CZ20004869A3 - Adenosine derivatives - Google Patents

Abstract

The adenosine derivatives of the general formula I in which the individual the general symbols have the meaning given in the description are substances with adenosine A 2 receptor agonist activity therefore, they can be used to treat conditions that are potentially beneficial by reducing the concentration of free fatty acids in plasma, by reducing heart rate, or for treatment ischemic heart disease, peripheral vascular diseases, stroke, painful conditions, central nervous disorders system or apnea states in sleep. Part of essence The invention also provides a pharmaceutical composition containing the same and the use of said derivatives for production of the pharmaceutical composition.

Description

Technical field

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

BACKGROUND OF THE INVENTION

Adenosine derivatives are described, for example, in WO 98/16539 (Novo Nordisk. A / S), where they are used to treat cardiac muscle ischemia, cerebral ischemia and epilepsy. WO 98/04126 (Rhone-Poulenc Rorer Pharmaceuticals Inc.) discloses adenosine derivatives having antihypertensive, cardioprotective, anti-ischemic and antilipolytic activity and finally WO 98/01459 (Novo Nordisk A / S) describes N, 9-disubstituted adenine derivatives which are substituted at the 4 'position by an unsubstituted oxazolyl or isoxazolyl group and are useful for the treatment of disorders in which cytokines are involved.

SUMMARY OF THE INVENTION

The present invention provides adenosine derivatives of the general formula IR ¹

O) • · · · · · · · ·

2 where X stands for 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 6-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 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) denotes a C1-C3 alkylene group and n denotes 0 or 1, (2) an aliphatic heterocyclic group containing 4 to 3

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 C 1 -C 3 alkyl, -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 , 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 / wherein n is 0, 1 or 2 and N, the alkyl groups are optionally substituted with one or more substituents from the group 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

wherein B is a 5 or β-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 -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 -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 ^e represents C 1 -C 3 alkyl, as well as the salts and solvates of these compounds, especially the physiologically acceptable salts and solvates for use in therapy, said derivatives being agonists at the adenosine A1 receptor.

Preferred derivatives of the invention are the adenosine derivatives of formula I and _R1

NH

N

Xs

ÓR ^S

X.

(la) where X is O or CH2, (la) wherein X is O or CH2,

^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 an atom 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 (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) denotes a C1-C3 alkylene group and n denotes 0 or 1, (2) an aliphatic heterocyclic group containing 4 to 3

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 C1-C3alkyl, -CO2-Cl • 4444 ·· 4444

4 4 · 4 4 4 4 4 4 4 4 4

-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 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

wherein B is a 5 or β-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 -CO ₂ -Cl-3 alkyl, (5) a phenyl group optionally substituted by one or more substituents selected from halogen, SO 3 H, - (alk) _n 0H, - (alk) _n CN, - (O) _n -Cl-C6alkyl optionally substituted with at least one halogen atom;

4 4 4 '

4

4 4 4

4 4

- (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 ^a, - (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 ^e represents C 1 -C 3 alkyl, as well as the salts and solvates of these compounds, especially the physiologically acceptable salts and solvates for use in therapy, said derivatives being agonists at the adenosine A1 receptor.

The present invention also provides pharmaceutical compositions comprising a compound of Formula I or Ia together with a pharmaceutically acceptable diluent or carrier.

It will be appreciated that some compounds of Formula I are novel. A particular group of these derivatives can be represented by the formula Ib. Accordingly, the present invention also provides adenosine derivatives of Formula Ib

4 4 4 4

44 4 4

4 4

R ¹

NH

wherein X represents 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, halogen Straight 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 group,

R ¹ represents a hydrogen atom or one of the groups

4 ···

(4) (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 and n is 0 or 1, (2) an aliphatic heterocyclic group containing from 4 to β-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, -CO ₂ -C 1 -C 4 alkyl, -CO (CI-C3 alkyl), -S (= 0) _N -Cl-3 alkyl, -C0NR ^and R ^b wherein R ^a and R ^b are independently hydrogen or Cl-C3-alkyl, or = 0 if the heterocyclic the ring contains a sulfur atom, which 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 0, S groups in the alkyl chain (= 0) _n where n is 0, 1 or 2 and N, the alkyl groups are optionally substituted with one or more phenyl, halogen, hydroxy, C 3 -C 7 cycloalkyl or NR ^a R ^b substituents, wherein R ^a and R ^b independently represent a hydrogen atom, a straight or branched C 3 -C 7 cycloalkyl or a C 1 -C 6 alkyl optionally substituted with a C3-C7 cycloalkyl radical; 14) a fused bicyclic aromatic ring of formula

0000

0000

Wherein B is 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 via ring A and ring B is optionally substituted with - CO ₂ -C 1 -C 3 alkyl, (5) phenyl, 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 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 -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-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 ^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 other than methyl, ethyl, n-propyl, isopropyl or cyclopropyl, from the group CH (0H) CH3 and from 9 9 9

9 99

C1-C3alkoxy groups as well as salts and solvates of these compounds, in particular their physiologically acceptable salts and solvates.

Preferred adenosine derivatives of formula I are those of formula Ic

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 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 2 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 another hydrogen atom is evident,

4

4444

445 44 4

4445 4 4 4

4 4 4 4 4 5

4 4 4 4 4

Provided that when W is CH, Z is N and Y is O, R ^{3 has a} meaning other than 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 (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, -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, this sulfur atom is optionally substituted with (= O) _n where n is 1 or 2, (3) straight or branched C1-C12 alkyl optionally containing in the alkyl chain one or more groups in 0, S (= 0) _n / · wherein n is 0, 1 or 2 and n, the alkyl groups are optionally substituted by one or more substituents selected from phenyl, halogen, hydroxy, C3-C7cycloalkyl, or NR ^a R ^b, wherein R ^a and R ^b independently represent a hydrogen atom, a straight or branched C 3 -C 7 cycloalkyl or a C 1 -C 6 alkyl optionally substituted with a C 3 -C 7 cycloalkyl radical, 4 · 4 · 4 (4) a fused bicyclic aromatic ring of the formula

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 -CO ₂ -Cl-3 alkyl, (5) a phenyl group optionally substituted by one or more substituents selected from halogen, SO ₃ H, - (alk) nOH, - (alk) _n -cyano, - (O) _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 β-membered heterocyclic ring optionally containing additional heteroatoms, wherein: ··· · · · · · · · · · · ·

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

this heterocyclic ring is optionally further substituted with 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 other than 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.

Generally, the derivatives of Formula I have greater potency at the adenosine A1 receptor than on other adenosine receptor subtypes, especially A3. In particular, the derivatives of the invention have little or no agonist activity at A3 receptors.

It will be appreciated that when 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.

Alkyl radical during the application means a straight or branched chain alkyl group. Examples of such groups represented by R ¹ and R ² include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and 2,2-dimethylpropyl.

Alkylene means a straight or branched chain radical having 1 to 6 carbon atoms, for example a methylene radical.

94 ··

4 ····

C 2 -C 6 alkenyl is a straight or branched chain alkenyl group having 2 to 6 carbon atoms. An example of a suitable group of this type is allyl.

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

Aliphatic heterocyclic group R ¹ means a cyclic group containing 4 to 6 carbon atoms, one or more carbon atoms being 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 groups R ¹ includes an aromatic monocyclic or bicyclic ring system containing 5 to 10 carbon atoms, at least one of which is replaced by a heteroatom or non-heteroatoms independently selected from nitrogen, oxygen or sulfur, the ring the system is optionally substituted as described above.

Pharmaceutically acceptable salts of the compounds of formula (I) include those 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-sulfone and 000

00 0 0

000

0 •

0

0 · benzenesulfonic acid. A particularly suitable pharmaceutically acceptable salt of the derivatives of formula I is the hydrochloride. Salts of other acids, such as oxalic acid, are not pharmaceutically acceptable per se but may be used as intermediates for the preparation of the derivatives of the invention and their pharmaceutically acceptable acid addition salts. Of the solvates, for example, hydrates are suitable.

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

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

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

A preferred value for R ¹ is (alk) _n -C 3 -C 6 cycloalkyl wherein n is 0 or 1 and the cycloalkyl moiety is substituted by at least one substituent from the group of a halogen atom, 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 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

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

Preferably, 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 bonded directly to that nitrogen atom.

The heterocyclic ring is preferably 6-membered and preferably contains only one O, N or S atom. In a most preferred embodiment in which the heterocyclic ring is not substituted, the heteroatom is an oxygen atom. When the heterocyclic ring is substituted, the heteroatom is a nitrogen atom.

R ¹ may also represent a Cl-C6 alkyl, straight or branched chain, optionally containing at least one S (= 0) _n. When present, R < ¹ > is optionally substituted with a nitrogen atom adjacent to said group. When there is only one such group in the chain, substitution by a nitrogen atom in the position immediately adjacent to that group is most preferred. A preferred value for n is 1 or 2, preferably 2. The alkyl group may be unsubstituted or may be substituted with at least one hydroxy group.

R ¹ may also be a phenyl group substituted with one or two substituents from OH, alkyl, especially C 1 -C 4 alkyl, and halogen. The phenyl group is preferably disubstituted at positions 2 and 4.

Both substituents are preferably halogen atoms, especially 4444

18 *

4 • · «· 4 44

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

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

A suitable value for R ⁴ and R ⁵ are hydrogen. It is to be understood that the invention encompasses 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-, ethyl ester yl] -9H-purin-6-ylamino} -piperidine-1-carboxylic acid, (2S, 3S, 4R, 5R) -2- (5-isopropyl- [1,3,4] oxadiazol-2-yl) -5 4- {9- [5S- (5-cyclopropyl- [1,3,4] oxadiazole) - [6- (tetrahydropyran-4-ylamino) -purin-9-yl] -tetrahydrofuran-3,4-diol, ethyl ester -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] oxadazol-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-oxadiazole- 5-yl) tetrahydrofuran-3,4-diol, 2 - ({9 - [(2R, 3R, 4S, 5S) -3,4-dihydroxy-5- (3-isopropyl-1,2,4-oxadiazole- 5-yl) tetrahydrofuran-2-yl] -9H-purin-6-yl} amino) -N-methylethanesulfonamide, (2R, 3R, 4S, 5S) -2- [6- (3,4-difl. uoroanilino-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-fluoroanilino) -9H-purin-9-yl] -5 - (5-Isopropyl-4H-1,2,4-triazole-3)

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

- [(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-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) -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 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-2 H -pyran-4-ylamino) -9 H -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] tetrahydro-furan-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-fluoroanilino) -9H-purin-9-yl] -5- (3-methylisoxazol-5-yl) tetrahydrofuran-3,4-diol, (2R, 3R, 4S, 5S) -2- [6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] -5- (3-propylisoxazol-5-yl) tetrahydrofuran-3,4-diol, (2R, 3R) 4S, 5S) -2- [2-chloro-6- (tetrahydro-2H-pyran-4-ylamino) -9H-purin-9-yl] -5- (3-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- (2R) -chloro-6 - {[2- (ethylsulfonyl) ethyl] amino} -9H-purine -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-ol] - (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-ethyl-iso) xazol-5-yl) tetrahydrofuran-3,4-diol, (2R, 3R, 4S, 5S) -2- [6- (2-chloro-4-fluoroanilino) -9H-purin-9-yl] -5- (3-ethylisoxazol-5-yl) tetrahydrofuran-3,4-diol, (2S, 3S, 4R, 5R) -2- (3-ethylisoxazol-5-yl) -5- [6- (2-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-ethylisoxazole- 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) isoxazole -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) piperidine-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-fluoro)] anilino-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-purine -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] piperidin-1 -carboxylate, (2R, 3R, 4 -2, 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-fluoroanilino) -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-fluoroanilino) -9H-purin-9-yl] -5- [3- (hydroxymethyl) isoxazol-5-yl] tetrahydrofuran-3, 4-diol, (2R, 3R, 4S, 5S) -2- [6- (2-chloro-4-fluoroanilino) -9H-purin-9-yl] -5- [3- (hydroxymethyl) isoxazole-5- yl] tetrahydrofuran-3,4-diol, (2R, 3R, 4S, 5S) -2- [6- (2-fluoroanilino) -9H-purin-9-yl] -5- [3- (hydroxymethyl) isoxazole- 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- (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) isoxazole-526]

-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 (2S, 3S, 4R, 5R) -2-Methoxy-9H-purin-6-yl} amino) piperidine-1-carboxylate (2S, 3S, 4R, 5R) -2-ethylisoxazol-5-yl) -3,4-dihydroxytetrahydrofuran-2-yl] - (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-ethyl-isoxazol-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-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 present invention can be used as lipolysis inhibitors, i.e., as plasma free fatty acid lowering agents. Thus, the compounds can be used to treat hyperlipidemia. In addition, due to these effects, these agents may reduce the elevated blood glucose concentration, insulin and ketone levels, and can therefore be used in diabetics. Since antilipolytic agents have hypolipidemic and hypofibrinogenemic effects, they also have an anti-sclerotic effect. The effect on fats has been demonstrated by the ability of these substances to reduce the concentration of non-esterified fatty acids (NEFA) in fasting rats by oral administration according to P. Strong et al., Clinical Science, 1993, 84, 663-669.

In addition to the antilipolytic effect, the compounds of the invention can independently influence cardiac function by reducing cardiac sequence and conductivity. Thus, they can be used in a variety of cardiac and vascular disorders, for example in the case of arrhythmias, particularly those resulting from a heart attack and in the case of angina pectoris.

Furthermore, the compounds of the invention may be used as cardioprotective agents in ischemic heart disease. Damage occurring in cardiac muscle ischemia and reperfusion, for example, in conjunction with CABG bypass, coronary PTCA angioplasty, cardioplegia, acute myocardial infarction, thrombolysis, angina pectoris and during surgical pectoris heart interventions, especially in transplantation. In addition, the compounds of the invention may prevent ischemic damage to other organs. In addition, they can be used to treat disorders resulting from atherosclerosis, for example in peripheral vascular disease PVD and stroke.

The compounds of the invention may also inhibit renin release and can therefore be used to treat elevated blood pressure and heart failure. In addition, the compounds have a central nervous system soothing effect and can be used as hypnotics, sedatives, analgesics and / or anticonvulsants, particularly in the case of epilepsy.

Further, the compounds of the invention may be used to treat respiratory arrest during sleep.

The compounds of formula I and their pharmaceutically acceptable acid addition salts are good analgesics in the treatment or prevention of pain. They can be used in the treatment of acute pain such as bone and muscle pain, in postoperative pain and surgical pain as well as in chronic pain such as during chronic inflammation such as rheumatoid arthritis RA, osteoarthritis OA, in neuropathic pain e.g. PHN herpes, in the trigeminal neuralgia, in the case of neuropathy associated with diabetes and also in the case of pain associated with cancer and fibromyalgia. In addition, the compounds of formula (I) may be used in the case of migraine and other types of headache, as well as in functional gastrointestinal pain such as irritable bowel disease and digestive disorders not caused by ulcer.

• · · · · · φ ·

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

The present invention also provides the use of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of a human or other animal suffering from a condition in which blood plasma concentrations of free fatty acids are preferred. frequency and conductivity, in addition, the pharmaceutical compositions can be used to treat ischemic heart disease, peripheral vascular disease and the like, to treat central nervous system disorders, alleviate pain, or reduce respiratory arrest during sleep.

In the treatment of ischemic disorders mentioned above, it has been found that administration of the compounds of formula I protects against ischemic heart disease against heart attack, but protection can also be obtained when the compound of formula I is administered after ischemia and reperfusion . This means that the compounds of the invention may be administered not only in the case of expected ischemia, eg in surgery, but also in the case of sudden and unexpected ischemia, eg in heart attack and the like.

• · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

It will be appreciated that when the compounds of the invention are used for therapeutic purposes, they may also be used for preventive purposes.

The pharmaceutical composition according to the invention contains as an active ingredient at least one compound of the 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 concentration of free fatty acids in blood plasma or reduce heart rate and conductivity, these agents should also be administered in case of risk of coronary artery disease, peripheral vascular disease and stroke as well as central nervous system disorders, painful conditions and arrest breathing during sleep.

The pharmaceutical compositions of the invention may be prepared by admixing 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 for topical or oral administration, for oral mucosa administration, for parenteral or rectal administration, or by inhalation or insufflation. Oral administration is particularly preferred, in which the composition can also be adapted for sustained release of the active ingredient.

For topical administration, the formulation of the active ingredient into a transdermal patch is also contemplated.

«· ♦» ··

Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example boiled starch or polyvinylpyrrolidone, fillers such as lactose, microcrystalline cellulose or corn starch, glidants such as stearic acid or magnesium stearate, disintegrating agents, such as potato starch, cross-linked carmellose sodium, or sodium starch glycolate, or also wetting agents, such as lauryl sulphate. The tablets may be coated by known methods. Liquid compositions for oral administration may take the form of, for example, a suspension, solution or emulsion in water or oil, syrup, or elixir, or it may be a dry product to be mixed with water or other suitable vehicle just prior to use.

Liquid formulations 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. . The pharmaceutical compositions may also contain buffers, flavorings, colorants and sweeteners, such as mannitol as desired.

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

The compounds of formula (I) may be formulated for parenteral administration as a single injection, or

continuous infusion and can be dispensed into single dose ampoules or vials containing multiple doses and a preservative. They may be suspensions, solutions or emulsions in an oily or aqueous medium, in addition to which they may contain adjuvants, for example suspending, stabilizing and / or dispersing agents. The active ingredient may also be presented as a powder to be reconstituted in a suitable environment, for example, sterile pyrogen-free water just before use.

The compounds of formula (I) may also be formulated into suppositories containing a conventional suppository base, for example, cocoa butter or other glycerides.

The anticipated dose of the compounds of the invention for administration to a human with an approximate weight of 70 kg is 1 mg to 2 g, preferably 1 to 100 mg, of the active ingredient per unit dose, which may be administered, for example, 1 to 4 times daily. It will be appreciated that the dosage will need to be varied depending upon the age and condition of the patient as well as the route of administration chosen.

The compounds of formula (I) and their physiologically acceptable salts or solvates can be prepared by the following procedures, which also form part of the present 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 procedure (A), compounds of formula (I) may be prepared by reacting a compound of formula (II):

* W w # # # # # # # # # # # # #

Wherein L represents a leaving group, for example a halogen atom such as chlorine or a linking group, capable of binding to the solid phase of the polymeric carrier, for example a polystyrene resin, it can be, for example, a -SO2Cl-C4alkylene group,

P ¹ and P ² represent a hydrogen atom, a straight or branched C ¹ -C 6 alkyl group 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 formula R ^X NH 2 or a salt thereof; basic conditions. The heterocyclic group at the 4 'position can optionally be protected as described in procedures Bb and V.

Compounds of formula II may be used to produce 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 may be an alcohol, for example a lower alkanol such as isopropanol, t-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.

»4 ··»

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

Where at least one of X, Z and W is a nitrogen atom, the nitrogen atom may optionally be alkylated at any suitable stage of the synthesis, for example, as further described in Procedure 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 may be removed, for example, by treatment with ammonia or tert-butylamine in a solvent such as methanol, or when P ¹ and P ² are an alkylidene group, this may be removed by acid hydrolysis, e.g. trifluoroacetic acid TFA.

The interconversion of the protective groups P ¹ and P ² can be carried out at any stage of the preparation of the compounds of the formula II. For example, when P ¹ and P ² are acetyl, compounds of formula II may be prepared from compounds wherein P ¹ and P ² are an alkylidene protecting group by removal of this group, for example by treatment with hydrogen chloride in methanol followed by acylation directly in the reaction mixtures, for example by treatment with acetic anhydride in

i:

in the presence of a base such as pyridine in a solvent such as 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 formula II.

It will be appreciated by those skilled in the art that in the preparation of compounds of formula II or I a 4-position heterocyclic group may be formed at any stage. Heterocyclic groups may be prepared, for example, from carboxylic acids or acetylene starting materials prior to purine ring addition as described in Schemes 1, 1a and 2, or a heterocyclic group may be formed after purine ring addition as shown in Schemes 3, 4 and 5 and procedure W.

Compounds of formula II wherein X = O may be prepared by reacting compounds of formula III

where P ³ is a protecting group, for example acetyl or a substituent, for example C 1 -C 3 alkyl and P ¹ , P ² and P ³ are as defined above, with compounds of formula IV

L

wherein L and R ² are as hereinbefore defined.

The reaction may 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 may be silylated by treatment with a suitable silylating agent such as hexamethyldisilazane and then reacting the silylated intermediate with a compound of formula I and a suitable Lewis acid such as trimethylsilyl trifluoromethanesulfonate in a suitable solvent such as acetonitrile.

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

As mentioned above, compounds of formula III may be prepared from protected compounds by replacing the protective groups P ¹ and P ² other groups P ¹ and P ^second It is therefore an exchange of one protecting group for another protecting group. The compounds of formula III can be prepared, for example, as follows:

If the heterocyclic group represented by W, Y and Z is isoxazole or>> Φ · · ♦ ♦ φ φ · · · · · · · •

φ φ

«Φ φ substituted, these compounds can be obtained according to the following scheme 1.

P ⁴ O OP ⁵

CDI / pyridine / ch ₂ or ₂

Scheme 1

(Hla)

AcO OAc

Degree

1. MeOd / HC!

2. Ac, O /

The general conditions for steps 1 to 4 will be known to those skilled in the art. It will also be appreciated that the reagents and reaction conditions are given by way of example only, and other reagents and reaction conditions can be used equally well to achieve the same chemical transformation. 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 illustrates the preparation of compounds of Formula III in which the heterocyclic group is an isoxazole group, it will be understood that compounds of Formula III may also be prepared in this manner. * ···

Containing other heterocyclic groups, starting from carboxylic acids, as will be described hereinafter for example for compounds IIIa.

A further process for the preparation 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

Stup.4

The general conditions for steps 1 to 5 in Scheme 1a will be known to those skilled in the art. R ³ , P ⁴ , P ⁵ and P ⁶ are as defined above.

Scheme 2 illustrates a process for preparing compounds of formula III wherein Y is N, Z

4 · · ♦ ··

9

999 • 4

4 • • 4,999 «* ··· ♦ •

• 4

4 the NH, W group of these substances.

CH and R ^{3 are} hydrogen or tautomers χ ₂ 6 ·

Ρ, P and P are as defined above.

Scheme 2

PhMe

In another method B, compounds of formula I can be converted to other compounds of formula I by modification of the groups R ¹ , R ² and / or R ³ .

All of the compounds of formula (III) are novel intermediates which also form part of the invention.

Compounds of formula R ¹ NH ₂ are either known compounds or may be prepared from known compounds by conventional procedures.

Specific optical isomers of the compounds of formula (I) may be prepared by conventional methods, for example by synthesis from the appropriate asymmetric starting materials using procedures known in the art. or a mixture of isomers of the compounds of formula (I) may be separated by conventional means, for example, fractional crystallization or chromatography.

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

VI.

NHR ¹

P'O O ² (V!)

P ¹ O OP ² (V) wherein R ¹ , R ² , X, L, P ¹ and P ² are as defined above.

Compounds of formula (VI) may be prepared from compounds of formula (V) by the methods described above in Method A.

The synthesis of the compounds of the formula I from the corresponding acids of the formulas V and VI is carried out according to known methods.

By way of example, when W is O, Y is N, and Z is N, to form 1,3,4-oxadiazole, the synthesis can be carried out according to Scheme 3. In this example, The symbol J denotes a leaving group L as defined above or NHR ¹ . R ^2, X, P ¹ and P ² are as defined above.

Scheme 3

Stage 1

Method b

RaCONHNHytBuCOCl / iPr ₂ NEt / THF

Method A

EEDQ / RSCONHNHYDME ----> - -

proceed as - method A

Compounds of formula I wherein Z = O, Y = N and W = N to form a 1,2,4-oxadiazole group can be prepared from compounds of formula V or VI by first activating the carboxyl group and then reaction with an amidoxime of the formula HO-N = C (R ³ ) NH ₂ in a solvent such as tetrahydrofuran or chloroform in the presence of a base such as pyridine or diisopropylethylamine followed by cyclization at 20 to 150 ° C in a solvent such as toluene · 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 an acid anhydride in the presence of a base, for example a tertiary amine such as diisopropylethylamine or thionyl chloride in dimethylformamide (DMF). ). Activating agents used in peptide chemistry such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline EEDQ or

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

In Scheme 4, R ² , R ³ , X, J, P ¹ and P ^{2 are} as defined above.

Scheme 4

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

4 * 4444 4

4

444 444

4

Compounds of formula (II) may also be prepared from compounds of formula (VII) as further described in Procedure U. It will be understood that analogous procedures could also be used to produce compounds of formula (I) containing other 4 'heterocyclic groups as is shown below for Procedure M.

O

point ² (VII)

According to general procedure D, compounds of formula I can be prepared from compounds of formula V by the method of Scheme 5 followed by 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 can be used to produce compounds of formula I with other 4 'heterocyclic groups. The general symbols R ¹ , R ³ , J, P ¹ and P ² have the meanings given above.

♦ · ·· ·

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 (Autoprepant HPOL) was performed using a Supelco ABZ + 5 IU of 100 mm x 22 mm (internal diameter of the column), and eluting with a mixture of solvents containing:

(I) 0, 1% formic acid in water,

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

Unless otherwise stated, the eluent was used over 18.50 minutes, within a gradient of 0.0 - 95.0%, (II),

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

Four alternative liquid chromatography systems, 8 mass spectrometry, were used. (LC / MS) J φ φ φ φ Φ φ φ φ φ φ · · φ φ φ φ φ φ φ φ φ φ φ · · · • φ φ φ φ φ φ φ φ

φφφ

System Α)

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

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

A) 0.1% (v / v), formic acid + 0.077% (w / v), smonium acetate in water, and

Ac;) Acetonitrile water, (95 t 5 * v / v) + 0.05% (v / v) formic acid, at a flow rate of 1.0 mL, per minute.

The following sequence of gradients t 100 (Q% A) _t was used over 0.70 min. Of mixture A + B, gradient profile 0-100.0% B) over 3.5 min, at 100.0% B). for 3.5 minutes, and again 100.0. % A) for 0.30 minutes.

System B)

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

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

A) 0.1% (v / v), formic acid + 0.05% (w / v), ammonium acetate in water.

• · ··· · · · · · ·

·· · · · · · · · · · ·

B) 95.0% strength mixture of acetonitrile :: water + 0.05% _y (volume ratio) ,, formic acid at a flow rate of 0.80 ml per minute _r.

The following gradient sequence was used:

A + K mixtures, gradient profile from 0.0 to 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 nr O

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

3.3 cm x 4.60 mm, (inside column diameter), and eluting with the following solvent mixture:

A) 0.1% (v / v), formic acid + 0.077% (w / v), emonium acetate in water.

and

B) 95.0% mixture. acetonitrile: water _r + 0.05% ( _{v / v} ), formic acid at a flow rate of 3.0 ml, per minute.

The following sequence of gradients r was used

100.0%, over 0.70 minutes, mixture A + B, gradient profile 0.0 - 100.0% B), over 3.70 minutes, at 100), 0% B.) _; for 0.90 minutes, and again 100.0% A) _r for 0.20 minutes.

• · ··

S 'y s t e m)

Within this system the column ABZ + PLUSJ was used

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

A) 0 ^ 1% (volume ratios), caric acid in water, ⁸

B) 95.0% acetonitrile / water, + 0.07% (v / v) formic acid, at a flow rate of 1.50 mL, per minute.

The following sequence of gradients was used:

100, 0% A), over 0.20 minutes _{r of} mixture A + B, gradient profile 0.0 - 100.0% B), over time

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

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

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

All temperature data were expressed in? Deň: 32 ° C.

Table 1) - Examples

Example Name n:

Detailed Characteristic Experiment, Analytical Data: Assay (Note 1) (2R, 3R, 4S, 5S) -2- (6-2R- Analogous hydroxy-cyclopent- (R) - yl method) -amino-purine-9 -yl. - process AT 5 -isopropyl- (1,3,4) -oxa

(D-azol-2-yl) -tetrahydro

-furan-3,4-diol

TLC, SiO ₂ , (CH ₂ Cl ₂ : MeOH: 880 NH 4 O), (90: 10: 1 Ϊ,

R _f = 0.39;

Analytical evaluation of the compound according to the summary, formula C CH ^N NO O.

Calculated:

H, 5.8; N, 22.7;

Found:

C 52.9, H 5.9, N 22.7

2) (2R, 3R, _4S: 5S) -2- (6-cyklopentylamiho analogous method according purine (9-yl-5- (5-phenyl- / procedure A 1,3,4) oxadiazol-2-yl -tetrahydrofuran-3,4-diol

TLC, SiO ₂ , (CH ₂ Cl ₂ : MeOH: 880 NH 4), (94: 6: 1),

R _f = 0.1 on;

Analytical evaluation of the compound according to the summary, of 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:: In detail Characteristic number :: experiment, data, (note 1) analytical data ε

(2S, 3S, 4R, 5R) -2- (5-tert. See below See below butyl / i, _{3I, R4} / oxadiazol-2-yl) -5- / 6- (tetrahydro-pyran-4-ylamino) -purin-9-yl / -tetrahydro-furan3,4-diol (Procedure A ') (procedure A)

4) ethyl 4- Analogous LC / MSJ (System B) 9- / 5S- (5-tert-Butyl- work method - 2.55 min. Z2,3 _R 4 / oxadiazol-2-yl) - Procedure A) 3R, 4S-dihydroxy trahyd Mass spectra: ro-furan-2R-yl / -9H-purin-6-yl-amino-piperidine-1-carboxylic acid (m / z), = 517.0, (MH ^{&lt; + &gt;)}

5) (2S, 3S, 4R, 5R) -2- (5 S: ErriY Analogous LC / MS (System B), butyl- (1,3,4) -bxadiazole method according to Rt ₌ 2.35 min. -2-yl) -5- / 6- (2S-hydroxy method A) -cyclopent- (S) -yl-amino) Mass spectra: -t -purin-9-yl / -tetrahydro- (m / z), - 446.0, (MH +) furan-3,4-diol

• ·

Table 1) - Examples

Example number ::

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

6) (2S, 3S ₍ 4R, 5R) -2- (5-Isopropyl-1H, 3,4H-oxadiazol-2-yl) -5- (6-tetrahydro-pyran-4-ylamino) -purin-9-) yΙλte trahydro-furan-3,4-diol

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] oxadiazol-2-yl) -5- (6-cyclopentylamino-pur-9-yl) -tetrahydro-furan -3,4-diol

Analogous method according to procedure A)

LC / MS (System B)

Rt = 2.61 min. t

Mass Spectrum: (m / z) = 430.0 (mh ⁺ );

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

-6- (tetrahydro-pyran

4-yl-amino) -purin-9-yl-tetrahydro-furan-1,4-diol-formate

Table 1) - Examples

Example number:

9)

Name:; Detailed. ňxpěřiffiět. data, (note 1) Characteristic analytical data: (2S, 3S, 4Y, 5Y) -2- (5- Analogous LC / MS (System A) tert-butyl1- / 1,3,4 / - method according to R.t. = 4.35 min. pxadiazol-2-yl-) - 5- (2- Procedure B) chloro-6-cyclopentyl- Mass spectra: amino-purin-9-yl) - (m / z) = 464.0 (MH ⁺ ); te trahydro-furan-3,4- diol. formate

10)

(2S, 3S, 4R, 5R) -2- (4S-cyclopropyl- [1,3,4] oxadiazol-2-yl) -5- / 6 (2S-hydroxy-cyclopent (S) -y1-amino) ) -Purin-9-yl-tetrahydro-furan- Analogous method according to procedure A) LC / MS, (System D), Rt ₌ 2.32 min. Mass Spectrum: (m / z) = 430.0 (MH ⁺ ); 3,4-diol (2R, 3R, 4S, 5S) -2- (6- Analogous LC / MS (System D) cyclopentylamino-pu- method according to R t 2.44 min. rin-9-yl) -6- (5-cyclo- Procedure A) propy1- / 1,3,4 / -oxadia- Mass spectra: and zol-2-yl) -tetrahydro- (m / z) = 414.0 (MH); furan-3,4-diol

• · ·

Τ 8 b u 1 k θ 1) - Examples

• · ·

Example number:

Michal

Detailed experiment, ud's, (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-process A) hydro-furan-2R-yl / -9Hpurin-6-yl-amino] -piperidine-1- carboxylic acid ethyl ester

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

Mass spectra: (m / z) = 50O, O, (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

Analogous LC / MS, (System B), Method R t = 2.74 min.

Procedure A)

Mass Spectrum: (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-process A) fluoro-phenylamino) -purine

-9-yl] -tetrahydro-furan -3,4-diol

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

Mass Spectrum: (m / z) = 490.0, (MH ⁺ );

Table 1) - Examples

Example Title:

číalo ::

Detailed experiment, data, (note 1)

15) (2R, 3R, 4S, 5S) -2- (6- See below cyclopentylamino-purine- (piperidin-9-yl) -5- (1,3,4) -oxadiazol-2-yl) -tetrahydro-furan

-3,4-úiol

Characteristic analytical data:

See below, (Procedure C)

16) (2S, 3S, 4R, 5R) -2- (5'-) / See below See below, (Procedure D) ethyl-oxazol-2-yl) -5-, (Procedure 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-. See below See below, (Procedure F) propylamino-purin-9-yl) - (Procedure F)

5- (5-Methyl-4G- [1,2,4] triazol-3-yl) -tetrahydrofuran-3,4-diol. trifluoroacetate

Table Example number: Name: 19) (2S, 3S, 4R, 5R) -2- (3-cyclopropyl- [1,2,4] oxadiazol-5-yl) -5- [6- (2S-hydroxy-cyclopent (S) -yl-amino)] -purine- 9-yl-trahydro-furan-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 Spectrum: (m / z) = 430.0, (MH ⁺ );

20) (2S, 3S, 4R, 5R) -2- (3-phenyl- [1,2,4] oxadiazol-5-yl) -5- [6- (tetrahydro-pyran-4-yl) -amino] -purin-9-yl-tetrahydro-furan-3,4-diol

Analogous TLC, SiO ₂ , (CH 2 Cl 2):

method according to EtOH: 880 NH4, procedure G) (100: 8: 1),

R _f = 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: In detail experiment. 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-anino) -purin-9-yl-tetrahydro-furan-3,4-diol Analogous method according to procedure G) LC / MS, (System B) R t 2.57 min. Mass Spectrum: (m / z) = 446.0 (MH ⁺ )

22) (2S, 3S, 4R, .5R) -2- (3- Analogous LC / MS (System B) cyclopropyl- (1,2,4) - method according to R _t = 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) - 43 O, O, (MH);

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

-yl-amino) -purin-9-yl] - process G)

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

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

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

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

444 s?

Table 1) - Examples

Example Name: Detailed j? Characteristic číalo experiment, data, (Note 1Ϊ) analytical data: ) 24) (2S, 3S, 4Y, 5Y) -2- (3- Analogous ¹ H-NMR, δ (DMSO): methyl- (1,2,4) -oxa- method according to 8.42 (1H, s, CH), diazol-5-yl) -5- [6- (tetrahydro-pyran-4-yl-emino) -purin-9-yl] -tetrahydro-furah-3,4-diol Procedure G) 8.20, (1H, bs, CH), 7.82, (1H, bs, NH), 6.18, (1H, d, CH), 6.02, (1H, b. bw, OH), 5.90, (1H, bw, OH) *,

5.22, (1H, d, CH), 4.38, (1H, bs, CH), 3.94, (2H, bs, 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 Title:

number:

Detailed experiment, ud's, (note 1)

Characteristic analytical data:

29) (2R, 3R, 4S, 5S) -2- [6- (3-Analogous Fluoro-4-hydroxy-phenyl- amino method) -purin-9-yl] -5-. Procedure G) (3-Methyl- (1,2,4) -oxadiazol-5-yl) -tetrahydro-

-furan-3,4-diol

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

Mass Spectrum: (m / z) = 430.0, (MH ⁺ );

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

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

Mass Spectrum: (m / z) = 517.0 (MH ⁺ );

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

- (S) -Y1-amino) -purin-9-yl

- Tetrahydro-furan-3,4-diol · 44

4 4

*

Table

1) - Examples

Example Title ::

number:

28) (2S, 3S, 4R, 5R) -2- (3-tert-Butyl-isoxazol-5-yl) -5- [6- (tetrahydro-pyran-4-ylamino) -purin-9-yl] - tetrahydro-furan-3,4-diol

29) (2R, 3R, 4S, 5R) -2- (2H-pyrazol-3-yl) -5- (6-tetrahydro-pyran-4-ylamino-purin-9-yl) -tetrahydro-furan-3,4-diol

In detail 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) -tetrahydro-furan-3,4-diol

See below (Procedure K),

31) (2R, 3R, 4S, 5S) -2- / 6- (1S- See below See below, (Procedure L), hydroxymethyl-2-phenyl- (Procedure 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

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9 99

Example Name: In detail Characteristic Number: experiment, data, (note 1) analytical data:

32) (1S, 2R, 3S, 5R) -3- (3-. See below See below, (Procedure M), cyclopropyl- (1,2,4) - (Procedure M) ox8-diszol-5-yl) -5 - (2S-Hydroxy-cyclopent- (S) -ylamino) -purin-9-yl] -cyclopentane-1,2-diol

33) (2R, 3R, 4S, 5S) -2- / 6- Analogous (tert-butylamino) -9H- purin-9-yl / -5- (cyclo-process G) propyl-1,2, 4-Oxediazol-5-yl) -tetrahydrofuran-3,4-diol

LC / MS, (System C), R t = 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) 9-Hpurin-9-yl] -tetrahydrofuran-3,4-diol

Analogous method according to procedure G)

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

Mass Spectrum: (m / z) = 388.0, (MH ⁺ );

34)

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Table

1) - Examples

Example Name Number:

Detailed experiment.

data, (Note 1)

Characteristic analytical data:

35) (2R, 3R, 4S, 5S) -2- (6- (4R, 2R) -2-hydroxy analogous to the cyclopentyl / amino-9H method G) -purin-9-yl) - 5- (3-Methyl-1,2,4-oxadiazol-5-yl) -tetrahydro-furan-3,4-diol

LC / MS, (System C) R t 2.32 min ¹ .

Mass Spectrum: (m / z) = 404.0, (MH ⁺ );

36) (2S, 3S, 4R, 5R) -2- (3-Methyl-1,2,4-oxadiazol-5-yl) -5- [6- (tetrahydro-2H-thiopyren-4-ylamino) -9H- Purin-9-yl-tetrahydro-furan-3,4-diol

Analogous method according to procedure G)

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

Mass Spectrum: (m / z) = 420.0, (MH ⁺ );

37) ethyl 4 - ({9 - / (2R, 3R, 4S, Analogous 5S) -3,4-dihydroxy-5- (3-methyl-1,2,4-oxadiezol-method G) 5- yl) -tetrehydrofuran-2-yl / -9H-purin-6-yl-4-imino) -piperidine-1-carboxylate

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

Mass Spectrum: (m / z) = 475.0 (MH ⁺ );

·

Table 1) - Examples

Gl • ♦ «

♦ · · ♦ · • ♦ · · · · · · · ·

Example number: Name:: In detail experiment, data, (note f) Characteristic analytical data: 38) (2R, 3R, 4S, 5S) -2- / 6- Analogous LC / MS (System C) (also with obutylamino) -9H- method according to R t = 2.51 min. Purin-9-yl--5- (3-methyl) Procedure G) -1,2,4-oxadiazol-5-yl) - Mass spectra: te trahydrofuren-3,4- (m / z) = 376.0, AlH ⁺ ); diol

39) (2R, 3R, 4S, 5S) -2- [6- (cyclopentylamino) -9H-purin-9-yl] -5- (3-methyl-1,2,4-oxadiazol-5-yl) -tetrahydro-furan-3,4- diol Analogous method according to procedure G) LC / MS, (System C) R t 2.47 min. in Mass Spectrum: (m / z) = 388.0, (MH +); 40) (2R _ø 3R _r 4S „5S) -2- £ 6- Analogous LC / MS, (System C). / (cyclopropylmethyl) - method according to R ^ - $ 2.4 rate amino / -9H-purin-9-yl- Procedure G) 5- (3-Methyl-1,2,4-oxa- Mass spectra: (18-azol-5-yl) -tetrahydro- (m / Z) x 374.0, (MH ⁺ ); furan-3,4-diol

99 ·· £ 3

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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- (3-methyl-1,2,4-oxadiazol-5-yl 1) th trahydrofuran -3,4-diol

Analogous LC / MS, (System G,), method R f = 2.17 min. Procedure G)

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

42) (2R, 3R, 4S _, 5S) -2- / 6- (2- Analogous fluoroaniline) -9H-purine 9-yl / -5- (3-methyl-1,2,4-process) G) oxadiazol-5-yD-te trahydrof uran-3 _t 4-diol

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

Mass Spectrum: (m / z) = 414.0 (MH ⁺ );

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

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

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

Mass Spectrum: (m / z) = 432.0 (MH ⁺ );

Table D- Example »♦ ··

Example number: Name:: In detail experiment. data, (note 1) Characteristic analytical data: 44) (2S, 3S, 4B, 5B) -2 - [(tert-butyl) -1,2,4-oxadiazol-5-yl] -5- (6-cyclopropylmethyl) amino] -9H-purin-9- yl-tetrahydrofuran-3,4-diol Analogous method according to procedure G) LC / MS * (System C), R _t = 2.77 min. Mass Spectrum: (m / z) = 416.0 (MH ⁺ );

45) (2S, 3S, 4R, .5R) -2- / 3-, (tert-butyl) -1,2,4-oxadiazol-5-yl] -5- [6- (isobutylamino) -9Hpurin-9-yl] -tetrahydro-furan-3,4-diol See below (Procedure N) LC / MS, (System C) R t 2.88 min. Mass Spectrum: (m / z) = 418.0 (MH ⁺ ); 46) 2 - / (9 - / (2R, 3R, 4S, 5S) -5- / 3- (tert-butyl) -1,2,4-oxadiazol-5-yl) -3,4-dihydroxytetrahydrofuran-2-yl) -9H-purin-6-yl) -emino / -N-methylethanesulfonamide Analogous method according to procedure N) LC / MS, (System C) R t 2.54 min. Mass Spectrum: (m / z) * 483, CI (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) -1,2,2,4 -oxadiazol-5-yl method (1, 1-dioxidetrahydro)

-2H-thiopyran-4-yl) amino] -9H-purin-9-yl-tetrahydrofuran-3,4-diol

LC / MS (System C)

R _t - 2.51 min »

Mass Spectrum: (m / z) = 494.0, (MH ⁺ );

48) (2S, 3S, 4R, 5R) -2- [3- (tert-butyl) -1,2,4-oxadiazol-5-yl] -5- / 6 (2-chloro-4-fluoroaniline) -9H-purin-9-yl / -tetraAnslogic method according to procedure Oj)

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

Mass Spectrum: (m / z) = 490.0, (MH ⁺ );

hy drofursn-3 _; 4-diol

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

LC / MS (System C)

Rt ₌ 3.03 min.

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

· · E e e e e e e e e e e e e e e e

· 9 ·

Table 1) - Examples

Example Name:

Detailed experiment, data, (note 1)

Characteristic analytical data:

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

Analogous method according to procedure 0)

LC / MS, (System C), Rt ₌ 3.32 min.

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

51) (2R, _{3R, 4S,} 5S) -2- / 6 (cyclopropylamino) -9 H -purin-9-yl / -5- (3-isopropyl-1,2,4-oxadiazol-5-yl 1) th trshydrof uranium ·

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 butylemino) -9H-purine-

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

_1.2; 4-oxadiazol-5-yl) -tetrahydrofuran-3,4-diol

LC / MS (System C)

R = 2.74 min.

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

Table

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

Example:

Detailed experiment, data, (note 1)

Characteristic analytical data:

53) (2R, 3R, 4S, 5S) -2- [6- (6-Analogy) ((cyclopropylmethyl) - amino method) -9H-purin-9-yl-procedure N)

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

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

Mass Spectrum: (m / z) = 402.0, (MH ⁺ );

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

3,4-dihydroxy-5- (3-iso method according to propyl-1,2,4-oxadiazol-process N-5-yl) -tetrahydrofuran-2-yl / -9H-purin-6-yl-amino) - me thy le thansulfonamide

LC / MS, (System O,

R t 2.58 min.

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

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

-difluoroanilino) -9H- purin-9-yl / -5- (3-isopro-method 0) polyl-1,2,4-oxadiazol-5-yl) -tetrahydrofuran-3,4-diol

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

Mass spectra: (m / z) = 46.0, O, (MH ⁺ );

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0000 • 0 · 00

0 ·

0 0 0 ··

0 • ·

Table 1) - Examples

Example Name:; In detail Characteristic number experiment, data, (note 1) analytical data :: 56) (2R, 3R, 4S, 5S) -2- / 6- (3, Analogous 4-Difluoroaniline) -9H- purin-9-yl / -5- (3-iso-process 0) propyl-1,2 method , 4, -oxadiazole- 5-yl) -tetrahydrofuran- 3,4-diol LC / MS - (System GL), R _t = 3.20 min. Mass spectra: (m / z) = 460.0, MH +;

57) (2R, 3R, 4S; 5S) -2- / 6- (4- Analogous LC / MS (System C) fluoro-2-methylaniline) - method according to R _t = 3.05 min. 9H-purin-9-yl] -5- (3-iso procedure 0) propyl-1,2,4-oxadiazole- Mass spectra :; 5-ethyl-trahydrofuran- (m / z) = 456.0, [MH]; 3,4-dicrl

58) (2S, 3S, 4R '5B) -2- / 3- (di-Anal TLC, SiO ₂ , (C1 ₂ GH ₂ : methylamino) -1,2,4-oxa method according to EtOH: 880 _{β β} ) diazol-5-yl--5- / 6- (method G) (95: 5: 0.5) trahydro-2H-pyren-4-yl- R _t = 0.20; amino) -9H-purin-9-yl- te trahydrofuran> 3,4- Analytical evaluation diol compounds according to summary

of formula ^(c) ₈ ^H 24 ^N 5 ° 5 ^:

Calculated:

C 49.5, H 5.65, N 1 -25.6;

Found ::

C 49.75 ,. H, 5.90; N, 25.2;

 · ** ·

6?

Table 1) - Examples

Example Title ::

number ::

Detailed experiment.

udsje, (note 1)

Characteristic analytical data:

59) (< 2R, 3R &apos; 4S, 5S) -2- (6H-rel- (1S, 2R, 4R) -bicyclo [2.2.1] hept-2-ylamino) -9H-purin-9-yl; -5- (3-cyclopropyl-1,2,4-oxadiazol-5-yl) -tetrahydrofuran-3,4-diol

Analogous LC / MS - (System B), method R t = 2.81 min. Procedure G)

Mass Spectrum: (m / z) = 440.0, (MH ⁺ );

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

5S) -5- (3-cyclopropyl-1, method according to

2,4-oxediazol-5-yl) -3,4-poet 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-yl (-5- / 6- (isopropyl- (G) amino) -9H-purin-9-yl) tetrahydrofuran-2,4-diol

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

Mass Spectrum: (m / z) = 501.0 (MH ⁺ );

LC / MS _r (System B &apos; 5 JR - 2.69 min.

Mass Spectrum: (m / z) = 404.0, (MH ⁺ );

····

Here

Table 1) - Example

Example number? : Title :: Detailed experiment, data, (note 1) Characteristic analytical data: 62) (2R, 3R, 4S, 5S) -2- / 6- Analogous LC / MS ^(! System B) (4-chloro-2-fluoroaniline) method according to S = 3.05 min. -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 ⁺ ); furen-3,4-diol

63) ethyl 1-4-4- (δ 2R, 3R, 4S, 5S) Analogous LC / MS _r (System B) R t 2.73 min. 3,4-dihydroxy-5- (3-iso- method according to propyl-1,2,4-oxadiazole T Procedure G) 5-y 1) -te trahydrofuran- Mass spectra: 2-yl / -9H-purin-6-yl-4- (m / z) = 503.0, (MH ⁺ ); amino) -piperidine-1-car- boxes of fabrics

64) (2R, 3R, 4S, 5S) -2- [6-rel- Analogous LC / MS (System A) (1S, 2R, 4R) -bicyclo [2.2.1] 2.2. method according to R t 4.27 min. 1 H -Hept-2-yl-amino / -9Hpurin-9-yl-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:: In detail experiment. data, (note 1) Characteristic analytical data: 65,) 2 - ({9 - / (2R, 3R, 4S, 5S) 5- (3-cyclopropyl-1,2,4-oxadiazol-5-yl) -3,4-dihydroxytatrehydrofuran-2-yl) -9H-purin-6 (γ-amino) -N-methylbutylsulfonamide Analogous method according to procedure G) LC / TOS _r (Sygtem B) - 2.33 min. Mass Spectrum: 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 Analogous method according to procedure I) LC / MS, (System A) R t 4.68 min. Mass Spectrum: (m / z) = 451.0 (MH +); 67) (2R, 3S, _4R,: 5R) -2- / 5- Analogous: LC / MS (System C) (tert-butyl) -4H-1,2, force method 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

• • • • • • • • • • • • • • 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, 5') - 2- / 6- (2-chloro-4-fluoroanilino) -9H-purin-9-yl] 5- (5-isopropyl-4H-1,24-triazole- 3-yl) -tetrahydrofuran-3,4-diol

Analogous method according to procedure F)

LC / MS. (System ©), R = 2.89 min.

Mass Spectrum: (m / z) = 475.0 (MH ⁺ );

69) 2 - (/ 9 - / (2R, 3R, 4S, 5S) -3,4-dihydroxy-5- (3-methyl-1.2 _t 4-oxadiazol-5-yl) -tetrahydro «2-yl / - 9H-purin-6-yl} -amino) -N-methyl-methanesulfonamide

Analogous method according to procedure G)

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

Calculated :(%)

C 40.9, H 4.63, N 25.24,

Found :(%)

H, 4.72; N, 24.89

Mass Spectrum: (m / z) = 441.0, (MH ⁺ );

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

Analogous method according to procedure D)

Mass Spectrum: (m / z) = 417.0 (MH +);

4 ··ÍXSS & SUŽSSoHBRWWB ^^ • ··· · · · ··· ··· ·································

Table 1) - Examples

He did Name:: In detail Characteristic number: experiment ♦ data (note 1) analytical data

71) (2S, 3S, 4Y, 5Y) -2- (3- Analogous Analytical evaluation methyl-1,2,4-ox oxdia- method according to compounds: čdlevaumár · zol-5-yl) -5- (6-E / (1R) - Procedure G) of formula ^C 21 ^ 23 ^ 7 ^ 4: 1-methyl-2-phenylethyl / amino-9H-purin-9-yl) -tetrahydrofuran-3,4-diol H, 5.42; N, 21.96. H, 5.32 _; N, 21.78

72) (2S, 3S, .4R, 5R) -2- (5- Analogous Analytical evaluation ethyl-1,3i-oxazole * 2- method according to compounds according to summary. yl) -5- [6- (trans-4-) Procedure D) of formula C _{2 O} H _{26 6} O ₅ r hydroxy cy klohexylami- Calculated: (%) (R) -9H-purin-9-yl- C 55.8, H 6.1, N 19.5, tetrehydrofuren-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 10 999 9

9 9 9 9 9

-you

Example number: Name:: In detail experiment, data, (note 1) Characteristic analytical data: 73) (2S, 3S '4R _y 5E0-2- (5- Analogous Analytical evaluation ethyl-1,3-oxazol-2-yl) method according to compounds according to the summary. 5- / 6- (3-fluoro-4-hydro- Procedure D) of formula C ^ qH ^ ^ FN ^ O ^: xyanilin) -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%, N 4.65 Mass spectra: (m / z) = 443.0 (MH ⁺ ); 74) (2R, 3R, 4S, .5S) -2- / 6- (3- Analogous Mass Spectrometer fluoraniline) -9H-purine- method according to (m / z) - 413.0 (MH ⁺ ); 9-yl] -5- (5-methyl-1,3-) Procedure D)

oxa from ol-2-yl) -tetrahydrofuran-3,4-diol

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

1,3-oxazol-2-yl) -57 (6- method according to N / (1S, 2R) -2-fluoro-cycl D) penty-1-amino-9H-purin-9-yl) -tetrahydrofuran- 3,

4-diol

Mass Spectrum: (m / z) = 419.0 (MH ⁺ );

and

Table 1) - Examples 99 9 9

99 9 9

Example číalo :: Name:: In detail experiment, the point is, (note 1) Characteristic analytical data: 76) (2R, 3R, 4S, .5S) -2- / 6- Analogous _Rf = 0.18 (4-fluoroaniline) -9H- method according to (dichloromethane: purin-9-y1 / -5- (5- Procedure D) ethanol: 880 ammonia) methyl-1,3-oxazole-2- (100 · 10: 1) y 1) - te bunch hydrof ursn- See below, 3,4-diol (Procedure P) Mass spectra: pro synthe- (m / z) = 413.0 (MH ⁺ ); su mezro- dktu 77) (2S, 3S, 4R, .5R) -2- / 3- Analogous LC / MS. (System Sr.) (tert-butyl) -1,2,4- method according to R t 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- Analogous LC / MS, (System A), / rel- (1S, 2R, 4R) method according to R _t = 3.03; klo- (2.2.1.) - Hept-2-yl- Procedure G) amino / -9H-purin-9-yl- Mass Spectra :: 5- / 3- (tert-butyl) -1,2.2. (m / z) = 456.0 (MH ⁺ ); 4-Oxadiazol-5-yl / tetra -

hydrofurene-3,4-diol.

• ····················· · t ·

Ήό

Table

1) - Examples

Example number: Name: Detailed experiment, data, (note 1) Characteristic analytical data: 79) ethyl-4- / 19- {2R, 3R, Analogous LC / MS, (System A '), _4S: 5S) -5- / 3- (terc.bu- method according to R = 2.77 min. ethyl) -1,2,4-oxadiezol-5-yl / -3,4-dihydroxy- Procedure G) Mass spectra: tetrahydrofuran-2-yl-9H-purin-6-yl) amino / piperidine-1-carboxylate (m / z O = 451.7, (MH);

80) 2 - / (9 - {(2R, 3R, 4S, 5S) -5-- Analogous LC / MS (System B) /3-(terc.-butyl)-isoxa- method according to R = 3.76 min. zol-5-yl] -3,4-dihydroxy process -tetrahydrofuran-2-ylZ - Mass spectra: 1 9H-purin-6-yl) -amino / -N (m / z) = 482.0 (MH); -me thyle thansulfonamide

81) (2S, 3S _, 4R, 5K) -2- / 3- Analogous LC / MS ,, (Sygt _em β) _y (tert-butyl) -isoxazole method according to R t 4.20 min. -5> yl] -5- (6- $ / (1S, .2S) - procedure 2-fluorocyclopenty 1 / - Mass spectra: amino (-9H-purin-9-yl) - (m / z) = 447.0 (MH +) te trahvdrofuran-3,4- diol

• • ·· · · · · · • · · · · · · · · · · · · · · · · · · · ···· · · · · · T a b at 1 k and 1) - Examples Example; Name:; In detail Characteristic number: experiment. analytical data: data, (note 1) 82) ethyl 4 - / (9 - {(2R, 3R, Analogous LC / MS, (System B 4S, 5S) -5- / 3- (target ;, either- method according to R t = 4.06 min. ethyl) isoxazol-5-yl] -3, procedure 4-dihydroxytetrahydro- Mass spectra

furan-2-yl-9H-purin-6-yl) -amigo / -pipisridine-1-carboxylate (m / z) = 516.0 (MH) +

83) (2S, 3S _r 4R '5' -2- / 3- Analogous LC / MS, (System B), (tert-butyl) -isoxazole- method according to R = 4.18 min. 5-yl / -5- / 6- (cyclopentyl) procedure amino) -9H-purin-3-yl] - Mass spectra: te trahydrofuran-3,4- (m / z) = 429.0, / MH ^T /; diol

84) ([9 - / (2R, 3R, 4S, 5S) -5- VizlníŽeys Mass spectrum: (5-ethyl-1,3-oxazol-2-yl) -3,4-dihydroxytetrahydrofuran-2-yl / -9Hpurin-6-yl-amino) -N, N-dimethyl-thio-sulfonamide X process Q) process Q (m / z) = 468.0 (MH ⁺ );

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

99

Example Name Number:

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

85)

2 - ({9 - [(2R, 3R, 4S, [eta] &lt; 5 &gt;-( 5-ethyl-1,3-oxazol-2-yl) -3,4-dihydroxy trahydrofuran-2-yl) 9H-purin-6- yl] -amino) Ν-β-ethyl than sulfonamide

Analogous method according to procedure Q)

Mass Spectrum: (m / z) - 454.0 (MH ⁺ );

86) ethyl-4- (E9- / (2R, 3R, 4S, Analogous 5S) -5- (5-ethyl-1,3-oxe-zol-2-yl) -3,4- dihydroxy process Q) tetrhydrofuran-2-yl / -9H -purin-6-yl-4-amino-piperidine-1-carboxylate

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

87) (2R, 3R, 4S _, 5S) -2- {δ - [(2, Analogous 3-dihydroxypropyl) -amino-9H-purin-9- | -5- (5-procedure Q) (ethyl-1,3-oxazol-2-yl) tetrahydrofuran-3,4-diol

Mass Spectrum: (m / z) x 407.0, (MH ⁺ );

(2R, 3R, 4o, (S ')) - 2- / 6- (2. Analogous 4-difluoroaniliri) -9H- purin-9-yl] -5- (5-ethyl method Q 1,3-oxazole) -2-yl) -tetrahydrofuran-3,4-diol

Mass Spectrum: (m / z) x 445.0, (MH ⁺ );

88)

• • · • ?? ·: ···· ·· ···· ·· · • 9 9 · · · · · • · · · · · • · · · · · · · · · · • · · · · · · · · T a b at 1 k and 1) - Examples Example Name In detail Characteristic number í: experiment, data, (note 1) analytical data: 89) (2S, 3S, .4R, 5R) -2- (5- Analogous Mass spectra: ethyl-1,3-oxazol-2-yl) method according to (m / z) = 417.0 (MH ⁺ ); 5- (6 - ([(1S, 2S) -2-Hydroxy-cyclopentyl) -8-amino-9H-purin-9-yl) -tetrahydrofuran-3,4-diol procedure Q) 90) (28,3.8, 4 ^ 5 ^) - 2- (5- Analogous Mass spectra: ethyl-1,3-oxazol-2-yl) -5- (6 - [(3R) -tetrahydro-fur-3-yl-amino) -9Hpurin-9-yl] -tetrehydrofuran-3,4-diol method according to procedure Q) (m / z) = 403.0, (MH ⁺ ); 91) (2R, 3R '4S' 5S) -2- (6- Analogous 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 £ ·) of 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 Title ::

number:

Detailed experiment.

data, (Note 1)

The characteristic analytical element is:

92) (2R, 3R, 4S, .5S) -2- / 6- See below, TLC, SiO (ethyl- (cyclopentylsmino) -9H- (ppp.tup í) acetate with methanol, Purin-9-yl) -5- (3-methyl) (19: 1) -1,2,4-Oxadiazol-5-yl) - Rf ₌ 0.30; te trahydrofuran-3,4- diol NMR, (DMSO) :;

8.43 (1H, s, CH),

8.20, (1H, bs, CH), 7.79, <(1H, Sd, NH), 6.45, (2H, bs, 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: Title :: Detailed experiment, data, (note 1) Characteristic analytical data: 930 (2R, 3R, 4S, 5S) -2- (6- Analogous TLC, SiO ₂ , (CH ₂ Cl ₂ r E / (1R, 2R) -2-h, ydroxy- method according to MeOH: 880 NH4), cyclopenty1 / -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 Compound (s) of formula 2 ^ 23 ^ 7¾ ^t Calculated: (%) G 55.7, H 5.1, N 20.7, Found: (%) C 55.7, H 5.1, N 20.5J

94) (2R, 3R '4S, 5S) -2- [6-]. .Analogical Analytical evaluation / rel- _(5S,, 6R) -bi- method according to compounds according to the summary. cyclo- (3,2,0) -hept-6- Procedure G) of formula C ^ HH NN ^O ^. yl-amino-9H-purine-9- 0.5 MeOH yl] -5- (3-methyl-1,2,4) Calculated: (%) oxediazol-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 (δ- (rel- (1S, 2S, 4R) - bicycl- (2.2.1) -hept- procedure G) 2-ylamino) -9H-purin9-yl-5- (3-methyl-1,2,2-oxadiazol-5-yl) tetrahydrofuran-3,4-diol

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

Calculated: (%)

C 54.25 _r H 5.7 _r 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-ylamino) -9H-purine -9 -yl] -5- [5- (tert-butyl) -1,3,4-oxadiezol-2-yl] -tetrahydrofuran -3,4-diol

Analogous method according to procedure A)

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

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

97) (2R, 3R, 4S _r 5S) -2- (6 / rel- (1S, 2R ,, 4B) bicyclo / 2.2.1 / hept-2-y1-amino / -9H-purin-9-yl -5- (5-isopropyl-1,3,4-oxadiazol-2-yl) -tetrahydrofuran-3,4-diol

Analogous method according to procedure A)

LC / MS, (System B1),

R. - 2.66 min. t

Mass spectra:

( _m / z) = 442.0 (MH ⁺ );

• 0

0 »0000 ··« · • 0 0 0 ·

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

T a b at 1 k. and 1) - Examples Example Name:; In detail Characteristic number: experiment. analytical data: úde je, (note 1) 98) ethyl 4 - (? 9 - / (2 R, 3 R, Analogous LC / MS (System B.) 4S, 5S) -3,4-dihydroxy- method according to R t 2.47 min. 5- (5-Isopropyl-1,3,4-) procedure A ·.) oxadiazol-2-yl) -tetra- Mass spectra hydrofuran-2-yl / -9H-pu- (m / z) = 503.0, O / MH ⁺

Rin-6-yl-amino) -pipe-? Ridine-1-carboxylate

99) 2 - / (9- £ (2®, 3R, 4S, 5S) -5 Analogous / 5- (tert-butyl) -1,3,4- oxadiazol-2-yl / -3,4 method (di-process (A)) (hydroxyhydroturan-2-yl-9H-purin-6-yl) amino] -N-methylethansulfonamide

100) (2S, _3S,, 4R, 5R) -2 / 5-tert. Analogous butyl) - ^1, 3,4-oxadiazol method according -2-Y1 / 5- (6 - (/ (1R, 2R) - procedure A ')

2-Fluorocyclopentyl / amino-9H-purin-9-yl4-tetrahydrofuran-3,4-diol

LC / MS, (System B -), R ~ 2.32 mih &quot;.

Mass Spectrum: (m / z) = 483.0, (MH ⁺ );

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

Mass spectra:

(m / z) = 448.0 (MH ⁺ );

Table 1) - Examples • 999 9 99 9999 99

999 98 9 999

99 99 99

9 9 9 9 9

Example number:

Name:;

Detailed experiment, data, (note 1)

Characteristic analytical data

101) (2S, _{3S, 4R,} 5R _f) -2 / 3-t-buty15-1,2,4oxadiazol-5-y1 / -5 / 6 (tetrahydro-2H-pyran-4-yl-amino) -9H Purin-9-yl-trahydrofuran-3,4-diol

Analogous LC / MS, (System B), Method R t = 2.53 min. Procedure G)

Mass Spectrum: (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- [3- (tert-butyl) 1,2,4-oxadiazol-5-yl] -tetrahydrofuran-3,4-diol

Analogous LC / MS. (System B), method according to Rf ~ 3.03 min. Procedure G)

Mass Spectrum: (m / z) = 456.0, (MH ⁺ );

ethyl 1-4 - / (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 fabrics

103)

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

Mass Spectrum:

(m / z) = 517.0 (MH ⁺ );

Table 1) - Examples • 44 ·· • 44 ·

4 4

4 4 4

4444 ··

4 4 4 4

4 4 ·

4 4 4 4 ·· 44 · 4,444

Example; number :: Ours :: Detailed experiment, data, (note 1) Characteristic analytical data: 10.4) 2- (9 - ((2S _, 3R, 4S, 5SU-5 / 3R) (tert-butyl) -isoxazol-5-yl) -3,4-dihydroxy-trahydrofuran-2-yl-9H-purine 6-yl) amino / -N-methylethane and sulfonamide Analogous method according to procedure I) LC / MS (System A) _r = 3.76 mim. Mass spectra (m / z) = 482.0 _R / MH ⁺ /;

105) (2S, 3S, _4R, 6R) -2- / 3> íterč.-butyl) isoxazol-5-yl - / - 5- (6 - (/ (S ,, 2SL) -2-fluorocyclopentyl (amino-9H-purin-9-yl) tetrahydrofuran: -3,4-diol Analogous Method L) LC / MS. (System A). Rt ₌ 4.20 min. :: Mass spectra (m / z) = 447 _R O / MH ⁺ /; 106) ethyl 4 - / (9 - ((2R, 3B _r 4S, Analogous LC / MS (System A), 5S) -5- / 3: - (tert-butyl) method according to R t = 4.06 min. Isoxazol-5-yl / -3,4-di- L) hydroxy te trahydrofuran Mass Spectra :: -2-yl-9H-purin-6-yl) - (m / z) = 516.0 (MH ⁺ );

8mino / -piperidine-1-carboxylate ····

99

9 9

9 9

9 · 9 9 9

9 9

Table 1 k

Example number :: N. á z e v In detail experiment data, (note 1) Characteristic analytical data: 107) (2S, 3S, 4Y, 5Y) -2- / 3- Analogous LC / MS (System A), (tert-butyl) -isoxa- method according to R t 4.18 min. zol-5-yl / -5- / 6- (cyclo- procedure 1) penty lamino) -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-1,3,1 _: 4-ox8- method according to R t 2.28 min. diazol-2-yl) -5- / 6- (method A) trahydro-2H-pyrene-4. Mass Spectra :: -y1-amino) -9H-purine- (m / z) = 430.0 (MH ⁺ ); 9-yl] -tetrehydrofuran -3,4-diol

109) (2S, 3S, 4R, .5R) -2- (5- Analogous LC / MS (System D) cyclopentyl-1,3,4-oxa- method according to R t 2.59 min. diazol-2-yl) -5- (6R) (1S Procedure A) 2S,.) - 2-hydroxycyls clopene- Mass spectrum: γ-amino-9H-purin-9- (m / z) = 458.0 (MH ⁺ ); y1) -tetrahydrofuran-3,4 -diol

Π

I 8. b and 1 k

444

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

4 4 4 4 4 5

Example Title ::

number ::

Oj) ethyl-4 - ({9 - [(2R, 3R, 4S, 5S)) -5- (5-cyclopentyl-1, 2R, 3R, 4S, 5S;

3 ₁ 4-Oxadiazol-2-yl) -3,4-dihydroxytetrahydrofuran-2-yl / -9H-purin-6-yl-amino) piperidine-1-carboxylate

111) C2S ', 3S' 4R '5R) -2- (5-cyclopentyl-1,3,4-oxadiazol-2-yl) -6- (6 - (/ (1R, 2R) -2-fluorocyclopenty) laminol-9H-purin-9-yl) - tra drofuran-3,4-dial

112) (2R, 3R _, 4S, 5S) -2- [6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] -5- (5-cyclopropyl-1,3,4-oxadiazole-2-yl) - yl) -tetrahydrofuran-3,4-diol and 1) - Examples

Detailed Characteristic experiment, analytical data: data ,.

(note 1)

Analogous LC / MS, (System D.) method according to Rf = 2.82 min.

procedure A-)

Mass spectrum (m / z) = 529.0 (MH ⁺ )

Analogous LC / MSy (System ES), method according to Rf = 2.93 mim.

procedure A-)

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

Analogous LC / MS), (System Eb), Method Rt = 2.84 min. Procedure A)

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

B a b u 1 k a 1) - Examples

Example number ::

Name::

Detailed experiment, data is, (Note 1) 5.

Characteristic analytical data:

113) (2R, 3R 5S _{r r} R, 4 S -) '2 / V & 6- chloro-2-fluoroanilino) -9H-purin-9-y1 / -5- (5cyklopentyl-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) = 502.0, O / MH7;

114) (2S, 3S, 4R _, 5E,) - 2- / 5. Analogous (tert-butyl) -1,3, - oxa- diazol-2-yl method - / - 5 - [6- (2- procedure A-) fluoroanilino] -9H-purin9-yl] -tetrahydrofuran-3,4-diol

115) (2S, 3S, 4R, .5R) -2- / 5-Analogous (tert-butyl) -1,3,4-0X8- diazol-2-yl / -5- / 6- (2 3-Process A) (ifluoroanilino) -9H-purin9-yl / -tetrahydrofuran 3,4-diol

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

Mass Spectrum: (m / z) = 456 _(f) , (MH +) / ·

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

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

• · · ·

Table

1) - Examples

Example:

99 9 9

999

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

1 16) (2S _, 3S, 4B, 5R) -2- [5- (tert-butyl) -1,3,4-oxadiazol-2-yl] -5- [6- (2-chloro-4-fluoroaniline)] 9H-purine- 9-yl] -tetrahydrofuran-3,4-diol Analogous method according to procedure A) LC / MS - (System D), - 3.05 min. Mass Spectrum: (m / Z) * 490.0, (MH ⁺ ); 117) (2S, 3S * 4R '5R) -2- / 5- Analogous LC / MS (System D), (tert-butyl) -1,3,4-oxa- method according to R t = 2.86 min. diazol-2-yl-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- Analogous LC / MS, (System 0) | 2-chloro-6- (1-ethyl-) method according to R = 3.41 min. propyl) -amino / -9H-purine procedure S) -9-yl-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-) Analogous LC / MS, (System C), (tert-Butyl) -isoxazole- method according to Rt 2.61 min. 5-yl) -5- [6 -] - (1,1-dioxide) procedure I), te-trahydro-2H-thiopyran- (last 2 Mass Spectrum :: 4-y 1) -amino / -9Hipurin- degree in (m / z) = 493.0, (MH +); 9-yl] -tetrahydrofuran oferácenéfe -3,4-diol order)

120)

(2S, 35, 0.520-2- / 3- Analogous LC / MS ^: (System C) (tert-butyl) -isoxazole- method according to ~ R _t 3.29 min. 5-yl- ~ 5- / 6- (2-chloro-4- Procedure I) Fluorinol-9H-purine (last 2 Mass Spectra :: 1 9-yl / -transhydrofuran- degree in (m / z) = 489.0 (MH); 3,4-diol inverted order}

(2S '33,42,520-2- / 33- Analogous LC / MS (System C) (tert-butyl) -isoxazole- method according to R. 3.09 min. 5-y1 / -5- / 6- (4-fluoro-2- procedure 1) t ¹ methylaniline) -9H-purine- (last 2 Mass spectra: 9-yl-trahydrofuran. degree in (m / z) = 469.0, (MH +); 3,4-diol inverted order)

121)

Table 1) - Examples

Example number ::

NI á z e ::

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-process 1) anilino) -9H-purin-9-yl) - (last 2 te trahydrofuran-β 3,4-degree in diol reverse order)

LC / MS, (System C.), Rf = 3.25 m.p.

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

123)

2- / (9- {(2R, 3R, 4S, 5S> -5) - Analogous (5 - ₍ tert-butyl) -1,3,4-oxadiazol-2-yl) -3,4 (di) Procedure T) hydroxytetrahydrofuran (2-71) -9H-purin-6-yl) amino / -N-ethylethanesulfonamide

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

Mass Spectrum: (m / z) = 497.0, (MH ⁺ );

(2S, 35,, 4R, 5R) -2- / 5-Analogous (tert-butyl) -1,3,4-oxa-diazol-2-yl / -5- (6- £ / 2-method) - Procedure A) (Ethylsulfonyl) -ethyl-amino-9H-purin-9-yl tetrehydrofuran-3,4-diol

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

Mass Spectrum: (m / z) = 482.0, (MH ⁺ );

124) •

η. ..........

I. 8 h u 1 k e 1) - Examples

Example Name number: · In detail experiment, data * (note 1) Characteristic analytical data: 125) (2S, 3S, 4Y * 6Y) -2- / 5- Analogous LC / MS * (System < L), (tert-butyl) -1,3,4-oxa method according to R ^ - 2.60 min * Diazol-2-yl] -5- (6- [6-] - 2- Procedure A) (butylsulfonyl) -ethyl] - Mass spectra: amino-9H-purin-9-yl) - (m / z) = 51 P, O, / MH +; te tnahydrofuran-3,4- diol

126) 2- (9- ((2R, 3R, 4S * 5S) -5- Analogous LC / MS (System 0), /5-(tern.-butyl)-1,3,4- method according to ® = 2.79 min. oxadiazol-2-yl / -3,4-di- postup 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) Analogous Mass spectra 4-Dihydroxy-5- (5-methyl); method according to (m / Z) = 44.0, O, (MH), -1,3-oxazol-2-yl) -tetrahydrofuran-2-yl / -9Hpurin-6-yl-1-amino) -methyl-thio-sulfonamide Procedure V) TLGL * SiO ₂ , (dichloromethane: (ethanol: ammonia)

(50 :: 8: 1,0), E _f = 0.21 · ················· · · · · · · · · · · • · • · • · · · · · · ·

1) - Examples

Příkls number id Name :: • * In detail experiment, data, (note ú) Characteristic analytical data: 128) 2 - / (9 - {(2R, 3H, 4S, 5S) - Analogous LC / MS _Rt (System C) 5- / 5- (target, -but1-1,3, metod8 according to R t 2.70 min. 4-Oxadiazol-2-yl] -3-4 Procedure A) dihydroxyte trahydr ofuran Mass spectra: -2-yl-9H-purin-6-yl) - (m / z) = 545.0 (MH ⁺ ); amino / -N * -phenylene than sulphonamide)

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

!

1) - Examples

4445 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] -tetrahydrofuran -3,4diol

Analogous Method (E), from intermediate 17) Analytical evaluation of the compound according to the summary, model C ^ HH ^N NO ^. 0.1 CH ₂ Cl 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) _Rf = 0.21;

t 4444

Table

1) - Examples

Example číalo :: Name:: Detailed experiment, data, (note 1) Characteristic analytical data: · 132) (2R, 3R, 4S, 5S) -2- (6 (1 (1S, 2S) -2-hydroxycyclopentyl) amino) 9H-purin-9-yl) -5- (5-methyl-1,3,4-oxadiazole) -2-yl) -tetrahydrofuran -3,4-diol Analogous method according to procedure A) Analytical evaluation of the compound according to the summary of formula C ^H^^N 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, SiO ₂ , (ethyl

acetate: methenol; (7: 1.0), R _f = 0.45; 133) (2S, 3S, 4Y, 5Y) -2- / 3- Analogous LC / MS (System C) (methyl) -1,2,4-oxadia- method according to R t = 2.9t min. from ol-5-yl- -5- / 6- (2-chloro Procedure G) -4-fluoroanilino) -9H- Mass spectra: Purin-9-yl / -tetrahyd- (m / z) = 448.0 (MH ⁺ ); rofuran-3,4-diol

Table 1) - Examples · «» · ··· ··

Example Title: number: Detailed experiment, data is., (note 1) Characteristic analytical data: 134) (2R, 3R, 4S, 5S) -2- (2 ~ Analogous LC / MS (System ©) chloro-6 - [(1-ethylpropyl)] method according to R t = 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- Analogous LC / MS. (System C) ethylisoxazol-5-yl) -5- metod8 according to R t 2.46 min. 6- (tetrahydro-2H-pyran) L) -4-yl-8-amino-9H-purin-9 Mass spectra: -yl] -tetrahydrofuran-3,4 (m / z) = 417.0, [MH]; -diol

136) (2S, 3S, 4R, 5R) -2- (3-Analogous) LC / MS (System C) ethylisoxazol-5-yl) -5- method according to R t 2.51 min. (6 - (/ (1S, 2S) -2-hydroxy-procedure L) cyclopentyl-amino-9H- Mass spectra: 1 purin-9-y1) -the tragedy- (m / z) = 417.0 (MH); furan-3,4-diol

·· ··· ··

Table

1) - Examples

Example:

Detailed experiment, data is, (Note 1)

137) N-Ethyl-2 - ((9- (2R, Analogous 3R, 4S, 5S) -5- (3-ethyl) isoxazol-5-yl) -3,4-di-process 11) hydroxyte trahydrofuran

-2-yl / -9H-purin-6-yl-amino) -ethanesulfonamide

138) ethyl-4- ({9 - / (2R, 3R, 4S, Analogous 5S) -5- (3-ethylisoxazole) - method according to 5-yl) -3- ₍ 4-hydroxyhydroxy-process L) rahydrofuran-2 -yl-9Hpurin-6-yl] amino (-piperidine-1-carboxylate)

Characteristic analytical data:

LC / MS _r System O

R t 2.53 min.

Mass Spectrum: (m / z) = 468.0, (MH ⁺ );

LC / MS, (System C) R t 2.74 mins.

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

139) (2R, 3S, 4R, 5R) -2- [5- (tert-butyl) -4H-1,2,4-triazol-3-yl] -5- / 6- (tetrahydro-2H-pyrimidin-4-one) ylamino) -9H-purin-9-yl tetrhydrofuran-3,4-diol

Analogous LC / MS, (System O method R t = 2.30 min.

Procedure P)

Mass Spectrum: (m / z) = 445.0, (MH ⁺ );

0000

999

00 * 0

0 0

0 0 0 0 0 0 0 0 0 00 00

Table

1) - Examples

Example:

number ::

Detailed experiment.

data, (Note 1)

Characteristic analytical data:

140) (2R, 3R, 4S, 5R) -2- [6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] -5- (4H, 1,2,4-triazole-3- yl) te trahydrofuran-3,4-diol

Analogous method according to procedure F1

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

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

141) (2R, 3S, 4R; 5H0-2- (5-iso-Analogous propyl-4H-1,2,4-triezol method according to -3-yl) -5- / 6- (tetr8hydro procedure F) -2H-pyran-4-yl-amino) 9H-purin-9-yl] -tetrahydrofuran-3,4-diol

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

Mass Spectrum: (m / z) = 431.0, (MH ⁺ );

·· ····

Table

1) - Examples

Example Name: In detail 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 1-Tetrahydrofuran-3,4-diol Analogous method according to procedure Q) Analytical evaluation of the compound according to the summary, formula C CH ^^^ SíGG ^Cl. 0.1 cp ₃ co ₂ h) Calculated: (%) C 43.54, H 3.63, N 23.08 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 Fluoroanilino) -9H-purine-method (Q) 9-yl] -5- (5-methyl-1,3-) - ox8zol-2-yl) -tetrshylamino- furan-3,4-diol LC / MS, (System C), R _t = 3.19 min. Mass Spectrum: (m / z) = 482.0, (MH ⁺ ); 144) (2R, 3R _, 4S, 5S) -2- / 6- (4- Analogous chloro-2-fluoroaniline) - Method according to 9H-purin-9-yl / -5- (3- procedure Wb) methylisoxazole-5- yl) tetrahydrofuran-3,4-diol LC / MS. (System C) R t 2.95 min. Mass Spectrum: (m / Z) = 447.0, (MH ⁺ );

• 4 ··· ♦

4oo • 44 ··

4444 4 ·

· 4 4 4 • 4 4 4 • 44 444 4 · · *

Τ a b u 1 to 8 1) - Examples

Example Name: number: In detail experiment. data, (note 1) Characteristic analytical data: 145) (2R, .3R, 4S, 5S) -2- / 6- Analogous LC / MS. (System C) (4-chloro-2-fluoroaniline) method according to R t 3.23 min. 9H-purin-9-yl] -5- (3 ') procedure Wb) propylisoxazol-5-yl) - Mass spectra: tetrahydrofuran-3,4- (m / z) = 475, Ο, / ΜΗ ⁺ /; diol

146) 2 - / (9 - ((2R, 3R, 4S, 5S) -5 / 3- (tert-butyl) -isoxazol-5-yl) -3,4-dihydroxy tetrahydrofuran-2-yl) 9H-purin-6 -yl) -8mino / Ni with propyl thansulfonamide Analogous method according to procedure I) LC / MS. (System C) R _t = 32.75 min. Mass Spectrum: (m / z) = 510.0 (MH ⁺ ); 147) (2R, 3R _, 4S, 5S) -2- / 2-chloro Analogous LC / MS, .. -6- (te trahydro-2H-pyran- metode podle R t 2.83 min. -4-yl-amino) -9H-purin-yl / procedure L) -5- (3-ethylisoxazole-5- Mass spectra: y1) -1e trahydrofuran-3,4- (m / z? = 451.0 / 453.0, t diol (mh ⁺ );

Table 1) - Examples *> φ

Example Title: Detailed Characters with shadow number: experiment, data, (note 1) analytical data: (148) ethyl 4- (ε 2-chloro) Analogous LC / MS (System C) 9 - / (2R, 3R, 4S, .. 5S) -5- (3-ethylisoxazol-5-yl) -3, method L) R _t = 3.10 min. 4-dihydroxyte trshvdro- Mass spectra: furan-2-yl / -9H-purin-6 (m / z) = 522.0 / 524.0. -yl-amino) -piperidine-1-carboxylate (MH ⁺ ) J

149) (2R, 3R, 4S, 5S) -2- (2- Analogous LC / MS (System C) chloro-6 - [(1S, 2S) -2- method according to R t 2.81 min. hydroxycyclopenty 1 / - J 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- Analogous LC / MS (System C) ethyl- [2- (ethyl- method according to Rt 2.75 min. sulfonyl 1-ethylthiamine 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: In detail experiment. data, (note 1) Characteristic analytical data: 151) (2R, 3R, 4S, 5S5-2-) Analogous LC / MS, (System C 5 Chloro-6- (4-chloro-2- method according to R _t = 3.33 min. fluoraniline) -9H-purine L) 9-y1 / -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-4-fluoro-phenyl) -9H-purin-9-yl] -5- (3-ethyl-isoxazol-5-yl) -tetrahydrofuran-3,4 -diol Analogous Method L) LC / MS, (System C) R t 3.23 min. Mass spectra: (m / Z) = 495.0, MH ⁺ / J 153) (2R, 3R, 4S, 5S) Analogous LC / MS (System C) chloro-6- (2-fluoroaniline) method according to Rt ₌ 3.08 min. -9H-Purin-9-yl / -5- (3- L) ethylisoxazol-5-yl) - Mass spectra: t e tra d nofura n-3 * 4- (m / z) = 461.0 / 463.0, J, diol / mh /;

• ·

Table 1) - Examples

Example Title:

number:

Detailed experiment, data, (note 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.) ethylisoxa zol-5-yl) tetrahydrofuran-3,4-diol

LC / MS (System C)

R at 3.22 min.

Mass Spectrum: (m / z) = 477.0, (MH ⁺ );

155) (2R, 32.4S, 5S) -2- (6H / (1S, 2S) -2-hydroxycyclopentyl) -amino 9H-purin-9-yl) -5- / 3 (hydroxymethyl) isoxazole-5 -yl] -tetrahydrid: hydrofuran-3,4-diol

Analogous LC / MS, (System C), Method R f = 2.25 min. Procedure V)

Mass Spectrum: (m / z) = 419.0 (MH ⁺ );

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

5S) -3,4-dihydroxy-5-method according to (3- (hydroxymethyl) -iso- procedure V) xazol-5-yl] -tetrahydrofuran-2-yl-9H-purin-6-yl) -amino) -piperidine-1-carboxylate

LC / MS (System C)

R t 2.46 min.

Mass spectra: (m / z) = 49O, O, (MH ⁺ );

• 4

Table 1) - Examples

3 ·· «3 · Κ>. Ϋί: Κ ·>» Α ««υοΣ ^

Example number:

Name:

Detailed experiment, data, (note 1)

43 4 »4 4

4 4 4

4 4 »

Characteristic analytical data:

157) (2S, 3S, 4R y 5 R) -2- / 3- Analogous (hydroxymethyl) -isoxa- method according to -jol-5-yl / -5- / 6- (tetra-process V) hydro-2H-pyran -4-ylamino) -9H-purin-9-yl

-te trahydrofuran-4,4diol

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

in

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

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

Analogous method according to procedure L)

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

Mass Spectrum: (m / z) = 461.0, (MH ⁺ );

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

Analogous method according to procedure I)

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

Mass Spectrum: (m / z) = 461.0, (MH +) · · ·

Table

1) - Examples

Attachment & number s

CD)

Our :: :: Detailed experiment, data, (note 1) Characteristic analytical data (2S, 3S, 4R, 5K) -2- (3 -......) Analogous LC / MS (System E), 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- (2-Chloroanilino) -9H-purin9-yl] -5- (3-ethylisoxazol-5-yl) -tetrahydro furan-3,4-diol Analogous method according to procedure L) LC / MS, (System C), R t = 2.96 mim. Mass Spectrum: (m / z) = 443.0, MH +; (2S, 3S, 4R, 5R) -2- / 5-. Analogous LC / MS (System C.) (tert-butyl) -1,3,4-oxa- method according to R t = 2.11 min. Diazol-2-yl--5- [6- (piperidin-4-yl-emino) 9H-purin-9-yl] -tetrahydrofuran-3,4-diol procedure Y) Mass Spectrum: (m / z) = 445.0 (MH ⁺ );

163)

(2R, 3R, 4S, 5R) -2- (2- Analogous LC / MS, '(System C) chloro-6 - [(1-ethylpropyl)]. method according to R _t = 3.41 min. amino (-9H-purin-9-yl) -5- procedure S) (Ethyl soxa-zol-3-yl) - Mass spectra: t e trahydrofuram-3,4 · - (m / z) = 437.0 (MH ⁺ ); diol.formiát

I • · · ·

Table

1) - Examples

Example Title:

number ::

Detailed experiment, data, (note 1)

Characteristic analytical data:

164) (2S, 3S ₅ ',, 5K 4E) -2- (3- Analogous LC / MS (System C) bromisoxgzol-5-yl) -5- method according to R t = 3.22 min. / 6- (4-chloro-2-fluoro) - W) anilino-9H-purin-9-yl) Mass spectra: -tetrabydrofurai »-3 ,, .4 - (m / z) = 511.0 (MH ^{&lt; + &gt;} ) diol

165) (2R, 3E, 4S, 5S) -2- [6- (4-chloro-2-fluoroanilino) 9H-purin-9-yl] -5- [3- (3,5-difluorophenyl) -isoxa] -ol-5-yl t-trahydrofuran-3,4-diol- Analogous Method W) LC / MS. (System C) R _t = 3.55 mim. Mass spectra: (m / z) = 545.0, (MH +) 166) (2S, 3S '4R' 5R) -2- / 3- Analogous LC / MS (System ©) (tert-butyl) -isoxazole method according to R t = 2.69 min. -5-yl / -5- (6- [1- (methylsulfonyl) -piperidine-4-) procedure Y) Mass Spectra :: yl] -amino-9H-purin-9-yl) - trahy drof uran-3,4-diol (m / z) = 522.0 (MH +)

• · · · ···

Table 1) - Examples

Example:

Detailed analytical data, (Note 1)

Characteristic analytical data

167) (2S, 3S * 4R, 5E) -2- / 3-. Analogous LC / MS - (System C 1, (tert-butyl) -isoxazole-methods according to 5-yl / -5- (6 - {/ 1- (propyl-process Y) R _t = 2.90 min. sulfonyl) -piperidine-4- Mass spectra: 1 yl-amino-9H-purin-9yl) -tetrahydrofuran-3,4-diol (m / Z) = 550.0 (MH +);

168) (2S * 3S * 4R * 5R) -2- [3- (tert-butyl) -isoxazol-5-yl] -5- (6 - [[1- (isopropylsulfonyl) -piperidin-4-yl] amino] | ^-9? purin-9-y1) th trahydrofuran-3,4-diol Analogous method according to procedure Y) LC / MS, (System 0) R = 2.87 mins. Mass Spectrum: (m / z) = 550.0, (Me ¹ ); 169) (2S, 3S * 4R * 5H) Analogous LC / MS (System C) * (tert-butyl) -isoxazole- method according to R = 2.77 min. 5-yl] -5- (6-methyl-1- (ethyl- procedure Y ') sulfony1) -piperidine-4- Mass spectra: yl-amino-9H-purin-9-yl) -tetrahydrofuran-3,4-diol (m / z) = 536.0 (MH ⁺ );

• · · · · · · · · · · ·

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

Example Title ::

number ::

Detailed experiment.

data, (Note 1)

Characteristic analytical data:

170) (2S, 3S, 4R '5R) -2- / 3- Analogous LC / MS (System C) (tert-butyl) -i with οχθ of ol- method according to R t = 3.60 min :. 5-y1 / -5- / 2-chloro-6- (4- Procedure I) chloro-2-fluoroaniline) - Mass Spectra :: 9H-Purim-9-yl] -tetrahydrofuran-3,4-diol (m / z) = 524.0 (MH ⁺ )

171) (2S _, 3S, 4E, 5R) -2- / 3- Analogous (tert.-butyl) -isoxazole-methods according to 5-yl / -5- / 2-chloro-6- (2- process I) 4-fluoroanilino-9H-purin-9-yl] -tetra-drofuran-3,4-diol LC / MS, (System O, R _t = 3.50 mim. Mass spectra: '(m / z) = 524.0, (MH ⁺ ) 172) 2 - / (9 - {(2R '3R' 4S, 5S) -5- Analogous LC / MS (System G) (3- (tert-butyl) -isox 8) = c-method according to zol-5-yl) -3,4-dihydro-procedure I) R - 2,94 mim » xyte of drofuran-2-yl Mass Spectra :: »» -2-chloro-9H-purin-6-yl) - amino / -N-ethylethane- sulfonamide; (m / z) = 53.0, O, (MH)

0 0 · · · · · · · · · · · ·

4ο <ι

Table 1) - Examples

Example Title :: In detail Characteristic number: experiment. _information: (poznámma 1) The analytical task is: 173) 2 - / (9 - {(2R, 3R, 4S 5S _R) - -5- / 3- (tert-butyl) isoxazol-5-yl / 3,4-dihydro xyte trahydrof furan-2-yl ij 2-chloro-9H-purin-6-yl) amino-N-N-isopropylethanesulfonamide Analogous method according to procedure I) LC / MS, (System C), Rt = 3.04 min. Mass Spectrum: (m / z) = 544.0 (MH ⁺ );

174) (2S, _3S,, 4R, 5R) -2 / 3- (tert .Analogická butyl) isoxazol-5-yl / -5- method by / 2-chloro-6- (tetrahydro procedure 1) 2H- pyran-4-yl-amino) -9H -purin-9-yl-tetrahydro-furan-3,4-diol LC / MS. (System C), R t = 2.96 min. Mass spectrum (m / z) = 479.0, (MH ⁺ ); 175) (2R, 3R, 4S, 5S) -2- / 6- (4- Analogous LC / MS. (Systesr 0) chloro-2-fluoroaniline) - method according to 9H-purin-9-yl / -5- (3- procedure W) R t = 3.02 min pyridin-3-yl-isoxazole- Mass spectra: »» 5-yl) -te trahydrofuren- (m / z) = 510.0 (MH &lt; + &gt;);

3,4-diol / Μΰ

8 '8 ti; u 1 k s Ό - Examples

Example Example In detail Characteristic. number :: experiment. data, (note 1) analytical data :: 176) (2R _t ^3M r.5S) -2 / 6- (4-chloro-2-fluoroanilino) -9H-purin> 9 1-yl / -5- / 3- (4HY dr oxy buty1) -is ox8 from o15-yl / -tetrahydrofuran > 3,4-diol Analogous method according to procedure W) LC / MS, (Sysrem 0), x 3, -35min. Mass Spectrum: (m / z) = 505.0 (MH ⁺ )

177) (2 - / (9 - [(2R, 3R, 5S _y R, 4 S) -5. Analogous LC / MS, (System 0) -3- (tert-butyl) -isoxa- method according to P t = 2.65 min. tetrazol-5-yl / -3 4-dihydroxy _r te trahydrofuran-2-yl-9H-purin-6-yl) amino / - Procedure I) Mass Spectrum: (m / z) = 496.0 (MH ⁺ )

No thylethansulfonamid _(R 2 R 3 R _'s 4S 5S) -2- / 6 (cyclopentylamino) -9H-purine-9-yl / -5- / 5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl) -tetrahydro -3,4-diol

Analogous method according to procedure A)

LC / MS ( _y) (System O),

R f = 2.80 m.p.

Mass Spectrum: (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- (6R / (1S, 2S) -2-hydroxy-cyclopentyl) amino-9Hpurin-9-yl) -5- / 5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl] -tetrahydro-furan-3,4-diol

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

5S) -3,4-dihydroxy-5- [5- (trifluoromethyl) -1,3,4-oxadiazol-2-yl] -tetrahydrofuran-2-yl-9Hpurin * 6-yl) -amino / -piperidine-1-carboxylate

Analogous LC / MS, (System C), Method R t = 2.48 min 2, Method A)

Mass Spectrum: (m / z) = 458.0 (M + H) +;

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

Mass Spectrum: (m / z) = 529.0 (MH ⁺ );

12R, 5S) -2- [6- (4-chloro-2-fluoroanilino) 6Hapurin-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 Spectrum: (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 (4-chloro-2-fluoroaniline) - method according to 9H-purin-S-yl) -5- (3-cycle W) propylisoxazole -5-yl) -tetrahydrofurene-3,4-diol

LC / MS _r (System O, Rt ₌ 3.15 mim.

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

183) (2S „35 ,, 4R, 5 R) -2- / 3- Ans logic (tert-butyl) -isox8zole- method according to

5-y1 / -5-6 - / (1-Y procedure butyryl) -piperidin-4-yl) -amino / 9Jffi purin'-9-yl} -tetrahydro-trahydr0LC / MS (System C) R _t R.t. = 2.74 min.

Mass Spectrum: (m / z) = 5U, 0 (MH ⁺ );

fursn-3, 4-diol

184) isopropy1-4 - / (£ 9- (2R, _3?,;. Analogue

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

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

LC / MS. (System O, Rt ₌ 3.10 min.

Mass spectra: (m / z) = 530.0, (MH ⁺ );

· · 9 9 9 9 9 9 9 9 9 9 9 99 9

I s b a 1 k a,) - Examples

Example: number :: Detailed experiment, data ,, (Note 1) Characteristic analytical data: 185?) (2S, .38, R 4 _R 5 S) -2 / 3- Analogous LC / MS (System G) (tert -butyl) -1 soxazole- method according to R. - 3.05 min. 5- (6- [eta] &lt; 1 &gt;-( 2.2.2-trifluoro procedure Y) at acetyl) -piperidin-4-yl] - Mass spectra: aminoj - 9H-purin-9-y li- (m / z) = 54.0, O, (MH ⁺ ) te trahydrofuran-3,4- diol

186) methyl-4 - / (9 - [(2R, 3E, 4S 55) -5- / 3½ (tert-butyl) is oxa-ol-5-yl] -3,4-dihydroxy-trahydrofuran-2-yl -yl- (9H-purin-6-yl) amino] -piperidine-1-carboxylate Analogous method according to procedure Y) LC / MS, (System G), R _t = 2.73 min. Mass Spectrum: (m / z) - 5-2, Ο, / ΜΗ ⁺ / 187) (2R, 3B, 4S, 5S) -2- / 6- (4½ Analogous LC / MS (System G.) chloro-2-fluoroaniline) - method according to R t 2.67 min. 9H-purin-9-y1 / -5- (3- Procedure V) (hydroxydyl) -i soxa- 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: number-: Detailed experiment *, data, (note 1) Characteristic analytical data: 188) (2R, 3B, .4S, 5S) -2- / 6.- (2 Analogous LC / MS, (System CJ, -chloro-4-fluoroaniline) - method according to R t 2.56 min. 9H-purin-9-yl / -5- (3) Procedure V) in (hydroxymethyl) -isoxa- Mass spectra: zol-5-yl / -tetrahydro- (m / z) = 463, C (MH ⁺ ); furan-3,4-diol

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

190) (2R, 3R _r 4S _ø 5S) -2- / 6- (2- Analogous LC / MS, (System O, chloraniline) -9H-purine- method according to R t = 2.54 min. 9-y1 / -5- / 3- (hydroxy- Procedure V) methyl-1-oxa of ol-5-yl) - Mass Spectrum: tetrhydrofuran-33,4,4-diol (m / z) = 445.0 (MH ⁺ )

yyr

Table 1) - Examples ·· ♦ · · »·

Example N? á z e v :: number :: Detailed experiment, data, (note 1) Characteristic analytical data: 19D (2R.3R, .4S, 53) -2- (2- Analogous LC / MS (System C), chloro-6 - (/ (1S ,, 2S) -2- method according to R.t. = 2.32 min. hydroxycyclopentyí / - procedure Bb) amino-9H-purin-9-yl) - Mass Spectrum :. 5- / 3- (hydroxymethyl) - (m / z) - 453.0 / 455.0 isoxazol-5-yl / -tetra- / mh7; hydrofuran-3,4-diol

192) _{(2R,; r} 3K ^AS, 5S) -2- / 2-chloro-6- (tetrahydro-2H-pyran-4-yl-amino) -9 H -purin-9-Y1 / -5- / 3- (hydroxy-methylbenzoyl 1) -is oxa-ol-5-yl / -tetrahydrofuran-3,4-diol Analogous method according to procedure Bb) LC / MS (System C) Rt - 2.32 min. t Mass Spectrum (m / z) = 453.0 / 455.0, (MH +) 193) 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] -Ne thyle than sulfonamide Analogous method according to procedure Bb) LC / MS, (System O, R = 2.32 min. Mass Spectrum: (m / Z) = 504.0 / 506.0, (mh ⁺ );

Τ 8 b u 1 k a) - Examples

Example:

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 R.t. = 2.60 min. hydroxy-5 / -3- (hydroxy-process Bb) methyl) -oxoxazol-5-yl] - Mass spectra: tetrahydrofuran> 2-yl | - (m / z) = 524.0. 9HiPurin-6-yl) -amino] - piperidine-1-carboxylate

195) (2R, 3R '4S, 5S) -2- / 2- / 2- Analogous LC / MS (System C) Chloro-6- (4-chloro-2- method according to R _t = 3, 10 min. fluoroaniline) -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> 5S) Analogous LC / MS _Rt (System C) chloro-6- (2-chloro-4-) method according to R t 3.02 min. fluoraniline) -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 b. U 1 to 8

1) - Examples i

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-fluoro-phenyl) -9H-purin-9-yl] -5- [3- (hydroxymethyl) -isoxazol-5'-yl] -te trans hydrofuran-3,4-diol Analogous method according to procedure Bb) LC / MS, (System O, Rt = 2.72 min. Mass spectra: (m / z) = 463.0, (MH ⁺ ); 198) (2S, 3S, 4R, 5B) -2- (3 &gt;) Analogous LC / MS (System C) ethylisoxazol-5-yl) -5- method according to R = 2.57 min. / 2-Methoxy-6- (te trahyd- L) ro-2H-pyran-4-yl-amino) Mass spectrum: -9H-purin-9-yl / -tetra-r (m / z) = 447.0 (MH ⁺ ); hydrofurene-3,4-diol

199) ethyl-4- [19 - [(2R _, 3R, 4S, Analogous) LC / MS, R = 2.75 min " 5S) -5- (3-Ethylisoxazole) method according to (§1) -3,4-dihydroxy- L) t e tr8 hydrofuran-2-y1 / Mass spectra: 2-methoxy-9H-purin-6-yl-amino) -piperidine-1-carboxylate (m / z) = 518.0 (MH ⁺ );

• 9

Example. Name::

number: ::

9 9 9 9 9 9

99 ///

T, a b u 1 to 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) tetr8hydrofuran-3 * 4-diol

LC / MS (System C)

R t 2.66 min. at

Mass Spectrum: (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

Analogous LC / MS, (System ©), Method R t = 2.42 min ~. 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-Ethylxsoxazol-5-yl)

-tetrahydrofuran-3,4-diol

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

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

Ml

T a b u 1 k a 1) - Examples

Example. N o z v :: number :: In detail experiment. data, (note 1) Characteristic analytical data: 203) (2S, 3S, 4-R, 52) -2- (3- Analogous LC / MS (System C) ethylisoxazol-5-yl) -5- method according to R t 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- (4-chloro-2-fluoroanilino) -2-methoxy-9H-purin-9-yl / 5- (3-ethylisoxazol-5-yl) -tetrahydrofuran -3. ', 4- diol Analogous method according to procedure 2) LC / MS, (System O, R _t = 3.20 min. Mass spectra: (m / z) = 491.0, (MH ⁺ ); 205) (2S, 3S, 4Y, 5Y) -2- / 3- Analogous LC / MS, (System C), (tert-butyl) -1,2,4- method according to R t 2.53 min. oxadiazol-5-yl / -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 experiment. data _; (note 1) Characteristic analytical data: 206) (2S '3JS; 4' '5R) -2- / 5- Analogous LC / MS, (System O, (tert-butyl) -1,3,4- method according to R t 3.32 min. oxadiazol-2-yl- -5- / 2- procedure Cc) E-chloro-6- (4-chloro-2- Mass spectra: fluoraniline) -9H-purine- (m / z) = 524.0 (MH ⁺ ); 9-yl / -tetrahydrofuran- 3,4-diol

207) (2R, .3R, .4S, 5S) -2- / 6- (4- Analogous 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-οχε- 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 (3aS, 4S, 6R, 6aR) -6- (6-Chloro-purin-9-yl) -2,2-dimethyl-tetrahydro-furo N - (2,2-dimethyl-propionyl) -hydrazide - [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, up to 100,0 ml,

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

The mixture was then poured into 250.0 ml of an aqueous solution of citric acid (citric acid = 2-hydroxypropane-1,2,3-tricarboxylic acid), followed by extraction with ethyl acetate. After separation of the organic and aqueous phases, the organic layer was washed successively with citric acid, and brine, and, after drying with magnesium sulfate, was evaporated in vacuo.

The residue, as a crude product, was purified by flash chromatography using silica gel (Biotage cartridge) and ethyl acetate: cyclohexane (65.0: 35.0) as eluent.

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

Combined Liquid Chromatography and Mass Spectrometry (LC / MS '}, (System B):

R = 2.49 minutes,

Mass Spectrometry, (m / z) i 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-4-yl / -6-chloro-9H-purine

Solution prepared by dissolving 1.30 g of (3aS * 4S * 6R, 6aR) -6- (6-chloro-purin-9-yl) -2,2-dime, N- (2,2-dimethylpropionyl) -hydrazide 4-carboxylic acid * (obtained in the above procedure for the preparation of Intermediate 1) in 15.0 ml of thionyl chloride * was irradiated with thyl-1-tetrahydrofuro [3,4-d] 1,3] -dioxole 4-carboxylic acid * in a microwave oven, at an output of 150.0 W * for 7, -0 minutes.

Thereafter, the excess thionyl chloride from the reaction mixture was evaporated in vacuo * and the crude product * residue was taken up in 6.0 ml of dried acetonitrile, and the solution was heated under reflux for 3.0 hours. After evaporation of the solvent, the resulting residue was purified by flash chromatography on silica gel, using ethyl acetate: cyclohexane * v 35.0: 65.0 - 40.0: 1. 60.0) as eluent.

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

LC / MS (System B)

R ^ - 2.86 minutes *

MS (m / z): 421 (MH ⁺ );

Intermediate 3)) · · · · · · · · · · · ·

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

Total CD, 64 g _of 9- (6S- <5-thienyl-butyl 1- (1,3,4) -oxadiazol-2-yl) -2,2-dimethyl-tetrahydro- (3aB, 6aS) ^: 0 -f furo / 3,4-d // 1,3 / -dioxol4S »yl / -6-chloro-9H-puržnu _r (diethyl oxalate, the above described process of preparation of intermediate 2) was treated at 0 0 ° C, with a mixture of trifluoroacetic acid and water (10.0: 1.0?), For 5.0 hours (9.0 mL volume), and then the reaction mixture was allowed to stand in the refrigerator, at 2.0 ° C ·, over ηοσ.

The reaction mixture was then evaporated to about 1.0 ml in vacuo, then poured into ice-cold aqueous sodium bicarbonate, and then extracted 3 times with 50.0 ml of ethyl acetate each time. aqueous phase, the organic layer was washed with brine, and, after drying with magnesium sulfate, was evaporated in vacuo.

371.0 mg of the title compound are obtained as a crude product

LC / MS (System Eb):

R = 2.42 minutes, «I *

MS (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-2-yl) -5- [6- (tetrahydro-pyran-4-amino) -purine] -9-yl] -tetrahydrofuran-3,4-diol. · · 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4

·· ··· ✓2

The mixture was prepared by mixing 41.0 ,, MGJ (2S 3S _r,: 4R, 5R) -2- (5> tero.-butyl / 1, 3, 4 / -oxadÍ8zol-2-yl) -5- (6th (chloro-purin-9-yl) tetrahydro-furan-3,4-diol (obtained as described in the preceding procedure for the preparation of Intermediate 3) with 59.0 mg of 4-aminotetrahydropyran hydrochloride, followed by 0.11 ml, diisopropylethylamine, 8 with 5.0 ml, isopropanol. was heated under reflux for 15.0 hours.

The solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography using ethyl acetate & methanol (100.0, 0.0-90.0, 10.0) as eluent.

37.0 mg of the title compound are obtained.

Ζ? '- ϊ.

LO / MS, (System B)

= 2.31 minutes,

MS (m / z): 446.0 (MH ⁺ );

Detailed experimental data using BS):

Intermediate 40

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

Acetic acid 4R-acetoxy-5B-acetoxymethyl-2R * - (2,6-dichloro-purin-9-yl) -tetrahydro-furan-3R-yl ester, followed by 5.70 ml , diisopropylethylemine ,. and 2.02 g _{4-Amino-tetrahydropyra.hydrochloridu} ,, in 200.0 ml isopropanol ,, was heated at 50.0 ° C for 4 hours G. T

I · · · · · · ·

Then,. After> cooling, the reaction mixture was evaporated in vacuo ,, and the residue was dissolved in 200.0 _ml,: methanol, and the solution was bubbled with ammonia gas for 2.0 hours.

The reaction mixture was then stirred at 22.0 ° C over neat and then evaporated to a brown color after evaporation in vacuo. An oily solid which was purified by flash chromatography on silica gel. (Merck 93855, eluting with dichloromethane: ethanol :: 880 ammonia (75: 0: 8.0: 1.0)).

7.81 g of the title compound are obtained in the form of a slightly brown oil.

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-amin.o) -purin-9-yl / -. 2 _r 2-dimethyl-tetn8hydro- (3AE, 68H.) - furo / 3,4-di-dioxol 4H-yl] -methanol

A solution prepared by dissolving 7.81 g of 2-chloro-N- (tetrahydro-pyran-4-yl) -adenosine (obtained as described in the foregoing Preparation of Intermediate 4) in 500 ml of acetone. , was mixed with 14.70 ml 2,2-dimethoxypropane, 3.80 g of 8, p-toluenesulfonic acid, and the resulting reskční mixture was stirred at 22.0 ° C for overnight .. _r

WC

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 separating the organic and aqueous phases, the organic layer washed 2 * 250.0 mL of aqueous sodium bicarbonate, _r and dried over sodium sulfate, evaporated in vacuo.

7.0 g of a slightly brownish foam were obtained, which was purified by flash chromatography on silica gel (Merck 9385) using ethyl acetate: cyclohexane *. (4.0 1.0) as eluent.

5.70 g of the title compound are obtained as a pale yellow foam.

LC / MS, (System &) ::

Rt = 2.68 minutes,

MS (m / z): 426.0 (MH ^{&lt; + &gt;} )

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-di [1,3] dioxole-4-carboxylic acid

Solution * prepared by dissolving 2,50 g, 6,6- [2-chloro-6 (tetrahydro-pyran-1-amino) -purin-9-yl] -2,2-dimethyl-tetrahydro- (3aB '6aB) (R) -furo [3,4-d] 1,3] dioxol-4R-yl] -methenol; (Obtained under the previous * popdahého above procedure for preparing Intermediate 50 J in 90.0 ml ethyl acetate * was mixed with 60.0 ml saturated aqueous sodium bicarbonate solution, and the resulting biphasic mixture was rapidly stirred at Oyo ° C. P _o After the mixture was stirred for 5 minutes at 0.0 ° C, 70.0 mg of potassium bromide was added, followed by 4.60 µm of the 2,2,6,6-th tram-thi-1-piperidines loxy free radical.

Then, 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 to the cooled and stirred mixture over 15.0 minutes. further, stirred at a temperature of 0.0 ° C for 2, 0 minutes, followed by a double addition of potassium bromide2,2,

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

After each addition, the reaction mixture was stirred at room temperature for 15 to 20.0 minutes. Subsequently, the reaction mixture was poured into 400.0 ml of ethyl acetate, and after being shaken with 10.0 g of sodium sulfite, it was diluted with 300.0 ml of water, and after the aqueous and organic phases were separated, the aqueous layer was acidified. with 2N hydrochloric acid solution to pH 1.0 - 2.0, and extracted twice with 300.0 ml of ethyl acetate each. 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 title compound are obtained in the form of a cream colored foam.

LC / MS (System B):

= 2.81 minutes,

MS, (m / z): 440.0 (MH);

Intermediate Τ ’)

Preparation of (3aS, 4S, 6B, 6aBi) -6- / 2-chloro-6- (tetrahydro-pyran-4-ylamino) -purin-9-yl N- (2,2-dimethyl-propionyl) -hydrazide (-2,2,2-Dimethyl-tetrahydro-furo-) [3,4-d] [1,3] dioxole-4-carboxylic acid

To the solution, prepared to dissolve: 350 350.0 mg, (3aS _r 4 S, 6B _r 6a R) -6- (2-chloro-6-tetrahydro-pyran-4-ylamino) purin-9-yl) -2,2-dimethyl-tetrahydro-furo- [3,4-d] 1,3] -dioxole-4-carboxylic acid (obtained as described in the previous Preparation of Intermediate 6 above) in 8.0 ml, dried of tetrahydrofuran, was added under stirring, under a nitrogen atmosphere, and at a temperature of 90 ° C, 0.487 ml, of diisopropylethylamine.

After 5.0 minutes, 0.098 ml of pivaloyl chloride (2,2-dimethylpropsic acid chloride) was added to the reaction mixture, which was then stirred at 0.0 ° GL for 2.50 hours. addition of 2,2-dimethylpropionic acid hydrazide, in 2.0 mL of tetrahydrofuran, the reaction mixture should be continuously stirred at 0 to 22.0 ° C through it.

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

357.0 mg of the desired compound was obtained in the form of a cream colored solid.

LC / CD, (System B - 2.76 minutes,

MS (m / z): 538.0 (M + H) +

ffieziprodukt S)

Preparation of γ- [6S- (5-tert-Butyl- [1,3,4] oxoxiazol-2-yl) -2,2,2-dimethyl-tetrahydro- (3aK, 6aS) -furo- [3,4] - [(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 _r 2dimethylpropionyl) -hydr8zidu (3aS, 4S, 6R "68R) -6- / 2- / chloro-6- (tetrahydro-pyran-on 4-yl -amino) -purin-9-yl] -2,2-dimethyl-trifluoromethyl- [3,4-d] -1,3-dioxole-4-carboxylic acid (obtained within of the foregoing procedure for the preparation of Intermediate 7), in 1.20 ml of Ν, Ν-dimethylformamide, and cooled to 0.0 ° C, 0.039 ml of phosphorus oxychloride was added under stirring under nitrogen. the resulting reaction mixture was stirred at 0 ° C for 10 hours, then at 22.0 ° C for 16.0 hours.

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

After evaporation of the mixture in vacuo, the residue was shaken twice with 30.0 ml each 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 in vacuo to a yellow oil having an oil consistency which, after purification by flash chromatography with silica gel, using 30.0% 8% to 100.0% ethyl acetate / cyclohexane as the eluent, afforded 60.0 mg, , the title compound.

LO / MS), (System Ac):

K - 4.41 minutes,

Mass Spectrometry, (m / z): 520.0 (MH);

• ··· · · 4 4 4 4 4

4 ·· 44

444 4,444 4

44 44 444

Example 8)

Preparation of ^(2S, 3S, R, 4 S, 5 »-2- ((5> t» butyl / 1,3,4 / -ox8diazol2-yl) -5- / 2-chloro-6- (tetnahydro-pyran 4-yl-amino) -purin-9-yl-tetrahydro-furan-3,4-diol formate

Solution prepared by dissolving 60.0 mg of 9- [6S- (5-tert-butyl- [1,3,4] oxoxiazol-2-yl) -2,2-dimethyl-tetrahydro- (3aR, 6a) (R) -furo- [3,4-d] -1,3] -dioxol-4B-yl] -2-chloro-9Hipurin-6-yl (tetrahydro-pyran-4-yl) -8min, (obtained in under the previous procedure described above for the preparation of Intermediate 8) in 2.0-0 ml of the "mixture" obtained by mixing trifluoroacetic acid and water (10.0: 1.0) was mixed at 0.0 ° C after for 1.0 hour, and then at 22.0 ° C for 4.0 hours

Thereafter, the reaction mixture was evaporated in vacuo, and the resulting residue was ezotropically treated with 6.0 ml of toluene each. Thereafter, the residue was purified by preparative high performance liquid chromatography (gradient profile 5.0 -90.0-%, (II), during

18.50 minutes.

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

LC / MS (System A):

R = 3.86 minutes,

MS, (m / z): 480.0 (MH);

Detailed experimental data using O) ytangasaaagGnL-nunuTiiiT ·

9 9 9 · 9 999 9

998 9 9 9

9 9 9

9 9 9

9 9 9 9 9

•OF?·/

EN e zip product 9)

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

4-di [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-tetrahydrofuro [3,4-d] 1,3] dioxole-4-carboxylic acid , and 2.66 g of 2-ethoxy-1-ethoxycarbonyl-1,1,2-dihydro-quinoline, in 120.0 ml of methanol, was heated at reflux for 17.0 hours.

Then the resulting reaction mixture was concentrated in vacuo, and the residue was dissolved in 150.0 mL of ethyl acetate, and the solution was washed 3 times with 25.0 mL each; A 0.5 M aqueous solution of citric acid (citric acid - 2-hydroxypropane-1,2,3-carboxylic acid) and then with 50.0 ml of brine, and dried over magnesium sulfate, was evaporated in vacuo.

The residue, as a white solid, pan-like solid, was purified by silica gel column chromatography using ethyl acetate: cyclohexane (1.0: 1.0) as eluent.

2.32 g of the title compound are obtained as a white colored solid.

Thin layer chromatography, (TLC); SiO 2, dichloromethane: methanol: 880 ammonia (94.0: 6.0 tL, GD). R ' _t 'G>,62;

M ^r eziprodukt 1 CC ¹⁾

I • 9 · 9 ···

432Příprava (3aS, 4S _R 6N, 6aR) -6- (6-cyclopentylamino-purin-9-yl) -2 '2-dimethyl-tetrahydro-furo / 3,4-d // 1, 3 / dioxole -4-carboxylic acid

Mixture prepared by dissolving (3aS, 4S * 6Ki * 6aR) -6- (6-cyclopentylamino-purin-9-yl) -2,2-dimethyl-tetrahydro-furo- / 3,4-d // 1 * 3 methyl ester (D) -dioxole-4-carboxylic acid (obtained as described in the foregoing procedure for the preparation of Intermediate 9) * 8 0.29 mL * hydrazine hydrate in 10.0 mL of methanol was heated at reflux for a period of time 28,0 hours.

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, m.p. in the form of a white colored solid.

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

9.40 * (1H * bs * NH), 8.32 (1H, bs, CH), 8.20 * (1H, bs,

CH), 7.90 * (1H * N, NH) * 6.35 * (1H * N, CH), 5 * 28 * (2H * N, 2 x CH) * 4.65 * (1H * bs * CH) * 4.50 * (1H, bs, CH). 4 * 20 * (* 2H br s, _NH2), 2 * 00 - 1 * 550 * (m 2 * 11h. * + S. X _CH2 + _CH3).

Intermediate 11)

Preparation of 1- [9- (2,2-Dimethyl-6S-) - (1,3,4) -oxadiazol-2-yl] -tetrshydro- (3aR * 6aS) -furo- [3,4-d] // 1 3H-dioxol-4H-yl) 9H-purin-6-yl-amine

433

The mixture prepared by mixing 0.50 g of (38S, 4S _, 6B, 6aE) - 6- (6-Cyclopentylamino-purin-9-yl) -2,2-dimethyl-tetrahydro-furo-3-acid hydride. 4-di [1,3] -dioxole-4t-carboxylic acid (obtained as described in the preceding procedure for the preparation of Intermediate 1GD), and 5.0 ml, (4.45 g), triethyl orthoformate, were heated. under reflux for 48.0 hours. Then, after cooling, the reaction mixture was evaporated, and a brown oily-colored consistency was obtained, which was purified by flash chromatography using silica gel and ethyl acetate: cyclohexane (3.0: 1.0) as eluent. .

0.157 g of the title compound is obtained in the form of a cream-colored foam.

TLC * (SiO ₂ - 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) * 4H-oxadiazol-2-yl-t-tetrahydrofuran- 3,4-diol

To 0 * 157 g * cyclopentyl- [9- (2,2-dimethyl-6S- (1,3,4) -disodazol-2-yl] -tetrahydro- (3Bi * 6aS;) - furo-] 3,4-d [1 * (3-Dioxol-4-yl) -9Hipurin-6-yl] -amine * (obtained as described in the above Intermediate 11 above procedure) was added at 0.0 ° C; 1.50 ml of trifluoroacetic acid, and 0 * 15 ml of water * 8 the reaction mixture was stirred for 2.0 h.

The reaction mixture was then poured into 10.0 ml of an 8.0% aqueous sodium bicarbonate solution and the mixture was

extracted four times with 20.0 ml of ethyl acetate each time. After separation of the organic and aqueous phases, the organic layer was dried with magnesium sulfate, and filtered to dryness to give 0.148 g of a slightly cream-colored foam, to which was added 20.0 mL of methanol and a solid. was filtered.

0.46 g of the 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, H5, H, N 25.53,%

Detailed experimental data using procedure, D)

Intermediate 12)

Preparation of (2-oxo-butyl) -8midu (3aS _of 4S, 6R, 6a®) -6- (6-chloro-purin-9-y1) -2,2-Dimethyl-tetrahydro-furo ~ / 3 4-d [1,3] dioxole-4-carboxylic acid

To a solution prepared by dissolving 1.30 g of (3aS, 4S, 6B; 6aR) -6- (6-chloro-purin-9-yl) -2,2-dimethyl-tetrahydro-furo-3,4-acid. -d // 1,3 / -dioxole-4-carboxylic acid, in 30.0 ml of dried, tetrahydrofuran was added after cooling to 3.0 ° C, · · · ······ 1.07 ml of triethylamine. After stirring at 3.0 ° C for 15 minutes, 0.56 mL of trimethylacetyl chloride was added and the resulting suspension was stirred at 3.0. The suspension was then added with stirring to a mixture prepared by mixing 2-oxobutylamine hydrochloride in 50.0 ml ace of tonitrile containing 2.30 ml triethylamine. .

The mixture was allowed to warm to room temperature and was stirred between 150.0 mL of ethyl acetate after stirring overnight. 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 each of ethyl acetate, and then the combined organic extracts were washed with 70.0 ml of brine, and, after drying, were concentrated in vacuo.

1.83 g of a deep red colored gum was obtained, which was purified by chromatography on silica gel (Merck 7734), eluting with dichloromethane: ethanol 880, ammonia (250.0: 8, CL). 1.11 g of the title compound is obtained as a yellowish brown foam (1.11 g).

NMR, .delta., (CDCl3):

8,68, (1H, s., CH), 8, 27, (1H, a., ££ H ), 6.73, ( 1H, š, »T ·, NH), 6,30, (1 H, d., CH ) 5,64, (ih, a .a., (gh) 5,46, (1H d · d., GH), 4.80 (1 H, ď., CH), 3,76, ( 2H, ABX CH), 2.26 (25, k., Gfi I ₂ ), 1, .65 ,, ( 3H , p., -oh ₃ ) 1.42, (3H , -GH) 0,99, (3H, m.p. (GH +).

13) • · φφφφ φφφφ φ

φφφ φ

»Φ <

»Φ Φ 4

ΦΦ ΦΦ

Preparation of 6-Chloxp-9- [6S- (5-ethyl-oxazol-2-yl) -2,2-dimethyl-tetrahydro- (3aR, 5aS) -furo- [3,4-d] 1,3] -dioxol-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-2-oxo-butyl) -amide -tetrahydro-fluoro- [3,4-d] 1,3] -dioxole-4-carboxylic acid (obtained as described in the preceding Preparation of Intermediate 12 above) in 60.0 ml of acetonitrile , 1.43 g of phosphorus oxychloride was added with stirring, and the resulting reaction mixture was heated to reflux for 5.50 hours with stirring.

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

0.86 g of the title compound was obtained as a yellowish gum.

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

R _f = 0.50;

9999 99 9 4 9 9 9 9 999 99 9 99 9 9 9 9 9 9

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

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

The reaction mixture was then stored in the refrigerator overnight and then, after concentration under vacuum 8, a yellow colored residue was obtained which was azeotroped with dichloromethane: ethanol: ammonium, (75.0: 8.0: 1.0), . (3 x 40.0 mL) to give a yellow colored liquid (4.0 mL) which was undiluted with 5.0 mL of ethanol and then purified by silica gel chromatography (Merck 7734) using 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, δ, (DMSO δ:

9.00, (1H, s, CH), 8.85, (1H, s, CH), 6.99, (1H, neat 1, CH), 6.10 - 5.90, ( 2H, 2 x bs, 2 x OH), 5.05, (1H, d,

CH), 4.89 (1H "t. OH) ,, 4.70 (1H" t. "CH), 2.70 (2H, dk ,, _CH2) ,, 1.20 ( 3H, t, CH ₃ ).

Example; 16)

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

4,444,444

444 444 44 44 44 444

Preparation of (2S, 3S, 1B, 5S) -2- (5-ethyl-oxazol-2-yl) -5- [6- (tetrhydro-pyran-1-amino) -purin-9-yl] tert -hydro-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-furst -3,4-diol, (obtained as described above for the preparation of Intermediate 14 above), in 15.0 mL of isopropanol, was added 0.30 mL of diisopropylethylamine, and 0.135 g of 4-aminotranshydropyyran hydrochloride.

After the resulting reaction mixture was heated at reflux for 16.0 hours, an additional 0.20 mL of diisopropylethylamine and 60.0 mg of 4-aminotetrahydropyran hydrochloride were added while heating, while stirring. stirring, under reflux, for a further 20.0 hours.

The reaction mixture was then cooled and concentrated in vacuo to give 0.80 g of a yellowish gum which was purified by silica gel chromatography (Merck 7734) using dichloromethane: ethanol: ammonia (250.0: (100.0: 8.0: 1.0), as eluent, to give 0.182 g of the title compound as a white foam, foam-like in nature. .

MS (m / z): 417.0 (MH);

NMR, .delta., (CDCl3):

8.27, (1H, a, CH) 8.13, (1H, s, OH), 6.72, (1H, a, CH) 6.60-6.20, ( 1H, bs, -OH), 6.21, (1H, d, OH), 5.98, (1H, bd, NH), 5.31, (1H , d., OH), 4.79, (2H, m, 2 x OH), 4.40, (1H, bs, CH), 4.02, (2H, bs, 2 x CH, equatorial), 3.57, (2H, t, 2 x OH, axial), 2.66, (20t, k, CH3, 2.07, (2H, bd); 2.times.CH, equatorial., 1.63, (2H, broad, 2.times.CH, axial.), 1.23, (3H, t, CH3).

0000 0 0 0 0 0

0 0 0 0

0 0 0

000 000 00

0000

0 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 of 12.0 mg N / 6R ^ - (6-cyklopentyl8mino-purin-9-yl) -2 _of 2-dimethyl-tetr8hydro- (3aS, 6AE) -furo / 3,4d // 1 3-Dioxole-4S-carbonyl] -cyclopeopaneberoxylic acid hydrazide, with 19.0 mg, Lawesson's reagent, i.e. [2,4-bis- (4-methoxyphenyl) -1,3-dithii8-2,4- diphosphetin-2,4'-disulfide was heated in 2.0 mL acetonitrile at 80.0 ° C for 8.0 hours in

An additional 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 silica gel chromatography (Varian Bondelut cartridge) using ethyl acetate :: cyclohexane 20.0 :: 80.0 - 100.0 and ethyl acetate :: methanol, (98.2 - 95.5) to afford 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 an ice-cooled aqueous sodium bicarbonate solution (15.0 mL), and this mixture was extracted 3 times with 15.0 mL each of ethyl acetate. After separating the orange and aqueous phases, the organic layers were washed with brine, and After drying with magnesium sulfate, it was evaporated in vacuo.

A colorless gum was obtained which was purified by automated high performance liquid chromatography (HPCL) _r (Gradient Profile 30.0 - 60.0%, (II), over 20.0 minutes).

1.33 g of the title compound are obtained.

• 9,999,999,999,999,999 • 9,999,999 ·

9,999,999

99999 99 99 99 999

410

LC / MS (System A):

R = 4.0 min

MS, (m / z): 430.0, (MH ⁺ )

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] dioxol-4 -carboxylic acids

Mixture prepared by mixing 5,82 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, with 7.27 mL of isopropylamine, in 20.0 mL of isopropanol, was heated to reflux for 40 hours.

After cooling to room temperature, the mixture was concentrated in vacuo, and the resulting residue was shaken between 75.0 mL, ethyl acetate and 75.0 mL of a 0.5 M citric acid solution (kvsr citric acid = 2-hydroxypropane-1). (2,3-tricarboxylic acid), After separation of 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, water, and 80 1.0 mL, brine, and, after drying with magnesium sulfate, were filtered, and concentrated in vacuo.

4.49 g of the title compound are obtained in the form of a slightly brown colored foam.

• ··· «• · · · ··· 9 9)

TEGL ,. SiO ₂ (ethyl acetate): R _f = 0.35;

Intermediate 16)

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

The mixture prepared by mixing 4.82 g of (3aS, 43.6R, 6aR) -6-isopropylamino-purin-9-yl) -2,2-dimethyl-tetrshydro-furo / 3,4-d // 1, 3 H -dioxole-4-carboxylic acid (obtained as described in the foregoing procedure for the preparation of Intermediate 15), and 3.36 g. 2-Ethoxy-N-ethoxycarbones of 1,1,2-dihydroquinol, (EEDQ), in 150.0 ml of methanol was heated at reflux for 60.0 hours.

After cooling to room temperature, the reaction mixture was concentrated under vacuum, and the resulting residue was partitioned between 100.0 mL of ethyl acetate and 75.0 mL of a 0.5 M 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 each of ethyl acetate, and the combined organic extracts were then washed with 50.0 ml of water, and 75.0 ml of brine, and dried over magnesium sulfate. 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 of the title compound are obtained as a white solid.

• 4444 • 4 4 • 4 4 4 4 4

4 4 4

444444 44

44 44

4

4 * 4 4

4 4 4

4 4

44

TLC, SiO ₂ (ethyl acetate: cyclohexane, (1.0: 1.0): Rf ₌ 0.20;

M e zip product 17)

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

Mixture prepared by mixing 3.76 g of (3aS, 4S, 6R, 6aB) -6- (6-isopropylamino-purin-9-yl) -2,2-dimethyl-trahydro-fluoro- 3,4-di [1,3] -dioxole-4-carboxylic acid (obtained as described in the foregoing procedure for the preparation of Intermediate 16), and 1.26 ml of hydrazine hydrate in 140.0 ml of methanol, was refluxed for 48.0 hours.

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

3.30 g of the title compound are obtained in the form of a white solid.

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

Calculated: C 51, Oj H16.40, N 23.80,%

Found Gt 51.5 ^ H 6.50, N 23.60,%

• 445 · «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, _i 4S, 5R) -2- (6-isopropylamino-purin-9-yl) -5- (5-methyl-4H- / 1,2 4 / triazol-3-yl) - tetrahydro-furen-3,4-dioltrifluoroacetate.

A mixture of 0.50 _g,: hydrszidu (3aS, _4S, 6R ,, 6aR) -6- (6-isopropylamino-purin-9-y1) -2,2-dimethyl-furo thyltetrahydro / 3 4-di [1,3] -dioxole-4-carboxylic acid (obtained as described in the foregoing procedure for the preparation of Intermediate 17), followed by 0.24 g of ethylacretimidate hydrochloride and 0.55 ml of triethylamine, in 10.0 mL of ethanol was heated at reflux for 72.0 hours.

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 This gave 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 the addition of toluene, the mixture was evaporated again to dryness. The resulting residue was mechanically worked up and taken up with ethyl acetate to give 0.41 g of the title compound as a white solid. .

NMR (.delta., DMSO):

8.71, (1H, bs, NH), 8.40-8.20, (2H, bs + bs, 2 x CH), 6.11, (1H, d, CH ), 5.00, (1H, d, CH), 4.73, (1H, t, CH 4.44, (2H, t. + Sm, 2.times.CH), 2.42, (3H, s., _{1-CH 2?} (d 6Hý., 2 x _CH3).

• • •• 0 • 0 ···· ·· · 00 • £ 0 · 0 « 00 • • • 0 • · • • • • • · • 0 • 0 • • 0 0 · 00 00 0 ·

Analytical evaluation of the compound according to the summary formula ^:

H, 4.40; N, 23.60.

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

Detailed experimental data using procedure G)

M e z i o t u k t 118)

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

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

After 10.0 minutes, the reaction mixture was treated with 1.65 ml of piveloyl chloride, and the mixture was stirred at 0.03 ° C for 1.0 hour, and was then stirred for 1.0 hour. warmed to room temperature * after re-cooling the mixture to 5, © g ^0, to the mixture was added dropwise 1.47 g, cyklopropylamidooximu and after weaning cooling bath, the mixture was stirred at 22.0 ° C for 18 0 hours.

Then, diisopropylethylamine hydrochloride was filtered off, and washed with 100.0 ml of tetrahydrofuran. The resulting filtrate was heated at reflux for 10.0. hours, and then, after cooling, was concentrated in vacuo, the residue was obtained in 8, and the residue was obtained. Purified by chromatography on silica gel (Variant Mega Bondelut cartridge), using ethyl acetate / cyclohexane * (3 *). 0: 1.0) as eluent.

1 * 99 g * of the title compound * was obtained in the form of a white solid. colored solids.

LC / MS) (System B): &lt; tb &gt;

S. ss 2,91 minutj v

Mass Spectrometry, (m / z):, 405 (0), (MH +);

Me zip product 19)

Preparation of (2R, 3R * 4S * 5S) -2- (6-Chloro-purin-9-yl) -5- (3-cyclopropyl / 1,2,4'-oxadiazol-5-yl) -tetrahydro-furan- 3,4-diol

Solution * prepared by dissolving 1 * 99 g * 6-chloro-9- [6S- (3-cyclopropyl-1 ', 1', 2 ', 4'-oxadiazol-5-yl) -2]. 2-Dimethyl-tetrahydro (3afi * 6aS)) - furo- [3 ', 4'-d [1,3'] -dioxol-4R-yl] -9H * -purone * (obtained within the previous * above) of the described procedure for the preparation of 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 minutes. , 0 hours. Then, the resulting solution in an ice-cooled bath was basified with 200.0. ml of a saturated aqueous sodium bicarbonate solution, and then extracted 3 times with 70.0 ml each of ethyl acetate, and the extract obtained was dried over magnesium sulphate, and concentrated in vacuo.

The residue, as an oily brown solid, was purified by chromatography on silica gel (Warian Mega Bondelut cartridge) using dichloromethane / methanol as eluent (10.0: 1.0).

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

Λΐ «Ε t- fcte-

LC / MSy (System B) ::

R t 2.42 minutes;

MS, (m / z): 365 (Q), (MH ^{&lt; + &gt;} )

Annexes 19)

Preparation of (2S, 3S, 4S) -2- (3'-cyclopropyl-1- (1,2,4) -oxadiazol-5'-yl) -5-yl) -5- / 6- (2S-hydroxy-cy clopent- (S) -y 1-amino) -purin-9-yl] -tetrahydrofuran and n-3,4-diol

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

After cooling to room temperature, the reaction mixture was concentrated to dryness under vacuum, and the resulting residue was purified over a solid phase, (5.0 g) (Varian Mega Bondelut cartridge, bound aminopropyl base) and eluted with (I). (II), ethyl acetate :: cyclohexane, (1.0: 1, 1.0), (II), ethyl acetate, (IV), dichloromethane (V), mixed dichloromethane :: methano 1, (20.0: 1.0), (VI), dichloromethane (methanol: (10: 1.0)), at VII), methanol, as extracting agents.

47-30 mg of the title compound are obtained.

no / MSy G System B) ::

2.37 minutes;

Mass Spectrometry (m / Z) r

(MhI);

Detailed experimental data using the procedure »

It can be 20)

Preparation of 4- / 9- ^(R 60-carboxy-2,2-dimetfeylte trahydro- ( '3 © R, 6a') - furo / 3,4-d * 1 // 3 / di oxol- 4E-yl) -9H-purin-6-yl-amino] -piperidine-H-carboxylic acid

Mixture prepared by mixing 1.80 ml * ethyl 4-amino-piperidinecarboxylate * further 2 * 0 g * (3aS * 4S, 6R * 6aR) -6- (6-chloro-purin-9-yl) 2,2,2 -dimethyl-tra- [3,4-d] 1,3,5-dioxole-4'-carboxylic acid * and 2.74 ml * diisopropylethylamine were heated at reflux in 100.0 ml * isopropanol * for 70.0 hours.

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

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

LC / MS &lt; + &gt; (System B): &lt; tb &gt;

- 2 * 62 minutes *

9 9 9

Mass spectrometry, (m / z):

477.0, (MH ⁺ );

MKe zip product 21)

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

Solution prepared by dissolving 2,56 g of 4- [9- (6S-carboxy-2,2-dimethyl-1-tetrshydro- (3a®, 6aS) -furo- / 3,4d // 1,3) -ethyl ester. (-dioxol-4-yl) -9H-purin-6-yl-amino / -piperidine-1-carboxylic acid ((obtained as described in the above Preparation of Intermediate 20 above) in 50.0 ml of anhydrous dichloromethane After cooling to 0.0 ° C with 0.82 ml of triethylamine and with 02.73 ml of pivaloyl chloride was added.

Ammonia was bubbled through the reaction mixture for 70 minutes, then the reaction mixture was evaporated to dryness under vacuum, and the crude product residue was dissolved in ethyl acetate and washed 3 times with 70.0 ml of water. The solution was then dried with magnesium sulfate and concentrated in vacuo.

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

LC / MS, (System E B):

- 2.54 minutes;

Mass Spectrometry, (m / Z): 476, .alpha. (MH @ ⁺ ) @ ⁺ 9 9 9 9 9 9 9 9 9

Μ

Intermediate 22)

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

A solution prepared by dissolving 1.97 g of 4- [9- (6S5-carbonyl) -2,2-dimethyl-1-tetrahydrate- (3aH, 6aSU-furo) 3,4-d // ethyl ester 3'-dioxol-4R-yl) -9H-purin-6-yl-amino / -piperidine-1-carboxylic acid (obtained as described in the above Preparation of Intermediate 21 above), in 40.0 ml, anhydrous of acetonitrile, was mixed with 1.01 g of 4-dimethylaminopyridine, and to the resulting reaction mixture, cooled to 0.0 ° C, was added 1.93 ml of phosphorus oxychloride by dropwise addition »

The reaction mixture was then evaporated to dryness in vacuo, and the residue, as 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 title compound was obtained as a slightly orange colored solid (1.91 g) »

LC / MS (System A)

R t = 4.09 min J

MS (m / z): 458.0 (MH ⁺ )

Intermediate, t 23)

Preparation of 4-4- (9- [6K- (N-hydroxycarbamimidoyl) -2,22-dimethyl-tetrahydro- (3HR, 6aR) -thiro- [3,4-d] -1,3] -dioxol-4B-yl) ethyl ester (9H-Purin-6-yl-amino) -piperidine-1-carboxylic acid

Mixture prepared by combining 4- [9- (6R-cyano-2,2-dimethyl-(3aR, 6aR) -tetrahydro-furo [3,4-d] 1,3] dioxol-4R-yl) ethyl ester The -9H-purin-6-yl-amino / -piperidine-1-carboxylic acid (obtained in the previous procedure described above for the preparation of Intermediate 22), with 0.29 ml, 50% hydroxylamine, was heated to reflux. with a condenser in the presence of 25.0 ethanol for 9.0 hours.

After cooling, the reaction mixture was concentrated in vacuo and the residue was co-evaporated with 50.0 mL of toluene to give 1.25 g of the desired compound as a yellow solid.

LC / M5> (System A)

R = 3.82 minutes;

MASS (m / z): 490 _ø d, / MH ⁺ /;

Intermediate k, t 240 Preparation of 4- (9- [6- (5-tert-Butyl- / 1,2,4) oxadiazol-3-yl) -2,2-dimethyl-tetrahydro- (3fe) -ethyl ester (6aR) -fluo [3,4-d] 1,3] dioxol-4R-yl] -9H-purin-6-yl-amino-4-piperidine-1-carboxylic acid

Mixture prepared by mixing 1,0 g of ₍ 49- [6R- (N * hydroxycarbamimidoyl) -2,2-dimethyl-tetrahydro- (3aR, aR) -furo- [3,4-d] ethyl ester) 1,3'-dioxol-4R-yl / -9H-purin-6-yl-amino-1-piperidine-1-carboxylic acid (obtained in the foregoing, above described for the preparation of Intermediate 23) 15.0 ml of pivalic acid (pivalic acid, 2,2-dimethylpropanoic acid), and 0.49 ml of pivalic anhydride were stirred first at room temperature for 2.0 hours, and then was heated at reflux for 9.0 hours.

After cooling 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 under vacuum to give a solid. The resulting residue was added with 100.0 mL of diethyl ether, and the brown precipitate that formed was filtered off, and the filtrate was concentrated in vacuo to give a crude product which was purified by silica gel chromatography using a Varian Mege Bondelut cartridge. , and elution with ethyl acetate.

0.360 g of the title compound is obtained in the form of a slightly orange colored oil.

LC / MS, (System B.): &lt; tb &gt;

R.t. = 3.13 min.

Mass spectroscopy, (m / z): 557.0. ^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

Solution prepared by dissolving 360.0 mg of 4- (9- [6R- (5-tert-butyl-1- (1,2,4) -ox8-diazol-3-yl) -2,2-dimethyl) -ethyl ester) trahydro- (3aR, 6aR) -furo- (3,4-d [1,3] -dioxol-4R-yl) -9H-purin-6 • 9 · 9 99 99 99 9 • 9 9 9 9 999 9 • 9 9 · 9 9

999,999,999,999,991-Amino-4-piperidine-1-carboxylic acid (obtained in the foregoing procedure for the preparation of Intermediate 24 above). in a cooled mixture (5.0 mL) of trifluoroacetic acid and water (9.0%: 1 * 0) was cooled to 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, rinsed sodium bicarbonate solution, and then extracted three 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 (HPCL) was performed on a Supelcosil LC-ABZ column (21.2 mm x 10.0 cm) using a flow rate of 8.0 mL / min. (eluents were: A): 0.1% trifluoroacetic acid / water E0) 0.01% trifluoroacetic acid in acetonitrile: water, (95.0: 5.0), (gradient profile 15, 0 - 95.0%), B), for 25 minutes);

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

LC / MB (System B):

R = 2.76 minutes;

MS, (m / z): 517.0 (MH ^&lt; ⁺ &gt;);

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 0 0000 0000

Preparation of (3aS _, 4S, 6R, 6aR) -6-Imethoxy-2,2-dimethyl-methyl-trichloro-furo [3,4-d] 1,3] -dioxol-methoxymethyl-amide -4-carboxylic acid

To a solution prepared by dissolving 11.0 g of (3S, 4S _, 6R, 6R, 68R) -6-methoxy-2,2-dimethyl-tetrahydro-furo- (3,4-d) / 1,3 t -dioxol-4-carboxylic acid, in 100.0 mL, dichloromethane, was added portionwise, at 22.0 ° C, over 10.0 minutes,

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

After that a mixture added Ν, Ο-dimethylhvdroxylamin, (12.5 g), dissolved in 50 ml ^of water, 8 followed by 20.0 mL of 10N NaOH, the mixture was extracted 3 times with 50.0 ml of dichloromethane. The combined dichloromethane extracts were dried with sodium sulfate, and filtered, and the resulting solution was added to the solution prepared above. After stirring for 3.0 days, the reaction mixture was washed with 200.0 mL of citric acid (acidic citric = 2-hydroxypropane-1,2,3-tricarboxylic acid) followed by 8.0% bicarbonate solution. sodium sulfate (200.0 mL), and dried over sodium sulfate, dried in vacuo.

14.20 g of the title compound were obtained as a colorless oil.

Thin Layer Chromatography (TLGL), Si0 ₂ , ether:

R _f = 0.33;

Intermediate 26)

Preparation of 1- (6R-methoxy-2,2-Dimethyl-te trahydro- (3aS, 6aR) -furo / _FF 3 3 / dioxol-4S-yl) -4,4-Dimethyl-pent-2- yn-1 -on ··· 4 4 · 4 4 4 4

4 4 4 4 4444 4444 4

444444 44 44 44 444

To a solution prepared by dissolving 3,3-dimethyl-1-butyne in 90.0 mL of tetrahydrofuran was added, under a nitrogen atmosphere, and at a temperature of 0.0-5.0 ° C, a 3.0 M solution of methylmagnesium chloride in 50 mL. 1.0 ml of tetrahydrofuran, and the mixture was stirred at 5,0ΟΟ to 5.0 ° C for 5.0 hours.

To the above-prepared mixture was then added over 20.0 minutes, with the temperature at 0.0 to 5.0 solution obtained by dissolving 14.17 g, methoxy-methyl-amide (3aS, R, 4 _S,; 6aR,) - 6 -methoxy-2,2-dimethyl tetrahydro-furo- [3,4-d] 1,3] -dioxole-4-carboxylic acid, in 20.0 ml, tetrahydrofuran, and the reaction mixture was stirred at 0.0 - 5.0 ° C for 2.0 hours.

Then, after the reaction mixture was mixed with 150.0 ml of a 30.0% ammonium chloride solution and 15.0 ml of a 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 with sodium sulfate, and evaporated in vacuo, and the 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 title compound are obtained as a colorless solid.

TLC, SiO ₂ , (ether):

R _t = 0.55 *

Intermediate 27)

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

9

999 • 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) -dioxol4S-). yl) -4,4-dimethyl-pent-2-yn-1-one _(obtained by the previous process described above ,, of Intermediate Compound 26) in 6.0 ml ,. methanol ,. 0.19 ml of 50% aqueous hydroxylamine solution was added.

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

0.635 g of the title compound is obtained as a colorless oil.

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

R _f = 0.16 *

Intermediate 28)

Acetic acid 4R-acetoxy-2S- (3-tert-butyl-1-oxa-5-yl) -5-methoxy-tetrahydro-furan-3R-yl 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 above-described procedure for the preparation of Intermediate 27) in 15.0 ml of methanol was added; 0 mL of concentrated hydrochloric acid, and the resulting reaction mixture was heated to reflux in 10.0 mL of pyridine to which 1.0 mg of 4-dimethylaminopyridine and 2.0 mL of acetic anhydride were added.

«« ··

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 a 8.0% sodium bicarbonate solution, the solution was dried over sodium sulfate, and evaporated in vacuo.

575.0 mg of the title compound is obtained as a slightly yellowish gum. MS, (m / z): 342.0 (MH ⁺ );

Intermediate 29)

Preparation of 4R-8-Cethoxy-5S- (3-tert-butyl-isoxazol-5-yl) -2R- (6-chloro-purin-9-yl) -tetrahydro-furan-3R-yl-ester

The mixture, prepared by mixing 1.36 g of 6-chloropurine, further 26.0 ml of toluene, and 10.0 ml of hexamethyldisilazine, was heated under a nitrogen atmosphere at reflux for 2.0 hours. After evaporation of the reaction mixture in vacuo, 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, 4R- acetoxy-2S- (3-tert-butyl-isoxazol-5-yl) -5-methoxy-tetrahydrofuran-SR-yl ester octogé, (diethyl oxalate, the above-described procedure for preparing ^M eziproduktu 26) and 1.80 ml , trimethylsilyl trifluoromethanesulfonate, and the resulting reaction mixture was heated to 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 extracted twice with 100.0 ml of ethyl acetate. The combined extracts were then filtered. • 4 ·· 4 4 · «44 •» 444 44 ·· 4 • 4,444 · 44 4

444 444 44 44 44 444 dried over sodium sulphate and evaporated in vacuo. The residue was purified by flash chromatography on silica using cyclohexane: ether (1.0: 1.0 - 1.0: 4.0). ) as eluent.

0.953 g of the title compound is obtained as a colorless foam.

LC / MS (System A)

= 4.35 minutes}

Example 27)

Rříprava (2S, 3S, 4R, ^5R,) -2- (3-tert-butyl-isoxazol-5-yl) -5 / 6 (2S-hydroxy-cyclopent (S) -yl-amino) - Purin-9-yl] -threhydro-furan-3,4-diol

To a solution prepared by dissolving 70.0 mg of 4R-acetoxy5S- (3-tert-butyl-isoxazol-5-yl) -2R- (6-chloro-purin-9-yl) -tetrshydrofuran-3R-yl ester acetic acid (obtained as described in the preceding Preparation of Intermediate 26), and 62.0 mg of trans- (1S, 2S) -2-aminocyclopentahol hydrochloride, in 10.0 ml of isopropanol, were added at 0. 16 ml of diisopropylethylamine, and the resulting reaction mixture was heated at reflux pdd for 17 hours.

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 the mixture was allowed to stand for 3.0 hours. Then, after removal of the solvent from the vacuum, the residue was purified by silica chromatography (5.0 g) using ethyl acetate: methanol (10.0: 1.0) as eluent.

• · · · * · • · * * * * * * * *

999999 99 99 ♦ ·· · • 9 99

9 9

9 9

9 9

99 9

Purification by 8-preparative high-performance liquid chromatography (HPCL) afforded the title compound (40.0 mg) as a colorless gum.

LC / MS (System A)

R = 3.81 minutes at

MS (m / z): 445.0 (MH);

Example 2 &) ^r Preparation of (2S, 3S, .4R, 5R) -2- (3-tert-butyl-isoxazol-5-yl) -5 / 6 (tetrahydro-pyran-4-y1-amino) - Purin-9-yl] -tetrahydro-furan-3,4-diol

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

After removal of 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 in vacuo, and the residue was purified over the solid phase using an Aminopropyl-bound Varian Bondelut cartridge and ethyl acetate: methano (10.0: 1.0) as eluent.

44 4 •

444 ·· 4

4 4

· 4

44 ·

4

4

4

4

Further purification by autoprep. High performance liquid chromatography afforded 31.0 mg of the title compound as a colorless gum.

LC / MS (System A)

Rt = 3.78 minutes;

MS (m / z): 445.0 (MH ⁺ );

Detailed experimental data using procedure J)

Intermediate 3®)

Preparation of (E) -3-dimethylamino-1- (6R-methoxy-2,2-dimethylamino-3- (3S, 6aR) -furo- [3,4-d] 1,3) -dioxol-4S-yl) -pe openenone

To a stirred solution of 0.62 g 1- (6B-methoxy-2,2-dimethyl-tetrahydro- (3SS _F 6aR) -furo / 3,4-d // 1,3 / dioxol-4S-yl 1-ethanone, in 25.0 mL of "toluene" was added 5.0 mL of dimethylformamide dimethylacetal, and the resulting reaction mixture was heated to reflux under a nitrogen atmosphere for 17.0 hours.

After removal of 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.

The title compound (0.102 g) was obtained as a yellowish gum.

9999

9 99 9

998 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) -tetrahydro- (3aR, 6aR) -furo / 3,4- (1 H) -1,3-Dioxol-4S-yl) -propenone (obtained as described in the preceding procedure for the preparation of Intermediate 30), 15.0 ml of methanol, 0.50 ml of hydrazine was added. hydrate, and the resulting reaction mixture was heated to reflux for 1.5 ^W hours.

The solvents were then removed from the reaction mixture in vacuo and the residue was purified by silica gel flash chromatography, eluting with diethyl ether.

47.0 mg of the title compound is obtained as a colorless gum.

MS, (m / z): 241, OJ / MH ⁺ / J

Intermediate 32)

4R-scetoxy-2R- (1-acetyl-1H-pyrazol-3-yl) ^-5R> -methoxytetrshydro-furan-3R-yl ester • ···· ·· 44 · 4444

4 44 44 4444

444 444 444

4444 4444 3

4,444 · 4 4

444 444 44 44 44 444

Solution, prepared by dissolving 1,66 g, 6- (6R-methoxy-2,2-dimethyl-tetrahydro- (38R, 6aR) -furo- [3,4-d] 1,3] dioxol-4R-yl) 1H - the pyrazole (obtained as described in the above-described Preparation of Intermediate 31) in 120.0 ml of methanol was heated to reflux for 22 after mixing with 1.0 ml of hydrochloric acid (concentrated), 0 jbodin.

After cooling, and evaporation in vacuo, the resulting residue was dissolved in 80.0 ml of pyridine, and after addition of 4.0 ml of acetic anhydride to the prepared solution, the mixture was allowed to stand for 3.0 hours. After removal of the solvents under vacuum, the residue was taken up in 200.0 ml of ethyl acetate, followed by a prorayt of the solution obtained with 100.0 ml of 0.5 citric acid solution (citric acid = 2-hydroxypropane-1,2 acid). (3-tricarboxylic acid), followed by 100.0 ml of 8% sodium bicarbonate solution and 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 cyclohexane: diethyl ether, (2.0: 1.0-1.0: 1, 0) as eluent.

646 mg of the title compound was obtained as a colorless gum.

Mass spectrometry (m / z): 327, /, / / ⁺ / ζ 344.0, / MH ⁺ / J

Intermediate 33)

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

..

9999 9999

99 99 999

To the suspension prepared to suspend 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 to 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, followed by the addition of 645.0 mg of 4R-acetoxyl-2R- (1-acetyl-1H-pyrazol-3-yl) -5R-methoxy-tetrahydro-furan A 3R-yl acetic acid ester (obtained as described in the foregoing procedure for the preparation of Intermediate 32), followed by 1.0 mL of 1,8-diazabicyclo [5,4.0.0] -undee-7-ene (DBU), and 1.0 ml of trimethylsilyl trifluoromethanesulfonate in the reaction mixture was excellent, and the mixture was heated to reflux under a nitrogen atmosphere for 3.0 hours.

The reaction mixture was then poured into 150.0 ml of a 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. a mixture was obtained which was purified by flash chromatography using silica gel and diethyl ether: cyclohexane (3.0: 1.0) as eluent.

42.0 mg of the desired product was obtained. of the title compound. MS (m / z): 449.0, (451), OJ / 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

9 · · · · ·

999 999 9 9 9 9 9

9

999 999 «10 99

999 *

To a solution prepared by dissolving 42.0 mg of 4R-acetoxy-5- (1-8-acetyl-1H-pyrrol-3-yl) -2R- (6-chloro-purin-9-yl) -tetrahydro-furan-32-yl ester of acetic acid (obtained as described in the previous Preparation of Intermediate 33 above) in 3.0 mL of methanol and cooled to 0.0 ° C. was added 0.20 mL of tert-butylamine * 8. The reaction was allowed to stand, at a temperature of 0.0 ° C, for 25.0 minutes.

The solvents were then removed in vacuo to give the title compound (35.0 mg). MS, (m / Z): 323 * 0, / 325, 0, (MH ⁺ )

Example 29)

Preparation of (2R * 3B * 4S ^: * 5E) -2- (2H-Pyrazol-3-yl) -5- (6-tetrahydro-pyran-4-yl-amino-purin-9-yl) -tetrahydro-furan-3 4-diol

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

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

After removal of the solvent from the reaction mixture in vacuo, the residue was dissolved in 10.0 ml of methanol and 3.0 ml of an 8% sodium bicarbonate solution were added thereto, followed by 3.0 g of silica gel. solvent under vacuum, the residue was applied to a flash column of silica gel in dichloromethane. After ·

0000 0000 00 00 00 00 0 0 0 0 0 0 0 0 0 0

Elution with dichloromethane: methanol (4.0: 1.0) yielded 5.20 g of the desired title compound as a clear viscous gum.

LC / MS (System A ^{&lt; -1 &gt};):

Rt ₌ 3.34 min

MS (m / z): 388.0 (MH);

Detailed experimental data using procedure K)

Me zip product 35)

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

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 (1) of Acarbonyldiimidazole, with ice cooling.

After stirring at 22.0 ° C for 1.0 hour, the resulting reaction mixture was mixed with 12.30 g of Ν, Ο-dimethyl hydroxylamine, hydrochloride, and 15.0 mL of pyridine, and The mixture was further stirred at 22.0 ° C for 24.0 hours. The mixture was then washed with 250.0 ml of a 0.5 M citric acid solution (citric acid = 2-hydroxypropane-1,2,3-). tricarbonyl), and with 200.0 ml of an 8% sodium bicarbonate solution.

4444

444 • 4 4

4 4 • 4 4 4

4 «

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

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

LC / MS (System A)

H _t = 3.77 minutes;

MS, (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] methoxy-methyl-amide // 1,3] -dioxol-4-carboxylic acid

To the suspension, prepared by suspending 23.30 g of (3SS, 4S, 6R, 6aR) -6- (6-chloro-purin-9-yl) 2,2-dimethyl-tetrahydro-furo- 4-di [1,3] -dioxide-4-carboxylic acid (obtained as described in the above-described Preparation of Intermediate 35?), To 250.0 mL of ethanol was added 10.0 g of sodium bisulfide, and the resulting reaction mixture was heated to reflux, under a nitrogen atmosphere, for 3.0 h.

After cooling and evaporating 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 0.5 M citric acid solution (citric acid = acid 2). -hydroxypropane-1,2,3-carboxylic acid), and filtered. The solids on the filter were washed with 250.0 ml of <RTIgt; ml. </RTI>. Water, and with 100 µl of 0 ml of isopropanol, and then dried under vacuum.

16.30 g of the title compound are obtained as a yellow solid.

LC / MS), (System A):

Rt = 3.53 minutes;

MS (m / z): 382.0;

Me zip product 37)

Preparation of 9- [6RT- (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-cyclopentyl-amine

A solution prepared by hot dissolving 1.0 g of (3aS, 4S, 6R, 6aR) -2,2-dimethyl-6- (6-thioxol-6-dihydro-purin-9-yl) -tetrahydro-methoxymethyl-amide -furo- (3,4-di [1,3] -dioxole-4-carboxylic acid (obtained as part of the above-described 3: 6 Intermediate Preparation) described above) in 25.0 mL of N, N-dimethylformamide was filtered while still hot, and the filtrate was mixed with 0.50 mL, di-isopropvlethylamine, and 2.0 g, Merrifield resin, (chloromethyl form, 0.8mmmol / g, 1.0%, crosslinked), and this the reaction mixture was shaken for 24.0 hours.

The mixture was then filtered, and the filtered resin was washed twice with 15.0 ml each of Ν, Ν-dimethylformamide and then with 3x0.0 ml of ether each time. The above resin was added to a solution of N, N-dimethyl-4-iodobutynylmagnesium chloride (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 a 2M hydrochloric acid solution and 12.0 ml of tetrhydrofuran were added, and after shaking for 10 minutes, the resin was filtered off and washed twice with 15.0 ml each of tetrhydrofuran, then twice. each with 15.0 ml of ether.

The resin was re-suspended in 25.0 mL of N, Ndimethylformamiidu and after addition _of 2.0 ml, hydrazinu.hydrátu, 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 twice with 10.0 ml _of dichloromethane each, and three times with 10.0 ml of ether each, followed by suspension to 15.0 ml. ml _of dichloromethane ,, was mixed with a mixture _of 0.50 g of 3 «-chlorperoxybenzoové (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 three times with 10.0 ml each of dichloromethane and then twice with 10.0 ml of ether each time, and the residue in 10 ml of tetrahydrofuran was mixed with 88.0 ml. The compound was stirred at 22.0 ° C for 17.0 hours. The mixture was then filtered and washed twice with 10.0 ml, tetrshydrofuran :: methanol (3.0: 1.0), and the filtrate and washings were evaporated in vacuo.

Purification of the residue by automatic preparative high-performance liquid chromatography gave 20.0 mg of the title compound.

LC / MS _Rt (System A):

- 4.48 minutes;

MS (m / z) 468.0 (MH &lt; ⁺ &gt;);

• · · ·

Example 1 to 3 ©)

Preparation of (2R, 3R, 4S, 5E:) -2- (5-tert-Butyl-2H-pyrazol-3-yl) -5 (6-cyclopentylamino-purin-9-yl) -tetrahydro-furan-3 4-diol

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-di [1,3] -dioxol-4R-yl] -9H-purin-6-yl] -cyclopentylamine (obtained as described in the preceding Preparation of Intermediate 37 above) in 4.0 mL, Trifluoroacetic acid: water (9.0: 1.0) was allowed to stand at 0-10.0 ° C for 17.0 hours.

Then, the solution was evaporated in vacuo (bath temperature < 3 ° C, 0 ° C) and mixed with 15 ml of a 2M sodium carbonate solution. Thereafter, the reaction mixture was extracted twice with 15.0 ml of ethyl acetate each time, and the combined extracts were dried over sodium sulfate and then evaporated in vacuo. The resulting residue was purified by silica gel chromatography (Varian Bondelut cartridge), eluting with ethyl acetate: methanol (9.0: 1.0).

19.0 mg of the title compound was obtained as a clear gum.

LC / MS (System A)

R = 4.0 min;

MS, (M / Z): 428.0 (MH ⁺ );

Detailed experimental data using procedure L)

Intermediate 38)

Preparation of 3-ethyl-5- (6R-methoxy-2,2-dimethylethyl) (3 and R, 6aE) -furo- / 3,4-d // 1 3'-dioxol-4S-yl) -isoxazole '

To the mixture * prepared by mixing 0.271 g * 4B-ethynyl-6B-methoxy-2 * 2-dimethyl-tetrhydro- (3eS, 6aR) -furo- [3,4-d] 1,3 / dioxole * (see reference to an article in the journal Helv.Chim. Acta * 63 * 1181 - 1189, (1980), and 0.328 ml, phenyl isocyanate, in

1.50 ml * of dried toluene, was added under a nitrogen atmosphere, over 5 minutes, a mixture prepared by mixing 0.134 ml of 1-nitropropane *. and 0.038 ml of triethylamine in 1.0 ml of dried toluene. During this operation, a precipitate formed in the reaction mixture.

The resulting mixture was heated in a 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 with ether first, followed by a mixture of 40% ethyl acetate in cyclohexane. After removal of the solvent in vacuo, a light brown color was obtained. solid (0.487 g) which was further subjected to flash chromatography on silica gel * using ethyl acetate: cyclohexane * (20.0: 80.0 - 30.0: 70.03) as eluent.

The title compound (03.329 g) was obtained as a clear oil.

TLC * (cyclohexane: ethyl acetate; 3.0: 2.0):

Rf = 0.49;

M e zip product 339a)

Preparation of 4H * 5S '-diacetoxy-2S- (3-ethyl-isoxazol-5-yl) -tetrahydrofuran-3E * -yl-ester * and

• 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9.9

99999 99 99 99

JTD

M e zip product 39b)

Preparation of acetic acid 4S, 5B-disethoxy-2S- (3-ethyl-isoxazol-5-yl) -tetrahydrofuran-3R * -yl ester

A solution of 0.355 g 3-ethyl-5- (2-methoxy 6Rme, 2-Dimethyl-te trahydro- (3a _R, 6a R) -f furo / 3,4-d // 1,3 / dioxol -4S-yl) -isoxazole (obtained as described in the preceding 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 hours. It was then evaporated in vacuo.

The resulting residue was azeotroped with toluene 3 times and then dissolved in 10.0 mL of dichloromethane under nitrogen atmosphere, and the resulting solution was cooled to 0.0 ° C. Subsequently, 0.048 g of 4- (N, N-dimethylaminopyridine, followed by 8.30 ml of triethylamine and 2.49 ml of acetic anhydride) was added sequentially, and the resulting mixture was stirred at 0.0 ° C to room temperature over and then evaporated in vacuo to give 1.34 g of a brown colored 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 acetic acid ester, in the form of a slightly brown oil of oily consistency, i.e. Intermediate 39a).

and

0.16 g _of acetic acid 4R, 5R-diethoxy-2S- (3-ethyl-1-isoxazol-5-yl) -tetrahydrofuran-3®-yl ester, in the form of a slightly brown oil of oily consistency, ie Intermediate 39b).

M e zip product

y? /

39a):

TLO (SiO ^ J cyclohexane: ethylacetátj 3.0: 2.0): _Rf = 0.28;

and

M e zip product 39b) ::

TLC (SiO _2;. Cyclohexane: ethylacetátj 3.0: 2.0): _Rf = 0,22J

Intermediate 4SO)

Preparation of 4S-acetoxy-2R- (2 _r 6-dichloro-purin-9-yl) -5S- (3-ethyl-isoxazol-5> yl) -tetrahydro-furan-3R-acetic aster

To the mixture, prepared by mixing 0.909 g of acetic acid, 4R, 5SZ-d 6 -cetoxy2S- (3-ethyl-isoxazol-5'-yl) -tetrahydro-furan-3R-yl ester, and 4R, 5K * diacetoxy-2S- (3 acetic acid-ethyl-isoxiazol-5-yl) -tetrahydro-furan-3R-yl ester (i.e., Intermediate 39a), and Intermediate 39b) obtained in the foregoing process for the preparation of both said intermediates), in Dry acetonitrile (5.0 mL) at room temperature under nitrogen atmosphere was added 0.779 g, 2,8-dichloropurine, and 0.692 mL, 1,8-diazabicyclo [5.4.0] -undee-7-ene, (DBU), and the resulting reaction mixture was stirred at room temperature for 20.0 hours »

Thereafter, the reaction mixture was mixed with 30.0 mL of saturated aqueous sodium bicarbonate solution, and was then extracted 3 times with 40.0 mL of ethyl acetate each time to obtain.

···· · ·

3.54 g of a brown liquid which was purified by flash chromatography ηβ silica gel using ethyl acetate: cyclohexane (40.0 60.0 - 50.0 :: 50.0) as eluent.

0.798 g of the title compound is obtained in the form of a cream-white colored foam. TLG., (SiO2, cyclohexane: ethyl acetate; 2.0: 3.0):

R _f = 0.25;

Intermediate 41)

Preparation of 4R-Acetoxy-2R- / 2-chloro-6- (1S-hydroxymethyl-1-phenylmethyl-lamino) -purin-9-yl / -5S- (3-ethyl-oxazole) Acetic acid ester of tetrahydrofuran-3R-yl)

HPLC solution prepared by dissolving 151.0 mg of acetic acid 4R-acetoxy-2R (2,6-dichloro-purin-9-yl) -5S- (3-ethyl-isoxazol-5-yl) -tetrahydrofuran-3R-yl ester (obtained in the preceding procedure for the preparation of Intermediate 40), further 53.0 mg of (s) -phenylalaninol, and 67.0 ml of di-isopropylethylamine in 2.0 ml of isopropanol were heated at 50 ° C. , 0 ° G ', for 7.50 hours ..

The reaction mixture was worked up by removing the solvent in vacuo to give 260.0 mg of the desired product. the title compound in crude form, such as a clear, gum-like substance.

LC / MS, (System):

R t 4.63 min;

MS, (m / z): 585.0, (587.0, (MH ⁺ ));

• 9 9 9 9 9 9 9

9 9 9 9 9

9 99 99 999

473

Example 1 a d 31)

Preparation of (2R, 3R, 4S, 5S) -2- / 6- (1S-Hydroxymethyl-2-phenyl-ethyl-araino) -2-methoxy-purin-9-yl) -5- (3-ethyl-1- ia oxazol-5-yl) -trans of dr of ur and 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) -purine- 9-yl) -5SL (3-ethyl-oxooxazol-5-yl) -tetrahydro-furan-3B-yl acetic acid ester * (obtained as described in the foregoing Preparation of Intermediate 41) * and the resulting reaction mixture was stirred at at 22 ° C for 8.0 hours.

Then the solvent was removed from the reaction mixture under vacuum, and the resulting residue was purified by flash chromatography over silica gel, eluting with ethyl acetate: methanol * (10.0: 1.0) *.

101.0 mg of the desired title compound was obtained as a slightly yellowish gum.

LC / MS (System A):

Rt ₌ 4.04 min

MS (m / z) 497 (MH +)

Detailed experimental data using the procedure

Me ziiprodu k t 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] -dioxol- 4-carboxylic acids

S $ SS, prepared by mixing 3.0 g. potassium permanganate, and 1.0 g of potassium hydroxide in 60.0 mL of water were stirred at room temperature overnight and then cooled to 0.0 °.

Then, [3aS- (3a, 4,6,6a)] - 1,9-dihydro-9-] tetrshydro-6- (hydroxymethyl) -2,2-dimethyl-4B-cyclopenta-1,3-dioxol was added to the above solution. -4H-yl / 6H-purin-6-one (2.92 g) and that _of the addition was slow, the reaction temperature was maintained below the temperature 5,0- ° C. The mixture was then stirred at room temperature for 5.0 hours, and then, after cooling to 0.0 ° C, was mixed with 4.20 g of sodium metabisulfite. pH of the reaction mixture adjusted to about 3.5 ·

Thereafter, the reaction mixture was stored at 4.0 ° C overnight, and the resulting precipitate was collected, washed with chilled water _r and then dried in vacuo.

_R 1 were obtained 82 g, of the title compound as a white solid.

MS, (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) -Dioxol4S-yl / -9H-purine • · · ·

Ό5 ~

Solution prepared by dissolving 118.0 mg of (3aS, 4S, 6R, 6aHt) -2,2-dimethyl-6- (6-oxo-1,6-dihydro-purin-9-yl) - cyclopenta- (1,3) -dioxole-4-carboxylic acid (obtained as part of the above procedure for the preparation of Intermediate 42), in 4.50 ml of anhydrous chloroform, was heated with 29.0 ml of N; of thylformamide, and 108.0 ml of thionyl chloride at reflux for 4.0 hours.

After cooling to room temperature, excess solvent and reagent from the reaction mixture was 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 at reflux for 24 hours and then, after cooling, evaporated to dryness, and the residue was purified by flash chromatography on silica gel, using ethyl acetate: cyclohexane, (40.0). : 60.0) as eluent »

Evaporation gave 56.0 mg of the title compound as a colorless gum.

Mass Spectrometry, (m / z) :; 403.0, (MH);

Me ziproduct 44)

Preparation of (1H, 2S, 3R '58) -3- (6-chloro-purin-9-yl) -5- (3-cyclopropyl- [1,2,4] oxoxiazol-5-yl) -eyclopentane- 1,2-diol

Total 50.0 mg, 6-chloro-9- (2,2-dimethyl-6S- (3-cyclopropyl) -1,2,4) -oxadiazol-5-yl) -ethyl-8-hydro- (3aS, 6affi) -cyclopent8 - (1,3) dioxol-4E-yl) -9H-purine (obtained within the foregoing, φφφφ · · φ · * ·

The above procedure for the preparation of Intermediate 43) was mixed with 2.0 mL at 0 ° C, 0 ° C. chilled trifluoroacetic acid: water (9.0: 1.0), and the resulting reaction mixture was stored at 4.0 ° C overnight and then evaporated to dryness »

60.0 mg of the title compound are obtained as a colorless gum.

MS (m / z): 363.0 (MH ⁺ ) ·

Example 1 a d 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-1,2-diol

A solution prepared by dissolving 57.0 mg * (1B -., 2S * 3R * 5S) -3- (6-chloro-purin-9-yl) -5- (3> 'cyclopropyl- / 1,2 * 4i) 1-oxadiazol-5-yl) -cyclo-pentane * -1,2-diol * (obtained as described in the above Preparation of Intermediate 44), in 5.0 ml. isopropanol ,. was mixed with 34.0 mg * (1S * 2S) -2-aminocyclopentanol. hydrochloride ,. and with 85.0 µl of diisopropylethylamine, and the resulting reaction mixture was heated at reflux overnight »

Thereafter, excess solvent was evaporated from the mixture, and the residue was purified by automated preperative high performance liquid chromatography (HPGL) to give 15.0 mg of the title compound as an almost colorless glass.

• 9,999 »♦ 999 · 4 4 • 44 4 · 4 9 9 9

EC / MS), (System C)

Rt ^: 2.40 min;

MS, (m / z): 428.0 (MH ⁺ );

Detailed experimental data using Ni)

We can get 45)

Preparation of 9- {(3aR, .4R, 6 _R, 6a R) -6- / 3- (ter®.-butyl) -1,2,4-oxadiazol-5-yl / -2,2-dimethyltetrahydrofuro- / 3 4-d // 1,3,3-dioxol-4-yl} 6- (1H-1,2,3> benzotriazol-1-yloxy) -9H-purine

To a solution prepared by dissolving 10.0 g _{of (3aS,} 6R _y 4S, 6SR) -6- (6-chloro-purin-9-yl) -2,2-dimethyl-tetrahydro-furo / 3,4-D (1,3,3) -dioxo-4-carboxylic acid, in 200.0 ml of N, N-dimethylformamide, 3.96 g of 1-hydroxybenzotriazole, and 5.62 g of 1- (3-dimethylaminopropyl) were added - 13i-ethylcarbodiimide hydrochloride; followed by a solution prepared by dissolving 3.40 g of t-butylacetamidoxime in 30.0 ml of Ν, Ν-dimethylformamide, and the resulting reaction mixture was stirred at 20 ° C, 0 ° C for 24.0 hours, under nitrogen atmosphere. . The mixture was then heated at 70 0 _r) ° C for a further 36.0 hours ,, and the resultant mixture was then cooled to 20.0) ° C and zalkalizovánť 200.0 mL saturated aqueous sodium bicarbonate, was extracted 2x with 150.0 ml of ethyl acetate each.

After separation of the organic and aqueous phases, the organic layers were washed with 300.0 ml, brine and dried over magnesium sulfate and evaporated to dryness under vacuum).

After subsequent mechanical treatment and removal of the residue «♦ ··· ♦

0000 · »0 0 0 * 0 00 ···· 00 000 00 ·· * · 000 with ether ,. 11.08 g of the title compound are obtained as a yellow solid, which is purified by chromatography on silica gel, eluting with ethyl acetate: cyclohexane (3.0: 7, δ), as eluent.

4.75 g of the title compound are obtained as a white solid.

LC / MS, (C):

E _t = 3.46 minutes;

Mass Spectrometry, (m / z) (52%), 0.1 (MH);

M 'e zip product 46)

Preparation 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] -Ni-butyl-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-dimethyltetrahydrofuran- [3,4-d] 1,3] -dioxol-4-yl] -6- (1H-1,2,3) benzotriazol-1-yloxy - 9H-purine (obtained as described in the above Preparation of Intermediate 45), in 0 ^s , 40 ml of dimethylsulfoxide, 0.10 ml of diisopropylethylamine and 0.038 ml of isobutylamine were added and the resulting reaction mixture was stirred at a temperature of 20 ° C for 16.0 hours under a nitrogen atmosphere *

Then, the reaction mixture was evaporated to dryness in vacuo, and the resulting residue was purified by automatic preparative high-performance liquid chromatography (HPCL) to give 14.0; mg of the title compound as a white compound *

I • 4 ····

9 9 • ·

9 9 4

9 ·

LC / MS - (System C):

= 3.38 minutes;

MS, (m / z): 458, G, (5 (1H ⁺ ));

To lei 45?)

Preparation of (2S, 3S ', 4-R, 5R) -2- [3- (tert-butyl) -1,2,4-oxadiazol-5-yl] -5- / 6- (isobutylamino) -9H-purine- 9-yl] -tetrahydirofuran-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] dioxole- 4 < - &gt; -B-isobutyl-9H-purin-6-amine (obtained as described above in the preparation of Intermediate 48 above) in 1.0 mL of a cooled trifluoro-acetic acid: water mixture (9.0: 1, Was stored at 4.0 ° C for 18.0 hours at rest.

The solution was basified in an ice-cooled bath by the addition of 20.0 ml of saturated aqueous sodium bicarbonate solution and then extracted twice with 20.0 ml of ethyl acetate each time. The combined extracts were dried over magnesium sulphate and evaporated to dryness in vacuo to give 7.66 mg of the title compound as a white solid.

LC / MS, (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 0 Í O

Detailed experimental data using procedure 0)

Intermediate 447)

Preparation of 9- ^ _(r 3SR 4®, 6S, 6aK) -6- / 3- (tem.-butyl) -1 _r 2 _r 4 oxediazol-5-yl / 2 ^ -2-dimethyltetrahydrofuro- / 3.4 N - (2,4-difluorophenyl) -9 H -purin-6-amine

A solution of 50.0 mg of 9- ,, ^ _{(3RS, 4R,} 6S, 6aR)

6- (3- (tert-butyl) -1,2,4-oxadiazol-5-yl) -2,2-dimethyltetrahydro-furo [3,4-d] 1,3-dioxole-4- yl-6- (1H-1,2,3-benzotriazol-1-yloxy) -9H-purine in 0.40 ml. _Of 2,4-difluoroaniline was heated to 80 teplptě) ,. 0) _r C for 96.0 hours.

Then the reaction mixture was cooled to 20.0 ^° C, and shaken 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 automatic preparative high performance liquid chromatography (HPCL) to give the title compound (18.30 mg) as a dark red gum.

LC / MS (System C):

S ~ 2.85 minutes;

MS (m / z): 418.0 (MH);

Example. 4i9) • 4444 * · ···· 44 4

4 »4 ♦ 4 4 · 4 44 ···» 4 4 444

4 4 4 4> 445 4

4,444 44 4

* 4 444 44 44 44 444

Preparation of (2S, 3S, 4R, 5®) -2- / 3 - ((tert-butyl) -1 * 2,4-oxadiazol-5-yl) -5- / 6- (2 * 4-difluoroaniline) - 9H-Purin-9-yl] -tetrahydrofuran 3,4-diol

Solution, prepared by dissolving 18.30 mg, 9 - {(3sR, 4K, 6S, 6aR) -6- [3- (tert-butyl) -1,2,4-oxadiazol-5-yl] -2,2 -dimethyl-methyl-3,4-di (1,3'-dioxol-4-yl) -N- (2,4-difluorophenyl) -9H-purin-6-amine, (obtained in the foregoing, of the above-described procedure for the preparation of Intermediate 47), in 1.0 mL, chilled trifluoroacetic acid: water, (9.0: 1.0), was ·; alkaline in an ice-cooled bath by the addition of 20.0 ml of saturated aqueous sodium bicarbonate solution, and this mixture was extracted twice 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 title compound * as a red solid.

LC / MS (System C)

R t = 3.03 minutes;

Mass Spectrometry, (m / z) 474.0 (MH ⁺ );

Detailed experimental data using procedure P)

Intermediate 48)

Preparation of (3aB * 4S, 6R, 6aR) -? - (6-Chloro-9H-purin-9-yl) -N- (2-hydroxypropyl) -2,2-dimethyltetrahydrofuro- / 3,4-d // 1 3 &apos; -dioxol-4-carboxamide

9999 • 9999 99 • 9 9 · · · ·

999 * 9 9 · 9 9 9 9 9 999 99 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 - (1,3) -dioxole-4-carboxylic acid in 100.0 ml of chloroform was added with stirring to 4.30 ml of thionyl chloride and the resulting reaction mixture was heated to 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 azeotroped 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 obtained by dissolving 2.30 ml of 1-amino-2-propanol and 5.10 ml of diisopropylethylamine in 50 ml. 0 ml of chloroform was added to 50.0 ml of chloroform at 0 ° C. Then the reaction mixture was stirred at 20.0 '; ° C for 18.0 hours and then, after the addition of 100.0 ml, 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 with sodium sulfate, and the solvent was removed in vacuo.

The title compound (6.63 g) was obtained as a white foam.

MS, (m / z): 398.0 (MH);

Intermediate 49)

Preparation of (3aR, 4S _, 6R, 6aR) -6- (6-chloro-9H-purin-9-yl) -2,2-dimethyl-N- (2-oxopropyl) -tetrahydrofuro [3,4- d) (1,3) -dioxole-4-carboxamide

To a mixture prepared by combining (3α, 4S, 6R, 6αR) -6- (6-chloro-9H-purin-9-yl) -N- (2-hydroxypropyl) -2,2-dimethyltetrahydrofuro. «9 · 4 9499

9 9 9 9 9 9 9 9 9 49

4 · 4 9 4

4 9

4 9

444

1 (3,4-d) -1,3] -dioxole-4-carboxamide (obtained as part of the foregoing procedure for the preparation of Intermediate 48) with 10.0 g, a powdered form of 4 &apos; molecular sieve at 165.0 mL of dichloromethane, at a temperature of 0.0 ° C, was added 3.0 ml of acetic acid derivatives, and then, in portions, 9.36 g _of pyridiniumdichlormanu.

The resulting reaction mixture was stirred at 0.0 ° C for 15 minutes, 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 ( ^M erck 9385) and 165.0 ml of ethyl acetate, the reaction mixture was stirred for further 15.0 minutes.

Then, the reaction mixture was filtered through silica, and the filter cake was washed with 300.0 mL of ethyl acetate. The resulting filtrate was evaporated in vacuo, and the residue as a brown solid was purified by flash chromatography on silica gel using dichloromethane: methanol (100.0: 3.0) as eluent to give a slightly brown color. The foam was purified by chromatography on silica gel (Merck 9385) using ethyl acetate, followed by ethyl acetate: methanol (? 00: 2.0) as eluents.

4.60 g of the title compound are obtained in the form of a white foam.

TLC, (SiO ₂ J ethyl acetate: methanol; 100.0: 20.0):

_Rf = ° 4o;

Detailed experimental data using procedure Q) 9 9 9 9

9 9 9 9 9 9 9

9 9 9 9 9

9,999 99 9

999 999 99 99 99 999

Me zip product 50))

Preparation of (3aR, _4S, 6R, 6AB) -N- (2-hydroxybutyl) -6-methoxy-2,2-Dimethyl trahydrof furo / 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 was added 4.83 g of carbonyldiidazole. , and the resulting reaction mixture was stirred at 20.0 ° C for 20.0 minutes. Then, after the addition of 2.45 g of 1-amino-2-butanol, the reaction mixture was stirred under a nitrogen atmosphere at 20.0 ° C for 18.0 hours and then, after dilution with 50.0 ml. The ether was washed with 100.0 ml of a saturated aqueous solution of citric acid (citric acid - 2-hydroxypropane-1,2,3-tricarboxylic acid) and with 100.0 ml of a saturated aqueous solution of 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, eluting with ethyl acetate: cyclohexene (1.0: 1.0).

3.81 g of the title compound are obtained in the form of a clear gum.

MS, (m / z): 29 O, O (MH);

Intermediate 51)

Preparation of (3aR _R4S ,, 6R, 6SR) -6-methoxy-2,2-dimethyl-N- (2-oxobutyl) tetrahydrofuro / 3,4-1 // 3 / dioxole-4-carboxamide

To a solution prepared by dissolving 3.81 g, (3aR, 4S, 6%

4444

4 44 4 • • 44 44 4444

4444 44 4 44

4 4 ♦ · 4,444 · ·

4,444 44 4

44 444 44 * 44 444

6aR) -N- (2-hydroxybutyl) -6-methoxy-2,2-dimethyltetrahydrofuro [3,4-d] 1,3] -dioxole-4-carboxamide, (obtained as described above) of Intermediate 50), in 115.0 mL of anhydrous dichloromethane containing 5.70 g, of a powder of the $ 4.00 molecular sieve at 0.0 ° C and under a nitrogen atmosphere, was added 2.59 mL of acetic acid. , and 7.93 g ,. potassium dichromate such that the addition was carried out in portions.

The reaction mixture was then stirred at 0.0 ° C for 15 minutes and then at 20.0 ° C for 2.0 hours. Thereafter, the reaction mixture was mixed with 40.0 mL of isopropanol, and after stirring for 30 minutes, 40.0 g of silica gel (Merck 9385) and 100.0 mL of ethyl acetate were added thereto. and this mixture was stirred for an additional 30.0 minutes.

(r)

The mixture was 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.

Yield 1.91 g, of the title compound * 'H NMR delta _r ,:

7.405, (1H, bs, -NH), 5.125, (1H, bs, CH), 5.095, (1H, dd, CH), 4.655, (1H, bs, CH) _r 4.565, (1H, d., CH),

4155 ,, (2H ,. m., CH ,,), 3.555 (3H, s., OMe), 2.505 (2H, q., CH _2), 1.505 (3H, s., Me), 1.355, (3H, s, -Me), 1.105, (3H, t,

Intermediate 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, 6a R) -6-methoxy-2 ', 2-dimethyl-N- (2-oxobutyl) -te trahydrofuro [3,4d] 1,3'-dioxole-4-carboxamide (obtained as described above in the preparation of Intermediate 51 above) in 10.0 ml of dry toluene was added 1.44 ml of phosphorus oxychloride under nitrogen atmosphere and the resulting the reaction mixture was heated to reflux for 3.50 hours.

Thereafter, the reaction mixture was cooled to 0.0 ° C and, after mixing with 30.0 mL of saturated aqueous sodium bicarbonate, the mixture was stirred vigorously for 30.0 minutes. Thereafter, the reaction mixture was extracted 4 times with 50.0 ml of ethyl acetate each time, and after separation of the organic and aqueous phases, the organic layers were combined, and after washing with 30.0 ml of brine, dried with magnesium sulfate, and concentrated under vacuum.

The crude product was purified by flash column chromatography on silica gel using cyclohexane: ethyl acetate (5.0: 1.0 to 7.0: 2.0) as eluent.

0.83 g of the title compound was obtained as a yellow oil.

MS (m / z): 270.0 (MH ^{&lt; + &gt;} )

Me zip product 53)

Preparation of (2S, 3R, 4R, 5S) -2,4-Bis- (acetyloxy) -5- (5-ethyl-1,3-oxazol-2-yl) -tetrahydrofuran-3-yl-8-acetate • · ···· • ···· • 9 9 9 9 9 9

9 9 9 9 9 99

9 9 9 9 9 9 9 9 9

999 999 99 99 99

Ήΐ

To 0.83 g, 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 as described in the foregoing procedure for the preparation of Intermediate 52) was added 3.56 mL of trifluoroacetic acid: water 8 (9.0: 1.0) to form the reaction mixture. was stirred at 20.0 ° C for 3.50 hours.

After the solvents were removed from the reaction mixture in vacuo, an orange-brown oil-like consistency was obtained. This was dissolved in 7.0 mL of pyridine under nitrogen, followed by addition of 2.76 mL of scetanhydride and stirred at 22.0 ° C for 18.0 hours.

The reaction mixture was then concentrated in vacuo and, after diluting with 50.0 ml of ethyl acetate, the resulting solution was washed with 50.0 ml,

1M hydrochloric acid solution, then 3 times with 50.0 ml each, saturated aqueous sodium hydrogen carbonate solution, and finally with 50.0 ml, brine, and the organic layer was dried with magnesium sulfate.

After evaporation of the solvent to dryness, 0.854 g of the title compound is obtained as an orange-brown solid, oil-like in consistency.

MS (m / z): 342.0 (MH ⁺ )

Intermediate 54)

Preparation of (2R ^; 3B, 4R, 5S) -4- (acetyloxy) -2- (6-chloro-9H-purin-9-yl) -5- (5-ethyl-1,3-oxezole-2- yl) -tetrahydrofuran-3-yl acetate

To 0.854 g of 6-chloropurine were added 4.0 mL, 1,1,1,3,3,3 hexamethyldisilazane, and 15.0 mL of toluene, and the resulting reaction mixture was heated to reflux for · · <444

2.0 hours. After the solvent was removed from the reaction mixture in vacuo, the residue was treated azeotropically with 1 x 8.0 mL of toluene, and the mixture was evaporated to dryness.

0.854 g was then added to the residue _; (2S, 3R, 4R, 5S) -2,4-bis- (acetyloxy) -5- (5-ethyl-1,3-oxazol-2-yl) -tetrahydrofuran-3-yl acetate (obtained within the foregoing, previously described) of Intermediate 53), in 20.0 mL of acetonitrile, followed by 0.624 mL of trimethylsilyl trifluoromethanesulfonate (triflate), and 0.374 mL of 1,8-diazabicyclo [5.4.0] undec-7-ene, and the reaction mixture was stirred 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 was then extracted 4 times with 40.0 ml of dichloromethane each. 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 a 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).

355.0 g of the title compound are obtained as a clear gum.

MS, (m / z): 436.0 (MH);

Example 1 and 84)

Preparation of 2- ((9 - / (2R, 3R, 4S, 5S) -5- (5-ethyl-1,3-oxazol-2-yl) -3,4-hydroxy-tetrahydro-furan-2-yl) -9H (purin-6-yl) -amino) -N, N-dimethyl-thanesulfonamide

4 · «4

4 4

444

4

4 44 444 * · 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, 4®, 5S) -4- (acetyloxy) -2- (6-chloro-9H-purin-9-yl) -5- (5-ethyl- 1,3'oxazol-2-yl) -tetrahydrofuran-3-yl acetate (obtained as described in the above Preparation of Intermediate 54) in 5.0 mL of isopropanol was added 0.120 mL of N, N diisopropylethylamine, and 86.0 mg of N, N-dimethyl-2-aminoethanesulfonamide hydrochloride, and the resulting reaction mixture was stirred under reflux and under nitrogen atmosphere for 48 hours, and then cooled.

After the 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 automatic preparative high-performance liquid chromatography (HPGL) to give 8.60 mg of the title compound.

Mass spectrometry (m / z):

468.0, (MH ⁺ );

Detailed experimental data using procedure S)

Intermediate 55)

Preparation of (9 - / (3aR, 4R, 6S, 6aR) -2,2-Dimethyl-6- (3-methyl-1,2,45-oxadiazol-5-yl) -te-trehydrofuro [3,4-a] - d // 1,3'-Di-oxol-4-yl] -9Hpurin-6-yl} -N-cyclopentylamine

Mixture prepared by mixing 0,20 g of (3aS, 4S, 6R, 6afic) -6- (6-cyclopentylamino-purin-9-yl) -2,2-dimethyl-trahydrofuran- / 3,4- d // 1,3] -dioxole-4-carboxylic acid, then 146.0 mg, 2-ethoxy 1-ethoxycarbonyl-1,2-dihydroquinoline, 76.0 mg, acetaldoxime, and

9 • 999 • 9 • 9

9999 • 9

9 9 • 9 9

9 · 99

9 '9 • 9 9

9

Mo

25.0 mL of * dimethoxyethane * was heated at 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, 0.5 M citric acid solution (citric acid = 2-hydroxypropane-1,2,3-tricarboxylic acid), and the aqueous wash medis was extracted 3 times with 20.0 each. ml, ethyl acetate. The combined organic extracts were washed with 20.0 mL of water, and with 30.0 mL of brine, and, after drying with magnesium sulfate, were concentrated in vacuo.

The residue was purified by silica gel chromatography, eluting with ₅ : ethyl acetate; cyclohexane (1.0: 1.0) as eluent.

It afforded 63.0 mg of the title compound, ¹ H-NM2 * (CDC1 ₃₎ delta ;,

8.03, (1H * bs * heteroeyl CH) * 7.84, (1H * bs heterocyclic CH), 6.29 * (1H, bs, CH) * 5.84, (1H * dd, CH), 5.64, (1H, a. * CH), 5.48, (1H, d, CH), 4.56, (1H, b.

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

Mixture prepared by mixing 63.0 mg of N- (9E) - (3eR, 4R, 6S, 6aR) 2,2-dimethyl-6- (3-methyl-1,2,4-oxadiszol-5-yl) - tetrahydrofuro [3,4,4] 1,3-dioxol-4-yl] -9H-purin-6-yl] -N-cyclopentylamine (obtained in the above-described Preparation of Intermediate 559, hereinafter); 1.0 mL of trifluoroacetic acid and 0.1 mL of water were stirred at C 0 ° C for 6.0 hours, and then diluted with 20.0 mL of ethyl acetate.

Then the reaction mixture was 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 each time. The combined organic extracts were then washed with 8.0 mL, water, and 10 mL, 0 mL, brine, and then dried with 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.

The title compound (42.0 mg) was obtained as a white foamy foam.

TLO (SiO 2, ethyl acetate methanol; 19.0: 1.0):

R _f = 0.30;

¹ H-NME, (DMSO), .delta .:

8.43 (1H, s, CH), 8.20 (1H, bs, CH), 7.79, C 1H, bs,

NH), 6.45, (2H, bs, 2x OH)), 6.16, (1H, d, CHI), 5.24, (1H, d, CH) 4, 89 (1H, t _T, CHI), 4.73 (1H, m., CH),

4.58, (1H, bs, CHi), 2.42, (3H, s, Me), 2.10-1.50, (8H, m, 4x CHp.

Detailed experimental data using procedure S)

M? e zip product 9 · 9 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Preparation 1 - / (38®, 4E, 6R, 6aR) -6-Methoxy-2,2-dimethyl-trahydrofuro [3,4-d] -1,3] -dioxol-4-yl] -pent-1 -yn-3-ol

A solution prepared by dissolving ,,, 4E-ethynyl-6E-methoxy-2,2-dimethyl-tetrahydro- (3a®, 6aR) -furo / 3,4-d // 1,3 / dioxole, (1.503 g) at _r 20.0 ml of tetrahydrofuran was cooled at minus 78 ° C, under nitrogen atmosphere, for 15.0 minutes. Thereafter, a solution obtained by dissolving 1.0.9 ml of propionaldehyde was added via syringe. in 0.50 mL of tetrahydrofuran, and the reaction mixture was further stirred for 5.0 hours.

The reaction mixture was then heated to 22.0 ° C and stirred for an additional 16.0 hours. After removal of the solvents under vacuum, the resulting orange-colored residual oil was shaken 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 dried over magnesium sulphate and concentrated in vacuo to give a yellow colored oil which was purified by silica gel chromatography (Vérian Bondelut cartridge) ), using (2), cyclohexane, (II), dichloromethane, (III), ether, (IV), ethyl acetate as eluents to give 1.33 g of the title compound as a white solid, m.p. colorless substances, oily consistency,

TLC, (SiO ₂ , ether :: cyclohexane J 1.0 :: 1.0) ::

R _f = Q), 39;

M; e zip product 57 / ')

Preparation 1 - [(3sR, 4R, 62.6aR) -6-Methoxy-2,2-dimethyltetrahydro-furo [3,4,4-d] [1,3] dioxol-4-yl] - pent-1-yn-3-one • · · ·

AND

Solution prepared by dissolving 1,30 g of 1 - [(3aR, 4R, 6R, 6aR) 6-methoxy-2,2-dimethyltehydrofuran] - [3,4-d] 1,3] dioxol -4-yl / pent-1-yn-2-ol (obtained as described in the above Preparation of Intermediate 56) in 100.0 ml of dichloromethane was added to the suspension prepared for suspending 60 while stirring, 0 g of manganese dioxide, at d, 0 ° C, into dichloromethane.

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 in vacuo to give 550.0 mg, m.p. the title compound as a colorless oil.

¹ H-d 6, CD 3, (CDCl 3) 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, s, Me)

t., Me) *

Intermediate 58)

Preparation 1 - [((3aR, 4R, 6R, 6eR) -6-methoxy-2,2-dimethyltetrahydrofuro [3,4-d] 1,3] -dioxol-4'-yl] -pentane-1,3 -dione-1-oxime

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 as described above for the preparation of Intermediate 57 above), and 0.20 ml of a 50% solution of hydroxylamine in water in 10.0 ml of ethanol were stirred at a temperature of 22 ° C overnight.

The resulting reaction mixture was concentrated in vacuo to give 554.0 mg of the title compound as a yellow oil.

¹ H-NMR, δ, (GE 1 Cl 2):

5.36, 5.31, (1H, 2x d, CH), 5.00, (1H, d, GHi), 4.92, (1H, d, CH). , (1H, 2x d., CH), 3.40, 3.35, (3H, 2x a., OMe), 3.03 - 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).

We can have 59)

Preparation of (3R, 4S, 5R) -5- (5-ethylisoxazol-3-yl) -tetrahydrofuran-2,3,

Of 4-triol

Solution prepared by dissolving 0, 50 g, 1 - [(3aR, 4R, 6R, 6aR) 6-methoxy-2,2-dimethylphtetrahydrofuro [3,4-d] 1,3] dioxol-4-yl] of pentane-1,3-dione-1-oxime (obtained as described in the above-described Preparation of Intermediate 58) in 18.0 mg of aqueous acetic acid and the resulting reaction mixture was heated to 100.0 ° C. G for 2.0 hours.

After the resulting reaction mixture was cooled and concentrated in vacuo, the resulting brown-colored oily consistency was obtained. 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 title compound are obtained, m.p.

TLG, (SiO ₂ , ether):

R _f = 0.17;

···· · ··· · ··· · · · · ·

4 4 · 4 · ·

4 4 4 4 · 4 · · · · ·

W e zip product 60))

Preparation of (2R, 3K, 4R) -4,5-Bis- (acetyloxy) -2- (5-ethyl-oxoxazol) -3-yl) -tetrahydrofuran-3-yl-8-acetate

Solution prepared by dissolving 150.0 mg, 1 *, (3R, 4S 5R) -5- (5-ethylisoxazol-3-yl) -tetrahydrofuran-2,3,4-triol isomers, (obtained above, supra) of the 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.

Thereafter, the reaction mixture was concentrated in vacuo to give a brown oil which was purified by silica gel chromatography (Varien Bondelut silica cartridge) using (I) dichloromethane, (II), ether (III), ethyl acetate as eluents.

The title compound was obtained as a pale yellow solid (142.0 mg).

TLC, (SiO ₂ J ether):

Rf = 0.53;

Intermediate 61)

Preparation of (2R, 3R, 4R, 5B) -4- (Acetyl-oxy) -2- (2,6-dichloro-9H-purin-9-yl) -5- (5-ethyl-isoxazol-3-yl) -tetrahydrofuran-3 -yl-scetate

Solution, prepared by dissolving 193.0 mg, of the isomers 1j (2R, 3B4Ri) -4,5-bis- (acetyloxy) -2- (5-ethylsulpha-ol-3-yl) -te of trahydrofuran-3-yl-8-acetate (obtained as described in the above-described 44 procedure for the preparation of Intermediate 60)) in 5.0 ml of acetonitrile was mixed sequentially over 5.0 minutes using an injection syringe. syringe, with 213.0 mg * 2,6-dichloropurine * further with 0.186 ml * 1 * 8-diazabicyclo [5.4.0] -undec-7-ene * (DBU), and with 0.225 ml, trimethylsilyl trifluoromethanesulfonate * (TMSOTf), and the resulting clear, yellow colored reaction mixture was stirred at 22.0) for 40 ', 0 hours, then at 60.03 ° C, for 21' hours, and at 803 * 03 ° C for 6.0 hours.

The reaction mixture was then cooled to room temperature and an additional 0.186 mL * 1,8-diazabicyclo [5.4.0] undec-7-ene * (DBU) and 0.225 mL * trimethylsilyl trifluoromethanesulfonate were added thereto. * (> TMSOTf).

Then, after further stirring at 22.0 ° C for 36.0 hours, the yellow colored reaction mixture was heated at 60.0 ° C overnight and then at 80 ° C for a further 6.0 hours. After removal of the solvents under vacuum *, the resulting residue as a brown oil was taken up in ethyl acetate and then washed with 20.0 mL of water (3.0 L * 0). layer was extracted with ethyl acetate, and the combined organic extracts were dried with magnesium sulfate * and evaporated in vacuo. The residue, as a brown solid, oily consistency * was mechanically treated and taken up with dichloromethane, and the white colored solid was collected by filtration. Evaporation of the filtrate gave a tan solid, which was purified by flash chromatography on silica gel using ether: cyclohexane (1.0: 1.0) as eluent.

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

O,

LC / MS * (System C): R _t = 3.34 min;

ι. &.

4,444 w

MS (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

Solution prepared by dissolving 125.0 mg of (2R _, 3R, 4R, 5®) -4 (acetyloxy) -2- (2,6-dichloro-9H-purin-9-yl) -5- (5-ethylisoxezole) (Yl) —transhydrofuran-3-yl-acetate (obtained as described in the previous Preparation of Intermediate 61 above) in 5.0 ml of isopropanol was first mixed with 0.06 ml , diisopropylethylemine, followed by 0.044 ml of 1-ethylpropylamine.

The resulting reaction mixture was heated under nitrogen at 50.0 ° C for 16.0 hours. Then, the solvent was removed from the mixture under vacuum, and the mixture was partitioned between ethyl acetate and a 1® hydrochloric acid solution. After separation of the organic and aqueous phases, the organic layers were washed with a saturated aqueous solution of sodium bicarbonate, and with brine, and, after drying with magnesium sulfate, were evaporated in vacuo.

The residue was purified by chromatography on silica gel, using a Vari8n Bondelut cartridge, and eluting with (i), dichloromethane _r (II) _r ether, and (III) ethyl acetate,

It was obtained 108.0 mg _of the desired, title compound ,, as a colorless oil.

TLG. (SiO ₂ ; ether): R 3. - 0.26;

··. .UvjExample163)

Preparation of (2R, 3H, 4S _, 5R) -2- [2-Chloro-6 - [(1-ethyl-propyl) -amino] -9H-purin-9-yl] -5- (5-ethyl-isoxazol-3-yl) - of trahydrofuran-3,4 diol formate

Mixture prepared by mixing 30.0 mg of (2R, 3R, 4R, 5B) -4- (acetyloxy) -2- {2-chloro-6 - [(1-ethylpropyl) amino] -9H-purin-9- (5- (5-ethylisoxazol-3-yl) -tetrahydrofuran-3-yl acetate) (obtained as described above for the preparation of Intermediate 62 above) with 0.037 ml of 2-morpholinethylamine was heated at 90 ° C, 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.

Purified by preparative high-performance liquid chromatography (HPCL), (gradient profile 5.0-95.0% (II), over 18.25 min.). 6.0 mg of the title compound was obtained as a white solid.

LC / MS, (System C):

R t = 3.41 minutes;

Mass Spectrometry, (m / z) t 437.0, (MH) *

Detailed experimental data using procedure T)

It can be 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

Preparation 9- (3eR, 4R, 6S, 6aR) -6- [5 '- (tert-Butyl-1,3,4-oxadiazol-2-yl) -2,2-dimethyltetrahydrofuro [3,4-d] 1,3H-dioxol-4-yl] -NU (4-chloro-2-fluorophenyl) -9H-purin-6-emine

Mixture prepared by mixing 2,80 g of 9- (6S- (5-tert-butyl) 1,3,4-oxadia-ol-2-yl) -2,2-dimethyl-tetrahydro 4-chloro-2-fluoroaniline, with 4.48 ml of 4-chloro-2-fluoroaniline, followed by 146.0 ml of 4-chloro-2-fluoroaniline. mg, palladium acetate, and 620.0 mg, (R) -2,2-bis- (diphenylphosphine) -1,1-binaphthyl, in 34.0 ml of dried tiluene, were stirred at room temperature for 5, 0 min (reaction was carried out in 7 batches).

After adding 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 batches were combined * were shaken between 200.0 ml of water, and three times with 120.0 ml of dichloromethane each. After separation of the organic and aqueous phases, the organic layers were washed with brine, and dried over magnesium sulfate and evaporated in vacuo. The residue as a brown oil (8.70 g) was purified by silica gel chromatography eluting with ethyl acetate: cyclohexane (30.0 :: 70.0).

2.35 g of the title compound are obtained as a white solid.

LC / MS, (System O:

- 3.41 minutes;

Mass Spectrometry (m / z). 53O, O, (MH ⁺ )

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] -tetrahydro-furan-3,4-diol

A solution prepared by using an ice-cooled bath by dissolving 2.35 g. Of 9- {(38 R, .4R, 6S _'r 6aH) -6- / 5- (tere.-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 as described above for the preparation of Intermediate 63 above) in 20.0 trifluoroacetic acid, and 2.0 mL of water, were allowed to stand at 4.0 ° C for 17.0 hours.

The reaction mixture was then poured slowly into 400.0 ml of ice-cooled saturated sodium bicarbonate solution and was then 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, were evaporated in vacuo.

2.30 g of the title compound are obtained as a yellow-brown solid.

LC / MS, (C):

Rt = 3.04 min;

MS, (m / Z): 490.0 (MH ⁺ );

Detailed experimental data using procedure U)

Me zip product 64)

9999 99 9999 99

98 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-tetrahydro- (3aR _, 6aS) -furo-] 3,4-di [1,3] dioxole-4E- 1 '-6-chloro-9H-purine

To the solution / prepared by dissolving 0.40 g of 1-deoxy-1- (1,6-dihydro-6-oxo-9H-purin-9-yl) -2,3-O- (1-methylthylidene) beta-β-ribofuran (refer to J. Med. Chem., 29, 1683 (1986) by RAOlsson et al.), in 10.0 mL of tetrahydrofuran, was added 0.075 mL, diisopropylethylamine, and the resulting reaction mixture was stirred at 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. A solution obtained by dissolving 0.36 g of t-butylhadrazide trifluoroacetate in tetrahydrofuran and cooled to 0.0 ° C was added to the reaction mixture, followed by mixing with 0.24 ml of diisopropylethylamine, and the reaction mixture was after you tempering at a temperature of 20.0 ° _C,:. stirred for 20.0 hours.

After removal of the solvent in vacuo, the resulting residue was purified by flash chromatography over silica gel, eluting with 5% methanol in dichloromethane to give 0.41 g of the corresponding diacylhydrazide.

To a solution prepared by dissolving 30.0 mg of the above diacylhydrazide intermediate in 3.0 ml. Of Ν, Ν-dimethylformamide, and cooled to 0.0 ° C, was added 45.0 mg of phosphorus oxychloride, and the reaction mixture was stirred at room temperature first for $ 8.0 hours and then at 90 ° C. 0 ° C for 2.0 hours. After removal of the solvent in vacuo, the resulting residue was purified by automatic preparative high performance liquid chromatography (HPCL) to give the title compound (20.0 mg).

9999 99

9 9 9 9 9 9

9999 98 9 99

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] oxazol-5-yl | -2- (6-chloro-9H-purin-9-yl) -tetrahydrofuran-3-yl acetate

The mixture, prepared by mixing 1.0 g of 6-chloropurine, with 20.0 ml. 1,1,1,3,3,33-hexamethyldisilazane was heated under nitrogen at 100 ° C, 0 ° C for 2.50 hours »

After cooling, the solvent was removed from the reaction mixture in vacuo, and the residue was azeotroped with anhydrous toluene (2 x 2.50 mL), and the mixture was then evaporated to dryness to give a whitish-colored solid. which was added under a nitrogen atmosphere of 450.0 mg of acetic acid 4R-acetoxy-2S- (3-scetoxymethyl-isoxazol-5-yl) -5B-methoxy-tetrahydro-furan-3E-yl ester in 15.0 ml, anhydrous acetonitrile, and then trimethylsilyl trifluoromethanesulfonate (1.40 mL) was added to the reaction mixture, cooled to CF, 0,

After the reaction mixture was heated to 20 ° C over 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 each of ethyl acetate. After separation of the organic and aqueous phases, the organic layers were combined, and after washing with 50.0 ml, the brine was dried with magnesium sulfate, and concentrated to dryness.

The crude product was 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 oil of oil consistency.

• 9 • 9999

9 • 999

9

9 • 9,999

9 9

9 9

9 9

9 9 9

99

9

LC / MS, (System C): &lt; tb &gt;

E ^. = 2.76 minutes

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] * and amino] -9H-purin-9-yl) -5- / 3- (hydroxymethyl) 1-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 as described in the above-described Preparation of Intermediate 65) in 2.0 mL of isopropyl alcohol was added 0.043 mL, Ν, Ν diisopropylethylamine, and 11.40 mg of 2-hydroxycyclopentylamine hydrochloride, and the resulting reaction mixture was stirred at 50.0 ° C, under a nitrogen atmosphere, for 18.0 hours.

After cooling, the mixture was evaporated to dryness in vacuo, and the resulting residue was purified by automatic preparative high performance liquid chromatography (HPCL), (gradient profile 5.0% - 90.0% (II), over 20.0 minutes). .

The intermediate 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. Evaporation of the solvent in vacuo gave 5.0 mg of the title compound as a white solid.

4 4 4 4 4

4 • 4 4 4 4

4 44 · 44 444 4 · 44 44 444

LC / MS, (System C): &lt; tb &gt;

R = 2.25 minutes;

L

MS (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-scetate

The mixture prepared by mixing 0.965 g of 4E-ethynyl-6R-methoxy2,2-dimethyl-tetrahydro- (3aE, 6sE) -furo [3,4-d] 1,3] -dioxol with 1 0.1 ml of concentrated hydrochloric acid at 30.0; ml, methanol, was heated at reflux for 6.0 hours »

Then, after evaporating the methanol under vacuum, additional methanol was added to the reaction mixture, and the mixture was further heated at reflux for 16.0 hours. After subsequent addition of 1.60) ⁵ ml of pyridine, the methanol from the mixture again evaporated in vacuo and, after further addition of methanol, the mixture was evaporated in vacuo to dryness.

The resulting residue was dissolved in dried dichloromethane, and 1.60 ml of pyridine, followed by 25.0 mg of 4-dimethylaminopyridine, and 1.37 ml of acetic anhydride were added thereto, and the mixture was stirred at 22.0). ° C, under nitrogen atmosphere, for 18.0 hours. Then the mixture was evaporated to dryness in vacuo, and the residue was shaken between 100.0 ml of a saturated aqueous solution of citric acid (citric acid = 2-hydroxypropanil, 2,3-tricarboxylic acid), and twice with 75.0 ml of dichloromethane. .

4444 44 4444 44

444 44 4,444

4444 44 4 44 • 444 4444

£ 44 £ 444

After separation of the organic and aqueous phases, the organic layers were washed with a saturated aqueous sodium hydrogencarbonate solution and, after drying with magnesium sulfate, evaporated in vacuo.

1.19 g of a slightly yellow colored oily consistency * was obtained, which was purified by chromatography on silica gel. (Varian Bondelut cartridge, 10.0 g), using ethyl acetate: cyclohexane (5.0: 95.0 - 30.0 :: 70.0) as eluent.

724.0 mg of the title compound was obtained as a colorless oil.

TLC, (SiO ₂ , ethyl acetate: cyclohexane * 25.0: 75.0):

R _f = 0.30;

Me zip product 67)

Preparation of (2R * 3R * 4R, 5R) -4- (Aeetyloxy) -2- (6-chloro-9H-purin-9-yl) -5-ethynyl-trahydrofuran-3-yl-acetate

The mixture, prepared by mixing 250.0 mg of 6-chloropurine, see 10 ml of hexamethyldisilazane, was heated with stirring * under nitrogen atmosphere * in an oil bath at 130.0 ° C for 2.0 hours.

Thereafter, the excess reagent from the reaction mixture was evaporated in vacuo and the residue was azeotroped with dried toluene (3 x 5.0 mL) to give a slightly yellow colored solid.

Thereafter, 121.0 mg of (2R * 3R, 4R, 5R) -4- (acetyloxy) -2-ethynyl-5-methoxytetrahydrofuran-3-yl acetate (obtained as described in the above Preparation of Intermediate 66) was dissolved after reconstitution. azeotropic treatment with dried toluene, j (2 x 5.0 ml), dissolved in dried acetonitrile, to yield

2.0C

9 9999 99 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

The solution was added to the silylated purine prepared in the above operation, and then, after the addition of 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, followed by extraction three times with 60.0 ml of ethyl acetate. After separation of the organic and aqueous phases, the organic layers were washed with brine, and, after drying with magnesium sulfate, were evaporated in vacuo.

203.0 mg of a yellow-colored oily consistency was obtained, which was purified by silica gel chromatography (Varian Bondelut cartridge), using ethyl acetate cyclohexane (10.0: 90.0 - 60.0: 40), as a leukemia agent.

84.0 mg of the title compound was obtained as a colorless gum.

TLC, (SiO ₂ , ethyl acetate: cyclohexane, 50.0: 50.0):

R _f = OJ, 25;

Me zip product 68)

Preparation of (2R, 3R, 4R, 5R) -4- (Acetyloxy) -2- [6- (1H-1,2,3-benzotriazol-1-yloxy) -9H-purin-9-yl] -5 -ethinyltetrahydrofuren-3-yl acetate

Mixture prepared by mixing 104.0 mg of (2R, 3R, 4R, 5R) -4 (acetyloxy) -2- (6-chloro-9H-purin-9-yl) -5-ethynyl-tetrahydro-furan-3-yl acetate, ( diethyl oxalate, as described above for preparing intermediate popstupu 67í) was 136.0 mg _of 1-hydroxybenzotriazole in 3.0 mL dry N, N-dimethylformamide was heated at 22.0 ° C for 45.0 hours.

• ·

9999 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 three times with 25.0 ml each of dichloromethane. After separation of 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 dried over magnesium sulfate, and evaporated in vacuo.

148.0 mg of the title compound was obtained as a colorless gum.

LC / MS _Rt (System C)

= 3.19 minutes J

MS (m / z): 464.0 (MH +)

Me zip product 69)

Preparation of (2 _R 3R, 4R, 5R) -4- (acetyloxy) -2- / 6- (, 4-chloro-2-fluoroanilino) -9H-purin-9-yl / -5-ethinyltetrahydrofuran * 3-yl- acetate

Mixture prepared by mixing (2R, 3R, 4R, 5R) -4- (acetyloxy) -2 / 6- (1H-1,2,3-benzotriazol-1-yloxy) -9H-purin-9-yl (5-Ethyltetrahydrofuran-3-yl acetate ₎ (obtained as described above in the preparation of Intermediate 68 above). with 0.63 ml of 2-fluoro-4-chloroaniline was heated at 60.0 ° C for 22.50 hours.

Then, the reaction mixture was purified by silica gel chromatography (Varian Bondelut cartridge), using ethyl acetate: cyclohexane (10.0: 90.0 - 60.0: 40.0) as eluent.

55.0 mg of the title compound are obtained.

9999 99 9999 99

999 999 99 9

9 9 9 9 9 9 9 9

999 999 99 99 99 999

2M

TLC, (SiO ₂ , ethyl acetate: cyclohexane, 50.0: 50.0): R _f = 0.30;

Intermediate 70) (2R * 32 * 4R * 6S) -4- (acetyloxy) -5- (3-bromo-isoxazol-5-yl) -2- [6- (4-chloro-2-fluoroaniline) -9H-purin-9-] - yl) -tetrahydrofuran-3-yl acetate

Mixture prepared by mixing 20 mg (22,32,42,52) -4- (acetyl pxy) -2- [6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl] - 5-Ethyltetrefuran-3-yl acetate (obtained as described above in the preparation of Intermediate 69 above), 12.50 mg, dibromformaldoxime, 39.0 mg, sodium bicarbonate, 0.075 ml water, and 1.50 mL of ethyl acetate was stirred at 22.0 ° C for 88.0 hours.

The resulting reaction mixture was shaken between 20.0 mL of water, and 3x each and 10.0 mL of ethyl acetate, and after separation of the organic and aqueous phases, the combined organic layers were washed with brine, and then evaporated in vacuo.

The residue, as a gummy gum, was purified by silica gel chromatography (Varian Bondelut cartridge) using ethyl acetate: cyclohexane (20.0: 80.0 - 80.0: 20.0) as eluent. .

The title compound (16.80 g) was obtained as a colorless gum.

LC / MS, (System)):

Rt ₌ 3.60 min;

Mass spectrometry (m / z):

595.0; 597; (MH ⁺ ), (MH + 2 ⁺ ); ^R • · · · • · • · • · * 9

99 ···

Zoq

Example 164)

H- f:

Preparation of (2S, 3S, _{4R, 5R)} -2- (3-bromisoxazol) -5-yl.) - 5- / 6- (4-chloro-2-fluoroanilino) -9H-purin-9-yl / -te trahydrofuran- 34-diol

Mixture prepared by mixing 16.80 mg of (2R, 3R, 4R, 5S) -4- (acetyloxy) -5- (3-bromoisoxszol-5-yl) -2- / 6- (4-chloro-2-fluoroaniline) (9-Purpurin-9-yl) -tetrahydrofuran-3-yl-acetate (obtained as described in the above-described Preparation of Intermediate 70) with 0.08 ml of t-butylamine in 0.60 ml; of methanol, was reacted at 0.0 ° C for 1.50 hours, and then evaporated to dryness to give 16.0 mg of the title compound.

LC / MS, (System C): &lt; tb &gt;

R _t = 3.22 minutes;

MS (m / z): 511.0 (MH &lt; ⁺ &gt;);

Detailed experimental data using Wb)

Example 144)

Preparation of (2R, 3R, 4S, 5S) -2- [6- (4-chloro-2-fluoroanilino) -9H-purin-9yl] -5- (3-methyl-oxa-ol-5-yl) - te-tetrahydrofuran-3,4-diol

A mixture prepared by mixing 20 mg of (2R, 3R, 4R, 5R) -4- (acetyl oxy) -2- (6-chloro-9H-purin-9-yl) -5-ethynyl-tetrahydrofuran-3-yl acetate, with 0.50 mL of anhydrous toluene was further mixed with.

• ·· ·

24ο · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

0.006 ml triethylamine, 0.004 ml nitroethane and 0.012 ml,

Of 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 eutomatic preparative high-performance liquid chromatography (HPCL) to obtain an intermediate which was cooled to 0.0 ° C after dissolution in anhydrous methanol. was treated with 0.02 mL of t-butylamine for 1.0 hour.

The reaction mixture was then concentrated in vacuo to give 143.0 mg of the title compound as a white solid.

LC / MS, (System C): &lt; tb &gt;

Rt 2.95 min;

MS (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 25 mg of 0-9- (2,2-dimethyl-6R- (5-methyl-4H- / 1,2,4) -triazol-3-yl) -the methyl- (3eR, 5aR) -furo- [3,4-d] 1,3] -dioxol-4R-yl] -9H-purin-6-yl] -cyclopropyl-amine, in 10.0 ml of anhydrous toluene was added 0.47 ml of dimethylformamide dimethylacetal, and the resulting reaction mixture was heated to 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, eluting with ethyl acetate: methanol (19.0: 1.0).

The resulting intermediate was mixed with trifluoroacetic acid ^: water, 9.0: 1.0) and reacted at 6.0 ° C for 6.0 hours. Thereafter, the reaction mixture was concentrated in vacuo, and after mechanical treatment and removal of the residue with ethyl acetate, 143.0 mg of the title compound was obtained as a white solid.

Analytical evaluation of the compound according to the general formula ^C 18 ^H 24 ^N 8 ° 3 · ^CF 3 ^CO 2 ^H · ¹ » ^{5 H} 2 ⁰

Calculated: C 44.40, H 5.20, N 20.70,%

Found: C 44.40, H 4.80 _r 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-fluoroaniline) -9H-purin-9 -yl] -tetrahydro-furan-3-yl acetate

To the solution prepared by dissolving 1.0 g, 2,6-dichloro-9 (2,3,5-tri-Q-ethyl-beta-D-ribofuranosyl) -9H-purine, (see <··· ··· »· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Chem., 59.07), 2608 (1981), by ^J MJRobina and B. Uznanski), in 25.0 mL of toluene, was added sequentially 50.0 mg of palladium acetate, followed by 0.50 mL, 4- chloro-2-fluoreniline, and 120.0 mg of bis- [2- (diphenylphosphine) -phenyl] -ether (see Tett.2ett., 5327-5330, (1998) by PJ Sadighi, MCHarris and Buchwald SL), and the resulting reaction mixture was stirred at 20.0 ° C for 15.0 minutes.

Following the addition of 872.0 mg 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 shaken 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.

Purification of the residue by flash chromatography on silica gel, eluting with ethyl acetate: cyclohexane (1.0: 1.0), afforded the title compound (400.0 mg).

MS (m / z): 556.0 (MH ⁺ )

M e zip product 72)

Preparation of (3aR, 4R, 6R, 6aR) -6- [2-Chloro-6- (4-chloro-2-fluoroanilino) 9H-purin-9-yl] -2,2-dimethyl-trahydrofuran-3, 4-yl (1,3-dioxol-4-yl) -methanol

To a suspension prepared by suspending 400.0 mg of (2R, 3R, 4R, 5R) -4- (ace thyloxy) -2 - [(ace thyloxy) methyl] - $ - / 2-chloro-6- ( 4-chloro-2-fluoro-hilino-9H-purin-9-yl] -tetrahydrofuran-3-yl-acetate, (obtained in the foregoing procedure described above) · · · · ·

·. Preparation of Intermediate 70, into 7.0 ml of methanol, 3 drops of 25% sodium methoxide solution were added. in methanol, and the resulting reaction mixture was stirred at 20.0 ° C for 15 minutes when the mixture became clear.

P _on further stirring the reaction mixture at 20.0 ° C for 90.0 minutes, a precipitate formed which was isolated by filtration and then dried stalks under vacuum for 16.0 hours. The resulting precipitate was dissolved in a mixture prepared by mixing 15.0 mL of acetone and 3.0 mL of 2,2-dimethoxy propane. and 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 removal of the solvent from the mixture under vacuum, the residue was dissolved in 50.0 ml of ethyl acetate, and the obtained solution was gradually prorayt with 50.0 ml of water, 8 with 30.0 ml of brine, and after drying with magnesium sulfate, it was solvent removed in vacuo. Purification of the residue by silica gel chromatography (Varian Bondelut cartridge), eluting with cyclohexane: ethyl acetate (1.0: 1.0), afforded the title compound (240.0 mg), m.p. white colored fabric, foamy character.

Mass Spectrometry, (m / z): 470.0 (MH);

Detailed experimental data using procedure Y)

Me zip product 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-scetoxy5S- (3-tert-butyl-isoxazol-5-yl) -2R- (6-chloro-purin-9-yl) -tetrahydro-furan-3R-yl of 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 ° C. 0 ° C for 60.0 hours.

Then, the reaction mixture was cooled, and evaporated to dryness in vacuo, and the resulting residue was dissolved in 20.0 mL of pyridine, and 19.0 mL of 8-acetic anhydride was added. Then the reaction mixture was 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 separation of the organic θ aqueous phase, the aqueous layers were extracted with 100.0 mL of ethyl acetate.

The combined ethyl acetate extracts were dried over magnesium sulfate, filtered, and evaporated in vacuo.

The title compound was obtained as a yellow solid (500.0 mg).

LC / MS, (System C): &lt; tb &gt;

R ^and 3.59 minutes *,

MS (m / z): 628.0 (MH);

Me zip product 74)

Preparation of (2R, 3R, 4R, 5S) -4- (8-Acyloxy) -5- [3- (tert-butyl) -isoxa] -ol-5-yl] -2- [6- (piperidin-4-yl) -is- amino) -9H-purin-9-yl] -trans of drofuran-3-yl 1-8-cetate urea

Solution prepared by dissolving 500.0 mg of tert-butyl-4 '(9- (2R, 3R, 4R * 5S) -3,4-bis- (acetyloxy) -5- / 3- (tert-butyl) isoxezole-5-tetrahydrofuran-2-yl-9H-purin-6-yl) amino-1-piperidine-1-carboxylate (obtained as described above for the preparation of Intermediate 73 above); 20.0 ml, trifluoroacetic acid: dichloromethane (1.0: 9.0), was stored at 3.0 ° C for 16.0 hours at rest.

Then, after mixing with 100.0 mL of saturated aqueous sodium bicarbonate, the mixture was extracted with 100.0 mL of dichloromethane. After separation of 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 title compound was obtained as a yellowish-colored solid of glassy character.

LC / MS, (System C): &lt; tb &gt;

R _t = 2.45 minutes;

MS (m / z): 528.0 (MH);

Intermediate 75)

Preparation of (2R, 3R, 4R, 5S) -4- (Acetyloxy) -5- [3- (tert-butyl) -isoxazol-5-yl] -2- (6- [eta] &lt; 1 &gt;-( methylsulfonyl) - piperidin-4-yl) amino (9H-purin-9-yl) -tetrahydrofuran-3-yl-acetate

To a solution prepared by dissolving 40.0 mg of (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 as described in the preceding Preparation of Intermediate 74 above) in 4.0 mL of tetrahydrofuran was added 0.0088 mL of methanesulfonyl chloride, and 0.0212 mL of triethyl min and the resulting the reaction mixture was stirred at 20.0 ° C for 16.0 hours.

Then the mixture was triturated between ethyl acetate (2 x 100.0 mL) and 100.0 mL of water, and after separation of the organic and aqueous phases, the organic layers were washed with 100.0 mL of water, and after drying with sulfate magnesium, were evaporated under vacuum.

36.70 mg of the title compound are obtained as a colorless gum.

LC / MS, (System C): &lt; tb &gt;

Rt = 3.20 min

Mass spectrometry (m / z): 606, O, (MH ⁺ )

Example 167)

Preparation of (2S, 3S, 4R, 5R) -2- [3- (tert-butyl) -1-oxazol-5-yl] -5- (6R / 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- (1- (methylsulfonyl) -piperidin-4-yl) -8mino-9H-purin-9-yl) tetrahydrofuran-3-yl-acetate, (obtained in the preceding procedure for the preparation of Intermediate 75 above), at 2, 0 mL of chilled methanol was added to 0.038 mL of t-butylamine at Ο ° C, and the resulting reaction mixture was stored at 3.0 ° C at room temperature for 1.50 hours.

Subsequent evaporation of the mixture gave the title compound as a white solid (30.80 mg).

• 4 · · · · · · · · · · ·

4 4 · · 4 4 4 · 4 · 4 44

4444 4444

-LC / MS, (System C):

R t ⁵⁸ 2.69 min

MS (m / z): 522.0 (MH);

Detailed experimental data using procedure Bb)

Me zip product 76)

Preparation of (2R, 3R, 4R, 5S) -4- (acetyloxy) -3,3- ((scetyloxy) methyl) oxazol-5-yl] -2- [2-chloro-6- (4-chloro-2-carboxylic acid)] 2-fluoroanilino-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) -tetral-3-furan-3R-yl ester of acetic acid, in 2.0 mL of toluene, was added 2.20 mg of palladium acetate, (palladium (II) acetate), followed by 6.0 mg, 2,2-bis- (diphenylphosphine) -1 , 1-binaphthyl, and

28.50 mg of 4-chloro-2-fluoroaniline, and the resulting reaction mixture was stirred under nitrogen for 20.0 minutes.

Then, after the addition of 38.0 mg cesium carbonate, the reaction mixture was further stirred at 80.0 ° C for 24.0 hours. After cooling, the mixture was diluted with 25.0 mL of ethyl acetate, and after successive washing with 25.0 mL of water, and 25.0 mL of brine, it was evaporated in vacuo.

The residue was purified by automatic high-performance liquid chromatography (HPCL), (gradient profile 5.0 90.0, #) »(II), over 18.5 minutes) to give 3.02 mg, desired, m.p. the title compound as a white solid.

• »

LC / MS, (System C):

Rt ₌ 3.52 min;

MS (m / z): 623.0 (MH ⁺ )

Intermediate 77)

Preparation of (2R, 3R, 4S, 5S) -2- [2-Chloro-6- (4-chloro-2-fluoroanilino) 9H-purin-9-yl] -5- / 3- (hydroxymethyl) - is oxa from ol-5-yl / -1e trahydrofuran-3,4-diol

To a 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-fluoroaniline) -9H-purin-9 tert -hydrofuren-3-yl acetate (obtained as described in the preceding Preparation of Intermediate 76 above) at 0.0 ° C in 2.0 mL of methanol was added 0.012 mL of tert-butyl. -butylamine, and the resulting reaction mixture was allowed to stand at 0.0 ° C for 3.0 hours.

Subsequent evaporation of the solvent in vacuo gave 2.48 mg of the title compound as a yellow gum.

LC / MS, (C):

of

R _t ^3.10 minutes;

• φ »

MS (m / z): 497.0 (MH);

4 4 4 9 9 999 9 99 4 4 9 9 99

999 4 4 9 ·· ·

9 9 9 9 9 9 9 • 4444 44 4

444 44 44 44 444

Detailed experimental data using procedure Cc)

Meaiprodukt 78)

Preparation of (3S, 4S, 6R, 6aR) -N- Acety 1- [6- (4-Chloro-2-fluoro-linin) -9H-purin-9-yl] -2,2-dimethyl-trahydrofuran-3, 4-di [1,3] -dioxole-4-carbohydrazide

To a solution prepared with stirring at 0.0 ° C, by dissolving 50.0 mg of (3aR, 4S, 6R, 6sR) -6- / 6- (4-chloro-2-fluoroaniline) -9H-purin-9 - 1 '- 2,2-dimethyl-trahydrofuran- (3,4-d) (1,3) -dioxole-4-carbohydrazide, in 2.0 ml, Ν, Ν-dimethylformamide, was added 28.0 4 µl of diisopropylethylamine, and 9.0 mg of acetyl chloride, and the resulting reaction mixture was stirred at 0.0 ° C for 5.0 hours.

Then the reaction mixture was shaken between 20.0 mL of ethyl acetate and 20.0 mL of water, and after separation of the organic and aqueous phases, the organic layer was washed with 20.0 mL of brine, and after drying with magnesium sulfate, the solvent was evaporated. vacuum removed.

The resulting residue was purified by autometrepreparative high performance liquid chromstography, (HPCL), (gradient prod. 5.0 -.95.0%, (II), over 18.5 minutes), and 25.0 mg, desired, was obtained in the title compound.

LC / MS,

R «2.87 minutes *,

MS, (m / z): 506.0, (MH);

The following steps are analogous to procedure A).

• «· · · ·

220

Reporter gene experiments

Agonist potency was measured on Chinese hamster ovary cells, CHO containing CRE / SPAP / HYG system (CRE = cyclic element for AMP, HYG = element for resistance to hygromycin, SPAP = element for secretion of alkaline phosphatase from placenta), stimulation of cAMP occurs based on this system to produce SPAP. A cell line was used that was stably transfected with the human adenosine A 1 receptor gene or the human adenosine A 3 receptor gene in addition to the above elements. Cells were plated in 96 well plates containing culture medium and incubated for 1 hour at 37 ° C. To measure the efficacy of agonists were added to the appropriate wells in concentrations of IO ^"10 to ΙΟ ^-5 M. After 15 minutes of stimulation of cAMP was performed by adding the maximal concentration of forskolin. All cells were then incubated for an additional 5 hours at 37 ° C, then cooled to room temperature, followed by the addition of a phosphatase substrate (p-nitrophenol phosphate, pNPP), which was converted by SPAP to a color reagent, and the plate was plated. deducted by the appropriate device. Concentration-dependent inhibition of forskolin-stimulated SPAP production can be calculated from the readings. One of the agonists used was a standard non-selective agonist, N-ethylcarboxamidadenosine, NECA, and the potency of all agonists subjected to this assay was expressed relative to the potency of this NECA standard.

ECR = concentration value as effective as NECA, whose efficacy is considered to be 1.

221

Table 2. Efficacy in reporter gene assay

Example # Adenosine A1 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 Dec 5.15 172 21 23.26 321 22nd 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 • 9 9 · 9 9 99

999 99 9 9 · 9

999 9,999 9 9

9999 98 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 considered to be 1 (see description in 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.