PL2013211T3

Purine derivatives for use as adenosin a2a receptor agonists

Abstract

This record has no abstract on file.

Term

0.6 yearsto projected expiry

Projected expiry 19 April 2027, counted from filing; an application has no term until it is granted.

1 claim: 1 independent, 0 dependent

1
Patent claims Zastrzeżenia patentowe 1. A compound of the general formula (I) or stereoisomers or pharmaceutically acceptable salts thereof, wherein R1, R2 and R3 mean 1. Związek o wzorze ogólnym (I), albo jego stereoizomery lub farmaceutycznie dopuszczalne sole, gdzie R1, R2 i R3 oznaczają 217 217 218 218 219 219 220 220 221 221 222 222 223 223 224 224 225 225 226 226 227 227 228 228 229 229 230 230 231 231 232 232 233 233 234 234 235 235 236 236 237 237 238 238 239 239 240 240 241 241 242 242 243 243 244 244 245 245 246 246 247 247 248 248 249 249 250 250 251 251 252 252 253 253 254 254 255 255 256 256 257 257 258 258 259 259 260 260 2. A compound according to claim 1 or stereoisomers or pharmaceutically acceptable salts thereof, being the methyl ester of ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2261 [(R) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxycyclopentyl) -carbamic compound with the general formula 2. Związek według zastrzeżenia 1 albo jego stereoizomery lub farmaceutycznie dopuszczalne sole, stanowiący ester metylowy kwasu ((1S,2R,3S,4R)-4-{6-(2,2-difenylo-etyloamino)-2261 [(R)-3-(3-pirydyn-3-ylo-ureido)-pirolidyn-1-ylo]-puryn-9-ylo}-2,3-dihydroksycyklopentylo)-karbamowego o wzorze ogólnym 3. A compound according to claim 1 or stereoisomers or pharmaceutically acceptable salts thereof, being the methyl ester of ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 [(R) -3- ((R) -3-pyrrolidin-3-ylureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxycyclopentyl) -carbamic acid with general formula 3. Związek według zastrzeżenia 1 albo jego stereoizomery lub farmaceutycznie dopuszczalne sole, stanowiący ester metylowy kwasu ((1S,2R,3S,4R)-4-{6-(2,2-difenylo-etyloamino)-2[(R)-3-((R)-3-pirolidyn-3-yloureido)-pirolidyn-1-ylo]-puryn-9-ylo}-2,3-dihydroksycyklopentylo)-karbamowego o wzorze ogólnym 4. A compound according to claim 1, or stereoisomers or pharmaceutically acceptable salts thereof, being N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-phenylureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide of the general formula 4. Związek według zastrzeżenia 1 albo jego stereoizomery lub farmaceutycznie dopuszczalne sole, stanowiący N-((1S,2R,3S,4R)-4-{6-(2,2-difenylo-etyloamino)-2-[(R)-3-(3-fenyloureido)-pirolidyn-1-ylo]-puryn-9-ylo}-2,3-dihydroksy-cyklopentylo)-propionamid o wzorze ogólnym 262 262 5. A compound according to claim 1, or stereoisomers or pharmaceutically acceptable salts thereof, being N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (3-hydroxy-phenyl) -ureido] -pyrrolidin-1-yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] propionamide of the general formula 5. Związek według zastrzeżenia 1 albo jego stereoizomery lub farmaceutycznie dopuszczalne sole, stanowiący N-[(1S,2R,3S,4R)-4-(6-(2,2-difenylo-etyloamino)-2-{(R)-3-[3-(3hydroksy-fenylo)-ureido]-pirolidyn-1-ylo}-puryn-9-ylo)-2,3-dihydroksy-cyklopentylo]propionamid o wzorze ogólnym 6. A compound according to any one of claims 1 to 5 or stereoisomers or pharmaceutically acceptable salts thereof for use as a pharmaceutical. 6. Związek według dowolnego z zastrzeżeń 1 do 5 albo jego stereoizomery lub farmaceutycznie dopuszczalne sole do zastosowania jako środek farmaceutyczny. 7. A compound according to any one of claims 1 to 5 or stereoisomers or pharmaceutically acceptable salts thereof in combination with an anti-inflammatory, bronchodilator, antihistamine or antitussive drug substance, said compound and said second drug substance present in the same or different pharmaceutical compositions. 7. Związek według dowolnego z zastrzeżeń 1 do 5 albo jego stereoizomery lub farmaceutycznie dopuszczalne sole w kombinacji z substancją leczniczą przeciwzapalną, rozszerzająca oskrzela, antyhistaminową lub przeciwkaszlową, przy czym wspomniany związek i wspomniana druga substancja lecznicza występuje w tej samej lub różnych kompozycjach farmaceutycznych. 263 263 8. A compound according to any one of claims 1 to 5 or stereoisomers thereof or pharmaceutically acceptable salts thereof in combination with a compound of the general formula ο 8. Związek według dowolnego z zastrzeżeń 1 do 5 albo jego stereoizomery lub farmaceutycznie dopuszczalne sole w kombinacji ze związkiem o wzorze ogólnym ο OH albo jego farmaceutycznie dopuszczalną solą. OH or a pharmaceutically acceptable salt thereof. 9. A pharmaceutical composition comprising as an active ingredient a compound according to any one of claims 1 to 5 or stereoisomers or pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable diluent or carrier. 9. Kompozycja farmaceutyczna zawierająca jako składnik czynny związek określony w dowolnym z zastrzeż e ń od 1 do 5 albo jego stereoizomery lub farmaceutycznie dopuszczalne sole, razem z farmaceutycznie dopuszczalnym rozcieńczalnikiem lub nośnikiem. 10. Związek według dowolnego z zastrzeżeń 1 do 5 albo jego stereoizomery lub farmaceutycznie dopuszczalne sole do zastosowania w leczeniu zapalnej lub obturacyjnej choroby dróg oddechowych. Of 10. A compound according to any one of claims 1 to 5 or stereoisomers or pharmaceutically acceptable salts thereof for use in the treatment of inflammatory or obstructive airway disease. Novartis AG, Switzerland Novartis AG, Szwajcaria Pełnomocnik:Proxy:

1,287 paragraphs in 5 sections, as filed

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

[0002] In an aspect of the present invention there are provided compounds of formula (I) or their stereoisomers or pharmaceutically acceptable salts,

HO OH

2 Where R, R and R are

<td> 12</td><td>H’cYCHsHJC ° C < II about</td><td></td><td> . r.about γ-ΛΑ 0</td>

<td> 14</td><td>II 0</td><td>ΛΛ ΛΛ</td><td> . r.about 0</td>

<td> 15</td><td>ho 'Xxxc> xII about</td><td>ζλ</td><td>Ά ΝΗ οΧ ΝΗ γΛ ΗΝ ^ /</td>

<td> 17</td><td>HJCfrom</td><td>II about</td><td>ΛΛ</td><td>"Ο-ν 0</td><td>Ά ~</td>

<td> 23</td><td>h3cfrom</td><td>II 0</td><td>ΟΗ</td><td>you</td><td>Ρ RZ</td>

<td></td><td></td><td>about</td><td>ο</td><td></td>

<td> 27</td><td>KCA-l ^ cAs II about</td><td>ΑΛ / Λ</td><td colspan="2">ο Ά Τη Χζ Η</td>

<td> 29</td><td>H</td><td>and</td><td>ΊΧ</td><td>about</td>

<td></td><td>about</td><td>αλ "7</td><td>γ X-</td><td>θ</td>

<td> 32</td><td>° Υ 0</td><td>behind Η</td><td>ZZ Κ 0</td>

<td> 34</td><td>Ύ M, C °</td><td>BEHIND ΖΑ</td><td>\ χΝΗ</td>

<td> 40</td><td>HC 'XX'C/1 II 0</td><td>ABOUT</td><td>. vGrV ' 0-Ό</td>

<td> 47</td><td>XI h3A ^ o</td><td></td><td> . r.about y ~~, A 0 L</td>

<td> 49</td><td>ΗΧ ' "Χ'' Ά3 II about</td><td>ΛΛ \ ~ Λ</td><td>° / ΐ _ ^ ° "r ΗΝ 0 Ο ch3</td>

<td> 50</td><td>AND about</td><td>λλ Υλ</td><td>X ΗΝ</td>

<td> 53</td><td>HJC "</td><td>II about</td><td>3Λ</td><td>Υ \ τ</td>

<td> 59</td><td>h3c "</td><td>XX II about</td><td>ΑΛ</td><td>ΟΧη "Χ Α" ΑΉ' Ο-κ</td>

<td> 60</td><td>HJCx</td><td>X about</td><td></td><td>ο Ρί Uy Η °</td>

<td> 61</td><td>HC "</td><td>x ^ It 0</td><td>ABOUT</td><td>iO-Arr0' 9</td>

<td> 62</td><td>HJC ''</td><td>X ' II about</td><td>ΛΛ</td><td></td>

<td> 69</td><td>HJC '</td><td>II about</td><td>Λ</td><td>AND</td><td colspan="2"></td>

<td> 75</td><td>HJC "</td><td>II about</td><td></td><td>Λ</td><td colspan="2">ο ί *1! ο</td>

<td></td><td></td><td>about</td><td></td><td></td><td>ο</td><td>χΛ</td>

<td> 78</td><td>H3Cfrom</td><td>II 0</td><td>/ Γ '/ Γ</td><td>Λ Λ</td><td>XVV I> * «ΝΗ</td><td>nineteenths-ch’</td>

<td> 79</td><td>h3c "</td><td>II about</td><td>F</td><td>Λ</td><td>"Σ-Λ</td><td> ,___ CH, B-Ο ''</td>

<td> 81</td><td>HSC "</td><td></td><td>FROM</td><td>Λ</td><td></td><td>ABOUT</td>

<td> 89</td><td>HJC ''</td><td>'χχ II about</td><td>x \ Υλ</td><td>ON z = \ Ό Y_NFROM</td>

<td></td><td></td><td></td><td></td><td>about -N</td>

<td> 93</td><td>HC C. ABOUT</td><td>^ ch3\ -CH3</td><td>NH '>! ° ch3</td>

<td> 94</td><td>II 0</td><td>BEHIND BEHIND</td><td>X NH about 3</td>

<td> 95</td><td>H, C/ XCFROM3 II 0</td><td>BEHIND BEHIND</td><td>H5s3N. .CH, "f VA</td>

<td> 96</td><td>1 II 0</td><td>BEHIND BEHIND</td><td>X NH about 3</td>

<td> 97</td><td>3 II 0</td><td>BEHIND BEHIND</td><td>'Q NH r ° oxCH> h3c</td>

<td> 98</td><td>3 II 0</td><td>BEHIND BEHIND</td><td>H N zz \ CH CH,</td>

<td> 99</td><td> 0</td><td>AND ΑΛ</td><td>ABOUT</td>

<td></td><td>l about</td><td></td><td>Π</td>

<td> 101</td><td>Hsc C 0</td><td>ΑΛ</td><td>erABOUT Φ</td>

<td> 105</td><td>X II 0</td><td>ΑΛ ΑΛ</td><td>"P NH from ° about scH> / CH H ^ C ^Π3</td>

<td> 113</td><td>HJC '</td><td> 7</td><td>BEHIND</td><td>Awri *)</td>

<td></td><td></td><td> 0</td><td>BEHIND</td><td>sjaf " MW about</td>

<td> 114</td><td>h3c "</td><td>II 0</td><td>BEHIND BEHIND</td><td> "X!O ^ ' ml H</td>

<td> 115</td><td>HSC "</td><td>II 0</td><td>BEHIND BEHIND</td><td>xa "1 · "- '"' of · IW 0 = ^ 0 '' 'CH</td>

<td> 116</td><td>HandC "</td><td>II 0</td><td>BEHIND BEHIND</td><td>AND. .1 ti ♦ * β</td>

<td> 117</td><td>HJC "</td><td>II 0</td><td>HJC ABOUT</td><td>'Q N-CH / 3HJC</td>

<td></td><td></td><td></td><td>BEHIND</td><td></td>

<td></td><td></td><td></td><td>about f HJC</td><td></td>

<td> 118</td><td>HJC "</td><td>II 0</td><td>BEHIND</td><td>'Q</td>

<td></td><td></td><td></td><td>BEHIND</td><td>N —CH. and Η, Ο</td>

<td></td><td></td><td></td><td>from about</td><td>N-CH . 7 * h3c</td>

<td> 125</td><td>h3c "</td><td>'rr II about</td><td>about <* "NM,</td><td>AND</td>

<td> 136</td><td> 0</td><td colspan="2">ch3HjC CH,</td><td>'0 / analysissHJC</td>

<td> 137</td><td>3 II 0</td><td>f )</td><td> 0 0</td><td>FROMN'CHSHJC</td>

<td></td><td></td><td></td><td>ABOUT</td><td></td><td> ></td><td></td><td></td>

<td></td><td></td><td>II 0</td><td>ABOUT</td><td></td><td></td><td rowspan="2">and</td><td>N></td>

<td></td><td></td><td></td><td rowspan="2"></td><td></td><td>about</td><td>from</td><td></td>

<td></td><td></td><td>about</td><td></td><td></td>

<td> 172</td><td>HTY</td><td>XX II 0</td><td>behind X</td><td>TYO</td>

<td> 173</td><td>HSC "</td><td>X ' II 0</td><td>BEHIND BEHIND</td><td>Ν ^ / N-CK Η</td>

<td> 174</td><td>HJC ''</td><td>X ^ II about</td><td>-Η</td><td>nW n-ch3Η</td>

<td> 178</td><td>η, ¢ 7773 II 0</td><td>BEHIND BEHIND</td><td></td>

<td> 179</td><td>J II 0</td><td>BEHIND BEHIND</td><td>Of NH.</td>

<td> 180</td><td>H’c^ f about</td><td>BEHIND BEHIND</td><td>'Q NH o = < 9NH3</td>

<td> 181</td><td>eN, HO 'X*XC 'XII about</td><td>BEHIND BEHIND</td><td>ABOUT , M "C NH d</td>

<td> 182</td><td>CH, 1 ho ^ A II about</td><td>BEHIND BEHIND</td><td>about H d "</td>

<td> 183</td><td>HO. fi Q</td><td>BEHIND BEHIND</td><td>X k ~ C NH dv-N</td>

<td></td><td></td><td>ABOUT</td><td>Ó 0</td>

<td></td><td></td><td>ABOUT</td><td>d N</td>

<td></td><td></td><td>about</td><td> 0 0</td>

<td></td><td> 0</td><td>BEHIND</td><td>c</td>

<td></td><td></td><td>V #</td><td> 0 about</td>

<td> 194</td><td>HOFROM about</td><td> 3></td><td>id</td>

<td></td><td></td><td>MO</td><td>thesev-N</td>

<td> 195</td><td>KO "X'^ Lysine- II about</td><td>vz</td><td>Q " 'd</td>

<td></td><td> 0</td><td> -5</td><td>BEHIND</td>

<td> 202</td><td>ho "</td><td>X about</td><td></td><td>Λ</td>

<td></td><td></td><td></td><td>OH</td><td>about</td>

<td></td><td></td><td></td><td>OH</td><td>ABOUT</td>

<td></td><td></td><td></td><td>behind</td><td>NK / = \</td>

<td> 218</td><td>ho "</td><td>you" 0</td><td>BEHIND BEHIND</td><td>X from*h</td>

<td></td><td></td><td></td><td></td><td>about</td>

<td> 219</td><td>ho "</td><td>II 0</td><td></td><td>AND/ s \ XLH BEHIND</td>

<td> 220</td><td>ho "</td><td>XX II 0</td><td>BEHIND BEHIND</td><td>you NH 0</td>

<td> 221</td><td>ho "</td><td>X II about</td><td>OH ZX</td><td>X χ-fi</td>

<td></td><td></td><td></td><td>BEHIND</td><td>NH / = <</td>

<td> 243</td><td>h3ch>c'Y < about</td><td>ΛΛ Υλ</td><td>Ρ ^ ΟΝΗΝΗ 0</td>

<td> 244</td><td>AND CH, 0</td><td>αλ Υλ</td><td>ΡΝΗΝΗ 0</td>

<td> 250</td><td>about [ch3° v 0</td><td>ΑΛ ΛΆ</td><td>"Mr. NH ° Y NH 0 AND</td>

<td> 251</td><td>about 0</td><td>AND</td><td>"Mr.</td>

<td> 252</td><td>about ΗΟ-Ογ</td><td>ΑΛ</td><td>hllUI</td>

<td> 254</td><td>CHπθΧτ 0</td><td></td><td>"Mr.NHo ^ NH 0</td>

<td> 255</td><td>CHhoZJĘ 0</td><td rowspan="2"></td><td>o ^NH</td>

<td> 256</td><td>h3c ch3HOV about</td><td>p</td><td> 0</td>

<td> 257</td><td>HO 'XxxCjX" II 0</td><td><a HO</td><td>Q NH?</td>

<td> 258</td><td>0 ° C (0 I II ch3 about</td><td>about ΛΛ</td><td>Q nh2</td>

<td> 259</td><td>ΗΟ '^^' Ο '^ II about</td><td> *></td><td>° T0</td>

<td> 262</td><td>about</td><td>ΛΑ</td><td>p</td>

[0003] Compounds of formula (I) can be obtained, for example, using the reactions and techniques described below and in the examples. The compounds of formula (1) can be obtained analogously to the preparation methods described in the patent applications

Applicant PCT / EP2005 / 011344, GB 0500785.1 and GB 0505219.6. The reactions can be carried out in a solvent suitable for the reagents and materials used and appropriate for the transformations carried out. It should be obvious to those skilled in the art of organic synthesis that the functional groups present in the molecule should be appropriate for the intended transformations. This will sometimes require an assessment of the need to modify the order of the synthetic steps or select one particular process scheme from among others to obtain the desired compound.

[0004] The various substituents of the synthesis intermediates and end products shown in the schemes below may be present in their fully developed forms with appropriate protecting groups, where required and obvious to those skilled in the art, or in precursor forms which can then be develop into final forms by methods known to those skilled in the art. Substituents can also be added at or after different stages of the synthesis sequence. In many cases, typical functional group operations can be used to transform one intermediate into another intermediate, or one compound of formula (I) into another compound of formula (I). Exemplary operations of this type are the conversion of an ester or ketone into an alcohol, conversion of an ester into a ketone, interconversion of esters, acids and amides; alkylation, acylation and sulfonylation of alcohols and amines and many others. Substituents can also be added in typical reactions such as alkylation, acylation, halogenation or oxidation. These operations are well known in the art, and many procedures have summarized the procedures and methods for these operations. Some of the papers that contain examples and references to reference literature on organic synthesis on multi-functional operations as well as other transformations typically performed in the field of organic synthesis are March's

Organic Chemistry, ed. 5, Wiley and Chichester, ed. (2001); Comprehensive Organic

Transformations, Larock, ed., VCH (1989); Comprehensive Organic Functional Group Transformations, Katritzky et al. (Series editor), Pergamon (1995); and Comprehensive Organic Synthesis, Trost and Fleming (series editors), Pergamon (1991). It should also be borne in mind that another important factor to consider in planning any synthesis route in this field is the proper choice of the protecting group used to protect the reactive functional groups present in the compounds described in the present invention. Multiple functional groups in the same molecule can be selected so that each of these groups can be removed without removing other protecting groups present in that molecule, or so that several groups can be removed in the same reaction step, depending on the desired result. A credible description of many alternatives to those skilled in the art can be found in Green and Wuts, Protective Groups In Organic Synthesis, Wiley and Sons (1999). It is obvious to those skilled in the art that the embodiments of the present invention are only combinations of substituents that are chemically possible.

[0005] Compounds of general formula (I) in free form can be converted into salt forms in a conventional manner and vice versa. The compounds in free or salt form can be obtained as hydrates or solvates containing the solvent used for crystallization. Compounds of general formula (I) can be recovered from reaction mixtures and purified in a conventional manner. Isomers, such as stereoisomers, can be obtained in a conventional manner, for example, by fractional crystallization or asymmetric synthesis from appropriate, asymmetrically substituted, e.g. optically active, starting materials.

[0006] The compounds of general formula (I) and their pharmaceutically acceptable salts are useful as medicaments. In particular, they activate the A2A adenosine receptor, i.e. act as A2A receptor agonists. Their agonist properties can be demonstrated by the method described by LJ Murphree et al. In Molecular Pharmacology 61, 455-462 (2002).

[0007] The compounds of the following examples have K values below 1.0 μΜ in the above test. For example, the compounds of Examples 1, 14, 20, 36, 69 and 178 K values of 0.0083, 0.0025, 0.0016, 0.0030, 0.0043 and 0.0080 μM, respectively.

[0008] In the aspect of A2A adenosine receptor activation, compounds of general formula (I), in free form or in pharmaceutically acceptable salt form, herein alternatively referred to as "agents of the present invention", are useful in treating conditions responsive to receptor activation adenosine A2A, in particular inflammatory or allergic diseases. The treatment according to the invention can be symptomatic or prophylactic treatment. Accordingly, the agents of the present invention are useful in the treatment of inflammatory or obstructive airway diseases, resulting in, for example, reduced tissue damage, airway inflammation, bronchial hyperreactivity, modification or progression of the disease. Inflammatory or obstructive airway diseases or conditions to which the present invention applies include acute lung injury (ALI), acute respiratory distress syndrome ( ARDS), chronic obstructive pulmonary disease or chronic obstructive airway disease COPD (COPD, COAD or COLD), including chronic bronchitis and dyspnoea associated with it, emphysema, as well as exacerbation of airway hyperreactivity as a result of treatment with other drugs, in particular inhalation drugs. The present invention is also used for the treatment of bronchitis of any type and origin, including, for example, acute, irritant to peanut, catarrhal, crustal, chronic or associated with tuberculous diseases. Further inflammatory or obstructive airway diseases to which the present invention applies include bronchiectasis, pneumoconiosis (inflammatory, usually occupational lung disease, often accompanied by airway obstruction, chronic or acute, caused by repeated inhalation of dust), of any type or origin, including, for example, aluminum silage, carbon silage, asbestos silage, masculine pulmonary silage, pneumococcal mycosis, pneumococcal mycosis, mycosis caused by inhalation of feather dust, iron scum, silicosis, tobacco sclerosis and cotton sclerosis.

[0009] Other inflammatory or obstructive airway diseases to which the present invention applies include asthma of any type and origin, including intrinsic (non-allergic) and extrinsic (allergic), mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise asthma, occupational asthma and asthma caused by bacterial infection. Asthma therapy should also be understood to include the treatment of patients, for example, under 4 or 5 years of age who have wheezing symptoms and are diagnosed or diagnosed in the category of "wheezing child", which is an established disease category for patients who deserve special attention and is now often identified as the early or early stages of asthma. (For convenience, this particular asthmatic condition is referred to as "wheezing child syndrome").

[0010] Prophylactic efficacy in the treatment of asthma is confirmed by a reduction in the frequency or severity of symptomatic seizures, for example acute asthmatic seizures or bronchoconstriction, improved lung function or an improvement in the aspect of airway hyper-responsiveness. The proof of effectiveness can also be a reduction in the need for symptomatic treatment, i.e. treatment aimed at reducing or interrupting symptomatic attacks at the time of their occurrence, e.g. need for anti-inflammatory drugs (e.g. corticosteroids) or bronchodilators. The benefits in preventing asthma may be particularly noticeable in patients prone to the "morning crisis". The "morning crisis" is a recognized symptom of asthma, commonly found in a significant percentage of asthmatics, and characterized by an asthma attack, for example, between 4 and 6 am, i.e. at a time relatively distant from any symptomatic asthma treatment previously used.

[0011] Considering anti-inflammatory activity, in particular with regard to the ability to inhibit the activation of eosinophils, the agents of the present invention are also useful for the treatment of disorders involving eosinophils, for example for the treatment of eosinophilia, in particular respiratory diseases in which eosinophils are involved (for example, diseases associated with eosinophilic infiltration of lung tissues), with the inclusion of hypereosinophilia affecting the respiratory tract and / or lungs and, for example, respiratory disorders in which eosinophils are involved and following or co-existing with Loffler syndrome, eosinophilic pneumonia, parasitosis (in particular infestation with multicellular parasites) including tropical eosinophilia , bronchopulmonary aspergillosis, nodular arteritis including Churg-Strauss syndrome, eosinophilic granuloma and respiratory tract disorders involving eosinophils and caused by a reaction to the drug.

[0012] The agents of the present invention are also useful for the treatment of inflammatory or allergic skin conditions, e.g. psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpetic dermatitis, scleroderma, vitiligo, allergic vasculitis, urticaria , bullous pemphigoid, lupus erythematosus, pemphigus, acquired epidermal vesicular separation and other inflammatory or allergic skin conditions. The agents of the present invention may also be useful for the treatment of diseases or conditions, in particular diseases or conditions with the inflammatory component, for example, treatment of diseases or conditions of the eye such as conjunctivitis, dry keratoconjunctivitis and spring conjunctivitis, nasal diseases including allergic rhinitis, and inflammatory diseases in which autoimmune reactions are implied or have an autoimmune component or etiology, including autoimmune hematological diseases (e.g. hemolytic, aplastic, pure red cell and idiopathic thrombocytopenia), systemic lupus erythematosus, polymyositis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myopathy myopathy , autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), hormonal ophthalmopathy, Graves disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonia, multiple sclerosis, primary hepatic cirrhosis, uveitis (anterior and posterior segment of the eye), dry conjunctivitis and keratoconjunctivitis and spring conjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with or without nephrotic syndrome, for example, including idiopathic nephrotic syndrome or nephropathy of minimal changes).

[0013] In addition, the agents of the present invention may be used to treat cystic fibrosis, pulmonary hypertension, pulmonary fibrosis, inflammatory bowel disease, wound healing, diabetic nephropathy as described in WO05 / 107463, reduce inflammation in transplanted tissues as described in US 2005 / 182018, for the treatment of inflammatory diseases caused by pathogens as described in WO 03/086408 and cardiovascular diseases as described in WO 03/029264.

[0014] The agents of the present invention may also be used to assess the degree of coronary artery stenosis as described in WO 00/078774. In combination with radioactive indicators, they are also useful for coronary imaging and for adjunctive angioplasty treatment as described in WO 00/78779.

[0015] In combination with a protease inhibitor, the agents of the present invention are also useful for preventing ischemic and reperfusion injury of organs as described in WO 05/003150, and in combination with integrin antagonists for the treatment of platelet aggregation disorders as described in WO 03/090733 .

[0016] The agents of the present invention are also useful in promoting wound healing in bronchial epithelial cells as described in AJP-Lung 290: 849-855.

[0017] Other diseases or conditions that can be treated with the agents of the present invention include diabetes, for example type I diabetes mellitus (juvenile diabetes) and type II diabetes, diarrheal diseases, ischemia reperfusion injury, retinopathy such as retinopathy diabetic or hyperbaric oxygen-induced retinopathy, and disease states characterized by increased intraocular pressure or increased secretion of aqueous humor, such as glaucoma, ischemic tissue / organ damage as a result of reperfusion, pressure sores, as a means to promote sleep, for the treatment of demyelinating diseases, e.g. multiple sclerosis, and as neuroprotective agents, e.g. for the treatment of cerebral hemorrhagic stroke and ischemic reperfusion injury .

[0018] The effectiveness of the agent of the present invention in inhibiting inflammatory reactions, for example in inflammatory diseases of the respiratory tract, can be demonstrated in an animal model, for example in a mouse or rat, respiratory tract inflammation or other inflammatory conditions, for example as described by Szarek and et al., J. Immunol. Methods (1997) 202: 49-57; Renzi et al., Am. Rev. Respir. Dis. (1993) 148: 932-939; Tsuyuki et al., J. Clin. Invest., (1995) 96: 2924-2931;

Cernadas et al. (1999) Am. J. Respir. Cell Mol. Biol. 20: 1-8; and Fozarda et al. (2002) European Journal of Pharmacological 438, 183-188.

[0019] The agents of the present invention are also useful as cooperating agents for use in combination with other therapeutic agents such as anti-inflammatory, bronchodilators, antihistamines or cough suppressants, in particular for the treatment of obstructive or inflammatory airways diseases such as those mentioned above, for example as agents that enhance the therapeutic activity of such drugs or as agents that reduce the required dosage, or potential side effects of such drugs. The agent of the present invention may be mixed with another drug substance in a predefined pharmaceutical composition or may be administered separately, before, simultaneously or after the administration of another drug.

[0020] Accordingly, the present invention includes the above-described combination of an agent of the present invention with an anti-inflammatory, bronchodilator, antihistamine or antitussive agent, said agent of the present invention and said drug substance present in the same or different pharmaceutical compositions.

[0021] Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids, such as budesonide, beclometasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate, or the steroids described in WO 02/88167, WO 02/12266, WO 02/100879, WO 02 / 00679 (especially those of examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73, 90, 99 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 glucocorticoid receptor agonists such as those described in 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, WO04 / 18429, WO04 / 19935 and WO04 / 26248; LTB4 agonists such as BIIL 284, CP-195543, DPC11870, LTB4 ethanolamide, LY 293111, LY 255283, CGS025019C, CP-195543, ONO-4057, SB 209247, SC54

53228 and those described in US 5,451,700; LTD4 agonists such as montelukast, pranlukast, zafirlukast, accolate, SR2640, Wy-48,252, ICI 198615, MK-571, LY-171883, Ro 24-5913 and L-648051; PDE4 inhibitors such as cilomilast (Ariflo® GlaxoSmithKline), roflumilast (Taurus Gulden), V-11294A (Napp), BAY 19-8004 (Bayer), SCH-351591 (Schering-Plow), Arofylline (Almirall Prodesfarma), PD189659 / PD168787 (ParkeDavis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SelCID (TM) CC-10004 (Celgene), VM554 / UM565 (Vernalis), T-440 (Tanabe), KW-4490 (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; and A2B adenosine receptor antagonists such as those described in WO 02/42298; and beta-2 adrenergic agonists such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol, phenoterol, procaterol, in particular formoterol, carmoterol and their pharmaceutically acceptable salts, and compounds (in free form, in salt or solvate form) formula I of WO 0075114, preferably the compounds of the examples therein, especially the compound of formula ο

OH and its pharmaceutically acceptable salts, as well as compounds (in free or salt or solvate form) of formula I of WO 04/16601, as well as compounds of 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, WO04 / 33412, WO04 / 37768, WO04 / 37773, WO04 / 37807, WO04 / 39762, WO04 / 39 766, WO04 / 45618 WO 04/46083, WO 04/80964, EP1460064, WO 04/087142, WO

04/089892, EP 01477167, US 2004/0242622, US 2004/0229904, WO 04/108675, WO 04/108676, WO 05/033121, WO 05/040103, WO 05/044787, WO 05/058867, WO 05 / 065650, WO 05/066140 and WO 05/07908.

[0022] Suitable bronchodilators include anti-cholinergic or anti-muscarinic agents, in particular ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi) and glycopyrrolate, as well as those described in 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.

[0023] Suitable drugs with both anti-inflammatory and bronchodilatory effects include beta2 adrenoceptor agonists / muscarinic receptor antagonists, such as those disclosed in US 2004/0167167, US 2004/0242622, US 2005/182092, WO 04/74246 and WO 04 / 74,812.

[0024] Suitable antihistamines include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratadine, desloratadine, diphenhydramine and fexofenadine hydrochloride, acrivastine, astemizole, azelastine, ebastine, epinastine, WO, mefa, tefa / 099807 and WO 04/026841.

[0025] Other useful combinations of agents of the present invention with anti-inflammatory drugs are those with chemokine receptor antagonists, for example CCR-1,

CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, in particular CCR-5 antagonists , such as antagonists from Schering-Plow SC-351125, SCH-55700 and SCH-D, antagonists from Takeda, such as N - [[4 - [[[6,7-dihydro-2- (4-methylphenyl) chloride ) -5H-benzocyclohepten-8-yl] carbonyl] amino] phenyl] methyl] tetrahydro-N, N-dimethyl-2H-pyran-4-ammonium (TAK-770), and CCR-5 antagonists described in US 6,166,037 (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.

[0026] In another aspect, the present invention provides a compound of formula (I) in free form or in pharmaceutically acceptable salt form for the manufacture of a medicament for treating a condition responsive to the activation of the A2A adenosine receptor, particularly inflammatory or obstructive airways diseases.

[0027] The agents of the present invention may be administered by any appropriate route, for example, orally, for example in the form of tablets or capsules; parenterally, for example intravenously; by inhalation, for example in the treatment of inflammatory or obstructive airway diseases; intranasally, for example in the treatment of allergic rhinitis; topically to the skin, for example in the treatment of atopic dermatitis; or rectally, for example in the treatment of inflammatory bowel diseases.

[0028] In a further aspect, the present invention provides a pharmaceutical composition comprising the compounds of general formula (I) in free form or in the form of a pharmaceutically acceptable salt, optionally together with a pharmaceutically acceptable diluent or carrier. The composition may contain an accompanying therapeutic agent such as anti-inflammatory, bronchodilator, antihistamine or antitussive drug as described above. Such compositions can be obtained using conventional diluents or excipients, by methods known in the art of galenical preparations. Thus, oral administration forms may include tablets and capsules. Formulations for topical use may take the form of creams, ointments, gels or transdermal delivery systems, e.g. patches. Inhalable compositions may include aerosols or other sprays, or dry powders.

[0029] If the composition is in the form of an aerosol formulation, it preferably contains, for example, hydrofluoroalkane (HFA) as a propellant, such as HFA134a or

HFA227, or a mixture thereof, and may contain one or more co-solvents known in 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 fillers such as lactose. If the composition is in the form of a powder formulation, it preferably contains, for example, a compound of general formula (I) with a particle diameter of up to 10 microns, optionally together with a diluent or carrier, for example lactose, with the desired particle size distribution and a weakening compound moisture effects, for example magnesium stearate. If the composition is in the form of a nebulization formulation, it preferably contains, for example, a compound of general formula (I) dissolved or suspended in a vehicle containing water, a cosolvent such as ethanol or propylene glycol, and a stabilizer, which may be a surfactant active.

[0030] The invention includes (A) a compound of general formula (I) in inhalable form, n p. in the form of an aerosol composition or other nebulization composition, or in the form of solid particles for inhalation, for example in micronized form; (B) an inhalant drug containing a compound of general formula (I) in inhalable form; (C) a pharmaceutical product comprising a compound of the general formula (I) in inhalable form in association with an inhalation device; and (D) an inhalation device containing a compound of general formula (I) in inhalable form.

[0031] The dosage of the compounds of general formula (I) used in the practice of the present invention will of course depend, for example, on the particular condition being treated, the desired result and the mode of administration. In general, suitable daily doses when administered by inhalation are on the order of 0.005-10 mg, while when administered orally the appropriate daily doses are on the order of 0.05-100 mg.

Preparation of intermediates [0032] The following abbreviations are used: CDI 1,1'-carbonyldiimidazole, DCM dichloromethane, DIPEA diisopropylethylamine, DMAP 4-dimethylaminopyridine, DMF dimethylformamide, DMSO dimethyl sulfoxide, LCMS liquid chromatography with detection, T-mass spectrometry TFA trifluoroacetic acid, THF tetrahydrofuran, Et ethanol, IPA isopropyl alcohol and TLC thin layer chromatography.

Intermediate product

1- (R) -pyrrolidin-3-yl-3- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) urea hydrochloride:

[0033]

A1: (3,4,5,6-Tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -imidazole-1-carboxylic acid:

A suspension containing CDI (2.29 g, 14 mmol) and triethylamine (3.8 mL, 27 mmol) in dry DCM (20 mL) is treated with portions of 3,4,5,6-tetrahydro-2H [1,2 'dihydrochloride ] bipyridinyl-4-ylamine (obtained by the method described in international patent application WO 01/94368) (2.88 g, 13 mmol) for 5 minutes. The reaction mixture is stirred at room temperature for 4.5 hours to give the title compound as a 0.43 M solution in DCM.

A2: (R) -3- [3- (3,4,5,6-tetrahydro-2H [1,2 '] bipyridinyl-4-yl) -ureido] -pyrrolidine-1-carboxylic acid tert-butyl ester trifluoroacetate

To a solution of (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -amide, imidazole-1-carboxylic acid (18 ml of 10 mg / ml solution in DCM) (A1) is added (R) -359 amino-1-N-Boc-pyrrolidine (136 mg, 0.74 mmol) in isopropanol (3 mL). The reaction mixture is stirred at room temperature overnight and then diluted with DCM (25 ml). This mixture is washed with 0.1 M HCl, water, brine, dried (MgSO 4) and concentrated in vacuo. Purification of the crude residue by C18 reverse phase column chromatography eluting with acetonitrile: water: TFA (0.1%) (gradient 0 to 100% acetonitrile) affords the title compound.

A3: 1- (R) -pyrrolidin-3-yl-3- (3,4,5,6-tetrahydro-2H [1,2 '] bipyridinyl-4-yl) urea hydrochloride:

Trifluoroacetate solution of (R) -3- [3- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -ureido] -pyrrolidine-1-carboxylic acid tert-butyl ester (0 , 2 g, 0.51 mmol) in 1.25 M HCl in methanol (10 mL) is stirred at room temperature overnight. The solvent is removed in vacuo to give the title compound.

Intermediate product B

1,3-Di (R) -pyrrolidin-3-yl-urea [0034]

B1: 1,3-Bis - ((R) -1-benzyl-pyrrolidin-3-yl) -urea

A solution containing (R) -1-benzyl-pyrrolidin-3-ylamine (5.0 g, 28.4 mmol) in DCM (10 mL) is treated with CDI (2.3 g, 14.2 mmol) and the reaction mixture is stirred at room temperature for 48 hours. The solvent is removed in vacuo and the residue obtained is dissolved in ethyl acetate. This portion is washed with water followed by brine, dried (MgSO4) and concentrated in vacuo to afford the title compound as a pale orange solid.

B2: 1,3-Di (R) -Pyrrolidin-3-yl-urea

To a solution of 1,3-bis - ((R) -1-benzyl-pyrrolidin-3-yl) -urea (5.34 g, 14.1 mmol) in ethanol (80 ml) under an inert gas-argon atmosphere is added palladium hydroxide on carbon (1.07 g). Argon is bubbled through the reaction mixture and placed under an atmosphere of hydrogen for two days, then the mixture is filtered and the catalyst is washed with ethanol. The organic portions are combined and concentrated in vacuo to give the title compound as a white solid.

Intermediate C (3,4,5,6-Tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) imidazole-1-carboxylic acid amide [0035] Mixed CDI solution (1.1 g, 6.77 mmol ) in DCM (100 ml) is treated with 3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-ylamine (WO 9965895 EP 21973) (1 g, 5.64 mmol in 50 ml DCM ) added dropwise within 30 minutes. The reaction mixture is stirred at room temperature for 15 minutes to give the title compound as a 10 mg / ml solution in DCM. The compound is used in solution in subsequent reactions. This solution consists of imidazole urea (intermediate C) together with various amounts of the corresponding isocyanate and imidazole. This solution is used in the next steps because the imidazole urea intermediate and the isocyanate intermediate are equally suitable as precursors for ureas.

Intermediate product D.

(2S, 3S, 4R, 5R) -5- [2-Amino-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -3,4-dihydroxy-tetrahydrofuran-2-carboxylic acid ethylamide [ 0036]

Step D1: (3aS, 4S, 6R, 6aR) -acetylamide -6- [2-chloro-6- (2,2-diphenylethylamino) -ppurin-9-yl] -2,2-dimethyl-tetrahydrofururo [3 4-d] [1,3] dioxole-4-carboxylic acid

The title compound is obtained by the synthesis of aminopurine-bD-ribofuranuronamide derivatives as anti-inflammatory agents. Di Ayres, Barry Edward; Gregson, Michael; Ewan, George Blanch; Keeling, Suzanne Elaine; Bell, Richard. (Glaxo Group Limited, UK). PCT Int. Appl. (1996), 49 pp. WO 9602553.

Step D2: (2S, 3S, 4R, 5R) -5- [2-chloro-6- (2,2-diphenylethylamino) -purin-9-yl] -3,4-dihydroxy-tetrahydrofuran-2 acid ethylamide -carboxylic acid [0037] (3aS, 4S, 6R, 6aR) acid ethylamide solution -6- [2-chloro-6- (2,2-diphenylethylamino) -ppurin-9-yl] -2,2-dimethyl-tetrahydrofuro [ 3,4-d] [1,3] dioxole-carboxyl (step D1) in TFA / water (2: 1) is stirred at room temperature overnight. The reaction mixture is concentrated in vacuo to afford the title compound.

Intermediate product E

(2S, 3S, 4R, 5R) acid ethylamide trifluoroacetate -5- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -3,4-dihydroxy-tetrahydrofuran-210 carboxylic acid [0038]

Step E1: (2S, 3S, 4R, SR) -5- [6- (2,2-diphenyl-ethylamino) -2 - ((R) 3-BOC-amino-pyrrolidin-1-yl) -purine acid ethylamide -9-yl] -3,4-dihydroxy-tetrahydro-furan-2-carboxylic acid

(2S, 3S, 4R, 5R) -5- [2-chloro-6- (2,2-diphenyl-ethylamino) -ppurin-9-yl] -3,4-dihydroxy-tetrahydrofuran-2-carboxylic acid ethylamide ( Intermediate D) (1 g, 1.91 mmol), (3R) -3- (BOC-amino) -pyrrolidine (1.068 g, 5.74 mmol) and sodium iodide (287 mg, 1.91 mmol) are dissolved in acetonitrile (10 ml) and NMP (0.5 ml). The reaction mixture is heated using microwave radiation at 160 ° C for 30 minutes in a Personal Chemistry Emrys ™ Optimizer microwave reactor. The reaction mixture is concentrated in vacuo and purified by C-18 reverse phase column chromatography eluting with acetonitrile: water (0.1% TFA) (0-100% acetonitrile gradient) to afford the title compound.

[0039] Step E2: (2S, 3S, 4R, 5R) acid ethylamide trifluoroacetate -5- [2 - ((R) -325 amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -3,4-dihydroxytetrahydro-furan-2-carboxylic acid

(2S, 3S, 4R, 5R) -5-[6- (2,2-diphenyl-ethylamino) -2 - ((R) -3-BOCamino-pyrrolidin-1-yl) -purin-9-yl acid ethylamide ] -3,4-dihydroxy-tetrahydrofuran-2-carboxyl (step E1) is dissolved in DCM and TFA and stirred at room temperature overnight. The reaction mixture is concentrated in vacuo to afford the title compound.

Intermediate product F

[4- (2-Amino-ethyl) -imidazol-1-yl] -acetic acid cyclohexyl ester:

[0040] F1: [4- (2-Amino-ethyl) -imidazol-1-yl] -acetic acid methyl ester sulfate:

Solution containing [4- (2-amino-ethyl) -imidazol-1-yl] -acetic acid (prepared according to the Jain, Rahul; Cohen, Louis A. Regiospecific alkylation of histidine and histamine at N-1 procedure. Tetrahedron (1996 ), 52 (15), 5363-70) (7.6 g, 44.8 mmol) in methanol (100 ml) is treated with concentrated sulfuric acid (3 drops) and heated to reflux for 18 hours. Molecular sieves are added to the reaction mixture, followed by heating to reflux for a further 3 days. The mixture is filtered and concentrated in vacuo. The precipitate is taken up in water and basified with pH10 using sodium hydroxide. The solution is extracted with DCM using a liquid-liquid continuous extraction system to give the title product.

F2: [4- (2-Amino-ethyl) -imidazol-1-yl] -acetic acid cyclohexyl ester sulfate:

[4- (2-Amino-ethyl) -imidazol-1-yl] -acetic acid methyl ester sulfate (1 g, 3.6 mmol) is suspended in cyclohexanol (50 mL) and treated with concentrated sulfuric acid (5 drops). The reaction mixture is heated to 110 ° C for 4 hours and concentrated in vacuo. The residue is dissolved in a saturated sodium bicarbonate solution and the mixture is concentrated in vacuo. The resulting solid is triturated with methanol, filtered and the filtrate evaporated in vacuo. The crude solid is dissolved in water, washed with DCM and the aqueous portion is concentrated in vacuo to afford the title product.

Intermediate product G

[(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -2,3-dihydroxy-cyclopentyl] -propionyl-carbamic acid tert-butyl ester:

[0041] G 1: (1S, 4R) -4- (2,6-Dichloro-purin-9-yl) -cyclopent-2-enol

2,6-Dichloropurine (10 g, 52.90 mmol), (1S, 4R) -cis-4-acetoxy-2-cyclopentene-1ol (10 g. 70.40 mmol), tris (dibenzylideneacetone) dipalladium (0) (3.20 g, 3.50 mmol) and polymer supported triphenylphosphine (3 mmol / g, 11.60 g, 35.00 mmol) are placed in an oven-dried flask under an argon atmosphere. Dry deoxygenated THF (80 ml) is added and the reaction mixture is stirred gently for 5 minutes. Triethylamine (20 mL) is added and the reaction mixture is stirred at 50 ° C. LCMS analysis shows the end of the reaction after 1 hour. The reaction mixture is allowed to cool, filtered and the solvent removed in vacuo. The title compound is obtained after purification by Flash column chromatography (silica gel, dichloromethane / methanol 25: 1).1H

NMR (CDCl3, 400 MHz); 8.30 (s, 1H), 6.40 (m, 1H), 5.90 (m, 1H), 5.50 (m, 1H), 4.95 (m, 1H), 3.05 (m , 1H), 2.10 (m, 1H), MS (ES +) m / e 271 (MH)+.

G2: (1S, 4R) -4- (2,6-dichloro-purin-9-yl) -cyclopent-2-enyl-ethyl-carbonyl ester (1S, 4R) -4- (2,6-Dichloro-purine -9-yl) -cyclopent-2-enol (9.5 g, 35.05 mmol) is placed in an oven-dried flask under an argon atmosphere. Dry THF (200 mL) is added 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 rise above 40 ° C and the reaction mixture is stirred at room temperature. LCMS analysis shows the end of the reaction after 1 hour. The solvent is removed in vacuo and the residue is partitioned between dichloromethane (200 ml) and water (200 ml). The organic layer is washed with water (150 ml) and brine (150 ml), dried over MgSO 4, filtered and the solvent removed in vacuo. The title compound is obtained after crystallization from methanol.11 H NMR (CDCl 3, 400 MHz);

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

G3: [(1S, 4R) -4- (2,6-dichloro-purin-9-yl) -cyclopent2-enyl] -propionyl-carbamic acid tert-butyl ester

Carbonic acid (1S, 4R) -4- (2,6-dichloro-purin-9-yl) -cyclopent-2-enyl-ethyl ester (1.00 g, 2.92 mmol), propionylcarbamic acid tert-butyl ester (intermediate W) (0.55 g, 3.21 mmol) and triphenylphosphine (0.115 g, 0.44 mmol) are placed under an inert gas-argon atmosphere. THF (10 ml) is added followed by tris (dibenzylideneacetone) dipalladium (0) (0.13 g, 0.15 mmol). The reaction mixture is stirred at 50 ° for 1 hour. The solvent is removed in vacuo and after purification by silica gel chromatography eluting with ethyl acetate / hexane (1: 4) the title product is obtained. 11 H NMR (CDCl 3, 400 MHz); 8.70 (s, 1H), 6.15 (m, 1H), 5.85 (m, 1H), 5.80 (m, 1H), 5.60 (m, 1H), 3.15 (m , 1H), 2.75 (q, 2H), 2.10 (m, 1H), 1.55 (s, 9H), 1.15 (t, 3H), MS (ES +) m / e 426 (MH+).

G4: [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -2,3-dihydroxy-cyclopentyl] -propionyl-carbamic acid tert-butyl ester:

[(1S, 4R) -4- (2,6-dichloro-purin-9-yl) -cyclopent-2-yl] -propionyl-carbamic acid tert-butyl ester (11.37 g, 26.7 mmol), methanesulfonamide ( 2.54 g, 26.7 mmol) and AD-mix-a (55 g) are placed in a flask with water (100 ml) and t-butanol (100 ml). Osmium tetroxide (4% in water) is added and the reaction mixture is stirred vigorously at room temperature overnight. Sodium sulfite (40 g) is added and the mixture is stirred at room temperature for another hour and then partitioned between ethyl acetate and water. The organic portion is separated, dried (MgSO4) and concentrated in vacuo. The crude product is purified by silica gel chromatography eluting with DCM: methanol (25: 1, going to 10: 1) to afford the title compound.

Intermediate H (3,4,5,6-Tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -amide

4 - [(imidazole-1-carbonyl) -amino] -piperidine-1-carboxylic acid ethyl ester:

[0042]

H1: [1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-ylcarbamoyl) -piperidin-4-yl] -carbamic acid tert-butyl ester:

To a suspension of 4-N-Boc-amino-piperidine (0.396 g, 1.85 mmol) in isopropanol (5 mL) is added (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4 imidazole-1-carboxylic acid -amide (50 mL 10 mg / mL solution in DCM, 1.85 mmol) and the reaction mixture is stirred at room temperature overnight. The solvent is removed in vacuo and the title product is obtained after recrystallization of the solid from methanol.

H2: 4-Amino-piperidine-1-carboxylic acid dihydrochloride (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridin-4-yl) -amide

[1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-ylcarbamoyl) -piperidin-4-yl] -carbamic acid tert-butyl ester (0.45 g, 1.12 mmol ) is treated with 4 M HCl (in dioxane) (2.5 mL) and methanol (1 mL, cosolvent) and the reaction mixture is stirred at room temperature for 1 hour. The solvent is removed in vacuo and the residue obtained is dried in a vacuum oven to afford the title product.

H3: (3,4,5,6-Tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -amide 4 - [(imidazole-1-carbonyl) -amino] -piperidine-1-carboxylic acid:

The title product is obtained in analogy to imidazole-1-carboxylic acid (3,4,5,6-tetrahydro-2H [1,2 '] bipyridin-4-yl) -amide (intermediate A1) to replace dihydrochloride 3,4,5 , 6-tetrahydro-2H- [1,2 '] bipyridinyl-4-ylamine with (3,4,5,6-tetrahydro-2H- [1,2'] bipyridin-4-yl) -amide, 4-aminopiperidine acid -1-carboxyl (intermediate H2).

Intermediate I [0043]

4 - [(Imidazole-1-carbonyl) -amino] -piperidine-1-carboxylic acid 2H- [1,2 '] bipyridinyl-4-yl) -amide (intermediate H) replacing (3,4,5,6-tetrahydro -2H5 [1,2 '] bipyridinyl-4-yl) -amide, imidazole-1-carboxylic acid (3,4,5,6-tetrahydro-2H [1,2'] bipyridinyl-4-yl) -amide 4 - [(imidazole-1-carbonyl) -amino] -piperidine-1-carboxylic.

Intermediate product J.

N - {(1S, 2R, 3S, 4R) -4- [2-Chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,310 dihydroxy-cyclopentyl} -propionamide [0045]

J1: (1S, 4R) -4- (2,6-Dichloro-purin-9-yl) -cyclopent-2-enol

2,6-Dichloropurine (10 g, 52.90 mmol), (1S, 4R) -cis-4-acetoxy-2-cyclopentene-1ol (10 g, 70.40 mmol), tris (dibenzylideneacetone) dipalladium (0) (3.20 g, 3.50 mmol) and polymeric triphenylphosphine (3 mmol / g, 11.60 g, 35.00 mmol) are placed in an oven-dried flask under an argon atmosphere. Dry deoxygenated THF (80 ml) is added and the reaction mixture is stirred gently for 5 minutes. Triethylamine (20 mL) is added and the reaction mixture is stirred at 50 ° C. LCMS analysis shows the end of the reaction after 1 hour. The reaction mixture is allowed to cool, filtered and the solvent removed in vacuo. The title compound is obtained after purification by Flash column chromatography (silica gel, dichloromethane / methanol 25: 1).1H

NMR (CDCl3, 400 MHz); 8.30 (s, 1H), 6.40 (m, 1H), 5.90 (m, 1H), 5.50 (m, 1H), 4.95 (m, 1H), 3.05 (m , 1H), 2.10 (m, 1H), MS (ES +) m / e 271 (MH+).

J2: (1S, 4R) -4- (2,6-dichloro-purin-9-yl) -cyclopent-2-enyl-ethyl-carbonyl 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. Dry THF (200 mL) is added 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 rise above 40 ° C and the reaction mixture is stirred at room temperature. LCMS analysis shows the end of the reaction after 1 hour. The solvent is removed in vacuo and the residue is partitioned between dichloromethane (200 ml) and water (200 ml). The organic layer is washed with water (150 ml) and brine (150 ml), dried over MgSO 4, filtered and the solvent removed in vacuo. The title compound is obtained after crystallization from methanol.11 H NMR (CDCl 3, 400 MHz); 8.20 (s, 1H), 6.45 (m, 1H), 6.25 (m, 1H), 5.75 (m, 1H), 5.70 (m, 1H), 4.25 (q , 2H), 3.20 (m, 1H), 2.05 (m, 1H), 1.35 (t, 3H), MS (ES +) m / e 343 (MH+).

J3: Di-Boc - [(1S, 4R) -4- (2,6-dichloro-purin-9-yl) -cyclopent-2-enyl] -amine

Carbonic acid (1S, 4R) -4- (2,6-dichloro-purin-9-yl) -cyclopent-2-enyl-ethyl ester (2.5 g, 7.29 mmol), di-t-butyl iminodicarboxylate (1.74 g, 8.02 mmol), tris (dibenzylideneacetone) dipalladium (0) (0.33 g, 0.36 mmol) and triphenylphosphine (0.29 g, 1.09 mmol) are placed in a flask dried in furnace in an argon atmosphere. Dry deoxygenated THF (30 mL) is added and the reaction mixture is stirred at room temperature. LCMS analysis shows reaction complete after 3 hours. The solvent is removed in vacuo and the title compound is obtained after purification by flash column chromatography (silica gel, ethyl acetate / isohexane 4: 1) 11 H NMR (CDCl 3, 400 MHz); 8.70 (s, 1H), 6.20 (m, 1H), 5.85 (m, 1H), 5.80 (m, 1H), 5.40 (m, 1H), 3.20 (m , 1H), 2.15 (m, 1H), 1.55 (s, 18H), MS (ES +) m / e 470 (MH+).

J4: (1S, 2R, 3S, 5R) -3- (Di-Boc-Amino) -5- (2,6-dichloro-purin-9-yl) cyclopentane-1,2-diol

The title compound is obtained from di-Boc - [(1S, 4R) -4- (2,6-dichloro-purin-9-yl) cyclopent-2-enyl] -amine using a procedure analogous to that used to prepare (1R, 2S, 3R, 5S) -3- (6 - {[bis- (4-methoxy-phenyl) -methyl] -amino} -2-chloro-9-yl) -5- (di-Boc-amino) -cyclopentane -1,2-diol (intermediate in the process of obtaining intermediate ZA). 11 H NMR (CDCl 3, 400 MHz); 8.35 (s, 1H), 4.80 (m, 1H), 4.70 (m, 1H), 4.50 (m, 1H), 3.85 (m, 1H), 3.75 (m , 1H), 3.10 (m, 1H), 2.75 (m, 1H), 2.55 (m, 1H), 1.55 (s, 18H), MS (ES +) m / e 504 (MH+).

J5: (1S, 2R, 3S, 5R) -3-amino-5- (2,6-dichloro-purin-9-yl) cyclopentane-1,2-diol trifluoroacetate

Solution (1S, 2R, 3S, 5R) -3- (di-Boc-amino) -5- (2,6-dichloro-purin-9-yl) cyclopentane-1,2-diol (0.550 g, 1.09 mmol) in DCM (4 ml) is treated with TFA (2 ml) and stirred at room temperature for 2 hours. The solvent is removed in vacuo to give the title product which is used in the next step without further purification. MS (ES +) m / e 304 (MH+).

J6: N - [(1S, 2R, 3S, 4R) -4- (2,6-Dichloro-purin-9-yl) -2,3-dihydroxycyclopentyl] -propionamide

A solution of 1S, 2R, 3S, 5R) trifluoroacetate -3-amino-5- (2,6-dichloro-purin-9-yl) cyclopentane-1,2-diol (0.304 g, 1.00 mmol) in THF (10 ml) is treated with DIPEA (0.387 g, 3.00 mmol) followed by propionyl chloride (0.093 g, 1.00 mmol). The reaction mixture is stirred 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 (Isolute ™ C18, 0-100% acetonitrile in water 0.1% TFA). MS (ES +) m / e 360 (MH+).

J7: N - {(1S, 2R, 3S, 4R) -4- [2-Chloro-6- (2,2-diphenyl-ethylamino) -ppurin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide

N - [(1S, 2R, 3S, 4R) -4- (2,6-Dichloro-purin-9-yl) -2,3-dihydroxy-cyclopentyl] propionamide (160 mg, 0.44 mmol) is dissolved in THF (5 ml) under argon. Diisopropylamine (69 mg, 0.53 mmol) is added followed by 2,2-diphenylethylamine (96 mg, 0.49 mmol) and the reaction mixture is stirred at 50 ° C. LCMS analysis shows the end of the reaction after 2 hours. The solvent is removed in vacuo and the title compound is obtained after purification by reverse phase column chromatography (Isolute ™ C18, 0-100% acetonitrile in water - 0.1% TFA). 11 H NMR (MeOD, 400 MHz); 8.00 (s, 1H), 7.40-7.15 (m, 10H), 4.75 (m, 1H), 4.60 (m, 1H), 4.50 (m, 1H), 4 , 20 (m, 3H), 3.95 (m, 1H), 2.85 (m, 1H), 2.40 (q, 2H), 2.10 (m, 1H), 1.20 (t, 3H), MS (ES +) m / e 521 (MH+).

[0046] The final compound intermediate intermediate J can also be obtained using the following process:

JJ1: {2-Chloro-9 - [(1R, 4S) -4- (di-Boc-amino) -cyclopent-2-enyl] -9H-purin-6-yl} - (2,2-diphenyl-ethyl) - amine (1S, 2R, 3S, 5R) -3- (di-Boc-amino) -5- (2,6-dichloro-purin-9-yl) -cyclopentane-1,2-diol (13.0 g, 27, 66 mmol) is dissolved in THF (250 mL) under an argon atmosphere. Diisopropylamine (4.28 g, 33.19 mmol) is added followed by 2.2-diphenylethylamine (6.0 g, 30.43 mmol) and the reaction mixture is stirred at 50 ° C. LCMS analysis shows the end of the reaction after 18 hours. The solvent is removed in vacuo and the reaction mixture is partitioned between dichloromethane (250 ml) and 0.1 M HCl (250 ml). The organic layer is washed with water (200 mL) and brine (200 mL), dried over MgSO 4, filtered and the solvent removed in vacuo to afford the title compound.11 H NMR (CDCl 3, 400 MHz); 8.05 (s, 1H), 7.30-7.10 (m, 10H), 6.00 (m, 1H), 5.70 (m, 2H), 5.60 (m, 1H), 5 , 20 (m, 1H), 4.30 (m, 1H), 4.20 (m, 1H), 3.65 (m, 1H), 3.05 (m, 1H), 2.00 (m, 1H), 1.70 (m, 1H), 1.40 (s, 18H), MS (ES +) m / e 631 (MH+).

JJ2: (1R, 2S, 3R, 5S) -3- [2-Chloro-6- (2,2-diphenyl-ethylamino) -ppurin-9-yl] -5- (diBoc-amino) -cyclopentane-1, 2-diol

{2-chloro-9 - [(1R, 4S) -4- (di-Boc-amino) -cyclopent-2-enyl] -9H-purin-6-yl} - (2,2-diphenyl-ethyl) -amine solution (2.9 g, 4.6 mmol) in THF (60 mL) is treated with N-oxide

4-methylmorpholine (1.1 g, 9.3 mmol) and osmium tetroxide (4% solution in water) (6 ml) and the mixture is stirred at room temperature for 48 hours. The solvent is removed under reduced pressure and the residue is purified by silica gel column chromatography eluting with a gradient of methanol: dichloromethane (0: 100 by volume) gradually moving to methanol: dichloromethane (4:96 by volume) to afford the title compound. LCMS (electrospray): m / z [MH+] 665,34

JJ3: (1S, 2R, 3S, 5R) -3-amino-5- [2-chloro-6- (2,2-diphenylethylamino) -ppurin-9-yl] -cyclopentane-1,2-diol trifluoroacetate (1R , 2S, 3R, 5S) -3- [2-Chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -5- (di-Bocamino) -cyclopentane-1,2-diol ( 10.3 g, 15.50 mmol) is dissolved in dichloromethane (50 mL). TFA (25 mL) is added and the reaction mixture is stirred at room temperature. LCMS analysis shows the end of the reaction after 2 hours. The solvent is removed in vacuo to give the title compound.11 H NMR (MeOD, 400 MHz); 7.90 (s, 1H), 7.307.10 (m, 10H), 4.65 (m, 1H), 4.50 (m, 1H), 4.40 (m, 1H), 4.20 (m , 1H), 4.10 (m, 2H), 3.50 (m, 1H), 2.75 (m, 1H), 2.15 (m, 1H), MS (ES +) m / e 465 (MH+).

JJ4: N - {(1S, 2R, 3S, 4R) -4- [2-Chloro-6- (2,2-diphenyl-ethylamino) -ppurin-9-yl] 2,3-dihydroxy-cyclopentyl} -propionamide

(1S, 2R, 3S, 5R) -3-amino-5- [2-chloro-6- (2,2-diphenyl-ethylamino) purin-9-yl] -cyclopentane-1,2-diol trifluoroacetate (9, 50 g, 16.42 mmol) and diisopropylethylamine (6.36 g, 49.27 mmol) are placed in a dry THF flask (150 mL). Propionyl chloride (1.52 g, 16.42 mmol) is added dropwise and the reaction mixture is stirred at room temperature. LCMS analysis shows the end of the reaction after 1 hour. The solvent is removed in vacuo and the residue is partitioned between dichloromethane (250 ml) and water (250 ml). The organic layer is washed with water (200 ml) and brine (200 ml), dried over MgSO 4, filtered and the solvent removed in vacuo. The solid is recrystallized from 1,2-dichloroethane to give the title compound.11 H NMR (MeOD, 400 MHz); 8.00 (s, 1H),

7.40- 7.15 (m, 10H), 4.75 (m, 1H), 4.60 (m, 1H), 4.50 (m, 1H), 4.20 (m, 3H), 3.95 (m, 1H), 2.85 (m, 1H), 2.40 (q, 2H), 2.10 (m, 1H), 1.20 (t, 3H), MS (ES +) m / e 521 (MH+).

Intermediate K {(1S, 2R, 3S, 4R) -4- [2-Chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -amide, cyclobutanecarboxylic acid :

[0047] (1S, 2R, 3S, 5R) -3-amino-5- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -cyclopentane-1,2-diol hydrochloride solution (intermediate JJ3) (100 mg, 0.2 mmol) in dry THF (1 mL) is treated with diisopropylethylamine (0.17 mL, 1 mmol) and cyclobutanecarboxylic acid chloride (0.023 mL, 0.2 mmol) and the mixture is stirred room temperature for 48 hours. The solvent is removed under reduced pressure. The residue is purified by reverse phase chromatography eluting with a gradient of acetonitrile (0.1% TFA): water (0.1% TFA) (0: 100 by volume) gradually switching to acetonitrile (0.1% TFA): water ( 0.1% TFA) (100: 0 by volume) to give the title compound (51 mg). LCMS (electrospray): m / z [MH+] 547,26. 11 H NMR (MeOD, 400 MHz); 8.00 (s, 1H),

7.40- 7.25 (m, 8H), 7.20-7.15 (m, 2H), 4.70 (m, 1H), 4.50 (m, 2H), 4.20 (m, 2H) , 3.95 (m, 1H), 2.85 (m, 1H), 2.30 (m, 2H), 2.20 (m, 2H), 2.05 (m, 2H), 1.90 ( m, 1H)

Intermediate product L.

Acid benzyl ester {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6 (2,2-diphenyl-ethylamino) -purin-9- yl] -2,3-dihydroxy-cyclopentyl} -carbamic [0048]

L1: Preparation of intermediate L1

A cooled (0 ° C) solution of benzyl carbamate (4.0 g, 27 mmol) in THF (100 mL) under inert gas-argon is treated with portions of potassium iodide (3.2 g 35% w / w oil dispersion) , 28 mmol) within 10 minutes. The reaction mixture is allowed to warm to room temperature for 30 minutes, after which benzyl chloroformate (5.0 g, 29 mmol) is added. The reaction mixture is stirred at room temperature for 2 hours and then quenched with water (20 ml). THF is removed in vacuo and the resulting mixture is partitioned between ethyl acetate and 2 M HCl. The organic portion is separated and washed with brine, dried (MgSO4) and concentrated in vacuo.

The oil obtained is purified by silica gel chromatography eluting with 1: 3 ethyl acetate / isohexane to give a product which is recrystallized from DCM / isohexane to give the title product.

Solution containing (1S, 4R) -4- (2,6-dichloro-purin-9-yl) -cyclopent-2-ethyl-ethyl carbonate ester (intermediate J2) (2.0 g, 5.83 mmol), product intermediate L1 (2.2 g, 7.58 mmol) and triphenylphosphine (229 mg, 0.9 mmol) in THF (20 mL) are stirred at room temperature for 30 minutes. Tris (dibenzylideneacetone) dipalladium (0) (238 mg, 0.3 mmol) is added and the resulting mixture is stirred at room temperature for 1.5 hours. The solvent is removed in vacuo and the crude product is purified by silica gel chromatography eluting with methanol / DCM (gradient 0 to 1% methanol) to afford the title compound.

This compound is obtained in a manner analogous to 2-chloro-9 - [(1R, 4S) -4- (diBoc-amino) -cyclopent-2-enyl] -9H-purin-6-yl} - (2,2-diphenyl) -ethyl) -amines (intermediate JJ1) replacing (1S, 2R, 3S, 5R) -3- (di-Boc-amino) -5- (2,6-dichloro-purin-9-yl) cyclopentane-1, 2-diol (intermediate J4) intermediate L2.

L4: Preparation of intermediate L4:

This compound is obtained analogously to (1R, 2S, 3R, 5S) -3- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -5- (di-Boc-amino) - cyclopentane-1,2-diol (intermediate JJ2) replacing {2-chloro-9 - [(1R, 4S) -4- (di-Boc-amino) -cyclopent-2-enyl] -9Hpurin-6-yl} - (2,2-diphenyl-ethyl) -amine intermediate L3.

L5: {(R) -1- [9 - ((1R, 2S, 3R, 4S) -4-benzyloxycarbonylamino-2,3-dihydroxy-cyclopentyl) -6- (2,2-diphenyl-ethylamino) tert-butyl ester 9H-purin-2-yl] -pyrrolidin-3-yl} -carbamic acid

A suspension of intermediate L4 (1.03 g, 1.4 mmol) and (3R) - (+) - 3- (Bocamino) pyrrolidine (1.03 g, 5.5 mmol) in acetonitrile (2 mL) is treated with iodide sodium (approx. 2 mg) and then heated using microwave radiation in a Personal Chemistry Emrys ™ Optimizer microwave reactor at 160 ° C. After 1 hour, the solvent is removed in vacuo and the crude residue is partitioned between DCM and 0.2 M HCl. The organic layer is separated and the aqueous portion is extracted with DCM. The combined organic extracts are washed with saturated sodium bicarbonate solution, water, brine, dried (MgSO 4) and concentrated in vacuo to afford the title compound as a brown oil. MS (ES +) m / e 745 (MH+).

L6: Benzyl ester of {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) 6- (2,2-diphenyl-ethylamino) -purin- 9-yl] -2,3-dihydroxy-cyclopentyl} -carbamic

{(R) -1- [9 - ((1R, 2S, 3R, 4S) -4-benzyloxycarbonylamino-2,3-dihydroxy-cyclopentyl) -6- (2,2-diphenylethylamino) -9Hpurin- acid tert-butyl ester solution 2-yl] -pyrrolidin-3-yl} -carbamate (intermediate L5) (1.24 g, 1.7 mmol) in Me-OH (3 mL) is treated with 4 M HCl in dioxane (5 mL) and stirred at room temperature for 2 hours. The solvent is removed in vacuo and purification is carried out by reverse phase column chromatography (Isolute ™ C18, 0-100% acetonitrile in water - 0.1% HCl). Fractions are collected and MeCN is removed in vacuo. The remaining aqueous portion is basified with saturated sodium bicarbonate solution and extracted with DCM. The combined organic extracts are dried (MgSO4) and concentrated in vacuo to afford the title product. MS (ES +) m / e 649 (MH+).

Intermediate product M.

N - {(3aR, 4S, 6R, 6aS) -6- [2 - ((R) -3-Amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,2-dimethyl-tetrahydro-cyclopenta [1,3] dioxol-4-yl} -propionamide:

[0049]

M1: Benzyl ester of {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H -purin-2-yl] -pyrrolidin-3-yl} -carbamic

A solution of (R) -pyrrolidin-3-ylcarbamic acid benzyl ester hydrochloride (0.88 g, 3.45 mmol) in DCM is converted to the free base using a sodium bicarbonate solution to give (R) pyrrolidin-3-yl acid benzyl ester -carbam (0.487 g, 2.22 mmol). The resulting amine is added to N {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -ppurin-9-yl] -2,320 dihydroxycyclopentyl} -propionamide (product intermediate J) (0.5 g, 0.96 mmol) and TEA (0.224 g, 2.22 mmol), and then dissolved in NMP (7 mL). The reaction mixture is heated using microwave radiation in a microwave reactor

Personal Chemistry Emrys ™ Optimizer at 190 ° C for 1 hour. The resulting mixture is purified by silica gel chromatography eluting with 5% methanol in DCM to afford the title compound.

M2: Benzyl ester of {(R) -1- [9 - ((3aS, 4R, 6S, 6aR) -2,2-dimethyl-6-propionylamino-tetrahydro-cyclopenta [1,3] dioxol-4-yl) -6 - (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -carbamic

Solution of {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-45-propionylamino-cyclopentyl) -benzyl ester -6- (2,2-diphenyl-ethylamino) -9H -purin-2-yl] -pyrrolidin-3-yl} -carbamic acid (0.63 g, 0.89 mmol) in acetone (10 mL) and 2,2-dimethyloxypropane (5 mL) are treated with toluene sulfonic acid (ca, 60 mg ) and then stirred at room temperature overnight. The mixture is basified with ammonium hydroxide and the solvent removed in vacuo. The crude product is partitioned between DCM and water and the organic portion is washed with brine, dried over MgSO 4, filtered and the solvent removed in vacuo to afford the title compound. [MH + 745].

M3: N - {(3aR, 4S, 6R, 6aS) -6- [2 - ((R) -3-Amino-pyrrolidin-1-yl) -6- (2,2-diphenylethylamino) -purin-9- yl] -2,2-dimethyltetrahydro-cyclopenta [1,3] dioxol-4-yl} -propionamide:

To the {(R) -1- [9 - ((3aS, 4R, 6S, 6aR) benzyl ester solution of acid (2,2-dimethyl-6-propionylamino-tetrahydro-cyclopenta [1,3] dioxol-4-yl) -6 - (2,2-diphenyl-ethylamino) 9H-purin-2-yl] -pyrrolidin-3-yl} -carbamic acid (0.598 g, 0.79 mmol) in ethanol (7.5 ml) under an atmosphere of inert gas-argon palladium hydroxide on carbon (10 mg) is added. Argon is bubbled through the reaction mixture and placed under an atmosphere of hydrogen overnight.

The mixture is filtered and purified by silica gel chromatography eluting with 5% methanol in DCM to afford the title compound. [MH + 611].

Intermediate N (R) - [1,3 '] Bipyrrolidinyl [0050] N1: (R) -1'-Benzyl- [1,3'] bipyrrolidinyl:

An ice-cold solution of 2,5-dimethoxytetrahydrofuran (19.11 mL, 0.147 mol) and 6 M sulfuric acid (37.2 mL) in THF (200 mL) is treated dropwise with (R) - (1) -benzyl-377 aminopyrrolidine (10 g, 0.057 mol), 6 M sulfuric acid (37.2 ml) in THF (150 ml) and sodium borohydride pellets (8.62 g, 0.227 mol) simultaneously, ensuring that the temperature remains below 10 ° C. The reaction mixture is allowed to warm to room temperature and water (10 ml) is added to facilitate the dissolution of sodium hydroxide pellets. The reaction mixture is stirred at room temperature for 12 days, then cooled in an ice bath and water (500 ml) added. The solution is basified by the addition of sodium hydroxide pellets (pH <10) and then filtered under vacuum. The filtrate is extracted with diethyl ether and DCM and the organic portions are combined and concentrated in vacuo. The crude residue is sonicated in diethyl ether and filtered under vacuum. The filtrate is evaporated in vacuo again and the obtained crude material is dissolved in MeCN (8 ml) and purified by reverse phase column chromatography (Isolute ™ C18, 0-100% MeCN in water 0.1% TFA) to give the title product.

N2: (R) - [1,3 '] Bipyrrolidinyl:

A solution of (R) -1'-benzyl- [1,3 '] bipyrrolidinyl (0.517 g, 2.24 mmol) in methanol (25 mL) under argon is treated with palladium hydroxide on carbon (0.1 g). The reaction mixture is placed under an atmosphere of hydrogen and stirred at room temperature overnight, then filtered through Celite ™. The filtrate is concentrated in vacuo to afford the title product as a dark orange oil.

Intermediate O (R) -N-Pyrrolidin-3-yl-isonicotinamide:

[0051]

O1: (R) -3 - [(pyridine-4-carbonyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester:

Cooled (0 ° C) mixed solution of (R) -3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 5.36 mmol) and TEA (1.5 mL, 11.0 mmol) in THF (10 ml) is treated dropwise with pyridine-4-carbonyl chloride hydrochloride (0.935 g, 5.25 mmol) over 1 minute. After 5 minutes, the reaction mixture is allowed to warm to room temperature and stirred overnight. The resulting mixture is diluted with ethyl acetate and washed twice with saturated sodium bicarbonate solution and then with brine. The organic portion is dried (MgSO4) and concentrated in vacuo. The crude product is purified by recrystallization from ethyl acetate / isohexane to give the title product. [MH + 292].

O2: (R) -N-Pyrrolidin-3-yl-isonicotinamide:

A solution of (R) - 3 - [(pyridine-4-carbonyl) amino] pyrrolidine-1-carboxylic acid tert-butyl ester (1.38 g, 4.74 mmol) in methanol (6 mL) is treated with 2 M HCl (5 mL) and left at room temperature overnight. The resulting mixture is diluted with methanol and added to 12 ml of Dowex resin (50Wx2-200). After 30 minutes, the resin is washed with water until neutralization and then further eluted with methanol and 2% ammonia. The solvent is removed in vacuo to give the title compound as a crystalline solid. [MH + 192].

Intermediate P (R) -Pyrrolidin-3-ylamide of 5-methyl-isoxazole-3-carboxylic acid:

[0052] TEA (0.42 mL, 3.0 mmol) is added to a cooled (-10 ° C) solution of 5-methyl-isoxazole-3-carbonyl chloride (0.44 g, 2.95 mmol) in THF ( 5 ml). To the resulting cloudy mixture, (R) -3-amino-1-N-pyrrolidine (0.5 g, is added dropwise)

2.68 mmol) in THF (2 mL) and the reaction mixture is allowed to warm to room temperature for 30 minutes. The reaction mixture is allowed to stand at room temperature overnight, then diluted with ethyl acetate (30 ml) and washed with water (2 x 5 ml), brine, dried (MgSO 4) and concentrated in vacuo. The oil obtained is dissolved in methanol (5 ml) and treated dropwise with 6 M HCl (1.15 ml). The reaction mixture is left for four days at room temperature, then concentrated in vacuo and co-evaporated with methanol / ethyl acetate. The crude residue is triturated with ethyl acetate to give the title compound. [MH + 196].

Intermediate product Q

N - {(1S, 2R, 3S, 4R) -4- [2-Chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-hydroxy- acetamide [0053]

Q1: {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -ppurin-9-yl] 2.3-dihydroxy-cyclopentylcarbamoyl} methyl acetic acid ester

(1S, 2R, 3S, SR) -3-amino-5- [2-chloro-6- (2,2-diphenylethylamino) -ppurin-9-yl] -cyclopentane-1,2-diol dihydrochloride suspension (intermediate) JJ3) (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), followed by stirring at room for 30 minutes. The solvent is removed in vacuo and the residue is partitioned between DCM and 0.1 M HCl. The organic portion is separated and washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title product.

Q2: N - {(1S, 2R, 3S, 4R) -4- [2-Chloro-6- (2,2-diphenyl-ethylamino) -ppurin-9-yl] 2.3-dihydroxy-cyclopentyl} -2-hydroxyacetamide :

To the suspension of {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) purin-9-yl] -2,3-dihydroxycyclopentylcarbamoyl} methyl acetic acid ester ( 0.2 g, 0.35 mmol) in methanol (10 mL) potassium carbonate (0.098 g, 0.7 mmol) is added and the reaction mixture is stirred at room temperature for 1 hour. The solvent is removed in vacuo and the residue is partitioned between DCM and water. The organic portion is separated, dried (MgSO4) and concentrated in vacuo to afford the title product.

Intermediate product R

3-Isocyanato-benzenesulfonamide:

[0054] To a vigorously stirred solution of 3-aminobenzenesulfonamide (1 g, 5.8 mmol) in dry dioxane (25 mL), trichloromethyl chloroformate (1.72 g, 8.7 mmol) is added and the reaction mixture is heated to reflux. for 3 hours. The solvent is removed in vacuo to give the title product which is used without further purification.

Intermediate product

4-Isocyanato-benzenesulfonamide:

[0055] This compound is obtained analogously to intermediate R, replacing 3-aminobenzenesulfonamide with 4-aminobenzenesulfonamide.

Intermediate product T.

{(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) purin-9-yl] -2,3-dihydroxy-cyclopentyl} -carbamic acid methyl ester:

[0056] This compound is obtained analogously to {(1S, 2R, 3S, 4R) -4- [2-chloro-6 (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy cyclobutanecarboxylic acid -cyclopentyl} -amide (intermediate K) replacing cyclobutanecarboxylic acid chloride with methyl chloroformate.

Intermediate product UA

(3-Hydroxy-benzyl) -carbamic acid phenyl ester 3-Hydroxybenzylamine (200 mg, 1.62 mmol) and sodium bicarbonate (273 mg, 3.25 mmol) are suspended in a water / DCM mixture (4 mL, 1: 1) and treated with phenyl chloroformate (0.204 mL, 1.62 mmol). The reaction mixture is stirred at room temperature overnight, then diluted with another portion of DCM / water and the organic phase separated. The organic portion is concentrated in vacuo to afford the title compound. (MH + 244)

UB intermediate

Pyridin-3-yl-carbamic acid phenyl ester [0058] Phenyl chloroformate (0.733 mL, 5.84 mmol) is suspended in a pyridine / DCM mixture (3 mL, 2: 1). The solution is stirred at 0 ° C and 3-aminopyridine (500 mg, 5.31 mmol) dissolved in DCM (1 mL) is added dropwise. The reaction mixture is stirred at 0 ° C for 1 hour. The solvent is removed in vacuo and the residue dissolved in ethyl acetate. The resulting organic portion is washed with 0.1 M HCl and then concentrated in vacuo to afford the title compound. (MH + 215).

Intermediates UC-UE [0059] These compounds, namely, • (3-sulfamoyl-phenyl) -carbamic acid phenyl ester (intermediate UC) • (4-sulfamoyl-phenyl) -carbamic acid phenyl ester (intermediate UD) • pyridin-2-ylmethyl-carbamic acid phenyl ester (EU intermediate) is obtained analogously to intermediate UB by replacing 3 aminopyridine with the appropriate amine.

Intermediate product VA

3 - ((R) -3-Pyrrolidin-3-yl-ureido) -benzenesulfonamide

VA1: 3- [3 - ((R) -1-Benzyl-pyrrolidin-3-yl) -ureido] -benzenesulfonamide

A solution of (R) -N-benzyl-3-aminopyrrolidine (14.9 g, 0.084 mol) in methanol (100 ml) is added to a suspension of (3-sulfamoyl-phenyl) -carbamic acid phenyl ester (25 g, 0.084 mol) . The resulting pale orange solution is stirred under gentle reflux (DrySyn @ 80 ° C) for two hours and then allowed to cool to room temperature, after which the volatile components are removed under reduced pressure. The orange syrup is purified and purified by flash column chromatography (silica gel; DCM / methanol 10: 1) to give a beige foam-like solid.

VA2: 3 - ((R) -3-Pyrrolidin-3-yloureido) benzenesulfonamide

Nitrogen is bubbled through a solution of 3- [3 - ((R) -1-benzyl-pyrrolidin-3-yl) -ureido] -benzenesulfonamide (25 g, 0.067 mol) in ethanol (250 ml) and palladium hydroxide (2, 5 g, 20% w / w). Hydrogen is bubbled through the suspension and mixed under positive pressure of hydrogen for 24 hours. After filtration through Celite® (filter material) and removal of the solvent under reduced pressure, the product is obtained in the form of a colorless waxy solid.

Intermediate product VB

1-Pyridin-3-yl-3-pyrrolidin-3-yl-urea [0061] VB1: 1 - ((R) -1-Benzyl-pyrrolidin-3-yl) -3-pyridin-3-yl-urea 10 A solution of pyridin-3-yl-carbamic acid phenyl ester (1.6 g) in dry

THF (20 mL) is treated with (R) -1-benzyl-pyrrolidin-3-ylamine (1.9 g, 1.05 eq) and then heated using microwave irradiation at 110 ° C for 1000 seconds. The solvent is removed in vacuo and after purification of the crude product by silica gel chromatography eluting with DCM followed by ethyl acetate and ethanol the title compound is obtained as an oil. (MH + 297).

VB2: 1-Pyridin-3-yl-3- (R) -pyrrolidin-3-yl-urea

The title compound is obtained from 1 - ((R) -1-benzyl-pyrrolidin-3-yl) -3-pyridin-3-urea analogously to 3 - ((R) -3-pyrrolidin-3-ylureido) -benzenesulfonamide ( step VA1).

VC intermediate

1-Pyridin-3-yl-3- (R) -pyrrolidin-3-yl-urea. This compound is obtained from (4-sulfamoylphenyl) -carbamic acid phenyl ester (intermediate UD) analogous to intermediate VA.

Intermediate product VD

N - {(1S, 2R, 3S, 4R) -4- [6 - ((S) -1-benzyl-2-hydroxy-ethylamino) -2-chloro-purin-9-yl] -2,3-dihydroxy-cyclopentyl } -2-hydroxy-acetamide:

[0063] This compound is obtained analogously to trifluoroacetate (N ((1S, 2R, 3S, 4R) -4- {6- [2,2-bis- (4-hydroxyphenyl) ethylamino] -2 - [(R) -3- (3-pyridin-3-ylureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxyacetamide (example 7 step 3) replacing 4.4 ' - (2-aminoethylidene) bis-phenol (Example 7 step

1) (S) -2-amino-3-phenylpropan-1-ol.

Intermediate product

Propionyl-carbamic acid tert-butyl ester [0064] The title compound is obtained from propylcarbamic acid tert-butyl ester using the procedure described by Ken-Ichi Takana et al. In Chem. Pharm. Bull. 1988, 36, 3125.11 H NMR (CDCl 3, 400 MHz); 7.25 (br s, 1H), 2.75 (q, 2H), 1.50 (s, 9H), 1.15 (t, 3H).

Intermediate product X

Bis- (4-methoxy-phenyl) -methanone oxime 4,4'-Dimethoxybenzophenone (25 g, 103 mmol) is suspended in ethanol (150 ml) and pyridine (30 ml). Hydroxylamine hydrochloride (21.50 g, 310 mmol) is added and the reaction mixture is heated to reflux. TLC analysis shows the end of the reaction after 3 hours. The reaction mixture is allowed to cool and the solvent is removed in vacuo. The residue is partitioned between ethyl acetate (500 ml) and water (500 ml). The organic layer is dried over MgSO4, filtered and the solvent removed in vacuo. The title compound is obtained after crystallization from ethyl acetate / cyclohexane.11 H NMR (CDCl 3, 400 MHz); 7.70 (s, 1H), 7.40 (d ofd, 4H), 6.95 (d, 2H), 6.85 (d, 2H), 3.85 (s, 3H), 3.80 ( s, 3H).

Intermediate Y

C, C-Bis- (4-methoxy-phenyl) -methylamine [0066] Bis- (4-methoxy-phenyl) -methanone oxime (20 g, 77.82 mmol) is suspended in 880 ammonia (450 ml) and ethanol (90 ml). Ammonium acetate (3.00 g, 38.91 mmol) is added followed by portions of zinc dust (25.29 g, 389.10 mmol). After the addition is complete, the reaction mixture is slowly heated to 50 ° C. After cessation of agitation, the reaction mixture is heated to reflux. TLC analysis shows the end of the reaction after 4 hours. The reaction mixture is allowed to cool and ethyl acetate (250 ml) is added. The reaction mixture is filtered through Celite ™ and the phases are separated. The organic layer is dried over MgSO4, filtered and the solvent removed in vacuo to afford the title compound.11 H NMR (CDCl 3, 400 MHz); 7.25 (d, 4H), 6.80 (d, 4H), 5.10 (s, 1H), 3.75 (s, 6H).

Intermediate product

Biphenyl-2-yl-carbamic acid 1- [2 - ((R) -3-amino-pyrrolidin-1-yl) -2-oxo-ethyl] -piperidin-4-yl ester [0067]

Z1: {(R) -1- [2- (4-hydroxy-piperidin-1-yl) -acetyl] pyrrolidin-3-yl} -carbamic acid tert-butyl ester:

To a solution of (R) -pyrrolidin-3-yl-carbamic acid tert-butyl ester (1.5 g, 8.1 mmol) in THF (150 mL) is added TEA (2.3 mL, 16.1 mmol), and then dropwise with chloroacetyl chloride (0.67 mL, 8.5 mmol). The reaction mixture is stirred at room temperature for 2 hours and then treated with TEA (2.3 mL, 16.1 mmol) followed by 4-piperidinol (4.07 g, 40.3 mmol). The reaction mixture is stirred at 50 ° C for 18 hours, the solvent removed in vacuo and the crude residue purified by reverse phase column chromatography (Isolute ™ C 18, 0-100% methanol in water - 0.1% TFA) to give the title product . [MH + 328.19].

Z2: ((R) -1- {2- [4- (biphenyl-2-ylcarbamoyloxy) piperidin-1-yl] -acetyl} -pyrrolidin-3-yl) -carbamic acid tert-butyl ester:

{(R) -1- [2- (4-hydroxy-piperidin-1-yl) -acetyl] pyrrolidin-3-yl} -carbamic acid tert-butyl ester (intermediate Z1) (520 mg, 1.6 mmol ) and 285 biphenylisocyanate (930 mg, 2.65 mmol) are dissolved in NMP (2 mL) and heated to 70 ° C overnight. Purification is performed by reverse phase column chromatography (Isolute ™ C 18, 0-100% methanol in water - 0.1% TFA). The product containing fractions are concentrated in vacuo to remove acetonitrile and the aqueous solution is treated with saturated sodium bicarbonate solution. The product is extracted with DCM and the combined organics are concentrated in vacuo to afford the title product. [MH + 523.24].

Z3: Biphenyl-2-yl-carbamic acid 1- [2 - ((R) -3-amino-pyrrolidin-1-yl) -2-oxo-ethyl] -piperidin-4-yl ester:

Solution of ((R) -1- {2- [4- (biphenyl-2-ylcarbamoyloxy) piperidin-1-yl] -acetyl} -pyrrolidin-3-yl) -carbamic acid tert-butyl ester (intermediate Z2) ( 1.17 g, 2.24 mmol) in DCM (10 mL) is treated with TFA (5 mL) and stirred at room temperature for 2 hours. The solution is basified by the addition of a saturated sodium bicarbonate solution and then extracted with DCM. The combined organic portions are washed with water, brine, dried (MgSO4) and concentrated in vacuo to afford the title product. [MH + 423.20].

Intermediate product ZA

N - [(1S, 2R, 3S, 4R) -4- (6-amino-2-chloro-purin-9-yl) -2,3-dihydroxy-cyclopentyl] -propionamide trifluoroacetate

Bis- (4-methoxy-phenyl) -methyl] - (2-chloro-9H-purin-6-yl) -amine 2,6-Dichloropurine (9.50 g, 50.29 mmol) is dissolved in THF (200 ml) under an argon atmosphere. Diisopropylamine (7.14 g, 55.32 mmol) is added followed by C, C-bis- (4-methoxyphenyl) methylamine (see preparation of intermediates) (12.22 g, 50.29 mmol) and the reaction mixture is stirred at 50 ° C. LCMS analysis shows the end of the reaction after 5 days. The solvent is removed in vacuo and exchanged for methanol (250 ml). The resulting precipitate is filtered off and dried to give the title compound. 11 H NMR (d686

DMSO, 400 MHz); 8.20 (br s, 1H), 7.25 (d, 4H), 6.90 (d, 4H), 3.75 (s, 6H), 3.15 (m, 1H), MS (ES +) m / e 396 (MH+).

(1S, 4R) -4- (6 - {[Bis- (4-methoxy-phenyl) -methyl] amino} -2-chloro-purin-9-yl) cyclopent-2-enol [0069] Bis- (4 -methoxy-phenyl) -methyl] - (2-chloro-9H-purin-6-yl) -amine (13 g,

32.87 mmol) are placed in an oven-dried flask under an argon atmosphere. Dry deoxygenated THF (100 ml) and dry DMSO (2 ml) are added and the suspension is cooled in an ice bath. Sodium hydride 95% (0.79 g, 32.87 mmol) is then slowly added and the solution is stirred at room temperature for 30 minutes. (1S, 4R) -cis-4-Acetoxy-210 cyclopenten-1-ol (4.9 g. 34.5 mmol) and triphenylphosphine (1.36 g, 5.17 mmol) are placed in an oven-dried flask argon atmosphere. Dry deoxygenated THF (50 ml) is added. The resulting solution is added to the anion solution via syringe. Then tetrakis (triphenylphosphine) palladium (0) (2 g, 1.73 mmol) is added and the mixture is stirred at 50 ° C. LCMS analysis shows the end of the reaction after 2 hours. The reaction mixture is allowed to cool and the solvent is removed in vacuo. The residue is taken up in methanol (50 ml) and the resulting precipitate is filtered off and dried to afford the title compound.11 H NMR (CDCl 3, 400 MHz); 9.10 (m, 1H), 8.10 (m, 1H), 7.30 (d, 4H), 6.90 (d, 4H), 6.55 (d, 1H), 6.20 (m , 1H), 5.95 (m, 1H), 5.40 (m, 1H), 5.30 (d, 1H), 4.70 (m, 1H), 3.70 (s, 6H), 2 , 90 (m, 1H), 1.70 (m, IH), MS (ES +) m / e 478 (MH+).

Ester (1S, 4R) -4- (6 - {[bis- (4-methoxy-phenyl) -methyl] -amino} -2-chloro-purin-9-yl) -cyclopent-2-enyl-ethyl carbonic acid [0070 ] (1S, 4R) -4- (6 - {[Bis- (4-methoxy-phenyl) -methyl] -amino} -2-chloro-purin-9-yl) -cyclopent-2-enol (8.00 g, 16.75 mmol) are placed in an oven-dried flask under an argon atmosphere. Dry pyridine (80 ml) is added followed by diisopropylamine (16 ml). A catalytic amount of DMAP is added followed by 3-oxybenzotriazole-1-carboxylic acid ethyl ester (6.94 g, 33.50 mmol, see preparation of intermediates). The reaction mixture is stirred at room temperature. TLC analysis shows the end of the reaction after 18 hours. The solvent is removed in vacuo and the residue is partitioned between ethyl acetate (500 ml) and 2 M HCl (200 ml). The organic layer is washed with water (150 ml) and brine (150 ml), dried over MgSO 4, filtered and the solvent removed in vacuo. The title compound is obtained after purification by Flash column chromatography (silica gel, dichloromethane / methanol 50: 1).11 H NMR (CDCl 3, 400 MHz); 7.80 (s, 1H), 7.25 (dd, 4H), 6.85 (dd, 4H), 6.65 (m, 1H), 6.50 (m, 1H), 6.35 (m , 1H), 6.15 (m, 1H), 5.65 (m, 2H), 4.25 (q, 2H), 3.80 (s, 6H), 3.10 (m, 1H), 1 , 95 (m, 1H), 1.35 (t, 3H).

[Bis- (4-methoxy-phenyl) -methyl] - {2-chloro-9 - [(1R, 4S) -4- (di-Boc-amino) -cyclopent-2-enyl] -9H-purin-6- yl} -amine [0071] (1S, 4R) -4- (6 - {[bis- (4-methoxy-phenyl) -methyl] -amino} -2-chloropurin-9-yl) -cyclopent-2- ester carbonyl enyl ethyl (2.00 g, 3.64 mmol), di-t-butyl iminodicarboxylate (0.87 g, 4.00 mmol) and triphenylphosphine (0.14 g, 0.55 mmol) are placed in oven-dried flask under an argon atmosphere. Dry deoxygenated THF (20 ml) is added followed by tetrakis (triphenylphosphine) palladium (0) (0.21 g, 0.18 mmol) and the mixture is stirred at room temperature. LCMS analysis shows reaction complete after 3 hours. The solvent is removed in vacuo and the title compound is obtained after purification by flash column chromatography (silica gel, isohexane / ethyl acetate 4: 1).11 H NMR (CDCl 3, 400 MHz); 8.20 (s, IH), 7.25 (d, 4H), 6.85 (d, 4H), 6.60 (m, 1H), 6.35 (m, 1H), 6.10 (m , 1H), 5.80 (m, 1H), 5.65 (m, 1H), 5.35 (m, 1H), 3.80 (s, 6H), 3.15 (m, 1H), 2 , 10 (m, 1H), 1.55 (s, 18H).

(1R, 2S, 3R, 5S) -3- (6 - {[Bis- (4-methoxy-phenyl) -methyl] -amino} -2-chloro-purin-9-yl) -5- (di-Boc-amino ) -cyclopentane-1,2-diol [0072] [Bis- (4-methoxy-phenyl) -methyl] - {2-chloro-9 - [(R, 4S) -4- (di-Boc-amino) cyclopent -2-enyl] -9H-purin-6-yl} -amine (0.75 g, 1.11 mmol) is dissolved in THF (15 mL). N-methylmorpholine N-oxide (0.26 g, 2.22 mmol) is added followed by osmium tetroxide (1.5 mL, 4% in water). The reaction mixture is stirred at room temperature. LCMS analysis shows the end of the reaction after 18 hours. The solvent is removed in vacuo and the title compound is obtained after purification by Flash column chromatography (silica gel, dichloromethane / methanol 50: 1).11 H NMR (CDCl 3, 400 MHz); 7.75 (s, 1H), 7.25 (m, 4H), 6.85 (m, 4H), 6.60 (m, 2H), 5.70 (m, 1H), 4.70 (m , 2H), 4.60 (m, 1H), 4.45 (m, 1H), 3.80 (s, 6H), 3.70 (m, 1H), 3.40 (m, 1H), 3 , 25 (m, 1H), 2.65 (m, 1H), 2.50 (m, 1H), 1.55 (s, 18H).

(1S, 2R, 3S, SR) -3-amino-5- (6-amino-2-chloro-purin-9-yl) cyclopentane-1,2-diol trifluoroacetate (1R, 2S, 3R, 5S ) -3- (6 - {[Bis- (4-methoxy-phenyl) -methyl] -amino} -2-chloro-9-yl) -5- (di-Boc-amino) -cyclopentane-1,2- diol (600 mg, 0.84 mmol) is dissolved in dichloromethane (4 mL). TFA (2 mL) is added and the reaction mixture is stirred at room temperature. LCMS analysis shows the end of the reaction after 18 hours. The solvent is removed in vacuo and the title compound is obtained after purification by reverse phase column chromatography (Isolute ™ C 18, 0-100% acetonitrile in water - 0.1% TFA). 11 H NMR (MeOD, 400 MHz); 8.10 (s, 1H), 4.80 (m, 1H), 4.60 (m, 1H), 4.30 (m, 1H), 3.60 (m, 1H), 2.85 (m , 1H), 2.30 (m, 1H). MS (ES +) m / e 285 (MH+).

N - [(1S, 2R, 3S, 4R) -4- (6-amino-2-chloro-purin-9-yl) -2,3-dihydroxy-cyclopentyl] -propionamide trifluoroacetate [0074] Trifluoroacetate (1S, 2R, 3S , SR) -3-amino-5- (6-amino-2-chloro-purin-9-yl) cyclopentane-1,2-diol (intermediate to prepare the compound of Example 1) (20 mg, 39 mmol) and diisopropylethylamine (25 mg, 190 mmol) is placed in a dry THF flask (1 ml). Propionyl chloride (3.6 mg, 39 mmol) is added and the reaction mixture is stirred at room temperature. LCMS analysis shows reaction complete after 3 hours. The solvent is removed in vacuo to give the title compound which can be purified by reverse phase column chromatography (Isolute ™ C18, 0-100% acetonitrile in water - 0.1% TFA)11 H NMR (MeOD, 400 MHz); 8.10 (s, 1H), 4.75 (m, 1H), 4.60 (m, 1H), 4.20 (m, 1H), 4.00 (m, 1H), 3.75 (m , 1H), 3.25 (m,

1H), 2.85 (m, 1H), 2.40 (q, 2H), 2.10 (m, 1H), 1.20 (t, 3H), MS (ES +) m / e 341 (MH+.

Intermediate product ZB

Pyridin-3-yl-carbamic acid phenyl ester:

[0075] A solution of pyridine (2 ml) in DCM (10 ml) is treated with phenyl chloroformate (1.83 g, 11.7 mmol). To the resulting solution, 3-aminopyridine (1.0 g,

10.6 mmol) in DCM (8 ml), which causes the solution to heat automatically by 20 ° C. The reaction mixture is stirred at room temperature for 2 hours and then concentrated in vacuo. The residue is partitioned between ethyl acetate and water and the organic portion is separated. The resulting organic portion is washed with water, saturated sodium bicarbonate solution, dried (MgSO4) and concentrated in vacuo to afford the title compound as a white solid. (MH + 215.13)

Intermediate product ZC

Pyridin-2-ylmethyl-carbamic acid phenyl ester [0076] The title compound is obtained analogously to pyridin-3-yl-carbamic acid phenyl ester, replacing C-pyridin-2-yl-methylamine with 3-aminopyridine.

Intermediate product ZD

(3-Hydroxy-benzyl) -carbamic acid phenyl ester [0077] The title compound is obtained analogously to pyridin-3-yl-carbamic acid phenyl ester, replacing 3-aminomethyl-phenol with 3-aminopyridine.

ZE intermediate

(4-Sulfamoyl-phenyl) -carbamic acid phenyl ester [0078] The title compound is obtained analogously to pyridin-3-yl-carbamic acid phenyl ester, replacing 4-aminobenzenesulfonamide with 3-aminopyridine.

ZF intermediate

(3-Sulfamoyl-phenyl) -carbamic acid phenyl ester [0079] The title compound is obtained analogously to pyridin-3-yl-carbamic acid phenyl ester, replacing 3-aminobenzenesulfonamide with 3-aminopyridine.

Intermediate product ZG

N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-Amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxy-propionamide [0080]

ZG1: 3-tert-Butoxy-N - [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -2,3-dihydroxy-cyclopentyl] -propionamide

The title compound is obtained as described for (R) -2-benzyloxy-N [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -2,3-dihydroxy-cyclopentyl ] -propionamide (example 181, step 1), replacing (R) -2-benzyloxy-propionic acid with 3-tert-butoxypropionic acid.

ZG2: 3-tert-Butoxy-N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) purin-9-yl] -2,3- dihydroxy-cyclopentyl} -propionamide

The title compound is obtained analogously to N - {(1S, 2R, 3S, 4R) -4- [2-chloro6- (2,2-diphenyl-ethylamino) -ppurin-9-yl] -2,3-dihydroxy-cyclopentyl } -propionamide (intermediate J7), replacing 3-tert-butoxy-N - [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin9-yl) -2,3-dihydroxy-cyclopentyl ] -propionamide (intermediate ZG1) with N [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -2,3-dihydroxy-cyclopentyl] propionamide.

ZG3: {(R) -1- [9 - [(1R, 2S, 3R, 4S) -4- (3-tert-butoxypropionylamino) -2,3-dihydroxy-cyclopentyl] -6- acid tert-butyl ester 2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -carbamic acid

The title compound is obtained analogously to 5 {(R) -1- [9 - [(1R, 2S, 3R, 4S) -4 - ((R) -2-benzyloxy-propionylamino) -2,3 tert-butyl ester -dihydroxycyclopentyl] -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -carbamic (example 181, step 3), replacing 3-tert-butoxy-N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy- cyclopentyl} propionamide (intermediate ZG2) (R) -2-benzyloxy-N - {(1S, 2R, 35.4R) -4- [2-chloro-610 (2,2-diphenyl-ethylamino) -purin-9 -yl] -2,3-dihydroxy-cyclopentyl} -propionamide (example 181, step 2).

ZG4: N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-Amino-pyrrolidin-1-yl) -6- (2,2-diphenylethylamino) -purin-9- yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxy-propionamide

The title compound is obtained analogously to (R) -N - {(1S, 2R, 3S, 4R) -4- [215 ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2- diphenyl-ethylamino) -ppurin-9-yl] -2,3-dihydroxycyclopentyl} -2-benzyloxypropionamide (example 181, step 4), replacing {(R) -1- [9 - [(1R, 2S, 3R, 4S) -4- (3-tert-butoxy-propionylamino) -2,3-dihydroxy-cyclopentyl] -6- (2,2-acid tert-butyl ester) -diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -carbamic acid (intermediate ZG3) with {(R) -1- [920 [(1R, 2S, 3R, 4S] tert-butyl ester ) -4 - ((R) -2-benzyloxy-propionylamino) -2,3-dihydroxy-cyclopentyl] -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl } carbamic (example 181, step 3).

Intermediate product ZH

N - ((1S, 2R, 3S, 4R) -4- {2-S ((R) -3-Amino-pyrrolidin-1-yl) -6- [2,2-bis- (4-hydroxy-phenyl)) -ethylamino] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -3-hydroxy-propionamide [0081] The title compound is obtained analogously to N - {(1S, 2R, 3S, 4R) -4- [ 2 ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -3-hydroxy-propionamide (product intermediate ZG), replacing 4,4 '- (2-aminoethylidene) bisphenol (obtained as described by Schelkun, RM et al.

Bioorg. Med. Chem. Lett. (1999), 9 (16), pp. 2447-2452) with 2,2-diphenyl-ethylamine.

Intermediate product ZI

2-Amino-1,1-bis- (4-chloro-phenyl) -ethanol [0082] The title compound is obtained by combining 4,4'-dichlorobenzophenone (5 g, 20 mmol) and zinc iodide (480 mg, 1.49 mmol) in DCM (100 ml). Trimethylsilyl cyanide (2.17 g, 21.9 mmol) is added and the reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is washed with water (100 ml) and dried with magnesium sulfate, then filtered and the solvent is removed under reduced pressure. The residue is redissolved in dry THF (40 ml), 1.0 M borate in THF (40 ml) is added and the reaction mixture is stirred under reflux for 24 hours. After cooling, the volatile components are removed under reduced pressure and the residue is taken up in methanol (100 ml). Concentrated hydrochloric acid is added and the reaction mixture is refluxed for a further 2 hours, then the volatile components are again removed under reduced pressure to give the title compound as the hydrochloride salt.

Intermediate product ZJ

Acetic acid [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -2,3-dihydroxy-cyclopentylcarbamoyl] methyl ester [0083] The title compound is obtained analogously to the product intermediate J6, from intermediate J5, replacing propionyl chloride with acetoxyacetyl chloride.

ZK intermediate product

Ester ((1S, 2R, 3S, 4R) -4- {6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -2-chloropurin-9-yl} -2,3-dihydroxy- acetic acid cyclopentylcarbamoyl) methyl [0084] Acetic acid [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -2,3-dihydroxycyclopentylcarbamoyl] methyl intermediate ZJ; 1 eq.) and 4,4 '- (2-aminoethylidene) bisphenol (1.1 eq .; obtained as described by Schelkun, RM et al. Bioorg. Med. Chem. Chem. Lett. (1999), 9 (16), p. 2447-2452) are combined in dry THF and treated with DIPEA (1.2 equiv) and stirred at 50 ° C overnight. The reaction mixture is diluted with ethyl acetate and washed successively with water (x2) and brine, then dried over magnesium sulfate, filtered and the volatiles removed under reduced pressure to afford the title compound.

Intermediate product ZL

Ester ((1S, 2R, 3S, 4R) -4- {6- [2,2-bis- (4-chloro-phenyl) -2-hydroxy-ethylamino] -2-chloro-purin-9-yl} -2, Acetic acid 3-dihydroxycyclopentylcarbamoyl) methyl [0085] The title compound is obtained analogously to the ester ((1S, 2R, 3S, 4R) -4 {6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -2-chloro-purin-9-yl} -2,3-dihydroxycyclopentylcarbamoyl) methyl acetic acid (intermediate ZK), replacing

2-amino-1,1-bis- (4-chloro-phenyl) -ethanol (intermediate ZI) 4,4 '- (2-aminoethylidene) bis-phenol.

Intermediate product ZM

Ester {(1S, 2R, 3S, 4R) -4- [2-chloro-6 - ((S) -1-hydroxymethyl-2-phenylethylamino) -ppurin-9-yl] -2,3-dihydroxy-cyclopentylcarbamoyl} -methyl acetic acid [0086] The title compound is obtained by combining [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -2,3-dihydroxy-cyclopentyl-carbamoyl] -methyl ester acetic acid (1 eq) and (S) -2-amino-3-phenyl-propan-1-ol (1 eq) in dichloromethane with triethylamine (1.1 eq) and stirring overnight. The reaction mixture is diluted with dichloromethane and washed successively with 0.1 M hydrochloric acid, water and brine, and then dried over magnesium sulfate. After filtration and removal of volatile components under reduced pressure, the title compound is obtained.

Intermediate product ZN

Ester ((1S, 2R, 3S, 4R) -4- {2-chloro-6 - [(S) -1-hydroxymethyl-2- (4-hydroxyphenyl) ethylamino] pipin-9-yl} -2, Acetic acid 3-dihydroxy-cyclopentylcarbamoyl) methyl [0087] The title compound is obtained analogously to the {(1S, 2R, 3S, 4R) -4 [2-chloro-6 - ((S) -1-hydroxymethyl-2- ester phenyl-ethylamino) -ppurin-9-yl] -2,3-dihydroxy-cyclopentylcarbamoyl} -methyl acetic acid (intermediate ZM), replacing

4 - ((S) 2-amino-3-hydroxy-propyl) -phenol (S) -2-amino-3-phenyl-propan-1-ol.

ZO intermediate product

N - ((1S, 2R, 3S, 4R) -4- {2 - ((R) -3-Amino-pyrrolidin-1-yl) -6- [2,2-bis- (4-chlorophenyl) -2 -hydroxy-ethylamino] -ppurin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxyacetamide [0088]

ZO1: Ester {(1S, 2R, 3S, 4R) -4- [6- [2,2-bis- (4-chloro-phenyl) -2-hydroxyethylamino] -2 - ((R) -3-tert- acetic acid butoxycarbonylamino-pyrrolidin-1-yl) -ppurin-9-yl] -2,3-dihydroxy-cyclopentylcarbamoyl} methyl

Ester suspension ((1S, 2R, 3S, 4R) -4- {6- [2,2-bis- (4-chloro-phenyl) -2-hydroxyethylamino] -2-chloro-purin-9-yl} -2 , 3-dihydroxy-cyclopentylcarbamoyl) -methyl acetic acid (intermediate ZL; 1 eq.) And (3R) - (+) - 3- (Boc-amino) pyrrolidine (4 eq.) In acetonitrile is treated with a catalytic amount of sodium iodide and then heated using microwave radiation in a Personal Chemistry microwave reactor

Emrys ™ Optimizer at 160 ° C. After 1 hour, it removes the solvent in vacuo; purification by column chromatography / crystallization gives the title compound.

ZO2: N - ((1S, 2R, 3S, 4R) -4- {2 - ((R) -3-Amino-pyrrolidin-1-yl) -6- [2,2-bis- (4-chlorophenyl) -2 -hydroxy-ethylamino] -ppurin-9-yl} -2,3-dihydroxy-cyclopentyl) -hydroxyacetamide

{(1S, 2R, 3S, 4R) ester solution -4- [6- [2,2-bis- (4-chloro-phenyl) -2-hydroxyethylamino] -2 - ((R) -3-tert-butoxycarbonylamino pyrrolidin-1-yl) -ppurin-9-yl] -2,3-dihydroxy-cyclopentylcarbamoyl} -methyl acetic acid (intermediate ZO1) in methanol (~ 0.5 M) is treated with the same volume of 4 M HCl in dioxane and stirred at room temperature for 2 hours. The solvent is removed in vacuo and purification is carried out by column chromatography / crystallization to afford the title compound.

Intermediate product ZP

N - {(1S, 2R, 3S, 4R) -4- [2- (Amino-pyrazol-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3 -dihydroxy-cyclopentyl} -2-hydroxy-acetamide [0089]

ZP1: N - {(1S, 2R, 3S, 4R) -4- [6- (2,2-Diphenyl-ethylamino) -2-hydrazine-purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2- hydroxy-acetamide

The title compound is obtained analogously to N - [(1S, 2R, 3S, 4R) -4- (6 - {[bis- (420 methoxy-phenyl) -methyl] -amino} -2-hydrazine-purin-9-yl ) -2,3-dihydroxycyclopentyl] propionamide (example 168, step 2), replacing the {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -ppurin-9-yl] -2,3-dihydroxycyclopentylcarbamoyl} methyl acetic acid ester (intermediate) Q1) N [(1S, 2R, 3S, 4R) -4- (6 - {[bis- (4-methoxy-phenyl) -methyl] -amino} -2-chloro-purin-9-yl) -2,325 dihydroxy -cyclopentyl] -propionamide (example 168, step 1).

ZP2: N - {(1S, 2R, 3S, 4R) -4- [6- (2,2-Diphenyl-ethylamino) -2- (4-nitro-pyrazol-1-yl) purin-9-yl] - 2,3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide

The title compound is obtained in a manner analogous to 1- [6 - {[bis- (4-methoxy-phenyl) -methyl] -amino} -9 - ethyl acid ((1R, 2S, 3R, 4S) -2,3- dihydroxy-45 propionylamino-cyclopentyl) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic acid (example 168, step 3), in the N - {reaction (1S, 2R, 3S, 4R) -4- [ 6- (2,2-diphenyl-ethylamino) -2-hydrazine-purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide (intermediate ZP1) and sodium nitromalonaldehyde (prepared as described by Fanta PE Org. Syntheses, Coll. vol. 4 (1963), pp. 844-845).

ZP3: N - {(1S, 2R, 3S, 4R) -4- [2- (4-Amino-pyrazol-1-yl) -6- (2,2-diphenylethylamino) -purin-9-yl] -2 3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide

The title compound is obtained by dissolving N - {(1S, 2R, 3S, 4R) -4- [6- (2,2-diphenyl-ethylamino) -2- (4-nitro-pyrazol-1-yl) -purin-9-yl ] -2,3-dihydroxy-cyclopentyl} 2-hydroxy-acetamide (intermediate ZP2) in methanol (~ 1.0 M) by adding the mixture

2: 1 weight activated carbon and iron chloride and excess hydrazine monohydrate and by stirring the resulting mixture at 65 ° C for four hours. After filtration through Celite ™, removal of volatile components under reduced pressure and purification by column chromatography / crystallization, the title compound is obtained.

ZQ intermediate

N - ((1S, 2R, 3S, 4R) -4- {2- (4-Amino-pyrazol-1-yl) -6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -purin -9-yl} -2,3-dihydroxycyclopentyl) -2-hydroxyacetamide [0090] The title compound is obtained analogously to N - {(1S, 2R, 3S, 4R) -4- [2 (4-amino-pyrazole) -1-yl) -6- (2,2-diphenylethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -2-hydroxyacetamide (intermediate ZP), replacing the ester ((1S, 2R, 3S, 4R) -4- {6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -2-chloro-purin-9-yl} -2,3-dihydroxy -cyclopentylcarbamoyl) methyl acetic acid (intermediate ZK) with ester {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -ppurin-9-yl] - 2,3-dihydroxy-cyclopentylcarbamoyl} -methyl acetic acid (intermediate Q1).

Intermediate product ZR

N - {(1S, 2R, 3S, 4R) -4- [2- (4-Amino-pyrazol-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2 , 3-dihydroxy-cyclopentyl} -propionamide [0091] The title compound is obtained analogously to N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-pyrazol-1-yl) -6- ( 2,2-diphenylethylamino) -ppurin-9-yl] -2,3-dihydroxycyclopentyl} -2-hydroxyacetamide (intermediate ZP), replacing N {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (product intermediate J) with {(1S, 2R, 3S, 4R) -4- [2-chloro-6 (2,2-diphenyl-ethylamino) -ppurin-9-yl] -2,3-dihydroxy-cyclopentylcarbamoyl} methyl ester acetic (intermediate Q1).

Intermediate product ZS

1- [9 - [(1R, 2S, 3R, 4S) -2,3-dihydroxy-4- (2-hydroxyacetylamino) -cyclopentyl] -6- (2,2-diphenyl-ethylamino) -9H acid methyl ester -purin-2-yl] -1H-pyrazole-4-carboxylic acid [0092] The title compound is prepared in a manner analogous to 1- [6 - {[bis- (4-methoxy-phenyl) -methyl] -amino} -9-ethyl acid ester - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -9H-purin-2-yl] -1H-pyrazole-420 carboxyl (example 168, step 3), replacing N - {(1S, 2R, 3S, 4R) -4- [6- (2,2-diphenylethylamino) -2-hydrazine-purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-hydroxyacetamide (intermediate ZP1) N - [(1S, 2R, 3S, 4R) -4- (6 - {[bis- (4-methoxy-phenyl) methyl] -amino} -2-hydrazine-purin-9-yl) -2,3-dihydroxy-cyclopentyl] -propionamide (example 168, step 2).

Intermediate ZT

N - {(1S, 2R, 3S, 4R) -4- [2- (4-Amino-pyrazol-1-yl) -6 - ((S) -1-hydroxymethyl-2-phenyl-ethylamino) -purin-9- yl] -2,3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide [0093] The title compound is obtained analogously to N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-pyrazol- 1-yl) -6- (2,2-diphenylethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide (intermediate ZP), replacing the ester {(1S, 2R, 3S, 4R) -4- [2-chloro-6 - ((S) -1-hydroxymethyl-2-phenyl-ethylamino) -purin-9-yl] 2,3-dihydroxy- cyclopentylcarbamoyl} methyl acetic acid (intermediate ZM) with ester {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -ppurin-9-yl] -2 , 3-hydroxy-cyclopentylcarbamoyl} -methyl acetic acid (intermediate Q1).

Intermediate product ZU

N - {(1S, 2R, 3S, 4R) -4- [2- (4-Amino-imidazol-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2, 3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide [0094]

ZU1: N - {(1S, 2R, 3S, 4R) -4- [6- (2,2-Diphenyl-ethylamino) -2- (4-nitro-imidazol-115-yl) -purin-9-yl] - 2,3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide

The title compound is obtained by dissolving {(1S, 2R, 3S, 4R) -4- [2-chloro6- (2,2-diphenyl-ethylamino) -ppurin-9-yl] -2,3-dihydroxy-cyclopentylcarbamoyl} methyl ester acetic acid (intermediate Q1) in N-methyl-2-pyrrolidinone, followed by the addition of potassium carbonate (5 eq) and 4-nitro-1H-imidazole (10 eq). The mixture is heated by microwave irradiation to 150 ° C for two hours, then diluted with ethyl acetate and washed successively with water (x2) and brine, then dried with magnesium sulfate. After filtration, removal of volatile components under reduced pressure and purification by Flash column chromatography / crystallization, the title compound is obtained.

ZU2: N - {(1S, 2R, 3S, 4R) -4- [2- (4-Amino-imidazol-1-yl) -6- (2,2-diphenylethylamino) -purin-9-yl] -2 3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide

The title compound is obtained analogously to N - {(1S, 2R, 35.4R) -4- [2- (4 amino-pyrazol-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9- yl] -2,3-dihydroxycyclopentyl} -2-hydroxyacetamide (intermediate ZP3), replacing N {(1S, 2R, 3S, 4R) -4- [6- (2,2-diphenyl-ethylamino) -2- (4-nitro-imidazol-1-yl) -purin-9-yl] 2, 3-dihydroxy-cyclopentyl} -2-hydroxyacetamide (intermediate ZU1) N {(1S, 2R, 3S, 4R) -4- [6- (2,2-diphenyl-ethylamino) -2- (4-nitro-pyrazole -1-yl) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide (intermediate ZP2).

Intermediate product ZV

N - ((1S, 2R, 3S, 4R) -4- {2- (4-Amino-imidazol-1-yl) -6- [2,2-bis- (4-hydroxyphenyl) ethylamino] -puryn- 9-yl} -2,3-dihydroxycyclopentyl) -2-hydroxy-acetamide [0095] The title compound is obtained analogously to N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-imidazole 1-yl) -6- (2,2-diphenylethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -2-hydroxyacetamide (intermediate ZU) replacing the ester ((1S, 2R, 3S, 4R) -4- {6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -2-chloro-purin-9-yl} -2,3-dihydroxy-cyclopentylcarbamoyl) -acetic acid methyl (intermediate) ZK) ester {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -ppurin-9-yl] -2,3-dihydroxy-cyclopentylcarbamoyl} methyl acetic acid (intermediate product Q1) in step ZU1.

Intermediate product ZW

N - {(1S, 2R, 3S, 4R) -4- [2- (3-Amino- [1,2,4] triazol-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9 -yl] -2,3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide [0096] The title compound is obtained analogously to N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-imidazole -1-yl) -6- (2,2-diphenylethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -2-hydroxyacetamide (intermediate ZU) from ester {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -ppurin-9-yl] -2,3-dihydroxy-100 cyclopentylcarbamoyl} -methyl (intermediate) Q1) replacing 3-nitro-1H [1,2,4] triazole with 4-nitro-1H-imidazole in step ZU1.

ZX intermediate

N - ((1S, 2R, 3S, 4R) -4- {2- (3-Amino- [1,2,4] triazol-1-yl) -6- [2,2-bis- (4-hydroxyphenyl ) -ethylamino] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide [0097] The title compound is obtained analogously to N - {(1S, 2R, 3S, 4R) -4- [2- (4-Amino-imidazol-1-yl) -6- (2,2-diphenylethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -2-hydroxyacetamide (intermediate ZU) replacing the ester ((1S, 2R, 3S, 4R) -4- {6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -2-chloro-purin-9-yl} -2,3-dihydroxy-cyclopentylcarbamoyl ) acetic acid methyl (intermediate ZK) with ester {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -ppurin-9-yl] -2, Acetic acid 3-hydroxy-cyclopentylcarbamoyl} -methyl acid (intermediate Q1) and 3-nitro-1H- [1,2,4] triazole with 4-nitro-1H-imidazole in step ZU1.

ZY intermediate

(2S, 3S, 4R, 5R) -5- [2-chloro-6- (2,2-diphenyl-ethylamino) -ppurin-9-yl] -3,4-dihydroxy-tetrahydrofuran-2-carboxylic acid ethylamide [ The title compound is obtained by the method described in WO 9602553. Example 1

N - {trifluoroacetate (1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl ] -2,3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide Step 1: 2-benzyloxy-N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} - acetamide [0099] The title compound is obtained analogously to N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3 dihydroxy-cyclopentyl} propionamide (intermediate J) replacing propionyl chloride with benzyloxyacetyl chloride.

101

Step 2: N - {(1S, 2R, 3S, 4R) Trifluoroacetate -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6 (2,2-diphenyl-ethylamino) -purine -9-yl] -2,3-dihydroxy-cyclopentyl} -2-benzyloxyacetamide [0100] 2-benzyloxy-N - {(1S, 2R, 3S, 4R) solution -4- [2-chloro-6- (2 , 2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -acetamide (80 mg, 0.13 mmol) in NMP: MeCN (1 ml of a 1: 1 mixture) is treated with sodium iodide ( 6 mg, 0.04 mmol) followed by (3R) -3-aminopyrrolidine (34 mg, 0.4 mmol). The reaction mixture is heated using microwave radiation in a Personal Chemistry Emrys ™ Optimizer microwave reactor at 200 ° C. LCMS analysis shows the end of the reaction after 30 minutes. The title compound is obtained after purification by reverse phase column chromatography (Isolute ™ C 18, 0-100% acetonitrile in water 0.1% TFA).

Step 3: N - {(1S, 2R, 3S, 4R) Trifluoroacetate -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6 (2,2-diphenyl-ethylamino) -purine -9-yl] -2,3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide [0101] N - {Trifluoroacetate solution (1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-benzyloxy-acetamide (0.022 g, 0.03 mmol) in ethanol (2 ml) under argon is treated with palladium hydroxide on carbon (0.05 g, 20% w / w carbon). The reaction mixture is placed under an atmosphere of hydrogen and stirred at room temperature for 30 hours, then filtered through Celite ™. The filtrate is concentrated in vacuo and the crude material is purified by reverse phase column chromatography (Isolute ™ C 18, 0-100% acetonitrile in water - 0.1% TFA) to afford the title product. (MH + 573.4)

Example 2

102 [0102] N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-Diphenyl-ethylamino) -2 - {(R) -3- [3- (3-hydroxy-benzyl) -ureido ] -pyrrolidin-1-yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -2-hydroxy-acetamide

To a mixed solution of N - {trifluoroacetate (1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purine -9-yl] -2,3-dihydroxy-cyclopentyl} 2-hydroxy-acetamide (example 1) (1.1 g, 2 mmol) in NMP (2 ml) and methanol (10 ml) phenyl chloroformate (dropwise) 0.47 g, 3 mmol). The reaction mixture is stirred at room temperature for 3 hours and then treated with 3-hydroxybenzylamine (0.55 g, 4.45 mmol) and stirred for a further 2 hours at 80 ° C. Purification of the product by C-18 reverse phase column chromatography eluting with acetonitrile: water: TFA (0.1%) (gradient 0 to 100% acetonitrile) affords the title compound. (MH + 722.31)

Example 3

Acid benzyl ester ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -315 (3-pyridin-2-ylmethyl-ureido) -pyrrolidine -1-yl] -purin-9-yl} -2,3-dihydroxycyclopentyl) -carbamic. [0103] This compound is obtained analogously to Example 2 replacing N - {trifluoroacetate (1S, 2R, 3S, 4R) -4- [ 2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenylethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide ester benzyl acid {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2 , 3-dihydroxy-cyclopentyl} -carbam (intermediate)

L). (MH + 783.3)

Example 4

N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (325 pyridin-2-ylmethyl-ureido) -pyrrolidine hydrochloride -1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide

103 [0104] Solution containing N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-aminopyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) - purin-9-yl] -2,3-dihydroxy-cyclopentyl} 2-hydroxy-acetamide (example 1) (0.5 g, 0.87 mmol) and pyridin-3-ylcarbamic acid phenyl ester (intermediate ZB) (0.198 g , 0.87 mmol) in NMP (1 mL) is stirred at 100 ° C for 1 hour. The solvent is removed in vacuo and the title compound is obtained after purification by reverse phase column chromatography (Isolute ™ C18, 0-100% acetonitrile in water - 0.1% HCl). (MH + 70.65)

Example 5

N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (310 sulfamoyl-phenyl) -ureido] hydrochloride pyrrolidin-1-yl} -ppurin-9-yl) -2,3-dihydroxy-cyclopentyl] -2-hydroxy-acetamide. This compound is obtained in analogy to Example 4 replacing pyridin-3-yl-carbamic acid phenyl ester ( intermediate ZB) (3-sulfamoyl-phenyl) -carbamic acid phenyl ester (EP 365484). (MH + 70.65)

Example 6

N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (4-sulfamoyl-phenyl) -ureido] hydrochloride pyrrolidin-1-yl} -ppurin-9-yl) -2,3-dihydroxy-cyclopentyl] -2-hydroxy-acetamide. This compound is obtained in analogy to Example 4 replacing pyridin-3-yl-carbamic acid phenyl ester ( intermediate ZB) (4-sulfamoyl-phenyl) -carbamic acid phenyl ester (JP 2002283758). (MH + 771.60)

Example 7

N - [(1S, 2R, 3S, 4R) -4- (6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -2 - {(R) -3- [3- (3-hydroxy -benzyl) -ureido] -pyrrolidin-1-yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -225-hydroxy-acetamide

Level 1:

104

[0108] A reaction mixture containing (1S, 2R, 3S, 5R) -3- (di-Boc-amino) -5 (2,6-dichloro-purin-9-yl) -cyclopentane-1,2-diol (product intermediate J4) (3.00 g, 5.95 mmol) and 4.4 '- (2-aminoethylidene) bis-phenol (obtained by the method of

RMSchelkuna et al. Bioorg. Med. Chem. Lett. 9 (1999) 2447-2452.) (1.5 g, 6.54 mmol) in dry THF (20 ml) is treated with DIPEA (1.2 ml, 7.14 mmol) and stirred at 50 ° C for night. The solvent is removed in vacuo and the residue is partitioned between DCM and 2 M HCl. The organic portion is separated, dried (MgSO4) and concentrated in vacuo to afford the title compound.

Step 2: (1S, 2R, 3S, SR) -3-Amino-5- {6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] 2-chloro-purin-9-yl} - cyclopentane-1,2-diol [0109] The solution of Example 7 step 1 (3.45 g, 5.80 mmol) in methanol (7 mL) is treated with 4 M HCl in dioxane (3 mL) and the reaction mixture is stirred at peace overnight. The solvent is removed in vacuo and the residue is partitioned between saturated sodium bicarbonate solution and DCM. The organic portion is separated, dried (MgSO4) and concentrated in vacuo to afford the title compound.

Step 3: N - ((1S, 2R, 3S, 4R) Trifluoroacetate) -4- {6- [2,2-bis- (4-hydroxy-phenyl) ethylamino] -2 - [(R) -3- (3 -pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl] -2,320 dihydroxy-cyclopentyl) -2-hydroxy-acetamide:

105 [0110] A mixture containing (1S, 2R, 3S, 5R) -3-amino-5- {6- [2,2-bis-4-hydroxyphenyl) ethylamino] -2-chloro-purin-9-yl} - cyclopentane-1,2-diol (1.03 g, 1.93 mmol) and potassium carbonate (1.34 g, 9.65 mmol) in DMF (5 mL) are treated with acetoxyacetyl chloride (0.499 g, 4.63 mmol ) and TEA (0.78 g, 7.72 mmol) and stirred at room temperature overnight. The solvent is removed in vacuo and the residue is dissolved in methanol and 5 M KOH. The resulting mixture is filtered to remove insoluble potassium carbonate and then concentrated in vacuo. Purification of the residue by preparative HPLC eluting with acetonitrile: water: TFA (0.1%) (gradient 5 to 100% acetonitrile) affords the title compound. (MH + 555.42).

Stage 4: ((R) -1- {6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -9 - [(1R, 2S, 3R, 4S) -2,3-dihydroxy acid tert-butyl ester hydrochloride -4- (2-hydroxyacetylamino) -cyclopentyl] -9H-purin-2-yl} -pyrrolidin-3-yl) -carbamic acid [0111] Mixture containing N - ((1S, 2R, 3S, 4R) -4- trifluoroacetate {6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -2 - [(R) -3- (3-pyridin-3-ylureido) -pyrrolidin-1-yl] -purin-915-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (475 mg, 0.71 mmol), (R) -pyrrolidin-3-yl-carbamic acid tert-butyl ester (0.529 g, 2.84 mmol) and sodium iodide (106 mg, 0.71 mmol) in acetonitrile (0.5 mL) are heated using microwave radiation Personal Chemistry Emrys ™ Optimizer microwave reactor

160 ° C. LCMS analysis shows the end of the reaction after 30 minutes. The title compound is obtained after purification by reverse phase column chromatography (Isolute ™ C18, 0-100% acetonitrile in water - 0.1% HCl).

Step 5: N - ((1S, 2R, 3S, 4R) -4- {2 - ((R) -3-amino-pyrrolidin-1-yl) -6 [2,2-bis- (4-hydroxyphenyl) hydrochloride ) ethylamino] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide

106 [0112] This compound is obtained analogously to (1S, 2R, 3S, SR) -3-amino-5- {6 [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -2-chloro-purine -9-yl} -cyclopentane-1,2-diol (step 2).

Step 6: N - [(1S, 2R, 3S, 4R) -4- (6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -2 - {(R) 5 3- [3 - (3-hydroxy-benzyl) -ureido] -pyrrolidin-1-yl} -purin-9-yl) -2,3-dihydroxycyclopentyl] -2-hydroxy-acetamide [0113] Solution containing N - ((1S, 2R, 3S, 4R) -4- {2 - ((R) -3-amino-pyrrolidin-1-yl) -6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -purin-9- yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (15 mg, 0.02 mmol) and (3-hydroxybenzyl) -carbamic acid phenyl ester (obtained by the McDonnell ME method et al. Bioorganic and Medicinal Chemistry Letters 14 (2004) 531-534) (6 mg, 0.026 mmol) in methanol (0.5 ml) is treated with TEA (33 ml, 0.23 mmol) and then heated at 100 ° C for 30 minutes. Purification of the crude product by preparative HPLC eluting with acetonitrile: water: TFA (0.1%) (10 to 100% gradient acetonitrile) affords the title compound. (MH + 803.46)

Examples 8-10 [0114] These compounds, namely, N - [(1S, 2R, 3S, 4R) trifluoroacetate -4- (6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] 2- {(R) -3- [3- (3-sulfamoyl-phenyl) -ureido] -pyrrolidin-1-yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -2-hydroxy-acetamide (MH + 803.46) (example 8), [0115] N - [(1S, 2R, 3S, 4R) trifluoroacetate -4- (6- [2,2-bis- (4-hydroxy-phenyl) ethylamino] -2 - {(R) -3- [3 - (4-sulfamoyl-phenyl) -ureido] -pyrrolidin-1-yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -2-hydroxy-acetamide (MH + 803.45) (example 9) and trifluoroacetate N - ((1S, 2R, 3S, 4R) -4- {6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] 2 - [(R) -3- (3-pyridinium- 2-ylmethyl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxycyclopentyl) -2-hydroxy-acetamide (MH + 739.36) (Example 10)

107 obtained in analogy to Example 6 by replacing (2-hydroxy-benzyl) -carbamic acid phenyl ester with (2-sulfamoylbenzyl) -carbamic acid phenyl ester, respectively (3-sulfamoyl-benzyl) -carbamic acid phenyl ester and pyridin-2-phenyl ester ylmethyl-carbamic acid. These carbamic acid phenyl esters are obtained by the method of McDonnell ME et al. Bioorganic and Medicinal Chemistry Letters 14 (2004) 531-534.

Example 11

Trifluoroacetate ((1S, 2R, 3S, 4R) -4- (6- (2,2-diphenylethylamino) -2 - [(R) -3- (3-pyridin-2-ylmethyl-ureido) -pyrrolidine methyl ester -1-yl-purin-9-yl} -2,310 dihydroxy-cyclopentyl) -carbamic acid

Level 1: Acid benzyl ester ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) 2 - [(R) -3- (3-pyridin-2-ylmethyl-ureido) -pyrrolidine -1-yl] -purin-9-yl} -2,3-dihydroxycyclopentyl) -carbamic acid [0116] Benzyl ester solution {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3 -amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -carbamic (intermediate product L) (0.2 g, 0, 31 mmol) in NMP / THF (3 ml of a 1: 2 mixture) is treated with TEA (0.05 g, 0.46 mmol), followed by the phenyl ester of chloroformic acid (0.053 g, 0.34 mmol). The reaction mixture is stirred at room temperature for 2 hours and then treated with 2-amino-methylpyridine (0.076 g, 0.62 mmol). The mixture is heated to 50 ° C overnight and then the solvent is removed in vacuo. Purification by C-18 reverse phase column chromatography eluting with acetonitrile: water: HCl (0.1%) (0 to 100% acetonitrile gradient) gives the product in acetonitrile, which is washed successively with saturated sodium bicarbonate solution and extracts DCM (3 times).

The combined organic portions are dried (MgSO4) and concentrated in vacuo to afford the title compound. (MH + 783.3)

108 [0117]

Step 2: 1 - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -4-Amino-2,3-dihydroxy-cyclopentyl) -6 (2,2-diphenyl-ethylamino) - 9H-purin-2-yl] -pyrrolidin-3-yl} -3-pyridin-2-ylometylomocznik

Acid benzyl ester solution ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R) -3- (3-pyridin-2-ylmethyl-ureido) -pyrrolidine -1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -carbamic acid (0.13 g, 166 mmol) in ethanol (9 ml) under an atmosphere of inert gas-argon is treated with palladium (10% on carbon active) (44 mg). The reaction mixture is placed under an atmosphere of hydrogen and stirred at room temperature overnight, then filtered through Celite ™. The filtrate is concentrated in vacuo to afford the title compound. (MH + 649.89)

Step 3: Trifluoroacetate methyl acid ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-2-ylmethyl-ureido) ) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -carbamic acid [0118] Solution 1 - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -4-amino-2,3-dihydroxycyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -3-pyridin-2-methyl-urea (17 mg , 26 mmol) in THF (1 mL) is treated with TEA (5 mg, 50 mmol) followed by methyl chloroformate (2.7 mg, 29 mmol). The reaction mixture is stirred at room temperature overnight, after which the crude mixture is purified by preparative LC-MS to afford the title compound. (MH + 707.49)

Example 12

Acid tert-butyl ester [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenyl-ethylamino) -2- {2 [3- (3,4,5,6-tetrahydro-2H - [1,2 '] bipyridinyl-4-yl) -ureido] -ethylcarbamoyl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -carbamic

Step 1: 9 - [(1R, 4S) -4- (tert-butoxycarbonyl-propionylamino) -cyclopent-2-enyl] -6- (2,2-diphenyl-ethylamino) -9H-purine-2- acid methyl ester carboxylic acid ethyl ester:

109 [0119] This compound is obtained analogously to di-Boc - [(1S, 4R) -4- (2,6-dichloro-purin-9-yl) -cyclopent-2-enyl] -amine (intermediate J3) by replacing iminodicarboxylate with di -t-butyl propionylcarbamic acid tert-butyl ester.

[0120]

Step 2: 9 - [(1R, 2S, 3R, 4S) -4- (tert-butoxycarbonylpropionylamino) -2,3-dihydroxy-cyclopentyl] -6- (2,2-diphenyl-ethylamino) - methyl ester 9H-purine-2-carboxylic acid

To a mixed suspension containing 9 - [(1R, 4S) -4- (tert-butoxycarbonyl-propionyl-amino) -cyclopent-2-enyl] -6- (2,2-diphenyl-ethylamino) -9H10 purine-2- carboxylic acid (6.6 g, 10.82 mmol), methanesulfonamide (1.03 g, 10.82 mmol) and

AD-mix-a (16.23 g) in t-butanol (40 ml) and water (40 ml) osmium tetroxide (3 ml of a 4% solution in water) is added. The reaction mixture is stirred vigorously for 36 hours. The reaction mixture is partitioned between ethyl acetate and water and the organic portion dried (MgSO 4) and concentrated in vacuo. The title product is precipitated from methanol. Further product is obtained from the mother liquor after chromatography on silica gel eluting with DCM: methanol (25: 1).

Step 3: {(1S, 2R, S3,4R) -4- [2- (2-aminoethylcarbamoyl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2 acid tert-butyl ester , 3-dihydroxycyclopentyl} -carbamic acid [0121] Solution containing 9 - [(1R, 2S, 3R, 4S) -4- (tert-butoxycarbonyl-propionyl-amino) -2,3-dihydroxy-cyclopentyl] -6- ( 2,2-diphenylethylamino) -9H-purine-2-carboxylic acid (3.00 g, 4.66 mmol) in ethylenediamine (5 ml, 75 mmol) is heated at 90 ° C for 1 hour. After cooling to room temperature, the ethylenediamine is removed in vacuo and purification is performed by C-18 reverse phase column chromatography eluting with water (100%) followed by methanol (100%) to afford the title compound.

110

Stage 4: Acid tert-butyl ester [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenylethylamino) -2- {2- [3- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -ureido] ethylcarbamoyl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -carbamic acid [0122] To the suspension of tert-butyl ester {(1S, 2R , 3S, 4R) -4- [2- (2-amino-5-ethylcarbamoyl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -carbamic acid (2.5 g . 4.05 mmol) in IPA (10 mL) is added (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -imidazole-1-carboxylic acid (intermediate C) ( 151 ml of 10 mg / ml solution in DCM, 5.56 mmol) and the reaction mixture is stirred at room temperature overnight. The solvent is removed in vacuo and the crude product is purified by silica gel chromatography eluting with DCM / methanol (25: 1 going to 15: 1). The resulting precipitate is further purified by dissolving in DCM and washing the solution with water, drying (MgSO4) and concentrating in vacuo to afford the title product. (MH + 820.7)

Example 13

Trifluoroacetate [[1S, 2R, S, 4R) -4- (6- (2,2-diphenylethylamino) -2- {2- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -ureido] -ethylcarbamoyl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -carbamic

Level 1: 9 - ({(1R, 2S, 3R, {2- [3- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridin-4-yl) ureido] -ethyl} -amide dihydrochloride 4S) -4-amino-2,3-dihydroxy-cyclopentyl) -620 (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid [0123] The title compound is obtained analogously to (1S, 2R, 3S, SR) -3-amino5- {6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -2-chloro-purin-9-yl} -cyclopentane-1,2-diiol (example 7 stage 2) replacing the hydrochloride salt N - ((1S, 2R, 3S, 4R) -4- {6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -2-chloro-purin-9-yl} -2,3-dihydroxy -cyclopentyl) propionamide with (1S, 2R, 3S, 4R) -4- (6- (2,2-diphenylethylamino) -2- {2- [3- (3,4,5,6- tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -ureido] 111-ethylcarbamoyl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -carbamic acid (example 12).

Stage 2: Trifluoroacetate [[1S, 2R, 3S, 4R) -4- (6- (2,2-diphenyl-ethylamino) -2- {2- [3- (3,4,5,6-tetrahydro-2H- [ 1,2 '] bipyridinyl-4-yl) -ureido] ethylcarbamoyl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -carbamic acid [0124] Mixture containing {2- [3- (3.4) dihydrochloride 9 - ((1R, 2S, 3R, 4S) -4-amino-2,3-dihydroxy-, 5,6-tetrahydro-2H [1,2 '] bipyridinyl-4-yl) -ureido] -ethyl} -amide. cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxyl (20 mg, 25 mmol), TEA (12.7 mg, 125 mmol) in THF (2 mL) is treated with methyl chloroformate (6.0 mg, 63 mmol) and allowed to stir at room temperature overnight. The solvent is removed in vacuo and the crude product is purified by reverse phase column chromatography (Isolute ™ C18, 0-100% acetonitrile in water 0.1% TFA) to give the title product. (MH + 778.6)

Example 14

9 - [(1R, 2S, 3R, {2- [3- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridin-4-yl) -ureido] ethyl} -amide trifluoroacetate 4S) -2,3-dihydroxy-4- (2-hydroxy-acetylamino) -cyclopentyl] -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid

Step 1: Trifluoroacetate ester of [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenyl-ethylamino) -2- {2 [3- (3,4,5,6-tetrahydro-2H - [1,2 '] bipyridinyl-4-yl) -ureido] -ethylcarbamoyl} -purin-9-yl) 2,3-dihydroxy-cyclopents [carbamoyl] methyl acetic acid [0125] This compound is prepared analogously to an example 13 replacing methyl chloroformate with acetoxyacetyl chloride.

Step 2: Trifluoroacetate {2- [3- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) ureido] ethyl} -amide 9 - [(1R, 2S , 3R, 4S) -2,3-dihydroxy-4- (2-hydroxy-acetylamino) -cyclopentyl] -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid

112 [0126] Solution of ester trifluoroacetate [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenylethylamino) -2- {2- [3- (3,4,5,6-tetrahydro-2H - [1,2 '] bipyridinyl-4-yl) -ureido] ethylcarbamoyl} -ppurin-9-yl) -2,3-dihydroxy-cyclopentylcarbamoyl] methyl acetic acid (0.015 g, 16 mmol) in methanol (1 mL ) is treated with potassium carbonate (0.01 g, 10 mmol) and the reaction mixture is stirred at room temperature for 1 hour. The solvent is removed in vacuo and the crude material is purified by reverse phase column chromatography (Isolute ™ C18, 0-100% acetonitrile in water 0.1% TFA) to give the title product. (MH + 778.6)

Example 15

N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-Diphenyl-ethylamino) -2 - [(R) -3 - ((R) -3-pyrrolidin-3yloureido) -pyrrolidin -1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxyacetamide [0127] N - {(1S, 2R, 3S, 4R) -4- [2-Chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] 2,3-dihydroxy-cyclopentyl} -2-hydroxyacetamide (intermediate Q) (60 mg, 0.11 mmol) and 1,3-di (R ) -pyrrolidin-3-yl-urea (intermediate B) (91 mg, 0.46 mmol) in dry DMSO (0.2 mL) is stirred at 100 ° C for 2 hours. Purification of the obtained mixture by C-18 reverse-phase column chromatography eluting with acetonitrile: water: TFA (0.1%) (20 to 70% acetonitrile gradient) gives a product which is treated with saturated sodium bicarbonate solution and passed through. again through the C-18 reverse phase column. The column is washed first with water and then with methanol (with 1% ammonia) to elute the product, which is concentrated in vacuo to afford the title compound. (MH + 685.2)

Example 16

N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-Diphenyl-ethylamino) -2 - {(R) -3- [3- (3,4,5,625 tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -ureido] -pyrrolidin-1-yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -2-hydroxy-acetamide

113 The title compound is obtained analogously to N - ((1S, 2R, 3S, 4R) 4- {6 (2,2-diphenyl-ethylamino) -2 - [(R) -3 - ((R) -3 -pyrrolidin-3-yl-ureido) -pyrrolidin-1-yl] -purin9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (example 15) replacing 1,3-di (R) -pyrrolidin-3- yl urea (intermediate B) 1- (R) -pyrrolidin-3-yl-3- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) urea hydrochloride (product) intermediate A).

(MH + 388.8)

Example 17

Acid trifluoroacetate 4 - [(R) -3- (3 - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2 2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -ureido) -pyrrolidine-1-carbonyl] -benzoic acid

Level 1: N - ((1S, 2R, 3S, 4R) trifluoroacetate -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) 3 - ((R) -3-pyrrolidin-3-yloureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxycyclopentyl) -propionamide [0129] The title compound is obtained in analogy to N {(1S, 2R, 3S, 4R) -4- [2- ((R) -3-Amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-benzyloxy-acetamide from Example 1 (stage 2) replacing 2-benzyloxy-N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -acetamide N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6 (2,2-diphenyl-ethylamino) -ppurin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (intermediate J) and replacing (3R) -3-aminopyrrolidine with 1,3-di (R) -pyrrolidin-3-urea (intermediate B).

[0130]

Step 2: 4 - [(R) -3- (3 - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6 trifluoroacetate - (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -ureido) -pyrrolidine-1-carbonyl] -benzoic acid

114

N - ((1S, 2R, 3S, 4R) trifluoroacetate solution 4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) 3- ((R) -3-pyrrolidin-3-yloureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxycyclopentyl) -propionamide (step 1) (0.02 g, 29 mmol), DIPEA (0.0075 g, 58 mmol) in NMP ( 0.2 ml) is treated with a solution of terephthaloyl chloride (0.006 g, 14.5 mmol) in NMP (0.1 ml). The reaction mixture is stirred at room temperature for 1 hour, then purified by C-18 reverse phase column chromatography eluting with acetonitrile: water: TFA (0.1%) (gradient 0 to 100% acetonitrile) to afford the title compound . (MH + 831.6)

Example 18

N - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine trifluoroacetate -2-yl] -pyrrolidin-3-yl} -6-morpholin-4-yl-nicotinamide

Step 1: {(R) -1- [9 - (1R, 2S, 3R, 4S) 2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl) tri-fluoroacetate ester trifluoroacetate -ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -carbamic acid:

[0131] A reaction mixture containing N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl } -propionamide (intermediate J) (2.5 g, 4.80 mmol) and (3R) - (+) - (3-Boc-amino) pyrrolidine (2.5 g, 13.6 mmol) in DMSO ( 8 ml) heated at 100 ° C overnight. The resulting mixture is purified by reverse phase column chromatography (Isolute ™ C18, 0100% methanol in water - 0.1% TFA) to give the title product.

[0132]

Step 2: N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenylethylamino) -purin-9 yl] -2,3-dihydroxy-cyclopentyl} -propionamide

Trifluoroacetate of {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) - tert-butyl ester 9H-purin-2115-yl] pyrrolidin-3-yl} -carbamic acid (3.22 g, 4.80 mmol) is dissolved in 1.25 M HCl in methanol (60 mL, 75 mmol) and allowed to stir at temperature room for the night. The solvent is removed in vacuo and the crude product is dissolved in a minimum volume of ethanol / saturated sodium carbonate solution and purified by reverse phase column chromatography (Isolute ™ C 18, 0-100% methanol in water) to give the title product.

Step 3: N - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) - trifluoroacetate 9H-purin-2-yl] pyrrolidin-3-yl} -6-morpholin-4-yl-nicotinamide [0133] Solution N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) - 3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (22.8 mg, 0.04 mmol) in THF (1 ml) is treated with TEA (7.3 mg, 0.072 mmol) and then added to 6-morpholinonicotinoyl chloride (8.2 mg, 0.036 mmol). The reaction mixture is shaken and then left at room temperature overnight. The solvent is removed in vacuo and purified by C-18 reverse phase column chromatography eluting with acetonitrile: water: TFA (0.1%) (gradient 0 to 100% acetonitrile) to afford the title compound. (MH + 761.4)

Example 19

N - ((1S, 2R, 3R, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (320 pyridin-2-ylmethyl-ureido) -pyrrolidine trifluoroacetate -1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) propionamide [0134] The suspension of N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3 -amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (example 18 step 2) (0.12 mg, 230 mmol) and sodium bicarbonate (27 mg, 253 mmol) in DMSO (300 mL) are treated with phenyl chlorocarbonate (36 mg, 230 mmol) and then stirred at room temperature for 3 hours. The resulting reaction mixture is added to

116

2-picolylamines (4.1 mg, 38 mmol) and stirred at 80 ° C for 5 hours. Purification of the crude product by C-18 reverse phase column chromatography eluting with acetonitri: water: TFA (0.1%) (gradient 0 to 100% acetonitrile) affords the title compound. (MH + 705.4)

Example 20

N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-4-ylmethyl-ureido) -pyrrolidinium trifluoroacetate 1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide

Step 1: {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-Dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine -2-yl] -pyrrolidin-3-yl} -amide, imidazole-1-carboxylic acid:

[0135] A mixture containing N - {(3aR, 4S, 6R, 6aS) -6- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purine -9-yl] -2,2-dimethyl-tetrahydrocyclopenta [1,3] dioxol-4-yl} -propionamide (intermediate M) (0.24 g, 394 mmol) and CDI (0.275 g, 1.7 mmol ) in dry DCM (6 ml) is stirred at room temperature for 3 hours. The resulting solution is purified by silica gel chromatography eluting with 100% DCM switching to 5% methanol in DCM to afford the title compound as a yellow oil. The oil contains the imidazolurea intermediate together with various amounts of the corresponding isocyanate and imidazole, which are also suitable as urea precursors.

Step 2: N - ((1S, 2R, 3S, 4R) Trifluoroacetate -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) 3- (3-pyridin-4-ylmethyl-ureido) ) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxycyclopentyl) -propionamide [0136] Pyridylmethylamine (4.3 mg, 40 mmol) is treated with a solution of {(R) -1- [9 ( (1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -amide imidazole-1-carboxylic acid

117 (25 mg, 40 mmol) in DCM (1 mL) and the reaction mixture is stirred at room temperature overnight. The solvent is removed in vacuo and the residue is treated with TFA (0.5 ml) and water (0.5 ml). The reaction mixture is stirred at room temperature for 3 hours, then concentrated in vacuo and the obtained crude material is purified by preparative liquid chromatography detection by LC-MS mass spectroscopy elution with acetonitrile: water: trifluoroacetic acid to give the title compound. (MH + 705.4)

Example 21

N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (3-hydroxy-benzyl) -ureido] trifluoroacetate pyrrolidin-1-yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] propionamide. This compound is prepared in analogy to Example 20 by replacing 4-pyridylmethylamine with 3-hydroxybenzylamine. (MH + 720.4)

Example 22

N - {(R) -1- [6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -9 hydrochloride ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4 propionylamino-cyclopentyl) -9H-purin-2-yl] pyrrolidin-3-yl} -6-morpholin-4-yl-nicotinamide

Step 1: N - ((1S, 2R, 3S, 4R) -4- {6- [2,2-bis- (4-hydroxyphenyl) ethylamino] -2-chloro-purin-9-yl} - hydrochloride 2,3-dihydroxy-cyclopentyl) -propionamide [0138] A reaction mixture containing [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -2 acid tert-butyl ester. 3-dihydroxy-cyclopentyl] -propionylcarbam (intermediate G) (2.00 g, 4.35 mmol) and 4,4 '- (2-aminoethylidene) bis-phenol (obtained by RMSchelkuna et al. Bioorg. Med. Chem. Lett 9 (1999) 24472452.) (1.19 g, 5.20 mmol) in dry THF (40 mL) is treated with DIPEA (0.67 g, 5.20 mmol) and stirred at room temperature for 2 days. The solvent is removed in vacuo and the title compound is obtained after purification by chromatography

118 reverse phase column (Isolute ™ C 18, 20-70% acetonitrile in water 0.1% HCl).

Step 2: 2R, 3S, 4R) -4- {6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -2-chloropurin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide [0139] This compound is obtained analogously to (1S, 2R, 3S, 5R) -3-amino-5- {6 [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -2-chloro -purin-9-yl} -cyclopentane-1,2-diol (example 7 step 2).

Step 3: {(R) -1- [6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -9 - tert-butyl ester trifluoroacetate ((1R, 2S, 3R, 4S) -2, 3-dihydroxy-4-propionylaminocyclopentyl) -9H-purin-2-yl] -pyrrolidin-3-yl} -carbamic acid [0140] This compound is obtained in analogy to ((R) -1- {6- [ 2,2-bis- (4-hydroxy-phenyl) -ethylamino] -9 - [(1R, 2S, 3R, 4S) -2,3-dihydroxy-4- (2-hydroxy-acetylamino) -cyclopentyl] -9H- purin-2-yl} -pyrrolidin-3-yl) -carbamate (Example 7 step 4).

Step 4: N - ((1S, 2R, 3S, 4R) -4- {2 - ((R) -3-Amino-pyrrolidin-1-yl) -6- [2,2-bis- (4-hydroxyphenyl) - ethylamino] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide

Trifluoroacetate solution of {(R) -1- [6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -9 - tert-butyl ester ((1R, 2S, 3R, 4S) -2,3- dihydroxy-4-propionylaminocyclopentyl) -9H-purin-2-yl] pyrrolidin-3-yl} -carbamic acid (0.4 g, 0.57 mmol) in DCM (5 ml) and TFA (2.5 ml) at room temperature for 2 hours. The solvent is removed in vacuo to give the title compound.

Stage 5: N - {(R) -1- [6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -9 hydrochloride ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4 -propionylamino-cyclopentyl) -9H-purin-2-yl] pyrrolidin-3-yl} -6-morpholin-4-yl-nicotinamide [0141] N - ((1S, 2R, 3S, 4R) -4- {suspension { 2 - ((R) -3-amino-pyrrolidin-1-yl) -6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -purin-9-yl} -2,3-dihydroxy-cyclopentyl ) 119 propionamide (20 mg, 33 mmol) in dry THF is treated with NMP (0.5 mL) followed by TEA (13.4 mg, 0.13 mmol) and 6-morpholinonicotinoyl chloride (8.3 mg, 37 mmol). The reaction mixture is stirred at room temperature for 30 minutes and then the solvent is removed in vacuo. Purification by C-18 reverse phase column chromatography eluting with acetonitrile: water: HCl (0.1%) (gradient 0 to 100% acetonitrile) affords the title compound. (MH + 793.4)

Example 23

N - ((1S, 2R, 3S, 4R) -4- {6- [2,2-bis- (4-hydroxy-phenyl) -10-ethylaminol-2-1 (R) -3- (3-pyridine- 2-ylmethyl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide

Level 1: Phenyl ester {(R) -1- [6- [2,2-bis- (4-hydroxy-phenyl) ethylamino] -9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4 -propionylamino-cyclopentyl) -9Hpurin-2-yl] -pyrrolidin-3-yl} -carbamic [0142] Mixture containing N - ((1S, 2R, 3S, 4R) -4- {2 - ((R) -3 -amino-pyrrolidin-1-yl) -6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -purin-9-yl} -2,3-dihydroxycyclopentyl) -propionamide (example 22 step 4) ( 50 mg, 83 mmol) and potassium carbonate (46 mg, 332 mmol) in NMP (1 mL) is treated with phenyl chloroformate and stirred at room temperature for 90 minutes. The resulting mixture is used in the next step without purification.

Stage 2: N - ((1S, 2R, 3S, 4R) -4- {6- [2,2-bis- (4-hydroxy-phenyl) ethylamino] -2 - [(R) -3- (3-pyridine- 2-ylmethyl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide [0143] Mixture containing phenyl ester {(R) -1- [6- [2, 2-bis- (425 hydroxy-phenyl) -ethylamino] -9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -9H-purin-2-yl] pyrrolidin-3 -yl} -carbamic acid (12 mg, 16 mmol) and 2120 (aminomethyl) pyridine (5.4 mg, 50 mmol) in NMP (0.5 ml) is heated to 100 ° C for 2 hours. After cooling to room temperature, purification by C-18 reverse phase column chromatography eluting with acetonitrile: water: HCl (0.1%) (gradient 0 to 100% acetonitrile), the title compound is obtained. (MH + 737.5)

Example 24

N - [(1S, 2R, 3S, 4R) -4- (6- [2,2-bis- (4-hydroxyphenyl) ethylaminol-2 - {(R) -3- [3- (3- hydroxy-benzyl) -ureido] -pyrrolidin-1-yl} -purin-9-yl) 2,3-dihydroxy-cyclopentyl] -propionamide. This compound is obtained analogously to N ((1S, 2R, 3S, hydrochloride), 4R) -4- {6- [2,2-bis- (4-hydroxyphenyl) ethylamino] -2 - [(R) -3- (3-pyridin-2-ylmethyl-ureido) -pyrrolidin-1-yl] - purin-9-yl} -2,3-dihydroxy-cyclopentyl) propionamide (example 23) replacing 2- (aminomethyl) pyridine with the appropriate amine. (MH + 752.5)

Example 25

N - ((1S, 2R, 3S, 4R) -4- (6- (2,2-Diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1 yl] -purin-9-yl) -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide:

[0145] N - {(1S, 2R, 3S, 4R) trifluoroacetate solution -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purine -9-yl] -2,3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide (0.2 g, 0.28 mmol) in dry THF (10 mL) is treated with TEA (113 mg, 1.12 mmol), and then 3-isocyanato-pyridine (38 mg, 0.31 mmol). The reaction mixture is heated at 50 ° C overnight. The solvent is removed in vacuo and purified by reverse phase column chromatography (Isolute ™ C18, 10-50% acetonitrile in water - 0.1% TFA) to give the product. The product is further purified by dissolving in methanol and treating with saturated sodium bicarbonate solution. The mixture is passed through a pre-washed (400 ml

121 methanol followed by 400 mL water) column eluting with 0.5% ammonia 880: water (100 mL) followed by water (400 mL) and finally methanol to give the title compound. (MH + 693.4)

Example 26

(1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R) -3- (3-pyridin-3-yl-ureido) -pyrrolidine hydrochloride -1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -carbamic acid

Level 1: Benzyl ester trifluoroacetate ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3-yl-ureido) -pyrrolidine -1-yl] -purin-9-yl} 2,3-dihydroxy-cyclopentyl) -carbamic acid [0146] Solution containing {(1S, 2R, 3S, 4R) benzyl ester) -4- [2 - ((R ) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -carbamic acid (intermediate L) (0.1 g, 0 g , 15 mmol), pyridine-3-isocyanate (0.02 g, 0.17 mmol) and TEA (0.017 g, 0.17 mmol) in THF (2 mL) is stirred at room temperature overnight. The solvent is removed in vacuo and purification is carried out by reverse phase column chromatography (Isolute ™ C 18, 0-100% acetonitrile in water - 0.1% TFA). Fractions are collected and MeCN is removed in vacuo. The remaining aqueous portion is basified with saturated sodium bicarbonate solution and extracted with DCM. The combined organic extracts are dried (MgSO4) and concentrated in vacuo to afford the title product. MS (ES +) m / e 769 (MH+).

Step 2: 1 - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -4-Amino-2,3-dihydroxy-cyclopentyl) -6 (2,2-diphenyl-ethylamino) - 9H-purin-2-yl] -pyrrolidin-3-yl} -3-pyridin-3-yl-urea

To the solution of trifluoroacetate ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3-ylureido) pyrrolidine -1-yl] -purin-9-yl} -2,325 dihydroxy-cyclopentyl) -carbamic acid (step 1) (35 mg, 46 mmol) in ethanol (1 ml) under an inert gas-argon atmosphere, 10% palladium catalyst is added to carbon (10

122 mg). Argon is bubbled through the reaction mixture and put under positive pressure overnight after which the mixture is filtered through Celite and the catalyst washed with ethanol. The organic portions are combined and concentrated in vacuo to afford the title compound.

MS (ES +) m / e 635 (MH+).

Stage 3: (1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3-yl-ureido) -pyrrolidine hydrochloride -1-yl] -purin-9-yl} 2,3-dihydroxy-cyclopentyl) -carbamic. [0147] This compound is obtained analogously to Example 11 by replacing 1 {(R) -1- [9 - ((1R, 2S , 3R, 4S) -4-amino-2,3-dihydroxy-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -3-pyridine- 2-ylmethyl-urea 1 - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -4-amino-2,3-dihydroxy-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin 2-yl] -pyrrolidin-3-yl} -3-pyridin-3-yl-urea. (MH + 693.5)

Example 27

N - [(1S, R, 3S, 4R) -4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (315 sulfamoyl-phenyl) -ureido] hydrochloride pyrrolidin-1-yl} -ppurin-9-yl) -2,3-dihydroxy-cyclopentyl] propionamide [0148] N - {Suspension (1S, 2R, 3S, 4R) -4- [2- (R) - 3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (example 18 step 2) (20 mg, 0.035 mmol ) and 3-isocyanato-benzenesulfonamide (intermediate

S) (17.7 mg, 0.095 mmol) in THF (1 mL) and DMF (1 mL) are stirred at room temperature overnight. The solvent is removed in vacuo and purified by reverse phase column chromatography (Isolute ™ C 18, 0-100% acetonitrile in water - 0.1% HCl) to afford the title compound. (MH + 769.5)

Example 28

123

N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (4-sulfamoyl-phenyl) -ureido] hydrochloride pyrrolidin-1-yl} -ppurin-9-yl) -2,3-dihydroxy-cyclopentyl] propionamide. This compound is prepared in analogy to Example 27 using the corresponding isocyanate. (MH + 769.5)

Example 29

1 - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -4-Amino-2,3-dihydroxy-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin 2-yl] -pyrrolidin-3-yl} -3-pyridin-2-ylmethyl-urea

Level 1: Acid benzyl ester ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) 10 2 - [(R) -3- (3-pyridin-2-ylmethyl-ureido) - pyrrolidin-1-yl] -ppurin-9-yl} -2,3-dihydroxycyclopentyl) carbamic acid [0150] Benzyl ester solution {(1S, 2R, 3S, 4R) -4- [2 - ((R) - 3-aminopyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -carbamic (intermediate product L) (0.2 g, 0, 31 mmol) in NMP / THF (3 ml of a 1: 2 mixture) is treated with TEA (0.05 g, 0.46 mmol), followed by the phenyl ester of chloroformic acid (0.053 g, 0.34 mmol). The reaction mixture is stirred at room temperature for 2 hours and then treated with 2-aminomethylpyridine (0.076 g, 0.62 mmol). The mixture is heated to 50 ° C overnight and then the solvent is removed in vacuo. Purification by C-18 reverse phase column chromatography eluting with acetonitrile: water: HCl (0.1%) (0 to 100% acetonitrile gradient) gives the product in acetonitrile, which is washed successively with saturated sodium bicarbonate solution and extracts DCM (3 times). The combined organic portions are dried (MgSO4) and concentrated in vacuo to afford the title compound. (MH + 783.3)

124

Step 2: 1 - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -4-Amino-2,3-dihydroxy-cyclopentyl) -6 (2,2-diphenyl-ethylamino) - 9H-purin-2-yl] -pyrrolidin-3-yl} -3-pyridin-2-ylometylomocznik

Acid benzyl ester solution ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-2-ylmethyl-ureido) - pyrrolidin-1-yl] -ppurin-9-yl} -2,3-dihydroxy-cyclopentyl) -carbamic acid (0.13 g, 166 mmol) in ethanol (9 ml) under an atmosphere of inert gas-argon is treated with palladium (10% on activated carbon) (44 mg). The reaction mixture is placed under an atmosphere of hydrogen and stirred at room temperature overnight, then filtered through Celite ™. The filtrate is concentrated in vacuo to afford the title compound. (MH + 649.89)

Example 30-32

These compounds, namely, N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-2-ylmethyl- trifluoroacetate) ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) acetamide (MH + 691.5) (Example 30), [0151] Trifluoroacetate ((1S, 2R, 35.4R) -4- (6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-2-ylmethylureido) -pyrrolidin-1 cyclopropanecarboxylic acid (MH + 717.5) (Example 31) and trifluoroacetate ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (320 pyridin-2-ylmethyl-ureido) -pyrrolidin-1-yl] -purin-9-yl] -2,3-dihydroxy- cyclobutanecarboxylic acid cyclopentyl) amide (MH + 731.5) (Example 32) is prepared analogously to Example 11 replacing methyl chloroformate with the appropriate acid chloride. Example 33

125

N - ((15,2R, 35,4R) -4- {6- (2,2-Diphenyl-ethylamino) -2 - [(R) -3- (N'-cyano-N "-pyridin-3-ylmethyl guanidino) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide

Level 1: (1S, 2R, 3S, 4R) -acetylamide -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) 5 3- (3-cyano-2-phenyl-isoureido) -pyrrolidine- 1-yl] -purin-9-yl} -2,3-dihydroxycyclopentanecarboxylic solution [0152] N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidine- 1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (example 18 step 2) (50 mg) and cyanocarbodiimidic acid diphenyl ester (21 mg ) in dry DCM (2 ml) is treated with TEA (13 ml), and then stirred at room temperature for 5 hours. The solvent is removed in vacuo and the residue is partitioned between ethyl acetate and water. The organic portion is separated, dried (Na2SO2) and concentrated in vacuo to give the crude product which is purified by preparative HPLC to afford the title compound. (MH + 715).

Stage 2: N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-Diphenyl-ethylamino) -2 - [(R) -3- (N'-cyjanoN "-pyridin-3-ylmethyl guanidino) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxycyclopentyl) -propionamide [0153] Mixture containing acid ethylamide ((1S, 2R, 3S, 4R) -4- {6- (2 , 2-diphenyl-ethylamino) -2 - [(R) -3- (3-cyano-2-phenyl-isoureido) -pyrrolidin-1-yl] -purin-920-yl} -2,3-dihydroxy-cyclopentanecarboxylic acid (80 mg , 0.11 mmol) and 2- (aminomethyl) pyridine (35 ml, 0.33 mmol) in absolute ethanol (1 ml) is heated using microwave radiation in a Personal Chemistry microwave reactor

Emrys ™ Optimizer at 100 ° C for 2500 s, followed by 120 ° C for 1 hour. The solvent is removed in vacuo and purification is carried out by preparative HPLC.

Fractions are combined, treated with saturated sodium bicarbonate solution and then

126 extracted with ethyl acetate (3x). The organics are dried (Na2SO4) and concentrated in vacuo to afford the title compound. (MH + 729)

Example 34

Acid methyl ester ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -35 ((R) -3-pyrrolidin-3-yloureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxycyclopentyl) -carbamic acid [0154] This compound is obtained in analogy to {(R) -1- [9 - ((1R, tert-butyl ester trifluoroacetate 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -carbamic (example 18 stage 1) replacing N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (intermediate) J) {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenylethylamino) -ppurin-9-yl] -2,3-dihydroxy-cyclopentyl} -carbamic acid methyl ester (intermediate T) and replacing (3R) - (+) - (3-Boc-amino) pyrrolidine with 1,3-di (R) -pyrrolidin-3-yl-urea (intermediate B). (MH + 685.2)

Example 35

N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-phenyl-ureido) -pyrrolidin-1-yl] hydrochloride -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide. This compound is obtained in analogy to Example 27 by replacing 320 isocyanate-benzenesulfonamide (intermediate S) with phenyl isocyanate. (MH + 690.9) Example 36

4 - [(R) -3- (3 - {(R) -1- [9 - (1R, 2S, 3R, 4S1-2,3-dihydroxy-4-propionylamino-cyclopentyl) acid methyl ester) -6- (2 , 2-diphenyl-ethylaminol-9H-purin-2-yl] -pyrrolidin-3-yl} -ureido) -pyrrolidine-1-carbonyl] -benzoate [0156] This compound is obtained in analogy to Example 17 replacing 4-chlorocarbonyl terephthaloyl chloride methyl benzoate

127 by reverse phase column chromatography eluting with acetonitrile: water: HCl (0.1%) (20 to 100% acetonitrile gradient) to afford the title compound. (MH + 845.58)

Example 37

N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3-ylmethyl-ureido) -pyrrolidinium trifluoroacetate 1-yl] -purin-9-yl} -2-dihydroxy-cyclopentyl) propionamide [0157] The suspension of N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino- pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (example

18 step 2) (20 mg, 38 mmol) and sodium bicarbonate (4.5 mg, 42 mmol) in DMSO (300 mL) are treated with phenyl chloroformate (36 mg, 230 mmol) and then stirred at room temperature for 3 hours. The resulting reaction mixture is added to

3-picolylamine (4.1 mg, 38 mmol) and stirred at 80 ° C for 5 hours. Purification of the crude product by C-18 reverse phase column chromatography eluting with acetonitrile: water: TFA (0.1%) (gradient 0 to 100% acetonitrile) affords the title compound. (MH + 705.4)

Example 38

Benzyl ester trifluoroacetate ((1S, 2R, 3S, 4R) -4- (6- (2,2-diphenylethylaminol-2 - [(R) -3- (3-pyridin-3-yl-ureido) -pyrrolidine- 1-yl] -purin-9-yl) -2,320 dihydroxy-cyclopentyl) -carbamic acid [0158] Solution containing {(1S, 2R, 3S, 4R) benzyl ester) -4- [2 - ((R) -3amino- pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -carbamic acid (intermediate L) (0.1 g, 0.15 mmol) , pyridine-3-isocyanate (0.02 g, 0.17 mmol) and TEA (0.017 g, 0.17 mmol) in THF (2 mL) is stirred at room temperature overnight. The solvent is removed in vacuo and purification is carried out by reverse phase column chromatography (Isolute ™

128

C18, 0-100% acetonitrile in water - 0.1% TFA). Fractions are collected and MeCN is removed in vacuo. The remaining aqueous portion is basified with saturated sodium bicarbonate solution and extracted with DCM. The combined organic extracts are dried (MgSO4) and concentrated in vacuo to afford the title product. (MH + 769.5)

Example 39

N - [(1S, 2R, 3S, 4R) -4- (6-2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (3-hydroxy-phenyl) -ureido] -pyrrolidine trifluoroacetate -1-yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -propionamide

Step 1: {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-Dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H- purin-2-yl] -pyrrolidin-3-yl} -amide, imidazole-1-carboxylic acid:

[0159] A mixture containing N - {(3aR, 4S, 6R, 6aS) -6- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purine -9-yl] -2,2-dimethyl-tetrahydrocyclopenta [1,3] dioxol-4-yl} -propionamide (intermediate M) (0.24 g, 394 mmol) and

CDI (0.275 g, 1.7 mmol) in dry DCM (6 ml) is stirred at room temperature for 3 hours. The resulting solution is purified by silica gel chromatography eluting with 100% DCM switching to 5% methanol in DCM to afford the title compound as a yellow oil. The oil consists of the imidazolurea intermediate together with various amounts of the corresponding isocyanate and imidazole, which are equally suitable as urea precursors.

Step 2: N - [(1S, 2R, 3S, 4R) Trifluoroacetate -4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) 3- [3- (3-hydroxy-phenyl) -ureido] -pyrrolidin-1-yl} -purin-9-yl) -2,3-dihydroxycyclopentyl] -propionium :

[0160] 3-Aminophenol (4.3 mg, 40 mmol) is treated with a {(R) -1- [925 ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) solution Imidazole-1-carboxylic acid -6- (2,2-diphenylethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -amide

129 (25 mg, 40 mmol) in DCM (1 mL) and the reaction mixture is stirred at room temperature overnight. The solvent is removed in vacuo and the residue is treated with TFA (0.5 ml) and water (0.5 ml). The reaction mixture is stirred at room temperature for 3 hours, then concentrated in vacuo and the crude material obtained is purified by preparative liquid chromatography detection with LCMS mass spectroscopy elution with acetonitrile: water: trifluoroacetic acid to give the title compound. (MH + 706.4)

Example 40

N - {(1S, 2R, 3S, 4R) trifluoroacetate -4- [2 - [(R) -3- (4-acetylamino-benzenesulfonylaminol-pyrrolidin-1-yl] -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide [0161] N - {(11S, 2R, 3S, 4R) -4- [2 - ((R) -3-Amino-pyrrolidin-1- yl) -6- (2,2-diphenylethylamino) -ppurin-9-yl] -2,3-dihydroxycyclopentyl} -propionamide (example 18 step 2) (23 mg, 40 mmol) is treated with a solution of 4-acetamidobenzenesulfonyl chloride (9 , 5 mg

0.039 mmol) in NMP (0.5 ml) and stirred at room temperature overnight. Purification by preparative LCMS affords the title compound. (MH +

768,50)

Example 41

N - {(1S, 2R, 3S, 4R) -4- [2-1 (R) -3- (4,5-Dihydro-1H-imidazol-2-ylamino) -pyrrolidin-1-yl] -6- ( 2,2-diphenyl-ethylamino) -purin-9-yl-2,3-dihydroxy-cyclopentyl} propionamide [0162] Mixture containing N - {(1S, 2R, 3S, 4R) -4- [2 - ((R ) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (example 18 step 2) (30 mg, 0.053 mmol) and 4,5-dihydro-1H-imidazole-225 thiol iodide (24 mg, 0.106 mmol) in absolute ethanol (2 mL) is treated with DMAP (catalytic amount) and TEA (29 mL, 0.212 mmol). The resulting mixture is heated with

130 microwave radiation in a Personal Chemistry Emrys ™ Optimizer microwave reactor at 150 ° C for 4000 s. The solvent is removed in vacuo and the crude product is purified by preparative HPLC ((30-95% acetonitrile in water - 0.1% TFA) to afford the title compound. (MH + 639.63)

Example 42

N - {(1S, 2R, 3S, 4R1-4- [2- {N '- [1-cyclohexyl-methylidene] -hydrazino} -6- (2,2-diphenyl-etyloaminolo-purin-9-yl] -2, 3-dihydroxy-cyclopentyl} -propionamide

Step 1: N - {(1S, 2R, 3S, 4R) -4- [6- (2,2-Diphenyl-ethylamino) -2-hydrazine-purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide :

[0163] N - {(1S, 2R, 3S, 4R) -4- [2-Chloro-6- (2,2-diphenyl-ethylamino) -ppurin-9-yl] 2,3-dihydroxy-cyclopentyl} - propionamide (intermediate J) (1.0 g, 1.91 mmol) and hydrazine monohydrate (12 ml) are stirred for 72 hours and then isopropyl alcohol (10 ml) is added. The solvent is removed in vacuo and the remaining water (10 ml) is stirred for 12 hours. The resulting fine solid is filtered, washed with water and dried in vacuo to give the product. LC-MS (0.1% formic acid, acetonitrile) (MH + 517)

Step 2: N - {(1S, 2R, 3S, 4R) -4- [2- {N '- [1-Cyclohexylmethylidene] hydrazino} -6 (2,2-diphenyl-ethylamino) -purin-9 yl] -2,3-dihydroxy-cyclopentyl} -propionamide

To a solution of N- {4- [6- (2,2-diphenyl-ethylamino) -2-hydrazine-purin-9-yl] -2,320 dihydroxy-cyclopentyl} -propionamide (step 1) (0.1 g, 0, 19 mmol) in dry methanol (5 ml) cyclohexanecarboxaldehyde (0.026 g, 0.23 mmol) is added. The reaction mixture is heated to reflux for 12 hours. The reaction mixture is concentrated in vacuo and purified by preparative TLC to afford the title compound. LC-MS (0.1% formic acid, acetonitrile): (MH + 611.45)

Example 43

131

1 - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propylaminocyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine hydrochloride -2-yl-pyrrolidin-3-yl} -3-pyridin-3-urea [0164] Solution 1 - {(R) -1- [9 - ((LR, 2S, 3R, 4S) -4-amino- 2,3-dihydroxy-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H purin-2-yl] -pyrrolidin-3-yl} -3-pyridin-3-urea (example 26 step 2) (17 mg, 26 mmol) in DCE (1 mL) is treated with propanaldehyde (1.5 mg, 26 mmol) and put under argon. Sodium triacetoxyborohydride (10 mg, 51 mmol) is added and the reaction mixture is stirred at room temperature overnight. The reaction is quenched with 2 M NaOH (5 drops) and the solvent removed in vacuo. The residue is purified by reverse phase C-18 column chromatography eluting with acetonitrile: water: HCl (0.1%) (20 to 100% acetonitrile gradient) to afford the title compound. (MH + 677.14)

Example 44

N - [(1S, 2R, 3S, 4R) -4- (6-Amino-2- {N '- [1-cyclohexylmethylidene] hydrazino} purin-9-yl) -2,3-dihydroxycyclopentyl] propionamide [0165] This compound is obtained in analogy to Example 42 by replacing N {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3 dihydroxycyclopentyl} propionamide (intermediate J) with N - [(1S, 2R, 3S, 4R) -4- (620 amino-2-chloro-purin-9-yl) -2,3-dihydroxy-cyclopentyl] - propionamide (intermediate ZA). (MH + 431.33)

Example 45

(R) -3- (3 - {(R) -1- [9-1 (1R, 2S, 3R, 4S) 2,3-dihydroxy-4-propionylamino-cyclopentyl) -6-pyridin-3-ylamide hydrochloride - (2,2-diphenyl-ethylaminol-9H-purin-2-yl] -pyrrolidin-3-yl} -ureido) -pyrrolidine-1-carboxylic acid

132 [0166] This compound is obtained in analogy to Example 23 replacing {(R) -1- [6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -9 - acid phenyl ester ((1R, 2S , 3R, 4S) 2.3-dihydroxy-4-propionylamino-cyclopentyl) -9H-purin-2-yl] -pyrrolidin-3-yl} -carbamic trifluoroacetate with N - ((1S, 2R, 3S, 4R) -4- {6 - (2,2-diphenyl-ethylamino) -2 - [(R) 3- ((R) -3-pyrrolidin-3-ylureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3 dihydroxycyclopentyl) propionamide (example 17 step 1) and replacing (aminomethyl) pyridine with an ester phenyl pyridin-3-yl-carbamic acid (intermediate ZB). (MH + 803.8)

Examples 46-47

These compounds, namely, 9- [{(1R, 2S) {2- [3- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridin-4-yl) ureido] -ethyl} -amide trifluoroacetate , 3R, 4S) -4- (3,3-dimethyl-ureido) -2,3-dihydroxycyclopentyl] -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxyl (MH + 791.6) (example 46) and ester trifluoroacetate [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenyl-ethylamino) -2- {2 [3- (3,4,5,6-tetrahydro -2H- [1,2 '] bipyridinyl-4-yl) -ureido] -ethylcarbamoyl} -ppurin-9-yl) 2.3-dihydroxy-cyclopentylcarbamoyl] -methyl acetic acid (example 47) obtained in analogy to Example 13 replacing methyl chloroformate, respectively, with dimethylcarbamyl chloride or acetoxyacetyl chloride.

Example 48 (9-((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H- (2-methanesulfonylamino-ethyl) -amide purine-2-carboxylic acid

Step 1: 6- (2,2-Diphenylethylamino) -9H-purine-2-carboxylic acid methyl ester 6- (2,2-Diphenylethylamino) methyl ester hydrochloride -9H-Purine-2-carboxylic acid (prepared by described in the international

133 Patent Application WO 2001/94368) (35 g, 85.3 mmol) is placed in a flask under an argon atmosphere. Dry CHCl3 (300 mL) and N, O-bis (trimethylsilyl) acetamide (61 mL) are added and the reaction mixture is heated to reflux for 1 hour. The reaction mixture is allowed to cool and all volatile components are removed in vacuo. Methanol (300 ml) is added to the oil obtained. The resulting white precipitate is filtered and washed with methanol (2 x 200 mL) and then dried in a vacuum oven to afford the title compound. 11 H NMR (DMSO, 400 MHz).

Step 2: 6- (2,2-Diphenyl-ethylaminol-9 - ((1R, 4S) -4-hydroxy-cyclopent-2-enyl) -9H-purine-2-carboxylic acid methyl ester [0169] To methyl ester 6 - (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid (5 g 13.4 mmol), dry deoxygenated tetrahydrofuran (100 ml) and dry dimethyl sulfoxide (2 ml) are added under argon, then sodium hydride is added. % (0.32 g, 13.4 mmol) and the solution is stirred at 40 ° C. Separately to (1S, 4R) -cis 4-acetoxy-2-cyclopenten-1-ol (1.89 g. 13.4 mmol), triphenylphosphine (0.53 g, 2.0 mmol) and tris (dibenzylideneacetone) dipalladium (0) (0.69 g, 0.67 mmol), dry deoxygenated tetrahydrofuran (20 ml) is added and the mixture is stirred at room temperature for 10 minutes. The resulting solution is added to the anion solution via syringe and the resulting mixture is then stirred at 80 ° C. LCMS analysis shows the end of the reaction after 2 hours. The reaction mixture is allowed to cool, methanol is added and the precipitate is filtered off. The filtrate is concentrated in vacuo and the title compound is obtained after precipitation from dichloromethane / hexane. 11 H NMR (MeOD, 400 MHz); 8.15 (s, 1H), 7.40-7.15 (m, 10H), 6.20 (m, 1H), 5.95 (m, 1H), 5.50 (m, 2H), 4 , 75 (m, 2H), 4.55 (m, 1H), 4.10 (m 2H), 3.90 (s, 2H), 3.80 (s, 1H), 2.9 (m, 1H ), 1.75 (m, 1H).

Step 3: 6- (2,2-Diphenylethylamino) -9 - ((1R, 4S) -4-ethoxycarbonyloxy-cyclopent-2-enyl) -9H-purine-2-carboxylic acid methyl ester

134 [0170] 6- (2,2-Diphenylethylamino) -9 - ((1R, 4S) -4-hydroxy-cyclopent-2-enyl) -9H-purine-2-carboxylic acid methyl ester (2.80 g, 6 , 14 mmol) is placed in an oven-dried flask under an argon atmosphere. Dry tetrahydrofuran (30 ml) is added followed by dry pyridine (0.97 g, 12.3 mmol). Ethyl chloroformate (2.66 g, 24.6 mmol) is slowly added and the reaction mixture is stirred at room temperature. LCMS analysis shows reaction complete after 3 hours. The solvent is removed in vacuo and the residue is partitioned between dichloromethane (200 ml) and 1 M HCl (2 x 200 ml). The organic layer is washed with water (2 x 100 mL) and brine (2 x 100 mL), dried over MgSO 4, filtered and the solvent removed in vacuo. The title compound is obtained after purification by Flash column chromatography (silica gel, 4% methanol in dichloromethane). MS (ES +) m / e 528.3 (MH+).

Step 4: 9 - ((1R, 4S) -4-di-tert-butoxycarbonylaminocyclopent-2-enyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid methyl ester [0171] 6- (2,2-diphenyl-ethylamino) methyl ester -9 - ((1R, 4S) -415 ethoxycarbonyloxy-cyclopent-2-enyl) -9H-purine-2-carboxylic acid (2.2 g, 4.2 mmol) is dissolved in deoxygenated tetrahydrofuran. The resulting solution is stirred under argon at room temperature. Di-t-butyl iminodicarboxylate (0.9 g, 4.2 mmol), triphenylphosphine (0.16 g, 0.63 mmol) and triethylamine (0.42 g, 4.2 mmol) are added, followed by tris ( dibenzylideneacetone) dipalladium (0) (0.22 g, 0.21 mmol). The reaction mixture is then stirred at 45 ° C for 4 hours, allowed to cool to room temperature, methanol is added and the reaction mixture is filtered. The filtrate is concentrated in vacuo. The oil obtained is purified by column chromatography (silica gel, 80% ether in hexane) to afford the title compound, MS (ES +) m / e 536.4 (MH+).

135

Stage 5: 9 - ((1R, 2S, 3R, 4S) -4-di-tert-butoxycarbonylamino-2,3-dihydroxy-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid methyl ester ] The title compound is obtained from 9 - ((1R, 4S) -4-di-tert-butoxycarbonylamino-cyclopent-2-enyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid methyl ester using the procedure analogous to that for (1R, 2S, 3R, 5S) -3- [2-chloro-6- (2,2-diphenyl-ethylamino) -ppurin-9-yl] -5- (di-Boc-amino) -cyclopentane- 1,2-diol (intermediate JJ2). MS (ES +) m / e 689.4 (MH+).

Step 6: 9 - ((1R, 2S, 3R, 4S) -4-amino-2,3-dihydroxycyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid methyl ester [ 0173] 9 - ((1R, 2S, 3R, 4S) -4-di-tert-butoxycarbonylamino-2,3-dihydroxy-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid methyl ester (0.5 g, 0.73 mmol) is dissolved in dioxane and stirred under argon. 4 M HCl in dioxane (3.68 mL, 14.5 mmol) is added and the resulting solution is stirred for 20 hours and then concentrated in vacuo. The title compound is obtained after subjecting to Flash column chromatography (Isolute ™ C18, 0-100% acetonitrile in water). MS (ES +) m / e 489.3 (MH+).

Step 7: 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid methyl ester [0174] 9 - ((1R, 2S, 3R, 4S) -, 4-amino-2,3-dihydroxy-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid methyl ester hydrochloride (200 mg, 0.36 mmol) is dissolved in tetrahydrofuran (5 mL). Diisopropylethylamine (0.16 mL, 0.9 mmol) is added and the solution is stirred for 10 minutes. Propionyl chloride (33 mg, 0.36 mmol) is added and the reaction mixture is stirred at room temperature for 1 hour. The reaction is quenched with methanol and the title compound

136 obtained after flash column chromatography (Isolute ™ C18, 0-100% acetonitrile in water). MS (ES +) m / e 545.3 (MH+).

Step 8: 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H (2-amino-ethyl) -amide -purine-25-carboxylic acid [0175] 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) methyl ester -6- (2,2-diphenyl-ethylamino) -9H-purine -2-carboxy (62 mg, 1.0 mmol) is dissolved in ethylenediamine (3.4 mL, 51 mmol) and the solution is stirred at 105 ° C. LCMS analysis shows the end of the reaction after 45 minutes.

The reaction mixture is concentrated in vacuo and the title compound is obtained after purification by reverse phase column chromatography (Isolute ™ C18, 0-100% acetonitrile in water). MS (ES +) m / e 573.4 (MH+).

Step 9: 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H (2-methanesulfonylamino-ethyl) -amide -purine-215 carboxylic acid 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2- (2,2-amino-ethyl) -amide solution diphenyl-ethylamino) -9H-purine-2-carboxylic acid (0.01 g, 0.017 mmol) in chloroform (1 ml) is treated with mesyl chloride (1 ml 3 mg / ml solution in chloroform) and TEA (0.003 ml). The reaction mixture is stirred at 5 ° C for 1 hour then diluted with DCM and extracted with 1 M HCl. The organic portion is isolated and concentrated in vacuo to afford the title product. (MH +

651,5)

Example 49-55

These relationships,

137 9- ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl trifluoroacetate {2- [3- (3-methoxy-phenyl) -ureido] -ethyl} -amide -6- (2,2-diphenylethylamino) -9H-purine-2-carboxyl (MH + 722.4) (example 49), trifluoroacetate {2- [3- (3-cyano-phenyl) -ureido] -ethyl} - 95 ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) -9H-purine-2-carboxylic acid amide (MH + 717.5) (example 50), trifluoroacetate [3- (2 - {[9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H- Purin-2-carbonyl] amino} -ethyl) -ureido] -acetic acid (MH + 702.5) (Example 51), 9 - ((1R, trifluoroacetate [2- (3-ethyl-ureido) -ethyl] -amide) 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid (MH + 644.5) (example 52), {2- [3- (4-methoxy-phenyl) -ureido] -ethyl} -amide trifluoroacetate 9 ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxyl (MH + 722.5) (example 53), 9 {((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) trifluoroacetate {2- [3- (4-cyano-phenyl) -ureido] -ethyl} -amide (2,2-diphenylethylamino) -9H-purine-2-carboxylic acid (MH + 717.5) (Example 54) and 4- [3- (2 - {[9 - ((1R, 2S, 3R, methyl ester trifluoroacetate) 4S) -2,320 dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carbonyl] -amino} -ethyl) -ureido] -benzoate (MH + 750,4) (example 55) is obtained analogously to Example 48 replacing chloride methanesulfonyl (step 9) with the appropriate isocyanate.

Example 56

138

N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenyl-ethylamino) -2 - ((R) -3- [3- (4-phenoxy-phenyl) -ureido] - trifluoroacetate pyrrolidin-1-yl} -ppurin-9-yl) -2,3-dihydroxy-cyclopentyl] propionamide [0178] N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3 -Amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -ppurin-9-yl] -2,3-dihydroxycyclopentyl} -propionamide (example 18 step 2) (0.023 g, 40 mmol) is treated solution of 4-phenoxyphenyl isocyanate (0.0078 g, 39 mmol) in NMP (0.5 ml). The reaction mixture is stirred at room temperature overnight and purification is carried out by preparative LC-MS elution with acetonitrile: water: trifluoroacetic acid to give the title compound. (MH + 782.5)

Examples 57-90 [0179] These compounds, namely, N - [(1S, 2R, 3S, 4R) trifluoroacetate -4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (2-phenoxy-phenyl) -ureido] -pyrrolidin-1-yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -propionamide (MH + 782.5) (example 57), N- trifluoroacetate ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (4-trifluoromethyl-benzenesulfonylamino) -pyrrolidin-1-yl] -puryn- 9-yl} -2,3-dihydroxycyclopentyl) -propionamide (MH + 777.4) (example 58), N - [(1S, 2R, 3S, 4R) trifluoroacetate -4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [320 (3,4,5-trimethoxyphenyl) - ureido] -pyrrolidin-1-yl} -purin-9-yl) -2,3-dihydroxycyclopentyl] -propionamide (MH + 780.5) (example 59), N - trifluoroacetate ((1S, 2R, 3S, 4R) - 4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3 - ((E) -2fenylo-entenosulfonyloamino) -pyrrolidin-1-yl] -purin-9-yl} -2, 3-dihydroxycyclopentyl) propionamide (MH + 737.5) (example 60),

139 trifluoroacetate (3 - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) ethyl ester -9H-purin-2-yl] pyrrolidin-3-yl} -ureido) -acetic acid (MH + 700.5) (Example 61), {(R) -1- [9 - ((1R, 2S, 3R, acid trifluoroacetate, 4S) -2,3-dihydroxy-45 propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -amide, cyclopropanecarboxylic acid (MH + 639.5) (example 62), N - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine trifluoroacetate -2-yl] pyrrolidin-3-yl} propionamide (MH + 627.5) (Example 63), N - {trifluoroacetate (1S, 2R, 3S, 4R) -4- [2 - [(R) -3- (3,3-dimethyl-ureido) -pyrrolidin-1-yl] -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} propionamide (MH + 642.5) ( example 64), N - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine trifluoroacetate -2-yl] -pyrrolidin-3-yl} -benzamide (MH + 689.5) (Example 65), N - trifluoroacetate ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl -ethylamino) -2 - [(R) -3- (3-isopropyl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) propionamide (MH + 656.5) (example 66) N - ((1S, 2R, 3S, 4R) trifluoroacetate -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (320-ethyl-ureido) -pyrrolidin-1-yl ] -purin-9-yl} -2,3-dihydroxycyclopentyl) -propionamide (MH + 642.5) (example 67), trifluoroacetate {(R) -1- [9 - ((1R, 2S, 3R, benzyl ester 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -carbamic acid (MH + 705.3) (example 68 ) and

140 N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (4-hydroxy-phenyl) -ureido] trifluoroacetate pyrrolidin-1-yl} -ppurin-9-yl) -2,3-dihydroxy-cyclopentyl] propionamide (MH + 745.6) (example 69), N - {trifluoroacetate (1S, 2R, 3S, 4R) -4- [2 - {(R) -3- [3- (2,3-dihydro-benzo [1,4] dioxin-5-yl) -ureido] -pyrrolidin-1-yl} -6- (2,2-diphenyl -ethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -propionamide (MH + 748.5) (example 70), trifluoroacetate {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2 benzo [1,2,5] thiadiazole-5-carboxylic acid (MH + 733.4) (Example 71), trifluoroacetate {(R) -1- [9 - (-]] -yl] -pyrrolidin-3-yl} -amide. 1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenylethylamino) -9H-purin-2-yl] pyrrolidin-3-yl} quinoxaline acid amide 6-carboxyl (MH + 727.5) (example 72), N - {(1S, 2R, 3S, 4R) trifluoroacetate -4- [2 - {(R) -3- [3- (3,4-dihydro-2Hbenzo [b] [1,4] dioxepin-7-yl ) -ureido] -pyrrolidin-1-yl} -6- (2,2-diphenylethylamino) purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (MH + 762.5) (example 73), N - {trifluoroacetate (1S, 2R, 3S, 4R) -4- [2 - {(R) -3- [3- (4-cyano-phenyl) -ureido] pyrrolidin-1-yl} -6- (2 , 2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} propionamide (MH + 715.5) (example 74), trifluoroacetate {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin- 4- (4-chloro-benzenesulfonyl) -3-methyl-thiophene-2-carboxylic acid (MH + 870.5) (example 75), trifluoroacetate {(R) - 2-yl] -pyrrolidin-3-yl} -amide (4-) 1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-325-yl } -3-chloro-4- (propane-2-sulfonyl) -thiophene-2-carboxylic acid amide (MH +

821.4) (example 76),

141 N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (4-trifluoromethoxyphenyl) -ureido] -pyrrolidinium trifluoroacetate 1-yl} -purin-9-yl) -2,3-dihydroxycyclopentyl] propionamide (MH + 774.4) (example 77), N - [(1S, 2R, 3S, 4R) trifluoroacetate -4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (3-methylsulfanyl-phenyl) -ureido] -pyrrolidin-1-yl} -purin-9-yl) -2,3-dihydroxy ] -propionamide (MH + 736.4) (example 78), N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (4-methylsulfanyl-phenyl) -ureido] - trifluoroacetate pyrrolidin-1-yl} -ppurin-9-yl) -2,3-dihydroxycyclopentyl] propionamide (MH + 736.4) (example 79), trifluoroacetate {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenylethylamino) -9H-purin-2-yl] pyrrolidin-3-yl} -quinoxaline-2-carboxylic acid ( MH + 727.5) (example 80), trifluoroacetate {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2 benzo [1,2,5] thiadiazole-4-carboxylic acid (MH + 733.4) (Example 81), 5- (3 - {(R) dimethyl ester trifluoroacetate] -yl] -pyrrolidin-3-yl} -amide. -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3 -yl} -ureido) -isophthalic (MH + 806.5) (example 82), N - [(1S, 2R, 3S, 4R) trifluoroacetate -4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [2- (1Hindol-3-yl) -2 -oxo-acetylamino] -pyrrolidin-1-yl} -purin-9-yl) -2,3-dihydroxycyclopentyl] -propionamide (MH + 742.5) (example 83), trifluoroacetate {(R) -1- [9- ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenylethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -amide pyridine-2-carboxyl (MH + 676.5) (example 84), trifluoroacetate {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2 yl] -pyrrolidin-3-yl} -amide

142 1- (4-Methoxy-phenyl) -5-methyl-1H-pyrazole-4-carboxylic acid (MH + 785.5) (example 85), trifluoroacetate 3 - {(R) -1- [9- ( (1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-25] pyrrolidin-3-ylcarbamoyl} -piperidine- 1-carboxyl (MH + 816.6) (Example 86), N - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine trifluoroacetate -2-yl] -pyrrolidin-3-yl} -4-dipropylsulfamoyl-benzamide (MH + 838.4) (example 87), trifluoroacetate {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2 1,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -amide of 1- (4-trifluoromethyl-pyrimidin-2-acid -yl) -piperidine-4-carboxyl (MH + 828.4) (example 88), N - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H- trifluoroacetate purin-2-yl] pyrrolidin-3-yl} nicotinamide (MH + 676.4) (example 89), N - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2 trifluoroacetate , 3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -isonicotinamide (MH + 667.3) (example 90), obtained analogously to N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (4-phenoxy-phenyl) trifluoroacetate) -ureido] -pyrrolidin-1-yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -propionamide (example 56) replacing 4-phenoxyphenyl isocyanate with the appropriate isocyanate or acid chloride. Excess triethylamine is also added to the reaction with acid chlorides.

Example 91-92 [0180] These compounds, namely,

143 N - {(R) -1- [9 - ((R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (1-ethyl-propylamino) -9H-purin-2 hydrochloride -yl] -pyrrolidin-3-yl} isonicotinamide (MH 566.4+) (Example 91) and N - {(R) -1- [9 - ((1R, 2S, 3R, 4S) hydrochloride -2,3 dihydroxy-4-propionylaminocyclopentyl) -6- (3,3-dimethylbutylamino) -9H-purin-2-yl] pyrrolidin-3-yl} isonicotinamide (MH + 580.5) (example 92), obtained in analogy to N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purine trifluoroacetate -9-yl] -2,3-dihydroxycyclopentyl} -2-benzyloxy-acetamide (example 1 step 2) replacing (3R) -3aminopyrrolidine (R) -N-pyrrolidin-3-yl-isonicotinamide (intermediate O) and replacing 2-benzyloxy-N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -acetamide with a suitable starting compound. Preparation of starting compounds is described herein or can be obtained from tert-butyl ester of [(1S, 2R, 3S, 4R) -4- (2,6-dichloropurin-9-yl) -2,3-dihydroxy-cyclopentyl] -propionyl-carbam (intermediate G) and the corresponding amine using a procedure analogous to 2R, 3S, 4R) -4- {6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -2-chloro-purin- 9-yl} -2,3-dihydroxy-cyclopentyl) propionamide (example 22 steps 1 and 2).

Example 93

{(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (1-ethyl-propylamino) -9H-purin-2-yl hydrochloride ] acid-pyrrolidin-3-yl} -amide

5-methyl-isoxazole-3-carboxy [0181] This compound is obtained analogously to N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3 - ((R) -3-pyrrolidin-3-yloureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (example 15) replacing N { (1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-hydroxyacetamide (intermediate) Q) N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (1-ethyl-propylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide [obtained from the ester tert-butyl [[1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) 2,3-dihydroxy-cyclopentyl] -propionyl-carbamic acid (intermediate G) and the corresponding amine using a procedure analogous to (2R, 3S, 4R) -4- (6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -2-chloro-purin-9-yl} -2,3-dihydroxy -cyclopentyl) propionamide (example 22 steps 1 and 2)] and replacing 1,3-di (R) -pyrrolidin-3-yl-urea (intermediate B) (R) -pyrrolidin-3-ylamide of 5-methylisoxazole-3-carboxylic acid (intermediate P). (MH + 570.4)

Example 94

Trifluoroacetate {(1S, 2R, 3S, 4R) -4- [2 - ((R) -1-benzyl-pyrrolidin-3-ylamino) -6 (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -amide of cyclobutane carboxylic acid [0182] This compound is obtained analogously to N {(1S, 2R, 3S, 4R) trifluoroacetate) -4- [2 - ((R) -3-amino-pyrrolidine -1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl-2-benzyloxy-acetamide from Example 1 (step 2) replacing 2-benzyloxy-N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -acetamide {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -ppurin-9-yl] -2,3-dihydroxy-cyclopentyl} -amide, cyclobutanecarboxylic acid ( intermediate K) and replacing (3R) -3-aminopyrrolidine (R) -1-benzyl-pyrrolidin-3-ylamine. (MH + 687.5)

Example 95

9- ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) trifluoroacetate {2- [3- (2-diisopropylamino-ethyl) -ureido] -ethyl} -amide (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid

145 [0183] To a solution containing (2-amino-ethyl) -amide 9 ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) -9H -purine-2-carboxylic acid (25 mg, 0.04 mmol) (example 48 step 8) in toluene (0.8 ml) and IPA (0.4 ml) imidazolo (2-diisopropylamino-ethyl) -amide is added -1-carboxyl (10 mg, 0.04 mmol) in DCM (0.44 mL). The reaction mixture is stirred at room temperature under an inert argon atmosphere overnight and then the solvent is removed in vacuo. Purification of the obtained crude product by reverse phase column chromatography (Isolute ™ C18, 0-100% acetonitrile in water - 0.1% TFA) gives the title product. (MH + 372.3)

Example 96-98 [0184] These compounds, namely, N - {trifluoroacetate (1S, 2R, 3S, 4R) -4- [2 - ((R) -1-benzyl-pyrrolidin-3-ylamino) -6 (2 , 2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (MH + 661.6) (example 96), trifluoroacetate of {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) - tert-butyl ester 9H-purin-2-yl] -pyrrolidin-3-yl} -carbamic acid (MH + 661.6) (example 97) and (R) -3- [9 - tert-butyl ester trifluoroacetate ((1R, 2S, 3R, 4S ) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2-ylamino] -pyrrolidine-1-carboxylic acid (MH + 671.5) (example 98), obtained in analogy to N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purine trifluoroacetate -9-yl] -2,3-dihydroxycyclopentyl} -2-benzyloxy-acetamide from Example 1 (step 2) replacing 2-benzyloxy-N {(1S, 2R, 3S, 4R) -4- [2-chloro-6 - (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -acetamide N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2 , 2-diphenyl-ethylamino) 146 purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (intermediate J) and replacing (3R) -3-aminopyrrolidine with the appropriate amine.

Example 99 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H- (99-2-propionylamino-ethyl) -amide purine-2-carboxylic acid

Step 1: 9 - ((1R, 2S, 3R, 4S) -4-di-tert-butoxycarbonylamino-2,3-dihydroxy-cyclopentyl) -6- (2,2-diphenyl-ethylamino) 2-amino-ethyl-amide -9H-purine-2-carboxylic acid:

[0185] The title compound is obtained in a manner analogous to 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) 6- (2,2- (2,2-aminoethyl) -amide) diphenyl-ethylamino) -9H-purine-2-carboxyl (Example 48, step 8) replacing 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid methyl ester 9 - ((1R, 2S, 3R, 4S) -4-di-tert-butoxycarbonylamino-2,3-dihydroxycyclopentyl) -6- (2,2-diphenylethylamino) -9H-purine-2-carboxylic acid methyl ester (example 48 stage 5).

Step 2: 9 - ((1R, 2S, 3R, 4S) -4-amino2,3-dihydroxy-cyclopentyl) -6- (2,2-diphenyl-ethylamino) - (2-amino-ethyl) -amide hydrochloride - 9H-purine-2-carboxylic acid [0186] The title compound is obtained from 9 - ((1R, 2S, 3R, 4S) -4-amino-2,3-dihydroxy-cyclopentyl hydrochloride (2-amino-ethyl) -amide hydrochloride ) -6- (2,2-diphenylethylamino) -9H-purine-2-carboxylic acid analogously to (1S, 2R, 3S, 5R) -3amino-5- {6- [2,2-bis- (4-hydroxyphenyl) ethylamino ] -2-chloro-purin-9-yl} cyclopentane-1,2-diol (Example 7 step 2).

147

Stage 3: 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine- (2-propionylamino-ethyl) -amide 2-carboxylic acid [0187] The title compound is obtained in a manner analogous to 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6-methyl ester 5 - 2,2-diphenyl-ethylamino ) -9H-purine-2-carboxylic acid (example 48 step 7) replacing 9 - methyl acid hydrochloride ((1R, 2S, 3R, 4S) -, 4-amino-2,3-dihydroxycyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid (2-amino-ethyl) -amide hydrochloride 9 - ((1R , 2S, 3R, 4S) -4-amino-2,310 dihydroxy-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid.

(MH + 629.5)

Example 100

N - ((1S, 2R, 3S, 4R) trifluoroacetate -4- [2- (2-amino-ethylamino) -6- (2,2-diphenylethylamino) -purin-9-yl] -2,3-dihydroxy- cyclopentyl) -propionamide [0188] The title compound is obtained in analogy to N {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (trifluoroacetate) 2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-benzyloxy-acetamide (example 1 step 2) replacing

2-benzyloxy-N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -acetamide N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -ppurin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (intermediate J) and replacing (3R) -3-aminopyrrolidine with ethylenediamine. (MH + 545.4)

Example 101

Trifluoroacetate (2- {3- [1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-ylcarbamoyl) -piperidin-4-yl] -ureido} -ethyl) -amide 9 - ((1R, 2S, 3R, 4S) -2,325 dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid

148

Level 1: Acid tert-butyl ester {(1S, 2R, 3S, 4R) -4- [6- (2,2-diphenylethylamino) -2- (2- {3- [1- (3,4,5,6-tetrahydro -2H- [1,2 '] bipyridinyl-4-ylcarbamoyl) piperidin-4-yl] -ureido} -ethylcarbamoyl) -ppurin-9-yl] -2,3-dihydroxy-cyclopentyl} -carbamic [0189] The title compound is obtained analogous to tert-butyl ester of [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenyl-ethylamino) -2- {2- [3- (3,4,5,6 tetrahydro-2H- [1,2 '] bipirydynylo4-yl) -ureido] -ethylcarbamoyl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -carbamic (example 12) replacing (3,4,5,6-tetrahydro-2H [1,2 '] bipyridinyl-4-yl) -imidazole-1-carboxylic acid (intermediate C) (3,4,5,6 -tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -amide 4 - [(imidazole-1-carbonyl) -amino] -piperidine-1-carboxylic acid (intermediate H).

Stage 2: (2- {3- [1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-ylcarbamoyl) -piperidin-4-yl] -ureido} -ethyl) -amide dihydrochloride 9 - ((1R, 2S, 3R, 4S) -4-amino2,3-dihydroxy-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxyl [0190] Tert-butyl ester solution acid {(1S, 2R, 3S, 4R) -4- [6- (2,2-diphenylethylamino) -2- (2- {3- [1- (3,4,5,6-tetrahydro-2H- [ 1,2 '] bipyridinyl-4-ylcarbamoyl) piperidin-4-yl] -ureido} -ethylcarbamoyl) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -carbamic acid (76.7 mg, 81 mmol) in methanol (0.5 mL) is treated with 4 M HCl in dioxane (0.5 mL). The reaction mixture is stirred at room temperature for 1 hour, the solvent removed in vacuo to give the title compound which is used crude in the next step.

Step 3: Trifluoroacetate (2- {3- [1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-ylcarbamoyl) -piperidin-4-yl] -ureido} -ethyl) - 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid amide

149 [0191] The title compound is obtained in a manner analogous to 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6-methyl ester (2,2-diphenyl-ethylamino) - 9H-purine-2-carboxylic acid (example 48 step 7) replacing 9 - methyl ester hydrochloride ((1R, 2S, 3R, 4S) -, 4-amino-2,3-dihydroxy-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic dihydrochloride (2- {3- [1- (3,4, 9 - ((1R, 2S, 3R, 45) -4- 5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-ylcarbamoyl) piperidin-4-yl] -ureido} -ethyl) -amide. amino-2,3-dihydroxy-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid. (MH + 451.8)

Example 102-104

These compounds, namely, {1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl) trifluoroacetate, tert-butyl ester -ethylamino) -9H-purin-2-yl] -piperidin-4-yl} -carbamic acid (MH + 685.6) (example 102), N - {trifluoroacetate (1S, 2R, 3S, 4R) -4- [2- ( 1-benzyl-piperidin-4-ylamino) -6- (2,215 diphenyl-ethylamino) -ppurin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (MH +

675.5) (example 103) and N - {(1S, 2R, 3S, 4R) trifluoroacetate) -4- [2- [1,4] diazepan-1-yl-6- (2,2-diphenylethylamino) -purine -9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (MH + 585.5) (Example 104) is obtained analogously to N - {trifluoroacetate (1S, 2R, 3S, 4R) -4- [2- ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -2-benzyloxy-acetamide from Example 1 (step 2) replacing 2-benzyloxy-N- {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -acetamide N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide ( intermediate J) and replacing (3R) -3-aminopyrrolidine with a suitable amine.

150

Example 105 and 106 [0193] These compounds, namely, trifluoroacetate of {(R) -1- [9 - [(1R, 2S, 3R, 4S) -4 (cyclobutanecarbonylamino) -2,3-dihydroxy-cyclopentyl] -6- (2,2- diphenylethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -carbamic acid (MH + 697.3) (example 105) and (S) -3- [9 - [(1R, tert-butyl acid trifluoroacetate) 2S, 3R, 4S) -4 (cyclobutanecarbonyl-amino) -2,3-dihydroxy-cyclopentyl] -6- (2,2-diphenylethylamino) -9H-purin-2-ylamino] -pyrrolidine-1-carboxylic acid (MH + 697.3) (Example 106) is obtained analogously to N - {trifluoroacetate (1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl ] -2,3-dihydroxycyclopentyl} -2-benzyloxy-acetamide from Example 1 (step 2) replacing 2-benzyloxy-N {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2, 2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -acetamide {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino ) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -amide, cyclobutanecarboxylic acid (intermediate K) and replacing (3R) -3-aminopyrrolidine with the appropriate amine.

Example 107

N - {Trifluoroacetate (1S, 2R, 3S, 4R) -4- [6- (2,2-diphenyl-ethylamino) -2- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl- 4-ylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} propionamide [0194] This compound is obtained analogously to N {(1S, 2R, 3S, 4R) -4- [2 - (( R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -ppurin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-benzyloxy-acetamide from Example 1 (step 2) replacing 2-benzyloxy-N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -acetamide N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6151 (2,2-diphenyl-ethylamino) -ppurin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (intermediate J) and replacing (3R) -3-aminopyrrolidine 3,4,5,6-tetrahydro-2H [1,2 '] bipyridinyl-4-ylamine. (MH + 331.7)

Example 108

4- [3- (2 - {(9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) benzyl ester of -6- (2,2-diphenyl-ethylamino) -9H -purine-2-carbonyl] amino} -ethyl) -ureido] -piperidine-1-carboxylic acid [0195] To solution of 9 - ((1R, 2S, 3R, 4S) -2 (amino-ethyl) -amide , 3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-210-carboxylic acid (example 48 step 8) (0.1 g, 174 mmol) in chloroform (5 ml) is added himself

4-Isocyanate-Z-piperidine (0.045 g, 0.174 mmol) in chloroform (5 mL). The reaction mixture is stirred at room temperature overnight and then methanol is added to neutralize the isocyanate residue. The solvent is removed in vacuo to give the title compound. (MH + 833.5)

Example 109

9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy- trifluoroacetate {2- [3- (5-methyl-3-phenyl-isoxazol-4-yl) -ureido] -ethyl} -amide 4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid [0196] This compound is prepared in a manner analogous to 4- [3- (2 - {[9- ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carbonyl] -amino} -ethyl) - ureido] -piperidine-1-carboxylic acid (example 108) replacing 4-isocyanato-Z-piperidine 4-isocyanato-5-methyl-3-phenyl-isoxazole. (MH + 773.5)

Examples 110-112 [0197] These compounds, namely,

152 N - {trifluoroacetate (1S, 2R, 3S, 4R) -4- [2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -6 (2,2-diphenyl-ethylamino) -purin-9- yl] -2,3-dihydroxy-cyclopentyl} -propionamide (MH + 599.5) (Example 110), N - {trifluoroacetate (1S, 2R, 3S, 4R) -4- [6- (2,2-diphenyl-ethylamino) -2 - ((R) -35 methylamino-pyrrolidin-1-yl) -purin-9- yl] -2,3-dihydroxy-cyclopentyl} -propionamide (MH + 585.4) (Example 111) and acid trifluoroacetate (4- {2- [9 - ((1R, 2S, 3R, 4S) -2,3- dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2-ylamino] ethyl} -imidazol-1-yl) -acetic (MH + 654.3) (example 112) is obtained analogous to trifluoroacetate N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -2-benzyloxy-acetamide from Example 1 (step 2) replacing 2-benzyloxy-N {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2.2 -diphenyl-ethylamino) -ppurin-9-yl] -2,3-dihydroxycyclopentyl} -acetamide N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl) ethylamino) purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (intermediate J) and replacing (3R) -3-aminopyrrolidine with an appropriate amine.

Example 113

9 - ((1R, 25.3R, 4S) -2,3-dihydroxy trifluoroacetate (2- {3- [1- (4-methoxy-phenylcarbamoyl) -piperidin-4-yl] -ureido} ethyl) -amide -4-propionylamino-cyclopentyl) -620 (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid Step 1: 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2 (3-Piperidin-4-yl-ureido) -ethyl] -amide -diphenyl-ethylamino) -9H-purine-2-carboxylic acid [0198] Benzyl ester solution 4- [3- (2 - {[9 - ((1R, 2S, 3R, 4S) -2,325 dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carbonyl] -amino} -ethyl) -ureido] -piperidine-1-carboxylic acid (example 108) (0.145 g,

153

0.174 mmol) in methanol (1 mL) under argon is treated with palladium hydroxide on carbon (0.054 g, 20% w / w carbon). The reaction mixture is placed under an atmosphere of hydrogen and stirred at room temperature for 72 hours and then filtered. The filtrate is concentrated in vacuo to afford the title compound as a green oil.

Stage 2: 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy trifluoroacetate (2- {3- [1- (4-methoxy-phenylcarbamoyl) -piperidin-4-yl] ureido} -ethyl) -amide -4-propionylaminocyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid [0199] This compound is prepared in a manner analogous to 4- [3- (2 - {[9- ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carbonyl] -amino} -ethyl) - ureido] -piperidine-1-carboxylic acid (example 108) replacing 9 - ((1R, 2S, 3R, 4S) 2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2 (2-amino-ethyl) -amide -carboxylic acid [2- (3-piperidin-4-yl-ureido) -ethyl] -amide 9 ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- ( 2,2-diphenylethylamino) -9H-purine-2-carboxylic acid and replacing 4-isocyanate-Z-piperidine and 1-isocyanate-4-methoxy-benzene. (MH + 848.6)

Example 114-115 [0200] These compounds, namely, 2- {3- [1- (4-Cyano-phenylcarbamoyl) -piperidin-4-yl] -ureido} -ethyl) -amide 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy trifluoroacetate 4-propionylamino-cyclopentyl) 6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid (MH + 843.6) (Example 114) and trifluoroacetate ethyl acid ester ({4- [3- (2 - ([9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carbonyl] -amino) -ethyl ) -ureido] -piperidine-1-carbonyl} -amino) -acetic acid (MH +

828.6) (example 115)

154 obtained in analogy to Example 113 by replacing 1-isocyanato-4-methoxy-benzene with the appropriate isocyanate.

Example 116

Trifluoroacetate [2- (3- {1- [1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-45-carbamoyl) -piperidin-4-ylcarbamoyl] -piperidin-4-yl } -ureido) -ethyl] -amide

9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) -9H-purine-2-carboxyl [0201] The title compound is obtained by analogy to 2- {3- [1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-ylcarbamoyl) piperidin-4-yl] -ureido} -ethyl trifluoroacetate) - 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid ((example 101) replacing 4 - [(Imidazole-1-carbonyl) -amino] -piperidine-1-carboxylic acid intermediate I. (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridin-4-yl) -amide MH + 514.9)

Examples 117-125 [0202] These compounds, namely, N - {trifluoroacetate (1S, 2R, 3S, 4R) -4- [6- [2,2-bis- (4-methoxy-phenyl) -ethylamino] -2 ((R) -3-dimethylamino-pyrrolidin-1-yl) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} propionamide (MH + 659.4) (example 117), N - ((1S, trifluoroacetate 2R, 3S, 4R) -4- {2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -6- [2- (4-fluoro-phenyl) -2-phenyl-ethylamino] -purin-9 -yl} -2,3-dihydroxy-cyclopentyl) propionamide (MH + 617.4) (example 118), N - {trifluoroacetate (1S, 2R, 3S, 4R) -4- [2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -6 (1-ethyl-propylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (MH +

489.3) (example 119),

155 N - ((1S, 2R, 3S, 4R) trifluoroacetate -4- {2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -6 [(9H-fluoren-9-ylmethyl) -amino] - purin-9-yl} -2,3-dihydroxy-cyclopentyl) propionamide (MH + 597.4) (example 120), N - {trifluoroacetate (1S, 2R, 3S, 4R) -4- [2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -65 ((S) -1-hydroxymethyl-2-phenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} propionamide (MH + 553.4 ) (example 121), N - ((1S, 2R, 3S, 4R) -4- {2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -6 [(naphthalen-1-ylmethyl) -amino] -purin- trifluoroacetate 9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (MH + 559.4) (example 122), N - {trifluoroacetate (1S, 2R, 3S, 4R) -4- [6 - [(2'- cyano-biphenyl-4-ylmethyl) -amino] -2 ((R) -3-dimethylamino-pyrrolidin-1-yl) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} propionamide (MH + 610.3 ) (example 123), N - {trifluoroacetate (1S, 2R, 3S, 4R) -4- [2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -6 (3,3-dimethyl-butylamino) -purin-9- yl] -2,3-dihydroxy-cyclopentyl} -propionamide (MH + 503.4) (Example 124) and N - ((1S, 2R, 3S, 4R) trifluoroacetate) -4- {2 - ((R) -3- dimethylamino-pyrrolidin-1-yl) -6 [2- (4-sulfamoyl-phenyl) -ethylamino] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) propionamide (MH + 602.3) (example 125) obtained analogously to N - {trifluoroacetate (1S, 2R, 3S, 4R) -4- [2 - ((R) -320 amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -2-benzyloxy-acetamide (example 1 step 2) replacing (3R) -3aminopyrrolidine dimethyl- (R) -pyrrolidin-3-yl-amine and replacing 2-benzyloxy-N {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino ) -purin-9-yl] -2,3-dihydroxycyclopentyl} -acetamide with suitable starting compounds. Preparation of starting compounds is described herein or can be obtained from tert-butyl ester of [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -2,3-dihydroxy cyclopentyl acid ] -propionyl-carbam (intermediate G) and the corresponding amine using a procedure analogous to 2R, 3S, 4R) -4- {6- [2,2-bis- (4-hydroxyphenyl) ethylamino] -2-chloro purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (example 22 steps 1 and 2)

Example 126

N - {(1S, 2R, 3S, 4R) trifluoroacetate -4- [2 - [(R) -3- (2-acetylamino-4-methyl-thiazole-5-sulfonylamino) -pyrrolidin-1-yl] -6- ( 2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide [0203] N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) - 3-Amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -propionamide (example 18 step 2) (0.023 g, 40 mmol) is treated with a solution of 2-acetamido-4-methyl-5-thiazole sulfonyl chloride (0.0104 g, 39 mmol) in NMP (0.5 mL). The reaction mixture is stirred at room temperature overnight and purification is performed by preparative liquid chromatography detection with LCMS mass spectrometry elution with acetonitrile: water: trifluoroacetic acid to give the title compound. (MH + 789.4)

Examples 127-132 [0204] These compounds, namely, N - [(1S, 2R, 3S, 4R) trifluoroacetate) -4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (320 Phenyl-isoxazol-4-yl) -ureido] -pyrrolidin-1-yl} -purin-9-yl) -2,3-dihydroxycyclopentyl] -propionamide (MH + 771.5) (Example 127), trifluoroacetate {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2 5-pyridin-2-yl-thiophene-2-carboxylic acid -yl] -pyrrolidin-3-yl} -amide (MH + 758.4) (Example 128), trifluoroacetate 4- {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) - benzyl ester 9H-purin-2157-yl] pyrrolidin-3-ylcarbamoyl-piperidine-1-carboxylic acid (MH + 816.6) (example 129), N - [(1S, 2R, 3S, 4R) trifluoroacetate -4- (6- ( 2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (3-methyl-5-phenyl-isoxazol-4-yl) -ureido] -pyrrolidin-1-yl} -purin-9-yl ) -2,3-dihydroxycyclopentyl] propionamide (MH + 771.5) (example 130), trifluoroacetate {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2 1,3-dimethyl-1H-thieno [2,3-c] pyrazole-5-carboxylic acid (MH + 749.4) (example 131), trifluoroacetate {(R) -yl] -pyrrolidin-3-yl} -amide -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin 1-methyl-1H-benzotriazole-5-carboxylic acid -3-yl} -amide (MH + 730.5) (Example 132), obtained in analogy to Example 126 by replacing 2-acetamido-4-methyl-5-thiazole sulfonyl chloride with the appropriate isocyanate or acid chloride. Triethylamine is also used in acid chloride reactions.

Example 133

N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3-yl-ureido) -pyrrolidine hydrochloride 1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) formamide

158 room temperature overnight. The solvent is removed in vacuo and purification is carried out by reverse phase column chromatography (Isolute ™ C18, 0-100% acetonitrile in water - 0.1% TFA). Fractions are collected and MeCN is removed in vacuo. The remaining aqueous portion is basified with saturated sodium bicarbonate solution and extracted with DCM. The combined organic extracts are dried (MgSO4) and concentrated in vacuo to afford the title product. MS (ES +) m / e 769 (MH+).

Step 2: 1 - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -4-Amino-2,3-dihydroxy-cyclopentyl) -6 (2,2-diphenyl-ethylamino) - 9H-purin-2-yl] -pyrrolidin-3-yl} -3-pyridin-3-yl-urea [0206] To the solution of benzyl ester trifluoroacetate ((1S, 2R, 3S, 4R) -410 {6- ( 2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -carbamic acid (35 mg, 46 mmol) in ethanol (1 ml) under an inert gas-argon atmosphere, 10% palladium on carbon (10 mg) is added. Argon is bubbled through the reaction and placed under positive pressure of hydrogen overnight, then the mixture is filtered through Celite and the catalyst is washed with ethanol. The organic portions are combined and concentrated in vacuo to afford the title compound. MS (ES +) m / e 635 (MH+).

Step 3: N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) 3- (3-pyridin-3-yl-ureido hydrochloride) ) pyrrolidin-1-yl] -ppurin-9-yl} -2,3-dihydroxy-cyclopentyl) formamide [0207] Acetic anhydride (1.9 mg, 19 mmol) and formic acid (1.4 mg, 30 mmol ) are mixed together for 30 minutes and then added to the solution 1 - {(R) -1- [9 ((1R, 2S, 3R, 4S) -4-amino-2,3-dihydroxy-cyclopentyl) -6- ( 2,2-diphenyl-ethylamino) -9Hpurin-2-yl] -pyrrolidin-3-yl} -3-pyridin-3-yl-urea (11 mg, 17 mmol) in THF (0.5 mL). The reaction mixture is stirred at room temperature overnight and purified by reverse phase column chromatography (Isolute ™ C18, 0-100% acetonitrile in water - 0.1% HCl) to afford the title compound. (MH + 663.5)

159

Example 134 [0208] Trifluoroacetate {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) - (R) -3-Dimethylamino-pyrrolidine-1-carboxylic acid 9H-purin-2-yl] -pyrrolidin-3-yl} -amide

Step 1: {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-Dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenylethylamino) -9H-purin-2 imidazole-1-carboxylic acid -yl] -pyrrolidin-3-yl} -amide:

Mixture containing N - {(3aR, 4S, 6R, 6aS) -6- [2 - ((R) -3-amino-pyrrolidin-1-yl) 6- (2,2-diphenyl-ethylamino) -purin-9 -yl] -2,2-dimethyl-tetrahydro-cyclopenta [1,3] dioxol-10-yl} -propionamide (intermediate M) (0.24 g, 394 mmol) and CDI (0.275 g, 1.7 mmol) in dry DCM (6 ml) is stirred at room temperature for 3 hours. The resulting solution is purified by silica gel chromatography eluting with 100% DCM to 5% methanol in DCM to give the title compound as a yellow oil. The oil consists of an imidazole urea intermediate together with various amounts of the corresponding isocyanate and imidazole, which are also suitable as urea precursors.

Step 2: Trifluoroacetate {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin- (R) -3-Dimethylamino-pyrrolidine-1-carboxylic acid 2-yl] -pyrrolidin-3-yl} -amide:

[0209] Dimethyl- (R) -pyrrolidin-3-ylamine (4.6 mg, 40 mmol) is treated with a solution of {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2 , 3-dihydroxy-4-propionylamino-cyclopentyl) -6 (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -amide, imidazole-1-carboxylic acid (25 mg, 40 mmol ) in DCM (1 mL) and the reaction mixture is stirred at room temperature overnight. The solvent is removed in vacuo and the residue is treated with TFA (0.5 ml) and water (0.5 ml). The reaction mixture is stirred at room temperature for 3 hours, then concentrated in vacuo and the crude material obtained

160 purified by preparative liquid chromatography with LC-MS mass spectroscopy detection eluting with acetonitrile: water: trifluoroacetic acid to give the title compound. (MH + 71.5)

Example 135

Trifluoroacetate {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2 4- (2-cyano-ethyl) -piperazine-1-carboxylic acid -yl] -pyrrolidin-3-yl} -amide [0210] This compound is obtained analogously to trifluoroacetate {(R) -1- [9 ((1R , 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -amide ( R) -3-dimethylaminopyrrolidine-1-carboxyl (Example 134) replacing dimethyl- (R) -pyrrolidin-3-ylamine with an appropriate amine. (MH + 697.4)

Example 136 -155 [0211] These compounds, namely, N - [(1S, 2R, 3S, 4R) trifluoroacetate) -4- (2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -6 {[ (1R, 3S) -2,2-dimethyl-3- (2-methyl-propenyl) -cyclopropylmethyl] -amino} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -propionamide (MH + 555.6) ( example 136), N - {(1S, 2R, 3S, 4R) trifluoroacetate -4- [6 - ((1R, 2R) -2-benzyloxycyclopentylamino) -2 ((R) -3-dimethylamino-pyrrolidin-1-yl ) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (MH + 593.5) (example 137), N - {trifluoroacetate (1S, 2R, 3S, 4R) -4- [6 - ((1S, 2S) -2-benzyloxycyclopentylamino) -2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -purine -9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (MH + 593.5) (example 138), N - {trifluoroacetate (1S, 2R, 3S, 4R) -4- [6 - ((1S, 2S) -bicyclopropyl-2-ylamino) -2 - ((R) 3-dimethylamino-pyrrolidin-1-yl) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} propionamide (MH + 555.6) (example 139 )

161 N - {trifluoroacetate (1S, 2R, 3S, 4R) -4- [6 - ((R) -1-benzyl-pyrrolidin-3-ylamino) -2 ((R) -3-dimethylamino-pyrrolidin-1-yl ) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} propionamide (MH + 578.5) (Example 140), N - {trifluoroacetate (1S, 2R, 3S, 4R) -4- [6 - (( S) -1-benzyl-pyrrolidin-3-ylamino) -25 ((R) -3-dimethylamino-pyrrolidin-1-yl) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} propionamide (MH + 578 , 5) (example 141), N - {trifluoroacetate (1S, 2R, 3S, 4R) -4- [2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -6 (2-piperidin-1-yl-ethylamino) -purin- 9-yl] -2,3-dihydroxycyclopentyl} -propionamide (MH + 530.5) (example 142), N - {trifluoroacetate (1S, 2R, 3S, 4R) -4- [6- [2- (4-benzyl -piperidin-1-yl) ethylamino] -2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -purin-9-yl] -2,3-dihydroxycyclopentyl} -propionamide (MH + 620.5) ( example 143), N - {trifluoroacetate (1S, 2R, 3S, 4R) -4- [2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -6 ((S) -2-phenyl-1-pyrrolidin-1 -ylmethyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (MH + 606.5) (example 144), N - {trifluoroacetate (1S, 2R, 3S, 4R) -4- [ 2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -6- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-ylamino) -purin-9-yl ] -2,3-dihydroxycyclopentyl} -propionamide (MH + 579.5) (example 145), N - {trifluoroacetate (S, 2R, 3S, 4R) -4- [2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -620 ((S) -1-hydroxymethyl-3-methyl-butylamino ) -purin-9-yl] -2,3-dihydroxycyclopentyl} -propionamide (MH + 519.5) (example 146), N - {trifluoroacetate (1S, 2R, 3S, 4R) -4- [2 - ((R ) -3-dimethylamino-pyrrolidin-1-yl) -6 ((S) -1-hydroxymethyl-3-methylsulfanyl-propylamino) -ppurin-9-yl] -2,3-dihydroxycyclopentyl} -propionamide (MH + 537.5 ) (example 147),

162 N - {trifluoroacetate (1S, 2R, 3S, 4R) -4- [6 - ((R) -1-benzyl-2-hydroxyethylamino) -2 ((R) -3-dimethylamino-pyrrolidin-1-yl ) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} propionamide (MH + 553.5) (example 148), N - {trifluoroacetate (1S, 2R, 3S, 4R) -4- [2 - (( R) -3-dimethylamino-pyrrolidin-1-yl) -6- ((1S, 2S) -2-hydroxy-1-hydroxymethyl-2-phenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (MH + 569.5) (example 149), N - ((1S, 2R, 3S, 4R) trifluoroacetate -4- {2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -6 [(S) -2-hydroxy-1- (4- hydroxy-benzyl) -ethylamino] -purin-9-yl} -2,3-dihydroxycyclopentyl) -propionamide (MH + 569.5) (example 150), N - trifluoroacetate ((S, 2R, 3S, 4R) -4- {2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -6 [(S) -2-hydroxy-1- (1H-imidazol-4-ylmethyl) -ethylamino] -purin-9-yl} -2,3-dihydroxycyclopentyl) -propionamide (MH + 543.5) (Example 151), N - ((1S, 2R, 3S, 4R) trifluoroacetate -4- {2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -6 [(S) -2-hydroxy-1- (1H- indol-3-ylmethyl) ethylamino] pipin-9-yl} -2,3-dihydroxycyclopentyl) propionamide (MH + 592.4) (example 152), N - {trifluoroacetate (1S, 2R, 3S, 4R) - 4- [6 - ((S) -1-benzyl-2-methoxy-ethylamino) -2- ((R) -3-dimethylamino-pyrrolidin-1-yl) -purin-9-yl] -2,3-dihydroxy -cyclopentyl} propionamide (MH + 567.4) (example 153), N - {trifluoroacetate (1S, 2R, 3S, 4R) -4- [6 - [(S) -1- (4-benzyloxy-benzyl) -2-hydroxyethylamino] -2 - ((R) -3-dimethylamino- pyrrolidin-1-yl) -ppurin-9-yl] -2,3-dihydroxycyclopentyl} -propionamide (MH + 659.4) (example 154) and N - trifluoroacetate ((1S, 2R, 3S, 4R) -4- { 2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -6 [(1S, 2S) -2-hydroxy-1-hydroxymethyl-2- (4-methylsulfanyl-phenyl) -ethylamino] -purin-9-yl } -2,3-dihydroxy-cyclopentyl) -propionamide (MH + 615) (Example 155) is obtained analogously to trifluoroacetate N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-163 cyclopentyl} -2-benzyloxy-acetamide (example 1 step 2) replacing (3R) -3-aminopyrrolidine, dimethyl- (R) -pyrrolidin-3-yl-amine and replacing 2-benzyloxy-N {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -ppurin-9-yl] -2,3-dihydroxycyclopentyl} -acetamide with suitable starting compounds. Preparation of starting compounds is described herein or can be obtained from tert-butyl ester of [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -2,3-dihydroxycyclopentyl] -propionyl-carbam (intermediate G) and the corresponding amine using a procedure analogous to 2R, 3S, 4R) -4- {6- [2,2-bis- (4-hydroxy-phenyl) ethylamino] -2-chloro-purine -9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (example 22 steps 1 and 2).

Example 156

N - {(R) -1- [6- (2,2-bis- (4-methoxy-phenyl) -ethylamino] -9 hydrochloride ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4 -propionylamino-cyclopentyl) -9H-purin-2-yl] pyrrolidin-3-yl} -isonicotinamide [0212] This compound is obtained analogously to N {(1S, 2R, 3S, 4R) -4- [2- ( (R) -3-Amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-benzyloxy-acetamide (example stage 1 2) replacing (3R) -3-aminopyrrolidine (R) -N-pyrrolidin-3-yl-isonicotinamide (intermediate O) and replacing 2-benzyloxy-N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) purin-9-yl] -2,3- dihydroxy-cyclopentyl} -acetamide N - ((1S, 2R, 3S, 4R) -4- {6- [2,2-bis- (4-methoxy-phenyl) -ethylamino] -2-chloro-purin-9-yl} -2,3-dihydroxy-cyclopentyl) propionamide {obtained from tert-butyl ester of [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -2,3-dihydroxy-cyclopentyl ] -propionyl-carbam (intermediate G) and the corresponding amine using a procedure analogous to 2R, 3S, 4R) -4- {6- [2,2-bis- (4-hydroxyphenyl) ethylamino] -2-chloro-purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (example 22 stages 1 and 2)}. (MH + 736.5)

164

Example 157

{(R) -1- [6- [2,2-bis- (4-methoxy-phenyl) -ethylamino] -9 hydrochloride ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino -cyclopentyl) -9H-purin-2-yl] pyrrolidin-3-yl} -amide 5-methyl-isoxazole-3-carboxylic acid [0213] is prepared analogously to Example 93 by replacing N - {(1S , 2R, 3S, 4R) -4- [2-chloro-6- (1-ethyl-propylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide N - ((1S, 2R, 3S, 4R) -4- {6- [2,2-bis- (4-methoxy-phenyl) -ethylamino] -2-chloro-9-yl} -2,3-dihydroxy -cyclopentyl) -propionamide [obtained from tert-butyl ester of [(1S, 2R, 3S, 4R) -4- (2,6-dichloropurin-9-yl) -2,3-dihydroxy-cyclopentyl] -propionyl-carbamic acid (intermediate) G) and the corresponding amine using a procedure analogous to 2R, 3S, 4R) -4- {6- [2,2-bis- (4-hydroxy-phenyl) ethylamino] -2-chloro-purin-9-yl-2, 3-dihydroxy-cyclopentyl) -propionamide (example 22 steps 1 and 2)]. (MH + 740.5)

Example 158

N - {(R) -1- [6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -9 hydrochloride ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4 -propionylamino-cyclopentyl) -9H-purin-2-yl] pyrrolidin-3-yl} -isonicotinamide [0214] A mixture containing N - ((1S, 2R, 3S, 4R) -4- {2 - ((R) - 3-amino-pyrrolidin-1-yl) -6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (example 22 step 4 ) (20 mg, 33 mmol) in THF (0.5 mL) and NMP (0.5 mL) are treated with TEA (13 mg, 0.13 mmol), followed by isonicotinoyl chloride hydrochloride (16 mg, 83 mmol). The reaction mixture is stirred at room temperature for 2 hours, the solvent removed in vacuo and purified by C-18 reverse phase column chromatography eluting with acetonitrile: water: HCl (0.1%) (gradient 0 to 100% acetonitrile) getting the title compound. (MH + 708.4)

165

Example 159

{(R) -1- [6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -9 hydrochloride ((1R, 2S, 3R, 1-Methyl-1H-benzotriazole-5-carboxylic acid 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -9H-purin-2-yl] pyrrolidin-3-yl} -amide [0215] This compound receives analogously to N - {(R) -1- [6 [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -9 - hydrochloride ((1R, 2S, 3R, 4S) -2,3- dihydroxy-4-propionylamino-cyclopentyl) -9H-purin-2-yl] -pyrrolidin-3-yl} -isonicotinamide (example 158) replacing isonicotinoyl chloride hydrochloride with 1-methyl-1H1,2,3-benzotriazole-5-carbonyl chloride. (MH + 762.4)

Example 160-162 [0216] These compounds, namely, N - ((1S, 2R, 3S, 4R) -4- {6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] hydrochloride - 2- [(R) -3- (3-pyridin-3-ylmethyl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxycyclopentyl) -propionamide (MH + 737.5) (example 160 ), hydrochloride N - ((1S, 2R, 3S, 4R) -4- {6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] 2 - [(R) -3- (3- pyridin-4-ylmethyl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxycyclopentyl) -propionamide (MH + 737.2) (Example 161), N - ((1S, 2R, 3S, 4R) -4- {6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] hydrochloride 2 - [(R) -3- (3-pyridine- 4-ylmethyl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (MH + 740.5) (example 162), obtained in analogy to N - ((1S, 2R, 3S, 4R) -4- {6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -2 - [(R) -3- (3) hydrochloride pyridin-2-ylmethyl-ureido) -pyrrolidin-1-yl] purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (example 23) replacing 2- (aminomethyl) pyridine with the appropriate amine.

Example 163

166

2-Amino-N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 [(R) -3- (3-pyridin-3-yl- ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxycyclopentyl) -acetamide [0217] Solution 1 - {(R) -1- [9 - ((1R, 2S, 3R, 4S ) -4-amino-2,3-dihydroxy-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -3-pyridin-3-urea ( example 26 step 2) (17 mg, 26 mmol) in THF (1 ml) is treated with 2,5-dioxo-pyrrolidin-1-yl ester of tert-butoxycarbonylaminoacetic acid (9 mg, 29 mmol) and stirred at room temperature overnight. The resulting solution is treated with 1.25 M HCl in ethanol (1 mL) and stirred at room temperature for 2 days. After purification by C-18 reverse phase column chromatography eluting with acetonitrile: water: HCl (0.1%) (gradient 0 to 100% acetonitrile), the title compound is obtained. (MH + 691.99)

Example 164

N - {(1S, 2R, 3S, 4R) -4 - [(R) -2- [1,3 '] bipyrrolidinyl-1'-yl-6- (2,215 diphenyl-ethylamino) -purin-9-yl hydrochloride ] -2,3-dihydroxy-cyclopentyl} -propionamide [0218] The title compound is obtained analogously to N {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidine- 1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-benzyloxy-acetamide (example 1 step 2) replacing 2-benzyloxy-N- { (1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] 20 2,3-dihydroxy-cyclopentyl} -acetamide N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenylethylamino) -purin-9-yl] -2,3 dihydroxy-cyclopentyl} -propionamide (intermediate J) and replacing (3R) -3-aminopyrrolidine (R) - [1,3 '] bipyrrolidinyl (intermediate N). (MH + 625.4)

Example 165

167

N- (1S, 2R, 35.4R) trifluoroacetate -4- (6- (2,2-diphenyl-ethylamino) -2- {2- [3- (3,4,5,6-tetrahydro-2H- [1, 2 '] bipyridinyl-4-yl) -ureido] -ethylamino} -purin-9-yl) -2,3-dihydroxycyclopentyl] -propionamide [0219] N - {Trifluoroacetate solution (1S, 2R, 3S, 4R) -4 - [2- (2-Amino-ethylamino) -65 (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (Example 100) (27 mg, 37 mmol) in IPA (0.5 ml) is treated with (3,4,5,6-tetrahydro-2H [1,2 '] bipyridinyl-4-yl) imidazole-1-carboxylic acid amide (intermediate C) ( 1.1 ml 10 mg / ml solution in DCM, 40 mmol). The reaction mixture is stirred at room temperature for 7 days, the solvent is removed in vacuo and the residue is purified by C-18 reverse phase column chromatography eluting with acetonitrile: water: TFA (0.1%) (gradient 0 to 100% acetonitrile ) to obtain the title compound. (MH + 748.6)

Example 166

Ester trifluoroacetate 1- {2 - [(R) -3- (3 - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-415 propionylamino-cyclopentyl) - 6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -ureido) -pyrrolidin-1-yl] -2-oxo-ethyl} -piperidin-4-yl acid biphenyl -2-ylcarbamic compound [0220] This compound is obtained analogously to {(R) -1- [9 ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- trifluoroacetate (6-) 2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -amide (R) -3-Dimethylaminopyrrolidine-1-carboxyl (Example 134) replacing dimethyl- (R) -pyrrolidin-3-ylamine with intermediate Z. (MH + / 2,510.62)

Example 167

N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-Diphenyl-ethylamino) -2 - {(R) -3- [3- (2-methyl-525 phenyl-furan- 3-yl) -ureido] -pyrrolidin-1-yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -propionamide

168 [0221] This compound is obtained in analogy to Example 126 by replacing 2-acetamido-4-methyl-5-thiazolosufonyl chloride with 3-isocyanato-2-methyl-5-phenylfuran and exchanging the solvent with THF. (MH + 770.48)

Example 168

1- [6-Amino-9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic acid ethyl ester

Step 1: N - [(1S, 2R, 3S, 4R) -4- (6 - {[Bis- (4-methoxy-phenyl) -methyl] -amino} -2-chloro-purin-9-yl) -2, 3-dihydroxy-cyclopentyl] -propionamide [0222] For N - [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -2,310-dihydroxy-cyclopentyl] -propionamide solution ( intermediate J7) (2.6 g, 7.22 mmol) in dry THF (26 ml) C, C-bis- (4-methoxy-phenyl) -methylamine (intermediate Y) (3.5 g, 14.44 mmol). The mixture is heated at 50 ° C for 12 hours and then concentrated in vacuo. The residue is dissolved in chloroform and washed successively with 1.5 N HCl, water and brine. The organic phase is dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product is purified by silica gel chromatography (grain size 60-120) eluting with 2% methanol in chloroform to give the title product. LC-MS (0.1% formic acid, acetonitrile): (MH + 567)

Step 2: N - [(1S, 2R, 3S, 4R) -4- (6 - {[Bis- (4-methoxy-phenyl) -methyl] -amino} -220 hydrazine-purin-9-yl) -2 , 3-dihydroxy-cyclopentyl] -propionamide [0223] Mixture containing N - [(1S, 2R, 3S, 4R) -4- (6 - {[bis- (4-methoxy-phenyl) methyl] -amino} -2 -chloro-purin-9-yl) -2,3-dihydroxy-cyclopentyl] -propionamide (1.6 g,

2.82 mmol) and hydrazine monohydrate (14 ml) are stirred at room temperature for 72 hours. Isopropyl alcohol (10 mL) is then added and the solvent decant to give a gummy mixture. This mixture is dissolved in water (10 ml) and stirred for 12 hours. The fine solid obtained is filtered, washed with water and

169 dried in vacuo to give the title product which is used in the next step without further purification. LC-MS (0.1% formic acid, acetonitrile): (MH + 563).

Step 3: 1- [6 - {[Bis- (4-methoxy-phenyl) -methyl] -amino} -9-ethyl ethyl ester ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino -cyclopentyl) -9H-purin-2-yl] -1H-pyrazolo-4-carboxylic acid:

[0224] For N - [(1S, 2R, 3S, 4R) -4- (6 - {[bis- (4-methoxy-phenyl) -methyl] amino} -2-hydrazine-purin-9-yl) solution -2,3-dihydroxy-cyclopentyl] -propionamide (0.1 g, 0.177 mmol) in dry ethyl alcohol (5 ml) 2-methyl-3-oxo-propionic acid ethyl ester (obtained from 3,3-diethoxy-propionate ethyl, as described in: Bertz SH, Dabbagh G. and Cotte P .; J. Org. Chem. (1982) 47, pp. 2216-2217) (0.033 g, 0.231 mmol). The reaction mixture is heated to reflux for 8 hours and then concentrated in vacuo. The crude residue is purified by silica gel method (grain size 60-120) eluting with 3% methanol in chloroform to give the title compound. LC-MS (0.1% formic acid, acetonitrile): (MH + 671).

Step 4: 1- [6-Amino-9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -9H-purin-2-yl] -1H-pyrazole acid ethyl ester 4-carboxylic acid:

[0225] Cooled (0 ° C) solution of 1- [6 - {[Bis- (4-methoxyphenyl) methyl] amino} -9 - ethyl ester ((1R, 2S, 3R, 4S) -2.3 -dihydroxy-4-propionylaminocyclopentyl) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic acid (0.1 g, 0.149 mmol) in dry dichloromethane (4 ml) is treated dropwise with TFA (2 ml). The mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is co-evaporated with chloroform three times to remove excess trifluoroacetic acid and purify the residue by preparative HPLC to afford the title compound. LC-MS (0.1% formic acid, acetonitrile): (MH + 445.3).

Example 169

170 {(1S, 2R, 3S, 4R) -4- [2-Chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -oxooxazole-5-carboxylic acid [ 0226] This compound is obtained analogously to N - {(1S, 2R, 3S, 4R) -4- [2-chloro6- (2,2-diphenyl-ethylamino) -ppurin-9-yl] -2,3-dihydroxy -cyclopentyl} -propionamide (intermediate JJ4) replacing propionyl chloride with isoxazole-5-carbonyl chloride. (MH + 560.28)

Example 170

N - {(1S, 2R, 3S, 4R) -4- [6-Amino-2- (4-quinolin-4-yl-pyrazol-1-yl) -purin-9-yl] 2,3-dihydroxy cyclopentyl} -propionamide [0227] This compound is prepared in analogy to Example 168 by replacing 2-formyl-3-oxopropionic acid ethyl ester with 2- (4-quinolyl) malmaldehyde. (MH + 500.3)

Example 171

N - {(1S, 2R, 3S, 4R) -4- [6- (2,2-Diphenyl-ethylamino) -2- (4-pyridin-2-yl-pyrazol-115-yl) -purin-9-yl ] -2,3-dihydroxy-cyclopentyl} -propionamide [0228] This compound is prepared in analogy to Example 42 by replacing cyclohexanecarboxaldehyde with 2-pyridinyl-propanedial. The reaction is carried out in ethanol. (MH + 630.40)

Example 172

N - {(1S, 2R, 3S, 4R) -4- [6- (2,2-Diphenyl-ethylamino) -2- (4-pyridin-4-yl-pyrazol-1-yl) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide [0229] This compound is prepared in analogy to Example 42 by replacing cyclohexanecarboxaldehyde with 4-pyridinyl-propanedial. The reaction is carried out in ethanol. (MH + 630.41)

Example 173

171

1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] - 1H-pyrazole-4-carboxylic acid

Level 1: 1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-45-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl acid ethyl ester ] -1H-Pyrazole-4-carboxylic acid [0230] This compound is prepared in a manner analogous to 1- [6 - {[bis- (4-methoxy-phenyl) -methyl] -amino} -9 - (1R, 2S acid , 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -9H-purin-2-yl] -1H-pyrazole-4-carboxyl (example 168 step 3) replacing N - [(1S, 2R, 3S, 4R) -4- (6 - {[bis- (4-methoxy-phenyl) -methyl] -amino} -2-hydrazino-purin-9-yl) -2,3- dihydroxy-cyclopentyl] -propionamide N {(1S, 2R, 3S, 4R) -4- [6- (2,2-diphenyl-ethylamino) -2-hydrazine-purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide.

Step 2: 1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-415 propionylamino-cyclopentyl) -methylamide -6- (2,2-diphenyl-ethylamino) -9H-purin-2 -yl] -1H-pyrazole-4-carboxylic acid [0231] Mixture of 1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- ethyl ester (2,2- diphenyl-ethylamino) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic acid (0.07 g, 0.112 mmol) and 40% aqueous methylamine solution (3 ml) is heated to 65 ° C for 12 hours. The reaction mixture is concentrated in vacuo and the crude product is purified by silica gel chromatography eluting with 4% methanol in chloroform to afford the title compound. LC-MS (0.1% formic acid, acetonitrile): (MH + 610.41)

Example 174

1- [6-Amino-9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic acid methylamide

172

Step 1: 1- [6 - {[Bis- (4-methoxy-phenyl) -methyl] -amino} -9 acid methylamide ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino- cyclopentyl) -9H-purin-2-yl] -1H-pyrazolo-4-carboxylic acid:

[0232] Mixture of 1- [6 - {[Bis- (4-methoxy-phenyl) -methyl] 5-amino} -9 - ethyl ester ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4 -propionylamino-cyclopentyl) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic acid (example 168, step 3) (0.2 g, 0.298 mmol) and 40% aqueous methylamine solution (5 ml) is heated to 65 ° C for 12 hours. The reaction mixture is concentrated in vacuo and the crude residue is purified by silica gel chromatography eluting with 3% methanol in chloroform to afford the title compound. LC-MS (0.1% formic acid, acetonitrile): 656 (MH +).

Step 2: 1- [6-Amino-9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic acid methylamide [0233] Cooled (0 ° C) solution of 1- [6 - {[bis- (4-methoxy-phenyl) -methyl] -amino} -9 - acid methylamide ((1R, 2S, 3R, 4S) -2.3 dihydroxy-4-propionylaminocyclopentyl) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic acid (0.08 g, 0.122 mmol) in dry dichloromethane (4 ml) is treated slowly with trifluoroacetic acid (2 ml). The reaction mixture is stirred at room temperature for 48 hours and then concentrated in vacuo. The residue is co-evaporated with chloroform three times to remove excess trifluoroacetic acid and the crude product is purified by preparative HPLC to afford the title compound. LC-MS (0.1% formic acid, acetonitrile): (MH + 430.28)

Example 175

N - ((1S, 2R, 3S, 4R) trifluoroacetate -4- {6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] 2 - [(R) -3- (3-pyridine -3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide:

173 [0234] This compound is obtained in analogy to Example 23 replacing {(R) -1- [6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -9 - acid phenyl ester ((1R, 2S , 3R, 4S) 2,3-dihydroxy-4-propionylamino-cyclopentyl) -9H-purin-2-yl] -pyrrolidin-3-yl} -carbamic hydrochloride N - ((1S, 2R, 3S, 4R) -4- {2 - ((R) -3-amino-pyrrolidin-1-yl) -65 [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -purin-9-yl} -2,3-dihydroxy -cyclopentyl) -2-hydroxy-acetamide (example 7 step 5) and replacing 2- (aminomethyl) pyridine with an ester phenyl pyridin-3-yl-carbamic acid (intermediate ZB). (MH + 725.32)

Example 176

Trifluoroacetate 4 {[(R) -3- (3 - {(R) -1- [9 - ((1R, 2S, 3R, 4S) benzyl ester of 2,3-Dihydroxy-4-propionylamino-cyclopentyl) - 6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -ureido) -pyrrolidine-1-carbonyl] -amino} -piperidine-1-carboxylic acid [0235] The title compound is obtained by the method of analogous to 4- [3- (2 - {[9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-415 benzyl ester of benzyl acid propionylaminocyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2-carbonyl] amino} -ethyl) -ureido] -piperidine-1-carboxylic acid (example 108) replacing (2-aminoethyl) -amide 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6 (2,2-diphenylethylamino) -9H-purine-2-carboxylic acid N-trifluoroacetate ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3 - ((R) -3-pyrrolidin-3-ylureido) -pyrrolidin-1-yl] - purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (example 17 step 1). (MH + 943.4)

Example 177

N - ((1S, 2R, 3S, 4R) trifluoroacetate -4- {2 - [((S) -1-benzyl-pyrrolidin-3-yl) methylamino] -6- [2- (4-fluoro-phenyl) ) -2-phenyl-ethylamino] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide

174 [0236] This compound is obtained analogously to N {(1S, 2R, 3S, 4R) trifluoroacetate) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2- diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-benzyloxy-acetamide (example 1 step 2) replacing (3R) -3- (Boc-amino) pyrrolidine ((S) -1- benzyl-pyrrolidin-3-yl) -methyl-amine and substitution

2-benzyloxy-N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} - acetamide with N - ((1S, 2R, 3S, 4R) -4- {2-chloro6- [2- (4-fluoro-phenyl) -2-phenyl-ethylamino] -purin-9-yl} -2,3- dihydroxy-cyclopentyl) propionamide [obtained from tert-butyl ester of [(1S, 2R, 3S, 4R) -4- (2,6-dichloropurin-9-yl) -2,3-dihydroxy-cyclopentyl] -propionyl-carbamic acid (intermediate product

G) and the corresponding amine using a procedure analogous to 2R, 3S, 4R) -4- {6- [2,2-bis- (4-hydroxyphenyl) ethylamino] -2-chloro-purin-9-yl} -2,3- dihydroxy-cyclopentyl) propionamide (example 22 steps 1 and 2)]. (MH + 693.5)

Example 178

N - {(1S, 2R, 3S, 4R) trifluoroacetate 4- [2 - {(R) -3- [3- (4-benzyloxy-phenyl) -ureido] 15-pyrrolidin-1-yl} -6- (2 , 2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} propionamide. This compound is obtained in analogy to Example 126 replacing 2-acetamido-4-methyl-5-thiazolosufonyl chloride 1- benzyloxy-4-isocyanato-benzene. (MH + 796.49)

Example 179-180 [0238] These compounds, namely, trifluoroacetate {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2, (R) -3-Amino-pyrrolidine-1-carboxylic acid (MH + 677.5) (Example 179) 2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -amide (MH + 677.5) (Example 179)

175 trifluoroacetate {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2 (S) -3-Amino-pyrrolidine-1-carboxylic acid (MH + 683.4) (Example 180) -yl] -pyrrolidin-3-yl} -amide (analogous to trifluoroacetate {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,35 dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} - (R) -3-Dimethylamino-pyrrolidine-1-carboxylic acid amide (example 134) replacing dimethyl- (R) -pyrrolidin-3-ylamine with a suitable amine.

Example 181 (R) -N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-Diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-310-yl) ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxypropionamide

Step 1: (R) -2-Benzyloxy-N - [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -2,3-dihydroxy-cyclopentyl] -propionamide [0239 ] The title compound is obtained by dissolving (R) -2-benzyloxy-propionic acid (1 eq) in dichloromethane with 1,3-dicyclohexylcarbodiimide (1 eq) and a catalytic amount of 4-dimethylaminopyridine, stirring for five minutes and then adding (1S , 2R, 3S, SR) -3-amino-5- (2,6-dichloro-purin-9-yl) -cyclopentane-1,2-diol (intermediate J5; 1-eq) in dichloromethane. The reaction mixture is stirred at room temperature until it is considered complete, the solvent is removed under reduced pressure and the title compound is purified by column chromatography / crystallization.

Step 2: (R) -2-Benzyloxy-N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenylethylamino) -ppurin-9-yl] -2, 3-dihydroxy-cyclopentyl} -propionamide [0240] The title compound is obtained in analogy to N - {(1S, 2R, 3S, 4R) -4- [225 chloro-6- (2,2-diphenyl-ethylamino) -purin- 9-yl] -2,3-dihydroxy-cyclopentyl} propionamide (intermediate J7), replacing (R) -2-benzyloxy-N - [(1S, 2R, 3S, 4R) -4176 (2,6-dichloro- acetic acid purin-9-yl) -2,3-dihydroxy-cyclopentyl] -propionamide

N - [(S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -2,3-dihydroxy-cyclopentyl] -propionamide.

Stage 3: {(R) -1- [9 - [(1R, 2S, 3R, 4S) -4 - ((R) -25 benzyloxy-propionylamino) -2,3-dihydroxy-cyclopentyl] -6- acid tert-butyl ester (2,2-diphenylethylamino) 9H-purin-2-yl] -pyrrolidin-3-yl} -carbamic acid [0241] Suspension of (R) -2-benzyloxy-N - {(1S, 2R, 3S, 4R) -4 - [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (1 eq) and (3R) - (+) - 3- ( Boc-amino) pyrrolidine (4 eq.) In acetonitrile is treated with a catalytic amount of sodium iodide and then heated using radiation in a Personal Chemistry Emrys ™ Optimizer microwave reactor at 160 ° C. After 1 hour, the solvent is removed in vacuo; the residue is purified by column chromatography / crystallization to afford the title compound.

Step 4: (R) -N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-Amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) - purin-9-yl] -2,3-dihydroxycyclopentyl} -2-benzyloxypropionamide [0242] {(R) -1- [9 - [(1R, 2S, 3R, 4S) acid tert-butyl ester solution (R) -2-Benzyloxy-propionylamino) -2,3-dihydroxy-cyclopentyl] -6- (2,2-diphenyl-ethylamino) 9H-purin-2-yl] -pyrrolidin-3-yl} -carbamic acid in methanol (~ 0.5 M) is treated with the same volume of 4 M HCl in dioxane and stirred at room temperature for 2 hours.

The solvent is removed in vacuo and purification is carried out by column chromatography / crystallization to afford the title compound.

Step 5: (R) -2-Benzyloxy-N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 [(R) -3- (3- pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide

177 [0243] A solution containing (R) -N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl- ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-benzyloxy-propionamide (1 eq) and pyridin-3-yl-carbamic acid phenyl ester (intermediate ZB) (1 eq) in NMP stirred at 100 ° C for 1 hour. The solvent is removed in vacuo and the title compound is obtained after purification by column chromatography / crystallization.

Step 6: (R) -N - ((1S, 2R, 3S, 4R) 4- {6- (2,2-Diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3-yl- ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-propionamide [0244] For a mixed solution of (R) -2-benzyloxy-N - ((1S, 2R , 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9 -yl} 2,3-dihydroxy-cyclopentyl) -propionamide in ethanol is added 10 eq. ammonium formate and 20 mol% 10% palladium-on-carbon catalyst. The mixture is stirred at 80 ° C for five hours, allowed to cool and filtered through Celite ™. Removal of the solvent under reduced pressure gives the title compound.

Example 182 (S) -N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-Diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3- ylureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxypropionamide

Step 1: (S) -1 - [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -2,3-dihydroxycyclopentylcarbamoyl] -ethyl ester of acetic acid [0245] The title compound is obtained analogously to intermediate J6, from intermediate J5, replacing propionyl chloride with (S) -1-chlorocarbonylethyl ester of acetic acid.

Step 2: Ester (S) -1 - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) purin-9-yl] -2,3- dihydroxy-cyclopentylcarbamoyl} ethyl acetic acid

178 [0246] The title compound is obtained analogously to N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3- dihydroxy-cyclopentyl} propionamide (intermediate J7), replacing ester (S) -1 - [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -2,3-dihydroxy- acetic acid cyclopentylcarbamoyl] ethyl (Example 182, step 1) N - [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -2,3-dihydroxycyclopentyl] -propionamide .

Step 3: (S) -1 - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-tert-butoxycarbonylaminopyrrolidin-1-yl) -6- (2,2-diphenyl) ester -ethylamino) -purin-9-yl] -2,3-dihydroxycyclopentylcarbamoyl} -ethyl acetic acid.

[0247] The title compound is obtained analogously to {(R) -1- [9 - [(1R, 2S, 3R, 4S) -4 - ((R) -2-benzyloxy-propionylamino) tert-butyl ester. 2,3-dihydroxycyclopentyl] -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -carbamic (example 181, step 3), replacing ester (S) -1 - {(1S, 2R, 3S, 4R) -4- [2-chloro-6 (2,2-diphenyl-ethylamino) -ppurin-9-yl] -2,3-dihydroxy-cyclopentylcarbamoyl} -ethyl acetic acid ( example 182, step 2) (R) -2-benzyloxy-N - {(1S, 2R, 3S, 4R) -4- [2-chloro6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2, 3-dihydroxy-cyclopentyl} -propionamide (example 181, step 2).

Stage 4: (S) -N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-Amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -puryn- 9-yl] -2,3-dihydroxycyclopentyl} -2-hydroxy-propionamide [0248] The title compound is obtained analogously to (R) -N - {(1S, 2R, 3S, 4R) -4 [2 - ((R ) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-benzyloxy-propionamide (example 181, step 4 ) replacing ester (S) -1 - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-tert-butoxycarbonylamino-pyrrolidin-1-yl) -6 (2,2-diphenyl- acetic acid ethylamino) -ppurin-9-yl] -2,3-dihydroxy-cyclopentylcarbamoyl} ethyl (example 182, step 3) with {(R) -1- [9 [(1R, 2S, 3R tert-butyl ester , 4S) -4 - ((R) -2-benzyloxy-propionylamino) -2,3-dihydroxy-cyclopentyl] -6179 (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3 -yl} -carbamate (Example 181, step 3).

Stage 5: (S) -N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-Diphenyl-ethylamino) -2 - [(R) -3- (3-Pyridin-3-yl-ureido) pyrrolidin-1-yl] -ppurin-9-yl} -2,3-dihydroxy-cyclopentyl) -hydroxy-propionamide [0249] The title compound is obtained analogously to (R) -2-benzyloxy-N ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin -9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (example 181, step 5), replacing (S) -N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin- 9-yl] -2,3-dihydroxy-cyclopentyl} -2-hydroxypropionamide (example 182, step 4) (R) -N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-benzyloxy-propionamide (example 181, step 4).

Example 183

N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-Diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1 -yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -3-hydroxypropionamide [0250] The title compound is obtained analogously to (R) -2-benzyloxy-N ((1S, 2R, 3S, 4R ) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl } -2,3-dihydroxy-cyclopentyl) -propionamide (example 181, step 5), replacing N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenylethylamino) -purin-9-yl ] -2,3-dihydroxy-cyclopentyl} -3-hydroxy-propionamide (intermediate ZG) (R) -N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3- aminopyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-benzyloxy-propionamide (example 181, step 4).

Example 184

180

N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-Diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-2-ylmethyl-ureido) -pyrrolidin-1 -yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -3-hydroxy-propionamide [0251] The title compound is obtained analogously to (R) -2-benzyloxy-N5 ((1S, 2R, 3S, 4R ) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (example 181, step 5), replacing N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenylethylamino) -purin-9-yl ] -2,3-dihydroxy-cyclopentyl} -3-hydroxy-propionamide (intermediate ZG) (R) -N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3- aminopyrrolidin-1-yl) -6- (2,210 diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-benzyloxypropionamide (example 181, step 4) and pyridin-2-ylmethyl- carbamic (intermediate ZC) with phenyl ester of pyridin-3-yl-carbamic acid (intermediate ZB).

Example 185

N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-Diphenyl-ethylamino) -2 - {(R) -3- [3- (3-hydroxy-benzyl) -ureido] -pyrrolidin -1yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -3-hydroxypropionamide [0252] The title compound is obtained analogously to (R) -2-benzyloxy-N ((1S, 2R, 3S, 4R ) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl } -2,3-dihydroxy-cyclopentyl) -propionamide (example 181, step 5), replacing N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenylethylamino) -purin-9-yl ] -2,3-dihydroxy-cyclopentyl} -3-hydroxy-propionamide (intermediate ZG) (R) -N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3- aminopyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-benzyloxy-propionamide (example 181, step 4) and (3-hydroxy-benzyl) 181 carbamic acid phenyl ester (intermediate intermediate ZD) with phenyl ester of pyridin-3-ylcarbamic acid (intermediate ZB).

Example 186

N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-Diphenyl-ethylamino) -2 - {(R) -3- [3- (4-sulfamoyl-phenyl) -ureido] - pyrrolidin-1-yl} -ppurin-9-yl) -2,3-dihydroxy-cyclopentyl] -3-hydroxypropionamide [0253] The title compound is obtained analogously to (R) -2-benzyloxy-N ((S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9 -yl} -2,3-dihydroxy-cyclopentyl) -propionamide (example 181, step 5), replacing N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenylethylamino) -purin-9-yl ] -2,3-dihydroxy-cyclopentyl} -3-hydroxy-propionamide (intermediate ZG) (R) -N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3- aminopyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-benzyloxypropionamide (example 181, step 4) and (4-sulfamoyl-phenyl) -carbamic acid phenyl ester (intermediate ZE) with pyridin-3-yl-carbamic acid phenyl ester (intermediate ZB).

Example 187

N - ((1S, 2R, 3S, 4R) -4- (6- (2,2-Diphenyl-ethylamino) -2 - {(R) -3- [3- (3-sulfamoyl-phenyl) -ureido] -pyrrolidin -1-yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -3-hydroxy-propionamide [0254] The title compound is obtained analogously to (R) -2-benzyloxy-N ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9 -yl} -2,3-dihydroxy-cyclopentyl) -propionamide (example 181, step 5), replacing N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9- yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxy-propionamide (intermediate ZG) (R) -N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3 -aminopyrrolidin-1-yl) -6- (2,2182 diphenyl-ethylamino) -ppurin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-benzyloxypropionamide (Example 181, step 4) and (3-sulfamoyl-phenyl) -carbamic acid phenyl ester (intermediate ZF) with pyridin-3-yl-carbamic acid phenyl ester (intermediate ZB).

Example 188

N - [(1S, 2R, 3S, 4R) -4- (6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -2 - {(R) -3- [3- (4sulfamoilo -phenyl) -ureido] -pyrrolidin-1-yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -3-hydroxy-propionamide [0255] The title compound is obtained analogously to N - [(1S, 2R, 3S, 4R) -4- (610 (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (4-sulfamoyl-phenyl) -ureido] -pyrrolidin-1-yl} -purin- 9-yl) -2,3-dihydroxy-cyclopentyl] -3-hydroxy-propionamide (example 186), replacing N - ((1S, 2R, 3S, 4R) -4- {2 - ((R) -3-amino-pyrrolidin-1-yl) -6- [2,2-bis- (4-hydroxyphenyl) - ethylamino] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -3-hydroxy-propionamide (intermediate ZH) N - {(1S, 2R, 3S, 4R) -4- [2 - ((R ) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxypropionamide (intermediate ZG).

Example 189

N - ((1S, 2R, 3S, 4R) -4- {6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -2 - [(R) -3- (3-Pyridin-2- ylmethyl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) 3-hydroxy-propionamide [0256] The title compound is obtained analogously to N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-2-ylmethyl-ureido) -pyrrolidin-1-yl] purin-9- yl} -2,3-dihydroxy-cyclopentyl) -3-hydroxy-propionamide (example 184), replacing N - ((1S, 2R, 3S, 4R) -4- {2 - ((R) -3-amino-pyrrolidin-1-yl) -6- [2,2-bis- (4-hydroxy-phenyl)) -ethylamino] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -3-hydroxy-propionamide (intermediate ZH) N - {(1S, 2R, 3S, 4R) -4- [2 - (( R) -3-amino-pyrrolidin-1-yl) -6- (2,2183 diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxypropionamide (intermediate ZG).

Example 190

N - [(1S, 2R, 3S, 4R) -4- (6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -2 - {(R) -3- [3- (35 hydroxy-benzyl) -ureido] -pyrrolidin-1-yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -3-hydroxy-propionamide [0257] The title compound is obtained analogously to N - [(1S, 2R , 3S, 4R) -4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (3-hydroxy-benzyl) -ureido] -pyrrolidin-1-yl} -purin -9-yl) -2,3-dihydroxy-cyclopentyl] -3-hydroxy-propionamide (example 185), replacing N - ((1S, 2R, 3S, 4R) -4- {2 - ((R) -3-amino-pyrrolidin-1-yl) -6- [2,2-bis- (4-hydroxyphenyl) - ethylamino] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -3-hydroxy-propionamide (intermediate ZH) N - {(1S, 2R, 3S, 4R) -4- [2 - ((R ) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -ppurin-9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxypropionamide (intermediate ZG).

Example 191

N - [(1S, 2R, 3S, 4R) -4- (6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -2 - {(R) -3- [3- (3sulfamoilo -benzyl) -ureido] -pyrrolidin-1-yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] 3-hydroxy-propionamide [0258] The title compound is obtained analogously to N - [(1S, 2R , 3S, 4R) -4- (620 (2,2-diphenyl-ethylamino) -2 - {(R) - 3- [3- (3-sulfamoyl-phenyl) -ureido] -pyrrolidin-1-yl} -purine -9-yl) -2,3-dihydroxy-cyclopentyl] -3-hydroxy-propionamide (example 187), replacing N - ((1S, 2R, 3S, 4R) -4- {2 - ((R) -3-amino-pyrrolidin-1-yl) -6- [2,2-bis- (4-hydroxyphenyl) - ethylamino] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -3-hydroxy-propionamide (intermediate ZH) N - {(1S, 2R, 3S, 4R) -4- [2 - ((R ) -3-amino-pyrrolidin-1-yl) -6- (2,225 diphenyl-ethylamino) -ppurin-9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxypropionamide (intermediate ZG).

184

Example 192

N - ((1S, 2R, 3S, 4R) -2,3-Dihydroxy-4- {6- (2-hydroxy-2,2-diphenyl-ethylamino) -2- [(R) -3- (3-pyridin -3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -cyclopentyl) -2-hydroxy-acetamide

Step 1: N - ((1S, 2R, 3S, 4R) -4- {6- [2,2-Bis- (4-chloro-phenyl) -2-hydroxyethylamino] -2 - [(R) -3- ( 3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide [0259] Solution containing: N - ((1S, 2R , 3S, 4R) -4- {2 - ((R) -3-amino-pyrrolidin-1-yl) -6- [2,2-bis- (4-chloro-phenyl) -2-hydroxy-ethylamino] -purin -9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (intermediate ZO; 1 eq) and pyridin-3-yl-carbamic acid phenyl ester (intermediate ZB; 1 eq.) in NMP is stirred at 100 ° C for 1 hour. The solvent is removed in vacuo and the title compound is obtained after purification by column chromatography / crystallization.

Step 2: N - ((1S, 2R, 3S, 4R) -2,3-Dihydroxy-4- {6- (2-hydroxy-2,2-diphenyl-ethylamino) -2 - [(R) -3- ( 3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} cyclopentyl) -2-hydroxy-acetamide [0260] For a mixed solution of N - ((1S, 2R, 3S, 4R) -4- {6- [2,2-bis- (4-chlorophenyl) -2-hydroxy-ethylamino] -2 - [(R) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1 10-yl] purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide in ethanol is added 10 eq. ammonium formate and 20 mol% 10% palladium-on-carbon catalyst. The mixture is stirred at 80 ° C for five hours, allowed to cool and filtered through Celite ™. Removal of the solvent under reduced pressure gives the title compound.

Example 193

185

N - {(1S, 2R, 3S, 4R) -2,3-Dihydroxy-4- [2 - {(R) -3- [3- (3-hydroxy-benzyl) -ureido] -pyrrolidin-1-yl} -6- (2-hydroxy-2,2-diphenyl-ethylamino) -purin-9-yl] -cyclopentyl} -2-hydroxy-acetamide [0261] The title compound is obtained analogously to N - ((1S, 2R, 3S, 4R ) -2.35 dihydroxy-4- {6- (2-hydroxy-2,2-diphenylethylamino) -2 - [(R) -3- (3-pyridin-3-yl-ureido) pyrrolidin-1-yl] -purin-9-yl} -cyclopentyl) -2-hydroxy-acetamide (example 192), replacing phenyl (3-hydroxy-benzyl) -carbamic acid ester (intermediate intermediate ZD) with phenyl ester of pyridin-3-yl-carbamic acid (intermediate ZB).

Example 194

N - ((1S, 2R, 3S, 4R) -2,3-Dihydroxy-4- {6 - ((S) -1-hydroxymethyl-2-phenyl-ethylamino) -2 - [(R) -3- (3- pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} cyclopentyl) -2-hydroxy-acetamide [0262] The title compound is obtained analogously to (R) -2-benzyloxy-N (( 1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl ] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (example 181, step 5), replacing the ester {(1S, 2R, 3S, 4R) -4- [2-chloro-6 - ((S) -1-hydroxymethyl-2-phenylethylamino) -ppurin-9-yl] -2,3-dihydroxy-cyclopentylcarbamoyl } -methyl acetic acid (intermediate ZM) (R) -N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-aminopyrrolidin-1-yl) -6- (2,2 -diphenyl-ethylamino) -ppurin-9-yl] -2,3-dihydroxy-cyclopentyl} -220-benzyloxy-propionamide (example 181, step 4).

Example 195

N - ((1S, 2R, 3S, 4R) -2,3-Dihydroxy-4- {6 - [(S) -1-hydroxymethyl-2- (4-hydroxyphenyl) ethylamino] -2 - [(R) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} cyclopentyl) -2-hydroxy-acetamide [0263] The title compound is obtained analogously to (R) -2 -benzyloxy-N ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3-yl-ureido) Pyrrolidin-1-yl] -ppurin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (example 181, step 5), replacing the ester {(1S, 2R, 3S, 4R) -4- [2-chloro-6 - ((S) -1-hydroxymethyl-2- (4-hydroxy-phenyl) -ethylamino) -purin-9-yl] -2 , 3-dihydroxy-cyclopentylcarbamoyl} methyl acetic acid (intermediate ZN) (R) -N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -35 amino-pyrrolidin-1-yl ) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -2-benzyloxy-propionamide (example 181, step 4).

Example 196

N - ((1S, 2R, 3S, 4R) -2,3-Dihydroxy-4- {2 - {(R) -3- [3- (3-hydroxy-benzyl) -ureido] -pyrrolidin-1-yl} -6 - [(S) -1-hydroxymethyl-2- (4-hydroxy-phenyl) -ethylamino] -purin-910-yl} -cyclopentyl) -2-hydroxy-acetamide [0264] The title compound is obtained analogously to N- ((1S, 2R, 3S, 4R) -2,3-Dihydroxy-4- {6 - [(S) -1-hydroxymethyl-2- (4-hydroxy-phenyl) -ethylamino] -2 - [(R) -3 - (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -cyclopentyl) -2-hydroxyacetamide (example 195), replacing phenyl (3-hydroxy-benzyl) -carbamic acid ester (intermediate intermediate ZD) with phenyl ester of pyridin-3-yl-carbamic acid (intermediate ZB).

Example 197

N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-Diphenyl-ethylamino) -2- [4- (3-pyridin-3-yl-ureido) -pyrazol-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide [0265] The title compound is obtained analogously to (R) -2-benzyloxy-N ((1S, 2R, 35.4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} - 2,3-dihydroxy-cyclopentyl) -propionamide (example 181, step 5), replacing N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-pyrazol-1-yl-6- (2,2-diphenylethylamino) -purin-9-yl] -2,3 -dihydroxy-cyclopentyl} -2-hydroxy-acetamide (intermediate ZP) (R) -N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1 -yl) -6- (2,2-diphenyl-187 ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-benzyloxy-propionamide (example 181, step 4).

Example 198

N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-Diphenyl-ethylamino) -2- [4- (3-pyridin-2-ylmethyl-ureido) -pyrazol-1-yl] - purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide [0266] The title compound is obtained analogously to N - ((1S, 2R, 3S, 4R) -4- {6 (2, 2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-2-ylmethyl-ureido) -pynolidyn-1-yl] purin-9-yl} -2,3-dihydroxy-cyclopentyl) - 3-hydroxy-propionamide (example 184), replacing N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-pyrazol-1-yl) -6- (2,2-diphenyl-ethylamino) purin-9-yl] -2 , 3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide (intermediate ZP) N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl ) -6- (2,2-diphenyl-ethylamino) -purin9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxy-propionamide (intermediate ZG).

Example 199

N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-Diphenyl-ethylamino) -2- {4- [3- (3-hydroxy-benzyl) ureido] pyrazol-1-yl } -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -2-hydroxy-acetamide [0267] The title compound is obtained analogously to N - [(1S, 2R, 3S, 4R) -4- (6 ( 2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (3-hydroxy-benzyl) -ureido] -pyrrolidin-1-yl} purin-9-yl) -2,3-dihydroxy -cyclopentyl] -3-hydroxy-propionamide (example 185), replacing N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-pyrazol-1-yl) -6- (2,2-diphenyl-ethylamino) purin-9-yl] -2 , 3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide (intermediate ZP) N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl ) -6- (2,2-diphenyl-ethylamino) -purin9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxy-propionamide (intermediate ZG).

Example 200

N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-Diphenyl-ethylamino) -2- {4- [3- (3-sulfamoyl-phenyl) ureido] -pyrazol-1- yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -2-hydroxy-acetamide

188 [0268] The title compound is obtained analogously to N - [(1S, 2R, 3S, 4R) -4- (6 (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (3 -sulfamoyl-phenyl) -ureido] -pyrrolidin-1-yl} purin-9-yl) -2,3-dihydroxy-cyclopentyl] -3-hydroxy-propionamide (example 187), replacing N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-pyrazol-1-yl) -6- (2,2-diphenyl-ethylamino) purin-9-yl] -2 , 3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide (intermediate ZP) N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl ) -6- (2,2-diphenyl-ethylamino) -purin9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxy-propionamide (intermediate ZG).

Example 201

N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-Diphenyl-ethylamino) -2- {4- [3- (4-sulfamoyl-phenyl) ureido] -pyrazol-1- yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -2-hydroxy-acetamide [0269] The title compound is obtained analogously to N - [(1S, 2R, 3S, 4R) -4- (6 (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (4-sulfamoyl-phenyl) -ureido] -pyrrolidin-1-yl} purin-9-yl) -2,3- dihydroxy-cyclopentyl] -3-hydroxy-propionamide (example 186), replacing N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-pyrazol-1-yl) -6- (2,2-diphenyl-ethylamino) purin-9-yl] -2 , 3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide (intermediate ZP) N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl ) -6- (2,2-diphenyl-ethylamino) -purin9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxy-propionamide (intermediate ZG).

Example 202

N - ((1S, 2R, 3S, 4R) -4- {6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -2- [4- (3-Pyridin-3-yl-ureido) -pyrazol-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide [0270] The title compound is obtained analogously to (R) -2-benzyloxy-N ((1S, 2R , 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -puryn- 9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (example 181, step 5), replacing N - ((1S, 2R, 3S, 4R) -4- {2- (4-amino-pyrazol-1-yl) -6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -purine -9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy189 acetamide (intermediate ZQ) (R) -N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-benzyloxy-propionamide (example 181, step 4).

Example 203

N - ((1S, 2R, 3S, 4R) 4- {6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -2- [4- (3-Pyridin-2-ylmethyl-ureido) - pyrazol-1-yl] -ppurin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide [0271] The title compound is obtained analogously to N - ((1S, 2R, 3S, 4R) -O- {6 (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-2-ylmethyl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3 -dihydroxy-cyclopentyl) -3-hydroxy-propionamide (example 184), replacing N - ((1S, 2R, 3S, 4R) -4- {2- (4-amino-pyrazol-1-yl) -6- [2,2-bis- (4-hydroxyphenyl) ethylamino] - purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (intermediate ZQ) N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3 -amino-pyrrolidin-1-yl) -6- (2,2-diphenylethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxy-propionamide (intermediate ZG).

Example 204

N - [(1S, 2R, 3S, 4R) -4- (6- [2,2-Bis- (4-hydroxy-phenyl) ethylamino] -2- {4- [3- (3-hydroxy-benzyl) - ureido] pyrazol-1-yl} -pu-rin-9-yl) -2,3-dihydroxy-cyclopentyl] -2-hydroxy-acetamide [0272] The title compound is obtained analogously to N - [(1S, 2R, 3S, 4R ) -4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (3-hydroxy-benzyl) -ureido] -pyrrolidin-1-yl} purin-9-yl ) -2,3-dihydroxy-cyclopentyl] -3-hydroxy-propionamide (example 185), replacing N - ((1S, 2R, 3S, 4R) -4- {2- (4-amino-pyrazol-1-yl) -6- [2,2-bis- (4-hydroxyphenyl) ethylamino] - purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (intermediate ZQ) N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3 -amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-190-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxy-propionamide (intermediate ZG).

Example 205

N - [(1S, 2R, 3S, 4R) -4- (6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -2- {4- [3- (sulfamoyl-phenyl)) -ureido] -pyrazol-1-yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -2-hydroxy-acetamide [0273] The title compound is obtained analogously to N - [(1S, 2R, 3S, 4R ) -4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (3-sulfamoyl-phenyl) -ureido] -pyrrolidin-1-yl} purin-9-yl ) -2,3-dihydroxy-cyclopentyl] -3-hydroxy-propionamide (example 187), replacing N - ((1S, 2R, 3S, 4R) -4- {2- (4-amino-pyrazol-1-yl) -6- [2,2-bis- (4-hydroxyphenyl) ethylamino] - purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (intermediate ZQ) N - {(1S, 2R, 3S, 4R) 4- [2 - ((R) -3- aminopyrrolidin-1-yl) -6- (2,2-diphenylethylamino) -ppurin-9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxy-propionamide (intermediate ZG).

Example 206

N - [(1S, 2R, 3S, 4R) -4- (6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -2- (4- [3- (4-sulfamoylphenyl) - ureido] pyrazol-1-yl) -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -2-hydroxy-acetamide [0274] The title compound is obtained analogously to N - [(1S, 2R, 3S, 4R) - 4- (620 (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (4-sulfamoyl-phenyl) -ureido] -pyrrolidin-1-yl} purin-9-yl) - 2,3-dihydroxy-cyclopentyl] -3-hydroxy-propionamide (example 186), replacing N - ((1S, 2R, 3S, 4R) -4- {2- (4-amino-pyrazol-1-yl) -6- [2,2-bis- (4-hydroxyphenyl) ethylamino] - purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (intermediate ZQ) N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3 -aminopyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxy-propionamide (intermediate ZG).

191

Example 207

N - ((1S, 2R, 3S, 4R) -4- (6- (2,2-Diphenyl-ethylamino) -2- {4- [3- (3-hydroxy-benzyl) -ureido] -pyrazol-1- yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] propionamide [0275] The title compound is obtained analogously to N - [(1S, 2R, 3S, 4R) -4- (6 (2,2- diphenyl-ethylamino) -2 - {(R) -3- [3- (3-hydroxy-benzyl) -ureido] -pyrrolidin-1-yl} purin-9-yl) -2,3-dihydroxy-cyclopentyl] - 3-hydroxy-propionamide (example 185), replacing N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-pyrazol-1-yl) -6- (2,2-diphenyl-ethylamino) purin-9-yl] -2 , 3-dihydroxy-cyclopentyl} -propionamide (intermediate ZR) N {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- ( 2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxy-propionamide (intermediate ZG).

Example 208

N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-Diphenyl-ethylamino) -2- [4- (3-pyridin-2-ylmethyl-ureido) -pyrazol-1-yl] - purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide [0276] The title compound is obtained analogously to N - ((1S, 2R, 3S, 4R) -4- {6 (2,2-diphenyl- ethylamino) -2 - [(R) -3- (3-pyridin-2-ylmethyl-ureido) -pyrrolidin-1-yl] purin-9-yl} -2,3-dihydroxy-cyclopentyl) -3-hydroxy- propionamide (example 184), replacing N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-pyrazol-1-yl) -6- (2,2-diphenyl-ethylamino) purin-9-yl] -2 , 3-dihydroxy-cyclopentyl} -propionamide (intermediate ZR) N {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- ( 2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxy-propionamide (intermediate ZG).

Example 209

1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2 -3-hydroxy-benzylamide -yl] -1H-pyrazole-4-carboxylic acid [0277] The title compound is prepared in a manner analogous to 1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -amide. 6- (2,2192 diphenyl-ethylamino) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic acid (example 173), replacing 3-hydroxybenzylamine with methylamine.

Example 210 (Pyridin-2-ylmethyl) -amide 1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-45 propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) ) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic acid [0278] The title compound is prepared in a manner analogous to 1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy- 4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic acid (example 173), replacing C-pyridin-2-yl-methylamine with methylamine.

Example 211 (Pyridin-2-ylmethyl) -amide 1- [9 - [(1R, 2S, 3R, 4S) -2,3-dihydroxy-4- (2-hydroxy-acetylamino) -cyclopentyl] -6- (2, 2-diphenyl-ethylamino) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic acid [0279] The title compound is obtained in a manner analogous to 1- [9 - (1R, 2S, 3R, 4S) -2 , 3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-Z-yl] -1H-pyrazole-4-carboxyl (Example 173), replacing 1- [9 - [(1R, 2S, 3R, 4S) -2,3-dihydroxy-4- (2-hydroxyacetylamino) -cyclopentyl] -6- (2,2-diphenyl-ethylamino) -9H acid ethyl ester -purin-2-yl] -1H-pyrazole-420 carboxylic acid (intermediate ZS) with ethyl ester 1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6 - (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -1H-pyrazole-4-carboxyl (Example 173, step 1) and C-pyridin-2-yl-methylamine methylamine.

Example 212

193

1- [9 - [(1R, 2S, 3R, 4S) -2,3-dihydroxy-4- (2-hydroxy-acetylamino) -cyclopentyl] -6- (2,2-diphenyl-ethylamino) 3-hydroxy-benzylamide. -9H-purin-2-yl] -1H-pyrazole-4-carboxylic acid [0280] The title compound is obtained in a manner analogous to 1- [9 - [(1R, 2S, 3R, 4S) - (pyridin-25-ylmethyl) -amide 2,3-dihydroxy-4- (2-hydroxyacetylamino) -cyclopentyl] -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -1H-pyrazole-4-carboxyl (example 211), replacing 3-hydroxybenzylamine with C-pyridin-2-ylmethylamine.

Example 213 1- [9 - [(1R, 2S, 3R, 4S) -2,3-dihydroxy-4- (2-hydroxyacetylamino) cyclopentyl] -6- (2, (3, Sulfamoyl-phenyl) -amide) 2-diphenyl-ethylamino) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic acid [0281] The title compound is obtained in a manner analogous to (1- pyridin-2-methylmethyl) -amide [1- [9 - [(1R, 2S, 3R, 4S) -2,3-dihydroxy-4- (2-hydroxyacetylamino) -cyclopentyl] -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic acid ( example 211), replacing 3-amino-benzenesulfonamide with C-pyridin-2-ylmethylamine.

Example 214 1- [9 - [(1R, 2S, 3R, 4S) -2,3-dihydroxy-4- (220 hydroxyacetylamino) cyclopentyl] -6- (2-sulfamoyl-phenyl) -amide , 2-diphenyl-ethylamino) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic acid [0282] The title compound is obtained in a manner analogous to 1- [9 - [(1R, 2S (pyridin-2-methyl)) -amide , 3R, 4S) -2,3-dihydroxy-4- (2-hydroxyacetylamino) -cyclopentyl] -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -1H-pyrazole-425 carboxylic acid (example 211), replacing 4-amino-benzenesulfonamide with C-pyridin-2-ylmethylamine.

194

Example 215

N - {(1S, 2R, 3S, 4R) -2,3-Dihydroxy-4- [2- {4- [3- (3-hydroxy-benzyl) -ureido] pyrazol-1-yl} -6- ( (S) -1-hydroxymethyl-2-phenyl-ethylamino) -purin-9-yl] -cyclopentyl} 2-hydroxy-acetamide [0283] The title compound is obtained analogously to N - [(1S, 2R, 3S, 4R) 4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (3-hydroxy-benzyl) -ureido] -pyrrolidin-1-yl} purin-9-yl) -2,3-dihydroxy-cyclopentyl] -3-hydroxy-propionamide (example 185), replacing N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-pyrazol-1-yl) -6 - ((S) -1-hydroxymethyl-2-phenyl-ethylamino) -purin-9 -yl] -2,3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide (intermediate ZT) N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino- pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxypropionamide (intermediate ZG).

Example 216

N - [(1S, 2R, 3S, 4R) -2,3-Dihydroxy-4- (6 - ((S) -1-hydroxymethyl-2-phenyl-ethylamino) -2- {4- [3- (4- sulfamoyl-phenyl) -ureido] -pyrazol-1-yl} -purin-9-yl) cyclopentyl] -2-hydroxy-acetamide [0284] The title compound is obtained analogously to N - [(1S, 2R, 3S, 4R) 4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (4-sulfamoyl-phenyl) -ureido] -pyrrolidin-1-yl} purin-9-yl) -2,3-dihydroxy-cyclopentyl] -3-hydroxy-propionamide (example 186), replacing N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-pyrazol-1-yl) -6 - ((S) -1-hydroxymethyl-2-phenyl-ethylamino) -purin-9 -yl] -2,3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide (intermediate ZT) N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino- pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxypropionamide (intermediate ZG).

Example 217

195

N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-Diphenyl-ethylamino) -2- [4- (3-pyridin-3-yl-ureido) -imidazol-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide [0285] The title compound is obtained analogously to (R) -2-benzyloxy-N ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3-yl-ureido) 5-pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (example 181, step 5), replacing N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-imidazol-1-yl) -6- (2,2-diphenylethylamino) -purin-9-yl] -2, 3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide (intermediate ZU) (R) -N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidine- 1-yl) -6- (2,2-diphenylethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-benzyloxy-propionamide (example 181, step 4).

Example 218

N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-Diphenyl-ethylamino) -2- [4- (3-pyridin-2-ylmethyl-ureido) -imidazol-1-yl] - purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide [0286] The title compound is obtained analogously to N - ((1S, 2R, 3S, 4R) -4- {615 (2, 2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-2-ylmethyl-ureido) -pyrrolidin-1-yl] purin-9-yl} -2,3-dihydroxy-cyclopentyl) - 3-hydroxy-propionamide (example 184), replacing N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-imidazol-1-yl) -6- (2,2-diphenyl-ethylamino) purin-9-yl] -2 , 3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide (intermediate ZU) N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl ) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxy-propionamide (intermediate ZG).

Example 219

N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-Diphenyl-ethylamino) -2- {4- [3- (3-hydroxy-benzyl) -ureido] -imidazol-1- yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -2-hydroxy-acetamide [0287] The title compound is obtained analogously to N - [(1S, 2R, 3S, 4R) -4- (625 (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (3-hydroxy-benzyl) -ureido] -pyrrolidin-1-yl} purin-9-yl) -2,3- dihydroxy-cyclopentyl] -3-hydroxy-propionamide (Example 185),

196 replacing N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-imidazol-1-yl) -6- (2,2-diphenyl-ethylamino) purin-9-yl] -2 , 3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide (intermediate ZU) N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl ) -6- (2,2-diphenyl-ethylamino) -purin9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxy-propionamide (intermediate ZG).

Example 220

N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-Diphenyl-ethylamino) -2- {4- [3- (3-sulfamoyl-phenyl) ureido] -imidazol-1- yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -2-hydroxy-acetamide [0288] The title compound is obtained analogously to N - [(1S, 2R, 3S, 4R) -4- (6 (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (3-sulfamoyl-phenyl) -ureido] -pyrrolidin-1-yl} purin-9-yl) -2,3- dihydroxy-cyclopentyl] -3-hydroxy-propionamide (example 187), replacing N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-imidazol-1-yl) -6- (2,2-diphenyl-ethylamino) purin-9-yl] -2 , 3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide (intermediate ZU) N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl ) -6- (2,2-diphenyl-ethylamino) -purin9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxy-propionamide (intermediate ZG).

Example 221

N - ((1S, 2R, 3S, 4R) -4- {6- [2,2-Bis- (4-hydroxy-phenyl] -etyloaminolo-2- [4- (3-Pyridin-3-yl-ureido) - imidazol-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide [0289] The title compound is obtained analogously to (R) -2-benzyloxy-N ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9 -yl} -2,3-dihydroxy-cyclopentyl) -propionamide (example 181, step 5), replacing N - ((1S, 2R, 3S, 4R) -4- {2- (4-amino-imidazol-1-yl) -6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -purine -9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxyacetamide (intermediate ZV) (R) -N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) - 3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-benzyloxy-propionamide (example 181, step 4).

197

Example 222

N - ((1S, 2R, 3S, 4R) -4- {6- [2,2-Bis- (4-hydroxy-phenyl) -etyloaminolo-2- [4- (3-Pyridin-2-ylmethyl-ureido) - imidazol-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) 2-hydroxy-acetamide [0290] The title compound is obtained analogously to N - ((1S, 2R, 3S, 4R) 4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-2-ylmethyl-ureido) -pyrrolidin-1-yl] purin-9-yl} -2,3- dihydroxy-cyclopentyl) -3-hydroxy-propionamide (example 184), replacing N - ((1S, 2R, 3S, 4R) -4- {2- (4-amino-imidazol-1-yl) -6- [2,2-bis- (4-hydroxyphenyl) ethylamino] purin -9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (intermediate ZV) N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3- amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxypropionamide (intermediate ZG).

Example 223

N - [(1S, 2R, 3S, 4R) -4- (6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -2- {4- [3- (315 hydroxy-benzyl) -ureido] -imidazol-1-yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -2-hydroxy-acetamide [0291] The title compound is obtained analogously to N - [(1S, 2R, 3S, 4R ) -4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (3-hydroxy-benzyl) -ureido] -pyrrolidin-1-yl} purin-9-yl ) -2,3-dihydroxy-cyclopentyl] -3-hydroxy-propionamide (example 185), replacing N - ((1S, 2R, 3S, 4R) -4- {2- (4-amino-imidazol-1-yl) -6- [2,2-bis- (4-hydroxyphenyl) ethylamino] purin -9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (intermediate ZV) N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3- aminopyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxypropionamide (intermediate ZG).

Example 224

198

N - [(1S, 2R, 3S, 4R) -4- (6- [2,2-Bis- (4-hydroxy-phenyl) -etyloaminolo-2- {4 - [- 3- (3-sulfamoyl-phenyl) - ureido] -imidazol-1-yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -2-hydroxy-acetamide [0292] The title compound is obtained analogously to N - [(1S, 2R, 3S, 4R) -4- (65 (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (3-sulfamoyl-phenyl) -ureido] -pyrrolidin-1-yl} purin-9-yl) -2,3-dihydroxy-cyclopentyl] -3-hydroxy-propionamide (example 187), replacing N - ((1S, 2R, 3S, 4R) -4- {2- (4-amino-imidazol-1-yl) -6- [2,2-bis- (4-hydroxyphenyl) ethylamino] purin -9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (intermediate ZV) N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3- amino-pyrrolidin-1-yl) -6- (2,210 diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxypropionamide (intermediate ZG).

Example 225

N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-Diphenyl-ethylamino) -2- [3- (3-pyridin-3-yl-ureido) [1,2,4 ] triazol-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide [0293] The title compound is obtained analogously to (R) -2-benzyloxy-N ((1S , 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] - purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (example 181, step 5), replacing N - {(1S, 2R, 3S, 4R) -4- [2- (3-amino- [1,2,4] triazol-1-yl) -6- (2,2-diphenylethylamino) -purin- 9-yl] -2,3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide (intermediate ZW) (R) -N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenylethylamino) -ppurin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-benzyloxy-propionamide (example 181, step 4) .

Example 226

N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-Diphenyl-ethylamino) -2- [3- (3-pyridin-2-ylmethyl-ureido) - [1,2,4 ] triazol-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide

199 [0294] The title compound is obtained analogously to N - ((1S, 2R, 3S, 4R) -4- {6 (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridinyl) 2-ylmethyl-ureido) -pyrrolidin-1-yl] purin-9-yl} -2,3-dihydroxy-cyclopentyl) -3-hydroxy-propionamide (example 184), replacing N - {(1S, 2R, 3S, 4R) -4- [2- (3-amino- [1,2,4] triazol-1-yl) -6- (2,2-diphenyl-ethylamino) -purine -9-yl] -2,3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide (intermediate ZW) N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3- amino-pyrrolidin-1-yl) -6- (2,2-diphenylethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxy-propionamide (intermediate ZG).

Example 227

N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-Diphenyl-ethylamino) -2- {3- [3- (3-hydroxy-benzyl) -ureido] - [1,2 , 4] triazol-1-yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -2-hydroxyacetamide [0295] The title compound is obtained analogously to N - [(1S, 2R, 3S, 4R) -4- (6 (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (3-hydroxy-benzyl) -ureido] -pyrrolidin-1-yl} -purin-9-yl ) -2,3-dihydroxy-cyclopentyl] -3-hydroxy-propionamide (example 185), replacing N - {(1S, 2R, 3S, 4R) -4- [2- (3-amino- [1,2,4] triazol-1-yl) -6- (2,2-diphenylethylamino) -purin- 9-yl] -2,3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide (intermediate ZW) N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino pyrrolidin-1-yl) -6- (2,2-diphenylethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxy-propionamide (intermediate ZG).

Example 228

N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-Diphenyl-ethylamino) -2- {3- [3- (3-sulfamoyl-phenyl) ureido] - [1,2 , 4] triazol-1-yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -2-hydroxyacetamide [0296] The title compound is obtained analogously to N - [(1S, 2R, 3S, 4R) -4- (6 (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (3-sulfamoyl-phenyl) -ureido] -pyrrolidin-1-yl} 200-purin-9-yl ) -2,3-dihydroxy-cyclopentyl] -3-hydroxy-propionamide (example 187), replacing N - {(1S, 2R, 3S, 4R) -4- [2- (3-amino- [1,2,4] triazol-1-yl) -6- (2,2-diphenylethylamino) -purin- 9-yl] -2,3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide (intermediate ZW) N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxy-propionamide (intermediate ZG).

Example 229

N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-Diphenyl-ethylamino) -2- {3- [3- (4-sulfamoyl-phenyl) ureido] - [1,2 , 4] triazol-1-yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -2-hydroxy-acetamide [0297] The title compound is obtained analogously to N - [(1S, 2R, 3S, 4R ) -4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (4-sulfamoyl-phenyl) -ureido] -pyrrolidin-1-yl} purin-9-yl ) -2,3-dihydroxy-cyclopentyl] -3-hydroxy-propionamide (example 186), replacing N - {(1S, 2R, 3S, 4R) -4- [2- (3-amino- [1,2,4] triazol-1-yl) -6- (2,2-diphenyl-ethylamino) -purine -9-yl] -2,3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide (intermediate ZW) N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3- amino-pyrrolidin-1-yl) -6- (2,2-diphenylethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxy-propionamide (intermediate ZG).

Example 230

N - ((1S, 2R, 3S, 4R) -4- {6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -2- [3- (3-Pyridin-3-yl-ureido) - [1,2,4] triazol-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide [0298] The title compound is obtained in analogy to (R) -2-benzyloxy -N ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3-yl-ureido) pyrrolidine -1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (example 181, step 5), replacing N - ((1S, 2R, 3S, 4R) -4- {2- (3-amino- [1,2,4] triazol-1-yl) -6- [2,2-bis- (4201 hydroxy phenyl) ethylamino] -ppurin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxyacetamide (intermediate ZX) (R) -N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-benzyloxy-propionamide (example 181, step 4).

Example 231

N - ((1S, 2R, 3S, 4R) -4- {6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -2- [3- (3-Pyridin-2-ylmethyl-ureido) - [1,2,4] triazol-1-yl] -purin-9-yl} -2,3-dihydroxycyclopentyl) -2-hydroxyacetamide [0299] The title compound is obtained analogously to N - ((1S, 2R , 3S, 4R) -4- {610 (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-2-ylmethyl-ureido) -pyrrolidin-1-yl] -purin-9 -yl} -2,3-dihydroxy-cyclopentyl) -3-hydroxy-propionamide (example 184), replacing N - ((1S, 2R, 3S, 4R) -4- {2- (3-amino- [1,2,4] triazol-1-yl) -6- [2,2-bis- (4- hydroxyphenyl) ethylamino] pipin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (intermediate ZX) N - {(1S, 2R, 3S, 4R) -4- [2- ((R) -3-aminopyrrolidin-1-yl) -6- (2,215 diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxypropionamide (intermediate ZG).

Example 232

N - [(1S, 2R, 3S, 4R) -4- (6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -2- {3- [3- (3-hydroxy-benzyl) - ureido] - [1,2,4] triazol-1-yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -2-hydroxy-acetamide [0300] The title compound is obtained analogously to N - [( 1S, 2R, 3S, 4R) -4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (3-hydroxy-benzyl) -ureido] -pyrrolidin-1 yl} purin-9-yl) -2,3-dihydroxy-cyclopentyl] -3-hydroxy-propionamide (example 185), replacing N - ((1S, 2R, 3S, 4R) -4- {2- (3-amino- [1,2,4] triazol-1-yl) -6- [2,2-bis- (4- hydroxy-phenyl) -ethylamino] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (intermediate ZX) N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2202 diphenyl-ethylamino) -ppurin-9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxypropionamide (intermediate) Z G).

Example 233

N - [(1S, 2R, 3S, 4R) -4- (6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -2- {3- [3- (sulfamoyl-phenyl)) -ureido] - [1,2,4] triazol-1-yl} -purin-9-yl) -2,3-dihydroxycyclopentyl] -2-hydroxyacetamide [0301] The title compound is obtained analogously to N - [( 1S, 2R, 3S, 4R) -4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (3-sulfamoyl-phenyl) -ureido] -pyrrolidin-1 yl} purin-9-yl) -2,3-dihydroxy-cyclopentyl] -3-hydroxy-propionamide (example 187), replacing N - ((1S, 2R, 3S, 4R) -4- {2- (3-amino- [1,2,4] triazol-1-yl) -6- [2,2-bis- (4- hydroxyphenyl) ethylamino] pipin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (intermediate ZX) N - {(1S, 2R, 3S, 4R) -4- [2- ((R) -3-Amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxypropionamide (intermediate ZG) .

Example 234

N - [(1S, 2R, 3S, 4R) -4- (6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -2- {3- [3- (4-sulfamoylphenyl) - ureido] - [1,2,4] triazol-1-yl} -purin-9-yl) -2,3-dihydroxycyclopentyl] -2-hydroxyacetamide [0302] The title compound is obtained analogously to N - [(1S , 2R, 3S, 4R) -4- (620 (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (4-sulfamoyl-phenyl) -ureido] -pyrrolidin-1-yl } purin-9-yl) -2,3-dihydroxy-cyclopentyl] -3-hydroxy-propionamide (example 186), replacing N - ((1S, 2R, 3S, 4R) -4- {2- (3-amino- [1,2,4] triazol-1-yl) -6- [2,2-bis- (4- hydroxyphenyl) ethylamino] pipin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (intermediate ZX) N - {(1S, 2R, 3S, 4R) -4- [2- ((R) -3-Amino-pyrrolidin-1-yl) -6- (2,225 diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxypropionamide (intermediate ZG).

203

Example 235

N - {(1S, 2R, 3S, 4R) -4- [2- [2- (4-Chloro-phenyl) -ethoxy] -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2 3-dihydroxy-cyclopentyl} -propionamide

Step 1: N - {(3aR, 4S, 6R, 6aS) -6- [2-Chloro-6- (2,2-diphenyl-ethylamino) -ppurin-95-yl] -2,2-dimethyl-tetrahydro-cyclopenta [1,3] dioxol-4-yl} -propionamide [0303] The title compound is obtained by dissolving N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} propionamide (intermediate J) in a 2: 1 mixture of acetone and 2,2-dimethoxypropane with a catalytic amount of toluene-4-sulfonic acid and stirring at room temperature overnight . Volatile components are removed under reduced pressure to give the title compound.

Step 2: N - {(3aR, 4S, 6R, 6aS) -6- [2- [2- (4-Chloro-phenyl) -ethoxy-6- (2,2-diphenylethylamino) -purin-9-yl] -2,2-dimethyltetrahydro-cyclopenta [1,3] dioxol-4-yl} propionamide [0304] The title compound is obtained by adding N - {(3aR, 4S, 6R, 6aS) -6- [2-chloro6- (2 , 2-diphenyl-ethylamino) -purin-9-yl] -2,2-dimethyl-tetrahydrocyclopenta [1,3] dioxol4-yl} -propionamide (example 235, step 1) to a previously mixed solution of sodium hydride (60 % in oil) and 2- (4-chloro-phenyl) -ethanol (1 eq) in dry THF. The reaction mixture is stirred at 50 ° C for 48 hours before neutralizing the residue with sodium hydride with an aqueous solution of ammonium chloride in excess. The reaction mixture is then partitioned between ethyl acetate and water; the organic phase is washed successively with water and brine, then dried with magnesium sulfate. Filtration and removal of volatile components under reduced pressure gives a crude product; purification by column chromatography / crystallization gives the title compound.

Step 3: N - {(1S, 2R, 3S, 4R) -4- [2- [2- (4-Chloro-phenyl) -ethoxy-6- (2,2-diphenylethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide

204 [0305] The title compound is obtained by dissolving N - {(3aR, 4S, 6R, 6aS) -6- [2 [2- (4-Chloro-phenyl) -ethoxy] -6- (2,2-diphenyl-ethylamino) -purine -9-yl] -2,2-dimethyltetrahydro-cyclopenta [1,3] dioxol-4-yl} -propionamide (example 235, step 2) in THF, adding the same volume of 1.0 M hydrochloric acid and stirring at room for 48 hours, then diluted with water and extracted into ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and the volatiles removed under reduced pressure to afford the title compound.

Example 236

4- {3- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-410-propionylamino-cyclopentyl) -6-methyl ester -6- (2,2-diphenyl-ethylamino) -9H-purin- 2-yl] -prop-2-ynyl} -cyclohexanecarboxylic acid [0306] The title compound is obtained by combining N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6 (2,2-diphenyl-ethylamino) - purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (intermediate J), 4-prop-2-ynyl-cyclohexanecarboxylic acid methyl ester (obtained by the method of Rieger JM, Brown ML, Sullivan G. W., Linden J. and Macdonald TL '; J. Med. Chem. (2001), 44, 531-539), copper (I) iodide, triphenylphosphine and dichlorobis (triphenylphosphine) palladium (II) in a 2: 1 triethylamine / DMF mixture and heating by microwave irradiation for 3600 seconds at 120 ° C. Purification by column chromatography gives the title compound.

Example 237

(2S, 3S, 4R, 5R) -5- (6- (2,2-diphenyl-ethylamino) -2- {4- [3- (3-hydroxy-benzyl) -ureido] -pyrazol-1-yl} -acetylamide -purin-9-yl) -3,4-dihydroxy-tetrahydro-furano2-carboxylic acid

Step 1: (2S, 3S, 4R, 5R) -5- [2- (4-amino-pyrazol-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -3 acid ethylamide 4-dihydroxy-tetrahydro-furan-2-carboxylic acid

205 [0307] The title compound is obtained analogously to N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-pyrazol-1-yl) -6- (2,2-diphenylethylamino) -purin- 9-yl] -2,3-dihydroxycyclopentyl} -2-hydroxyacetamide (intermediate ZP), replacing acid ethylamide (2S, 3S, 4R, 5R) -5- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -3,4-dihydroxytetrahydrofuran-2-carboxylic acid (intermediate ZY) with ester {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxycyclopentylcarbamoyl} -methyl-acetic acid (intermediate Q1) in step ZP1.

Stage 2: (2S, 3S, 4R, 5R) -5- (6- (2,2-diphenyl-ethylamino) -2- {4- [3- (3-hydroxy-benzyl) -ureido] -pyrazol-1-yl acid ethylamide } -purin-9-yl) -3,4-dihydroxy-tetrahydrofuran-2-carboxylic acid [0308] The title compound is obtained analogously to N - [(1S, 2R, 3S, 4R) -4- (6 (2.2 diphenyl-ethylamino) -2 - {(R) -3- [3- (3-hydroxy-benzyl) -ureido] -pyrrolidin-1-yl} purin-9-yl) -2,3-dihydroxy-cyclopentyl] -3-hydroxy-propionamide (Example 185), replacing (2S, 3S, 4R, 5R) acid ethylamide -5- [2- (4-amino-pyrazol-1-yl) -6- (2,2-diphenylethylamino) -purin-9-yl] -3,4 -dihydroxy-tetrahydrofuran-2-carboxyl (Example 237, step 1) N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-aminopyrrolidin-1-yl) -6 - (2,2-diphenylethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxy-propionamide (intermediate ZG).

Example 238

(2S, 3S, 4R, 5R) -5- (6- (2,2-diphenyl-ethylamino) -2- {4- [3- (3-hydroxy-benzyl) -ureido] -imidazol-1-yl} -acetylamide -purin-9-yl) -3,4-dihydroxy-tetrahydro-furan-2-carboxylic acid

Step 1: (2S, 3S, 4R, 5R) -5- [2- (4-amino-imidazol-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -3 acid ethylamide 4-dihydroxy-tetrahydro-furan-2-carboxylic acid

206 [0309] The title compound is obtained analogously to N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-imidazol-1-yl) -6- (2,2-diphenylethylamino) -purin- 9-yl] -2,3-dihydroxycyclopentyl} -2-hydroxyacetamide (intermediate ZU), replacing acid ethylamide (2S, 3S, 4R, 5R) -5- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -3,4-dihydroxy-tetrahydrofuran-2-carboxylic acid (intermediate product ZY) with the ester {( 1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxycyclopentylcarbamoyl} -methyl acid acetic acid (intermediate Q1) in step ZU1.

Stage 2: (2S, 3S, 4R, 5R) -5- (6- (2,2-diphenyl-ethylamino) -2- {4- [310 (3-hydroxy-benzyl) -ureido] -imidazol-1-yl acid ethylamide } -purin-9-yl) -3,4-dihydroxy-tetrahydrofuran-2-carboxyl [0310] The title compound is obtained analogously to N - [(1S, 2R, 3S, 4R) -4- (6 (2.2 diphenyl-ethylamino) -2 - {(R) -3- [3- (3-hydroxy-benzyl) -ureido] -pyrrolidin-1-yl} purin-9-yl) -2,3-dihydroxy-cyclopentyl] -3-hydroxy-propionamide (Example 185), replacing (2S, 3S, 4R, 5R) acid ethylamide -5- [2- (4-amino-imidazol-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -3,4 -dihydroxy-tetrahydrofuran-2-carboxyl (Example 238, step 1) N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-aminopyrrolidin-1-yl) -6 - (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxypropionamide (intermediate ZG).

Example 239

(2S, 3S, 4R, 5R) -5- (6- (2,2-diphenyl-ethylamino) -2- {3- [3- (3-hydroxy-benzyl) -ureido] - [1,2,4 ] triazol-1-yl} -purin-9-yl) -3,4-dihydroxy-tetrahydro-furan-2-carboxylic acid

Step 1: (2S, 3S, 4R, 5R) -5- [2- (3-amino- [1,2,4] triazol-1-yl) -625 (2,2-diphenyl-ethylamino) acid ethylamide purin-9-yl] -3,4-dihydroxy-tetrahydro-furan-2-carboxylic acid

207 [0311] The title compound is obtained analogously to N - {(1S, 2R, 3S, 4R) -4- [2 (3-amino- [1,2,4] triazol-1-yl) -6- (2, 2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -2-hydroxy-acetamide (intermediate ZW), replacing (2S, 3S, 4R, 5R) -5- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -3,4-dihydroxy-tetrahydrofuran-2- acid ethylamide carboxyl (intermediate ZY) ester {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -ppurin-9-yl] -2,3-dihydroxycyclopentylcarbamoyl} - acetic acid methyl (intermediate Q1).

Stage 2: (2S, 3S, 4R, 5R) -5- (6- (2,2-diphenyl-ethylamino) -2- {3- [3- (3-hydroxy-benzyl) -ureido] - [1,2, 4] triazol-1-yl} -purin-9-yl) -3,4-dihydroxy-tetrahydrofuran-2-carboxylic acid [0312] The title compound is obtained analogously to N - [(1S, 2R, 3S, 4R) - 4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (3-hydroxy-benzyl) -ureido] -pyrrolidin-1-yl} purin-9-yl) - 2,3-dihydroxy-cyclopentyl] -3-hydroxy-propionamide (example 185), replacing (2S, 3S, 4R, 5R) acid ethylamide -5- [2- (3-amino- [1,2,4] triazol-1-yl) -6- (2,215 diphenyl-ethylamino) -purin-9- yl] -3,4-dihydroxy-tetrahydrofuran-2-carboxyl (Example 239, step 1) N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-aminopyrrolidine- 1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -3-hydroxypropionamide (intermediate ZG).

Example 240

(2S, 3S, 4R, 5R) -5- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (3-hydroxy-benzyl) -ureido] -pyrrolidine- 1-yl} -purin-9-yl) -3,4-dihydroxy-tetrahydrofuran-2-carboxylic acid [0313] Ethyl trifluoroacetate (2S, 3S, 4R, 5R) -5- [2 - ((R) -3 -aminopyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -3,4-dihydroxy-tetrahydrofuran-2-carboxylic acid (intermediate E) and phenyl ester of acid (3 -hydroxybenzyl) -carbam (intermediate intermediate UA) is dissolved in methanol and TEA.

208

The reaction mixture is heated using microwave radiation at 100 ° C for 30 minutes in a Personal Chemistry Emrys ™ Optimizer microwave reactor. The reaction mixture is concentrated in vacuo and purified by C-18 reverse phase column chromatography eluting with acetonitrile: water (0.1% TFA) (gradient 0-100% acetonitrile) to afford the title compound.

Example 241

(2S, 3S, 4R, 5R) -5- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (4-sulfamoyl-phenyl) -ureido] -pyrrolidine- 1-yl} -purin-9-yl) -3,4-dihydroxy-tetrahydrofuran-2-carboxylic acid. This compound is obtained in analogy to Example 240 replacing (3-hydroxybenzyl) -carbamic acid phenyl ester (intermediate intermediate UA) (4-sulfamoyl-phenyl) -carbamic acid phenyl ester (intermediate UD).

Example 242

(2S, 3S, 4R, 5R) -5-(6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (315 sulfamoyl-phenyl) -ureido] -pyrrolidine ethyl ethylamide -1-yl} -purin-9-yl) -3,4-dihydroxy-tetrahydrofuran-2-carboxylic acid [0315] This compound is obtained analogously to Example 240 replacing (3-hydroxybenzyl) -carbamic acid phenyl ester (intermediate UA ) (3-sulfamoyl-phenyl) -carbamic acid phenyl ester (intermediate UC).

Example 243

(2S, 3S, 4R, 5R) acid ethyl amide -5- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-2-ylmethyl-ureido) -pyrrolidin-1- yl] -ppurin-9-yl} -3,4-dihydroxy-tetrahydrofuran-2-carboxylic compound [0316] This compound is obtained in analogy to Example 240 replacing (3-Hydroxybenzyl) -carbamic acid phenyl ester (intermediate of UA) with phenyl ester pyridin-2-ylmethyl-carbamic acid (EU intermediate).

209

Example 244

(2S, 3S, 4R, 5R) -5-[2 - {(R) -3- (3,4-dioxo-2- (pyridin-3-ylamino) -cyclobut-1-enylamino] -pyrrolidin-1- yl} -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -3,4-dihydroxy-tetrahydro-furan-2-carboxylic acid

Step 244a: (2S, 3S, 4R, 5R) -5-{6- (2,2-diphenyl-ethylamino) -2 [(R) -3- (2-methoxy-3,4-dioxo-cyclobut acid) -1-enylamino) -pyrrolidin-1-yl] -purin-9-yl} -3,4-dihydroxy-tetrahydrofuran-2-carboxylic acid [0317] A mixture containing (2S, 3S, 4R, 5R) ethylamide trifluoroacetate [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -3,410-dihydroxy-tetrahydrofuran-2-carboxylic acid (product intermediate E) and 3,4-dimethoxy-3-cyclobutene-1,2-dione in absolute ethanol and cat. DMAP is heated using microwave radiation in a Personal Chemistry Emrys ™ Optimizer microwave reactor at 120 ° C for 1 hour. The solvent is removed in vacuo and the crude product obtained is partitioned between ethyl acetate and water. The organic portion is separated, dried (Na2SO4) and concentrated in vacuo. Purification by silica gel column chromatography eluting with ethyl acetate / isohexane (30-100% ethyl acetate) gives the title compound.

Stage 244b: (2S, 3S, 4R, 5R) acid ethyl amide -5- {6- (2,2-diphenyl-ethylamino) -2 [(R) -3- (2-methoxy-3,4-dioxo-cyclobut-1- enylamino) -pyrrolidin-1-yl] -purin-9-yl} -3,420 dihydroxy-tetrahydrofuran-2-carboxylic acid [0318] A mixture containing (2S, 3S, 4R, 5R) ethylamide (5-, 6- (2, 2difenylo-ethylamino) -2 - [(R) -3- (2-methoxy-3,4-dioxo-cyclobut-1-enylamino) -pirolidyn1-yl] -purin-9-yl} -3,4-dihydroxy tetrahydrofuran-2-carboxyl (step 244a) in absolute ethanol and the catalytic amount of TsOH is heated at using microwave radiation in the Personal Chemistry Emrys ™ Optimizer microwave reactor

150 ° C for 4000 seconds. The solvent is removed in vacuo and the crude obtained is obtained

210 product partition between ethyl acetate and water. The organic portion is separated, dried (Na2SO4) and concentrated in vacuo. Purification by C18 reverse phase column chromatography eluting with acetonitrile: water (0.1% TFA) (gradient 0-100% acetonitrile) affords the title compound.

Example 245

(2S, 3S, 4R, 5R) -5- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [2- (3-hydroxy-benzylamino) -3,4-dioxo acid ethylamide -cyclobut-1-enylamino] -pyrrolidin-1-yl} -purin-9-yl) -3,4-dihydroxy-tetrahydrofuran-2-carboxylic compound. This compound is obtained in analogy to Example 244 by replacing 310-aminopyridine with 3-hydroxybenzylamine .

Example 246-253 [0320] These compounds are obtained from the product of example 26 step 2 using an analogous procedure to example 26 step 3, replacing with methyl chloroformate with the appropriate acid chloride or anhydride.

Example 254 (R) -N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-Diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3-yl- ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxypropionamide

Level 1: (R) -N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-Diphenyl-ethylamino) -2 - [(R) -3- (320 pyridin-3-yl-ureido ) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-phenoxy-propionamide [0321] HATU (61 mg, 0.16 mmol) and R - (+) - 2 acid -benzyloxypropionic (32 mg, 0.16 mmol) is dissolved in DMF (5 mL) and the reaction mixture is stirred for 5 minutes, the solution is treated with 1 - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -4-amino-2,3-dihydroxy-cyclopentyl) -6- (2,2-diphenyl-ethylamino) - 9H-purin-2-yl] pyrrolidin-3-yl} -3-pyridin-3-urea (example 26 step 2) (0.1 g, 0.16 mmol) in DMF (0.5 mL). Is added

211

DIPEA (56 ml, 0.32 mmol) and the resulting solution is stirred for 2 hours. The mixture is then treated with us. Na2CO3 and 1 mL methanol and then partitioned between ethyl acetate and water. The organic portion is separated and concentrated in vacuo. The obtained crude product is purified by reverse phase column chromatography (Isolute ™ C18, 0-100% acetonitrile in water - 0.1% HCl) to give the title product.

Step 2: (R) -N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-Diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3-yl -ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-propionamide [0322] Solution (R) -N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -310 (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} - 2,3-dihydroxy-cyclopentyl) -2-phenoxy-propionamide (83 mg, 0.104 mmol) in ethanol (20 mL) and THF (5 mL) under an inert atmosphere are treated with palladium hydroxide (20% w / w). on carbon, 32 mg) followed by acetic acid (2 ml). The reaction mixture is placed under an atmosphere of hydrogen for two weeks, then the mixture is filtered and concentrated in vacuo.

The resulting crude product is washed with ethanol (3 times), filtered and then concentrated in vacuo. The residue is dissolved in methanol (2 mL) and purified by reverse phase column chromatography (Isolute ™ C18, 0-100% acetonitrile in water - 0.1% NH3) to give the title compound as a white solid. (MH + 707.4)

Example 255 (S) -N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-Diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3- yloureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxypropionamide [0323] A mixture containing 1 - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -4-amino-2,325 dihydroxy-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} 3-pyridin-3- yl urea (Example 26 step 2) (0.1 g, 0.16 mmol) and TEA (24 ml, 0.18

212 mmol) in THF (7 ml) at room temperature is treated with (S) - (-) - 2-acetoxypropionyl chloride (24 mg, 0.16 mmol) in MeCN (1 ml) at (0 ° C) for 1 minute. The mixture is stirred at room temperature for 18 hours and then treated with sat. Na2CO3 (1 ml) and methanol (1 ml), followed by stirring for a further 2 days. The solvent is removed in vacuo and purified by reverse phase column chromatography (Isolute ™ C 18, 0-100% acetonitrile in water - 0.3% NH3) to give the title compound as a white solid. (MH + 707.7)

Example 256

N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-Diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3-yl-ureido) -yrrolidin- 1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-2-methyl-propionamide [0324] This compound is obtained analogously to Example 255 by replacing (S) - (-) - 2 chloride -acetoxy-propionyl 2-acetoxy-isobutyryl chloride. The ester hydrolysis is carried out in the presence of 1 M NaOH in methanol. (MH + 721.5)

Example 257

N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-Amino-pyrrolidin-1-yl) -6 - ((S) -1-hydroxymethyl-2-phenyl-ethylamino) - purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide [0325] This compound is obtained from N - {(1S, 2R, 3S, 4R) -4- [6 - ((S ) -1-benzyl-2-hydroxy-ethylamino) -2-chloro-purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide (intermediate VD) analogous to the hydrochloride N - ((1S, 2R, 3S, 4R) -4- {2 ((R) -3-amino-pyrrolidin-1-yl) -6- [2,2-bis- (4-hydroxy-phenyl) - ethylamino] -purin-9-yl} 2,3-dihydroxy-cyclopentyl) -2-hydroxyacetamide (Example 7 step 5). (MH + 527.26)

Example 258

Trifluoroacetic acid methyl ester {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9 yl] -2,3-dihydroxy-cyclopentyl} carbamic acid

213 [0326] This compound is obtained from {(1S, 2R, 3S, 4R) -4 [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3 acid methyl ester -dihydroxy-cyclopentyl} carbam (intermediate T) analogously to N - ((1S, 2R, 3S, 4R) -4 {2 - ((R) -3-aminopyrrolidin-1-yl) -6- [2, 2-bis- (4-hydroxy-phenyl) -ethylamino] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (example 7 step 5). (MH + 572.21)

Examples 259-261 [0327] These compounds, namely, N - ((1S, 2R, 3S, 4R) -4- {6 - ((S) -1-Benzyl-2-hydroxyethylamino) -2 - [(R) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} 2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (MH + 647.01) (example 259) N [(1S, 2R, 3S, 4R) -4- (6 - ((S) -1-benzyl-2-hydroxy-ethylamino) -2 - {(R) -3- [3- (4-sulfamoyl-phenyl) -ureido] -pyrrolidin-1-yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -2-hydroxyacetamide (MH + 724.99) (Example 260) and acid methyl ester [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (3-sulfamoyl-phenyl) -ureido] -pyrrolidin-1-yl} -puryn- 9yl) -2,3-dihydroxy-cyclopentyl] -carbamate (MH + 771.34) (Example 261) is obtained from the appropriate starting materials and the corresponding pyrrolidinyl urea (the preparation method is described herein) analogously to example 15.

Example 262 1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) (pyridin-2-ylmethyl) -amide -9H-purin-2-yl] -1H-pyrazolo-4-carboxylic acid

Step 1: Acid 1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl ] -1H-pyrazole-4-carboxylic QBA289 [0328] Solution containing 1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2, 2-diphenylethylamino) -9H-purin-2214-yl] -1H-pyrazole-4-carboxylic acid (example 173 step 1) (0.4 g, 0.64 mmol) in water (3 ml) is treated with 1 M KOH in methanol (6 ml) and stirred at room temperature for 48 hours. The solvent is removed in vacuo and the crude product obtained is dissolved in water (5 ml) and this is acidified with pH 3-4 with 1.5 N HCl. The solution is extracted with ethyl acetate and the organic portion is dried over sodium sulfate and concentrated in vacuo. Purification by silica gel chromatography eluting with 5% methanol in chloroform affords the title compound.

Stage 2: 1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H (pyridin-2-ylmethyl) -amide -purin-2-yl] -1H10 pyrazole-4-carboxylic acid A mixture containing 1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- ( 2,2-diphenyl-ethylamino) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic acid (0.06 g, 0.01 mmol) in dry DCM (10 ml) is treated with 2 aminomethyl pyridine (0.021 g, 0, 2 mmol) followed by HOBt (0.027 g, 0.2 mmol), 315 1- [bis (dimethylamino) methylene] -1H-benzotriazolium HBTU hexafluorophosphate oxide (0.076 g, 0.2 mmol), N-methylmorpholine (0.02 g, 0.2 mmol) and DMAP (1 mL). The resulting mixture is stirred at room temperature for 24 hours and then concentrated in vacuo. The residue is purified by preparative TLC eluting with 10% methanol in chloroform to give the title compound. (MH + 68.11)

Example 263

N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylaminol-2 - [(R) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1 hydrochloride -yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -3-hydroxy-propionamide [0330] This compound is obtained analogously to (R) -N - ((1S, 2R, 3S, 4R) -4 - {625 (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3- dihydroxy-cyclopentyl) -2-phenoxy-propionamide (example 254 step 1)

215 replacing R - (+) - 2-benzyloxypropionic acid with 3-tert-butoxypropionic acid. (MH + 707.4)

Example 264

(R) -2-benzyloxy-N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridinyl- 3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide [0331] This compound is obtained analogously to (R) -N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl } -2,3-dihydroxy-cyclopentyl) -2-phenoxy-propionamide (example 254 step 1) replacing R - (+) - 2-benzyloxypropionic acid with (R) -2-benzyloxy-propionic acid. (MH + 797.7)

Novartis AG, Switzerland Representative:

216

Z-9627

EP 2 013 211 B1

Contents5

11 priority claims, no other members on record

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Priority claims
Document	Office	Kind	Date
0607947	United Kingdom	A	2006-04-21
0607947	United Kingdom	A	2006-04-21
07101483	European Patent Office (EPO)	A	2007-01-31
07101483	European Patent Office (EPO)	A	2007-01-31
07724372	European Patent Office (EPO)	A	2007-04-19
2007003435	European Patent Office (EPO)	W	2007-04-19
2007003435	European Patent Office (EPO)	W	2007-04-19
EP20070101483	–	–	–
EP20070724372	–	–	–
GB20060007947	–	–	–
WO2007EP03435	–	–	–

Purine derivatives for use as adenosin a2a receptor agonists

Abstract

Term

HO OH

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

Z-9627

EP 2 013 211 B1

Priority claims11

Numbers

Titles2

Classification