LU505117B1 - A pan-KRAS inhibitor compound - Google Patents
A pan-KRAS inhibitor compound Download PDFInfo
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- LU505117B1 LU505117B1 LU505117A LU505117A LU505117B1 LU 505117 B1 LU505117 B1 LU 505117B1 LU 505117 A LU505117 A LU 505117A LU 505117 A LU505117 A LU 505117A LU 505117 B1 LU505117 B1 LU 505117B1
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 265
- 229940124785 KRAS inhibitor Drugs 0.000 title abstract description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 61
- 125000002947 alkylene group Chemical group 0.000 claims description 49
- 150000003839 salts Chemical class 0.000 claims description 42
- 229910052757 nitrogen Inorganic materials 0.000 claims description 39
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 27
- 229910052760 oxygen Inorganic materials 0.000 claims description 27
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 26
- 125000005842 heteroatom Chemical group 0.000 claims description 26
- 229910052717 sulfur Inorganic materials 0.000 claims description 24
- 230000000155 isotopic effect Effects 0.000 claims description 22
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 21
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 15
- 229910052705 radium Inorganic materials 0.000 claims description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 10
- 125000004429 atom Chemical group 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 229910052792 caesium Inorganic materials 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 210000004072 lung Anatomy 0.000 claims description 3
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- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 10
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- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 229950003081 volasertib Drugs 0.000 description 1
- SXNJFOWDRLKDSF-STROYTFGSA-N volasertib Chemical compound C1CN([C@H]2CC[C@@H](CC2)NC(=O)C2=CC=C(C(=C2)OC)NC=2N=C3N(C(C)C)[C@@H](C(N(C)C3=CN=2)=O)CC)CCN1CC1CC1 SXNJFOWDRLKDSF-STROYTFGSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D515/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Claims (2)
- on fo) © © 4e, ee, ele GO LU505117 / o "ox, Le de TH fon Os SN 0 ° N 76H / yA on / o oA A I Fy oN © N J, N ® 0 ñ © / NTN N SS = > Nes Pa n=l," ” = NS A > NA = N = N N Ny ÿ 4 — J N — A + / oN où Jd / A) - (a \ ON \ Os X oO o GA 0 ©) A $ N ©) i 5 N 9 Oy neo Og NG / NON O on, À à Mel À EN i o N J NN / Neo / o Mol doe 3 N= LUN a n=l " (Le ‘yg N © ° H X N SS 5 N= 2 N= ®\_0 N = S NA NA N = N AS N N (4 7 rN N J J _ ) — f — Ÿ Ÿ / J oj J WN dN ON Oy GA IN d Or GA 0 0. Gr 0 0 © 0 Toy A TN 1 3 N 1 hi wre { / NT NS 0 ol, A 0 ex, À Ho N © NN oS NN / a / © ue, 5 Na 5 wd #10 0 H 0 H > > © N= ANN a, N= © <>; = N: 5 N LS > Ss } 4 "Ng NS NA > N — N N Va Ÿ — J — J oh oN ( / dN / / \ oN o la de GA GA | © N Ou NO es d Ho X bi N 1 oy N° e vs esp / N oO (S) o Hu À SON o 9 N / N / NN o fy or © N qd, H 0 H / N N = NA, Sy N= (Le Og F o NA À N= > N = S X v / rN N > > N N ON ÿ / J J N — AN — / oq N Jd 7 —_ À — \ _ oN oo A oy Ge 95 Os lod oO ©. 6 oO ex N a 9 SONT a OSSI SE / 9 hd, / oT Ay 5 / 3 Fo LE, 3 Mol AC 0 ñ N 3 NA + 9 Nn Og nA * Og EO 9 dy 6 N = N Ss Ss N= A MN = MN 0 = NA | 7 N N N = + + N I — 7 7 yo oN \— \ ON oO N A ox, Ge °, mn Os es o 4 o. fo o o. fa o Hu Jete q N s) 1 3 N 9 + N D; J N / NON / 9 9 n° Los / © Fy 5 N 9, HOLA 9 H 9 0 N N ~ SL, N=" (8) 5] N Ls N AS s Ne an MN Mg > My = o” N — N N 7 J — J J — — MH 4 oN oN oN ON y \ \ ooo où © N Os NL50 HO AS 6) A Fe 1 = 0H TON 4 A Os à 7 Ox ® NO / NN o "Ah om 6 "A J | IN L = d MONT / NOONTSH / NON Fel N 5 = Q H o H ©) / NON © 5 Na © N J OC N = N Ss s 2 N= NÉ X N > 5 4 7 rN N > 5 N N NZ Ÿ y A 4 J N IN — 4 ÿ — IN IN IN — Àf i \ oN dN i ole) 0 Os GA 0 ©} ©} J H © 1 TH q Oy Na ose J NONE / oO 128 , o Mok J @ JH ie 3 YA» en Og Ea © de nd A ty d, OR © NA 7 > NA => N VS Me Ÿ 4 } 4 A NS 7 > N J J J N IN 4 + Ÿ ÿ ÿ — dN / 7 ON aN i ole do ole No © © 8) 5 38 OO NO OS 3 H (5), A A H 5) 1 1 N i 5 hy N ’ fi id y Te 0 (5) © ô ok, À Ho À J J, N 5 J SLIN N 5 J ON NT / © SN > #55 PE 9 QT 5 @ nA Og Lo Ng = N SS N Ds N Na N AN ¢ UNNA yo — N N Va fo — J J A — — 7 7 oN oN od nN 9 i \ NBL-5758 GO 6 6 ©) LU505117 5) Ss) 5) oy NN °° Os WN © oy NN à Op ZN °, o "eu À © o Hoel Je / o FM © o "Tu À © J NA 9 n°6 0 N J NRE 5) N= 5) N= > 5) N= > 5) N= N 2/8 = = = NA NA 4 NA 7 A N N N N J = , À 1 À — NS Nu N N Lg > /os. yh Pa os y °9 Og y” °e ; 1 te o (9 oO (3) go) fo) (3) (9 70 J, VE d NE d NE “a nl S) N= > Ss) N=" > S) N= > N Ss = = = Lu A NS 7 PN 4 MN Da N N N J / Jo Jo ya 7 & ® & © N N N N / / GA © 6.1 oA Op SN 9 Os EN oy oy SN °° Oy y" 95 o Hu Je à Hel Jeg o Hoel Je , o ON J 6 À n°6 J SE 5 HG S) N= S) N= S) N= 5) N= s A AN A NA 9 > N > N a o / / . © ® N N— cy N N\0. lo ° 0, fk Pa oa ° os. oH °0 oO & bs) oO ©) bs) oO (3) (5) oO (3) (5) J, ONE d, WE dd. Ty Ed Thy Vo NA Ms NN AR N _ N N / / J = Jo — A (9 ® Hn NP N Un oy GA °° Oy GA °e Oy GA °° Oy GA 90 H H H H ° oh Js 0 ok Js ° SA, À o À, Js4. de VE d, ONE dd. aL d. Ba SS = 8 Ss NS 9 A Mg NA N N — DB mn / / / = og N Sn CN oN Oy A 9 Os GA 99 Os GA °o Oxy GA 99 , o Hel Je 1 Hol Je , o Hoel Je , o "ek Je d. a 4. ve J. a 4. RA NS 9 Mg NA 9 NA N N _ N 4 J —A / / as 0/7 N SON N N: HN Ny Cr OH 0 \ 119 ogo, ogo, ols Ge LU505117 H CN © SUNT a oO aly Ms o "ell J H 5 / nH y AD A 0 oN, À a Hou “2 A © Os N= H © Jd NRE J N pe > 5 N= ( = N = N ee LS 5 (> 4 CN Pv ny > JN { N N / ÿ # \ y N u a — Ny X y NN Ney X Os X o 6) X i N o Os. EN Os ©. oy feds 1 FFLier SDS TCs 0 À, Ao 9 H S / © Pa / © Ta de A ve N 2 = “a IE ve Og, EO ve = 5 5 Ng ~~ @ 4 oO NA 7 @ NA > N A ç N N / Q ( ÿ N ÿ N ® Q SS cl N NS NH,ox. oy o Shen Q a a sly À, Oso NO Osi NO © d N te Z TN 1 SUN 9 Oy NMC © H 0 oN Jo o ol À H . = d Ne / N C6 A / a © ws NA 7 7 = N= “ea nA © A wel " © N = SS 5 > NS NA NS = 7 5 N N / Ÿ : # — \ ÿ — CO 9 CN IN © 7 — \ AN = 9 OS NO rE NO OO M0 / A “© y Te J Ho 5 © / 2 He 5 © J He 3 (DS a LVO de NUR de Na dr NZ > N= = n= N = 5 SS 5 CS Mg > Nv NS 4 > - A Bm _ 5 > . / FN ~ 4 SN ÿ IN A \ o N Og N Om N \ od Ho Os, © 9, Oy © 06 Os 6) o o. 6) o COTY, , 2° A o YC, WLS 5) / (5) ad, wd # Vo Os N= N de Na N A dq, N No N > = N = 5 5 Mg ad n=) = Lu ~ N N J J _— } A Ÿ + À / J + ON 9 ay © ay N Cw “Ron 5 PR) is) Ho OH on Os © 9, Ox. 6) o Os © o 0. © o oo ee AL PEE TL d N © NRE / No © © n= de vd # © od WL Hh ve J N NRA N os 5 > A a Da © 4 5 7 7 — 5 N N — J ya J ore a or Ow d d \ \oc lao oc lado on le he oo lao LUS05117 1 He 3 (8) 3 He 3 © 3 How 3 © 3 He 3 © o N RE o N Ci o N Ci o N Ci 3 N= a N= a N= a N= YN 7 > NE 7 > "A > MN 7 > _— _— _— _—HO.45) Ÿ HOW) Ÿ EF. 7 Fa® 7 DO Tn © +, or bod °e DR O5 on °e DR 9a H i H | Hol À ° A, Js à Hl J. y Ô SA, Ais y o [A A x A iv] 4, N N qd, N Ne J, ea J Ss = Ss 8 NA > Nf 7 as Mg N N N N Jo / / J — PR 99 ou ih ° 0 ou oh 05 or lh °°N . ; ° sh is o Hk Jl H | H (5 4 hte do LWA Cw 4 = = a = . = x = 5 Hy . = 4 PN a Ne N N N ZA 4 a vo ° N > Og LP (D Dr {Ln Oy GA Oo Ope (A © Oy GA 99 Os (A 9 / © A te @ qd Hol de , o "el Je , o "eg el @ Og Ea d N IE 0 of To d H ¥ N Ny © N= 2 n= Q N= LÀ N = N => N — N A yg a J Bi > > N 7 I A any ÿ I 4 ! gn $ N d N GS \ \ \ 5 Oy GA a Oy GA © Oy GA 99 Oxy GA o H ON a 0 hy Hu o Hel J. o Tel J. TH oO Adee X Ver 4 Ver LA Re 2 N= 9 N= Q N= °g Ea N VS N Ny N = SS Di AS NS NEA 5 5 N 7 A A Jo N N N \ al N o <q ol J N 0 ©) nn H | H I o ol Mg / Tha o ok, Ag o EX, hs J A 6 Ce 14 A VO of N°75 J on ec 3 NA, N Ts 3 N= 3 N= Ç = NA > ai NA NA à N N N N AN J ya = J N Ÿ \ N Y . Ÿ N N N = TS > oS \_/ N ° 121BL-5758 LU505117 Ansprüche1. Verbindung mit einer Struktur der Formel (I) oder ein pharmazeutisch annehmbares Salz, Isotopenderivat oder Stereoisomer davon: NT O o O (R) yo N= Rs" Ra s N J Re / \ Ÿ — N J Re’ Ry Ra m R7 R7' (D wobei Rı steht für C1-Ce-Alkyl, vorzugsweise C1-C3-Alkyl; o— o— Ra steht für = , Vorzugsweise À ; Rs steht fur -O(C1-C6)-Alkyl, -O (Co-Cs-Alkylen) (C3-Cs) Zykloalkyl, -O (Co-Ce-Alkylen) (3-8 gliedriges) Heterocycloalkyl, -O (Cz-C6-Alkylen )RL oder Wasserstoff, -Cy1-(R4) in der Formel (I) ist ausgewählt aus den folgenden: 1BL-5758 on > Fo ; . bn me LU505117 (9) {0 +. x “né NA + Ve 7 V6 Re “RA F NTP " (> “rh WAN SA Ey © LUN _o who EN Ss) N° N (S) N RS #8 . N A N. 7 RR NC 70 Ne * © NLP “Rg ©? ©) O s) N (s) (Ss) (s) (R) S N N N — re LM / (9 Ro *.(5) - “er “As NA ue 76 oH in OH “6 © / ~, HO | oO o cor + d Soo. * AN ; * + (9/R N 3 QG .. 6 0 NG a A 9 N A O À+. NT te WK we do x, = | 208 # IJ (S) ) un Lo wobei, * steht für die Stelle, an der -Cy1-(R4)p mit der Verknüpfungsstelle in Formel (I) verbunden ist; Rs steht fiir-Cy2-(Rs)q oder-NRoRo', wobei, -Cy2-(R5)q in der Formel (I) ausgewählt ist aus den folgenden: 2BL-5758 . ; , LU505117 . * ÿ * ®) = ei © (R) (Ss) = of of ot CN Ë Ci- N (7 / / \ cS X as D d X 37 N- LH a N-* DR 7 a \ = rn Yen ja or a A AS N Cop (s) (A) Cx NTT AAMT 4 4 Co Cg NT _, / NX, Ses _ /\ /\ IN {Nm 0 Re = * Sp Op N° Le Aer “Un OH Q HO Ho OH nd _ HO.(s) HOR) 0 N IN De * Re ee “Un AD IN x OST = = CH QC = TS Ne ANT M MN SM A SG 84 N-N NH, N N wobei, * steht für die Stelle, an der -Cyz-(Rs)g mit der Verknüpfungsstelle in Formel (I) verbunden ist;Ro and Ro jeweils stehen unabhängig voneinander für C1-C6-Alkyl , das gegebenenfalls durch q Rs substituiert sein kann;Rs steht für Wasserstoff, Halogen, C1-Ce-Alkyl, -(Co-Cs-Alkylen) ORa, -(Co-C6- Alkylen) NRaRa'; oder Rs an den beiden C-Atomen von Cyz zusammen mit den damit verbundenen C-Atomen und den Atomen zwischen den beiden C-Atomen einen 3-8- gliedrigen Ring bilden kann, und der 3-8-gliedrige Ring gegebenenfalls 0, 1, 2 oder 3 Heteroatome, ausgewählt aus N, O oder S, enthalten kann; oder zwei Rs an demselben C-Atom von Cy: sind und das damit verbundene C-Atom einen 3-8-gliedrigen Ring bilden kann, und der 3-8-gliedrige Ring gegebenenfalls 0, 1, 2 oder 3 Heteroatome, ausgewählt aus N, O oder S, enthalten kann;3BL-5758 Rs und Re stehen jeweils unabhängig voneinander fiir Wasserstoff, Halogen, C1- LU505117 Cs-Alkyl, C3-Cs-Cycloalkyl oder -(Co-Ce-Alkylen)CN; R7 und R7 stehen jeweils unabhängig voneinander für Wasserstoff, C1-Cs-Alkyl; oder R7, R7 bilden einen 3- bis 8-gliedrigen Ring mit dem daran gebundenen C-Atom, und der Ring kann gegebenenfalls 0, 1, 2 oder 3 Heteroatome, ausgewählt aus N, O, S, enthalten; besonders bevorzugt steht R für Wasserstoff, wobei p und q stehen unabhängig voneinander für 0, 1 oder 2; m steht für 0, 1, 2 or 3; Ra und Ra' stehen unabhängig voneinander für Wasserstoff, C1-C6-Alkyl und Cs- Cs-Cycloalkyl; wobei, wenn Ra und Ra' mit demselben N-Atom verbunden sind, Ra und Ra' mit dem gemeinsamen N-Atom verbunden sein können, um einen 4-8- gliedrigen Ring zu bilden, der gegebenenfalls 0, 1, 2 oder 3 Heteroatome, ausgewählt aus N, O oder S, enthalten kann; jedes der Alkyl-, Zykloalkyl-, Heterocycloalkyl- und Alkylengruppen kann unabhängig voneinander durch 0, 1, 2, 3, 4, 5 oder 6 Halogenatome substituiert sein.2. Verbindung mit der folgenden Struktur: Ce TVR DR aS 0220 rr avan avan SA rrr SA aan 4Ou © oO On ex oO Os CA oO 0 Go oO U505 TON a SON 9 TN 9 N SOON 9 _ / © 9 120 / 9 TONNE on / © eg / 0" nw a 0 H © o H ® J H © 9 N ® Q N= 9 = 3, N= 9 N= 5 5 N = N = s NM NA 4 > AN N = J 5 _ N / / / vo I I an I ag NN aN oN oN GA © © © os, yn IN Os un 0, Og y" IN Og y" CIR x 0 ©) od J 0 & Ad J 0 ©) y" 980 / 0 ©) y" 06 5 nA LUN. g n=l Lo 3 NA, Og N= N 0 NA > NS > NS 7 = AR = — A 0 N / ÿ / J I I I I oN ON CN ON / \ \ \ 6 / ©) 6) N S) S) (5) Oa „N oO Os y" 0, 9% Oy y" IN os, y" 2 5% 0 \ ©) / 0 © Ve J 0 ©) ih d 0 © y 0 J 0 172 Og NA " ©, N= Ao 9 N= N N © NA, © 5 5 5 N = N S N = NS 4 > SA NS NS N N N N — D — ro + / / / oN oN ON ON / \ \ \9. es 9 0. © 0 0. fn 0 N 61 SONT 0 SON 0 SON 9 > ur No ; à He N , J Hg N , à Hg . A à Hg SE N ( / N Ca = H Od N= H 0x N= H L_o Og Na H 0 5 5 5 N = N N N = 5 MN NA CS ARN = J J N J J ÿ yo oN aN oN JN dN GA © GA © Oy NN 09 Oy i 90 Oy y" 09 N oy i 0 à (5), 6) , Lu Ne ON. de Ne 0e N= 0 de wl 5 5 5 s s A > NS > NA > NI > _ A A N / A / yo Van I I I oN oN oN ON \ \ \ NS bla, N © | © 0 Oxy goN_0 à Op y" 0, 0 Oy y" IN SR s , o Hg Arado , 0 A, Ly , 0 © me , ° oh A X “ 0 H Se n=l Hf Oa N= A UN RT N= Too 2 N= 5 N N 0 A > Mg > AN > RZ N N N N — J — Ÿ — Ÿ ÿ Ÿ I IN IN Jd N A \ \ \ Q Q Q Q os y” °0 om os NO HO ON 5, = ONO _ 0 oh JF 6 Hoel JL em o Mol Je J So Falk LN J N NT / NOONTTR J N oN / N NT & N= Og Ne a N= Og nH 5 s 5 N = N = N N 5 NS A rN Nv — N N N / Jo Ÿ yo oN oN oN SN oN \_Y \ \ \ © GA © a] Oy y" 0, Os u IN | Oxy y” à os; y” 20 / © 9 Hd / © On 2 / © 9 N N° 9 / 0 wd ho 5 Og N ON Og n=l © Og N= ®" Og N= qu æ Ss <5 N 5 s NA NA 4 NS NA = — — — J 4 A A A oN | oN ( CN ‘ CN g / / \ \ © © © en ON os, NO à Os NO 5% ow o "aN leg o Hel À @ o Hel | 7 0 a) À, x / SN / OR NTN 0 / SON NY / SN Q oH © 9 oH 9 oH Og oH Q N= ® 3) N= © 3) NAD NAD N Ts] N IN N 5 N 5 7 % 2 Ny rN Ny N N N N — — / —A — / ÿ J oN ON oN oN / / \ \BL-5758 GO GC N ©) LU505117 0 9 NO Oo, NO Ose SN oy Oo, GN o + H (3) io / 4 H & J © / 1 Ho u Lo / d Hos) A © J, Ne N To a, wel A VE a, nd # Vo 9 nd # To N 0 NA 7 NA 7 NX 7 N D N N = / A 0 NS N° (@æ N A + Ce / o lol o ol lon o el o TN 9 1 H ) Jo d H 5) 3 © + H ) Jo J ° / ve; J N To J N To J N Go S N= Ss) N= S) N= S) N= N 8 8 SS SS X ZZ A NA NA 4 \ N N N N — / / J / — ÿ — y on (® o=( Ca Cy N N \ \ Oo, on oO oon oO Os où oO Ou GA o ° d He Î © 1 He fe , d He A © , A How Ae d. N N Ve J, Ne N © J, y À ve 0, a Vo =F SS SA N SS NA 7 AR NA 4 rN HAM N N N N — J J — J — / ©, ey A ve oy GA 9 Os GA 99 oy lo ° 0 Oy GA 9 o Hol Je o MeN Jus o Hoel lg o "ul ly d NE d NE J N°6 J N°6 © N= N & N= s 2 N= > 3) N= > NA 7 > Mg > ha > AN = N N N N yo = yj / — A (9 ®HN. A N Th. Oxy GA 9 or on 99 Oy GA °° Ose GA 99 à Hol Je o Hol Jw + Hol Je + Hol Je J NE d NRE d y J NE © N= > @ N= s 3) N= > N= N My = Mg = Mg = A > N N N _ oy y= N — / 7 0)» Cn oo N Oo N ° NS Oy A 9 Oy GA 99 Os GA 90 Os GA 99 H H H | Hal 1 © De o a A © À, Hs 0 © (8)d. x N N J. a J. a 4. RA AN AR NS 9 NS N N N _ An NN © AR. / J HN OH 9 6© © re Og NO N © NO >" ° Cs ou lah °° Oy Hol Ie TN Ae J 8 A / J H 151 Os Na = , > = 3 N= = . ‚ 7 NA ES . N » / NÉ a : ; N { 7 X Ÿ _ Ÿ N _ u NON N 2 Nf Ny NN N SN fo) S N lo 1 H SA, durs q Hs hie J N a 3 DE oh , H 8 J H (sr & Ny à "ee a, N= vi 5 wl 7 ; - J N is) N SS x ] wo) > Es NL Oo N= CJ , N N = N ; A a N J ç J { _ €? < N ÿ X + N NHz Nr N ENO D. olor °> o. a o Oy N © EN TN | SN 0 Ho, Ie , N - oO sh Mis Hog Js y ° N / . N << N 718) y o N < 4, a N ’ ; - „ © ig Oy N= N . =~ Le N = NA a PA Bad + DB N , q / / / { ÿ = ra / he WW M ap oN \ “ Go Og GN 9 63 oy i “a pa of J 0 (SMS, ee Dane VIe / NR TA | diel dy / Se i _ o ©) A , N y €, _ < d À Ve de na = wi : i > NE y=] N } . NA | NÉ | ; 5 N J / _ — A # I ÿ ( ON 7 2 J 7 Ho— 2 \ HO fo) ogo ane TLR ON o Hel de b À due , y z TH Ie ; eZ J vez ‘ a / NTS de N= 5 wel, A g H > = ; i / 5 NA Ng N =? rN ÿ | ~ rN N = ; — Ÿ ÿ Oh ÿ IN N X I Le) x x Le 7 OH Ho (5) oO N a N ] Ogu GA 2, Oy NSP © A fol ds , 4 ol Jw . 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