ES2384337T3

Purine derivatives for use as adenosin a2a receptor agonists

Abstract

Compound of formula (I) or stereoisomers or pharmaceutically acceptable salts thereof, ** Formula ** in which: R1, R2 and R3 are ** Tables **.

ES2384337T3, drawing sheet 1 — Sheet 1 of 9

Term

0.6 yearsto projected expiry

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

10 claims: 1 independent, 9 dependent

1
ES 2 384 337 Τ3 IS 2 384 337 Τ3 CLAIMS REIVINDICACIONES 1. Compound of formula (I) or stereoisomers or pharmaceutically acceptable salts thereof, 1. Compuesto de fórmula (I) o estereoisómeros o sales farmacéuticamente aceptables del mismo, HO OH (I) en el que:HO OH (I) in which: R1, R2 and R3 are Ex. R1R2R3 AA \ = / 1 HOXC II O He 0 NH2 R1, R2 y R3 son Ej. R1 R2 R3 AA \=/ 1 HOX C II O Va 0 NH2 AA 2 HO o nQ 'Ά' /OH AA V AA o \—/ \........H 3 y N = J o J HO AA /= 4 \ Y Vz 3 X \\ N- ) \ AA y >......H \=/ AA 2 HO or nQ 'Ά' / OH AA V AA or \ - / \ ........ H 3 Y N = J or J HO AA / = 4 \ Y Vz 3 X \\ N- ) \ AA Y > ...... H \ = / 124 124 ES 2 384 337 T3 Ej. R1 R2 R3 ho F F XN o Λ 7 ->.......N < ES 2 384 337 T3 Ex. R1R2R3 ho F FXN or Λ 7 -> .......N < 5 A L b F F o> .....S / N2N A Ά ho F F o 7 A 6 A Y /......N E 7 F F \ ,o 'S' o'' ' nn2 on ho F A N-A s........H 7 s F A A EA M oh on on ho F A ........N 8 s F A O d\ o A >A-nn2 on 9 ho A F on A A^ .......a o ( 7 F A on A A o \ nh2 5 TO L b F F or> ..... S / N2N TO Ά ho F F or 7 A 6 TO Y /......NE 7 F F \, or 'S' or '' ' nn2 on ho F TO NAs........ H 7 s F TO TO EA M oh on on ho F TO ........ N 8 s F TO OR d \or TO > A-nn2 on 9 ho TO F on TO A ^ .......toor ( 7 F TO on TO TO o \ nh2 125 125 ES 2 384 337 T3 Ej. R1 R2 r3 OH A A 10 h° A H ..... N \ H n—n N=\ \ A A o w OH h3c 3\ o A A y O Λ ........N NH 11 °Ά H N \ i G \ A A AA H,C. .CH, A A H C 1 o 12 3 °'A C o A A ° -naG A A 13 ΞΕ ω O \ o / 0=0 \ A A ° GO A A Μ 14 h°^^A II o A A ° -Á.-0 Ό X ^x A A Q .. y NH 15 h° c II °=( o NH A A S ES 2 384 337 T3 Ex. R1R2r3 Oh TO TO 10 h ° TO H ..... N \ H n — n N = \ \ TO TO or w Oh h3c3\ or TO TO Y OR Λ ........ N NH eleven ° Ά H N \ i G \ TO TO AA H, C. .CH, TO TO HC 1 or 123 ° 'A C or TO TO ° -naG TO TO 13 ΞΕ ω O \ o / 0 = 0 \ TO TO ° GO TO TO Μ 14 h ° ^^ A II or TO TO ° -A.-0 Ό X ^ x TO TO Q .. Y NH fifteen h ° c II ° = ( or NH TO TO S 126 126 ES 2 384 337 T3 Ej. R1 R2 R3 A A A N x A / 16 H0X C A O II 0 A A 5 «A Γ Λ η N N N---' A A 17 h3cx V II 0 0 / -H A C- Y A A 0 A A 0 ES 2 384 337 T3 Ex. R1R2R3 TO TO TO N x TO / 16 H0XC TO OR II 0 TO TO 5 "TO Γ Λ η N N N --- ' TO TO 17 h3cxV II 0 0 / -H TO C- Y TO TO 0 TO TO 0 N ^ \ hczI, > ....... N TO 18 C L / | 3 II 0 TO TO N Ό TO TO 19 hC V II TO-3OR Xn /<or N 0 TO TO I \ ....... N N^\ h cz I , >.......N A 18 C L / | 3 II 0 A A N Ό A A 19 hC V II A-3 O Xn / <o N 0 A A I \.......N Ar ·· ll twenty H, CX^ CXTO TO N ) ...... N TO 3 II OR 0 TO TO 0 •TO. TO N TO TO twenty-one H3C V IIHORHN N ^ H γ ah AZ 0 TO TO 0 TO Ar·· l-l 20 H,CX ^CX A A N )...... N A 3 II O 0 A A 0 •A. A N A A 21 H3C V II HO H · N N^ H γ ah AZ 0 A A 0 A 127 127 ES 2 384 337 T3 Ej. R1 R2 R3 OH AÁ N--/ h3cx \=/ 22 C II 0 N A N aa \ —-' \ / —Z h V OH O OH AÁ A^ \ N \--/ 1 > \ __ / 23 h3cx C II V-/ A \ 0 γ \=Ί O OH OH AÁ am^A AA 24 h3cx AA II ¿A N X X H N \ )--OH 0 a —/ A \—/ 0 OH AA ^x N \ H0X /^=7 l A 25 C / O II 0 / V H jA AA N γ// 7=7 '---N 0 AA X A 26 H.X 0-4 )=7 X........N / ^NH | 3 || / ( *—- i 0 AA pil YN ES 2 384 337 T3 Ex. R1R2R3 Oh AÁ N - / h3cx\ = / 22 C II 0 N TO N aa \ —- ' \ / —Z h V Oh OR Oh AÁ A ^ \ N \ - / 1 > \ __ / 2. 3 h3cxC II V- / TO \ 0 γ \ = Ί OR Oh Oh AÁ tom^ A AA 24 h3cxAA II TO NX X H N \) - OH 0 to -/ TO \ - / 0 Oh AA ^ x N \ H0X /^=7l TO 25 C / OR II 0 / V H jA AA N γ // 7=7'--- N 0 AA X TO 26 HX0-4 )=7X ........ N / ^ NH | 3 || / ( * —- i 0 AA pil YN 128 128 ES 2 384 337 T3 Ej. R1 R2 R3 27 KC^^A 3 C o AA AA O yy^NH, o VO En O......N 28 HX^^A 3 C o AA AA nh2 OX 2 X Ao X O......N 29 H- AA AA «y o 30 HC c/ II o AA AA «y o 31 ^A II o AA AA «y o 32 Oy C o AA AA x A «y o ES 2 384 337 T3 Ex. R1R2R3 27 KC ^^ A3 C or AA AA OR yy ^ NH, or VO In O ...... N 28 HX ^^ A3 C or AA AA nh2OX 2FORor X O ...... N 29 H- AA AA "Y or 30HC c / II or AA AA "Y or 31 ^ A II or AA AA "Y or 32 Oy C or AA AA for "Y or 129 129 ES 2 384 337 T3 Ej. R1 R2 R3 33 H,C^^A 3 II Q AA AA / N A NH pj 34 Ύ ZQ H3C AA AA Ά.......» H L-Ύ xn 35 H,C^^A 3 II Q AA AA qA H O'N 36 H,C^^A 3 II Q AA AA '°>Α o 37 H,C^^A 3 II Q AA AA QW / C a· O.......N ES 2 384 337 T3 Ex. R1R2R3 33 H, C ^^ A3 II Q AA AA / N TO NH pj 3. 4 Ύ ZQH3C AA AA Ά ....... »H L-Ύ xn 35 H, C ^^ A3 II Q AA AA qA H O'N 36 H, C ^^ A3 II Q AA AA '°> Α or 37 H, C ^^ A3 II Q AA AAQW / C to· O ....... N 130 130 ES 2 384 337 T3 Ej. R1 R2 R3 o x Ί F A Aa N o >........ ES 2 384 337 T3 Ex. R1R2R3 ox Ί F TO Aa N or > ........ 38 La 7 'N A L F A o ¥ F A A' H 39 h3cx -F II ·· N A zoh o A o F LL F A H 40 H,A CX o A A 3 1 Ex y o o F A A „5 N H o F A N A 41 h3cx F II A ^NH o F A >··< 38 The 7 'N TO L F TO or ¥ F TO TO' H 39 h3cx-F II ·· N TOzoh or TO or F LL F TO H 40 HE HAS CXor AA 3 1 Ex me or F TO TO „5 NH or F TO N TO 41 h3cxF II TO ^ NH or F TO > ·· < L ¥ F A L ¥ F TO 42 h.A C II o F A ^N- N H F A A^ \ H 43 n3c y Y ?.....k H N 3 o AA F A An \___i 42 he has C II or F TO ^ N- N H F TO A ^ \ H 43 n3c Y Y?..... k H N 3 or AA F TO TOn \ ___ i 131 131 ES 2 384 337 T3 Ej. R1 R2 r3 44 H,C^^A 3 C 0 -H H 45 H,C^^A 3 C 0 AA AA YU- 0 AA 46 CH, 1 3 /Nx / H,C C 3 C o W AA yag 0 47 0 AA A o H,C ^° AA AA vA.G 0 48 n,c^^A 3 C o W AA \ o A n N - S — H 11 O 49 H,C^^A 3 C 0 AA AA GHk 0 / ¡•G HN 0 O CN, ES 2 384 337 T3 Ex. R1R2r3 44 H, C ^^ A3 C 0 -H H Four. Five H, C ^^ A3 C 0 AA AA YU-0 AA 46 CH, 1 3 / Nx / H, CC3 C or W AA yag 0 47 0 AA To or H, C ^ ° AA AA vA.G 0 48 n, c ^^ A3 C or W AA \ or A n N - S - H 11OR 49 H, C ^^ A3 C 0 AA AA GHk0 / ¡• G HN 0 O CN, 132 132 ES 2 384 337 T3 Ej. R1 R2 R3 50 hx^^A 3 II O OO ΑΛ VL ° » tí 51 hx^A 3 II o A\ ΑΛ Va ° ( ' / O A H 0° O ^ch, 52 hx^A 3 II o AL AL y_ A hn h,c 53 hx^A 3 II o AL AL Υλ j _ vA O C_3 54 hx^A 3 II o AL AL Ax _ v% ES 2 384 337 T3 Ex. R1R2R3 fifty hx ^^ A3 II OR OO ΑΛ VL ° »You 51 hx ^ A3 II or TO\ ΑΛ He ° ( '/ O TO H 0 ° OR ^ ch, 52 hx ^ A3 II or TO THE TO THE Y_ TO hn h, c 53 hx ^ A3 II or TO THE TO THE Υλ j _ he OR C_3 54 hx ^ A3 II or TO THE TO THE Ax _ v% 133 133 ES 2 384 337 T3 Ej. R1 R2 R3 A A Ah ° Ί ° A 55 HC C HN 3 II 0 A i 0 ES 2 384 337 T3 Ex. R1R2R3 TO TO Ah ° Ί ° TO 55 HC C HN 3 II 0 TO i 0 A 0° ° ch3 A A ^x X 00 56 H3C C II 0 0 Aa A A A......a « ^0 57 H3C II A A A -·· n N Η H ? O 0 A A Íí ίί. 0 A A F F H3C T 58 C II 0 \\ A 0 0 A A _S N \χ H 0 A A 0 59 H3C ^CX Ό......N Ah N. aa _,CH3 0 II A 0. TO 0 ° ° ch3 TO TO ^ x X 00 56 H3C C II 0 0 Aa TO TO A ...... a « ^ 0 57 H3C II TO TO A - ·· n N Η H ? OR 0 TO TO Yes ίί. 0 TO TOF F H3C T 58 C II 0 \\ TO 0 0 TO TO _S N \χH 0 TO TO 0 59H3C^ CXΌ ...... N Ah N. aa _, CH30 II TO 0. 0 ch3 A A 0 1 ch3 A A 60 H3C II 0 0A........ 0 \\ /.S N Y A |A, 00 A A H 0 0 ch3 TO TO 0 1 ch3 TO TO 60 H3C II 0 0A ........ 0 \\ /.SNY TO | A, 00 TO TO H 0 134 134 ES 2 384 337 T3 Ej. R1 R2 R3 A A 0 61 H3C II 0 Ό- A /\/ O_/c “N N Y A A O A A 0 ^x / \ A? ES 2 384 337 T3 Ex. R1R2R3 TO TO 0 61 H3C II 0 Ό- A / \ / O_ /c"NNY TO TO OR TO TO 0 ^ x / \ TO? 62 H3C C II 0 A A N >....... 62 H3C C II 0 TO TO N > ....... A A 0 63 H3C AA II 0 A A- \........ Ά N ) A H3C A A 0 64 H3C AA II N S........An-0Hs 0 A A A^ / / H3C A A 0 65 H3C Ax || N >........ TO TO 0 63 H3C AA II 0 TO TO- \ ........ ΆN ) TO H3C TO TO 0 64 H3C AA II N S ........ An-0Hs 0 TO TO A ^ / / H3C TO TO 0 65 H3C TOx || N > ........ 0 A A A A 0 66 H3C Ax A^ 1/ CH3 3 II 0 X.III N \ / A A A / H N^\ H CH3 0 TO TO TO TO 0 66H3CTOxA ^ 1 / CH3 3 II 0 X.III N \ / TO TO TO / HN ^ \H CH3 135 135 ES 2 384 337 T3 Ej. R1 R2 R3 A A o 67 H3C 04 II o A A ό ml N'^'Z Η Ν’ H CH3 A A z ^x X ( ) 68 HC C O^. ES 2 384 337 T3 Ex. R1R2R3 TO TO or 67 H3C 04 II or TO TO ό ml N '^' Z Η Ν ' H CH3 TO TOz ^ x X () 68 HC C O ^. 3 II o A A \—ζ 7 H / V V [/ o Z =/ A A x AH 69 H3C V II o ..... JA N N Η H í A A O A A A \........ NH ^x X L y h i 70 H3C C II X p o A A o t JJ Xx° A A \ _ rXX χΝ. 3 II or TO TO \ —Ζ 7 h / V V [/ or Z = / TO TO x AH 69 H3C V II or ..... HA NN Η H í TO TO OR TO TO TO \ ........ NH ^ x X L Y h i 70 H3C C II X p or TO TO ot JJ Xx ° TO TO \ _ rXX χΝ. 71 H3C ^ CXII or TO OR- H ΝχΧΧχΧ S ^ N TO OR TO TO Z \ S X___. XX, AA 72 HC XN \ H | 3 II or TO or..... Νχ-'ΧΧ AA N 71 H3C ^CX II o A O- H ΝχΧΧχΧ S ^N A O A A Z\ S X___. XX, A A 72 HC X N \ H | 3 II o A o..... Νχ-'ΧΧ A A N A O TO OR 136 136 ES 2 384 337 T3 Ej. R1 R2 R3 A A Q G ^χ / /=\ 73 H3C C II Q A A >......Nv H Aa ~~Q Q A A 74 H3C II Q O ......n^'''n· H H o A A A A H3C O C Ύα 75 C II Q A A A -GA w X r \\ O N3C A A 03) ‘ CH X Cl Xx o 76 H3C C 3 II Οχ P Q A A A-'' \ 's 0, ).......NH A A F 77 H3C o h__( AV A II Q x\ VN .......NH ES 2 384 337 T3 Ex. R1R2R3 TO TO Q G ^ χ / / = \ 73 H3C C II Q TO TO > ......NvH Aa ~~ Q Q TO TO 74 H3C II Q OR ...... n ^ '' 'n H H or TO TO TO TO H3C OR CΎα 75 C II Q TO TO TO -GA w X r \\ OR N3C TO TO 03) 'CH X Cl Xx or 76H3CC 3 II Οχ P Q TO TO TO-'' \ 's 0, ) ....... NH TO TO F 77H3Cor h __ ( av TO II Qx\ VN ....... NH 137 137 ES 2 384 337 T3 Ej. R1 R2 r3 A A 79 H,CX A/ II 0 A 0 A N Ν' H H O CH, / 3 A A A A ^N H,C' <a A y. ES 2 384 337 T3 Ex. R1R2r3 TO TO 79 H, CXTO/ II 0 TO 0 TO N Ν ' H H OR CH, / 3 TO TO TO TO ^ N H, C ' <a TO Y. 80 C II x.y N^\ O A A .......N A A A 0 y N \ / yZ G 81 H,CX C II u >.......N A O A A z N 11 .N S CH, A A 0 o=¿ CH3 ^x y “A 0 82 H,C' C || O A A o v 0 • y Vn N A H A A N Nx y y V n Ά \\ Tí A 83 HC C N \ N Ά___// II O A A Ly .......N Z 80 C IIx.Y N ^ \ OR TO TO ....... N TO TO TO 0 Y N \ / and Z G 81 H, CXC II or > ....... N TO OR TO TO z N eleven .N S CH, TO TO 0 o = CH3 ^ xy "TO 0 82 H, C ' C || OR TO TO ov 0 • Y Vn N TO H TO TO N Nx yy V n Ά \\ You TO 83 HC C N \ N Ά ___ // II OR TO TO Ly ....... N Z O O A A O 84 H,C' W II O XN-' \ 0 “G } A A L ).......N N- OR OR TO TO OR 84 H, C ' W II ORXN- ' \ 0 "G } TO TO L ) ....... N N- 138 138 ES 2 384 337 T3 Ej. R1 R2 R3 O χ. Α Λ k y _ ll x h.c^ N ^x X I 85 h,cx c 3 II O A ί s ES 2 384 337 T3 Ex. R1R2R3 OR χ. Α Λ k Y _ ll x hc ^ N ^ x X I 85 h, cxc 3 II OR TO ί s X X O h,c Λ II O OO 86 h3cx Λ Α Αχ Λ γ O Ό Λ X O _cx Ο 11 ΤΊ X 87 c 3 II S-._ / // O Λ 0 L ch, X ......_x° Λ Λ ^x tí [ 1 88 h.X c L J 3 II O Λ N^O 1 II A xX: A F Λ \Κ1^ -χ \ h ^x X 1 >.......N / =\ 89 cx c L / \ / \ 3 II O Λ A tí O \ N X X OR h, c Λ II OR OO 86 h3cxΛ Α Αχ Λ γ O Ό Λ X OR _cxΟ11 ΤΊ X 87 c 3 II S -._ / // OR Λ0 L ch, X ......_ x ° Λ Λ ^ x you [ 1 88 hX c LJ 3 II OR Λ N ^ O 1 II TO xX: TO F Λ \Κ1^ -χ \ h ^ x X 1 > ....... N / = \ 89 cxc L / \ / \ 3 II OR Λ TO you O \ N 139 139 ES 2 384 337 T3 Ej. R1 R2 R3 F A Α--Λ V\ N 90 HCX C >..... 1 N / — \ 3 II \__/ N LA o F A rA o ES 2 384 337 T3 Ex. R1R2R3 F TO Α - Λ V \ N 90 HCXC > .....1 N / - \ 3 II \ __ / N THE or F TO rA or N F HCX r~ CN3 Λ NH 91 C __/ 3 II ~A o o A -CN3 \) V N N F HCXr ~ CN3 Λ NH 91 C __ / 3 II ~ A or or TO -CN3 \) V N N 92 h3cx A/ II o CHCh3 o y NH \) V·· N A N > N 92 h3cxTO/ II or CHCh3or Y NH \) V·· N TO N > HCX r~ CN3 \ NH 93 C 3 II A o=A o v_ -CN3 N A o ' ch HCXr ~ CN3 \ NH 93 C 3 II TO o = A or v_ -CN3 N TO or 'ch 140 140 ES 2 384 337 T3 Ej. R1 R2 R3 NH A A A 94 L II O A A A O A A \ C3 95 H3C AA II 0 A A A0 HN-x./ y A CH3 /---N H H \ NH A A A 96 H3C Ax II 0 A A O o A A q 97 H3C Ax II 0 A A NH T 0 0 H30 0H3 A A H A, 98 H3C Ax II 0 A A Ay° \ 0H3 A- h 03 ES 2 384 337 T3 Ex. R1R2R3 NH TO TO TO 94 L II O TO TO TO OR TO TO \ C3 95 H3C AA II 0 TO TO TO0HN-x./ Y TO CH3 / --- N HH \ NH TO TO TO 96 H3C TOxII 0 TO TO OR or TO TO what 97 H3C TOxII 0 TO TO NH T 00H30 0H3 TO TO H TO, 98 H3C TOxII 0 TO TO Ay ° \ 0H3 TO- h 03 141 141 ES 2 384 337 T3 Ej. R1 R2 R3 99 H3C II A A A o NH 0 A A ΗΝΥΖ O A A 100 H3C II 0 A A XN' H ^xZH2 A A 101 H3C II 0 A A V-Á ° < N N A A z 102 H3C II 0 A A J A \ L·- CH3 H 0^. CH3 A A \ H A H3C II L xx Nx 103 Y 0 A A 0 A A 104 H3C II 0 A A Q H ES 2 384 337 T3 Ex. R1R2R3 99 H3C II TO TO TO or NH 0 TO TOΗΝΥΖ OR TO TO 100 H3C II 0 TO TOXN ' H ^ xZH2 TO TO 101 H3C II 0 TO TO GOES ° <NN TO TO z 102 H3C II 0 TO TO JA \ L · - CH3 H 0 ^.CH3 TO TO \ H TO H3C II L xx Nx 103 Y 0 TO TO 0 TO TO 104 H3C II 0 TO TO Q H 142 142 ES 2 384 337 T3 Ej. R1 R2 R3 \ F A A / 105 c II o \ NN A F A o N3C CN3 H N A F A F η 106 V ^A II o A Vo F A 1 CH, h3c 3 F A A 107 H,C' \ ¥ A 3 II o F A I NN ES 2 384 337 T3 Ex. R1R2R3 \ F TO TO / 105 c II or \ NN TO F TO or N3C CN3 H N TO F TO F η 106 V ^ A II or TO Vor F TO1 CH, h3c 3 F TO TO 107 H, C ' \ ¥ A 3 II or F TO I NN N H F A A o ) 108 A FF II o o ü /\ o O/Z F A A O F A ¥ o N N V o H3C 109 A FF ( N A Ja 3 II o N N —< N A N N H F TO TO or ) 108 TO FF II or or or / \ o O / Z F TO TO OR F TO ¥ or NN V or H3C 109 TO FF ( N AHA 3 II or N N - < NAN F A Ax F TO Ax F A N A FF II 7 v 110 A o F A N — / F TO N TO FF II 7 v 110 TO or F TO N - / 143 143 ES 2 384 337 T3 Ej. R1 R2 R3 111 H,C^^A 3 II Q AA AA p NH h3c 112 H,C^^A 3 II Q AA AA \ OH H \ || 113 H,C^^A 3 II Q AA AA k 0 1 ° nJX^° HN ó °'ch3 114 H,C^^A 3 II Q AA AA Ln G q NYy HN 115 H,C^^A 3 II Q AA AA Th Ί ° H X^Q HN ° A AH3 116 H,C^^A 3 II Q AA AA ^-JnO nN ll ES 2 384 337 T3 Ex. R1R2R3 111 H, C ^^ A3 II Q AA AA p NH h3c 112 H, C ^^ A3 II Q AA AA \ OH H \ || 113 H, C ^^ A3 II Q AA AA k0 1 ° nJX ^ ° HN or ° 'ch3 114 H, C ^^ A3 II Q AA AA Ln G qNYy HN 115 H, C ^^ A3 II Q AA AA Th Ί °H X ^QHN ° A TOH3 116 H, C ^^ A3 II Q AA AA ^ -JnOnNll 144 144 ES 2 384 337 T3 Ej. R1 R2 R3 HZ O AÁ A 117 H3C 04 II l \ o aa N / H3C -CH3 O h3c AA \ 118 H3C V II /-A l Λ o AA N / H3C -CH3 F 119 H3C 04 II ^CS3 A 7 o Αχ N / H3C -CH3 Aa A 120 H3C 04 II XA] l \ o o N / H3C -CH3 vZ \ 121 H3C V II l \ o HO N / H3C -CH3 7=\ A 122 H3C 04 II /A l \ o AJ N / H3C -CH3 ES 2 384 337 T3 Ex. R1R2R3 HZ OR AÁ TO 117 H3C 04 II l \ or aa N / H3C -CH3 OR h3c AA \ 118 H3C V II /-TO l Λ or AA N / H3C -CH3 F 119 H3C 04 II ^CS3 TO 7 or Αχ N / H3C -CH3 Aa TO 120 H3C 04 II FOR] l \ or or N / H3C -CH3 vZ \ 121 H3C V II l \ or HO N / H3C -CH3 7 = \ TO 122 H3C 04 II /TO l \ or AJ N / H3C -CH3 145 145 ES 2 384 337 T3 Ej. R1 R2 R3 123 h, AA 3 II O Ox A — ch3 / h,c 124 h.AA 3 II O A X'\,X Ch A — ch3 / h,c 125 h.AA 3 II O 0 A° A — ch3 / h,c 126 h.AA 3 II O AA AA o Tm xq.......Λ S A 127 h.AA 3 II O AA AA 0 ........ 0—N 128 h.AA 3 II O AA AA 0 Ά Acs /=\ o........ ES 2 384 337 T3 Ex. R1R2R3 123 h, AA3 II OR Ox TO - ch3 / h, c 124 h.AA3 II OR TO X '\, X Ch TO - ch3 / h, c 125 h.AA3 II OR 0 A ° TO - ch3 / h, c 126 h.AA3 II OR AA AA or Tmxwhat ....... Λ S TO 127 h.AA3 II OR AA AA 0 ........ 0 — N 128 h.AA3 II OR AA AA 0 Ά Acs / = \ o ........ 146 146 ES 2 384 337 T3 Ej. R1 R2 r3 O A A A N >.........\ 129 H,C' II 0 A A 1 A U A A H,C 3 í=N . y O 130 H,C' C II 0 A ΧΝ··\ o ) \ v. ES 2 384 337 T3 Ex. R1R2r3 OR TO TO TO N > ......... \ 129 H, C ' II 0 TO TO 1 TO OR TO TO H, C3= N . Y OR 130 H, C ' C II 0 TOΧΝ ·· \ o) \ v. A 1 , >.......h H w H A A 0 CH, . y X ^-x ......As- An 131 H,C' C II 0 . TO 1 , > ....... h Hw H TO TO 0 CH, . Y X ^ -x ......TOs- An 131 H, C ' C II 0 . ky N II A A A CH, A A ^N Ά O 132 H,C' II )....... N XXAZ--N H II Ύ .N 0 A A v N 1 CH, 0 A A A- y k H || N .......... J . NH I 133 A 1 0 A A pil aa- A A Χ·Ν···Χ s.......H / . y V \—N A 134 H,C' C II .A 4 0 A A N~CN, / H,C ky N II TO TO TO CH, TO TO ^ N Ά OR 132 H, C ' II ) ....... N XXAZ - N H II Ύ .N 0 TO TOv N 1 CH, 0 TO TO TO- Y k H || N .......... J. NH I 133 TO 1 0 TO TO pil aa- TO TOΧ· Ν ···Χyes .......H / . Y V \ —N TO 134 H, C ' C II .TO 4 0 TO TO N ~ CN, / H, C 147 147 ES 2 384 337 T3 Ej. R1 R2 R3 135 HX^^A 3 0 0 AA AA aa........ O oOA 136 HX^^A 3 0 0 0 ΆCH30 cH3 A A\ k /~03 H3O 137 HX^^A 3 0 0 0 X X /~03 H3O 138 HX^^A 3 0 0 Ίχ/ 0 X) X /~03 H3O 139 hx^^A 3 0 0 o... :o X /~03 H3O 140 hx^^A 3 0 0 X /~03 H3O ES 2 384 337 T3 Ex. R1R2R3 135 HX ^^ A3 0 0 AA AA aa ........ OR oOA 136 HX ^^ A3 0 0 0 ΆCH30 cH3 AA \ k / ~03 H3O 137 HX ^^ A3 0 0 0 X X / ~03 H3O 138 HX ^^ A3 0 0 Ίχ / 0 X) X / ~03 H3O 139 hx ^^ A3 0 0 or... :or X / ~03 H3O 140 hx ^^ A3 0 0 X / ~03 H3O 148 148 ES 2 384 337 T3 Ej. R1 R2 R3 141 H.C^^C^ 3 II 0 ,o y ,Α ΙΗ3 H3C 142 H.C^^C^ 3 II 0 A Χ\/Ν\χΧ Y ,Α ΙΗ3 H3C 143 H.C^^C^ 3 II 0 C \xí ΥΧ,^Χ/ y /~ch3 H3C 144 3 II 0 O, r y /~ch3 H3C 145 H.C^^C^ 3 II 0 ,c° y /~ch3 H3C 146 H.C^^C^ 3 II 0 ch3 q HO y /~ch3 H3C ES 2 384 337 T3 Ex. R1R2R3 141 HC ^^ C ^3 II 0 ,or Y , Α ΙΗ3 H3C 142 HC ^^ C ^3 II 0 TO Χ \ /Ν\χΧ Y , Α ΙΗ3 H3C 143 HC ^^ C ^3 II 0 C \ xí ΥΧ, ^ Χ / Y / ~ch3 H3C 1443 II 0 OR, rY / ~ch3 H3C 145 HC ^^ C ^3 II 0 , c ° Y / ~ch3 H3C 146 HC ^^ C ^3 II 0 ch3what HO Y / ~ch3 H3C 149 149 ES 2 384 337 T3 Ej. R1 R2 R3 147 HX^^A 3 C O HX 3 \ S HO y /~CH3 H3C 148 hx^A^ 3 C O V/ HO -y / ^3 H3C 149 HX^^A 3 C O Va \........... HO -y / ^3 H3C 150 hx^^A 3 C O HO v) HO '7 /~CH3 H3C 151 HX^^A 3 C O HnX\ HO y / ^3 H3C ES 2 384 337 T3 Ex. R1R2R3 147 HX ^^ A3 C OR HX3 \ S HO Y / ~CH3 H3C 148 hx ^ A ^3 C OR V / HO -Y / ^ 3 H3C 149 HX ^^ A3 C OR He \ ........... HO -Y / ^ 3 H3C 150 hx ^^ A3 C OR HO v) HO '7 / ~CH3 H3C 151 HX ^^ A3 C OR HnX \ HO Y / ^ 3 H3C 150 150 ES 2 384 337 T3 Ej. R1 R2 R3 152 A II A 7 o ho N / H3C CH3 VV 153 A FF II ) \ o o \ CN3 N / H3C CH3 154 A FF II M o \ZL A 7 o Ho N / H3C -CH3 cn3 / 3 S \\ // 155 h3cx ^F II o __// \.......o· 1 V N / H3C ~CH3 no ES 2 384 337 T3 Ex. R1R2R3 152 TO II TO 7 or ho N / H3C CH3 VV 153 TO FF II ) \ or or \ CN3 N / H3C CH3 154 TO FF II M or \ ZL TO 7 or Ho N / H3C -CH3 cn3 / 3 S \\ // 155 h3cx^ F II or __ // \.......or· 1 V N / H3C ~CH3 do not 151 151 ES 2 384 337 T3 Ej. R1 R2 R3 _C c\ 0 n' AÁ L V 156 h,cx /7 nh 3 II O AA °~ ES 2 384 337 T3 Ex. R1R2R3 _C c \ 0 n ' AÁ L V 156 h, cx /7nh 3 II OR AA ° ~ o 0 h,c '---N or 0 h, c '--- N _c \ 0 \ / AÁ A — \ ^x tí \=/ H 157 h,cx c 4 / 3 II O AA O: _c \ 0 \ / AÁ TO - \ ^ x you \ = / H 157 h, cxc 4 / 3 II OR AA OR: O AL h3c ° ch, oh X / \ ΑΆ L / ^x tí \=/ //° 158 h3cx c II v_/ -X/ h \ O AA O oh oh aá / x X-ch, x 159 h,cx n x 3 II >----¿ O AA N — \=< h o oh OR TO THE h3c ° ch, oh X / \ ΑΆ L / ^ x you \ = / // ° 158 h3cxc II v_ / -X / h \ OR AA OR oh oh aha / x x-ch, x 159 h, cxn x 3 II > ---- OR AA N - \ = < h or oh 152 152 ES 2 384 337 T3 Ej. R1 R2 R3 OH aá X X A \ / N \ N \---1 1 > ES 2 384 337 T3 Ex. R1R2R3 Oh aha X X TO \ / N \ N \---1 1 > 160 H3C C II A \ H 0 aa H \=\ o OH OH AÁ X — N \\ ^x X \--/ 1 > 160 H3C C II TO \ H 0 aa H \ = \ or Oh Oh AÁ X - N \\ ^ x X \ - / 1 > 161 H3C C II A \ H 0 aa H \=\ o OH OH ch33 AÁ \ X > 161 H3C C II TO \ H 0 aa H \ = \ or Oh Oh ch33 AÁ \ X > HC \ - / N \ Y 162 C . / 1 \\ - N 3 II '- ( X ~ XH OR AA \ H-- P Oh 0 AA TO- XN \ / 163 hnxAA II 0 ΓΛ L and X X / \ __ or TO X aa < 7 N AA TO) ^ x X \ = / L / 164 HC C / \ 3 II OR AA N · - < HC \--/ N \ y 162 C . / 1 \\ — N 3 II '—( X ~X H O AA \ H-- P OH 0 AA A- X N \ / 163 hnx AA II 0 ΓΛ L y X X / \__ o A X aa < 7 N AA A) ^x X \=/ L/ 164 HC C / \ 3 II O AA N·— < 153 153 ES 2 384 337 T3 Ej. R1 R2 R3 A A (TA 165 H3C II 0 r vU 0 A A A- H ,,Ν^Ά' HH A A A 166 H3C II 0 A A O··· Ir O A AoA A A AA 167 H3C II 0 A A XN.Í > H3O' NH E 0 0 Λ N H A 168 H3C ^A II 0 -H \ N Nü A 0 CH3 A A · 169 \ O O A A -Cl 170 H3C ^A II 0 -H \ 1 Ni A A “A A ES 2 384 337 T3 Ex. R1R2R3 TO TO (TA 165 H3C II 0 r vU 0 TO TO A- H ,, Ν ^ Ά ' H H TO TO TO 166 H3C II 0 TO TO OR··· Go or TO AoA TO TO AA 167 H3C II 0 TO TOXNEITHER > H3O 'NH AND 0 0 Λ NH TO 168 H3C ^ A II 0 -H \ N Wildebeest TO 0 CH3 TO TO · 169 \ OR OR TO TO -Cl 170 H3C ^ A II 0 -H \ 1 Ni TO TO "TO TO 154 154 ES 2 384 337 T3 Ej. R1 R2 R3 A A> ES 2 384 337 T3 Ex. R1R2R3 TO A> ^ x X X N 171 H3C C II O TO TO N 1 N ) TO TO ^ x X ~ x r ~ - \ 172 H3C C II O TO TO N 1 v 173 HC TO TO Foror 3 II OR TO TO « X N -ch3 ^x X X N 171 H3C C II O A A N 1 N ) A A ^x X ~x r~— \ 172 H3C C II O A A N 1 v 173 HC A A Xa o 3 II O A A « X N -ch3 H , 0 174 HC ^ A -H N Vj / 3 II OR « X N -ch3 H ,0 174 HC ^A -H N Vj / 3 II O « X N -ch3 H OH 175 HOX VA II O Γ 4 'lZ \......H? > O H N ) A A ( N OH 'o-y. H Oh 175 HOXVA II O Γ 4 'lZ \ ......H? > OR H N ) TO TO ( N Oh 'oy. ¥ A ' N O X H3C X NH 176 C II O A Ó o^ O b ¥ TO ' N OX H3C X NH 176 C II O TO OR or ^ OR b 155 155 ES 2 384 337 T3 Ej. R1 R2 r3 X XCH, AA 177 HC ^CX JT ó II 0 /T\ A ES 2 384 337 T3 Ex. R1R2r3 XXCH, AA 177 HC ^ CXJT or II 0 / T \ TO o AA 178 h,C ^CX II r\ o ° 0 O...... or AA 178 h, C ^ CX II r \ o ° 0 OR...... AA Ay ,,. AA Ay ,,. h, C ^ CX II \ = / 1 /.....\ NY. h,C ^CX II \=/ 1 /.....\ Ny. 179 / —Ζ 0 G>or G, nn2 ZA 'Q ^ xy \ - / NH 180 h, C C IIor= 4 0 aa 4 nh2 / CH3 AA 181 HO ' V .TO II AA NH or / = < 179 /—ζ 0 G> o G, nn2 ZA 'Q ^x y \—/ NH 180 h,C C II o=4 0 aa 4 nh2 / CH3 AA 181 HO' V .A II AA NH o /=< Y) '--- N y) '---N 156 156 ES 2 384 337 T3 Ej. R1 R2 R3 182 ch3 A II O AA AA 1 /N O 3° A NH d '---N 183 HO. xx / XX C II O AA AA 1 N O . A NH rt 184 HO. χχ x XX C II O AA AA Ó A NH 8 185 HO. χχ x XX C II O AA AA 1 .N O ° nA NH HO ES 2 384 337 T3 Ex. R1R2R3 182 ch3TO II OR AA AA 1 / NOR 3rd TO NH d '--- N 183 HO. xx / XX C II OR AA AA 1 N O. TO NH rt 184 HO. χχ x XX C II OR AA AA OR TO NH 8 185 HO. χχ x XX C II OR AA AA 1 .N O ° nA NH HO 157 157 ES 2 384 337 T3 Ej. R1 R2 R3 1 ,N O o nox ^F || \=/ A 186 /----( NH o /r~\ 0 ES 2 384 337 T3 Ex. R1R2R3 1 , N Or or do notx^ F || \ = / TO 186 / ---- ( NH or / r ~ \ 0 o^ / >o H2N FF Ó o nox ^F || \=F H 187 !---( NH o FF 0 or ^ / > or H2N FF Or or do notx^ F || \ = F H 187 ! --- ( NH or FF 0 \ -o o W A NH2 oH FF Ó o hox AA/ || A 188 \—/ NH o 0 \ -o or WA NH2 oH FF Or or hoxAA / || TO 188 \ - / NH or 0 oH o<- / Fo H2N oH 1 F\ AÁ Q o Ή 189 nox ^F II o O oH NH 8 oH or <- / Fo H2N oH 1 F \ AÁ What Ή 189 do notx^ F II or OR oH NH 8 158 158 ES 2 384 337 T3 Ej. R1 R2 R3 1 A oh A z° ho. ll A 190 nh O AA ( \=/ AA oh ho 1 A oh AA ------ O ho. ll A 191 H O AA 0 ES 2 384 337 T3 Ex. R1R2R3 1 A oh A z ° ho. ll TO 190 nh OR AA ( \ = / AA oh ho 1 A oh AA ------ O ho. ll TO 191 H OR AA 0 oh \ ;;°,;S ' O \ H2 AA 1 0 192 hox^ A II \J , 0, TO oh \ ;;° ,;S' O \ H2 AA 1 0 192 hox ^A II \ J ,0, A ° AA nh A \^/ '—. ° AA nh TO \ ^ / '-. AA or 193 hox^ A ll \ nL nh AA ó 193 hox ^A ll \ nL nh O AA < OR AA < AA ho AA ho 159 159 ES 2 384 337 T3 ES 2 384 337 T3 160 160 ES 2 384 337 T3 Ej. R1 R2 R3 198 HO^^íA II o AA XA b 8 199 II o XA xa 1 N M / NA NH HO 200 HO^^íA II o XA AA 1 A X NA NH ά _y.S^ o \ nh2 201 HO^^íA II o AA AA / N N X NA NH 0 'o / A h2n ES 2 384 337 T3 Ex. R1R2R3 198 HO ^^ íA II or AA FOR b 8 199 II or FOR for 1 NM / NA NH HO 200 HO ^^ íA II or FOR AA 1 TO X NA NH ά _y.S ^ o \ nh2 201 HO ^^ íA II or AA AA / N NX NA NH 0 'or / TO h2n 161 161 ES 2 384 337 T3 Ej. R1 R2 R3 Γ OH 1 ,N A N \ M ° 202 HO II \__// NA O y A NH /=< ES 2 384 337 T3 Ex. R1R2R3 Γ Oh 1 , N TO N \ M ° 202 HO II \ __ // NA OR Y TO NH / = < OH o Oh or OH / U/Nx N X Γ A M o 203 HO II O H A A NH < Oh /OR/ Nx NX Γ TO M o 203 HO II OR H TO TO NH < \ —N Oh \ J Oh 1 N Γ TO Q, ° HO ^ A nA 204 || NH OR TO TO ( AA Oh HO Oh 1 TO Γ TO 1 // M ° 205 HO ^ A ll nA NH OR TO 0 \—N OH \J OH 1 N Γ A Q ,° HO ^A nA 204 || NH O A A ( AA OH HO OH 1 A Γ A 1 // M ° 205 HO ^A ll nA NH O A 0 OH \ ;;° oS'' O \ NH2 Oh \ ;;° you'' O \ NH2 162 162 ES 2 384 337 T3 Ej. R1 R2 R3 OH / ·. Γ 4 \\ // M Ό 206 HOX || nX NH O A 0 ES 2 384 337 T3 Ex. R1R2R3 Oh / ·. Γ 4 \\ // M Ό 206 HOX|| nX NH OR TO 0 OH O Oh O Y TO M o HOX^ 0 ^ Ayj 207 || NH OR / TO ( AA HO /Nx \ TO TO What 208 H30xII OR H / TO NH < y A M o H OX ^0^ Ayj 207 || NH O / A ( AA HO / Nx\ A A Q o 208 H30x II O H / A NH < ) - or )— o / A Y /O / TO Y /OR 209 h3cx 0 || HN O A “A ) VA OH 209 h3cx0 || HN OR TO "TO ) GOES Oh 163 163 ES 2 384 337 T3 Ej. R1 R2 R3 /Νχ AA o 210 h3c' ^A C 2=o HN O ES 2 384 337 T3 Ex. R1R2R3 / Νχ AA or 210 h3c ' ^ AC 2 = or HN OR \ _ / N=\ He ............ 4 aa X = o 211 HO C || , - / N OR AA n = A w / Nx N 7 AA \TO \ - / ) 212 HO C || , - ( HN OR AA ) W He Oh V AA NA \ = / > = or 213 HO C || , - / HN \ OR / \ __ AA or TO/ ° </ Year h2n \_/ N=\ Va ............ 4 aa X=o 211 HO C || ,—/ N O AA n=A w /Nx N 7 AA \A \ — / ) 212 HO C || ,—( HN O AA ) W Va OH V AA NA \=/ >=o 213 HO C || ,—/ HN \ O / \__ AA o A/ °< / Ao h2n 164 164 ES 2 384 337 T3 Ej. R1 R2 R3 ES 2 384 337 T3 Ex. R1R2R3 / 7 (\ N.> /7 (\ N. > \ 7 Az / =70 = or 214 do notxC || , - / HN \ or / \ -. / \ GOES W 0 WA ca wo nh2 1 4 and NA 215 do notx^ A \ _ / J || ] NH or 5 h do not W / Ho na V H do notx^ A \ __ / J 216 || / NH or - / / = < \ 7 Az /=7 0=o 214 nox C || ,—/ HN \ o / \—. /\ VA W 0 W A cA w o nh2 1 4 y NA 215 nox ^A \_/J || ] NH o 5 h no W / Ho nÁ V H nox ^A \__/J 216 || / NH o —/ /=< \ GOES do not or ^. / > or H2N 1 TO\ í> \ VA no o^. / >o H2N 1 A\ í > 217 do notx^ A II Λ / or FF NH W '--- N 217 nox ^A II Λ/ o FF NH W '---N 165 165 ES 2 384 337 T3 Ej. R1 R2 r3 / YN\ A A .G •y o 218 HOX C O sA / A NH < ES 2 384 337 T3 Ex. R1R2r3 / YN\ TO TO .G •me 218 HOXC OR sA / TO NH < / --- N OR / • TO TO To or HOX^ C ^ sA 219 || NH OR / "TO ( AA HO 1 TO "TO To or 220 HO || "TO NH / OR f = \ / TO M \ ^ <or Y W o nh2 Oh 1 / N. /---N O / • A A A o HOX ^C^ sA 219 || NH O / “A ( AA HO 1 A “A A o 220 HO || »A NH / O f=\ / A M \ ^<o y W o nh2 OH 1 /N. Γ 4 0/0 N 221 HO II O a A NH /A OH O Γ 4 0/0 N 221 HO II OR to TO NH /TO Oh OR 166 166 ES 2 384 337 T3 Ej. R1 R2 R3 OH / PN\ Γ 4 Q o 222 HO II O H a A NH < ES 2 384 337 T3 Ex. R1R2R3 Oh / PN\ Γ 4 What 222 HO II OR H to TO NH < \ —N Oh 7. \ \ = / 1 Oh Γ 4 7 z ° HO P 223 || NH OR to TO ( AA Oh \ = / HO 1 Oh \\ # Γ 4 To or 224 HO || nP NH OR Y TO 0 \—N OH 7 .\ \=/ 1 OH Γ 4 7 z° HO P 223 || NH O a A ( AA OH \=/ HO 1 OH \\ # Γ 4 A o 224 HO || nP NH O y A 0 OH \ ^o o \ NH2 7 ”A 1 ,N 4/ N 225 HO II O / “A NH /P o* '---N Oh \ ^ o or \ NH2 7 "TO 1 , N 4/ N 225 HO II OR / "TO NH / P or* '--- N 167 167 ES 2 384 337 T3 Ej. R1 R2 R3 / x\ 226 hox ^A II O A A A A A Ά * nh b 1 „,-x 227 hox ^A ll A A A z? nh O A A ho 1 Αχ 228 hox ^A ll A A A _j> X H O A A 0 \ ^O tí O \ H2 1 tí 229 hox ^A ll A A A H O A A 0 o;> / Ao h2 ES 2 384 337 T3 Ex. R1R2R3 / x \ 226 hox^ A II OR TO TO TO TO TO Ά * nh b 1 „, -x 227 hox^ A ll TO TO A z? nh OR TO TO ho 1 Αχ 228 hox^ A ll TO TO A _j> X H OR TO TO 0 \ ^ O you O \ H2 1 you 229 hox^ A ll TO TO TO H OR TO TO 0 or;> / Year h2 168 168 ES 2 384 337 T3 Ej. R1 R2 R3 OH 1 ,N Γ a o nY N H 230 HO ^A II 0 O y A NH r- =< ES 2 384 337 T3 Ex. R1R2R3 Oh 1 , N Γ to or nY N H 230 HO ^ A II 0 OR Y TO NH r- = < OH { A — N OH / Αχ 231 HO ^A II O Γ A í / N—'J N — < NH A A < Oh { TO - N Oh / Αχ 231 HO ^ A II OR Γ TO í / N —'J N - < NH TO TO < \ —N Oh / \\ \ = / / N Oh Z \ HO ^ A Γ TO \\ //NTO N \ 232 || NH OR TO TO ( AA Oh \ = / HO 1 N Oh 233 HO ^ A || Γ TO í //NN — 7 N- NH OR TO c TO J Oh Y ° O \ NH2 \—N OH / \\ \=/ / N OH Z \ HO ^A Γ A \\ //N A N \ 232 || NH O A A ( AA OH \=/ HO 1 N OH 233 HO ^A || Γ A í //N N—7 N- NH O A c A J OH Y° O \ NH2 169 169 ES 2 384 337 T3 Ej. R1 R2 R3 234 hA^c^ II O OH AÁ AA OH 1 O X/ nX NH 0 O< / /% H2N 235 AA 3 II O AA AA --O Cl 236 l-LC^^O^ 3 II O AA AA u W'-',, ^OMe O 237 O A AA AA H A H A A 238 5 AA AA xq _ H A NH 0 ES 2 384 337 T3 Ex. R1R2R3 2. 3. 4 hA ^ c ^ II O Oh AÁ AA Oh 1 OR X / nX NH 0 O </ /%H2N 235 AA 3 II OR AA AA --OR Cl 236 l-LC ^^ O ^3 II OR AA AA or W'- ',, ^ OMe OR 237 OR TO AA AA H Ah TO TO 238 5 AA AA why _ H A NH 0 170 170 ES 2 384 337 T3 Ej. R1 R2 R3 A A Y> ES 2 384 337 T3 Ex. R1R2R3 TO TO And> 239 HCO O A A A NH A NH 0 A A XX 240 o_ NU O A A Λ NH V NH 0 A 239 HCOROR TO TO TO NH A NH 0 TO TO XX 240 or_ WILDEBEEST OR TO TO Λ NH V NH 0 TO O A A 241 O A A NH o=^ NH 0 A OR TO TO 241 OR TO TO NH o = ^ NH 0 TO A A XX 242 A ¥ o A A \ 0 NH A NH 0 HC A A 243 H3C'N-m' 3 N A. / O A A NH V NH 0 A TO TO XX 242 TO ¥ or TO TO \ 0 NH TO NH 0 HC TO TO 243 H3C 'N-m' 3 N TO. / OR TO TO NH V NH 0 TO 171 171 ES 2 384 337 T3 Ej. R1 R2 r3 244 CN, .y Cn, ° W AA NH 0¾^ NH 0 ^N 245 o yV Ay- w AA NH 0¾^ NH 0 ^N 246 OV AA AA NH V NH 0 ^-N 247 cn3 j°v n3c 0 W AA _ NN y NN 0 248 N0 0 0 W AA _ NN y NN 0 ES 2 384 337 T3 Ex. R1R2r3 244 CN,. And Cn, ° W AA NH 0¾ ^ NH 0 ^ N 245 o and V Ay- w AA NH 0¾ ^ NH 0 ^ N 246 Ov AA AA NH V NH 0 ^ -N 247 cn3j ° vn3c 0W AA _ NN and NN 0 248N00 0 W AA _ NN and NN 0 172 172 ES 2 384 337 T3 Ej. R1 R2 R3 ES 2 384 337 T3 Ex. R1R2R3 o n3c cn3 F F N \ A 249 AA _ NH A o F F NH CA on3c cn3F F N \ TO 249 AA _ NH TO or F F NH AC A Ak .-Ά N \ O F F NH 250 l CH3 A Ár F F NH /A o V 7 A o F F xq 251 o ~ NH A NH F F F o F F xq 252 ho - NH A NH o F F 0 A N>^W o o F F xq 253 n NH A NH F F 0 A TO TOk .-Ά N \ OR F F NH 250 l CH3 TO Ar F F NH /TO or V 7 TO or F F why 251 or ~ NH TO NH F F F or F F why 252 ho - NH TO NH or F F 0 TO N>^ W oo F F why 253n NH A NH F F 0 TO 173 173 ES 2 384 337 T3 Ej. R1 R2 R3 254 CN3 N 'v 0 AA AA XQ - NH A NH 0 X 255 cn3 νΧ o AA AA XQ - NH A NH 0 X 256 H3C CH3 A 3H0 Ϊ 0 AA AA \ _ NH 0;=γ NH 0 A 257 H^^ 0=0 \ AA AA ó % nh2 ES 2 384 337 T3 Ex. R1R2R3 254 CN3N 'v 0 AA AA WHY - NH To NH 0 X 255 cn3 νΧ or AA AA WHY - NH To NH 0 X 256 H3C CH3 TO 3H0 Ϊ 0 AA AA \ _ NH 0;= γ NH 0 A 257 H ^^ 0 = 0 \ AA AA or % nh2 174 174 ES 2 384 337 T3 Ej. R1 R2 R3 259 hox ^A II O va A '¥ό ho 260 hox ^A II O VA Ύ>........ A¿ Υ Η2 0 2 ho Γ A 261 0—0 F \ ^c^ 0 ϊ~ Ά Ύ> A>i-, Γ Ά O 262 h3cx ^A II O ϊ~ Ά \— Η ΐ =/ O ES 2 384 337 T3 Ex. R1R2R3 259 hox^ A II OR he TO '¥ ό ho 260 hox^ A II OR GOES Ύ> ........ TO Υ Η2 0 2 ho Γ TO 261 0—0 F \ ^ c ^ 0 ϊ ~ Ά Ύ> A> i-, Γ Ά OR 262 h3cx^ A II O ϊ ~ Ά \ - Η ΐ = / O Γ Ά A 263 ho ^A^ II O ϊ~ Ά Α _ NH 0^ Η z ί tí N Γ Ά TO 263 ho ^ A ^ II OR ϊ ~ Ά Α _ NH 0 ^ Ηz ί you N 175 175 ES 2 384 337 T3 Ej. R1 R2 R3 264 ch3 CtA Y NH 0^ NH X A ES 2 384 337 T3 Ex. R1R2R3 264 ch3CtA Y NH 0 ^ NH XA

2,172 paragraphs in 99 sections, as filed

ES 2 384 337 T3

DESCRIPTION

Purine derivatives for use as adenosine A2A receptor agonists

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

One aspect of the present invention provides compounds of formula (I) or stereoisomers or pharmaceutically acceptable salts thereof:

R3 (I) in which R1, R2 and R3 are

ES 2 384 337 T3

ES 2 384 337 T3

ES 2 384 337 T3

ES 2 384 337 T3

ES 2 384 337 T3

<td> 27</td><td>H3C^^®3 yl O</td><td> ®® ®®</td><td>O now-»H. O H O.......Women</td>

<td> 28</td><td>hc ^ V ^3 yl O</td><td> ®® ®®</td><td>NS2 / 2O......Women</td>

ES 2 384 337 T3

<td> 34</td><td>Ύ WithOH3C</td><td>La La</td><td>Ό ....... VNos</td>

<td> 36</td><td>H.C^^C^3 C O</td><td>La</td><td>'° WandO</td>

ES 2 384 337 T3

<td> 41</td><td colspan="2">H.-C^</td><td colspan="2">yl</td><td></td><td></td><td>\^ SMALL</td>

ES 2 384 337 T3

<td> 46</td><td colspan="2">/Nx / h3c c3 yl O</td><td>/ Γ</td><td>A</td><td>O</td><td>Number</td><td colspan="2">M</td>

<td> 48</td><td>-A</td><td>'A eleven</td><td></td><td></td><td>A , 0 N</td><td>0 H 11N - S -</td><td colspan="2"></td>

ES 2 384 337 T3

ES 2 384 337 T3

<td rowspan="2"> 55</td><td>hcWith</td><td>C</td><td></td><td></td><td></td><td>HN</td><td></td><td></td>

ES 2 384 337 T3

ES 2 384 337 T3

ES 2 384 337 T3

ES 2 384 337 T3

<td></td><td></td><td></td><td></td><td></td><td>N</td><td>eleven .N</td>

<td></td><td></td><td></td><td></td><td></td><td>A n 'A</td><td></td><td>\\ A little</td><td>A)</td>

ES 2 384 337 T3

<td></td><td rowspan="2">HC</td><td></td><td></td><td></td><td>O.......Women</td><td></td><td></td>

<td rowspan="2"> 87</td><td>C</td><td></td><td></td><td></td><td>A zX. ί.</td><td>Withch</td>

ES 2 384 337 T3

<td rowspan="2"> 90</td><td>hcWith</td><td>C</td><td></td><td></td><td>I</td><td> >.....</td><td>1 N</td><td> / — \</td>

<td></td><td rowspan="2">hcWith</td><td></td><td>r~</td><td>-ch3</td><td></td><td></td><td rowspan="2">a NS</td><td></td>

<td></td><td rowspan="2">hcWith</td><td></td><td>r~</td><td>cn3</td><td></td><td> ---</td><td>\ NS</td><td></td>

ES 2 384 337 T3

<td> 97</td><td>hC</td><td>yl O</td><td>A</td><td>A</td><td></td><td>NS rOOHH3C CH3</td>

ES 2 384 337 T3

<td> 100</td><td>h3cx</td><td>^CX II O</td><td> 7~</td><td>A</td><td>A H</td><td>^\^ SMALL2</td>

ES 2 384 337 T3

ES 2 384 337 T3

ES 2 384 337 T3

ES 2 384 337 T3

ES 2 384 337 T3

<td></td><td></td><td></td><td> 0</td><td>A</td><td>A</td><td></td><td></td><td>N~Father /</td>

ES 2 384 337 T3

<td> 139</td><td>h.c^A3 yl O</td><td>O... already</td><td>A / 'CH, h,c</td>

<td> 140</td><td>h.c^A3 yl O</td><td>q _- ALREADY</td><td>A A'CH3h,c</td>

ES 2 384 337 T3

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ES 2 384 337 T3

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ES 2 384 337 T3

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ES 2 384 337 T3

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<td></td><td></td><td></td><td>a little</td><td>“A</td><td colspan="2"> \=/</td>

ES 2 384 337 T3

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<td> 252</td><td>O Ηθ ·χ^/ XXcΧO</td><td>AA AA</td><td>why _ NS A NH 0</td>

ES 2 384 337 T3

<td> 256</td><td>h3c ch33 v 3HO is the</td><td>AA aa</td><td>\ _ NS O^ SMALL A</td>

ES 2 384 337 T3

<td> 263</td><td rowspan="2">II o</td><td></td><td></td><td></td><td>I heard-/</td>

ES 2 384 337 T3

Compounds of formula (I) can be prepared, for example, using the reactions and techniques described below and in the examples. The compounds of formula (I) can be prepared analogously to the preparations described in the applicant's patent applications PCT / EP2005 / 011344, GB 0500785.1 and GB 0505219.6. The reactions can be carried out in a solvent appropriate for the reagents and materials used and suitable for the transformations being carried out. It will be understood by those skilled in the art of organic synthesis that the functionality present in the molecule must be consistent with the proposed transformations. This will sometimes require judgment to modify the order of the synthetic steps, or to select one particular process scheme over another in order to obtain a desired compound of the invention.

The various substituents on the synthetic intermediates and end products shown in the following reaction schemes may be present in their fully manufactured forms, with suitable protecting groups where required, as understood by one skilled in the art, or in forms precursors that can later be made into their final forms by methods familiar to one of ordinary skill in the art. Substituents can also be added at various stages throughout the synthetic sequence or after the synthetic sequence ends. In many cases, commonly used functional group manipulations can be used to transform an intermediate into another intermediate, or a compound of formula (I) into another compound of formula (I). Examples of such manipulations are a conversion of an ester or a ketone to an alcohol; the conversion of an ester to a ketone; ester, acid and amide interconversions; alkylation, acylation, and sulfonylation of alcohols and amines; and many others. Substituents can also be added using common reactions, such as alkylation, acylation, halogenation, or oxidation. Such manipulations are well known in the art, and many reference works summarize the procedures and methods for such manipulations. Some reference works that give examples and references to the primary organic synthesis literature for many manipulations of functional groups, as well as other transformations commonly used in the organic synthesis technique are March's Organic Chemistry, 5a edición, Wiley and Chichester, Ed. (2001); Comprehensive Organic Transformations, Larock, Ed., VCH (1989); Comprehensive Organic Functional Group Transformations, Katritzky et al (editores de series), Pergamon (1995); and Comprehensive Organic Synthesis, Trost and Fleming (editores de series), Pergamon (1991). It will also be recognized that another important consideration in planning any synthetic route in this field is the judicious choice of the protecting group used for the protection of reactive functional groups present in the compounds described in this invention. Multiple protecting groups can be selected within the same molecule, such that each of these protecting groups can be removed without removing other protecting groups from the same molecule or in such a way that several protecting groups can be removed using the same step of reaction, depending on the desired result. An authoritative account that outlines many alternatives for the trained practitioner is TW Greene and PGM Wuts, Protective Groups In Organic Synthesis, Wiley and Sons, 1999. It will be understood by those skilled in the art that only combinations of substituents that are chemically possible are embodiments of the present invention.

Compounds of formula (I) in free form can be converted to salt form, and vice versa, in a conventional manner. The compounds in free or salt form can be obtained in the form of hydrates or solvates containing a solvent used for crystallization. Compounds of formula (I) can be recovered from reaction mixtures and can be 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 correspondingly asymmetrically substituted, for example optically active, starting materials.

The compounds of formula (I) and their pharmaceutically acceptable salts are useful as products

ES 2 384 337 T3 pharmaceuticals. In particular, they activate the adenosine A2A receptor, that is, they act as agonists of the A2A receptor. Their properties as A2A agonists can be demonstrated using the method described by LJ Murphree et al in Molecular Pharmacology 61,455-462 (2002).

The compounds of the examples found hereinafter have Ki values below 1.0 pM in the above assay. For example, the compounds of Examples 1, 14, 20, 36, 69, and 178, have Ki values of 0.0083, 0.0025, 0.0016, 0.0030, 0.0043, and 0.0080 pM, respectively. .

Taking into consideration their activation of the adenosine A2A receptor, the compounds of formula I, in free or pharmaceutically acceptable salt form, alternatively referred to hereinbelow as "agents of the invention", are useful in the treatment of states that respond to the activation of the adenosine A2A receptor, in particular inflammatory or allergic states. The treatment according to the invention can be symptomatic or prophylactic. Accordingly, the agents of the invention are useful in the treatment of inflammatory or obstructive airway diseases resulting, for example, in a reduction in tissue damage, airway inflammation, bronchial hyperresponsiveness, remodeling, or disease progression. Inflammatory or obstructive airway diseases and conditions to which the present invention is applicable include acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary airway disease, or lung (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated with it, emphysema, as well as exacerbation of airway hyperresponsiveness as a result of other drug therapy, particularly other inhaled drug therapy. The invention is also applicable to the treatment of bronchitis of any type or genesis, including, for example, acute, arachidic, catarrhal, croup, chronic or phtinoid bronchitis. Additional inflammatory or obstructive airway diseases to which the present invention is applicable include bronchiectasis, pneumoconiosis (an inflammatory disease of the lungs, commonly occupational, often accompanied by airway obstruction, either chronic or acute, and caused by repeated inhalation of dusts) of any kind or genesis, including, for example, aluminosis, anthracosis, asbestosis, calicosis, ptilosis, siderosis, silicosis, tobacco and byssinosis.

Other inflammatory or obstructive airway diseases to which the present invention is applicable include asthma of any type or genesis, including both intrinsic (non-allergic) and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, asthma. bronchitis, exercise-induced asthma, occupational asthma, and induced asthma followed by bacterial infection. It should also be understood that asthma treatment encompasses the treatment of subjects, for example, those younger than 4 or 5 years of age, who present with wheezing symptoms and who are diagnosed or diagnosable as “wheezing babies”, an established patient category of important medical concern and now frequently identified as incipient or early stage asthmatics. (For convenience, this particular asthmatic state is called "wheezing baby syndrome.")

Prophylactic efficacy in the treatment of asthma will be evidenced by a reduced frequency or severity of the symptomatic attack, eg, acute or broncho-constrictive asthma attack, improvement in lung function, or better airway hyperresponsiveness. Furthermore, it may be evidenced by a reduced requirement for other symptomatic therapy, ie, therapy for, or intended to, restrict or abort the symptomatic attack when it occurs, for example anti-inflammatory (eg, corticosteroid) or bronchodilator. The prophylactic benefit in asthma may be evident in particular in subjects susceptible to "morning drowning". "Morning drowning" is a recognized asthmatic syndrome, common to a substantial percentage of asthmatics, and characterized by an asthma attack, for example between the hours of approximately 4 to 6 am, that is, at a time normally substantially distant from any previously administered symptomatic asthma therapy.

Taking into consideration their anti-inflammatory activity, in particular in relation to the inhibition of eosinophil activation, the agents of the invention are also useful in the treatment of disorders related to eosinophils, for example eosinophilia, in particular disorders of the respiratory tract. related to eosinophils (for example, involving morbid eosinophilic infiltration of lung tissues), including hypereosinophilia as it affects the airways and / or lungs, as well as, for example, eosinophil-related airway disorders as a result of, or concomitant with, Loffler's syndrome, eosinophilic pneumonia, parasitic infestation (particularly of metazoans) (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma, and eosinophil-related airway disorders caused by drug reaction.

The agents of the invention are also useful in the treatment of inflammatory or allergic conditions of the skin, for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiform, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigoid, epidermolysis bulosa acquisita, and other inflammatory or allergic conditions of the skin. The agents of the invention can also be used for the treatment of other diseases or conditions, in particular diseases or conditions that have an inflammatory component, for example, the treatment of diseases and conditions of the eyes, such as conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis. , diseases that affect the nose,

ES 2 384 337 T3 including allergic rhinitis, and inflammatory disease in which autoimmune reactions are involved, or which have an autoimmune component or etiology, including autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, anemia of pure red blood cells, and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, sclerodoma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic pruritus, autoimmune inflammatory bowel disease (eg, ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, and glomerulonephritis (with and without nephrotic syndrome, eg including idiopathic nephrotic syndrome or minimal change nephropathy).

Furthermore, the agents of the invention can also be used for the treatment of cystic fibrosis, pulmonary hypertension, pulmonary fibrosis, inflammatory bowel syndrome, wound healing, diabetic nephropathy as described. written in WO 05/107463, reduction of inflammation in transplanted tissue as described in document US 2005/182018, inflammatory diseases caused by pathogenic organisms as described in document WO 03/086408, and cardiovascular conditions as described in WO 03/029264.

Furthermore, the agents of the invention can be used to assess the severity of coronary artery stenosis, as described in WO 00/078774, and useful in conjunction with radioactive imaging agents to image the activity of the coronary arteries and useful in angioplasty adjunct therapy, as described in 00/78779.

The agents of the invention are also useful in combination with a protease inhibitor for the prevention of organ ischemia and reperfusion injury, as described in WO 05/003150, and in combination with an integrin antagonist for the treatment platelet aggregation, as described in WO 03/090733.

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

Other diseases or conditions that can be treated with the agents of the invention include diabetes, for example type 1 diabetes mellitus (juvenile diabetes) and type II diabetes mellitus, diarrheal diseases, ischemia / reperfusion injury, retinopathy, such as diabetic retinopathy or induced retinopathy. by hyperbaric oxygen, conditions characterized by elevated intraocular pressure or secretion of ocular aqueous humor, such as glaucoma, ischemic tissue / reperfusion organ damage, pressure ulcers, as agents to promote sleep, as agents for the treatment of demyelinating diseases, eg multiple sclerosis, and as neuroprotective agents, eg hemorrhagic brain injury and ischemia-reperfusion injury of the spinal cord.

The effectiveness of an agent of the invention to inhibit inflammatory conditions, for example in inflammatory diseases of the airways, can be demonstrated in an animal model, for example a mouse or rat model, of inflammation of the airways or others. inflammatory states, for example as described by Szarka 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 Fozard et al, (2002), Eur. J. Pharmacol. 438: 183-188.

The agents of the invention are also useful as co-therapeutic agents for use in combination with other pharmacological substances, such as anti-inflammatory, bronchodilator, antihistamine or antitussive pharmacological substances, particularly in the treatment of inflammatory or obstructive diseases of the airways, such such as those mentioned hereinabove, for example as enhancers of the therapeutic activity of such drugs, or as a means of reducing the required dosage or potential side effects of these drugs. An agent of the invention can be mixed with the other drug substance in a fixed pharmaceutical composition, or it can be administered separately, before, simultaneously with or after the other drug substance.

Accordingly, the invention includes a combination of an agent of the invention as described hereinabove, with an anti-inflammatory, bronchodilator, antihistamine, or antitussive drug substance, said agent of the invention and said drug substance being in the same composition. pharmacy or a different one.

Anti-inflammatory drugs include steroids, in particular glucocorticosteroids, such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate, or the steroids are 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

ES 2 384 337 T3

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, WO 04/18429, WO 04/19935, and WO 04/26248; LTB4 antagonists such as BIIL 284, CP-195543, DPC11870, LTB4 ethanolamide, LY 293111, LY 255283, CGS025019C, CP-195543, ONO-4057, SB 209247, SC-53228 and those described in US 5451700; LTD4 antagonists include montelukast, pranlukast, zafirlukast, accolato, SR2640, Wy-48,252, ICI 198615, MK-571, LY-171883, Ro 24-5913, and L-648051; PDE4 inhibitors such as cilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plow), Arofilina (Almirall Prodesfarma), PD189659 / pD168787 (Parke-Davis), AwD-12-281 (Asta Medica), CDC-801 (Celgene), SelCID (TM) CC-10004 (Celgene), VM554 / UM565 (Vernalis), T-440 (Tanabe), KW4490 (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; adenosine A2B receptor antagonists, such as those described in WO 02/42298; and beta-2 adrenoceptor agonists, such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol, fenoterol, procaterol, and especially, formoterol, carmoterol, and the pharmaceutically acceptable salts thereof, and the compounds (in free or salt or solvate) of the formula (I) of WO 00/75114, preferably the compounds of the examples thereof, especially a compound of the formula:

° h° h

oh and pharmaceutically acceptable salts thereof, as well as the compounds (in free or salt or solvate form) of formula I of WO 04/16601, and also the 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, WO 04/33412, WO 04/37768, WO 04/37773, WO 04/37807, WO 04/39762, WO 04/39766, WO 04/45618 WO 04/46083, WO 04/80964, EP 1460064, WO 04/087142, WO 04/ 089892, EP 01477167, US 2004/0242622, US 2004/0229904, WO 04/108675, WO 04/108676, WO 05/033121, WO 05/040103, WO 05/044787, WO 05/058867, WO 05/065650, WO 05/066140 y WO 05/07908.

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

Suitable anti-inflammatory and dual bronchodilator drugs include beta2 adrenoceptor agonists / dual muscarinic antagonists, such as those disclosed in US 2004/0167167, US 2004/0242622, US 2005/182092, WO 04/74246 and WO 04/74812.

Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine, and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, and known as the selastine, myelastine, and quephenadizole. in JP 2004107299, WO 03/099807 and WO 04/026841.

Other useful combinations of agents of the invention with anti-inflammatory drugs are those with chemokine receptor antagonists, eg, CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR -7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists, such as the Schering-Plow antagonists SC-351125, SCH-55700 and SCH-D, Takeda antagonists such as N - [[4 - [[[6,7-dihydro-2- (4-methyl-phenyl) -5H-benzo-cyclohepten-8-yl] -carbonyl] -amino] -phenyl] chloride -methyl] -tetrahydro-, - dimethyl2H-pyran-4-aminium (TAK-770), and the CCR-5 antagonists described in US 6166037 (particularly claims 18 and 19), WO 00/66558 (particularly claim 8), WO 00/66559 (particularly the

ES 2 384 337 T3 claim 9), WO 04/018425 and WO 04/026873.

In another aspect, the invention provides a compound of formula (I), in free form or in the form of a pharmaceutically acceptable salt, for use in the manufacture of a medicament for the treatment of a condition that responds to the activation of the receptor of adenosine A2A, particularly an inflammatory or obstructive airway disease.

The agents of the invention can be administered by any appropriate route, for example orally, for example in the form of a tablet or capsule; parenterally, for example intravenously; by inhalation, for example in the treatment of an inflammatory or obstructive airway disease; 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 disease.

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

When the composition comprises an aerosol formulation, it preferably contains, for example, a hydro-fluoro-alkane (HFA) propellant, such as HFA134a or HFA227, or a mixture thereof, and may contain one or more known co-solvents. 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 bulking agents, such as lactose. When the composition comprises a dry powder formulation, it preferably contains, for example, the compounds of formula (I), having a particle diameter of up to 10 microns, optionally together with a diluent or carrier, such as lactose, from the distribution of desired particle size, and a compound that helps protect against deterioration of product performance due to moisture, for example magnesium stearate. When the composition comprises a nebulized formulation, it preferably contains, for example, the compound of formula (I), either dissolved or suspended in a vehicle containing water, a co-solvent, such as ethanol or propylene glycol, and a stabilizer, which can be a surfactant.

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

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

Preparation of intermediate compounds

The abbreviations used are as follows: CDI is 1,1'-carbonyldiimidazole, DCM is dichloromethane, DIPEA is diisopropylethylamine, DMAP is 4-dimethylaminopyridine, DMF is dimethylformamide, DMSO is dimethyl sulfoxide, LC-MS is liquid chromatography mass spectroscopy, TEA is triethylamine, TFA is trifluoroacetic acid, THF is tetrahydrofuran, EtOH is ethanol, IPA is isopropyl alcohol, and CCF is thin layer chromatography.

Intermediate product A

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

A1: Imidazole-1-carboxylic acid (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -amide: A suspension comprising CDI (2.29 g, 14 mmol ) and triethylamine (3.8 ml, 27 mmol) in dry DMC (20 ml) is treated portionwise for 5 minutes with 3,4,5,6-tetrahydro-2H- [1,2 '] - bipyridinyl- dihydrochloride. 4-ylamine (prepared using the procedure described in international patent application WO 01/94368) (2.88 g, 13 mmol). The reaction mixture is stirred at room temperature for 4.5 hours to provide the title compound as a 0.43 M solution in DMC.

ES 2 384 337 T3

A2: (R) -3- [3- (3,4,5,6-tetrahydro-2H- [1,2 '] - b¡pyridinl-4 tert-butyl ester trifluoroacetate -¡L) -ureido] pyrrolidine-1-carboxylic acid: To a solution of (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -amide of imidazole-1-carboxylic acid ( 18 ml of a 10 mg / ml solution in DMC) (A1), (R) -3-amino-1-N-Boc-pyrrolidine (136 mg, 0.74 mmol) in iso-propanol (3 ml). The reaction mixture is stirred at room temperature overnight and then diluted with DMC (25 ml). This mixture is washed with 0.1M HCl, water, brine, dried (MgSO4), and concentrated in vacuo. Purification of the crude residue by C-18 reverse phase column chromatography, eluting with acetonitrile: water: TFA (0.1%) (gradient 0-100% acetonitrile) provides the title compound.

A3: 1- (R) -Pyrrolidin-3-yl-3- (3,4,5,6-tetrahydro-2H- [1,2 '] - bipyridinyl-4-yl) -urea hydrochloride: A solution of (R) -3- [3- (3,4,5,6-Tetrahydro-2H- [1,2 '] - bipyridinyl-4-yl) -ureido] -pyrrolidine-1-carboxylic acid tert-butyl ester trifluoroacetate (0.2 g, 0.51 mmol) in 1.25 M HCl in MeOH (10 mL) stir at room temperature overnight. The solvent is removed in vacuo to provide the title compound.

Intermediate product B

1,3-Di (R) -pyrrolidin-3-yl-urea

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

A solution comprising (R) -1-benzyl-pyrrolidin-3-ylamine (5.0 g, 28.4 mmol) in DMC (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 resulting residue is dissolved in ethyl acetate. This portion is washed with water, followed by brine, dried (MgSO4), and concentrated in vacuo to provide the title compound as a pale orange solid.

B2: 1,3-Di (R) -pyrrolidin-3-yl reagent

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 atmosphere of argon , palladium hydroxide on carbon (1.07 g) is added. The reaction mixture is purged with argon, and placed under a hydrogen atmosphere for two days, after this time, the mixture is filtered and the catalyst is washed with ethanol. The organic parts are combined and concentrated in vacuo to provide the title compound as a white solid.

Imidazole-1-carboxylic acid intermediate C (3,4,5,6-tetrahydro-2H- [1,2 '] - bipyridinyl-4-yl) -amide

A stirred solution of CDI (1.1 g, 6.77 mmol) in DMC (100 mL) is treated with 3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-ylamine ( WO 9965895 and EP 21973) (1 g, 5.64 mmol in 50 ml of DMC), which is added dropwise over 30 minutes. The reaction mixture is stirred at room temperature for 15 minutes to provide the title compound as a 10 mg / ml solution in DMC. The compound is used in solution in subsequent reactions. This solution consists of the imidazole-urea (intermediate C) together with varying amounts of the corresponding isocyanate and imidazole. This solution is used in the following steps because the imidazole-urea intermediate and the isocyanate intermediate are equally suitable as precursors for ureas.

Intermediate product D

Ethylamide del acid (2S, 3S, 4R, 5R) -5- [2-amino-6- (2,2-diphenylethylamino) purin-9-yl] -3,4-dihydroxytetrahydrofuran-2-carboxylic acid

Step D1: Acid ethylamide (3aS, 4S, 6R, 6aR) -6- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,2-dimethyl-tetrahydrofuro [ 3,4-d] [1,3] dioxole-4-carboxylic

The title compound is prepared by the method of preparing amino-purin-b-Dribo-furan-uronamide derivatives as anti-inflammatories. Di Ayres, Barry Edward; Gregson, Michael; Ewan, George Blanch; Keeling, Suzanne Elaine; Bell, Richard. (Glaxo Group Limited, UK). PCT International Application (1996), 49 pages, WO 9602553.

Step D2: (2S, 3S, 4R, 5R) -5- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -3,4-dihydroxy-tetrahydrofuran acid ethylamide 2-carboxylic

ES 2 384 337 T3

An ethylamide solution of the acid (3aS, 4S, 6R, 6aR) -6- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,2-dimethyltetrahydro-furo- [3,4-d] [1,3] dioxole-4-carboxylic (step D1) in TFA / water (2: 1) is stirred at room temperature overnight. The reaction mixture is concentrated in vacuo to provide the title compound.

Intermediate product E

Trifluoroacetate of ethylamide with acid (2S, 3S, 4R, 5R) -5- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenylethylamino) -purin9- yl] -3,4-dihydroxytetrahydrofuran-2-carboxylic acid

Step E1: Ethylamide del acid (2S, 3S, 4R, 5R) -5- [6- (2,2-diphenylethylamino) -2 - ((R) -3-BOC-amino-pyrrolidin-1-yl) -purin-9-yl] 3,4-dihydroxytetrahydrofuran-2-carboxylic acid

(2S, 3S, 4R, 5R) -5- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -3,4-dihydroxy-tetrahydro-furan- 2-carboxylic (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), dissolve in acetonitrile (10 ml) and NMP (0.5 ml). The reaction mixture is heated using microwave radiation at 160 ° C for 30 minutes in the 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 provide the title compound .

Step E2: Trifluoroacetate of ethylamide with acid (2S, 3S, 4R, 5R) -5- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenylethylamino) -purine -9-yl] -3,4-dihydroxytetrahydrofuran-2-carboxylic acid

(2S, 3S, 4R, 5R) -5- [6- (2,2-diphenyl-ethylamino) -2 - ((R) -3-BoC-amino-pyrrolidin-1-yl) -purin acid ethylamide -9-yl] -3,4-dihydroxy-tetrahydro-furan-2-carboxylic acid (step E1) is dissolved in DMC and TFA, and stirred at room temperature overnight. The reaction mixture is concentrated in vacuo to provide the title compound.

Intermediate product F

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

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

A solution comprising [4- (2-amino-ethyl) -imidazol-1-yl] -acetic acid (prepared according to the procedure of Jain, Rahul; Cohen, Louis A. Regiospecific alkylation of histidine and histamine at N-1. Tetrahedron (1996), 52 (15), 5363-70) (7.6 g, 44.8 mmol) in methanol (100 ml), treated with concentrated sulfuric acid (3 drops), and refluxed for 18 hours. Molecular sieves are added to the reaction mixture which is refluxed for an additional 3 days. The mixture is filtered and concentrated in vacuo. The solid is absorbed in water, and basified to a pH of 10 using sodium hydroxide. The solution is extracted with DMC using a continuous liquid-liquid extraction system to provide 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 at 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 is reduced in vacuo. The crude solid is dissolved in water, washed with DMC, and the aqueous portion is concentrated in vacuo to provide 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:

G1: (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-cyclopenten-1-ol (10 g, 70.40 mmol), tris (dibenzylidene acetone) -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 atmosphere of argon. Deoxygenated tetrahydrofuran (80 ml) is added, and the reaction mixture is gently stirred for 5 minutes. Triethylamine (20 ml) is added, and the reaction mixture is stirred at 50 ° C. The reaction is shown to be complete by LCMS after 1 hour. The reaction mixture is allowed to cool, filtered, and the solvent is removed in vacuo. The title compound is obtained after purification by flash column chromatography (silica, dichloromethane / methanol,

ES 2 384 337 T3

25:1). 1H-RMN (CDCls, 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), EM (ES+) m/e 271 (MH)+.

G2: Ethyl ester of carbonic acid (1S, 4R) -4- (2,6-dichloro-purin-9-yl) -cyclopent-2-enyl ester

The (1S, 4R) -4- (2,6-dichloro-purin-9-yl) -cyclopent-2-enol (9.5 g, 35.05 mmol) is placed in an oven-dried flask under an atmosphere argon. Dry tetrahydrofuran (200 ml) is added, followed by dry pyridine (5.54 g, 70.1 mmol). Ethyl chlorformate (15.21 g, 140.2 mmol) is added slowly, so that the temperature does not rise above 40 ° C, and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 1 hour. The solvent is removed in vacuo and the residue is partitioned between DMC (200 ml) and water (200 ml). The organic phase is washed with water (150 ml) and brine (150 ml), dried over MgSO4, filtered, and the solvent is removed in vacuo. The title compound is obtained after crystallization from methanol.1H-RMN (CDCls, 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), EM (ES+) m/e 343 (MH)+.

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

Carbonic acid (1S, 4R) -4- (2,6-dichloro-purin-9-yl) -cyclopent-2-enyl ester ethyl ester (1.00 g, 2.92 mmol), tertiary ester propionyl carbamic acid butyl (intermediate W) (0.55 g, 3.21 mmol), and triphenylphosphine (0.115 g, 0.44 mmol), are placed under an inert atmosphere of argon. Tetrahydrofuran (10 ml) is added, followed by tris (dibenzylidene acetone) -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 purification by chromatography on silica, eluting with EtOAc / hexane (1: 4) provides the title product. 1H-RMN (CDCla, 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), EM (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-enyl] 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 flash evaporator of water (100 ml) and tert-butanol (100 ml). Osmium tetroxide (4% in water) is added, and the reaction mixture is vigorously stirred at room temperature overnight. Sodium sulfite (40 g) is added, and the mixture is stirred at room temperature for an additional hour, and then partitioned between EtOAc and water. The organic part is separated, dried (MgSO4), and concentrated in vacuo. The crude product is purified by chromatography on silica, eluting with DMC: MeOH (25: 1 increasing to 10: 1), to provide the title compound.

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

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 iso-propanol (5 ml), is added (3,4,5,6-tetrahydro-2H- [1,2 ' ] -Bipyridinyl-4-yl) -imidazole-1-carboxylic acid amide (50 ml of a 10 mg / ml solution in DMC, 1.85 mmol), and the reaction mixture is stirred at room temperature overnight . The solvent is removed in vacuo, and recrystallization of the solid from methanol provides the title product.

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

[1- (3,4,5,6-Tetrahydro-2H- [1,2 '] - bipyridinyl-4-yl-carbamoyl) -piperidin-4-yl] -carbamic acid tert-butyl ester (0, 45 g, 1.12 mmol) is treated with 4M HCl (in dioxane) (2.5 ml) and methanol (1 ml, co-solvent), and the reaction mixture is allowed to stir at room temperature for 1 hour. The solvent is removed in vacuo and the resulting solid is dried in a vacuum oven to provide the title product.

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

The title product is prepared analogously to imidazole-1-carboxylic acid (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -amide (intermediate A1), replacing 3,4,5,6-tetrahydro-2H- [1,2 '] - bipyridinyl4-ylamine dihydrochloride with (3,4,5,6-tetrahydro-2H- [1,2'] - bipyridinyl dihydrochloride 4-Amino-piperidine-1-carboxylic acid -4-yl) -amide (intermediate H2).

Intermediate product I

ES 2 384 337 T3

This compound is prepared in a manner analogous to 4 [(imidazole-1-carbonyl) -amino] (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -amide -piperidine-1-carboxylic acid (intermediate H), replacing (3,4,5,6-tetrahydro-2H [1,2 '] bipyridinyl-4-yl) -amide of imidazole-1-carboxylic acid with (3 4 - [(imidazole-1-carbonyl) -amino] -piperidine-1-carboxylic acid, 4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -amide.

Intermediate product J

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

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-cyclopenten-1-ol (10 g, 70.40 mmol), tris (dibenzylidene acetone) -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 atmosphere argon. Deoxygenated tetrahydrofuran (80 ml) is added, and the reaction mixture is gently stirred for 5 minutes. Triethylamine (20 ml) is added, and the reaction mixture is stirred at 50 ° C. The reaction is shown to be complete by LCMS after 1 hour. The reaction mixture is allowed to cool, filtered, and the solvent is removed in vacuo. The title compound is obtained after purification by flash column chromatography (silica, DMC / methanol, 25: 1).1HRM (CDCl,, 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), EM (ES+) m/e 271 (MH+).

J2: (1S, 4R) -4- (2,6-dichloro-purin-9-yl) -cyclopent-2-enyl carbonic acid ester ethyl ester

The (1S, 4R) -4- (2,6-dichloro-purin-9-yl) -cyclopent-2-enol (9.5 g, 35.05 mmol) is placed in an oven-dried flask under an atmosphere argon. Dry tetrahydrofuran (200 ml) is added, followed by dry pyridine (5.54 g, 70.1 mmol). Ethyl chloroformate (15.21 g, 140.2 mmol) is added slowly so that the temperature does not rise above 40 ° C, and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 1 hour. The solvent is removed in vacuo and the residue is partitioned between DMC (200 ml) and water (200 ml). The organic phase is washed with water (150 ml) and brine (150 ml), dried over MgS ° 4, filtered, and the solvent is removed in vacuo. The title compound is obtained after crystallization from methanol.1H-RM (CDCl,, 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), EM (ES+) m/e 343 (MH+).

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

Ethyl ester of carbonic acid (1S, 4R) -4- (2,6-dichloro-purin-9-yl) -cyclopent-2-enyl ester (2.5 g, 7.29 mmol), imino-dicarboxylate of ditert-butyl (1.74 g, 8.02 mmol), tris- (dibenzylidene acetone) -dipalladium (0) (0.33 g, 0.36 mmol), and triphenylphosphine (0.29 g, 1, 09 mmol), are placed in an oven-dried flask under an argon atmosphere. Dry deoxygenated tetrahydrofuran (30 ml) is added, and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by LC-MS after 3 hours. The solvent is removed in vacuo, and the title compound is obtained after purification by flash column chromatography (silica, ethyl acetate / isohexane, 4: 1)1H-RM (CDCl,, 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), EM (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 prepared 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-purin-9-yl) -5- (di -Boc-amino) -cyclopentane-1,2-diol (intermediate in the preparation of intermediate ZA). 1H-RM (CDCl,, 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), EM (ES+) m/e 504 (MH+).

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

A solution of (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 DMC (4 ml), treat with TFA (2 ml), and stir at room temperature for 2 hours. The solvent is removed in vacuo and provides the title product which is used in the next step without further purification.

ES 2 384 337 T3

MS (ES +) m / e 304 (MH)+).

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

A trifluoroacetate solution of (1S, 2R, 3S, 5R) -3-amino-5- (2,6-dichloro-purin-9-yl) -cyclopentane-1,2-diol (0.304 g, 1.00 mmol ) in THF (10 ml), 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) -purin-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) was dissolve in tetrahydrofuran (5 ml) under an argon atmosphere. Di-isopropylamine (69 mg, 0.53 mmol) is added, followed by 2,2-diphenyl-ethylamine (96 mg, 0.49 mmol), and the reaction mixture is stirred at 50 ° C. The reaction is shown to be complete by LCMS 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). 1H-RMN (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), EM (ES+) m/e 521 (MH+).

The final compound of intermediate J can also be prepared using the following process:

JJ1: {2-cloro-9 - [(1R, 4S) -4- (di-Boc-amino) -ciclopent-2-enil] -9H-purin-6- (2,2-difenil-etil) -amina

The (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), dissolved in tetrahydrofuran (250 ml) under an argon atmosphere. Di-isopropylamine (4.28 g, 33.19 mmol) is added, followed by 2,2-diphenyl-ethylamine (6.0 g, 30.43 mmol), and the reaction mixture is stirred at 50 ° C. The reaction is shown to be complete by LCMS after 18 hours. The solvent is removed in vacuo, and the reaction mixture is partitioned between DMC (250 ml) and 0.1 M HCl (250 ml). The organic phase is washed with water (200 ml) and brine (200 ml), dried over MgSO4, filtered, and the solvent is removed in vacuo to give the title compound.1H-RMN (CDCl3, 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), EM (ES+) m/e 631 (MH+).

JJ2: (1R, 2S, 3R, 5S) -3- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -5- (di-Boc-amino) -cyclopentane- 1,2-diol

A solution of {2-chloro-9 - [(1R, 4S) -4- (di-Boc-amino) -cyclopent-2-enyl] -9H-purin-6-yl} - (2,2-diphenyl- ethyl) -amine (2.9 g, 4.6 mmol) in tetrahydrofuran (60 ml), treated with 4-methyl-morpholine N-oxide (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 column chromatography on silica gel, eluting with a gradient system of methanol: DMC (0: 100 by volume), gradually changing to methanol: dichloromethane (4:96 by volume), to provide the title compound. LC-MS (electrospray): m / z [MH+] 665,34

J3: Trifluoroacetate (1S, 2R, 3S, 5R) -3-amino-5- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -cyclopentano-1,2- diol

The (1R, 2S, 3R, 5S) -3- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -5- (di-Boc-amino) -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. The reaction is shown to be complete by LCMS after 2 hours. The solvent is removed in vacuo to give the title compound.1H-RMN (MeOD, 400 MHz); 7,90(s, 1H), 7,30-7,10(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), EM (ES+) m/e 465 (MH+).

JJ4: N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-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 DIPEA (6.36 g, 49.27 mmol), are placed in a flask with dry tetrahydrofuran (150 ml). Propionyl chloride (1.52 g, 16.42 mmol) is added dropwise, and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 1 hour. The solvent is removed in vacuo and the residue is partitioned between DMC (250 ml) and water (250 ml). The organic phase is washed with water (200 ml) and brine (200 ml), dried over MgSO4, filtered, and the solvent is removed in vacuo. The solid is recrystallized from 1,2-dichloroethane to give the title compound.1H-RmN (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), EM (ES+) m/e 521 (MH+).

ES 2 384 337 T3

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

A solution of (1S, 2R, 3S, 5R) -3-amino-5- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -cyclopentane-1,2-diol hydrochloride (intermediate JJ3) (100 mg, 0.2 mmol) in dry THF (1 ml), treated with diisopropylethylamine (0.17 ml, 1 mmol) and cyclobutanecarboxylic acid chloride (0.023 ml, 0.2 mmol), and the mixture is stirred at room temperature for 48 hours. The solvent is removed under reduced pressure. The residue is purified by reverse phase chromatography eluting with a gradient system of acetonitrile (0.1% TFA): water (0.1% TFA) (0: 100 by volume) gradually changing to acetonitrile (0 TFA). , 1%): water (0.1% TFA) (100: 0 by volume), to provide the title compound (51 mg). LC-MS (electrospray): m / z [MH +] 547.26.1H-RMN (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 acid ester {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin- 9-il] -2,3dihidroxi-cyclopentyl} -carbámico

L1: Preparation of intermediate product L1

A cooled (0 ° C) solution of benzyl carbamate (4.0 g, 27 mmol) in tetrahydrofuran (100 ml), under an inert atmosphere of argon, is treated with potassium iodide (3.2 g of an aqueous dispersion 35% w / w in oil, 28 mmol) in portions over 10 minutes. The reaction mixture is allowed to warm to room temperature over 30 minutes, after which time benzyl chloroformate (5.0 g, 29 mmol) is added. After stirring at room temperature for 2 hours, the reaction is quenched with water (20 ml). Tetrahydrofuran is removed in vacuo, and the resulting mixture is partitioned between EtOAc and 2M HCl. The organic part is separated and washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting oil is purified by chromatography on silica, eluting with 1: 3 EtOAc / iso-hexane, to provide a product that is recrystallized from DMC / iso-hexane, to provide the title product.

L2: Preparation of intermediate product L2:

A solution comprising carbonic acid (1S, 4R) -4- (2,6-dichloro-purin-9-yl) -cyclopent-2-enyl ester ethyl ester (intermediate J2) (2.0 g, 5 , 83 mmol), intermediate L1 (2.2 g, 7.58 mmol), and triphenylphosphine (229 mg, 0.9 mmol) in tetrahydrofuran (20 ml), stir at room temperature for 30 minutes. Tris (dibenzylidene acetone) -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 chromatography on silica, eluting with MeOH / DMC (gradient 0-1% MeOH), to provide the title compound.

L3: Preparation of intermediate product L3:

ES 2 384 337 T3

This compound is prepared analogously to 2-chloro-9 - [(1R, 4S) -4- (di-Boc-amino) -cyclopent-2-enyl] -9H-purin-6-yl} (2,2 -Diphenyl-ethyl) -amine (intermediate JJ1) replacing (1S, 2R, 3S, 5R) -3- (Di-Boc-amino) -5- (2,6-dichloro-purin9-yl) -cyclopentane-1 , 2-diol (intermediate J4) with intermediate L2.

L4: Preparation of intermediate L4:

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

L5: Ester tert-butylic acid {(R) -1- [9 - ((1R, 2S, 3R, 4S) -4-benzyloxycarbonylamino-2,3-dihydroxycyclopentyl) -6- (2 , (2-diphenylethylamino) -9H-purin-2-yl] pyrrolidin-3-yl} carbamico

A suspension of intermediate L4 (1.03 g, 1.4 mmol) and (3R) - (+) - 3- (Boc-amino) -pyrrolidine (1.03 g, 5.5 mmol) in acetonitrile (2 ml), treated with sodium iodide (approximately 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 DMC and 0.2M HCl. The organic phase is separated, and the aqueous part is extracted with DMC. The combined organic extracts are washed with saturated sodium bicarbonate solution, water, brine, dried (MgS ° 4), and concentrated in vacuo to provide the title compound as a brown oil. MS (ES +) m / e 745 (MH+).

L6: Acid acid ester {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) - purin-9-yl] -2,3dihidroxi-cyclopentyl} -carbámico:

A solution of {(R) -1- [9 - ((1R, 2S, 3R, 4S) -4-benzyloxycarbonyl-amino-2,3-dihydroxycyclopentyl) -6- (2, 2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -carbamic (intermediate L5) (1.24 g, 1.7 mmol) in MeOH (3 ml), treated with 4M HCl in dioxane (5 ml), and stir 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). The fractions are collected and the MeCN is removed in vacuo. The remaining aqueous part is made basic with a saturated sodium bicarbonate solution, and extracted with DMC. The combined organic extracts are dried (MgSO4), and concentrated in vacuo, to provide 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- il] -2,2-dimethyl-tetrahidrocyclopenta [1,3] dioxol-4-yl} -propionamide:

ES 2 384 337 T3

M1: Ester benzylic acid {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) - 9H-Purin-2-yl] -pyrrolidin-3-yl} -carbamic:

A solution of (R) -pyrrolidin-3-yl-carbamic acid benzyl ester hydrochloride (0.88 g, 3.45 mmol) in DMC is made free base using a sodium hydrogen carbonate solution, to provide the ester (R) -Pyrrolidin-3-yl-carbamic acid benzyl (0.487 g, 2.22 mmol). This amine is added to the N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6 (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy- cyclopentyl} -propionamide (intermediate J) (0.5 g, 0.96 mmol) and triethylamine (0.224 g, 2.22 mmol), and then dissolved in NMP (7 ml). The reaction mixture is heated using microwave radiation in a Personal Chemistry Emrys ™ Optimizer microwave reactor at 190 ° C for 1 hour. The resulting mixture is purified by chromatography on silica, eluting with 5% MeOH in DMC, to provide the title compound.

M2: Éster bencílico del ácido {(R) -1- [9 - ((3aS, 4R, 6S, 6aR) -2,2-dimethyl-6-propionylamino-tetrahidrociclopenta [1,3] dioxol-4-yl) - 6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -carbámico:

A solution of {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6 (2,2-di-phenyl) acid benzyl ester -ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -carbamic (0.63 g, 0.89 mmol) in acetone (10 ml) and 2,2-dimethyloxypropane (5 ml), Treat with toluenesulfonic acid (approximately 60 mg), and then stir at room temperature overnight. The mixture is made basic using ammonium hydroxide, and the solvent is removed in vacuo. The crude product is partitioned between DMC and water, and the organic part is washed with brine, dried over MgSO4, filtered, and the solvent is removed in vacuo to give the title compound. [MH + 745].

M3: N - {(3aR, 4S, 6R, 6aS) -6- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin- 9-yl] -2,2-dimethyl-tetrahidrocyclopenta- [1,3] -dioxol-4-yl} -propionamide:

To a solution of benzyl acid {(R) -1- [9 - ((3aS, 4R, 6S, 6aR) -2,2-dimethyl-6-propionylamino-tetrahydrocyclopenta- [1,3] -dioxole-4 -yl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -carbamic (0.598 g, 0.79 mmol) in ethanol (7.5 ml) Palladium hydroxide on carbon (10 mg) is added under an inert argon atmosphere. The reaction mixture is purged with argon, and placed under an atmosphere of hydrogen overnight. The mixture is filtered and purified by chromatography on silica, eluting with 5% MeOH in DMC, to provide the title compound. [MH + 611].

Intermediate N (R) - [1,3 '] Bi-pyrrolidinyl

N1: (R)-1'-selfish-[1,3']-bi-pyrrolidinolo:

An ice-cold solution of 2,5-dimethoxy-tetrahydrofuran (19.11 ml, 0.147 mol) and 6M sulfuric acid (37.2 ml) in tetrahydrofuran (200 ml) is treated dropwise with (R) - (1) -benzyl-3-aminopyrrolidine (10 g, 0.057 mol), 6M sulfuric acid (37.2 ml) in tetrahydrofuran (150 ml), and sodium borohydride granules (8.62 g, 0.227 mol), simultaneously, making sure the temperature stays below 10 ° C. The reaction mixture is allowed to warm to room temperature, and water (10 ml is added to aid dissolution of the sodium hydroxide granules. After stirring at room temperature for 12 days, the mixture is cooled with the use of a ice bath, and water (500 ml) is added. The solution is made basic by adding granules of sodium hydroxide (pH <10), and then filtered under vacuum. The filtrate is extracted with diethyl ether and DMC, and the parts Organics are combined and concentrated in vacuo. The crude residue is sonicated in diethyl ether, and filtered under vacuum. The filtrate is reduced in vacuo again, and the resulting crude product is dissolved in MeCN (8 ml), and purified by reverse phase column chromatography (Isolute ™ C18, 0 to 100% MeCN in water - 0 TFA, 1%), to provide the title product.

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

A solution of (R) -1'-benzyl- [1,3 '] bi-pyrrolidinyl (0.517 g, 2.24 mmol) in methanol (25 ml) under an argon atmosphere 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, and then filtered through Celite.TM. The filtrate is concentrated in vacuo to provide the title product as a dark orange oil.

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

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

ES 2 384 337 T3

A cooled (0 ° C) and stirring solution of (R) -3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 5.36 mmol) and triethylamine (1.5 ml, 11.0 mmol) in tetrahydrofuran (10 ml), treated dropwise for 1 minute with pyridine-4-carbonyl chloride hydrochloride (0.935 g, 5.25 mmol). After 5 minutes, the reaction mixture is allowed to warm to room temperature and stir overnight. The resulting mixture is diluted with EtoAc, and washed twice with a saturated sodium bicarbonate solution followed by brine. The organic part is dried (MgSo4) and concentrated in vacuo. The crude product is purified by recrystallization from EtoAc / iso-hexane to provide 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 MeoH (6 mL), It is treated with 2M HCl (5 ml), and allowed to stand at room temperature overnight. The resulting mixture is diluted with MeoH, and added to 12 ml of Dowex Resin (50Wx2-200). After 30 minutes, the resin is washed with water until neutral, and then further washed with MeoH and 2% ammonia. The solvent is removed in vacuo to provide the title compound as a crystalline solid. [MH + 192].

5-methyl-isoxazole-3-carboxylic acid intermediate P (R) -pyrrolidin-3-yl-amide:

Triethylamine (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 tetrahydrofuran ( 5 ml). To this cloudy mixture is added dropwise, (R) -3-amino-1-Npyrrolidine (0.5 g, 2.68 mmol) in tetrahydrofuran (2 ml), and the reaction mixture is allowed to warm to temperature environment for 30 minutes. After standing at room temperature overnight, the reaction mixture is diluted with EtoAc (30 ml) and washed with water (5 ml, 2 times), brine, dried (MgSo4), and concentrated in vacuo. The resulting oil is dissolved in MeoH (5 ml), and treated dropwise with 6M HCl (1.15 ml). After standing at room temperature for 4 days, the reaction mixture is concentrated in vacuo and co-evaporated with MeoH / EtoAc. The crude residue is triturated with EtoAc to provide 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

Q1: Ester {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl-carbamoyl} -methyl acetic acid

A suspension of (1S, 2R, 3S, 5R) -3-amino-5- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] cyclopentane-1,2- dihydrochloride diol (intermediate JJ3) (250 mg, 0.46 mmol) in dry tetrahydrofuran (10 ml) is treated with triethylamine (0.188 g, 1.86 mmol), followed by acetoxyacetyl chloride (0.064 g, 0.46 mmol) , and then stirred at room temperature for 30 minutes. The solvent is removed in vacuo and the solvent is partitioned between DMC and 0.1 M HCl. The organic part is separated and washed with brine, dried (MgSo4) and concentrated in vacuo to provide the title product.

Q2: N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} - 2-hydroxy-acetamide:

To an ester suspension {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentylcarbamoyl} -methyl acetic acid (0.2 g, 0.35 mmol) in MeoH (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 solvent is partitioned between DMC and water. The organic part is separated, dried (MgSo4) and concentrated in vacuo to provide the title product.

Intermediate product R

3- isocyanate-benzenesulfonamide:

To a solution with vigorous stirring of 3-amino-benzenesulfonamide (1 g, 5.8 mmol), in dry dioxane (25 ml), is added trichloromethyl chloroformiate (1.72 g, 8.7 mmol ), and the reaction mixture is heated under reflux for 3 hours. The solvent is removed in vacuo to provide the title product, which is used without further purification.

Intermediate product S

4- isocyanate-benzenesulfonamide:

ES 2 384 337 T3

This compound is prepared analogously to intermediate R, replacing 3-aminobenzenesulfonamide with 4-amino-benzenesulfonamide.

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 :

This compound is prepared analogously to {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl } -cyclobutanecarboxylic acid 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 hydrogen carbonate (273 mg, 3.25 mmol) suspended in water / DMC (4 ml, 1: 1), are treated with phenyl chloroformate (0.204 ml, 1.62 mmol). After stirring at room temperature overnight, the reaction mixture is diluted with more DMC / water, and the organic phase is separated. The organic part is concentrated in vacuo to provide the title compound. (MH + 244)

Intermediate product UB

Pyridin-3-yl-carbamic acid phenyl ester

Phenyl chloroformate (0.733 ml, 5.84 mmol) is suspended in pyridine / DMC (3 ml, 2: 1). The solution is stirred at 0 ° C, and 3-aminopyridine (500 mg, 5.31 mmol) dissolved in DMC (1 ml) is added dropwise. The reaction mixture is left at 0 ° C for 1 hour. The solvent is removed in vacuo, and the residue is dissolved in ethyl acetate. This organic part is washed with 0.1M HCl, and then concentrated in vacuo, to provide the title compound. (MH + 215).

Intermediate products UC-UE

These compounds, specifically, • (3-sulfamoyl-phenyl) -carbamic acid phenyl ester (intermediate UC), • (4-sulfamoyl-phenyl) acid phenyl ester - (intermediate UD), • Pyridine phenyl ester -2-ylmethyl- (intermediate EU), are prepared analogously to intermediate UB, replacing 3-aminopyridine with the appropriate amine.

Intermediate product VA

3 - ((R) -3-Pyrrolidin-3-ylureido) -benzenesulfonamide

VA1: 3-[3-((R)-1-Self-pyrrolidin-3-yl)-ureido]-bencenosulfonamide

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, then allowed to cool to room temperature, before removing volatiles under reduced pressure. The orange syrup is purified by flash column chromatography (silica; DMC / methanol, 10: 1) to give a foamed beige solid.

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

A solution of 3- [3 - ((R) -1-benzyl-pyrrolidin-3-yl) -ureido] -benzenesulfonamide (25 g, 0.067 mol) in ethanol (250 ml), purge with nitrogen, and add palladium hydroxide (2.5 g, 20% w / w). The suspension is purged with hydrogen and stirred under positive hydrogen pressure for 24 hours. Filtration through Celite® (filter material) and removal of the solvent under reduced pressure gives the product as a colorless waxy solid.

ES 2 384 337 T3

Intermediate product VB

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

VB1:1-((R)-1-Baseline-pyrrolidin-3-yl)-3-pyridin-3-yl-urea

A solution of pyridin-3-yl-carbamic acid phenyl ester (1.6 g) in dry tetrahydrofuran (20 ml) is treated with (R) -1-benzyl-pyrrolidin-3-ylamine (1.9 g, 1.05 equivalents), and then heated using microwave radiation at 110 ° C for 1000 seconds. The solvent is removed in vacuo, and purification of the crude product by chromatography on silica, eluting with DMC followed by EtOAc and EtOH, provides the title compound as an oil. (MH + 297).

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

The title compound is prepared from 1 - ((R) -1-benzyl-pyrrolidin-3-yl) -3-pyridin-3-yl-urea in a manner analogous to 3 ((R) -3-pyrrolidin- 3-ylureido) -benzenesulfonamide (step VA1).

Intermediate product VC

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

This compound is prepared from (4-sulfamoyl-phenyl) -carbamic acid phenyl ester (intermediate UD), analogously 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-hydroxyacetamide:

This compound is prepared analogously to (N - ((1S, 2R, 3S, 4R) -4- {6- [2,2-Bis- (4-hydroxyphenyl) -ethylamino] -2 - [(R ) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (example 7, step 3 ) replacing 4,4 '- (2-amino-ethylidene) -bis-phenol (example 7, step 1) with (S) -2-amino-3-phenylpropan-1-ol.

Intermediate product W

Propionyl-carbamic acid tert-butyl ester

The title compound is prepared from propyl-carbamic acid tert-butyl ester, using the procedure described by Ken-ichi Takana et al in Chem. Pharm. Bull. 1988, 36, 3125.1H-RMN (CDCl3, 400 MHz); 7,25(s a, 1H), 2,75(q, 2H), 1,50(s, 9H), 1,15(t, 3H).

Intermediate product X

Bis- (4-methoxy-phenyl) -methanone-oxima

The 4,4'-dimethoxy-benzophenone (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 refluxed. The reaction is shown to be complete by thin layer chromatography 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 phase is dried over MgS ° 4, filtered, and the solvent is removed in vacuo. The title compound is obtained immediately by crystallization from ethyl acetate / cyclohexane.1H-RMN (CDCl3, 400 MHz); 7,70(s, 1H), 7,40 (d de d, 4H), 6,95(d, 2H), 6,85(d, 2H), 3,85(s, 3H), 3,80(s, 3H).

Intermediate product Y

C, C-Bis- (4-metoxi-fenil) -metilamina

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 portionwise addition of zinc powder (25.29 g, 389.10 mmol). After the addition is complete, the reaction mixture is slowly heated to 50 ° C. When effervescence has ceased, the reaction mixture is refluxed. The reaction is shown to be complete by TLC after 4 hours. The reaction mixture is allowed to cool and ethyl acetate (250 ml) is added. The

ES 2 384 337 T3 reaction mixture is filtered through CeliteTM, and the phases are separated. The organic phase is dried over MgSO4, filtered, and the solvent is removed in vacuo to give the title compound.1H-RMN (CDCl3, 400 MHz); 7,25 (d, 4H), 6,80 (d, 4H), 5,10(s, 1H), 3,75(s, 6H).

Intermediate product Z

Ester 1- [2 - ((R) -3-aminopyrrolidin-1-yl) -2-oxoethyl] piperidin-4-ylcarbido biphenyl-2-ylcarbamic acid

Z1: Ester tert-butylic acid {(R) -1- [2- (4-hydroxypiperidin-1-yl) acetyl] pyrrolidin-3-yl} carbamic acid

To a solution of (R) -pyrrolidin-3-yl-carbamic acid tert-butyl ester (1.5 g, 8.1 mmol) in THF (150 ml), TEA (2.3 ml, 16 , 1 mmol), followed by the dropwise addition of chloroacetyl chloride (0.67 ml, 8.5 mmol). The reaction mixture is allowed to stir at room temperature for 2 hours, and is then treated with TEA (2.3 ml, 16.1 mmol), followed by 4-piperidinol (4.07 g, 40.3 mmol). After stirring at 50 ° C for 18 hours, the solvent is removed in vacuo and purification of the crude residue by reverse phase column chromatography (Isolute ™ C18, 0 to 100% MeOH in water - 0.1 TFA %) provides the title product. [MH + 328.19].

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

{(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 2-biphenyl isocyanate (930 mg, 2.65 mmol), are dissolved in NMP (2 ml), and heated at 70 ° C overnight. Purification is carried out by reverse phase column chromatography (Isolute ™ C18, 0-100% MeOH in water - 0.1% TFA). The fractions containing the product are concentrated in vacuo to remove acetonitrile, and the aqueous phase is treated with a saturated sodium bicarbonate solution. The product is extracted with DMC, and the combined organics are concentrated in vacuo to provide the title product. [MH + 523.24].

Z3: Ester 1- [2 - ((R) -3-Amino-pyrrolidin-1-yl) -2-oxo-ethyl] -piperidin-4-yl-delicido biphenyl-2-yl-carbamic acid:

A 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 DMC (10 ml), treated with TFA (5 ml), and stirred at room temperature for 2 hours. The solution is made basic by adding a saturated sodium bicarbonate solution, and then extracted with DMC. The combined organics are washed with water, brine, dried (MgSO4), and concentrated in vacuo to provide 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-methoxi-phenyl) -methyl] - (2-chloro-9H-purin-6-yl) -amine

The 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-methoxy-phenyl) -methylamine (see preparation of intermediates) (12.22 g, 50.29 mmol) , and the reaction mixture is stirred at 50 ° C. The reaction is shown to be complete by LC-MS after 5 days. The solvent is removed in vacuo and replaced with MeOH (250 ml). The resulting precipitate is filtered and dried to give the title compound. 1H-RmN (d6-DMSO, 400 MHz); 8.20 (sa, 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-methoxi-phenyl) -methyl] -amino} -2-chloro-purin-9-yl) -cyclopent-2-enol

The bis- (4-methoxy-phenyl) -methyl] - (2-chloro-9H-purin-6-yl) -amine (13 g, 32.87 mmol) is placed in an oven-dried flask under an atmosphere of argon. Dry deoxygenated THF (100 ml) and dry dimethylsulfoxide (2 ml) are added, and the suspension is cooled on an ice bath. Then 95% sodium hydride (0.79 g, 32.87 mmol) is slowly added, and the solution is stirred at room temperature for 30 minutes. The (1S, 4R) -cis-4-acetoxy-2-cyclopenten-1ol (4.9 g, 34.5 mmol) and triphenylphosphine (1.36 g, 5.17 mmol) are placed in an oven-dried flask under an argon atmosphere. Dry deoxygenated THF (50 ml) is added. This solution is added to the anion solution by means of a syringe. Then tetrakis- (triphenylphosphine) -palladium (0) (2 g, 1.73 mmol) is added, and the mixture is stirred at 50 ° C. The reaction is shown to be complete by LCMS 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 and dried to give the title compound.1H-RMN (CDCl3, 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, 1H), EM (ES+) m/e 478 (MH+).

ES 2 384 337 T3

(1S, 4R) -4- (6 - {[bis- (4-methoxy-phenyl) -methyl] -amino} -2-chloro-purin-9-yl) -cyclopent-2-enyl ester ethyl ester carbonic acid

(1S, 4R) -4- (6 - {[bis- (4-methoxy-phenyl) -methyl] -amino} -2-chloro-purin-9-yl) -cyclopent-2-enol (8.00 g, 16.75 mmol) is 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 4-dimethylaminopyridine is added, followed by 3-oxy-benzotriazole-1-carboxylic acid ethyl ester (6.94 g, 33.50 mmol, see preparation of intermediates). The reaction mixture is stirred at room temperature. The reaction is shown to be complete by thin layer chromatography after 18 hours. The solvent is removed in vacuo and the residue is partitioned between ethyl acetate (500 ml) and 2M HCl (200 ml). The organic phase is washed with water (150 ml) and brine (150 ml), dried over MgSO4, filtered, and the solvent is removed in vacuo. The title compound is obtained after purification by flash column chromatography (silica, DmC / methanol, 50: 1). 1H-RMN (CDCl3, 400 mHz); 7,80(s, 1H), 7,25(d de d, 4H), 6,85(d de d, 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-methoxi-phenyl) -methyl] - {2-chloro-9 - [(1R, 4S) -4- (di-Boc-amino) -cyclopent-2-enyl] -9H-purin-6 -il} -amine

(1S, 4R) -4- (6 - {[bis- (4-methoxy-phenyl) -methyl] -amino} -2-chloro-purin-9-yl) -cyclopent-2-enyl ester ethyl ester of carbonic acid (2.00 g, 3.64 mmol), di-tert-butyl iminodicarboxylate (0.87 g, 4.00 mmol), and triphenylphosphine (0.14 g, 0.55 mmol), are placed in an 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. The reaction is shown to be complete by LCMS after 3 hours. The solvent is removed in vacuo and the title compound is obtained after purification by flash column chromatography (silica, iso-hexane / ethyl acetate, 4: 1).1H-RMN (CDCl3, 400 MHz); 8,20(s, 1H), 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-methoxi-phenyl) -methyl] -amino} -2-chloro-purin-9-yl) -5- (di-Boc -amino) -cyclopentane-1,2-diol

[Bis- (4-methoxy-phenyl) -methyl] - {2-chloro-9 - [(1R, 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-methyl-morpholine 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. The reaction is shown to be complete by LCMS after 18 hours. The solvent is removed in vacuo and the title compound is obtained after purification by flash column chromatography (silica, DMC / methanol, 50: 1). 1HRMN (CDCl3, 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).

Trifluoroacetate de (1S, 2R, 3S, 5R) -3-amino-5- (6-amino-2-chloro-purine-9-yl) -cyclopentane-1,2-diol

The (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 (600mg, 0.84mmol) is dissolved in DMC (4ml). TFA (2 ml) is added, and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 18 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). 1H-RMN (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). EM (ES+) m/e 285 (MH+).

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

(1S, 2R, 3S, 5R) -3-amino-5- (6-amino-2-chloro-purin-9-yl) -cyclopentane-1,2-diol trifluoroacetate (intermediate product for the preparation of the example 1) (20 mg, 39 pmol) and DIPEA (25 mg, 190 pmol), are placed in a flask with dry THF (1 ml). Propionyl chloride (3.6 mg, 39 pmol) is added, and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 3 hours. The solvent is removed in vacuo and the title compound is obtained, which can be purified by reverse phase column chromatography (Isolute ™ C18, 0-100% acetonitrile in water - 0.1% TFA). 1H-RMN (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), EM (ES+) m/e 341 (MH+).

Intermediate product ZB

Pyridin-3-yl-carbamic acid phenyl ester:

A solution of pyridine (2 ml) in DMC (10 ml) is treated with phenyl chloroformate (1.83 g, 11.7 mmol). To this solution is added 3-aminopyridine (1.0 g, 10.6 mmol) in DMC (8 ml) resulting in an exotherm of

ES 2 384 337 T3

20 ° C. The reaction mixture is stirred at room temperature for 2 hours and then concentrated in vacuo. The residue is partitioned between EtOAc and water and the organic part is separated. This organic part is washed with water, a saturated sodium bicarbonate solution, dried (MgSO4) and concentrated in vacuo to provide the title compound as a white solid. (MH + 215.13)

Intermediate product ZC

Pyridin-2-ylmethyl-carbamic acid phenyl ester

The title compound is prepared analogously to pyridin-3-yl-carbamic acid phenyl ester, substituting 3-aminopyridine for C-pyridin-2-yl-methylamine.

Intermediate product ZD

(3-Hydroxy-benzyl) -carbamic acid phenyl ester

The title compound is prepared analogously to pyridin-3-yl-carbamic acid phenyl ester, substituting 3-aminopyridine for 3-amino-methylphenol.

Intermediate product ZE

(4-Sulfamoyl-phenyl) -carbamic acid phenyl ester

The title compound is prepared analogously to pyridin-3-yl-carbamic acid phenyl ester, substituting 3-aminopyridine for 4-amino-benzenesulfonamide.

Intermediate product ZF

(3-Sulfamoyl-phenyl) -carbamic acid phenyl ester

The title compound is prepared analogously to pyridin-3-yl-carbamic acid phenyl ester, substituting 3-aminopyridine for 3-amino-benzenesulfonamide.

ZG intermediate product

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

ZG1: 3-tert-butoxy-N - [(1S, 2R, 3S, 4R) -4- (2,6-dichloropurin-9-yl) -2,3-dihydroxycyclopentyl] propionamide

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

ZG2: 3-tert-butoxy-N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenylethylamino) purin-9-yl] -2.3 -dihydroxycyclopentyl} propionamide

The title compound is prepared 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), substituting 3-tert-butoxy-N [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -2,3-dihydroxy-cyclopentyl] -propionamide (intermediate ZG1) by the N [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -2,3- dihydroxy-cyclopentyl] -propionamide.

ZG3: Ester tert-butylic acid {(R) -1- [9 - [(1R, 2S, 3R, 4S) -4- (3-tert-butoxypropionylamino) -2,3-dihydroxycyclopentyl] 6 - (2,2-Diphenylethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -carbamic acid

2,3-dihydroxy-cyclopentyl} -propionamide (intermediate ZG2) by (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).

ZG4: N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenylethylamino) -purin- 9-yl] -2,3-dihydroxycyclopentyl} -3

ES 2 384 337 T3 hydroxy-propionamide

The title compound is prepared 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), substituting {(R) -1- [9 - [(1R, 2S, 3R, 4S) -4- (3-tert-butoxy-propionylamino) -2,3-dihydroxycyclopentyl] -6- for tert-butyl acid (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -carbamic (intermediate ZG3) by the acid tert-butyl ester {(R) -1- [9 - [( 1R, 2S, 3R, 4S) -4 - ((R) -2-benzyloxy-propionylamino) -2,3-dihydroxy-cyclopentyl] -6- (2,2-diphenylethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -carbamic (example 181, step 3).

Intermediate product ZH

N - ((1S, 2R, 3S, 4R) -4- {2 - ((R) -3-aminopyrrolidin-1-yl) -6- [2,2-bis- (4-hydroxyphenyl) -ethylamino] -purin-9-yl} -2,3-dihydroxycyclopentyl) -3-hydroxypropionamide

The title compound is prepared 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} -3-hydroxy-propionamide (intermediate ZG), substituting the 4,4 '- (2-amino-ethylidene) -bis-phenol (prepared as described by Schelkun, RM et al. Bioorg. Med. Chem. Lett. (1999), 9 (16), pages 2447-2452) by 2,2-diphenyl-ethylamine.

Intermediate product ZI

2-amino-1,1-bis- (4-chloro-phenyl) -ethanol

The title compound is prepared by combining 4,4'-dichlorobenzophenone (5 g, 20 mmol) and zinc iodide (480 mg, 1.49 mmol) in DMC (100 ml). Trimethylsilyl cyanide (2.17 g, 21.9 mmol) is added, and the reaction is stirred at room temperature for 18 hours. The reaction is washed with water (100 ml), and dried over magnesium sulfate, before filtering and removing the solvent under reduced pressure. The residue is redissolved in dry THF (40 ml), 1.0 M borane in THF (40 ml) is added, and the reaction is stirred under reflux for 24 hours. After cooling, volatile components are removed under reduced pressure, and the residue is absorbed in methanol (100 ml). Concentrated hydrochloric acid is added, and the reaction is refluxed for an additional 2 hours, before the volatile components are once again removed under reduced pressure, to give the title compound as a hydrochloride salt.

ZJ intermediate product

Acetic acid [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -2,3-dihydroxy-cyclopentyl-carbamoyl] -methyl ester

The title compound is prepared analogously to 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-chloro-purin-9-yl} -2,3- dihydroxy-cyclopentyl-carbamoyl) methyl acetic acid

Acetic acid [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -2,3-dihydroxy-cyclopentyl-carbamoyl] -methyl ester (intermediate ZJ; 1 equivalent) and 4,4 '- (2-amino-ethylidene) -bis-phenol (1.1 equivalents; prepared as described by Schelkun, RM et al. Bioorg. Med. Chem. Lett. (1999), 9 ( 16), pages 2447-2452) are combined in dry THF, and treated with DIPEA (1.2 equivalents), and stirred at 50 ° C overnight. The reaction is diluted with ethyl acetate and washed consecutively with water (2 times) and brine, before drying over magnesium sulfate, filtered and volatile components removed under reduced pressure to provide the title compound.

ZL intermediate product

Ester _______ ((1S, 2R, 3S, 4R) -4- {6- [2,2-bis- (4-chloro-phenyl) -2-hydroxy-ethylamino] -2-chloro-purin-9-yl} - 2,3-dihydroxy-cyclopentylcarbamoyl) -methyl acetic acid

The title compound is prepared analogously to the ester ((1S, 2R, 3S, 4R) -4- {6- [2,2-bis- (4-hydroxy-phenyl) ethylamino] -2-chloro-purin- 9-yl} -2,3-dihydroxy-cyclopentyl-carbamoyl) -methyl acetic acid (intermediate ZK), substituting 2-amino-1,1-bis- (4-chloro-phenyl) -ethanol (intermediate ZI) by 4,4 '- (2-amino-ethylidene) -bis-phenol.

Intermediate product ZM

ES 2 384 337 T3

Ester {(1S, 2R, 3S, 4R) -4- [2-chloro-6 - ((S) -1-hydroxy-methyl-2-phenyl-ethylamino) -purin-9-yl] -2,3- acetic acid dihydroxy-cyclopentyl-carbamoyl} methyl

The title compound is prepared by combining the [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -2,3-dihydroxy-cyclopentyl-carbamoyl] -methyl ester of acetic (1 equivalent) and (S) -2-amino-3-phenyl-propan-1-ol (1 equivalent) in DMC with TEA (1.1 equivalents), and stirring overnight. The reaction is diluted with dichloromethane, and washed consecutively with 0.1M hydrochloric acid, water, and brine, before drying over magnesium sulfate. Filtration and removal of volatile components under reduced pressure provide the title compound.

Intermediate product ZN

Ester ((1S, 2R, 3S, 4R) -4- {2-chloro-6 - [(S) -1-hydroxy-methyl-2- (4-hydroxy-phenyl) -ethylamino] -purin-9-yl Acetic acid} -2,3-dihydroxy-cyclopentylcarbamoyl) -methyl

The title compound is prepared analogously to the ester {(1S, 2R, 3S, 4R) -4- [2-chloro-6 - ((S) -1-hydroxy-methyl-2-phenyl-ethylamino) -purin-9 -yl] -2,3-dihydroxy-cyclopentyl-carbamoyl} -methyl of acetic acid (intermediate ZM), substituting 4 - ((S) -2-amino-3-hydroxy-propyl) -phenol for (S ) -2-amino-3-phenyl-propan-1-ol.

Intermediate product ZO

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

ZO1: ester {(1S, 2R, 3S, 4R) -4- [6- [2,2-bis- (4-chloro-phenyl) -2-hydroxy-ethylamino] -2 - ((R) -3- tert-butoxycarbonylaminopyrrolidin-1-yl) purin-9-yl] -2,3-dihydroxycyclopentylcarbamoyl} methyl acetic acid

A suspension of the ester ((1S, 2R, 3S, 4R) -4- {6- [2,2-bis- (4-chloro-phenyl) -2-hydroxy-ethylamino] -2-chloro-purin-9- yl} -2,3-dihydroxy-cyclopentyl-carbamoyl) -methyl acetic acid (intermediate ZL; 1 equivalent) and (3R) - (+) - 3- (Bocamino) -pyrrolidine (4 equivalents) in acetonitrile, treated with a catalytic amount of sodium iodide, 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; purification by column chromatography / crystallization provides the title compound.

ZO2: 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

An ester solution {(1S, 2R, 3S, 4R) -4- [6- [2,2-bis- (4-chloro-phenyl) -2-hydroxy-ethylamino] -2 - ((R) -3 -tert-butoxy-carbonylamino-pyrrolidin-1-yl) -purin-9-yl] -2,3-dihydroxy-cyclopentyl-carbamoyl} -methyl acetic acid (intermediate ZO1) in MeOH (~ 0.5 M) , treated with an equal volume of 4M HCl in dioxane, and stirred at room temperature for 2 hours. The solvent is removed in vacuo and purification by column chromatography / crystallization is carried out to provide the title compound.

Intermediate product ZP

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-hydroxyacetamide.

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

The title compound was prepared analogously to N - [(1S, 2R, 3S, 4R) -4- (6 - {[bis- (4-methoxy-phenyl) -methyl] -amino} 2-hydrazino- purin-9-yl) -2,3-dihydroxy-cyclopentyl] -propionamide (example 168, step 2), substituting the ester {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2 Acetic acid, 2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl-carbamoyl} -methyl acetic acid (intermediate Q1) by the N - [(1S, 2R, 3S, 4R) - 4- (6 - {[Bis- (4-methoxy-phenyl) -methyl] -amino} -2-chloro-purin-9-yl) -

2,3-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-hydroxyacetamide

The title compound is prepared analogously to 1- [6 - {[bis- (4-methoxy-phenyl) -methyl] amino} -9 - ((1R, 2S, 3R, 4S) -2 , 3-dihydroxy-4-propionylamino-cyclopentyl) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic acid (example 168, step 3), by the reaction of the N - {(1S, 2R, 3S , 4R) -4- [6- (2,2-diphenyl-ethylamino) -2-hydrazino-purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide (intermediate ZP1) and nitro- sodium malonaldehyde (prepared as

ES 2 384 337 T3 is described by Fanta PE org. Syntheses, Coll. Volume 4 (1963), pages 844-845).

ZP3: 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

The title compound is prepared by dissolving the 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), adding a 2: 1 by weight mixture of activated carbon and ferric chloride , and an excess of hydrazine monohydrate, and stirring the resulting mixture at 65 ° C for four hours. Filtration through CeliteTM, removal of volatile components under reduced pressure, and purification by column chromatography / crystallization, provide the title compound.

ZQ intermediate product

N - ((1S, 2R, 3S, 4R) -4- {2- (4-amino-pyrazol-1-yl) -6- [2,2-bis- (4-hidroxi-phenyl) -ethylamino] - purin-9-yl} -2,3-dihidroxi-cyclopentyl) -

2-hydroxy-acetamide

The title compound is prepared analogously to 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), substituting the ester ((1S, 2R, 3S, 4R) -4- {6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -2-chloro-purin-9-yl} -2, 3-dihydroxy-cyclopentyl-carbamoyl) methyl acetic acid (intermediate ZK) by the ester {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) purin -9-yl] -2,3-dihydroxy-cyclopentyl-carbamoyl} -methyl of acetic acid (intermediate Q1).

ZR intermediate product

N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-pyrazol-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2 , 3-dihidroxi-cyclopentyl} -propionamide

The title compound is prepared analogously to 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), substituting N {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (intermediate J) by the ester {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy -cyclopentylcarbamoyl} -methyl acetic acid (intermediate Q1).

ZS intermediate product

Ester methyl acid 1- [9 - [(1R, 2S, 3R, 4S) -2,3-dihydroxy-4- (2-hydroxyacetylamino) cyclopentyl] -6- (2,2-diphenylethylamino) -9H -purin-2-yl] -1H-pyrazole-4-carboxylic acid

The title compound is prepared analogously to 1- [6 - {[bis- (4-methoxy-phenyl) -methyl] amino} -9 - ((1R, 2S, 3R, 4S) -2 , 3-dihydroxy-4-propionylamino-cyclopentyl) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic (example 168, step 3), substituting N - {(1S, 2R, 3S, 4R) -4- [6- (2,2-diphenyl-ethylamino) -2-hydrazino-purin-9-yl] -2,3-dihydroxycyclopentyl} -2- hydroxy-acetamide (intermediate ZP1) by the N - [(1S, 2R, 3S, 4R) -4- (6 - {[Bis- (4-methoxy-phenyl) -methyl] amino} -2-hydrazino-purin -9-yl) -2,3-dihydroxy-cyclopentyl] -propionamide (example 168, step 2).

ZT intermediate product

N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-pyrazol-1-yl) -6 - ((S) -1-hydroxy-methyl-2-phenyl-ethylamino) - purin-9-yl] -2,3-dihydroxiciclopentyl} -2-hydroxy-acetamide

The title compound is prepared analogously to 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), substituting the ester {(1S, 2R, 3S, 4R) -4- [2-chloro-6 - ((S) -1-hydroxy-methyl-2-phenyl-ethylamino) -purin-9-yl] -2, Acetic acid methyl 3-dihydroxy-cyclopentyl-carbamoyl} (intermediate ZM) by the ester {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) purin -9-yl] -2,3-dihydroxy-cyclopentyl-carbamoyl} -methyl of acetic acid (intermediate Q1).

ZU intermediate product

N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-imidazol-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2 , 3-dihidroxi-cyclopentyl} -2-hidroxiacetamida

ZU1: 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-hydroxy-acetamide

ES 2 384 337 T3

The title compound is prepared by dissolving the ester {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -

2,3-dihydroxy-cyclopentyl-carbamoyl} -methyl acetic acid (intermediate Q1) in N-methyl-2-pyrrolidinone, followed by potassium carbonate (5 equivalents) and 4-nitro-1H-imidazole (10 equivalents) . The mixture is heated by microwave irradiation at 150 ° C for two hours, then diluted with ethyl acetate, and washed consecutively with water (2 times) and brine, before drying over magnesium sulfate. Filtration, removal of volatile components under reduced pressure, and purification by flash column chromatography / crystallization provide the title compound.

ZU2: 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

The title compound is prepared analogously to 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 ZP3), substituting 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) by the N - {(1S, 2R, 3S, 4R) -4- [6- (2,2-diphenyl-ethylamino) -2- (4-nitro-pyrazol-1-yl) -purin9-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-hydroxy-phenyl) -ethylamino] - purin-9-yl} -2,3-dihydroxiciclopentyl) -2-hydroxy-acetamide

The title compound is prepared analogously to 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) substituting the ester ((1S, 2R, 3S, 4R) -4- {6- [2,2 -bis- (4-hydroxy-phenyl) -ethylamino] -2-chloro-purin-9-yl} -2,3-dihydroxy-cyclopentyl-carbamoyl) methyl of acetic acid (intermediate ZK) by the ester {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) purin-9-yl] -2,3-dihydroxy-cyclopentyl-carbamoyl} -methyl acid acetic (intermediate 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

The title compound is prepared analogously to 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) from the ester {(1S, 2R, 3S, 4R) -4- [2-chloro-6 - (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl-carbamoyl} -methyl acetic acid (intermediate Q1), substituting 3-nitro-1H- [1, 2,4] -triazole by the 4-nitro-1H-imidazole in the ZU1 step.

ZX intermediate product

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-dihydroxycyclopentyl) -2-hydroxy-acetamide

The title compound is prepared analogously to 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) substituting the ester ((1S, 2R, 3S, 4R) -4- {6- [2,2 -bis- (4-hydroxy-phenyl) -ethylamino] -2-chloro-purin-9-yl} -2,3-dihydroxy-cyclopentyl-carbamoyl) methyl of acetic acid (intermediate ZK) by the {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) purin-9-yl] -2,3-dihydroxy-cyclopentyl-carbamoyl} -methyl ester of acetic acid (intermediate Q1), and the 3-nitro-1H [1,2,4] triazole by the 4-nitro-1H-imidazole in the ZU1 step.

Intermediate product ZY

Ethylamide (2S, 3S, 4R, 5R) -5- [2-chloro-6- (2,2-diphenylethylamino) purin-9-yl] -3,4-dihydroxytetrahydrofuran-2-carboxylic acid

The title compound is prepared as described in WO 9602553.

Example 1

Trifluoroacetate N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenylethylamino) purine] 9-yl] -2,3-dihydroxycyclopentyl} -2-hydroxyacetamide

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

ES 2 384 337 T3 acetamida

Step 2: N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) trifluoroacetate -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-benzyloxy-acetamide

A solution of 2-benzyloxy-N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3- dihydroxycyclopentyl} -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. The reaction is shown to be complete by LC-MS after 30 minutes. The title compound is obtained after purification by reverse phase column chromatography (Isolute ™ C18, 0-100% acetonitrile in water - 0.1% TFA).

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

A trifluoroacetate solution 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} -2-benzyloxy-acetamide (0.022 g, 0.03 mmol) in ethanol (2 ml) under an argon atmosphere, 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, and then filtered through Celite.TM. The filtrate is concentrated in vacuo, and purification of the crude product by reverse phase column chromatography (Isolute ™ C18, 0-100% acetonitrile in water - 0.1% TFA) provides the title product. (MH + 573.4)

Example 2

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

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

Example 3

Benzyl ester ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R) -3- (3-pyridin-2-ylmethyl-ureido)) -pyrrolidin-1-yl] purin-9-yl} -2,3-dihydroxycyclopentyl) carbamico

This compound is prepared analogously to Example 2 by replacing trifluoroacetate 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} -2-hydroxy-acetamide with benzyl acid 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 (intermediate L). (MH + 783.3).

Example 4

Chlorohydrate N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R) -3- (3-pyridin-2-ylmethyl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxycyclopentyl) -2-hydroxyacetamide

A solution comprising N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenylethylamino) - trifluoroacetate purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide (example 1) (0.5 g, 0.87 mmol) and pyridin-3-yl-carbamic acid phenyl ester (product 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 + 707.65).

ES 2 384 337 T3

Example 5

Chlorohydrate N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenylethylamino) -2 - {(R) -3- [3- (3-sulfamoylphenyl) - ureido] -pyrrolidin-1-yl} -purin9-yl) -2,3-dihydroxycyclopentyl] -2-hydroxyacetamide

This compound is prepared analogously to Example 4 by replacing pyridin-3-ylcarbamic acid phenyl ester (intermediate ZB) with (3-sulfamoyl-phenyl) -carbamic acid phenyl ester (EP 365484). (MH + 707.65).

Example 6

Chlorohydrate N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenylethylamino) -2 - {(R) -3- [3- (4-sulfamoylphenyl) - ureido] -pyrrolidin-1-yl} -purin9-yl) -2,3-dihydroxycyclopentyl] -2-hydroxyacetamide

This compound is prepared analogously to Example 4 by replacing pyridin-3-ylcarbamic acid phenyl ester (intermediate ZB) with (4-sulfamoyl-phenyl) -carbamic acid phenyl ester (JP 2002 283758). (MH + 771.60).

Example 7

N - [(1S, 2R, 3S, 4R) -4- (6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -2 - {(R) -3- [3- (3 (hydroxybenzyl) ureido] pyrrolidin-1-yl} purin-9-yl) -2,3-dihydroxycyclopentyl] -2-hydroxyacetamide

Etapa 1:

A reaction mixture comprising (1S, 2R, 3S, 5R) -3- (Di-Boc-amino) -5- (2,6-dichloro-purin-9-yl) -cyclopentane-1,2diol (intermediate product J4) (3.00 g, 5.95 mmol) and 4,4 '- (2-amino-ethylidene) -bis-phenol (prepared according to the preparation of RMSchelkun et al. Bioorg. Med. Chem. Lett. 9 ( 1999) 2447-2452.) (1.5 g, 6.54 mmol) in dry THF (20 ml), treat with DIPEA (1.2 ml, 7.14 mmol), and stir at 50 ° C for the night. The solvent is removed in vacuo and the residue is partitioned between DMC and 2M HCl. The organic part is separated, dried (Mg SO4) and concentrated in vacuo to provide the title compound.

Etapa 2: (1S, 2R, 3S, 5R) -3-amino-5- {6- [2,2-bis- (4-hidroxi-phenyl) -ethylamino] -2-chloro-purin-9-yl} -cyclopentane-1,2-diol

A solution of Example 7, Step 1 (3.45 g, 5.80 mmol) in methanol (7 ml), is treated with 4M HCl in dioxane (3 ml), and the reaction mixture is stirred at room temperature for the night. The solvent is removed in vacuo, and the residue is partitioned between a saturated sodium bicarbonate solution and DMC. The organic part is separated, dried (MgSO4), and concentrated in vacuo to provide the title compound.

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

A mixture comprising (1S, 2R, 3S, 5R) -3-amino-5- {6- [2,2-bis- (4-hydroxy-phenyl) -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), treated with acetoxyacetyl chloride (0.499 g , 4.63 mmol) and TEA (0.78 g, 7.72 mmol), and stir 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 undissolved potassium carbonate, and then concentrated in vacuo. Purification of the residue by preparative HPLC eluting with acetonitrile: water: TFA (0.1%) (gradient from 5 to 100% acetonitrile) provides the title compound. (MH + 555.42).

Step 4: ((R) -1- {6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -9 - [(1R, 2S, 3R, 4S) acid tert-butyl ester hydrochloride ) -

2,3-Dihydroxy-4- (2-hydroxyacetylamino) cyclopentyl] -9H-purin-2-yl} pyrrolidin-3-yl) carbamic acid

ES 2 384 337 T3

A mixture comprising N - ((1S, 2R, 3S, 4R) -4- {6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -2 - [(R) -3 trifluoroacetate - (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (475 mg, 0.71 mmol), ester (R) -Pyrrolidin-3-yl-carbamic acid tert-butyl (0.529 g, 2.84 mmol), and sodium iodide (106 mg, 0.71 mmol) in acetonitrile (0.5 ml), heat using microwave radiation in a Personal Chemistry Emrys microwave reactorTM Optimizer at 160 ° C. The reaction is shown to be complete by LC-MS 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: Chlorohydrate 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-dihydroxycyclopentyl) -2-hydroxyacetamide

This compound is prepared 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 (step 2).

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

A solution comprising 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) -2-hydroxy-acetamide (15 mg, 0.02 mmol) and phenyl acid ester (3-hydroxy-benzyl) -carbamic (prepared according to McDonnell ME method et al Biioorganic and Medicinal Chemistry Letters 14 (2004) 531-534) (6 mg, 0.026 mmol) in MeOH (0.5 ml), treated with TEA (33 ml, 0.23 mmol), and then heated to 100 ° C for 30 minutes. Purification of the crude product by preparative HPLC eluting with acetonitrile: water: TFA (0.1%) (10-100% acetonitrile gradient) provides the title compound. (MH + 803.46).

Examples 8 to 10

Compounds, concretes, trifluoroacetate of N - [(1S, 2R, 3S, 4R) -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-dihydroxycyclopentyl] -2-hydroxy-acetamide (MH + 803.46) ( ejemplo 8), trifluoroacetate N - [(1S, 2R, 3S, 4R) -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-dihydroxycyclopentyl] -2-hydroxy-acetamide (MH + 803.45) (ejemplo) 9), and trifluoroacetate of 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) -2-hydroxy-acetamide (MH + 739.36) (example 10), prepare Analogously to Example 6, replacing (2-hydroxy-benzyl) -carbamic acid phenyl ester with the (2-sulfamoyl-benzyl) -carbamic acid phenyl ester, the (3-sulfamoyl-benzyl) -carbamic acid phenyl ester - carbamic, and the phenyl ester of pyridin-2-ylmethyl-carbamic acid, respectively. These phenyl esters of carbamic acid are prepared according to the method of McDonnell ME et al. Biioorganic and Medicinal Chemistry Letters 14 (2004) 531-534.

Example 11

Trifluoroacetate and methyl acetic acid ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R) -3- (3-pyridin-2-ylmethylureido)) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxycyclopentyl) carbamico

Step 1: Ester benzylic acid ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R) -3- (3-pyridin-2-ylmethyl) -ureido) pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxycyclopentyl) -carbamico

A solution of {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) acid benzyl ester purin-9-yl] -2,3-dihydroxy-cyclopentyl} -carbamic (intermediate 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 chloroformic acid phenyl ester (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%) (gradient from 0 to 100% acetonitrile) provides the product in acetonitrile which is subsequently washed with a saturated solution of sodium bicarbonate, and extracted with DMC (3 times). The combined organics are dried (MgSO4) and concentrated in vacuo to provide the title compound. (MH + 783.3).

Step 2: 1 - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -4-amino-2,3-dihydroxycyclopentyl) -6- (2,2-diphenylethylamino) -9H-purin-2-yl] -pyrrolidine

3-yl}-3-pyridin-2-ylmethyl-urea

ES 2 384 337 T3

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

Step 3: Trifluoroacetate and methyl acetic acid ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R) -3- (3-pyridin-2-ylmethyl) (ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxycyclopentyl) -carbamic acid

A solution of 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 (17 mg, 26 mmol) in THF (1 ml), treated with TEA (5 mg, 50 mmol) , followed by methyl chloroformiate (2.7 mg, 29 mmol). The reaction mixture is stirred at room temperature overnight, and purification of the crude product mixture by preparative LC-MS provides the title compound. (MH + 707.49).

Example 12

Ester tert-butylic acid [(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-dihydroxycyclopentyl] carbamic acid

Step 1: 9 - [(1R, 4S) -4- (tert-butoxy-carbonyl-propionylamino) -cyclopent-2-enyl] -6- (2,2-diphenylethylamino) -9H-purin-2 acid methyl ester -carboxylic:

This compound is prepared analogously to Di-Boc - [(1S, 4R) -4- (2,6-dichloro-purin-9-yl) -cyclopent-2-enyl] -amine (intermediate J3) replacing ditert-butyl imino-dicarboxylate with propionyl-carbamic acid tert-butyl ester.

Step 2: Methyl ester of 9 - [(1R, 2S, 3R, 4S) -4- (tert-butoxycarbonylpropionylamino) -2,3-dihydroxycyclopentyl] -6- (2,2-diphenylethylamino) ) -9H-purine-2-carboxylic acid

To a stirred suspension comprising 9 - [(1R, 4S) -4- (tert-butoxy-carbonylpropionylamino) -cyclopent-2-enyl] -6- (2,2-diphenyl-ethylamino) -9H acid methyl ester -purin-2-carboxylic acid (6.6 g, 10.82 mmol), methanesulfonamide (1.03 g, 10.82 mmol), and AD-mixture-a (16.23 g) in tert-butanol (40 ml) and water (40 ml), osmium tetroxide (3 ml of a 4% solution in water) is added. The reaction mixture is vigorously stirred for 36 hours. The reaction mixture is partitioned between ethyl acetate and water, and the organic part is dried (MgSO4) and concentrated in vacuo. The title product is precipitated from methanol. Additional product is derived from the mother liquor by chromatography on silica, eluting with DMC: methanol (25: 1).

Step 3: {(1S, 2R, 3S, 4R) -4- [2- (2-amino-ethyl-carbamoyl) -6- (2,2-diphenyl-ethylamino) -purin-9 acid tert-butyl ester -il] -

2,3-dihydroxycyclopentyl} carbamico

A solution comprising 9 - [(1R, 2S, 3R, 4S) -4- (tert-butoxycarbonyl-propionylamino) - acid methyl ester

2.3-dihydroxy-cyclopentyl] -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid (3.00 g, 4.66 mmol) in ethylene diamine (5 ml, 75 mmol), heat at 90 ° C for 1 hour. After cooling to room temperature, the ethylene diamine is removed in vacuo, and purification by C-18 reverse phase column chromatography eluting with water (100%), followed by MeOH (100%), provides the title compound. .

Step 4: Ester tert-butylic acid [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenylethylamino) -2- {2- [3- (3,4,5, 6-Tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -ureido] -ethyl-carbamoyl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -carbamico

To a suspension of the tert-butyl acid {(1S, 2R, 3S, 4R) -4- [2- (2-amino-ethyl-carbamoyl) -6- (2,2-diphenylethylamino) -purin-9- yl] -2,3-dihydroxy-cyclopentyl} -carbamic (2.5 g, 4.05 mmol) in isopropyl alcohol (10 ml), add the (3,4,5,6-tetrahydro-2H- [ Imidazole-1-carboxylic acid 1,2 '] bipyridinyl-4-yl) -amide (intermediate C) (151 ml of a 10 mg / ml solution in DMC, 5.56 mmol), and the reaction mixture stir at room temperature overnight. The solvent is removed in vacuo, and the crude product is purified by chromatography on silica, eluting with DMC / MeOH (25: 1 increasing to 15: 1). The resulting solid is further purified by dissolving in DmC and washing the solution with water, drying (MgS ° 4) and concentrating in vacuo to provide the title product. (MH + 820.7).

Example 13

Trifluoroacetate and methyl acetic acid [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenylethylamino) -2- {2- [3- (3,4,5,6-tetrahydro -2H- [1,2 '] Bipyridinyl-4-yl) -ureido] -ethyl-carbamoyl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -carbamico

ES 2 384 337 T3

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

The title compound is prepared 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), replacing hydrochloride of 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 the 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] -ethyl-carbamoyl} -purin-9-yl) -2,3-dihidroxi-cyclopentyl] -carbámico (ejemplo 12).

Step 2: [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenyl-ethylamino) -2- {2- [3- (3,4,5, 6tetrahydro-2H- [1,2 '] - bipyridinyl-4-yl) -ureido] -ethyl-carbamoyl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -carbamic

A mixture comprising the dihydrochloride of {2- [3- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -ureido] -ethyl} -amide of acid 9- ((1R, 2S, 3R, 4S) -4-amino-2,3-dihydroxy-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic (20 mg, 25 mmol) , and TEA (12.7 mg, 125 mmol) in THF (2 ml), treated with methyl chloroformiate (6.0 mg, 63 mmol) and left stirring at room temperature overnight. The solvent is removed in vacuo and purification of the crude product by reverse phase column chromatography (Isolute ™ C18, 0-100% acetonitrile in water 0.1% TFA) provides the title product. (MH + 778.6).

Example 14

Trifluoroacetato de {2- [3- (3,4,5,6-tetrahidro-2H- [1,2']-bipiridinil-4-il) -ureido] -etil} -amida del ácido 9-[(1R,, 2S, 3R, 4S)-

2,3-dihydroxy-4- (2-hydroxy-acetylamino) -cyclopentyl] -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid

Step 1: 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] -ethyl-carbamoyl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl-carbamoyl] -methyl acetic acid

This compound is prepared analogously to Example 13 by replacing methyl chloroformate with acetoxyacetyl chloride.

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

A solution of the 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] -ethyl-carbamoyl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl-carbamoyl] -methyl acetic acid (0.015 g, 16 mmol) in methanol (1 ml), treated with potassium carbonate (0.01 g, 10 mmol), and the reaction mixture was allowed to stir at room temperature for 1 hour. The solvent is removed in vacuo and purification of the crude product by reverse phase column chromatography (Isolute ™ C18, 0-100% acetonitrile in water - 0.1% TFA) provides the title product. (MH + 778.6).

Example 15

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

N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2 -hydroxy-acetamide (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 dimethylsulfoxide (0.2 ml), stir at 100 ° C for 2 hours. Purification of the resulting mixture by C-18 reverse phase column chromatography eluting with acetonitrile: water: TFA (0.1%) (gradient 20 to 70% acetonitrile) provides the product, which is treated with a saturated sodium bicarbonate solution, and passed through the C-18 reverse phase column again. The column is washed first with water, followed by MeoH (with 1% ammonia), to elute the product which is concentrated in vacuo to provide the title compound. (MH + 685.2).

Example 16

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

The title compound is prepared analogously to 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-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (example 15) replacing 1,3-di- (R) -pyrrolidin-3-yl-urea (intermediate B) with 1- (R) -pyrrolidin-3-yl-3- (3,4,5,6-tetrahydro-2H- [1,2 '] hydrochloride bipyridinyl-4-yl) -urea (intermediate A). (MH + 388.8).

ES 2 384 337 T3

Example 17

Trifluoroacetate with acid 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

Step 1: Trifluoroacetate N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R) -3 - ((R) -3-pyrrolidine -3-ylureido) pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxycyclopentyl) -propionamide

The title compound is prepared analogously to 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-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 with 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 1,3-di (R) -pyrrolidin-3-yl-urea (intermediate B).

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

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

Example 18

Trifluoroacetate N - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) - 9H-Pururin-2-yl] -pyrrolidin-3-yl} -6-morpholin-4-yl-nicotinamide

Step 1: Trifluoroacetate with tert-butyl acid {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2- Diphenylethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -carbamic:

A reaction mixture comprising N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl } -propionamide (intermediate J) (2.5 g, 4.80 mmol) and (3R) - (+) - (3-Boc-amino) -pyrrolidine (2.5 g, 13.6 mmol) in dimethylsulfoxide (8 ml), heat to 100 ° C overnight. The resulting mixture is purified by reverse phase column chromatography (Isolute ™ C18, 0-100% MeOH in water - 0.1% TFA) to provide the title product.

Etapa 2: N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin -9-yl] -2,3-dihidroxyyclopentyl} -propionamide

{(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) 6- (2,2-diphenyl) tert-butyl ester trifluoroacetate -ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -carbamic (3.22 g, 4.80 mmol) is dissolved in 1.25 M HCl in MeOH (60 ml, 75 mmol), and left stirring at room temperature overnight. The solvent is removed in vacuo and the crude product is dissolved in a minimum volume of EtOH / saturated sodium carbonate solution, and purified by reverse phase column chromatography (Isolute ™ C18, 0-100% MeOH in water ) to provide the title product.

Step 3: Trifluoroacetate N - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) -9H-Purin-2-yl] -pyrrolidin-3-yl} -6-morpholin-4-yl-nicotinamide

A solution of 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 (22.8 mg, 0.04 mmol) in THF (1 ml), treat with TEA (7.3 mg, 0.072 mmol), and then add to 6-morpholino-nicotinoyl chloride (8.2 mg, 0.036 mmol). The reaction mixture is stirred, and then allowed to stand at room temperature overnight. The solvent is removed in vacuo, and purification by C-18 reverse phase column chromatography eluting with acetonitrile: water: TFA (0.1%) (gradient 0-100% acetonitrile) provides the title compound. (MH + 761.4).

Example 19

Trifluoroacetate N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R) -3- (3-pyridin-2-ylmethyl-ureido) -pyrrolidin-1-yl] purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide

ES 2 384 337 T3

A 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 pmol) and sodium hydrogen carbonate (27 mg, 253 pm) in dimethylsulfoxide (300 µl), it is treated with phenyl chlorocarbonate (36 mg, 230 pmol), and then stirred at room temperature for 3 hours. This reaction mixture is added to the 2-picolyl-amine (4.1 mg, 38 pm) 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 0-100% acetonitrile) provides the title compound. (MH + 705.4).

Example 20

Trifluoroacetate N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R) -3- (3-pyridin-4-ylmethyl-ureido) -pyrrolidin-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-diphenylethylamino) -9H -purin-2-yl] pyrrolidin-3-yl} -amide of the acid imidazole-1-carboxylic acid:

A mixture comprising 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 (intermediate M) (0.24 g, 394 pm) and CDI (0.275 g, 1, 7 mmol) in dry DMC (6 ml), stir at room temperature for 3 hours. The resulting solution is purified by chromatography on silica, eluting with 100% DMC, changing to 5% MeOH in DMC, to provide the title compound as a yellow oil. The oil consists of the imidazole-urea intermediate, along with varying amounts of the corresponding isocyanate and imidazole, both of which are equally suitable as precursors for ureas.

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

Pyridyl-methylamine (4.3 mg, 40 pmol) is treated with a solution of {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl Imidazole-1-carboxylic acid) -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -amide (25 mg, 40 pmol) in DMC (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). After stirring at room temperature for 3 hours, the reaction mixture is concentrated in vacuo, and the resulting crude product is purified by LC-MS of mass directed preparation, eluting with acetonitrile: water: TFA, to provide the compound of the qualification. (MH + 705.4).

Example 21

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

This compound is prepared analogously to Example 20 by replacing 4-pyridylmethylamine with 3-hydroxybenzylamine. (MH + 720.4).

Example 22

Chlorohydrate N - {(R) -1- [6- [2,2-Bis- (4-hydroxyphenyl) ethylamino] -9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy -4-Propionylaminocyclopentyl) -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-hydroxy-phenyl) -ethylamino] -2-chloro-purin-9-yl hydrochloride } -2,3-dihydroxycyclopentyl) -propionamide

A reaction mixture comprising [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -2,3-dihydroxy-cyclopentyl] tert-butyl ester of propionyl acid- carbamic (intermediate G) (2.00 g, 4.35 mmol) and 4,4 '- (2-amino-ethylidene) -bisphenol (prepared by the procedure of RMSchelkun et al. Bioorg. Med. Chem. Lett. 9 (1999) 2447-2452.) (1.19 g, 5.20 mmol) in dry THF (40 ml), treat with DIPEA (0.67 g, 5.20 mmol), and stir at room temperature for 2 days. The solvent is removed in vacuo and the title compound is obtained after purification by reverse phase column chromatography (Isolute ™ C18, 20-70% acetonitrile in water-0.1% HCl).

Step 2: 2R, 3S, 4R) -4- {6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -2-chloro-purin-9-yl} -2,3-dihydroxy cyclopentyl) -propionamide

This compound is prepared analogously to (1S, 2R, 3S, 5R) -3-mino-5- {6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -2-chloro-purin-9 -yl} -cyclopentane-1,2-diol (example 7, step 2).

ES 2 384 337 T3

Step 3: Trifluoroacetate and tert-butyl acetate {(R) -1- [6- [2,2-Bis- (4-hydroxyphenyl) ethylamino] -9 ((1R, 2S, 3R, 4S)) -2,3-Dihydroxy-4-propionylamino-cyclopentyl) -9H-purin-2-yl] -pyrrolidin-3-yl} -carbamico

This compound is prepared analogously 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) -carbamic (example 7, step 4).

Step 4: 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

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

Step 5: N - {(R) -1- [6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -9 - ((1R, 2S, 3R, 4S) -2 hydrochloride 3-dihydroxy-4-propionylamino-cyclopentyl) -9H-purin-2-yl] -pyrrolidin-3-yl} -6-morpholin-4-yl-nicotinamide

A suspension of the N - ((1S, 2R, 3S, 4R) -4- {2 - ((R) -3-amino-pyrrolidin-1-yl) -6- [2,2-bis- (4- hydroxy-phenyl) -ethylamino] -purin-9yl} -2,3-dihydroxy-cyclopentyl) -propionamide (20 mg, 33 mmol) in dry THF, treated with NMP (0.5 ml), followed by TEA (13 , 4 mg, 0.13 mmol) and 6-morpholino-nicotinoyl 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 0-100% acetonitrile) provides the title compound. (MH + 793.4)

Example 23

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) -propionamide

Step 1: Ester phenylacid {(R) -1- [6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -9 - ((1R, 2S, 3R, 4S) -2, 3-Dihydroxy-4-propionylamino-cyclopentyl) -9H-purin-2-yl] -pyrrolidin-3-yl} -carbamico

A mixture comprising the 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) (50 mg, 83 mmol) and potassium carbonate (46 mg, 332 mm) in NMP (1 ml), treat with phenyl chloroformate, and stir at room temperature for 90 minutes. This mixture was used in the next step without further purification.

Step 2: N - ((1S, 2R, 3S, 4R) -4- {6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -2 - [(R) -3- hydrochloride (3-pyridin-2-ylmethyl-ureido) pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide

A mixture comprising {(R) -1- [6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -9 - ((1R, 2S, 3R, 4S) -

2,3-dihydroxy-4-propionylamino-cyclopentyl) -9H-purin-2-yl] -pyrrolidin-3-yl} -carbamic (12 mg, 16 mm) and 2- (amino-methyl) pyridine (5.4 mg, 50 mm) in NMP (0.5 ml), heat at 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 0-100% acetonitrile) provides the title compound. (MH + 737.5).

Example 24

Chlorohydrate 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] -propionamide

This compound is prepared analogously to 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) -propionamide (example 23) replacing 2- (amino- methyl) -pyridine with the appropriate amine. (MH + 752.5).

Example 25

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

A solution of the trifluoroacetate 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} -2-hydroxy-acetamide (0.2 g, 0.28 mmol) in dry THF (10 ml), treated with TEA

ES 2 384 337 T3 (113 mg, 1.12 mmol), followed by 3-isocyanato-pyridine (38 mg, 0.31 mmol). The reaction mixture is heated to 50 ° C overnight. The solvent is removed in vacuo, and purification by reverse phase column chromatography (Isolute ™ C18, 10 to 50% acetonitrile in water - 0.1% TFA) provides the product. The product is further purified by dissolving in MeOH and treating with a saturated sodium bicarbonate solution. The mixture is passed through a pre-wash (400 ml of MeOH followed by 400 ml of water) eluting with 0.5% ammonia 880: water (100 ml), followed by water (400 ml), and finally MeOH , to provide the title compound. (MH + 693.4).

Example 26

Chlorohydrate and methyl acetic acid ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R) -3- (3-pyridin-3-yl) ureido) pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxycyclopentyl) carbamico

Step 1: Trifluoroacetate with benzylic acid ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R) -3- (3-pyridin-3-yl) (ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxycyclopentyl) -carbamico

A solution comprising {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) acid benzyl ester -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -carbamic (intermediate L) (0.1 g, 0.15 mmol), pyridine 3-isocyanate (0.02 g, 0.17 mmol), and TEA (0.017g, 0.17mmol) in THF (2ml), stirred at 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). The fractions are collected and the MeCN is removed in vacuo. The remaining aqueous part is made basic with a saturated sodium bicarbonate solution, and extracted with DMC. The combined organic extracts are dried (MgSO4) and concentrated in vacuo to provide the title product. MS (ES +) m / e 769 (MH+).

Etapa 2: 1 - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -4-amino-2,3-dihidroxi-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pirrolidin3-yl} -3-pyridine-3-yl-urea

To a solution of benzyl acid ester trifluoroacetate ((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) -carbamic (step 1) (35 mg, 46 mmol) in ethanol (1 ml) under an atmosphere inert argon, 10% palladium on carbon (10 mg) is added. The reaction mixture is purged with argon, and placed under a positive hydrogen atmosphere overnight, after which time the mixture is filtered through Celite and the catalyst is washed with ethanol. The organic parts are combined and concentrated in vacuo to provide the title compound. MS (ES +) m / e 635 (MH +).

Step 3: Methyl chloride hydrochloride ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R) -3- (3-pyridin-3 -ylureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxycyclopentyl) -carbamico

This compound is prepared analogously to Example 11 by replacing 1 - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -4-amino-

2,3-Dihydroxy-cyclopentyl) -6- (2,2-diphenylethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -3-pyridin-2-ylmethyl-urea con la 1- {(R) -1- [9 - ((1R, 2S, 3R, 4S) -4-amino-2,3-dihydroxycyclopentyl) -6- (2,2-diphenylethylamino) -9H-purin-2 -yl] -pyrrolidin-3-yl} -3-pyridin-3-ylurea. (MH + 693.5).

Example 27

N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (3-sulfamoyl-phenyl) - hydrochloride ureido] -pyrrolidin-1-yl} -purin9-yl) -2,3-dihydroxy-cyclopentyl] -propionamide

A suspension of the 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, 0.035 mmol) and 3-isocyanato-benzenesulfonamide (intermediate S) (17.7 mg, 0.095 mmol) in THF (1 ml) and DMF (1 ml), stir at room temperature overnight. The solvent is removed in vacuo and purification by reverse phase column chromatography (Isolute ™ C18, 0-100% acetonitrile in water - 0.1% HCl) provides the title compound. (MH + 769.5)

Example 28

N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (4-sulfamoyl-phenyl) - hydrochloride ureido] -pyrrolidin-1-yl} -purin9-yl) -2,3-dihydroxy-cyclopentyl] -propionamide

This compound is prepared analogously to Example 27 with the appropriate isocyanate. (MH + 769.5).

Example 29

ES 2 384 337 T3

1 - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -4-amino-2,3-dihydroxycyclopentyl) -6- (2,2-diphenylethylamino) -9H- Purin-2-yl] -pyrrolidin-3-yl} -3-pyridin-2-ylmethyl-urea

Step 1: Ester benzylic acid ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R) -3- (3-pyridin-2-ylmethyl) -ureido) pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxycyclopentyl) -carbamic.

A solution of {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) acid benzyl ester purin-9-yl] -2,3-dihydroxy-cyclopentyl} -carbamic (intermediate 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 chloroformic acid phenyl ester (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%) (gradient from 0 to 100% acetonitrile) provides the product in acetonitrile which is subsequently washed with a saturated solution of sodium bicarbonate, and extracted with DMC (3 times). The combined organics are dried (MgSO4) and concentrated in vacuo to provide the title compound. (MH + 783.3).

Step 2: 1 - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -4-amino-2,3-dihydroxycyclopentyl) -6- (2,2-diphenylethylamino) -9H-Purin-2-yl] -pyrrolidin-3-yl} -3-pyridin-2-ylmethyl-urea

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

Examples 30-32

The compound, concretament, trifluoroacetate N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R) -3- (3-pyridin-2 -ylmethyl-ureido) -pyrrolidin-1-yl] purin-9-yl} -2,3-dihydroxycyclopentyl) -acetamide (MH + 691.5) (ex 30), trifluoroacetate de (1S, 2R, 3S, 4R) -4- {6- (2,2-Diphenylethylamino) -2 - [(R) -3- (3-pyridin-2-ylmethyl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxycyclopentyl) amide to acyclopropanocarboxylic acid (MH + 717.5) (see 31), and ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridin-2-ylmethyl-ureido) - trifluoroacetate pyrrolidin-1-yl] -purin-9yl} -2,3-dihydroxy-cyclopentyl) -amide of cyclobutanecarboxylic acid (MH + 731.5) (example 32), they are prepared in a similar way to (example 11), replacing chloroformate of methyl with the appropriate acid chloride.

Example 33

N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R) -3- (N'-cyano-N '' - pyridin-3 -ylmethyl-guanidino) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide

Step 1: Ethylamide del acid (1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R) -3- (3-cyano-2-phenyl-isoureido) ) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxycyclopentanocarboxylic acid

A solution of the 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) (50 mg) and diphenyl cyanocarbodiimidate (21 mg) in dry DMC (2 ml), treated with TEA (13 ml) , and then stirred at room temperature for 5 hours. The solvent is removed in vacuo and the resulting residue is partitioned between EtOAc and water. The organic part is separated, dried (Na2SO2) and concentrated in vacuo to provide the crude product which is purified by preparative HPLC to provide the title compound. (MH + 715).

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

A mixture comprising 1S, 2R, 3S, 4R acid ethylamide) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-cyano-2-phenylisoureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentanecarboxylic (80 mg, 0.11 mmol) and 2- (amino-methyl) -pyridine (35 ml, 0.33 mmol) in absolute ethanol (1 ml), work up using microwave radiation in a Personal Chemistry Emrys ™ Optimizer microwave reactor at 100 ° C for 2500 seconds, followed by 120 ° C for 1

ES 2 384 337 T3 hour. The solvent is removed in vacuo, and purification by preparative HPLC is carried out. The fractions are combined, treated with a saturated sodium bicarbonate solution, and then extracted with ethyl acetate (3 times). The organic parts are dried (Na2SO4) and concentrated in vacuo to provide the title compound. (MH + 729).

Example 34

Ester methyl acid ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R) -3 - ((R) -3-pyrrolidin-3- ylureido) -pyrrolidin-1-yl] purin-9-yl} -2,3-dihydroxycyclopentyl) carbamico

This compound is prepared analogously to {(R) -1- [9 ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6 tert-butyl ester trifluoroacetate - (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} carbamic (example 18, step 1), replacing - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (intermediate J) with {(1S, 2R, 3S, 4R) -4- [2-chloro6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl acid methyl ester } -carbamic (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) -pyrrolidine-1 hydrochloride -yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide

This compound is prepared analogously to Example 27 by replacing 3-isocyanate-benzenesulfonamide (intermediate S) with phenyl isocyanate. (MH + 690.9)

Example 36

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

This compound is prepared analogously to Example 17, replacing terephthaloyl chloride with methyl-4-chlorocarbonyl benzoate. Purification is carried out by C-18 reverse phase column chromatography eluting with acetonitrile: water: HCl (0.1%) (gradient 20 to 100% acetonitrile), to provide the title compound. (MH + 845.58).

Example 37

Trifluoroacetate N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R) -3- (3-pyridin-3-ylmethyl-ureido) -pyrrolidin-1-yl] purin-9-yl} -2,3-dihydroxycyclopentyl) -propionamide

A suspension of the 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 mm) and sodium hydrogen carbonate (4.5 mg, 42 mm) in dimethylsulfoxide (300 ml), were Treat with phenyl chloroformate (36 mg, 230 mmol), and then stir at room temperature for 3 hours. This reaction mixture is added to the 3-picolyl-amine (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 0-100% acetonitrile) provides the title compound. (MH + 705.4).

Example 38

Trifluoroacetate and benzylic acid ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R) -3- (3-pyridin-3-yl) ureido) pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxycyclopentyl) carbamico

A solution comprising {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) acid benzyl ester -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -carbamic (intermediate L) (0.1 g, 0.15 mmol), pyridine 3-isocyanate (0.02 g, 0.17 mmol), and TEA (0.017g, 0.17mmol) in THF (2ml), stirred at 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). The fractions are collected and the MeC is removed in vacuo. The remaining aqueous part is made basic with a saturated sodium bicarbonate solution, and extracted with DMC. The combined organic extracts are dried (MgS ° 4) and concentrated in vacuo to provide the title product. (MH + 769.5).

Example 39

ES 2 384 337 T3

Trifluoroacetate N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenylethylamino) -2 - {(R) -3- [3- (3-hydroxyphenyl) - ureido] -pyrrolidin-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-diphenylethylamino) -9H -purin-2-yl] pyrrolidin-3-yl} -amide of the acid imidazole-1-carboxylic acid:

A mixture comprising N - {(3aR, 4S, 6R, 6aS) -6- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9yl] -2,2-dimethyl-tetrahydro-cyclopenta [1,3] -dioxol-4-yl} -propionamide (intermediate M) (0.24 g, 394 mmol) and CDI (0.275 g, 1 , 7 mmol) in dry DMC (6 ml), stir at room temperature for 3 hours. The resulting solution is purified by chromatography on silica, eluting with 100% DMC, changing to 5% MeoH in DMC, to provide the title compound as a yellow oil. The oil consists of the imidazole-urea intermediate together with varying amounts of the corresponding isocyanate and imidazole, both of which are equally suitable as precursors for ureas.

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

The 3-aminophenol (4.3 mg, 40 mmol) is treated with a solution of the {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl Imidazole-1-carboxylic acid) -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -amide (25 mg, 40 mmol) in DMC (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). After stirring at room temperature for 3 hours, the reaction mixture is concentrated in vacuo, and the resulting crude product is purified by LC-MS of mass directed preparation, eluting with acetonitrile: water: TFA to provide the title compound. . (MH + 706.4).

Example 40

Trifluoroacetate N - {(1S, 2R, 3S, 4R) -4- [2 - [(R) -3- (4-acetylamino-benzenesulfonylamino) -pyrrolidin-1-yl] -6- (2 (2-Diphenylethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide

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) (23 mg, 40 mmol) is treated with a solution of 4-acetamido-benzenesulfonyl chloride (9.5 mg, 0.039 mmol) in NMP (0.5 ml), and stir at room temperature overnight. Purification by preparative LC-MS provides the title compound. (MH + 768.50).

Example 41

N - {(1S, 2R, 3S, 4R) -4- [2 - [(R) -3- (4,5-Dihidro-1H-imidazol-2-yl-amino) -pirrolidin-1-yl] - 6- (2,2-diphenyl-ethylamino) -purin-9-yl] -

2,3-dihydroxy-cyclopentyl} -propionamide

One method includes N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-il] -

2,3-dihydroxy-cyclopentyl} -propionamide (Example 18, step 2) (30 mg, 0.053 mmol) and 4,5-dihydro-1Himidazole-2-thiolhydroiodide (24 mg, 0.106 mmol) in absolute ethanol (2 ml), treated with 4-dimethylaminopyridine (catalytic amount) and TEA (29 ml, 0.212 mmol). The resulting mixture is heated using microwave radiation in a Personal Chemistry Emrys ™ optimizer microwave reactor at 150 ° C for 4000 seconds. The solvent is removed in vacuo and purification of the crude product by preparative HPLC (30 to 95% acetonitrile in water - 0.1% TFA) provides the title compound. (MH + 639.63).

Example 42

N - {(1S, 2R, 3S, 4R) -4- [2- {N '- [1-cyclohexyl-methylidene] -hydrazino} -6- (2,2-diphenyl-ethylamino) -purin-9-yl ] -2,3-dihydroxycyclopentyl} -propionamide

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

N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-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 residue is water (10 ml), and it is stirred for 12 hours. The fine solid obtained is filtered, washed with water, and dried under vacuum to provide the product. LC-MS (0.1% formic acid, acetonitrile) (MH+ 517).

Step 2: N - {(1S, 2R, 3S, 4R) -4- [2- {N '- [1-cyclohexyl-methylidene] -hydrazino} -6- (2,2-diphenyl-ethylamino) -purine 9-yl] -2,3-dihydroxycyclopentyl} -propionamide

ES 2 384 337 T3

To a solution of N- {4- [6- (2,2-diphenyl-ethylamino) -2-hydrazino-purin-9-yl] -2,3-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 refluxed for 12 hours. The reaction mixture is concentrated in vacuo, and purification by preparative thin-layer chromatography provides the title compound. LCMS (0.1% formic acid, acetonitrile): (MH + 611.45).

Example 43

1 - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihidroxi-4-propyl-amino-cyclopentyl) -6- (2,2-diphenyl-ethylamino hydrochloride ) -9H-purin-2yl] -pirrolidin-3-yl} -3-pyridine-3-yl-urea

A solution of 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 (example 26, step 2) (17 mg, 26 mmol) in dichloroethane (1 ml), it is treated with propanaldehyde (1.5 mg, 26 mmol), and placed under an argon atmosphere. Sodium triacetoxy borohydride (10 mg, 51 pmol) is added, and the reaction mixture is stirred at room temperature overnight. The mixture is quenched with 2M NaOH (5 drops), and the solvent is removed in vacuo. The residue is purified by C-18 reverse phase column chromatography eluting with acetonitrile: water: HCl (0.1%) (gradient 20 to 100% acetonitrile) to provide the title compound. (MH + 677.14).

Example 44

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

This compound is prepared analogously to Example 42, replacing N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2 , 3-dihydroxy-cyclopentyl} -propionamide (intermediate J) with the trifluoroacetate of N - [(1S, 2R, 3S, 4R) -4- (6-amino-2-chloro-purin-9-yl) -2 , 3-dihydroxy-cyclopentyl] -propionamide (intermediate ZA). (MH + 431.33).

Example 45

Chlorohydrate of pyridin-3-yl amide delacido (R) -3- (3 - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl ) -6- (2,2-Diphenylethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -ureido) -pyrrolidine-1-carboxylic acid

This compound is prepared analogously to Example 23, replacing {(R) -1- [6- [2,2bis- (4-hydroxy-phenyl) -ethylamino] -9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -9H-purin-2-yl] -pyrrolidin-3yl} -carbamic with the trifluoroacetate of 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-dihydroxy-cyclopentyl) -propionamide (example 17, step 1), and replacing (amino-methyl) -pyridine with pyridin-3-yl-carbamic acid phenyl ester (intermediate ZB). (MH + 803.8).

Examples 46-47

These compounds, specifically, acid {2- [3- (3,4,5,6-tetrahydro-2H- [1,2 '] - bipyridinyl-4-yl) -ureido] -ethyl} -amide trifluoroacetate - [(1R, 2S, 3R, 4S) -4 (3,3-dimethyl-ureido) -2,3-dihydroxy-cyclopentyl] -6- (2,2-diphenyl-ethylamino) -9H-purin-2- carboxylic (MH + 791.6) (example 46), and trifluoroacetate ester [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenyl-ethylamino) -2- {2- [3- (3,4,5,6-tetrahydro-2H Acetic acid - [1,2 '] - bipyridinyl-4-yl) -ureido] -ethyl-carbamoyl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl-carbamoyl] -methyl acetic acid (Example 47) are prepared from Analogously to Example 13, replacing methyl chloroformate with either dimethylcarbamyl chloride or acetoxyacetyl chloride, respectively.

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

Step 1: 6- (2,2-Diphenyl-ethylamino) -9H-purine-2-carboxylic acid methyl ester

6- (2,2-Diphenyl-ethylamino) -9H-purine-2-carboxylic acid methyl ester hydrochloride (prepared using the procedure described in international 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 refluxed for 1 hour. The reaction mixture is allowed to cool, and any volatiles are removed in vacuo. MeOH (300 ml) is added to the resulting oil. The resulting white solid is filtered and

ES 2 384 337 T3 washes with MeOH (200 ml, 2 times), and then dried in a vacuum oven, to give the title compound. 1H-RMN (DMSO, 400 MHz).

Step 2: 6- (2,2-Diphenyl-ethylamino) -9 - ((1R, 4S) -4-hydroxy-cyclopent-2-enyl) -9H-purine-2-carboxylic acid methyl ester

To the 6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid methyl ester (5 g, 13.4 mmol) under an argon atmosphere, add dry deoxygenated THF (100 ml) and dry dimethylsulfoxide (2 ml). Then 95% sodium hydride (0.32 g, 13.4 mmol) is added, and the solution is stirred at 40 ° C. Separately, al (1S, 4R) -cis-4-acetoxy-2-cyclopenten-1-ol (1.89 g, 13.4 mmol), triphenylphosphine (0.53 g, 2.0 mmol), and tris- ( dibenzylidene-acetone) -dipalladium (0) (0.69 g, 0.67 mmol), dry deoxygenated THF (20 ml) is added, and the mixture is stirred at room temperature for 10 minutes. This solution is added to the anion solution by means of a syringe, and the resulting mixture is then stirred at 80 ° C. The reaction is shown to be complete by LC-MS after 2 hours. The reaction mixture is allowed to cool, methanol is added, and the solid is filtered. The filtrate is concentrated in vacuo and the title compound is obtained by precipitation from DMC / hexane.1H-RMN (MeOD, 400 MHz); 8,15(s, 1H), 7,407,15(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-Diphenyl-ethylamino) -9 - ((1R, 4S) -4-ethoxy-carbonyloxy-cyclopent-2-enyl) -9H-purine-2-carboxylic acid methyl ester

6- (2,2-Diphenyl-ethylamino) -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 THF (30 ml) is added, followed by dry pyridine (0.97 g, 12.3 mmol). Ethyl chloroformate (2.66 g, 24.6 mmol) is added slowly, and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 3 hours. The solvent is removed in vacuo, and the residue is partitioned between DMC (200 ml) and 1 M HCl (200 ml, 2 times). The organic phase is washed with water (100 ml, 2 times) and brine (100 ml, 2 times), dried over MgS ° 4, filtered, and the solvent is removed in vacuo. The title compound is obtained after purification by flash column chromatography (silica, 4% MeOH in DMC). MS (ES +) m / e 528.3 (MH+).

Step 4: 9 - ((1R, 4S) -4-di-tert-butoxy-carbonyl-amino-cyclopent-2-enyl) -6- (2,2-diphenyl-ethylamino) 9H-purin- methyl ester 2-carboxylic

6- (2,2-Diphenyl-ethylamino) -9 - ((1R, 4S) -4-ethoxycarbonyloxy-cyclopent-2-enyl) -9H-purine-2-carboxylic acid methyl ester (2.2 g, 4, 2 mmol) is dissolved in deoxygenated THF. The resulting solution is stirred under an argon atmosphere, at room temperature. Di-tert-butyl imino-dicarboxylate (0.9 g, 4.2 mmol), triphenylphosphine (0.16 g, 0.63 mmol), and TEA (0.42 g, 4.2 mmol) are added, followed by tris- (dibenzylidene acetone) -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 resulting oil is purified by column chromatography (silica, 80% ether in hexane) to provide the title compound, MS (ES +) m / e 536.4 (MH+).

Step 5: Methyl ester 9 - ((1R, 2S, 3R, 4S) -4-di-tert-butoxycarbonylamino-2,3-dihydroxycyclopentyl) -6- (2,2-diphenylethylamino) -9H-purine-2-carboxylic acid

The title compound is prepared from 9 - ((1R, 4S) -4-di-tert-butoxy-carbonyl-aminocyclopent-2-enyl) -6- (2,2-diphenyl-ethylamino) acid methyl ester -9H-purine-2-carboxylic, using a procedure analogous to that of (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). MS (ES +) m / e 689.4 (MH+).

Step 6: 9 - ((1R, 2S, 3R, 4S) -4-amino-2,3-dihydroxy-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9Hpurine-2-carboxylic acid methyl ester

9 - ((1R, 2S, 3R, 4S) -4-di-tert-butoxy-carbonyl-amino-2,3-dihydroxy-cyclopentyl) -6- (2,2-diphenylethylamino) -9H methyl ester -purin-2-carboxylic (0.5 g, 0.73 mmol) is dissolved in dioxane and stirred under an argon atmosphere. 4M 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 by 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-purin-2- acid methyl ester carboxylic

9 - ((1R, 2S, 3R, 4S) -, 4-amino-2,3-dihydroxy-cyclopentyl) -6- (2,2-diphenyl-ethylamino) 9H-purin-2 acid methyl ester hydrochloride -carboxylic (200 mg, 0.36 mmol) is dissolved in THF (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 mixture

ES 2 384 337 T3 reaction is stirred at room temperature for 1 hour. The reaction is quenched with methanol, and the title compound is obtained by flash column chromatography (IsoluteTM C18, from 0 to 100% acetonitrile in water). MS (ES +) m / e 545.3 (MH)+).

Step 8: (2-amino-ethyl) -amide 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) - 9H-purine-2-carboxylic

9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9Hpurin-2-carboxylic acid methyl ester (62 mg, 1.0 mmol) is dissolved in ethylene diamine (3.4 ml, 51 mmol), and the solution is stirred at 105 ° C. The reaction is shown to be complete by LCMS 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: (2-methanesulfonyl-amino-ethyl) -amide of acid 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6 (2,2- diphenyl-ethylamino) -9H-purine-2-carboxylic

A solution of 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6 (2,2-diphenyl-ethylamino) acid (2-amino-ethyl) -amide ) -9H-purine-2-carboxylic acid (0.01 g, 0.017 mmol) in chloroform (1 ml) is treated with mesyl chloride (1 ml of a 3 mg / ml solution in chloroform) and TEA (0.003 ml) . After stirring at 5 ° C for 1 hour, the reaction mixture is diluted with DMC and extracted with 1M HCl. The organic part is isolated and concentrated in vacuo to provide the title product. (MH+ 651.5).

Examples 49-55

These compounds, {2- [3- (3-methoxy-phenyl) -ureido] -ethyl} -amide 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl trifluoroacetate ) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic (MH + 722.4) (example 49), {2- [3- (3-cyano-phenyl) -ureido] trifluoroacetate) 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid -ethyl} -amide (MH + 717.5) (Example 50), [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] -acetic (MH + 702.5 ) (Example 51), 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl acid [2- (3-ethyl-ureido) -ethyl] -amide trifluoroacetate) 6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic (MH + 644.5) (example 52), 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6 acid {2- [3- (4-methoxy-phenyl) -ureido] -ethyl} -amide trifluoroacetate - (2,2-Diphenyl-ethylamino) -9H-purine-2-carboxylic (MH + 722.5) (Example 53), {2- [3- (4-cyano-phenyl) -ureido] -ethyl} trifluoroacetate -9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid amide (MH + 717 , 5) (example 54), and 4- [3- (2 - {[9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6 (2,2-diphenyl) acid methyl ester trifluoroacetate -ethylamino) -9H-purine-2-carbonyl] -amino} -ethyl) -ureido] -benzoic (MH + 750.4) (example 55), are prepared analogously to example 48, replacing mesyl chloride (step 9 ) with the appropriate isocyanate.

Example 56

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

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) (0.023 g, 40 mmol) is treated with a solution of 4-phenoxyphenyl isocyanate (0.0078 g, 39 mmol) in NMP ( 0.5 ml). After stirring at room temperature overnight, purification is carried out using mass directed prep LC-MS eluting with acetonitrile: water: TFA to provide the title compound. (MH+ 782.5).

Examples 57-90

ES 2 384 337 T3

Compounds, concretes, trifluoroacetate N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenylethylamino) -2 - {(R) -3- [3- (2- Phenoxy-phenyl) -ureido] -pyrrolidin-1-yl} purin-9-yl) -2,3-dihydroxycyclopentyl] -propionamide (MH + 782.5) (Example 57), trifluoroacetate N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-Diphenylethylamino) -2 - [(R) -3- (4-trifluoromethylbenzenesulfonylamino) pyrrolidin-1-yl] purine -9-yl} -2,3-dihydroxycyclopentyl) propionamide (MH + 779.4) (ejemplo 58), trifluoroacetate N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenylethylamino) -2 - {(R) -3- [3- (3,4,5-trimethoxy) -phenyl) -ureido] -pyrrolidin-1-yl} -purin-9-yl) -2,3-dihydroxycyclopentyl] -propionamide (MH + 780.5) (ejemplo 59), trifluoroacetate N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-Diphenylethylamino) -2 - [(R) -3 - ((E) -2-phenylethenesulfonylamino) pyrrolidin-1-yl] purine-9- yl} -2,3-dihydroxycyclopentyl) -propionamide (MH + 737.5) (ejemplo 60), trifluoroacetate and ethyl acetate (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) -acetic (MH + 700.5) (Example 61), trifluoroacetate de {(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 to the acid cyclopropanocarboxylic acid (MH + 639.5) (e 62), trifluoroacetate N - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) - 9H-purin-2-yl] -pyrrolidin-3-yl} -propionamide (MH + 627.5) (ejemplo 63), trifluoroacetate N - {(1S, 2R, 3S, 4R) -4- [2 - [(R) -3- (3,3-Dimethyl-ureido) -pyrrolidin-1-yl] -6- (2,2-diphenylethylamino) -purin-9-yl] -

2,3-dihydroxycyclopentyl} -propionamide (MH + 642.5) (ejemplo 64), trifluoroacetate N - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy- 4-Propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -benzamide (MH + 689.5) (ejemplo 65), trifluoroacetate de N- ( (1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R) -3- (3-isopropyl-ureido) -pyrrolidin-1-yl] -purine -9-il} -

2.3- dihydroxy-cyclopentyl) -propionamide (MH + 656.5) (example 66),

Trifluoroacetate N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R) -3- (3-ethylureido) pyrrolidine-1 -yl] -purin-9-yl} -2,3-dihydroxycyclopentyl) -propionamide (MH + 642.5) (e.g. 67), trifluoroacetate and benzylic acid {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -carbamico (MH + 705.3) (ejemplo 68), and trifluoroacetate N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenylethylamino) -2 - {(R) -3- [3- (4-hydroxyphenyl) -ureido] -pyrrolidin-1-yl} purin-9-yl) -2,3-dihydroxycyclopentyl] -propionamide (MH + 745.6) (ex 69), trifluoroacetate N - {(1S, 2R, 3S, 4R) -4- [2 - {(R) -3- [3- (2,3-Dihydro-benzo [1,4] dioxin-6-yl) -ureido] -pyrrolidin-1-yl} -6- (2,2-Diphenylethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -propionamide (MH + 748.5) (ex 70), trifluoroacetate de {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) -9H-purine 2-yl] -pyrrolidin-3-yl} -amide to the acid benzo- [1,2,5] -thiadiazole-5-carboxylic acid (MH + 733.4) (ejemplo 71), trifluoroacetate de {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) -9H-purin-2-yl] -pyrrolidin-3- il} -amide of the quinoxaline-6-carboxylic acid (MH + 727.5) (ejemplo 72), trifluoroacetate of N - {(1S, 2R, 3S, 4R) -4- [2 - {(R) -3- [3- (3,4-dihydro-2H-benzo [b] [1,4] dioxepine) 7-yl) -ureido] -pyrrolidin-1-yl} -6- (2,2-diphenylethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -propionamide (MH + 762.5) ( (73), trifluoroacetate N - {(1S, 2R, 3S, 4R) -4- [2 - {(R) -3- [3- (4-cyano-phenyl) -ureido] -pyrrolidin-1-yl } -6- (2,2-diphenylethylamino) purin-9-yl] -2,3-dihydroxycyclopentyl} propionamide (MH + 715.5) (ex 74), {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9Hpurin- trifluoroacetate 4- (4-Chloro-benzenesulfonyl) -3-methyl-thiophene-2-carboxylic acid 2-yl] -pyrrolidin-3-yl} -amide (MH + 870.5) (example 75), {trifluoroacetate (R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9Hpurin-2-yl 3-Chloro-4- (Propan-2-sulfonyl) -thiophene-2-carboxylic acid] -pyrrolidin-3-yl} -amide (MH + 821.4) (example 76),

ES 2 384 337 T3 trifluoroacetate of N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (4- trifluoro-methoxy-phenyl) -ureido] -pyrrolidine-

1-yl} -purin-9-yl) -2,3-dihydroxycyclopentyl] -propionamide (MH + 774.4) (ejemplo 77), trifluoroacetate of N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-Diphenylethylamino) -2 - {(R) -3- [3- (3-methylsulfanyl-phenyl) -ureido] -pyrrolidin-1-yl} -purin-9-yl) - 2,3-dihydroxycyclopentyl] -propionamide (MH + 736.4) (ejemplo 78), trifluoroacetate N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenylethylamino) 2 - {(R) -3- [3- (4-Methylsulfanyl-phenyl) -ureido] -pyrrolidin-1-yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -propionamide (MH + 736.4) (ejemplo 79), trifluoroacetate de {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) -9H-purine 2-yl] -pyrrolidin-3-yl} -amide of the acid quinoxaline-2-carboxylic acid (MH + 727.5) (ejemplo 80), trifluoroacetate de {(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 del acid benzo [1 , 2,5] -thiadiazole-4-carboxylic acid (MH + 733.4) (ejemplo 81), trifluoroacetate methyl diacid 5- (3 - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) 6- (2,2 -diphenylethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -ureido) -isophthalic (MH + 806.5) (ejemplo 82), trifluoroacetate N - [(1S, 2R, 3S, 4R) ) -4- (6- (2,2-diphenylethylamino) -2 - {(R) -3- [2- (1H-indol-3-yl) -2-oxoacetylamino] pyrrolidin-1-yl } -purin-9-yl) -2,3-dihydroxycyclopentyl] -propionamide (MH + 742.5) (ejemplo 83), trifluoroacetate de {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) -9H-purine 2-yl] -pyrrolidin-3-yl} -amide to the acid pyridine-2-carboxylic acid (MH + 676.5) (ejemplo 84), trifluoroacetate de {(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 to the acid 1- (4 (methoxyphenyl) -5-methyl-1H-pyrazole-4-carboxylic acid (MH + 785.5) (ejemplo 85), trifluoroacetate and benzylic acid 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-ylcarbamoyl} -piperidine-1-carboxylic acid (MH + 816.6) (ejemplo 86), trifluoroacetate N - {(R) -1- [ 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl } -4-dipropylsulfamoyl-benzamide (MH + 838.4) (ejemplo 87), trifluoroacetate de {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) -9H-purine 2-yl] -pyrrolidin-3-yl} -amide to the acid 1- (4-trifluoromethyl-pyrimidin-2-yl) -piperidine-4-carboxylic acid (MH + 828.4) (Example 88), trifluoroacetate of N- { (R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) -9H-purin-2-yl ] -pyrrolidin-3-yl} -nicotinamide (MH + 676.4) (ejemplo 89), N - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) - trifluoroacetate 9Hpurin-2-yl] -pyrrolidin-3-yl} -isonicotinamide (MH + 676.3) (example 90), are prepared analogously to the trifluoroacetate of N - [(1S, 2R, 3S, 4R) -4- ( 6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (4-phenoxy-phenyl) -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. Reactions using acid chlorides also have excess TEA added.

Examples 91-92

These compounds, specifically, N - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (1-ethyl- propyl-amino) -9H-purin-

2- yl] -pyrrolidin-3-yl} -isonicotinamide (MH 566.4+) (example 91), and N - {(R) -1- [9 - ((1R, 2S, 3R, 4S) hydrochloride -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (3,3-dimethyl-butyl-amino) -9Hpurin-2-yl] -pyrrolidin-3-yl} -isonicotinamide (MH + 580.5) ( Example 92), are prepared 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 1, step 2), replacing (3R) -

3- aminopyrrolidine with (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 the appropriate starting compound. The preparation of the starting compounds is described herein or they may

ES 2 384 337 T3 prepared from tert-butyl acid [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -2,3-dihydroxy-cyclopentyl] propionyl-carbamic (intermediate G) and the appropriate amine, using a procedure analogous to that of 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-propionylamino-cyclopentyl) -6- (1-ethyl-propyl-amino) -9H- hydrochloride 5-Methyl-isoxazole-3-carboxylic acid purin-2yl] -pyrrolidin-3-yl} -amide

This compound is prepared in a manner analogous to 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-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-hydroxy-acetamide (intermediate Q) with N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (1-ethyl-propyl-amino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} propionamide [ prepared to starting from [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -2,3-dihydroxy-cyclopentyl] -propionyl-carbamic acid tert-butyl ester (intermediate G) and the appropriate amine, using a procedure analogous to that of (2R, 3S, 4R) -4- {6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -2-chloro-purin-9 -il} -2,3-dihydroxy-cyclopentyl) propionamide (example 22, steps 1 and 2), and replacing 1,3-di- (R) -pyrrolidin-3-yl-urea (intermediate B) with the (R) -pyrrolidin-3-yl-amide of 5-methyl-isoxazole-3-carboxylic acid (product intermediate P). (MH + 570.4).

Example 94

{(1S, 2R, 3S, 4R) trifluoroacetate -4- [2 - ((R) -1-bencil-pyrrolidin-3-yl-amino) -6- (2,2-diphenyl-ethylamino) -purin- 9-il] -2,3 dihidroxi-cyclopentyl} -amide of the cyclobutanocarboxílico acid

This compound is prepared in a manner analogous to N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidine- trifluoroacetate).

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] -2,3-dihydroxy-cyclopentyl} acetamide with acid {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -amide cyclobutanecarboxylic (intermediate K), and replacing (3R) -3-aminopyrrolidine with the (R) -1-benzylpyrrolidin-3-yl-amine. (MH + 687.5)

Example 95

9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino- {2- [3- (2-di-isopropyl-amino-ethyl) -ureido] -ethyl} -amide trifluoroacetate cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid

To a solution comprising 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenyl) acid (2-amino-ethyl) -amide ethylamino) -9H-purine-2-carboxylic (25 mg, 0.04 mmol) (example 48, step 8) in toluene (0.8 ml) and isopropyl alcohol (0.4 ml), add (2- Imidazole-1-carboxylic acid di-isopropyl-amino-ethyl) -amide (10mg, 0.04mmol) in DMC (0.44ml). 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 resulting crude product by reverse phase column chromatography (Isolute ™ C18, 0-100% acetonitrile in water - 0.1% TFA) provides the title product. (MH + 372.3).

Examples 96-98

These compounds, specifically, N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -1-benzyl-pyrrolidin-3-yl-amino) -6- (2,2- Diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (MH + 661.6) (Example 96), {(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 (MH + 661.6) (example 97), and (R) -3- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6 (2,2-diphenyl- ethylamino) -9H-purin-2-yl-amino] -pyrrolidine-1-carboxylic acid (MH + 671.5) (example 98), are prepared 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 2-benzyloxy-N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -acetamide with the 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 the appropriate amine.

ES 2 384 337 T3

Example 99 (2-Propionylamino-ethyl) -amide 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) -9H -purin-2-carboxylic

Step 1: (2-Aminoethyl) amide del acid 9 - ((1R, 2S, 3R, 4S) -4-di-tert-butoxycarbonylamino-2,3-dihydroxycyclopentyl) -6 ( 2,2-Diphenylethylamino) -9H-purine-2-carboxylic acid:

The title compound is prepared analogously to 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2-amino-ethyl) -amide acid , 2-diphenyl-ethylamino) -9H-purine-2-carboxylic (example 48, step 8), replacing 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) -9H-purine-2-carboxylic acid methyl ester with the 9 - ((1R, 2S, 3R, 4S) -4-di-tert-butoxy-carbonyl-amino-2,3-dihydroxy-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H- purine-2-carboxylic (example 48, step 5).

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

The title compound is prepared from 9 - ((1R, 2S, 3R, 4S) -4-amino-2,3-dihydroxy-cyclopentyl) -6- (2 , 2-diphenyl-ethylamino) -9H-purine-2-carboxylic, analogous 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: (2-propionylamino-ethyl) -amide of acid 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) - 9H-purine-2-carboxylic

The title compound is prepared analogously to the acid methyl ester 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) - 9H-purine-2-carboxylic (example 48, step 7), replacing 9 - ((1R, 2S, 3R, 4S) -, 4-amino-2,3-dihydroxy-cyclopentyl) -6- (2,2-diphenyl-ethylamino) 9H-purin-2 acid methyl ester hydrochloride -carboxylic with acid (2-amino-ethyl) -amide hydrochloride 9 - ((1R, 2S, 3R, 4S) -4-amino-2,3-dihydroxycyclopentyl) -6- (2,2-diphenyl- ethylamino) -9H-purine-2-carboxylic. (MH + 629.5).

Example 100

N - {(1S, 2R, 3S, 4R) -4- [2- (2-amino-ethylamino) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3 trifluoroacetate -dihydroxiciclopentyl} -propionamide

The title compound is prepared analogously to 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-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 with 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 the ethylene diamine. (MH + 545.4).

Example 101

Trifluoroacetato de (2- {3- [1-(3,4,5,6-tetrahidro-2H- [1,2']-bipiridinil-4-il-carbamoil)-piperidin-4-il] -ureido}- etil) -amida del ácido 9-((1R, 2S, 3R, 4S) -2,3-dihidroxi-4-propionilamino-ciclopentil) -6- (2,2-difenil-etilamino) -9H-purin-2- carboxílico

Etapa 1: Acid ether terc-butylic {(1S, 2R, 3S, 4R) -4- [6- (2,2-diphenyl-ethylamino) -2- (2- {3- [1- (3,4 , 5,6-tetrahidro-2H [1,2 '] - bipyridinyl-4-yl-carbamoyl) -piperidin-4-yl] -ureido} -ethyl-carbamoyl) -purin-9-yl] -2.3- dihidroxi-ciclopentil} -carbámico

The title compound is prepared analogously to [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenylethylamino) -2- {2- [3- (3 , 4,5,6-tetrahydro-2H- [1,2 '] bi-pi ridinyl-4-yl) -ureido] -ethyl-carbamoyl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] carbamic (example 12), replacing (3,4,5,6-tetrahydro-2H- [1,2 '] - bipyridinyl-4-yl) -amide of the imidazole-1-carboxylic acid (intermediate C) with the (3,4,5,6- 4 - [(imidazole-1carbonyl) -amino] -piperidine-1-carboxylic acid tetrahydro-2H- [1,2 '] - bipyridinyl-4-yl) -amide (intermediate H).

Step 2: (2- {3- [1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl-carbamoyl) -piperidin-4-yl] -ureido dihydrochloride } -ethyl) acid 9 - ((1 R, 2S, 3R, 4S) -4-amino-2,3-dihydroxy-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin- 2-carboxylic

A solution of {(1S, 2R, 3S, 4R) -4- [6- (2,2-diphenyl-ethylamino) -2- (2- {3- [1- (3,4 , 5,6tetrahydro-2H- [1,2 '] bipyridinyl-4-yl-carbamoyl) -piperidin-4-yl] -ureido} -ethyl-carbamoyl) -purin-9-yl] -2,3-dihydroxy- cyclopentyl} carbamic (76.7 mg, 81 mmol) in MeoH (0.5 ml) is treated with 4M HCl in dioxane (0.5 ml). After stirring at room temperature for 1 hour, the solvent is removed in vacuo to provide the title compound, which is used crude in the next step.

ES 2 384 337 T3

Etapa 3: Trifluoroacetato de (2-{3- [1-(3,4,5,6-tetrahidro-2H- [1,2']-bipiridinil-4-il-carbamoil)-piperidin-4-il]- ureido} -etil) amida del ácido 9-((1R, 2S, 3R, 4S) -2,3-dihidroxi-4-propionilamino-ciclopentil)-6- (2,2-difenil-etilamino) -9H-purin- 2 carboxílico

The title compound is prepared analogously to the acid methyl ester 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) - 9H-purine-2-carboxylic (example 48, step 7), replacing 9 - ((1R, 2S, 3R, 4S) -, 4-amino-2,3-dihydroxy-cyclopentyl) -6- (2,2-diphenyl-ethylamino) 9H-purin-2 acid methyl ester hydrochloride -carboxylic with the dihydrochloride of (2- {3- [1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl-carbamoyl) -piperidin-4-yl] -ureido} 9 - ((1R, 2S, 3R, 4S) -4-amino-2,3-dihydroxy-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin- -ethyl) -amide

2-carboxylic acid. (MH + 451.8).

Examples 102-104

These compounds, namely {1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl- ethylamino) -9H-purin-2-yl] -piperidin-4-yl} -carbamic (MH + 685.6) (example 102), N - {(1S, 2R, 3S, 4R) trifluoroacetate -4- [2 - (1-Benzyl-piperidin-4-yl-amino) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (MH + 675.5) (example 103), and N - {(1S, 2R, 3S, 4R) -4- [2- [1,4] diazepan-1-yl-6- (2,2-diphenyl-ethylamino) -purin-9-yl] trifluoroacetate -2,3-dihydroxycyclopentyl} -propionamide (MH + 585.5) (example 104), are prepared analogously to the trifluoroacetate 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} -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 with the 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 the appropriate amine.

Examples 105-106

These compounds, namely {(R) -1- [9 - [(1R, 2S, 3R, 4S) -4- (cyclobutane-carbonyl-amino) -2,3-dihydroxycyclopentyl] tert-butyl ester trifluoroacetate] -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -carbamic (MH + 697.3) (example 105), and tert-butyl acid trifluoroacetate (S) -3- [9 - [(1R, 2S, 3R, 4S) -4- (cyclobutane-carbonyl-amino) -2,3-dihydroxycyclopentyl] -6- (2,2-diphenyl-ethylamino) -9H -purin-2-yl-amino] -pyrrolidine-1-carboxylic (MH + 697.3) (example 106), are prepared analogously to N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) trifluoroacetate ) -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 with {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} - cyclobutanecarboxylic acid amide (intermediate K), and replacing (3R) -3-aminopyrrolidine with the appropriate amine.

Example 107

N - {(1S, 2R, 3S, 4R) -4- [6- (2,2-diphenyl-ethylamino) -2- (3,4,5,6-tetrahydro-2H- [1,2 ') trifluoroacetate ] -bipyridinyl-4-yl-amino) purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide

This compound is prepared in a manner analogous to N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl) trifluoroacetate -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 with the 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 3,4,5,6-tetrahydro-2H [1,2 '] bipyridinyl-4-yl-amine. (MH + 331.7).

Example 108

4- [3- (2 - {[9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) - 9H-purine-2-carbonyl] -amino} -ethyl) -ureido] -piperidine-1-carboxylic

ES 2 384 337 T3

To a solution of (2-amino-ethyl) -amide of acid 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6 (2,2-diphenyl-ethylamino ) -9H-purine-2-carboxylic (example 48, step 8) (0.1 g, 174 mmol) in chloroform (5 ml), 4-isocyanato-Z-piperidine (0.045 g, 0.174 mmol) is added in chloroform (5 ml). The reaction mixture is allowed to stir at room temperature overnight, and then methanol is added to quench any residual isocyanate. The solvent is removed in vacuo to provide the title compound. (MH + 833.5).

Example 109

Trifluoroacetate de {2- [3- (5-methyl-3-phenyl-isoxazol-4-yl) -ureido] -ethyl} -amide del acid 9 - ((1R, 2S, 3R, 4S) -2,3- dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) -9H-purine-2-carboxylic acid

This compound is prepared in a manner analogous to the benzyl ester of 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 (example 108), replacing 4- isocyanato-Z-piperidine with 4-isocyanato-5-methyl-3-phenyl-isoxazole. (MH + 773.5).

Examples 110-112

These compounds, specifically, N - {(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), trifluoroacetate of N - {(1S, 2R, 3S, 4R) -4- [6- ( 2,2-diphenyl-ethylamino) -2 - ((R) -3-methylamino-pyrrolidin-1-yl) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (MH + 585.4) (example 111), and (4- {2- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) 9H- purin-2-yl-amino] -ethyl} -imidazol-1-yl) -acetic (MH + 654.3) (example 112), are prepared analogously to the trifluoroacetate 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} -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 with the 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 the appropriate amine.

Example 113

Trifluoroacetato de (2- {3- [1- (4-metoxi-fenil-carbamoil) -piperidin-4-il] -ureido} -etil) -amida del ácido 9 - ((1R, 2S, 3R, 4S) -

2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid

Step 1: [2- (3-Piperidin-4-yl-ureido) -ethyl] -amide of acid 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) 6 - (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic

A solution of 4- [3- (2 - {[9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6 (2,2-diphenyl acid) -ethylamino) -9H-purine-2-carbonyl] -amino} -ethyl) -ureido] -piperidine-1-carboxylic acid (example 108) (0.145 g, 0.174 mmol) in methanol (1 ml) under an argon atmosphere, 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 provide the title compound as a green oil.

Step 2: (2- {3- [1- (4-Methoxy-phenyl-carbamoyl) -piperidin-4-yl] -ureido} -ethyl) -amide trifluoroacetate 9 ((1R, 2S, 3R, 4S ) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic

This compound is prepared analogously to 4- [3- (2 - {[9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy4-propionylamino-cyclopentyl) -6- (2 , 2-diphenyl-ethylamino) -9H-purine-2-carbonyl] -amino} -ethyl) -ureido] -piperidine-1-carboxylic (example 108), replacing 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H- (2-amino-ethyl) -amide purine-2-carboxylic acid with [2- (3-piperidin-4-yl-ureido) -ethyl] -amide of acid 9 ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino- cyclo-pentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid, and replacing 4-isocyanate-Z-piperidine with 1-isocyanate-4-methoxy-benzene. (MH + 848.6).

Examples 114-115

These compounds, specifically,

ES 2 384 337 T3 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic (MH + 843.6) (example 114), and trifluoroacetate of ({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 (MH + 828.6) (example 115), are prepared analogously to example 113, replacing 1-isocyanate-4-methoxy-benzene with the appropriate isocyanate.

Example 116

[2- (3- {1- [1- (3,4,5,6-tetrahidro-2H- [1,2 '] - bipyridinyl-4-yl-carbamoyl) -piperidin-4-yl-carbamoyl) trifluoroacetate ] -piperidin4-yl} -ureido) -ethyl] -acid starch 9 - ((1R, 2S, 3R, 4S) -2,3-dihidroxi-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl -ethylamino) 9H-purin-2-carboxílico

The title compound is prepared analogously to (2- {3- [1- (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl-carbamoyl) -piperidine trifluoroacetate -4-yl] -ureido} -ethyl) -amide of acid 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purine-2-carboxylic acid (example 101), replacing (3,4,5,6-tetrahydro-2H- [1,2 '] bipyridinyl-4-yl) -amide for 4 - [(imidazol-1 -carbonyl) -amino] -piperidine-1-carboxylic with intermediate I. (MH + 514.9).

Examples 117-125

Compounds, concretament, trifluoroacetate N - {(1S, 2R, 3S, 4R) -4- [6- [2,2-bis- (4-methoxyphenyl) ethylamino] -2 - ((R) - 3-Dimethylamino-pyrrolidin-1-yl) purin-9-yl] -2,3-dihydroxycyclopentyl} -propionamide (MH + 659.4) (ex 117), trifluoroacetate N - ((1S, 2R, 3S, 4R) -4- {2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -6- [2- (4-fluoro-phenyl) -2-phenyl-ethylamino] purin-9-yl} - 2,3-dihydroxycyclopentyl) -propionamide (MH + 617.4) (e.g. 118), trifluoroacetate of N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -6- (1-ethyl-propylamino) -purin- 9-yl] -2,3-dihydroxycyclopentyl} propionamide (MH + 489.3) (ex 119), trifluoroacetate N - ((1S, 2R, 3S, 4R) -4- {2 - ((R) -3 -dimethylamino-pyrrolidin-1-yl) -6 - [(9H-fluoren-9-ylmethyl) -amino] -purin-9-yl} -2,3-dihydroxycyclopentyl) -propionamide (mH + 597.4) ( 120), trifluoroacetate N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -6 - ((S) -1-hydroxymethyl-2 -phenyl-ethylamino) purin-9-yl] -2,3-dihydroxycyclopentyl} -propionamide (MH + 553.4) (ex 121), trifluoroacetate N - ((1S, 2R, 3S, 4R) -4- {2 - ((R) -3-Dimethylamino-pyrrolidin-1-yl) -6 - [(naphthalen-1-ylmethyl) -amino] -purin-9-yl} -

2,3-Dihydroxy-cyclopentyl) -propionamide (MH + 559.4) (Example 122), N - {(1S, 2R, 3S, 4R) -4- [6 - [(2'-cyano-biphenyl-) trifluoroacetate 4-yl-methyl) -amino] -2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (MH + 610.3) (example 123), N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -6- (3,3-dimethyl- trifluoroacetate butyl-amino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (MH + 503.4) (example 124), and N - ((1S, 2R, 3S, 4R) -4- {2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -6- [2- (4-sulfamoyl-phenyl) - trifluoroacetate ethylamino] -purin-9yl} -2,3-dihydroxy-cyclopentyl) -propionamide (Mh + 602.3) (example 125), are prepared 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-am inopyrrolidine with the 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-dihydroxy-cyclopentyl} -acetamide with the appropriate starting compound. The preparation of the starting compounds are described herein, or they can be prepared from the tert-butyl acid [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9 -il) -2,3-dihydroxy-cyclopentyl] -propionyl-carbamic (intermediate G) and the appropriate amine, using a procedure analogous to that of 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 126

ES 2 384 337 T3

N - {(1S, 2R, 3S, 4R) -4- [2 - [(R) -3- (2-acetylamino-4-methyl-thiazole-5-sulfonyl-amino) -pyrrolidin-1-yl trifluoroacetate ] -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide

5-thiazole sulfonyl (0.0104 g, 39 mmol) in NMP (0.5 ml). After stirring at room temperature overnight, purification is carried out using mass directed preparation LCMS eluting with acetonitrile: water: TFA to provide the title compound. (MH + 789.4).

Examples 127-132

Compounds, concretes, trifluoroacetate of N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenylethylamino) -2 - {(R) -3- [3- (3- Phenyl-isoxazol-4-yl) -ureido] -pyrrolidin-1-yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -propionamide (MH + 771.5) (e.g. 127), trifluoroacetate de {(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 of the acid 5-pyridin-2-yl-thiophene-2-carboxylic acid (MH + 758.4) (excl. 128), trifluoroacetate and benzylic acid 4 - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl- ethylamino) -9H-purin-2-yl] -pyrrolidin-3-ylcarbamoyl} -piperidine-1-carboxylic acid (MH + 816.6) (ejemplo 129), trifluoroacetate N - [(1S, 2R, 3S, 4R) ) -4- (6- (2,2-Diphenylethylamino) -2 - {(R) -3- [3- (3-methyl-5-phenylisoxazol-4-yl) ureido] pyrrolidin-1 -yl} -purin-9-yl) -2,3-dihydroxycyclopentyl] -propionamide (MH + 771.5) (ejemplo 130), trifluoroacetate de {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) -9H-purine 2-yl] -pyrrolidin-3-yl} -amide to the acid 1,3-dimethyl-1H-thieno [2,3-c] pyrazole-5-carboxylic acid (MH + 749.4) (eq. 131), and trifluoroacetate de {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) -9H-purine-2- yl] -pyrrolidin-3-yl} -amide of the acid 1-methyl-1H-benzotriazole-5-carboxylic acid (MH + 730.5) (method 132), They are prepared analogously to Example 126, replacing 2-acetamido-4-methyl-5-thiazole sulfonyl chloride with the appropriate isocyanate or acid chloride. Reactions using acid chlorides also have TEA added.

Example 133

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

2,3-dihydroxy-cyclopentyl) -formamide

Etapa 2: 1 - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -4-amino-2,3-dihidroxi-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pirrolidin3-yl} -3-pyridine-3-yl-urea

To a solution of the acid benzyl ester Trifluoroacetate ((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) -carbamic (35 mg, 46 mmol) in ethanol (1 ml) under an inert atmosphere of argon, 10% palladium on charcoal (10 mg) is added. The reaction mixture is purged with argon, and placed under a positive hydrogen atmosphere overnight, after which time, the mixture is filtered through Celite, and the catalyst is washed with ethanol. The organic parts are combined and concentrated in vacuo to provide 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) N-chlorohydrate -ureido) -pyrrolidin-1-yl]

ES 2 384 337 T3 purin-9-yl} -2,3-dihydroxy-cyclopentyl) -formamide

Acetic anhydride (1.9 mg, 19 mmol) and formic acid (1.4 mg, 30 mmol) are stirred together for 30 minutes, and then added to a solution of 1 - {(R) -1- [ 9 - ((1R, 2S, 3R, 4S) -4-amino-2,3-dihydroxy-cyclopentyl) -6- (2,2-diphenylethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl } -3-pyridin-3-yl-urea (11 mg, 17 pm) in THF (0.5 ml). The reaction mixture is stirred at room temperature overnight, and purification by reverse phase column chromatography (Isolute ™ C18, 0-100% acetonitrile in water - 0.1% HCl) provides the title compound . (MH + 663.5)

Example 134

Trifluoroacetate de {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) -9H-purine- 2-yl] -pyrrolidin-3-yl} -amide delacid (R) -3-dimethylamino-pyrrolidine-1-carboxylic acid

Step 1: {(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 of the acid imidazole-1-carboxylic acid:

A mixture comprising 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 (intermediate M) (0.24 g, 394 pm) and CDI (0.275 g, 1, 7 mmol) in dry DMC (6 ml) is stirred at room temperature for 3 hours. The resulting solution is purified by chromatography on silica, eluting with 100% DMC, changing to 5% MeOH in DMC, to provide the title compound as a yellow oil. The oil consists of the imidazole-urea intermediate together with varying amounts of the corresponding isocyanate and imidazole, both of which are equally suitable as precursors for ureas.

Step 2: Trifluoroacetate de {(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 delidido (R) -3-dimethylamino-pyrrolidine-1-carboxylic acid:

Dimethyl- (R) -pyrrolidin-3-yl-amine (4.6 mg, 40 pmol) 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 of imidazole-1-carboxylic acid (25 mg, 40 pmol) in DMC (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). After stirring at room temperature for 3 hours, the reaction mixture is concentrated in vacuo and the resulting crude product is purified by mass directed LC-MS preparation eluting with acetonitrile: water: TFA to provide the title compound. (MH + 71.5)

Example 135

Trifluoroacetate de {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) -9H-purine- 2-yl] -pyrrolidin-3-yl} -amide delidido 4- (2-cyanoethyl) -piperazine-1-carboxylic acid

This compound is prepared analogously to {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl) trifluoroacetate (R) -3-Dimethylaminopyrrolidine-1-carboxylic acid -ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -amide (example 134), replacing dimethyl- (R) -pyrrolidin-3- yl-amine with the appropriate amine. (MH + 697.4).

Examples 136-155

These compounds are, in particular, N - [(1S, 2R, 3S, 4R) -4- (2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -6 - {[(1R, 3S) trifluoroacetate -2,2-dimethyl-3- (2-methylpropenyl) -cyclopropyl-methyl] -amino} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -propionamide (MH + 555.6) (example 136) , N - {(1S, 2R, 3S, 4R) -4- [6 - ((1R, 2R) -2-benzyloxy-cyclopentyl-amino) -2 - ((R) -3-dimethylamino-pyrrolidine-trifluoroacetate 1-yl) purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (MH + 593.5) (example 137), N - {(1S, 2R, 3S, 4R) -4- [6 - ((1S, 2S) -2-benzyloxy-cyclopentyl-amino) -2 - ((R) -3-dimethylamino-pyrrolidine-1 trifluoroacetate -yl) purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (MH + 593.5) (example 138), N - {(1S, 2R, 3S, 4R) -4- [6] trifluoroacetate - ((1S, 2S) -bicyclo-pentyl-2-yl-amino) -2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (MH + 555.6) (example 139), trifluoroacetate N - {(1S, 2R, 3S, 4R) -4- [6 - ((R) -1-benzyl-pyrrolidin-3-ylamino) -2 - ((R) -3-dimethylamino-pyrrolidine -1-yl)

100

ES 2,384,337 T3 purin-9-yl] -2,3-dihydroxycyclopentyl} propionamide (MH + 578.5) (eq. 140), trifluoroacetate N - {(1S, 2R, 3S, 4R) -4- [6 - ((S) -1-benzyl-pyrrolidin-3-ylamino) -2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) purin-9-yl] -2,3-dihydroxy -cyclopentyl} -propionamide (MH + 578.5) (ejemplo 141), trifluoroacetate of N - {(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) (ex 142), trifluoroacetate N - {(1S, 2R, 3S, 4R) -4- [6- [2- (4-benzylpiperidine) -1-yl) -ethylamino] -2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) purin-9-yl] -2,3-dihydroxycyclopentyl} -propionamide (MH + 620.5) ( (143), trifluoroacetate N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -6 - ((S) -2-phenyl -1-Pyrrolidin-1-ylmethylethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -propionamide (MH + 606.5) (eq. 144), trifluoroacetate N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -6- (3,4,5,6-tetrahydro-2H - [1,2 '] bipyridinyl-4-amino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -propionamide (MH + 579.5) (eq. 145), trifluoroacetate N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -6 - ((S) -1-hydroxymethyl-3-methylbutylamino) purine -9-yl] -2,3-dihydroxycyclopentyl} -propionamide (MH + 519.5) (ejemplo 146), trifluoroacetate N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -6 - ((S) -1-hydroxymethyl-3 -methylsulfanylpropylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -propionamide (MH + 537.5) (ejemplo 147), trifluoroacetate of N - {(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) (ejemplo 148), trifluoroacetate of N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -6 - ((1S, 2S) -2-hydroxy-1 (hydroxymethyl-2-phenylethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -propionamide (MH + 569.5) (ejemplo 149), trifluoroacetate N - ((1S, 2R, 3S, 4R) -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) (ejemplo 150), trifluoroacetate N - ((1S, 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) (ex 151), trifluoroacetate N - (1S, 2R , 3S, 4R) -4- {2 - ((R) -3-dimethylamino-pyrrolidin-1-yl) -6 - [(S) -2-hydroxy-1- (1H-indol-3-ylmethyl) ) ethylamino] -purin-9-yl} -2,3-dihydroxycyclopentyl) -propionamide (MH + 592.4) (ex 152), trifluoroacetato de N-{(1S,2R,3S,4R)-4-[6-((S)-1-selfish-2-methoxy-ethylamino)-2-((R)-3-dimethylamino-pyrrolidine-1 -yl)-purin9-yl]-2,3-dihydroxy-ciclopentyl}-propionamida (MH+ 567.4) (ejemplo 153), trifluoroacetato de N-{(1S,2R,3S,4R)-4-[6- [(S)-1-(4-benciloxy-selfish)-2-hydroxy-ethylamino]-2-((R)-3-dimethylaminopyrrolidin-1-yl)-purin-9-yl]-2,3-dihydroxy -ciclopentyl}-propionamida (MH+ 659.4) (ejemplo 154), and trifluoroacetate N - ((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) (e.g. 155), prepared as an analogue and trifluoroacetate N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenylethylamino) -purin-9 -yl] -2,3-dihydroxycyclopentyl} -2-benzyloxyacetamide (Example 1, Step 2), replacing (3R) 3-aminopyrrolidine with 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-dihydroxy-cyclopentyl} -acetamide with the appropriate starting compound. The preparation of the starting compounds are described herein, or they can be prepared from the tert-butyl ester [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl ) -2,3-dihydroxy-cyclopentyl] - of propionyl-carbamic acid (intermediate G) and the appropriate amine, using a procedure analogous to that of 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 156

Chlorohydrate N - {(R) -1- [6- [2,2-Bis- (4-methoxyphenyl) ethylamino] -9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy -4-Propionylaminocyclopentyl) -9H-purin-2-yl] -pyrrolidin-3-yl} -isonicotinamide

This compound is prepared analogously to N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl) trifluoroacetate -ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-benzyloxy-acetamide (example 1, step 2),

101

ES 2 384 337 T3 replacing (3R) -3-aminopyrrolidine with (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 the N - ((1S, 2R, 3S, 4R) -4- {6- [2,2-bis- (4-methoxy-phenyl) -ethylamino] -2-chloro-purin-9-yl} -2,3-dihydroxycyclopentyl) -propionamide {prepared from [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) - acid tert-butyl ester

2,3-dihydroxy-cyclopentyl] -propionyl-carbamic (intermediate G) and the appropriate amine, using a procedure analogous to that of 2R, 3S, 4R) -4- {6- [2,2-Bis- (4 -hydroxy-phenyl) -ethylamino] -2-chloro-purin-9-yl} -2,3-dihydroxycyclopentyl) -propionamide (example 22, steps 1 and 2)}. (MH + 736.5).

Example 157

Chlorohydrate {(R) -1- [6- [2,2-bis- (4-methoxyphenyl) ethylamino] -9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4 -propionylaminocyclopentyl) -9H-purin-2-yl] -pyrrolidin-3-yl} -amide to the acid 5-methylisoxazole-3-carboxylic acid

It is prepared analogously to Example 93, replacing N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (1-ethyl-propyl-amino) purin-9-yl] -2, 3-dihydroxy-cyclopentyl} -propionamide with the N - ((1S, 2R, 3S, 4R) -4- {6- [2,2-bis- (4-methoxy-phenyl) -ethylamino] -2-chloro-purin- 9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide [prepared from tert-butyl acid [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9- yl) -2,3-dihydroxy-cyclopentyl] -propionyl-carbamic (intermediate G) and the appropriate amine, using a procedure analogous to that of 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

Chlorohydrate N - {(R) -1- [6- [2,2-bis- (4-hydroxyphenyl) ethylamino] -9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy -4-Propionylaminocyclopentyl) -9H-purin-2-yl] -pyrrolidin-3-yl} -isonicotinamide

A mixture comprising the 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 MP ( 0.5 ml) is treated with TEA (13 mg, 0.13 mmol), followed by isonicotinoyl chloride hydrochloride (16 mg, 83 mmol). After stirring at room temperature for 2 hours, the solvent is removed in vacuo and purification by C-18 reverse phase column chromatography eluting with acetonitrile: water: HCl (0.1%) (gradient 0 to 100% acetonitrile) provides the title compound. (MH + 708.4).

Example 159

Chlorohydrate {(R) -1- [6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4 -propionylaminocyclopentyl) -9H-purin-2-yl] -pyrrolidin-3-yl} -amide delidido 1-methyl-1H-benzotriazole-5-carboxylic acid

This compound is prepared analogously to N - {(R) -1- [6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -9 ((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 the 1-methyl chloride -1H-1,2,3-benzotriazole-5-carbonyl. (MH + 762.4).

Examples 160-162

These compounds, specifically, N - ((1S, 2R, 3S, 4R) -4- {6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -2 - [(R) - hydrochloride 3- (3-pyridin-3-ylmethyl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (MH + 737.5) (example 160), N hydrochloride - ((1S, 2R, 3S, 4R) -4- {6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -2 - [(R) -3- (3-pyridin-4 -ylmethyl-ureido) -pyrrolidin1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (MH + 737.2) (example 161), chlorhydrode N-((1S,2R,3S,4R)-4-{6-[2,2-bis-(4-hydroxy-phenyl)-ethylamino]-2-[(R)-3-(3-) pyridin-4-ylmethyl-ureido)-pyrrolidine-

1- yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (MH + 740.5) (example 162), are prepared analogously to the hydrochloride of N - ((1S, 2R, 3S , 4R) -4- {6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -2 - [(R) -3 (3-pyridin-2-ylmethyl-ureido) -pyrrolidin-1 -il] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (example 23), replacing

2- (amino-methyl) -pyridine with the appropriate amine.

Example 163

2-amino-N hydrochloride - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridine-3- il-ureido) -pirrolidin-1-yl] purin-9-yl} -2,3-dihidroxi-cyclopentyl) -acetamide

102

ES 2 384 337 T3

A solution of 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 (example 26, step 2) (17 mg, 26 mmol) in THF (1 ml) is treated with ester 2 Tert-Butoxycarbonyl-aminoacetic acid, 5-dioxopyrrolidin-1-ylic (9mg, 29mm), and stir at room temperature overnight. The resulting solution is treated with 1.25M HCl in EtOH (1 mL), and stirred at room temperature for 2 days. Purification by C-18 reverse phase column chromatography eluting with acetonitrile: water: HCl (0.1%) (gradient 0-100% acetonitrile) provides the title compound. (MH + 691.99).

Example 164

N - {(1S, 2R, 3S, 4R) -4 - [(R) -2- [1,3 '] - bipyrrolidinyl-1'-yl-6- (2,2-diphenyl-ethylamino) - chlorohydrate purin-9-yl] -2,3-dihydroxiciclopentyl} -propionamide

The title compound is prepared analogously to 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-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 with the 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 the (R) - [1,3 '] - bipyrrolidinyl (intermediate N). (MH + 625.4).

Example 165

N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenyl-ethylamino) -2- {2- [3- (3,4,5,6-tetrahydro-2H) trifluoroacetate - [1,2 '] bipyridinyl-4-yl) ureido] -ethylamino} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -propionamide

A dissolution of N - {(1S, 2R, 3S, 4R) -4- [2- (2-amino-ethylamino) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] trifluoroacetate] -

2.3- dihydroxy-cyclopentyl} -propionamide (example 100) (27 mg, 37 mmol) in isopropyl alcohol (0.5 ml) is treated with (3,4,5,6-tetrahydro-2H- [1,2 '] Imidazole-1-carboxylic acid bipyridinyl-4-yl) -amide (intermediate C) (1.1 ml of a 10 mg / ml solution in DMC, 40 mmol). After stirring at room temperature for 7 days, the solvent is removed in vacuo, and purification of the residue by C-18 reverse phase column chromatography, eluting with acetonitrile: water: TFA (0.1%) (gradient of the 0 to 100% acetonitrile), provides the title compound. (MH + 748.6).

Example 166

Trifluoroacetate ester 1- {2 - [(R) -3- (3 - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl ) -6- (2,2-Diphenylethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -ureido) -pyrrolidin-1-yl] -2-oxoethyl} -piperidin-4-yl] of the biphenyl-2-ylcarbamic acid

Example 167

N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3- (2-methyl-5-phenyl-furan) -3-yl) -ureido] -pyrrolidin-1-yl} -purin-9-yl) -

2.3- dihydroxy-cyclopentyl] -propionamide

This compound is prepared analogously to (example 126), replacing 2-acetamido-4-methyl-5-thiazole-sulfonyl chloride with 3-isocyanato-2-methyl-5-phenyl-furan, and changing the solvent to 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-pyrazol-4- ethyl ester carboxylic

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

To a solution of N - [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -2,3-dihydroxy-cyclopentyl] -propionamide (intermediate J7) (2 , 6 g, 7.22 mmol) in dry THF (26 ml), add 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

103

ES 2 384 337 T3 residue is dissolved in chloroform and washed sequentially with 1.5N HCl, water, and a saturated aqueous solution of brine. The organic phase is dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product is purified by chromatography on silica, (60-120 mesh), eluting with 2% methanol in chloroform, to provide 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} -2-hydrazino-purin-9-yl) - 2,3-dihydroxy-cyclopentyl] propionamide

A mixture comprising 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), stir at room temperature for 72 hours. Isopropyl alcohol (10 ml) is then added, and the solvent is decanted, to provide a gummy mixture. Dissolve in water (10 ml) and stir for 12 hours. The fine solid obtained is filtered, washed with water, and dried in vacuo to provide the title product, which is used in the next step without further purification. LCMS (0.1% formic acid, acetonitrile): (MH + 563).

Step 3: Ethyl ester 1- [6 - {[bis- (4-methoxyphenyl) methyl] amino} -9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino) -cyclopentyl) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic acid:

To a solution of N - [(1S, 2R, 3S, 4R) -4- (6 - {[bis- (4-methoxy-phenyl) -methyl] -amino} -2-hydrazino-purin-9-yl) -2,3-dihydroxycyclopentyl] -propionamide (0.1 g, 0.177 mmol) in dry ethyl alcohol (5 ml), 2-formyl-3-oxo-propionic acid ethyl ester (synthesized from 3,3- Ethyl diethoxy propionate, as described in: Bertz SH, Dabbagh G. and Cotte P .; J. org. Chem. (1982) 47, pages 2216-2217) (0.033 g, 0.231 mmol). The reaction mixture is refluxed for 8 hours, and then concentrated in vacuo. The crude residue is purified by chromatography on silica, (60-120 mesh) eluting with 3% methanol in chloroform, to provide the title compound. LCMS (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-4-carboxylic:

A cooled (0 ° C) solution of ethyl acid 1- [6 - {[bis- (4-methoxy-phenyl) -methyl] -amino} -9 - ((1R, 2S, 3R, 4S) -2 , 3dihydroxy-4-propionylamino-cyclopentyl) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic (0.1 g, 0.149 mmol) in dry DMC (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 TFA, and purification of the residue by preparative HPLC provides the title compound.

LC-MS (0.1% formic acid, acetonitrile): (MH+ 445.3).

Example 169 {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -amide isoxazole-5-carboxylic acid

This compound is prepared analogously to N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-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-dihidroxi -cyclopentyl} -propionamide

This compound is prepared analogously to Example 168, replacing 2-formyl-3-oxopropionic acid ethyl ester with 2- (4-quinolyl) -malonaldehyde. (MH + 500.3).

Example 171

N - {(1S, 2R, 3S, 4R) -4- [6- (2,2-diphenyl-ethylamino) -2- (4-pyridine-2-yl-pyrazol-1-yl) -purin-9- il] -2,3-dihidroxi-cyclopentyl} propionamide

This compound is prepared analogously to Example 42, replacing cyclohexanecarboxaldehyde with 2-pyridinyl propanediol. The reaction is carried out in ethanol. (MH + 630.40).

104

ES 2 384 337 T3

Example 172

N - {(1S, 2R, 3S, 4R) -4- [6- (2,2-diphenyl-ethylamino) -2- (4-pyridine-4-yl-pyrazol-1-yl) -purin-9- il] -2,3-dihidroxi-cyclopentyl} propionamide

This compound is prepared analogously to Example 42, replacing cyclohexanecarboxaldehyde with 4-pyridinyl propanediol. The reaction is carried out in ethanol. (MH + 630.41).

Example 173

1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H-purin2-yl] acid methylamide -1H-pyrazole-4-carboxylic

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

This compound is prepared analogously to 1- [6 - {[Bis- (4-methoxy-phenyl) -methyl] -amino} -9 ((1R, 2S, 3R, 4S) -2.3 -dihydroxy-4-propionylamino-cyclopentyl) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic (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-dihydroxycyclopentyl] -propionamide with the N - {(1S, 2R, 3S, 4R) -4- [6- (2,2-diphenyl-ethylamino) -2-hydrazino-purin-9-yl] -2,3-dihydroxycyclopentyl} -propionamide.

Step 2: 1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) 9H-purin- methylamide 2-yl] -1H-pyrazole-4-carboxylic

A mixture of 1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) -9H-purin- 2-yl] -1H-pyrazole-4-carboxylic acid (0.07 g, 0.112 mmol) and a 40% aqueous methylamine solution (3 ml) is heated at 65 ° C for 12 hours. The reaction mixture is concentrated in vacuo, and purification of the crude residue by chromatography on silica, eluting with 4% methanol in chloroform, provides 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

Step 1: Methylamide del acid 1- [6 - {[bis- (4-methoxyphenyl) methyl] amino} -9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino) cyclopentyl) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic acid:

A mixture of 1- [6 - {[bis- (4-methoxy-phenyl) -methyl] -amino} -9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino acid ethyl ester -cyclopentyl) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic acid (example 168, step 3) (0.2 g, 0.298 mmol) and a 40% aqueous solution of methylamine (5 ml) were heat at 65 ° C for 12 hours. The reaction mixture is concentrated in vacuo, and purification of the crude residue by chromatography on silica, eluting with 3% methanol in chloroform, provides the title compound. LCMS (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 acid methylamide -4-carboxylic

A cooled (0 ° C) solution of 1- [6 - {[bis- (4-methoxy-phenyl) -methyl] -amino} -9 - ((1R, 2S, 3R, 4S) -2, 3dihydroxy-4-propionylamino-cyclopentyl) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic acid (0.08 g, 0.122 mmol) in dry DMC (4 ml) is slowly treated with TFA (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 TFA, and purification of the crude product by preparative HPLC provides the title compound. LC-MS (0.1% formic acid, acetonitrile): (MH + 430.28).

Example 175

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

This compound is prepared analogously to Example 23 by replacing {(R) -1- [6- [2,2

105

ES 2 384 337 T3 bis- (4-hydroxy-phenyl) -ethylamino] -9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -9H-purin-2- yl] -pyrrolidin-3yl} -carbamic with N - ((1S, 2R, 3S, 4R) -4- {2 - ((R) -3-amino-pyrrolidin-1-yl) -6- [hydrochloride 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 pyridin-3-yl-carbamic acid phenyl ester (intermediate ZB). (MH + 725.32).

Example 176

Trifluoroacetate and benzylic acid 4 - {[(R) -3- (3 - {(R) -1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-Diphenylethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -ureido) -pyrrolidine-1-carbonyl] -amino} -piperidine-1-carboxylic acid

The title compound is prepared analogously 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 (example 108), replacing 9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H- (2-amino-ethyl) -amide purine-2-carboxylic acid with the Trifluoroacetate of 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). (MH + 943.4).

Example 177

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

This compound is prepared in a manner analogous to N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl) trifluoroacetate -ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-benzyloxy-acetamide (example 1, step 2), replacing (3R) -3- (Boc-amino) -pyrrolidine with the ( (S) -1-benzyl-pyrrolidin-3-yl) -methylamine, 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 the trifluoroacetate of N - ((1S, 2R, 3S, 4R) -4- {2-chloro-6- [2- (4-fluoro-phenyl) -2-phenyl-ethylamino] -purin-9 -yl} -2,3-dihydroxycyclopentyl) -propionamide [prepared from tert-butyl acid [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -

2,3-dihydroxy-cyclopentyl] -propionyl-carbamic (intermediate G) and the appropriate amine, using a procedure analogous to that of (2R, 3S, 4R) -4- {6- [2,2-Bis- ( 4-hydroxy-phenyl) -ethylamino] -2-chloro-purin-9-yl} -2,3-dihydroxycyclopentyl) -propionamide (example 22, steps 1 and 2)]. (MH + 693.5).

Example 178

Trifluoroacetate N - {(1S, 2R, 3S, 4R) -4- [2 - {(R) -3- [3- (4-benzyloxy-phenyl) -ureido] -pyrrolidin-1-yl} -6- (2,2-Diphenylethylamino) purin-9-yl] -2,3-dihydroxycyclopentyl} propionamide

This compound is prepared analogously to Example 126, replacing 2-acetamido-4-methyl-5-thiazole-sulfonyl chloride with 1-benzyloxy-4-isocyanate-benzene. (MH + 796.49).

Examples 179-180

Compounds, concretament, trifluoroacetate {(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 delidido (R) -3-amino-pyrrolidine-1-carboxylic acid (MH + 677.5) (ejemplo 179), and trifluoroacetate de {(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 of the acid (S) -3-amino-pyrrolidine-1-carboxylic acid (MH + 683.4) (ejemplo 180), a preparation analogous to 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 delidido (R) -3-dimethylamino-pyrrolidine-1-carboxylic acid (Example 134), reemplandandimethyl- (R) -pyrrolidin-3-yl- amina con la amina apropiada.

Example 181 (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-dihydroxycyclopentyl) -2-hydroxy-propionamide

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

The title compound is prepared by dissolving (R) -2-benzyloxy-propionic acid (1 equivalent) in DMC with 1,3

106

ES 2 384 337 T3 dicyclohexyl-carbodi-imide (1 equivalent) and a catalytic amount of 4-dimethylaminopyridine, stirring for five minutes, and then adding the (1S, 2R, 3S, 5R) -3-amino-5- (2,6-Dichloro-purin-9-yl) -cyclopentane-1,2-diol (intermediate J5; 1-equivalent) in DMC. The reaction is stirred at room temperature until it is determined to be 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-diphenyl-ethylamino) -purin-9-yl] - 2,3-dihydroxy-cyclopentyl} propionamide

The title compound is prepared 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), substituting the (R) -2-benzyloxy-N [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9- yl) -2,3-dihydroxy-cyclopentyl] -propionamide of acetic acid by the N [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -2,3- dihydroxy-cyclopentyl] -propionamide.

Step 3: Ester tert-butylic acid {(R) -1- [9 - [(1R, 2S, 3R, 4S) -4 - ((R) -2-benzyloxypropionylamino) -2,3-dihydroxycyclopentyl] -6- (2,2-Diphenylethylamino) -9H-purin-2-yl] pyrrolidin-3-yl} carbamic acid

A suspension of (R) -2-benzyloxy-N - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -propionamide (1 equivalent) and (3R) - (+) - 3- (Boc-amino) -pyrrolidine (4 equivalents) in acetonitrile, treated with a catalytic amount of sodium iodide, and it is 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; purification by column chromatography / crystallization provides 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

A solution of the acid tert-butyl ester {(R) -1- [9 - [(1R, 2S, 3R, 4S) -4 - ((R) -2-benzyloxy-propionylamino) -2,3-dihydroxy-cyclopentyl] -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -carbamic in MeOH (approximately 0.5 M) is treated with an equal volume of 4 M HCl in dioxane, and stirred at room temperature for 2 hours. The solvent is removed in vacuo, and purification by column chromatography / crystallization is carried out to provide the title compound.

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

A solution comprising (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 equivalent) and pyridin-3-ylcarbamic acid phenyl ester (intermediate ZB) (1 equivalent) 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

To a stirring 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, 10 equivalents of ammonium formate are added and the 20 mole% 10% palladium on carbon. The mixture is stirred at 80 ° C for five hours, allowed to cool, and filtered through Celite.TM. Removal of the solvent under reduced pressure provides the title compound.

Example 182 (S) -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) -2-hydroxy-propionamide

Step 1: (S) -1 - [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) -2,3-dihydroxy-cyclopentyl-carbamoyl] -ethyl ester of acetic acid

The title compound is prepared analogously to intermediate J6, from intermediate J5, replacing propionyl chloride with acetic acid (S) -1-chlorocarbonyl-ethyl ester.

Step 2: ester (S) -1 - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2.3 -dihydroxy-cyclopentyl-carbamoyl} ethyl acetic acid

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The title compound is prepared 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), substituting the ester (S) -1 [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9-yl) - 2,3-dihydroxy-cyclopentyl-carbamoyl] -ethyl acetic acid (example 182, step 1) by the N - [(1S, 2R, 3S, 4R) -4- (2,6-dichloro-purin-9- yl) -2,3-dihydroxy-cyclopentyl] -propionamide.

Step 3: Ester (S) -1 - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-tert-butoxycarbonylamino-pyrrolidin-1-yl) -6- (2,2-Diphenylethylamino) purin-9-yl] -2,3-dihydroxycyclopentylcarbamoyl} ethyl acetate.

The title compound is prepared analogously to {(R) -1- [9 - [(1R, 2S, 3R, 4S) -4 - ((R) 2-benzyloxy-propionylamino) - acid tert-butyl ester 2,3-dihydroxy-cyclopentyl] -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -pyrrolidin-3-yl} -carbamic (example 181, step 3), substituting the ester ( S) -1 - {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl-carbamoyl} - ethyl acetic acid (example 182, step 2) by (R) -2-benzyloxy-N {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -propionamide (example 181, step 2).

Step 4: (S) -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-hydroxy-propionamide

The title compound is prepared 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), substituting the ester (S) -1 - {( 1S, 2R, 3S, 4R) -4- [2 - ((R) -3-tert-butoxy-carbonyl-amino-pyrrolidin-1-yl) -6- (2,2-diphenylethylamino) -purin-9- yl] -2,3-dihydroxy-cyclopentyl-carbamoyl} -ethyl acetic acid (example 182, step 3) by the tert-butyl acid {(R) -1- [9 - [(1R, 2S, 3R, 4S) -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).

Step 5: (S) -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.

2,3-dihydroxy-cyclopentyl} -2-hydroxy-propionamide (example 182, step 4) by (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-diphenylethylamino) -2 - [(R) -3- (3-pyridin-3-yl-ureido) - Pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxycyclopentyl) -3-hydroxypropionamide

The title compound is prepared analogously to (R) -2-benzyloxy-N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R ) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (example 181, step 5), substituting the 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) by the (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

N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R) -3- (3-pyridin-2-ylmethyl-ureido) - Pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxycyclopentyl) -3-hydroxypropionamide

The title compound was prepared analogously to (R) -2-benzyloxy-N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R ) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (example 181, step 5), substituting the 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) by the (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 pyridin-2-ylmethylcarbamic acid (intermediate ZC) by the phenyl ester of pyridin-3-ylcarbamic 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-1-yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -3-hydroxy-propionamide

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The title compound was prepared analogously to (R) -2-benzyloxy-N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R ) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (example 181, step 5), substituting the 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) by the (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) -carbamic acid phenyl ester (intermediate ZD) by pyridin-3-yl-carbamic acid phenyl ester (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} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -3-hydroxy-propionamide

The title compound was prepared analogously to (R) -2-benzyloxy-N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R ) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (example 181, step 5), substituting the 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) by the (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 (4-sulfamoyl-phenyl) -carbamic acid phenyl ester (intermediate ZE) by 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

The title compound was prepared analogously to (R) -2-benzyloxy-N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R ) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (example 181, step 5), substituting the 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) by the (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-sulfamoyl-phenyl) -carbamic acid phenyl ester (intermediate ZF) by 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- (4 (sulfamoyl-phenyl) -ureido] -pyrrolidin-1-yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -3-hydroxy-propionamide

The title compound is prepared 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), substituting the 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) by the 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 product ZG).

Example 189

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) -3-hydroxy-propionamide

The title compound is prepared analogously to N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridine -2-ylmethyl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -3-hydroxy-propionamide (example 184), substituting the 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) by the 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 product ZG).

Example 190

N - [(1S, 2R, 3S, 4R) -4- (6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -2 - {(R) -3- [3- (3 (hydroxybenzyl) ureido] pyrrolidin-1-yl} purin-9-yl) -2,3-dihydroxycyclopentyl] -3-hydroxypropionamide

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The title compound is prepared 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), substituting the 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) by the 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 product ZG).

Example 191

N - [(1S, 2R, 3S, 4R) -4- (6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -2 - {(R) -3- [3- (3 (sulfamoyl-benzyl) -ureido] -pyrrolidin-1-yl} -purin9-yl) -2,3-dihydroxy-cyclopentyl] -3-hydroxy-propionamide

The title compound is prepared 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), substituting the 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) by the 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 product ZG).

Example 192

N - ((1S, 2R, 3S, 4R) -2,3-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

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

A solution comprising: N - ((1S, 2R, 3S, 4R) -4- {2 - ((R) -3-amino-pyrrolidin-1-yl) -6- [2,2-bis- (4 -chloro-phenyl) -2-hydroxyethylamino] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (intermediate ZO; 1 equivalent) and pyridin-3-yl acid phenyl ester -carbamic (intermediate ZB; 1 equivalent) in MP, 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-diphenylethylamino) -2 - [(R) -3- (3-Pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -cyclopentyl) -2-hydroxy-acetamide

To a stirred solution of N - ((1S, 2R, 3S, 4R) -4- {6- [2,2-Bis- (4-chloro-phenyl) -2-hydroxy-ethylamino] -2 - [( R) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide in ethanol, add 10 equivalents of ammonium formate and 20 mole% of 10% palladium on carbon. The mixture is stirred at 80 ° C for five hours, allowed to cool, and filtered through Celite ™. Removal of the solvent under reduced pressure provides the title compound.

Example 193

N - {(1S, 2R, 3S, 4R) -2,3-dihydroxy-4- [2 - {(R) -3- [3- (3-hydroxybenzyl) ureido] pyrrolidin-1-yl } -6- (2-hydroxy-2,2-diphenylethylamino) purin-9-yl] cyclopentyl} -2-hydroxyacetamide

The title compound is prepared analogously to N - ((1S, 2R, 3S, 4R) -2,3-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), substituting the phenyl ester of (3-Hydroxy-benzyl) -carbamic acid (intermediate ZD) by the 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-phenylethylamino) -2 - [(R) -3 - (3-Pyridin-3-yl-ureido) -pyrrolidin-1-yl] purin-9-yl} -cyclopentyl) -2-hydroxy-acetamide

The title compound is prepared analogously to (R) -2-benzyloxy-N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R ) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (example 181, step 5), substituting the ester {(1S, 2R, 3S, 4R) -4- [2-chloro-6 - ((S) -1-hydroxy-methyl-2-phenyl-ethylamino) -purin-9-yl] -2, 3dihydroxy-cyclopentyl-carbamoyl} -methyl acetic acid (intermediate ZM) by the (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).

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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

2,3-dihydroxy-cyclopentyl-carbamoyl} -methyl acetic acid (intermediate ZN) by the (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 196

N - ((1S, 2R, 3S, 4R) -2,3-dihydroxy-4- {2 - {(R) -3- [3- (3-hydroxybenzyl) ureido] pyrrolidin-1-yl } -6 - [(S) -1-hydroxymethyl-2- (4-hydroxyphenyl) ethylamino] purin-9-yl} cyclopentyl) -2-hydroxyacetamide

The title compound is prepared analogously to N - ((1S, 2R, 3S, 4R) -2,3-dihydroxy-4- {6 - [(S) -1-hydroxy-methyl-2 (4- hydroxy-phenyl) -ethylamino] -2 - [(R) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -cyclopentyl) -2-hydroxy- acetamide (Example 195), substituting (3-hydroxy-benzyl) -carbamic acid phenyl ester (intermediate ZD) for pyridin-3-yl-carbamic acid phenyl ester (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-dihydroxycyclopentyl) -2-hydroxy-acetamide

The title compound is prepared analogously to (R) -2-benzyloxy-N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R ) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (example 181, step 5), substituting N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-pyrazol-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -2-hydroxy-acetamide (intermediate ZP) by the (R) -N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino -pyrrolidin-1yl) -6- (2,2-diphenyl-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) -pyrazole-1- yl] -purin-9-yl} -2,3-dihydroxycyclopentyl) -2-hydroxy-acetamide

The title compound is prepared analogously to N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridine -2-ylmethyl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -3-hydroxy-propionamide (example 184), substituting N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-pyrazol-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -2-hydroxy-acetamide (intermediate ZP) by the 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 199

N-[(1S,2R,3S,4R)-4-(6-(2,2-diphenyl-ethylamino)-2-{4-[3-(3-hydroxy-selfish)-ureido]-pyrazole-1 -yl}-purin-9-yl)-2,3-dihydroxyciclopentyl]-2-hydroxy-acetamida

The title compound is prepared 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), substituting N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-pyrazol-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -2-hydroxy-acetamide (intermediate ZP) by the 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 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-dihydroxycyclopentyl] -2-hydroxy-acetamide

111

ES 2 384 337 T3 cyclopentyl} -2-hydroxy-acetamide (intermediate ZP) by the 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 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-dihydroxycyclopentyl] -2-hydroxy-acetamide

The title compound is prepared 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), substituting N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-pyrazol-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -2-hydroxy-acetamide (intermediate ZP) by the 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 202

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

2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (intermediate Zq) by the (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] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide

The title compound is prepared analogously to N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridine -2-ylmethyl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -3-hydroxy-propionamide (example 184), substituting the 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-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (intermediate ZQ) by the 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).

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} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -2-hydroxy-acetamide

The title compound is prepared 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), substituting the 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-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (intermediate ZQ) by the 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).

Example 205

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

The title compound is prepared 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), substituting the 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-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (intermediate ZQ) by the 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).

Example 206

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ES 2 384 337 T3

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

The title compound is prepared 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), substituting the 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-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (intermediate ZQ) by the 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).

Example 207

N-[(1S,2R,3S,4R)-4-(6-(2,2-diphenyl-ethylamino)-2-{4-[3-(3-hydroxy-selfish)-ureido]-pyrazole-1 -yl}-purin-9-yl)-2,3-dihydroxiciclopentyl]-propionamide

The title compound is prepared 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), substituting N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-pyrazol-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -propionamide (intermediate Zr) by the 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) -pyrazole-1- yl] -purin-9-yl} -2,3-dihydroxycyclopentyl) -propionamide

The title compound is prepared analogously to N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridine -2-ylmethyl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -3-hydroxy-propionamide (example 184), substituting N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-pyrazol-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -propionamide (intermediate Zr) by the 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

3-Hydroxy-benzylamide del acid 1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) -9H-purine 2-yl] -1H-pyrazole-4-carboxylic acid

Example 210 1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2 -diphenylethylamino) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic

Example 211 1- [9 - [(1R, 2S, 3R, 4S) -2,3-dihydroxy-4- (2-hydroxy-acetylamino) -cyclopentyl] - (pyridin-2-yl-methyl) -amide 6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic

The title compound is prepared analogously 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 (example 173), substituting 1- [9 - [(1R, 2S, 3R, 4S) -2,3-dihydroxy-4- (2-hydroxy-acetylamino) -cyclopentyl] -6- (2,2-diphenylethylamino) ethyl ester -9H-purin-2-yl] -1H-pyrazole-4-carboxylic (intermediate ZS) by ethyl acid 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, step 1), and C-pyridin-2-yl- methylamine for methylamine.

Example 212

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3-Hydroxy-benzylamide del acid 1- [9 - [(1R, 2S, 3R, 4S) -2,3-dihydroxy-4- (2-hydroxy-acetylamino) -cyclopentyl] -6- (2,2-diphenylethylamino) ) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic acid

The title compound is prepared analogously to 1- [9 - [(1R, 2S, 3R, 4S) - acid (pyridin-2-yl-methyl) -amide

2,3-dihydroxy-4- (2-hydroxy-acetylamino) -cyclopentyl] -6- (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic (example 211 ), substituting C-pyridin-2-yl-methylamine for 3-hydroxybenzylamine.

Example 213 1- [9 - [(1R, 2S, 3R, 4S) -2,3-dihydroxy-4- (2-hydroxy-acetylamino) -cyclopentyl] -6- acid (3-sulfamoyl-phenyl) -amide (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic

The title compound is prepared analogously to 1- [9 - [(1R, 2S, 3R, 4S) - acid (pyridin-2-yl-methyl) -amide

Example 214 1- [9 - [(1R, 2S, 3R, 4S) -2,3-dihydroxy-4- (2-hydroxy-acetylamino) -cyclopentyl] -6- acid (4-sulfamoyl-phenyl) -amide (2,2-diphenyl-ethylamino) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic

The title compound is prepared analogously to 1- [9 - [(1R, 2S, 3R, 4S) - acid (pyridin-2-yl-methyl) -amide

Example 215

N-{(1S,2R,3S,4R)-2,3-dihydroxy-4-[2-{4-[3-(3-hydroxy-selfish)-ureido]-pyrazol-1-yl}-6- ((S)-1-hydroxy-methyl-2-phenylethylamino)-purin-9-yl]-ciclopentyl}-2-hydroxy-acetamida

The title compound is prepared 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), substituting N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-pyrazol-1-yl) -6 - ((S) -1-hydroxy-methyl-2-phenyl-ethylamino ) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide (intermediate ZT) by the 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).

Example 216

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

The title compound is prepared 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), substituting N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-pyrazol-1-yl) -6 - ((S) -1-hydroxy-methyl-2-phenyl-ethylamino ) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide (intermediate ZT) by the 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).

Example 217

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-dihydroxycyclopentyl) -2-hydroxy-acetamide

The title compound is prepared analogously to (R) -2-benzyloxy-N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R ) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (example 181, step 5), substituting 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) by the (R) -N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-aminopyrrolidine -1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl} -2-benzyloxy-propionamide (example 181, step 4).

Example 218

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ES 2 384 337 T3

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-dihydroxycyclopentyl) -2-hydroxy-acetamide

The title compound is prepared analogously to N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridine -2-ylmethyl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -3-hydroxy-propionamide (example 184), substituting N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-imidazol-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -2-hydroxy-acetamide (intermediate ZU) by the 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-selfish)-ureido]-imidazole-1 -yl}-purin-9-yl)-2,3-dihydroxyciclopentyl]-2-hydroxy-acetamida

The title compound is prepared 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), substituting the N - {( 1S, 2R, 3S, 4R) -4- [2- (4-amino-imidazol-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -2-hydroxy- acetamide (intermediate ZU) by the 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 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-dihydroxycyclopentyl] -2-hydroxy-acetamide

The title compound is prepared 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), substituting N - {(1S, 2R, 3S, 4R) -4- [2- (4-amino-imidazol-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -2-hydroxy-acetamide (intermediate ZU) by the 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 221

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

The title compound is prepared analogously to (R) -2-benzyloxy-N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R ) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (example 181, step 5), substituting the N - ((1S, 2R, 3S, 4R) -4- {2- (4-amino-imidazol-1-yl) -6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino ] -purin-9yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (intermediate ZV) by the (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 , stage 4).

Example 222

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

The title compound is prepared analogously to N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridine -2-ylmethyl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -3-hydroxy-propionamide (example 184), substituting the N - ((1S, 2R, 3S, 4R) -4- {2- (4-amino-imidazol-1-yl) -6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino ] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (intermediate ZV) by the 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).

Example 223

N-[(1S,2R,3S,4R)-4-(6-[2,2-Bis-(4-hydroxy-phenyl)-ethylamino]-2-{4-[3-(3-hydroxy-selfish) )-ureido]-imidazol-1-yl}-purin-9-yl)-

2,3-dihydroxy-cyclopentyl] -2-hydroxy-acetamide

115

ES 2 384 337 T3 dihydroxy-cyclopentyl) -2-hydroxy-acetamide (intermediate ZV) by the 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).

Example 224

N - [(1S, 2R, 3S, 4R) -4- [6- [2,2-Bis- (4-hydroxy-phenyl) -ethylamino] -2- {4- [3- (3-sulfamoyl-phenyl) ) -ureido] -imidazol-1-yl} -purin-9-yl) -

2,3-dihydroxy-cyclopentyl] -2-hydroxy-acetamide

The title compound is prepared 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), substituting the N - ((1S, 2R, 3S, 4R) -4- {2- (4-amino-imidazol-1-yl) -6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino ] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (intermediate ZV) by the 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).

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-dihydroxycyclopentyl) -2-hydroxy-acetamide

The title compound is prepared analogously to (R) -2-benzyloxy-N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R ) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (example 181, step 5), substituting 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 (intermediate ZW) by the (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, stage 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-dihydroxycyclopentyl) -2-hydroxy-acetamide

The title compound is prepared analogously to N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridine -2-ylmethyl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -3-hydroxy-propionamide (example 184), substituting 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) by the 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 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-hydroxy-acetamide

The title compound is prepared 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), substituting the 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- dihidroxiciclopentil} -2-hidroxi-acetamida (intermediate product ZW) for N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6 (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihidroxi-cyclopentyl} -3-hidroxi-propionamide (ZG intermediate product).

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-hydroxy-acetamide

The title compound is prepared 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), substituting 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) by the 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

116

ES 2 384 337 T3

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

The title compound is prepared 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), substituting 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) by the 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 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

The title compound is prepared analogously to (R) -2-benzyloxy-N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenylethylamino) -2 - [(R ) -3- (3-pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -propionamide (example 181, step 5), substituting the 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) by the (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-dihydroxy-cyclopentyl) -2-hydroxy-acetamide

2,3-dihydroxy-cyclopentyl) -2-hydroxy-acetamide (intermediate ZX) by the 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).

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

Example 233

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

The title compound is prepared 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), substituting the 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) by the 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).

Example 234

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

The title compound is prepared analogously to N - [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenyl-ethylamino) -2 - {(R) -3- [3

117

ES 2,384,337 T3 (4-Sulfamoyl-phenyl) -ureido] -pyrrolidin-1-yl} -purin-9-yl) -2,3-dihydroxy-cyclopentyl] -3-hydroxy-propionamide (ejemplo 186), substituting the 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) by the 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).

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

Etapa 1: N - {(3aR, 4S, 6R, 6aS) -6- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,2-dimethyl-tetrahidro- cyclopenta [1,3] dioxol4-yl} -propionamide

The title compound is prepared by dissolving the 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 provide the title compound.

Step 2: N - {(3aR, 4S, 6R, 6aS) -6- [2- [2- (4-chloro-phenyl) -ethoxy] -6- (2,2-diphenyl-ethylamino) -purine-9 -yl] -2,2-dimethyl-tetrahydrocyclopenta [1,3] dioxol-4-yl} -propionamide

The title compound is prepared by adding the N - {(3aR, 4S, 6R, 6aS) -6- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -

2,2-dimethyl-tetrahydro-cyclopenta [1,3] dioxol-4-yl} -propionamide (example 235, step 1) to a pre-mixed solution of sodium hydride (60% in oil) and 2- (4 -chloro-phenyl) -ethanol (1 equivalent) in dry THF. The reaction is stirred at 50 ° C for 48 hours, before quenching residual sodium hydride with excess aqueous ammonium chloride. The reaction mixture is then partitioned between ethyl acetate and water; the organic phase is washed consecutively with water and brine, before drying over magnesium sulfate. Filtration and removal of volatile components under reduced pressure provides the crude product; purification by column chromatography / crystallization provides the title compound.

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

The title compound is prepared by dissolving the N - {(3aR, 4S, 6R, 6aS) -6- [2- [2- (4-chloro-phenyl) -ethoxy] -6- (2,2-diphenylethylamino) - purin-9-yl] -2,2-dimethyl-tetrahydro-cyclopenta [1,3] dioxol-4-yl} -propionamide (example 235, step 2) in THF, adding an equal volume of 1.0 M hydrochloric acid , and stirring at room temperature for 48 hours, before diluting with water, and extracting into ethyl acetate. The organic phase is dried over magnesium sulfate, filtered, and the volatile components are removed under reduced pressure to provide the title compound.

Example 236

4- {3- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenyl-ethylamino) -9Hpurin- methyl ester 2-yl] -prop-2-ynyl} -cyclohexane-carboxylic acid

The title compound is prepared by combining the 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 (prepared as described by Rieger JM, Brown ML, Sullivan GW, Linden J. and Macdonald TL '; J. Med Chem. (2001), 44, 531-539), copper (I) iodide, triphenylphosphine, and dichloro-bis- (triphenylphosphine) -palladium (II) in a 2: 1 mixture of TEA / dimethylformamide, and heating by microwave irradiation for 3600 seconds at 120 ° C. Purification by column chromatography provides the title compound.

Example 237

Acid ethylamide (2S, 3S, 4R, 5R) -5- (6- (2,2-diphenyl-ethylamino) -2- {4- [3- (3-hidroxi-bencil) -ureido] -pirazol-1 -il} -purin-9-il) -

3,4-dihydroxytetrahydrofuran-2-carboxylic acid

Step 1: Acid ethylamide (2S, 3S, 4R, 5R) -5- [2- (4-amino-pyrazol-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl ] -3,4-dihydroxytetrahydro-furan-2-carboxyl

118

ES 2 384 337 T3 carboxylic acid (intermediate ZY) by the ester {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy-cyclopentyl-carbamoyl} -methyl of acetic acid (intermediate Q1) in step ZP1.

Step 2: Ethylamide del acid (2S, 3S, 4R, 5R) -5- (6- (2,2-diphenylethylamino) -2- {4- [3- (3-hydroxybenzyl) ureido] - pyrazol-1-yl} purin-9-yl) -3,4-dihydroxytetrahydrofuran-2-carboxylic acid

The title compound is prepared 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), substituting the ethylamide of the acid ( 2S, 3S, 4R, 5R) -5- [2- (4-amino-pyrazol-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -3,4-dihydroxy-tetrahydro -furan-2-carboxylic (example 237, step 1) by 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 238

Ethylamide del acid (2S, 3S, 4R, 5R) -5- (6- (2,2-diphenylethylamino) -2- {4- [3- (3-hydroxybenzyl) ureido] imidazole-1 -yl} purin-9-yl) -3,4-dihydroxytetrahydrofuran-2-carboxylic acid

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

The title compound is prepared analogously to 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), substituting (2S, 3S, 4R, 5R) -5- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -3,4-dihydroxy-tetrahydro-furan acid ethylamide -2carboxylic (intermediate ZY) by the ester {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxy -cyclopentyl-carbamoyl} -methyl acetic acid (intermediate Q1) in step ZU1.

Step 2: Ethylamide del acid (2S, 3S, 4R, 5R) -5- (6- (2,2-diphenylethylamino) -2- {4- [3- (3-hydroxybenzyl) ureido] - imidazol-1-yl} purin-9-yl) -3,4-dihydroxytetrahydrofuran-2-carboxylic acid

The title compound is prepared 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), substituting the ethylamide of the acid ( 2S, 3S, 4R, 5R) -5- [2- (4-amino-imidazol-1-yl) -6- (2,2-diphenyl-ethylamino) -purin-9-yl] -3,4-dihydroxy-tetrahydro -furan-2-carboxylic (example 238, step 1) by 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 239

Ethylamide del acid (2S, 3S, 4R, 5R) -5- (6- (2,2-diphenylethylamino) -2- {3- [3- (3-hydroxybenzyl) ureido] - [1, 2,4] Triazol-1-yl} purin-9-yl) -3,4-dihydroxytetrahydrofuran-2-carboxylic acid

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

The title compound is prepared 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-dihydroxy-cyclopentyl} -2-hydroxy-acetamide (intermediate ZW), substituting the ethylamide of the acid (2S, 3S, 4R, 5R) -5- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -3,4-dihydroxy-tetrahydro-furan-2-carboxylic (intermediate ZY) by the {(1S , 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl-carbamoyl} -acetic acid methyl ester (product intermediate Q1).

Step 2: Ethylamide del acid (2S, 3S, 4R, 5R) -5- (6- (2,2-diphenylethylamino) -2- {3- [3- (3-hydroxybenzyl) ureido] - [1,2,4] triazol-1-yl} purin-9-yl) -3,4-dihydroxytetrahydrofuran-2-carboxylic acid

3,4-dihydroxy-tetrahydro-furan-2-carboxylic acid (example 239, step 1) by the 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).

Example 240

Ethylamide del acid (2S, 3S, 4R, 5R) -5- (6- (2,2-diphenylethylamino) -2 - {(R) -3- [3- (3-hydroxybenzyl) ureido] -pyrrolidin-1-yl} purin-9-yl) -3,4-dihydroxytetrahydrofuran-2-carboxylic acid

119

ES 2 384 337 T3

(2S, 3S, 4R, 5R) -5- [2 - ((R) -3-amino-pyrrolidin-1-yl) -6- (2,2-diphenyl-ethylamino) purin- 9-yl] -3,4-dihydroxy-tetrahydro-furan-2-carboxylic (intermediate E) and (3-hydroxybenzyl) -carbamic acid phenyl ester (intermediate UA) are dissolved in methanol and TEA. The reaction mixture is heated using microwave radiation at 100 ° C for 30 minutes in the 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 provide the compound of the title.

Example 241

Ethylamide del acid (2S, 3S, 4R, 5R) -5- (6- (2,2-diphenylethylamino) -2 - {(R) -3- [3- (4-sulfamoyl-phenyl) -ureido] -pyrrolidin-1-yl} purin-9-yl) -3,4-dihydroxytetrahydrofuran-2-carboxylic acid

This compound is prepared analogously to Example 240 by replacing (3-hydroxybenzyl) -carbamic acid phenyl ester (intermediate UA) with (4-sulfamoyl-phenyl) -carbamic acid phenyl ester (intermediate UD).

Example 242

Ethylamide del acid (2S, 3S, 4R, 5R) -5- (6- (2,2-diphenylethylamino) -2 - {(R) -3- [3- (3-sulfamoyl-phenyl) -ureido] -pyrrolidin-1-yl} purin-9-yl) -3,4-dihydroxytetrahydrofuran-2-carboxylic acid

This compound is prepared analogously to Example 240, replacing (3-hydroxybenzyl) -carbamic acid phenyl ester (intermediate UA) with (3-sulfamoyl-phenyl) -carbamic acid phenyl ester (intermediate UC).

Example 243

Ethylamide del acid (2S, 3S, 4R, 5R) -5- {6- (2,2-diphenylethylamino) -2 - [(R) -3- (3-pyridin-2-ylmethyl-ureido) -pyrrolidine -1-yl] -purin9-yl} -3,4-dihydroxytetrahydrofuran-2-carboxylic acid

This compound is prepared analogously to Example 240, replacing (3-hydroxybenzyl) -carbamic acid phenyl ester (intermediate UA) with pyridin-2-ylmethyl-carbamic acid phenyl ester (intermediate EU).

Example 244

Ethylamide del acid (2S, 3S, 4R, 5R) -5- [2 - {(R) -3- [3,4-dioxo-2- (pyridin-3-ylamino) -cyclobut-1-enyl- Amino] -pyrrolidin-1-yl} -6- (2,2-diphenylethylamino) -purin-9-yl] -3,4-dihydroxytetrahydrofuran-2-carboxylic acid

Step 244a: Ethylamide del acid (2S, 3S, 4R, 5R) -5- {6- (2,2-diphenylethylamino) -2 - [(R) -3- (2-methoxy-3,4-dioxo) (Cyclobut-1-phenylamino) -pyrrolidin-1-yl] -purin-9-yl} -3,4-dihydroxy-tetrahydro-furan-2-carboxylic acid

A mixture comprising the acid ethylamide trifluoroacetate (2S, 3S, 4R, 5R) -5- [2 - ((R) -3-amino-pyrrolidin-1-yl) 6- (2,2-diphenyl-ethylamino ) -purin-9-yl] -3,4-dihydroxy-tetrahydro-furan-2-carboxylic acid (intermediate E) and 3,4-dimethoxy3-cyclobutene-1,2-dione in absolute EtOH and DMAPcat., heat 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 resulting crude product is partitioned between ethyl acetate and water. The organic part is separated, dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography on silica gel, eluting with EtOAc / isohexane (30 to 100% EtOAc) provides the title compound.

Step 244b: Ethylamide del acid (2S, 3S, 4R, 5R) -5- {6- (2,2-diphenylethylamino) -2 - [(R) -3- (2-methoxy-3,4-dioxo) (Cyclobut-1-phenylamino) -pyrrolidin-1-yl] -purin-9-yl} -3,4-dihydroxy-tetrahydro-furan-2-carboxylic acid

A mixture comprising the acid ethylamide (2S, 3S, 4R, 5R) -5- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (2-methoxy-3,4-dioxo -cyclobut-1-enyl-amino) -pyrrolidin-1-yl] -purin-9-yl} -3,4-dihydroxy-tetrahydro-furan-2-carboxylic acid (step 244a) in absolute EtOH and a catalytic amount of TsOH heated using microwave radiation in a Personal Chemistry Emrys ™ Optimizer microwave reactor at 150 ° C for 4000 seconds. The solvent is removed in vacuo, and the resulting crude product is partitioned between ethyl acetate and water. The organic part is separated, dried (Na2SO4) and concentrated in vacuo. Purification by C-18 reverse step column chromatography eluting with acetonitrile: water (0.1% TFA) (0-100% acetonitrile gradient) provides the title compound.

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Example 245

Ethylamide del acid (2S, 3S, 4R, 5R) -5- (6- (2,2-diphenylethylamino) -2 - {(R) -3- [2- (3-hydroxybenzylamino) - 3,4-Dioxo-cyclobutyl-enylamino] -pyrrolidin-1-yl} -purin-9-yl) -3,4-dihydroxy-tetrahydro-furan-2-carboxylic acid

This compound is prepared analogously to Example 244 by replacing 3-aminopyridine with 3-hydroxybenzylamine.

Examples 246 to 253

These compounds are prepared from the product of example 26, step 2, following a procedure analogous to that of example 26, step 3, replacing the 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-dihydroxycyclopentyl) -2-hydroxy-propionamide

Step 1: (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.

HATU (61 mg, 0.16 mmol) and R - (+) - 2-benzyloxy-propionic acid (32 mg, 0.16 mmol) are dissolved in dimethylformamide (5 ml) and, after stirring 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-yl-urea (example 26, step 2) (0.1 g, 0.16 mmol) in dimethyl-formamide ( 0.5 ml). DIPEA (56 ml, 0.32 mmol) is added, and the resulting solution is stirred for 2 hours. The mixture is then treated with Na2CO3 saturated and 1 ml of MeOH, and then partition between EtOAc and water. The organic part is separated and concentrated in vacuo. The resulting crude product is purified by reverse phase column chromatography (Isolute ™ C18, 0-100% acetonitrile in 0.1% HCl water) to provide 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

A solution of the (R) -N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (3-pyridine- 3-yl-ureido) -pyrrolidin-1-yl] purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-phenoxy-propionamide (83 mg, 0.104 mmol) in EtOH (20 ml) and THF ( 5 ml) under an inert atmosphere, it is treated with palladium hydroxide (20% by weight on carbon, 32 mg) followed by acetic acid (2 ml). The reaction mixture is placed under an atmosphere of hydrogen for two weeks, after which time the mixture is filtered and concentrated in vacuo. The resulting crude product is washed with EtOH (3 times), filtered, and then concentrated in vacuo. The residue is dissolved in MeOH (2 ml), and purification by reverse phase column chromatography (Isolute ™ C18, 0-100% acetonitrile in water - 0.1% NH3) provides the title compound as a white solid. (MH + 707.4)

Sample 255 (S) -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) -2-hydroxy-propionamide

A mixture comprising 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 (example 26, step 2) (0.1 g, 0.16 mmol) and TEA (24 ml 0.18 mmol) in THF (7 ml) at room temperature, treated with (S) - (-) - 2-acetoxy-propionyl chloride (24 mg, 0.16 mmol) in MeCN (1 ml) to (0 ° C) for 1 minute. The mixture is left stirring at room temperature for 18 hours and then treated with Na2CO3 saturated (1 ml) and MeOH (1 ml), then stirred for an additional 2 days. The solvent is removed in vacuo, and purification by reverse phase column chromatography (Isolute ™ C18, 0-100% acetonitrile in water - 0.3% NH3) provides 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-pi ridin-3-yl-ureido) - pyrrolidin-1-yl] -purin-9-yl} -2,3-dihidroxiciclopentil) -2-hidroxi-2-methyl-propionamide

This compound is prepared analogously to Example 255, replacing (S) - (-) - 2-acetoxy-propionyl chloride with 2-acetoxy-isobutyryl chloride. The ester hydrolysis is carried out in the presence of 1M NaOH in MeOH. (MH + 721.5)

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Example 257

N - {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-aminopyrrolidin-1-yl) -6 - ((S) -1-hydroxymethyl-2-phenyl -ethylamino) -purin-9-yl] -2,3-dihydroxycyclopentyl} -2-hydroxyacetamide

This compound is prepared from N - {(1S, 2R, 3S, 4R) -4- [6 - ((S) -1-benzyl-2-hydroxy-ethylamino) -2-chloro-purin-9- il] -

2,3-dihydroxy-cyclopentyl} -2-hydroxy-acetamide (intermediate VD), analogously to the hydrochloride of 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) -2-hydroxy-acetamide (example 7, stage 5). (MH + 527.26).

Example 258

Trifluoroacetate and methyl acetic acid {(1S, 2R, 3S, 4R) -4- [2 - ((R) -3-aminopyrrolidin-1-yl) -6- (2,2-diphenylethylamino) purine -9-yl] -2,3-dihydroxycyclopentyl} carbamico

This compound is prepared from the acid methyl ester {(1S, 2R, 3S, 4R) -4- [2-chloro-6- (2,2-diphenyl-ethylamino) purin-9-yl] -2,3 -dihydroxy-cyclopentyl} -carbamic (intermediate T), analogously to N ((1S, 2R, 3s, 4R) -4- {2 - ((R) -3-amino-pyrrolidin-1-yl hydrochloride ) -6- [2,2-bis- (4-hydroxy-phenyl) -ethylamino] -purin-9-yl} -2,3-dihydroxycyclopentyl) -2-hydroxy-acetamide (example 7, step 5). (MH + 572.21).

Examples 259-261

These compounds, specifically,

N-((1S,2R,3S,4R)-4-{6-((S)-1-selfish-2-hydroxy-ethylamino)-2-[(R)-3-(3-pyridine-3-) yl-ureido)-pyrrolidin-1-yl]-purin-9-yl}-2,3dihydroxy-ciclopentyl)-2-hydroxy-acetamida (MH+ 647.01) (ejemplo 259),

N - [(1S, 2R, 3S, 4R) -4- (6 - ((S) -1-benzyl-2-hydroxyethylamino) -2 - {(R) -3- [3- (4-sulfamoyl) (phenyl) -ureido] -pyrrolidin-1-yl} -purin-9-yl) -2,3-dihydroxycyclopentyl] -2-hydroxy-acetamide (MH + 724.99) (ejemplo 260) and methyl acid [(1S, 2R, 3S, 4R) -4- (6- (2,2-diphenylethylamino) -2 - {(R) -3- [3- (3-sulfamoyl-phenyl) -ureido] -pyrrolidine -1-yl} purin-9-yl) -2,3-dihydroxycyclopentyl] carbamic acid (MH + 771.34) (ejemplo 261), They are prepared from the appropriate starting compounds and the corresponding pyrrolidinyl urea (the preparation is described herein), analogously to Example 15.

Example 262 1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2 -diphenylethylamino) -9H-purin-2-yl] -1H-pyrazole-4-carboxylic

Step 1: Acido 1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) -9H-purin-2 -yl] 1H-pyrazole-4-carboxylic QBA289

A solution comprising 1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylaminocyclopentyl) -6- (2,2-diphenyl-ethylamino) -9H- purin-2-yl] -1H-pyrazole-4-carboxylic (example 173, step 1) (0.4 g, 0.64 mmol) in water (3 ml), treated with 1 M KOH in MeOH (6 ml ), and stirred at room temperature for 48 hours. The solvent is removed in vacuo, and the resulting crude product is dissolved in water (5 ml) and acidified to pH 3 to 4 with 1.5N HCl. The solution is extracted with EtOAc, and the organic part is dried over sodium sulfate. and concentrated in vacuo. Purification by chromatography on silica, eluting with 5% MeOH in chloroform, provides the title compound.

Step 2: 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

A mixture comprising 1- [9 - ((1R, 2S, 3R, 4S) -2,3-dihydroxy-4-propionylamino-cyclopentyl) -6- (2,2-diphenylethylamino) -9H-purin-2 acid -yl] -1H-pyrazole-4-carboxylic acid (0.06 g, 0.01 mmol) in dry DMC (10 ml), treated with 2-aminomethyl-pyridine (0.021 g, 0.2 mmol), followed by HOBt (0.027 g, 0.2 mmol), 1- [bis (dimethylamino) -methylene] -1H-benzotriazolium hexafluorophosphate 3-oxide hBtU (0.076 g, 0.2 mmol), N-methyl-morpholine ( 0.02 g, 0.2 mmol), and 4-dimethylaminopyridine (1 ml). The resulting mixture is stirred at room temperature for 24 hours, and then concentrated in vacuo. The resulting residue is purified by preparative thin-layer chromatography, eluting with 10% MeOH in chloroform, to provide the title compound. (MH + 687.1).

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Example 263

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

2,3-dihydroxy-cyclopentyl) -3-hydroxy-propionamide

This compound is prepared analogously to (R) -N - ((1S, 2R, 3S, 4R) -4- {6- (2,2-diphenyl-ethylamino) -2 - [(R) -3- (35 pyridin-3-yl-ureido) -pyrrolidin-1-yl] -purin-9-yl} -2,3-dihydroxy-cyclopentyl) -2-phenoxy-propionamide (example 254, step 1), replacing acid R - (+) - 2-benzyloxy-propionic with 3-tert-butoxy-propionic acid. (MH + 707.4).

Example 264

Chlorhydroto de (R)-2-benciloxi-N-((1S,2R,3S,4R)-4-{6-(2,2-diphenyl-ethylamino)-2-[(R)-3-(3-) pyridin-3-yl-ureido)-pyrrolidin-1yl]-purin-9-yl}-2,3-dihydroxy-ciclopentyl)-propionamide

This compound is prepared 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 acid R- (+) - 2-benzyloxy-propionic with (R) -2-benzyloxy-propionic acid. (MH + 797.7).

123

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Priority claims
Document	Office	Kind	Date
0607947	United Kingdom	A	2006-04-21
0607947	United Kingdom	A	2006-04-21
0607947	United Kingdom	–	2006-04-21
07101483	European Patent Office (EPO)	A	2007-01-31
07101483	European Patent Office (EPO)	A	2007-01-31
07101483	European Patent Office (EPO)	–	2007-01-31
2007003435	European Patent Office (EPO)	W	2007-04-19
2007003435	European Patent Office (EPO)	W	2007-04-19
0607947	–	–	–
07101483	–	–	–
EP20070101483	–	–	–
GB20060007947	–	–	–
PCTEP2007003435	–	–	–
WO2007EP03435	–	–	–