CZ20004869A3 - Adenosine derivatives - Google Patents

Abstract

Adenosine derivatives of the general formula I, in which the individual general symbols have the meaning given in the description, are substances with an agonistic effect on adenosine Al receptors and can therefore be used to treat conditions that can be favorably influenced by reducing the concentration of free fatty acids in the blood plasma, reducing the heart rate, or to treat conditions of ischemic heart disease, peripheral vascular diseases, stroke, pain conditions, central nervous system disorders or sleep apnea. The essence of the invention also includes a pharmaceutical composition containing the said substances and the use of the said derivatives for the production of this pharmaceutical composition.

Description

Technical area

The invention relates to novel adenosine derivatives, a process for their production and pharmaceutical compositions containing these derivatives.

State of the art

Adenosine derivatives are described, for example, in WO 98/16539 (Novo Nordisk. A/S), where they are used for the treatment of myocardial ischemia, cerebral ischemia and epilepsy. WO 98/04126 (Rhone-Poulenc Rorer Pharmaceuticals lne.) describes adenosine derivatives with antihypertensive, cardioprotective, antiischemic and antilipolytic effects and finally WO 98/01459 (Novo Nordisk A/S) describes N, 9-disubstituted adenine derivatives which are substituted in the 4' position with an unsubstituted oxazolyl or isoxazolyl group and are useful for the treatment of disorders in the development of which cytokines are involved.

The essence of the invention

The invention consists of adenosine derivatives of the general formula IR ¹

O) • · · · · · • ·

2«····· ·· ·· ·· ·· ·· where X represents O or CH ₂ ,

R ² represents a C 1 -C 3 alkyl, a C 1 -C 3 alkoxy group, a halogen atom or a hydrogen atom,

R ³ represents a hydrogen atom, phenyl, optionally substituted by a halogen atom, a 5- or 6-membered heteroaryl group, a C1-C6alkoxy group, a C1-C6alkylO(CH ₂ ) _n , where n represents 0 to 6, C3-C7cycloalkyl, C1-C6hydroxyalkyl, a halogen atom, a C1-C6alkyl with a straight or branched chain,

C1-C6alkenyl or C1-C6alkynyl, optionally substituted with at least one halogen atom,

Y and Z are O, N, CH or N(C1-C6alkyl),

W represents CH, O, N, S or N(C1-C6alkyl), wherein at least one of the symbols W and Z represents a heteroatom and in the case where Y, Z and/or W represents a nitrogen atom, the absence of a further hydrogen atom is obvious, provided that in the case where W represents a CH group,

Z represents a nitrogen atom and Y represents an oxygen atom, R ³ has a meaning other than a hydrogen atom,

R ⁴ and R ⁵ independently represent a hydrogen atom or a straight or branched chain C 1 -C 6 alkyl,

R ¹ represents a hydrogen atom or one of the groups (1) - (alk) _n -C3-C7cycloalkyl, including a bridged cycloalkyl group, wherein the cycloalkyl group is optionally substituted with at least one substituent from the group OH, a halogen atom, a C1-C3alkoxy group, (alk) represents a C1-C3alkylene group and n represents 0 or 1, (2) an aliphatic heterocyclic group containing 4 to

6-membered rings containing at least one heteroatom from the group O, N or S, optionally substituted with at least one substituent from the group Cl-C3alkyl, -CO ₂ -C1-

-C4alkyl, -CO(Cl-C3alkyl), -S (=0) _n -Cl-C3alkyl, -CONR ^a R ^b , where R ^a and R ^b independently represent a hydrogen atom or Cl-C3alkyl, or =0 and in the case that the heterocyclic ring contains a sulfur atom, this sulfur atom is optionally substituted by a group (=0) _n , where n represents 1 or 2, (3) Cl-C12alkyl with a straight or branched chain, optionally containing in the alkyl chain one or more groups 0, S(=0) _n / where n represents 0, 1 or 2 and N, the alkyl groups are optionally substituted by one or more substituents from the group phenyl, halogen atom, hydroxy group, C3-C7cycloalkyl or NR ^a R ^b , where R ^a and R ^b independently represent a hydrogen atom, C3-C7cycloalkyl or Cl-C6alkyl with a straight or branched chain chain, optionally substituted with a C3-C7cycloalkyl residue, (4) a fused bicyclic aromatic ring of the formula

where B represents a 5- or β-membered heterocyclic aromatic ring containing at least one heteroatom from the group O, N or S, wherein the bicyclic ring is bonded to the nitrogen atom in the compound of formula I through an atom in ring A and ring B is optionally substituted with a group -CC>2-Cl-C3alkyl, (5) a phenyl group, optionally substituted with one or more substituents from the group halogen atom, SO ₃ H, -(alk)nOH, -(alk) _n -cyano group, - (0) _n -Cl-C6alkyl, optionally substituted with at least one halogen atom,

- (alk) "nitro group, - (0) _m - (alk) _n -CO ₂ R ^c , - (alk) _n ~CONR ^c R ^d ,

- (alk) _n -COR ^c , - (alk)n-SOR ^e , - (alk) n-SO ₂ R ^e , - (alk) n-SO2NR ^c R ^d , -(alk)nOR ^c , - (alk)n-(CO)m-NHSO2R ^e , - (alk) n-NHCOR ^c ,

- (alk) _n NR ^c R ^d , where n and n are 0 or 1 and alk is a C1-C6alkylene group or a C2-C6alkenyl group, (6) a phenyl group substituted with a 5- or 6-membered heterocyclic aromatic group, said heterocyclic aromatic group being optionally substituted with a C1-C3alkyl group or a -NR ^c R ^d group,

R ^c and R ^d independently represent a hydrogen atom or a C1-C3alkyl group or, in the case of the group -NR ^c R ^d , these substituents may form with the nitrogen atom a 5- or 6-membered heterocyclic ring, optionally containing other heteroatoms, wherein this heterocyclic ring is optionally further substituted with at least one C1-C3alkyl group,

R ^e represents C 1 -C 3 alkyl, as well as salts and solvates of these compounds, especially physiologically acceptable salts and solvates for use in medicine, said derivatives being agonists at the adenosine A 1 receptor.

Preferred derivatives according to the invention are adenosine derivatives of the general formula Ia _R i

NH

N

Xs

OR ^S

X.

(la) • ···· · · ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · where X is O or CH2,

R ² represents a C 1 -C 3 alkyl, a C 1 -C 3 alkoxy group, a halogen atom or a hydrogen atom,

R ³ represents a hydrogen atom, phenyl, optionally substituted by a halogen atom, a 5- or β-membered heteroaryl, a C1-C6 alkoxy group, a C1-C6 straight-chain or branched-chain alkyl, optionally substituted by at least one halogen atom, a C3-C7 cycloalkyl, a C1-C6 hydroxyalkyl or a halogen atom,

Y and Z represent O, N or CH,

W represents CH, O, N or S, wherein at least one of W and Z represents a heteroatom and in the case where Y, Z and/or W represents a nitrogen atom, the presence or absence of a further hydrogen atom is obvious, provided that in the case where W represents CH, Z represents a nitrogen atom and Y represents an oxygen atom, R ³ has a meaning other than a hydrogen atom,

R ⁴ and R ⁵ independently represent a hydrogen atom or a straight or branched chain C 1 -C 6 alkyl.

R ¹ represents a hydrogen atom or one of the groups (1) - (alk) _n -C3-C7cycloalkyl, including a bridged cycloalkyl group, wherein the cycloalkyl group is optionally substituted with at least one substituent from the group OH, a halogen atom, a C1-C3alkoxy group, (alk) represents a C1-C3alkylene group and n represents 0 or 1, (2) an aliphatic heterocyclic group containing 4 to

6-membered rings containing at least one heteroatom from the group O, N or S, optionally substituted with at least one substituent from the group Cl-C3alkyl, -CO2-Cl• 4444 ·· 4444

4 4 · · · • 4 · 4 4 4 4 • 4 4 4 4 4

-C4alkyl, -CO(Cl-C3alkyl), -S (=0) _n -Cl-C3alkyl, -CONR ^a R ^b , where R ^a and R ^b independently represent a hydrogen atom or Cl-C3alkyl, or =0 and in the case that the heterocyclic ring contains a sulfur atom, this sulfur atom is optionally substituted by a group (=0) _n , where n represents 1 or 2, (3) Cl-C12alkyl with a straight or branched chain, optionally containing in the alkyl chain one or more groups 0, S(=0) _n , where n represents 0, 1 or 2 and N, the alkyl groups are optionally substituted by one or more substituents from the group phenyl, halogen atom, hydroxy group, C3-C7cycloalkyl or NR ^a R ^b , where R ^a and R ^b independently represent a hydrogen atom, C3-C7cycloalkyl or Cl-C6alkyl with a straight or branched chain chain, optionally substituted with a C3-C7cycloalkyl residue, (4) a fused bicyclic aromatic ring of the formula

where B represents a 5 or β-membered heterocyclic aromatic ring, containing at least one heteroatom from the group O, N or S, wherein the bicyclic ring is bonded to the nitrogen atom in the compound of formula I through an atom in ring A and ring B is optionally substituted with a group -CO ₂ -Cl-C3alkyl, (5) a phenyl group, optionally substituted with one or more substituents from the group halogen atom, SO3H, -(alk) _n 0H, - (alk) _n 'cyano group, - (O) _n -Cl-C6alkyl, optionally substituted with at least one halogen atom, ·· 4 4*4

4 4 4 '

4

4 4 4

4 4

- (alk) _n nitro group, - (O) _m -(alk) _n -CO ₂ R ^c , - (alk) _n -CONR ^c R ^d ,

- (alk) _n -COR ^c , - (alk)n-SOR ^e , - (alk) n-SO ₂ R ^s , - (alk) n-SO2NR ^c R ^d , -(alk)nOR ^c , - (alk)n- (CO) m-NHSO2R ^e , - (alk) n-NHCOR ^c ,

- (alk) _n NR ^c R ^d , where n and n are 0 or 1 and alk is a C1-C6alkylene group or a C2-C6alkenyl group, (6) a phenyl group substituted with a 5- or 6-membered heterocyclic aromatic group, said heterocyclic aromatic group being optionally substituted with a C1-C3alkyl group or a -NR ^c R ^d group,

R ^c and R ^d independently represent a hydrogen atom or a C1-C3alkyl group or, in the case of the group -NR ^c R ^d , these substituents may form with the nitrogen atom a 5- or 6-membered heterocyclic ring, optionally containing other heteroatoms, wherein this heterocyclic ring is optionally further substituted with at least one C1-C3alkyl group,

R ^e represents C 1 -C 3 alkyl, as well as salts and solvates of these compounds, especially physiologically acceptable salts and solvates for use in medicine, said derivatives being agonists at the adenosine A 1 receptor.

The invention also provides pharmaceutical compositions comprising compounds of formula I or Ia together with a pharmaceutically acceptable diluent or carrier.

It is clear that some of the compounds of general formula I are novel. A special group of these derivatives can be expressed by general formula Ib. The invention therefore also includes adenosine derivatives of general formula Ib

4 4 4 · 4 • 4

44 4 4

4 4

R ¹

NH

where X represents O or CH ₂ ,

R ² represents a C 1 -C 3 alkyl, a C 1 -C 3 alkoxy group, a halogen atom or a hydrogen atom,

R ³ represents a hydrogen atom, phenyl, optionally substituted by a halogen atom, a 5- or β-membered heteroaryl group, a C1-C6alkoxy group, a C1-C6alkylO(CH2) _n , where n represents 0 to 6, C3-C7cycloalkyl, C1-C6hydroxyalkyl, a halogen atom, a C1-C6alkyl with a straight or branched chain,

C1-C6alkenyl or C1-C6alkynyl, optionally substituted with at least one halogen atom,

Y and Z are O, N, CH or N(C1-C6alkyl),

W represents CH, O, N, S or N(C1-C6alkyl), wherein at least one of the symbols W and Z represents a heteroatom and in the case where Y, Z and/or W represents a nitrogen atom, the absence of a further hydrogen atom is obvious, provided that in the case where W represents a CH group,

Z represents a nitrogen atom and Y represents an oxygen atom, R ³ has a meaning other than a hydrogen atom,

R ⁴ and R ⁵ independently represent a hydrogen atom or a straight or branched chain C 1 -C 6 alkyl,

R ¹ represents a hydrogen atom or one of the groups * 4 4 4

4···

4 4 (1) -(alk) _n ^- C3-C7cycloalkyl, including bridged cycloalkyl, wherein the cycloalkyl is optionally substituted by at least one substituent from the group OH, halogen, C1-C3alkoxy, (alk) means a C1-C3alkylene group and n means 0 or 1, (2) an aliphatic heterocyclic group, containing 4 to β-membered rings containing at least one heteroatom from the group O, N or S, optionally substituted by at least one substituent from the group Cl-C3alkyl, -CO ₂ -C1-C4alkyl, -CO(Cl-C3alkyl), -S (=0) _n -Cl-C3alkyl, -C0NR ^a R ^b , where R ^a and R ^b independently mean a hydrogen atom or Cl-C3alkyl, or =0 and in the case that the heterocyclic ring contains a sulfur atom, this sulfur atom is optionally substituted by the group (=0) _n , where n means 1 or 2, (3) C1-C12 straight-chain or branched alkyl, optionally containing in the alkyl chain one or more groups O, S(=O) _n , where n means 0, 1 or 2 and N, the alkyl groups are optionally substituted by one or more substituents from the group phenyl, halogen atom, hydroxy group, C3-C7cycloalkyl or NR ^and R ^b , where R ^a and R ^b independently mean a hydrogen atom, C3-C7cycloalkyl or C1-C6 straight-chain or branched alkyl, optionally substituted by a C3-C7cycloalkyl residue, !4) a fused bicyclic aromatic ring of the formula

0000

0000

00 where B represents a 5 or 6-membered heterocyclic aromatic ring containing at least one heteroatom from the group O, N or S, wherein the bicyclic ring is bonded to the nitrogen atom in the compound of formula I through an atom in ring A and ring B is optionally substituted with a -CO ₂ ~Cl-C3alkyl group, (5) a phenyl group, optionally substituted with one or more substituents from the group halogen atom, SO3H, -(alk) _n OH, - (alk) _n -cyano group, - (0) _n -Cl-C6alkyl, optionally substituted with at least one halogen atom,

- (alk) _n nitro group, - (0) _m -(alk) _n -C0 ₂ R ^c , - (alk) _n -CONR ^c R ^d ,.

- (alk) _n -C0R ^c , - (alk)n-S0R ^e , - (alk) n-SO ₂ R ^e , - (alk) n-S02NR ^c R ^d , -(alk)n0R ^c , - (alk)n- (CO) m-NHSO2R ^e , - (alk) n-NHC0R ^c ,

- (alk) _n NR ^c R ^d , where n and n are 0 or 1 and alk is a C1-C6alkylene group or a C2-C6alkenyl group, (6) a phenyl group substituted with a 5- or 6-membered heterocyclic aromatic group, said heterocyclic aromatic group being optionally substituted with a C1-C3alkyl group or a -NR ^c R ^d group,

R ^c and R ^d independently represent a hydrogen atom or a C1-C3alkyl group or, in the case of the group -NR ^c R ^d , these substituents may form with the nitrogen atom a 5- or 6-membered heterocyclic ring, optionally containing other heteroatoms, wherein this heterocyclic ring is optionally further substituted with at least one C1-C3alkyl group,

R ^e represents C1-C3alkyl, provided that when R ⁴ and R ⁵ represent hydrogen atoms and R ² represents a halogen atom, R ³ has a meaning other than methyl, ethyl, n-propyl, isopropyl or cyclopropyl, CH(OH)CH3 and ···· • ·» ·· ··*· • · · · • · · · • · · · 9 9 9

9 99

C1-C3alkoxy groups, as well as salts and solvates of these compounds, especially physiologically acceptable salts and solvates thereof.

Preferred adenosine derivatives of general formula I are compounds of general formula Ic

R’

where X represents 0 or CH ₂ ,

R ² represents a C 1 -C 3 alkyl, a C 1 -C 3 alkoxy group, a halogen atom or a hydrogen atom,

R ³ represents a hydrogen atom, phenyl, optionally substituted by a halogen atom, a 5- or β-membered heteroaryl, a C1-C6alkoxy group, a C1-C6 straight-chain or branched alkyl, optionally substituted by at least one halogen atom, a C3-C7cycloalkyl, a C1-C6hydroxyalkyl or a halogen atom,

Y and 2 represent 0, N or CH,

W represents CH, O, N or S, wherein at least one of W and Z represents a heteroatom and in the case where Y, Z and/or W represents a nitrogen atom, the presence or absence of an additional hydrogen atom is obvious,

4

4444

444 44 4

4444 4 4 4

4 4 4 4 4 4

4 4 4 4 4

2_2*·* ··· ·· ·· provided that when W represents CH, Z represents a nitrogen atom and Y represents an oxygen atom, R ³ has a meaning other than a hydrogen atom,

R ⁴ and R ⁵ independently represent a hydrogen atom or a straight or branched chain C 1 -C 6 alkyl.

R ¹ represents a hydrogen atom or one of the groups (1) - (alk) _n -C3-C7cycloalkyl, including a bridged cycloalkyl group, wherein the cycloalkyl group is optionally substituted by at least one substituent from the group OH, a halogen atom, a C1-C3alkoxy group, (alk) represents a C1-C3alkylene group and n represents 0 or 1, (2) an aliphatic heterocyclic group, containing 4 to β-membered rings containing at least one heteroatom from the group O, N or S, optionally substituted by at least one substituent from the group C1-C3alkyl, -CO ₂ -C1-C4alkyl, -CO(C1-C3alkyl), -S (=0) _n -C1-C3alkyl, -CONR ^and R ^b , where R ^a and R ^b independently represent a hydrogen atom or C1-C3alkyl, or =0 and in the case that the heterocyclic ring contains a sulfur atom, this sulfur atom is optionally substituted group (=0) _n , where n is 1 or 2, (3) straight or branched chain Cl-Cl2alkyl, optionally containing one or more 0 groups in the alkyl chain, S(=0) _n /· where n is 0, 1 or 2 and N, the alkyl groups are optionally substituted by one or more substituents from the group phenyl, halogen atom, hydroxy group, C3-C7cycloalkyl or NR ^and R ^b , where R ^a and R ^b independently mean a hydrogen atom, C3-C7cycloalkyl or straight or branched chain Cl-C6alkyl, optionally substituted by a C3-C7cycloalkyl residue, ···· • 99 ·· ···· • · 4 • · · 4 ·· ·· • · · · · (4) a fused bicyclic aromatic ring of the formula

where B represents a 5 or 6-membered heterocyclic aromatic ring containing at least one heteroatom from the group O, N or S, wherein the bicyclic ring is bonded to the nitrogen atom in the compound of formula I through an atom in ring A and ring B is optionally substituted with a -CO ₂ -Cl-C3alkyl group, (5) a phenyl group, optionally substituted with one or more substituents from the group halogen atom, SO ₃ H, -(alk)nOH, -(alk) _n -cyano group, - (O) _n -Cl-C6alkyl, optionally substituted with at least one halogen atom,

-(alk) _n nitro group, - (0) _m -(alk) _n -CO ₂ R ^c , - (alk) _n -CONR ^c R ^d ,

- (alk) _n -COR ^c , - (alk) n-SOR ^e , - (alk) n-SO ₂ R ^e , - (alk) n-SO2NR ^c R ^d , ~(alk)nOR ^c , - (alk)n- (CO) m-NHSO2R ^e , - (alk) n-NHCOR ^c ,

- (alk) _n NR ^c R ^d , where n and n are 0 or 1 and alk is a C1-C6alkylene group or a C2-C6alkenyl group, (6) a phenyl group substituted with a 5- or 6-membered heterocyclic aromatic group, said heterocyclic aromatic group being optionally substituted with a C1-C3alkyl group or a -NR ^c R ^d group,

R ^c and R ^d independently represent a hydrogen atom or a C1-C3alkyl or in the case of the group -NR ^c R ^d these substituents may form with the nitrogen atom a 5 or β-membered heterocyclic ring, optionally containing other heteroatoms, whereby • ·· · ·· ··· ·

14...... *........

this heterocyclic ring is optionally further substituted with at least one C1-C3alkyl group,

R ^e represents C 1 -C 3 alkyl, provided that when R ⁴ and R ⁵ represent hydrogen atoms and R ² represents a halogen atom, R ³ has a meaning other than methyl, ethyl, n-propyl, isopropyl or cyclopropyl, CH(OH)CH 3 and C 1 -C 3 alkoxy, as well as salts and solvates of these compounds, especially physiologically acceptable salts and solvates thereof.

Typically, the derivatives of formula I have greater activity at the adenosine A1 receptor than at other adenosine receptor subtypes, particularly A3. In particular, the derivatives of the invention have little or no agonist activity at A3 receptors.

It is understood that where the R ¹ and/or R ² groups in the derivatives of formula I contain one or more asymmetric carbon atoms, the invention encompasses all diastereoisomers of the compounds of formula I and mixtures thereof. The stereochemical configuration of the compounds of the invention is shown above in formula I.

An alkyl radical is understood throughout the application to mean a straight-chain or branched alkyl group. Examples of such groups for R ¹ and R ² include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl and 2,2-dimethylpropyl.

An alkylene radical is understood to mean a straight-chain or branched radical containing 1 to 6 carbon atoms, for example a methylene radical.

94··

4 ····

A C2-C6alkenyl radical means a straight-chain or branched alkenyl group containing 2 to 6 carbon atoms. An example of a suitable group of this type is allyl.

A halogen atom throughout the application is understood to mean a fluorine, chlorine, bromine or iodine atom.

An aliphatic heterocyclic group as R ¹ is a cyclic group containing 4 to 6 carbon atoms, wherein one or more carbon atoms are replaced by a heteroatom or heteroatoms independently selected from nitrogen, oxygen or sulfur. This group may be optionally substituted as described above.

The term heterocyclic aromatic group in the meaning of R ¹ includes an aromatic monocyclic or bicyclic ring system containing 5 to 10 carbon atoms, wherein at least one of these carbon atoms is replaced by a heteroatom or heteroatoms independently selected from the group of nitrogen, oxygen or sulfur, wherein the ring system is optionally substituted in the manner indicated above.

Pharmaceutically acceptable salts of the compounds of formula I include salts derived from pharmaceutically acceptable inorganic and organic acids. Suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malic, naphthalene-2-sulfonic and • 000

00 0 0

000

0 •

0

0· benzenesulfonic acid. A particularly suitable pharmaceutically acceptable salt of the derivatives of the general formula I is the hydrochloride. Salts of other acids, for example oxalic acid, are not themselves pharmaceutically acceptable, but they can be used as intermediates for the preparation of the derivatives according to the invention and their pharmaceutically acceptable acid addition salts. Suitable solvates include, for example, hydrates.

Examples of W, Y and Z groups containing heterocyclic groups include isoxazole, oxadiazole, pyrazole, oxazole, triazole and thiadiazole derivatives.

Preferred groups for W, Y and Z are isoxazoles and 1,2,4- and 1,3,4-oxadiazoles.

R ² preferably represents a hydrogen atom, methyl, methoxy or halogen atom, preferably a hydrogen atom or a chlorine atom.

A preferred value for R ¹ is (alk) _n -C3-C6cycloalkyl, in which n is 0 or 1 and the cycloalkyl moiety is substituted by at least one substituent selected from the group consisting of halogen, especially fluorine or hydroxy, or is unsubstituted. A preferred value for n is 0. Preferably, the cycloalkyl group is unsubstituted or substituted by one hydroxy group, in another preferred embodiment the cycloalkyl ring contains 5 carbon atoms. Most preferably, the cycloalkyl group is hydroxycyclopentyl.

··»·

0« ···* ·* • · · « · • · « · · • « « 1» · · »· ·* ··

R ¹ may also represent a substituted or unsubstituted aliphatic heterocyclic group in which the substituent is selected from the group -CO 2 -C 1 -C 4 alkyl.

Preferably, the aliphatic heterocyclic group is unsubstituted or, in the case where the substituent is -CO2-C1-C4alkyl, the heteroatom is a nitrogen atom and the substituent is bonded directly to this nitrogen atom.

The heterocyclic ring is preferably 6-membered and in a preferred embodiment contains only one O, N or S atom. In a most preferred embodiment, in which the heterocyclic ring is unsubstituted, the heteroatom is an oxygen atom. In the case where the heterocyclic ring is substituted, the heteroatom is a nitrogen atom.

R ¹ may also be a straight or branched C 1 -C 6 alkyl group, optionally containing at least one S(=O) _n group. If this group is present, the R ¹ substituent is optionally substituted by a nitrogen atom in a position adjacent to said group. If there is only one such group in the chain, substitution by a nitrogen atom in a position immediately adjacent to this group is most preferred. The preferred value for n is 1 or 2, preferably 2. The alkyl group may be unsubstituted or may be substituted by at least one hydroxy group.

R ¹ can also represent a phenyl group substituted by one or two substituents from OH, alkyl, especially C 1 -C 4 alkyl and halogen. The phenyl group is preferably disubstituted in the 2- and 4-positions.

Both substituents are preferably halogen atoms, especially • •44 ·· 4444

18*

4 • · « · 4 4 44

444 · · 4 · 4 4 • 444 4 · 4 · 4 • · · · · 4 · 4

444 44 44 44 444 fluorine and chlorine. A particularly preferred combination is a fluorine atom in position 2 and a chlorine atom in position 4.

The preferred values for R ⁴ and R ⁵ are hydrogen atoms. It is understood that the invention includes any combination of the above preferred groups.

Preferred adenosine derivatives according to the invention are the following novel compounds:

(2S,3S,4R,5R)-2-(5-tert.butyl-[1,3,4]oxadiazol-2-yl)-5-[6-(tetrahydropyran-4-ylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol, 4-{9- [5S-(5-tert.butyl-[1,3,4]oxadiazol-2-yl)-3R,4S-dihydroxytetrahydrofuran-2R-yl]-9H-purin-6-ylamino}-piperidine-1-carboxylic acid, (2S,3S,4R,5R)-2-(5-isopropyl-[1,3,4]oxadiazol-2-yl)-5-[6-(tetrahydropyran-4-ylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol, 4-{9-[5S-(5-cyclopropyl-[1,3,4]-ethyl ester) oxadiazol-2-yl)-3R,4S-dihydroxytetrahydrofuran-2R-yl]-9H-purin-6-ylamino}-piperidine-1-carboxylic acid, (2S,3S,4R,5R)-2-(5-tert.butyl-[1,3,4]oxadiazol-2-yl)-5-[6-(4-chloro-2-fluorophenylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol, (2S,3S,4R,5R)-2-(5-ethyloxazol-2-yl) -5-[6-(tetrahydropyran-4-ylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol, (2S, 3S, 4R, 5R)-2-(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-5-[6-(2S-hydroxycyclopent-(S)-ylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol, (2S,3S,4R,5R)-2-(3-tert.butyl-[1,2,4]oxadiazol-5-yl)-5-[6-(2S-hydroxycyclopent-(S)-ylamino)-purin-9-yl]• ·

-tetrahydrofuran-3,4-diol, (2S,3S,4R,5R)-2-(3-cyclopropyl- [1,2,4]oxadiazol-5-yl)-5-[6-(tetrahydropyran-4-ylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol, (2S,3S,4R,5R)-2-(3-tert.butylisoxazol-5-yl)-5- [6- (tetrahydropyran-4-ylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol, ethyl 4-({9-[(2R,3R,4S,5S)-3,4-dihydroxy-5-(3-methyl-1,2,4-oxadiazol-5-yl)tetrahydrofuran-2-yl]-9H-purin-6-yl}amino)piperidine-1-carboxylate, (2S,3S,4R,5R)-2-[3-(tert.butyl)-1,2,4-oxadiazol-5-yl]-5-{6-[(cyclopropylmethyl)amino]-9H-purin-9-yl}tetrahydrofuran-3,4-diol, (2S,3S,4R,5R)-2-[3-(tert.butyl) -1,2,4-oxadiazol-5-yl]-5-[6-[(isobutylamino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5S)-2-[6-(cyclopropylamino)-9H-purin-9-yl]-5-3-isopropyl-1,2,4-oxadiazol-5-yl] tetrahydrofuran-3,4-diol, 2— ({ 9— [ (2R, 3R, 4S, 5S) -3,4-dihydroxy-5-(3-isopropyl-1,2,4-oxadiazol-5-yl)tetrahydrofuran-2-yl]-9H-purin-6-yl}amino)-N-methylethanesulfonamide, (2R,3R,4S,5S)-2-[6-(3,4-difluoroaniline)-9H-purin-9-yl]-5-(3-isopropyl-1,2-yl) 4-oxadiazol-5-yl)tetrahydrofuran-3,4-diol, (2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroaniline)-9H-purin-9-yl]-5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)tetrahydrofuran-3,4-diol, (2R,3S,4R,5R)-2-[5- (tert.butyl) -4H-1,2,4-triazol-3-yl]-5-[6-(4chloro-2-fluoroaniline)-9H-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-[6-(2-chloro-4-fluoroaniline)-9H-purin-9-yl]-5-(5-isopropyl-4H-1,2,4-triazol-3-yl) ·

-yl)tetrahydrofuran-3,4-diol, (2S,3S,4R,5R)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-5-[6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol, (2S,3S,4R,5R)-2-[5-(tert.butyl) -1,3,4-oxadiazol-2-yl]-5-[6-(2-chloro-4-fluoroaniline)-9H-purin-9-yl]tetrahydrofuran-3,4-diol, (2S,3S,4R,5R)-2-[3-(tert.butyl)isoxazol-5-yl] — 5— { 6 [ (1,1 — -dioxidotetrahydro-2H-thiopyran-4-yl)amino] -9H-purin-9-yl}tetrahydrofuran-3,4-diol,

- [(9-{(2R,3R,4S,5S)-5-[(tert.butyl)-1,3,4-oxadiazol-2-yl]-3,4-dihydroxytetrahydrofuran-2-yl}-9H-purin-6-yl)amino]-N-ethylethanesulfonamide,

2-[ (9-{ (2R,3R,4S,5S)-5-[ (tert.butyl)-1,3,4-oxadiazol-2-yl]-3,4-dihydroxytetrahydrofuran-2-yl}-9H-purin-6-yl)amino]-N-(3-methylphenyl)ethylethanesulfonamide,

2- ({ 9- [ (2R, 3R, 4S, 5S) -3,4-dihydroxy-5-(5-methyl-1, 3-oxazol-2-y] -9H-purin-9-yl) tetrahydrofuran-2-yl] -9H-purin-6-yl}amino)-N-methylethanesulfonamide, (2R, 3R, 4S, 5S) -2- [6- (cyclopentylamino)-9H-purin-9-yl]-5-[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]tetrahydrofuran-3,4-diol, (2S,3S,4R,5R)-2-(5-ethyl-1,3,4-oxadiazol-2-yl)-5-[6-(isopropylamino)-9H-purin-9-yl] tetrahydrofuran-3,4-diol, (2R,3R,4S,5S)-2~(6-{ [ (1S, 2S) -2-hydroxycyclopentyl] amino }-9H-purin-9-yl)-5-(5-methyl-1, 3,4-oxadiazol-2-yl) tetrahydrofuran-3,4-diol, (2R, 3R, 4S, 5S) -2-{2-chloro-6 [ (1-ethylpropyl)amino] -9H-purin-9-yl}-5-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)tetrahydrofuran-3,4-diol formate (1:2), (2R, 3R, 4S, 5S) -2- [2-chloro-6-(1-ethylpropylamino)-purin-9-yl]-5-(3-cyclopropyl-[1,2,4] oxadiazol-5-yl) • · · · • ·

-tetrahydrofuran-3,4-diol diformate, (2S,3S,4R,5R)-2-(3-ethylisoxazol-5-yl)-5-[6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol, (2S,3S,4R,5R)-2-(3-ethylisoxazol-5-yl)-5-(6-{[(1S,2S)-2-hydroxycyclopentyl]amino}-9H-purin-9-yl)tetrahydrofuran-3, 4-diol, ethyl 4-({9-[(2R,3R,4S,5S)-5-(3-ethylisoxazol-5-yl) -3,4-dihydroxytetrahydrofuran-2-yl]-9H-purin-6-yl}amino)piperidine-1-carboxylate, (2R,3S,4R,5R)-2-[5-(tert.butyl)-4H-1,2,4-triazol-3-yl]-5-[6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9~

-yl]tetrahydrofuran-3,4-diol, (2R,3S,4R,5R)-2-(5-isopropyl-4H-1,2,4-triazol-3-yl)-5-[6--(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5S)-2-[2-chloro-6-(2-chloro-4-fluoroaniline)-9H-purin-9-yl]-5-(5-methyl-1,3-oxazol-2-yl)tetrahydrofuran-3,4-diol, (2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroaniline)-9H-purin-9-yl]-5-(3-methylisoxazol-5-yl)tetrahydrofuran-3,4-diol, (2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroaniline)-9H-purin-9-yl]-5-(3-propylisoxazol-5-yl)tetrahydrofuran-3,4-diol, (2R,3R,4S,5S)-2-[2-chloro-6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl]-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol, ethyl 4-({2-chloro-9-[(2R,3R,4S,5S)-5-(3-ethylisoxazol-5-yl)-3,4-dihydroxytetrahydrofuran-2-yl]-9H-purin-6-yl}amino)piperidine-1-carboxylate, (2R,3R,4S,5S)-2-(2-chloro-6-{[(1S,2S)~2-hydroxycyclopentyl]amino]-9H-purin-9-yl)-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol, • · · · ···· (2R,3R,4S,5S)-2-(2-chloro-6-{[2-(ethylsulfonyl)ethyl]amino}-9H-purin-9-yl)-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol, (2R, 3R,4S,5S)-2-[2-chloro-6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol, (2R,3R,4S,5S)-2-[2-chloro-6-(2-chloro-4-fluoroanilino)-9H-purin-9-yl]-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol, (2R,3R,4S,5S)-2- [2-Chloro-6-(2-fluoroanilino)-9H-purin-9-yl]-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol, (2R,3R,4S,5S)-2-[2-chloro-6-(2-chloroanilino)-9H-purin-9-yl]-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol, (2R,3R,4S,5S)-2-(6-{ [ (1S,2S)-2-hydroxycyclopentyl]amino}-9H-purin-9-yl)-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol, ethyl 4-[(9-{(2R,3R,4S,5S)-3,4-dihydroxy-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-2-yl} -9H-purin-6-yl)amino]piperidine-1-carboxylate, (2S,3S,4R,5R)-2-[3-(hydroxymethyl)isoxazol-5-yl]-5-[6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5S)-2-[6- (4-Chloro-2-fluoroaniline)-9H-purin-9-yl]-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol, (2R,3R,4S,5S)-2-[6-(2-chloro-4-fluoroaniline)-9H-purin-9-yl]-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol, (2S,3S,4R,5R)-2-(3-ethylisoxazol-5-yl)-5-[6-(2-fluoroaniline)-9H-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5S)-2-[6-(2-chloroanilino)-9H-purin-9-yl]-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol, (2S,3S,4R,5R)-2-[5-(tert.butyl)-1,3,4-oxadiazol-2-yl]-5-[6-(piperidin-4-ylamino)-9H-purin-9-yl]tetrahydrofuran• ·

-3,4-diol, (2R,2R,4S,5R)-2-{-chloro-6-[(1-ethylpropyl)amino]-9H-purin-9-yl}-5-(5-ethylisoxazol-3-yl)tetrahydrofuran-3,4-diol formate, (2S,3S,4R,5R)-2-(3-bromoisoxazol-5-yl)-5-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol, (2S,3S,4R,5R)-2-[3-(tert-butyl)isoxazol-5-yl]-5-(6-{[1-(methylsulfonyl)piperidin-4-yl]amino}-9H-purin-9-yl)tetrahydrofuran-3,4-diol, (2S,3S,4R,5R)-2-[3-(tert-butyl)isoxazol-5-yl] —5—(6—{ [1-(propylsulfonyl)piperidin-4-yl]amino}-9H-purin-9-yl)tetrahydrofuran-3,4-diol, (2S,3S,4R,5R)-2-[3-(tert-butyl)isoxazol-5-yl]—5—(6—{[1-(isopropylsulfonyl)piperidin-4-yl]amino}-9H-purin-9-yl)tetrahydrofuran-3,4-diol, (2S,3S,4R,5R)-2-[3-(tert-butyl)isoxazol-5-yl]-5-(6-{[1-(ethylsulfonyl)piperidin-4-yl]amino}-9H-purin-9-yl)tetrahydrofuran-3,4-diol, (2S,3S,4R,5R)-2-[3-(tert-butyl)isoxazole-5[2-chloro-6-(4-chloro-2-fluoroaniline)-9H-purin-9-yl]tetrahydrofuran-3,4-diol, (2S,3S,4R,5R)-2-[3-(tert-butyl)isoxazole-5[2-chloro-6-(2-chloro-4-fluoroaniline)-9H-purin-9-yl]tetrahydrofuran-3,4-diol,

2-[(9-{(2R,3R,4S,5S)-5-[3-(tert.butyl)isoxazol-5-yl]-3,4-dihydroxytetrahydrofuran-2-yl}-2-chloro-9H-purin-6-yl)amino]-N-ethylethanesulfonamide,

2- [ ( 9-{ (2R,3R,4S,5S)-5-[3-(tert-butyl)isoxazol-5-yl]-3,4-dihydroxytetrahydrofuran-2-yl}-2-chloro-9H-purin-6-yl)amino]-N-isopropylethanesulfonamide, (2S,3S,4R,5R)-2-[3-(tert-butyl)isoxazol-5-yl] -5-[2-chloro-6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9·· · ·

-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-(3-pyridin-3-ylisoxazol-5-yl)tetrahydrofuran-3,4-diol, (2R,3R,4S,5S)-2- [6- (4-chloro-2-fluoroanilino)-9H-purin-9-yl]-5-[3-(4-hydroxybutyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol,

2—[(9—{(2R,3R,4S,5S)-5-[3-(tert.butyl)isoxazol-5-yl]-3,4-dihydroxytetrahydrofuran-2-yl}-9H-purin-6-yl)amino]-N-ethylethanesulfonamide, (2R,3R,4S,5S)—2 —[6-(cyclopentylamino)-9H-purin-9-yl] -5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5S)-2-(6-{ [ (1S,2S)-2-hydroxycyclopentyl] amino }-9H-purin-9-yl)-5-[5-(trifluoromethyl) -1,3,4-oxadiazol-2-yl]tetrahydrofuran-3,4-diol, ethyl 4-[(9-{(2R,3R,4S,5S)-3,4-dihydroxy-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]tetrahydrofuran-2-yl}-9H-purin-6-yl)amino]piperidine-1-carboxylate, (2R,3R,4Ξ,5S)-2-[6-(4-chloro-2-fluoroaniline) -9H-purin-9-yl]-5-(5-methyl-1,3,4-oxadiazol-2-yl)tetrahydrofuran-3,4-diol, (2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroaniline)-9H-purin-9-yl]-5-(3-cyclopropylisoxazol-5-yl)tetrahydrofuran-3,4-diol, (2S,3S,4R,5R)-2 - [3 - (tert.butyl)isoxazol-5-yl]-5-{6- [ (1-butylpiperidin-4-yl)amino]-9H-purin-9-yl}tetrahydrofuran-3,4-diol, isopropyl 4-[ (9-{2R, 3R, 4S, 5S)-5-[3-(tert.butyl) isoxazol-5-yl]-3,4-dihydroxytetrahydrofuran-2-yl}-9H-purin-6-yl)amino]piperidine-1-carboxylate, (2S,3S,4R,5R)-2-[3-(tert.butyl)isoxazol-5-yl]—5— (6— { [1• · · · ··· t

-(2,2,2-trifluoroacetyl)piperidin-4-yl]amino}-9H-purin-9-yl)tetrahydrofuran-3,4-diol, methyl 4-[(9-{(2R,3R,4S,5S)-5-[3-(tert.butyl)isoxazol-5-yl]-3,4-dihydroxytetrahydrofuran-2-yl}-9H-purin-6-yl)amino]piperidine-1-carboxylate, (2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroaniline)-9H-purin-9-yl]-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5S)-2-[6-(2-chloro-4-fluoroaniline)-9H-purin-9-yl]-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5S)-2-[6-(2-fluoroaniline)-9H-purin-9-yl]-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5S)-2-[6-(2-chloroaniline)-9H-purin-9-yl]-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5S)-2-(2-chloro-6-{[(1S,2S)-2-hydroxycyclopentyl]amino}-9H-purin-9-yl)-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5S)-2-[2-chloro-6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl]-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol,

2-[(2-chloro-9-{(2R,3R,4S,5S)-3,4-dihydroxy-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-2-yl}-9H-purin-6-yl)amino]-N-ethylethanesulfonamide, ethyl 4- [ (2-chloro-9-{ (2R,3R,4S,5S)-3,4-dihydroxy-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-2-yl}-9H-purin-6-yl)amino]piperidine-1-carboxylate, (2R,3R,4S,5S)-2-[2-chloro-6-(4-chloro-2-fluoroaniline)-9H-purin-9-yl]-5-[3-(hydroxymethyl)isoxazol-5-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5S)-2-[2-chloro-6-(2-chloro-4-fluoroaniline)-9H-purin-9-yl]-5-[3-(hydroxymethyl)isoxazol-526

-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5S)-2-[2-chloro-6-(2-fluoroaniline)-9H-purin-9-yl]-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-pyran-4-ylamino)-9H-purin-9-yl]]tetrahydrofuran-3,4-diol, methyl 4-({9-[(2R,3R,4S,5S)-5-(3-ethylisoxazol-5-yl)-3,4-dihydroxytetrahydrofuran-2-yl]-2-methoxy-9H-purin-6-yl}amino)piperidine-1-carboxylate, (2S,3S,4R,5R)-2-(3-ethylisoxazol-5-yl)-5-(6-{[(1S,2S)-2-hydroxycyclopentyl]amino}-2-methoxy-9H-purin-9-yl)tetrahydrofuran-3,4-diol, (2S,3S,4R,5R)-2-(3-ethylisoxazol-5-yl)-5-(6-{[2-(ethylsulfonyl)ethyl]amino}-2-methoxy-9H-purin-9-yl)tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-[6-(2-chloro-4-fluoroaniline)-2-methoxy-9H-purin-9-yl]-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol, (2S,3S,4R,5R)-2-(3-ethylisoxazol-5-yl)—5—[6—(2—

-fluoroaniline)-2-methoxy-9H-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5R)-2-[6-(4-chloro-2-fluoroaniline)-2-methoxy-9H-purin-9-yl]-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-3,4-diol, (2S, 3S,4R,5R)-2-[3-(tert.butyl)-1,2,4-oxadiazol-5-yl]-5-[6-(cyclopropylamino)-9H-purin-9-yl]tetrahydrofuran-3,4-diol, (2S, 3S,4R,5R)-2-[5-(tert.butyl)-1,3,4-oxadiazol-2-yl]-5-[2-chloro-6-(4-chloro-2-fluoroaniline)-9H-purin-9-yl]tetrahydrofuran-3,4-diol, (2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroaniline)-9H-purin-9• · « · • ·

-yl]-5-(5-isopropyl-1,3,4-oxadiazol-2-yl)tetrahydrofuran-3,4-diol.

The compounds of the invention can be used as lipolysis inhibitors, i.e. as substances that reduce the concentration of free fatty acids in plasma. The said substances can therefore be used to treat hyperlipidemia. In addition, due to these effects, the said substances can reduce the increased concentration of glucose in the blood, the level of insulin and ketone and therefore can be used in diabetics. Since antilipolytic substances have hypolipidemic and hypofibrinogenemic effects, the said substances also have an antisclerotic effect. The effect on fats was demonstrated by the ability of these substances to reduce the concentration of non-esterified fatty acids (NEFA) in fasting rats when administered orally by the method according to the publication P. Strong et al., Clinical Science, 1993, 84, 663-669.

In addition to their antilipolytic effect, the compounds of the invention can independently affect cardiac function by reducing cardiac sequence and conduction. They can therefore be used in a wide range of cardiac and vascular disorders, for example in the case of arrhythmia, especially that resulting from myocardial infarction, and in the case of angina pectoris.

Furthermore, the compounds of the invention can be used as cardioprotective agents in ischemic heart disease. This term refers to the damage that occurs during ischemia of the heart muscle and during reperfusion, for example in connection with coronary artery bypass grafting (CABG), coronary angioplasty (PTCA), cardioplegia, acute myocardial infarction, thrombolysis, angina pectoris and during cardiac surgery, especially transplantation. The compounds of the invention can also prevent ischemic damage to other organs. Furthermore, these substances can be used to treat disorders that are a result of atherosclerosis, for example in the case of peripheral vascular disease (PVD) and stroke.

The compounds of the invention may also inhibit renin release and are therefore useful in the treatment of hypertension and heart failure. In addition, the compounds have central nervous system depressant effects and may be useful as hypnotics, sedatives, analgesics and/or anticonvulsants, particularly in epilepsy.

Furthermore, the compounds of the invention can be used in the treatment of sleep apnea.

The compounds of formula I and their pharmaceutically acceptable acid addition salts are good analgesics for the treatment or prevention of pain. They can be used in the treatment of acute pain, for example bone and muscle pain, in postoperative pain and surgical pain, and in chronic pain, for example in the course of chronic inflammation, such as rheumatoid arthritis RA, osteoarthritis OA, in neuropathic pain, for example in postherpetic neuralgia PHN, in trigeminal neuralgia, in diabetic neuropathy, and also in cancer-related pain and fibromyalgia. The compounds of formula I can also be used in migraine and other types of headache, and also in functional gastrointestinal pain, for example in irritable bowel syndrome and in non-ulcerative gastrointestinal disorders.

• · · · · · · φ·

When administered topically, the compounds of the invention have analgesic and anti-inflammatory effects and can therefore be used in a variety of chronic inflammatory pain conditions such as OA, RA and in neuropathic conditions such as fibromyalgia and PHN.

The invention also provides the use of compounds of formula I or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a pharmaceutical composition for the treatment of humans or other animals suffering from a condition in which it is advantageous to reduce the concentration of free fatty acids in the blood plasma or in which it is advantageous to reduce heart rate and conductivity. In addition, the pharmaceutical compositions may be intended for the treatment of ischemic heart disease, peripheral vascular disease and the like, for the treatment of central nervous system disorders, for the relief of pain or for the reduction of sleep apnea.

In the case of the above-mentioned treatment of ischemic disorders, it has been found that administration of compounds of general formula I before the ischemic state protects against the occurrence of myocardial infarction, but protection can also be achieved when the compound of general formula I is administered after the ischemia has already occurred and before reperfusion. This means that the compounds of the invention can be administered not only in the case of expected ischemia, e.g. during surgery, but also in the case of sudden and unexpected ischemia, e.g. during a heart attack and the like.

• · · · ·» · · • » · · · • · · t • · · · · • · · · · φ« ·♦ ··

It is clear that in the case of using the compounds according to the invention for therapeutic purposes, they can also be used for preventive purposes.

The pharmaceutical composition according to the invention contains as its active ingredient at least one compound of the general formula I or a pharmaceutically acceptable salt or solvate thereof together with a pharmaceutical carrier and/or excipient and is intended in particular for the treatment of humans or other animals suffering from a condition in which it is advantageous to reduce the concentration of free fatty acids in the blood plasma or to reduce heart rate and conductivity. These compositions are also suitable for administration in cases of risk of ischemic heart disease, peripheral vascular diseases and in the case of stroke and also in the case of central nervous system disorders, in painful conditions and in the case of respiratory arrest during sleep.

The pharmaceutical compositions of the invention can be prepared by mixing at least one compound of formula I or a pharmaceutically acceptable salt or solvate thereof with a pharmaceutically acceptable carrier and/or excipients.

The pharmaceutical compositions of the invention may be intended for topical or oral administration, for administration to the buccal mucosa, for parenteral or rectal administration or by inhalation or insufflation. Oral administration is particularly preferred, in which case the composition may also be adapted for prolonged release of the active ingredient.

For topical administration, processing the active substance into a patch for transdermal administration is also a consideration.

«· ♦»··

Tablets and capsules for oral administration may contain conventional excipients such as binders, for example pregelatinized starch or polyvinylpyrrolidone, fillers such as lactose, microcrystalline cellulose or corn starch, lubricants such as stearic acid or magnesium stearate, disintegrating agents such as potato starch, croscarmellose sodium or sodium starch glycolate or wetting agents such as sodium lauryl sulfate. The tablets may be coated in a known manner. Liquid preparations for oral administration may, for example, take the form of a suspension, solution or emulsion in water or oil, a syrup or elixir, or may be a dry product intended to be mixed with water or other suitable vehicle immediately before use.

Liquid compositions may contain conventional additives such as suspending agents, for example sorbitol syrup, methylcellulose or carboxymethylcellulose, emulsifiers, for example sorbitan monooleate, non-aqueous vehicles including edible oils, for example propylene glycol or ethyl alcohol, and preservatives, such as methyl or propyl p-hydroxybenzoates or sorbic acid. Pharmaceutical compositions may also contain buffers, flavoring agents, colorants and sweeteners, such as mannitol, as appropriate.

For administration via the oral mucosa, the compositions of the invention may take the form of tablets or lozenges, manufactured in a conventional manner.

Compounds of general formula I can be formulated for parenteral administration in the form of a single injection or • 44 ·

continuous infusion and can be placed in ampoules containing a single dose or in vials containing a plurality of doses and a preservative. This may be a suspension, solution or emulsion in an oily or aqueous medium, in addition, these preparations may contain excipients, for example suspending, stabilizing and/or dispersing agents. The active substance may also be supplied in the form of a powder intended for reconstitution in a suitable medium, for example in sterile pyrogen-free water immediately before use.

The compounds of formula I can also be formulated into suppositories containing conventional suppository bases, for example cocoa butter or other glycerides.

The expected dose of the compounds of the invention for administration to a human weighing approximately 70 kg is 1 mg to 2 g, preferably 1 to 100 mg of active ingredient per dose, which may be administered, for example, 1 to 4 times daily. It will be appreciated that the dose will need to be varied depending on the age and condition of the patient and also on the route of administration chosen.

The compounds of formula I and their physiologically acceptable salts or solvates can be prepared by the processes described below, which also form part of the essence of the invention. In the following description, the groups R ¹ , R ² and R ³ have the meaning given in formula I, unless otherwise stated.

According to the first general process A, it is possible to prepare compounds of general formula I by reacting a compound of general formula II i*·

« * · · · w ♦ · · # · · • · · « · · * « · *·

«« ·»· where L represents a leaving group, for example a halogen atom such as chlorine or a linking group, capable of binding to a solid phase of a polymeric carrier, for example a polystyrene resin, it may for example be a -SO2Cl-C4alkylene group,

P ¹ and P ² represent a hydrogen atom, a straight or branched C 1 -C 6 alkyl or a suitable protecting group, for example acetyl or a group in which P ¹ and P ² together form an alkylidene group, with a compound of the general formula R ^X NH 2 or a salt thereof under basic conditions. The heterocyclic group at the 4' position may optionally be protected as described further in Procedures Bb and V.

Compounds of formula II can be used to prepare compounds of formula I directly by reaction with a compound of formula R ¹ NH 2 in the presence or absence of a solvent. The solvent can be an alcohol, for example a lower alkanol such as isopropanol, tert-butanol or 3-pentanol, an ether such as tetrahydrofuran or dioxane, a substituted amide such as dimethylformamide, a halogenated hydrocarbon such as chloroform, an aromatic hydrocarbon such as toluene, dimethylsulfoxide DMSO or acetonitrile, the process being

»4 ··»· i :

· • * • 4 is preferably carried out at a higher temperature up to the boiling point of the solvent used under reflux in the presence of a substance capable of binding the acid, for example an inorganic base, such as sodium, cesium or potassium carbonate or in the presence of an organic base, such as triethylamine, diisopropylethylamine or pyridine, optionally in the presence of a palladium-based catalyst, for example palladium acetate and a phosphine-type ligand, such as R(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl.

In the event that at least one of the symbols X, Z and W represents a nitrogen atom, it is optionally possible to carry out alkylation on this nitrogen atom at any suitable stage of the synthesis, for example as will be described below in process X.

Before or after the above reactions, the protecting groups P ¹ and P ² can be removed directly in the reaction mixture. In the case of acetyl groups, these groups can be removed, for example, by the action of ammonia or tert-butylamine in a solvent such as methanol, or in the case of P ¹ and P ² representing an alkylidene group, this group can be removed by hydrolysis with the action of an acid, for example trifluoroacetic acid TFA.

The interconversion of the protecting groups P ¹ and P ² can be carried out at any stage of the preparation of compounds of general formula II. For example, in the case where P ¹ and P ² represent acetyl groups, compounds of general formula II can be prepared from compounds in which P ¹ and P ² represent an alkylidene protecting group by removing this group, for example by treatment with hydrogen chloride in methanol, followed by acylation directly in the reaction mixture, for example by treatment with acetic anhydride in

and :

in the presence of a base, for example pyridine, in a solvent, for example dichloromethane. Otherwise, the interconversion of the protecting groups P ¹ and P ² can be carried out at any stage of the preparation of the compounds of general formula II.

It will be apparent to those skilled in the art that in the preparation of compounds of formula II or I, the heterocyclic group can be formed at the 4' position at any stage. For example, the heterocyclic groups can be prepared from carboxylic acid or acetylenic starting materials before addition of the purine ring, as described in Schemes 1, 1a and 2, or the heterocyclic group can be formed after addition of the purine ring, as illustrated in Schemes 3, 4 and 5 and in Procedure W.

Compounds of general formula II, in which X=O, can be prepared by reacting compounds of general formula III

where P ³ represents a protecting group, for example acetyl or a substituent, for example C1-C3alkyl and P ¹ , P ² and P ³ have the above meanings, with compounds of general formula IV ·

L

where L and R ² have the above meanings.

The reaction can be carried out in a suitable solvent, such as acetonitrile, in the presence of a silylating agent, such as trimethylsilyl trifluoromethanesulfonate, and a base, such as diazobicyclo[5.4.0]undec-7-ene, DBU. Alternatively, the compound of formula IV can be first silylated with a suitable silylating agent, such as hexamethyldisilazane, and the silylated intermediate can then be reacted with a compound of formula I and a suitable Lewis acid, such as trimethylsilyl trifluoromethanesulfonate, in a suitable solvent, such as acetonitrile.

Compounds of formula IV are known or can be prepared from known materials using processes analogous to those used for the preparation of known compounds of formula IV.

As already mentioned above, compounds of general formula III can be prepared from protected compounds by replacing the protecting groups P ¹ and P ² with other groups P ¹ and P ² . This is therefore a replacement of one protecting group for another protecting group. Compounds of general formula III can be prepared, for example, in the following way:

In the case where the heterocyclic group represented by the symbols W, Y and Z is isoxazole, or > Φ··Φ ♦ ♦ · φ φφ· < · φ · φφφ φφ· φ* φφφφ •

φ φ

• «φ φ substituted, these substances can be obtained according to the following scheme 1.

P ⁴ O OP ⁵

CDI/pyridine / ch ₂ ci ₂

Scheme 1

(Hello)

AcO OAc

Degree

1. Method/HC!

2. Ac,O/ <

The general conditions for steps 1 to 4 will be known to those skilled in the art. It is also understood that the reagents and reaction conditions shown in the scheme are exemplary only and that other reagents and reaction conditions may be used to achieve the same chemical transformation. The symbols P ⁴ and P ⁵ together form alkylidene protecting groups. P ⁶ is C 1 -C 4 alkyl and R ³ is as defined above.

Although Scheme 1 shows the preparation of compounds of general formula III, in which the heterocyclic group is an isoxazole group, it is clear that compounds of formula III can also be prepared in this way, • · · • · * · · • 9 • 9 · ·-»* ···

♦ · 99 ···♦ containing other heterocyclic groups, from the starting carboxylic acids, as will be described below, for example, for compounds IIIa.

Another process for the production of compounds of the general formula

III is shown in Scheme 1a.

and

Scheme 1a

R ³ CHO

MnO ₂

Stage 2

h ₂ feet

TFA

Step 4

The general conditions for steps 1 to 5 in Scheme 1a will be known to those skilled in the art. The general symbols R ³ , P ⁴ , P ⁵ and P ⁶ have the meanings given above.

Scheme 2 shows a method for preparing compounds of general formula III, in which Y represents a nitrogen atom, Z

4· ·♦··

9

999 • 4

4 • •4 999 «* ···♦ •

• 4

4 NH, W group of these substances.

group CH and R ³ hydrogen atom or tautomers χ ₂ 6 ·

Ρ , P and P have the meanings given above.

Scheme 2

PhMe

According to another process B, it is possible to convert compounds of general formula I into other compounds of general formula I by modifying the groups R ¹ , R ² and/or R ³ .

All compounds of general formula III are novel intermediates which also form part of the subject matter of the invention.

Compounds of the general formula R ¹ NH ₂ are known substances or can be prepared from known substances using conventional procedures.

Specific optical isomers of the compounds of general formula I can be prepared by conventional methods, for example «·*· *♦* ·♦ • · ·* * * • · · • · · • · ·♦ · by synthesis from the appropriate asymmetric starting materials using the methods described throughout the application, or it is possible to separate a mixture of isomers of the compounds of general formula I in a conventional manner, for example by fractional crystallization or chromatography.

According to the third process C, compounds of general formula I can be prepared from compounds of general formula V or

VI.

NHR ¹

P'Ó ÓP ² (V!)

P ¹ Ó ÓP ² (V) where R ¹ , R ² , X, L, P ¹ and P ² have the above-mentioned meaning.

Compounds of formula VI can be prepared from compounds of formula V by the procedures described above in method A.

The synthesis of compounds of general formula I from the corresponding acids of general formulae V and VI is carried out by known procedures.

As an example, if W is an oxygen atom, Y is a nitrogen atom and Z is also a nitrogen atom, so that 1,3,4-oxadiazole is formed, the synthesis can be carried out according to the following scheme 3. In this scheme, the symbol J represents a leaving group L as defined above or a group NHR ¹ . R ² , X, P ¹ and P ² have the meanings given above.

Scheme 3

Stage 1

Method b

RaCONHNHítBuCOC!/ iPr ₂ NEt/THF

Method A

EEDQ/RSCONHNHýDME ---->- -

continues as — in method A

Compounds of general formula I, in which Z=0, Y=N and W=N, so that a 1,2,4-oxadiazole group is formed, can be prepared from compounds of general formula V or VI by first activating the carboxyl group and then reacting with an amidoxime of formula HO-N=C (R ³ )NH ₂ in a solvent, for example tetrahydrofuran or chloroform in the presence of a base, such as pyridine or diisopropylethylamine, followed by cyclization at a temperature of 20 to 150 °C in a solvent, for example toluene, «« ·Μ· ·4Η • 4 4 4 4 4 • 4 4 4 4 • 4 · 4 4 4

4 4 4 4 4 «4 4 4 ♦* · tetrahydrofuran THF or chloroform according to Scheme 4. Activation of the carboxyl group involves reaction with an acid chloride, such as pivaloyl chloride or acid anhydride in the presence of a base, for example a tertiary amine such as diisopropylethylamine or with thionyl chloride in dimethylformamide (DMF). It is also possible to use activating agents used in peptide chemistry, such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline EEDQ or

1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The protecting group on the hydroxyl groups can be removed in a conventional manner. For example, the acetonide group can be removed by treatment with an acid at a temperature of 0 to 150 °C, for example by treatment with trifluoroacetic acid at a temperature of 0 to 20 °C or acetic acid at a temperature of 50 to 150 °C.

In Scheme 4, the general symbols R ² , R ³ , X, J, P ¹ and P ² have the meanings given above.

Scheme 4

Modification of J and other protecting groups as needed ··»«

4* 4444 • 4

4

444 444

4

Compounds of formula II can also be prepared from compounds of formula VII, as described below in process U. It is understood that analogous processes could also be used to prepare compounds of formula I containing other heterocyclic groups in the 4' position, as illustrated below in process M.

O

p'ó óp ² (VII)

According to general procedure D, compounds of general formula I can be prepared from compounds of general formula V by the method of scheme 5 with subsequent removal of the protecting groups P ¹ and P ² as described in procedure A. It will be apparent to those skilled in the art that analogous procedures as in scheme 5 can be used to prepare compounds of general formula I with other heterocyclic groups in the 4' position. The general symbols R ¹ , R ³ , J, P ¹ and P ² have the meanings given above in scheme 5.

♦ · ·· ·*·« *·

9999 ··· ___2_2_2_Z_®_^_®_S_í___Z_Z_2_<L1_Í“_5_3

Column standard automated preparative high-performance liquid chromatography, ( HPC.L ),

Conditions and eluents:

Automated preparative high-performance liquid chromatography, (autopreparative HPLC), was performed using a Supelco ABZ + 5 mj column 100 mm x 22 mm, (column internal diameter), and eluting with a solvent mixture containing:

I) 0.1% formic acid in water,

II) 0.05% formic acid in acetonitrile with the eluent expressed as a percentage II), in a mixture of solvents, at a flow rate of 4.0 ml per minute

Unless otherwise stated, the eluent was used within 18.50 minutes, in the gradient range 0.0 - 95.0%, (II),

LC/MS system, i.e. a combined liquid chromatography with mass spectrometry system

4 alternative systems were used, combining liquid chromatography, 8 mass spectrometry,. ( LC/MS ) J φ φφφφ φφ φ φ Φφφ φ ♦ φ · φφφ φφφ φφ φφφφ φφφ φφφ · * φ φ · · φφ φφ • Φ φ φ φ φ φ φ φ φφ φ

φφφ

System A)

Within this system, the column used was: ABZ + PLUSJ

3.3 cm x 3.60 mm, (inner diameter of the column), and elution with the following solvent mixture:

A) 0.1% (volume ratio), formic acid + 0.077%, (weight/volume), ammonium acetate in water, and

B;) Acetonitrile water, (95 t 5 * volume ratios) + 0.05% (volume ratios), formic acid, at a flow rate of 1.0 ml per minute.

The following gradient sequence was used: 100.0% A) _for 0.70 minutes of the A + B mixture, a gradient profile of 0 - 100.0% B) over 3.5 minutes, at 100.0% B) for 3.5 minutes, and again 100.0% A) for 0.30 minutes.

System B)

Within this system, the ABZ + PLUS ¹ column was used,

3.3 c.m x 2.0 mm, (inner diameter of the column), and elution with the following solvent mixture::

A) 0.1% (volume ratio), formic acid + 0.05%, (weight/volume), ammonium acetate in water.

• · ··«· ·· ···· • · • ' ·

·· • · · • · • · · · · ·

B) 95.0% acetonitrile::water, + 0.05 _% (volumetric ratios), formic acid, at a flow rate of 0.80 _ml /min.

The following gradient sequence was used::

A + K mixture, gradient profile 0.0 - 100.0%, over 3.5 minutes _, at 100.0% B), for 1.5 minutes, and again 100:.0% A), for 0.50 minutes.

S y s t e n r O

Within this system, the ABZ + PLUS column was used,

3.3 cm x 4.60 mm, (inner diameter of the column), and elution with the following solvent mixture:

A) 0.1% (volume ratio), formic acid + 0.077%, (weight/volume), ammonium acetate in water.

and

B) 95.0% mixture of acetonitrile :: water _r + 0.05%, (volume ratios), formic acid at a flow rate of 3.0 ml, per minute.

The following gradient sequence r was used

100.0%, for 0.70 minutes, mixtures A + B, gradient profile 0.0 - 100.0% B), for 3.70 minutes, at 100.0% B.) _, for 0.90 minutes, and again 100.0% A) _r for 0.20 minutes.

• · ··

System E)

Within this system, the ABZ + PLUSJ column was used

3.3 cm x 4.60 mm, (inner diameter of the column), β elution with the following solvent mixture:

A) 0^1% (volume ratio), carbolic acid in water, ⁸

B) 95.0% acetonitrile/water mixture + 0.07% (volumetric ratios) formic acid at a flow rate of 1.50 ml per minute.

The following gradient sequence was used:

100,,0 % A), for 0.20 minutes _r mixture A + B, gradient profile 0.0 - 100.0 % B), for

3.3 minutes, at 100.0% B), for 1.0 minute, and again 100.0% A), for 0.20 minute.

A spectrometer (micromass platform) was used in all L.C/MS systems, applying the electrospray ionization method, positive and negative ion switching, and a mass range of 80 - 100 atomic mass units.

Flash chromatography was performed using either Merck silica gel, (Merc 9385), or using pre-filled silica gel cartridges, (Biotage).

All temperature data were expressed in °C.

Table 1)- Examples

Example Name number í:

Detailed experimental characteristics, analytical data: (note 1) (2R,3R,4S,5S)-2-(6-2R- hydroxy-cyclopent-(R)- yl)-amino-purin-9-yl. - procedure AT 5-isopropyl-/1,3,4/-oxa

-diazol-2-yl)-tetrahydro

-furan-3,4-diol

TLC, SiO ₂ , ( CH ₂ C1 ₂ : MeOH : 880 NH^, ), ( 90 : 10:1 Ϊ ,

_Rf = 0.39;

Analytical evaluation of the compound according to the summary formula C^H^N^O,.

Calculated:

C 52.9, H 5.8, N 22.7;

Found:

C 52.9, H 5.9, N 22.7J

2) (2R,3R,4S, _: 5S)-2-(6- Analogous cyclopentylamino-purine method according to (9-yl-5-(5-phenyl-/1,3,4 procedure A) oxadiazol-2-yl-tetrahydro-furan-3,4-diol

TLC, SiO ₂ , ( CH ₂ C1 ₂ : MeOH : 880 NH^ ), ( 94 : 6:1 ),

R _f = 0.1°;

Analytical evaluation of the compound according to the summary formula ^S 22 ^H 23 ^N 7°2 ^: Calculated ::

C 57.2, H 5.3, N 21.2;

Found ::

d 57.1, H 5.3, N 21.OJ • · • · · ·

Table 1)- Examples

Example Name:: Detailed Characteristic number :: experiment data (note 1) analytical data ε

(2S ,35 »4R, 5R )-2- (5-target. See below See below butyl-[1, _: 3i, _ø 4/-oxadiazol-2-yl)-5-(6-(tetrahydro-pyran-4-yl-amino)-purin-9-yl]-tetrahydro-furan-3,4-diol (procedure A') ( procedure A)

4) ethyl ester of 4- Analog LC/MSJ (System B), í 9-/5S-(5-tert.-butyl- method of work - 2.55 minutes. Z2,3 ₍ 4(-oxadiazol-2-yl)- procedure A) 3R,,4S«-dihydroxy-tetrahyd Mass spectrum: β-furan-2R-yl[9H-purin-6-yl-amino]-piperidine-1-carboxylic acid (m/z), = 517.0, (MH ⁺

5) (2S,3S„4R,,5R)-2-(5£tè:ErriY Analogous LC/MS* (System B), butyl-/1,3,4/-bxadiazole method acc _Rt - 2.35 min. -2-yl)-5-(6-(2S-hydroxy of procedure A) -cyclopent-(S)-yl-amino) Mass spectrum: -t -purin-9-yl/-tetrahydro- (m/z), - 446.0,(MH furan-3,4-diol

• ·

Table 1)- Examples

Example number ::

Name:; Detailed experiment characteristics, analytical data :: data, (note 1)

6) (2S,3S _r 4R,5R)-2-(5isopropyl-/),3,4/-oxadiazol-2-yl)-5-(/6-tetrahydro-pyran-4-ylamino)-purin-9-yltetrahydrofuran-3,4diol

Analogous method according to procedure A)

LC/MS, (System H), = 2.24 min.

Mass spectra: (m/z) = 432.0,/MH ⁺ /J

7) (2S,3S,,4B,5R)-2-(5-tert-butyl-[1,3,4]ox8diazol-2-yl)-5-(6-cyclopentylamino-purm-9-yl)-tetrahydro-furan-3,4-diol

Analogous method according to procedure A)

LC/MS, (System B),

R. = 2.61 min. t

Mass spectrum: (m/z) = 43O.0;/mh ⁺ /;

(2S,3S,4R,5R)-2-(5-tert. Analogous See below procedure B )J butyl-/1,3,4/-oxadia- method according to zol-2-yl)-5-/2-chloro- procedure B)

-6-(tetrahydropyran)

-4-yl-amino)-purin-9-yl/-tetrahydro-furan, ,4-diol-formate • · · · · ·

Table 1)- Examples

Example number:

9)

Name:; Detailed . ìexper. data, (note 1) Characteristic analytical data: (2S,3S,4R,5R)-2-(5- Analog LC/MS, (System A), target.buty1-/1,3,4/- method according to = 4.35 minutes (2-oxadiazol-2-yl-)-5-(2- procedure B) chloro-6-cyclopentyl- Mass spectra: amino-purin-9-yl)- (m/z) = 464.0,/MH ⁺ /; tetrahydrofuran-3,4- diol formate

10)

(2S,3S,4R,5R)-2-(54->' cyclopropyl-[1,3,4]oxadiazol-2-yl)-5-(2S-hydroxy-cyclopent(S)-yl-amino)-purin-9-yl[-tetrahydro-furan- Analog method according to procedure A) LC/MS, (System D), _Rt - 2.32 min. Mass spectra: (m/z) = 430.0./MH ⁺ /; 3,4-diol (2R,3R,4S,5S)-2-(6- Analog LC/MS, (System D), cyclopentylamino-pu- method according to R = 2.44 min. rin-9-yl1)-6-(5-cyclo- procedure A) propyl1-/1,3,4/-oxadia- Mass spectra: i zol-2-yl)-tetrahydro- (m/z) = 414.0,/MH/; furan-3,4-diol

• · ·

Τ 8 b u 1 k θ 1)- Examples

• · ·

Example number:

Name :

Detailed experiment, úds is, (note 1)

Characteristic analytical data:

12) 4-^ 9-/5S-(5-cyclopropyl) Analogous

-(1,3,4)-oxadiazol-2-yl) method according to -3R,4S-dihydroxy-tetra- procedure A) hydro-furan-2R-yl/-9Hpurin-6-yl-aminoJ -piperidine-1-carboxylic acid ethyl ester

LC/MS, (System D), R _t = 2.57 min.

Mass spectra: (m/z) = 5O1.0./MH ⁺ /;

13) (2R,3R,4S„5S)-2-(6-cyclo

-pentylamino-purin-9-yl)-5-(5-cyclopentyl-[1,3,4]-oxadiazol-2-yl)-tetra-hydro-furan-3,4-dil

Analog LC/MS, (System B), method according to R^ = 2.74 min.

procedure A)

Mass spectra: (m/z) = 442.0,/MH ⁺ /;

1<) (2S,3S,.4R,5R)-2-(5£tert. Analogous butyl-/1,3,4/-oxadiazole- method according to

2-yl)-5-(6-(4-chloro-2- of procedure A) fluoro-phenylamino)-purine

-9-yl/-tetrahydrofuran-3,4-diol

LC/MS, (System B), R _t = 2.99 min.

Mass spectra: (m/z) = 490.0,/MH ⁺ /;

Table 1) - Examples

Example Name:

number ::

Detailed experiment, data, (note 1)

15) (2R,3R,4S,5S)-2-(6- See below cyclopentylamino-purine-(pog^up j£)9-yl)-5-(1,3,4)-oxadiazol-2-yl-tetrahydro-furan

-3,4-niol

Characteristic analytical data:

See below (procedure C)

16) (2S,3S,4R,5R)-2-(5-[(method D)ethyl-oxazol-2-yl)-5-, (method D)/6-(tetrahydro-pyran-4-yl-amino)-purin-9-yl/tetrahydro-furan-3,4-diol

17) (2S,3S,4R _r 5R)-2-(6- See below See below,(procedure E)

-cyclopentylamino-purine- (procedure E)

9-yl)-5-(5-cyclopropyl/1,3,4/-thiadiazol-2-yl)tetrahydrofuran-3,4-dil

18) (2R,3R,4S,5R)-2-(6-iso- propylamino-purin-9-yl)- (see below, procedure F)

5-(5-methyl-4G-/1,2φ4/triazol-3-yl)-tetrahydrofuran-3,4-diol. trifluoroacetate

Table Example number : Name: 19) (2S,3S,4R,5R)-2-(3cyclopropyl-[1,2,4-(oxadiazol-5-yl)-5-(2S-hydroxy-cyclopent(S)-yl-amino)-purin-9yl]-tetrahydrofuran-3,4-diol

1) - Examples

Detailed Characteristic experiment, analytical data: data, (note 1)

See below LC/MS, System B), (procedure G) = 2.37 min.

Mass spectra: (m/z) = 430.0,/MH ⁺ /;

20) (2S,3S,4R,5R)-2-(3phenyl-/1,2,4/-oxadiazol-5-yl)-5-(6-(tetra*hydro-pyran-4-yl1-amino)-purin-9-yl1/-tetrahydro-furan-3,4-diol

Analogous TLC, SiO ₂ , ( CH^l^ :

method according to EtOH : 880 NH^, procedure G) ( 100 : 8 : 1 ),

_Rf = 0.50;

Analytical evaluation of the compound:

Calculated:

C 55.3, H 5.3, N 19.6; Found:

C 54.8, H 4.9, N 20.0;

Table 1)- Examples

Example number : Name: Detailed experimental. data, (note 1) Characteristic analytical data: 21 ) (2S,3S,4R,5R)-2-(3-tert-butyl-[1,2,4]-oxadiazol-5-yl)-5-(6-(2S-hydroxy-cyclopent(S)-yl-aniline)-purin-9yl)-tetrahydrofuran-3,4-diol Analog method according to procedure G) LC/MS,(System B ), R ~ 2.57 min. Mass spectra: (m/z) = 446.0,/MH ⁺ /J

22) (2S,3S,4R,.5R)-2-(3- Analog LC/MS, (System B), cyclopropyl-/1,2,4/- method according to _Rt = 2.39 min. oxadiazol-5-yl)-5-/6- procedure G) ( tetrahydro-pyran-4- Mass spectra: yl-amino)-purin-9-yl/tetrahydro-furan-3,4 - diol (m/z) - 43O,O,/MH /;

23) (2R,3R,4S,5S)-2-/6- Analogous (tetrahydro-pyran-4 method according to

-yl-amino)-purin-9-yl/- of procedure G)

5-(3-thiazol-5-yl-[1,2,4]

- oxadiazol-5-yl)-tetrahydro-furan-3,4-diol

LC/MS, ( System B ), R - 2.29 min.

Mass spectra: (m/z) = 473.0,/MH ⁺ /;

444 seconds?

Table 1)- Examples

Example Name: Detailed j ? Characteristic number experiment, data, (note 1Ϊ analytical data : ) 24) (2S,3S,4R,5R)-2-(3- Analog ¹ H-NMR, delta, (DMSO): methyl-/1,2,4/-oxa- method according to 8.42, ( 1H,s.,CH ), diazol-5-yl)-5-(6-(tetrahydro-pyran-4-yl-imino)-purin-9-yl)-tetrahydrofuran-3,4-diol procedure G) 8.20, ( 1H, n.s., CH ), 7.82, ( 1H, n.d., NH ), 6.18, ( 1H, d., CH ), 6.02, ( 1H, n.d., OH ), 5.90, ( 1H, n.d., OH ) *,

5.22, ( 1H, d., CH ), 4.38, ( 1H, w.s., CH), 3.94, ( 2H, w.d., 2x CH, ( equatorial.),

3.42, (2H, t., 2x CH, (axial), 2.40, (3H, a., CH ₃ ), 1.90 - 1.60, (4H, 2xi., 2x CH )J

Analytical evaluation of the compound:

Calculated:

C 50.6, H 5.25, N 24.3*,

Found :

C 50.6, H 5.20, N 24.3J ···· ···

5#

Table 1)- Examples

Example Name:

number :

Detailed experiment, úds is, (note 1)

Characteristic analytical data:

29) (2R,3R,4S,5S)-2-/6-(3- Analogous fluoro-4-hydroxy-phenyl-method according to amino)-purin-9-yl/-5-. procedure G) (3-methyl-(1,2,4)-oxadiazol-5-yl)-tetrahydro-'

-furan-3,4-diol

LC/MS, ( System G ), R 2 = 2.53 min.

Mass spectra: (m/z) = 430.0,/MH ⁺ /;

26) 4-£ 9-/5R-(5-tert- See below, butyl-/1,2,4/-oxadia- (method H) from ol-3-yl)-3R,4S-dihydroxy-tetrahydro-furan-2Ryl/-9H-purin-6-yl-amino^ -piperidine-1-carboxylic acid ethyl ester

LC/MS,. (System B), R - 2.76 min.

Mass spectra: (m/z) = 517.0/MH ⁺ /;

27) (2S,3S,4R,5R)-2-(3-tert.See below,(process I),butyl-isoxezol-5-yl)-5-((process I)/6-(2S-hydroxy-cyclopent

-(S)-y1-amino)-purin-9-y1/

- tetrahydrofuran-3,4diol · ♦· • •44

4 4

*

Table

1) - Examples

Example Name::

number :

28) (2S,3S,4R,5R)-2-(3-tert-butyl-1-isoxazol-5-yl)-5-(6-(tetrahydro-pyran-4-yl-amino)purin-9-yl)-tetrahydro-furan-3,4-diol

29) (2R,3R,4S,5R)-2-(2Hpyrazol-3-yl)-5-(6tetrahydro-pyran-4yl-amino-purin-9-yl)tetrahydrofuran-3,4diol

Detailed Characteristic experimental data, (note 1) analytical data: See below (procedure I) See below,(procedure I), See below (procedure J) See below,( procedure J),

30) (2R,3R,4S, _; 5R)-2-(5- See below tert-butyl-2H-pyrazole- (method K)

3-yl)-5-(6-cyclopentylamino-purin-9-yl)-tetrahydrofuran-3,4-diol

See below (procedure K),

31) (2R,3R,4S,5S)-2-[6-(1S- See below,(method L), hydroxymethyl-2-phenyl- (method L) ethylamino)-2-methoxypurin-9-yl]-5-(3-ethylisoxazol-5-yl)-tetrahydrofuran-3,4-diol • 9

T 8 b u 1 k e O, - Examples ·»··

999 999

9999 · * ' · · « t 4 • · · ·

9 99

Example Name: Detailed Characteristic Number : experiment data (note 1) analytical data:

32) (1S,2R,3S,5R)-3-(3- See below, (method M), cyclopropyl-[1,2,4]- (method M) oxodisol-5-yl)-5-[2S-hydroxy-cyclopent-(S)yl-amino)-purin-9-yl]cyclopentane-1,2-diol

33) (2R,3R,4S,5S)-2-[6- (tert-butylamino)-9H- propyl-1,2,4-oxediazol-5-yl]-5-(cyclo- )-tetrahydrofuran-3,4-diol Analogous method according to procedure G

LC/MS, ( System C ), R 2 = 2.91 min.

Mass spectrum: (m/z) = 402.0, /MH ⁺ /* (2S,3S,4R,5R)-2-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-5-[6-(isopropylamino)-9H-purin-9-yl]-tetrahydrofuran-3,4-diol

Analogous method according to procedure G)

LC/MS, ( System C ), R = 2.54 min.

Mass spectra: (m/z) = 388.0,/MH ⁺ /;

34)

9 • ΦΦΦ £Ί ♦

999 ·

Φ « ·

Φ * • ΦΦΦ

Table

1) - Examples

Example Name number:

Detailed experiment.

data, (note 1)

Characteristic analytical data:

35) (2R,3R,4S,5S)-2-(6- Analogous ^/( 1R,2R)-2-hydroxy- method according to cyclopentyl/-amino^-9H procedure G) -purin-9-yl)-5-(3methyl-1,2,4-oxadiazol5-yl)-tetrahydrofuran3,4-diol

LC/MS, (System C), R - 2.32 min ¹ .

Mass spectra: (m/z) = 404.0,/MH ⁺ /;

36) (2S,3S,4R,,5R)-2-(3methyl-1,2,4-oxadiazol-5-yl)-5-(6-(tetrahydro-2H-thiopyrene-4yl-amino)-9H-purin-9yl)-tetrahydrofuran-3,4-diol

Analogous method according to procedure G)

LC/MS, ( System C ), R = 2.54 min.

Mass spectra: (m/z) = 420.0,/MH ⁺ /;

37) ethyl 4-({9-/(2R,3R,4S,5S)-3,4-dihydroxy-5-(3-method according to methyl-1,2,4-oxadiezol- procedure G) 5-yl)-tetrahydrofuran2-yl/-9H-purin-6-yl^ -emino)-piperidine-1-carboxylate

LC/MS, ( System CR _t = 2.56 min,

Mass spectra: (m/z) = 475.0/MH ⁺ /;

·

Table 1)- Examples

Gl • ♦ «

·♦ ···· * · · · • · ♦ · • · ♦ # · • · * · » ·· **

Example number : Name:: Detailed experiment, data, (note f) Characteristic analytical data: 38) (2R,3R,4S,,5S)-2-/6- Analog LC/MS, ( System C ), (isobutylamino)-9H- method according to R^ = 2.51 min. purin-9-yl1/-5-(3-methyl procedure G) -1,2,4-oxodiazol-5-yl)~ Mass spectra: tetrahydrofuran-3,4- (m/z) = 376.0, AlH ⁺ /; diol

39) (2R,3R,4S,5S)-2-(6-(cyclopentylamino)9H-purin-9-yl)-5-(3methyl-1,2,4-oxadiazol-5-,yl)-tetrahydrofuran 3,4-diol Analog method according to procedure G) LC/MS, ( System C ), R - 2.47 min. v Mass spectra:: (m/z) = 388.0,/MH*/; 40) (2R _ø 3R _ø 4S„5S)-2-£ 6- Analog LC/MS,, ( System C ),. /(cyclopropylmethyl)- method according to R^ - 2.4$ peace amino/-9H-purin-9-yl- procedure G) 5-( 3-methyl-1,2,4-oxa- Mass spectra: (diazol-5-yl)-tetrahydro- (m/Z) x 374.0,/MH ⁺ /; furan-3,4-diol

99·· £3

9 9

999 ♦ * *

• 9« 9 9 9 ·· 99« 9

9 · • 99 »9 9

9 9 9 »9 99 «9 9

9 ··

9 9 · · « 9 · »99

Table ) - Examples

Example; Name::

number ::

Detailed experiment, data, (note 1)

Characteristic analytical data

41) (2R, _; 3R„4S„5S)-2-(6(cyclopropylamino)9H-purity>9-yl)-5-(3methyl-1,2,4-oxadiazol-5-yl)-tetrahydrofuran-3,4-diol

Analog LC/MS, (System G,), method according to R^ - 2.17 min. procedure G)

Mass spectrum: (m/z) = 360.0,/MH?/;

42) (2R,.3R„4S _r 5S )-2-/6-(2- Analogous fluoroaniline)-9H-purine- method according to 9-yl/-5-(3-methyl-1,2,4-procedure G)oxadiezol-5-yD-te trahydrofuran-3 _t 4-diol

LC/MS , ( System C ), R - 2.71 min.

Mass spectra: (m/z) = 414.0/MH ⁺ /;

43) (2R,3R _r 4S„5S)-2-/6-(2, Analogous

4-difluorosnilin)-9H- method according to purin-9-yl/-5-(3-methyl procedure G)-1,2,4-oxadiazol-5-yl)tetrahydrofuran-3,4diol

LC/MS (System C), R^ = 2.75 min.

Mass spectra: (m/z) = 432.0/MH ⁺ /;

Table D- Exemplary »♦··

Example number : Name:: Detailed experimental. data, (note 1) Characteristic analytical data: 44) (2S,3S,4B,5B)-2-(tert-Butyl)-1,2,4oxadiazol-5-yl]-(cyclopropylmethyl)amino-(9H-purin-9-yl)-tetrahydrofursn-3,4diol Analog method according to procedure G) LC/MS* (System C), _Rt = 2.77 min. Mass spectra: (m/z) = 416.0/MH ⁺ /;

45) (2S,3S,4R,.5R)-2-/3- , ( tert -Butyl)-1,2,4oxadiazol-5-y1/ -5-/6( isobutylamino)-9Hpurin-9-y1/ -tetrahydro -furan-3,4-diol See below (procedure N) LC/MS, (System C), R - 2.88 min. Mass spectra: (m/z) = 418.0,/MH ⁺ /; 46) 2-(9-(9-(2R,3R,4S,5S)-5-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)-3,4-dihydroxytetrahydrofuran-2-yl)-9H-purin6-yl)-imino-N-methylethanesulfonamide Analog method according to procedure N) LC/MS, (System C), R = 2.54 min. Mass spectra: (m/z) * 483,C,/MH ⁺ /;

9 ·

9 9

9 ·

9 9 9

99

9

9 •

·« ·

Table 1)- Examples

Example Name number:

Detailed experiment.

data, (note 1) characteristic analytical data:

47) (2S,3S >4R,,5R )-2-/3- Analogous (tert.-butyl)-1 ,2,,4- method according to oxadiazol-5-yl/-5>^6.- procedure NJ) /(1 ,,1-dioxidetetrahydro

-2H-thiopyran-4-yl)smino/-9H-purin-9-yl te trahydrofursn-3,4?diol

LC/MS, (System C)

_Rt - 2.51 min»

Mass spectra: (m/z) = 494.0,/MH ⁺ /;

48) (2S,3S,4£,.5R )-2-/3(tert Φ» -butyl)-1,2,4oxadiazol-5-yl/-5-/6(2-chloro-4-fluoroaniline) -9H-purin-9-yl/-tetraAnslogan method according to procedure Oj)

LC/MS, (System C), R ^; t ~ 3.20 min.

Mass spectra: (m/z) = 490.0./MH ⁺ /;

hydrofursn-3, _; 4-diol

49) (2S,3S,4R,5R)-2-/3- See below (tert-butyl)-1,2,4-(procedure,0) oxadiazol-5-yl/-5-/6(2,4-difluoroanilin)-9H-purin-9-yl/-tetrahydrofuran-3,4-diol

LC/MS, (System C)

_Rt - 3.03 min.

Mass spectra: (m/z) = 474.0,/MH ⁺ /;

·· a··· &e ·· · • ··· » ··« ··· • · • · · ·♦ « ♦

·9·

Table 1)- Examples

Example Number name:

Detailed experiment, data, (note 1)

Characteristic analytical data:

50) (2S,3S,.4R„5R)-2-(tert-butyl)-1,2,4oxadiazol-5-yl 1 H -5-(6-(3,4-difluoroaniline)9H-ourin-9-yl)-tetrahydrofuran-3,4-diol

Analogous method according to procedure 0)

LC/MS, (System C), R _t - 3.32 min.

Mass spectra: (m/z) = 474.0,/MH7;

51) (2R,3R _r 4S, _; 5S)-2-(6(cyclopropylamine)-9Hpurin-9-yl)-5-(3-isopropyl-1,2,4-oxadiazol-5-yl)-te trishydrofuran·

3,4-diol

Analogous method according to procedure N)

LC/MS, ( System C ) R _t - 2.39 min.

Mass spectrum: (m/z) = 388.0,/MH ⁺ /;

52) (2R,3R,,48,,5S)-2-/6-(iso Analogous butylimino)-9H-purine- method according to

9-yl/-5-(3-isopropyl- N)

1,2, _; 4-ox8diazol-5-yl)tetrahydrofuran-3,4diol

LC/MS, (System C)

R - 2.74 minutes.

Mass spectra: (m/z) = 404.0,/Mh7;

Table

1) - Examples • 0 0·· 00 · • ··· • 0 ··*·

Example Name number:

Detailed experiment, data, (note 1)

Characteristic analytical data:

53) (2R,3R,4S,5S)-2-^6- Analogous /(cyclopropylmethyl)- amino/-9H-purin-9-yl^ method according to procedure N)

5-(3-isopropyl-1,2,4oxadiazol-5-yl)-tetrahydrofuran-3,4-diol

LC/MS, (System C), R^ = 2.65 min.

Mass spectra: (m/z) = 402.0,/MH ⁺ /;

54) 2-(^9-/(2R,3R,4S,5S)- Analogous

3,4-dihydroxy-5-(3-iso method according to the propyl-1,2,4-oxadiazole-procedure N)5-yl)-tetrahydrofuran2-yl/-9H-purin-6-yl^amino)-Νί-methy lethansulfonamide

LC/MS, (System O,

R = 2.58 minutes.

Mass spectra: (m/z) = 469.0,/MH7;

55) (2R,3R,,4S,5S)-2-/6-(2,4 Analog

-difluoroaniline)-9H- method according to purin-9-yl/-5-(3-isopro-??procedure 0)pyl-1,2,4-oxadiazol-5yl)-tetrahydrofuran-3,4diol

LC/MS, (O R system ~ 2.96 min.

Mass spectra: (m/z) = 460.0./MH ⁺ /;

»3^^·έ·3£ :·£* • 000 ·

000 0

000···

0000 • 0 · • 00

0 ·

0 0 0 ··

0 • ·

Table 1)- Examples

Example Name:; Detailed Characteristic number experiment data (note 1) analytical data:: 56) (2R,3R,4S,5S)-2-/6-(3, Analogous 4-difluoroaniline)-9H- method according to purin-9-yl/-5-(3-iso- procedure 0) propyl-1,2,4,-oxadiazole- 5-yl)-tetrahydrofuran- 3,4-diol LC/MS?, (System GL), _Rt = 3.20 min. Mass spectra: (m/z) = 460.0,/MH7;

57) (2R,3R,4S;,5S)-2-/6-(4- Analog LC/MS, ( System C ), fluoro-2-methylaniline)- method according to _Rt = 3.05 min. 9H-purin-9-yl/-5-(3-iso procedure 0) propyl-1,2,4-oxadiazole- Mass spectra:; 5-yl)-tetrahydrofuran- (m/z) = 456.0,/MH7; 3,4-dicr

58) (2S,3S,4R„5B)-2-/3-(di- Analogous TLC, Si0 ₂ , (C1 ₂ GH ₂ : methylamino)-1,2,4-oxa method according to EtOH: 880 NH _β ), diazol-5-yl1/-5-/6-( te- procedure G) (95 : 5 : 0.5 ), tetrahydro-2H-pyren-4-yl- _Rt = 0.20; amino)-9H-purin-9-yl- tetrahydrofuran>3,4- Analytical evaluation diol compounds according to summary

formula ^c i ₈ ^H 24 ^N 5°5 ^:

Calculated:

C 49.5, H 5.65, N' -25.6;

Found ::

C 49.75, H 5.90, N 25.2;

·**·

6?

Table 1)- Examples

Example Name::

number ::

Detailed experiment.

(note 1)

Characteristic analytical data:

59) (<2R,3R„4S,,5S )-2-(6/rel-(1S,2R,4R)-bicyclo-/2.2.1/-hept-2yl-amino/-9H-purin-9yl^-5-(3-cyclopropyl-1,-2,4-oxadiazol-5-yl)tetrahydrofuran-3,4diol

Analogue LC/MS (System B), method according to R^ = 2.81 min. procedure G)

Mass spectra: (m/z) = 440.0,/MH ⁺ /;

60) ethyl-4-((9-/(2R,3R, ₎ 4S,, Analogous

5S)-5-(3-cyclopropyl-1, method acc

2,4-oxediazol-5-yl)-3,4-poetup G) dihydroxytetrahydrofuran

-2-yl/-9H-purin-6-yl] amino)-piperidine-1-carboxylate

61) (2S,3S,4R,5P)-2-/3-tert. Analogous butyl)-1,2,4-oxadiazole- method according to 5-y 1/-5-/6-(isopropyl- procedure G>)amino)-9H-purine-9-y1/tetrahydrofuran-2,4-diol

LC/MS _r ( System B ) _t R _t - 2.57 min.

Mass spectra: (m/z) = 501.0,/MH ⁺ /;

LC/MS _r ( System B'5 JR - 2.69 min.

Mass spectra: (m/z) = 404.0,/MH ⁺ /;

····

Here

Table 1)- Exemplary

Example number? : Name :: Detailed experiment, data, (note 1) Characteristic analytical data: 62) (2R,3R,4S,,5S)-2-/6- Analog LC/MS, ( ^! System B), (4-chloro-2-fluoroaniline) method according to S = 3.05 minutes. -9H-purin-9-yl/-5-(3- procedure G) cyclopropyl-1,2,4-ox.a- Mass spectra: diazol-5-yl)-tetrahydro- (m/z) = 474.0/MH ⁺ /; furene-3,4-diol

63) ethyl-4-4-(£2R,3R,4S,5S) Analog LC/MS _r ( System B ), R = 2.73 min. 3,4-dihydroxy-5-(3-iso- method according to propyl-1,2,4-oxadiazoleT procedure G) 5-y 1)-tetrahydrofuran- Mass spectra: 2-yl/-9H-purin-6-yl^ - (m/z) = 5O3.0./MH ⁺ /; amino)-piperidine-1-car- cloth boxes

64) (2R,3R,4S,5S)-2-[6-rel- Analog LC/MS, (System A), (1S, 2R,,4R)-bicyclo-/,2.2. method according to R = 4.27 minutes. 1 N -hept-2-yl-amino N -9 H -purin-9-yl N -5-(3-isopropyl-1,2,4-oxadiazole— procedure G) Mass spectrum: (m/z) = 442.0,(MH ⁺ /J

5_y1)-tetrahydrofuran-3, 4-diol ·» 4··· ····

9 • · • · · • « • 4

« · ·

T e b u 1 k. e 1) - Examples

Example number : Name:: Detailed experimental. data, (note 1) Characteristic analytical data: 65,) 2-({9-/(2R,3R,4S,5S)5-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-3,4dihydroxytetrahydrofuran-2-yl/-9H-purin-6-y^amino)-N-methy le thansulfonamide Analogous method according to procedure G) LC/ _MS (System B), t = 2.33 min. Mass spectra: m/z = 467.0,/MH ⁺ /;

66) (2R,3R,4S,5S)-2-/2- . chloro-6-(1-ethyl-propylamine)-purin-9-yl/5-(3-propyl-isoxazol-5-yl)-tetrahydrofuran-3,4-diol. formate Analog method according to procedure I) LC/MS, ( System A ), R = 4.68 min. Mass spectra: (m/z) = 451.0,/MH+/; 67) (2R,3S,4R, _: 5R)-2-/5- Analog: LC/MS, ( System C ), (tert-butyl)-4H-1,2, the method of force _Rt - 3.01 min. 4-triazol-3-yl/-5-/6- procedure P) (4-chloro-2-fluoroaniline) Mass spectra: -9*yl/-tetrahydrofuran- (m/z) = 489.0,/MH ⁺ /', 3,4-diol

• ···· »4 · • ··· 4 • · ♦ · € · · ··· 444 • 4 4444 • 4 *··· · · · · • · • 4 4

44

Table 1)- Examples

Example Number:

Name

Detailed experiment, data, (note 1)

Characteristic analytical data

68) (2R,3R,4S,5R)-2-(6-(2-chloro-4-fluoroaniline)-9H-purin-9-yl)-5-(5-isopropyl-4H-1,24-triazol-3-yl)-tetrahydrofuran-3,4-diol

Analogous method according to procedure F)

LC/MS,. ( System © ), R - 2.89 min.

Mass spectra: (m/z) = 475.0/MH ⁺ /;

69) 2-(/9-((2R,3R,4S,.5S)3,4-dihydroxy-5-(3methyl- _1,2t 4-oxadiazol-5-yl)-tetrahydrofuran«2-yl/-9H-purin6-yl}-amino)-N-methylethanesulfonamide

Analogous method according to procedure G)

Analytical evaluation of the compound according to the summary formula Ο^Η^θΝθΟ^ε:

Calculated:( %)

C 40.9, H 4.63, N 25.24,

Not found :( %)

G 40.93, H 4.72, N 24.89

Mass spectra: (m/z) = 441.0,/MH ⁺ /;

70) (2R,3R _r 4S,53)-2-(6[(trans-4-hydroxycyclohexyl)-amino]-9H-purin9-yl^-5-(5-methyl-1,3oxazol-2-yl)-tetrahydrofuran-3,4-diol

Analogous method according to procedure D)

Mass spectra: (m/z) = 417.0/MH7;

4·· íXSS&SUŽSSoHBRWWB^^ • ··♦· ·· · • ··· • · • · ··· ··· ·· ···· » · · · ·· ·· ··

Table 1)- Examples

Example Name:: Detailed Characteristic number : experiment♦ data, (note 1) analytical data

71) (2S,3S,4R,5R)-2-(3- Analog Analytical evaluation methyl-1,2,4-oxadi- method according to compounds:members of the family· zol-5-yl)-5-(6~£/( 1R)- procedure G) formulas ^C 21^23^7^4 : 1-methyl-2-phenylethyl (amino-9H-purin-9-yl)tetrahydrofuran-3,4diol Calculated: (%) C 56.49, H 5.42, N 21.96 Found: (%) C 56.41, H 5.32 _, N 21.78

72) (2S,3S,.4R,5R)-2-(5- Analog Analytical evaluation ethyl-1,3i~oxazole*2- method according to compounds according to summary. yl) -5-.^6-/ (trans-4- procedure D) formula C _2O H ₂₆ » ₆ O ₅ r hydroxycyclohexylami- Calculated: ( %) n -9H-purin-9-yl N- C 55.8, H 6.1, N 19.5, tetrahydrofuran-3 ,Adiol Found: (%} C 54.5, H 6.0, N 18.8,

Mass spectra: (ra/z), = 432.0,/MH ⁺ /J

Table 1)- Examples »9 9 9 9 9 9

999 9 999 9

9 9 9 9 9 9

-you

Example number : Name:: Detailed experiment, data, (note 1) Characteristic analytical data: 73) (2S,3S„4R _y 5E0-2-(5- Analog Analytical evaluation ethyl-1,3-oxazol-2-yl) method according to compounds according to summary. 5-/6-(3-fluoro-4-hydro- procedure D) formula C^qH^ ^FN^O^: xyaniline)-9H-purine-9- Calculated: (%) yl/-tetrahydrofuran-3, C 53.2, H 4.5, N 18.6, 4-diol Found: (%) C 53.6, H 4.6§j, N 4.65 Mass spectra: (m/z) = 443.0/MH ⁺ /; 74) (2R,3R,4S,.5S)-2-/6-(3- Analog Mass spectrum (fluoroaniline)-9H-purine- method according to (m/z) - 413.0; (MH ⁺ ); 9-yl/-5-(5-methyl-1,3- procedure D)

oxa from ol-2-yl)-te trahydrofuran-3,4-diol

75) (2S,3S,4R,5B)-2-(5-ethyl- Analogous

1,3-oxazol-2-yl)-57(6- method according to £/( 1 S,,2R)-2-fluoro cyclo- procedure D) pentyl/-aminoj -9H-purin9-yl)-tetrahydrofuran-3,

4-diol

Mass spectrum: (m/z) = 419.0/MH ⁺ /;

and

Table 1)- Examples • · · · · • · · · · · · • •99 9 9

99 9 9

Example number :: Name:: In detail experiment, it will be (note 1) Characteristic analytical data: 76) (2R,3R,4S,.5S )-2-/6- Analog _Rf = 0.18, (4-fluoroaniline)-9H- method according to ( dichloromethane : purine-9-y1/-5-(5- procedure D) ethanol : 880 ammonia) methyl-1,3-oxazol-2- (100: 10: 1), y 1) - te trs hydrof ursn- See below, 3,4-diol (procedure P) Mass spectra: for synthe- (m/z) = 413.0./MH ⁺ /; are intermediate- duct 77) (2S,3S,4R,.5R)-2-/3- Analog LC/MS,. ( System Sr. ), (tert-butyl)-1,2,4- method according to R = 3.53 min. oxadiazol-5-yl/-5- procedure G) /6-(tetrahydro-2H- Mass spectra: pyran-4-yl-amino)-9H- (m/z) x 446.0,/MH ⁺ /; purin-9-yl/-tetrahydro- furan-3 , 4-diol 78) (2R,3R _, 4S, _; 5S)-2-{6- Analog LC/MS,, ( System A ), /rel-(1S,2R,4R)-bicy- method according to _Rt = 3.03; clo-/2.2.1./-hept-2-yl- procedure G) amino/-9H-purin-9-ylJ - Mass spectra:: 5-/3-( tert.butyl)-1 ,.2,. (m/z) = 456.0/MH ⁺ /; 4-oxadiazol-5-yl/-tetra« -

hydrofurene-3,4-diol.

• ···· ·· ···· ·· ··· · · · · · · ···· · · · · · • ···· · t f ·

Io

Table

1) - Examples

Example number : Name: Detailed experiment, data, (note 1) Characteristic analytical data: 79) ethyl-4-/l9-{2R,3R, Analog LC/MS, (System A'), 4S, _: 5S)-5-/3-(tert.bu- method according to R - 2.77 minutes. tyl)-1,2,4-oxadiezol5-yl/-3,4-dihydroxy- procedure G) Mass spectra: tetrahydrofuran-2-yl(9H-purine-6-yl)-amino/piperidine-1-carboxylate (m/zO = 451.7,/MH /;

80) 2-/(9~{(2R,3R,4S,5S)-5-- Analogous LC/MS, (System B), /3-(tert-butyl)-isoxa- method according to R - 3.76 minutes. zol-5-yl/-3,4-dihydroxy procedure -tetrahydrofuran-2-ylZ - Mass spectra: 1 9H-purin-6-yl)-amino/-N (m/z) = 482.0,/MH/; -methylethanesulfonamide

81 ) (2S,3S _t; 4R,5K)-2-/3- Analog LC/MS, (Sygt _em β) _ý (tert-butyl)isoxazole method according to R = 4.20 min. -5>yl/-5-(6-$/(1S,.2S)- procedure 2-fluorocyclopentane 1/- Mass spectra: amino^-9H-purin-9-yl)- (m/z) = 447.0,/MH / the trihydrofuran-3,4- diol

• • ·· · · · ··♦· ·· · • ·· · · · · · · · · ··· ♦ · · · · ··· · · · · · · T a b l e 1 k and 1) - Examples Example; Name:; Detailed Characteristic number : experiment. analytical data: data, (note 1) 82) ethyl-4-/(9-{(2R,3R, Analog LC/MS, (System B 4S,5S )-5-/3-( target;, bu- method according to R^ = 4.06 min. tyl)-isoxazol-5-yl/-3, procedure 4-dihydroxytetrahydro- Mass spectra

furan-2-yl 3 -9H-purin-6yl )-amigo 3 -piperidin-1 x carboxylate (m/z) = 516.0,/MH /\

83) (2S,3S _r 4R„5»-2-/3- Analog LC/MS,, ( System B ), (tert-butyl)-isoxazole- method according to R - 4.18 minutes. ”5-yl/-5-/6-(cyclopentyl1 procedure amino)-9H-purin-3-yl/- Mass spectra: tetrahydrofuran-3,4- (m/z) = 429.0,/MH ⁺ ; diol

84) ([9-/(2R,3R,4S,5S)-5- Seeing Mass spectrum: (5-Ethyl-1,3-oxazol-2yl)-3,4-dihydroxytetrahydrofuran-2-yl/-9Hpurin-6-yl(amino)-N,N-dimethylethanesulfonamide X procedure Q) procedure Q (m/z) = 468.0,/MH ⁺ /;

Table 1)- Examples • · · · 4 • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 99

99

Example Name number:

Detailed Characteristic experiment, analytical data: data, (note 1)

85)

2-({ 9-/(2R,3R,4S,®5-(5-ethyl-1,3-oxazol-2-yl)-3,4-dihydroxytetrahydrofuran-2-yl/9H-purin-6-ylJ -amino)Ν-ψβthylethanesulfonamide

Analogous method according to procedure Q)

Mass spectra: (m/z) - 454.0/MH ⁺ /;

86) ethyl-4-(£9-/(2R,3R,.4S·, Analogous 5S)-5-(5-ethyl-1,3-oxe- zol-2-yl)-3,4-dihydroxy method Q) tetrahydrofuran-2-yl/-9H -purin-6-yl^ -amino)-piperidine-1-carboxylate

Mass spectra: (m/z) = 488.0,/MH ⁺ /;

87) (2R,3R,,4S _r 5S )-2-{o-/(2, Analogous 3-dihydroxypropyl)-ami- method according to n/-9H-purine-9-|-5-(5- procedure Q) ethyl-1,3-oxazol-2-yl)tetrahydrofuran-3,4-diol

Mass spectra: (m/z) x 407.0,/MH ⁺ /;

(2R,3R,4o,/S')-2-/6-(2. Analogous 4-difluoroaniliri)-9H- method according to purin-9-yl/-5-(5-ethyl procedure Q 1,3-oxazol~2-yl)-tetrahydrofuran-3,4-diol

Mass spectra: (m/z) x 445.0,/MH ⁺ /;

88)

• • · • ?? ·: ···· ·· ··· ··· ·· · • 9 9 · · · · · • · · · · · · · · * • · · · · · · · · · · • · · · · · · · T a b l e 1 k and 1) - Examples Example Name Detailed Characteristic number: experiment data (note 1) analytical data: 89) (2S,3S,.4R,,5R)-2-(5- Analog Mass spectra: ethyl-1,3-oxazol-2-yl) method according to (m/z) = 417.0/MH ⁺ /; 5-(6-(/(1S,2S)-2-hydroxy-cyclopentyl)-8mino[9H-purin-9-yl)-tetrahydrofuran-3,4-diol procedure Q) 90) (28,3.8,,4^5^)-2-(5- Analog Mass spectra: ethyl-1,3-oxazol-2-yl)-5-(6-((3R)-tetrahydrofurans-3-yl-amino)-9Hpurin-9-yl)-tetrahydrofuran-3,4-diol method according to procedure Q ) (m/z) = 4O3.0./MH ⁺ /; 91 ) (2R,3R„4S„5S)-2-(6- Analog Analytical evaluation (/ (1R.) - 2-methoxy-1 - method according to compounds according to summary methylethyl[-amino](9H-purin-9-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)-tetrahydrofuran-3,4-diol procedure £·) formula C^H^N^O,-: Calculated: (%) C 46.9, H 5.7, N 23, Found: (%) C 46.7, H 5.3, N 23,

Table

1) - Examples

0 0 0 0 0 0 0·· 0 0 0 0

000 0 0 ·

0 0 0 0

0 0 0 0 0 0

Example Name::

number :

Detailed experiment.

data, (note 1)

The characteristic analytical member is:

92) (2R,3R,4S,.5S)-2-/6- See below, TLC, SiO .( ethyl- (cyclopentylamino)-9H- (ppp.tup í) acetate with methanol, purin-9-yl)-5-(3-methyl (19:1), -1,2,4-oxadiazol-5-yl)- _Rf ≤ 0.30; tetrahydrofuran-3,4- diol NMR, ( DMSO. ):;

8.43,(1H,s.,.CH),

8.20, (1H, w.s.s.,CH ), 7.79,<(1H, S.d., NH ), 6.45, (2H,v.w.s.,2xOH), 6.16, (1H,d.,CH ),

5.24, (1H,d.,CH),

4.89, (1H, t., CH ), 4.73, (1H, t., CH ),

4.58, (1H, g.m.,CH ), 2.42,, (3H, s.,Me ),

2.10 - 1.50, (8H, m.,

4x ch ₂ );

Table 1) - Examples

Example number : Name :: Detailed experiment, data, (note 1) Characteristic analytical data: 930 (2R,3R,4S,5S)-2-(6- Analog TLC,, SiO ₂ ,(CH ₂ Cl ₂ r £/(1R,2R)-2-h,ydroxy- method according to MeOH :: 880 NH^ ), cyclopentyl1/-amino^- procedure A) (92 8 0.3 ), 9H-purin-9-yl)-5-(5-phenyl-1,3,4-oxadiazole R _f * o,u; 2-yl)-tetrahydrofuran- Analytical evaluation 3,4-diol compounds according to the summary, formula 2^23^7¾ ^t Calculated: (%) G 55.7, H 5.1, N 20.7, Not found: (%) C 55.7, H 5.1, N 20.5J

94) (2R,3R„4S,5S)-2-[6-·. .Analog Analytical evaluation /rel-(1S,5S, _; 6R)-bi- method according to compounds according to summary. cyclo-/3,2,0/-hept-6- procedure G) formula C^H^N^O^. yl-amino-9H-purin-9- 0.5 MeOH ylj-5-(3-methyl-1,2,4 Calculated: (%) oxadiazol-5-yl)-tetrahydrofuran-3,4-diol C 54.5, H 5.9, N 22.8, Found: (%) C 54.2, H 5.7, N 22.65

Table 1)- Examples //

Example number:

Name

Detailed experiment*, data, (note 1)

Characteristic analytical data:

95) (2R,3R,4S,5S)-2- Analogous (o-(rel-(1S,2S,4R)-method according to bicyclo-/2.2.1/-hept- procedure G) 2-yl-amino/-9H-purin9-y 1^-5-(3-methyl 1-1,2,4-oxadiazol-5-yl)tetrahydrofuran-3,4diol

Analytical evaluation of the compound according to the summary* formula C^H^N^O^*0.4H ₂ 0

Calculated : (%)

C 54.25 _, H 5.7 _, N 23.3,

Found: (%)

C 54.4, H 5.7, N 23.1;

96) (2R,3R„4S„5S)-2-(6/rel-(1S,2R,4R)-bicyclo-/2.2.1/-hept 2-yl-amino/-9H-purin-9-yl]-5-(5-(tert-butyl)-1,3,4-oxadiezol2-yl/-tetrahydrofuran-3,4-diol)

Analogous method according to procedure A)

LC/MS, ( System B. ), R _t = 3.18 min.

Mass spectra: (m/z) = 544.0,/WV;

97) (2R,3R,4S _r 5S )-2-(6[rel-(1S,2R,,4B)-bicyclo-/2.2.1/-hept2-yl-amino]-9H-purine-9-yl-5-(5-isopropyl-1,3,4-oxadiazol-2-yl)-tetrahydrofuran3,4-diol

Analogous method according to procedure A)

LC/MS, (System B; ),

R. - 2.66 min. t

Mass spectra:

( _m /z) = 442.0,/MH ⁺ /;

• 0

0» 0000 ··«· • 0 0 0 ·

000 0 0 0 0 0 0 000 0 000 0 0 0 0 0 0 0 000 00 00

T a b l e 1 k. and 1) - Examples Example Name:; Detailed Characteristic number : experiment. analytical data: it is, (note 1) 98) ethyl-4-(^9-/(2R,3R, Analog LC/MS, (System B. 4S,5S)-3,4-dihydroxy- method according to R « 2.47 min. 5-(5-isopropyl-1,3,4- procedure A·.) oxadiazol-2-yl)-tetra- Mass spectra hydrofuran-2-yl1/-9H-pu- (m/z) = 5O3.O./MH ⁺

(6-yl)-amino)-piperidine-1-carboxylate

99) 2-((9-[(2®,3R,4S,5S)-5-hydroxytetrahydrofuran-2-yl)-1,3,4-di-9H-purin-6-yl)amino)-5-methyleth8nesulfonamide Analogous method according to oxadiazol-2-yl/-3,4-di- hydroxytetrahydrofuran-2-yl)-9H-purin-6-yl)amino/-N-methyleth8nesulfonamide

100) (2S,3S, _; 4R,-5R )-2-/5-tert. Analogous butyl)- ¹ ,3,4-oxadiazole method according to -2-yl/-5-(6-(/(1 R,2R)- procedure A')

2-Fluorocyclopentyl/amino-9H-purine-9-yl-4-tetrahydrofuran-3,4-diol

LC/MS, ( System B- ), R ~ 2.32 mih''.

Mass spectra: (m/z) = 483.0,/MH ⁺ /;

LC/MS, ( System B ), R _t = 2.63 min.

Weight profile:

(m/z) = 448.0,/MH ⁺ /',

Table 1)- Examples • 999 9 99 9999 99

999 99 9 999

999 99 9 99

9 9 9 9 9 9 9 9

Example number:

Name:;

Detailed experiment, data, (note 1)

Characteristic analytical data

101) (2S,3S _r 4R , _f 5R )-2-(3-tert.-butyl15-1,2,4oxadiazol-5-yl)-5-(6-(tetrahydro-2H-pyran4-yl-amino)-9H-purin-9yl)-tetrahydrofuran-3,4-diol

Analog LC/MS, (System B), method according to R^ = 2.53 min. procedure G)

Mass spectra: (m/z) ® 446.0,/MH*/J

102) (2R,3R„4S, _: 5S)-2.{6[rel-(1S,2R,4R)-bicyclo-[2.2.1]-hept-2-ylamino[-9H-purin-9-yl]-5-(tert-butyl 1)1,2,4-oxadiazol-5-yl)tetrahydrofuran-3,4-diol

Analog LC/MS,. (System B), method according to R^ ~ 3.03 min. procedure G)

Mass spectra: (m/z) = 456.0,/MH ⁺ /;

ethyl-4-/(9-(?2R,3R,4S, Analogous in 5S)-5-/3-(tert.-butyl) method according to

1.2.4-oxadiazol-5-yl/- procedure G)

3,4-dihydroxytetrahydrofuran-2-yl]-9H-purine

(6-yl)-amino/-piperidine

-1-car boxes of fabric

103)

LC/MS, ( System B- ), R = 2.77 min.

Mass spectrum:

(m/z) = 517.0/MH ⁺ /;

Table 1)- Examples • 44·· • 44 ·

4·4 4

4 4 4

4444 ··

4 4 4 4

4 4 ·

4 4 4 4 ·· 44 ·4 444

Example; number :: Name :: Detailed experiment, data, (note 1) Characteristic analytical data:: 10.4) 2-(9-((2S _r 3R,4S "5SÚ-5 /3?» (tert,-butyl)-isoxazol-5-yl)-3,.4-dihydroxy tetrahydrofuran-2-yl, -9H-purin-6-yl)smino/-N-methylethane sulfonamide Analog method according to procedure I) LC/MS (System A) _r - 3.76 mm. Mass spectra: (m/z) = 482.0 _r /MH ⁺ /;

105,) (2S',3S,4R _r 6R )-2-(3> tert -butyl)-isoxazol-5-yl-/-5-(6-(/(1S,,2S1)-2-fluorocyclopentyl/amino^-9H-purin-9-yl)tetrahydrofuran:-3,4-diol Analog method according to procedure L) LC/MS,. (System A),. R _t - 4.20 min. Mass spectra:: (m/z) = 447 _ø O,/MH ⁺ /; 106) ethyl-4-/(9-((2R,3B _r 4S, Analog LC/MS (System A), 5S )-5-/3:- (tert., -butyl) method according to R^ = 4.06 min. isoxazol-5-yl/-3,4-di- procedure L) hydroxytetrahydrofuran Mass spectra:: -2-yl\ -9H-purin-6-yl)- (m/z) = 516.0./MH ⁺ /;

8-mino/-piperidine-1-carboxylate ····

99

9 9

9 9

9 · • 9 9 9

9 9

Taboo 1 k. a

Example number:: N. a s e v Detailed experimental data, (note 1) Characteristic analytical data:: 107) (2S,3S,4R,5R)-2-/3- Analog LC/MS (System A), (tert-butyl)-isoxa- method according to R = 4.18 min. zol-5-yl/-5-/6-(cyclo- procedure 1) pentylamino') -9H-purine- Mass spectra: t 9-yl/-tetrahydrofuran- (m/z) = 429.0,/MH/; 3 _r 4«-diol

108) (2S ,.3S ,.4R,.5R)-2- (5- Analogous LC/MS,. ( System E ), cyclopropyl-1,3, _: 4-ox8- method acc R = 2.28 min. diazol-2-yl)-5-(6-(te- procedure A) tetrahydro-2H-pyrene-4. Mass spectra:: -y1-amino)-9H-purine- (m/z) = 430.0./MH ⁺ /; 9-yl/-tetrahydrofuran -3,4-diol

109) (2S,3S,4R,.5R) -2-(5- Analog LC/MS, (System D), cyclopentyl-1,3,4-oxa- method according to R = 2.59 minutes. diazol-2-yl)-5-(6-£/(1S procedure A) 2S,.)-2-hydroxycyclopentene- Mass spectrum: ty l/-aminoV -9H-purin-9- (m/z) = 458.0,/MH ⁺ /; y1)-tetrahydrofuran-3,4 -diol

Π

I 8. b a 1 k

4* »444

444 4 4 4 4 4 > 4 4 4 4 4 4 4 4

4 4 4 4 4 4

Example Name::

number ::

Oj)e thyl-4-({9-(2R,3R„4S,5S;)-5-(5-cyclopentyl-1,

3 ₁ 4-oxadiazol-2-yl)-3,4-dihydroxytetrahydrofuran-2-yl[-9H-purin-6yl]amino.;)*piperidine-1carboxylate

111) C2S',,3S„4R„5R)-2-(5-cyclopentyl-1,3,4-oxadiazol-2-yl)-6-(6-(/(1R,2R)-2-fluorocyclopentylamino^ -9H-purin-9-yl)-tetrahydrofuran-3,4-dial

112) (2R, 3R _{, 4S} ,,.5S)-2-[6-(4chloro-2-fluoroaniline)9H-purin-9-yl]-5-(5cyclopropyl-1,3,4-oxadiazol-2-yl)-tetrahydrofuran-3,4-diol and 1) - Examples

Detailed Characteristic experiment, analytical data: data,.

(note 1)

Analog LC/MS, (System D. )„ method according to R^ = 2.82 min.

procedure A-)

Mass spectrum (m/z) = 529.0,/MH ⁺ /J

Analog LC/MSy (System ES), method according to R^ = 2.93 mim.

procedure A-)

Mass spectra: (m/z) = 460.0 (MH+);

Analog LC/MS), (System Eb), method according to R^ - 2.84 min. procedure A)

Mass spectra :: (m/z) = 474.0,/MH ⁺ /;

Τ a b u 1 k a 1 ) - Examples

Example number ::

Name::

Detailed experiment, data is, (note 5).

Characteristic analytical data:

113) (2R,.3R _r .4S _r 5S-)«2-(6-N?chloro-2-fluoroaniline)9H-purin-9-yl)-5-(5-cyclopentyl-1,3,4-oxadiazol-2-yl)-tetrahydrofuran-3,4-diol

Analogous method according to procedure A')

LC/MS', (System B), R _t = 3.05 min.

Mass spectra: (m/z) = 5O2.0,/MH7;

114) (2S,.3S£,,4R _r 5E,)-2-/5- .Analogous (tert.-butyl)-1,3,/--oxa- method according to diazol-2-yl-/-5-/6-(2- fluoroanilin)-9H-purin9-yl/-tetrahydrofuran3,4-diol

115) (2S,3S,4R,.5R)-2-/5- Analogous (tert-butyl)-1,3,4-0X8- method according to diazol-2-yl/-5-/6-(2,3- procedure A) difluoroaniline)-9H-purin9-yl/-tetrahydrofuran3,4-diol

LC/MS,. (System D), R^ = 2.88 min*

Mass spectra: (m/z) = 456 _f 0,/MH*/·

LC/MS, (System D), R = 2.96 min.

Mass spectra: (m/z) = 474.0,/MH ⁺ /;

• · · ·

Table

1) - Examples

Example Name number:

99 9 9

999

Detailed Characteristic experiment, analytical data:: data* (note 1)

1 16) (2S _r 3S„4B„5R)-2-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)-5-(6-(2chloro-4-fluoroaniline)9H-purin-9-yl)-tetrahydrofuran-3,4-diol Analog method according to procedure A) LC/MS', (System D), - 3.05 min. Mass spectra: (m/Z) * 490.0,/MH ⁺ /; 117) (2S,3S*4R„5R)-2-/5- Analog LC/MS* (System D), (tert-butyl)-1,3,4-oxa- method according to R^ - 2.86 min. diazol-2-yl1/-5-/6-(4- procedure A) fluoro-2-methylaniline)- Mass spectra: 9H-purin-9-yl/~tetrB- (m/z) = 470.0,/MH ⁺ /; hydrofuran-3,4-diol

118) (2R„3R, 4S *5R)-2- (2- Analog LC/MS, (System 0), | 2-chloro-6-/(1-ethyl- method according to R - 3.41 minutes. propyl(1)-amino/-9H-purine procedure S) -9-ylj -5-r(5-ethylisoxa- Mass spectra: zol-3-yl)-tetrahydrofuran-3,4-diol. formate (m/z) = 437.0,/MH /'

Table 1)- Examples •9 9999

Example number:

119)

Name:: Detailed experiment, data, (note 1) Characteristic analytical data: (2S,3S,42,520-2-/3- Analog LC./MS, (System C), (tert,Tbutyl)-isoxazole- method according to R - 2.61 minutes. 5-yl/-5-£ 6-/(1,1-dioxide procedure I), tetrahydro-2H-thiopyran~ (last 2 Mass spectrum:: 4-y 1) -amino/-9Hipurine- degrees in '(m/z) = 493.0,/MH+/; 9-ylJ -tetrahydrofuran offered -3,4-diol order )

120)

(2S,35 ,0,520-2-/3- Analog LC/MS ^: , ( System C ), (tert. -butyl)-isoxazole- method according to _Rt ~ 3.29 min. 5-yl/~5-/6- (2-chloro-4i- procedure I) f luorani lin) - 9H-purÍEe~ (last 2 Mass spectra:: 1 9-yl/-tetrahydrofuran- degrees in (m/z) = 489.0,/MH/; 3,4-diol reverse order}

(2S "33,42,520-2-/33- Analog LC/MS, ( System C ), (tert-butyl)-isoxazole- method according to R. « 3.09 min. 5-yl-5-/6-(4-fluoro-2- procedure 1) t ¹ methylaniline)-9H-purine- (last 2 Mass spectra: 9-yl/-tetrahydrofuran. degrees in (m/z) = 469.0,/MHi/;. 3, 4-diol reverse order)

121 ) • · • · «

Table 1) - Examples

Example number ::

DOWNLOAD ::

Detailed experiment.

data, (note 1)

Characteristic analytical data:

122) (2S,3S„4S^,5R)-2-/3I- Analogous (tert.-butyl)-isoxazole- methods according to

-5-yl/-5-/6-(2-chloro- aniline)-9H-purin-9-yl/- (last 2 tetrahydrofuran-?3,4- diol steps in reverse order)

LC/MS, ( System C. ), R^ - 3.25 mm.

Mass spectra: (m/z) = 471.0/473.0/, /MH ⁺ /;

123)

2-/ (9-{ (2R,.3R, 4S, 5S>—5— Analogous /5-(tert-butyl)-1,3, _; 4- method according to oxadiazol-2-yl/-3,4-di- procedure T) hydroxytetrahydrofuran2-71} -9H-purin-6-yl)amino/-N-ethylethanesulfonamide

LC/MS, ( System C ), R _t = 2.52 min.

Mass spectra: (m/z) = 497.0,/MH ⁺ /;

(2S,35,,4R, 5R)-2-/5- Analogous method according to diazol-2-yl/-5-(6-£/2- (ethylsulfony1)-ethyl/amino^ -9H-purin-9-yl/tetrahydrofuran-3,4-diol

LC/MS, ( System C ), E - 2.45 min.

Mass spectra: (m/z) = 482.0,/MH ⁺ /;

124) • ·

η. ..........

I. 8 h u 1 k e 1) — Examples

Example Name number :· Detailed experiment, data* (note 1) Characteristic analytical data:: 125) (2S,3S,4R*6R)-2-/5- Analog LC/MS* (System <L), (tert-butyl)-1,3,4-oxa method according to R^ - 2.60 min* diazol-2-yl/-5~(6-£/2- procedure A) (butylsulfonyl)-ethyl/- Mass spectra: amino^-9H-purin-9-yl) - (m/z) = 51P,O,/Mh7; trihydrofuran-3,4- diol

126) 2-(9-( (2R,3R,4S*5S)-5- Analog LC/MS* (System 0), /5-(tert-butyl)-1,3,4- method according to ® = 2.79 minutes. oxadiazol-2-yl/-3,4-di- procedure Ař:) hydroxytetrahydrofuran- Mass spectra: 2-yl[-9H-purin-6-yl]amino[-N-(3-methylphenyl)-ethanesulfonamide (m/z) = 559.0/MH ⁺ /;

t.27) 2- ((9-/ (2R*3R ,4S *5S )-3, Analog Mass spectra^ 4-dihydroxy-5-(5-methyl method according to (m/Z) = 44O,O,/MH /, -1,3-oxazol-2-yl)-tetrahydrofuran-2-yl (-9H-purin-6-yl)-amino)-methylethanesulfonamide procedure V) TLGL* SiO ₂ , ( dichloromethane : (ethanol : ammonia )

( 50 :: 8 : 1.0), E _f = 0.21 • ···· ·· ···· ·· · • · · · · · ···· • ··· · · · · · · • · · · · ···· · • ········ ······ ·· ·· ····

1) - Examples

Example number id Name:: • * In detail experiment data (note ú) Characteristic analytical data: 128) 2-/(9-{(2R,,3H„4S„5S)- Analog LC/ _MS (System C), 5-/5-(t,-buty1-1,3, method8 according to R ~ 2.70 min. 4-oxadiazol-2-yl/-3„4- procedure A) dihydroxytetrahydrofuran Mass spectra: -2-ylJ-9H-purin-6-yl)- (m/z) = 545.0/MH ⁺ /; amino/-N*-phenylethane- sulfonamide)

129) (2R,3R,4S,5S)-2-(6-(cyclopentylamino)-9H-purin-9-yl)-5-(3-(methoxymethyl)-1,2,4-oxediazol-5-yl)-tetrahydrofuran-3,4-diol. Analog method according to procedure G) Analytical evaluation of the compound according to the summary formula ^C 18 ^H 23°7°5' 1.2 H ₂ 0, Calculated: (%) C 49.3, H 5.8, N 22.3 Found: (%) C 49.5, H 5.4, N 21.9 130) (2R,3R„4S„5E)-2-/6- Analog Analytical evaluation (cyclopentylamino)-9H- •method according to compounds according to summary. purine-9-yl 1 H -5-(1,5-dimethyl-1H-1,2,4-triezol-3-yl)-tetrahydrofuran>3,4-diol trifluoroacetate procedure X) formula ^C 18 ^H 24 ^N 8°2* GF^CO^HI.5 H ₂ 0: Calculated: (%) C 44.4, H 5.2 _r N 20.7 Found: (%) C 44.4, H 4.8, N 20.4

!

1) - Examples

4444 4 4 4

444 444

4 4 4

4 4 «

444 44 44

Example Name

Number ::

Detailed Characteristic experiment, analytical data:; data, (note 1)

131) (2S,3S,.4R,6R)-2-(5-ethyl-1,3,4-oxadiazol-2-yl)-5-(6-(isopropylamino)-9H-purin-9-yl)-tetrahydrourane-3,4diol

Analogous method according to procedure (E), from intermediate 17) Analytical evaluation of the compound according to the formula C^H^N^O^. 0.1 CH ₂ C1 ₂ , 0.1 H ₂ O: Calculated: (%) C 50.1 , H 5.6, N 25.4, Found: ($) C 50.0, H: 5.7, N 24.7, TLC., SiO ₂ , (dichloromethane :: methanol : ammonia, ) (94 6 : 1 ), R _f = 0.21;

t •4 4444

Table

1)- Examples

Example number :: Name:: Detailed experiment, data, (note 1) Characteristic analytical data: 132) (2R,3R„4S„5S)-2-(6(/(1S,2S)-2-hydroxycyclopentyl/-amino}9H-purin-9-yl)-5-(5methyl-1,3,4-oxadiazol-2-yl)-tetrahydrofuran-3,4-diol Analog method according to procedure A) Analytical evaluation of the compound according to the summary formula C^H^^NyO^. 0.9 H ₂ 0.0.4 EtOAc: Calculated: (%) C 49.1, H 5.8, N 21, Found:: (%) C 48.9, H 5.4, N 21,!

TLC, Si0 ₂ ,( ethyl

acetate: methanol; ( 7 : 1.0 ), R _f = 0.45; 133) (2S,3S,4R,5R)-2-/3- Analog LC/MS, (System C), (methyl)-1,2,4-oxadia- method according to R = 2.9t min. z ol-5-y1/-5-/6-(2-chloro procedure G) -4-fluoroaniline)-9H- Mass spectra: purin-9-yl/-tetrahyd- (m/z) = 448.0,/MH ⁺ /; rofuran-3,4-diol

Table 1)— Examples ·«»· ··· ··

Example Name: number : Detailed experiment, the figure is., (note 1) Characteristic analytical data: 134) (2R,3R,4S,5S)-2-(2~ Analog LC/MS( System ©), 6-chloro-1-ethylpropyl method according to R^ = 3.22 min. -amino/-9H-purin-9-yl )- procedure B) 5-(3-cyclopropyl-1,2,4- and R) Mass spectra: oxadiazol-5-yl)-tetra - (m/z) = 450.0,/MH ⁺ /; hydrofuran-3,4-diol

135) (2S,3S„4E,5R)-2-(3- Analog LC/MS,. (System C), ethylisoxazol-5-yl)-5- method8 according to R = 2.46 min. /6-(tetrahydro-2H-pyran procedure L) -4-yl-8amino)-9H-purin-9 Mass spectra: -yl/-tetrahydrofuran-3,4 (m/z) = 417.0,/MH7; -diol

136) (2S,3S,4R,5R)-2-(3- Analogous LC/MS, (System C), ethylisoxazol-5-yl)-5- method according to R = 2.51 min. (6-(/(1S,2S)-2-hydroxy- procedure L) cyclopentyl/-aminoJ-9H- Mass spectra: 1 purin-9-yl1)-tetrahydro- (m/z) = 417.0,/MH/; furan-3,4-diol

·· ··· ··

Table

1) - Examples

Example N a m e n t number ::

Detailed experiment, the limb is, (note 1)

137) N-ethyl-2-((9-[2R, 3R,,4S,5S)-5-[3-ethyl- isoxazol-5-yl)-3,4-di-hydroxytetrahydrofuran) Analogous method according to the procedure

-2-yl[-9H-purin-6-yl(amino)-ethanesulfonamide

138) ethyl-4-( { 9-/(2R,3R,4S, 5S)-5-(3-ethylisoxazole·- Analogous method according to 5«yl)-3 _t 4-<alihydroxytetra- L) trahydrofuran-2-yl-9Hpurin- 6-ylj -amino(-piperidine-1-carboxylate

Characteristic analytical data:

LC/MS _r System O ,

R = 2.53 minutes.

Mass spectra: (m/z) = 468.0,/MH ⁺ /;

LC/MS, (System C), R = 2.74 min.

Mass spectra: (m/z) = 488.0,/MH+/;

139) (2R,3S,4R,5R)-2-(tert-butyl)-4H-1,2,4triazol-3-yl 1/-5-(6-(tetrahydro-2H-pyrsn-4-ylamino)-9H-purin-9-yl)-1/tetrahydrofuran-3,4diol

Analog LC/MS, (System O method according to R^ = 2.30 min.

procedure P)

Mass spectra: (m/z) = 445.0,/MH ⁺ /;

0000

999

00*0

0 0

0 0 0 0 0 0 0 0 00 00

Table

1) - Examples

Example Name, ::

number ::

Detailed experiment.

data, (note 1)

Characteristic analytical data:

140) (2R,3R,4S,5R)-2-(6-(4-chloro-2-fluoroaniline)-9H-purin-9-yl)-5-(4H,1,2,4-triazol-3-yl)tetrahydrofuran-3,4diol

Analogous method according to procedure Fl

LC/MS,. ( System C ), R - 2.47 min.

Mass spectra: *, (m/z) = 433.0, /MH ⁺ /;

141) (2R,3S„4R;,,5H0-2-(5-iso- Analogous propyl-4H-1,2,4-triezole method according to -3-yl)-5-/6~(tetrahydro procedure F) -2H-pyran-4-yl-amino)9H-purin-9-yl/-tetrahydrofuran-3,4-diol

LC/MS, ( System C ), R = 2.21 min.

Mass spectra: (m/z) = 431.0,/MH ⁺ /;

·· ····

Table

1) - Examples

Example Name: Detailed Characteristic number : experiment data (Note 1) analytical data:

142) (2R,3R, _; 4S, _; 5S )-2-(6-amino-2-chloro-9H-purin-9-yl)-5-(5-methyl-1,3-oxazol-2-yl)-tetrahydrofuran-3,4-diol Analog method according to procedure Q) Analytical evaluation of the compound according to the summary formula C^H^^SígG^Cl. 0.1 cp ₃ co ₂ h ) Calculated:: (%) C 43.54, H 3.63, NI 23.08 Not found: (#) C 43.73, H 3.32, N 23.04 Mass spectra:

(m/z) = 353.0/MH ⁺ /;

143) (2R,3R,4S,5S)-2-/2- Analogous chloro-6-(2-chloro-4- method according to fluoroaniline)-9H-purine- of procedure Q) 9-yl/-5-(5-methyl-1,3?- ox8zol-2-yl)-tetrahydro- furan-3,4-diol LC/MS, (System C), _Rt = 3.19 min. Mass spectra: (m/z) = 482.0,/MH ⁺ /; 144) (2R,3R _r 4S,.5S )-2-/6-(4- Analogous chloro-2-fluoroaniline)- method according to 9H-purin-9-yl/-5-(3- procedure Wb) methylisoxazol-5-yl)-tetrahydrofuran-3,4-diol LC/MS, (System C), R = 2.95 min. Mass spectra: (m/Z) = 447.0,/MH ⁺ /;

• 4 ···♦

4oo • 44·· • 4 4 4 ·

4444 4 · ·

Φ · 4 4 4 • 4 4 4 4 • 44 444 4· ·*

Τ a b u 1 k 8 1)- Examples

Example Name : Number : Detailed experimental. data, (note 1) Characteristic analytical data: 145) (2R,.3R,4S,5S)-2-/6- Analog LC/MS,. (System C), (4-chloro-2-fluoroaniline) method according to R = 3.23 min. 9H-purin-9-yl/-5-(3> procedure Wb) propylisoxazol-5-yl)- Mass spectra: tetrahydrofuran-3,4- (m/z) = 475.0,/MH ⁺ /; diol

146) 2-(9-((2R,3R,4S,5S)-5/3-(tert-butyl)-isoxazol-5-yl)-3,4-dihydroxy tetrahydrofuran-2-yl)-8H-purin-6-yl)-8mino/N-isopropylethanesulfonamide Analog method according to procedure I) LC/MS, (System C), _Rt = 32.75 min. Mass spectra: (m/z) = 510.0./MH ⁺ /; 147) (2R,3R _, 4S,5S)-2-/2-chloro Analog LC/MS,.. ( System 0 ) -6-(tetrahydro-2H-pyran- method according to R = 2.83 min. -4-yl-amino)-9H-purin-yl/Procedure L) -5-(3-ethylisoxazole-5- Mass spectra: y1)-1etrahydrofuran-3,4- (m/z? = 451.0/453.0, t diol /mh ⁺ /;

Table 1)- Examples ··«>· ··<* · · · φ · · · • ··· · · · · · · • * · · ·«·· ·

Example Name: Detailed Characteristics number : experiment, data, (note 1) analytical data: 148) ethyl1-4-( £ 2-chloro- Analogous LC/MS,( System C), 9-/(2R,3R,4S,..5S)-5-(3-method according to ethylisoxazol-5-yl)-3, procedure L) _Rt = 3.10 min. 4-dihydroxytetrahydro- Mass spectra: furan-2-yl/-9H-purin-6 (m/z) = 522.0/524.0, -ylj-amino)-piperidine1-carboxylate /MH ⁺ /J

149) (2R,3R,4S,5S)-2-(2- Analog LC/MS, (System C), 6-chloro-1- (1S,2S)-2- method according to R = 2.81 min. hydroxycyclopentyl 1/- J procedure L) amino}-9H-purin-9-yl)- Mass spectra: 5-(3-ethylisox8zol-5 - (m/z) = 451.0/453.0;< y1)-te tnahydrofunsn- /mh ⁺ /; 3,4-diol

150) (2R,3M.S„5S)-2-(2- Analog LC/MS, ( System C ), ehlor-£«í[/2- (ethyl- method according to R with 2.75 min. sulf ony 1) -ethy V-smino^ procedure L) -9H-purin-9-yl)-5-(3- Mass spectra: ethylisoxazol-5-yl )- (m/Z) = 487.0/489.0, J. tetrahydrofuran-3,4 - /mh/; diol

Table • •9 9 • 99 • ·

9999 • 9 9 · · • 9 9

9 9 9

99

9 9

Λ 9

999

1) - Examples

Example number : Name: Detailed experimental. data, (note 1) Characteristic analytical data: 151) (2R,3R,4S,5S5-2-/2- Analog LC/MS, (System C 5 chloro-6-(4-chloro-2- method according to _Rt = 3.33 min. (fluoroaniline)-9H-purine~ procedure L) 9-yl-5-(3-ethylisoxa- Mass spectra: zol-5-yl)-tetrahydro- (m/z) = 495.0/497.0, furan-3,4-diol /mh ⁺ /;

152) (2R,3R,4S,5S)-2-(2-chloro-6-(2-chloro-4fluoro8niline)-9H-purin9-yl)-5-(3-ethylisoxazol-5-yl)-tetrahydrofuran-3,4-diol Analog method according to procedure L) LC/MS, ( System C ), R - 3.23 min. Mass spectra: (m/Z) = 495.0,/MH ⁺ /J 153) (2R,3R,4S,5S)-2-/2- Analog LC/MS, ( System C ), chloro-6-(2-fluoroaniline) method according to _Rt - 3.08 min. -9H-purin-9-yl/-5-(3- procedure L) ethylisoxazol-5-yl)- Mass spectra: t e trahy d nofura n-3*4- (m/z) = 461.0/463.0, J, diol /mh/;

• ·

Table 1)- Examples

Example Name:

number :

Detailed experiment, facts, (identifier 1)

Characteristic analytical data:

154) (22,3R,4S,5S)-2-/2- Analogous chloro-6-(2-chloroaniline) method according to -9H-purin-9-yl)-5-(3- procedure L.) and thylisoxazol-5-yl)tetrahydrofuran-3,4diol

LC/MS, (System C),

R and 3.22 min.

Mass spectra: (m/z) = 477.0,/MH ⁺ /;

155) (2R,32,4S,5S)-2-(6[(1S,2S)-2-Hydroxycyclopentyl]-amino[9H-purin-9-yl)-5-([3-(hydroxymethyl)-isoxazol-5-yl]]-tetrahydrofuran-3,4-diol

Analog LC/MS, (System C), method according to R^ - 2.25 min. procedure V)

Mass spectra: (m/z) = 419.0/MH ⁺ /;

156) ethyl-4-[(9-[(2R,3H,4S, Analogous

5S)-3,4-dihydroxy-5-method according to (3-(hydroxymethyl)-iso- xazol-5-yl)-tetrahydrofuran-2-yl^-9H-purin-6yl)-amino4o/-piperidine-1carboxylate

LC/MS, (System C),

R = 2.46 minutes.

Mass spectra: (m/z) = 490.0./MH ⁺ /;

• 4

Table 1)- Examples

ΓΛ··«3·Κ>.ϋ·ϋί:Κ·>»Α«·ΛυοΣ^

Example number:

Name:

Detailed experiment, data, (note 1)

44 4 » 4 4

4 4 4

4 4 » · · ·

Characteristic analytical data:

157) (2S,,3S,,4Ry5R)-2-(3- (hydroxymethyl)-isoxa- Analogous method according to procedure V) -5-yl-5-(6-(tetrahydro-2H-pyran-4-ylamino)-9H-purin-9-yl 1/

-tetrahydrofuran-4,4diol

LC/MS, (System C), R - 2.20 min.

in

Mass spectra: (m/z) = 4.19.0,/MH ⁺ /',

158) (2R,3R,4S,5S)-2-(6-(4chloro-2-fluoroaniline)9H-purin-9-yl)-5-(3ethylisoxazol-5-yl)tetrahydrofuran-3,4diol

Analogous method according to procedure L)

LC/MS, (System C-), R = 3.10 min.

Mass spectra: (m/z) = 461.0,/MH ⁺ /;

159) (2R,3R„4S,5S)-2-(6-(2-chloro-4-fluoroaniline)-9H-purin-9-yl)-5-(3ethylisoxazol-5-yl)tetrahydrofuran-3,4diol

Analogous method according to procedure I)

LC/MS, (System G), R = 2.99 min.

Mass spectra: (m/z) = 461.0,/MH /\ • · ·

Table

1) - Examples

Example & number with

CD)

T a m e :: :: Detailed experiment, data, (note 1) Characteristic analytical data (2S,3S,,4R,5K)-2-(3-...... Analog LC/MS, (System £), ethylisoxezol-5-yl)-5- method according to R. - 2.81 min. /6-(2-fluoroaniline)-9H* procedure I) in purin-9-yl/-tetrahydro Mass spectra:: furan-3,4-diol (m/z) = 427.0,/MH ⁺ /;

161 )

162)

(2R,3R,4S"5S)-2-(6-(2chloroaniline)-9H-purin9-yl)-5-yl3-ethylisoxazol-5-yl)-tetrahydrofuran-3,4-diol Analogous method according to procedure L) LC/MS, ( System C), R^ = 2.96 mm. Mass spectra: (m/z) = 443.0,/MH7; (2S,,3S,4R„5R )-2-/5-. Analog LC/MS, (System C.), (tert-butyl)-1,3,4-oxa- method according to R^ = 2.11 min. diazol-2-yl 1 H -5-(6-(piperidin-4-yl-imino)9H-purin-9-yl)-tetrahydrofuran-3,4-diol procedure Y) Mass spectra: (m/z) = 445.0/MH ⁺ /;

163)

(2R,3R,4S„5R)-2-(2- Analog LC/MS,’ (System C), chloro-6-/( 1-ethylpropyl). method according to _Rt = 3.41 min. amino/-9H-purin-9-yl)-5- procedure S) (ethyl soxazol-3-yl)- Mass spectra: tetrahydrofuran-3,4· - (m/z) = 437.0/MH ⁺ /; diol.formate

I • · · ·

That lump

1) - Examples

Example Name:

number ::

Detailed experiment, data, (note 1)

Characteristic analytical data:

164) (2S, ₅ 3S„4E,,5K)-2-(3- Analog LC/MS, ( System C ) bromisoxgzol-5-yl)-5- method according to R^ = 3.22 min. /6-(4-chloro-2-fluoro. - procedure W) anilin)-9H-purin-9-yl/ Mass spectra: -tetrahydrofuran-3,,.4 - (m/z) = 511.0,/MH ⁺ / diol

165) (2R„3E,4S„5S)-2-(6-(4chloro-2-fluoroaniline)9H-purin-9-y1/-5-(3,5-difluorophenyl)-isoxa z ol-5-yl)-tetrahydrofuran-3,4-diol- Analog method according to procedure W) LC/MS, (System C) R _t = 3.55 min. Mass spectra: (m/z) = 545.0,/MH7 166) (2S,3S„4R„5R)-2-/3- Analog LC/MS, ( System © ) (tert-butyl)-isoxazole method according to R^ =2.69 min. -5-yl N -5-(6-N N -(methylsulfonyl)-piperidin-4- procedure Y) Mass spectra:: yl/-aminoj-9H-purine-9y 1)-te tracks droph uran-r3,4-diol (m/z) = 522.0,/MH /

• · · · · · · ·

Table 1)- Examples

Example N a m e n t number ::

Detailed analytical data, (note 1)

Characteristic analytical data

167) (2S,3S*4R,,5E )-2-/3- . Analog LC/MS'* (System C 1, (tert-butyl)-isoxazole- method according to 5-yl/-5-(6-{/1-(propyl- procedure Y) _Rt = 2.90 min. sulfonyl)piperidin-4- Mass spectra: 1 yl(-amino(9H-purin-9yl)-tetrahydrofuren-3,4-diol). (m/Z) = 550.0^/MH /;

168) (2S*3S*4R*5R)-2-(tert-butyl)-isoxazol-5-yl]-5-(6-[[1-(iso-propylsulfonyl)-piperidin-4-yl]-amino|-9H ^? purin-9-yl)-tetrahydrofuran-3,4-diol Analog method according to procedure Y) LC/MS, (System 0) R = 2.87 min. Mass spectra;· (m/z) = 550.0,/MÉ ¹ /; 169) (2S,3S*4R*5H)-2-/3- Analog LC/MS* (System C)* (tert-butyl)-isoxazole- method according to R - 2.77 minutes. 5-yl/-5-(6-^/1-(ethyl- procedure Y') sulfonyl 1)-piperidin-4- Mass spectra: yl(-amino)-9H-purin-9-yl)-tetrahydrofuran-3,4-diol (m/z) = 536.0/MH ⁺ /;

• · · · • · · ·

Table 1)- Examples • · · · · · · · »·· ·· ·· ·· ·· ··

Example Name::

number ::

Detailed experiment.

data, (note 1)

Characteristic analytical data:

170) (2S ,3S ,4R„5R )-2-/3- Analog LC/MS, (System C), (tert.-buty1)-i with οχθ from ol- method according to R^ = 3.60 min:. 5-y1/-5-/2-chloro-6-(4- procedure I) chloro-2-fluoroaniline)- Mass spectra:: 9H-purim-9-yl N -tetrahydrofuran-3,4-diol (m/z) = 524.0,/MH ⁺ /

171 ) (2S _r 3S,4E,,5R )-2-/3- Analogous (ter.-butyl)-isoxazole- methods according to 5-yl/-5-/2-chloro-6-(2- procedure I) chloro-4-fluoroaniline)-9H-purin-9-yl/-tetrahydrofuran-3"4-diol LC/MS, (System O, _Rt = 3.50 min. Mass spectra:' (m/z) = 524.0,/MH ⁺ / 172) 2-/(9-{(2R„3R„4S,5S)-5- Analogous LC/MS, (System G), /3-(tert-butyl)-isoxyl/=c-method according to zol-5-yl/-3,4-dihydro- procedure I) R - 2.94 million» xyte trahy drofuran-2-ylJ Mass spectra:: » -2-chloro-9H-purine-6-yr)- amino/-N-ethylethane- sulfonamide; (m/z) = 53O,O,/MH /

0 0 • · · · · · 0 0 0 ··· ··· ·· ·· ·* ·9·

4ο<ι

Table 1)- Examples

Example Name:: Detailed Characteristic number : experiment. data, _: (note 1) analytical member is:: 173) 2-/(9-{(2R,3R,4S _ø 5S)-5-/3-(tert-butyl)-isoxazol-5-yl/-3,4-dihydro xyte trahydrofuran-2-yl ij 2-chloro-9H-purin-6-yl)aminoZ-NJ-isopropylethanesulfonamide Analog method according to procedure I) LC/MS, (System C), Rt - 3.04 min. Mass spectra: (m/z) = 544.0,/MH ⁺ /;

174) (2S,.3S, _; 4R,5R)-2-/3-(tert. Analogous butyl)-isoxazol-5-yl/-5- method according to /2-chloro-6-(tetrahydro- method 1) 2H-pyran-4-yl1-amino)-9H-purin-9-yl/-tetrahydrofuran-3,4-diol LC/MS, (System C), Rf = 2.96 min. Mass spectrum (m/z) = 479.0,/MH ⁺ /; 175) (2R,,3R,4S,,5S)-2-/6-(4- Analog LC/MS,. (System 0), chloro-2-fluoroaniline) - method according to 9H-purin-9-yl/-5-(3- procedure W) R^ = 3.02 min pyridin-3-yl-isoxazole- Mass spectra: » 5-y1)-tetrahydrofuran- (m/z) = 510.0,/MHI/;

3,4-diol /Μΰ

Τ' 8 ti; u 1 k s Ό - Examples

Example T a m e n t Detailed Characteristic . number :: experiment. data, (note 1) analytical data:: 176) (2R _t 3M ^s r.5S)-2-[6-(4-chloro-2-fluoroaniline)9H-purine>9-y 1/-5-/3-(4hydroxybuty1)-is ox8 z o15-yl/-te trahydrofuran> 3,,4-diol Analogous method according to procedure W) LC/MS, ( Sysrem 0), x 3.-35 min. Mass spectra:.' (m/z) = 5O5.O,/MH ⁺ /

177) (2-/( 9-[( 2R, 3R,.4S _y 5S )-5. Analog LC/MS, (System 0), -3-(tert-butyl)-isoxa- method according to P^/= 2.65 min. zol-5-yl(-3 _r 4-dihydrofuran-2-yl(9H-purin-6-yl)-amino/- procedure I) Mass spectra: (m/z) = 496.0./MH ⁺ /

Ne thyleethanesulfonamide (2R _r 3R„4S _y 5S)-2-(6-(cyclopentylamino)-9Hpurin-9-yl)-5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)-tetrahydrofuran-3,4-diol

Analogous method according to procedure A)

LC/ _MS (System O),

R^ = 2.80 mm.

Mass spectra: (m/z) = 442.0,/MH ⁺ /;

178) ·* · 9 9 ·

Table

1) - Examples

Example Name, number ::

Detailed experiment, data, (note 1)

Characteristic analytical data:

179) (2R„3R„4S,,5S)-2-(6£(1S„2S)-2-hydroxy-.cyclopentyl)-aminoJ-9Hpurin-9-yl)-5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)-tetrahydrofuran-3,4-diol

CD) e thy 1-4-/ < (2R ,3R, 4S ,

5S )-3,.4-Dihydroxy-5-(5-(trifluoroethyl)-1,3,4oxadiazol-2-yl)-tetrahydrofuran-2-yl)-9Hpurin*6-yl)-amino]-piperidin-1-carboxylate

Analog LC/MS, (System C), method according to R^ = 2.48 min?, procedure A)

Mass spectra: (m/z) = 458.0,/),)!:*/;

Analogous _L C/MS, (System C), method according to „ ₌ 2.74 procedure A) ^τ

Mass spectra: (m/z) = 529.0/MH ⁺ /;

N 2 R ,5 S )-2-(6-(4-Chloro-2-fluoroaniline)-6H-purin-9-yl)-5-(5-methyl-1,3,4-oxadiezol-2-yl)-tetrahydrofuran-3,4-diol

Analogous method according to procedure Cc)

LC/MS, (System G),

_Rt - 2.77 min.

Mass spectra: (m/z) = 448.0,/MH ⁺ /;

181 )

M2.

Table 1)- Examples

Example Name number ::

Detailed experiment.

data, (note 1)

Characteristic analytical data

182) (2R,3R,>4S„5S )-2-/6- Analogous method according to 9H-purin-5-yl/-5-(3-cyclopropylisoxazol-5-yl)tetrahydrofuran-3,4diol (4-chloro-2-fluoroaniline)-

LC/MS _r ( System O, R _t - 3.15 mm.

Mass spectra: (m/z) = 473.0,/MH ⁺ /;

183) (2S „35 ,,4R,5 R)-2-/3- Ans logical (tert.-butyl)-isox8zol- method according to

5-y1/-5-[6-(1-butyryl-Procedure Y)piperidin-4-yl)-amino/9[alpha]-purin'-9-yl}-tetrahydroLC/MS, (System C), R _t = 2.74 min.

Mass spectra: (m/z) = 5U.0./MH ⁺ /;

fursin-3,,4-di.ol

184) isopropyl-4-[(9-£(2R,3&, _; . Analogous

4S,,580-5-/3-(teuxE*- method according to butyl)-isoxazol-5-yl/-3, procedure Y)

4-Dihydroxytetrahydrofuran-2-yl N-9H-purine (6-yl)-amino N-piperidine-1-carboxylate

LC/MS,. (System O, R _t - 3.10 min.

Mass spectra: (m/z) = 530.0,/MH ⁺ /;

«· ···· • · · · · · · · · · · · · · · · 99 ·· 99 9

I s b a 1 k a ,) - Examples

Example N a m e :: number :: Detailed experiment, data,, (note 1) Characteristic analytical data: 185?) (2S,.38 ,4-R _r 5S)-2-/3- Analog LC/MS, (System G), (tert.-butyl)-isoxazole- method according to R. - 3.05 min. 5-(6-£/1-(2.2.2-trifluoro procedure Y) at acetyl)-piperidin-4-yl/- Mass spectra: aminoj - 9H-purin-9-yl li- (m/z) = 54O.O./MH ⁺ / tetrahydrofuran-3,4- diol

186) methyl-4-[(9-[(2R,3E,4S55)-5-[3½ (ter.-butyl 1) i s oxa z ol-5-yl]-3,4-dShydroxy tetrahydrofuran -2-yl^ -9H-purin-6-yl)amino/-piperidine-1carboxylate Analog method according to procedure Y) LC/MS, ( System G), R _t = 2.73 min. Mass spectra: (m/z) - 5Ο2,Ο,/ΜΗ ⁺ / 187) (2R, 3B,4S, 5S )-2-/6- (4½ Analog LC/MS, (System G.), chloro-2-fluoroaniline)- method according to R = 2.67 min. 9H-purin-9-y 1/-5- (3- procedure V) (hydroxymethyl)-isoxa- Mass spectra: zol-5-yl/-tetrahydro- (m/z) = 463.0,/MH ⁺ / furan-3,4-diol

T s b u 1 fe s 1) - Examples

Example N a m e :: number- : Detailed experiment*, data, (note 1) Characteristic analytical data:: 188) (2R, 3B,.4S,5S)-2-/6.- (2 Analog LC/MS, (CJ System, -chloro-4-fluoroaniline)- method according to R = 2.56 min. 9H-purin-9-yl/-5-/3>· procedure V) in (hydroxymethyl)-isoxa- Mass spectra: zol-5-yl/-tetrahydro- (m/z) = 463, C 2 H 2 O MH ⁺ /; furan-3,4-diol

189) (2R,3R>4S _r 5S)-2-/6-(2- Analog LC/MS, (System C), (fluoroaniline)-9H-purine- method according to R = 2.40 min. 9-yl/-5-/3>(hydroxy- procedure Know methyl)-isoxazol-5-yl/- Mass spectrometer tetrahydrofuran-3,4 - (m/z) = 429.0,/MH ⁺ /; diol

190) (2R,3R _r 4S _ø 5S)-2-/6-(2- Analog LC/MS, (System O, chloroaniline)-9H-purine- method according to R = 2.54 min. 9-y1/-5-/3-(hydroxy- procedure V) methy1)-isoxazol-5-yl/- Mass spectrum: te trahydrofuran-33,,4-diol (m/z) = 445.0./MH ⁺ /

yyyy

Table 1)- Examples ··♦· ·»·

Example N? n e v :: number :: Detailed experiment, data, (note 1) Characteristic analytical data: 19D (2R.3R,.4S, 53)-2-( 2- Analog LC/MS „ (System C), chloro-6-(/(1S,,2S)-2- method according to = 2.32 minutes hydroxycyclopenty/- procedure Bb) amino^-9H-purin-9-yl)- Mass spectra:. 5-/3-(hydroxymethyl)- (m/z) - 453.0/455.0, isoxazol-5-yl/-tetra~ /mh7; hydrofursn-3,4-diol

192) (2R, _; 3K _r AS ^: ,5S)-2-(2chloro-6-(tetrahydro-2Hpyran-4-yl-amino)-9Hpurin-9-yl1/-5-/3-(hydroxy methyl 1)-isoxazol -5-yl/-tetrahydrofuran3,4-diol Analog method according to procedure Bb) LC/MS, ( System C), Ri - 2.32 min. t Mass spectrum (m/z) = 453.0/455.0, /MH+/J 193) 2-(2-chloro-9-((2R,3R, 4S,5S)-3,4-dihydroxy5-[3-(hydroxymethyl)isoxazol-5-yl]-tetrahydrofuran-2-yl|-9H purin-6-yl)-amino]-Neethylthansulfonamide Analog method according to procedure Bb) LC/MS, (System O, R = 2.32 min. Mass spectra: (m/Z) = 504.0/506.0, /mh ⁺ /;

Τ 8 b u 1 k a ) - Examples

Example Name ::

number ::

··♦« • φφ φφ ·Φ

Detailed experiment.

data, (note 1)

Characteristic analytical data::

194) ethyl-4.-/(2-chloro>9- Analogous LC./MS,. (System O, ^(2R,3S,4S,5S)-3,4-di- method according to = 2.60 minutes. hydroxy-5/-3^ (hydroxy- procedure Bb) methyl)-idoxazol-5-yl/- Mass spectra: tetrahydrofuran>2-yl| - (m/z) = 524.0,/Mffi7; 9H.purin-6>yl)-amino/ - piperidine-1-carboxylate

195) (2R,3R„4S,5S)-2-/2-/2- Analog LC/MS( System C), chloro-6-(4-chloro-2- method according to _Rt = 3, 10 min. fluoEaniline)-9H-purine- procedure Bb) 9-yl/-5-/3-(hydroxy- Mass spectra:: methyl)-isoxezol-5-yl/tetrahydrofuran-3,4-diol (m/z) = 497.0,/W/

196) (2R, 3.R, 4S>5 S) - 2-/2- Analog LC/ _MS (System C), chloro-6- (2-chloro-4- method according to R = 3.02 min. (fluoroaniline)-9H-purine- procedure Bb) 9-y1/-5-/3-(hydroxy- Mass spectra: methyl)-isoxazol-5-yl/- (m/z) = 497.0,/499, tetrahydrofuran-3,4- /mh ⁺ /; dioi

T 8 points at 1 to 8

1) - Examples and

4 · 4

4 4

•

4

Example number:

Name::

Detailed experiment, data, (note 1)

Characteristic analytical data:

197) (2R,3R>4S,.5S)-2-(2-Chloro-6-(2-fluoroanyl)-9H-purin-9-yl)-5-(3-(hydroxymethyl)-isoxazol-5*-yl)-tetrahydrofuran-3,4-diol Analog method according to procedure Bb) LC/MS, (System O, Rf 2.72 min. Mass spectra: (m/z) = 463.0,/MH ⁺ /; 198) (2S,3S„4R,5B)-2-(3> Analog LC/MS, (System C), ethylisoxazol-5-yl)-5- method according to R - 2.57 minutes. /2-methoxy-6-(tetrahyd- procedure L) (2H-pyran-4-ylamino) Mass spectrum: -9H-purin-9-yl/-tetra-r (m/z) = 447.0,/MH ⁺ /; hydrofurane-3,4-diol

199) ethyl-4-[(2R _,3R ,4S)-[(2R,3R,4S)], Analogous LC/MS, (System © ), R = 2.75 min„ 5S)-5-(3-ethylisoxazole method according to ~§>y1)-3,4-dihydroxy- procedure L) the tr8 hydr ofur8n-2-y1/ Mass spectra: -2-Methoxy-9H-purin6-yl(amino)-piperidine-1-carboxylate (m/z) = 518.0/MH ⁺ /;

• 9

Example. Name::

number: ::

··♦· ··♦· • 9 · • · · • « 9 9 • · · ·

99 ///

T, a b u 1 k a

Detailed experiment, data, (note 1)

Characteristic analytical data:

20©) (2S,3S,.4R,520-2-(3.- Analogous ethylisoxazol-5-yl)-5- method according to (6-£/(1S,.2S)-2-hydroxy- procedure L)cyclopentyl/-amino^-2 methoxy-9H-purin-9-yl)tetra8hydrofuran-3*4diol

LC/MS, (System C),

R = 2.66 min. at

Mass spectra: (m/z) = 447.0,/MH ⁺ /;

201) (2S,3S,4R,520-2-(3-ethylisoxazol-5-yl)-5-(6-[2-(ethylsulfonyl)-ethyl-amino]-2-methoxy-9H-purin-9-yl)tetrahydrofuran-3,4diol

Analog LC/MS, (System ©), method according to R^ = 2.42 min~. procedure L)

Mass spectrum: (m/z) = 483.0,/MH ⁺ /;

202) (2R,,32,4S,5S)-2-/6-(2- Analogous chloro-4-fluoroaniline(-2- methoxy-9H-purin-9-yl/- procedure L)

5-(3-ethyl-isoxazol-5-yl)

-tetrahydrofuran-3,4-diol

LC/MS, (System C), E = 3.12 min..

Mass spectrum: (m/z) = 491.0,/MH+/;

Ml

T a b l e 1 k a 1) - Examples

Example. N a m e t :: number :: Detailed experimental. data, (note 1) Characteristic analytical data:: 203) (2S, 3S ,,4-R , 52) -2- (3- Analog LC/MS, (System C), ethylisoxazol-5-yl)-5- method according to R - 2.95 min. /6-(2-fluoroaniline)-2- procedure 2) methoxy-9H-purin-9-yl/- Mass spectra:: tetrahydrofuran-3,4» (m/z) = 457.0,/MH ⁺ /; diol

204) (2R,3R,4S,5S)-2-(6-(4chloro-2-fluoroaniline)-2methoxy-9H-purin-9-yl)-5-(3-ethylisoxazol-5-yl)-tetrahydrofuran-3.',4- diol Analog method according to procedure 2) LC/MS, (System O, _Rt = 3.20 min. Mass spectra: (m/z) = 491.0,/MH ⁺ /; 205) (2S,3S,4R,5R)-2-/3- Analog LC/MS,, (System C), (tert-butyl)-1,2,4- method according to R = 2.53 min. oxadiazol-5-yl1/-5-/6- procedure N) (cyclopropylamino)-9H- Mass spectra: purin-9-yl/-tetrahydro- (m/z) = 402.0,/MH ⁺ /; furan-3,4-diol

42.Ό

Table 1)- Examples

Example N; á z e v :: number: :: Detailed experimental data, _; (note 1) Characteristic analytical data:: 206) ( 2S„3jS;,4®„5R)-2-/5- Analog LC/MS, (System O, (tert-butyl)-1,3,4— method according to R^ « 3.32 min. oxadiazol-2-yl1/-5-/2- procedure Cc) e chlor-6-(4-chloro-2- Mass spectra: (fluoroaniline)-9H-purine- (m/z) = 524.0/MH ⁺ /; 9-yl/-tetrahydrofuran- 3,4-diol

207) (2R,.3R,.4S ,5S )-2-/6- (4- Analog LC/MS (System C), chloro-2-fluoroaniline)- method according to _Rt - 2.96 min. 9H-purin-9-yl-5-(5- procedure Z) isopropyl-1,3,4-oxo- Mass spectra: diazol-2-yl)-tetrahydrofuren-3,4-diol (m/z) = 476.0,/MH ⁺ /;

0000

00

0000 0 · ·

0 ·

0* * *

Detailed experimental data using procedure A):

Intermediate 11)

Preparation of N-(2,2-dimethyl-propionyl)-hydrazide 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

Suspension, prepared by suspending 2.50 g 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, in 100.0 ml,

of 1,2-dimethoxymethane was mixed with 1.10 g of 2,2-dimethylpropionic acid hydrazide and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), and the resulting reaction mixture was heated under reflux for 16.0 hours.

Then the mixture was poured into 250.0 ml of an aqueous solution of citric acid (citric acid = 2-hydroxypropane-1,2,3 tricarboxylic acid), and was subsequently extracted with ethyl acetate. After separating the organic and aqueous phases, the organic layer was washed successively with citric acid and brine, and after drying with magnesium sulfate, it was evaporated in vacuo.

The residue, in the form of a crude product, was purified by flash chromatography using silica gel (Biotage cartridges) and a mixture of ethyl acetate:cyclohexane (65.0:35.0) as eluent.

1.92 g of the desired title compound was obtained as a white solid.

Combined liquid chromatography/mass spectrometry system, (LC/MS’}, (System B):

R = 2.49 minutes,

Mass spectrometry, (m/z) 1 439.0,/MH /;

• 444 4

44 •

·«

4 • 4 • 4

4 4 <

4ZL

Intermediate 2)

Preparation of 2-[6S-(5-tert:.-butyl-/1,3,4/-oxadiazol-2-yl)-2,2-dimethyl-tetrahydro-(3eR,6aS')-furo-/3,4-d//1,3/-dioxol-4Ky1/-6-chloro-9H*-purine

A solution prepared by dissolving 1.30 g of (3aS*4S*6R,6aR)-6-(6-chloro-purin-9-yl)-2,2-dimethyl-1-tetrahydro-furo-/3,4-d//1,3/-dioxole-4-carboxylic acid N-(2,2-dimethylpropionyl)-hydrazide* (obtained in the previous, above-described procedure for the preparation of Intermediate 1), in 15.0 ml of thionyl chloride* was irradiated in a microwave oven at a power of 150.0 W* for 7.0 minutes.

The excess thionyl chloride from the reaction mixture was then evaporated in vacuo* and the residue* in the form of a crude product* was dissolved in 6.0 ml of dried acetonitrile, and the resulting solution was heated under reflux for 3.0 hours. Then, after evaporation of the solvent, the resulting residue was purified by flash chromatography on silica gel, using a mixture of ethyl acetate :: cyclohexane* (35.0 : 65.0 - 40.0 : 60.0) as eluent.

0.645 g of the desired title compound was obtained as a white solid.

LC/MS, (System B):

R^ - 2.86 minutes*

Mass spectrometry, (m/z): 421*0,/MH ⁺ /;

Intermediate product 3)) «··· ·· *··· ··· ··· • ♦ · · «· ··

Preparation of (2S,3S,4R,5E)-2-(5-tert-butyl-[1,3;,4]-oxadiazol-2yl)-5-(6-chloro-purin-9-yl)-tetrahydro-furan-3,4-diol

A total of CD.64 g _of 9-/6S-<5-tert-butyl-/1,3,4/-oxadiazol-2yl)-2,,2-dimethyl-tetrahydro-(3aB,6aS ^: 0-furo-/3,4-d//1,3/-dioxol4S»yl)-6-chloro-9H- _purine (obtained in the previous, above-described procedure for the preparation of Intermediate 2), was reacted at a temperature of 0.0 °C, with a mixture of trifluoroacetic acid and water, (10.0 :: 1.0?), for 5.0 hours, (volume of the mixture 9.0 ml),, and then the reaction mixture was left undisturbed in a refrigerator, at a temperature of 2.0 °C·, over ηοσ.

The reaction mixture was then evaporated under vacuum to a volume of approximately 1.0 ml, and then poured into an ice-cold aqueous solution of sodium bicarbonate, and then extracted 3 times with 50.0 ml of ethyl acetate each time. After separating the organic and aqueous phases, the organic layer was washed with brine, and after drying with magnesium sulfate, it was evaporated under vacuum.

371.0 mg of the desired title compound was obtained as crude product.

LC/MS (System Eb):

R = 2.42 minutes, «I*

Mass spectrometry, (m/z): 381.-0(, /MH,/J

Example 1 8 d 3)

Preparation of (2S,3S„4H,5S)-2-(5-tert-butyl-/1,3,4/-oxadiazol-2yl)-5-/6-(tetrahydro-pyran-4-amino)-purin-9-yl/- tetrahydrofuran-3,4-diol ___________________ • ··*· ·· · • ··· • · • · ··· ··· ·· ···· • · • · • · • · · »4 ·· « * • · • · · • · ·· e

·· ··· ✓2nd

A mixture prepared by mixing 41.0 mg of (2S _, 3S _, 4R, 5R)-2-(5-tert-butyl-[1,3i,4]-oxadiazol-2-yl)-5-(6-chloro-purin-9-yl)tetrahydro-furan-3,4-diol (obtained in the previous, above-described procedure for the preparation of Intermediate 3) with 59.0 mg of 4-aminotetrahydropyran hydrochloride, further with 0.11 ml of diisopropylethylamine, and 5.0 ml of isopropanol was heated under reflux for 15.0 hours.

Then the solvent from the reaction mixture was evaporated in vacuo, and the residue was purified by chromatography on silica gel, using a mixture of ethyl acetate & methanol, (100.0, 0.0 - 90.0, 10.0), as eluent.

37.0 mg of the desired title compound was obtained.

Ζ?'-ϊ .

LO/MS, (System B):

= 2.31 minutes,

Mass spectrometry, (m/z): 446,.O,./MH ⁺ /;

Detailed experimental data using the BS procedure):

Intermediate 40

Preparation of 2-chloro-N-(tetrahydro-pyran-4-yl)-8-adenosine

A mixture prepared by mixing 10.0 g of 4R-acetoxy-5B-acetoxymethyl-2R*-(2,>6-dichloro-purin-9-yl)-tetrahydro-furan-3R-yl acetic acid ester, 5.70 ml of diisopropylethylamine, and 2.02 g _of 4-amino-tetrahydropyra hydrochloride in 200.0 ml of isopropanol was heated at 50.0 °C for 4.0 hours. T

I • · · · · · · · * ·..··..· ·..·

Then, after cooling, the reaction mixture was evaporated in vacuo, and the resulting residue was dissolved in 200.0 ml _of methanol, and the resulting solution was bubbled with ammonia gas for 2.0 hours.

The reaction mixture was then stirred at 22.0°C over a period of 10 min, and after subsequent evaporation in vacuo a brown solid of oily consistency was obtained, which was purified by flash chromatography on silica gel (Merck 93855, using a mixture of dichloromethane:ethanol:880 ammonia (750:8.0:1.0)) as eluent.

7.81 g of the desired title compound were obtained in the form of a slightly brown colored substance of oily consistency.

EC/MS,, ( System B-) ): x 2.24 minutes,

Mass spectrometry, (m/z): 3.8β,./Μ& ⁺ /;

Intermediate 55)

Preparation of £ 6R*-[2-chloro-6~ (tetrahydro-pyran-4-yl-amino)-purin9-yl]-.2 _r 2-dimethyl-tetrahydro-(3aE,68H.)-furo-[3,4-d/-dioxole 4H- yl]-methanol

A solution, prepared by dissolving 7.81 g* of 2-chloro-N-(tetrahydro-pyran-4-yl)-adenosine, (obtained in the previous, above-described procedure for the preparation of Intermediate 4), in 500.0 ml of acetone, was mixed with 14.70 ml of 2,2-dimethoxypropane, 8 with 3.80 g of p-toluenesulfonic acid, and the resulting reaction mixture was stirred at a temperature of 22.0 °C _overnight .

Toilet

A white precipitate formed. The mixture was then evaporated in vacuo, and the residue was partitioned between 700.0 mL of ethyl acetate and 500.0 mL of aqueous sodium bicarbonate solution.

After separation of the organic and aqueous phases, the organic layer was washed twice with 250.0 ml of aqueous sodium bicarbonate solution, _and after drying with sodium sulfate, it was evaporated in vacuo.

7.0 g of a slightly brown-colored substance of foamy character were obtained, which was purified by flash chromatography on silica gel (Merck 9385), using a mixture of ethyl acetate::cyclohexane* (4.0:1.0) as eluent.

5.70 g of the desired title compound were obtained in the form of a slightly yellow, foamy substance.

LC/MS, (System &)::

R^ = 2.68 minutes,

Mass spectrometry, (m/z): 426.0, /MH ⁺ /

Intermediate 6)

Preparation of (3αS*4S,6R,6aR)-6-[2-chloro-6-(tetrahydro-pyran-4-ylamino)-purin-9-yl]-2,3-dimethyl-tetrahydro-furo-[3,4-d//1,3/dioxole-4-carboxylic acid]

A solution* prepared by dissolving 2.50 g of 6-[2-chloro-6(tetrahydropyran-1-yl-amino)-purin-9-yl]-2,2-dimethyl-tetrahydro-(3aB„6aB)-furo-[3,4-d//1,3/-dioxol-4R-yl]-methanol, obtained in the previous* above-mentioned procedure for the preparation of Intermediate 50 J in 90.0 ml of ethyl acetate* was mixed with 60.0 ml of saturated aqueous sodium bicarbonate solution, and the resulting two-phase mixture was stirred rapidly at a temperature of 0.0 °C. _After stirring the mixture for five minutes at a temperature of 0.0 °C, 70.0 mg of potassium bromide was added, followed by 4.60 ml of 2,2,6,6-tetramethyl-1-piperidinyloxy free radical.

Then, to the cooled and stirred mixture, a freshly prepared solution, obtained by dissolving 185.0 mg of sodium bicarbonate in 3.20 ml of sodium hypochlorite and water, was added dropwise over 15.0 minutes. The resulting reaction mixture was then further stirred at 0.0 °C for 2.0 minutes, followed by the addition of potassium bromide twice more.

6,6-tetramethyl 1-1-piperidinyloxy free radical, 8 freshly prepared sodium bicarbonate solution and aqueous sodium hypochlorite solution in the same quantities as mentioned above.

After each addition of the above components, the reaction mixture was stirred at room temperature for 15.0 to 20.0 minutes. Subsequently, the reaction mixture was poured into 400.0 ml of ethyl acetate, and after shaking with 10.0 g of sodium sulfite, it was diluted with 300.0 ml of water, and after separating the aqueous and organic phases, the aqueous layer was acidified with 2N hydrochloric acid solution to pH 1.0 - 2.0, and extracted 2x each with 300.0 ml of ethyl acetate. After separating the organic and aqueous phases, the organic layers were combined with extracts from a second, identical reaction, and then evaporated under vacuum.

4.47 g of the desired title compound were obtained as a cream-colored, foamy substance.

LC/MS (System B):

= 2.81 minutes,

Mass spectrometry, (m/z): 440.0,/MH/;

Intermediate product Τ’)

Preparation of (3aS, 4S, 6B„6aBí)-6-[2-chloro>6-(tetrahydro-pyran-4-yl-amino)-purin9-yl]-2,,2-dimethyl-tetrahydro-furo-[3,4-d//1,.3]-dioxole-4-carboxylic acid N-(2,2-dimethyl-propionyl)-hydrazide

To a solution prepared by dissolving:® 350.0 mg of (3aS _r 4S?,6B _r 6aR)-6-[2-chloro-6-C tetrahydro-pyran-4-yl-amino)purin-9-yl]-2,2-dimethyl-tetrahydro-furo-[3,4-d//1,3/-dioxole-4-carboxylic acid, (obtained in the previous^, above-described procedure for the preparation of Intermediate 6), in 8.0 ml of dried tetrahydrofuran, was added with constant stirring, in a nitrogen atmosphere, and at a temperature of Q;0 °CJ 0.487 ml of diisopropylethylamine.

After 5.0 minutes, 0.098 ml of pivaloyl chloride (2,2-dimethylpropionic acid chloride) was added to the resulting reaction mixture, and the mixture was then stirred at 0.0 °C for 2.50 hours. After subsequent addition of 2,2-dimethylpropionic acid hydrazide in 2.0 ml of tetrahydrofuran, the reaction mixture was continuously stirred at 0 to 22.0 °C over 10 min.

The mixture was then concentrated in vacuo and partitioned between ethyl acetate (2 x 30.0 ml) and saturated aqueous sodium bicarbonate (30.0 ml). After separating the organic and aqueous phases, the organic layer was washed with brine (50.0 ml) and dried over magnesium sulfate, then evaporated in vacuo. The resulting residue was azeotroped with dichloromethane (10.0 ml).

357.0 mg of the desired title compound was obtained as a cream-colored solid.

LC/ffiS, ( System B - 2.76 minutes,

Mass spectrometry, (m/z): 538.0^MH/ *

semi-product S)

Preparation of γ-[6S-(5-tert-butyl-[1,3,4]-oxsdiazol-2-yl)-2,,2-dimethyl-tetrahydro-(3αK,6αS)-furo-[3,4-d//1,3/-dioxol-4R-yl]-2-chloro-9H-purin-6-yl-(tetrahydro-pyran-4-yl)-amine

To a solution prepared by dissolving 150 mg of N-(2 _- dimethylpropionyl)-hydrazide of (3aS,4S,6R,68R)-6-[2-chloro-6-(tetrahydro-pyran-4-yl-amino)-purin-9-yl]-2,2-dimethyl-tetrahydro-furo-[3,4-d//1,3/-dioxole-4-carboxylic acid (obtained in the previous, above-described procedure for the preparation of Intermediate 7) in 1.20 ml of N,N-dimethylformamide and cooled to 0.0 °C, 0.039 ml of phosphorus oxychloride was added under nitrogen atmosphere with constant stirring, and the resulting reaction mixture was stirred at 0.0 °C for 15.0 hours, and then at 1.20 ml of N,N-dimethylformamide. 22.0 °C for 16.0 hours.

After cooling the reaction mixture to 0.0°C, another 0.026 ml of phosphorus oxychloride was added, and the mixture was stirred at 0.0°C for 1.0 hour, and then at 22.0°C for another 20.0 hours.

After subsequent evaporation of the mixture under vacuum, the residue was extracted twice with 30.0 ml of ethyl acetate and 30.0 ml of aqueous sodium bicarbonate solution. After separation of the organic and aqueous phases, the organic layer was dried with magnesium sulfate and concentrated under vacuum to a yellow oily substance, from which, after purification by flash chromatography on silica gel using a mixture of 30.0% ethyl acetate in cyclohexane as eluent, 60.0 mg of the desired title compound was obtained.

LO/MS),, ( System Ač ):

K - 4.41 minutes,

Mass spectrometry, (m/z): 52O.O./MH/;

• ··· · · 4 4 4 4 4 4 • 4 4 · · ·

4·· 44 4 44

444 4 444 4

44 44 444

Example 8)

Preparation of (2S ^? ,3S,4S,5'-2- ((5'tert-butyl-/1,3,4'-oxodiazol2-yl)-5-/2-chloro-6- (tetrahydro-pyran-4-yl-amino)-purin-9yl/-tetrahydro-furan-3',4-diol. formate

A solution prepared by dissolving 60.0 mg of 9-[6S-(5-tert. butyl-[1,3,4]-oxodiazol-2-yl)-2,2-dimethyl-tetrahydro-(3aR,6aR)-furo-[3,4-d/[1,3]-dioxol-4B-yl]-2-chloro-9-Hipurin-6-yl(tetrahydropyran-4-yl)-8-mine (obtained in the previous, above-described preparation procedure of Intermediate 8) in 2.0 ml of a mixture obtained by mixing trifluoroacetic acid and water (10.0:1.0) was stirred at 0.0 °C for 1.0 hour and then at 22.0 °C for 4.0 hours.

The reaction mixture was then evaporated under vacuum, and the resulting residue was azeotropically treated with 6.0 ml of toluene each time. The residue was then purified by preparative high-performance liquid chromatography (gradient profile 5.0 -90.0-%, (II), during

18.50 minutes.

37.0 mg of the desired title compound was obtained as a white solid.

LC/MS',,( System A ):

R = 3.86 minutes,

Mass spectrometry, (m/z): 480.0,/MH/;

Detailed experimental data using the O) ytangasaaagGnL-ťnuTiiíiT procedure

9 9 9 · 9 999 • · 9

999 9 9 9

9 9 9

9 9 9

9 9 9 9 9 9

•FROM?·/

SK eziproduct 9)

Preparation of (3sS,4S,6R,6aR)-6-(6-cyclopentylamino-purin-9-yl)-2,2-dimethyl-tetrahydro-furo-/3,

4-D//1,3/-dioxole-4-carboxylic acid

A solution prepared by dissolving 3.018 g of acid (3aS,

4S,.6K,,6aR)-6-(6-cyclopentylamino-purin-9-yl)-2,2-dimethyl tetrahydro-furo-[3,4-d//1,3/-dioxole-4-carboxylic acid, and 2.66 g, 2-ethoxy-1-ethoxycarbonyl-1,,2-dihydroquinoline, in 120.0 ml, methanol, were heated under reflux for 17.0 hours.

Then the resulting reaction mixture was concentrated under vacuum, and the residue was dissolved in 150.0 ml of ethyl acetate, and the obtained solution was washed 3 times each with 25.0 ml of 0.5M aqueous citric acid solution (citric acid - 2-hydroxypropane1,2,3-carboxylic acid) and then with 50.0 ml of brine, and after drying with magnesium sulfate it was evaporated under vacuum.

The residue, in the form of a white, powdery solid, was purified by column chromatography on silica gel using ethyl acetate:cyclohexane (1.0:1.0) as eluent.

2.32 g of the desired title compound were obtained as a pale yellow solid.

Thin layer chromatography (TLC); SiO^), dichloromethane:methanol:880 ammonia (94.0:6.0, 1.GD). R't _< G>.62;

M ^{e r} e product 1 CC ¹ )

I • 9 · · · · • 9·9 ···

432Preparation of (3aS,4S _6fi ,6aR)-6-(6-cyclopentylamino-purin-9-yl)-2,2-dimethyl-tetrahydro-furo-[3,4-d//1,3i/dioxole-4-carboxylic acid hydrazide

A mixture prepared by dissolving (3aS, 4S*6Ki*6aR)-6-(6-cyclopentylamino-purin-9-yl)-2,2-dimethyl tetrahydro-furo-[3,4-d//1*3/-dioxole-4-carboxylic acid methyl ester (obtained in the previous, above-described procedure for the preparation of Intermediate 9) * 8 0.29 ml* hydrazine hydrate, in 10.0 ml,, methanol* was heated under reflux for 28.0 hours.

Then, after cooling to room temperature*, the reaction mixture was concentrated in vacuo* and the resulting residue was evaporated twice with dichloromethane* (2 x 20.0 ml) to give 0.49 g of the desired title compound as a white solid.

NMR*(S®0):: (nuclear magnetic resonance spectra)

9.40* ( 1H* s.s.* NH ), 8.32, ( 1H,„ s., CH ), 8.20* ( 1H, s.,

CH ), 7.90* ( 1H* w.d.., NH )* 6.35* ( 1H* w.s.,, CH ), 5*28* ( 2H* w.m., 2 x CH')* 4.65* ( 1H* w.s.* CH )* 4.50* ( 1H, w.s., CH ),. 4*20* ( 2H* s.s., NH ₂ ), 2*00 - 1 *550* ( 11h* 2x m. * + s., x CH ₂ + CH ₃ ).

Intermediate 11)

Preparation of cyclopenta 1-/9-( 2,2-dithy 1.-6S-/1,3,4/-oxadiazol2-yi-tetrashydro-(3aR*6aS)-furo-/3,4-d//1,3/-dioxol-4H-yl ) 9f-purin-6-y1/-amine • · • · ·

433

A mixture, prepared by mixing 0.50 g* of (38S, 4S _r 6B,,6aE.)-6-(6-Gyclopentylamino-purin-9.-yl)-2,2-dimethyltetrahydro-furo-[3,4-d//1,3/-dioxole-4'-carboxylic acid hydrazide, (obtained in the previous,, above-described procedure for the preparation of Intermediate 1GD),, and 5.0 ml, (4.45 g), of triethyl orthoformate, was heated under reflux for 48.0 hours. Then, after cooling, the reaction mixture was evaporated, and a brownish-reddish oily substance was obtained, which was purified by flash chromatography* using silica gel,, and a mixture of ethyl acetate :: cyclohexane,/ 3.0 :: 1.0), as eluent.

0.157 g of the desired title compound was obtained as a cream-colored foamy substance.

TLC*(SiO ₂ "mixture of ethyl acetate :: cyclohexane, (3.0 : 1*0 ).

= 0*17**

Example 15)

Preparation of (2B*,3R,4S,5S)-2-(6-cyclopentylamino-purin-9-yl)-5[1,3]*4]-oxadiazol-2-yl-tetrahydro-furan-3,4-diol

To 0.157 g of cyclopentyl-[9-(2,2-dimethyl-6S-[1,3,4]-diazol-2-yl]-tetrahydro-(3sBi*6aS;)-furo-[3,4-d//1 *3/-dioxol-4Ryl)-9Hipurin-6>yl]-amine* (obtained in the previous* above-described procedure for the preparation of Intermediate 11), was added at a temperature of 0.0 °C; 1.50 ml* of trifluoroacetic acid, and 0.15 ml, of water* 8 the resulting reaction mixture was stirred for 2.0 hours.

Then the reaction mixture was poured into 10.0 ml of 8.0% aqueous sodium bicarbonate solution, and this mixture was • ·

extracted 4x with 20.0 ml of ethyl acetate each. After separation of the organic and aqueous phases, the organic layer was dried with magnesium sulfate, and after filtration it was evaporated to dryness, and 0.148 g of a slightly cream-colored foamy substance was obtained, to which 20.0 ml of methanol was added, and the solid was filtered off.

0.46 g of the desired title compound was obtained as a white solid.

TLG.,( SiO ₂ ; ethyl acetate ):

= 0.13;

Analytical evaluation of the compound according to the summary formula σ ₁₆ Η ₁₉ Νγ0 ₄ .0.2 MéOH. 0.10 H^::

Calculated:: C 50.99,- H 5.30, N 25.70, %

Found: C 50.77, H 5,H, N 25.53, %

Detailed experimental data using the procedure,D)

Intermediate 12)

Preparation of (3aS _4S ,6R,6a®)-6-(6chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo-[3,4-d//1,3/dioxole-4-carboxylic acid (2-oxo-butyl)-8-imide

To a solution prepared by dissolving 1.30 g of (3aS,.4S "6B;,,6aR)-6-(6-chloro-purin-9-yl)-2,2-dimethyl-tetrahydrofuro-/3,4-d//1,3/-dioxole-4-carboxylic acid in 30.0 ml of dried "tetrahydrofuran" was added 1.07 ml of triethylamine after cooling to 3.0 °C. After the resulting reaction mixture was stirred at 3.0 °C for 15.0 minutes, 0.56 ml of trimethylacetyl chloride was added thereto, and the resulting suspension was stirred at 3.0 °C for 40.0 minutes. Then, the suspension was added with constant stirring to mixture, prepared by mixing 2-oxobutylamine hydrochloride in 50.0 ml of acetonitrile, containing 2.30 ml of triethylamine.

This mixture was warmed to room temperature, and after stirring overnight it was partitioned between 150.0 ml of ethyl acetate and 100.0 ml of 10% aqueous sodium chloride solution. After separation of the aqueous and organic phases, the aqueous layer was further extracted twice with 100.0 ml of ethyl acetate, and then the combined organic extracts were washed with 70.0 ml of brine, and after drying they were concentrated in vacuo.

1.83 g of a dark red gummy substance was obtained, from which, after purification by silica gel chromatography (Merck 7734), using a mixture of dichloromethane:ethanol:880) ammonia (diameter 250.0::8.0::1.0) as eluent, 1.11 g of the desired title compound was obtained in the form of a yellow-brown foamy substance.

NMR, delta, (CDCl^):

8.68, ( 1H, p., CH ), 8, 27, ( 1H, a., ££H ), 6.73, ( 1H, w, »t ·, NH ), 6.30, ( 1H, d., CH ), 5.64, ( ih, and .a., gh ), 5.46, ( 1H d · d., GH), 4.80, ( 1H, d., CH ), 3.76, ( 2H, ABX, - CH ), 2.26 ( 25, k. , Gfí I ₂ ), 1 ,.65,, ( 3H , p., -oh ₃ ), 1.42, ( 3H , p., -GH ) 0.99, ( 3H, t., GH^).

13) • · φφφφ φφφφ φ

φφφ φ

» φ <

» Φ Φ 4

ΦΦΦΦ

Preparation of 6-chloro-9-[6S-(5-ethyl-oxazol-2-yl)-2,2-dimethyltetrahydro-(3aR,5aS)-furo-[3,4-d//1,3/-dioxole-9H-purine]

To a solution prepared by dissolving 1.05 g 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 (2-oxo-butyl)-amide (obtained in the previous, above-described procedure for the preparation of Intermediate 12), in 60.0 ml of acetonitrile, 1.43 g of phosphorus oxychloride was added with constant stirring, and the resulting reaction mixture was heated under reflux under constant stirring for 5.50 hours.

After the reaction mixture was allowed to stand at room temperature overnight, it was stirred and heated under reflux for another 4.50 hours. Then, after cooling, the reaction mixture was partitioned between 150.0 ml of ethyl acetate and 100.0 ml of 8% aqueous sodium bicarbonate solution. After separating the aqueous and organic phases, the aqueous layer was further extracted with ethyl acetate (1 x 100.0 ml), and then the combined organic extracts were dried and concentrated in vacuo to give 1.80 g of a red gum which was purified by chromatography on silica gel* (Merck 7734) using dichloromethane:ethanolammonia (250.0:8.0:1.0) as eluent.

0.86 g of the desired title compound was obtained as a yellow gummy substance.

TLC* SiO ₂ , ( CH ₂ C1 ₂ : EtOH : 880 ΝΗ _β ; 100 : 8 : 1 ):

_Rf = 0.50;

• ···· ·· 9999 99 · • · 9 4 9 9 « 9 · 9 • 999 99 9 99 9 • 9 9 9 9 9999 9 • * 9999 999

999 999 99 99 99 999

Intermediate 14)

Preparation of (2R,,3R,,4S, 5S)-2-(6-chloro-purin-9-yl)-5-(5-ethyl-oxazol-2-yl)-tetrahydro-furan-3,4-diol

To the cooled (0.0 °C) 6-chloro-9-[6S-(5-ethyl-oxezol-2-yl)-2,2-dimethyl-tetrahydro-(3aB,6aS)-furo-[3,4-d//1,3/dioxol-4R-yl]-9H-purine, (0.85 g), (obtained in the previous, above-described procedure for the preparation of Intermediate 13), was added a cooled (0.0 °C) mixture obtained by mixing 8.20 ml of trifluoroacetic acid and 0.80 ml of water, and the resulting reaction mixture was stirred at 0jO °C for 5.0 hours.

The reaction mixture was then stored in the refrigerator overnight, and subsequently, after concentration under vacuum, a yellow residue was obtained, which was azeotropically treated with a mixture of dichloromethane:ethanol:ammonia (75.0:8.0:1.0) (3 x 40.0 ml) to obtain a yellow liquid (4.0 ml), which was undiluted with 5.0 ml of ethanol and then purified by chromatography on silica gel (Merck 7734) using a mixture of dichloromethane:ethanol:ammonia (100.0:8.0:1.0) as eluent to give 0.355 g of the desired title diol as a pale yellow solid.

NMR, delta,(DMSO 5:

9.00, ( 1H, s., CH ), 8.85,, ( 1H, s.,, CH ), 6.99, ( 1H, pure 1, CH ), 6.10 - 5.90, ( 2H, 2 x w.s., 2 x OH ), 5.05, ( 1H, d.,

CH ), 4.89, ( 1H„ t., OH ),, 4.70, ( 1H„ t.„ CH ), 2.70, ( 2H, dk,, CH ₂ ), 1.20,,, ( 3H, t., CH ₃ ).

Example; 16)

444· • 44 · 9 9 4 · 4 4 • 444 · 4 4 4 4 4 • 4444 4444 4

4 4444 444

444 444 44 44 444

Preparation of (2S,.3S, 1B, 5B)-2-(5-ethyl-oxazol-2-yl)-5-/6-(tetrahydro-pyran-yl-amino)-purin-9-yl/-tetrahydro-furan-3,4-diol

To a solution prepared by dissolving 0.19 g of (2R,3R,4S,5S)2-(6-chloro-purin-9-yl)-5-(5-ethyl-oxazol-2-yl)-tetrahydro-furan-3,4-diol (obtained in the previous, above-described procedure for the preparation of Intermediate 14) in 15.0 ml of isopropanol, 0.30 ml of diisopropylethylamine and 0.135 g of 4-aminotetrahydropyran hydrochloride were added.

After the resulting reaction mixture was heated under reflux for 16.0 hours, an additional 0.20 ml of diisopropylethylamine and 60.0 mg of 4-aminotetrahydropyran hydrochloride were added, and the mixture was heated, with constant stirring, under reflux for an additional 20.0 hours.

The reaction mixture was then cooled and concentrated in vacuo to give 0.80 g of a yellow gummy substance which was purified by chromatography on silica gel (Merck 7734) using dichloromethane:ethanol:ammonia (250.0:8.0:1.0) - (100.0:8.0:1.0) as eluent to give 0.182 g of the desired title compound as a white foamy substance.

Mass spectrometry, (m/z): 417.0,/MH/;

NMR,delta,(CDCl^):

8.27. ), 5.31,, ( 1H, d., OH ), 4.79, ( 2H, m., 2 x OH ), 4.40, ( 1H,. h.s., CH ), 4.02, ( 2H, n.d., 2 x CH, equatorial), 3.57, ( 2H, t., 2 x OH, axial. ), 2.66, ( 20t, k., CH^, 2.07.

0000 0 0 0 0 0 • 000 0 0

0 0 0 0

0 0 0

000 000 00

0000

0 0 • 0 0

0 0 0

0 0

00

Detailed experimental data using procedure E)

Example? 17)

Preparation of (2S,3S,4R,5R)-2-(6-cyclopentylamino-purin-9-yl)-5-(5-cyclopropyl-[1,3,4]-thiadiazol-2-yl)-tetrahydro-furan-3,4-diol

A mixture prepared by mixing 12.0 mg of N-(6R^-(6-cyclopentyl8mino-purin-9-yl) _-2,2 -dimethyl-tetra8hydro-(3aS,6aE)-furo-[3,4d//1,3/-dioxole-4S-carbonyl/-hydrazide of cyclopentylpyrrolidinic acid, with 19.0 mg of Lawesson's reagent, i.e. [2,4-bis-(4-methoxyphenyl)-1,3-dithiyl8-2,4-diphosphetn-2,4<-disulfide, was heated in 2.0 ml of acetonitrile at 80.0 °C for 8.0 hours.

Then, another 40.0 mg of Lawesson's reagent was added to the reaction mixture and the mixture was heated at 70.0 °C for 16.0 hours. After evaporation of the solvent from the mixture, the residue was purified by chromatography on silica gel (Varian Bondelut cartridge) using ethyl acetate :: cyclohexane 20.0 :: 80.0 - 100.0 and ethyl acetate :: methanol (98.2 - 95.5) to give the protected product (31.0 mg).

This material was treated with 1.0 mL of trifluoroacetic acid and 0.10 mL of water, and the resulting solution was allowed to stand at 4.0 °C overnight (19.0 hours). The reaction mixture was then poured into ice-cold aqueous sodium bicarbonate (15.0 mL), and the mixture was extracted three times with 15.0 mL of ethyl acetate. After separation of the organic and aqueous phases, the organic layers were washed with brine, dried over magnesium sulfate, and evaporated in vacuo.

A colorless, gummy substance was obtained, which was purified by automated high-performance liquid chromatography (HPLC ₎ (Gradient profile 30.0 - 60.0%, (II), over 20.0 minutes.

1.33 g of the desired title compound was obtained.

•9 9999 • 999 999 999 • 9999 9999 ·

9 9999 999

999999 99 99 99 999

410

LC/MS (System A):

R = 4.0 minutesJ

Mass spectrometry, (m/z): 43O,O,/MH ⁺ /J

Detailed experimental data using procedure P)

Intermediate 15)

Preparation of (3aS,4S,.6R,6aR)-6-(6-isopropylamino-purin-9-yl)-2,2-dimethyl-tetrahydro-furo-[3,4-d//1,3/-dioxole-4-carboxylic acid

A mixture prepared by mixing 5.82 g of the acid (3aS,4S,6R,

6aR-(6-chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo-[3,4-d][1,3]-dioxole-4-carboxylic acid, with 7.27 ml of isopropylamine, in 20.0 ml of isopropanol, was heated under reflux for 40.0 hours.

Then, after cooling to room temperature, the mixture was concentrated in vacuo, and the resulting residue was partitioned between 75.0 ml of ethyl acetate and 75.0 ml of 0.5M citric acid solution (citric acid = 2-hydroxypropane-1,2,3-tricarboxylic acid). After separating the organic and aqueous phases, the organic layer was washed with citric acid solution (2 x 50.0 ml), and the combined organic extracts were washed successively with 50.0 ml of water and 80.0 ml of brine, and after drying with magnesium sulfate, they were filtered and concentrated in vacuo.

4.49 g of the desired title compound were obtained in the form of a slightly brown colored substance of foamy character.

• ···« • · · • ··· • · • 9 ··) ··«· ·« ·· ··

TEGL, _SiO2 , (ethyl acetate): _Rf = 0.35;

Intermediate 16)

Preparation of (3aS,4S,6R,6aR)-6-[(6-isopropylamino-purin-9-yl)-2,2-dimethyl-tetrahydro-furo-[3,4-d//1,3]-dioxole-4-carboxylic acid methyl ester

A mixture prepared by mixing 4.82 g of (3aS,43,6R,6aR)-6-isopropylamino-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d//1,3/-dioxole-4-carboxylic acid (obtained in the previous, above-described procedure for the preparation of Intermediate 15), and 3.36 g of 2-ethoxy-N-ethoxycarbonyl-1,..2-dihydroquinol, (EEDQ), in 150.0 ml of methanol, was heated under reflux for 60.0 hours.

Then, after cooling to room temperature, the reaction mixture was concentrated in vacuo, and the resulting residue was partitioned between 100.0 ml of ethyl acetate and 75.0 ml of 0.5M citric acid solution (citric acid ~ 2-hydroxypropane-1,2,3-tricarboxylic acid). After separation of the aqueous and organic phases, the aqueous layer was extracted 4 times with 25.0 ml of ethyl acetate each time, and the combined organic extracts were then washed with 50.0 ml of water and 75.0 ml of brine, and after drying with magnesium sulfate, they were filtered, and concentrated in vacuo.

The resulting residue was purified by flash chromatography on silica gel, using ethyl acetate:cyclohexene, (1.0:1.0), as eluent.

3.76 g (desired) of the title compound was obtained as a white solid.

• 4444 • · · 4 * • · * 4 · 4 • 4 4 4 4

4 4 4

444444 44

4 44 44

4

4 4 * 4 4

4 4 4

4 4

44

TLC, SiO _{2 >} (ethyl acetate :: cyclohexane, (1.0 : 1.0): R _f ≤ 0.20;

Intermediate 17)

Preparation of (3aS,4S,6R,6aR)-6-(6-isopropylamino-purin-9-yl)-2,2-dimethyl-tetrahydro-furo-/3,4-d//1,3/dioxole-4-carboxylic acid hydrazide

A mixture prepared by mixing 3.76 g of (3aS,,4S,,6R,6aB)-6-(6-isopropylamino-purin-9-yl)-2,2-dimethyltetrahydro-furo-[3,4-d//1,3/-dioxole-4-carboxylic acid methyl ester (obtained in the previous, above-described procedure for the preparation of Intermediate 16), and 1.26 ml of hydrazine hydrate, in 140.0 ml of methanol, was heated under reflux for 48.0 hours.

After the reaction mixture was cooled to room temperature, it was concentrated in vacuo, and the resulting residue was mechanically worked up and taken up with ethyl acetate.

3.30 g of the desired title compound was obtained as a white solid.

Analytical evaluation of the compound according to the general formula C^H^O^.O^ EtOC:

Calculated:: C 51.0, H 16.40, N 23.80, %

Found Gt 51.5^ H 6.50, N 23.60, %

• 444· «4 «444 44 4 4 4 • 4 • • 4 4 4 4 4 4 44 · • 4 4 4 4 4 4 4 4 • • 4 4 4 44 • 4 4 4

Example; 18)

Preparation of (2R,3R, _4S ,5R)-2-(6-isopropylamino-purin-9-yl)-5-(5-methyl-4H-[1,2,,4]-triazol-3-yl)-tetrahydro-furene-3,4-diol trifluoroacetate.

A mixture prepared by mixing 0.50 g _of (3aS, 4S _, 6R, 6aR)-6-(6-isopropylamino-purin-9-yl)-2,2-dimethyltetrahydro-furo-[3,4-d//1,3/-dioxole-4-carboxylic acid hydrazide (obtained in the previous, above-described procedure for the preparation of Intermediate 17), further 0.24 g of ethyl acetimidate hydrochloride, and 0.55 ml of triethylamine, in 10.0 ml of ethanol, was heated under reflux for 72.0 hours.

Then, after cooling to room temperature, the solvent from the reaction mixture was evaporated in vacuo, and the resulting residue was purified by flash chromatography on silica gel (Merck 9385) using ethyl acetate:methanol (9.0:1.0) as eluent to give 0.37 g of a white solid, which was mixed with 3.60 ml of trifluoroacetic acid and 0.36 ml of water, and the mixture was stirred at 0.0 °C for 6.0 hours.

The resulting solution was evaporated to dryness, and after addition of toluene, the mixture was evaporated again to dryness. The resulting residue was triturated and taken up in ethyl acetate to give 0.41 g of the desired title compound as a white solid.

NMR, (delta*, DMSO):

8.71, ( 1H, w.s., NH ), 8.40 - 8.20, ( 2H, s. + w.s., 2 x CH ), 6.11, ( 1H, d., CH ), 5.00, ( 1H, d., CH ), 4.73, ( 1H, t., CH 4.44, ( 2H, t. + Sm, 2 x CH ), 2.42, (3H, s., CH^ _{1 2?} (6Hý d., 2 x CH ₃ ).

• • ••0 • 0 ···· ·· · 00 • € 0 · 0 « 00 • • •0 • · • • • • • · • 0 • 0 • • 0 0· 00 00 0·

Analytical evaluation of a compound according to its molecular formula ^::

Calculated: C 43.0, H 4.40, N 23.60*%

Found:: C 42.9, H 4.45, N 23.50; %

Detailed experimental data using procedure G)

Between product _t 118)

Preparation of 6-chloro-9-[6S-(3-cyclopropyl-[1,2,4R]-oxadiazol-5-yl)2,2-dimethyl-tetrahydro-(3aR,6aS)-furo-[3,4-d//1,3/-dioxol-4R> yl]-9H1-purine

To a suspension, prepared by suspending 4.17 g of (3eS,4S,6R,6a&bgr;)-6-(6-chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-.d//1,3/-dioxole-4-carboxylic acid, in 80.0 ml of anhydrous tetrahydrofuran, and cooled under a nitrogen atmosphere to a temperature of 5.0) °C, was added 4.68 ml of diisopropylethylamine.

After 10.0 minutes, 1.65 ml of piveloyl chloride was added to the resulting reaction mixture, and this mixture was stirred at a temperature of 0.03 °C for 1.0 hour, and then it was warmed to room temperature over 1.0 hour. After the mixture was cooled again to a temperature of ^5.0 °C, 1.47 g of cyclopropylamidooxime was added dropwise to the mixture, and after the cooling bath was turned off, the mixture was stirred at a temperature of 22.0 °C for 18.0 hours.

The diisopropylethylamine hydrochloride was filtered off and washed with 100.0 ml of tetrahydrofuran. The filtrate obtained was heated under reflux for 10.0 hours, and then, after cooling, was concentrated in vacuo to give a residue which was purified by chromatography on silica gel (Variant Mega Bondelut cartridge) using ethyl acetate:cyclohexane (3:1.0) as eluent.

1.99 g of the desired title compound was obtained as a white solid.

LC/MS), (System B):

S. ss 2.91 minutesj in

Mass spectrometry, (m/z):: , 405*0),/MH /;

Intermediate 19)

Preparation of (2R, 3R*4S*5S)-2-(6-chloro-purin-9-yl)-5-(3-cyclopropyl[1,2,4-t]-oxadiazol-5-yl)-tetrahydro-furan-3,4-diol

A solution* prepared by dissolving 1*99 g* of 6-chloro-9-[6S-(3cyclopropyl-[1*2,4]-oxadiazol-5-yl)-2,2-dimethyl-tetrahydro(3a’*6aS))-furo-[3*4r-d//1,3'/-dioxol-4R-yl]-9H*-purone* (obtained in the previous* above-described preparation procedure for Intermediate 18)* in a cooled mixture obtained by mixing trifluoroacetic acid and water, (9.0 : 1.0), (total 25.0 ml), was kept at 4.0 °C for 20.0 hours. Then the resulting solution was acidified with 200.0 in an ice-cooled bath. ml, saturated aqueous sodium bicarbonate solution, and then it was extracted 3x each with 70.0 ml, ethyl acetate, and the obtained extract was dried with magnesium sulfate, and concentrated in vacuo

The residue, in the form of a brown-colored oily substance, was purified by chromatography on silica gel (Warian Mega Bondelut cartridge), using a mixture of dichloromethane and methanol as eluent (10.0:1.0).

1.29 g of the desired title compound was obtained as a white solid.

Λΐ «Ε t- fcte-.ŮRÍ ue

LC/MS (System B)::

R = 2.42 minutes;

Mass spectrometry, (m/z): 365, Q),/MH ⁺ /J

Example 19)

Preparation of (2S,3S„4S)-2-(3i-cyclopropy1-(1,2,4)-oxadiazol-5>-yl)5-yl)-5-(6-(2S-hydroxy-cyclopent-(S)-yl-amino)-purin-9-yl)-tetrahydrofuran-3,4-diol

To a solution prepared by dissolving 50.0 mg of (2R,3R,4S,5S)-2-(6-chloro-purin-9-yl)-5-(3-cyclopropyl-[1,2,4]-oxodiazol-5-yl)-tetrahydrofuran-3,4-diol (obtained in the previous procedure for the preparation of Intermediate 19 described above) in 5.0 ml of isopropanol, 0.072 ml of diisopropylethylamine and 37.80 mg of trans-(1S,2S)-2-aminocyclopentanol hydrochloride were added, and the resulting reaction mixture was heated under reflux for 48.0 hours.

After cooling to room temperature, the reaction mixture was concentrated to dryness in vacuo, and the resulting residue was purified over solid phase (5.0 g) (Varian Mega Bondelut cartridge, bonded aminopropyl base, and eluted with (I), chloroform; (II), ethyl acetate:cyclohexane mixture (1.0:1.0), (II), ethyl acetate:cyclohexane mixture (IV), dichloromethane:methane mixture (20.0:1.0), (VI), dichloromethane:methanol mixture (10:1.0), and (VII), methanol as extraction agents.

47.30 mg of the desired title compound was obtained.

no/MSy G System B )::

2.37 minutes;

Mass spectrometry,(m/Z)r

430-,®;/mhÍ/;

Detailed experimental data using the procedure »

M e z i p r o d u c t 20)

Preparation of 4-[9-( ^[ 60-carboxy-2,2-dimethyltetrahydro-('3©R, 6aS')-furo-[3,4-d//1 *3/-dioxol-4E-yl)-9H-purin6-yl-amino]-piperidine-H-carboxylic acid ethyl ester

A mixture prepared by mixing 1.80 ml* of ethyl 4-amino-piperidinecarboxylate*, 2*0 g* of (3aS*4S,6R*6aR)-6-(6-chloro-purin-9-yl)2,,2-dimethyl-tetrahydro-furo-[3,4-d//1 ,35]-dioxole-4i-carboxylic acid* and 2.74 ml* of diisopropylethylamine, was heated under reflux in 100.0 ml* of isopropanol* for 70.0 hours.

After cooling to room temperature, the reaction mixture was concentrated under vacuum* and 100.0 ml of water was added to the resulting residue, and this mixture was acidified to pH 4.0 with citric acid (citric acid - 2-hydroxypropane-1,2,3-tricarboxylic acid). The mixture was then rapidly extracted 3x with 50.0 ml* of dichloromethane each time, and the combined extracts were dried with magnesium sulfate and concentrated under vacuum.

2.56 g of the desired title compound were obtained as a yellow solid.

LC/MS* (System B):.

- 2*62 minutes*

9 9 9

Mass spectrometry, (m/z):

477.0,/MH ⁺ /;

MKeziproduct 21)

Preparation of 4-(9-(6S-carbamoyl-2,2-dimethyltetrahydro-(3js®,6aS)-furo-[3,4-d//1,3/-dioxol-4B-yl)-9H-purin-6-yl-amino]-piperidine-1-carboxylic acid ethyl ester

A solution prepared by dissolving 2.56 g of ethyl ester of 4-(9-(6S-carboxy-2,2-dimethyl-1-tetrahydro-(3a®., 6aS)-furo-(3,4d//1,3/-dioxol-4®-yl)-9H-purin-6-yl-amino)-piperidine-1-carboxylic acid, (obtained in the previous, above-described procedure for the preparation of Intermediate 20), in 50.0 ml of anhydrous dichloromethane, was mixed after cooling to 0.0. °C with 0.82 ml of triethylamine and 02.73 ml of pivaloyl chloride.

Ammonia was bubbled through the reaction mixture for 70.0 minutes, then the reaction mixture was evaporated to dryness in vacuo, and the residue, in the form of a crude product, was dissolved in ethyl acetate, washed 3 times with 70.0 ml of water. The solution was then dried over magnesium sulfate and concentrated in vacuo.

The desired title compound was obtained as an orange solid (1.97 g).

LC/MS, (System Eb):

- 2.54 minutes;

Mass spectrometry, (m/Z):: 476.0 (MH ⁺ )\ •··· ·· ···· ·· » · · 9 9 9 9 • · · 9 9 9 9 9

M

Intermediate 22)

Preparation of 4-[9-(6E-(cyano-2,2-dimethyl-(3αR,6αR)-tetrahydro-furo-[3,4-d//1,3/-dioxol-4R»yl)-9H-purin-6-ylamino]-piperidine-1-carboxylic acid ethyl ester

A solution prepared by dissolving 1.97 g of ethyl ester of 4-[9-(6S5-carbylamino-2,2-dimethyl-tetrahydro-(3aH,6aS5-furo[3,4-d//1,3/-dioxol-4R-yl)-9H-purin-6-ylamino]-piperidine-1-carboxylic acid (obtained in the previous, above-described procedure for the preparation of Intermediate 21) in 40.0 ml of anhydrous acetonitrile was mixed with 1.01 g of 4-dimethylaminopyridine, and 1.93 ml of phosphorus oxychloride was added to the resulting reaction mixture, cooled to 0.0 °C, in such a way that the addition proceeded dropwise.

The reaction mixture was then evaporated to dryness in vacuo, and the residue, in the form of a crude product, was dissolved in 50.0 ml of water. The resulting solution was extracted 3 times with 70.0 ml of ethyl acetate each time, and the combined extracts were concentrated in vacuo.

The desired title compound was obtained as a pale orange solid (1.91 g).

LC/MS, (System A):

R^ = 4.09 minutes J

Mass spectrometry, (m/z): 458.0,/MH ⁺ /J

Intermediate 23)

Preparation of 4-4-(9-[6K-(N-hydroxycarbamimidoyl)-2[2-dimethyl-tetrahydro-(3hR,6aR)-fluoro-[3,4-d//1 "3/-dioxol-4B-yl/ 9H-purin-6-yl-amino]-piperidine-1-carboxylic acid ethyl ester

A mixture prepared by mixing 4-(9-(6Rcyano-2,2-dimethyl-(3aR,6aR)-tetrahydro-furo-[3,4-d//1,3/-dioxol4R-yl)-9H-purin-6-yl-amino]-piperidine-1-carboxylic acid ethyl ester (obtained in the previous, above-described procedure for the preparation of Intermediate 22), with 0.29 ml of 50% hydroxylamine, was heated under reflux in the presence of 25.0 ethanol for 9.0 hours.

Then, after cooling, the reaction mixture was concentrated in vacuo, and the resulting residue was coevaporated with 50.0 ml of toluene to give 1.25 g of the desired title compound as a yellow solid.

LC/M5>( System A ):

R - 3.82 minutes;

Mass spectrometry, (m/z): 490 _ø d,/MH ⁺ /;

Intermediate, t 240 Preparation of 4-(9-[61-(5-tert-butyl-[1,2,4]oxadiazol-3-yl)-2,2-dimethyl-tetrahydro-(3feS,.6aR)-furo-[3,4-d//1,3/-dioxol-4R-yl]-9H-purin-6-yl-emino^-piperidine-1-carboxylic acid ethyl ester

A mixture prepared by mixing 1.0 g _of ethyl ester of 49-[6R-(N*hydroxycarbamimidoyl)-2,2-dimethyl-tetrahydro-(3aR, aR)-furo-[3,4-d//1,3/-dioxol-4R-yl]-9H-purin-6-yl-amino]-piperidine-1-carboxylic acid (obtained in the previous, above-described procedure for the preparation of Intermediate 23), further 15.0 ml of pivalic acid (pivalic acid,'e 2,2-dimethylpropanoic acid), and 0.49 ml of pivalic anhydride, was stirred first at room temperature for 2.0 hours, and then heated under reflux for 9.0 hours.

After subsequent cooling of the reaction mixture, the residue was mixed with 100.0 ml of saturated aqueous sodium bicarbonate solution, and this mixture was extracted 4 times with 100.0 ml of ethyl acetate. The combined extracts were dried with magnesium sulfate and concentrated in vacuo. 100.0 ml of diethyl ether was added to the resulting residue, and the brown precipitate that formed was filtered off, and the filtrate was concentrated in vacuo to give the crude product, which was purified by chromatography on silica gel using a Varian Mege Bondelut cartridge, eluting with ethyl acetate.

0.360 g of the desired title compound was obtained as a slightly orange-colored oily substance.

LC/MS, (System B):

= 3.13 minutes.

Mass spectroscopy, (m/z): 557.0./Mh! ^H /*.

Example, 26)

Preparation of 4-[9-[5R-(5-tert-butyl-[1,2,4]oxadiazol-3-yl]-3R,4S-dihydroxy-tetrahydro-furan-2R-yl]-9H-purine piperidine-1-carboxylic acid ethyl ester

Solution, prepared by dissolving 360.0 mg of ethyl ester of 4-(9-[6R-(5-tert-butyl-[1,2,4]-oxodiazol-3-yl)-2,2-dimethyltetrahydro-(3aR,6aR)-furo-[3,4-d//1,3/-dioxol-4R-yl]-9H-purin-6• 9 · •999 99 9 99 9 • 9 · 9 9 9 999 9 • 9 9 · · 9 · 9 9

999 999 99 9· 99 999 yl-amino-piperidine-1-carboxylic acid, (obtained in the previous, above-described procedure for the preparation of Intermediate 24), in a cooled mixture (5.0 ml), trifluoroacetic acid and water, (9.0j :: 1*0), was cooled to a temperature of 0.0 °C and left at this temperature for 20.0 hours.

The resulting reaction mixture was then neutralized with 70.0 ml of ice-cold saturated sodium bicarbonate solution, and then extracted 3 times with 50.0 ml of ethyl acetate each time. The combined extracts were dried with magnesium sulfate and concentrated in vacuo.

Preparative high-performance liquid chromatography (HPLC) was performed on a Supelcosil LC-ABZ column, (size 21.2 mm x 10.0 cm), using a flow rate of 8.0 ml/min. (eluents were: A): 0.1% trifluoroacetic acid/water E£) 0.01% trifluoroacetic acid in a mixture of acetonitrile:water, (95.0:5.0), (gradient profile 15.0-95.0%), B), for 25 minutes);

6.90 mg of the desired title compound was obtained as a white solid.

LC/MB* (System B):

R - 2.76 minutes;

Mass spectrometry, (m/z): 517.0,(MH ⁺ );

Detailed experimental data using procedure I)

Intermediate 25)

I I

• 0 0 0 0 0 0 · 0 · 0 ·0 0 0 0 · · · 0 0 0

0 0 0 0 0 · · 0 0 0000 0000

Preparation of (3aS _r 4S,6R,6aR)-6*imethoxy-2,2-dimethyl-tetrahydro-furo-/3,4-d//1,3/-dioxole-4-carboxylic acid methoxy-methyl-amide

To a solution prepared by dissolving 11.0 g of (3eS "4S _r 6R "68R)-6?-methoxy-2,2-dimethyl-tetrahydro-furo-/3,4-d/ /1,3/-dioxole-4-carboxylic acid in 100.0 ml of dichloromethane was added portionwise, at a temperature of 22.0 °C, over 10.0 minutes,

8.47 g of carbonyldiimidazole were added, and the resulting reaction mixture was stirred at 22.0°C for 0.5 hour.

Then, Ν,Ο-dimethylhydroxylamine (12.5 g) dissolved in 50 ^ml of water, 8 further 20.0 ml of 10N sodium hydroxide solution was added to the mixture, and this mixture was extracted 3 times with 50.0 ml of dichloromethane each time. The combined dichloromethane extracts were dried with sodium sulfate, and filtered, and the resulting solution was added to the solution prepared above. After subsequent stirring for 3.0 days, the reaction mixture was washed with 200.0 ml of citric acid (Citric acid = 2-hydroxypropane-1,2,3-tricarboxylic acid), and then with 8.0% sodium bicarbonate solution (200.0 ml), and after drying with sodium sulfate, it was dried under vacuum.

14.20 g of the desired title compound were obtained as a colorless oily substance.

Thin layer chromatography, (TLCL), Si0 ₂ , ether:

_Rf = 0.33;

Intermediate 26)

Preparation of 1-(6R-methoxy-2,2-dimethyl-tetrahydro-(3aS,6aR)-furo / _3ff3 /-dioxol-4S-yl)-4,4-dimethyl-pent-2-yn-1-one ··· 4 4 · 4 4 4 4

4 4» 4 4 · 44 · * 4 4 4 4 4444 4

444444 44 44 44 444

To a solution prepared by dissolving 3,3-dimethyl-1-butyne in 90.0 ml* of tetrahydrofuran, a 3.0M solution of methylmagnesium chloride in 50.0 ml* of tetrahydrofuran was added under a nitrogen atmosphere and at a temperature of 0.0 - 5.0 °C*, and this mixture was stirred at a temperature of ΟφΟ to 5.0 °C* for 5.0 hours.

To the above prepared mixture was then added over 20.0 minutes, at a temperature of 0.0 - 5.0, a solution obtained by dissolving 14.17 g of (3aS,.4S, _; 6aR,)-6-methoxy-2,2-dimethyl tetrahydrofuro-[3,4-d//1,3/-dioxole-4-carboxilic acid methoxymethylamide in 20.0 ml of tetrahydrofuran, and this reaction mixture was stirred at a temperature of 0.0 - 5.0 °C for 2.0 hours.

Then, after mixing the reaction mixture with 150.0 ml of 30.0% ammonium chloride solution and 15.0 ml of 2M hydrochloric acid solution, the mixture was extracted twice with 50.0 ml of ethyl acetate each time. The combined organic extracts were then dried over sodium sulfate and evaporated in vacuo, and the resulting residue was purified by flash chromatography on silica (150.0 g), using cyclohexane:diethyl ether (2.0:1.0) as eluent.

4.01 g of the desired title compound were obtained as a colorless solid.

TLC, _SiO2 , (ether):

_Rt = 0.55*

Intermediate 27)

Preparation of 1-(6R-methoxy-2,2-dimethyl-tetrahydro-(3as,6eR)-furo[3,4-d[/1,3]-dioxol-4S-yl)-dimEthyl-pentan-1,3-dione-3-oxime

9 9 9 9

999 • 9 9 • 9*9 * 9 9

9 9

9 9

9 9 9 9

To a solution prepared by dissolving 573.0 mg of 1-(6R-methoxy-2,2-dimethyl-tetrahydro-(3aS, 6aR)-furo-(3,4-d//1,3/-dioxol-4S-yl)-4,4-dimethyl-pent-2-yn-1-one ₍ obtained in the previous, above-described procedure for the preparation of Intermediate 26), in 6.0 ml of methanol, 0.19 ml of a 50% aqueous solution of hydroxylamine was added.

After the resulting reaction mixture was allowed to stand at 23.0 °C for 5.0 hours, it was concentrated in vacuo and, after dilution with 10.0 ml of water, was extracted twice with 15.0 ml of water each time. The combined extracts were dried with sodium sulfate and evaporated in vacuo.

0.635 g of the desired title compound was obtained as a colorless substance of oily consistency.

TLC, SiO ₂ , (cyclohexane : diethyl ether,, 3.0 : 2.0):

_Rf = 0.16*,

Intermediate 28)

R-properties of 4R-acetoxy-2S-(3-tert-butyl-isoxazol-5-yl)-5-methoxytetrahydrofuran-3R-yl-acetic acid ester

To a solution prepared by dissolving 632.0 mg of 1-(6R-methoxy-2,2-dimethyl-tetrahydro-(3aS,6aR)-furo-[3,4-d//1,3/-dioxole-4Syl)-4,4-dimethyl-pentane-1,3-dione-3-oxime, (obtained in the previous, above-described procedure for the preparation of Intermediate 27), in 15.0 ml of methanol, was added 1.0 ml of concentrated hydrochloric acid, and the resulting reaction mixture was heated under reflux in 10.0 ml of pyridine, to which was added 1.0 mg of 4-dimethylaminopyridine, and 2.0 ml of acetic anhydride.

««··

999

The resulting reaction mixture was then allowed to stand at 22.0 °C for 3.0 hours, and then the solvents were removed in vacuo. The residue was dissolved in 100.0 mL of ethyl acetate, and after washing the resulting solution with 50.0 mL of 8.0% sodium bicarbonate solution, the solution was dried over sodium sulfate, and evaporated in vacuo.

575.0 mg of the desired title compound was obtained as a pale yellow gum. Mass spectrometry (m/z): 342.0/MH ⁺ /;

Intermediate 29)

Preparation of 4R-8-cetoxy-5S-(3-tert-butyl-isoxazol-5-yl)-2R-(6-chloropurin-9-yl)-tetrahydro-furan-3R-yl-acetic acid ester

A mixture prepared by mixing 1.36 g of 6-chloropurine, 26.0 ml of toluene, and 10.0 ml of hexamethyldisilazine was heated under a nitrogen atmosphere, under reflux, for 2.0 hours. Then, after evaporation of the reaction mixture under vacuum, the resulting residue was co-evaporated with 12.0 ml of dried toluene, and then, after removal into dried acetonitrile (20.0 ml), 1.01 g of 4R-acetoxy-2S-(3-tert-butyl-isoxazol-5-yl)-5-methoxy-tetrahydrofuran-5R-yl acetic acid ester (obtained in the previous, above-described procedure for the preparation ^{of Intermediate} 26) and 1.80 ml of trimethylsilyl trifluoromethanesulfonate were added to the resulting solution, and the resulting reaction mixture was heated under reflux under a nitrogen atmosphere for 5.0 hours.

Then the reaction mixture was cooled, and poured into 150.0 ml,

8% sodium bicarbonate solution, and then the mixture was extracted twice with 100.0 ml of ethyl acetate. The combined extracts were then • ··«· >4 ···· ·9 4 • · * · « · 4 · · 4 • 4·· 4 4 · «44 • »444 44·· 4 • 4 444· 44 4

444 444 44 44 44 444 dried with sodium sulfate, and evaporated in vacuo. The residue was purified by flash chromatography on silica, using a mixture of cyclohexane:ether, (1.0:1.0 - 1.0:4.0), as eluent.

0.953 g of the desired title compound was obtained as a colorless, foamy substance.

LC/MS, (System A):

= 4.35 minutes}

Example 27)

Preparation of (2S, 3S, 4R, 5R ⁾ -2-(3-tert-butyl-isoxazol-5-yl)-5-[6(2S-hydroxy-cyclopent-(S)-yl-amine)-purin-9-yl]-tetrehydro-furan-3,4-diol

To a solution prepared by dissolving 70.0 mg of 4R-acetoxy-5S-(3-tert-butyl-isoxazol-5-yl)-2R-(6-chloro-purin-9-yl)-tetrahydrofuran-3R-yl acetic acid ester (obtained in the previous, above-described procedure for the preparation of Intermediate 26), and 62.0 mg of trans-(1S, 2S)-2-aminocyclopentahol hydrochloride, in 10.0 ml of isopropanol, 0.16 ml of diisopropylethylamine was added, and the resulting reaction mixture was heated under reflux for 17.0 hours.

Then, after evaporation of the solvent from the reaction mixture, under vacuum, the resulting residue was dissolved in 7.0 ml of saturated methanolic ammonia solution, and this mixture was left to stand for 3.0 hours. Then, after removal of the solvent under vacuum, the residue was purified by chromatography on silica, (5.0 g), using ethyl acetate:methanol, (10.0:1.0), as the eluent.

• ···· ·· «· · · · « • ··· · · · · • · * · · · • · ♦ · · ·

999999 99 99 ♦ ·· · • 9 99

9 9

9 9

9 9

99 9

After subsequent purification by autopreparative high-performance liquid chromatography (HPLC), 40.0 mg of the desired title compound was obtained as a colorless gummy substance.

LC/MS, (System A):

R - 3.81 minutes

Mass spectrometer (m/z): 445.0 (MH);

Example 2a) ^Preparation of (2S,3S,.4R,.5R)-2-(3-tert-butyl-isoxazol-5-yl)-5-[6(tetrahydro-pyran-4-yl-amino)-purin-9-yl]-tetrahydro-furan-3,4-diol

To a solution prepared by dissolving 70.0 mg of 4R-acetoxy-5&apos;(3-tert-butyl-isoxazol-5-yl)-2R-(6-chloro-purin-9-yl)-tetrahydrofuran-3R-yl acetic acid ester (obtained in the above-described preparation of Intermediate 26) _, and 62.0 mg _of 4-aminotetrahydropyran hydrochloride in 10.0 ml of isopropanol, 0.16 ml of di-isopropylethylamine was added, and the resulting reaction mixture was heated under reflux for 17.0 hours.

Then, after removing the solvent from the mixture under vacuum, the residue was dissolved in 7.0 ml of saturated methanolic ammonia solution, and the resulting solution was allowed to stand for 3.0 hours. Then, the solvent was removed under vacuum, and the residue was purified through solid phase using a Varian Bondelut cartridge with aminopropyl bonded, and a mixture of ethyl acetate:methanol, (10.0:1.0), as eluent.

44 4 •

444 ·· 4

4 4

4 4 · · 4

44 ·

4

4

4

4

Further purification by autopreparative high performance liquid chromatography afforded 31.0 mg of the desired title compound as a colorless, gummy substance.

LC/MS, (System A):

R t - 3.78 minutes;

Mass spectrometry, (m/z): 445,,O,/MH ⁺ /;

Detailed experimental data using procedure J)

Intermediate 3®)

Preparation of (E)-3-dimethylamino-1-(6R-methoxy-2,2-dimethyl-1-tetrahydro-(3sS,6aR)-furo-/3,4-d//1,3/-dioxol-4S-yl)-pe openenone

To a solution prepared by dissolving 0.62 g of 1-(6B-methoxy-2,2-dimethyl-tetrahydro-(3sS _F 6aR)-furo-/3,4-d//1,3/-diox-4S yl)-ethanone in 25.0 ml of toluene, 5.0 ml of dimethylformamide dimethyl acetal was added. The resulting reaction mixture was heated under reflux under a nitrogen atmosphere for 17.0 hours.

Then, after removing the solvents from the reaction mixture under vacuum, the resulting residue was purified by flash chromatography using 30.0 g of silica and ethyl acetate as eluent.

0.102 g of the desired title compound was obtained in the form of a yellow-colored substance of gummy character.

9999

9 99 9

999 9 9 9

9 9 9 9 9

9 9 9 9 9

999 999 99 99 ·♦ 9999

Mass spectrometry, (m/z):

272.0, (MH+);

Intermediate 31)

Preparation of 5-(6R-methoxy-2,2-dimethyl-tetrahydro-(3aB,6aR)-furo[3,4-d//1,3/-dioxol-4R-yl)-1H-pyrazole

To a solution prepared by dissolving 102.0 mg of (E)-3-dimethylamino-1-(6R-methoxy-2,2-dimethyl-1)-tetrahydro-(3aR, 6aR)-furo[3,4-d//1,3/-dioxol-4S-yl)-propenone (obtained in the previous, above-described procedure for the preparation of Intermediate 30), in 15.0 ml of methanol, 0.50 ml of hydrazine hydrate was added, and the resulting reaction mixture was heated under reflux for 1.5 ^W hours.

The solvent was then removed from the reaction mixture in vacuo, and the residue was purified by flash chromatography on silica gel using diethyl ether as eluent.

47.0 mg of the desired title compound was obtained as a colorless gummy substance.

Mass spectrometry, (m/z): 241, OJ/MH ⁺ /J

Intermediate 32)

Preparation of 4R-scetoxy-2R-(1-acetyl-1H-pyrazol-3-yl)-5R ^> -methoxytetrahydrofuran-3R-yl acetic acid ester • ···· ·· 4444 44 ·

4 4 44 4 4444

444 444 444

4444 4444 4

4 4444 · 4 4

444 444 44 44 444

A solution prepared by dissolving 1.66 g of 6-(6R-methoxy-2,2-dimethyl-tetrahydro-(38R,6aR)-furo-[3,4-d//1,3/-dioxol-4R-yl)1H-pyrazole, (obtained in the previous, above-described procedure for the preparation of Intermediate 31), in 120.0 ml of methanol, was mixed with 1.0 ml of hydrochloric acid (concentrated), and heated from reflux for 22.0 hours.

After subsequent cooling and evaporation under vacuum, the resulting residue was dissolved in 80.0 ml of pyridine, and after adding 4.0 ml of acetic anhydride to the prepared solution, this mixture was left to stand for 3.0 hours. Then, after removing the solvents under vacuum, the residue was taken up in 200.0 ml of ethyl acetate, and then the resulting solution was successively extracted with 100.0 ml of 0.5% citric acid solution (citric acid = 2-hydroxypropane-1,2,3-tricarboxylic acid), then with 100.0 ml of 8% sodium bicarbonate solution, and with 100.0 ml of brine.

After separation of the organic and aqueous phases, the organic layer was dried with sodium sulfate, and after evaporation in vacuo the residue was purified by flash chromatography using silica gel, and a mixture of cyclohexane:diethyl ether, (2.0:1.0-1.0:1.0), as eluent.

646 mg of the desired title compound was obtained as a colorless, gummy substance.

Mass spectrometry, (m/z): 327.0,/MH ⁺ /ζ 344.0,/MH ⁺ /J

Intermediate 33)

Preparation of 4R-acetoxy-5S-(1-acetyl-1H-pyrazol-3-yl)-2R-(6-chloropurin-9-yl)-tetrahydro-fur8n-3H’-yl acetic acid ester • 9449 ·· 9944 94 ·· 9 4 9 » 999

999 999 99

9999 9999

99 99 999

To a suspension prepared by suspending 1.0 g of 6-chloropurine in 40.0 ml of toluene was added 10.0 ml of hexamethyldisilazane, and the resulting reaction mixture was heated under reflux for 1.0 hour.

After cooling, the solvents from the reaction mixture were evaporated in vacuo, followed by co-evaporation of the residue with 10.0 ml of toluene. The residue was then dissolved in 40.0 ml of dried acetonitrile, and after subsequent addition of 645.0 mg of 4R-acetoxy-2R-(1-acetyl-1H-pyrazol-3-yl)-5R-methoxy-tetrahydro-furan-3R-yl acetic acid ester (obtained in the previous, above-described procedure for the preparation of Intermediate 32), 1.0 ml of 1,8-diazabicyclo-[5*4i.0]-undee-7-ene, (DBU), and 1.0 ml of trimethylsilyl trifluoromethanesulfonate, the reaction mixture was heated under reflux under a nitrogen atmosphere for 3.0 hours.

The reaction mixture was then poured into 150.0 ml of 8% sodium bicarbonate solution and extracted twice with 100.0 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give a mixture which was purified by flash chromatography using silica gel and a mixture of diethyl ether:cyclohexane (3.0:1.0) as eluent.

42.0 mg of the desired title compound was obtained. Mass spectrometry (m/z): 449.0/451.0/MH ⁺ /J

Intermediate 34)

Preparation of (2R,3B,>4S,5B)-2-(6-chloro-purin-9-yl)-5-(2H-pyrazol-3-yl)-tetrahydro-furen-3,4-diol • 999·

9· · · · ·

999 999 • 9 9 9 9 9

9 9 9 9 9

999 999 «9 99

999*

To a solution prepared by dissolving 42.0 mg* of 4R-acetoxy-5-(1-8-cetyl-1H-pyrazol-3-yl)-2R-(6-chloro-purin-9-yl)-tetrahydro-furan-3-yl acetic acid ester (obtained in the previous, above-described procedure for the preparation of Intermediates 33) in 3.0 ml* of methanol, and cooled to 0.0 °C, 0.20 ml of tert.-butylamine* 8 was added. The resulting reaction mixture was left to stand at 0.0 °C for 25.0 minutes.

The solvents were then removed from the mixture under vacuum, yielding 35.0 mg of the desired title compound. Mass spectrometry, (m/Z): 323*0./325.0./MH ⁺ /J

Example 29)

Preparation of (2R*3B*4S ^: *5E)-2-(2H-pyrazol-3-yl)-5-(6-tetrahydropyran'4-yl-amino-purin-9-yl)-tetrahydrofuran-3,4-diol

To the solution prepared by dissolving 35.0 mg, (2R,3R,4S,5R)-2-(6-chloro-purin-9-yl)-5-(2H-pyrazol-3-yl)-tetrahydro-furan·

3,4-diol (obtained in the previous, above-described procedure for the preparation of Intermediate 34), in 3.0 ml, isopropanol, 0.12 ml* of N,N-isopropylethylamine, and 46.0 mg, tetrahydro-pyran-4-yl-amine hydrochloride were added, and the resulting reaction mixture was heated under reflux under a nitrogen atmosphere* for 17.0 hours.

After removing the solvent from the reaction mixture under vacuum, the residue was dissolved in 10.0 ml of methanol* and to the obtained solution were added 3.0 ml of 8% sodium bicarbonate solution, and then 3.0 g of silica gel. After removing the solvents under vacuum, the residue was applied to a flash chromatography column with the silica gel in dichloromethane. After subsequent

0000 ·» 0000 00 • · » 0 0 0 0 0·0 0 0 0 0 0 • 00 0 000 0

00 00 000 eluting with dichloromethane:methanol (4.0:1.0) gave 5.20 g of the desired title compound as a clear viscous gummy substance.

LC/MS^(System A' ¹ · ):

R _t - 3.34 minutesJ

Mass spectrometry, (m/z): 388.0, /MH /;

Detailed experimental data using procedure K)

Intermediate 35)

Preparation of (3aS,4S,6R,6aS)-6-(6chloropurin-9-yl)-2,2-dimethyl-tetrahydrofuro-/3,4-d//1,3/dioxole-4-carboxylic acid methoxy-methyl-amide

A solution prepared by dissolving 35.88 g of (3aS,4S,6R,6aE)6-(6-chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo-[3,4-d] [1,3]-dioxole-4-carboxylic acid in 300.0 ml of dichloromethane was mixed with 20.5 g of 1,A-carbonyldiimidazole, while constantly cooling with ice.

The resulting reaction mixture was stirred at 22.0°C for 1.0 hour, then mixed with 12.30 g of N,O-dimethyl hydroxylamine hydrochloride and 15.0 ml of pyridine, and this mixture was further stirred at 22.0°C for 24.0 hours. The mixture was then washed with 250.0 ml of 0.5M citric acid solution (citric acid = 2-hydroxyprop8n-1,2,3-tricarboxylic acid) and 200.0 ml of 8% sodium bicarbonate solution. 444* • 4

4444

444 • 4 4

4 4 • · 4 · » » 4 4 4

4«

After subsequent drying of the mixture with sodium sulfate and evaporation under vacuum, the resulting residue was purified by flash chromatography, using silica gel and ethyl acetate as eluent.

26.40 g of the desired title compound were obtained as a colorless solid.

LC/MS, (System A):

_Ht = 3.77 minutes;

Mass spectrometry, (m/z): 384.0/386.0,/MH ⁺ /;

Intermediate 36)

Preparation of (3aS,4S,6R,6aR)-2,2-dimethyl-6-(6-thioxo-1,6-dihydro-purin-9-yl)-tetrahydro-furo[3,4-d//1,3/-dioxole-4-carboxylic acid methoxy-methyl-amide

To a suspension prepared by suspending 23.30 g of (3sS,4S,6R,6aR)-6-(6-chloropurin-9-yl)-2,2-dimethyl-tetrahydrofuro-[3,4-d//1,3/-dioxide-4-carboxylic acid methoxymethylamide (obtained in the previous, above-described procedure for the preparation of Intermediate 35?), in 250.0 ml of ethanol, 10.0 g of sodium hydrogen sulfide was added, and the resulting reaction mixture was heated under reflux, under a nitrogen atmosphere, for 3.0 hours.

Then, after cooling and evaporation of the mixture under vacuum, the resulting residue was dissolved in 250.0 ml of water, and the resulting solution was acidified with about 40.0 ml of a 0.5M solution of citric acid (citric acid = 2-hydroxypropane-1,2,3-carboxylic acid), and filtered. The solid on the filter was washed with 250.0 ml of water and 100.0 ml of isopropanol, and then dried under vacuum.

16.30 g of the desired title compound was obtained as a yellow solid.

LC/MS), (System A):

R t - 3.53 minutes;

Mass spectrometry (m/z): 382.0;/Copper/;

Intermediate 37)

Preparation of 9-/6RT-(5-tert-butyl-2H-pyrazol-3-yl)-2,2-dimethyltetrahydro-(3aR,6aR)-furo-/3,4-d//1,3/-dioxol-4R-yl/-9H-purine·6-yl£- cyclopentylamine

A solution prepared by dissolving 1.0 g of (3aS,4S,6R,6aR)-2,2-dimethyl-6-(6-thioxo1,6-dihydro-purin-9-yl)-tetrahydro-furo-[3,4-d//1,3/-dioxole-4-carboxylic acid methoxymethylamide while hot (obtained in the above-described procedure for the preparation of Intermediate 3:6) in 25.0 ml of N,N-dimethylformamide was filtered while still hot, and the filtrate was mixed with 0.50 ml of diisopropylethylamine and 2.0 g of Merrifield resin (chloromethyl form, 0.8 mmol/g, 1.0%, crosslinked), and this reaction mixture was stirred for 24.0 hours.

The mixture was then filtered, and the filtered resin was washed twice with 15.0 ml of N,N-dimethylformamide, and then three times with 15.0 ml of ether. The above resin was added to a solution of S-dimethyl-1-butyne (prepared by mixing 2.0 ml of 3,3-dimethyl-1-butyne with 4.0 ml of 3.0 M methylmagnesium chloride in tetrahydrofuran) in 25.0 ml of tetrahydrofuran at 22.0 °C for 17.0 hours in tetrahydrofuran at 0.0-5.0 °C, and the reaction mixture was stirred at 0.0-5.0 °C for 6.0 hours. Then 6.0 ml of 2M hydrochloric acid solution and 12.0 ml of tetrahydrofuran were added, and after shaking for ten minutes, the resin was filtered off and washed twice with 15.0 ml of tetrahydrofuran, then twice with 15.0 ml of ether.

The resin was then resuspended in 25.0 ml of N,N- _{dimethylformamide} and after adding 2.0 ml of hydrazine hydrate, the reaction mixture was shaken for 17.0 hours. The mixture was then filtered and washed successively with 30.0 ml of N,N-dimethylformamide, then 2x each with 10.0 ml _of dichloromethane, and 3x each with 10.0 ml of ether, and after subsequent suspension in 15.0 ml _of dichloromethane, the mixture was mixed with 0.50 g of 3-chloroperoxybenzoic _acid (57.0 to 81.0% product), and then shaken at 22.0°C for 17.0 hours.

The resin was then filtered off and washed successively 3 times with 10.0 ml of dichloromethane and then 2 times with 10.0 ml of ether, and the residue, in 100 ml of tetrahydrofuran, was mixed with 88.0 ml of cyclopentylamine and 80.16 ml of di-isopropylethylamine, and this mixture was stirred at 22.0 °C for 17.0 hours. The mixture was then filtered and washed 2 times with 10.0 ml of tetrahydrofuran::methanol (3.0:1.0), and the filtrate and washings were evaporated under vacuum.

After purification of the residue by automated preparative high performance liquid chromatography, 20.0 mg of the desired title compound was obtained.

LC/ _MS (System A):

- 4.48 minutes;

Mass spectrometry, (m/z): 468.0,/MH ⁺ /;

• · · ·

Example 1 (3©)

Preparation of (2R,3R,4S,5E:)-2-(5-tert-butyl-2H-pyrazol-3-yl)-5(6-cyclopentylamino-purin-9-yl)-tetrahydra-furan-3,4-diol

A solution prepared by dissolving 20.0 mg of 9-[6R-(5-tert-butyl-2H-pyrazol-3-yl)-2,2-dimethyl-tetrahydro-(3aR,6aR)-furo[3,4-d/[1,3]-dioxol-4R-yl]-9H-purin-6-yl]-cyclopentylamine (obtained in the previous procedure for the preparation of Intermediate 37 described above) in 4.0 ml of a mixture of trifluoroacetic acid:water (9.0:1.0) was allowed to stand at a temperature of 0-5.0°C for 17.0 hours.

The solution was then evaporated in vacuo (bath temperature <χ3Ό'.0 °C) and mixed with 15.0 ml of 2M sodium carbonate solution. The reaction mixture was then extracted twice with 15.0 ml of ethyl acetate, and the combined extracts were dried over sodium sulfate and then evaporated in vacuo. The resulting residue was purified by chromatography on silica gel (Varian Bondelut cartridge) using ethyl acetate:methanol (9.0:1.0) as eluent.

19.0 mg of the desired title compound was obtained as a clear gummy substance.

LC/MS, (System A):

R - 4.0 minutes;

Mass spectrometry, (M/Z): 428.0,/MH ⁺ /;

Detailed experimental data using procedure L)

Intermediate 38)

Preparation of 3 -ethhy 1 - 5 - (6R-meth hoxy- 2,2-di meth hy 1-1 eth r ahy d r o - (3 a R, 6aE)-furo- /3,4-d//1 ,3/-dioxol-4S-yl)-isoxazole'

To the mixture* prepared by mixing 0.271 g* of 4B-ethynyl-6Bmethoxy-2 *2-dimethyl-tetrahydro-(3eS, 6aR)-furo-/3,4-d//1,3/dioxole* (see reference to the article in the professional journal Helv.Chim. Acta*63*1181 - 1189,/1980/), and 0.328 ml of phenylisocyanate, in

1.50 ml* of dried toluene was added under a nitrogen atmosphere, over 5;.0 minutes, to a mixture prepared by mixing 0.134 ml, 1-nitropropane*. and 0.038 ml, triethylamine, in 1.0 ml, dried toluene. During this operation, a precipitate formed in the reaction mixture.

The resulting mixture was heated in the temperature range of 73.0 to 82.0 °C for 18.0 hours, and then, after cooling, was filtered through silica gel, and washed thoroughly first with ether, and then with a mixture of 40% ethyl acetate in cyclohexane. After removal of the solvent in vacuo, a light brown solid was obtained, (0.487 g), which was further processed by flash chromatography on silica gel* using a mixture of ethyl acetate:cyclohexane* (20.0:80.0-30.0:70.03), as eluent.

03.329 g* of the desired title compound was obtained as a clear oily substance.

TLC* (cyclohexane : ethyl acetate; 3.0 : 2.0):

Rf = 0.49;

Intermediate 339a)

Preparation of 4H*5S’-diacetoxy-2S-(3-ethyl-isoxazol-5-yl)-tetrahydrofuran-3E*-yl-acetic acid ester* and

• 9 9 9 9 9 9 ·· ·· · · · 9 9 · 9 9 9 9 · · · · · · · · · · · · · · · · · · · · · 9 999· 9.9

999999 99 99 99

JTD

Intermediate 39b)

Preparation of 4S,5B-di-acetoxy-2S-(3-ethyl-isoxazol-5-yl)-tetrahydrofuran-3R*-yl acetic acid ester

A solution prepared by dissolving 0.355 g of 3-ethyl-5-(6Rmethoxy-2,,2-dimethyl-tetrahydro-( _3aR 6aR )-furo-/3,4-d//1,3/dioxol-4S-yl)-isoxazole, (obtained in the previous, above-described procedure for the preparation of Intermediate 38), in a mixture obtained by mixing 5.0 ml of trifluoroacetic acid and 0.05 ml of water, was stirred at room temperature for 27.0 hours, and then evaporated in vacuo.

The resulting residue was azeotropically treated 3 times with toluene, and then dissolved in 10.0 ml of dichloromethane under a nitrogen atmosphere, and the resulting solution was cooled to 0.0 °C. Then, 0.048 g of 4-(N,N-dimethylaminopyridine, 8.30 ml of triethylamine, and 2.49 ml of acetic anhydride were added to the solution in sequence. The resulting reaction mixture was then stirred at 0.0 °C to room temperature overnight, and then evaporated in vacuo to give 1.34 g of a brown liquid, which was purified by flash chromatography on silica gel using ethyl acetate::cyclohexane (20.0:80.0 - 40.0:60) as eluent.

0.192 g of 4R,5S-diacetoxy-2S-(3-ethyl-isoxazole) was obtained.

5-yl)-tetrahydrofuran-3R*-yl ester of acetic acid, in the form of a pale brown colored substance of oily consistency, i.e. Intermediate 39a).

and

0.16 g _of 4R,5R-diaethoxy-2S-(3-ethyl-isoxazol-5-yl)-tetrahydrofuran-3-yl acetic acid ester, in the form of a slightly brown colored substance of oily consistency, i.e. Intermediate 39b).

Intermediate product

y?/

39a):

TLO, (SiO 2 , cyclohexane : ethyl acetate 3.0 : 2.0): R _f = 0.28;

and

Intermediate 39b)::

TLC, ( _SiO2 ; cyclohexane:ethyl acetate 3.0:2.0): _Rf = 0.22J

Intermediate 4SO)

Preparation of 4S-acetoxy-2R-( _2R6 -dichloro-purin-9-yl)-5S-(3-ethylisoxazol-5-yl)-tetrahydro-furan-3R-acetic acid ester

To a mixture prepared by mixing 0.909 g of 4R,5SZ-diacetoxy-2S-(3-ethyl-isoxazol-5'-yl)-tetrahydro-furan-3R-yl acetic acid ester and 4R,5K*diacetoxy-2S-(3-ethyl-isoxazol-5-yl)-tetrahydro-furan-3R-yl acetic acid ester (i.e. Intermediate 39a) and Intermediate 39b) obtained in the previous, above-described procedure for the preparation of both said intermediates) in 5.0 ml of dried acetonitrile, at room temperature, under a nitrogen atmosphere, was added 0.779 g of 2,8-dichloropurine and 0.692 ml of 1,8-diazabicyclo-[5.4.0]-undee-7-ene, (DBU), and the resulting reaction mixture was stirred at room temperature, for 20.0 hours»

Then, the reaction mixture was mixed with 30.0 ml of saturated aqueous sodium bicarbonate solution, and was subsequently extracted 3 times with 40.0 ml of ethyl acetate each time, and was obtained.

···· • · * ·

3.54 g, brown colored liquid, which was purified by flash chromatography on ηβ silica gel, using a mixture of ethyl acetate :: cyclohexane, (40.0 60.0 - 50.0 :: 50.0), as eluent.

0.798 g of the desired title compound was obtained as a creamy-white foamy substance. TLG., (SiO^’, cyclohexane : ethyl acetate; 2.0 : 3.0):

_Rf = 0.25;

Intermediate 41)

Preparation of 4R-acetoxy-2R-[2-chloro-6-(1S-hydroxymethyl-2-phenylethylamino)-purin-9-yl]-5S-(3-ethyl-isoxazol-5-yl)-tetrahydrofuran-3R-yl acetic acid ester

The solution, prepared by dissolving 151.0 mg of 4R-acetoxy-2R(2,6-dichloro-purin-9-yl)-5S-(3-ethyl-isoxazol-5-yl)-tetrahydrofuran-3R-yl acetic acid ester (obtained in the previous, above-described procedure for the preparation of Szefiproduct 40), further 53.0 mg of (s)-phenylalaninol, and 67.0 ml of di-isopropylethylamine, in 2.0 ml of isopropanol, was heated at a temperature of 50.0 °C for 7.50 hours.

The resulting reaction mixture was then worked up by removing the solvent in vacuo to give 260.0 mg of the desired title compound in crude form as a clear, gummy substance.

LC/MS, (System):

R = 4.63 minutes;

Mass spectrometry, (m/z): 585.0,/587.0,/MH ⁺ /;

• ···· · · ··· ·· • · · · · · · · · · · · · · · · · · · 9 9

9 9 9 9 9 9 9 9

9 9 99 999

473

Example 31)

Preparation of (2R,3R,4S,5S)-2-(6-(1S-Hydroxymethyl-2-phenyl-ethylaraino)-2-methoxy-purin-9-yl)-5-(3-ethy 1-i and oxazol-5-yl)-te trahy d r of ur a n-3; *4- d i o lu

To 4.0 ml of 25.0% sodium methoxide in methanol was added 259.0 mg of 4R-acetoxy-2S-(2-chloro-6-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl)-5S-[3-ethyl-laxo-5-yl]-tetrahydrofuran-3B-yl acetic acid ester* (obtained in the previous, above-described procedure for the preparation of Intermediate 41)* and the resulting reaction mixture was stirred at 22.7 °C for 8.0 hours.

The solvent was then removed from the reaction mixture in vacuo, and the resulting residue was purified by flash chromatography over silica gel, using ethyl acetate:methanol* (10.0:1.0)* as eluent.

101.0 mg of the desired title compound was obtained as a slightly yellow gummy substance.

LC/MS* (System A):

R _t - 4.04 minutesJ

Mass spectrometry, (m/z)497*O;/MH /J

Detailed experimental data using the procedure

Product range 42)

9 9 · · » ·

4?if

Preparation of (3aS, ₍ 4S,,6B,.6aB)-2,2-dimethyl-6-(6-oxo-1,6-dihydro-purin-9j-yl)-cyclopenta-[1,3]-dioxole-4-carboxylic acid

S$Šs, prepared by mixing 3.0 g, potassium permanganate, and 1.0 g, potassium hydroxide, in 60.0 ml, water, was stirred at room temperature overnight, and then cooled to 0.0 °C.

Then, to the above solution was added /3aS-(3a,4,6,6a)/1,9-dihydro-9-/tetrahydro-6-(hydroxymethyl)-2,2-dimethyl-4Bcyclopenta-1,3-dioxol-4i-yl/-6H-purin-6-one, (2.92 g), _so that the addition proceeded slowly so that the temperature of the reaction mixture was maintained below 5.0°C. The mixture was then stirred at room temperature for 5.0 hours, and then, after cooling to 0.0°C, it was mixed with 4.20 g of sodium metabisulfite. The pH of the reaction mixture was adjusted to about 3.5 by the subsequent, careful addition of 5M hydrochloric acid solution.

The reaction mixture was then stored at 4.0 °C overnight, and the resulting precipitate was isolated, washed with chilled water _, and then dried under vacuum.

_1.82 g of the desired title compound was obtained as a white solid.

Mass spectrometry, (m/z): 321.0/MH ⁺ /;

Intermediate 4-3)

Preparation of 6-chloro-9-(2,2-dimethyl-6S-(3-cyclopropyl-(1,2,4)oxadiazol-5-yl)-tetrahydro-(3aS,6aB)-cyclopenta-(1,3)-dioxol-4S-yl)-9H-purine • · · ·

Ό5~

A solution prepared by dissolving 118.0 mg of (3aS,4S,6R,6aHt)-2-dimethyl-6-(6-oxo-1,6-dihydro-purin-9-yl)-cyclopenta-[1,3]-dioxole-4-carboxylic acid (obtained in the previous, above-described procedure for the preparation of Intermediate 42) in 4.50 ml of anhydrous chloroform was heated together with 29.0 ml of N,diethylformamide and 108.0 ml of thionyl chloride under reflux for 4.0 hours.

Then, after cooling to room temperature, the excess solvent and reagent from the reaction mixture were removed by evaporation, and the residue was taken up in 1.50 ml of anhydrous chloroform. This mixture was added to a cooled solution (0.0 °C) prepared by dissolving 110.0 mg of cyclopropylamidoxime and 41.0 ml of pyridine in 2.50 ml of chloroform. The resulting reaction mixture was then heated under reflux for 24.0 hours, and then, after cooling, it was evaporated to dryness, and the resulting residue was purified by flash chromatography on silica gel, using ethyl acetate:cyclohexane (40.0:60.0) as eluent.

After evaporation, 56.0 mg of the desired title compound was obtained as a colorless, gummy substance.

Mass spectrometry, (m/z): 403.0,/MH/;

Intermediate 44)

Preparation of (1H,2S,3R)-3¼(6-chloro-purin-9-yl)-5-(3-cyclopropyl-[1,2,4]-oxodiazol-5-yl)-cyclopentane-1,2-diol

A total of 50.0 mg, 6-chloro-9-[2,2-dimethyl-6S-(3-cyclopropyl/1,2,4/-oxadiazol-5>yl)-tetrahydro-(3aS,6a)-cyclopent8-(1,3/dioxol-4E-yl)-9H-purine, (obtained in the previous, φφφφ · · φ · * ·

Φ Φ · · · φ · I φ φ • · ΦΦΦΦ ··· •ΦΦΦΦΦ φ · φφ φ · φφφ of the above-described procedure for the preparation of Intermediate 43), was mixed with 2.0 ml,, at a temperature of 0),0 °C, of a mixture of trifluoroacetic acid :· water, ( 9.0 : 1.0 ), and the resulting reaction mixture was stored at a temperature of 4.0 °C overnight, and then evaporated to dryness»

60.0 mg of the desired* title compound was obtained as a colorless gummy substance.

Mass spectrometry, (m/z): 363.0,/MH ⁺ /·

Example 32)

Preparation of (1S*2R*3S*5R)-3-(3-cyclopropyl-[1,2,4]-oxadiazol-5-yl)5-[2Si-hydroxy-cyclopent-(A)-yl-amino-purin-9-yl]-cyclopentane-2-diol

A solution prepared by dissolving 57.0 mg* of (1B-.,2S*3R*5.S)-3-(6-chloro-purin-9-yl)-5>-(3>-Cyclopropyl-[1,2*4i/-oxadiazol-5-yl)-cyclopentane*-1,,2-diol* (obtained in the previous, above-described procedure for the preparation of Intermediate 44), in 5.0 ml,. isoprop8nol,. was mixed with 34.0 mg* of (1S*2S))-2-aminocyclopentanol. hydrochloride,. and with 85.0) ml of diisopropylethylamine, and the resulting reaction mixture was heated under reflux overnight»

Then, the excess solvent from the mixture was evaporated, and the residue was purified by automated preparative high-performance liquid chromatography (HPLC) to give 15.0 mg of the desired title compound as an almost colorless glassy solid.

• 9 999 »♦ 999· 4 4 • 44 4 · 4 9 9 9

EC/MS), (System C)::

R ^: t = 2.40 minutes;

Mass spectrometry, (m/z): 428.0,/MH ⁺ /;

Detailed experimental data using the procedure (N1)

M’ e z i p r o d u c t 45)

Preparation of 9-{(3aR,.4R, _6S 6aR)-6-[3-( tert.-butyl)-1,2,4-oxadisol-5-yl]-2,2-dimethyltetrahydrofuro-[3,4-d//1,.3;/-dioxol-4-yl}6-(1H-1,2,3>benzotriazol-1-yl-oxy)-9H-purine

To a solution prepared by dissolving: 10.0 g _of (3aS _y 4S _r 6R,6sR)6-(6-chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo-/3,4-d/ /1,35/-dioxcl-4-carboxylic acid, in 200.0 ml of N,.N-dimethylformamide, was added 3.96 g of 1-hydroxybenzotriazole, and 5.62 g of 1 — (3-dimethylaminopropyl) — 3i — ethylcarbodiimide.hydrochloride, and then a solution prepared by dissolving 3.40 g of t-butylacetamidoxime in 30.0 ml of N,N-dimethylformamide, and the resulting reaction mixture was stirred at 20.0 °C for 24.0 hours, under a nitrogen atmosphere. The mixture was then heated at 70 _± 0°C for another 36.0 hours, and the resulting mixture was subsequently cooled to 20.0°C and, after basifying with 200.0 ml of saturated aqueous sodium bicarbonate solution, was extracted twice with 150.0 ml of ethyl acetate each time.

After separation of the organic and aqueous phases, the organic layers were washed with 300.0 ml of brine, and after drying with magnesium sulfate, they were evaporated to dryness (in vacuo).

After subsequent mechanical processing and removal of the rest « ♦ ···♦

0000 ·»0 0 0 * 0 00····· •00 000 00 ·· *· 000 with ether, 11.08 g of the desired title compound was obtained as a yellow solid, which was purified by chromatography on silica gel, using ethyl acetate :: cyclohexane, (3.0 :: 7.©), as eluent.

4.75 g of the desired title compound was obtained as a white solid.

LC/MS, (System C):

E _t = 3.46 minutes;

Mass spectrometry, (m/z)r 52Q),O,/MH /;

Product 46)

Preparation of 9-[(3aR,4R,6S,6aR)-6-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethyltetrahydrofuro-[3,4-d//1,3/-dioxol-4-yl^-N-i]obutyl1-9H-purin-6-amine

To a solution prepared by dissolving 50.0 mg of 9-^(3aR,4S,6S,6aR)-6-[3>(tert-butyl)-1,2,4-oxadiazol-5>-yl]-2,2-dimethyltetrahydrofuro-(3,4-d//1,3/-dioxol-4-yl)-6-(1 H—1,2,3>benzotri8·zol-1-yl-oxy)-9H-purine, (obtained in the previous, above-described procedure for the preparation of Intermediate 45), in 0 ^s.40 ml of dimethyl sulfoxide, 0.10 ml of diisopropylethylamine and 0.038 ml of isobutylamine were added, and the resulting reaction mixture was stirred at 20^CD °C for 16.0 hours, under a nitrogen atmosphere*

The reaction mixture was then evaporated to dryness in vacuo, and the resulting residue was purified by automated preparative high-performance liquid chromatography (HPLC) to give 14.0 mg of the desired title compound as a white compound*.

I •4 ····

9 9 • ·

9 9 4

9 · • ·

LC/MS'., (System C):

= 3.-38 minutes;

Mass spectrometry, (m/z): 458.G,/5/1H ⁺ /;

Near lei 45?)

Preparation of (2S,3S',4-R,5R)-2-(tert-butyl)-1,2,4-oxadiazol-5-yl/-5-(6-(isobutylamino)-9H-purin-9-yl)-tert-tetrahydrofuran-3,4-diol

Solution, prepared by dissolving 14.0 mg, 9-( (3aR,4R,6S,

6aR)-6-[3-( tert. -butyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethyltetrahydrofuro-[3,4-d//1,3/-dioxol-4<-yl] -B-isobutyl-9H-purin-6-amine, (obtained in the previous, above-described procedure for the preparation of Intermediate 48), in 1.0 ml, a chilled mixture of trifluoroacetic acid::water, (9.0:1.0), was stored at rest at 4.0 °C for 18.0 hours.

The solution was then basified in an ice-cold bath by adding 20.0 ml of saturated aqueous sodium bicarbonate solution and then extracted twice with 20.0 ml of ethyl acetate. The combined extracts were then dried over magnesium sulfate and evaporated to dryness in vacuo to give 7.66 mg of the desired title compound as a white solid.

LC/MS, (System C):

- 2.85 minutes;.

Mass spectrometry, (m/z):

418.0,/MH ⁺ /;

• 0

0000 00 0000 0 0 0 0 ·

000 000 0 000 0 000 ·

0 0 0 0 0 0 'ÍÍO

Detailed experimental data using procedure 0)

Intermediate 447)

Preparation of 9- ^(3sR _r 4®,6S,6aK)-6-/3-( tert.-butyl)-1 _r 2 _r 4-oxediazol-5-yl/-2^2-dimethyltetrahydrofuro-/3,4-d//1,3/-dioxol-4-ylJ N*-( 2,4-difluorophenyl)-9ffi-purin-6-amine

Solution, prepared by dissolving 50.0 mg,, 9-^ (3sR _ø 4R,6S,6aR)

6-(3-(tert-butyl)-1,2,4-oxodiazol-5-yl)-2,2-dimethyltetrahydrofuro-[3>„4t-d//1,3/-dioxol-4-yl^ -6-(1H-1,2,3-benzotriazol-1-yloxy)-9I-purine, in 0.40 ml. _of 2,4-difluoroaniline was heated at 80),.0) ° _C for 96.0 hours.

The reaction mixture was then cooled to 20.0 ^° C and partitioned between 25.0 ml of dichloromethane and 15.0 ml of 1M hydrochloric acid. After separation of the aqueous and organic phases, the aqueous layer was further extracted once with 25.0 ml of dichloromethane and the combined organic extracts were evaporated to dryness in vacuo.

The resulting residue was purified by automated preparative high-performance liquid chromatography (HPLC) to give 18.30 mg of the desired title compound as a dark red gummy substance.

LC/MS (System C):

With ~ 2.85 minutes;

Mass spectrometry, (m/z): 418.0,/MH/;

Example. 4i9) • 4444 *· ···· 44 4

4» 4 ♦ 4 4 · 4 44 ··· » 4 4 444

4 4 4 4 >444 4

4 4444 44 4

4*4 444 44 44 44 444

Preparation of (2S,3S,4R,5®)-2-[3-(( tert.-butyl)-1*2,4-oxadiazol-5yl]-5-[6-(2*4-difluoroanilin)-9H-purin-9-yl]-tetrahydrofuran 3,4-diol

A solution prepared by dissolving 18.30 mg of 9-{(3sR,4K,6S,6aR)-6-[3-(tert-butyl)-1,2,4-oxadiazol-5-yl]-2,2-dimethyltetrahydro-[3,4l-d//1,3'/dioxol-4-yl]-N-(2,4-difluorophenyl)9H-purin-6-amine, (obtained in the previous, above-described preparation procedure of Intermediate 47), in 1.0 ml of a cooled mixture of trifluoroacetic acid:water, (9.0:1.0), was made alkaline in an ice-cooled bath by adding 20.0 ml of saturated aqueous sodium bicarbonate solution, and this mixture was extracted 2x with 20.0 ml of ethyl acetate each time.

The combined extracts were dried over magnesium sulfate and evaporated to dryness under vacuum to give 14.30 mg of the desired title compound* as a red solid.

LC/MS* (System C)

R^ = 3.03 minutes;

Mass spectrometry, (m/z) 474.0/MH ⁺ /;

Detailed experimental data using procedure P)

Intermediate 48)

Preparation of (3aB*4S,6R,6aR)-η-(6-chloro-9H-purin-9-yl)-N-(2-hydroxypropyl)-2,2-dimethyltetrahydrofuro-[3,4-d//1,3/-dioxole-4-carboxamide

9999 • 9 9999 99 • 9 9 · · · ·

999 * 9 9 · · • 9 · 9 9 9 9 9 9 • 999 99 99 999

Me,

To a solution prepared by dissolving 10.0 g of (3aS,4S,6S,6aR)-6-(6-chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo-/3,4-d/ /1,3/-dioxole-4-carboxylic acid in 100.0 ml of chloroform, 4.30 ml of thionyl chloride was added with constant stirring, and the resulting reaction mixture was heated under reflux under a nitrogen atmosphere for 60.0 minutes.

After cooling the mixture to 20.0 °C, the solvent was removed in vacuo, and the residue was azeotropically treated twice with 50.0 ml of toluene. The resulting residue was suspended in 50.0 ml of chloroform, and the resulting suspension was added dropwise over 10.0 minutes to a solution prepared by dissolving 2.30 ml of 1-amino-2-propanol and 5.10 ml of diisopropylethylamine in 50.0 ml of chloroform, and this mixture was added at 0.0 °C to 50.0 ml of chloroform. The reaction mixture was then stirred at 20.0 °C for 18.0 hours, and then, after adding 100.0 ml of phosphate buffer (pH 6.50), the organic and aqueous phases were separated.

The aqueous layer was extracted with 50.0 mL of chloroform, and the combined chloroform layers were dried over sodium sulfate, and the solvent was removed in vacuo.

6.63 g of the desired title compound were obtained as a white, foamy substance.

Mass spectrometry, (m/z): 398.0,/MH/;

Intermediate 49)

Preparation of (3aR,,4S _r 6R;,.6aR)-6-(6-chloro~9H-purin-9-yl)-2,2-dimethylN-(2-oxopropyl)-te trishydrofuro-(3,4-d/ (1,3)-dioxole-4-carboxamide

To the mixture prepared by mixing (3afi,4S,6R,6aR)-6-(6-chloro9H-purin-9-yl)-N-(2-hydroxypropyl)-2,2-dimethyltetrahydrofuran• 9·«9 ·4 9499

9» · 9 4 · • 9 99 9 * 9 • 9·9· · • 9 49

4 · • 4 9 4

4 9

4 9

444

To 10.0 g of 4-mole molecular sieve powder in 165.0 ml of dichloromethane at 0.0 °C was added 3.0 ml of acetic acid, followed by 9.36 g _of pyridinium dichloromethane in portions.

The resulting reaction mixture was stirred first at 0.0 °C for 15.0 minutes and then at 20.0 °C for 2.0 hours. After the subsequent addition of 10.0 ml of isopropanol, the mixture was stirred for 15.0 minutes, and then, after the addition of 9.90 g of silica gel ( ^Merck 9385) and 165.0 ml of ethyl acetate, the reaction mixture was stirred for another 15.0 minutes.

The reaction mixture was then filtered through silica, and the filter cake was washed with 300.0 ml of ethyl acetate. The filtrate was evaporated in vacuo, and the residue, a brown solid, was purified by flash chromatography on silica gel using dichloromethane:methanol (100.0:3.0) as eluent to give a pale brown foam which was further purified by chromatography on silica gel (Merck 9385) using ethyl acetate and then ethyl acetate:methanol (200:2.0) as eluents.

4.60 g of the desired title compound were obtained as a white, foamy substance.

TLC, ( _SiO2 ; ethyl acetate:methanol; 100.0:20.0):

R _f = °.4o;

Detailed experimental data using procedure Q) • ···* »· *··· ·· · • · · · ♦ · 9 9 9 9

9 99 9 9 9 99 9

9 9 9 9 9 9 9 9 9

9 9999 99 9

999 999 99 99 99 999

Intermediate product 50))

Preparation of (3aR,4S _r 6R,6aB)-N-(2-hydroxybutyl)-6-methoxy-2,2-dimethyl trahydrofluoro-/3,4-d//1,3/-dioxole-4-carboxamide

To a solution prepared by dissolving 5.0 g of furo-(3,4-d)-1,3-dioxole-beta-D-ribofuranic acid in 50.0 ml of dichloromethane, 4.83 g of carbonyldiidazole were added, and the resulting reaction mixture was stirred at 20.0 °C for 20.0 minutes. Then, after adding 2.45 g of 1-amino-2-butanol, the reaction mixture was stirred under nitrogen at 20.0 °C for 18.0 hours, and then, after dilution with 50.0 ml of ether, it was washed with 100.0 ml of saturated aqueous citric acid (citric acid - 2-hydroxypropane-1,2,3-tricarboxylic acid) and 100.0 ml of saturated aqueous sodium bicarbonate.

After separation of the organic and aqueous phases, the organic layer was concentrated in vacuo, and the resulting residue was purified by flash chromatography on silica gel, using a mixture of ethyl acetate:cyclohexene, (1.0:1.0), as eluent.

3.81 g of the desired title compound was obtained as a clear, gummy substance.

Mass spectrometry, (m/z): 29O.O./MH/;

Intermediate 51)

Preparation of (3aR _4S ,,6R,6sR)-6-methoxy-2,2-dimethyl-N-(2-oxobutyl)tetrahydrofuro-[3,4-d//1 ,3/-dioxole-4-carboxamide

To the solution prepared by dissolving 3.81 g, (3aR,4S,6%

4444

4 44 4 • •4 44 4 4444

4444 44 4 44 4

4 4 ♦ · 4 444 · ·

4 4444 44 4

44« 444 44 *4 44 444

6aR)-N-(2-hydroxybutyl)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d//1,3/-dioxole-4-carboxamide, (obtained in the previous, above-described procedure for the preparation of Intermediate 50), in 115.0 ml of anhydrous dichloromethane, containing 5.70 g of the powdered form of 4$ molecular sieve, at a temperature of 0.0 °C, and under a nitrogen atmosphere, was added 2.59 ml of acetic acid, and 7.93 g of potassium dichromate, so that the addition was carried out in portions.

The reaction mixture was then stirred at 0.0°C for 15.0 minutes and then at 20.0°C for 2.0 hours. The reaction mixture was then mixed with 40.0 ml of isopropanol, and after stirring for 30.0 minutes, 40.0 g of silica gel (Merck 9385) and 100.0 ml of ethyl acetate were added, and the mixture was stirred for another 30.0 minutes.

(r)

The mixture was then filtered through a Harbolite filter and the filtrate was concentrated in vacuo to give a crude product which was purified by flash chromatography on a silica gel column using ethyl acetate:cyclohexane (2.0:1.0) as eluent.

1.91 g of the desired title compound was obtained. 1 H-NMR _δ :

7.405 _.

4.155,, ( 2H,. m., CH,,), 3.555, ( 3H, s., OMe ), 2.505, ( 2H, k., CH ₂ ), 1.505, (3H, s., -Me ), 1.355, ( 3H, s., -Me ), 1.105, ( 3H, t.,

Intermediate product 52) • ·«·« «· ·»··· ·· ··· · · · · · · • · ·« · · * · · • 9 9 9 9 9 9 9 9

99 99 999

Jfc

Preparation of 2-/ (3aR,.4S, 6R, 6aR)-6-methoxy-2,2-dimethyltetrahydrofuro-/3,4-d//1,3/-dioxol-4-yl/-5-ethyl-1,3-oxazole

To a solution prepared by dissolving 740.0 mg of (3aR,4S,6R,6aR)-6-methoxy-2',2-dimethyl-N-(2-oxobutyl)-tetrahydrofuro-/3,4d//1,3/-dioxole-4-carboxamide (obtained in the previous, above-described procedure for the preparation of Intermediate 51), in 10.0 ml of dried toluene, 1.44 ml of phosphorus oxychloride was added under a nitrogen atmosphere, and the resulting reaction mixture was heated under reflux for 3.50 hours.

The reaction mixture was then cooled to 0.0°C, and after subsequent mixing with 30.0 ml of saturated aqueous sodium bicarbonate solution, the mixture was stirred vigorously for 30.0 minutes. The reaction mixture was then extracted 4 times with 50.0 ml of ethyl acetate each time, and after separating the organic and aqueous phases, the organic layers were combined, and after washing with 30.0 ml of brine, they were dried with magnesium sulfate, and then concentrated in vacuo.

The crude product was obtained and purified by flash chromatography on a silica gel column using cyclohexane:ethyl acetate (5.0:1.0 to 7.0:2.0) as eluent.

0.83 g of the desired title compound was obtained as a yellow colored substance of oily consistency.

Mass spectrometry, (m/z): 270.0,/MH ⁺ /J

Intermediate 53)

Preparation of (2S,3R,4R,5S)-2,4-bis-(acetyloxy)-5-(5-ethyl-1,3oxazol-2-yl)-tetrahydrofuran-3-yl-8-acetate • · ···· • ···· • 9 9 9 9 9 9 9

9 99 9 9 9 99

9 9 9 9 9 9 9 9 * 9 9 9 9 9 9 9

999 999 99 99 99

I

To 0.83 g of 2-((3aR,4S,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro-(3,4-d//1,3/-dioxol-4-yl)-5-ethyl-1,3-oxazoic acid (obtained in the previous, above-described procedure for the preparation of Intermediate 52), 3.56 ml of a mixture of trifluoroacetic acid:water (9.0:1.0) was added, and the resulting reaction mixture was stirred at 20.0 °C for 3.50 hours.

After the solvents were removed from the reaction mixture under vacuum, an orange-brown colored substance of oily consistency was obtained, which was dissolved in 7.0 ml of pyridine under a nitrogen atmosphere, and after subsequent addition of 2.76 ml of acetic anhydride, the mixture was stirred at a temperature of 22.0 °C for 18.0 hours.

The reaction mixture was then concentrated in vacuo, and after dilution with 50.0 ml of ethyl acetate, the resulting solution was washed with 50.0 ml of

1M hydrochloric acid solution, then 3x each with 50.0 ml of saturated aqueous sodium bicarbonate solution, and finally with 50.0 ml of brine, and the organic layer was dried with magnesium sulfate.

After evaporation of the solvent to dryness, 0.854 g of the desired title compound was obtained in the form of an orange-brown colored substance of oily consistency.

Mass spectrometry, (m/z): 342.0,/MH ⁺ /J

Intermediate 54)

Preparation of (2R ^; , 3B,4R, 5S)-4- (acetyloxy)-2-(6-chloro-9H-purin-9-yl)~ 5- (5-ethyl-1,3-oxezol-2-yl)-tetrahydrofuran-3-yl acetate

To 0.854 g of 6-chloropurine, 4.0 ml of 1,1,1,3,3,3 hexamethyldisilazane and 15.0 ml of toluene were added, and the resulting reaction mixture was heated under reflux for 444 h.

2.0 hours. After the solvent was removed from the reaction mixture in vacuo, the residue was treated zeotropically with 1 x 8.0 mL of toluene and the mixture was evaporated to dryness.

To the residue were then added 0.854 g _{of (} 2S,3R,4R,5S)-2,4bis-(acetyloxy)-5-(5-ethyl-1,3-oxazol-2-yl)-tetrahydrofuran-3-yl acetate (obtained in the previous, above-described procedure for the preparation of Intermediate 53), in 20.0 ml of acetonitrile, further 0.624 ml of trimethylsilyl trifluoromethanesulfonate (triflate), and 0.374 ml of 1,8-diazabicyclo-[5,4,0]-undec-7-ene, and this reaction mixture was stirred first at 20.0 °C for 18.0 hours, and then at 80.0 °C for 3.0 hours, and then cooled.

The reaction mixture was then poured into 40.0 ml of saturated aqueous sodium bicarbonate solution and extracted 4 times with 40.0 ml of dichloromethane. After separation of the organic and aqueous phases, the organic layers were combined and, after drying with magnesium sulfate, the solvent was removed in vacuo to give the crude product, which was purified by flash chromatography on silica gel using cyclohexane:ethyl acetate (first 4.0:1.0, then 3.0:2.0) as eluent.

355.0 g of the desired title compound were obtained as a clear, gummy substance.

Mass spectrometry, (m/z): 436.0,/MH/;

Example 84)

Preparation of 2-((9-(2R,3R,4S,.5S)-5-(5-ethyl-1,3-oxazol-2-yl)-3,4-hydroxytetra-hydrofuran-2-yl/-9H-purin-6-ylJ-amino)-N,N-dimethyl qethanesulfonamide

4·«4

4 4

444

4

4« 444* · 4

4 4

4 4 4

4 4 4

9»

4

9

9

9 4

4

4» 4

To a solution prepared by dissolving 50.0 mg of (2R,3R,4R,5S)-4-(acetyloxy)-2-(6-chloro-9H-purin-9-yl)-5-(5-ethyl-1,3'oxazol-2-yl)-tetrahydrofuran-3-yl acetate (obtained in the previous procedure for the preparation of Intermediate 54 described above) in 5.0 ml of isopropanol, 0.120 ml of N,N-diisopropylethylamine and 86.0 mg of N,N-dimethyl-2-aminoethanesulfonamide hydrochloride were added, and the resulting reaction mixture was stirred under reflux under a nitrogen atmosphere for 48.0 hours, and then cooled.

After subsequent addition of 4.0 ml of methanol/ammonia solution, the mixture was shaken and allowed to stand for 24.0 hours. After the solvent was evaporated from the mixture, the resulting residue was purified by automated preparative high performance liquid chromatography (HPLC) to give 8.60 mg of the desired title compound.

Mass spectrometry, (m/z):

468.0,/MH ⁺ /;

Detailed experimental data using procedure S)

Intermediate 55)

Preparation of (9-(3aR,4f,6S,6aR)-2,2-dimethyl 1-6-(3-methyl-1,2,45oxadiazol-5>yl)-te trehydrofuro-/3,4-d//1,3;/-di oxol-4-yl/-9Hpurin-6-ylJ -N-cyclopentylamine

A mixture prepared by mixing 0.20 g of (3aS,4S,6R,6afic)-6-(6-cyclopentylamino-purin-9-yl)-2,2-dimethyl-tetrahydrofuro-/3,4-d//1,3/-dioxole-4-carboxylic acid, further 146.0 mg of 2-ethoxy 1-ethoxycarbonyl-1,2-dihydroquinoline, 76.0 mg of acetaldoxime, and • ····

9 • 999 • 9 9 • 9

9999 • 9 9

9 9 • · 9 • · 9 9

9· 99

9 ' 9 • 9 9

9

Mo

25.0 ml* of dimethoxyethane* was heated under reflux for 4.0 days and then cooled to 22.0 °C.

The reaction mixture was then concentrated in vacuo, and 40.0 ml* of ethyl acetate was added to the residue. The resulting suspension was then washed with 3 x 20.0 ml of 0.5M citric acid solution (citric acid = 2-hydroxypropane-1,2,3-tricarboxylic acid), and the aqueous washings were extracted 3 x with 20.0 ml of ethyl acetate each. The combined organic extracts were washed with 20.0 ml of water and 30.0 ml of brine, and after drying with magnesium sulfate, they were concentrated in vacuo.

The residue was purified by chromatography on silica gel, using _ethyl acetate:cyclohexane, (1.0:1.0), as eluent.

63.0 mg of the desired title compound, ¹ H-NM2* ( CDCl ₃ ),delta;, was obtained.

8.03. 4.56, ( 1H,w.é.,

CH ), 2.19* ( 3H, a., Me ), 1.85 - 1.50, ( 9H, m., + a., 6x 1/2 CH ₂ + Me ), 1.45, ( 3H* s., Me ), 1.25 - 0.85, ( 2H, m.,

2x 1/2 CH ₂ ).

Example; 39)

Preparation of (2R*3R,4S,5S)-2-[6-(cyclopentylamino)-9H-purin-9-yl]5-(3-methyl-1,2,4-oxadiazol-5-yl)-tetrahydrofuran-3,4-diol

A mixture prepared by mixing 63.0 mg of N-£ 9-/(3eR,4R,6S,6aR)2,2-dimethyl-6-(3-methyl-1,2,4-oxadisol-5-yl)-tetrahydrofuro• · · /3,4-3//1,3/-dioxol-4-yl/-9H-purin-6-ylj - N-cyclopentylamine, (obtained in the previous, above-described procedure for the preparation of Intermediate 559, further 1.0 ml of trifluoroacetic acid, and 0.1 ml of water, was stirred at a temperature of C.O; °C for 6.0 hours, and then diluted with 20'.O ml of ethyl acetate.

The reaction mixture was then neutralized with sodium bicarbonate solution, and after separation of the aqueous and organic phases, the aqueous phase was extracted twice with 10.0 ml of ethyl acetate. The combined organic extracts were then washed with 8.0 ml of water and 10.0 ml of brine and then dried over magnesium sulfate. After concentration in vacuo, the residue was purified by flash chromatography on silica gel, using ethyl acetate:methanol (19.0:1.0) as eluent.

42.0 mg of the desired title compound was obtained as a white, foamy substance.

TLO, (SiiQ'^, e thylacetate methanol; 19.0 : 1.0 ):

_Rf = 0.30;

¹ H-NME, ( DMSO),delta::

8.43, ( 1H, s.„ CH ), 8.20, ( 1H, s.s., CH ), 7.79, C 1H, s.d.,

NH ), 6.45, ( 2H, v.s.s., 2x OH) ), 6.16, ( 1H, d., CHI ), 5.24, ( 1H, d., CH )„ 4.89, ( 1H, t _T , CHI ), 4.73, ( 1H, t., CH ),

4.58,, (1H„ s.m., CHi), 2.42, (3H, s., Me ), 2.10 - 1.50, (8H, m., 4x CHp.

Detailed experimental data using procedure S)

M? e z product • · 9 • · · · · · · • · · · · • · · · · ······ · · · ·

Preparation of 1-(38®,4E,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro-[3,4r-d//1,,3/-dioxol-4-yl/-pent-1-yn-3-ol

A solution prepared by dissolving 4E-ethynyl-6E-methoxy-2,2dimethyl-tetrahydro-(3a®, 6aR)-furo-[3,4-d//1,3/-dioxole, (1.503 g) _in 20.0 ml of tetrahydrofuran, was cooled at a temperature of minus 78.© °C, in a nitrogen atmosphere, for 15.0 minutes. Then, a solution obtained by dissolving 1.0.9 ml of propionaldehyde in 0.50 ml of tetrahydrofuran was added to the said solution using a syringe, and the reaction mixture was further stirred for 5.0 hours.

The reaction mixture was then warmed to 22.0°C and stirred for an additional 16.0 hours. After removal of the solvents in vacuo, the resulting orange-colored oily residue was partitioned between ether and aqueous ammonium chloride.

After separation of the organic and aqueous phases, the organic layers were further washed with aqueous ammonium chloride solution, 8 after drying with magnesium sulfate they were concentrated in vacuo, and a yellow-colored substance of oily consistency was obtained, which was purified by chromatography on silica gel, (Vérian Bondelut cartridge), using (2), cyclohexane, (II), dichloromethane, (III), ether, (IV), ethyl acetate, as eluents, and 1.33 g of the desired, title compound was obtained, in the form of a colorless substance of oily consistency,

TLC, ( SiO ₂ , ether :: cyclohexane J 1.0 :: 1.0 )::

R _f = Q),39;

M; e ziproduct 57/')

Preparation of 1-((3sR,4®, 62,6aR)-6-methoxy-2,2-dimethyltetrahydrofuran-[3,,4-d//1 ,3/-dioxol-4i-yl/-pent-1 -yn-3-one • · · ·

AND

A solution prepared by dissolving 1.30 g of 1-((3aR,4R,6R,6aR)6-methoxy-2,2-dimethyltetrahydrofuran-[3,4-d//1,3/-dioxol-4-yl]pent-1-yn-2-ol (obtained in the previous, above-described procedure for the preparation of Intermediate 56) in 100.0 ml of dichloromethane was added with constant stirring to a suspension prepared by suspending 60.0 g of manganese dioxide in dichloromethane at a temperature of 15°C.

The resulting reaction mixture was stirred at 0.0°C for 3.0 hours, and after filtration through magnesium sulfate (50.0 g), the solvent was removed under vacuum to give 550.0 mg of the desired title compound as a colorless, oily substance.

¹ H-ffi, delta,(CDCl^)f

5.07, (( 1H, a., CH ), 4.97, ( 1H, d., OH ), 4.93, ( 1H, a., CH ),

4.68, ( 1H, d. , CH ), 3.41, ( ( 3H, s., QMe ), 2.58, ( 2ff, k.,

0H ₂ ), 1.47, (( 3H, a,, Me ), 1.31, (( 3H, s., Me ), 1.14, (( 3H,

t., Me ) *

Intermediate 58)

Preparation of 1-[(3aR, 4R,6R,6eR)-6-methoxy-2,2-dimethyltetrahydrofuro [3,4-d//1 ,3/-dioxol-4?-yl]-pentane-1 ,3-dione-1-oxime

A mixture prepared by mixing 550.0 mg of 1-[(3sR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro-[3,4-d//1,3/-dioxol-4-yl]pent-1-yn-3-one, (obtained in the previous, above-described procedure for the preparation of Intermediate 57), and 0.20) ml of a 50% solution of hydroxylamine in water, in 10.0 ml of ethanol, was stirred at 22.6 °C overnight.

The resulting reaction mixture was concentrated in vacuo to give 554.0 mg of the desired title compound as a yellow-colored, oily substance.

¹ H-NMR, delta, (GECl^) :

5.36. 2.85, ( 2H, 2x ΑΒ,ΟΗρ, 1.92, ( 2H, m., GH ), 1.50, 1.34, ( 6H, 2x s., 2x Me ), 1.03, ( 3H, 2x t., Me ).·

M’ e z i p r o d u c t 59)

Preparation of (3R,4S,5R)-5-(5-ethylisoxazol-3>-yl)-tetrahydrofuran-2,3,

4-triol

A solution prepared by dissolving 0.50 g of 1-[(3aR,4R,6R,6aR)6-methoxy-2,2-dimethyltetrahydrofuro-[3,4-d//1,3/-dioxol-4-yl]pentane-1,3-dione-1-oxime, (obtained in the previous, above-described procedure for the preparation of Intermediate 58), in 18.0 mg of aqueous acetic acid, and the resulting reaction mixture was heated at 100.0) °C for 2.0 hours.

After the resulting reaction mixture was cooled and concentrated in vacuo, the resulting brown-colored oily substance was azeotropically treated with toluene. After purification of the residue by chromatography on silica gel (Varian Bondelut cartridge with silica gel), using (I), dichloromethane, (II), ether, (III), ethyl acetate, (IV), methanol as eluents.

150.0 mg of the desired title compound was obtained.

TLG,(SiO ₂ , ether):

_Rf = 0.17;

···· · · ··· · ·· • · · · ·

4 4 · 4 · ·

4 4 4 4 · 4 · · · · ·

We are the product of 60))

Preparation of (2R,3K,4R)-4,5-bis-(acetyloxy)-2-(5-ethyl-isoxazol-3-yl)-tetrahydrofuran-3-yl acetate

A solution prepared by dissolving 150.0 mg of isomers 1*, (3R,4S 5R)-5-(5-ethylisoxazol-3-yl)-tetrahydrofuran-2,3,4-triol, (obtained in the previous, above-described procedure for the preparation of Intermediate 59), in 4.0 ml of pyridine, was mixed with 0.983 ml of acetic anhydride, and the resulting reaction mixture was stirred at 22.0°C for 18.0 hours.

The reaction mixture was then concentrated in vacuo to give a brown oily substance which was purified by chromatography on silica gel (Varien Bondelut cartridge with silica) using (I) dichloromethane, (II) ether, (III) ethyl acetate as eluents.

The desired title compound was obtained as a pale yellow solid (142.0 mg)♦

TLC, ( _SiO2 in ether):

Rf = 0.53;

Intermediate 61)

Preparation of (2R,3R,4R,5B)-4-(acetyloxy)-2-(2,6-dichloro-9H-purin-9-yl)-5-(5-ethylisoxazol-3-yl)-tetrahydrofuran-3-yl acetate

A solution prepared by dissolving 193.0 mg of isomers 1j (2R,3B 4Ri) -4,5-bis— (acetyloxy) - 2-(5-ethylisoxazol-3-yl)-tetrahydrofuran-3-yl-8acetate, (obtained in the previous, above-described procedure for the preparation of Intermediate 60)), in 5.0 ml of acetonitrile, was mixed gradually* over 5.0 minutes, using a syringe, with 213.0 mg* of 2,6-dichloropurine*, then with 0.186 ml* of 1*8-diazabicyclo-/5,4,0/-undec-7-ene* (DBU), and with 0.225 ml of trimethylsilyl-trifluoromethanesulfonate* (TMSOTf), and the resulting, clear, yellow-colored reaction mixture was stirred at 22.0°C for 40.0 hours, then at 60.0°C for 21.0 hours, and at 80.0°C for 6.0 hours.

The reaction mixture was then cooled to room temperature, and an additional 0.186 ml* of 1,8-diazabicyclo-[5,4,0]undec;-7-ene* (DBU) and 0.225 ml* of trimethylsilyl trifluoromethanesulfonate* (> TMSOTf) were added.

Then, after further stirring at 22.0°C for 36.0 hours, the yellow reaction mixture was heated at 60.0°C overnight and then at 80.0°C for 6.0 hours. After removal of the solvents in vacuo*, the resulting residue, a brown oily substance, was taken up with ethyl acetate and then washed with 20.0 ml of water (3.0 L). After separation of the organic and aqueous phases*, the aqueous layer was extracted with ethyl acetate, and the combined organic extracts were dried over magnesium sulfate* and evaporated in vacuo. The residue, a brown oily solid*, was worked up mechanically and taken up with dichloromethane, and the white solid was isolated by filtration. After evaporation of the filtrate obtained, a yellow-brown solid was obtained, which was purified by flash chromatography on silica gel, using a mixture of ether:cyclohexane, (1.0::1.0), as eluent.

161.0 mg of the desired title compound was obtained as a white solid.

O,

LC/MS* ( System C ): R _f = 3.34 minutes;

ι.&.

4 4444 w

Mass spectrometry, (m/z): 470.0, 472.0, /MH ⁺ / _r /MH+2 ⁺ /J

Intermediate 62)

Preparation of (2R _, 3R, 4R, 5R)-4H-(acetoxyloxy)-2-(2-chloro-6-(1-ethylpropyl)amino)-9H-purin-9-yl)-5-(5-ethylisoxazol-3-yl)-tetrahydrofuran-3)-yl acetate

A solution prepared by dissolving 125.0 mg of (2R _, 3R, 4R, 5R)-4(acetyloxy)-2-(2,6-dichloro-9H-purin-9-yl)-5-(5-ethylisoxezol-3-yl)-tetrahydrofuran-3-yl acetate (obtained in the previous, above-described procedure for the preparation of Intermediate 61) in 5.0 ml of isopropanol was mixed first with 0.06 ml of diisopropylethylamine, and then with 0.044 ml of 1-ethylpropylamine.

The resulting reaction mixture was heated under nitrogen at 50.0°C for 16.0 hours. The solvent was then removed in vacuo, and the mixture was partitioned between ethyl acetate and 1% hydrochloric acid. After separation of the organic and aqueous phases, the organic layers were washed with saturated aqueous sodium bicarbonate, brine, and dried over magnesium sulfate, then evaporated in vacuo.

The residue was purified by chromatography on silica gel, using a Vari8n Bondelut cartridge, and eluting with (i), dichloromethane _, (II) _ether , and (III), ethyl acetate,

108.0 mg _of the desired title compound was obtained as a colorless oily substance.

TLG.„( SiO ₂ ; ether, ): Rj. - 0.26;

··. .UvjExample163)

Preparation of (2R,3H, _4S, 5R)-2-[2-chloro-6-[(1-ethylpropyl)amino]-9H-purin-9-yl]-5-(5-ethylisoxazol-3-yl)-tetrahydrofuran-3,4-diol formate

A mixture prepared by mixing 30.0 mg of (2R,3R,4R,5B)-4-(acetyloxy)-2-(2-chloro-6-(1-ethylpropyl)amino)-9H-purin-9-yl)-5-ethylisoxazol-3-yl)-tetrahydrofuran-3-yl acetate (obtained in the previous procedure for the preparation of Intermediate 62 above) with 0.037 ml of 2-morpholinoethylamine was heated at 90.0°C for 24.0 hours in 0.50 ml of dimethylsulfoxide, and the reaction mixture was further heated at 90.0°C for 60.0 hours.

After purification by preparative high performance liquid chromatography (HPLC) (gradient profile 5.0 - 95.0% (II) over 18.25 min.), 6.0 mg of the desired title compound was obtained as a white solid.

LC/MS, (System C):

R = 3.41 minutes;

Mass spectrometry, (m/z)t 437.0,/MH /*

Detailed experimental data using procedure T)

M' e z i p r o d u c t 63)

5£gg&88SSSS&&g£&iiSii2S&*SS^ φ 9 99 9 99 999 9 99

9 9 9 · · · · · · · 9 9 9 9 9

9 9 9 9 9 9 9 9

9 9 9 9 9 99 9

Preparation of 9-(3eR,4R,6S,6aR)-6-[5,-(tert-butyl-1,3 "4-oxadiazol-2-yl/-2,2-dimethyltetrahydrofuro-[3,4-d//1,3/-dioxol-4-yl]-NU (4-chloro-2-fluorophenyl)-9H-purin-6-emine

A mixture prepared by mixing 2.80 g of 9-[6S-(5-tert-butyl]-1,3,4-oxadiazol-2-yl]-2,2-dimethyl-tetrahydro-GaBio-[3,4-d]-1,3-dioxol-4E-yl]-6-chloro-9H-purine with 4.48 ml of 4-chloro2-fluoroaniline, further with 146.0 mg of palladium acetate, and 620.0 mg of (R)-2,2-bis-(diphenylphosphine)-1,1-bissulfite, in 34.0 ml of dried toluene, was stirred at room temperature for 5.0 minutes (the reaction was carried out in 7 batches).

After addition of 3.08 g of cesium carbonate (in 7 portions), the reaction mixture was heated at 86.0-96.0 °C for 16.0 hours, and after the individual batches were combined* they were partitioned between 200.0 ml of water and 3x 120.0 ml of dichloromethane. After separation of the organic and aqueous phases, the organic layers were washed with brine, and after drying with magnesium sulfate they were evaporated in vacuo. The residue, in the form of a brown-colored oily substance, (8.70 g), was purified by chromatography on silica gel, using a mixture of ethyl acetate :: cyclohexane, (30.0 :: 70.0) as eluent.

2.35 g of the desired title compound was obtained as a white solid.

LC/MS, (System O:

- 3.41 minutes;

Mass spectrometry, (m/z): 53O,O,/MH ⁺ /J

Example; 14) ·♦♦· • ♦ ·· · * · · « · · · · · · * ··· ·· · · · · • · · · · ' ♦ · · ·

2.00

Preparation of (2S,3S,4R,5B)-2-(5-tert-butyl-(1,3,4)-oxadiazol-2-yl)5-[6-(4-chloro-2-fluorophenylamino)-purin-9-yl]-tetrahydrofuran-3,4-diol

A solution prepared using an ice-cooled bath by dissolving 2.35 g, 9-{(38R,.4R,.6S _' 6aH)-6-[5-(tert-butyl)-1,3,4-oxadiazol-2-yl]-2,2-dimethyltetrahydrofuro-[3,4-d//1,3/-dioxol-4-yl} N-(4-chloro-2-fluorophenyl)-9H-purin-6-amine, (obtained in the previous, above-described procedure for the preparation of Intermediate 63) in 20.0 ml, trifluoroacetic acid, and 2.0 ml, water, was allowed to stand at 4.0 °C for 17.0 hours.

Then the reaction mixture was slowly poured into 400.0 ml of ice-cooled saturated sodium bicarbonate solution, and was subsequently extracted 3 times with 200.0 ml of ethyl acetate each time.

After separation of the organic and aqueous phases, the organic layers were washed with brine, and after drying with magnesium sulfate, they were evaporated in vacuo.

2.30 g of the desired title compound was obtained as a tan solid.

LC/MS, (System C):

R t - 3.04 minutes;

Mass spectrometry, (m/Z): 490.0,/MH ⁺ /;

Detailed experimental data using procedure U)

Intermediate 64)

9999 99 9999 99 • 9 9 9 9 9

99 9 9 9 9 9 9

9 9 9 9 · ·

2-04

Preparation of 9-/6S-(5-tert.-butyl 1-(1,3,4/-oxadiazol-2-yl)-2,2-dimethyl 1-tetrahydro-(3aR _r 6aS)-furo-/3,4-d//1,3/-dioxol-4E-„l/-6chloro-9H-purin

To a solution prepared by dissolving 0.40 g of 1-deoxy-1-(1,6-dihydro-6-oxo-9H-purin-9-yl)-2,3-0-(1-methyl thylidene)-beta-B-ribofuranic acid (see reference to the professional journal J.Med. Chem.,, 29, 1683,/1986/,, author R.A. Olsson et al.), in 10.0 ml of tetrahydrofuran, 0.075 ml of diisopropylethylamine was added, and the resulting reaction mixture was stirred at a temperature of 0.0.0°C for 10.0 minutes *

Then, 0.016 ml of pivaloyl chloride was added to the reaction mixture, and the mixture was then stirred at 0.0°C for 3.0 hours. Then, a solution obtained by dissolving 0.36 g of t-butylhydrazide trifluoroacetate in tetrahydrofuran, cooled to 0.0°C, and subsequently mixed with 0.24 ml of diisopropylethylamine was added to the reaction mixture, and this reaction mixture was stirred for 20.0 hours after warming to 20.0° _C .

After removal of the solvent in vacuo, the resulting residue was purified by flash chromatography over silica gel, using a mixture of 5% methanol in dichloromethane as eluent, to give 0.41 g of the corresponding diacyl hydrazide.

To a solution prepared by dissolving 30.0 mg of the above diacylhydrazide intermediate in 3.0 ml of N,N-dimethylformamide and cooled to 0.0°C was added 45.0 mg of phosphorus oxychloride, and the reaction mixture was stirred at room temperature for 8.0 hours and then at 90.0°C for 2.0 hours. After removing the solvent in vacuo, the resulting residue was purified by automated preparative high-performance liquid chromatography (HPLC) to give 20.0 mg of the desired title compound.

9999 99 9999 99

9 9 9 9 9 9 9

9999 99 9 99

9 9 9 9 9 9 9 9

99 «· 999

Detailed experimental data using procedure V)

Intermediate 65)

Preparation of (2R,3R,AR,5S)-4-(acetyloxy)-5-[3-(acetyloxy)-methyl]isoxazol-5-yl]-2-(6-chloro-9H-purin-9-yl)-tetrahydrofuran-3-yl acetate

A mixture prepared by mixing 1.0 g of 6-chloropurine with 20.0 ml of 1.1.1.3.3.3-hexamethyldisilazane was heated under nitrogen at 100.0 °C for 2.50 hours.

Then, after cooling, the solvent was removed from the reaction mixture in vacuo, and the residue was azeotropically treated with anhydrous toluene, (2 x 2.50 ml), and the mixture was then evaporated to dryness, and an off-white solid was obtained. To this was added, under a nitrogen atmosphere, 450.0 mg of 4R-acetoxy-2S-(3-scetoxymethyl-isoxazol-5-yl)-5B-methoxy-tetrahydro-furan-3E-yl acetic acid ester in 15.0 ml of anhydrous acetonitrile, and then trimethylsilyl trifluoromethanesulfonate, (1.40 ml), was added to this reaction mixture, cooled to 400°C.

After the reaction mixture was warmed to 20.0 °C for 20.0 minutes, it was heated at 80.0 °C for 16.0 hours. After cooling, the mixture was poured into 40.0 ml of saturated aqueous sodium bicarbonate solution and then extracted 3 times with 70.0 ml of ethyl acetate each time. After separating the organic and aqueous phases, the organic layers were combined, and after washing with 50.0 ml of brine, the organic layers were dried with magnesium sulfate and concentrated to dryness.

The crude product was obtained and purified by flash column chromatography on silica gel using ethyl acetate:cyclohexane (1.0:1.0) as eluent.

310.0 mg of the desired title compound was obtained as a clear, oily substance.

• 9 • 9999

9 9 • 999

9

9 • 9 9999

9 9

9 9

9 9

9 9 9

99

9

LC/MS, (System C):

E^. = 2.76 minutesJ

Mass spectrometry, (m/z): 480.0/482.0/MH ⁺ //MH+2 ⁺ /\

Example 1 β d; 155)

Preparation of (2R,3E,4S',5S3)-2-(6-{/(1S,2S)-2-hydroxycyclopentyl/*a amino J -9H-purin-9-yl)-5-/3-(hydroxymethyl)-isoxazol-5-yl/tetrahydrofuran-3,4-diol

To a solution prepared by dissolving 20.0 mg of (2R,3K,4R,5S)-4r-(acetyloxy)-5-[3-(acetyloxy)-methyl]-isoxazol-5-yl]2-(6-chloro-9H-purin-9-yl)-tetrahydrofuran-3-yl acetate (obtained in the previous, above-described procedure for the preparation of Intermediate 65) in 2.0 ml of isopropyl alcohol, 0.043 ml of N,N-diisopropylethylamine and 11.40 mg of 2-hydroxycyclopentylamine hydrochloride were added, and the resulting reaction mixture was stirred at 50.0 °C under a nitrogen atmosphere for 18.0 hours.

Then, after cooling, the mixture was evaporated to dryness under vacuum, and the resulting residue was purified by automated preparative high-performance liquid chromatography, (HPCL), (gradient profile 5.0% - 90.0% (II), for 20.0 minutes.

The intermediate product was obtained as a triacetoxy protected product, to which 1.0 mL of methanol and 0.013 mL of t-butylamine were added and the mixture was stirred at 0.0°C for 3.0 hours. After evaporation of the solvent in vacuo, 5.0 mg of the desired title compound was obtained as a white solid.

4 4 4 4 4

4 • 4 4 4 * 4 4 ·· ·

4 4······• 44 444 4· 44 444

LC/MS, (System C):

R - 2.25 minutes;

L

Mass spectrometry, (m/z):: 419,,0;,/MH ⁺ /;

Detailed experimental data using procedure W)

Intermediate 663 • Preparation of (2R,3E,4R,5R0-4-(acetyloxy)-2-ethynyl-5-methoxytetrahydrofuran-3-yl-acetate

A mixture prepared by mixing 0.965 g of 4E-ethynyl-6R-methoxy2,- 2-dimethyl-tetrahydro-(3aE,6sE)-furo~/3,4-d//1,3/-dioxole with 1.0 ml of concentrated hydrochloric acid in 30.0 ml of methanol was heated under reflux for 6.0 hours.

Then, after evaporation of methanol in vacuo, more methanol was added to the reaction mixture, and the mixture was further heated under reflux for 16.0 hours. After subsequent addition of 1.60) ⁵ ml, pyridine, methanol was again evaporated from the mixture in vacuo, and after further addition of methanol, the mixture was evaporated to dryness in vacuo.

The resulting residue was dissolved in dried dichloromethane, and to the resulting solution were added 1.60 ml of pyridine, 25.0 mg of 4-dimethylaminopyridine, and 1.37 ml of acetic anhydride, and this mixture was stirred at 22.0°C under nitrogen for 18.0 hours. The mixture was then evaporated to dryness in vacuo, and the residue was partitioned between 100.0 ml of saturated aqueous citric acid (citric acid = 2-hydroxypropane-1,2,3-tricarboxylic acid) and 2x 75.0 ml of dichloromethane.

4444 44 4444 44

444 44 4 444

4444 44 4 44 • «444 4444

44 44 444 £05

After separation of the organic and aqueous phases, the organic layers were washed with saturated aqueous sodium bicarbonate solution, and after drying with magnesium sulfate, they were evaporated in vacuo.

1.19 g* of a pale yellow colored substance of oily consistency* was obtained which was purified by chromatography over silica gel (Varian Bondelut cartridge, 10.0 g), using a mixture of ethyl acetate:cyclohexane (5.0:95.0 - 30.0::70.0) as eluent.

724.0 mg of the desired title compound was obtained as a colorless, oily substance.

TLC,( _SiO2 , ethyl acetate:cyclohexane* 25.0:75.0):

_Rf = 0.30;

Intermediate 67)

Preparation of (2R*3R*4R,5R)-4-(acetyloxy)-2-(6-chloro-9H-purin-9-yl)-5-ethynyltetrahydrofuran-3-yl acetate

A mixture prepared by mixing 250.0 mg* of 6-chloropurine, seeéyQ) ml, of hexamethyldisilazane, was heated with constant stirring* in a nitrogen atmosphere* on an oil bath at a temperature of 130.0'°C, for 2.0 hours.

The excess reagent was then removed from the reaction mixture under vacuum and the residue was azeotropically treated with dried toluene (3 x 5.0 ml) to give a pale yellow solid.

Then 121.0 mg of (2R*3R,4R,5R)-4-(acetyloxy)-2-ethynyl-5-methoxytetrahydrofuran-3-yl acetate, (obtained in the previous, above-described procedure for the preparation of Intermediate 66), was dissolved after azeotropic treatment with dried toluene, j (2 x 5.0 ml), dissolved in dried acetonitrile, and obtained

2.0C

9 9999 99 9 9 9 9 9 9 9 9 9 4 99 9 « 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

• 9

9

9 solution was added to the silylated purine prepared in the previous operation described above, and then, after adding 0.334 ml of trimethylsilyl trifluoromethanesulfonate, the reaction mixture was heated at 73.0-74.0 °C for 2.0 hours.

The mixture was then poured into a saturated aqueous solution of sodium bicarbonate, and subsequently extracted 3 times with 60.0 ml of ethyl acetate. After separating the organic and aqueous phases, the organic layers were washed with brine, and after drying with magnesium sulfate, they were evaporated in vacuo.

203.0 mg of a yellow-colored oily substance was obtained, which was purified by silica gel chromatography (Varian Bondelut cartridge), using a mixture of ethyl acetate and cyclohexane (10.0:90.0-60.0:40) as eluent.

84.0 mg of the desired title compound was obtained as a colorless, gummy substance.

TLC, (SiO ₂ , ethyl acetate : cyclohexane,, 50.0 : 50.0 ):

R _f , = OJ, 25;

Intermediate 68)

Preparation of (2R,3R,4R,5R)-4-(acetyloxy)-2-/6-(1H-1,2,3-benzotriazol-1-yloxy)-9H-purin-9-yl/-5-ethynyltetrahydrofuren-3-yl acetate

A mixture prepared by mixing 104.0 mg of (2R,3R,4R,.5R)-4(acetyloxy)-2-(6-chloro-9H*purin-9-yl)-5-ethynyltetrahydrofuran-3-yl acetate (obtained in the previous, above-described preparation of Intermediate 67) _with 136.0 mg of 1-hydroxybenzotriazole in 3.0 ml of dried N,N-dimethylformamide was heated at 22.0 °C for 45.0 hours.

• ·

Í.OJ999 9 99 99 9 9 99 • 9 9 9 9

999 99 · · · · • · · · ♦ 9 · · · • · 9 9 9 9 9 9

999 99 99 99 999

The reaction mixture was then poured into 50.0 ml of ice-cold 1M hydrochloric acid solution and extracted 3 times with 25.0 ml of dichloromethane each time. After separating the organic and aqueous phases, the organic layers were washed first with 20.0 ml of water and then with 20.0 ml of saturated aqueous sodium bicarbonate solution, and after drying with magnesium sulfate, they were evaporated in vacuo.

148.0 mg of the desired title compound was obtained as a colorless, gummy substance.

LC/ _MS (System C):

= 3.19 minutes J

Mass spectrometry, (m/z): 464.0,/MH /J

Intermediate 69)

Preparation of ( _2R 3R,4R,5R)-4-(acetyloxy)-2-[6-(4-chloro-2-fluoroaniline)-9H-purin-9-yl]-5-ethynyltetrahydrofuran-3-yl acetate

A mixture prepared by mixing (2R,3R,4R,5R)-4-(acetyloxy)-2/6-(1H-1,2,3-benzotriazol-1-yloxy)-9H-purin-9-yl/-5-ethynyltetrahydrofuran-3-yl acetate ₍ obtained in the previous, above-described procedure for the preparation of Intermediate 68), with 0.63 ml of 2-fluoro-N-chloroaniline, was heated at 60.0 °C for 22.50 hours.

The reaction mixture was then purified by chromatography over silica gel (Varian Bondelut cartridge), using a mixture of ethyl acetate:cyclohexane, (10.0:90.0 - 60.0:40.0), as eluent.

55.0 mg of the desired title compound was obtained.

9999 99 9999 99 · ··· · · · 9 9 99

999 999 99 9

9 9 9 9 9 9 9 9 · • · 9 9 9 9 9 9 9 9

999 999 99 99 99 999

2M

TLC, ( _SiO2 , ethyl acetate:cyclohexane, 50.0:50.0): _Rf = 0.30;

Intermediate 70) (2R*32*4R*6S)-4-(acetyloxy)-5-(3-bromosoxazol-5-yl)-2-(6-(4chloro-2-fluoroanilm)-9H-purin-9-yl)-tetrahydrofuran-3-yl-acetate

A mixture prepared by mixing 20.0 mg of (22,32,42,52)-4-(acetyl phenyl)-2-[6-(4-chloro-2-fluoroaniline)-9H-purin-9-yl]-5-ethynyltetrafuran-3-yl acetate (obtained in the previous, above-described procedure for the preparation of Intermediate 69), further 12.50 mg of dibromoformaldoxime, 39.0 mg of sodium bicarbonate, 0.075 ml of water, and 1.50 ml of ethyl acetate, was stirred at 22.0 °C for 88.0 hours.

The resulting reaction mixture was partitioned between 20.0 ml of water and 3x each 10.0 ml of ethyl acetate, and after separating the organic and aqueous phases, the combined organic layers were washed with brine, and then evaporated in vacuo* ”

The residue, in the form of a brown colored gummy substance, was purified by chromatography on silica gel (Varian Bondelut cartridge), using a mixture of ethyl acetate:cyclohexane, (20.0:80.0 - 80.0:20.0), as eluent.

16.80 g of the desired title compound was obtained as a colorless, gummy substance.

LC/MS, (System ©):

_Rt < 3.60 minutes;

Mass spectrometry, (m/z):

595.0; 597; /MH ⁺ /,/MH+2 ⁺ /; ^ø • · · · • · · • · · * • · 9

99 ···

Zoq

Example 164)

H-f:

Preparation of (2S,3S, _4R, 5R)-2-(3-bromoisoxazole)-5-yl)-5-[6-(4-chloro-2-fluoroanilin)-9H-purin-9-yl]-tetrahydrofuran-34-diol

A mixture prepared by mixing 16.80 mg of (2R,3R,4R,5S)-4-(acetyloxy)-5-(3-bromoisoxazol-5-yl)-2-[6-(4-chloro-2-fluoroanilin)-9Hpurin-9-yl]-tetrahydrofuran-3-yl acetate (obtained in the previous procedure for the preparation of Intermediate 70 described above) with 0.08 ml of t-butylamine in 0.60 ml of methanol was reacted at 0.0 °C for 1.50 h and then evaporated to dryness to give 16.0 mg of the desired title compound.

LC/MS, (System C):

_Rt = 3.22 minutes;

Mass spectrometry, (m/z): 511.0,/MH ⁺ /;

Detailed experimental data using procedure Wb)

Example 144)

Preparation of (2R,3R,4S,5S)-2-[6-(4-chloro-2-fluoroaniline)-9H-purin-9y1]-5-(3-methylisoxazol-5-yl)-tetrahydrofuran-3,4-diol

A mixture prepared by mixing 20.0 mg of (2R,3R,4R,5R)-4-(acetyl oxy)-2-(6-chloro-9H-purin-9-yl)-5-ethynyltetrahydrofuran-3-yl acetate with 0.50 ml of anhydrous toluene was further mixed.

• ·· · • · ·

24ο ·· · • · ·· • · · • · · • · · ·« ·· ·

0.006 ml, triethylamine, then 0.004 ml, nitroethane, and 0.012 ml,

I phenylisocyanate, and the resulting reaction mixture was heated at 100.0 °C for 24.0 hours.

After cooling to room temperature, the mixture was concentrated in vacuo, and the resulting residue was purified by automated preparative high-performance liquid chromatography (HPLC) to give an intermediate which was dissolved in anhydrous methanol, cooled to 0.0 °C, and then reacted with 0.02 mL of t-butylamine for 1.0 h.

The reaction mixture was then concentrated in vacuo to give 143.0 mg of the desired title compound as a white solid.

LC/MS, (System C):

R x 2.95 minutes;

Mass spectrometry, (m/z): 447.0,/MH /*

Detailed experimental data using procedure X)

Example 130)

Preparation of (2R,3R,4S,5R)-2-[6-(cyclopentylamino)-9H-purin-9-yl][5-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)-tetrahydrofuran-3,4-diol trifluoroacetate

To a solution prepared by dissolving 250.0 mg of 9-[2,2-dimethyl-6R-(5-methyl-4H-[1,2,4]-triezol-3-yl)-tetrahydro- (3eR, £aR)-furo-[3,4-d//1,3/-dioxol-4R-yl]-9H-purin-6-yl]-cyclopropyl···· amine in 10.0 ml of anhydrous toluene, 0.47 ml of dimethylformamide dimethyl acetal was added, and the resulting reaction mixture was heated under reflux for 7.0 hours.

The reaction mixture was then cooled to 20.0°C and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel using ethyl acetate:methanol (19.0:1.0) as eluent.

The resulting intermediate was mixed with a mixture of trifluoroacetic acid ^: water, 9.0:1.0), and reacted at 0.0 °C for 6.0 hours. The reaction mixture was then concentrated in vacuo, and after subsequent mechanical work-up and removal of the residue with ethyl acetate, 143.0 mg of the desired title compound was obtained as a white solid.

Analytical evaluation of the compound according to the summary formula ^C 18 ^H 24 ^N 8°3· ^CF 3 ^CO 2 ^H · ¹ » ^{5 H} 2 ^0í

Calculated: C 44.40, H 5.20, N 20.70, %

Found: C 44.40, H 4.80 _, N 20.40, %

Detailed experimental data using procedure Z)

Intermediate 71)

Preparation of (24,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy?-methyl]5-[2-chloro-6-(4-chloro-2-fluoroanilin)-9H-purin-9-yl]-tetrahydrofuran-3-yl acetate

To a solution prepared by dissolving 1.0 g of 2,6-dichloro-9(2,3,5-tri-Q-acetyl-beta-D-ribofuranosyl)-9H-purine (see <··· ··· »· ···· • < · • · · » ^« · · · · » ·· · Tett.2ett.,5327-5330,/1998/, authors PJ Sadighi, MC Harris and Buchwald SL ), and the resulting reaction mixture was stirred at 20.0 °C for 15.0 minutes.

After subsequent addition of 872.0 mg of cesium carbonate, the reaction mixture was heated at 90.0 °C for 16.0 hours. The reaction mixture was then cooled to 20.0 °C and partitioned between 100.0 mL of ethyl acetate and 100.0 mL of water. After separation of the organic and aqueous phases, the organic layer was washed with 100.0 mL of brine, and after drying with magnesium sulfate, the solvent was removed in vacuo.

After purification of the residue by flash chromatography on silica gel, using ethyl acetate:cyclohexane (1.0:1.0) as eluent, 400.0 mg of the desired title compound was obtained.

Mass spectrometry, (m/z): 556.0,/MH ⁺ /J

Intermediate 72)

Preparation of [(3aR,4R,6R,6aR)-6-[2-chloro-6-(4-chloro-2-fluoroanilin)9H-purin-9-yl]-2,2-dimethyltetrahydrofuro-[3,4-yl//1,3/-dioxol4-yl]-methanol

To the suspension, prepared by suspending 400.0 mg, (2R,3R,4R,5R)-4-(acetyloxy)-2-/(acetyloxy)-methyl/-$-/2-®chloro-6-(4chloro-2-fluoroshilin)-9H-purin-9-yl/-tetrahydrofuran-3-yl-acetate, (obtained in the previous, above-described procedure ·· · · • · · · · · · · · · · · · · · · · · · · ·

·. ··· · · · · · · • ·

_After further stirring the reaction mixture at 20.0°C for 90.0 minutes, a precipitate formed, which was isolated by filtration and then dried under vacuum for 16.0 hours. The precipitate formed was dissolved in a mixture prepared by mixing 15.0 ml of acetone and 3.0 ml of 2,2-dimethoxypropane. To the resulting solution was added 193.0 mg of per-toluenesulfonic acid, and the mixture was stirred at 20.0°C for 3.0 hours.

After removing the solvent from the mixture under vacuum, the residue was dissolved in 50.0 ml of ethyl acetate, and the resulting solution was successively washed with 50.0 ml of water, 8 with 30.0 ml of brine, and after drying with magnesium sulfate, the solvent was removed under vacuum. After purification of the residue by chromatography on silica gel (Varian Bondelut cartridge), using a mixture of cyclohexane:ethyl acetate (1.0:1.0) as eluent, 240.0 mg of the desired title compound was obtained as a white foamy substance.

Mass spectrometry, (m/z): 47O.O./MH/;

Detailed experimental data using procedure Y)

Intermediate 73)

Preparation of tert-butyl-4-[(9- (2R,3R,4R,5S)-3,4-bis-(acetyloxy)5-[3-( tert-butyl)-isoxazol-5-yl]-tetrahydrofuran-2-yl]-9H-purin-6-yl)-amino]-piperidine-1-carboxylate

To a solution prepared by dissolving 455.0 mg of 4R-scetoxy-5S-(3-tert-butyl-isoxazol-5-yl)-2R-(6-chloro-purin-9-yl)-tetrahydro-furan-3R-yl-acetic acid ester in 20.0 ml of isopropanol, 785.0 mg of tert-butyl-4-emino-1-piperidinecarboxylate and 1.03 ml of diisopropylethylamine were added, and the resulting reaction mixture was heated at 95.0 °C for 60.0 hours.

The reaction mixture was then cooled and evaporated to dryness in vacuo, and the resulting residue was dissolved in 20.0 ml of pyridine, and 19.0 ml of acetic anhydride was added to the resulting solution. The reaction mixture was then stirred at room temperature for 16.0 hours, and after evaporation in vacuo, the residue was dissolved in 50.0 ml of ethyl acetate. This solution was then shaken twice with 50.0 ml of citric acid (citric acid = 2-hydroxypropane-1,2,3-tricarboxylic acid), and after separating the organic phase from the aqueous phase, the aqueous layers were extracted with 100.0 ml of ethyl acetate.

The combined ethyl acetate extracts were dried with magnesium sulfate, filtered and evaporated in vacuo.

500.0 mg of the desired title compound was obtained as a yellow solid.

LC/MS, (System C):

R ^and 3.59 minutes*,

Mass spectrometry, (m/z): 628.0,/MH/;

Intermediate 74)

Preparation of (2R,3R,4R,5S)-4-(8-cetyloxy)-5-[3-(tert-butyl)-isoxazol-5-yl]-2-[6-(piperidin-4-yl-amino)-9H-purin-9-yl]-tetrahydrofuran-3-yl 1-8 acetate • »· · ··

A solution prepared by dissolving 500.0 mg of tert-butyl-4[(9-(2R,,3R»4R*5S)-3,4-bis-(acetyloxy)-5-[3-(tert-butyl)isoxazole-5-tetrahydrofuran-2-yl]-9H-purin-6-yl)-amino]-piperidine-1-carboxylate, (obtained in the previous, above-described procedure for the preparation of Intermediate 73), in 20.0 ml of trifluoroacetic acid:dichloromethane, (1.0:9.0), was stored at room temperature at 3.0 °C for 16.0 hours.

Then, after mixing with 100.0 ml of saturated aqueous sodium bicarbonate solution, the mixture was extracted with 100.0 ml of dichloromethane. After separating the organic and aqueous phases, the organic layer was washed with 100.0 ml of saturated aqueous sodium bicarbonate solution and then evaporated to dryness under vacuum.

407.0 mg of the desired title compound was obtained as a yellow, glassy solid.

LC/MS, (System C):

_Rt = 2.45 minutes;

Mass spectrometry, (m/z): 528.0,/MH/;

Intermediate 75)

Preparation of (2R,3R,4R,5S)-4-(acetyloxy)-5-[3-(tert-butyl)-isoxazol-5-yl]-2-(6-[1-(methylsulfonyl)-piperidin-4-yl)-amino]-9H-purin-9-yl]-tetrahydrofuran-3-yl-acetate

To the solution prepared by dissolving 40.0 mg, (2R,3R,4R,5S)

4-(acetyloxy)-5-[3-(tert-butyl)-isoxazol-5-yl]-2-[6-(piperidin-4-yl-amino)-9H-purin-9-yl]-tetrahydrofuran-3-yl-acetate, (obtained in the previous, above-described procedure for the preparation of Intermediate 74), in 4.0 ml, tetrahydrofuran, 0.0088 ml, methanesulfonyl chloride, and 0.0212 ml, triethylamine were added, and the resulting reaction mixture was stirred at 20.0 °C for 16.0 hours.

The mixture was then partitioned between ethyl acetate (2 x 100.0 ml) and 100.0 ml of water, and after separating the organic and aqueous phases, the organic layers were washed with 100.0 ml of water, and after drying with magnesium sulfate, they were evaporated in vacuo.

36.70 mg of the desired title compound was obtained in the form of a colorless, gummy substance.

LC/MS, (System C):

R^ * 3.20 minutesj

Mass spectrometryAm/z): 6O6,O,/MH ⁺ /J

Example 167)

Preparation of (2S,,3S,4R,5R).-2-[3-(tert-butyl)-isoxazol-5-yl]-5-(6E[1-(methylsulfonyl)-piperidin-4-yl)-amino]-9H-purin-9-yl)tetrahydrofuran-3,4-diol

To a solution prepared by dissolving 36.70 mg of (2R,3R,4R,5S)-4-(acetyloxy)-5-[3-(tert-butyl)-isoxazol-5-yl]-2-(6E-1-(methylsulfonyl)-piperidin-4-yl]-8amino-9H-purin-9-yl)tetrahydrofuran-3-yl acetate (obtained in the previous, above-described procedure for the preparation of Intermediate 75) in 2.0 ml of cooled methanol, 0.038 ml of tert-butylamine was added at a temperature of 0.030 °C, and the resulting reaction mixture was stored at rest at a temperature of 3.0 °C for 1.50 hours.

Subsequent evaporation of the mixture gave 30.80 mg of the desired title compound as a white solid.

• 4 · · · · · · · · 4 · ·

4 4 · · · 4 4 4 • 4 · 4 44 4 44

4444 4444

-LC/MS, (System. C):

R^ ⁵⁸ 2.69 minutesj

Mass spectrometry, (m/z): 522.0,/MH/;

Detailed experimental data using procedure Bb)

Intermediate product 76)

Preparation of (2R,3R,4R,5S)-4-(acetyloxy)-η,3-[(acetyloxy)-methyl]-oxazol-5-yl]-2-(2-chloro-6-(4-chloro-2-fluoroaniline)-9H-purin-9-yl)-tetrahydrofuran-3-yl-acetate

To a solution prepared by dissolving 50.0 mg of 4R-acetoxy-5S(3-acetoxymethyl-isoxazol-5-yl)-2R-(2,6-dichloro-purin-9-yl)tetrahydro-furan-3R-yl acetic acid ester in 2.0 ml of toluene, 2.20 mg of palladium acetate (palladium(II) acetate), 6.0 mg of 2,2-bis-(diphenylphosphine)-1,1-binaphthyl, and

28.50 mg of 4-chloro-2-fluoroaniline, and the resulting reaction mixture was stirred under a nitrogen atmosphere for 20.0 minutes.

Then, after adding 38.0 mg of cesium carbonate, the reaction mixture was stirred further at 80.0 °C for 24.0 hours. After subsequent cooling, the mixture was diluted with 25.0 ml of ethyl acetate, and after successively washing with 25.0 ml of water and 25.0 ml of brine, it was evaporated in vacuo.

The residue was purified by automated preparative high performance liquid chromatography (HPLC) (gradient profile 5.0-90.0.#)»(II), over 18.5 minutes) to afford 3.02 mg of the desired title compound as a white solid.

• »· · • · ·

LC/MS, (System C):

_Rt - 3.52 minutes;

Mass spectrometry, (m/z): 623.0,/MH ⁺ /J

Intermediate 77)

Preparation of (2R,3R,4S,5S)-2-[2-chloro-6-(4-chloro-2-fluoroaniline)9H-purin-9-yl]-5-[3-(hydroxymethyl)-isoxazol-5-yl]-tetrahydrofuran-3,4-diol

To the solution prepared by dissolving 4.02 mg, (2R,3R,4R,5S)

4-(acetyloxy)-5-(3-[(acetyloxy)-methyl]-isoxazol-5-yl]-2-(2-chloro-6-(4-chloro-2-fluoroanilin)-9H-purin-9-yl)-tetrahydrofuran-3-yl acetate, (obtained in the previous, above-described procedure for the preparation of Intermediate 76), at a temperature of 0.0 °C, in 2.0 ml, methanol, 0.012 ml, tert.-butylamine was added, and the resulting reaction mixture was left to stand at a temperature of 0.0 °C for 3.0 hours.

After subsequent evaporation of the solvent from the mixture under vacuum, 2.48 mg of the desired title compound was obtained in the form of a yellow-colored substance of gummy character.

LC/MS, (System C):

from

R _t ^s 3.10 minutes;

•φ»

Mass spectrometry, (m/z): 497.0,/MH/;

4 4 4 9 9 999 9 99 4 · • 4 4 · 9 9 99

999 4 4 9 ·· ·

9 9 9 9 9 9 9 4 • 4444 44 4

444 44 44 44 444

Detailed experimental data using procedure Cc)

Meat product 78)

Preparation of (3sR> 4S, 6R,6aR)-N-acetyl-[6-(4-chloro-2-fluoro-nitro)-9H-purin-9-yl]-2,2-dimethyltetrahydrofuran-[3,4-d//1,3/-dioxole4-carbohydrazide]

To a solution prepared with constant stirring, and at a temperature of 0.0 °C, by dissolving 50.0 mg, (3aR,4S,6R,6sR)-6-/6-(4rchloro-2fluoroaniline)-9H-purin-9-yl/- 2,2-dimethyltetrahydrofuran-/3,4-d/ /1,3/~dioxole-4-carbohydrazide, in 2.0 ml, N,N-dimethylformamide, was added 28.0 µl of diisopropylethylamine, and 9.0 mg, of acetyl chloride, and the resulting reaction mixture was stirred at a temperature of 0.0 °C for 5.0 hours.

Then the reaction mixture was partitioned between 20.0 ml, ethyl acetate, and 20.0 ml, water, and after separating the organic and aqueous phases, the organic layer was washed with 20.0 ml, brine, and after drying with magnesium sulfate, the solvent was removed in vacuo.

The resulting residue was purified by automated preparative high performance liquid chromatography (HPLC) (gradient gradient 5.0 - 95.0%, (II), over 18.5 minutes) to yield 25.0 mg of the desired title compound.

LC/MS, :

R « 2.87 minutes*,

Mass spectrometry, (m/z): 5O6.O,/MH /;

The following steps are analogous to procedure A).

• « · · · ·

220

Reporter gene experiments

Agonist activity was measured in Chinese hamster ovary cells, CHO containing the CRE/SPAP/HYG system (CRE = cyclic AMP element, HYG = hygromycin resistance element, SPAP = placental alkaline phosphatase secretion element), which produces SPAP upon cAMP stimulation. A cell line stably transfected with the human adenosine A1 receptor gene or the human adenosine A3 receptor gene in addition to the above elements was used. The cells were plated in 96-well plates containing culture medium and incubated for 1 hour at 37°C. To measure the efficacy, agonists were added to the respective wells at concentrations of ^{10 -10} to 10 ^-5 M. After 15 minutes, cAMP stimulation was performed by adding the maximum concentration of forskolin. All cells were then incubated for another 5 hours at 37 °C, then cooled to room temperature, after which a substrate for phosphatase (p-nitrophenol phosphate, pNPP) was added, which was converted by the action of SPAP into a colored reagent, after which the wells of the said plate were read using the appropriate device. From the read values, it is possible to calculate the dependence of the inhibition of SPAP production, stimulated by forskolin, by the action of the agonist on the concentration. One of the agonists used was the standard non-selective agonist, N-ethylcarboxamide adenosine, NECA, the efficacy of all agonists subjected to this test was then expressed relative to the efficacy of this standard NECA.

ECR = concentration value, as effective as NECA, whose effectiveness is considered to be 1.

221

Table 2. Efficacy in reporter gene assay

Example No. Adenosine Al receptor ECR* Adenosine A3 receptor 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 8.75 423 28 0.42 44.7 37 4.19 507 44 7.68 165.54 45 7.36 165.54 51 7.56 587.75 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 4.1.9 325.44 126 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 _

222

9 9 99 9

9 • 9 9 · 9 9 99

999 99 9 9· 9

999 9 999 9 9

9999 99 9

999 99 99 99 999

135 0.48 136 1.95 138 1.31 139 10.64 228 141 12.08 228 143 19.6 >74.1 144 2.8 145 24.9 163 1.34. 232 164 4.3 177 2.01 122 178 7.42 >471 179 12.6 180 18.1 >471 181 8.57 182 3.48

*ECR = concentration relative to the NEC A concentration, which is considered 1 (see description for reporter gene experiment!

Claims (24)

PATENT CLAIMS Adenosine derivatives of the general formula I NH R wherein X represents 0 or CH _2, ^R2 represents Cl-3 alkyl, Cl -C 3 alkoxy, halogen or hydrogen, R ³ is hydrogen, phenyl, optionally substituted with halogen, 5 or β-membered heteroaryl, C 1 -C 6 alkoxy, C 1 -C 6 alkylO (CH ₂ ) _n where n is 0-6, C 3 -C 7 cycloalkyl, C 1 -C 6 hydroxyalkyl, atom halogen, straight-chain or branched C1-C6 alkyl, C 1 -C 6 alkenyl or C 1 -C 6 alkynyl, optionally substituted with at least one halogen atom, Y and Z are O, N, CH or N (C1-C6 alkyl), W is CH, O, N, S or N (C1-C6alkyl), wherein at least one of W and Z is a heteroatom, and when Y, Z and / or W is a nitrogen atom, the absence of another hydrogen atom is apparent, provided that when W is CH, Z is nitrogen and Y is oxygen, R ³ has the meanings different from hydrogen, R ⁴ and R ⁵ independently represent a hydrogen atom or a straight or branched C 1 -C 6 alkyl; 224 R ¹ represents a hydrogen atom or one of (1) - (alk) _n -C 3 -C 7 cycloalkyl, including a bridged cycloalkyl group, the cycloalkyl group being optionally substituted with at least one substituent from OH, halogen, C 1 -C 3 alkoxy, (alk) means a C 1 -C 3 alkylene group and n is 0 or 1, (2) an aliphatic heterocyclic group containing 4 to β-membered rings containing at least one O, N or S heteroatom optionally substituted by at least one C 1 -C 3 alkyl substituent, - CO 2 -C 1 -C 4 alkyl, -CO (C 1 -C 3 alkyl), -S (= O) _n -C 1 -C 3 alkyl, -CO NR ^and R ^b , wherein R ^a and R ^b independently represent hydrogen or C 1 -C 3 alkyl, or = 0 and when the heterocyclic ring contains a sulfur atom, the sulfur atom is optionally substituted by (= O) _n , where n is 1 or 2, (3) straight or branched C1-C12 alkyl optionally containing one or more in the alkyl chain multiple groups O, S (= O) _n where n is 0, 1 or 2 and N, alkyl groups are optionally substituted with one or more substituents from phenyl, halogen, hydroxy, C 3 -C 7 cycloalkyl or NR ^a R ^b , wherein R ^a and R ^b independently represent hydrogen, C 3 -C 7 cycloalkyl or straight or branched C 1 -C 6 alkyl, optionally substituted with a C 3 -C 7 cycloalkyl radical, (4) a fused bicyclic aromatic ring of formula wherein B is a 5 or β-membered heterocyclic aromatic ring containing at least one heteroatom from the group O, N 225 · «» • · * Or S, wherein the bicyclic ring is bonded to the nitrogen atom in the compound of formula I via ring A and ring B is optionally substituted with -CO ₂ -Cl-C 3-6 alkyl (5) a phenyl group optionally substituted with one or more substituents selected from halogen, SO ₃ H, - (alk) _n OH, - (alk) _n -cyano, - (O) _n -Cl-C 6 alkyl, optionally substituted with at least one halogen atom, - (alk) _n- nitro, - (O) _m - (alk) _n -CO ₂ R ^c , - (alk) _n -CONR ^c R ^d , - (alk) _n -COR ^c , - (alk) n-SOR ®, - (alk) n-SO ₂ R ^e , - (alk) n-SO ₂ NR ^c R ^d , - (alk) n OR ^c , - (alk ) n- (CO) _m -NHSO ₂ R ®, - (alk) _n -NHCOR ^c , - (alk) _n NR ^c R ^d , where _n is 0 or 1 and alk is C 1 -C 6 alkylene or C 2 -C 6 alkenyl, (6) a phenyl group substituted with a 5 or 6-membered heterocyclic aromatic group, the heterocyclic aromatic group optionally substituted Cl-3 alkyl, or -NR ^c R ^d, R ^c and R ^d independently represent hydrogen or C 1 -C 3 alkyl, or in the case of -NR ^c R ^d , these substituents may form with the nitrogen atom a 5 or 6-membered heterocyclic ring optionally containing additional heteroatoms, which heterocyclic ring is optionally further substituted at least one C 1 -C 3 alkyl group, R @ 1 denotes C1 -C3 alkyl as well as the salts and solvates of these compounds, in particular the physiologically acceptable salts and solvates for use in therapy, said derivatives being agonists at the adenosine A1 receptor. 226 9 99 9 9 99 9 9 9 99 99 Second adenosine derivatives of general formula Ia R 'wherein X is O or CH _2, ^R2 represents Cl-3 alkyl, Cl -C 3 alkoxy, halogen or hydrogen, R ³ is hydrogen, phenyl, optionally substituted with halogen, 5 or β-membered heteroaryl, C 1 -C 6 alkoxy, C 1 -C 6 straight or branched chain alkyl, optionally substituted with at least one halogen atom, C 3 -C 7 cycloalkyl, C 1 -C 6 hydroxyalkyl or halogen , Y and Z are O, N or CH, W is CH, O, N or S, wherein at least one of W and Z is a heteroatom, and when Y, Z and / or W is a nitrogen atom, the presence or absence of an additional hydrogen atom is evident, provided that when W is CH, Z is nitrogen and Y is oxygen, R ^{3 has a} meaning different from hydrogen, R ⁴ and R ⁵ independently represent a hydrogen atom or a straight or branched C 1 -C 6 alkyl. R ¹ represents a hydrogen atom or one of the groups 227 • 0000 00 0000 00 '·· 0 0 0 0 * 00 0 0 0 0 0 0 0 • 0 0 0 0 0000 0 · 00 00 0 (1) - (alk) _n -C 3 -C 7 cycloalkyl, including a bridged cycloalkyl group, wherein the cycloalkyl group is optionally substituted with at least one substituent from OH, halogen, C 1 -C 3 alkoxy, (alk) means C 1 -C 3 alkylene group and n is 0 or 1, (2) an aliphatic heterocyclic group containing 4 to 6 membered rings containing at least one heteroatom from the group 0, N or s, optionally substituted by at least one substituent selected from Cl-C3-alkyl, _-CO2 -C1 -C 4 alkyl, -CO (C 1 -C 3 alkyl), -S (= O) _n -C 1 -C 3 alkyl, -CONR ^and R ^b , where R ^a and R ^{b are} independently hydrogen or C 1 -C 3 alkyl, or = 0 and in the case of that said heterocyclic ring contains a sulfur atom, said sulfur atom being optionally substituted by (= O) _n wherein n is 1 or 2, (3) straight or branched C1-C12 alkyl optionally containing one or more groups in the alkyl chain O, S (= O) _n where n is 0, 1 or 2 and N, alkyl groups are optionally substituted with one or more substituents from phenyl, halogen, hydroxy, C 3 -C 7 cycloalkyl or NR ^a R ^b , wherein R ^a and R ^b independently represent hydrogen, C 3 -C 7 cycloalkyl or C 1 -C 6 alkyl; (4) a fused bicyclic aromatic ring of the formula ## STR3 ## (4) a straight or branched chain optionally substituted with a C3-C7 cycloalkyl radical; · · * • • • • • • • • 228 ............ wherein B is a 5 or 6-membered heterocyclic aromatic ring containing at least one heteroatom selected from O, N or S, wherein the bicyclic ring is bonded to the nitrogen atom in the compound of formula I via ring A and ring B is optionally substituted with -CO2 -Cl-3 alkyl, (5) a phenyl group optionally substituted by one or more substituents selected from halogen, SO ₃ H, - (alk) _n OH, - (alk) _n -cyano, - (0) _n -Cl C 6 alkyl optionally substituted by at least one halogen atom, - (alk) _n- nitro, - (O) _m - (alk) _n -CO ₂ R ^c , - (alk) _n -CONR ^c R ^d , - (alk) _n -COR ^c , - (alk) n-SOR ^e , - (alk) n-SO ₂ R ^e , - (alk) n-SO ₂ NR ^c R ^d , - (alk) n OR ^c , - (alk ) n- (CO) m-NHSO 2 R ^e , - (alk) n -NHCOR ^c , - (alk) _n NR ^c R ^d , where _n is 0 or 1 and alk is C 1 -C 6 alkylene or C 2 -C 6 alkenyl, (6) a phenyl group substituted with a 5 or 6-membered heterocyclic aromatic group, the heterocyclic aromatic group optionally substituted Cl-3 alkyl, or -NR ^c R ^d, R ^c and R ^d independently represent hydrogen or C 1 -C 3 alkyl, or in the case of -NR ^c R ^d , these substituents may form with the nitrogen atom a 5 or 6-membered heterocyclic ring optionally containing additional heteroatoms, which heterocyclic ring is optionally further substituted at least one C 1 -C 3 alkyl group, R @ 1 denotes C1 -C3 alkyl as well as the salts and solvates of these compounds, in particular the physiologically acceptable salts and solvates for use in therapy, said derivatives being agonists at the adenosine A1 receptor. 229 9 99 9 • 99 99 9 Adenosine derivatives of the general formula 1b R ¹ where X is O or CH ₂ , ^R2 represents Cl-3 alkyl, Cl -C 3 alkoxy, halogen or hydrogen, R ³ is hydrogen, phenyl, optionally substituted with halogen, 5 or β-membered heteroaryl, C 1 -C 6 alkoxy, C 1 -C 6 alkylO (CH ₂ ) _n <where n is 0-6, C 3 -C 7 cycloalkyl, C 1 -C 6 hydroxyalkyl, atom halogen, straight-chain or branched C1-C6 alkyl, C 1 -C 6 alkenyl or C 1 -C 6 alkynyl, optionally substituted with at least one halogen atom, Y and Z are O, N, CH or N (C1-C6 alkyl), W is CH, O, N, S or N (C1-C6alkyl), wherein at least one of W and Z is a heteroatom, and when Y, Z and / or W is a nitrogen atom, the absence of another hydrogen atom is apparent, provided that when W is CH, Z is nitrogen and Y is oxygen, R ³ has the meanings different from hydrogen, 230 • 00 0 • · 0 R ⁴ and R ⁵ independently represent a hydrogen atom or a straight or branched C 1 -C 6 alkyl group, R ¹ represents a hydrogen atom or one of (1) - (alk) _n -C 3 -C 7 cycloalkyl, including a bridged cycloalkyl group, the cycloalkyl group being optionally substituted with at least one substituent from OH, halogen, C 1 -C 3 alkoxy, (alk) means a C 1 -C 3 alkylene group and n is 0 or 1, (2) an aliphatic heterocyclic group containing 4 to β-membered rings containing at least one O, N or S heteroatom optionally substituted with at least one C 1 -C 3 alkyl substituent, - CO 2 -C 1 -C 4 alkyl, -CO (C 1 -C 3 alkyl), -S (= O) _n -C 1 -C 3 alkyl, -CONR ^and R ^b , wherein R ^a and R ^b independently represent hydrogen or C 1 -C 3 alkyl, or = 0 and when the heterocyclic ring contains a sulfur atom, the sulfur atom is optionally substituted by (= O) _n , where n is 1 or 2, (3) straight or branched C1-C12 alkyl optionally containing one or more in the alkyl chain multiple groups O, S (= O) _n where n is 0, 1 or 2 and N, alkyl groups are optionally substituted with one or more substituents from phenyl, halogen, hydroxy, C 3 -C 7 cycloalkyl or NR ^a R ^b , wherein R ^a and R ^b independently represent a hydrogen atom, a C 3 -C 7 cycloalkyl or a straight or branched C 1 -C 6 alkyl, optionally substituted with a C 3 -C 7 cycloalkyl radical, (4) a fused bicyclic aromatic ring of formula φφφφφ Where Φ represents a 5 or 6-membered heterocyclic aromatic ring containing at least one heteroatom selected from the group consisting of 0, N or S, wherein the bicyclic ring is: the ring is bound to the nitrogen atom in the compound of formula I through ring A and ring B is optionally substituted with -CC 2 -C 1 -C 3 alkyl, (5) phenyl, optionally substituted with one or more substituents from halogen, SO 3 H, - (alk) _n OH, - (alk) _n -cyano, - (O) _n -Cl-C 6 alkyl, optionally substituted with at least one halogen atom, - (alk) _n- nitro, - (O) _m - (alk) _n -CC 2 R ^c , - (alk) _n -CONR ^c R ^d , - (alk) _n -COR ^c , - (alk) n-SOR ®, - (alk) n-SO ₂ R ^e , - (alk) n-SO ₂ NR ^c R ^d , - (alk) n OR ^c , - (alk ) n- (CO) _m -NHSO ₂ R 1 - (alk) _n -NHCOR ^c , - (alk) _n NR ^c R ^d , where _n is 0 or 1 and alk is C 1 -C 6 alkylene or C 2 -C 6 alkenyl, (6) a phenyl group substituted with a 5 or 6-membered heterocyclic aromatic group, the heterocyclic aromatic group optionally substituted Cl-3 alkyl, or -NR ^c R ^d, R ^c and R ^d independently represent hydrogen or C 1 -C 3 alkyl, or in the case of -NR ^c R ^d , these substituents may form with the nitrogen atom a 5 or 6-membered heterocyclic ring optionally containing additional heteroatoms, wherein the heterocyclic ring is optionally further substituted with at least one C 1 -C 3 alkyl group, R ^e represents C 1 -C 3 alkyl, 232 4 4444 44 4 4 444 4 4 4 4 · 4 4444 4 4 4 · · 4 4 4 4 4 Provided that when both R ⁴ and R ⁵ are hydrogen and R ² is halogen, R ³ is different from methyl, ethyl, n-propyl, isopropyl or cyclopropyl, from CH (OH) CH ₃ and from a C 1 -C 3 alkoxy group, as well as salts and solvates of these compounds, in particular their physiologically acceptable salts and solvates. 4. Adenosine derivatives of formula Ic R ¹ wherein X is O or CH 2, ^R2 represents Cl-3 alkyl, Cl -C 3 alkoxy, halogen or hydrogen, R ³ is hydrogen, phenyl, optionally substituted with halogen, 5 or β-membered heteroaryl, C 1 -C 6 alkoxy, C 1 -C 6 straight or branched chain alkyl, optionally substituted with at least one halogen atom, C 3 -C 7 cycloalkyl, C 1 -C 6 hydroxyalkyl or halogen , Y and Z are O, N or CH, W represents CH, O, N or S, 233 wherein at least one W and Z is a heteroatom, and when Y, Z and / or W is a nitrogen atom, the presence or absence of another hydrogen atom is evident, provided that when W is CH, Z is an atom nitrogen and Y represents an oxygen atom, R ^{3 has a} meaning different from that of a hydrogen atom, R ⁴ and R ⁵ independently represent a hydrogen atom or a straight or branched C 1 -C 6 alkyl. R ¹ represents a hydrogen atom or one of (1) - (alk) _n -C 3 -C 7 cycloalkyl, including a bridged cycloalkyl group, the cycloalkyl group being optionally substituted with at least one substituent from OH, halogen, C 1 -C 3 alkoxy, (alk) means a C 1 -C 3 alkylene group and n is 0 or 1, (2) an aliphatic heterocyclic group containing 4 to β-membered rings containing at least one O, N or S heteroatom optionally substituted by at least one C 1 -C 3 alkyl substituent, - CO ₂ -C ₁ -C 6 alkyl, -CO (C 1 -C 3 alkyl), -S (= O) _n -C 1 -C 3 alkyl, -CONR ^and R ^b , wherein R ^a and R ^b independently represent hydrogen or C 1 -C 3 alkyl, or = And, if the heterocyclic ring contains a sulfur atom, this sulfur atom is optionally substituted by (= O) _n / where n is 1 or 2, (3) straight or branched C1-C12 alkyl optionally containing one in the alkyl chain or more sku pin 0, S (= O) _n <where n is 0, 1 or 2 and N, the alkyl groups are optionally substituted with one or more phenyl, atom 234 halogen, hydroxy, C 3 -C 7 cycloalkyl or NR ^a R ^b , where R is ^a and R ^b independently represent hydrogen, C 3 -C 7 cycloalkyl or straight or branched C 1 -C 6 alkyl, optionally substituted with a C 3 -C 7 cycloalkyl radical, (4) a fused bicyclic aromatic ring of formula wherein B is a 5 or β-membered heterocyclic aromatic ring containing at least one heteroatom from O, N or S, wherein the bicyclic ring is bonded to the nitrogen atom in the compound of formula I via ring A and ring B is optionally substituted with -CO ₂ -Cl-C3alkyl, (5) phenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, SO ₃ H, - (alk) _n OH, - (alk) _n- cyano, - (O) _n -C 1 -C 6 alkyl, optionally substituted with at least one halogen atom, - (alk) _n- nitro, - (O) _m - (alk) _n -CO ₂ R ^c , - (alk) _n -CONR ^c R ^d , - (alk) _n -COR ^c , - (alk) n-SOR ^e , - (alk) n-SO ₂ R ^e , - (alk) n-SO ₂ NR ^c R ^d , - (alk) n OR ^c , - (alk ) n- (CO) tt-NHSO2R ^e , - (alk) n-NHCOR ^c , - (alk) _n NR ^c R ^d , where _n is 0 or 1 and alk is C 1 -C 6 alkylene or C 2 -C 6 alkenyl, (6) a phenyl group substituted with a 5 or 6-membered heterocyclic aromatic group, the heterocyclic aromatic group optionally substituted Cl-3 alkyl, or -NR ^c R ^d, ^ '^ ^ ifietóMŠéŤŠ3ÍÍ SSI ⁴ 4U! i 2? S' 235 R ^c and R ^d independently represent hydrogen or C 1 -C 3 alkyl, or in the case of -NR ^c R ^d , these substituents may form with the nitrogen atom a 5 or β-membered heterocyclic ring optionally containing additional heteroatoms, which heterocyclic ring is optionally further substituted at least one C 1 -C 3 alkyl group, R ^e is C 1 -C 3 alkyl, provided that when both R ⁴ and R ⁵ are hydrogen and R ² is halogen, R ³ is different from methyl, ethyl, n-propyl, isopropyl or cyclopropyl, from the group CH (OH) CH ₃ and from the C 1 -C 3 alkoxy group, as well as the salts and solvates of these compounds, in particular their physiologically acceptable salts and solvates. Adenosine derivatives of the general formula I according to claims 1 to 4 with little or no agonist activity at the A3 receptor. Adenosine derivatives of the general formula I according to claims 1 to 5, in which the heterocyclic groups containing W, Y and Z include an isoxazole, oxadiazole, pyrazole, oxazole, triazole and thiadiazole group. Adenosine derivatives of the general formula I according to claims 1 to 6, in which the heterocyclic groups containing W, Y and Z are an isoxazole group and a 1,2,4- and 1,3,4-oxadiazole group. Adenosine derivatives of the general formula I according to claims 1 to 7, wherein R ² represents a hydrogen atom, methyl, 236 is a methoxy or halogen atom, preferably a hydrogen or chlorine atom. Adenosine derivatives of the general formula I according to claims 1 to 8, wherein R ¹ represents a (alk) _n -C 3 -C 6 cycloalkyl group, wherein n represents 0 or 1 and the cycloalkyl moiety is unsubstituted or substituted by at least one substituent from the halogen atom, in particular fluorine and hydroxy, n = 0. Adenosine derivatives of the general formula I according to claims 9 wherein the cycloalkyl moiety is unsubstituted or substituted with one OH group. Adenosine derivatives of the general formula I according to claims 10, wherein the cycloalkyl group contains 5 carbon atoms in the ring. Adenosine derivatives of the general formula I according to claims 1 to 8, wherein R ¹ represents a substituted or unsubstituted aliphatic heterocyclic group, the substituent being selected from -CO ₂ -Cl-C4alkyl. Adenosine derivatives of the general formula I according to claim 12, wherein the aliphatic heterocyclic group is unsubstituted or, when the substituent is -CO ₂ -C 1 -C 4 alkyl, the heteroatom is a nitrogen atom and the substituent is directly bonded to the ring nitrogen atom. Adenosine derivatives of the general formula I according to claims 12 and 13, wherein the heterocyclic ring is 6-membered. 237 Adenosine derivatives of the general formula I according to claim 14, in which the heterocyclic ring contains only 1 heteroatom from the group O, N or S. Adenosine derivatives of the general formula I according to claims 1 to 8, wherein R ¹ represents straight or branched C1-C6 alkyl, optionally with a chain interrupted by at least one S (= O) _n and / or N group, that _n is preferably 1 or 2 and the group is unsubstituted or substituted by at least one hydroxy group. Adenosine derivatives of the general formula I according to claims 1 to 8, in which R ¹ represents phenyl, substituted by 1 or 2 substituents from the group hydroxy, alkyl, especially C 1 -C 4 alkyl and halogen. Adenosine derivatives of the general formula I according to claim 17, in which the phenyl is disubstituted in the 2,4-position. Adenosine derivatives of the general formula I according to claims 16 and 17, in which both substituents are halogen atoms. Adenosine derivatives of the general formula I according to any one of claims 1 to 19, in which both R ⁴ and R ⁵ are hydrogen atoms. Adenosine derivatives of the general formula I according to claim 1 selected from the group: (2S, 3S, 4R, 5R) -2- (5-tert-Butyl- [1,3,4] oxadiazol-2-yl) -5- [6- (tetrahydropyran-4-ylamino) -purin-9- yl] -tetrahydrofuran-3,4-diol e »» 238 4- {9- [5S- (5-tert-Butyl- [1,3,4] oxadiazol-2-yl) -3R, 4S-dihydroxytetrahydrofuran-2R-yl] -9H-purin-6-ylamino ethyl ester -piperidine-1-carboxylic acid, (2S, 3S, 4R, 5R) -2- (5-isopropyl- [1,3,4] oxadiazol-2-yl) -5- [6- (tetrahydropyran-4-ylamino)] -purin-9-yl] -tetrahydrofuran-3,4-diol, 4- {9- [5S- (5-cyclopropyl- [1,3,4] oxadiazol-2-yl) -3R, 4S-] ethyl ester dihydroxytetrahydrofuran-2R-yl] -9H-purin-6-ylamino} -piperidine-1-carboxylic acid, (2S, 3S, 4R, 5R) -2- (5-tert-butyl- [1,3,4] oxadiazole- 2-yl) -5- [6- (4-chloro-2-fluorophenylamino) -purin-9-yl] -tetrahydrofuran-3,4-diol, (2S, 3S, 4R, 5R) -2- (5- ethyloxazol-2-yl) -5- [6- (tetrahydropyran-4-ylamino) -purin-9-yl] -tetrahydrofuran-3,4-diol, (2S, 3S, 4R, 5R) -2- (3 -cyclopropyl- [1,2,4] oxadiazol-5-yl) -5- [6- (2S-hydroxycyclopent- (S) -ylamino) -purin-9-yl] -tetrahydrofuran-3,4-diol, ( 2S, 3S, 4R, 5R) -2- (3-tert-Butyl- [1,2,4] oxadiazol-5-yl) -5- [6- (2S-hydroxycyclopent- (S) -ylamino) -purin] -9-yl] -tetrahydrofuran-3,4-diol, (2S, 3S, 4R, 5R) -2- (3-cyclopropyl- [1,2,4] oxadiazol-5-yl) -5- [6- (tetr ahydropyran-4-ylamino) -purin-9-yl] -tetrahydrofuran-3,4-diol, (2S, 3S, 4R, 5R) -2- (3-tert-butylisoxazol-5-yl) -5- [6] - (tetrahydropyran-4-ylamino) -purin-9-yl] -tetrahydrofuran-3,4-diol, ethyl 4 - ({9 - [(2R, 3R, 4S, 5S) -3,4-dihydroxy-5- (3-methyl-1,2,4-oxadiazol-5-yl) tetrahydrofuran-2-yl] -9H-purin-6-yl} amino) piperidine-1-carboxylate (2S, 3S, 4R, 5R) - 2- [3- (tert-butyl) -1,2,4-oxadiazol-5-yl] -5- {6 - [(cyclopropylmethyl) amino] -9H-purine-9239 ···· · · ··· · · · · · · · · · · · · · · · · · · · · · -yl} tetrahydrofuran-3,4-diol, (2S, 3S, 4R, 5R) -2- [3- (tert-butyl) -1,2,4-oxadiazol-5-yl] -5- [6- [(isobutylamino) -9H-purin-9-yl] tetrahydrofuran-3,4-diol, (2R, 3R, 4S, 5S) -2- [6- (cyclopropylamino) -9H-purin-9-yl] -5 3-Isopropyl-1,2,4-oxadiazol-5-yl) tetrahydrofuran-3,4-diol, 2 - ({9 - [(2R, 3R, 4S, 5S) -3,4-dihydroxy-5- (3-Isopropyl-1,2,4-oxadiazol-5-yl) tetrahydrofuran-2-yl] -9H-purin-6-yl] amino) -N-methylethanesulfonamide, (2R, 3R, 4S, 5S) -2 - [6- (3,4-Difluoroanilino) -9H-purin-9-yl] -5- (3-isopropyl-1,2,4-oxadiazol-5-yl) tetrahydrofuran-3,4-diol, (2R) 3R, 4S, 5S) -2- [6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] -5- (3-cyclopropyl-1,2,4-oxadiazol-5-yl) ) tetrahydrofuran-3,4-diol, (2R, 3S, 4R, 5R) -2- [5- (tert-butyl) -4H-1,2,4-triazol-3-yl] -5- [6- (4-chloro-2-fluoroaniline) -9H-purin-9-yl] tetrahydrofuran-3,4-diol, (2R, 3R, 4S, 5R) -2- [6- (2-chloro-4-fluoroaniline) -9H -purin-9-yl] -5- (5-isopropyl-4H-1,2,4-triazol-3-yl) tetrahydrofuran-3,4-diol, (2S, 3S, 4R, 5R) -2- ( 5-Cyclopropyl-1,3,4-oxadiazol-2-yl) -5- [6- (tetrahydro-2H-pyran-4-y) lamino) -9H-purin-9-yl] tetrahydrofuran-3,4-diol, (2S, 3S, 4R, 5R) -2- [5- (tert-butyl) -1,3,4-oxadiazole-2- yl] -5- [6- (2-chloro-4-fluoroanilino) -9H-purin-9-yl] tetrahydrofuran-3,4-diol, (2S, 3S, 4R, 5R) -2- [3- ( tert-butyl) isoxazol-5-yl] -5- {6 [(1,1-dioxidotetrahydro-2H-thiopyran-4-yl) amino] -9H-purin-9-yl} tetrahydrofuran-3,4-diol, 2 - [(9 - {(2R, 3R, 4S, 5S) -5 - [(tert-butyl) -1,3,4-oxadiazol-2-yl] -3,4-dihydroxytetrahydrofuran-2-yl} - 9H-purine-6240 4444 44 44 ·· 44 4 444 44 44444 4444 4 4 · 444 • 4444 4 4 4 4 -yl-amino] -N-ethylethanesulfonamide, 2 - [(9 - {(2R, 3R, 4S, 5S) -5 - [(tert-butyl) -1,3,4-oxadiazol-2-yl] -3,4-dihydroxytetrahydrofuran-2-yl} - 9H-Purin-6-yl) amino] -N- (3-methylphenyl) ethylethanesulfonamide 2 - ({9 - [(2R, 3R, 4S, 5S) -3,4-Dihydroxy-5- (5-methyl-1,3-oxazol-2-yl) -9H-purin-9-yl) tetrahydrofuran -2-yl] -9H-purin-6-yl} amino) -N-methylethanesulfonamide, (2R, 3R, 4S, 5S) -2- [6- (cyclopentylamino) -9H-purin-9-yl] -5 - [3- (methoxymethyl) -1,2,4-oxadiazol-5-yl] tetrahydrofuran-3,4-diol, (2S, 3S, 4R, 5R) -2- (5-ethyl-1, 3, 4, 4) -oxadiazol-2-yl) -5- [6- (isopropylamino) -9H-purin-9-yl] tetrahydrofuran-3,4-diol, (2R, 3R, 4S, 5S) -2- (6 - {[ (1S, 2S) -2-hydroxycyclopentyl] amino} -9H-purin-9-yl) -5- (5-methyl-1,3,4-oxadiazol-2-yl) tetrahydrofuran-3,4-diol, ( 2R, 3R, 4S, 5S) -2- {2-chloro-6 [(1-ethyl-propyl) -amino] -9H-purin-9-yl} -5- (3-cyclopropyl-1,2,4-oxadiazole- 5-yl) tetrahydrofuran-3,4-diol (1: 2), (2R, 3R, 4S, 5S) -2- [2-chloro-6- (1-ethylpropylamino) -purin-9-yl] - 5- (3-Cyclopropyl- [1,2,4] oxadiazol-5-yl) -tetrahydrofuran-3,4-diol di-formate, (2S, 3S, 4R, 5R) -2- (3-ethylisoxazol-5-yl) -5- [6- (tetrahydro-2H-pyran-4-ylamino) -9H-purin-9-yl] tetrahydrofuran-3,4-diol, (2S, 3S, 4R, 5R) -2- (3-ethylisoxazole) -5-yl) -5- (6 - ([(1S, 2S) -2-hydroxycyclopentyl] amine) o} -9H-purin-9-yl) tetrahydrofuran-3,4-diol, ethyl 4 - ({9 - [(2R, 3R, 4S, 5S) -5- (3-ethylisoxazol-5-yl) -3) (4-dihydroxytetrahydrofuran-2-yl) -9H-purin-6-yl} amino) piperidine-1-carboxylate (2R, 3S, 4R, 5R) -2- [5- (tert-butyl) -4H-1] 2,4-triazol-3-yl] -5- [6- (tetrahydro-2H-pyran-4-ylamino) -9H-purin-9- 241-yl] tetrahydrofuran-3,4-diol, (2R, 3S, 4R, 5R) -2- (5-isopropyl-4H-1,2,4-triazol-3-yl) -5- [6- ( tetrahydro-2H-pyran-4-ylamino) -9H-purin-9-yl] tetrahydrofuran-3,4-diol, (2R, 3R, 4S, 5S) -2- [2-chloro-6- (2 -chloro-4-fluoroanilino-9H-purin-9-yl] -5- (5-methyl-1,3-oxazol-2-yl) tetrahydrofuran-3,4-diol, (2R, 3R, 4S, 5S) ) -2- [6- (4-chloro-2-fluoroaniline) -9H-purin-9-yl] -5- (3-methylisoxazol-5-yl) tetrahydrofuran-3,4-diol, (2R, 3R, 4S, 5S) -2- [6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] -5- (3-propylisoxazol-5-yl) tetrahydrofuran-3,4-diol, (2R) 3R, 4S, 5S) -2- [2-chloro-6- (tetrahydro-2H-pyran-4-ylamino) -9H-purin-9-yl] -5- (3-ethylisoxazol-5-yl) tetrahydrofuran -3,4-diol, ethyl 4 - ({2-chloro-9 - [(2R, 3R, 4S, 5S) -5- (3-ethylisoxazol-5-yl) -3,4-dihydroxytetrahydrofuran-2-yl] ] -9 H ^-purin-6-_. -yl} amino) piperidine-1-carboxylate, (2R, 3R, 4S, 5S) -2- (2-chloro-6 - {[(1S, 2S) -2-hydroxycyclopentyl] amino} -9H-purin-9 -yl) -5- (3-ethylisoxazol-5-yl) tetrahydrofuran-3,4-diol, (2R, 3R, 4S, 5S) -2- (2-chloro-6 - {[2- (ethylsulfonyl) ethyl] amino} -9H-purin-9-yl) -5- (3-ethylisoxazol-5-yl) tetrahydrofuran-3,4-diol, (2R, 3R, 4S, 5S) -2- [2-chloro-6] - (4-chloro-2-fluoroanilino) -9H-purin-9-yl] -5- (3-ethylisoxazol-5-yl) tetrahydrofuran-3,4-diol, (2R, 3R, 4S, 5S) -2 - [2-chloro-6- (2-chloro-4-fluoroanilino) -9H-purin-9-yl] -5- (3-ethylisoxazol-5-yl) tetrahydrofuran-3,4-diol, (2R, 3R) 4S, 5S) -2- [2-chloro-6- (2-fluoroanilino) -9H-purin-9-yl] -5- (3-ethylisoxazol-5-yl) tetrahydrofuran-3,4-diol, ( 2R, 3R, 4S, 5S) -2- [2-Chloro-6- (2-chloroanilino) -9H-purine-9 ·· ···· 242 -yl] -5- (3-ethylisoxazol-5-yl) tetrahydrofuran-3,4-diol, (2R, 3R, 4S, 5S) -2- (6 - {[(1S, 2S) -2-hydroxycyclopentyl] amino} -9H-purin-9-yl) -5- [3- (hydroxymethyl) isoxazol-5-yl] tetrahydrofuran-3,4-diol, ethyl 4 - [(9 - {(2R, 3R, 4S) 5S) -3,4-dihydroxy-5- [3- (hydroxymethyl) isoxazol-5-yl] tetrahydrofuran-2-yl} -9H-purin-6-yl) amino] piperidine-1-carboxylate, (2S, 3S, 4R, 5R) -2- [3- (Hydroxymethyl) isoxazol-5-yl] -5- [6- (tetrahydro-2H-pyran-4-ylamino) -9H-purin-9-yl] tetrahydrofuran-3 4-diol, (2R, 3R, 4S, 5S) -2- [6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] -5- (3-ethylisoxazol-5-yl) tetrahydrofuran-3,4-diol, (2R, 3R, 4S, 5S) -2- [6- (2-chloro-4-fluoroaniline) -9H-purin-9-yl] -5- (3-ethylisoxazole-5) -yl) tetrahydrofuran-3,4-diol, (2S, 3S, 4R, 5R) -2- (3-ethylisoxazol-5-yl) -5- [6- (2- -fluoroanilino-9H-purin-9-yl] tetrahydrofuran-3,4-diol, (2R, 3R, 4S, 5S) -2- [6- (2-chloroanilino) -9H-purin-9-yl] - 5- (3-ethylisoxazol-5-yl) tetrahydrofuran-3,4-diol, (2S, 3S, 4R, 5R) -2- [5- (tert-butyl) -1,3,4-oxadiazole-2- yl] -5- [6- (piperidin-4-ylamino) -9H-purin-9-yl] tetrahydrofuran-3,4-diol, (2R, 2R, 4S, 5R) -2- (-chloro-6- [(1-ethylpropyl) amino] -9H-purin-9-yl} -5- (5-ethylisoxazol-3-yl) tetrahydrofuran-3,4-diol formate, (2S, 3S, 4R, 5R) -2- ( 3-bromoisoxazol-5-yl) -5- [6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] tetrahydrofuran-3,4-diol, (2S, 3S, 4R, 5R) - 2- [3- (tert-butyl) isoxazol-5-yl] -5- (6 - {[1- (methylsulfonyl) piperidin-4-yl] amino} -9H-purin-9-yl) tetrahydrofuran-3, 4-diol, (2S, 3S, 4R, 5R) -2- [3- (tert-butyl) isoxazol-5-yl] -5- (6- ([1- (propylsulfonyl) piperidin-4-yl) amino) } -9H-Purin-9-yl) tetrahydrofuran-3,4-diol 243 • 443 «44 4 4 4 44 44 44 4444 4,444 444 44 4 4444 4444 44 44 44 444 (2S, 3S, 4R, 5R) -2- [3- (tert-butyl) isoxazol-5-yl] -5- (6 - ([1- (isopropylsulfonyl) piperidin-4-yl] amino) -9H-purin-9-yl) tetrahydrofuran-3,4-diol, (2S, 3S, 4R, 5R) -2- [3- (tert-butyl) isoxazol-5-yl] -5- (6- ([1- (ethylsulfonyl) piperidin-4-yl] amino} -9H-purin-9-yl) tetrahydrofuran-3,4-diol, (2S, 3S, 4R, 5R) -2- [3- (tert. butyl) isoxazole-5- [2-chloro-6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] tetrahydrofuran-3,4-diol, (2S, 3S, 4R, 5R) -2- [3- (tert-butyl) isoxazole-5- [2-chloro-6- (2-chloro-4-fluoroanilino) -9H-purin-9-yl] tetrahydrofuran-3,4-diol, 2 - [(9 - {(2R, 3R, 4S, 5S) -5- [3- (tert-butyl) isoxazol-5-yl] -3,4-dihydroxytetrahydrofuran-2-yl} -2-chloro-9H -purin-6-yl) amino] -N-ethylethanesulfonamide 2 - [(9 - {(2R, 3R, 4S, 5S) -5- [3- (tert-butyl) isoxazol-5-yl] -3,4-dihydroxytetrahydrofuran-2-yl} -2-chloro-9H -purin-6-yl) amino] -N-isopropylethanesulfonamide, (2S, 3S, 4R, 5R) -2- [3- (tert-butyl) isoxazol-5-yl] -5- [2-chloro-6] - (tetrahydro-2H-pyran-4-ylamino) -9H-purin-9-yl] tetrahydrofuran-3,4-diol, (2R, 3R, 4S, 5S) -2- [6- (4-chloro-2)] (fluoroanilino) -9H-purin-9-yl] -5- (3-pyridin-3-ylisoxazol-5-yl) tetrahydrofuran-3,4-diol, (2R, 3R, 4S, 5S) -2- [6] - (4-chloro-2-fluoroanilino) -9H-purin-9-yl] -5- [3- (4-hydroxybutyl) isoxazol-5-yl] tetrahydrofuran-3,4-diol, 2 - [(9 - {(2R, 3R, 4S, 5S) -5- [3- (tert-butyl) isoxazol-5-yl] -3,4-dihydroxytetrahydrofuran-2-yl} -9H-purin-6 -yl) amino] -N-ethylethanesulfonamide, (2R, 3R, 4S, 5S) -2- [6- (cyclopentylamino) -9H-purin-9-yl] -5- [5- (trifluoromethyl) -1,3] 4-Oxadiazole-2-00 244 • 00 ·· 00 00 * 00 0 0 0 0000 0 0 0 0 0 0 0 · 0 0 0 0 0 000 000 00 00 0 0 0 0 0 0 0 0 00 0 -yl] tetrahydrofuran-3,4-diol, (2R, 3R, 4S, 5S) -2- (6 - {[(1S, 2S) -2-hydroxycyclopentyl] amino} -9H-purin-9-yl) - 5- [5- (Trifluoromethyl) -1,3,4-oxadiazol-2-yl] tetrahydrofuran-3,4-diol, ethyl 4 - [(9 - {(2R, 3R, 4S, 5S) -3,4) -dihydroxy-5- [5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl] tetrahydrofuran-2-yl} -9H-purin-6-yl) amino] piperidine-1-carboxylate, (2R, 3R, 4S, 5S) -2- [6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] -5- (5-methyl-1,3,4-oxadiazol-2-yl) tetrahydrofuran-3,4-diol, (2R, 3R, 4S, 5S) -2- [6- (4-chloro-2-fluoroaniline) -9H-purin-9-yl] -5- (3-cyclopropylisoxazole-5) -yl) tetrahydrofuran-3,4-diol, (2S, 3S, 4R, 5R) -2- [3- (tert-butyl) isoxazol-5-yl] -5- {6 - [(1-butylpiperidin-4) -yl) amino] -9H-purin-9-yl} tetrahydrofuran-3,4-diol, isopropyl 4 - [(9- {2R, 3R, 4S, 5S) -5- [3- (tert-butyl) isoxazole] -5-yl] -3,4-dihydroxytetrahydrofuran-2-yl} -9H-purin-6-yl) amino] piperidine-1-carboxylate, (2S, 3S, 4R, 5R) -2- [3- (tert-butyl) butyl) isoxazol-5-yl] -5- (6 - ([1- (2,2,2-trifluoroacetyl) piperidin-4-yl] amino} -9H-purin-9-yl) tetrahydrofuran-3,4 -diol, me thyl-4 - [(9 - {(2R, 3R, 4S, 5S) -5- [3- (tert-butyl) isoxazol-5-yl] -3,4-dihydroxytetrahydrofuran-2-yl} -9H-purine -6-yl) amino] piperidine-1-carboxylate, (2R, 3R, 4S, 5S) -2- [6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] -5- [ 3- (hydroxymethyl) isoxazol-5-yl] tetrahydrofuran-3,4-diol, (2R, 3R, 4S, 5S) -2- [6- (2-chloro-4-fluoroaniline) -9H-purin-9- yl] -5- [3- (hydroxymethyl) isoxazol-5-yl] tetrahydrofuran-3,4-diol, (2R, 3R, 4S, 5S) -2- [6- (2-fluoroanilino) -9H-purine- 9-yl] -5- [3245 4 44 4 4 4 4 4 · · 4 4 4 4 4 4 4 4 443 44 4 44 444 4,444 4 44 44 44 444 - (hydroxymethyl) isoxazol-5-yl] tetrahydrofuran-3,4-diol, (2R, 3R, 4S, 5S) -2- [6- (2-chloroanilino) -9H-purin-9-yl] -5- [3- (hydroxymethyl) isoxazol-5-yl] tetrahydrofuran-3,4-diol, (2R, 3R, 4S, 5S) -2- (2-chloro-6 - {[(1S, 2S) -2-hydroxycyclopentyl] amino} -9H-purin-9-yl) -5- [3- (hydroxymethyl) isoxazol-5-yl] tetrahydrofuran-3,4-diol, (2R, 3R, 4S, 5S) -2- [2- chloro-6- (tetrahydro-2H-pyran-4-ylamino) -9H-purin-9-yl] -5- [3- (hydroxymethyl) isoxazol-5-yl] tetrahydrofuran-3,4-diol, 2 - [(2-chloro-9 - {(2R, 3R, 4S, 5S) -3,4-dihydroxy-5- [3- (hydroxymethyl) isoxazol-5-yl] tetrahydrofuran-2-yl} -9H- Purin-6-yl) amino] -N-ethylethanesulfonamide, ethyl 4 - [(2-chloro-9 - {(2R, 3R, 4S, 5S) -3,4-dihydroxy-5- [3- (hydroxymethyl) isoxazole] -5-yl] tetrahydrofuran-2-yl} -9H-purin-6-yl) amino] piperidine-1-carboxylate, (2R, 3R, 4S, 5S) -2- [2-chloro-6- (1,4) (chloro-2-fluoroanilino) -9H-. -purin-9-yl] -5- [3- (hydroxymethyl) isoxazol-5-yl] tetrahydrofuran-3,4-diol, (2R, 3R, 4S, 5S) -2- [2-chloro-6- ( 2-chloro-4-fluoroanilino-9H-purin-9-yl] -5- [3- (hydroxymethyl) isoxazol-5-yl] tetrahydrofuran-3,4-diol, (2R, 3R, 4S, 5S) - 2- [2-chloro-6- (2-fluoroanilino) -9H-purin-9-yl] -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-pyran-4-ylamino) -9H-purin-9-yl]] tetrahydrofuran -3,4-diol, methyl-4 - ({9 - [(2R, 3R, 4S, 5S) -5- (3-ethylisoxazol-5-yl) -3,4-dihydroxytetrahydrofuran-2-yl] -2 -methoxy-9H-purin-6-yl} amino) piperidine-1-carboxylate, (2S, 3S, 4R, 5R) -2- (3-ethylisoxazol-5-yl) -5- (6 ([(1S) , 2S) -2-hydroxycyclopentyl] amino} -2-methoxy-9H-purine-9246 ·· φφφφ -yl) tetrahydrofuran-3,4-diol, (2S, 3S, 4R, 5R) -2- (3-ethylisoxazol-5-yl) -5- (6 - {[2- (ethylsulfonyl) ethyl] amino} - 2-methoxy-9H-purin-9-yl) tetrahydrofuran-3,4-diol, (2R, 3R, 4S, 5R) -2- [6- (2-chloro-4-fluoroanilino) -2-methoxy-9H] -purin-9-yl] -5- (3-ethylisoxazol-5-yl) tetrahydrofuran-3,4-diol, (2S, 3S, 4R, 5R) -2- (3-ethylisoxazol-5-yl) -5 - [6- (2-fluoroanilino) -2-methoxy-9H-purin-9-yl] tetrahydrofuran-3,4-diol, (2R, 3R, 4S, 5R) -2- [6- (4-chloro-) - 2-fluoroanilino) -2-methoxy-9H-purin-9-yl] -5- (3-ethylisoxazol-5-yl) tetrahydrofuran-3,4-diol, (2S, 3S, 4R, 5R) -2- [ 3- (tert-butyl) -1,2,4-oxadiazol-5-yl] -5- [6- (cyclopropylamino) -9H-purin-9-yl] tetrahydrofuran-3,4-diol, (2S, 3S) 4R, 5R) -2- [5- (tert-butyl) -1,3,4-oxadiazol-2-yl] -5- [2-chloro-6- (4-chloro-2-fluoroaniline) -9H -purin-9-yl] tetrahydrofuran-3,4-diol, (2R, 3R, 4S, 5S) -2- [6- (4-chloro-2-fluoroaniline) -9H-purin-9-yl] -5 - (5-isopropyl-1,3,4-oxadiazol-2-yl) tetrahydrofuran-3,4-diol. 22. A pharmaceutical composition comprising as an active ingredient an adenosine derivative according to any one of claims 1 to 21 together with a pharmaceutically acceptable diluent or carrier. Use of adenosine derivatives of the general formula I according to any one of claims 1 to 12 for the preparation of pharmaceutical compositions for the treatment of conditions in which it is advantageous to reduce the concentration of free fatty acids in the 247 blood plasma or reduce heart rate or for treating conditions in which cardiac muscle ischemia, peripheral vascular disease or stroke, or for the treatment of pain conditions, central nervous system disorders or sleep apnea conditions. 24. A method of treating a patient suffering from a condition in which it is preferred to reduce the free fatty acid concentration in the blood plasma or to reduce the heart rate or a patient suffering from ischemic heart disease, peripheral vascular disease, stroke, pain, central nervous system or apnea conditions. A method according to any one of claims 1 to 21, wherein the effective amount of the adenosine derivatives of the formula I is administered.