Adenosine derivatives as a2a receptor agonists

Summary: A compound of formula (I), or steoisomers or pharmaceutically acceptable salts thereof, formula (1), or steoisomers or pharmaceutically acceptable salts thereof, wherein A, U, U², Ria, Ri٥, R² and R³ have meanings as set forth in the specification which are useful for the treatment of conditions mediated by activation of the ٨2A adenosine receptor, including obstructive or inflammatory airway disease. Also disclosed are pharmaceutical compositions containing the compounds and a process for preparing the compounds.

The present invention relates to organic compounds, their preparation and use as pharmaceutical substances.

One aspect of the invention provides compounds of formula (1), or stereoisomers or pharmaceutically acceptable salts thereof.

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M

<img file="MA30722B1_D0001.tif" />

in which and 2 لا are independently selected from CH ؛ and o provided that when Ui is o then Ria is not a substituent linked to N, and when 2 لا is o then Rib is not a substituent linked to N:

R¹ and R are independently selected from a 3 to 12 membered heterocyclic group containing 1-4 ring nitrogen atoms and optionally containing 1-4 other heteroatoms selected from the group consisting of oxygen and sulfur, this group being optionally substituted by oxo, O-Ci-Cg-alkyl, C6-Ci0-aryl, Rie or by Ci-Cg-alkyl optionally substituted by OH, or

R¹ and R^1b are independently selected from -NR⁴r4, -NR C-Cs-alkylcarbonyl, -NR⁵Cg-Cg-cycloalkylcarbonyle, -NRSO2-Ci-Cg-alkyl, -NR C7-Ci4-aralkylcarbonyle and -NR5c (= O) -C (= O) -NR C-Cg-alkyl optionally substituted by Rie, or

Ria and Rib are independently selected from NR4-C1-Cg-alkyl, NRC (O) C1-C8hydroxyalkyl, NR4OCi-Cg-alkyl, and NRCC-Cg-hydroxyalkyl, or

Ria and Rib are independently selected from C1-C8-hydroxyalkyl, CH-O-C1-Cg-alkyl, C (O) -O-C1-Cg-alkyl, C (O) NR R and C (O) - NH-C1-C8-alkyl:

Rie is a 3 or 12 membered heterocyclic ring containing at least one ring heteroatom chosen from the group consisting of nitrogen, oxygen and sulfur, said 3 or 12 membered heterocyclic ring optionally being substituted by halo, cyano, oxo, OH, carboxy, amino, nitro, Ci-Cs-alkyl, Ci-Cg-alkylsulfonyl,

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-3aminocarbonyl, C1-C6-alkylcarbonyl OR O-CC-alkyl optionally substituted by aminocarbonyl;

r2 is C1-Cg-alkyl optionally substituted by OH; halogen: C6-C10-aryl optionally substituted by OH, SO2R, SCi-Cg-alkyl, CN, halogen, O-C7-C14aralkyl or O-Ci-Ce-alkyl: a C3-C15-carbocyclic group optionally substituted byO-C7 -C14 aralkyl, C3-C5-carbocyclic, O-C1C-alkyl, C2-C8-alkenyl, C2-Cs-alkynyl or C1-Cg-alkyl; O-Ci-Cg-alkyl: -SO2-Ci-C8-alkyl, e: a 3 to 12 membered heterocyclic group containing 1-4 ring nitrogen atoms and optionally containing 1- 1-4 other heteroatoms chosen from the group consisting of oxygen and sulfur, this group being optionally replaced by a heterocyclic group of 3 12-membered containing 1-4 ring nitrogen atoms and optionally containing 1-4 other heteroatoms selected from the group consisting of oxygen and sulfur, C7-Ci4-aralky! E or C6-Ci4-aryl optionally substituted by 0-C7-Ci4-aralkyl: or r2 is a C3-C٦5-carbocyclic group optionally substituted by O-C7-C14aralkyl, C3-Cis-carbocyclic group, O-Ci-Ce-alkyl, or Ci-Cs-alkyl; or r2 is a 3 to 12 membered heterocyclic group containing 1-4 ring nitrogen atoms and optionally containing 1-4 other heteroatoms chosen from the group consisting of oxygen and sulfur, this group being optionally substituted by a group 3 to 12 membered heterocyclic containing 1-4 ring nitrogen atoms and optionally containing 1-4 other heteroatoms selected from the group consisting of oxygen and sulfur, C7-C14-aralky! e, or CeC14-aryl optionally substituted by O-C7-C١4-aralkyl;

R³ is hydrogen, halogeno, C2-C8-alkenyl, C2-Cs-alkynyl or C1-Cs-alkoxycarbonyl, or

R³ is amino optionally substituted by Cs-Ce-cycloalkyl optionally substituted by amino, hydroxy, C7-C14-aralkyloxy, -S02-C6-Cio-aryl or -NH-C (= O) -NH-R³, or

R³ is amino substituted by R³ -R³-C7-Ci4-aralkyl or a C5Ccarbocyclic group optionally substituted by OH, Ci-Cg-alkyl or Ci-Cealcoxycarbonyle, or

R³ is aminocarbonyl optionally substituted by R^3b, or

R³ is Ci-Cg-alkylamino optionally substituted by OH, R^3b, amino, di (C1-Cs_alkyljamino, -NH-C (= O) -Ci-C8-alkyl, -NH-SO2-C1-C8-a! kyle, -NH-C (= O) -NH-R³

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-4-NH-C (= O) -NH-Ci-C8-alkyl-R, a group C₅-This₅carbocyclic or by Ce-Cioaryl optionally substituted by C6-Cio-aryloxy, OR

R³ is CC-alkylaminocarbonyl or C3-Cg-cycloalkylaminocarbonyle optionally substituted by amino, Ci-Cs-alkylamino, di (Ci-Cg-alkyl) amino OR -NH-C (= ٠) -NH-R³٥, OR

R³ is a 3 to 12 membered heterocyclic group containing 1-4 ring nitrogen atoms and optionally containing 1-4 other heteroatoms chosen from the group consisting of oxygen and sulfur, this group being optionally substituted by O-3R4;

R^3a and R³٥ are each independently a 3 to 12 membered heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur; optionally substituted by halogeno, cyano, oxo, OH, carboxy, nitro, Ci-Cg-alkyl, Ci-Cg-alkylcarbonyle, OH-Ci-Cg-alkyl, Ci-Cg-haloalkyl, amino-c-Cg-alkyl, amin0 (OH) Ci-C8-alkyl or Ci-Cg-alkoxy optionally substituted by aminocarbonyl:

R³ is a 5- or 6-membered heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by a 5 or 6-membered heterocyclic group containing at least one ring heteroatom chosen from the group consisting of nitrogen, oxygen and sulfur:

R^Sd is independently a 5 or 6 membered heterocyclic ring containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, said 5 or 6 membered heterocyclic ring optionally being substituted by halogeno, cyano , oxo, OH, carboxy, amino, nitro, Οι-Cg-alkyl, Ci-Cgalkylsulfonyle, aminocarbonyle, Ci-Cg-alkylcarbonyle, Ci-Cg-alkoxy optionally substituted by aminocarbonyl, or a 5- or 6-membered heterocyclic ring containing at least one ring heteroatom chosen from the group consisting of nitrogen, oxygen and sulfur, said ring also being optionally substituted by halogeno, cyano, oxo, OH, carboxy, amino, nitro, Οι-Cg-alkyl, Ci-Cgalkylsulfonyle, aminocarbonyl, Ci-Ce-alkylcarbonyle, or Ci-Cg-alkoxy optionally substituted by aminocarbonyl;

R4 is chosen from OH, CCg-alkyl optionally substituted by OH, Ci-Cg-alkoxy,

CCaralkyl optionally substituted with OH, O-Ci-Cg-alkyl, halogen Cg-Cioaryl, or O-Cg-Cio-aryl, Οι-Cg-alkoxy, Cg-Cio-aryl optionally substituted by

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-5- ا

OH, CCg-alkyl, O-Ci-Cg-alkyl OR -halogen, OC-C aryl optionally j substituted by OH, Ci-Cg-alkyl, O-Ci-Cg-alkyl or -halogen, NR R b, NHC ( O) r4c, إ NHS (O) 2R «, NHS (O) 2R٩NRC (O) NRR NRC (٥) NRR NR'C (O) OR٩Ci ا Cg-alkylcarbonyl, Ci-Cg-alkoxycarbonyl, dC-Cg-alkyaminocarbonyl, COOR4K ,) C (O) R4i, NHC (O) r4٩, NHC (= NR4 ') N (r4) r4٥, and a 3 ل to 12 membered heterocyclic group containing at least one ring heteroatom chosen from the group ا constitutes by nitrogen, oxygen and sulfur optionally substituted by C00R4P;

؛ r4®, R, r4۴, R^4h and R⁴؛ are, 'independently. H, or C1-Cg-alkyl;

اً R4b is H, Ci-Cg-alkyl, a 3 to 12 membered heterocyclic group containing at least one ring atom chosen from the group consisting of nitrogen, إ oxygen and sulfur, optionally substituted by O- 3R5 or C6-C10-aryl:

إ r4٥, r4®, and r4J are, independently, C1-Cg-alkyl or a 12-membered heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, optionally substituted with O-3R5;

R49 is Ci-Cg-alkyl optionally substituted with a 3-membered heterocyclic group containing at least one ring heteroatom chosen from the group أ consisting of nitrogen, oxygen and sulfur, optionally substituted by SCR٥,

CN, or O-3R or r49 is Cg-Cio-aryl optionally substituted by OH, Ci-Cg-alkyl, Ο-Οι-Cg-alkyl, SCR ™ or -halogen, or r49 is Cf-C-aralkyl optionally substituted by OH, Ο-Οι-Cg-alkyl, halogen, Cg إ Cio-aryl, SCR٥, CN, -Ο (= ΝΗ) ΝΗ or O-C6-Ci0-ary! E, or

R49 is a 3 to 12 membered heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, optionally substituted with O-3R٥;

R4k is H, Οι-Cg-alkyl, Cg-Cio-aryl or a 3 to 12 membered heterocyclic group containing at least one ring heteroatom chosen from the group consisting of nitrogen, oxygen and sulfur ؛

R⁴'is Ci-Cg-alkyl, Ce-Cio-aryl, NHR⁶ or a 3 to 12 membered heterocyclic group containing at least one ring heteroatom chosen from the group consisting of nitrogen, oxygen and sulfur:

R⁴ isCN;

R⁴ is H or C1-Cg-alkyl;

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-6r4٥ is H, C٦-C8-alky) e optionally substituted by OH or by a 3 to 12 membered heterocyclic group containing at least one ring heteroatom chosen from the group consisting of nitrogen, oxygen and sulfur, possibly substituted by SO₂R⁴٥, CN, or O-3R5, CCg-alkoxy, C7-Ci4-ara! Kyle optionally substituted by OH, O-Ci-Cg-alkyl, halogen C6-C10-aryl, or OC-Cio-aryl, Ci-Cgalcoxy , Cg-Caryl optionally substituted by OH, Ci-Cg-alkyl, O-Ci-Cg-alkyl SO₂R ^ ٥ or -halogen;

r4p is H, C1-Cg-alkyl or C7-Ci4-ara! kyl:

r4٩ is C6-C10-aryl optionally substituted by OH, C (= NH) NH₂, or SO₂NH₂, or a 3 to 12 membered heterocyclic group containing at least one ring heteroatom chosen from the group consisting of nitrogen, oxygen and sulfur optionally substituted by O-3R5 or a 3 to 12 membered heterocyclic group containing at least one ring heteroatom chosen from the group consisting of nitrogen, oxygen and sulfur, optionally substituted by O-3R٥:

R⁵ is chosen from OH, Ci-Cg-alkyl optionally substituted by OH, CN, SO2Ri٥ or halogen, C7-Ci4-aralky! e optionally substituted by OH, O-Ci-Cg-alkyl, C6-C10aryl, or OC-Cio- aryl, Ci-Cg-alkoxy, C6-Ci0-aryl optionally substituted by OH, Ci-Cg-alkyl, O-Ci-Cg-alkyl or -halogen, 0-C6-Cio-aryl optionally substituted by OH, CCg-alkyl , O-Ci-Cg-alkyl optionally substituted by halogen, NRbaRbb, NHC (O) R٦ NHS (O) R٥, NHS (O) 2R5a, NR5^fC (O) NR⁵9R5h, NR⁵'C (O) OR5j, Ci-Cg-alkylcarbonyle, Ci-Cg-alkoxycarbonyle, di (Oi-Cgalkyl) aminocarbonyle, COORSk, C (O) R٩ C (0) -C6-Cio-aryl optionally substituted by OH, - COOH, CiCg-alkyl, Ο-Οι-Cg-alkyl, -halogen, or SO2Ri٥, C (O) NHR5m or a 3-12 membered heterocyclic group containing at least one ring heteroatom chosen from the group consisting of nitrogen , oxygenated and sulfur, optionally substituted by O-3R⁷ ;

R5a, R5b٠ r5c٠ r5٦ Rh and R⁵؛ are, independently. H, C1-Cg-alkyl or C6-C10-aryl;

R^5d, R^Se, R⁵⁹, RS and R⁵¹ are, independently, Οι-Cg-alkyl or a 3 to 12 membered heterocyclic group containing at least one ring heteroatom chosen from the group consisting of nitrogen, oxygen and sulfur, optionally substituted by COOR®;

R^sk is H, C1-Cg-alkyl, Cg-Cio-aryl or a 3 to 12 membered heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur:

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-7R is Ci-Cg-alkyl, C6-C10-aryl or a 3 to 12 membered heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, optionally substituted by COOR:

R⁶ is COOR^ea or a 3 to 12-membered heterocyclic group containing at least one ring heteroatom chosen from the group consisting of nitrogen, oxygen and sulfur, optionally substituted by COOR^bb ;

R^6a, R^6b, R⁷, R⁸ and R⁹ are selected from H, C 1 -C 6 -alkyl and C7-C14-aralkyl; and

Rio is Ci-Cs-alkyl optionally substituted by halogen, Οβ-Cio-aryl optionally substituted by OH, Οι-Cg-alkyl, O-Ci-Cs-alkyl or -halogen, or NR^4aR4b;

A is selected from -E-NR14-, -E-NRi⁴-G-NRi5-, -E-NR٩⁴C (O) NR14-G-NR1⁸-, -E-NRC (O) GNR15-, -E-NR14-G-NR¹⁴-E^at-, -NR١⁴C (O) -E-NRi⁴C (O) NRi⁴-, -NR G-NRIs-, -NR15 (CRi6Ri7) n-NRi⁵-, -NR15-X3-G-X4-NR15-. -NR C (O) NR-٠ NR C (O) NR -d-NR, NRi4C (O) - (CRRi7) nC (O) NRi4-, and NR1⁴C (O) NR1⁴-E-NR1⁴C (O) NR14⁴- :

E is chosen from a C3-Ci5-carbocyclic group optionally substituted by HO, Ci-Cg-alkyl, C6-Ci0-aryl, 3 to 12 membered heterocyclic group, Ce-Cioaryl optionally substituted by HO, Οι-Cg-alkyl, O- Οι-Cg-alkyl, halogen, and -E^at-C (O) R E-NRC (O) -E®-;

each E^at is independently selected from a 3 to 12 membered heterocyclic group containing 1-4 ring nitrogen atoms and optionally containing 1-4 other heteroatoms selected from the group consisting of oxygen and sulfur, a C3-C15-carbocyclic group , and Ce-C-aryl optionally substituted with HO, CCg-alkyl, Ο-Οι-Calkyle, or halogen;

E^b is chosen from a 3 to 12 membered heterocyclic group containing 1-4 ring nitrogen atoms and optionally containing 1-4 other heteroatoms selected from the group consisting of oxygen and sulfur, a C3-C15carbocyclic group, and 06 -Cio-aryl optionally substituted by HO, Ci-Cg-alkyl, O-CiCg-alkyl, or halogen;

G is chosen from 0 (0), NRCO), C (O) NR14, Οι-Cg-alkyl optionally substituted by

OH, halogen or 06-Cio-aryl, a 3 to 12 membered heterocyclic group containing 1-4 ring nitrogen atoms and optionally containing 1-4 other heteroatoms chosen from the group consisting of oxygen and sulfur optionally substituted by Rie, a C3-C15-carbocyclic group

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-8éoptionally substituted by HO, Ci-Cg-alkyl, and C6-Ci0-aryl optionally substituted by HO, Οι-Cg-alkyl, Ο-Οι-Cg-alkyl, or halogen:

ل is selected from C6-C10-aryl, SO2, and C6-Cio-aryl-SO2-;

Χ3 and Χ4 are independently selected from C1-Cg-alkyl optionally substituted by OH, halogen or C6-C10-aryl, a 3 to 12 membered heterocyclic group containing 1-4 ring nitrogen atoms and optionally containing 1-4 others heteroatoms selected from the group consisting of oxygen and sulfur optionally substituted by r18, a C3-C15-carbocyclic group, and C6-C10aryl;

each R^u is independently selected from H, C1-Cg-alkyl, and Cg-Cio-aryl: each r15 is independently selected from H, -CN, C1-Cg-alkyl, and 06-Cio-aryl; each R¹⁶ and celiac R¹⁷ are independently selected from H, halogen, OH, C1-Cgalkyl, and C6-C10-aryl;

r18 is a 3 or 12 membered heterocyclic ring containing at least one ring heteroatom chosen from the group consisting of nitrogen, oxygen and sulfur, said 3 or 12 membered heterocyclic ring being optionally substituted by halo, cyano, oxo, OH, carboxy, amino, nitro, Ci-Cg-alkyl, CiCg-alkylsulfonyl, aminocarbonyl, Ci-Cg-alkylcarbonyl or Ο-Οι-Cg-alkyl optionally substituted by 'aminocarbonyl; and n is an integer selected from 1-8.

Definitions

The terms used in this specification have the following meanings:

By the term “optionally substituted” is meant that the group to which one refers can be substituted at the level of one or more positions by any one or any combination of the radicals listed below.

By the terms “halo” or “halogen”, as used in this text, is meant fluorine, chlorine, bromine or iodine. Preferably, halo is chlorine.

"Hydroxy" as used in this text is OH.

By "Οι-Cg-alkyl", as used in this text, is meant straight or branched chain alkyl having 1-8 carbon atoms. Preferably Οι-Cg-alkyl is Ci-Calkyle.

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By "C1-C6-alkoxy", or as used herein, is meant straight or branched chain alkoxy having 1-8 carbon atoms (eg, O-C1-Cg-alkyl). Preferably, C1-C6-alkoxy is C1-Calcoxy.

By "Cs-Cg-cycloalkyl", as used in this text, is meant cycloalkyl having 3-8 ring carbon atoms, for example, a monocyclic group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl , any of which may be substituted by one or more, usually one or two, alkyl groups; or a bicyclic group, such as bicycloheptyl or bicyclooctyl.

By "Ci-Cg-alkylamino" and "di (Ci-Cs-alkyl) amino", as used in this text, is meant amino substituted respectively by one or two Ci-Cg-alkyl groups as defined in what preceded, which may be the same or different.

By “Ci-Cs-alkylcarbonyl” and “Ci-Cg-alkoxycarbonyl”, as used in this text, one understands Ci-Cg-alkyl or Ci-Cg-alkoxy, respectively, as defined in the preceding, fixed by a carbon atom to a carbonyl group.

By "C6-C10-aryl", as used in this text, is meant a monovalent carbocyclic aromatic group which contains 6-10 carbon atoms and which can be, for example, a monocyclic group, such as phenyl: or a bicyclic group, such as naphthyl.

By "CCaralkyl", as used in this text, is meant alkyl, for example, C1-C alkyl, as defined in the preceding, substituted by C6-C10-aryl as defined in the preceding. Preferably, CCaalkyl is Cf-Cio-aralkyl, such as phenyl-C1-C4٠ alkyl.

By “Ci-Cg-alkylaminocarbonyle” and “C3-Cs-cycloalkylaminocarbonyle”, as used in this text, one understands Ci-Cg-alkylamino and Cs-Cg-cycloalkylamino respectively as defined in the preceding, fixed by a carbon atom to a carbonyl group. Preferably C1-C8-alkylaminocarbonyl and Cs-Cg-cycloalkylaminocarbonyl are C1-Calkylaminocarbonyl and Cs-Cg-cycloalkylaminocarbonyl, respectively.

Mk

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By "C3-C١5-cart&gt; ocycli٩ue group", as used in this text, is meant a carbocyclic group having 3-15 ring carbon atoms, for example, a monocyclic group, either aromatic or non-aromatic, such as as cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or phenyl; or a bicyclic group, such as bicyclooctyl, bicyclononyl, bicyclodecyl, indanyl or indenyl, again any of which may be substituted by one or more, usually one or two, C1-Calkyl groups. Preferably, the C3-C15-carbocyclic group is a Cs-Cio-carbocyclic group, in particular phenyl, cyclohexyl or indanyl. The Cs-Ci.s-carbocyclic group can be unsubstituted or substituted. Substituents on the heterocyclic ring include halo, cyano, OH, carboxy, amino, aminocarbonyl, nitro, C1-Cio-alkyl, C1-C10-alkoxy and C3-Cio-cycloalkyl.

By "3 to 12 membered heterocyclic ring containing at least one ring heteroatom chosen from the group consisting of nitrogen, oxygen and sulfur, as used in this text, is meant, for example, furan, pyrrole , pyrrolidine, pyrazole, imidazole, triazole, isotriazole, tetrazole, thiadiazole, isothiazole, oxadiazole, pyridine, piperidine, pyrazine, oxazole, isoxazole, pyrazine, pyridazine, pyrimidine, piperazine, pyrrolidine, morpholino OR, triazine, oxazine. Preferred heterocyclic rings include piperazine, pyrrolidine, morpholino, imidazole, isotriazole, pyrazole, tetrazole, thiazole, triazole, thiadiazole, pyridine, piperidine, pyrazine, furan, oxazole, isoxazole, oxadiazole and azetidine. The 3- to 12-membered heterocyclic ring can be unsubstituted or substituted.

Throughout this specification and in the appended claims, unless the context indicates otherwise, by the term "comprising", or variations, such as "comprises" or "comprising", is meant the inclusion of an integer. or step or group of integers or steps mentioned, but not the exclusion of any other integer or step or group of integers or steps. As understood by those skilled in the art, only combinations of substituents which are chemically possible constitute embodiments of the invention.

particularly preferred specific compounds of formula (I) are those described below in the Examples.

Steoisomers are compounds in which there is an asymmetric carbon atom. The compounds exist in individual and optically active isomeric forms or as mixtures thereof, for example, as diasteoisomeric mixtures.

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The present invention encompasses both individual and optically active Rets isomers, as well as mixtures thereof. Individual isomers can be separated by methods well known to those skilled in the art, for example, by chiral high performance liquid chromatography (HPLC).

Tautomers are one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to the other.

The compounds of the invention can be found in both solvated and unsolvated forms, the term “solvate” is used in this text to describe a molecular complex comprising the compound of the invention and one or more molecules of pharmaceutically acceptable solvent, for example, ethanol. the term “hydrate” St used when said solvent is water.

According to formula (I), R^1a and Rib are, independently, suitably a 3 to 12 membered N-linked heterocyclic group containing 1-4 ring nitrogen atoms and optionally containing 1-4 other heteroatoms selected from the group consisting of oxygen and sulfur. , this group being optionally substituted by oxo, O-Ci-Cgalkyle, C6-C10-aryl, Rie or by CCg-alkyl optionally substituted by OH. 3- to 12-membered heterocyclic groups are preferably 5- or 6-membered heterocyclic groups (eg, tetrazole groups, pyrrole groups, pyrazole groups, pyridine groups, isoxazole groups, triazole groups, or hydantoin groups ). the heterocyclic groups Ria and Rib can be linked to N if necessary. The heterocyclic groups are preferably substituted by at least one group chosen from C1-Cg-alkyl optionally substituted by OH (for example, an ethyl group, a hydroxymethyl group or a hydroxyethyl group). These substitution groups on the heterocyclic groups can be linked by c or N to the heterocyclic group where appropriate.

According to formula (I), Ria and Rib are also, independently, suitably -NH-C1-C5-alkylcarbonyl or -NH-Ca-C8-cycloalkylcarbonyl. the group

-NH-C1-C6-alkylcarbonyl is preferably an acetamide group or a propionamide group. The -NH-Cs-Cg-cycloalkylcarbonyl is preferably a cyclobutanecarboxylic acid amide group.

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According to formula (I), R and R are also, independently, suitably C1-C6-hydroxyalkyl or CHO-C1-C6-alkyl.

According to the formula (1) R١a and Rib are also suitably independently NHC (O) C1-C8-hydroxyalkyl. R 'is preferably NHC (O) C1-C2-hydroxyalkyl (eg, a 2-hydroxy-acetamide group, a 2-hydroxypropionamide group, or a 3-hydroxy-propionamide group).

إ According to formula (1), r2 is suitably H, C1-Cg-alkyl optionally إ substituted by OH, halogen or C6-C aryl optionally substituted by OH or O-C1-Cg ل alkyl. if it is suitably substituted, C1-C8-alkyl is substituted by OH, phenyl, إ naphthalene, or preferably by two phenyl groups. when CCg-alkyl is إ substituted by two phenyl groups, one or the other of the phenyl groups, or both, are preferably unsubstituted, or substituted by at least one OCH, one OH or ا halogen.

According to formula (I), r2 is also suitably C1-C6-alkyl substituted for إ by phenyl. This phenyl can be further substituted by a phenyl when this phenyl is substituted by CN, halogen, or C1-Cg-alkyl.

According to formula (I), R2 is also suitably a C3-C15 ؛ group carbocyclic (eg, a fluorene group).

According to formula (I), R³ is suitably selected from amino substituted by r3c, -R³CC aralkyl, Ci-Cg-alkyl optionally substituted by r3c, and a C3-Ci5-carbocyclic group optionally substituted by OH, Ci-Cg-alkyl or CI-Cgalcoxycarbonyl. r3c is suitably a 3- to 12-membered heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur (eg, pyrrolidine or pyrazole) optionally substituted by halogeno , cyano, oxo, OH, carboxy, nitro, CCg-alkyl, Ci-Cg-alkylcarbonyl, ΟΗ-Ci-Cg-alkyl, Ci-Cs-halogenoalkyl, amino-CCg-alkyl, amino (OH) Ci-Cg-alkyl and ClCl-alkoxy optionally substituted by aminocarbonyl. Preferably the 3 to 12 membered heterocyclic group is substituted by at least one C 1 -C 8 -alkyl group.

According to formula (I), R³ is also, independently, suitably a 3 to 12 membered N-linked heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur. This grouping

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The heterocyclic is preferably pyrrolidine, pyrazole, triazole, tetrazole or imidazole. The heterocyclic group is optionally substituted with NR4 (C (O) NR49R4h, nr43r4٥, NHC (O) r2٥٩ and where r48 and R4٥ are preferably H or C1-Cg-alkyl (eg methyl) and R and R^4h are preferably H. R⁴9 is preferably a 3 to 12 membered heterocyclic group, such as pyridine.

According to formula (I), R³ is also suitably C6-C10-aryl optionally substituted with OH, C1-C6-alkyl, O-C1-Cg-alkyl, SO2R ™ or-halogen, where R ^ ٥ is suitably NH

According to formula (I), A is suitably selected from -E-NR14-, -E-NR14-GNR⁴⁴-, -E-NRC0) NR 14-G-NR14, -E-NRCO) G-NR٩ -E-NR 14-G-NR14-E٩, e is suitably selected from a 5-6 membered heterocyclic group, such as pyrrolidine and piperidine. E^at is suitably a C3-C15-carbocyclic group, such as cyclohexyl. Each r14 is independently suitably selected from H and C1-C8-alkyl, such as methyl. G is suitably selected from a C3-C15-carbocyclic group optionally substituted by HO or C1-C6-alkyl or G is suitably selected from a 5-6 membered heterocyclic group, such as pyrrolidine and piperidine. Preferably the C3-Cis-carbocyclic group is unsubstituted.

Another aspect of the invention provides compounds of formula (Ia), or stereoisomers or pharmaceutically acceptable salts thereof.

<img file="MA30722B1_D0002.tif" />

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-14 ا in which ا Ri and Rib are independently selected from a 3 to 12 ،-membered heterocyclic group containing 1 -4 ring nitrogen atoms and optionally containing 1 -4 إ other heteroatoms selected from the group consisting of oxygen and sulfur, this إ group being optionally substituted by oxo, O-Ci-Cs-alkyl, C6-Ci0-aryl,

Rie or by Ci-Cg-alkyl optionally substituted by OH, or

R¹ and Rib are independently selected from -NR4r4, and -NR C1-Cs-alkylcarbonyl:

R² is Ci-Cs-alkyl optionally substituted by OH, halogen 06-Cio-aryl optionally substituted by OH, SCi-Cg-alkyl, CN, halogen, 0-C7-Ci4-aralkyl, or O-Ci-Cs-alkyl, a C3-Ci5-carbocyclic group optionally substituted by O-C7-C14 aralkyl, C3-Ci5-carbocyclic group, O-Ci-Cs-alkyl, C2-C8 إ alkenyl, C2-Cs-alkynyl or Ci-Cg-alkyl, O- Ci-Cg-alkyl, -S02-Ci-C8-alkyl, a 3 to 12 membered heterocyclic group containing 1-4 ring nitrogen atoms and optionally containing 1-4 other heteroatoms selected from the group consisting of oxygen and sulfur, this group being optionally substituted with a heterocyclic group from 3 to 12 members containing 1-4 nitrogen atoms of the ring and optionally containing 1-4 other heteroatoms chosen from the إ group consisting of oxygen and sulfur, C7-Ci4-ara! kyle, or C6-Ci4-a ^ optionally substituted by OC-C-aralkyl, or أ R³ is hydrogen, halo, C2-Cg-alkenyl, C2-Cg-alkynyl or Ci-Cg-alkoxycarbonyl, أ or إ r2 is Ci-Cg-alkylamino optionally substituted by OH, R3b, amino, di (Ci-Caalkyljamino, -NH -C (= O) -Ci-C8-alkyl, -NH-SO2-Ci-C8-a! Kyle, -NH-C (= O) -NH-R3 °, إ NH-C (= O) -NH -Ci-C8-alkyl-R3b, a C3-Cis-carbocyclic group or by C6-C10 إ aryl optionally substituted by Cg-Cio-aryloxy, or أ r3 is a 3 to 12 membered heterocyclic group containing 1-4 ring nitrogen atoms and optionally containing 1 -4 other heteroatoms selected from ؛ group consisting of oxygen and sulfur, this group being optionally substituted by O-3R4:

R^3a and R3b are each independently a 3 to 12 membered heterocyclic group containing at least one ring heteroatom chosen from the group consisting of nitrogen, oxygen and sulfur: optionally substituted by halo, cyano, oxo, OH, carboxy, nitro, Ci-Cs-alkyl, Ci-Cs-alkylcarbonyl, ΟΗ-Ci-Ca-alkyl,

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-15- ؛ إ Ci-Cg-halogenoalkyl, amino-Ci-Cg-alkyl, amino (OH) Ci-Cg-alkyl and Ci-Cs-alkoxy ا optionally substituted by aminocarbonyl:

ا r3٠ is a 5 or 6 membered heterocyclic group containing at least one ا ring heteroatom selected from the group consisting of nitrogen, oxygen and إ sulfur, which is optionally substituted by a 5 or 6 ؛ heterocyclic group links containing at least one ring heteroatom chosen from the group consisting of nitrogen, oxygen and sulfur:

R is independently a 5 or 6 membered heterocyclic ring containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, said 5 or 6 membered heterocyclic ring being optionally substituted by halo, cyano , oxo, OH, carboxy, amino, nitro, Ci-Cg-alkyl, Ci-Cgalkylsulfonyl, aminocarbonyl, Ci-Cg-alkylcarbonyl, Ci-Cg-alkoxy optionally substituted by aminocarbonyl, or a 5- or 6-membered heterocyclic ring containing at least one ring heteroatom chosen from the group consisting of nitrogen, oxygen and sulfur, said ring also being optionally substituted by halo, cyano, oxo, OH, carboxy, amino, nitro, Ci-Cg-alkyl, Ci-Cg ا alkylsulfonyl, aminocarbonyl, Ci-Cg-alkylcarbonyl, or Ci-Cg-alkoxy optionally substituted by aminocarbonyl:

R⁴ is chosen from OH, Ci-Cg-alkyl optionally substituted by OH, Ci-Cg-alkoxy, C7-Ci4-ara! kyl optionally substituted by OH, O-Ci-Cg-alkyl, halogen Οδ-Οιοaryl, or 0-06 -Cio-aryl, Ci-Cg-alkoxy, C6-Ci0-aryl optionally substituted by OH, Ci-Cg-alkyl, O-Ci-Cg-alkyl or-halogen, O-Cg-Cio-aryl optionally substituted by OH, Ci-Cg-alkyl, Ο-Οι-Cg-alkyl or -halogen, NR⁴'C (O) NR R h;

R⁴', R⁴^ are, independently. H, or Οι-Cg-alkyl:

R⁴3 is a 3 to 12 membered heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur;

A is chosen from -ER⁴-, -E-NR G-NR٩ -E-NRC (O) NRG-NR٩ -E-NRC (O) GNR¹⁵-, -E-NR G- R ⁴-E٥-, and -NR15-G-NR15-;

E is chosen from a C3-C15-carbocyclic group optionally substituted by HO, Οι-Cg-alkyl, C6-Cio-a٢yle, heterocyclic group of 3 to 12 members, Cg-Cioaryl optionally substituted by HO, Οι-Cg-alkyl, Ο-Οι-Cg-alkyl, halogen, or E٩C (O) NR E b-NRC (O) -Ea-:

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-16 each E^at is independently selected from a 3 to 12 membered heterocyclic group containing 1-4 ring nitrogen atoms and optionally containing 1-4 other heteroatoms selected from the group consisting of oxygen and sulfur, a C3-C15-carbocyclic group , and Ce-Cio-aryl optionally substituted by HO, Ci-Cg-alkyl, O-Ci-Cg-alkyl, or halogen;

E^b is selected from a 3 to 12 membered heterocyclic group containing 1-4 ring nitrogen atoms and optionally containing 1-4 other heteroatoms selected from the group consisting of oxygen and sulfur, a C3-C15 carbocyclic group, and C6 -Ci0-aryl optionally substituted by HO, Ci-Cg-alkyl, O-CiCs-alkyl, or halogen:

G is chosen from 0 (0), NR 0 (0), C (O) NRi4, C1-Ce-alkyl optionally substituted with OH, halogen or Ce-Cio-aryl, a 3 to 12 membered heterocyclic group containing 1- 4 ring nitrogen atoms and optionally containing 1-4 other heteroatoms selected from the group consisting of oxygen and sulfur optionally substituted by R, a C3-C group₁₅-carbocyclic optionally substituted by HO, Ci-Cg-alkyl, and Cg-Cio-aryl optionally substituted by HO, Ci-Cs-alkyl, or Ο-Οι-Ca-alkyl, halogen: and

R * ® is a 3- or 12-membered heterocyclic ring containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, said 3 or 12-membered heterocyclic ring optionally being substituted by halo, cyano, oxo, OH, carboxy, amino, nitro, Οι-Cg-alkyl, Ci-Cg-alkylsulfonyl, aminocarbonyl, Ci-Cg-alkylcarbonyl or OC-Cg-alkyl optionally substituted by aminocarbonyl.

Another aspect of the invention provides compounds of formula (Ia), or stereoisomers or pharmaceutically acceptable salts thereof, wherein

R 1 and Rib are independently selected from a 3 to 12 membered heterocyclic group containing 1-4 ring nitrogen atoms and optionally containing 1-4 other heteroatoms selected from the group consisting of oxygen and sulfur, this group optionally being substituted with oxo. O-Ci-Cs-alkyl, C6-C10-aryl, R^{1 C} or by Ci-Cs-alkyl optionally substituted by OH, or

R1 and Rib are independently selected from -NR4r4, and -NR C-C6-alkylcarbonyl;

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-17- إ

R² is Ci-Cs-alkyl optionally substituted by OH, halogen C6-C10-aryl إ optionally substituted by OH, SCi-Ce-alkyl, CN, halogen, 0-C7-Ci4-aralkyl, أ or O-Ci-Cg-alkyl , a C3-Cis-carbocyclic group optionally substituted by O-C7-C14 aralkyl, C3-C5-carbocyclic group, O-Ci-Cg-alkyl, C2-C8alkenyl, C2-Cs-alkynyl or Ci-Cs-alkyl, O -Ci-Cg-alkyl, -S02-Ci-C8-alkyl, a 3 to 12 membered heterocyclic group containing 1-4 ring nitrogen atoms and optionally containing 1-4 other heteroatoms selected from the group consisting of oxygen and sulfur, this group being optionally substituted with a 3 heterocyclic group 12-membered containing 1-4 ring nitrogen atoms and optionally containing 1-4 other heteroatoms selected from the group consisting of oxygen and sulfur, C7-C14-ara! kyl, or C6-C14-aryl optionally substituted by 0-C7-C14-aralkyl, or

RS is hydrogen, halo, C2-C8-alkenyl, C2-Ce-alkynyl or C1-Cs-alkoxycarbonyl, or

R³ is Ci-Cs-alkylamino optionally substituted by OH, R³٩ amino, di (Ci-Csalkyl) amino, -NH-C (= O) -Ci-Cs-alkyl, -NH-SO2-Ci-C8-alkyl, -NH-C (= O) -NH-R³٥, NH-C (= O) -NH-C1-C8-alkyl-R³٥, a C3-Cis-carbocyclic group or by C6-C10aryl optionally substituted by C6-Cio-aryloxy, or

R³ is a 3 to 12 membered heterocyclic group containing 1-4 ring nitrogen atoms and optionally containing 1-4 other heteroatoms selected from the group consisting of oxygen and sulfur, this group being optionally substituted with 0-3R4;

RSa and r3٥ are each independently a 3 to 12 membered heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur: optionally substituted with halo, cyano, oxo, OH, carboxy , nitro, C1-C6-alkyl. Ci-Cs-alkylcarbonyl, OH-Ci-Ce-alkyl, Ci-Cs-haloalkyl, amino-Ci-Cs-alkyl, amin0 (OH) Ci-C8-alkyl or Ci-Ce-alkoxy optionally substituted by aminocarbonyl;

R^3c is a 5- or 6-membered heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted with a 5 or 6-membered heterocyclic group containing at least one ring heteroatom chosen from the group consisting of nitrogen, oxygen and sulfur:

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-18R^3d is independently a 5- or 6-membered heterocyclic ring containing at least one ring heteroatom chosen from the group consisting of nitrogen, oxygen and sulfur, said 5 or 6-membered heterocyclic ring being optionally substituted by halo, cyano, oxo, OH, carboxy, amino, nitro, CiO-alkyl, Ci-Csalkylsulfonyle, aminocarbonyle, Ci-Ce-alkylcarbonyle, Ci-Ca-alkoxy optionally substituted by aminocarbonyl, or a 5- or 6-membered heterocyclic ring containing at least one ring heteroatom chosen from the group consisting of nitrogen, oxygen and sulfur, said ring also being optionally substituted by halogeno, cyano, oxo, OH, carboxy, amino, nitro, Ci-Ca-alkyl, Ci-Caalkylsulfonyl, aminocarbonyl, Ci-Ca-alkylcarbonyle, Οι-Ca-alkoxy optionally substituted by aminocarbonyl;

R⁴ is chosen from OH, Οι-Ca-alkyl optionally substituted by OH, Οι-Ca-alkoxy, C7-Ci4-ara! kyle optionally substituted by OH, Ο-Οι-Ca-alkyl, halogen C₆-VS₁₀aryl, or O-Ca-Cio-aryl, Οι-Ca-alkoxy, Ca-Cio-aryl optionally substituted by OH, Ci-Cs-alkyl, Ο-Οι-Ca-alkyl or -halogen, 0-06-Cio- aryl optionally substituted by OH, Ci-Ca-alkyl, Ο-Οι-Ca-alkyl or -halogen, and NR⁴؛ C (O) NR⁴3R^4d ;

R⁴۴, R^4h are, independently. H, or C1-Ca-alkyl;

R⁴3 is a 3 to 12 membered heterocyclic group containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur: and

A is chosen from

MY

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NH

لانم

<img file="MA30722B1_D0003.tif" />

<img file="MA30722B1_D0004.tif" />

<img file="MA30722B1_D0005.tif" />

'NOT

HH

<img file="MA30722B1_D0006.tif" />

^!ملم ٦ ο

<img file="MA30722B1_D0007.tif" />

<img file="MA30722B1_D0008.tif" />

SYNTHESIS

Another embodiment of the present invention provides a process for the preparation of compounds of formula (I), in free form or as a pharmaceutically acceptable salt, comprising the steps of:

(i) reacting a compound of formula (II)

<img file="MA30722B1_D0009.tif" />

(II)

30722Β1

Case 50424Α / Η0 190

MA or

Ria, Rib, r2, Ui, u₂ are as defined in the above; and

T is a leaving group with a compound of formula (III)

H-r3 (III) where r3 is as defined in the above; and (ii) removing any protective group and recovering the resulting compound of formula (II), in free form or as a pharmaceutically acceptable salt.

The compound of formula (II) can be prepared by reacting a compound of formula (IV)

<img file="MA30722B1_D0010.tif" />

درب vo ov

<img file="MA30722B1_D0011.tif" />

(IV) in which

Ri is equivalent to R٦a and Rib;

r2 and U is equivalent to Ui and ا 2 لا and are as defined in claim 1;

is H or a protecting group:

T is a leaving group, with a compound of formula HAV, where A is as defined in the above; and

V is H or a protecting group to provide a compound of formula (VI)

<img file="MA30722B1_D0012.tif" />

(VI) compound (VI) can be reacted with a compound of formula (VII)

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<img file="MA30722B1_D0013.tif" />

(VII) in which

R * is equivalent to R^1a and Rib:

U is equivalent to Ui and ٧2;

V are defined according to claim 1; and

T and T² are halogen.

The compound of formula (VII) can be prepared by reacting a compound of formula (VIII)

ك ٦ vo ov (VIII) in which

Ri is equivalent to Ria and Rib;

U is equivalent to ٧1 and ٧2:

V are as defined according to claim 1; and

Q represents a leaving group or a protected derivative thereof with a 2,6dihalogenopurine, for example 2,6-dichloropurine, to provide a compound of formula (VII) ج

٧٥ 'Ov

T²

<img file="MA30722B1_D0014.tif" />

(VIII) in which

R * is equivalent to Ria and Rib;

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-22U is equivalent to Ui and 2 لا:

V are defined according to claim 1; and

T and T² are halogen.

The compounds of formula (I) can be prepared, for example, using the reactions and techniques described below and in the Examples. The compounds of formula (I) can be prepared in a manner analogous to the preparations described in the patent applications of the Applicant PCT ΕΡ2005 / 011344, GB 0500785.1, and GB 0505219.6. The reactions can be carried out in a solvent suitable for the reagents and materials employed and suitable for the transformations to be carried out. Those skilled in the art of organic synthesis will understand that the functionality present on the molecule must be consistent with the transformations proposed. This will sometimes require judgment in order to alter the order of the synthetic steps or to select a particular process scheme over another in order to obtain a desired compound of the invention.

The various substituents on the synthetic intermediates and end products illustrated in the following reaction schemes may be present in their fully elaborated form, with suitable protecting groups if any, as understood by those skilled in the art, or under suitable conditions. precursor forms which can be further developed into final forms by methods familiar to those skilled in the art. Substituents can also be added at various stages during the synthetic sequence or after the synthetic sequence is terminated. In many cases, commonly used functional group manipulations can be used in order to convert one intermediate into another intermediate, or one compound of formula (I) into another compound of formula (I). Examples of such manipulations are the conversion of an ester or a ketone into an alcohol; conversion of an ester to a ketone: inter-conversions of esters, acids and amides: alkylation, acylation and sulfonylation of alcohols and amines: and many others. Substituents can also be added using customary reactions, such as alkylation, acylation, halogenation or oxidation. Such manipulations are well known in the state of the art, and numerous reference works summarize the procedures and methods for such manipulations. Some reference books giving examples and references from primary organic synthesis literature for many manipulations of functional groups, as well as other transformations commonly used in the art of organic synthesis are March's Organic Chemistry, 5^th Edition, Wiley and Chichester, Eds.

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-23 (2001): Comprehensive Organic Transformations, Larock, Ed., VCH (1989); Comprehensive Organic Functional Group Transformations, لاخ ١ \ ٢ الأك ١ et al. (éà \ their جل ٢ أ collections), Pergamon (1995); and Comprehensive Organic Synthesis, Trost and Fleming '؛ (collection editors), Pergamon (1991). It will also be recognized that another major concern in the development of any synthetic route in this field relates to the judicious choice of the protective group used for the protection of the reactive functional groups present in the compounds described in the present ؛ invention. Multiple protecting groups within the same molecule can be chosen such that each of these protecting groups can be removed without إ removal of other protecting groups in the same molecule, or alternatively several إ protecting groups can be removed using the same reaction step, إ depending on the desired result. One authoritative account describing many alternatives available to the trained practitioner is Greene and Wuts, Protective Groups In Organic إ Synthesis, Wiley and Sons (1999). It will be understood by those skilled in the art that only ؛ Combinations of substituents which are chemically possible constitute embodiments of the present invention.

The compounds of formula (I) in free form can be converted to salt form, and vice versa, in a conventional manner. The compounds in free or salt form can be obtained in the form of hydrates or solvates containing a solvent used for crystallization. The compounds of formula (I) can be recovered from reaction mixtures and purified in a conventional manner, the isomers, such as stereoisomers, can be obtained in a conventional manner, for example, by fractional crystallization or asymmetric synthesis from the products of correspondingly asymmetrically substituted, eg, optically active.

The compounds of formula (I) and their pharmaceutically acceptable salts are useful as pharmaceutical substances. In particular, they activate the adenosine A receptor₂a, that is, they act as agonists of the A2A receptor. Their properties as agonists of A₂A can be demonstrated using the method described by Murphree et al., Mol Pharmacol, Vol. 61, PP. 455-462 (2002).

The compounds of the Examples in the following have values ​​of K ؛ less than 1.0 μΜ in the above assay. For example, the compound of) 'Example 1 has a Ki value of 0.76 μΜ.

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-24 Regarding their activation of the adenosine A receptor₂a, the compounds of formula (I), in free form or as a pharmaceutically acceptable salt, referred to alternatively in the following as "agents of the invention", are useful in the treatment of conditions which respond to the activation of the drug. adenosine receptor Α2Α, especially inflammatory or allergic conditions. The treatment according to the invention can be symptomatic or prophylactic.

Therefore, the agents of the invention are useful in the treatment of obstructive or inflammatory airway diseases resulting, for example, in the reduction of tissue damage, inflammation of the airways, bronchial hyperresponsiveness, remodeling or inflammation. pathological progression. Conditions and diseases of the obstructive or inflammatory airways to which the present invention is applicable include acute lung injury (APL), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary or airway disease ( COPD, COAD or COLD), including chronic bronchitis or associated dyspnea, emphysema, as well as the exacerbation of airway hyperresponsiveness following other drug therapy, in particular, other inhaled drug therapy. The invention is also applicable to the treatment of bronchitis of any type or origin including, for example, acute, arachidic, catarrhal, croupy, chronic or phthinoid bronchitis. Other obstructive or inflammatory airway diseases to which the present invention is applicable include pneumoconiosis (an inflammatory disease, usually occupational, of the lungs, frequently accompanied by obstruction of the airways, whether chronic or acute, and caused by repeated inlialation of dust) of any type or origin including, for example, aluminose, anthracosis, asbestosis, chalicosis, trichoptilosis, siderosis, silicosis, tabacosis and byssinosis.

Other diseases of the obstructive or inflammatory airways to which the present invention is applicable include asthma of any type or genesis including intrinsic (non-allergic) asthma as well as extrinsic (allergic) asthma, asthma mild, moderate asthma, severe asthma, bronchial asthma, exercise asthma, occupational asthma and asthma induced by bacterial infection. The treatment of asthma is also understood to encompass the treatment of subjects, for example, under the age of 4 or 5 years, exhibiting symptoms of cornage and diagnosed or capable of being diagnosed as "children with asthma", a category of patients.

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-25 established of major medical concern and now often identified as nascent or first phase asthma sufferers. (As a practical matter, this particular asthmatic condition is referred to as “astlimatic child syndrome”).

prophylactic efficacy in the treatment of asthma will be evidenced by a reduced frequency or severity of the symptomatic attack, for example, acute bronchial or asthma attack, improvement in lung function or ! 'improvement of the hyperresponsiveness of the respiratory tract. It can be further evidenced by a decrease in the need for other symptomatic therapies, i.e., therapies intended or intended to restrict or interrupt a symptomatic attack when it occurs, for example, anti -inflammatory (eg, corticosteroids) or bronchodilatory, prophylactic benefit for asthma may in particular be apparent in individuals prone to "morning fall". "morning fall" is a recognized asthmatic syndrome common to a substantial percentage of asthmatics and characterized by an astlimatic attack, for example, between around 4 and 6 a.m., that is, at a time usually significantly away from any previously administered symptomatic asthmatic therapy.

With regard to their anti-inflammatory activity, in particular in the context of inhibiting the activation of eosinophils, the agents of the invention are also useful in the treatment of disorders related to eosinophils, for example, eosinophilia. , especially disorders of the respiratory tract associated with eosinophils (for example, involving morbid eosinophilic infiltration of lung tissue) including hyper-eosinophilia affecting the respiratory tract and / or lungs as well as, for example, eosinophil-related disorders of the respiratory tract consecutive or concomitant with loffler syndrome, pneumonia eosinophil, parasitic infestations (in particular, metazoans) (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the airways caused by reactions to drugs.

the agents of the invention are also useful in the treatment of inflammatory or allergic conditions of the skin, for example, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, Goodpasture syndrome, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus, acquired epidermolysis bullosa, and other inflammatory or allergic conditions of the skin.

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The agents of the invention can also be used for the treatment of other diseases or conditions, in particular, diseases or conditions having an inflammatory component, for example, the treatment of diseases and conditions of the eye, such as conjunctivitis, keratoconjunctivitis sicca, and spring conjunctivitis, diseases affecting the nose, including allergic rhinitis, and inflammatory diseases in which autoimmune reactions are involved or having an autoimmune component or etiology, including autoimmune hematologic disorders (eg, haemolytic anemia, aplastic anemia, erythroblastopenia and idiopathic thrombocytopenia), systemic lupus erythematosus, polycliondritis, scleroderma, Wegener's granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory abdominal disease (for example, ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves disease, sarcoidosis, dry socket, pneumonia by chronic hypersensitivity, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and spring keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, for example, including idiopathic nephrotic syndrome or nephrotic syndrome with minimal glomerular damage).

In addition, the agents of the invention may also be used for the treatment of cystic fibrosis, pulmonary hypertension, pulmonary fibrosis, inflammatory abdominal disease, wound healing, diabetic nephropathy, such as described in document wo 05/107463, the reduction of inflammation in transplanted tissues as described in document us 2005/182018, inflammatory diseases caused by pathogenic organisms as described in document wo 03/086408, and cardiovascular conditions as described in document wo 03/029264.

Likewise, agents of the invention can be used to assess the severity of coronary artery stenosis as described in WO 00/078774, useful in conjunction with radioactive imaging agents and useful in therapy. accessory with angioplasty, as described in document wo 00/78779.

The agents of the invention are also useful in combination with a protease inhibitor for the prevention of organ ischemia and reperfusion injury, as described in WO 05/003150, and in combination with an antagonist of integrin

ΜΑ '30722Β1

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-27.

for the treatment of platelet aggregation, te! as described in the document

WO 03/090733.

The agents of the invention are also useful in promoting wound healing in bronchial epithelial cells, as described in AJP-Lung, Vol. 290, PP. 849-855.

Other diseases or conditions which may be treated by the agents of the invention include diabetes, for example, type I sugar diabetes (insulin dependent diabetes) and type II sugar diabetes, diarrheal diseases, ischemia / lesions. reperfusion, إ retinopathy, such as diabetic retinopathy or retinopathy induced by oxygenated hyperbaric, conditions characterized by high intraocular pressure or the secretion ا of ocular aqueous humor, such as glaucoma, ischemic organ / tissue damage following reperfusion, and pressure sores.

؛ The efficacy of an agent of the invention to inhibit inflammatory conditions, e.g., in inflammatory airway disease, can be demonstrated in an animal model, e.g., a rat or mouse model, respiratory tract inflammation or other inflammatory conditions, for example, as described by Szarka e ؛ al., ل Immunol Methods, Vol. 202, pp. 49-57 (1997): Renzi et al .. Am Rev Respir Dis, Vol. 148, pp. 932-939 (1993); Tsuyuki et al., ل Clin Invest, Vol. 86, pp. 2924-2931 (1995): Cernadas et al., Am ل Respir Cell Mol Biol, Vol. 20, pp. 1-8 (1999): and Fozard et al., Eur ل Pharmacol, Vol. 438, pp. 183-188 (2002).

The agents of the invention are also useful as co-therapeutic agents for use in combination with other medicinal substances, such as anti-inflammatory, bronchodilator, antihistamines or cough suppressants, particularly in the treatment of diseases of the respiratory tract. inflammatory or obstructive such as those mentioned in the above, for example, as potentiators of the therapeutic activity of such drugs or as a means of reducing the required dosage or potential side effects of such drugs. An agent of the invention can be mixed with the other drug substance in a specific pharmaceutical composition or it can be administered separately, before, simultaneously or after the other drug substance.

ΜΑ 30722Β1 إ Case 50424Α / ΗΟ 190

28- إ Consequently, the invention comprises a combination of an agent of the invention as described in the foregoing with an anti-inflammatory, bronchodilator, antihistamine or antitussive drug substance, said agent of the invention and said j drug substance being in the same pharmaceutical composition or a different pharmaceutical composition.

Suitable anti-inflammatory drugs include steroids, in particular, glucocorticosteroids such as budesonide, إ beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate, or the steroids described in documents wo 02/88167, wo 02/12266, wo 02/100879, اً WO 02/00679 (in particular those of Examples 3,11, 14, 17,19, 26, 34, 37, 39, 51, 60, 67, 90, 73, 72 إ and 101), wo 03/35668, wo 03/48181, wo 03/62259, wo 03/64445,

WO 03/72592, wo 04/39827 and wo 04/66920: non-steroidal agonists of the glucocorticoid receptor, such as those described in documents DE 10261874, wo 00/00531, WO 02/10143, wo 03/82280, wo 03/82787, wo 03/86294, wo 03/104195, wo 03/101932, WO 04/05229, wo 04/18429, wo 04/19935 etwo 04/26248; ΙΤΒ4 antagonists, such as Bill 284, ΟΡ-195543, DPC11870, L٢B4 ethanolamide, LY 293111, IY 255283 ؛, CGS025019C, ΟΡ-195543, ΟΝΟ-4057, SB 209247, SC-53228 and those described in us 5451700 ; L٢D4 antagonists include montelukast, pranlukast, zafirlukast, accolate, SR2640, Wy-48,252, ICI 198615, ΜΚ-571, LY-171883, Ro 24-5913 and 1-648051: PDE4 inhibitors, such as cilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A (Napp), Ι3ΑΥ19-8004 (Bayer), SCH-351591 (Schering-Plow), Arofylline (Almirall Prodesfarm) , PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SelCID (TM) CC-1OOO4 (Celgene), VM554 / UM565 (Vernalis), Τ-440 (Tanabe) ), KW-449O (Kyowa Hakko Kogyo), and those disclosed in wo 92/19594, wo 93/19749, wo 93/19750, wo 93/19751, WO 98/18796, wo 99/16766, wo 01/13953, wo 03/104204, wo 03/104205, wo 03/39544, WO 04/000814, wo 04/000839, wo 04/005258, wo 04/018450, wo 04/018451, WO 04/018457, wo 04/018465, wo 04/018431, wo 04/018449, wo 04/018450, WO 04/018451, wo 04/018457, wo 04/018465. wo 04/019944, wo 04/019945,

WO 04/045607 and wo 04/037805: antagonists of the adenosine A receptor_2B, such as those described in document WO 02/42298: and beta-2 adrenergic receptor agonists, such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol, fenoterol, procaterol, and in particular, formoterol, carmoterol and pharmaceutically acceptable salts thereof, and compounds (in free form or as a salt or

MY

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-29 of solvate) of formula (I) of document wo 00/75114, which document is incorporated in this text by reference, preferably the compounds of the Examples thereof, in particular a compound of formula

<img file="MA30722B1_D0015.tif" />

and the pharmaceutically acceptable salts thereof, as well as the compounds (in free form or as a salt or a solvate) of formula (I) of document wo 04/16601, and also the compounds of documents EP 1440966, JP 05025045, wo 93/18007, wo 99/64035, us 2002/0055651, us 2005/0133417, us 2005/5159448, wo 01/42193, wo 01/83462, wo 02/66422, WO 02/70490, wo 02/76933, wo 03/24439, wo 03/42160, wo 03/42164, wo 03/72539, WO 03/91204, wo 03/99764, wo 04/16578, wo 04/22547, wo 04/32921, wo 04/33412, WO 04/37768, wo 04/37773, wo 04/37807, wo 04/39762, wo 04/39766, wo 04/45618, WO 04/46083, wo 04/80964, EP 1460064, wo 04/087142. wo 04/089892, EP 01477167, US 2004/0242622, us 2004/0229904, wo 04/108675, wo 04/108 676, wo 05/033121, WO 05/040103, wo 05/044787, wo 05/058867, wo 05/065650, wo 05/066140, WO 05/07908, wo 2007018461, wo 2007027133, wo 2006051373, wo 2006056471, and WO 2004016601.

Suitable bronchodilator drugs include anticholinergic or antimuscarinic agents, in particular, ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi). and glycopyrrolate, but also those described in documents EP 424021, us 3714357, us 5171744, US 2005/171147, us 2005/182091, wo 01/04118, wo 02/00652, wo 02/51841, WO 02/53564, wo 03/00840, wo 03/33495, wo 03/53966, wo 03/87094, wo 04/018422, WO 04/05285 and wo 05/077361.

Suitable both anti-inflammatory and bronchodilator drugs include beta-2 adenergic receptor agonists / dual muscarinic antagonists such as those disclosed in us 2004/0167167, us 2004/0242622,

US 2005/182092, wo 04/74246 and wo 04/74812.

MY

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-30 Suitable antihistamine drugs include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tenadine, as well as those disclosed in documents JP 2004107299, wo 03/099807 and wo 04/026841.

Other useful combinations of agents of the invention with anti-inflammatory drugs are those with chemokine receptor antagonists, eg, CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR -6, CCR-7, CCR-8, CCR-9 and CCRIO, CXCRI, CXCR2, CXCR3, CXCR4, CX0R5, in particular CCR-5 antagonists, such as Schering-Plow antagonists SC-35H25, SCH-55700 and SCH-D, the Takeda antagonists, such as A / - [[4 - [[[6,7-dihydro-2- (4-methylphenyl) -5b / -benzocyclohepten-8yl] carb0nyl] amin0] phenyl] methyieahydr0- / ١ /, / ١ chloride / -dimethyl-2H-pyran-4-aminium (ΤΑΚ-770), and the CCR-5 antagonists described in US 6166037 (in particular claims 18 and 19), wo 00/66558 (in particular claim 8 ), wo 00/66559 (in particular claim 9), wo 04/018425 and wo 04/026873.

In accordance with the foregoing, the invention also provides a method of treating a condition responsive to activation of the adenosine A receptor.₂a, for example, an inflammatory or allergic condition, in particular an obstructive or inflammatory airway disease, comprising administering to a subject, particularly a human subject, in need thereof, a compound of formula (I) under free form or in the form of a pharmaceutically acceptable salt. In another aspect, the invention provides a compound of formula (!), In free form or in the form of a pharmaceutically acceptable salt, for use in the manufacture of a medicament for the treatment of a condition responsive to. activation of the adenosine A receptor₂a, in particular obstructive or inflammatory airway disease.

The agents of the invention can be administered by any suitable route, eg, orally, eg, in the form of a tablet or capsule; parenterally, for example, intravenously: by inhalation, for example, in the treatment of obstructive or inflammatory airway disease: intranasal, for example, in the treatment of allergic rhinitis; topically to the skin, for example, in the treatment of atopic dermatitis; or rectal, for example, in the treatment of inflammatory abdominal disease.

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In a further aspect, the invention also provides a pharmaceutical composition comprising a compound of formula (I), in free form or in the form of a pharmaceutically acceptable salt, optionally together with a pharmaceutically acceptable diluent or vehicle therefor. the composition may contain a co-therapeutic agent, such as an anti-inflammatory, bronchodilator, antiliistamine or antitussive drug, as described in the above. Such compositions can be prepared using conventional diluents or excipients and techniques known in the galenic art. Thus, oral dosage forms can include tablets and capsules. Formulations for topical administration may be presented as creams, ointments, gels or transdermal delivery systems, for example, patclis. Compositions for inlialation may include aerosol or other atomizable formulations or dry powder formulations.

When the composition comprises an aerosol formulation, it preferably contains, for example, a hydrofluoroalkane (HFA) propellant, such as HFA134a or HFA227 or a mixture thereof, and may contain one or more co-solvents known in the state of the art, such as ethanol (up to 20% by weight), and / or one or more surfactants such as oleic acid or sorbitan trioleate, and / or one or more diluents, such as lactose. When the composition comprises a dry powder formulation, it preferably contains, for example, the compounds of formula (I) having a particle diameter of up to 10 microns, optionally together with a diluent or vehicle, such as lactose, of desired particle size and a compound for promoting protection against deterioration in product performance due to moisture, for example, magnesium stearate. When the composition comprises a nebulized formulation, it preferably contains, for example, the compound of formula (I) either solubilized or suspended, in a vehicle containing water, a co-solvent, such as ethanol. or propylene glycol and a stabilizer, which may be a surfactant.

The invention comprises (A) a compound of formula (I) in inhalable form, for example, in an aerosol or other atomizable composition or in particulate inhalable form, for example, micronized, (B) an inhalable medicament comprising a compound of formula (I) in inhalable form: (C) a pharmaceutical product comprising a compound of formula (I) in inhalable form in association with an inhalation device; and (D) an inhalation device containing a compound of formula (I) in inhalable form.

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Dosages of compounds of formula (I) employed in the practice of the present invention will naturally vary, for example, depending on the particular condition to be treated, the effect desired and the mode of administration. In general, suitable daily dosages for administration by inhalation are on the order of 0.005-10 mg, while for oral administration suitable daily doses are on the order of 0.05-100 mg.

The invention is illustrated by the following Examples.

EXAMPLES

A compound of formula X is illustrated in the following table, the methods for preparing such a compound are described in the following.

<img file="MA30722B1_D0016.tif" />

<td>لأ</td><td>structure</td><td>Ri</td><td>R2</td><td>R٦</td><td>R4</td><td>؛ R</td>

<td> 1</td><td>٩٠ “احتج ( أر</td><td>جه</td><td>رللآ ٧</td><td>-Cl</td><td> ٠</td><td>١O&gt; ٠H</td>

Β ٠ϋ722Β٩

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<td>Ex</td><td>Structure</td><td> ٩١</td><td>R٦</td><td> ٩٦</td><td>Ra</td><td>؛ R</td>

<td> 2</td><td>تمحهي</td><td>.ذءدار</td><td>٩٠ HN \</td><td>ه</td><td></td><td>ب ١ لأ ١ لآ ٠_٠دح ٦</td>

<td> 3</td><td>٩٥ عمزحاً; لىر ٦ ٢ تمؤ ٥Η "رم"</td><td>خلابر</td><td> ٩٠</td><td>-THIS</td><td>٦٧ ببج يده</td><td>جن ٠٨٩</td>

<td> 4</td><td>٩ο ٢ لإ ٦ ه 'خلم (”ن j</td><td>١١ لآملر</td><td> ٩٠</td><td>HN</td><td>HjC. ، بمد</td><td>ه ٥٨٩</td>

<td> 5</td><td>٩٠ مزواً تزر ٦ 'ارز</td><td>H, c٠ ، ك'ر</td><td>٩٠ HN ا</td><td>-THIS</td><td>٦٧ تب ۴ بمب □</td><td>٠''ΝΗ %</td>

<td> 6</td><td>٩٠ ΗΝ اش لآلرن خلم (حرر</td><td></td><td> ٩٠</td><td>A</td><td>h₃c٦ كده</td><td>Ο''ΝΗ ٥٨٩</td>

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<td>Ex</td><td>Structure</td><td>R١</td><td>Ri</td><td>Ra</td><td>R *</td><td>Rs</td>

<td> 7</td><td>٥٦٠ H١١ ١٥٩١ HO 0 ني ٩ U</td><td>عج</td><td>٩٠ A \</td><td>-Cl</td><td></td><td>b , .لأ '</td>

<td> 8</td><td>ΟγΟ HO هي ٦ ى HO oh '</td><td>ي</td><td>٩٥ HN</td><td>مم CHj</td><td>HjC ^</td><td>:, ة لأ NH</td>

Preparation of intermediaries

The abbreviations used are as follows:

CDI l.l'-Carbonyldiimidazole

DCM Dichloromethane

DEAD Diethyl Azodicarboxylate

DIPEA Diisopropylethylamine

DMF Dimethylformamide

DMSO Dimethylsulfoxide

EDCI 1-Ethyl-3- (3'-dimethylaminopropyl) carbodiimide

AcOEt Ethyl Acetate

HPLC High Performance Liquid Chromatography

HCl Hydrochloric Acid

LCMS Liquid Chromatography / Mass Spectroscopy

MeOH Methanol

NMP n-Methylpyrrolidone

NMO /) / - Methylmorpholine /) / - Oxide

TEA Triethylamine

TFA Trifluoroacetic Acid

THF fetrahydrofuran

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-35 The following intermediates of formula (A)

NOT

<img file="MA30722B1_D0017.tif" />

.¾ ي ة

HO ΟΗ are illustrated in Table 1 below, their method of preparation being described in what follows.

TABLE 1

<td>Intermediate</td><td>Q</td><td>M / s ΜΗ +</td>

<td>AA</td><td>م 0</td><td> 521</td>

<td>AB</td><td> ٠٩٨٠</td><td> 475</td>

<td>AC</td><td>V</td><td> 553</td>

Intermediate AA

N - {(1S, 2R, 3S, 4R) -4- [2٠Chloro-6- (2,2-diphenylethylamino) purin-9-ylJ٠2,3-dihydroxycyclopentyljpropionamide

Step AAI (1S, 4R) -4- (2,6-Dichloropurin-9-yl) cyclopent-2-enol

2,6-dichloropurine (10 g, 52.90 mmol), (1S, 4F?) - cis 4-acetoxy-2-cyc) opentén1-οΙ (10 g, 70.40 mmol), tris ( dibenzylideneacetone) dipalladium (0) (3.20 g, 3.50 mmol) and triphenylphosphine on a polymer support (3 mmol / g, 11.60 g, 35.00 mmol) are placed in a flask dried in the oven under a argon atmosphere. Dry deoxygenated THF (80 ml) is added and the reaction mixture is stirred gently for 5 minutes. TEA (20 ml) is added and the reaction mixture is stirred at 5O٥C. We show by LCMS that the

٩ هقفى 1٠ Mk

Case 50424Α / Η0 190

-36 reaction is complete after 1 hour. The reaction mixture is allowed to cool, it is filtered and the solvent is removed in vacuo, the title compound is obtained after purification by flash column chromatography (silica, DCMZMeOH 25: 1).

NMR ¹H (CDC, 400 MHz); 8.30 (s, 1Η), 6.40 (m, 1Η), 5.90 (m, 1Η), 5.50 (m, 1Η), 4.95 (m, 1Η), 3.05 (m , 1Η), 2.10 (m, 1Η), MS (ES +) m / e 271 (MH *).

Step ΑΑ2: (1S, 4R) -4- (2,6-Dichloropurin-9-yl) cyclopent-2-enyl ester of carbonic acid ethyl ester

(1S, 4R) -4- (2,6-dichloropurin-9-yl) cyclopent-2-enol (9.5 g, 35.05 mmol) is placed in an oven-dried flask under an argon atmosphere. . Add dry TF (200 mL) followed by dry pyridine (5.54 g, 70.1 mmol). Ethyl chloroformate (15.21 g, 140.2 mmol) is slowly added so that the temperature does not exceed 4O٥C and the reaction mixture is stirred at room temperature. It is shown by LCMS that the reaction is complete after 1 hour. The solvent is removed in vacuo and the residue is partitioned between DCM (200 mL) and water (200 mL). The organic layer is washed with water (150 mL) and brine (150 mL), dried over MgSO4, filtered and the solvent is removed in vacuo. The title compound is obtained after crystallization from MeOH.

H NMR (CDC, 400 MHz); 8.20 (s, 1Η), 6.45 (m, 1Η), 6.25 (m, 1Η), 5.75 (m, 1Η), 5.70 (m, 1Η), 4.25 (q , 2Η), 3.20 (m, 1Η), 2.05 (m, 1Η), 1.35 (t, 3Η), MS (ES +) m / e 343 (MH *).

Step ΑΑ3: Di-Boc - [(1S, 4 /?) - 4- (2,6-dichloropurin-9-yl) cyclopent-2-enyl] amine

Carbonic acid (1S, 4R) -4- (2,6-dichloropurin-9-yl) cyclopent-2-enyl ester (2.5 g, 7.29 mmol), di- iminodicarboxylate tbutyl (1.74 g, 8.02 mmol), and triphenylphosphine (0.29 g, 1.09 mmol) are placed in an oven-dried flask under an argon atmosphere. Dry deoxygenated THF (30 ml) is added followed by tris (dibenzylideneacetone) dipalladium (0) (0.33 g, 0.36 mmol) and the reaction mixture is stirred at room temperature. It is shown by LCMS that the reaction is complete after 3 hours. The solvent is removed in vacuo and the title compound is obtained after purification by flash column chromatography (silica, AcOEt / fso-hexane 4: 1).

1 H NMR (CDC, 400 MHz); 8.70 (s, 1Η), 6.20 (m, 1Η), 5.85 (m, 1Η), 5.80 (m, 1Η),

5.40 (m, 1Η), 3.20 (m, 1Η), 2.15 (m, 1Η), 1.55 (s, 18Η), MS (ES +) m / e 470 (MH *).

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-37Step ΑΑ4.- (1S, 2R, 3S, 5R) -3- (Di-Boc-amino) -5- (2,6-dichloropurin-9-yl) cyclopentane-1,2diol

A mixture comprising di-Boc - [(1S, 4R) -4- (2,6-dichloropurin-9-yl) cyclopent-2enyljamine (1.30 g, 2.77 mmol) (1.49 g, 3 , 17 mmol), methanesulfonamide (0.30 g, 3.17 mmol) and AD-mix-α (6.75 g, 1.5 g / mmol) in t-butanol / water (20 ml of a 1: 1 mixture is treated with osmium tetroxide (1.5 mL, 4٥/٥ w / w in water). After vigorous stirring at room temperature overnight, the reaction mixture is partitioned between AcOEt and water. The organic portion is separated, washed with water, brine, dried (MgSO4) and concentrated in vacuo to yield the title compound which is used in the next step without further purification.

NMR ¹H (CDCIs, 400 MHz): 8.35 (s, 1Η), 4.80 (m, 1Η), 4.70 (m, 1Η), 4.50 (m, 1Η), 3.85 (m, 1Η), 3.75 (m, 1Η), 3.10 (m, 1Η), 2.75 (m, 1Η), 2.55 (m, 1Η), 1.55 (s, 18Η), SM ( ES +) m / e 504 (MH٠).

Step ΑΑ5: (1S, 2 / ?, 3S, 5Æ?) - 3-amino-5- (2,6-dichloropurin-9yl) cyclopentane-1,2-diol trifluoroacetate

A solution of (1S, 2R, 3S, 5ft) -3- (di-Boc-amino) -5- (2,6-dichloropurin-9yl) cyclopentane-1,2-diol (0.55 g, 1.09 mmol) in DCM (4 mL) is treated with TEA (2 mL) and stirred at room temperature. After 2 hours the solvent is removed in vacuo to yield the title compound which is used in the next step without further purification. SM (ES ؛) m / e 304 (MH٠).

Step ΑΑ6: N - [(1S, 2R, 3S, 4R) -4- (2,6-Dichloropurin-9-yl) -2,3-dihydroxycyclopentylJpropionamide

A solution of (1S, 2R, 3S, 5R) -3-amino-5- (2,6-dichloropurin-9yl) cyclopentane-1,2-diol trifluoroacetate (0.304 g, 1.0 mmol) in THF ( 10 ml) is treated with DIPEA (0.387 g, 3.0 mmol) followed by propionyl chloride (0.093 g, 1.0 mmol). After stirring at room temperature for 2 hours, the solvent is removed in vacuo and the title compound is obtained after purification by reverse phase column chromatography (IsoluteTM C18, 0-100٥ / ο acetonitrile in water - 0.1٥ / ٥ TFA). SM (ES ؛) m / e 360 ​​(MH٠).

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-38Step ΑΑ7Λ / - {(1 S, 2R, 3S, 4R) -4- [2-Chloro-6- (2,2-diphenylethylamino) purin-9-yl] -2,3dihydroxycyclopentyljpropionamide

Du / V - [(1S, 2R, 3S, 4R) -4- (2,6-dichloropurin-9-yl) -2,3-dihydroxycyclopentylJpropionamide (160 mg, 0.44 mmol) is solubilized in THF (5 mL) under an argon atmosphere. DIPEA (69 mg, 0.53 mmol) is added followed by 2,2-diphenylethylamine (96 mg, 0.49 mmol) and the reaction mixture is stirred at 5O٠C. It is shown by LCMS that the reaction is complete after 2 hours. The solvent is removed in vacuo and the title compound is obtained after purification by reverse phase column chromatography (isolute ™ C18, 0-100٥ / ο acetonitrile in water - 0.1٥ / ο TFA).

H NMR (MeOD, 400 MHz); 8.00 (s, 1Η), 7.40-7.15 (m, 10Η), 4.75 (m, 1Η), 4.60 (m, 1Η), 4.50 (m, 1Η), 4 , 20 (m, 3Η), 3.95 (m, 1Η), 2.85 (m, 1Η), 2.40 (q, 2Η), 2.10 (m, 1Η), 1.20 (t, 3Η), MS (ES +) m / e 521 (MH).

Intermediate AA can also be prepared using the following procedure:

AAH step: (2-Chloro-9 - [(1R, 4S) -4- (di-Boc-amino) cyclopent-2-enyl] -9H-purin-6-yl} - (2,2diphenylethyljamine

Du (1 S, 2R, 3S, 5R) -3- (di-Boc-amino) -5- (2,6-dichloropurin-9-yl) cyclopentane-1,2-diol (13.0 g, 27, 66 mmol) is solubilized in THF (250 mL) under an argon atmosphere. DIPEA (4.28 g, 33.19 mmol) is added followed by 2,2-dipheny! Ethyl amine (6.0 g, 30.43 mmol) and the reaction mixture is stirred at 5O٥C. It is shown by LCMS that the reaction is complete after 18 hours. The solvent is removed in vacuo and the reaction mixture is partitioned between dichloromethane (250 mL) and 0.1Μ HCl (250 mL). The organic layer is washed with water (200 ml) and brine (200 ml), dried over MgS0₄, filtered and the solvent is removed in vacuo to give the title compound.

H NMR (CDC, 400 MHz): 8.05 (s, 1Η), 7.30-7.10 (m, 10Η), 6.00 (m, 1Η), 5.70 (m, 2Η), 5 , 60 (m, 1Η), 5.20 (m, 1Η), 4.30 (m, 1Η), 4.20 (m, 1Η), 3.65 (m, 1Η), 3.05 (m, 1Η), 2.00 (m, 1Η), 1.70 (m, 1Η), 1.40 (s, 18Η), MS (ES +) m / e 631 (MH٠).

Step ΑΑΙ2: (1R, 2S, 3R, 5S) -3- [2-Chloro-6- (2,2-diphenylethylamino) purin-9-yl] -5- (di-Bocamino) cyclopentane-1,2-diol

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The title compound is prepared analogously to (1S, 2R, 3S٠5R) -3- (di-Bocamin0) -5- (2,6-dichl0r0purin-9-yl) cycl0pentane-1,2-diol by replacing di-Boc - [(1S, 4R) -4 (2,6-dichl0r0purin-9-yl) cycl0pent-2-enyl] amine by {2-chloro-9 - [(1R, 4S) -4- (di-Bocamino) cyclopent-2-enyl] -9H-purin-6-yl} - (2,2-diphenylethyl) amine.

NMR ¹H (MeOD, 400 MHz): 8.05 (s, 1Η), 7.35-7.15 (m, 10Η), 4.70-4.55 (m, 4Η), 4.50 (m, 1Η ), 4.35 (m, 1Η), 4.20 (m, 2Η), 2.55 (m, 1Η), 2.45 (m, 1Η), 1.60 (s, 18Η).

Step ΑΑΙ3: (1 S, 2R, 3S, 5R) -3-amino-5- [2-chloro-6- (2,2-diphenylethylamino) purin-9-yl] -cyclopentane-1,2-diol trifluoroacetate

Du (1R, 2S, 3R, 5S) -3- [2-chloro-6- (2,2-diphenylethylamino) purin-9-yl] -5- (di-Bocamino) cyclopentane-1,2-diol (10 , 3 g, 15.50 mmol) is solubilized in DCM (50 ml). TFA (25 ml) is added and the reaction mixture is stirred at room temperature. It is shown by LCMS that the reaction is complete after 2 hours. the solvent is removed in vacuo to give the title compound.

H NMR (MeOD, 400 MHz); 7.90 (s, 1Η), 7.30-7.10 (m, 10Η), 4.65 (m, 1Η), 4.50 (m, 1Η), 4.40 (m, 1Η), 4 , 20 (m, 1Η), 4.10 (m, 2Η), 3.50 (m, 1Η), 2.75 (m, 1Η), 2.15 (m, 1Η), SM (ES +) m / e 465 (MHj.

Step ΑΑΙ4. · / Ν - {(1 S, 2R, 3S, 4R) -4- [2-Chloro-6- (2,2-diphenylethylamino) purin-9-yl] -2,3dihydroxycyclopentyljpropionamide

(1S, 2R, 3S, 5R) -3-amino-5- [2-chloro-6- (2,2-diphenylethylamino) purin-9-yl] -cyclopentane-1,2-diol trifluoroacetate (9, 50 g, 16.42 mmol) and DIPEA (6.36 g, 49.27 mmol) are placed in a flask with dry THF (150 ml). Propionyl chloride (1.52 g, 16.42 mmol) is added dropwise and the reaction mixture is stirred at room temperature. It is shown by ICMS that the reaction is complete after 1 hour. The solvent is removed in vacuo and the residue is partitioned between DCM (250 mL) and water (250 mL). The organic layer is washed with water (200 mL) and brine (200 mL), dried over MgSO4, filtered and the solvent is removed in vacuo. The solid is recrystallized from 1,2-dichioroethane to give the title compound.

H NMR (MeOD, 400 MHz); 8.00 (s, 1Η), 7.40-7.15 (m, 10Η), 4.75 (m, 1Η), 4.60 (m, 1Η), 4.50 (m, 1Η), 4 , 20 (m, 3Η), 3.95 (m, 1Η), 2.85 (m, 1Η), 2.40 (q, 2Η), 2.10 (m, 1Η), 1.20 (t, 3Η), SM (ES *) m / e 521 (MH).

Β 2ϋ٦22.Β٩

Case 50424Α / ΗΟ 190

-40 Intermediate AB

Λ / - {(1 S, 2R, 3S, 4R) -4- [2-chloro٠6 - ((S) -1 -hydroxymethyl-2pheny hylamino) purin9-yl] ٠2,3-dihydroxycyclopentyl) propionamide trifluoroacetate

Step ΑΒ1: [(1 S, 4R) -4- (2,6-dichloropurin-9-yl) cyclopent-2enyljpropionylcarbamic acid tert-butyl ester

The title compound is prepared analogously to di-B0C - [(1S, 4R) -4- (2,6dichloropurin-9-yl) cyclopent-2-enyl] amine (replacing the iminodicarboxylate of di-f -butyl with tert-butyl ester of propionylcarbamic acid).

Step ΑΒ2: tert-butyl ester of [(1 S, 2R, 3S, 4R) -4- (2,6-dichloropurin-9-yl) -2,3dihydroxycyclopentyljpropionylcarbamic acid:

A mixture comprising [(1S, 4R) -4- (2,6dichloropurin-9-yl) cyclopent-2-enyl] propionylcarbamic acid tert-butyl ester (6.54 g, 15.8 mmol) , methanesulfonamide (1.46 g, 15.3 mmol) and AD-mix-α (23 g, 1.5 g / mmol) in ؛ -butanol / water (80 mL of a mixture 1 : 1) is treated with osmium tetroxide (3.5 ml, 4٥ / ο ρ / ρ in water). After vigorous stirring at room temperature for 72 hours, the reaction mixture is partitioned between AcOEt and water. The organic portion is separated, washed with water, brine, dried (MgS٥4) and concentrated in vacuo. The resulting residue is triturated in methanol to yield the title compound. MS (ES +) m / e 460 (MH).

Step ΑΒ3: / V - {(1S, 2R, 3S, 4F?) - 4- [2-chloro-6 - ((S) -1-hydroxymethyl-2phenylethylamino) purin-9-yl] -2.3 trifluoroacetate -dihydroxycyclopentyl} propionamide

A solution comprising [(1S, 2R, 3S, 4R) -4- (2,6dichloropurin-9-yl) -2,3-dihydroxycyclopentyl] propionylcarbamic acid tert-butyl ester (0.5 g , 1.1 mmol), DIPEA (0.227 mL, 1.3 mmol), (S) -2-amino-3-phenylpropan-1-ol (0.181 mg, 1.2 mmol) in 1.2 -dichloroethane (3 ml) is heated to 5O٥C overnight. 0.1Μ HCl (10 mL) is added to the reaction mixture and after stirring, the organic portion is separated and treated with TFA (1 mL). After standing at room temperature for 2 hours, the solvent is removed under vacuum to yield the title compound. MS (ES +) m / e 475.2 (MH٠).

Intermediate AC

ΜΑ 30722Β1

Case 50424ΑΉΟ 190

This compound is prepared analogously to Intermediate AB by replacing (S) -2-amino-3-phenylpropan-1-ol by 4,4 '- (2-aminoethylidene) bisphenol (prepared according to the preparation of Schelkun et al., Bioorg Med Chem Lett, Vol. 9, PP. 2447-2452 (1999) SM (ES *) m / e 553.2 (MH *).

Intermediate B

A / - {(1S, 2R, 3S&gt; 4R) -4 [2 - ((R) -3-aminopyrr٠lidin-1yl) -6- (2,2-diphenylethylamino) purin٠9.ylJ-2,3- dihydrochloride dihydroxycyclopentyl} propionamide:

Step Β1: {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4propionylaminocyclopentyl) -6- (2,2-diphenylethylamino) tert-butyl ester -9 / - / - purin-2-yl] pyrrolidin-3yljcarbamic:

A reaction mixture comprising N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2diphenylethylamino) purin-9-yl] -2,3-dihydroxycyclopentyl} propionamide (2,5 g, 4.80 mmol) and (3R) - (+) - (3-Boc-amino) pyrrolidine (2.5 g, 13.6 mmol) in DMSO (8 mL) is heated at 100 ° C for a period of night. Purification of the product by reverse phase column chromatography (Isolute⁷ C18, 0-20٥ / ٥ acetonitrile in water - 0.1٥ / ο TFA) leads to the title compound. MS (ES +) m / e 521.4 (MH *).

Step Β2.- W - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-aminopyrrolidin-1-yl) -6- (2,2diphenylethylamino) purin-9-yl dihydrochloride ] -2,3-dihydroxycyclopentyl) propionamide:

{(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4pr0pi0nylamin0cycl0pentyl) -6- (2,2-diphenylethylamin0) acid tert-butyl ester -9H-purin-2-yl] pyrr0lidin-3-yl} carbamic acid (approximately 4.80 mmol) is solubilized in 1.25 HCl in MeOH (60 ml). After stirring at room temperature for 3 days, the solvent is removed in vacuo to yield the title compound. MS (ES *) m / e 571.24 (MH *).

Intermediate C

N - {(1S, 2R, 3S, 4R) -4- [2-Chloro-6- (2,2-diphenylethylamino) purin-9-yl] -2,3dihydroxycyclopentyl} -2-hydroxyacetamide

ΜΑ 30722Β1

Case 50424ΑΟ 190

-42Step C1 .- {(1 S, 2F?, 3S, 4F?) - 4- [2-Chloro-6- (2,2-diphenylethylamino) purin-9-yl] -2,3dihydroxycyclopentylcarbamoyljmethyl ester of acetic acid

A suspension of (1S, 2R, 3S, 5F?) - 3-amino-5- [2-chloro-6- (2,2diphenylethylamino) purin-9-ylj-cyclopentane-1,2-diol dihydrochloride (Intermediate ΑΑΙ3 ) (250 mg, 0.46 mmol) in dry THF (10 ml) is treated with TEA (0.188 g, 1.86 mmol) followed by acetoxyacetyl chloride (0.064 g, 0.46 mmol) then stirred at room temperature for 30 minutes. The solvent is removed in vacuo and the solvent is partitioned between DCM and 0.1Μ HCl. The organic portion is separated and washed with brine, dried (MgSO ،) and concentrated in vacuo to yield the title product. MS (ES +) m / e 565.38 (MH *).

Step C2. · / V - {(1 S, 2R, 3S, 4F?) - 4- [2-Chloro-6- (2,2-diphenylethylamino) purin-9-yl] -2,3dihydroxycyclopentyl} -2- hydroxyacetamide:

To a suspension of {(1S, 2F?, 3S, 4F?) - 4- [2-chloro-6- (2,2-diphenylethylamino) purin-9yl] -2,3-dihydroxycyclopentylcarbamoyl} methyl ester of acetic acid (0.2g, 0.35mmol) in MeOH (10ml) add potassium carbonate (0.098g, 0.7mmol) and the reaction mixture is stirred at room temperature for 1 hour. The solvent is removed in vacuo and the solvent is partitioned between DCM and water. The organic portion is separated, dried (MgSO ،) and concentrated in vacuo to yield the title product. MS (ES +) m / e 522.4 / 524.5 (MH *).

Intermediate D {1 - [(1S, 4Æ) -4- (2,6-Dichloropurin-9-yl) cyclopent-2-enyl] -1W٠pyrazol٠4-yl} -methanol

A mixture comprising (1S, 4R) -4- (2,6-dichloropurin-9-yl) cyclopent-2-enyl ester of carbonic acid ethyl ester (Intermediate ΑΑ2) (1.00 g, 2.92 mmol), (1 / - / - pyrazol-4yljmethanol (preparation presented below) (0.34 g, 3.50 mmol) and triphenylphosphine (0.15 g, 0.44 mmol) in deoxygenated THF (10 mL) under an inert argon atmosphere is treated with / rts (dibenzylideneacetone) dipalladium (0) (0.13 g, 0.15 mmol) and stirred at 5O٥C for 1 hour. The solvent is removed in vacuo and the crude product is purified by chromatography on silica eluting with MeOH / DCM (1:25) to yield the title compound.

Preparation of (1H-pyraz0l-4yl) methanol

ΜΑ 2٢٢722Β٩

Case 50424Α / ΗΟ 190

4-Ethylpyrazole carboxylate (10 g, 71.40 mmol) is placed in an oven-dried flask under an argon atmosphere. Dry THF (100 mL) is added followed by the dropwise addition of lithium aluminum hydride (1M in THF, 100 mL, 100 mmol). Once the addition is complete, the reaction mixture is stirred at 5O٥C. It is shown by NMR that the reaction is complete after 4 hours, the reaction mixture is cooled on an ice bath and the reaction mixture is quenched with water (3.8 ml) then! 'Sodium hydroxide at 15٥ / ο (3.8 ml) and finally water again (11.4 ml). The solvent is removed in vacuo and the solid is placed in a Soxhlet apparatus. THF is refluxed in the system for 24 hours. The solvent is removed in vacuo to give the title compound.

NMR ¹H (MeOD, 400 MHz); 7.60 (s, 2Η), 4.55 (s, 2Η).

Intermediate E

[4٠٠ ((ft) -3-pyrr0lidin-3-ylureid0) cycl0hexyl] carbamic acid tert-butyl ester

Step Ε1: Phenyl ester of (4-tertio-butoxycarbonylaminocyclohexyl) carbamic acid

Phenyl chloroformate (1 eq.) Is added dropwise to a solution of pyridine / DCM. The reaction mixture is cooled to o٥c and a solution of tert-butyl ester of (4-aminocyclohexyl) carbamic acid (1 eq.) In DCM is added dropwise. the reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is partitioned between HCl (a٩) (0.2 M) and DCM. The organic phases are washed with water, a saturated solution of sodium hydrogencarbonate and brine. The combined organic phases are dried (MgSO4), filtered and reduced in vacuo to yield the title compound.

Step Ε2 {4- [3 - ((/?) - 1-benzylpyrrolidin-3-yl) ureido] cyclohexylcarbamic acid tert-butyl ester

A solution of (4-tertio-butoxycarbonylaminocycloheX) carbamic acid phenyl ester (1 eq.) And (R) -1-benzylpyrrolidin-3-ylamine (1 eq.) In MeOH is heated by micro radiation. -waves at 100٥C for 30 minutes. The resulting solution is purified by reverse phase column chromatography (IsoluteTM C18, 0100٥ / ο acetonitrile in water 0.1% HCl) to yield the title compound.

MY

30722Β1

Case 50424Α / ΗΟ 190

-44Step Ε3 .- [4 - ((F?) - 3-pyrrolidin-3-ylureido) cyclohexyl] carbamic acid tert-butyl ester

To a solution of tert-butyl ester of {4- [3 - ((F?) - 1-benzylpyrrolidin-3ylueidojcyclohexyljcarbamic acid in ethanol under an inert atmosphere of argon is added palladium hydroxide. on carbon, the reaction mixture is purged with argon and placed under a hydrogen atmosphere overnight, the mixture is filtered and the catalyst washed with ethanol. The organic portions are combined and concentrated in vacuo to yield in the title.

Intermediate F

[(R) -1 - ((/?) - pyrrolidin-3-ylcarbamoyI) pyrrolidin-3-yl] ٠ carbamic acid tert-butyl ester

This compound is prepared analogously to Intermediate E by replacing the tert-butyl ester of (4-aminocyclohexyl) carbamic acid with the tert-butyl ester of (R) -pyrrolidin-3-ylcarbamic acid. .

Intermediate F

[(Æ) -1 - ((Æ) -pyrrolidin-3-ylcarbamoyl) pyrrolidin-3yljcarbamic acid tert-butyl ester can also be prepared using the following method

Step 4; ام- ((R) -1-Benzylpyrrolidin-3-yl) carbamic acid nitrophenyl ester

4-Nitrophenyl cliloroformate (1 eq.) Is added dropwise to a solution of pyridine / DCM (1: 5) at o٠c. the reaction mixture is maintained at o٥c and a solution of (/?) - 1-benzylpy olidin-3-ylamine (1 eq.) in DCM is added dropwise. the reaction mixture is stirred at room temperature overnight, the reaction mixture is partitioned between HCl (aq) (0.2 M) and DCM. the organic phases are washed with water, a saturated solution of sodium hydrogencarbonate and brine. The combined organic phases are dried (MgSO4). filtered and reduced under vacuum to yield the title compound. MS (ES +) m / e 342.10 (MH *).

Step F2: [(R) -1 - ((R) -1-benzylpyrr0lidin-3-ylcarbam0yl) pyrrolidin-3-yl] carbamic acid tert-butyl ester

٦٠722Β٩

Case 50424Α / ΗΟ 190

-45A solution of ((R) -1-benzylpyrrolidin-3-yl) carbamic acid 4-nitrophenyl ester (1 eq.) And (3R) - (+) - 3- (Boc-amino) pyrrolidine in MeOH is heated by microwave radiation at 100 ° C for 1 hour, the reaction mixture is reduced under vacuum, the resulting oil is solubilized in DCM, isocyanate resin (3 eq.) Is added and the mixture is stirred overnight. . The resin was removed by filtration and the DCM was removed in vacuo to yield the title compound. MS (ES +) m / e 299.21 (MH *).

Step F3.- tert-butyl ester of [(R) -1 - ((/?) - pyrrolidin-3-ylcarbamoyl) pyrrolîdin-3yljcarbamic acid

To a solution of [(F?) - 1 - ((F?) - 1-benzylpyrrolidin-3ylcarbamoyl) pyrrolidin-3-yl] carbamic acid tert-butyl ester in ethanol under an inert atmosphere of argon, palladium hydroxide on carbon is added, the reaction mixture is purged with nitrogen and placed under a hydrogen atmosphere overnight. The mixture is filtered and the catalyst washed with ethanol. The organic portions are combined and concentrated in vacuo, the resulting brown oil is purified by column chromatography (IsoluteTM Si, 2٥/٥ MeOH in DCM) yielding the title compound. MS (ES +) m / e 389.25 (MH *).

Intermediate G

{4- [3- (4-amin0cycl0hexyl) ureid0jcycl٠hexyl} carbamic acid tert-butyl ester

This compound is prepared analogously to Intermediate E by replacing (R) -1-benzylpyrrolidin-3-ylamine (Step Ε2) with the benzyl ester of (4-aminocyclohexylcarbamic acid).

Intermediate H

[1 - ((/?) - pyrrolidin-3ÿlcarbam٥yl) piperidin-4yljcarbamic acid tert-butyl ester

This compound is prepared analogously to Intermediate F by replacing (3R) - (٠) -3- (BOC-amino) pyrrolidine with piperidin-4ylcarbamic acid tert-butyl ester in step F2. .

Mk H2B١

Case 50424Α / ΗΟ 190

-46 Intermediate I

{4- [4 (pyrrolidin-3-ylamino) - [1,3,5Jtriazin-2-ylaminoJcyclohexyljcarbamic acid tert-butyl ester

Step /1.- (R) -3- [4- (4-terti0-but0xycarb0nylamin0cyd0hexylamin0) [1,3,5] triazin-2-ylaminojpyrrolidine-1-carboxylic acid allylic ester

The allyfic ester of (/?) - 3-aminopyrrolidine-1-carboxylic acid (1 eq.) Is solubilized in DCM. the reaction mixture is cooled to o٠c and a solution of 2,4-dichloro [1,3,5] triazine (1 eq.) in DCM is added dropwise. The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is again cooled to o٠c and a solution of tert-butyl ester of (4-aminocyclohexyl) carbamic acid (1 eq.) In DCM is added dropwise. The reaction mixture is stirred at room temperature overnight. The reaction mixture is partitioned between HCl (a٩) (0.2 M) and DCM. The organic phases are washed with water, saturated NaHCO3 (aq) and brine. The combined organic phases are dried (MgS0₄), filtered and reduced in vacuo, to yield the title compound.

Step / 2 {4- [4 - ((R) -pyrrolidin-3-ylamino) - [1,3,5] triazin-2ylaminojcyclohexyljcarbamic acid tert-butyl ester

Can be produced from the product of Step 1 by following Ref. : Forns et al., Tetrahedron Lett, Vol. 44, η٥ 36, ρρ. 6907-6910 (2003), using (R) -3- [4- (4-terti0-but0xycarb0nylamin0cycl0hexylamin0) - [1,3,5] triazin-2ylaminojpyrrolidine-1-carboxylic acid allylic ester instead of the amine bound to the resin.

Preparation of Examples

Example 1 W - {(1S, 2R, 3S, 4R) -4- [2 - {(R) -3- [2-Chloro-9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy -4pr0pi0nylamin0cycl0pentyl) -9H-purin-6-ylamin0jpyolidin-1-yl} -6- (2,2diphenylethylamino) purin-9-yl] -23٠dihydroxycyclopentyl} propionamide

Case 50424Α / ΗΟ 190

-47Step 1 .٠ Tert-butyl ester of [(1S, 2R, 3S, 4R) -4- (2-chloro-6 - {(R) -1- [9 ((1F?, 2S, 3F ?, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2diphenylethylamino) -9 / - / - purin-2-yl] pyrrolidin-3-ylamino} purin-9-yl) -2, 3dihydroxycyclopentyl] -di-carbamic

Du (1 S, 2R, 3S, 5F?) - 3- (di-Boc-amino) -5- (2,6-dichloropurin-9-yl) cyclopentane-1,2-diol (Intermediate ΑΑ4) (52 mg , 0.10 mmol) and du / V - ((1S, 2R, 3S, 4F?) - 4- [2 - ((F?) - 3-amino-pyrrolidin1-yl) -6- (2,2- diphenylethylamin0) purin-9-yl] -2,3-dihydr0xycycl0pentyl} pr0pi0namide (Intermediate B) (58 mg, 0.10 mmol) are suspended in ؛ PrOH (1 mL). DIPEA (0.089 ml) is added. , 0.51 mmol) and the reaction mixture is heated by microwave radiation at 100٥C for 1 lieure. The reaction mixture is partitioned between water and AcOEt and the organic portion is dried (MgSO4), filtered and reduced in vacuo. Purification by reverse phase column chromatography (IsoluteTM C18, 0-100٥ / ٥ acetonitrile in water) yields the title compound. (ΜΗ + 1038/1040).

Step 2.- / V - {(1S, 2F?, 3S, 4R) -4- [2 - {(R) -3- [9 - ((1ft, 2S, 3F?, 4S) -4-Amino- 2,3-dihydroxycyclopentyl) -2-chloro-9 / ï-purin-6-ylamino] pyrrolidin-1-yl} -6- (2,2-dipl٦enylethylamino) purin-9-ylj-2,3-dihydroxycyclopentyl} propionamide

[(1S, 2 / 3S, 4ft) -4- (2-chloro-6 - {(Æ) -1- [9 ((1R, 2S, 3R, 4S) acid tert-butyl ester -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenylethylamino) -9 / ipurin-2-yl] pyrrolidin-3-ylamino} -purin-9-yl) -2,3-dihydroxycyclopentylJ- di-carbamic (39 mg, 0.038 mmol) is solubilized in MeOH (1 ml) and HCl (4 M) in dioxane (1 ml) is added. The reaction mixture is stirred at room temperature overnight. The reaction mixture is reduced in vacuo to yield the title compound. (ΜΗ + 838).

Step 3 .٠ / V - {(1S, 2R, 3S, 4R) -4- [2 - {(R) -3- [2-Chloro-9 - ((1R, 2S, 3F?, 4S) -2 , 3-dihydroxy-4propionylaminocyclopentyl) -9 // - purin-6-ylaminojpyrrolidin-1yl} -6- (2,2diphenylethylamino) purin-9-yl] -2,3-dihydroxycyclopentyl} propionamide

Du / V - {(1S, 2R, 3S, 4F?) - 4- [2 - {(R) -3- [9 - ((1R, 2S, 3F?, 4S) -4-amino-2,3 -dihydroxycyclopentyl) -2-chloro-9 / - / - purin-6-ylamino] pyrrolidin-1-yl} -6- (2,2-diphenylethylamino) purin-9-yl] -2.3dihydroxycyclopentyljpropionamide (32 mg, 0.038 mmol) and TEA (0.016 ml, 0.113 mmol) are suspended in THF (0.5 ml). MeOH (0.5 ml) is added to promote solubility. Add propionic acid chloride (0.0035 mL, 0.040 mmol) and

MK

30722Β1

Case 50424Α / ΗΟ 190

-48the reaction mixture is stirred at room temperature overnight, the reaction mixture is reduced under vacuum and purified by reverse phase column chromatography (Isolute ™ Cl 8, 0-100٥ / ٥ acetonitrile in water - 0.1٥ / ٥ TFA) to yield the title compound (ΜΗ + 894/895).

Example 2 / V - {(1S, 2R, 3S, 4R) -4- [2 “{(R) -3- [2 - [(R) -3 (3-Pyridin-3-ylureido) pyrrolidin-1yl] -9 - ((1R, 2S, 3R, 4S) -2,3-dihydoy-4-propionylaminocyclopentyl) -9Hpurin-6-ylaminolpyrrolidin٠1٠yl} ٠6- (2,2-dip! Ienylethylamîno) purin-9-yl] ٠ 2 , 3-dihydroxycyclopentylJpropionamide

DuA / - {(1S, 2R, 3S, 4R) -4- [2 - {(R) -3- [2-chloro-9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy- 4pr0pi0nylamin0cycl0pentyl) -9 / f-purin-6-ylamin0] pyrr0lidin-1-yl} -6- (2,2-diphenylethylamin0) purin-9-yl] -2,3-dihydroxycyclopentyl} propionamide (1 e٩.) And 1-pyridin-3-yl-3- (R) pyrrolidin-3-ylurea (3 é٩.) are solubilized in EtOH. The reaction mixture is refluxed at room temperature for 48 hours. The reaction mixture is reduced in vacuo and purified by reverse phase column chromatography (Isolute TM C18, 0-100٥ / ٥ acetonitrile in water - 0.1% TFA) to yield the title compound.

Examples 3-8 are prepared individually by the following methods described for multi-parallel synthesis.

the Examples of formula (I) are prepared in a multi-parallel sequence of reactions as described below.

<img file="MA30722B1_D0018.tif" />

١١١١٥ H

Z '/ qH

<img file="MA30722B1_D0019.tif" />

HN

Diagram 1

ΜΑ 30722Β1

Case 50424Α / ΗΟ 190

<img file="MA30722B1_D0020.tif" />

Intermediate ΑΑ3

<img file="MA30722B1_D0021.tif" />

Intermediate Y

Dihydroxylato

2ND STEP

<img file="MA30722B1_D0022.tif" />

Intermediate YA

Protection

STEP 3

<img file="MA30722B1_D0023.tif" />

Intermediate YB

XCI

STEP 4

<img file="MA30722B1_D0024.tif" />

Intermediate YX

ن. 1

ة

H٥C

2. Protection

٣ لآر ٠ ةج

HO * OH

<img file="MA30722B1_D0025.tif" />

؛ NH

STEP 6

STEP 5

Intermediate YXA

٦٠

٠٦٦٢ ٦٦٥ HO OH

<img file="MA30722B1_D0026.tif" />

عد

N١N

<img file="MA30722B1_D0027.tif" />

InerrdialYXB

رب

Intermediate ΑΑ4

<img file="MA30722B1_D0028.tif" />

; هج ٩

Intermediate YXZ

<img file="MA30722B1_D0029.tif" />

υ- "

2 ج

STEP 8

N ٣١ ؛

A?/

1 مكر. Deprotection فءهر

<img file="MA30722B1_D0030.tif" />

Intermediate YXC

HN

Xb

اء ح

Step 1 :

Reaction of Intermediate ΑΑ3, analogously to that used in the preparation of Intermediate ΑΑΙ1 by replacing diphenylethylamine with the appropriate amine, individually with amines Υ-Η gives Intermediate Y.

ΜΑ 39722Β1

Case 50424Α / ΗΟ 190

-50.

Amines Υ-Η

<img file="MA30722B1_D0031.tif" />

<img file="MA30722B1_D0032.tif" />

<img file="MA30722B1_D0033.tif" />

2nd step :

reaction of Intermediates Y individually with the dihydroxylating agent, osmium tetroxide or ruthenium tetroxide, gives Intermediates YA.

Step 3:

Reaction of Intermediates YA, analogously to that used in the preparation of Intermediate ΑΑΙ3 gives Intermediates YB.

Step 4:

Reaction of Intermediate YB with the appropriate acid chloride, analogously to that used in the preparation of Intermediate ΑΑΙ4 (with propionyl chloride) or Intermediate c (with acetoxyacetyl chloride) gives YX Intermediaries.

YX intermediaries

Where x_at = CHsCHCO) -, CHOC (O) -, HOCHC (O) -, HOCHCHCO) Step 5 ٠

Reaction of Intermediate YX with (3R) - (+) - (3-Boc-amino) pyrrolidine followed by deprotection analogously to that used in the preparation of Intermediate B gives Intermediates YXA.

Steps 6 and 7:

Reaction of Intermediates YXA, analogously to that used to prepare Example 1, individually using the appropriate acid chlorides in Step 3 results in Intermediates YXC.

YXC intermediaries

Mk

30722Β1

Where Xb = CH₃CH₂C (O) -, coco) -, HOCCO) -, HOCH (CH3) C (O) Case 50424Α / ΗΟ 190

Step 8:

Intermediate YXC is reacted in ethanol at reflux, or in DMSO at 9011O٥C, for 18-24 hours individually with a 3-fold excess of the appropriate Intermediate Z. Examples of Formula (I) are isolated after purification by mass directed reverse fold chromatography.

Intermediate Z

Where Z =

<img file="MA30722B1_D0034.tif" />

<img file="MA30722B1_D0035.tif" />

<img file="MA30722B1_D0036.tif" />

Examples of formula (II) can be prepared as described below in

Diagram 2:

<img file="MA30722B1_D0037.tif" />

ΜΑ 30722Β1

Case 50424Α / ΗΟ 190

-52 Diagram 2

Eto١۴٥

٠٠

<img file="MA30722B1_D0038.tif" />

٩ بج

<img file="MA30722B1_D0039.tif" />

Dihydroxylation

Intermediate ΑΑ2

STEP 1 Χ ، ΐ٢Ν

Intermediaries Χ2

2ND STEP

٠

HO OH a

<img file="MA30722B1_D0040.tif" />

STEP 3

Intermediaries Χ2Α

1. θ '

٦۴

HO 'oh

<img file="MA30722B1_D0041.tif" />

2. Protection

STEP 4

Intermediaries Χ2Υ

م ١

<img file="MA30722B1_D0042.tif" />

لن ٢

احاً h

دج Intermediate Z

حل-. "

<img file="MA30722B1_D0043.tif" />

Intermediaries Χ2Υ

STEP

<img file="MA30722B1_D0044.tif" />

+

<img file="MA30722B1_D0045.tif" />

Cl

Intermediaries Χ2Α

STEP 6

راً

مل

Intermediaries Χ2ΥΒ

<img file="MA30722B1_D0046.tif" />

Step 1 - Reaction of Intermediate ΑΑ2, analogously to that used in the preparation of Intermediate D, replacing (1 H-pyraz0l-4-yl) methanol with the appropriate heterocyde, individually with the heterocycles Xc-Η gives the Intermediaries Χ2.

XH heterocycles

<img file="MA30722B1_D0047.tif" />

The Χ-Η heterocycles are prepared as follows:

XI preparation is described with Intermediate D.

Χ2-Χ3 are prepared by following procedures in the literature.

٦٠722Β٩

Case 50424Α / ΗΟ 190

-53.

2nd step :

Reaction of Intermediates Χ2, individually with the dihydroxylating agent, osmium tetroxide or ruthenium tetroxide, gives Intermediates Χ2Α.

Step 3:

Reaction of Intermediates Χ2Α, analogously to that used in the preparation of Intermediate AB, Step ΑΒ3 by replacing (S) -2-amino-3-phenylpopanΙ-ol with the appropriate amine, individually with the amines Υ -Η gives the Intermediaries Χ2Υ.

Step 4:

Intermediates Χ2Υ are reacted with (3R) - (+) - (3-Boc-amino) pyrrolidine followed by deprotection analogously to that used in the preparation of Intermediate B to give Intermediates 2ΧΑ.

Step 5:

Reaction of Intermediates Υ2ΧΑ in a manner analogous to that used to prepare the teitio-butyl ester of [(1S, 2R, 3S, 4R) -4- (2-chloro-6 - {(F?) - T [9 ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenylethylamino) -9 / - / purin-2-yl] pyrrolidin-3-ylamino } purin-9-yl) -2,3-dihydroxycyclopentyldi-carbamic (Example

1, Step 7), individually using the corresponding Intermediate Χ2Α leads to the IntermediateX2YB.

Where Xd is chosen from

Step 6:

HQ.

HQ.

Intermediate Χ2ΥΒ is reacted in ethanol under reflux, or in DMSO at 9011O٥C, for 18-24 hours individually with a 3-fold excess of the appropriate Intermediate Z (as previously described). The examples of formula (III) are isolated after purification by directed mass reverse phase chromatography.

The examples of formula (III) are prepared as described below.

Mk ٦٩٦22Β٩

Case 50424Α / Η0 190

<img file="MA30722B1_D0048.tif" />

YXC Intermediates are reacted in acetonitrile // v-methylpyrrolidone in the presence of sodium iodide and triethylamine, individually with the Τ-Η amines. Heating by microwave radiation at temperatures of 12O-22O٥C gives all of the Examples of formula (III).

Amines Τ-Η

<img file="MA30722B1_D0049.tif" />

the Examples of formula (IV) are prepared as described below.

ΜΑ 30722Β1

Case 50424Α / ΗΟ 190

<img file="MA30722B1_D0050.tif" />

These examples are prepared from Intermediates Χ2ΥΒ in a manner analogous to that used in order to prepare the Examples of formula (III).

Examples of formula (V) are prepared as described below.

(٧)

Χ٠١Ν

<img file="MA30722B1_D0051.tif" />

Diagram 4:

Intermediate YX

NOT

٠ ب

! موا ”

2, Deprotection

لأري

HO OH Intermediate ΥΧΑ2

هدئخئ

HO OH ه ٦

»١٠

<img file="MA30722B1_D0052.tif" />

r

Intermediate K

Intermediate ΑΑ4

These examples are prepared from Intermediates ΥΧΑ2 in a manner analogous to the Examples of formula (III). Intermediates ΥΧΑ2 are prepared from

Intermediates YX analogously to that used in the preparation of Intermediate

B by replacing the (3R) - (+) - (3-Boc-amino) pyrrolidine with the appropriate Boc-protected amine (Boc) -AH.

ϋ٦22Β٩ &lt;؟ ΜΑ

B٥c-protected amine (Boc) -AH:

Case 50424Α / ΗΟ 190

<img file="MA30722B1_D0053.tif" />

<img file="MA30722B1_D0054.tif" />

Linkage arm A results:

<img file="MA30722B1_D0055.tif" />

Intermediate K is converted to Example V analogously to Example I.

Examples of formula (VI) are prepared as described below.

<img file="MA30722B1_D0056.tif" />

ΜΑ Ι22Β٩

<img file="MA30722B1_D0057.tif" />

Case 50424ΑΗΟ 190

-57 Diagram 5:

<td rowspan="2">هي HO OH</td><td>Η-Α عزده</td><td rowspan="2">u١١ HO Oh</td><td rowspan="2">ه</td>

<td>2. Deprotection</td>

<td>Intermediaries Χ2Υ</td><td></td><td colspan="2">Intermediaries Χ2ΥΑ2</td>

<img file="MA30722B1_D0058.tif" />

HO OH

Intermediaries Χ2Α

These examples are prepared from Intermediates Χ2ΥΑ2 in a manner analogous to the Examples of formula (III). Intermediates Χ2ΥΑ2 are prepared from Intermediates Χ2Υ in a manner analogous to that used in the preparation of Intermediate B by replacing (3R) - (+) - (3-Boc-amino) pyrrolidine with the Bocprotected amine (Boc ) -AH appropriate.

Examples of Ribose Examples of formula (VII) are prepared as described below.

<img file="MA30722B1_D0059.tif" />

born

ΜΑ 30722Β1

Case 50424Α / ΗΟ 190

-58 Diagram 6

<img file="MA30722B1_D0060.tif" />

Intermediaries RY wo 98/28319

1.

HjC

2. Protection

STEP 3

<img file="MA30722B1_D0061.tif" />

1.DCE.50C

STEP 4

2. K₂CO₃ (aq) CHClj / MeOH. YOUR

<img file="MA30722B1_D0062.tif" />

RYI intermediaries

<img file="MA30722B1_D0063.tif" />

RYIA Intermediates

<img file="MA30722B1_D0064.tif" />

<img file="MA30722B1_D0065.tif" />

<img file="MA30722B1_D0066.tif" />

Step 1 :

the reaction of (2R, 5R) -4-acetoxy-2- (2,6-dichloropurin-9-yl) -5- (2-ethyl-2R-tetrazol-5yl) tetrahydrofuran-3-yl ester of acetic acid (wo 98/28319) in DCE at 50 ° C with the appropriate amine Υ-Η in the presence of DIPEA leads to RY Intermediates Step 2:

The RY Intermediates are deprotected using potassium carbonate in MeOH / chloro elm at room temperature in order to lead to the RYI Intermediates.

Step 3;

Reaction of the RYI Intermediates individually with the appropriate BûC-protected amine (Boc) -AH followed by deprotection in a manner analogous to that used in the preparation of Intermediate B gives the RYIA Intermediates.

30722Β1

MY

Case 50424Α / ΗΟ 190

-59Step 4:

Reaction of RYIA Intermediates individually with (2R, 5R) -4-acetoxy-2 (2,6-dichloropurin-9-yl) -5- (2-ethyl-2H-tetrazol-5-yl) tetrahydrofuran-3- ylesting acetic acid (WO 98/28319) using conditions analogous to those described in Steps 1 and 2 leads to Intermediates RY1A2.

Step 5:

Intermediates RY1A2 are reacted in acetonitrile / N-methylpyrrolidone in the presence of sodium iodide and triethylamine, individually with am-Η amines. Heating by microwave radiation at temperatures of 12O-22O٥C gives all Examples of formula (VII).

the Examples of formula (VIII) are prepared as described below.

<img file="MA30722B1_D0067.tif" />

Figure 4.

<img file="MA30722B1_D0068.tif" />

<img file="MA30722B1_D0069.tif" />

آكاد ٠ OH

٠ ا

<img file="MA30722B1_D0070.tif" />

<img file="MA30722B1_D0071.tif" />

HO OH

Intermediaries Χ2Υ

؛ (SOC)

Intermediate L

Intermediaries Χ2ΥΑ2 ب ٥١٣

<img file="MA30722B1_D0072.tif" />

Intermediate ^

These examples are prepared from Intermediates Χ2ΥΑ2 in a manner analogous to the Examples of formula (III). Intermediates Χ2ΥΑ2 are prepared from Intermediates Χ2Υ in a manner analogous to that used in the preparation of Intermediate B by replacing fa (3Æ?) - (+) - (3-Boc-amino) pyrrolidine by the Bocprotected amine ( Boc) -AH appropriate.

I Ι22Β٩

Amine - (Boc) -AH:

Case 50424Α / ΗΟ 190

<img file="MA30722B1_D0073.tif" />

<img file="MA30722B1_D0074.tif" />

ΗΝ٥٠١١١Ν ١٢ N نمم

A H

0^0

<img file="MA30722B1_D0075.tif" />

Resultant Link Arm:

<img file="MA30722B1_D0076.tif" />

Intermediate 1 is converted to Example VII! analogously to Example I.

Examples of formula (IX) are prepared as described below.

MY

30722Β1

Case 50424Α / ΗΟ 190

<img file="MA30722B1_D0077.tif" />

<img file="MA30722B1_D0078.tif" />

PO Ch intermediate Χ2Α

<img file="MA30722B1_D0079.tif" />

<img file="MA30722B1_D0080.tif" />

Intermediate Μ

<img file="MA30722B1_D0081.tif" />

Diagram 5:

These examples are prepared as follows:

Step 1: Intermediates ΥΧΒΑ2 are prepared from Intermediates ΥΧ in a manner analogous to that used in the preparation of Intermediate B by replacing (3R) - (+) - (3-Boc-amino) pyrrolidine by the amine Boc-protegee (Boc) -AH appropriate.

Step 2: reaction of Intermediates ΥΧΒΑ2 in a manner analogous to that used to prepare the tert-butyl ester of [(1S, 2R, 3S, 4R) -4- (2-chloro-6 {(R) acid -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenylethylamino) -9H-purin-2-yl] pyrrolidin-3- ylamino} -purin-9-yl) -2,3-dihydroxycyclopentyl] -dicarbamic acid (Example 1, Step 1), individually using the corresponding Χ2Α Intermediate leads to Intermediate M.

Step 3: The Intermediates M are reacted in acetonitrile // v-methylpyr rolidone in the presence of sodium iodide and triethylamine, individually with the amines fH. Heating by microwave radiation at temperatures of 12O-22O٥C gives all of the Examples of formula (IX).

The Βοο-protected amine (Boc) -AH, the resulting A linkers and the Τ-Η amines are as previously described.