3,4]oxadiazol-2-y)- method to Rt 2.99 min.

5-[6-(4-chloro-2-fluoro- route A Mass Spectrum m/z 490 phenylamino)-purin-9-yl]- [MH 1.

tetra hyd ro-fu ra n-3 ,4-d iol (2R,3R,4S,5S)-2-(6- See below See below (route C) Cyclopentylamino-purin-9- (route C) yl)-5-[1 ,3,4]oxadiazol-2-yltetra hydro-fu ran-3,4-d iol 16 (2S,3S,4R,5R)-2-(5-Ethyl- See below See below (route D) oxazol-2-yl)-5-[6- (route D) (tetra hyd ro-pyra n-4ylamino)-pudn-9-yi]tetra hydro-fu ran-3 ,4-diol 17 (2S,3S,4R,5R)-2-(6- See below See below (route E) Cyclopentylamino-purin-9- (route E) yl (1,3,4]thiadiazol-2-yl)tetra hyd ro-fu ran-3,4-d iol Table 1. Examples Ex Name Expt Details Characterising data No I note 1)1I 18 (2R,3R,4S,5R)-2-(6- See below See below (route F) lsopropylamino-purin-9-yl)- (route F) 5-(5-methyl-4H- [1 ,2,4jtriazol-3-yI)tetra hydro-furan-3,4-diol trifluoroacetate 19 (2S,35,4R,5R)-2-(3- See below LC/MS (System B) Cyclopropyl- (route G) R, 2.37 min.

[1 ,2,4joxadiazol-5-y)-5-[6- Mass Spectrum m/z (2S-hydroxy-cyclopent-(S ylamino)-purin-9-yl]- 430 [MH~] tetra hyd ro-fu ra n-3,4-d iol (2S,3S,4R,5R)-2-(3- Analogous TLC SiO 2

(CH

2 01 2 :EtOH: Phenyl-[1 ,2,4]oxadiazol-5- method to 880NH 3 100:8:1 Rf yl)-5-[6-(tetrahydro-pyran- route G 4-ylamino)-purin-9-y]- Microanalysis Found: 0,54.8; tetrahydro-furan-3,4-diol H, 4.9; N, Requires C, 55.3; H, 5.3; N, 19.6.

21 (2S,3S,4R,5R)-2-(3-tert- Analogous LC/MS (System B) Butyl-[1 ,2,4]oxadiazol-5-yI)- method to Rt 2.57 min.

5-[6-(2S-hydroxy- route G Mass Spectrum m/z cyclopent-(S )-ylamino)purin-9-yl-tetrahydro- 446 furan-3,4-diol Table 1. Examples Ex Name Expt. Details Characterising data No I note 1)1I 22 (2S,3S,4R,5R)-2-(3- Analogous LC/MS (System B) Cyclopropyl- method to Rt 2.39 min.

f I 2,4]oxadiazol-5-yl)-5-[6- route G Mass Spectru m m/z (tetra hyd ro-pyra n-4ylamino)-purin-9-yl]- 430 [MHJI.

tetrahydro-furan-3,4-diol 23 (2R,3R,4S,5S)-2-[6- Analogous LC/MS (System B) (Tetra hydro-pyran-4- method to Rt 2.29 min.

ylamino)-purin-9-yl]-5-(3- route G Mass Spectrum m/lz [1 .2,4]oxadiazol-5-yl)- 473 [M Hi.

tetra hyd ro-furan-3 ,4-d il 24 (2S,3S,4R,5R)-2-(3-Methyl- Analogous 1 HNMR 8 (DMS0) [1 ,2,4]oxadiazol-5-y)-5-[6- method to 8.42 (1 H,s,CH), 8.20 (tetrahydro-pyran-4- route G (1H,brs,CH), 7.82 ylamino)-purin-9-y]- (1H,brd,NH), 6.18 (1H,d,CH), tetra hyd ro-fu ran-3,4-d io 1 6.02 (1 H,brd,OH), 5.90 (H,brd,OH), 5.22 (1H,d,CH), 4.38 (H,brsCH), 3.94 (2H,brd,2xCH equatorial), 3.42 (2H,t,2xCH axial), 2.40 (3H,s,CH 3 1.90-1.60 (4H,2xm,2xCH 2 Microanalysis Found: C, 50.6; H, 5.2; N, 24.3.

Requires C, 50.6; H, 5.25: N, 24.3.

ExName NoI (2R,3R.4S.5S)-2-[6-(3- Fluoro-4-hydroxy- (3-methyl-[1 ,2,4]oxadiazol- 5-yI)tetrahydro-furan-3,4diol Expt. Details (note 1) Analogous method to route G Mass Spectrumrmlz 430 [MH~j.

26 4-{9-[5R-(5-tert-Butyl- See below LC/MS (System B) [1,2,4]oxadiazol-3-yl)- (route H) R, 2.76 min.

3R,4S-dihydroxy- Mass Spectrum m/~z tetra hyd ro-fura n-2 R-yl]-9H purin-6-ylamino)- 517 piperidine-1 -carboxylic acid ethyl ester 27 (2S,3S,4R,5R)-2-(3-tert- See below See below (route 1) (route 1) (2S-hyd roxy-cyclopent-(S ylamino)-purin-9-y]tetra hyd ro-furan-3,4-d 10 28 (2S,3S,4R,5R)-2-(3-tert- See below See below (route 1) Butyl-isoxazol-5-yl)-5-16- (route 1) (tetra hyd ro-pyran-4ylamino)-purin-9-yI]tetrahydro-furan-3,4-d 29 (21R,31R,4S,51R)-2-(2H-- See below See below (route J) Pyrazol-3-yI)-5-(6- (route J) tetrahydro-0yran-4ylamino-purin-9-yi)- __tetra hyd ro-fu ran-3, 4-d io I Table 1. Examples Ex Name Expt. Details Characterising data No (note 1)1 (2R,3R,4S,5R)-2-(5-tert- See below See below (route K) Butyl-2H-pyrazol-3-yl).5-(6- (route K) cyclopentylamino-purin-9.

lyl-tetrahydro-furan-3,4-diol 31 (2R,3R,4S,5S)-2..{6{lS. See below See below (route L) hydroxymethyf-2-phenyl- (route L) ethyla mino)-2-methoxypurin-9-ylj-5-(3-ethylrofuran-3,4-diol 32 (1 S,2R,3S,5R)-3-(3- See below See below (route M) Cyclopropyl- (route M) [1,2 ,4]oxadiazol-5-yl)-5- [2S-hydroxy-cyclopent-(S ylamino)-pudn-9-yl]cyclopentane-1 ,2-diol 33 (2R,3R,4S,5S)-2-[6-(tert- Analogous LC/ MS (System C) butylamino)-9H-purin-9-yl]-5- method to route Rt 2.91 min.

(3-cyclopropyl-1 G Mass Spectrum m/iz 402 [MH1).

yl )tetrahydrofuran-3,4-diol 34 (2S,3S,4R,5R)-2-(3- Analogous LC/ MS (System C) cyclopropyl-1 ,2,4-oxadiazol- method to route Rt 2.54 min.

)-54[6-(isopropylamino)- G Mass Spectrum 9H-purin-9- m/lz 388 ylltetrahydrofuran-3,4-d lol Table 1. Examples Ex Name Expt. Details Characterising data No I note I)1 (2R,3R.4S.5S)-2-(6- Analogous LC/ MVS (System C) R,2R)-2- method to route Rt 2.32 min.

hydroxycyclopentyljamino}- G Mass Spectrum' 9H-purin-9-yl)-5-(3-methyl- m/lz 404 [MH]I.

1 ,2,4-oxadiazol-5- I ~tetrahydrofuran-3,4-diol 36 (2S,35,4R,5R)-2-(3-methyl- Analogous LC/ MS (System C) 1 .2,4-oxadiazol-5-yl)-5-[6- method to route Rt 2.54 min.

1(tetrahydro-2.1-f-thiopyran-4- 0 Mass Spectrum ylamino)-9H-purin-9- m/lz 420 [MHJ1.

ylltetrahydrofu ran-3 ,4-diol 37 ethyl Analogous LC/ MS (System C) 3,4-dihydroxy-5-(3-methyl- method to route Rt 2.56 min.

1 ,2,4-oxadiazol-5- G Mass Spectrum yl )tetrahydrofuran-2-yl]-9H- m/z 475 [MH+J.

purin-6-yl)amino)pipeddne- 1 -carboxylate_______ 38 (2R,3R,4S,5S)-2-[6- Analogous LC/IVMS (System-C) (isobutylamino)-9H-purin-9- method to route Rt 2.51 min.

yl]-5-(3-methyl-1 G Mass Spectrum oxad iazol-5- m/z 376 yl)tetrahydrofuran-3,4-diol 39 (2R,3R,4S,5S)-2-[6- Analogous LC/IVMS (System C) (cyclopentylamino)-9H-purin- method to route Rt 2.47 min.

9-yI]-5-(3-methyl-1 G Mass Spectrum oxad iazol-5- m/z 388 yl )tetrahydrofuran-3,4-diol Table 1. Examples Ex Name Expt. Details Characterising data No I note 1)I (2R,3R,4S,55)-2-{6- Analogous LC/ MS (System C) 9H-purin-9-yl}-5-(3-methyl- G Mass Spectrum 1 ,2,4-oxadiazol-5- m/lz 374 [MH~j.

yl tetrahydrofuran-3,4-diol 41 (2R,3R,4S,5S)-2-[6- Analogous MS (System C) I(cyclopropylamino)-9H-- method to route Rt 2. 17 min.

purin-9-yI]-5-(3-methyl- 1,2,4- G IMass Spectrum oxad iazol-5- m/z 360 [MH*J.

yl)tetrahydrofuran-3 .4-dial 42 (2R,3R,4S,5S)-2-[6-(2- Analogous MS (System C) fluoroanilino)-9H-purin-9-yl]- method to route Rt 2.71 min.

5-(3-methy-1 ,2,4-oxadiazol- G Mass Spectrum 5-yi)tetrahydrofuran-3,4-diol 414 [MHJI.

43 (2R,3R,4S,55)-2-[6-(2,4- Analogous LC/ MS (System C) difluoroanilino)-9H-purin-9- method to route Rt 2.75 min.

yl]-5-(3-methyl-1 G Mass Spectrum m/lz 432 -yl)tetrahydrofuran-3,4-diol 44 (2S,35,4R,5R)-2-[3-(tert- Analogous LC/ MS (System C) butyl)-1 ,2,4-oxadiazol-5-yl]- method to route Rt 2.77 min.

Mass Spectrum [(cyclopropylmethyl )a mino]- mnlz 416 [MH 4 9H-purin-9yltetrahydrofura n-3 ,4-d jol (2S,35,4R,5R)-3-(tert- See Below LC/ MS (System C) butyl)-1,2,4-oxadiazol-5-yl]- (route N) Rt 2.88 min.

5-[6-(isobutylamino)-9H- Mass Spectrum purin-9-yl]tetrahyd rofuran- m/z 418- IMHI].

3,4-dial__ Table 1. Examples Ex Name Expt. Details Characterising data No I note 1)1 46 Analogous LC/ MS (System C) (tert-butyl-1 ,2,4-oxadiazol- method to route Rt 2.54 min.

5-ylj-3,4- N Mass Spectrum dihydroxytetrahydrofuran-2- mlz 483 [MHJ].

yl-9H-purin-6-yl)amino]-NrmethylethanesulfonamideI 47 (2S,3S,4R,5R)-2-[3-(tert- Analogous LC/ MS (System C) butyl)-1 ,2,4-oxadiazol-5-ylj- method to route Rt 2.51 min.

5-6[11 -dioxidotetrahydro- IN IMass Spectrum 2H-thiopyran-4-yl)aminoj- m/z 494 [MH 4 9H-purin-9- __yltetrahyd rofuran-3 ,4-diol 48 (2S,3S,4R,5R-2-[3-(tert- Analogous LC/ MS (System C) butyl)-1,2,4-oxadiazol-5-yj- method to route R( 3.20 min.

5-[6-(2-chloro-4- 0 Mass Spectrum fluoroanilino)-9H-purin-9- m/z 490 [M HI.

_ylltetrahydrofuran-3,4-diol 49 (2S,3S,4R,5R)-2-[3-(tert- See below (route LC/ MS (System C) butyl)-1 ,2,4-oxadiazol-5-yl]- 0) Rt 3.03 min.

5-[6-(2,4-difiuoroanilino)-9H- Mass Spectrum pu dn-9-yl]tetrahydrofu ran- mlz 474 [MH1].

_3 ,4-di11ol__ (2S,3S,4R,5R)-2-[3-(tert- Analogous LC/ MS (System C) butyl)-11,2,4-oxadiazol-5-yl]- method to route Rt 3.32 min.

5-[6-(3,4-difluoroanilino)-9H- 0 Mass Spectrum purin-9-yljtetrahydrofuran- mfz 474 [MH1.

3,4-diol__ Table 1. Examples Ex Name Expt. Details Characterising data No I note 1)1I 51 (2R,3R,4S,S)-2-[6- Analogous LC/ MS (System C) (cyclopropylamino)-9H.. method to route RI 2.39 min.

purin-9-ylj-5-(3-isopropyl. N Mass Spectrum 1 2 ,4-oxadiazol-5- m/z 388 [MH +j.

yI tetrahydrofuran-3,4-diol 52 (2R,3R,45S2.[6. Analogous LC/ MS (System C) (isobutylamino)-9H-puring9 method to route Rt 2.74 min.

yfl-5-(3-isopropyl-1 N Mass Spectrum m/z 404 [MHJI.

y!)tetrahydrofuran-3,4-diol 53 (2R,3R,4S,5S)-2-{6- Analogous LC/ MS (System C) [(cyclopropylmethyl)aminoj- method to route Rt 2.65 min.

9 H-purin-9-yi}-5-(3-isopropyl. N Mass Spectrum 1 ,2,4-oxadiazol-5- m/z 402 yl)tetrahydrofuran-34-dijol 54 Analogous LC/ MS (System C) dihydroxy--(3-isopropyl. method to route Rt 2.58 min.

1 ,2,4-oxadiazol-5- N Mass Spectrum yl)tetrahydrofuran-2-yl]-9H. 1Z 469 [MHII.

purin-6-yl~amino)-Nmethylethanesulfonamide (2R,3R,4S,5S)-2-[6-(2,4- Analogous LC/ MS (System C) difluoroanilino)-9H-purin-9 method to route Rt 2.96 min.

yl]-5-(3-isopropyl-i 0 Mass Spectrum oxad iazol-5- m/~z 460 [MHJI.

-yl)tetrahydrofuran-3,4diol 56 (2R.3R,4S,5S)-2-[6-(3,4- Analogous LC/ MS (System C) difluoroanilino)9H-purin.9 method to route R, 3.20 min.

yII-5-(3-isopropyl-i 0 Mass Spectrum oxad iazol-5- m/z 460 yl)tetrahydrofuran-3 ,4-d jol Table 1. Examples Ex Name Expt. Details Characterising data No I note 1) 57 (2R,3R,4S,55)-2-[6-(4- Analogous LC/ MS (System C) fiuoro-2-methylanilino)-9H- method to route R 3.05 min.

purin-9-yIJ-5-(3-isopropyl- 0 Mass Spectrum.

1 ,2,4-oxadiazol-5- m/z 456 [MH+I.

i yltetrahydrofuran-3,4-diol 58 (2S,3S,4R,5R)-2-f3- Analogous TLC Si0 2 (dimethylamino)-1 method to route (Cl 2

CH

2 :EtOH:880NH 3 loxadiazol-5-yIJ-5-f6- JG !95:5:0.5) Rf 0.2 (tetra hyd ro-2 H-pyran-4- Microanalysis Found C, 49.75; ylamino)-9H-purin-9- H, 5.90: N, 25.2. C 18

H

24

N

8 0 yfltetrahydrofuran-3,4-diol requires C, 49.5; H, 5.65; N, 59 (2R,3R,4S,5S)-2-{6-[rel- Analogous LC/MS (System B) (1IS,2R,4R)- method to route R, 2.81min.

bicyclo[2.2.lI hept-2- G Mass Spectrum ylamino]-9H-purin-9-yI}-5-(3- mhz 440 [MH+] cyclopropy-1 ,2,4-oxadiazol- )tetrahydrofuran-3 ,4-diol ethyl Analogous LC/MS (System B) (3-cyclopropyl-1 method to route Rt 2.57mmn.

oxad iazol-5-yl-3 G Mass Spectrum dihydroxytetrahydrofu ran-2- m/z 501 [MHJ] yl]-9H-purin-6yl~amino)piperid ine- 1 Icarboxylate 61 (2S,3S,4R,5R)-2-[3-(tert- Analogous LCIMS (System B) butyt)-1,2,4-oxadiazol-5-y]- method to route Rt 2.69min.

5-[6-(isopropylamino)-9H- G Mass Spectrum pudn-9-yljtetrahyd rofuran- m/z 404 [M H+] 3,4-diol Table 1. Examples Ex Name Expt. Details Characterising data No I note 1)1I 62 (2R,3R,4S,5S)-2-[6-(4- Analogous LCIMS (System B) chloro-2-fluoroanilino)-9- method to route Rl 3.05min.

I ,2,4-oxadiazol-5- fnlz 474 [MH1j lI tetrahydrofuran-3,4-diol 63 ethyl Analogous LC/MS (System B) 3,4-dihydroxy-5-(3-isopropyl- method to route R, 2.73min.

1 ,2,4-oxadiazol-5- IG IMass Spectrum yl)tetrahydrofuran-2-ylj-9H- mnlz 503 [MH'j purin-6-yl~amino)piperidin'e- 64 (2R,3R,4S,5S)-246-[rel- Analogous LC/MS (System A) (1lS,2R,4R)- method to route Rt 4.27min.

bicyclo[2.2. 1]hept-2- G Mass Spectrum ylamino]-9H-pudn-9-yl)-5-(3- nhz 442 [M H-] isopropy-1 ,2,4-oxadiazol-5yI)tetrahydrofuran-3,4-d jol Analogous LC/MS (System B) cyclopropyl-I ,2,4-oxadiazol- method to route Rt 2.33min.

5-yI)-3,4- G Mass Spectrum dihydroxytetrahydrofuran-2- m/z 467 [MH'] yl]-9H-purin-6-yl~amino methylethanesulfona mide 66 (2R,3R,4S.5S)-2-[2-Chloro- Analogous LC/MS (System A) 6-(1-e-thyl -propylamino)- method to route Rt 4.68min.

purin-9-yt]-5-(3-propyl- L Mass Spectrum ro- mlz 451 [M Hi ifuran-3,4-diol formate I_ I_ butyl)-4H-1 ,2,4-triazol-3-ylj- method to route Rt 3.01min.

5-[6-(4-chloro-2- FMass Spectrum fluoroanilino)-9H-purin-9- mlz 489 [MH~] yiltetrahydrofuran-3 ,4-diol 68 (2R,3R,4S,5R)-2-[6-(2- Analogous LCIMS (System C) chloro-4-fluoroanilino)-9H- method to route Rt 2.89min.

purin-9-yl]-5-(5-isopropyl-4 H- F Mass Spectrum I ,2,4-triazol-3- m/lz 475 [MH-] yl)tetrahydrofuran-3,4-diol 69 2-({9-[(2R,3R,4S ,5S Analagous Analysis: Ci 5

H

2 oN 8 0 6

S

dihydroxy-5-(3-methyl-1 method to route Found C:40.93, H: 4.72 N: G 24.89 Required yl)tetrahydrofuran-2-y]-9H- C:40.9,H:4.63,N:25.24 M/Z purin-6-yl~amino)-N- [M+HJ 441 methylethanesulfonamide (21R,3R,4S,5SY-2-{6-[(trans- Analagous M/Z 417 4-hydroxycyclohexyl )aminol- method to route 9H-purin-9-yl}-5-(5-methyl- D 1 ,3-oxazol-2yl)tetrahydrofuran-3 .4-diol 71 (2S,3S,4R,5R)-2-(3-methyl- Analagous Analysis: C21 H23N704 I ,2,4-axadiazol-5-yl)-5-(6- method to route Found C:56.41, H: 5.32 N: {[(I1RY-1-methyl-2- G 21.78, Required phenylethylamino}-9H- C: 56.49,-H:5.42, N:21 .96 purin-9-yl)tetrahyd rofuran- I 13 4-dil__ Table 1. Examples Ex Name Expt. Details Characterising data No I note 1)1 72 (25,35 ,4R, 5R)-2-(5-ethyl- Analagous Analysis: C20H26N605 1 ,3-oxazol-2-yl)-5-{6-[trans- method to route Found C:54.5, H: 6.0 N: 4-hydroxycyclohexyl)aminol- D 18.8 Required 9H-purin-9- C:55.8,H:6.1,N:19.5 M/Z ylltetrahydrofuran-3,4-diol M+Hj 432 73 (2S,3S ,4R,5R)-2-(5-ethyl- Analagous Analysis. C2OH1I9FN605 1 ,3-oxazoI-2-yl)-5-[6-(3- method to route Found C:53.6, H: 4.65 N: fluoro-4-hydroxyanilino)-9H- D 18.1 *Required purin-9-yljtetrahydrofuran- C:53.2,H:4.5,N: 18.6 M/Z 3,4-diol 443 74 (2R,3R,4S,5S)-2-[6-(3- Analagoufs M/Z M+H] 413 fluoroanilino)-9H-purin-9-y]- method to route 5-(5-methyl-1 ,3-oxazol-2- D lyl)tetrahydrofuran-3,4-diol (2S,3S,4R,5R)-2-(5-ethyl- Analagous M/Z 419 1 ,3-oxazol-2-yl)-5-(6- method to route S,2R)-2- D fluorocyclopentyllamino}-9Hpurin-9-yl )tetrahydrofu ran- 3,4-diol__ 76 (2R,3R,4S,5S)-2-[6-(4- Analogous to Rf 0. 18 (Dichloromethane: fluoroanilino)-9H-purin-9-yl]- route D. See ethanol:880ammonia 5-(5-methyl-1 ,3-oxazol-2- below (route P) 100:10:1) yl)tetrahydrofuran-3,4-diol for synthesis of M/Z 413 intermedilate. 77 (2S,3S,4R,5R)-2-[3-(tert- Analogous LC/MS (System A) Rt2.53 butyl)-1 ,2,4-oxadiazol-5-yi]- method to route min.Mass Spectrum mlz 446 5-[6-(tetrahydro-2H-pyran-4- G [MH+I.

ylamino)-gH-purin-9ylltetrahydrofu ran-3 .4-diol Table 1. Examples Ex Name Expt. Details Characterising data No I note 1)1I 78 (2R,3R.4S,5S)-2-{6-[rel- Analogous LC/MS (System A) Rt 3.03 (I S,2R,4R)- method to route min.Mass Spectrum m/z 456 bicyclo[2.2.l1 hept-2- G [MH+I.

ylaminol-9H-purin-9-y}-5-[3- (tert-butyO-1 ,2,4-oxadiazol- I 5-yljtetrahyd rofuran-3 ,4-diol 79 ethyl Analogous LC/MS (System A) Rt 2.77 [3-(tert-butyi)-1 method to route min.Mass Spectrum m/z 4517 oxadiazol-5-yl]-3,4- IG [MH+J.

d ihyd roxytetrahyd rofu ran-2yl)-9H-purin-6yl)amino]piperidine-1 ___carboxylate Analogous LC/MS (System B) Rt 3.76 (tert-butyl)isoxazol-5-yl]-3,4- method to route I min.Mass Spectrum m/z 482 dihydroxytetrahyd rofu ran-2- [M H+1.

yI-9H-purin-6-yt)amino]-N- __methylethanesulfonamide 81 (2S,3S,4R,5R)-2-[3-(tert- Analogous LC/MS (System B) Rt 4.20 butyl)isoxazol-5-yl]-5-(6- method to route I min.Mass Spectrum mlz 447 S,25)-2- fluorocyclopentyijamino}-9Hpu rin-9-yl )tetrahydrofu ran- 3,4-diol__ 82 ethyl Analogous LC/MS (System B) Rt 4.06 method to route I min.Mass Spectrum m/z 516 3,4- [MH+j.

d ihydroxytetrahydrofuran-2yi}-gH-purin-6yl)amino]piperidine-1 ca rboxylate Table 1. Examples Ex Name Expt. Details Characterising data INo (note 1) 83 (2S,3S,4R,5R)-2-[3-(tert- Analogous LCIMS (System B) butyf)isoxazol-5-yl]-5-[6- method to route I Rt 4.18 min.

(cyclopentylamino)-9H-purin- Mass Spectrum 9- 1 tetrahydrofuran -3 ,4-diol 429 [MH+I.

84 See below (route Mass Spectrum ethyl- 1,3-oxazol-2-yl mlz[MHJ+ 468 dihyd roxytetrahydrofura n-2ylj-9H-purin-6-yl)amnino)-N, Ndimethylethanesulfonamide_____________________ 2-({9-[(2R,3R,4S,5S Analagous Mass Spectrum ethyl-I ,3-oxazol-2-yl)-3,4 method to route m/z[MHJ+ 454 dihydroxytetrahydrofuran-2-' 0.

yl]-9H-pudn-6-yl~amino)-N- 1methylethanesulfona mid 86 ethyl Analagous to Mass Spectrum ,3-oxazol-2-yl)-3,4- route Q. rn/z[MH]+ =488 dihydroxytetrahydrofu ran-2yl]-9H--purin-6yt~amino)pipeddine-1 lcarboxylate 87 (2R,3R,4S,5S-2-{6-[(2,3- Analagous to Mass Spectrum dihydroxypropyl)aminol-9H- route 0. mlz[MHJ+ 407 punn-9-y}-5-(5-ethyl-1 .3oxazol-2-yl)tetrahyd rofuran- 13,4-diol 88 (211 3RA4S5S- Analagous to Mass Spectrum difluoroanilino)-9H-purin-9- route Q. m/z[MHJ+ 445 yl]-5-(5-ethyl-1 ,3-oxazol-2yl)tetrahydrofuran-3,4-diol. Table 1. Examples Ex Name Expt. Details Characterising data No I note 1)I 89 (2S,3S,4R,5R)-2-(5-ethyl- Analagous to Mass Spectrum I ,3-oxazol-2-yl)-5-(6- route Q. m/z[MHJ+ 417 S,2S)-2hydroxycyclopentyijam ino}- 9H-purin-9- I_ Yl)tetrahydrofuran-3,4-diol (2S,3S,4R,5R)-2-(5-ethyl- Analagous to Mass Spectrum 1 ,3-oxazol-2-yl)-5-{6-[3R)- route Q. m/lz[MHJ+ 403 tetrahydrofuran-3-ylaminol- 9H-purin-9yltetrahydrofuran-3 ,4-d jol 91 (2R,3R,4S,5SY-2-(6-{[(1 Analagous Microanalysis methoxy-1- method to route Found: C,46.7; H.5.3; N,23.6.

methylethyljamino}-9H- c

C

1 61H 21

N

7 0 5 requires: purin-9-yt)-5-(5-methyl-1 1314- C,46.9; H, 5.7; N,23.95.

oxadiazol-2- ___yt)tetrahydrofuran-3 ,4-d iol 92 (2R,3R,4S,5S)-2-[6- See below (route TLC Si02 (ethyl (cyclopentylamino)-9H-purifl- acetate: methanol 19:1) Rf 9-yl]-5-(3-methyl-1 0.30 oxad iazol-5- NMR (DMS0) 8.43 yl)tetrahydrofuran-3,4-dioI (1 H,s,CH); 8.20 (1 H,br.s,CH); 7.79 (iIHbr.d,NH); 6.45 (2H, v.br.s ,2x OH); 6.16 (1 H,d,CH); 5.24 (jjj~d,CH); 4.89 4.73 (1H,t.CH); 4.58 (1IH,br.m,CH); 2.42 (3H,s,Me); 12.10-1.50 8BH,m,4xCH 2 Table 1. Examples Ex Name Expt. Details Characterising data No I note 1)1I 93 (2R,3R,4S,5S)-2-(6- Analagous TLC SiO 2

(CH

2

CI

2 :MeOH: method to route 880NH 3 92:8:0.3) Rf 0. 14 hydroxycyclopentyljamino}- A Microanalysis 9H-purin-9-yI)-5-(5-phony- Found: C,55.7; H,5.1; N,20.5.

1 ,3,4-oxadiazol-2- C 22

H

23 N70 5 requires: yI)tetrahydrofuran-3,4-diol 0,55.7; H, 5.1; N,20.7 94 (2R,3R,4S,5S)-2-{6-[rel- Analagous Microanalysis (lS,5S,6R)- method to route Found: C,54.2; H,5.7; N,22.65.

bicyclo[3.2.0]hept-6- G C 19

H

23

N

7 0 4 0. ylamino]-9H-purin-9-yI}-5-(3- requires: methyl-i ,2,4-oxadiazol-5- 0,54.5; H, 5.9; N,22.8.

yl )tetrahyd rofuran-3 ,4-diol (2R,3R,4S,5S)-2-{6-[rel- Analagous Microanalysis (1 S,2S,4R)- method to route Found: 0,54.4; H,5.7; N,23.1.

bicyclo[2.2. 1]hept-2- G C 19

H

23

N

7 0 4 0.4H 2 0 requires: ylamino]-9H-purin-9-yl}-5-(3- C,54.25; H, 5.7; N ,23.3.

methyl-i ,2,4-oxadiazol-5iyI)tetrahydrofu ran-3,4-diol 96 (2R,3R,4S,5S)-2-{6-[rel- Analagous LCIMS (System B) (1iS,2R,4R)- method to route Rt 3.18min bicyclo[2.2. 1 ]hept-2- A Mass Spectrum ylamino]-9H-purin-9-y}-5-[5- mlz 544 [MH+] (tert-butyl)-1 ,3,4-oxadiazol- 12-yljtetah yd rofu ra n-3 ,4-d 97 (2R,3R,4S,5S-2-{6-[rel- Analagous LCIMS (System B) (1S,2R,4R)- method to route Rt 2.66min bicyclo[2.2.lj]hept-2- A Mass Spectrum ylamino]-9H-purin-9-yI}-5-(5- m/z 442 [MH'] isopropyl-1 ,3,4-oxadiazol-2- I lyl )tetrahyd rofu ra n-3 .4-diol Table 1. Examples Ex Name Expt. Details* Characterising data No I note 1)1 98 ethyl Analagous LC/MS (System B) 3,4-dihydroxy-5-(5-isopropyl- method to route R, 2.47min 1 ,3,4-oxadiazol-2- A Mass Spectrum IyI)tetrahydrofuran-2-ylj-9H- mz 503

[MH'J

purin-6-yllamino)piperddine- 1-carboxylate 99 2-[(9-{(2R,3R,4S,5S Analagous LC/MS (System B) (tert-butyl)- 1,3,4-oxadiazol- method to route R, 2.32min 2-yl]-3,4- A IMass Spectrum dihydroxytetrahydrofuran-2-' m/z 483 [M H-1 yl}-9H-pu rn-6-yl)amino]-N.

__methylethanesulfonamide 100 (2S,3S,4R,5R)-2-[5-(tert- Analagous LC/MS (System B) butyl)-1,3,4-oxadiazo-2-yI]- method to route Rt 2.63min R,2R)-2- A Mass Spectrum fluorocyclopentyl]amino}-9H- m/z 448 [M H-] Pudrn-9-yl )tetrahyd rofuran- _3,4-diol 101 (2S,3S,4R,5R)-2-[3-(tert- Anatagous to LCIMS (System B) butyl)-1 ,2,4-oxadiazol-5-y]- route G Rt= 2.53min 5-[6-(tetrahyd ro-2H-pyran-4- Mass Spectrum ylamino)-9H-purin-9- m/z 446 [MH-] ___yljtetrahydrofuran-3 ,4-diol 102 (2R.3R,4S,5S)-2-{6-(rel- Analagous to LCIMS (System B) (1 S,2R,4R)- route G Rt= 3.03min bicyclo[2 .2.1 Jhept-2- Mass Spectrum ylamino]-9H-purin-9-yI}-5-[3- m/z 456 [MH-I (tert-butyl)-1 .2,4-oxadiazol- I_ 15-ylltetrahyd rofuran-3 ,4-diol Table 1. Examples Ex Name Expt. Details Characterising data No I note 1)1I 103 ethyl Analagous to LC/MS (System B) [3-tert-butyl)-1,2,4- route G 2.77min oxadiazol-5-ylj-3,4- Mass Spectrum dihydroxytetrahydrofuran-2- mluz 517 [MH-1 yl)-9H-purin-6yl)aminolpiperidine-1 Icarboxylate 104 Analagous to LCIMS (System A) (tert-butyl)isoxazol-5-yl]-3,4- route I RI= 3.76min dihydroxytetrahyd rofu ra n-2- Mass Spectru m yl)-9H-purin-6-yl)aminoj-N- m/z 482 (MH] methylethanesulfonamide 105 (2S,3S,4R,5R)-2-[3-(tert- Analagous to LCIMS (System A) butyl)isoxazol-5-yl]-5-(6- route I Rt= 4.20min S,2S)-2- Mass Spectrum fluorocyclopentyl]amino)-9H- m/z 44.7 [M H-] purin-9-yI )tetrahyd rofu ran- 13,4-diol_ 106 ethyl Analagous to LC/MS (System A) route I 4.06min 3,4- Mass Spectrum dihydroxytetrahydrofuran-2- m/z 516 [MH'] yl)-gH-purin-6yl)amino]piperidine-1 lcarboxyate 107 (2S,3S,4R,5R)-2-[3-(tert- Analagous to LCIMS (System A) butyl)isoxazol-5-yll-5-[6- route I 4.18min (cyclopentylamino)-9H-purin- Mass Spectrum i 9-ylltetrahydrofu ran-3 ,4-d lol 429 [MH'j Table 1. Examples Ex Name Expt. Details Characterising data No (note 1) 108 (2S,3S,4R,5R)-2-(5- Analagous to LCIMIS (System D) cyclopropyl-1 ,3,4-oxadiazol- route A Rt= 2.28min 2-yt)-5-[6-(tetrahydro-2H- Mass Spectrum pyran-4-ylamino)-9H-purin- jmlz430 [MH'j 9-y tetrahydrofuran-3,4-diol 109 (2S,3S,4R,5R)-2-(5- Analagous to LC/MS (System 0) cyclopentyl-1 ,3,4-oxadiazol- route A Rt= 2.59min 2 S,2S)-2- Mass Spectrum hydroxycyclopentyljamino)- mlz 458 [MH-] 9H-purin-9yI)tetrahydrofuran-3 ,4-d jol 110 ethyl Analagous to LC/MS (System D) (5-cyclopentyl-1 route A Rt= 2.82min oxadiazol-2-yl Mass Spectrum dihydroxytetrahydrofu ran-2- m/z 529 [M H-] yl]-9H--purin-6yl~amino)piperidine-1 Icarboxylate 111 (2S,3S,4R,5R)-2-(5- Analagous to LCIMS (System D) cyclopentyl-1 ,3,4-oxadiazol- route A 2.93min R,2R)-2- Mass Spectrum fluorocyclopentyl]amino}-9H- m/z 460 [MH-] pudn-9-yI )tetrahydrofuran- 112 (2R,3R,4S,5S)-2-[6-(4- Analagous to LC/MS (System B) chloro-2-fluoroanilino)-9H-- route A R 2.84min purin-9-yI]-5-(5-cyclopropyl- Mass Spectrum I ,3,4-oxadiazol-2- m/z 474 [MH-] yl)tetrahydrofuran-3 ,4-dio1 Table 1. Examples Ex Name Expt. Details Characterising data No I note 1)1I 113 (2R,3R.4S,5S)-2-[6-(4- Analagous to LC/MS (System B) chloro-2-tluoroanilino)-9H- route A Rt= 3.05min Pun rn9-ylJ-5-(5-cyclopentyl- Mass Spectrum 1 ,3,4-oxadiazol-2- m/lz 502 [MH-jJ ly tetrahydrofuran-3,4-diol 114 (2S,3S,4R,5R)-2-[5-(tert- Analagous to LC/MS (System D) R, butyl)-1 ,3,4-oxadiazol-2-ylj- route A =2.88min 5-[6-(2-fluoroanilino)-9H- Mass Spectrum purin-9-yIjtetrahydrofuran- mlz 456 [MH~] 3,4-diol__ 115 (2S,3S,4R,5R)-2-[5-(tert- Analagous to LC/MS (System D) butyl)-1 ,3,4-oxadiazol-2-yl]- route A Rt= 2.96min 54[6-(2 ,3-d ifl uo roan ili no-9 H- Mass Spectrum pu rin-9-yl]tetrahydrofu ran- m~z 474 [MH'] 13,4-diol__ 116 (2S,3S,4R,5R)-2-[5-(tert- Analagous to LC/MS (System D) butyl)-1 ,3,4-oxadiazol-2-yl]- route A Rt= 3.05min 5-[6-(2-chloro-4- Mass Spectrum fluoroanilino)-9H-purin-9- m/z 490 [MH'] ylltetrahydrofuran-3 ,4-d 0 11 7.(2S,3S,4R,5R)-2-[5-(tert- Analagous to LC/MS (System D) butyl)-1 ,3,4-oxadiazol-2-y]- route A Rt= 2.86min 5-[6-(4-fluoro-2- Mass Spectrum methylanilino)-9H-purin-9- m/z 470 [MHI] ylltetrahydrofuran-3,4-diol 118 (2R,3R,4S,5R-2-{2-chloro- See below (route LC/MS (System C) 6+[1 -ethyl propyl)a mino]-9H- Rj=3.41min purin-9-yl}-5-(5- Mass Spectrum ethyl isoxazol-3- mlz 437 [MH~j yl )tetrahydrofuran-3 .4-diol formate Table 1. Examples Ex Name Expt. Details Characterising data No I note 1)I 119 (2S,3S,4R,5R)-2-[3-(tert- Analagous to LC/MS (System C) butyl)isoxazol-5-ylJ-5-{6- route I (last 2 R, 2.61 min ,1-dioxidotetrahydro-2H- steps reverse Mass Spectrum thiopyran-4-yl)aminoj-9H- order) jm/z493 [MH*] purin-9-yl~tetrahydrofuran- 120 (2S,3S,4R,5R)-2-[3-(tert- Analagous to LC/MS (System C) butyl)isoxazol-5-ylJ-5-[6-(2- route I (last 2 R, =3.29min Ichloro-4-fl uo roan il ino)-9 H- Isteps reverse IMass Spectrum purin-9-ylltetrahydrofuran- 'order) m/z 489/491 [MH]j _3 .4-diol_ 121 (2S,3S,4R,5R)-2-[3-(tert- Analagous to LC/MS (System C) butyl)isoxazol-5-yl]-5-[6-(4- route I (last 2 Rt 3.09min fluoro-2-methylanilino)-9H- steps reverse Mass Spectrum purin-9-yljtetrahydrofuran- order) m/z 469 [M H-] 13,4-diol__ 122 (2S,3S,4R,5R)-2-[3-(tert- Analagous to LC/MS (System C) butyl)isoxazol-5-yt]-5-[6-(2- route I (last 2 Rt 3.25min chloroanilino)-9H--purin-9- steps reverse Mass Spectrum __ylltetrahydrofuran-3,4-diol orde) m/z 47 1/473 [MH+] 123 2-[(9-{(2R,3R,4S,5SY-5-[5- Analogous to LCI MS (System C) (tert-butyl)-1 ,3,4-oxadiazol- route T Rt 2.52 min.

2-yl]-3 Mass Spectrum dihydroxytetrahydrofuran-2- m/z 497 [MH 4 yl-9H-purin-6-yI)aminoJ-Nethylethanesulfonamide 124 (2S,3S,4R,5R)-2-[5-(tert- Analogous to LC/ MS (System C) butyl)-1 ,3,4-oxadiazol-2-yl]- route A Rt 2.45 min.

Mass Spectrum (ethyl suIfo nyl )ethylj am ino)- m/z 482 (MH]1.

1 9H-purin-9-II Table 1. Examples Ex Name Expt. Details Characterising data No I note 1) Iyl)tetrahydrofuran-3,4-diolI 125 (2S,3S,4R,5R)-2-[5-(tert- Analogous to LC/ MS (System C) butyl)-1,3,4-oxadiazol-2-y]- route A Rt 2..6 min.

5-(6{[2-Mass Spectrum (butylsulfonyl)ethyl]amino}- m/z 510 [M H~ 9H-punin-9yl)tetrahydrofuran-3 ,4-dilt 126 Analogous to LC/ MS (System C) (tert-butyl)-1 ,3,4-oxadiazot- route A Rt 2.79 min.

2-ylJ-3,4- Mass Spectrum dihydroxytetrahyd rofu ran-2- m/lz 559 [MH 4 yI}-9H-purin-6-yl )amino]-N- (3methyiphenyl )ethanesulfona 127 Route V Mass Spectrum dihydroxy-5-(5-methyl-1 mlz 440 [MH +1.

oxazol-2-yI )tetrahydrofuran- TLC SiO 2 2-yIJ-9H-purin-6-yI~amino)-N- (dichloromethane:ethanol:anmm methylethanesulfonamide onia 50:8:1) Rf 0.21.

128 Analogous to LC/ MS (System C) (tert-butyl)-1 ,3,4-oxadiazol- route A Rt 2.7 min.

2-yI]-3,4- !Mass Spectrum dihydroxytetrahyd rofuran-2- mriz 545 yl}-9H-purin-6-yt)aminol-Nlphenylethanesulfonamide Table 1. Examples Ex Name Expt. Details Characterising data No I note 1)1 129 (2R,3R,4S,5S)-2-[6- Analogous to Analysis: Found C 49.5; H (cyclopentylamino)-9H-purin- route G 5.4; N 21.9. Required for 9-ylJ-5-[3-(methoxymethyl)- 0 18

H

23

N

7 0O 5 1.2 H 2 0 C 49.3; H 1 ,2.4-oxadiazol-5- 5.8; N 22.3.

lltetrahydrofuran-3,4-diol 130 (2R,3R,4S,5R)-2-[6- Route X Analysis: Found C 44.4; H (cyclopentylamino)-9H-purin- 4.8; N 20.4. Required for 9 ,5-dimethyl-1 H- ICj 8

H

24

N

8 0 3

.CF

3 00 2 H. 1.5 H 2 0 1 ,2,4-triazol-3- C 44.4; H 5.2; N 20.7.

yl)tetrahydrofuran-3,4-diol Itrifluoroacetate 131 (2S,3S ,4R,5R)-2-(5-ethyl- From Analysis: Found C 50.0; H 1,3,4-oxadiazol-2-yl)-5-[6- Intermediate 17, 5.7; N 24.7. C 16

H-

21

N

7 0 4 .O.1 (isopropylamino)-9H-purin-9- analagous to CH 2

CI

2 0.1 H 2 0 requires C yl]tetrahydrofuran-3,4-diol route C 50.1; H 5.6; N 25.4.

TLC Si02 (dichloromethane: methanol: ammonia 94:6:1) Rf 0.21.

132 (2R,3R,4S,5S)-2-(6- Analagous to Analysis: Found C 48.9; H route A N 21.8. C1 7 Hv12N7O5. 0.9 hyd roxycyclopentylla mino)- H 2 0- 0 .4EtOAc requires C 9H-purin-9-yi)-5-(5-methyl- 49. 1; H 5.8; N 21.6.

1 ,3,4-oxadiazol-2- TLC Si0 2 (ethyl yI)tetrahydrofuran-3,4-diol acetate: methanol 7:1) Rf 0.45.

133 (2S,3S,4R,5R)-2-[3-(methyl)- Analagous to LC/ MS (System C) I ,2,4-oxadiazo-5-yI]-5-[6-(2- route G Rt 2.91 min.

chloro-4-fluoroanilino)-9H- Mass Spectrum purin-9-ytltetrahydrofu ran- m/~z 448 [MH-1.

3 ,4-diol Table 1.'Examples ExName J~ t Details Caracterising data No Tnto 1) I1 j(2R,3R,4S,55)-2-{2-,chloro- Analagous to -ethyl propyl)a minoj-91-1- routes B and R purin-9-yi}-5-(3-cyclopropyl- I ,2g4oxadiazol-5 yl)tetrahydrofuran-3,4-diol formate (1:2) LC/ MS (System C) R, 3.22 min.

Mass Spectrum rn/z 450 [MU+J.

I

S135 (2S,3S,4R,5R)-2-(3- (tetrahydro-2H-pyran-4ylamino)-9H-purin-9ylltetrahyd rofu ran-3 ,4-d jol Analagous to route L LC/ MIS (System C) R, 2.46 min.

Mass Spectrum m/z 417 [MH+J.

~136 (2S,3S,4R,5R)-2-(3- Analagous to LC/ MS (System C) ethylisoxazol-5-yl)-5-(6- route L Rt 2.51 min.

S,2S)-2- Mass Spectrum hydroxycyclopentyl]aminol- m/z 417 9 H-purl n-9yl)tetrahyd rofu ran-3,4-d mol 137 N-ethyl-2-({9- Analagous to LC/ MS (System C) [(2R,3R,4S,5S)-5-(3- route L Rt 2.53 min.

ethyl isoxazol-5-yI)-3,4- Mass Spectrum dihydroxytetrahydrofuran-2- m/z 468 yI]-9H-pu rin-6yl~amino 138 ethyl Analagous to LC/ MS (System C) (3-ethylisoxazol-5-yl)-3,4- route L Rt 2.74 min.

dihydroxytetrahydrofuran-2- Mass Spectrum yl]-9H-purin-6- m/z 488 [MH~I yI)amino)piperidine-1 Icarboxylate I Table 1. Examples Ex Name Expt. Details Characterising data No I note 1)1I 139 (2R,3S,4R,5R)-2-[5-(tert- Analogous to LC/ MS (System C) butyl)-4H-1 ,2,4-triazol-3-ylj- route F R, 2.30 min.

5-[6-(tetrahydro-2H-pyran-4- Mass Spectrum ylamino)-9H-purin-9- m/z 445 lylltetrahydrofuran-3 ,4-diol 140 (2R,3R.4S,5R)-2-[6-(4- Analogous to LC/ MS (System C) chloro-2-fluoroanilino)-9H- route F RI 2.47 min.

purin-9-yl]-5-(4H-1 ,2 IMass Spectrum triazol-3-yl)tetra hyd rofu ran- m/z 433 _3,4-diol 141 (2R,3S,4R,5R)-2-(5- Analogousto LC/ MS (System C) isopropyl-4H-1 ,2,4-triazol-3- route F Rt 2.21 min.

yl )-5-[6-(tetrahyd ro-2H- Mass Spectrum pyran-4-ylamino)-H-purin- rr/z 431 [MH1].

19-yl]tetrahyd rofuran-3 ,4-diol 142 (2R,3R,4S,5S)-2-(6-amino- Analogous to Analysis: Found C 43.73; 2-chloro-9H-purin-9-yI)-5-(5- route Q H 3.32; N 23.04.

methyl-i ,3-oxazol-2- C 1 3 H-1 31

N

6

O

4 Cl.0.1 CF 3 00 2

H).

yl)tetrahydrofuran-3,4-diol requires C 43.54; H 3.63; N 23.08.

Mass Spectrum m/z 353 [MHj.

143 (2R,3R,4S,5S)-2-[2-chloro-6- Analogous to LC/ MS (System C) (2-chloro-4-fluoroanilino)-9H- route 0 Rt 3.19 min.

pu rin-9-yI]-5-(5-methyl-1 Mass Spectrum oxazol-2-yl )tetrahyd rofuran- m/z 482 [M H].

3,4-diol__ Table 1. Examples Ex Name Expt. Details Chiaracterising data No I note 1)1 144 (2R.3R,4S,5S-2-[6-(4- Route Wb LC/ MS (System C) chloro-2-tluoroanilino)-9H- Rt 2.95 min.

purin-9-yJ-5-(3- Mass Spectrum m/z 447 yll)tetrahydrofuran-3,4-diol 14.5 (2R.3R,4S,5S)-2-[6-(4- Analogous to LC/ MS (System C) chloro-2-fluoroanilino)-9H- route Wb Rt 3.23 min.

purin-9-yj-5-(3- Mass Spectrum m/z 475 [MHII].

ytetrahydrofuran-3,4-diol'_____________ 146 Analogouis to. LC/ MS (System C) (tert-butyl)isoxazol-5-ylj-3,4- route I R, 32.75 min.

dihydroxytetrahydrofuran-2- Mass Spectrum yl}-9H-purin-6-yI)amino]-N- ml~z 510 [M H 4 isopropylethanesulfonamide 147 (2R.3R,4,5)-2-[2-chloro-6- Analogous to LC/ MS (System C) (tetrahydro-2H-pyran-4- route L Rt 2.83min.

ylamino)-9H-purin-9-y]-5-(3- Mass Spectrum m/z 451/453 [MH].

-yl)tetrahydrofuran-3,4-diol 148 ethyl 4-(2-chloro-9- Analogous to LC/ MS (System C) [(2R,3R,4S,5S)-5-(3- route L Rt 3.10mmn.

ethylisoxazol-5-yl)-3,4- Mass Spectrum d ihydroxytetrahydrofu ran-2- m/z 522/524 [M H].

yl]-9H-purin-6yl~amino)piperidine-1 ca rboxylate__ Table 1. Examples Ex Name Expt. Details. Characterising data No I note 1)1I 149 (2R,3R,4S,5S)-2-(2-chloro- Analogous to LC( MS (System C) route L Rt 2.81lmin.

hydroxycyclopentylamino}- Mass Spectrum 9H-pu rin-9-yl)-5-(3- m/z 451/453 [MH+J.

ethyl y!)tetrahydrofuran-3,4-diol 150 (2R,3R,4S,5S)-2-(2-chloro- Analogous to LC/ MS System C 6-[-route L Rt 2.75min.

(ethylsulfonyl)ethyljamino)- IMass Spectrum 9H-purin-9-yl)-5-(3- mlz487/489 -yl)tetrahydrofuran-3,4-diol 151 (2R,3R,4S,5S)-2-[2-chloro-6- Analogous to LC/ MS (System C) (4-chloro-2-fluoroanifino)-9H- route L Rt 3.33min.

purin-9-yi]-5-(3- Mass Spectrum ethyl isoxazol-5- m/z 495/497 [M HI.

lyl)tetrahydrofuran-3 ,4-diol 152 (2R,3R,4S,5S)-2-[2-chloro-6- Analogous to LC/ MS (System C) (2-chloro-4-fluoroanilino)-9H- route L Rt 3.23min.

pu rin-9-yli-5-(3- Mass Spectrum ethyl isoxazol-5- mlz 495 [M H~ yl)tetrahydrofuran-3 ,4-diol 153 (2R,3R,4S,5S)-2-[2-chloro-6- Analogous to LC/ MS (System C) (2-tluoroa nilino)-9H-purin-9- route L Rt 3.08min.

ylJ-5-(3-ethylisoxazol-5- Mass Spectrum yt)tetrahydrofuran-3 .4-diol m/z 461/463 IM Table 1. Examples Ex Name Expt. Details Characterising data No I note 1)1 154 (2R,3R,4S,5S)-2-[2-chloro-6- Analogous to LC/ MS (System C) (2-chloroanilino)-9H-purin-9- route L R, 3.22min.

ylj-5-(3-ethylisoxazol-5- Mass Spectrum yl)tetrahydrofuran-3,4-diol m/z 477 [MHJ].

155:(2R,3R,4S,5S)-2-(6- Analogous to LC/ MS (System C) R, 2.25min route V Mass Spectrum hydroxycyclopentyljamino)- Im/z 419 [MHI].

9H-purin-9-yl)-5-[3- (hyd yltetrahydrofuran-3,4-diol______________ 156 ethyl Analogous to LC/ MS (System C) 3,4-dihydroxy-5-[3- route V Rt 2.46min.

Mass Spectrum yl]tetrahydrofuran-2-y}-9H- mlz 490 purin-6-yI )amino]piperidine- 1 -carboxyl ate 157 (2S,3S,4R,5R)-2-[3- Analogous to LC/ MS (System C) route V Rt 2.20min.

ylJ-5-[6-(tetrahyd ro-2H- Mass Spectrum pyran-4-ylamino)-9H-purin- m/z 419 [M H~ 9-ylltetrahydrofura n-3,4-diol 158 (2R,3R,4S,55)-2-[6-(4- Analogous to LC/ MS (System C) chloro-2-fluoroanilino)-9H- route L Rt 3.10 min.

purin-9-ylj-5-(3- Mass Spectrum ethyl isoxazol-5- m/z 461 yl )tetrahydrofuran-3 ,4-diol Table 1. Examples Ex Name Expt. Details Characterising data No I note 1)1I 159 (2R,3R,4S,5S)-2-[6-(2- Analogous to LC/ MS (System C) chloro-4-fluoroanilino)-9H- route L R, 2.99min.

purin-9-yij-5-(3- Mass Spectrum m/z 461 [MHJI.

yl)tetrahydrofuran-3,4-diol 160 (2S.3S,4R,5R)-2-(3- Analogous to LC/ MS (System C) ethyiisoxazol-5-y)-5-[6-(2- route L R, 2.81min.

Ifluoroa nilino)-9H-pumn-9- IMass Spectrum yl]tetrahyd rofuran-3,4-diol mlz 427 [MH+I.

161 (2R,3R,4S,5S)-2-[6-(2- Analogous to LC/ MS (System C) chloroanilino)-9H-purin-9-y]- route L Rt 2 .98min.

5-(3-ethyl isoxazol-5- Mass Spectrum yt)tetrahydrofuran-3,4-diol m/z 443 162 (2S,3S,4R,5R)-2-[5-(tert- Analogous to LC/ MS (System C) butyl)-1 ,3,4-oxadiazol-2-yJ- route Y Rt 2.11 min.

5-[6-(piperidin-4-ylamino)- Mass Spectrum 9H-purin-9- m/z 445 yljtetrahyd rofuran-3,4-d jol 163 (2R,3R,4S,5R)-2-{2-chloro- Route S LC/ MS (System C) -ethyl propyl)a mino]-9H- Rt 3.41 min.

purin-9-yl}-5-(5- Mass Spectrum ethyl isoxazol-3- m/z 437 yl )tetrahydrofuran-3,4-diol formate Table 1. Examples Ex Name Expt. Details Characterising data No I note 1)1I 164 (2S,3S,4R,5R)-2-(3- Route W LC/ MS (System C) bromoisoxazol-5-yl)-5-[6-(4- R, 3.22min.

chloro-2-fluoroanilino)-9H- Mass Spectrum purin-9-yljtetrahydrofuran- m/z 511 (MH+jJ.

3,4-diol 165 (2R,3R,4S,55)-2-[6-(4- Analagous to LC/ MS (System C) chloro-2-fluoroanilino)-9H- route W Rt 3.55min.

Ipurin-9-yl]-5-[3-(3, 5- Mass Spectrum m/z 545 [MH+J.

yiltetrahydrofuran-3,4-diol 166 (2S,3S,4R,5R-2-[3-(tert- Analogous to LC/ MS (System C) butyl)isoxazol-5-yl]-5-(6-{[1 Route Y Rt 2.69 min.

(methylsulfonyl)pipeddin-4- Mass Spectrum yI]amino}-9H-purin-g- m/z 522 [M H+I yI)tetrahyd rofuran-3,4-dio1 167,(2S,3S,4R,5R)-2-[3-(tert- Analogous to LC/ MS (System C) butyl)isoxazol-5-yl]-5-(6-{[1 Route Y Rt 2.90 min.

(propylsulfonyl)piperidin-4- Mass Spectrum yi~amino}-9H-purin-9- m/z 550 [MH+] yI )tetrahydrofuran-3 ,4-diol 168 (2S,3S,4R,5R)-2-[3-(tert- Analogous to LC/ MS (System C) butyl)isoxazol-5-yl]-5-(6-{l 1- Route Y Rt 2.87 min.

(isopropylsulfonyl)piperidin- Mass Spectrum 4-yl]amino)-9H-purin-9- mlz 550 [MH yl)tetrahydrofuran-3,4-diol Table 1. Examples Name Expt. Details Characterising data I I (~note 1)1I (2S,3S,4R,5R)-2-[3-(tert- Analogous to LC/ MS (System C) butyl)isoxazol-5-ylJ-5-(6-{[1 Route Y Rt 2.77 min.

i(ethylsulfonyl)piperidin-4- Mass Spectrum yflamino)-9H-purin-9- m/z 536 [MH-j yl)tetrahyd rofu ra n-3 ,4-diol 170 (2S,3S,4R,5R)-2-[3-(tertbutyl)isoxazol-5-yl]-5-[2chloro-6-(4-chloro-2fiuoroanilino)-9H-purin-9yl]tetra hyd rofu ra n-3 ,4-diol RtAnalogous to LC/ MS (System C) Rt 3.60 min.

Mass Spectrum m/z 524 [MH'] 171 (2S,35,4R,5R-2-[3-(tert- Analogous to LC/ MS (System C) butyl)isoxazol-5-y]-5-[2- Route I Rt 3.50 min.

chloro-6-(2-chtoro-4- Mass Spectrum fluoroanilino)-9H-purin-9- mlz 524 [MHI1 yl]tetrahydrofuran-3 ,4-dil 172 Analogous to LC/ MS (System C) (tert-butyl)isoxazol-5-yiJ-3,4- Route I Rt 2.94 min.

dihydroxytetrahydrofu ran-2- Mass Spectrum yi-2-chloro-9H-purin-6- m/z 530 yI)amino]-Nethylethanesulfonamide 173 2-[(9-{(2R,3R,45 ,5S (tert-butyl )isoxazol-5-y]-3 .4dihydroxytetrahydrofuran-2yI-2-chloro-9H--purin-6yl)amino]-Nisopropylethanesulfonamide Analogous to Route I LC/ MS (System C) R, 3.04 min.

Mass Spectrum m/~z 544 [M-1

L-

I Table 1. Examples Ex Name Expt. Details Characterising data No I note 1)1I 174 (2S,3S,4R,5R)-2-[3-(tert- Analogous to LC/ MS (System C) butyl)isoxazol-5-ylJ-5-[2- Route I Rt 2.96 min.

Ichloro-6-(tetrahydro-2H- Mass Spectrum 9-yljjtetra hydrofuran-3 .4-diol 175 (2R,3R,4S,5S)-2-[6-(4- Analogous to LC/ MS (System C) chloro-2-fluoroanilino)-9H- Route W Rt 3.02 min.

purin-9-yl]-5.-(3-pyridin-3- Mass Spectrum m/z 510 [MH 4 yl )tetrahydrofuran-3,4-diol 176 (2R,3R,4S,5S)-2-[6-(4- Analogous to LC/ MS (System C) chloro-2-fluoroanilino)-9H- Route W Rt 3.35 min.

pu rin-9-yl]-5-[3-(4- Mass Spectrum m/z 505 [MH 4 yIltetrahyd rofuran-3 ,4-diol 177 Analogous to LC/ MS (System C) (tert-butyl)isoxazol-5-yI]-3,4- Route I Rt 2.65 min.

dihydroxytetrahydrofuran-2- Mass Spectrum yl}-9H-purin-6-yl )amino]-N- mlz 496 [M H+] ethylethanesulfonamide 178 (2R,3R,4S,5S)-2-[6- Analogous to LC/ MS (System C) (cyclopentylamino)-9H-purin- Route A R, 2.80 min.

9-yl]-5-[5-(trifluoromethyl)- Mass Spectrum 1 ,3,4-oxadiazol-2- m/z 442 [MH 4 yIjtetrahyd rofu ran-3 ,4-diol I Table 1. Examples Ex Name Expt. Details Characterising data No I note 1)1I 179 (2R,3R,4S,5S)-2-(6- Analogous to LC/ MS (System C) &[I1S,2S)-2- Route A Rt 2.48 min.

hyd roxycyclopentyl~aminol- Mass Spectrum 9H-purin-9-yl)-5-[5- m/z 458 [MH~] (tdfluoromethyl)-1 ,3,4oxad iazol-2ylltetrahydrofu 180 ethyl Analogous to LC/ MIS (System C) 3,4-dihydroxy-5-[5- Route A Rt 2.74 m i.

(tnfiuoromethyl)-1 3,4- Mass Spectrum oxadiazol-2- m/z 529 [MH"] yl]tetrahyd rofu ra n-2-yl}-9Hpurin-6-yI )amino]piperidine- 1_ -carboxylate 181 2R,3R,4S,5S)-2-[6-(4-chloro- Analogous to LC/ MS (System C) 2-fluoroanilino}-9H-purin-9- Route Cc Rt 2.77 min.

yl]-5-(5-methyl-1 93,4- Mass Spectrum oxadiazol-2- m/z 448 [M HJ yl)tetrahydrofuran-3 ,4-diol 182 (2R,3R,4S,55)-2-[6-(4- Analogous to LC/ MS (System C) chloro-2-fluoroanimno)-9H- Route W Rt 3.15 min.

punn-9-yl]-5-(3- Mass Spectrum rn/i 473 [MH-I yl )tetra hyd rofuran-3,4-d jot Table 1. Examples IExpt. Details C haracterising data (note 1I I1 (2S,3S,4R,5R)-2-f3-(tert- Analogous to LC/ MS (System C) butyl)isoxazol-5-ylJ-5-{6+[(- Route Y Rt 2.74 min.

butyrylpipe rid in-4-yl)am ino]- Mass Spectrum 9H-purin-9- m/z 514 [MHJ yltetrahydrofuran-3 .4-diol lisopropyl {(f2R,3R,4S,5S)-5-[3-(tertbujtyl)isoxzo-5-yl]-3 14dihydroxytetrahydrofuran-2yl}-9H-purin-6yl)aminojpiperidine-1 carboxylate IAnalogous to Route Y LC/ MS (System C) Rt 3. 10 min.

Mass Spectrum m/z 530 [MH'I 185 (2S,3S ,4R,5R)-2-[3-(tertbutyl)isoxazol-5-y]-5-(6-f[1 (2,2,2trifluoroacetyl)piperid in-4yllamino}-9H-purin-9yl)tetrahyd rofuran-3 ,4-diol Analogous to Route Y LC/ MS (System C) R(3.05 min.

Mass Spectrum m/z 540[MH'l 186 methyl Analogous to LC/ MS (System C) 5-[3-(tert-butyl)isoxazol-5-yJ- Route Y Rt 2.73 min.

3,4- Mass Spectrum d ihydroxytetrahyd rofu ran-2- m/z 502 [MH]) yl}-gH-purin-6yI)amino]piperidine-1 Table 1. Examples Ex Name Expt. Details Characterising data No 1 note 1)1I 187 (2R,3R,4S,5S)-2-[6-(4- Analogous to LC/ MS (System C) chloro-2-fi uoroa nilino)-9H- Route V Rt 2.67 min.

m~z 463 [MHJ yfltetrahydrofuran-3 ,4-diol 188 (2R,3R,4S,5S)-2-{6-(2- Analogous to LC/ MS (System C) chloro-4-fluoroanilino)-9H- Route V Rt 2.56 min.

purin-9-yl]-5-[3- IMass Spectrum mlz 463 [M HI yl]tetrahyd rofuran-3 ,4-diol 189 (2R,3R,4S,5S)-2-[6-(2- Analogous to LC/ MS (System C) fluoroanilino)-9H-pprin-9-yl]- Route V Rt 2.40 min.

5-[3-Mass Spectrum mn/z 429 [M H-] yiltetrahyd rofu ran-3 ,4-diol 190 (2R,3R,4S,55)-2-[6-(2- Analogous to LC/ MS (System C) chloroanilino)-9H-purin-9-yl]- Route V Rt2.54 min.

5-[3-Mass Spectrum m/z 445 (MH I ytjtetrahyd rofuran-3,4-diol 191 (2R,3R,45 ,5S)-2-(2-chloro- S,2S)-2hydroxycyclopentylia mino)- 9H-purin-9-yl (hydroxymethyl ylltetrahydrofuran-3 ,4-diol Analogous to- Route Bb LCI MS (System C) R, 2.32 min.

Mass Spectrum m/z 453/455 [MH'II hEx Name Table 1. Examnl es IExpt. Details (note 1) 192 (2R,3R,4S,5S-2-[2-choro.6 (tetra hydro-2H-pyra n.4 ylamino)-9H-pudn-9-yljs. -3.

yljtetrahydrofuran.34-diJol 193 2+[2-chloro-9-

A

{(2R,3R,4S,5S)-3,4-

R

dihydroxy-5-[3- (hyd roxymethyl)isoxazol.5ylj tetra h yd rofu ra n-2-yl}-9 H- Pu rin-6-yl )aminoJ-Nethylethanesulfonamide LC/ MS (System C) ite Bb Rt 2.32 min.

Mass Spectrum Im/z453/455

[MH~J

I

nalogous to oute Bb LC/ MS (System C) R, 2.32 min.

Mass Spectrum m/z 504/506 [MH~j 194 ethyl 4-[(2-chloro-9- Analogous to LC/ MS (System C) {(2R,3R,4S,SS)-3,4- Route Bb Rt 2.60min.

dihydroxy-5-[3- Mass Spectrum (hyd roxymethyl )isoxazol-5- m/z 524 [M Hi yljtetra hyd rofu ran-2-yl}-9H- Pu rin-6-yl)amino]piperidine- 1 -carboxylate________ 195 (2R,3R,4S,5S-2-[2-chloro.6 Analogous to LC/ MS (System C) (4-chloro-2-fluoroanilino)g9H Route Rb Rt 3.10 min.

pu rin-9-yl]-5-[3- Mass Spectrum m/z 497 [MHij yljtetrahyd rofuran-3,4-diol I Table 1. Examples Ex Name Expt. Details Characterising data No I note 1)1I 196 (2R,3R,4S,5S)-2-[2-chloro-6- Analogous to LC/ MS (System C) (2-chloro-4-fiuoroanilino)-9H- Route Bb Rt 3.02 min.

purin-9-ylJ-5-[3- Mass Spectrum m/z 497/499 [MH1 yljtetra hydrofuran-3,4-cliol 197 (2R,3R,4S,55)-2-[2-chloro-6- (2-fluoroanilino)-9H-purin-9yI]-5-[3- (hyd ylJtetrahydrofuran-3 ,4-diol jAnalogous to Route Bb !LC/ MS (System C) Rt 2.72 min. Mass Spectrum frnz 463 [MH-j 198 (2S,3S,4R,5R)-2-(3- Analogous to LC/ MS (System C) ethylisoxazol-5-yl)-5-[2- Route L Rt 2.57 min..

methoxy-6-(tetrahydro-2H- Mass Spectrum pyran-4-ylamino)-9H-purin- friz 447 [MHj] 9-yIltetrahyd rofuran-3,4-diol 199 ethyl Analogous to LC/ MS (System C) (3-ethylisoxazol-5-yl)-3,4- Route L Rt 2.75 min.

dihydroxytetrahydrofuran-2- Mass Spectrum yl]-2-methoxy-9-purin-6- m~z 518 [MH+] yl~amino)piperidine-1 carboxylate 200 (2S,3S,4R,5R)-2-(3- Analogous to LCI MS (System C) ethyl isoxazol-5-yI)Y5-(6- Route L Rt 2.66 min.

S,2S)-2- Mass Spectrum hydroxycyclopentyijamino)- m'z 447 [MH 4

J

2-methoxy-9H-purin-9yI )tetrahydrofuran-3,4-diol Table 1. Examples Ex Name Expt Details Characterising data No note 1) 201 Analogous to LC/ MS (System C) ethyl isoxazol-5-y)-5-(6.{(2- Route L Rt 2.42 min.

(ethylsulfonyl)ethyjaminoy.2- Mass Spectrum methoxy-9H-purin-9- m/z 483 [MH-J yl)tetra hydrofuran-3 ,4-diol 202 (2R,3R.4S5S)-2-[6-(2. Analogous to LC/ MS (System C) chloro-4-fluoroanilino)-2- Route L Rt 3.12 min.

methoxy-9 H-purin-9-yl]-5-(3- Mass Spectrum Im/z 491 [MH"] yf)tetrahydrofuran-3 .4-diol 203 (2S,3,4R,5R)2-(3-. Analogous to LC/ MS (System C) ethyl isoxazol-5-y)Y-[6-(2- Route L Rt 2.95 min.

fluoroanilino)-2-methoxy-gH- Mass Spectrum purin-9-yl]tetrahydrofuran- ml~z 457 [MH-] 3,4-diol 204- (2R,3R,4S5S)-2-[6-(4- Analogous to LC/ MS (System C) chloro-2-fluoroanilino)-2- Route L Rt 3.20 min.

methoxy-9H-purin-9-yl]-5-(3- Mass Spectrum m/lz 491 [MH'] yI )tetrahydrofuran-3,4-diol 205 (2S,3S,4R,5R)-2-[3-(tert- Analogous to LC/ MS (System C) butyl)-1 ,2,4-oxadiazol-5-yl]- Route N Rt 2.53 min.

5-[6-(cyclopropylamino)-9H- Mass Spectrum purin-9-ylltetrahydrofuran- ml~z 402 [MH"] 3,4-diol Table 1. Examples Ex Name Expt. Details Characterising data No (note 1) 206 (2S,3S 1 4R,5R)-2-[5-(tert- Analogous to LC/ MS (System C) butyl)-1,3,4-oxadiazoi-2-yf- route Cc R, 3.32 min.

5-[2-chioro-6-(4-chloro-2- Mass Spectrum fuoroanilino)-9H-purin-9- mz 524

[MU~J

yljtetrahydrofuran-3 ,4-diol 207 (2R,3R,4S5S)-2-[6-(4- Analogous to LC/ MS (System C) chloro-2-fluoroaniiino)-9H- Route Z Rt 2.96 min.

purin-9-yi]-5-(5-isopropy- Mass Spectrum I1 ,3,4-oxadiazol-2- m/z 476 [MH~J yl)tetrahydrofuran-3,4-diol Experimental details for route (A) Intermediate 1 (3aS,45 .6R.6aR)-6-(6-Cthloro-Durin-9-vl)-2.2-dimethyl-tetrahydro-furo[34-dll .3j dioxole-4-carboxvl ic acid N'-(2.2-dimethl-Dronionvl )-hvd razide (3aS ,4S ,6R,6aR)-6-(6-Chloro-purin-9-yI)-2,2-dimethyl-tetrahydro-furo[3,4-d][1 ,3] dioxole-4-carboxylic acid (2.5g) suspended in 1 ,2-dimethoxymethane (1 Q0mI) was treated with 2,2-dimethyl-propionic acid hydrazide (1.1g) and 2-ethoxy-1ethoxycarbonyl-1 ,2-dihydroquinoline (EEDQ), and the mixture heated under reflux for 16h. The mixture was poured into aqueous citric acid (250m1) and extracted with ethyl acetate; the organic layers were washed with citric acid and brine, dried (MgSO 4 and evaporated in vacuo to give the crude product.

Purification by flash chromatography on silica gel (Biotage cartridge), eluting with ethyl acetate: cyclohexa ne 65:35, gave the title compound as a white solid (1 .92g).

LC/MS (System B3): Rt 2.49 min Mass spectrum ,n'z 439 [MHJ].

Intermediate 2 9 -f6S-(5-tert-Butv-f1 .3 .4]oxadiazol-2-vl )-2,2-imethvl-tetrahvdro-(3aR.6aS 1furo 3.4-d 1 .3)dioxol-4R- I-6-chloro-9H-~urine (3aS ,4S ,6R,6a R)-6-(6-Chloro-pu rin-9-yl)-2 ,2-dimethyl-tetrahydro-furo[3,4-.

d)[1 ,3]dioxole-4-carboxylic acid imeth yl-prop ion y).hydrazide 5g) was dissolved in thionyl chloride (I Smi) and the solution irradiated in a microwave oven at 150W power for 7 min. The excess thionyl chloride was evaporated in vacuo to give the crude product which was dissolved in dry acetonitrile (6ml) and heated under reflux for 3h. The solvent was evaporated and the residue 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 (0.645g).

LC/MS (System Rt 2.86min Mass spectrum m/z 421 [MHI].

Intermediate 3 (2S .3S.4R.5R) -2-(5-tert-Butl.[1.3,41oxadiazol-2-vl )-5-(6-chloro-purin-9-vl) tetra hydro-fu ra n-3.4-d iol 9-[6S-(5-tert-Butyl-[1 ,3,4Joxadiazol-2-yl imethyl-tetrahyd ro-(3aR,6aS)furol3,4-dlll ,3]dioxol-4R-ylJ-6-chloro-9H-purine (0.64g) was treated with 10:1 trifluoroacetic acid:water (9ml) at 0 0 C for 5h, and the mixture was allowed to stand in the refrigerator (20) overnight. The mixture was evaporated in vacuo to low volume (ca. Iml), poured into ice cold aqueous sodium bicarbonate, and extracted with ethyl acetate (3x50m1). The organic layers were washed with brine, dried (MgSO 4 and evaporated in vacuo to give the crude product (371 mg).

LC/MS (System B) R, 2.42 min Mass spectrum m/z 381 Example 3 (2S .3S .4R.5R)-2-(5-tert-Bu-rl 1.3.4loxadiazol-2-vl )-5-l6-(tetrahvdro-D~vran-4via mino)-vu rn-9-ylJ-tetrahvdro-furan-3.4-dioI (2S ,3S,4R,5R-2-(5-tert-Buty-[1 ,3,4Joxadiazol-2-yf)-5-(6-chloro-purin-9-y)tetra hydro-furan-3,4-diol (41mg) was heated under refiux: with 4aminotetrahydropyran hydrochloride (59mg), diisopropylethylamine (0.11 ml), and isopropanol (5ml) for 15h. The solvent was evaporated in vacua and the residue purified by chromatography on silica gel, eluting with ethyl acetate:methanol 100:0 90:10, to give the title compound (37mg).

LC/MS (System B) Rt 2.31 min.

Mass Spectrum m/z 446 [MH]I.

Experimental details for route (B) Intermediate 4 2-Chloro-N-(tetrahvdro-ovran-4-vl )-adenosine A mixture of acetic acid 4R-acetoxy-5R-acetoxymethyl-2R-(2,6-dichloro-purin-9yl)-tetrahydro-furan-3R-yl ester (10g), d iisopropylethyla mine (5.7ml), and 4amino tetrahydropyran hydrochloride (2.02g), in isopropanol (200m1) was heated at 500 for 4h. The cooled mixture was evaporated in vacuo, the residue redissolved in methanol (200m1) and ammonia gas bubbled through the solution for 2h. The mixture was stirred at 22*C overnight, and evaporated in vacua to give a brown oily solid. Purification by flash chromatography on silica gel (Merck 9385), eluting with 75:8:1 DCM:EtOH:880NH 3 to 50:8:1 DCM:EtOH:880NH 3 gave the tite compounld as a pale brown oily solid (7.81g).

LCIMS (System B) Rt 2.24 min.

Mass spectrum tWz 3.86 Intermediate {6R-f2-Chloro-6-(tetrahvdro-vran-4-vamino)-Du rin-9-vtl-2.2-dimethvl-tetrahvdro- (3aR .6aR)-furo[3 .4-diM.31dioxol-4R-vll-methanoI A solution of 2-chloro-N-(tetrahydro-pyran-4-yl)-adenosine (7.81g) in acetone (500ml) was treated with 2,2-dimethoxypropane (14.7ml) and ptoluenesulphonic acid (3.8g) and the mixture was stirred at 22*C overnight. A white precipitate formed. The mixture was evaporated in vacuo, and the residue partitioned between ethyl acetate (700ml) and aqueous sodium bicarbonate solution (500ml). The organic layer was washed with aqueous sodium bicarbonate (2x250ml), dried (Na 2

SO

4 and evaporated in vacuo to give a pale brown foam 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 (5.7g).

LC/MS (System B) Rt 2.68 min.

Mass spectrum m/z 426 [MHI].

Intermediate 6 (3aS,4S,6R,6aR)-6-[2-Chloro-6-(tetrahvdro-pvran-4-ylamino)-purin-9-vll-2,2dimethvl-tetrahvdro-furo[3.4-dr[1.3dioxole-4-carboxvlic acid A solution of {6R-[2-chloro-6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-2,2dimethyl-tetrahydro-(3aR,6aR)-furo[3,4-d][1,3]dioxol-4R-yl}-methanol (2.5g) in ethyl acetate (90ml) was treated with saturated aqueous sodium bicarbonate solution (60ml) and the biphasic mixture stirred rapidly at 0°C. After stirring at 0°C for 5 min, potassium bromide (70mg) was added followed by 2,2,6,6tetramethyl-1-piperidinyloxy, free radical (TEMPO) (4.6mg). A freshly prepared solution of sodium bicarbonate (185mg) in aqueous sodium hypochlorite (3.2ml) and water was added dropwise to the cooled, stirred mixture over 15 min. The mixture was stirred for a further 20 min at 0°C. Two further additions were made of potassium bromide, TEMPO, and the freshly prepared sodium bicarbonate/ aqueous sodium hypochlorite solution same quantities as before, followed each time by stirring at 0°C for 15-20min. The mixture was poured into ethyl acetate (400ml), shaken with sodium sulphite (10g), diluted with water (300ml), shaken, and the organic and aqueous layers separated. The aqueous layer was acidified to pH 1-2 with 2N hydrochloric acid solution and extracted with ethyl acetate (2x 300ml). The organic layers were combined with those from a second, identical reaction, and evaporated in vacuo to give the product as a cream foam (4.47g).

LC/MS (System B) Rt 2.81 min.

Mass spectrum m/z 440 [MH'j.

Intermediate 7 (3aS .45 .6R.6a R)-6-l'2-Chloro-6-(tetrahydro-cpvran-4-vlamino )-n~urn-g-vfl-2.2dimethvl-tetrahydro-furof3 .4-din .3idioxole-4-carboxlic acid N'-(2.2-dimethvl- Dropionvi )-hydrazide Diisopropylethylamine (0.487m1) was added to a stirred solution of (3aS .45,6R,6aR)-6-[2-chloro-6-(tetrahydro-pyran-4-ylamino)-purin-9-ylJ-2,2dimethyl-tetra hyd ro-furo(3 ,4-dJ[1 ,3]dioxole-4-carboxylic acid (350mg) in dry tetrahydrofuran (8ml) at 0 0 C under nitrogen. After 5 min pivaloyl chloride (0.098m1) was added and the mixture was stirred at 0 0 C for 2.5h. 2,2-Dimethylpropionic acid hydrazide was added in tetrahydrofuran (2m1) at 00, and stirring was continued at 0-22*C overnight. The mixture was concentrated in vacuc and partitioned between ethyl acetate (2x30m1) and saturated aqueous sodium bicarbonate (30m1). The organic layers were washed with brine (50mI), dried (MgSO 4 and evaporated in vacuo. The residue was azeotroped with dichioromethane (1lOmi) to give the title compound as a cream solid- (357mg).

LC/MS (System B) Rt 2.76 min.

Mass spectrum m/z 538 Intermediate 8 f9-[6S-(5-tert-Butvl-l 1.3,41oxadiazol-2-yl)-2.2-dimethyl-tetrahydro-(3aR.6aS furor3 .4-dll .31d ioxol-4R-vll-2-chloro-9H-punn-6-vll-(tetrahvd ro-ovran-4-vI) amine (3aS ,4S ,6R,6a R)-6-[2-Chloro-6-(tetrahydro-pyran-4-ylamino)-pu rin-9-ylJ-2,2dimethyl-tetrahyd ro-furo[3 ,3]dioxole-4-carboxylic acid ,2-dimethyipropionyl)-hydrazide (150mg) was dissolved in N,N-dimethylformamide (1 .2m1) and the solution cooled to 0 0 C under nitrogen. To the cooled, stirred solution phosphorous oxychlonide (0.039ml) was added. The solution was stirred at 0 0

C

for 1 h, and at 22*C for 1 6h. The mixture was cooled to 0 0 C, more phosphorous oxychloride (0.026m1) was added, and the mixture was stirred at 0 0 C for 1lh, and at 22 0 C for 20h. The mixture was partially evaporated in vacuo, and partitioned between ethyl acetate (2x30ml) and aqueous sodium bicarbonate (30ml). The organic layers were dried (MgSO 4 and concentrated in vacua to give a yellow oil. Purification by flash chromatography on silica gel, eluting with 30-100% ethyl acetate in cyclohexane, gave the title compound LC/MVS (System A) R, 4.41 min.

Mass Spectrum mlz 520 [MH Example 8 (2S.35 .4R.5R)-2-(5-tert-Butyl-1 ,3.4loxad iazol-2-vl )-5-[2-chloro-6-(tetrahvdropyran-4-vla mino)-purin-9-vll-tetrahvdro-furan-3,4-d jol formate {9-[6S-(5-tert-Butyl-[1 ,3,4]oxad iazol-2-yI )2 ,2-dimethyl-tetrahydro-(3a R,6aS)fu ro[3 [1 ,3]d ioxol-4R-yl]-2-chloro-9H-pu rin-6-yl}-(tetrahydro-pyran-4-yl)amine (60mg) was dissolved in 10:1 trifluoroacetic acid:water (2m1) and the mixture was stirred at 000 for 1lh, and at 22 0 C for 4h. The mixture was evaporated in vacua, and azeotroped with toluene (2x6ml). The residue was purified by preparative HPLC (gradient profile 5-90% (ii) over 18.5 min) to give the title compound as a white solid (37mg).

LCIMS (System-A) R~t 3.86mmn Mass spectrum m/lz 480 [MHI Experimental details for route (C) Intermediate 9 (3aS .45 .6R.6aR)-6-(6-Cvclogentlamino-pu rin-9-vl .2-dimeth ltetrahydrofuror3 .4-dll .3ldioxole-4-carboxylic acid methyl ester A solution of (3aS ,4S, Ra)6(-ylpnyaio-ui--l-,-iehl tetra hyd ro-fu ro[3 ,4-d]l ,3]d ioxole-4-carboxyl ic acid (3.01 8g) and 2-ethoxy-1 ethoxycarbonyl-1 .2-dihydroquinoline (2.66g) in methanol (120m1) was heated under reflux for 1 7h. The resulting mixture was concentrated in vacua and the residue dissolved in ethyl acetate (150ml). The solution was washed with aqueous citric acid solution (3x25m1) and brine (50ml), dried (magnesium sulphate), and evaporated in vacuo to give a white foam. Purification by column chromatography on silica gel, eluting with ethyl acetate:cyclohexane gave the title compound as a white solid (2.32g).

TLC SiO 2

(CH

2 C1 2 :MeOH:880NH 3 94:6:1) Rf 0.62 Intermediate (3aS .4S .6R.6aR )-6-(6-Ovclopentvlamino-pu rin-9-vl .2-dimethyl-tetrahydrofuror3.4-dlrl .31dioxole-4-carboxvlic acid hydrazide A mixture of (3aS,4S,6R,6aR)-6-(6-cyclopentylamino-purin-9-y)-2,2-dimethyltetra hydro-fu ro[3,4-d[1 ,3]dioxole-4-carboxylic acid methyl ester (0.48 g) and hydrazine hydrate. (0.29 ml) in methanol (10 ml) was heated at reflux for 28h.

After cooling to room temperature, the mixture was concentrated in vacuo and the residue evaporated twice with dichloromethane (2 x 20 ml) to give the title compound as a white solid (0.49g).

NMR (DMSO) 9.4 (jjj, brs, NH), 8.32 (IH, s, OH), 8.20 CIH, s, OH), 7.90 brd, NH), 6.35 OIH, brs, OH), 5.28 (2H, brm, 2 x OH), 4.65 brs, OH), 4.50 (1 H, brm, OH), 4.20 QH brs, NH-2), 2.0-1.5 (11 H, 2xm s, 4 x OH 2

OH-

3 Intermediate 11 Cyclopentvl-f9-(2 .2-d imethyl-6S-fl .3,41oxad iazol-2-yl-tetrahvdro-(3aR.6aS)furol3 .4-dlfl .31dioxol-4R-yl)-9H-Durin-6-vll-amine A mixture of (3aS ,4S ,6R,6aR)-6-(6-cyclopentylamino-purin-9-yt)-2,2-dimethyltetra hyd ro-fu ro[3 I ,31d ioxole-4-carboxyl ic acid hydrazide (0.5g) and triethylorthoformate (5 ml, 4.45g) was heated at refiux for 48h; on cooling, the solution was evaporated to give a brown oil. Purification by flash chromatography on silica gel, eluting with ethyl acetate: cyclohexane afforded the title compoundas a cream foam (0.157 g).

TLC SiO 2 (Ethyl acetate:cyclohexane 3:1) Rf 0.17 Example (2R.3R .4S .5S )-2-(6-Cyctorpentylamino-punn-9-y )-5-fl'.3,4loxadiazol-2-vltetra hydro-fura n-3.4-diol Trifluoroacetic acid (1.5 ml) and water (0.15 ml) were added to cyclopentyl-[9- (2 ,2-dimethyl-6S-[1, 3,4joxadiazol-2-yl-tetrahydro-(3aR ,6a S)-furo[3,4- ,31d ioxol-4 R-yl)-9 H-purin-6-yl]-a mine (0.157 g) at 0 C and the mixture was stirred for 2 h. The resulting solution was poured 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 Methanol (20 ml) was added and the solid filtered off to afford the title compound as a white solid (0.46 g).

TLC SiO 2 (Ethyl acetate) Rf 0.13 Analysis Found: C, 50.77; H, 5.14; N, 25.53%

C

16

H

19

N

7 0 4 0.2MeOH. 0. 1H 2 0 requires: C 50.99; H, 5.3; N, 25.7% Experimental details for route (D) Intermediate 12 (3 aSA 4S. 6 R,6aR)-6-(6-Ch loro-nu rin-9-fl)-2 .2-d imethyl -tetra hyd ro-fu ro[3.4dfli. 31d loxol e-4-ca rboxylic acid (2-oxo-butyl mide A solution of (3aS,4S,6R,6aR)-6-(6-chloro-purin-9-y )-2,2-dimethyl-tetrahydrofuro[3,4-dJ[1 ,3]dioxole-4-carboxylic acid (1 in dry tetrahydrofuran (30ml) was cooled to 30C before triethylamine (1.07m1) was added. After strirning for 15 min at 30C, trimethylacetyl chloride (O.56ml) was added and the suspension stirred for 40 min at 300. This suspension was. added to a stirred mixture of the 2oxobutylami ne hydrochloride in acetonitrile (50ml) containing triethylamine (2.3ml). The mixture was allowed to warm to room temperature, stirred overnight, and partitioned between ethyl acetate (iS0mI) and 10% aqueous sodium chloride (lO0mI). The separated aqueous phase was further extracted with ethyl acetate-(2xOOml)-and' the combined organic extracts were washed with brine (70m1), dried and concentrated in vacuo to give a dark red gum-~ (1 .83g). 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 8 (C~DC 3 8.68 8.27 (IH,s,CH), 6.73 (IH,brt,NH), 6.30 (IH,d,CH), 5.64 (IL,dd,CH), 5.46 (IH,dd,CH), 4.80 3.76 (2H,ABXCH 2 2.26 (2H,q,CH 2 1.65 (3H,s,-CH 3 1.42 QH,s,-CH 3 0.99 (H,t,CH 3 Intermediate 13 6-Chloro-9-f6S-(5-ethyl.oxazol-2-vl .2-dimethvl-tetrahvdro-(3a R,6aS )-furol'3.4dll 3 )dioxol-4R-vll-9H-Durine Phosphorous oxychloride (1 .43g) was added to a stirred solution of (3aS ,4S ,6 R, 6aR)-6-(6-chloro-purin-9-y).2,2.d imethyl-tetrahydro-fu ro[3,4d][1 ,3Jdioxole-4-carboxylic acid (2-oxo-butyl)-amide (1 .05g), in acetonitrile (60m1). The solution was stirred at reflux for 5.5h before standing at room temperature overnight. Stirring was continued at reflux for a further 4.5h, and the mixture was cooled and partitioned between ethyl acetate (iS0ml) and 8% aqueous sodium bicarbonate (lO0mI). The separated aqueous phase was further extracted with ethyl acetate (1 x1 O0mI) and the combined organic extracts were dried and concentrated in vacuo to give a red gum (1 Purification by chromatography on silica gel (Merck 7734), eluting with d ichlo rometha ne: ethanol: ammonia (250:8:1) gave the title compound as a yellow gum (0.86g).

TLC SiO 2

(CH

2

CI

2 :EtOH:880NH 3 100:8:1) Rf Intermediate 14 (2 R.3 R.4 S.5S )-2-(6-Chloro-Du nn-9-yl 5-(5-ethyl-oxazol-2-vl )-tetrahyd ro-furan- 3.-iol To cooled (00) 6-chloro-9-[6S-(5-ethyl-oxazol-2-y )2 ,2-d imethyl-tetrahydro- (3aR,6aS)-furo[3,4-d[1 ,3]dioxol-4R-yl]-9H-purine (0.85g) was added a cold (0 0 C) mixture of trifluoroacetic acid (8.2ml) and water (0.8mi). The mixture was stirred at O 0 C for 5h 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) (3x40m1) to give a yellow liquid (4m1). This was diluted with ethanol (5mi) 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 (0.355g).

NMR 8 (DMSO) 9.00 (1H,s,CH), 8.85 (IH,s,CH), 6.99 (IH,fine t,CH), 6.1-5.9 (2H,2xbrs,2xOH), 5.05 (IH,d,CH), 4.89 4.70 2.7 (2H,dq,CH 2 1.20 (L,t,CH 3 Example 16 (25 .3S .4R.5R)-2-(5-Ethyl-oxazol-2-yl )-5-r6-(tetra hydro-Pyran-4-ylamino)-purin-9vll-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 19g), in isopropanol (1 5ml) was added diisopropylethylamine (0.3ml) and 4-aminotetrahydropyran hydrochloride (0.135g). After stirring at reflux for 16h, further dilsopropylethylamine (0.2ml) and 4-aminotetrahydropyran hydrochloride (60mg) were added. Stirring was continued at reflux for a further 20h before the mixture was cooled and concentrated in vacuo to give a yellow gum Purification by chromatography on silica gel (Merck 7734) with dichloromethane:ethanol: ammonia (250:8:1) (100:8:1), gave the title commound, as a white foam 182g).

Mass spectrum m/lz 417 [MH+] NMR 8 (CDC13) 8.27 (1H,s,CH), 8.13 (1H,s,CH), 6.72 (IH,s,CH), 6.6-6.2 (1H,Vbrs,-OH), 6.21 5.98 (1H,brd,NH), 5.31 (1H1dCH), 4.79 (2H,m,2xCH), 4.40 (1H,brs,CH), 4.02 (2H,brd,2xCH equatorial), 3.57 (2H,t,2xCH axial), 2.66 (2H,q,CH 2 2.07 (2H,brd,2xCH equatorial), 1.63 (Q,brq,2xCH axial), 1.23 (aH,t,CH 3 Experimental details for route (E) Example 17 (2S .3S .4R.5R) -2-(6-Cvclonentlamino-puin-9-vl f1.3,41thiadiazol-2-y)-tetrahvdro-furan-3 ,4-d iol Cyclopropanecarboxylic acid N'-[6R-(6-cyclopentylamino-purin-9-yl)-2,2dimethyl-tetrahydro-(3aS,6aR)-furo[3,4-dJ[1,3Jdioxole-4S-carbonyl]-hydrazide (12mg) was heated at 80°C with Lawesson's reagent (19mg) in acetonitrile (2ml) for 8h. Further Lawesson's reagent (40mg) was added, and the mixture heated at 70°C for 16h. The solvent was evaporated and the residue 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 (31mg). This material was treated with trifluoroacetic acid (Iml) and water (0.1ml) and the solution allowed to stand at 4°C overnight (19h). The mixture was poured into ice cold aqueous sodium bicarbonate and extracted with ethyl acetate (3x15ml). The organic layers were washed with brine, dried (MgSO 4 and evaporated in vacuo to give a colourless gum. Purification by automated HPLC (gradient profile 30-60% (ii) over 20 min) gave the title compound (1.33mg).

LC/MS (System A) Rt 4.0 min Mass spectrum m/z 430 [MH Experimental details for route (F) Intermediate (3aS.4S,6R.6aR)-6-(6-Isooproplamino-purin-9-vl)-2,2-dimethyl-tetrahvdrofuro[3.4-dr][1.3dioxole-4-carboxvlic acid A mixture of (3aS,4S,6R,6aR)-6-(6-chloro-purin-9-yl)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxole-4-carboxylic acid (5.82g) and isopropyl amine (7.27 ml) in isopropanol (20 ml) was heated under reflux for 40h, 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 washed with citric acid solution (2 x 50 ml).

The combined organic extracts were washed with water (50 ml) and brine ml), dried (MgSO 4 filtered and concentrated in vacuo to afford the title compound as a light brown foam (4.49 g).

TLC SiO 2 (ethyl acetate) Rf 0.35 Intermediate 16 (3aS.4S.6R.6aR)-6-(6-sorojlamino-nunn-9-l )-2.2-dimethvl-tetrahydrofurof3,4-dl'1.3ldioxole-4-carboxlic acid methyl ester A mixture of (3aS,4S,6R,6aR)-6-(6-isopropylamino-pu rin-9-yl)-2,2-dimethyltetra hyd ro-fu ro [3,4-dj 1 ,3Jdioxole-4-ca rboxylic acid (4.82 g) and 2-ethoxy-Nethoxycarbonyl- 1,2-dihydroquinoline (EEDQ, .3.36 g) in methanol (150 ml) was heated under reflux for 60h. After cooling to room temperature, the solution was concentrated in vacuo and the resulting residue partitioned between ethyl acetate (100 ml) and citric acid solution (0.5M, 75 ml). The aqueous 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 (MgSO 4 filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel, eluting with ethyl acetate: cyclohexane to afford the title compound as a white solid (3.76 g).

TLC SiO 2 (ethyl acetate:cyclohexane 1:1) Rf 0.20.

Intermediate 17 (3aS.4S .6R.6aR)-6-(6-soropylamino-Durin-9-yl .2-dimethyl-tetrahvdro furol3,4-dlfl,1 3dioxole-4-carboxlic acid hydrazide A mixture of (3aS ,4S ,6R,6aR)-6-(6-isopropylamino-purin-9-yl)-2,2-dimethyltetra hyd ro-fu ro [1 ,3]dioxole-4-carboxyl ic acid methyl ester (3.76 g) and hydrazine hydrate (1.26 ml) in methanol (140 ml) was heated under reflux for 48h. After cooling to room temperature, the mixture was concentrated in vacuo and the residue triturated with ethyl acetate to afford the title compound as awhite solid (3.3 g).

Analysis Found: C, 51.5; H, 6.5; N, 23.6%

C

16

H

23

N

7 0 4 Q.4EtOAc requires: C, 51.0; H, 6.4; N, 23.8% Example 18 (2R.3R .4S .5R)-2-(6-lsopropvlamino-purin-9-y )-5-(5-methyl-4H-[1 .2 ,4flrazol-3vI )-tetrahvdro-fura n-3 .4-diol trifluoroacetate A mixture of (3aS,4S,6R,6aR)-6-(6-isopropylamino-purin-9-yl)-2,2-dimethyltetrahydro-furo[3,4-dj[1,3Jdioxole-4-carboxylic acid hydrazide (0.5 g), ethylacetimidate hydrochloride (0.24 g) and triethylamine (0.55 ml) in ethanol ml) was heated under reflux for 72h and cooled to room temperature. The solvent was evaporated in vacuo and the residue purified by flash chromatography on silica gel (Merck 9385), eluting with ethyl acetate: methanol to afford a white solid (0.37 which was treated with trifluoroacetic acid (3.6 ml) and water (0.36 ml); the mixture stirred at 0°C for 6h. The resulting solution was evaporated to dryness, toluene was added and the mixture reevaporated to dryness. The resulting residue was triturated with ethyl acetate to afford the title compound as a white solid (0.41 g).

R (DMSO) 8.71 (IH, brs, NH), 8.40-8.20 (2H, s brs 2 x CH), 6.11 (1H, d, CH), 5.00 d, CH), 4.73 (1H, t, CH), 4.44 (2H, t brm, 2 xCH), 2.42 (3H, s, CH 3 1.27 (6H, d, 2 x CH 3 Analysis Found: C, 42.9; H, 4.45; N, 23.5% Ci 5

H

2 0

N

8 0 3 requires: C, 43.0; H, 4.4; N, 23.6% Experimental details for route Intermediate 18 6-Chloro-9-[6S-(3-cvclopropDl-[1,2,41oxadiazol-5-yl)-2,2-dimethyl-tetrahydro- (3aR,6aS)-furo[3,4-d[1,31dioxol-4R-vll-9H-purne A suspension of (3aS,4S,6R,6aR)-6-(6-chloro-purn-9-yl)-2,2-dimethyltetrahydro-furo[3,4-d][1,3]dioxole-4-carboxylic acid (4.17 g) in anhydrous tetrahydrofuran (80 ml) was cooled under nitrogen to 5°C. To the suspension was added diisopropylethylamine (4.68 ml). Pivaloyl chloride (1.65 ml) was added after 10 min, and the mixture was stirred at 0°C for 1 h, and allowed to warm to room temperature over 1 h. The mixture was again cooled to cyclopropylamidoxime (1.47 g) was added dropwise, the cooling bath was removed and stirring was continued at 220C for 18 h. The diisopropylethylamine hydrochloride was filtered off and washed with tetrahydrofuran (100 ml). The filtrate was heated at reflux for 10 h, 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 to afford the title compound as a white solid (1.99 g).

LC/MS (System B3): 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-f 1.2.4loxadiazol-5-yl tetra hvdro-furan-3 .4-d iol A solution of 6-chloro-9-[6S-(3-cyclopropyl-[1 ,2,4joxadiazol-5-yl)-2,2-dimethyltetra hyd ro-(3a R,6a S)-fu ro[3,4-d ,3]dioxol-4 R-ylJ-9 H-pu rine (1 .99g) in a cold mixture of trifluoroacetic acid: water 1; 25 ml) was kept at 4 0 C for 20 h. The resulting solution was basified in an ice baith with a saturated solution of sodium bicarbonate (200 ml), extracted with ethyl acetate 3 x 70 ml) and the extra 'cts 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 afford the title compound (1.29 g) as a white solid.

LC/MS (System B3): Rt 2.42 min Mass spectrum m/z 365 (MH t Example 19 (2S;*3S.4R.5R)-2-(3-Cycloroovl-[1 .2.4loxadiazol-5-vl )-5-E6-(2S-hvdroxycyclopent-(S)-vlamino rn-9-vll-tetrahyd ro-furan-3.4-d iol To a solution of (2R,3R,4S,5S )-2-(6-chloro-punn-9-y)-5-(3-cyclopropyl- [1 .2,4Joxadiazol-5-yl)-tetrahydro-furan-3,4-dioI (50 mg) in isopropanol (5 ml) was added diisopropylethylamine (0.072 -ml) and trans-(1 S,2S)-2aminocyclopentanol hydrochloride (37.8 mg). The mixture was heated at reflux for 48 h, cooled to room temperature and concentrated to dryness in vacuo to give a residue which was purified by solid phase extraction (5 g, Varian Mega Bondelut cartridge, aminopropyl bonded phase, eluting with CHCI 3 (ii) ethyl acetate: cyclohexane (iii) ethyl acetate, (iv) dichloromethane, (v) dichloromethane:methanol (vi) dichloromethane:methanol (10:1) and (vii) methanol to afford the title compound (47.3 mg).

LC/MS (System B3): Rt 2.37 min Mass spectrum m/z 430 (MH*) Experimental details for route (H) Intermediate 4-r9-(6S-Carboxw-2 .2-dimethyl -tetrahydro-(3a R.6aS )-furof3,4-dlf 1.3ldioxol-4Ryl)-9H-punn-6-vlaminol-piperidine-l1-carboxylic acid ethyl ester A mixture of ethyl-4-amino-piperidinecarboxylate (1.80 ml), (3aS,4S,6R,6aR)-6- (6-chloro-purin-9-y)-2,2-dimethyi-tetra hyd ro-furo[3 ,4-dJ[1 ,3]dioxole-4-carboxylic acid (2.0 g) and diisopropylethylamine (2.74 ml) was heated at reflux in isopropanol (100 ml) for 70 h. After cooling to room temperature the mixture was concentrated in vacuo. Water (100 ml) was added to the residue and the mixture acidified to pH 4 (citric acid). The mixture was rapidly extracted with dichloromethane (3 x 50 ml) and the extracts dried (MgSO 4 and concentrated in vacuo to afford the title compound as a yellow solid (2.56 g).

LCIMS (System B3): Rt 2.62 min Mass spectrum mlz 477 Intermediate 21 4-r9-(6S-Carbamol-2,2-dimethvl-tetrahydro-(3aR.6aS -uro3.4-dll.3ldioxol-4Rvi )-9H-nurin-6-vlaminol-r~dinime-l1-carboxylic acid ethyl ester A cooled (0 0 C) solution of 4-[9-(6S-carboxy-2,2-dimethyl-tetrahydro-(3aR,6aS)furo[3 ,4-dlll,3Jd ioxol-4R-yl )-9H-pu rin-6-ylaminoJ-pipenidine-1 -carboxylic acid ethyl ester (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 min. 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 afford the title compound as a pale orange solid (1.97 g).

LC/MS (System Rt 2.54 min Mass spectrum m/z 476 (MH Intermediate 22 4-f9-(6R-Cyano-2,2-dimethvl-(3aR.6aR)-tetrahydro-furof3 4-dll.3idioxol-4R-yI- 9 H-purin-6-ylamino-piperidine- 1 -carboxylic acid ethyl ester A solution of 4-[9-(6S-carbamoyl-2,2-dimethyl-tetrahydro-(3aR,6aS)-furo[3,4 d]l[ 3Jdioxol-4R-yl)-9H-purin-6-ylaminol-piperidine-1-carboxylic acid ethyl ester (1.97 g) in anhydrous acetonitrile (40 mi) was treated with 4dimethylaminopyridine (1.01 The mixture was cooled to 0 0 C and phosphorus oxychloride (1.93 mi) added dropwise. The mixture was allowed to warm to room temperature and stirred at this temperature for 1 h then heated at reflux for 7 h. After cooling, the mixture was evaporated to dryness in vacuo to give the crude product which was dissolved in water (50 mi) and extracted with ethyl acetate (3 x 70 ml). The extracts were concentrated in vacuo to afford the title compound as a pale orange solid (1.91 g).

LC/MS (System Rt 4.09 min Mass Spectrum m/z 458 (MH+) Intermediate 23 4-{9-[6R-(N-Hydroxvcarbamimidoyl)-2,2-dimethvl-tetrahvdro-(3aR.6aR)-furo[3,4di[l .,3]dioxol-4R-ll-9H-purin-6-vlamino}-pipedine- 1-carboxylic acid ethyl ester 4-[9-(6R-Cyano-2,2-dimethyl-(3aR,6aR)-tetrahydro-furo[3,4-d][1,3]dioxol-4R-yl)- 9 H-purin-6-ylamino-piperidine-1 -carboxylic acid ethyl ester (1.0 g) and hydroxylamine 0.29 ml) were heated at reflux in ethanol (25 mi) for 9 h.

After cooling, the mixture was concentrated in vacuo and the residue was coevaporated in toluene (50 ml) to give the title compound as a yellow solid (1.25g).

LC/MS (System Rt 3.82 min Mass spectrum m/z 490 (MH Intermediate 24 4-i9-f6R-(5-tert-Butyl-f 1.2.41oxadiazol-3-l .2-dimethyl-tetra hvdro-(3aR .6aR furof3 .4-dll .3JdioxolAR-vll-9H-purin-6-ylamino}-nileridine-I -carboxylic acid ethyl ester 4 -{9-[6R-(N-Hydroxycarbamimidoyl)-2,2-dimethyl-tetrahydro-(3aR6aRfuro3,4.

dJ[1 ,3]dioxol-4R-yl]-9H-purin-6-ylaminoj-piperidine- 1-carboxylic acid ethyl ester g) was stirred with pivalic acid (15 ml) and pivalic anhydride (0.49 ml) at ambient temperature for 2 h, then heated at reflux for 9 h. 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 (MgSO 4 and concentrated in vacuo. -To the residue was added diethylether (100 ml). A brown precipitate was formed and filtered off, and the filtrate was concentrated in vacuo to afford a crude product. Purification by chromatography on silica gel (Varian Mega Bondelut cartridge) eluting with ethyl acetate afforded- the title compound as a pale orange oil (0.360g).

LC/MS (System B):Rt 3.13 min Mass spectrum m/z 557 (MH+) Example 26 449-l5R-(5-tert-Buthl-f1.2 .41oxadiazol-3-vl )-3R.4S-d ihvd roxy-tetrahydro-furan- 2R-vll-9H-Du rin-6-vlaminol-oineridine-1 -carboxylic acid ethyl ester A solution of 4-{9-[6R-(5-tert-butyl-[1 ,2 ,4]oxad iazol-3-yl)-2 ,2-dimethyl-tetrahydro- (3a R,6a R)-fu ro[3,4-d] 3]d ioxol-4 R-yl]-9 H-pu ri n-6-yla m ino}-pipe rid ine-1I carboxylic acid ethyl ester (360 mg) in a cold mixture of trifluoroacetic acid:water 5 ml) was cooled to 0 0 C for 20 h. The resulting solution was neutralised with an ice-cold saturated solution of sodium bicarbonate (70 ml), extracted with ethyl acetate 3 x 50 ml) and the extracts dried (MgSO 4 and concentrated in vacuo. Preparative hplc was carried out on a Supelcosil LC-ABZ column (size 21.2mm x 10cm) operating at 8m1/min (eluents were A: 0.1% trifluoroacetic acid /water, B: 0.01% trifluoroacetic acid in 95:5 acetonitrile/water) (gradient profile 95% B over 25 min), to afford the title compound as a white solid (6.9 mg).

LC/MS, (System B1): Rt 2.76 min Mass spectrum m/z 517 (MH+) Experimental Details for route (1) Intermediate (3aS.4S.6R.6aR )-6-Methoxv-2 .2-dimethyl-tetrahvdro-furof3.4-dlf 1 .3dioxole-4carboxvlic acid methoxv-methvl-amide 3 aS, 4 S,6R,6aR.Methoxy.2,2-d4imethyl-tetrahydro..furo[34..g[1 ,3]dioxole-4carboxylic acid (11 g) was dissolved in dichloromethane (IlO0mI) and carbonyldiimidazole (8.47g) added portionwise over 10 min at 22'C and the solution stirred at 22 0 C for 0.5h. N,.O-Dimethylhydroxyla mine hydrochloride (12.5g) was dissolved in water (50mI) and ION sodium hydroxide '(20ml) added, and the solution extracted with dichloromethane (3x50ml). The dichloromethane extracts were dried (Na 2

SO

4 and filtered, and the solution added to the above solution. After stirring for 3 days, the solution was washed with 0.5M citric acid (200ml), 8% sodium bicarbonate (200m1), dried (Na 2

SO

4 and evaporated in vacuo to give the title compound as a colourless oil (14.2g).

TLC: SiO 2 (ether) Rf 0.33.

Intermediate 26 1 -(6R-Methoxv-2.2-dimethvl-tetrahydro-(3aS .6aR)-furor3.4-dl[1 .31dioxol-4S-vl)- 4 .4-dimethvl-pent-2-vn- 1 -one 3,3-Dimethyl-1-butyne (l0g) in THF (90m1) was added slowly to a 3.OM solution of methylmagnesiumn chloride in THF (50mI) under nitrogen at O-.500, and stirred at O-5*C for 5h. (3aS,4S ,6R,6aR)-6-Methoxy-2,2-dimethyl-tetrahydro-furo[3,4dI[1,3jdioxole-4-carboxylic acid methoxy-methyl-amide (14.17g) was added in THF (20m1) over 20 min at 0-5 0 C, and the solution stirred at 0-5 0 C for 2h. The reaction mixture was quenched with 30% ammonium chloride (1 50ml) and 2M hydrochloric acid (1 5m1) and extracted with ethyl acetate- (2x150m1). The combined organic phases were dried (Na 2

SO

4 and evaporated in vacua, and the residue purified by flash chromatography over silica (150~g) eluting with cyclohexane.diethyl ether 1) to afford the title compound as a colourless solid (4.01lg).

TLC: SiO 2 (ether) R 1 0.55 Intermediate 27 1 -(6R-Methoxy-2.2-dimethvl-tetra hydro-(3as 6a R )furof3.4-dlfl.3ldioxol-4S-yl 4.4-dimethl-entane-1 .3-dione-3-oxime 1 -(6R-Methoxy-2,2-dimethyl-tetrahydro-(3aS ,6a R)-furo[3,4-dll,3jdioxol-4S-yl)- 4,4-dimethyl-pent-2-yn-1 -one (573mg) was dissolved in methanol (6ml) and aqueous hydroxylamine (0.19ml) added. After standing at 23*C for 5h, the solution was concentrated in vacua, diluted with water (1 OmI) and extracted with ethyl acetate (2x1 Smi). The extracts were dried (Na 2

SO

4 and evaporated in vacua to afford the title -compound as a colourless oil (0.635g).

TLC: SiO 2 (cyclohexane-Et 2 O 3:2) Rf 0. 16 Intermediate 28 Acetic acid 4R-acetox-2S-(3-tert-butylkisoxazol-5-vi )-5-methoxy-tetrahvd rofuran-3R-Yt ester 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 3-oxime (632mg) was dissolved in methanol (15m1) and conc. hydrochloric acid (1mI) added. The resulting solution was heated under reflux under nitrogen for 20h, cooled and evaporated in vacua.

The residue was dissolved in pyridine (1lOmi) and 4-dimethylaminopyridine (1 mg) and acetic anhydride (2ml) added. The solution was allowed to stand at 22 0

C

/3h, and the solvents removed in vacua. The residue was dissolved in ethyl acetate (lO0mI), washed with 8% sodium bicarbonate (50m1), dried (Na 2

SO

4 and evaporated in vacuo to give the title compound as a pale yellow gum (575mg).

Mass spectrum m/z 342 (MH+) Intermediate 29 Acetic acid 4R-acetox-5S-(3 tert-butl-isoxazol-5-vI )-2R-(6-chloro-pu rin-vltetra hvdro-fu ran-3 R-yl ester 6-Chloropurine (1.36g), toluene (20m1) and hexamethyldisilazane (l0mI) were heated under reflux under nitrogen for 2h, cooled, and evaporated in vacuo.

The residue was co-evaporated with dry toluene (12m1) and taken into dry 100 acetonitrile (20m1) and acetic acid 4R-acetoxy-2S-(3-tert-butyl-isoxazol-5-yl)-5methoxy-tetrahydrofuran-3R-yl ester (1.01 g) and trimethysilyl trifluoromethanesulfonate (1.8ml) added, and the solution heated under reflux under nitrogen for 5h. The solution was cooled and poured into 8% sodium bicarbonate (1 S0mI) and extracted with ethyl acetate (2xlOOml). The extracts were combined, dried (Na 2

SO

4 and evaporated in vacuo. The residue was purified by flash chromatography over silica (200g) eluting with cyclohexaneether 1 to afford the title compound as a colourless foam (0.953g).

LCMS (system A) Rt 4.35 min.

Example 27 (2S .3S .4R. 5R)-2-(3-tert-Butvl-isoxazol-5-y 6-(2S-h ydroxy-cvclopent-(S vlamine )-purin-9-vll-tetrahvdro-furan-3.4-diol Acetic acid 4 R-acetoxy-5S-(3-tert-butyl-isoxazol-5-yl R-(6-chloro-purin-9-yl tetra hyd ro-fu ran-3R-yl ester (70mg) and tra ns-(l1S ,2S )2-aminocyclopentanol hydrochloride (62mg) were dissolved in isopropanol (l0mI) and diiso propyleth yl amine (0.16ml) added, and the solution heated under reflux for 1 7h. The solvent was evaporated in vacuo and the residue dissolved in saturated methanolic ammonia (7m1) and allowed to stand for 3h. The solvent was removed in vacuo and the residue purified by chromatography over silica eluting with ethyl acetate-methanol Further purification by autoprep HPLC afforded the title compound as a colourless gum LCMS (system Rt 3.81 min Mass spectrum: mn/z 445 (MH+) Example 28 (2S .3S .4R ,5R)-2-(3-tert-Butvl-isoxazol-5-yl )-5-[6-(tetrahvd ro-pvran-4-vlamino)- Pu rin-9-vl-tetrahvd ro-furan-3 .4-diol Acetic acid 4R-acetoxy-5S-(3-tert-butyl-isoxazol-5-yl )-2R-(6-chloro-purin-9-yl)tetra hydro-fu ra n-3R-yl ester (70mg) and 4-aminotetrahydropyran hydrochloride (62mg) were dissolved in isopropanol (l0mI) and d i-isopropylethyla mine (0.16ml) added, and the solution heated under reflux for 17h. The solvent was removed in vacuo and the residue dissolved in saturated methanolic ammonia (7ml), and allowed to stand for 3h. The solvent was removed in vacuo and the residue purified by solid phase extraction (Varian Bondelut aminopropyl bonded silica gel cartridge), eluting with ethyl acetate-methanol Further purification by autoprep HPLC gave the title compound as a colourless gum (31 mg).

LOMS (system R, 3.78 min Mass spectrum mlz 445 (MH+) Experimental details for route (J) Intermediate (F )-3-Dimethvla mino- I -(6R-methoxy-2.2-dimethvl-tetrahvdro-(3aS .6aR)-furof3.4dIll .3ldioxol-4S-vl)-oroPenone 1 -(6R-Methoxy-2,2-dimethyl-tetrahydro-(3aS,6aR)-furo[3 ,4-dJ[1 ,3]diox-4S-yl)ethanone (0.62g) was dissolved in toluene (25ml) and dimethytformamide dimethyl acetal (5m1) added and the solution heated under reflux under nitrogen for 1 7h. The solvents were removed in vacuo and the residue purified by flash chromatography over silica (30g) eluting with ethyl acetate to afford the title compound as a yellow gum (0.1 02g).

Mass spectrum m/z 272 (MH 4 Intermediate 31 5-(6R-Methoxv-2 .2-d imethvl-tetrahvdro-(3a R 6aR )-fu rof3 .4-difl,1 3d ioxol-4R-VI 1 H-Dvrazole (EY)3-Dimethylamino-1 -(6R-methoxy-2,2-dimethyl-tetrahydro-(3aR,6aR)furo[3,4-d][1 ,3]dioxol-4S-yI)-propenone (102mg) was dissolved in methanol (1 SmI) and hydrazine hydrate (O.5m1) added and the solution heated under reflux.for I1.5h. The solvents were removed in vacuo and the residue purified by flash chromatography over silica gel, eluting with diethyl ether to afford the title compound as a colourless gum (47mg).

Mass spectrum mlz 241 (MH+) Intermediate 32 Acetic acid 4R-acetoxv-2R-(1-acetyl- furan-3R-yl ester 5-(6R-Methoxy-2,2-dimethyl-tetrahydro-(3aR,6aR)-furo[3,4-dj[1,3Jdioxol-4R-yl)- 1H-pyrazole (1.66g) was dissolved in methanol (120ml), treated with conc.

hydrochloric acid (Iml), heated under reflux for 22h, cooled and evaporated in vacuo. The residue was dissolved in pyridine (80ml), acetic anhydride (4ml) added and the solution allowed to stand for 3h. The solvents were removed in vacuo and the residue taken into ethyl acetate (200ml) and washed successively with 0.5M citric acid (100ml), 8% sodium bicarbonate (100ml) and brine (100ml).

The organic phase was dried (Na 2

SO

4 evaporated in vacuo and the residue purified by flash chromatography over silica gel, eluting with cyclohexane-diethyl ether to afford the title compound as a colourless gum (646mg).

Mass spectrum m/z 327 344 (MNH* Intermediate 33 Acetic acid 4R-acetox-5R-(1-acetyl- H-pyrazol-3-l )-2R-(6-chloro-purin-9-yl)tetrahvdro-furan-3R-vl ester 6-Chloropurine (1g) was suspended in toluene (40ml), hexamethyldisilazane was added, and the mixture was heated under reflux for 1h. After cooling, the solvents were evaporated in vacuo followed by co-evaporation with toluene (10mi). The residue was dissolved in dry acetonitrile (40ml), acetic acid 4R-acetoxy-2R-( 1 -acetyl- H-pyrazol-3-yl)-5R-methoxy-tetrahydro-furan-3R-yl ester (645mg), DBU (1mi) and trimethylsilyl trifluoromethanesulfonate (1ml) were added, and the resulting solution was heated under reflux under nitrogen for 3h. The cooled solution was poured into 8% sodium bicarbonate (150ml) and extracted with ethyl acetate (2x100ml). The combined extracts were dried (Na 2

SO

4 and evaporated in vacuo to afford a mixture which was purified by flash chromatography over silica gel, eluting with ether-cyclohexane to afford the title compound (42mg).

Mass spectrum m/z 449/451 (MH') Intermediate 34 103 (2R.3R .4S 5R)-2-(6-C hloro-pu rn-9-vf )-5-(2H-pvrazol-3-vl )-tetrahydro-furan-3.4dial Acetic acid 4R-acetoxy-5-( I-acetyl-1 H-pyrazol-3-yi).-2R-(6-chloro-puin-9-yl)tetra hydro-furan-3R-yI ester (42mg) was dissolved in methanol (3m1) and cooled to 0 0 Tert-butylamine (0.2ml) was added and the solution allowed to stand for min. at 0 0 C. The solvents were removed in vacua to furnish the title compound Mass spectrum m/z 323/325 (MH+) Exampl~e 29 (2R.3R.4S .5R)-2-(2H-Pyrazol-3-vl )-5-(6-tetrahvdro-pyran-ylamino-Durin-9-yl)tetra hydro-fu ra n-3,4-d iol (2R,3R,4S ,5R)-2-(6-Chlora-purin-9-y )5-(2H-pyrazol-3-yl)-tetrahyd ro-furan-3 ,4dial (35mg) was dissolved in isoprapanol (3m1), N,N-di-isopropylethylamine (0.12mi) and tetrahyd ro-pyra n-4-yla mine hydrochloride (46mg) were added, and the resulting solution was heated under refiux under nitrogen for 17h. The solvent was removed in vacua, the residue dissolved in methanol (l0mi), and 8% sodium bicarbonate (3m1) added, followed by silica gel The solvents were removed in vacuo and the residue added to a flash column of silica gel packed in dichloromethane. Elution with dichloromethane-methanol (4:1) afforded the title comoaund as a clear viscous gum (5.2mg).

LCMS (system A) Rt 3.34 min.

Mass spectrum m/z 388 (MH+) Experimental details for route (K) Intermediate (3aS .4S .6R.6aR)-6-(6-Chloronu rin-9-yl .2-dimethyl-tetrahvdro-furor3 .4dIfl.31dioxole-4-carboxylic acid methoxy-methvl-amide (3aS ,4S ,6R,6aR)-6-(6-Chlaro-purin-9-yl imethyl-tetrahydro-furo[3,4dill ,3]dioxale-4-carboxylic acid (35.88g) was dissolved in dichloramethane (300ml) and treated with 1 ,1'-carbonyidiimidazate (20.5g) with ice-coaling. The 104 solution was stirred at 22*C for lh, N,O-d imethylhydroxyla mine hydrochloride (12.3g) and pyridine (i5mI) were added, and stirring was continued at 22C for 24h. The solution was washed with 0.5M citric acid (250ml) and 8% sodium bicarbonate (200ml), dried (Na 2

SO

4 and evaporated in vacuo. The residue was purified by flash chromatography over silica gel, eluting with ethyl acetate to afford the title compound as a colouiess solid (26.4g).

LCMS (system A) R, 3.77 min Mass spectrum m/z 384/386 (MH+) Intermediate 36 (3aS,4S.6R,6aR)-2 .2-Dimethl-6-(6-thioxo-1 ,6-d ihyd ro-Durin-9-vl )-tetrahvdrofuro[3,4-dlfl'.3ldioxole-4-carboxlic acid methoxy-methyl-amide (3aS ,4S,6R,6aR)-6-(6-Chloro-purin-9-yl)-2 1 2-dimethyl-tetrahydro-furo[3,4dliii,3ldioxide-4-carboxylic acid methoxy-methyl-amide (23.3g) was suspended in ethanol (250ml), and treated with sodium hydrogen sulfide (l0g). The mixture was stirred under reflux under nitrogen for 3h, cooled and evaporated in vacuo.

The residue in water (250ml) was acidified with 0.5M citric acid (gg. filtered, and the filtered solid washed with water (250m1) and isopropanol (1IQ0mI) and dried in vacuo to afford the title compound as a yellow solid (I16.3g).

LC/MS (system A) Rt 3.53 min Mass spectrum mlz 382 (MH 4 Intermediate 37 {9-[6R-(5-Tert-Butyl-2H-r~yrazol-3-vl )-2.2-dimethvl-tetrahydro-(3aR6aR)-furor3.4dill 1,31dioxol-4R-vll-9H-ou rin-6-A-cyclopentyla mine (3aS,4S ,6R,6aR)-2,2-Dimethyl-6-(6-thioxo-1 ,6-dihydro-purin-9-y )tetrahydrofurol3,4-d][1 ,3]dioxole-4-carboxylic acid methoxy-methyl-amide (1 g) 'was dissolved in N,N-dimethylformamide (DMF) (25m1) with heating and filtered whilst hot. The filtrate was treated with di-isopropylethylamine (O.5ml) and Merrifield resin (chloromethyl form, 2g, 0.8mmol/g, 1% cross-linked) and the mixture shaken for 24h. The mixture was filtered and the filtered resin washed with DMF (2x15ml), dichloromethane (2x15m1) and ether (3x15ml). The above resin was added to a solution of 3,3-dimethyl- 1 -butynyl magnesium chloride 105 (prepared by treating 3,3-dimethyl-1-butyne [2ml] with 3.OM methyl magnesium chloride in tetrahydrofuran (THF) [4mlJ in THF [25ml] at 22* for 17h) in THF at 0and the mixture was stirred at 0-5"C for 6h. 2M Hydrochloric acid (6ml) and THF (12ml) were added, and after 10 min shaking, the resin was filtered and washed with THF (2x15m) and ether (2x15ml). The resin was resuspended in DMF (25ml), hydrazine hydrate (2ml) was added, and the mixture was shaken for 17h. The mixture was filtered, washed with DMF dichloromethane (2x1 Oml) and ether (3x1Oml), re-suspended in dichloromethane (15ml), treated with 3-chloroperoxybenzoic acid (57-81%, 0.50g) and shaken at 22*C for 17h. The resin was filtered off, and washed with dichloromethane (3x10ml) and ether (2xlOml). The residue in THF (10ml) was treated with cyclopentylamine (88 1) and di-isopropylethylamine (0.16m1), and the mixture was shaken at 22"0 for 17h. The mixture was filtered, washed with THF-methanol 2x10ml), and the filtrate and washings were evaporated in vacuo. Purification by automated preparative HPLC afforded the title compound LC/MS (system A) Rt 4.48 min Mass spectrum m/z 468 (MH') Example (2R,3R4S,5R)-2-(5-tert-Butl-2H-vrazol-3-y )-5-(6-cycloDentylamino-purin-9-vl)tetrahyd ro-fura n-3,4-d iol {9-[6R-(5-tert-Butyl-2H-pyrazol-3-yl)-2,2-dimethyl-tetrahydro-(3aR,6aR)-furo[3,4d][1,3]dioxol-4R-yl]-9H-purin-6-yl)-cyclopentylamine (20mg) was dissolved in trifluoroacetic acid-water 4ml) and the mixture was allowed to stand at 0for 17h. The solution was evaporated in vacuo (bath temp <300C) and quenched with 2M sodium carbonate (15ml). The mixture was extracted with ethyl acetate (2x15mi), and the combined extracts dried (Na 2

SO

4 and evaporated in vacuo. The residue was purified by chromatography on silica gel (Varian Bondelut cartridge), eluting with ethyl acetate-methanol to afford the title compound as a clear gum (19mg).

LC/MS (system A) Rt 4.0 min Mass spectrum m/z 428 (MH') 106 Experimental details for route (L) Intermediate 38 3-Ethvf-5-(6R-methoxy-2 .2-dimethvl-tetrahydro-(3aR.6a R)-furof3 .4-dlfl .3idioxol- 4S-vl)-isoxazole To a stirring mixture of 4R-ethynyl-6R-methoxy-2,2-dimethyl-tetrahydro- (3aR,6aR)-furo[34-d][1 ,3]dioxole flit. compd.; ref: He/v. Chim. Acta 1980, 63, 1181-1189.] (0.271g) and phenyl isocyanate (0.328m1) in dry toluene under nitrogen, was added a mixture of 1-nitropropane (0.134ml) and triethylamine (0.038m1) in dry toluene (1iml) over 5min. A precipitate was formed slowly during the addition. The resultant mixture was heated at between 7300 to 8200 for 18h. The cooled reaction mixture was filtered through silica gel, washed well with ether and then 40% ethyl acetate cyclohexane. Removal of solvent in vacuo gave a light brown solid (0.487g) which was subjected to flash chromatography on silica gel, eluting with ethyl acetate: cyclohexane 20:80- 30:70, to give the title compound as a clear oil (0.329g).

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

Intermediate 39a Acetic acid 4 R.5S-d iacetoxv-2S-(3-ethVl-isoxazol-5-vl tetra hydro-fu ra n-3 R-yl ester and Intermediate 39b Acetic acid 2S-(3-ethyl-isoxazol-5-yI )-tetrahydro-fu ran-3R-yl ester A solution of 3-ethyl-5-(6R-methoxy-2 ,2-d imethyl-tetrahydro-(3aR,6a R)furo[3 ,4d][1 ,3]dioxol-4S-yl)-isoxazole (0.355g) in a mixture of trifluoroacetic acid and water (0.05mi) was stirred at room temperature for 27h and then evaporated in vacuo. The residue was azeotroped with toluene dissolved in dry dichioromethane (l0mI) under nitrogen, and cooled to 0CC. 4-(N,Ndimethylamino)pyridine (0.048g), triethylamine (8.3m1) followed by acetic anhydride (2.49m1) were added. The mixture was stirred at 00 to room temperature overnight. The resultant mixture was evaporated in vacuo to give a brown liquid (1 .34g). Purification by flash chromatography on silica-gel; eluting with ethyl acetate: cyclohexane 20:80-40:60, afforded acetic acid diacetoxy-2S-(3-ethyl-isoxazol-5-yl )-tetrahydro-furan-3R-yI ester (0.1 92g) as a 107 light brown oil, followed by acetic acid 4R,5R-diacetoxy-2S-(3-ethyl-isoxazol-5yl)-tetrahydro-furan-3R-yl ester 16g) as a light brown oil.

Intermediate 39a SiO 2 TLC (Cyclohexane-ethyl acetate Rf 0.28 Intermediate 39b SiO 2 TLC (Cyclohexane-ethyl acetate Rf 0.22 Intermediate Acetic acid 4 R-acetoxy-2R-(2 .6-dichloro-pu rin-9-yl )-5S-(3-ethvl-isoxazol-5-Y tetra hvd ro-fu ra n-3 R-YI ester To a mixture of acetic acid 4R,5S-diacetoxy-2S-(3-ethyl-isoxazol-5-yl)tetra hyd ro-fu ra n-3 R-yl ester and acetic acid 4R,5R-d iacetoxy-2S-(3-ethyl- )tetrahyd ro-furan-3R-yI ester (0.909g) in dry acetonitnile (5mI) at room temperature under nitrogen was added 2,6-dichioropurine (0.779g), DBU (0.692m1) followed by trimethylsilyl triflate (0.99m1). The reaction was stirred at room temperature for 20h, and quenched with saturated aqueous sodium bicarbonate solution (30ml). Extraction with ethyl acetate (3x40mI) gave a brown liquid (3.54g). Purification by flash chromatography on silica gel, eluting with ethyl acetate:cyclohexane 40:60-50:50, gave the title compound as a creamy white foam (0.798g).

TLC SiO 2 (Cyclohexane-ethyl acetate Ri 0.25.

Intermediate 41 Acetic acid 4 R-acetoxy-2 R-r2-chloro-6-( 1S-hydroxymethvl-2-nhenvl-ethlamino)purin-9-vl1-5S-(3-ethvl-isoxazol-5-vl )-tetrahyd ro-furan-3R-vl ester Acetic acid 4R-acetoxy-2R-(2 ,6-dichloro-punin-9-yl)-5S-(3-ethyl-isoxazol-5-yl tetrahydro-furan--3R-yl ester (151mg), (S)-phenylalaninol (53mg) and diisopropylethylamine (67 1) were dissolved in isopropanol (2m1) and heated at for 7.5h. The solvent was removed in vacuo to afford the crude title compound as a clear gum.. (260mg) LC/MS (sys tem Rt 4.63 min Mass spectrum m/z 585/587 108 Example 31 (2R .3 R.4S5S S-hydroxvmethvl-2-phen vi-ethylamino )-2-methoxv-Dunn-9vi )-5-(3-ethvl-isoxazol-5-vI)-tetrahvdrofuran-3.4-dioI Acetic acid 4R-acetoxy-2R-[2-chloro-6-( IS-hydroxymethyl-2-phenyl-ethylamino)purin-9-yIJ-5S-(3-ethyl-isoxazol-5-yI)-tetrahydro-fu ra n-3R-yI ester (259mg) was added to 25% sodium methoxide in methanol (4m1) and the mixture stirred at 22 0 C for 8h. The solvent was removed in vacuo and the residue purified by flash chromatography over silica gel, eluting with ethyl acetate-methanol (10:1) to give the title comPound as a pale yellow gum (10 1mg).

LC/MS (system A) Rt 4.04 min Mass spectrum m/z 497 (MH*) Experimental details for route (M) Intermediate 42 (3aS .4S .6R.6aR)-2.2-Dimethvl-6-(6-oxo-1I.6-d ihyd ro-purin-9-vI)-cvclopenta f 1,31dioxole-4-carboxylic acid Potassium permanganate (3.0g) and potassium hydroxide (1 .0g) in water (6Oml) were stirred together at room temperature overnight and the solution then cooled to 000. [3aS-(3a ,4 .6 6a 1 ,9-dihydro-9-[tetrahydro-6- (hyd roxymethyl ,2-dimethyl-4H-cyclopenta- 1,3-d ioxol-4-yl]-6H-pu nn-6-one (2.92g) was added slowly such that the temperature of the reaction mixture was maintained below 5 0 C. The mixture was stirred at room temperature for 5h then cooled to 000 and treated with sodium metabisulfite Hydrochloric acid was added cautiously to adjust the pH to about 3.5. The solution was stored at 400 overnight and the resultant precipitate collected, washed with chilled water and dried in vacuo. The title compound was obtained as a white solid (1.82g).

Mass spectrum mlz 321 Intermediate 43 109 6 -Chloro-9-f2.2-dimethvs..6S-(3-cycopropvl-f 1.2 .4loxad iazol-5-vl )-tetrahvdro- (3aS .6aR )-cvclopentafl.3ldioxol-4R-Vll-9H-oun (3aS .4S,6R,6aR)-2,2-Dimethyl.6-(6-oxo-1I,6-dihydro-purin-9-yl)-cyclopenta [1 ,3]dioxole-4-carboxylic acid (1 18mg) in anhydrous chloroform (4.5ml) was heated to reflux with dimethylformamide (29 1) and thionyl chloride (108 I) for 4h. After cooling to room temperature the excess solvent and reagents were removed by evaporation and the residue taken up in anhydrous chloroform (1 .5ml). The mixture was added to a cooled (0 0 C) solution of cyclopropylamidoxime (110 mg) and pyridine (41 1) in chloroform (2.5ml). The mixture was heated to reflux for 24h. After cooling, the mixture was evaporated to dryness and the residue purified by flash chromatography on silica gel), eluting with ethyl acetate/cyclohexane (40:60). On evaporation the title compound was obtained as a colourless gum (56mg).

Mass spectrum m/z 403 (MH+) Intermediate 44 (1 R,2S .3R.5S)-3-(6-Chloro-purin-9-yl)-5-(3-cclopropvl-rl .2 cyclopentane-1 .2-diol 6-Chloro-9-[2 ,2-dimethyl-6S-(3-cyclopropyl-[1 ,2 (3aS,6aR)-cyclopenta[1 ,3]dioxol-4R-ylJ-9H-purine (50mg) was treated with cold (0 0 C) trifluoroacetic acid-water (2ml; The mixture was stored at 4*C overnight and evaporated to dryness. The title compound was obtained as a colourless gum Mass spectrum m/z 363 Example 32 (1 S .2R.3S .5R)-3-(3-cyclo~ro~l- 1 .2 .41oxadiazol-5-vI )-5-[2S-hydroxv-cyclooent- (S )-vla mino-nu nn-9-yll-cyclopentane- 1.2-d jol (1 R,2S ,3R,5S )-3-(6-Chloro-punin-9-yl )-5-(3-cyclopropyl-[ 1,2 cyclopentane-1 .2-diol (57mg) in isopropanol (5ml) was treated with tra .ns- (1 S,2S)-2-aminocyclopentanol hydrochloride (34mg) and d iisopropylethyla mine (851Ad) at refiux temperature overnight. The excess solvent was evaporated and the residue purified by automated preparative hplc. The title compound was obtained as a near colourless glass LC/MS (System Rt 2.4 min Mass spectrum m/z 428 (MH+) Experimental details for route (N) Intermediate 9-U(3aR,4R.6S.6a R)-6-[3-(tert-butvl .2,4-oxadiazol-5-vl1-2.2dimethvltetrahydrofuro[3 .4-dlfl.31dioxol-4-vl-6-( I H-I .2.3-benzotdazol-1 -yloxy)- 9--urine To a solution of (3aS,4S,6,a)6(-hoop y)22dmty-erhdo furo[3,4-d[1 ,3]dioxole-4-carboxylic acid (10g) in dimethytforrnamide (200m1) was added I -hyd roxybenzotriazole (3.96g) and I -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.62g). t-Butylacetamidoxime (3.40g) in dimethylformamide (30ml) was added and the mixture was stirred at 20 0 C for 24 h under nitrogen. The mixture was then heated at 70 0 C for a further 36 h. The resulting mixture was then cooled to 200C, basified with a saturated solution of sodium bica rbonate (200ml) and extracted with ethyl acetate (2x1 SOmI). The organic layers were washed with brine (300m1), dried (MgSO4, evaporated to dryness in vacuo and tritu rated with ether to give a yellow solid (11 .08g).

Purification by chromatography on silica gel, eluting with ethyl acetate cyclohexane afforded the title compound (4.75g) as a white solid.

LC/MS (System R 1 3.46 min Mass Spectrum m/z 520 [MH Intermediate 46: 9-U(3aR.4R.6S .6aR)-6-l'3-(tert-butl 1.2 .4-oxadiazol-5-vll-2.

2 dimethyltetrahvdrofurol'3 4-dl[,i l4-I-Ni obtl9-ui--mn To a solution of 9-{(3aR,4R,6S,6aR)-6-p-(tert-butyl ,2,4-oxadiazol-5-ylj-2,2dimethyltetrahydrofuro[3,4-d[1 ,3Jdioxol-4-yl}-6-( 1 H- ,2,3-benzotriazol- I -yloxy)- 9H-purine (50mg) in dimethylsulfoxide (0.4ml) was added diisopropylethylamine (O.lml) and isobutylamine (.038m1). The mixture was stirred at 20 0 C for 16 h under nitrogen. The mixture was then evaporated to dryness in vacuo to give a residue that was purified by automated preparative HPLC to afford the title compound (14mg) as a white compound.

LC/MS (system R, 3.38 Mass Spectrum m/z 458 [MH'J Example (2S.35.4R,5R)-2-[3-(tert-butyl)-1 .2.4-oxadiazol-5-vll-5-f6-(isobutvlamino)-9H- Pu rin-9-vlltetra hvd rofu ran-3.4-diol A solution of 9-{(3aR,4R,6S,6aR)-6-[3-(tert-butyl)-1 ,2,4-oxadiazol-5-yl]-2,2dimethyltetrahydrofuro[3,4-d][1 ,3]dioxol-4-yl-N-isobutyl-9H-purif-6-amine (14mg) in a cold mixture of trifluoroacetic acid water Iml) was kept at for 18 h. The resulting solution was basified in an ice bath with saturated aqueous sodium bicarbonate (20m1), extracted with ethyl acetate (2x20ml), the extracts dried (MgS0 4 and evaporated to dryness in vacuo to afford the title compound (7.66mg) as a white solid.

LC/MS (System C):Rt 2.85 min Mass Spectrum m/z 418 [MH 4 Experimental details for route (0) Intermediate 47: 9-(3aR.4R.6S 6aR)-6-[3-(tert-butyl)-1 .2,4-oxadiazol-5-vll-2.2d imethyltetrahyd rofu ror3 .4-dl[ .31d ioxol-4-vll-N-(2 .4-difluorophenvl )-9H -u rin-6amine 112 9-{(3aR,4R,6S ,6aR)-6-[3-(tert-butyl)- 1,2 ,4-oxadiazol-5-ylj-2,2dimethyltetrahydrofuro3,4-d[1 ,3]dioxol-4-yl}-6-( 3-benzotriazol- 1-yloxy)- 9H--purine (50mg) was dissolved in 2,4-difluoroaniline (O.4ml) and the mixture heated at 80 0 C for 96 h. The mixture was then cooled to 20 0 C and partitioned between dichioromethane (25ml) and 1 M hydrochloric acid (15 ml). The separated aqueous phase was further extracted with dichloromethane (1x25 ml) and the combined organic extracts were evaporated to dryness in vacuo.

Purification by automated preparative HPLC afforded the title compound (18.3 mg) as a dark purple gum.

LC/MS (System Rt 2.85 min Mass Spectrum m/z 418 [MHJ Example 49 (2S.35 AR, 5R)-2-f3-(tert-butl 1.2 .4-oxadiazol-5-vll-5-[6-(2 .4-difluoroanilino)- 9H-pu rin-9-vlltetrahydrofuran-3,4-dioI A solution of 9-{(3aR,4R,6S,6aR)-6-[3-(tert-butyl)-1 ,2,4-oxadiazol-5-yI]-2,2dimethyltetrahydrofuro[3,4-d]1 ,3]dioxol-4-yI}-N-(2 ,4-difluorophenyl-9H-purin-6amine (18.3 mg) in a cold mixture of trifluoroacetic acid :water l) was kept at 40C for 18 h. The resulting solution was basified in an ice bath with a saturated solution of sodium bicarbonate (2Oml), extracted with ethyl acetate (2x2ml), the extracts dried (MgSO 4 and evaporated to dryness in vacuo to afford the title compound (14.3mg) as a purple solid.

LC/MS (System Rt 3.03 min Mass Spectrum m/z 474 [MH+] Experimental details for route (P) Intermediate 48: (3aR.4S .6R .6aR)-6-(6-chloro-9H-Du rin-9-yl )-N-(2-hvdroxvpropyl)-2 .2 dimethyltetrahvdrofuro[3.4-dlI 1.31dioxole-4-carboxamide 113 Thionyl chloride (4.3ml) was added to a stirred solution of (3aS,4S,6R,6aR)-6- (6-chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxole-4-carboxylic acid (10.0g), in chloroform (100ml). The mixture was heated at reflux temperature under nitrogen for 60 min. After cooling to 20"C the solvent was removed in vacuo and the residue azeotroped with toluene (2x50ml). A suspension of the residue in chloroform (50ml) was added dropwise at an equal rate with a solution of 1-amino-2-propanol (2.3ml) and diisopropylethylamine (5.1ml) in chloroform (50ml) over 10 min to chloroform (50ml) at 0"C. The mixture was stirred at 20"C for 18 hours. Phosphate buffer (pH 6.5, 100ml) was added and the phases separated. The aqueous phase was extracted with chloroform (50ml). The combined chloroform layers were dried with sodium sulphate and the solvent removed in vacuo to give the title compound as a white foam (6.63g).

Mass spectrum m/z 398 [MH*] Intermediate 49: (3aR,4S.6R,6aR)-6-(6-chloro-9H-purin-9-vl)-2.2-dimethvl-N-(2oxopropvl)tetrahvdrofuror3.4-dll.,31dioxole-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]dioxole-4-carboxamide (6.60g) and powdered 4A molecular sieves (10g) in dichloromethane (165ml) at 0°C, was added acetic acid (3.0ml) followed by the portionwise addition of pyridinium dichromate (9.36g). The mixture was stirred at 0°C for 15 min and then at for 2 hours. Isopropanol (10ml) was added and the mixture stirred for Silica gel (Merck 9385, 9.9g) and ethyl acetate (165ml) were added and the reaction stirred for a further 15 min. The mixture was filtered through celite and the filter cake washed with ethyl acetate (300ml). 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 (4.6g).

TLC SiO 2 (ethyl acetate:methanol 100:20) Rf 0.4 114 Experimental details for route (Q) Intermediate (3aR.4S,6R.6aR)-N-(2-hvdroxybutvl)-6-methoxv-2,2-dimethvltetrahvdrofurof3,4d]n .3]dioxole-4-carboxamide To a solution of furo[3,4-d]-1,3-dioxole-p-D ribofuranose acid (5.0g) in dichloromethane (50ml) was added carbonyl diimidazole (4.83g), the mixture was stirred for 20min at 200C and 1-amino-2-butanol (2.45g) was added and the mixture was stirred, under nitrogen, at 200C for 18 h. The mixture was diluted with ether (50ml) and washed with saturated citric acid solution (100ml) and saturated aqueous sodium bicarbonate (100ml). The layers were separated and the organic layers concentrated in vacuo; the resulting residue was purified by flash column chromatography on silica gel, eluting with 1:1 ethyl acetate:cyclohexane, to give the title compound as a clear gum (3.81g).

Mass Spectrum m/z 290 [MH]+ Intermediate 51: (3aR,4S,6R,6aR)-6-methoxv-2,2-dimethyl-N-(2-oxobutvl)tetrahydrofurof3,4d][1,31dioxole-4-carboxamide To a solution of (3aR,4S,6R,6aR)-N-(2-hydroxybutyl)-6-methoxy-2,2dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide (3.81g) in anhydrous dichloromethane (115ml), containing powdered 4A molecular sieves (5.7g) at 0°C, under nitrogen, were added acetic acid (2.59ml) and potassium dichromate (7.93g), portionwise. The reaction mixture was stirred at 0°C for 15min and at 200C for a further 2h. The mixture was quenched with isopropanol (40ml) and stirred for 30min, silica gel (Merck 9385) (40g) and ethyl acetate (100ml) were added, and the mixture was stirred for a further 30min. This mixture was filtered through 'harborlite®' filter aid and the filtrate concentrated in vacuo to give a crude product which was purified by flash column chromatography on silica gel, eluting with 2:1 ethyl acetate:cyclohexane to give the title compound (1.91g) 1Hnmr 6 7.405(1H, br t, 5.125(1H, br s, CH), 5.095(1-, dd, OH), 4.655(I H, br s, CH), 4.565(1IH, d, CH), 4.155(2H, m, CH2), 3.555(3H, s, OMe), 2.505(2H, q, CHj 2 1.505(3H, s, 1.355(3H-, s, 1.105(3H, t, -CH 3 Intermediate 52: 2-r(3aR.4S .6R.6aR )-6-methoxy-2 .2-dimethvltetrahvdrofuror3 .4-dlfl .3]dioxol-4vil-5-ethvl-1I. 3-oxazole To a solution of (3aR,4S,6R,6aR}-6-methoxy-2,2-dimethyl-N-(2oxobutyl)tetrahydrofuro[3,4-d][1 ,3jdioxole-4-carboxamide (740mg) in dry toluene (l0mi), under nitrogen was added phosphorous oxychioride (1 .44m1) and the mixture was heated under reflux for 3.5h. The reaction mixture was cooled to 000, quenched with saturated aqueous sodium bicarbonate (3Omls), stirred vigorously for 30min and extracted with -ethyl acetate (4x50ml); the organic layers were combined, washed with brine (30ml), dried (MgSO 4 and concentrated in vacua to give a crude product, which was purified by flash column chromatography on silica gel, eluting with a mixture of 5:1 to 7:2 cyclohexane: ethyl acetate, to give the title compound as a yellow oil (0.83g).

Mass Spectrum m/z 270 [M H 4 Intermediate 53: (2S .3R,4R. 5S )-2.4-bis(acetyloxy)-5-(5-ethvl-1 .3-oxazol-2-Yl )tetra hydrofuran-3-vl acetate To 2-[(3aR,4 S,6R,6a R)-6-methoxy-2 ,2-dimethyltetrahydrofu ro[3 ,3]dioxol- 4-yi]-5-ethyl-1 ,3-oxazole (0.83g) was added 9:1 trifluoroacetic acid:water (3.56ml). and the mixture was stirred at 200C for 3.5 hours. The solvents were removed in vacua to give an orange/brown oil. This material was dissolved in pyridine, (7m1), under nitrogen, acetic anhydride (2.76ml) was added and the mixture was stirred at 220C for 1 8h. The mixture was concentrated in vaCUO, diluted with ethyl acetate (50ml) and washed with 1M HCI (50m1), saturated aqueous sodium bicarbonate (3x50ml) and brine (50mI); the organic. layer was dried (MgSO 4 and the solvent evaporated to dryness to furnish the title comrnound as a brown/orange oil (0.854g) 116 Mass Spectrum mlz 342 (MIJ Intermediate 54: (2R.3R .4R. 5S )-4-(acetyoxv)-2-(6-chloro-9H-purin-9-vl )-5-(5-ethyl-1I.3-oxazol-2- YI )tetrahvdrofuran-3-l acetate To 6-chioropurine (0.854g) was added 1,1,1,3,3,3-hexamethyldisilazane (4ml) and toluene (I15m1) and the mixture was heated under reflux for 2h. The solvent was removed in vacuo, the residue azeotroped with toluene (lx8ml) and the mixture evaporated to dryness. To this residue was added (2S,3R,4R,5S)-2,4bis(acetyloxy)-5-(5-ethy-1 ,3-oxazol-2-yl )tetra hyd rofura n-3-yl acetate (0.854g) in acetonitrile (20ml), trim~ethylsilyl triflate (0.624m1) and 1,8diazabicyclo[5.4.0]undec-7-ene The reaction mixture was stirred at 2000 for 18h and at 80 0 C for 3h and then allowed to cool. The mixture was poured into saturated aqueous bicarbonate (40ml) and extracted with dichloromethane (4x40m1); the organic layers were combined, dried (MgSO 4 and the solvent removed in vacuo to give a crude product which was purified by flash chromatography on silica gel, eluting with 4:1 then 3:2 cyclohexane:ethyl acetate, to furnish the title compound as a clear gum (355mg).

Mass Spectrum mlz 436 (MHW) Example 84 2-(ff9-(2R.3R.4S .5S)-5-(5-ethl-1I.3-oxazol-2-yl )-3,4-hvdroxvtetra hydrofuran-2- Yll-9H-purin-6-vllamino)-N .N-dimethylethanesulfonamide To a solution of (2R,3R,4 R,5S )-4-(acetyloxy)-2-(6-chloro-9H-puin-9-yI)-5-(5ethyl- 1,3-oxazol-2-yI )tetrahyd rofu ran -3-yl acetate (50mg) in isopropanol (5m1), N, N-diisopropylethylamine (0.1 20m1) and N ,N-dimethyl-2aminoethanesulphonamide hydrochloride (86mg) were added. The mixture was stirred at reflux temperature, under nitrogen, for 48h and then cooled. A methanol/ammonia solution (4m1) was added, the mixture was shaken and left 117 to stand for 24h. The solvent was evaporated and the the resulting residue purified by automated preparative HPLC to give the title Product (8.6mg).

Mass Spectrum m/z 468 [MH~j Experimental details for route (R) Intermediate N-f9-f(3a R.4R.6S ,6aR)-2.2-dimethyl-6-(3-methvl- 1.2.4-oxadiazol-5yI )tetra hyd rofurol3 .4-dil 1. 31dioxol-4-vli-9 H -u ri n-6-yI I-N-dyclopentvla mine A mixture of (3aS,4S,6R,6aR-6-(6-cyclopentylamilo-puln-9-y)-2,2-dimethyltetra hyd ro-fu roll3,4-d] [1 3]dioxole-4-ca rboxyl ic acid 2-ethoxy- 1ethoxycarbonyl-1 ,2-dihydroquinoline (146mg), acetaldoxime (76mg) and dimnethoxyethane (DME, 25ml) was heated under reflux for 4 days and then cooled to 22 0 C. The mixture was concentrated in vacuo and ethyl acetate (40m1) added to the residue. The resulting suspension was washed with citric acid solution (3x20ml) and the aqueous washings were extracted with ethyl acetate (2x20m1). The combined organic extracts were washed with water (20m1) and brine (3Oml) and dried (MgSO 4 After concentration in vacuo the residue was purified by chromatography on silica gel, eluting with ethyl acetate: cyclohexane to give the title compound (63mg).

NMR (CDCI 3 8 8.03 (IH,br.s.,heterocyclic CH), 7.84 (1H, s, heterocyclic CH); 6.29 (1H,br.s,CH); 5.84 (IH,dd,CH); 5.64 (1H,d,CH); 5.48 4.56 (1H,br.s,CH); 2.19 (3H,s,Me); 1.85-1.5 (9H,m s, 6x 112CH 2 Me); 1.45 (3H,s,Me); 1.25-0.85 (ZH,m,2x 1/2CH 2 Example 39 (2R.3R.4S .5S)-2-l6-(cvcloientlamino)-9H-u rin-9-yll-5-(3-meth vt-I.2.4oxad iazol-5-yl )tetrahyd rofuran-3 .4-diol A mixture o f N-{9-[(3aR,4R,6S,6aR)-2 ,2-dimethyl-6-(3-methy-1 ,2,4-oxadiazol-5yl )tetrahydrofuro[3 .4-dir I 3]dioxol-4.yI]-9H-purin-6-yI}-N-cyclopentylamine (63mg), trifluoroacetic acid (1ml) and water (0.1ml) was stirred at 00 for 6h and then diluted with ethyl acetate (20ml). The mixture was neutralised with sodium bicarbonate solution and the aqueous phase was extracted with ethyl acetate (2x10ml). The combined organic extracts were washed with water (8ml) and brine (10ml) and dried (MgSO4). After concentration in vacuo the residue was purified by flahs column chromatography on silica gel, eluting with ethyl acetate:methanol (19:1) to give the title compound as a white foam (42mg).

TLC SiO 2 (ethyl acetate:methanol 19:1) Rf 0.30 NMR (DMSO) 6 8.43 8.20 (1H,br.s,CH); 7.79 (IH,br.d,NH); 6.45 (2H, v.br.s ,2x OH); 6.16 5.24 (IH,d,CH); 4.89 4.73 4.58 (1H,br.m,CH); 2.42 (3H,s,Me); 2.10-1.50 (8H,m,4xCH 2 Experimental details for route (S) Intermediate 56: 1-r(3aR,4R,6R.6aR)-6-methoxv-2.2-dimethyltetrahvdrofuro[3,4-d][1.3]dioxol-4vllDent-1-vn-3-ol A solution of 4R-ethynyl-6R-methoxy-2,2-dimethyl-tetrahydro-(3aR,6aR)furo[3,4-d][1,3]dioxole (1.5g) in tetrahydrofuran (20ml) was cooled to -780C for minutes under nitrogen. A solution of propionaldehyde (1.09ml) in tetrahydrofuran (0.5ml) was added via syringe and stirring continued for The mixture was allowed to warm to 220C and stirred for a further 16h. The solvents were removed in vacuo and the resultant orange oil partitioned between ether and aqueous ammonium chloride. The organic layers were washed with further aqueous ammonium chloride, dried (MgSO 4 and concentrated in vacuo to afford a yellow oil. Purification by chromatography on silica gel (Varian Bondelut cartridge), eluting with cyclohexane, (ii) dichloromethane, (iii) ether, (iv) ethyl acetate afforded the title compound as a colourless oil (1.33g).

TLC SiO 2 (ether:cyclohexane 1:1) Rr 0.39 Intermediate 57: 119 1 -[(3aR.4R.6R.6aR)-6-methoxv-2.2-dimethvltetrahvdrofurof3.4-dlf 1.3ldioxol-4- Aplent- 1 -n-3-one A solution of 1 -[(3aR.4 R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4dJ[1 ,3Jdioxol-4-yljpent-1 -yn-3-ol (1 .3g) in dichloromethane (1 00m1) was added to a stirred suspension of manganese dioxide (60g) in dichloromethane at 0 0

C.

The mixture was stirred at 0 0 C for 3h, filtered through magnesium sulphate and the solvent removed in vacuo to give the title compound as a colourless oil (550mg).

NMR 5 (CDCI 3 5.07 (1H,s,CH); 4.97 (1H,d,CH); '4.93 (IA,s,CH); 4.68 3.41 (3H,s,OMe); 2.58 (2H,q,CH 2 1.47 C3H,s,Me); 1.31 (3H,s,Me); 1.14 (3H,t,Me).

Intermediate 58: I -f(3a R.4R,6R.6aR)-6-methoxy-2 ,2-dimethvltetrahvdrofurof34-dl.31dioxol-4vllentane-1 .3-dione 1 -oxime A mixture of I -[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4d][1 ,3Jdioxol-4-yljpent-1 -yn-3-one (550mg) and hydroxytamine (50% solution in water) (0.2m1) in ethanol (1lOmi) was stirred overnight at 22 0 C. The mixture was concentrated in vacuo to afford the title compound as a yellow oil (554mg).

NMR 8 (CDCI 3 5.36, 5.31 (H,2 dH;50 (HdC) 49 idCH); 4.65 (1H,2x d,CH); 3.40, 3.35 (3H,2 .328 2,2x AB,CH 2 19 (2H,m,CH 2 1.50, 1.34 (GH,2x s,2x Me); 1.03 (.LH,2x t,Me).

Intermediate 59: (3R.4S.5R)-5-(5-ethylisoxazol-3-vlfletrahydrofuran-2.3.4-tnoI 1 -[(3aR,4R,6R,6aR)-6-methoxy-2 ,2-d im~thyltetrahydrofuro[3 ,3]dioxol-4yllpentane-1 .3-dione 1 -oxime (0.5g) was dissolved in aqueous acetic acid (18mg) and the mixture heated at 100 0 C for 2h. The solution was cooled and concentrated in vacua to afford a brown oil which was azeotroped with toluene.

Purification by chromatography on silica gel (Varian Bondelut silica gel cartridge), eluting with dichloromethane, (ii) ether, (iii) ethyl acetate, (iv) methanol, gave the title compound (1 TLC SiO 2 (ether) Rj 0. 17 Intermediate (2R .3 R.4R .5-bis(acetyloxy)-2-(5-ethyl isoxazol-3-yl )tetrahydrofuran-3-vl acetate (3R,4S ,5R)-5-(5-ethylisoxazol-3-yl )tetrahydrofuran-2,3,4-triol isomer 1 (150mg) was dissolved in pyridine (4m1) and the mixture treated with acetic anhydride (0.983ml). The resulting solution was stirred at 220C for 18h. The mixture was concentrated in vacua to afford a brown oil. Purification by chromatography on silica gel (Varian Bondelut SiO 2 cartridge), eluting with dichloromethane, (ii) ether (iii) ethyl acetate, afforded the title compound as a pale yellow solid (142mg).

TLC SiC 2 (ether) Rf 0.53 Intermediate 61: (2R.3R.4R.5R)-4-(acetvloxy)-2-(2 ,6-d ichloro-9H-Durin-9-vl)-5-(5-ethvlisoxazol- 3 vI )tetrahvdrofuran-3-yt acetate (2R,3R,4R)-4 ,5-bis(acetyloxy)-2-(5-ethylisoxazol-3-yl)tetrahydrofuran-3-yI acetate isomer 1 (193mg) was dissolved in acetonitrie (5ml) and treated sequentially with 2 .6-dichloropurine (213mg), 1 ,8-diazabicyclo[5.4.Ojundec-7ene (DBU) (0.1 86m1) and trimethylsilyl trifl uorometh anesui phonate (TMSOTf) (0.225m1) via a syringe over 5 min. The clear yellow solution was stirred at 2200 for 40h, at 60 0 C for 21h, and at 8000 for 6h. The mixture was cooled to room temperature and more DBU (0.186ml) and TMSOTf (0.225m1 were added.

After stirring at 2200 for 36h the yellow mixture was heated at 60 0 C overnight and at 80*C for 6h. The solvents were removed in vacua and the resultant brown oily solid. taken up in- ethyl acetate and washed with water (20m1, The aqueous layer was extracted with ethyl acetate and the combined organic layers dried (MgSO 4 and evaporated in vacuo o afford a brown oily solid. The 121 residue was triturated with dichioromethane and a white solid removed by filtration. Evaporation of the filtrate afforded a tan solid. Purification by flash chromatography on silica gel eluting with ether:cyclohexane afforded the title compound as a white solid (161 mg).

LC/MS (System C) R, 3.34min.

Mass spectrum m/z 470, 472 [MH+I, (MH+2+] Intermediate 62: (2R. 3 R.4R. 5R )-4-(acetyloxy)-2-(2-ch loro-6-[( 1 -ethylpropyl )aminol-9H-purin-9-yl}I 5-(5-ethvlisoxazol-3-vl)tetra hvd rofu ra n-3-yl acetate (2R,3R ,4 R,5R)-4-(acetyloxy)-2-(2, 6-dichloro-9H-purin-9-yl)-5-(5-ethylisoxazol-3yl)tettahydrofuran-3-yI acetate (1 25mg) was dissolved in isopropanol (5m1) and the solution was treated with diisopropylethylamine (0.06ml) followed by 1ethyl propyla mine (0.044m1). The mixture was heated at 50 0 C under nitrogen for 1 6h. The solvent was removed in vacuo and the mixture partitioned between ethyl acetate and I M hydrochloric acid. The organic layers were washed with saturated sodium bicarbonate solution and brine, dried (MgSO 4 and evaporated in vacuo. Purification by chromatography on silica gel (Varian Bondelut cartridge), eluting with dichloromethane, (ii) ether and (iii) ethyl acetate, gave the title compound as a colourless oil (108mg).

TLC SiO 2 (ether) Rf 0.26.

Example 163 (2R.3R.4S.5R)-24{2-chloro-6-i( -ethyl propyl )aminol-9H-pu rin-9-vl1-5-(5ethyl isoxazol-3-vfltetrahyd rofu ran -3A4-d iolI formate A mixture of (2R,3R,4R,5R)-4-(acetyloxy)-2-{2-chloro-6-[(lI-ethylpropyt)amino]- 9H-punin-9-yI}-5-(5-ethylisoxazol-3-yl )tetrahyd rofura n-3-yl acetate (30mfg) and 2morpholinoethylamine (0.037m1) was heated at 90'C for,_ 24h in dimethylsulphoxide (0.5ml). Heating was continued for 60h at 90 0

C.

Purification by preparative HPLC (gradient profile 5-95% (ii) over I8,?25min) gave the title compound as a white solid (6mg).

LCIMS (System C) Rt 3.41 min.

Mass Spectrum m/z 437 [MH"I Experimental details for route (T) Intermediate 63: 9-f(3aR.4R.6S .6aR)-6-f5-(tert-butyl )-l1.3,4-oxadiazol-2-ylI-2.2dimethyltetrahydrofurof3 .4-dlf 1, 3]dioxol-4-vl-N-(4-chloro-2-fluorophenyl )-9Hpurin-6-amine 9-[6S-(5-tert-Butyl-[1 ,3,4]oxadiazol-2-yl)-2 ,2-dimethyl-tetrahydro-(3aR,6aS)furof3,4-dJ[ 1,3ldioxol-4R-ylJ-6-chloro-9H-purine (2.8g) was treated with 4-chloro- 2-fluoro-aniline (4.48ml), palladium acetate (146mg) and bis(diphenylphosphino)-1,1'-binaphthy (620mg) in dry toluene (34ml) and the mixture stirred at room temperature for 5 mins (reaction carried out in seven portions). Caesium carbonate (3.08g, in seven portions) was added, and the mixtures heated at 86-96' C for 1 6h. The mixtures were combined and partitioned between water (200ml) and dichloromethane (3x120m1). The organic layers were washed with brine, dried (MgSO 4 and evaporated in vacuo to give a brown oil Purification by chromatography on silica gel, eluting with ethyl acetate:cyclohexane 30:70 gave an off-white solid (2.35g).

LC/MS (System C) Rt 3.41 min Mass Spectrum m/z 530 [MH]j Example 14 (2S.35 .4R,5R )-2-(5-tert-Butl-[ 1,3 .41oxadiazol-2-vl )-5-f6-(4-chloro-2-fluoroohenylamino)-purin-9-vll-tetrahvdro-furan-3.4-dioI 9-{(3aR,4 R,6S ,6aR)-6-[5-(tert-butyl 1,3,4-oxadiazol-2-y]-2 ,2d imethyltetrahyd rofu ro[3 1 ,31d ioxol-4-yl}-N-(4-chloro-2-fluorophenyl )-9Hpurin-6-amine (2.35g) was dissolved in trifluoroacetic acid (20m1) and water (2ml) with ice. bath cooling, and the mixture allowed to stand at 4 0 C for 17h. The mixture was poured slowly Into ice cold saturated aqueous sodium bicarbonate (400ml) and extracted with ethyl acetate (3x200ml). The organic layers were 123 washed with brine, dried (MgSO 4 and evaporated in vacuo to give the title compound as a buff solid (2.30g).

LC/MS (System C) Rt 3.04 min.

Mass Spectrum m/z 490 [MH*] Experimental details for route (U) Intermediate 64: 9-f6S-(5-tert-Butvl-1,.3,4]oxadiazol-2-yl)-2,2-dimethyl-tetrahydro-(3aR,6aS)furof3.4-d[1,3]dioxol-4R-vll-6-chloro-9H-purine 1-Deoxy-1-(1,6-dihydro-6-oxo-9H-purin-9-yl)-2,3,-O-(1-methylethylidene)-p-Dribofuranonic acid' (0.4g) was dissolved in tetrahydrofuran diisopropylethylamine (0.075ml) was added and the reaction mixture was stirred at 0°C for 10min. Pivaloyl chloride (0.016ml) was then added to the mixture and the reaction was stirred at 0°C for 3h. t-Butylhydrazide trifluoroacetate (0.36g) was dissolved in tetrahydrofuran, cooled to 0°C and treated with diisopropylethylamine (0.24ml); this solution was then added to the reaction mixture. The reaction was allowed to warm up to 200C and stirred for 20h. The solvent was removed in vacuo and the resulting residue purified by flash chromatography (silica gel, eluting with 5% methanol in dichloromethane) to afford the corresponding diacylhydrazide (0.41g).

The diacylhydrazide intermediate (30mg) was dissolved in dimethylformamide (3ml) and cooled to 0°C. Phosphorus oxychloride (45mg) was added, and the reaction mixture stirred at room temperature for 18h, and at 900C for 2h. The solvent was removed in vacuo, and the resulting residue, was purified by automated preparative HPLC to afford the title compound R.A. Olsson et al. J. Med. Chem., 1986, 29, 1683 Experimental details for Route (V) 124 Intermediate (2R.3R.4R. 5S )-4-(acetyloxv)-5-43-fUacetvloxv )methyllisoxazol-5-v)-h2-6-chloro- 9H-o~unn-g-vl )tetrahydrofuran-3-yI acetate To 6-chloropurine (1.08g) was added 1,1,1 .3,3,3-hexamethyldisilazane (20m1) and the mixture heated at 100 0 C, under nitrogen for 2.5h. The reaction was allowed to cool, the solvent was removed in vacuo, the residue azeotroped with anhydrous toluene (2x2.5m1) and the mixture evaporated to dryness to give an off-white solid. To this solid was added acetic acid 4R-acetoxy-2S-(3hydro-furan-3R-yl ester (450mg) in anhydrous acetonitrile (i5mi) under nitrogen, the mixture was cooled to 000 and trimethylsilyl trifluorometha nesul phonate (1 .4ml) added. The mixture was allowed to warm up to 20 0 C over 20min, then heated to 80 0 C for 16h. After cooling, the mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3x7m1); the organic layers were combined, washed with brine (50mI), dried (MgSO 4 and concentrated to dryness to give a crude porduct which was purified by flash column chromatography. on silica gel, eluting with 1:1 ethyl acetate~cyclohexane to furnish the title compound as a clear oil (3 LC/MS (System C) RI 2.76min Mass.Spectrum mlz 480/482 [MH+2+] Example 155 (2R.3R.4S HI S.2S )-2-hvdroxvcyclopentvllaminol-9H-punn-9-vfl (hyd roxymethvflisoxazol-5-vlltetrahvd rofu ra n-3 ,4-d iol To a solution of (2R,3R,4R,5S )--(acetyloxy)-5-{3-[(acetyloxy) methyl~isoxazol- 5 yl-2-(6-chloro-9H-punn-9-yl)tetrahyd rofura n-3-yI acetate (20mg) in isopropyl alcohol (2ml) was added N, N-d iisopropylethyla mine (0.043m1) and 2hydroxycyclopentylamine hydrochloride (1 1.4mg). The mixture was stirred at 0 C, under nitrogen-for 18h, cooled and evaporated to dryness in vacuo. The resulting residue was purified by automated preparative HPLC (gradient profile 5%-90% (ii) over 20mmn) to give the intermediate triacetoxy protected product.

125 To this residue was added methanol (1ml) and t-butylamine (0.013ml) and the mixture was stirred at 0°C for 3 hours. The solvent evaporated in vacuo to yield title compound as a white solid LC/MS (System C) Rt 2.25min Mass Spectrum m/z 419 [MH*] Experimental Details for route (W) Intermediate 66: (2R,3R,4R,5R)-4-(acetyloxy)-2-ethynyl-5-methoxytetrahydrofuran-3-yl acetate 4R-Ethynyl-6R-methoxy-2,2-dimethyl-tetrahydro-(3aR,6aR)-furo[3,4d][1,3]dioxole (0.965g) was heated under reflux with conc. hydrochloric acid in methanol (30ml) for 6h. The methanol was evaporated in vacuo, more methanol added, and heating under reflux continued for 16h. Pyridine (1.6ml) was added, the methanol was evaporated in vacuo, more methanol was added, and the mixture was evaporated to dryness in vacuo. Dry toluene was added and the mixture again evaporated to dryness. The residue was dissolved in dry dichloromethane and treated with pyridine (1.6ml), 4dimethylaminopyridine (25mg), and acetic anhydride (1.37ml), and the mixture was stirred at 22°C under nitrogen for 18h. The mixture was evaporated to dryness in vacuo and the residue partitioned between saturated aqueous citric acid (100ml) and dichloromethane (2x75ml). The organic layers were washed with saturated aqueous sodium bicarbonate, dried (MgSO 4 and evaporated in vacuo to give a pale yellow oil (1.19g).

Purification by chromatography on silica gel (10g Varian Bondelut cartridge), eluting with ethyl acetate: cyclohexane 5:95-30:70) gave the title compound as a colourless oil (724mg).

TLC SiO 2 (Ethyl acetate:cyclohexane 25:75) Rf 0.3 Intermediate 67: (2R.3R.4R.5R--(acetlox)-2-(6-chloro-9H-purin-9-yi ethvnyltetrahydrofuran-3-yl acetate 6-Chloropurine (250mg) was heated at 1300 (oil bath) with hexamethyldisilazane (6m1) with stirring under nitrogen for 2h. The excess reagent was evaporated in vacuo and the residue azeotroped with dry toluene (3x5ml) to give a pale yellow solid. (2R,3R,4 R, 5R)-4-(acetyl oxy)-2-ethynyl-5-methoxytetrahydrofura n-3-yl acetate (121mg) was azeotroped with dry toluene (2x5ml), dissolved in dry acetonitrile, and added to the silylated purine, followed by trimethylsilyl trifluoromethanesulphonate (0.334ml). The mixture was heated at 73-740 for 2h. The mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3x60ml). The organic layers were washed with brine, dried (MgSO 4 and evaporated in vacua to give a yellow oil (203mg)*.

Purification by chromatography on silica gel (Varian Bondelut cartridge), eluting with -ethyl acetate.,cyclohexane 10:90-60:40, gave the title compound as a colourless gum (84mg).

TLC Si02 (Ethyl acetate: cyclo hexa ne 50:50) Rf 0.25 Intermediate 68: (2R.3R.4R.5R)-4-(acetloxy)-2-r6-( 1 H-i ,2,3-benzotriazol- 1 -yloxy)-9H-Pu rin-9-ylln-3-yl acetate (2R,Z3R,4R,5R)-4-(acetyloxy)-2-(6-chloro-9H-pufln-9-yl)-5ethynyltetrahydrofuran-3-yl acetate (1 04mg) was treated With 1 hydroxybenzotriazole (136mg) in dry DMF (3m1) for 45h at 22 0 C. The mixture was poured into ice cooled 1 M hydrochloric acid (50ml) and extracted with dichloromethane (3x25ml), the organic layers were washed with water (20m1) and saturated aqueous sodium bicarbonate (20ml), dried (MgSO4) and evaporated in vacuo to give a colourless gum (148mg).

LC/MS (System Rt 3.19 min.

Mass Spectrum m/z 464 [MH"I Intermediate 69: 127 (2R ,3R.4R. 5R )-4-(acetvloxv)-2-f6-(4-chloro-2-fluoroanilino )-9H-o~unn-9-vll-5ethynvltetrahvdrofuran-3-vi acetate (2R, 3R,4R,5R)-4-(acetyloxy-2-[6-( 1H- 1,2, 3-benzotnazol- I-yloxy)-9H-purin-9-ylj- 5-ethynyltetrahydrofuran-3-yl acetate was treated with 2-fluoro-4-chloroaniline (0.63mI), and the mixture was heated at 60 0 C for 22.5h. The mixture was purified by chromatography on silica gel (Varian Bondelut cartridge), eluting with ethyl acetate: cycloh exa ne 10:90-60:40, to give the title compound TLC SiO 2 (Ethyi acetate: cycloh exa ne 50:50) Rf 0.3 Intermediate (2R .3R .4R.5S )-4-(acetvloxv)-5-(3-bromoisoxazol-5-vl )-2-f6-(4-chloro-2fluoroanilino )-9H-cpurin-9-vlltetrahydrofuran-3-yI acetate (2,R4,R--aeyoy--6(-hoo2furaiio-Hprn9y]5 ethynyltetrahydrofuran-3-yl acetate (20mg) was stirred at 22 0 C with dibromoformaldoxime (12.5mg), sodium bicarbonate (39mg), water (O.075ml) and ethyl acetate (1 .5m1) for 88h. The mixture was partitioned between water (20m1) and ethyl acetate (3xlOml), the organic layers were washed with brine and evaporated in vacua to give a brown gum (19mg). Purification by chromatography on silica gel (Varian Bondelut cartridge), eluting with ethyl acetate: cycloh exa ne 20:80-80:20) gave the title compound as a colourless gum (1 6.8mg).

LC/MS (System C) Rt 3.6min Mass Spectrum m/z 595, 597 [MH+2*] Example 164 (2S .3S.5R 2(-rmioao--y)5[-4clr--luraiio-Hpr 9-vlltetrahydrofu ran-3 ,4-d ioI (2 R,3R,4 R, 55)-4-(acetyloxy)-5-(3-bromoisoxazol-5-y )-2-[6-(4-chloro-2fluoroanilino)-9H-purin-9-ylltetrahydrofuran-3-yI acetate (16.8mg) was treated with t-butylamine (Q.08m1) in methanol (0.8ml) at 0 0 C for 1 .5h, and the mixture was evaporated to dryness to give the title comp~ound (1 6mg).

128 LC/MS (System C) Rt 3.22min Mass Spectrum m/z 511 [MH J Experimental details for route (Wb) Example 144 (2R.3R.4S.5S )-2-r6-(4-chloro-2-fluoroanilino )-9H-rpurin-9-vll-5-(3-methylisoxazol- 5-vl)tetrahvdrofuran-3 .4-diol (2R,3R,4R,5R)-4-(acetyloxy)-2-(6-chloro-9 H-pu ethynyltetrahydrofuran-3-yl acetate (20mg) was dissolved in anhydrous toluene and treated with triethylamine (0.006ml), nitroethane (0.004ml) and phenyl isocyanate (0.01 2ml). The reaction was heated at 10000C for 24h, cooled to room temperature and concentrated in vacuo. The resulting residue was purified by automated preparative HPLC, to produce an intermediate which was then dissolved in anhydrous methanol, cooled to 000 and treated with tbutylamine (0.02m1) for 1 h. The reaction mixture was concentrated in vacuo, to afford the title compound as a white solid (143mg).

LC/MS (system C) Rt 2.95min Mass Spectrum m/z 447 [MH+I Experimental details for route (X) Example 130 (2R.3R,4S.5R)-2-6-(ccloentlamino)-9H-purin-9-vll-5-(1 .5-dimethl-1 H-i .2.4triazol-3-vl )tetrahyd rofura n-3 .4-d iol trifluoroacetate ,2-Dimethyl-6R-(5-methyl-4H-[1.2 ,4]triazol-3-yl)-tetrahydro-(3aR,6aR)furo[3 .4-dill ,3]dioxol' -4R-yl]-9H-pu rin-6-yl}-cyclopropyl-amine (250mg) was dissolved in anhydrous toluene (1lOml) and treated with dimethylformamide dimethyl acetal (0.47ml). The mixture was heated at reflux temperature for 7h.

and then, cooled to 2000 and conce ntrated in vacuo. The resulting residue was purified by flash chromatography on silica gel, eluting with ethyl acetate: 129 methanol 19:1. The resulting intermediate was treated with a mixture of trifluoroacetic acid /water at 0 0 C for 6h. The reaction mixture was then concentrated in vacua, to afford, after tritu ration with ethyl acetate, the title comound as a white solid (143mg).

Analysis: Found C 44.4; H 4.8; N 20.4 Required for C 18

H

24 N0 3

.CF

3

CO

2 H. 1.5 H 2 0: C 44.4; H 5.2; N 20.7 Experimental details for route (Z) Intermediate 71: (2R.3R.4R.5R)-4-(acetloxv)-2-'(acetloxv)methl-5-E2-chloro-6-(4-chloro-2fluoroanilino)-9H-nurin-9-vlitetrahvd rofura n-3-vI acetate To a stirred solution of 2 ,6-dichloro-9-(2,3,5-tri-O-acetyl-p-D-ibofuralosyl )-9Hpurine 2(1 .Og) in toluene (25ml) was added palladium acetate (50mg), 4-chloro- 2-fluoroaniline (0.5ml) and bis[2-(diphenylphosphino)phenytJ ether 3 (l12Omg) and the reaction stirred at 20 0 C for 15 min. Caesium carbonate (872mg) was added and the mixture heated at 90 for 16 hours. The reaction mixture was cooled to 200C and partitioned between ethyl acetate (lO0mI) and water (lO0mI). The organic layer was washed with brine (lO0mI), dried with magnesium sulphate and the solvent removed in vacuo. Purification by flash chromatography on silica gel, eluting with ethyl acetate: cyclohexane gave the title compound (400mg).

Mass Spectrum m/lz 556 [MH 4 2. M. J. Robins and B. Uznanski Canad. J. Chem., 1981, 59(17), 2608 3, j. P. Sadighi, M. C. Harris and S. L, Buchwald Tefl. Left. 1998, 5327-5330 Intermediate 72: f(a.R6.a)6[-hoo6(-hoo2furaiio-Hgun9yl22 d imethvltetrahvd rofuro[3 .4-di 1, 31dioxol-4-vllmethanoI 130 To a suspension of (2R,3R,4R,5R)-4-(acetyloxy)-2-((acetyloxy)methylj-5-[2chloro-6-(4-chloro-2-fluoroanilino)-9H-purn-9-yljtetrahydrofuran-3-yl acetate (400mg) in methanol (7ml), sodium methoxide, 25% in methanol, (3 drops) was added. On stirring for 15 min at 20 0 C the reaction mixture went clear. On stirring at 20 0 C for a further 90 min a precipitate formed. The precipitate was collected by filtration and dried in vacuo for 16 hours. This was dissolved in a mixture of acetone (15ml) and 2-2-dimethoxypropane (3ml), and para-toluene sulphonic acid (193mg) added. The mixture was stirred at 20 0 C for 3 hours. The solvent was:-removed in vacuo and the residue dissolved in ethyl acetate washed with water (50ml) and brine (30ml), dried (MgSO 4 and the solvent removed in vacuo. Purification by chromatography on silica gel (Varian Bondelut cartridge), eluting with cyclohexane:ethyl acetate gave the title compound as a white foam (240mg).

Mass Spectrum 470 m/z [MH Experimental details for route (Y) Intermediate 73: tert-Butyl 4-[(9-{(2R,3R,4R,5S)-3.4-bis(acetyloxy)-5-[3-(tert-butvl)isoxazol-5yl]tetrahydrofuran-2-yll-9H-purin-6-yl)aminolpiperidine-1-carboxylate To a solution of acetic acid 4R-acetoxy-5S-(3-tert-butyl-isoxazol-5-yl)-2R-(6chloro-purin-9-yl)-tetrahydro-furan-3R-yl ester (455mg) in isopropanol was added tert-butyl-4-amino-1-piperidinecarboxylate (785mg) and diisopropylethylamine (1.03ml). The mixture was heated at 95 0 C for 60 h. The resulting mixture was then cooled and evaporated to dryness in vacuo. The resulting residue was dissolved in pyridine (20ml) and acetic anhydride (19ml) was added. The mixture was stirred at room temperature for 16h, evaporated to dryness in vacuo and redissolved in ethyl acetate (50ml). Citric acid (2 x was added to the mixture and the layers separated. The aqueous layers were extracted with ethyl acetate (100ml). The combined ethyl acetate layers were dried (MgSO 4 filtered and evaporated to dryness in vacuo to afford the title product (500mg) as a yellow solid.

LC/MS (System Rt 3.59 min Mass Spectrum m/z 628 [MH+J Intermediate 74: (2R.3R.4R.5S )-4-(Acetvloxv)-5-f3-(tert-buty )isoxazol-5-vl-2-F6-(Diperldin-4 vlamino)-9H-pu rin-9-vltetra hydrofuran-3-vl acetate tert-Butyl 4-[(9-{(2R,3R,4R,5S)-3,4-bis(acetyloxy)-5-[-(tert-butyl)isoxazol-5yl]tetrahydrofuran-2-yl)-9H-purin-6-yl)amino]piperidine- -carboxylate (500mg) was dissolved in trifluoroacetic acid dichloromethane 20ml) and the mixture kept at 3 0 C for 16h. The mixture was then quenched with saturated sodium bicarbonate solution .(100ml) and extracted with dichloromethane (100ml). The organic layer was washed with saturated sodium bicarbonate solution (100ml) and evaporated to dryness in vacuo to afford the title compound (407 mg) as a yellow glassy solid.

LC/MS (system Rt 2.45 min Mass Spectrum m/z 528 [MH t Intermediate (2R.3R,4R.5S )-4-(acetvloxvy-5-I3-(tert-butvl)isoxazol-5-VI1-2-(6-ffl (methvlsulfonvDiiiperid in-4-vlaminol-9H-punn-9-vI)tetrahvdrofuran-3-yI acetate To a solution of (2R,3R ,4R,5S)-4-(Acetyloxy)-5-3-(tert-butyl)i (piperidin-4-ylaminoH-purin-9-yl]tetr acetate (40mg) in tetrahydrofuran (4ml) was added methanesulfonyl chloride (O.0088m1) and triethylamine (.0212ml). The reaction mixture was stirred for 16h at 20 0 C, and partitioned between ethyl acetate (2xl00ml) and water (100ml). The organic layers were washed with water (100ml), dried (MgSO 4 and evaporated in vacuo to afford the title compound (36.7mg) as a colourless gum.

LC/MS (System R, 3.20 min Mass Spectrum m/z 606 [MH+] Example 167 (2S.3S.4R.5R)-2-r3-tert-butvl )isoxazol-5-vlJ-5-(6-fl -(methylsulfonvi )ioeridin-4vllamino)-9H-purin-9-l )tetrahvdrofuran-3.4-diol (2R,3R,4R,5SM-4-(Acetyloxy)5-[3-(tert-butyl)isoxazolyl2-(6.{[1 (methylsulfony)piperidin -4-yl]am ino}-9H-pu rin-9-yl)tetrahydrofuran-3-yl acetate (36.7mg) was dissolved in chilled methanol (2m1) and tert-butylamine (0.038ml) was added at OOC. The mixture was kept at 30C for 1.5h, and evaporated in vacuo to afford the title compound as a white solid (30.8mg).

LC/MS (System Rt 2.69 min Mass Spectrum m/z 522 [MH'J Experimental details for route (Bb) IntermedIate 76: (2R.3R.4R5S)-4-(aceloxy)-5-3-f(acetylow)methvllisoxazol-5-l-2-[2-chloro-6- (4-chloro-2-fluoroanilino)-9H-u rin-9-lltetrahvd rofu ran-3-vl acetate To acetic acid 4R-acetoxy-5S-(3-acetoxymethyl-isoxazol-5 )-2R-(2,6-dichioropurin-9-y)-tetrahydro-furan-3R-y ester (50mg) in toluene (2m) was added palladi.um (II) acetate (2.2mg), 2,2'-bis(diphenylphosphino)- ,l'-binaphthyl (6mg) and 4-chloro-2-fluoroaniline (28.5mg). The mixture was stirred under nitrogen for 20min, cesium carbonate (38mg) was added, and stirring was continued at 8000 for 24h. The mixture was cooled, diluted with ethyl acetate (25ml), washed with water (25m1) and. brine (25ml), and evaporated in vacuo. Purification by automated preparative HPLC (gradient profile 5-90% (ii) over 18.5min) gave the title compound as a white solid (3.02mg).

LC/MS (System C) Rt 3.52 min Mass Spectrum m/z= 623 [MH] Intermediate 77: 133 (2R.3R.4S.5S )2-[2-chloro-6-(4-chloro-2-fluoroanilino)-gH-ourin-9-Vfl-5[3hydrofuran-3.4-diol To (2R.3R,4R,5S)-4-(acetyloxy-53-[(acetyloxy)methylisoxazol-5-y}-2-[2chloro-6-(4-chloro-2-fluoroanilino)-9H-purin-9-yljtetrahydrofuran-3-y acetate (4.02mg) in methanol (2m1) at 0 0 OC was added tert-butyfamine 0 12ml), and the mixture was allowed to stand at 0 0 C for 3h. The solvent was evaporated in vacua to furnish the title compound as a yellow gum (2.48mg).

LC/MS (System C) R, 3.10mmni Mass Spectrum m/z 497 [MH*] Experimental details for Route Cc Intermediate 78: (3a R.4S,6R6a R)-N'-acetl -6[64-ch lo ro-2-fluo roa nil ing 9H-tud n-9-vl-2.2d imethltetrahvdrofuror3 .4-dll .31d ioxole-4-carbohvdrazide To a stirred solution of (3aR,4S,6R,6aR)-6-[6-(4-chloro-2-fluoroanilino)-9H-puif- 9 -yl]-2 ,2-dimethyltetrahyd rofu ro[3,4-d][1 ,3]dioxole-4-carbohydrazide (50mg) in N,N'-dimethylformamide (2m1) at 0 0 C was added diisopropylethylamine (28pl) and acetyl chloride (9mg). The reaction mixture was stirred at 000C for 5h. The mixture was partitioned between ethyl acetate (20ml) and water (20ml). The organic layer was washed with brine (20m1), dried (MgSO 4 and the solvent removed in vacuo. The residue was purified by automated preparative HPLC (gradient profile 5-95% (ii) over 18.5 min) to give the title compound LC/MS: Rt=2.87 min Mass Spectrum m/z 506.[MH-1 Subsequent steps analogous to route A.

Reporter Gene Experiments 134 Agonist activity was measured in Chinese hamster ovary (CHO) cells containing the CRE/SPAP/HYG (CRE cyclic AMP response element; HYG hygromycin resistance; SPAP secreted placental alkaline phosphatase) reporter gene elements, which upon stimulation of cAMP levels produced SPAP. A cell line was used, which was stably transfected with either the human adenosine Al receptor or the human adenosine A3 receptor in addition to the above elements.

Cells were plated out in 96-well plates in culture medium and incubated at 370C for 1 hour. For measurement of potency, agonists were added to the appropriate wells at a concentration range of approximately 10_ 1 0 10-sM. later. cAMP levels were stimulated by addition of a maximal concentration of forskolin. All cells were then incubated for a further 5 hours at 370C, and cooled to room temperature, after which a substrate for the phosphatase (paranitrophenol phosphate, pNPP); which is converted by SPAP to a coloured reagent) was then added and the 96-well plates were read in a plate reader.

From these readings, the concentration-dependence of the inhibition by the agonist for forskolin-stimulated SPAP production can be calculated. One of the agonists tested on each 96-well plate was the standard non-selective agonist, Nethylcarboxamidoadenosine (NECA), and the potency of all test agonists is expressed relative to that of the NECA standard.

(ECR equipotent concentration ratio relative to NECA 1) Table Potencies in the reporter gene assay Example No. Adenosine Al Adenosine A3 receptor receptor ECR* ECR* 3 4.16 152 4 5.65 152 6 1.71 134 12 2.28 254 14 5.8 1066.71 16 9.6 201 19 5.15 172 21 23.26 321 22 8.75 4293 28 0.42 44.7 37 4.19 507 44 7.68 165.54 7.36 165.54 51 7. 587.75 54 20.78 715.31 56 15.96 717.99 62 29.47 327 67 9.8 827.66 68 4;09 417.37 108 1.52 -254 116 27.26 955 119 2.83 154 123 4.19 325.44 126 13.9 127 0.21 21.62 129 15.5 >199 131 0.15 199.01 132 0.53 >22.4 133 25.47 466.92 134 3.28 >245.4 135 0.48 136 1.95 138 139 10.64 228 141 12.08 228 143 19.6 >74.1 144 145 24.9 163 1.34 232 136 164 4.3 177 2.01 122 178 7.42 >471 179 12.6 180 18.1 >471 181 8.57 182 3.48 *ECR equipotent concentration ratio relative to NECA 1 (see description in Reporter Gene Assay) Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

Claims (3)

1. 2-yl]-9H-purin-6-yl)amino)-N-methylethanesulfonamide; (2 R,3 R,4S, 5S 2 -[6-(cyclopentylamino)-gH-purin-9-ylq-5-[3-(methoxymethyl). 1,2 ,4-oxad iazol-5-yI]tetrahydrofu ran-3,4-d iol; (23 ,3S .4R,5R)-2-(5-ethyl- 1,3,4-oxadiazol-2-y )5-[6-(iso propylamino)-9H-pu rin-9- yIjtetrahyd rofuran-3,4-diol; S,2S)-2-hydroxycyclopentyllamino}-9H-purin-9-yl)-5-(5. methyl-i .3,4-oxadiazol-2-yI )tetrahyd rofuran-3 .4-diol; (2R,3R 43 ,5S)-2-{2-chloro-6-[( 1 -ethylpropyl)amino]-9H-purin-9-yl}-5-(3- cyclopropyl-1.2 ,4-oxadiazol-5-yl)tetrahydrofuran-3 .4-diol formate (2R,3R,4S,5S )-2-[2-chloro-6-( 1 -ethyl-propylamino)-purin-9-y]-5-(3..cyclopropyl- [1,2 .4]oxadiazol-5-yI)-tetrahyd ro-furan-3 ,4-d jol diformate; (2S,3S,4R5R)-2-(3-ethyisoxazo-5yl.5(6-(.flS.2S)-2- hydroxycyclopentyl]amino)-9H-pu rin-9-yl)tetrahydrofu ran-3,4-d jol; (2R, 3R,4S ,5S )2-(2-chloro-6-{(1S,2S )-2-hydroxycyclopentyljamino}-9H-purin-9- yl )-5-(3-ethylisoxazol-5-yI)tetra hydrofu ra n-3,4-diol; (2R,3 R,4S,5S )-2-(2-chloro-6-{(2-(ethylsu Ifonyl )ethyllaminol-9 H-pu rin-9-yI ethyl isoxa zol-5-yl )tetra hyd rofu ran -3,4-d iol; 4 'OPERW1AI\2O6eb-YUary2 232399) pages dom.I7O2O6 138 (2R I S ,2S )-2-hyd roxycyclopentyllamino}-9H-pu rin-9.yl)-5-[3- (hyd roxymethyl )isoxazol-5-yljtetrahydrofuran-3 ,4-diol; and (2R, 3R,4S ,5R)-2-{2-chloro-6-[(1 -ethyl propyl)amino]-9H-pu rin-9-yl}-5-(5- ethyl isoxazol-3-yl )tetra h yd rofu ra n-3 .4-diol formate; 2-[(9-f{(2R,3R AS, 5S)-5-[3-(tert-butyl )isoxazol-5-y ,4-dihydroxytetrahydrofu ran- 2-yI)-2-ch loro-9 H-purdin-6-yl )a m ino]-N-ethyletha nesulfon amid e; 2-[(9-{(2R,3R,4S,5S)-5-(3-(tert-butyl )isoxazol-5-yl]-3,4-dihydroxytetrahydrofuran- 2-yl}-2-chloro-9H-pu rin-6-yl)amino]-N-isopropylethanesulfonamide,; ,3R,4S, 5S)-5-[3-(tert-butyl )isoxazol-5-yI]-3,4-d ihyd roxytetra hydrofu ran- 2-yI}-9H-purin-6-yl )amino]-N-ethylethanesulfonamide; (2R, 3R ,4S ,5S)-2-[6-(cyclopentylamino)-9H-purin-9-yl]-5-[5-(trifiuoromethy)- 1,3 ,4-oxadiazol-2-ylltetrahyd rofura n-3 ,4-d jol:, (2R,3R 1 S .25)-2-hydroxycyclopentyllamino}-9H-pu rin-9-yl (triflIu oromrnethyl)-1I ,4-oxad iazol1-2-yl]tetra hyd rofu ra n-3 ,4-d iol; (2R,3R,4 S,5S 1 S 1 2S )-2-hydroxycyclopentylla mino}-9H-purin-9- yl (h ydroxymneth yl )isoxaz7ol -5-yi] tetra hyd rofu ra n-3,4 -d iol1; 2-[(2-chloro-9-{(2R, 3R,4S, 5S)-3 ,4-dihyd roxy-5-[3-(hydroxymethyl)isoxazol-5- yljtetrahyd rofuran-2-yl}-OH-purin-6-yl)amino]-N-ethylethanesulfonamide; (2S,3S ,4 R,5R)-2-(3-ethylisoxazol-5-yl IS,2S hydroxycyclopentylla mino}-2-methoxy-9H-pu rin-9-yl)tetrahyd rofu ran-3 ,4-diol; (2S ,3S ,4 R,5R)-2-(3-ethylisoxazol-5-yl)-5-(6-([2-(ethylsulfony)ethyl]amino}-2- methoxy-9H-purin-9-yl )tetrahydrofuran-3 ,4-d lol; (2S.3S,4R,5R)-2-[3-(tert-butyl)-1 ,2,4-oxadiazol-5-ylij-5-[6-(cyclopropylamino)-9H- Pu rin-9-ylltetra hydrofura n-3 1
2. 4-dioi; or a salt or solvate of any one thereof. 2. A compound according to claim 1 which exhibits little or no agonist activity at the the A3 receptor. 3. A pharmaceutical composition comprising a compound according to claim I or claim 2 together with a pharmaceutically acceptable diluent or carrier. 4. Use of a compound according to claim 1 or claim 2 in the manufacture of a med icament for the treatment of a patient suffering from a condition where there is an advantage in decreasing plasma free fatty acid concentration, or reducing heart rate. Use of a compound according to claim I or claim 2 in the manufacture of a medicament for the treatment of a patient suffering from or susceptible Q \OPER\MaK2006\Ybrary2O02323990 pagcs doc-27102/06
3. 139- to ischaemic heart disease, peripheral vascular disease or stroke or which subject is suffering pain, a CNS disorder or sleep apnoea. 6. A method of treating a patient suffering from or susceptible to ischaemic heart disease, peripheral vascular disease or stroke or which subject is suffering from or susceptible to ischaemic heart disease, peripheral vascular disease or stroke, or which subject is suffering pain, a CNS disorder or sleep apnea comprising administration of a therapeutically effective amount of a compound according claim 1 or claim 2, 7. A method of treating a patient suffering from a condition where there is an advantage in decreasing plasma free fatty acid concentration, or reducing heart rate comprising administration of a therapeutically effective amount of a compound according to claim 1 or claim 2. DATED this 24 th day of February, 2006 Glaxo Group Limited By DAVIES COLLISON CAVE Patent Attorneys for the Applicant