Aminopyrimidines as syk inhibitors

ΜΑ 33926Β1 2 JAN 2013 Dkpat Abu 0 Aradonkmhzt SYK) full description of the background of dissimulation additional 0 Bam Ieropn kinase spleen (Syk) appointed protein phrase described Nost Eadsa to send and signs of pain 0 Tqlat Abaih the breadwinner of the! Cells inflammatory .mma the Adla-A blood money, except 0 Da B , large Aullac Adalalo August. This is immune receptors, .mma in knead Syla't .Fc and Mnaqba. Of cells, each of Althsasah diseases and F ^ 1 Omatla; that Tesf 'objects Alamadanh Thus, Al Duwani interfering with. Syk can leads to treat these Alakhmabat 0 J 0 seen Akeab 1 Love of 7 C and asthma Almertbaalh diseases Pfaalat hyper Alahab ()}; and to Odat Alalth 1 endodontic 1 my time: Sun Yd'a types Klaya.mma the cells Bidiyah, eosinophilia, Khalaa 1 T Allaaa after 1 Krd core of sensitivity, erase 0 Sfielat Algeloyosh S ^ intention .lolvh d igGj IgE linked intertwined Y Bcihl Aasiaat, SV Abela and Gari cells from babysit Khala .ba lead to Atlavy Hit Dhlakhab and B't Achaabad Lada 7th exercisers 1 Vision. In one cell must 0 No, presented Sd 1 for example, realized Zach slipped JgE Lord? The I-Mex Olosh lead to 4 Talao 0 ft 'sniff S from 0 scratched ÂJ-L * Aial 4 well .tkhadd 1 framework 1 was fitting causes lipomas and Allyukotr yen 0.1 Zd Tditha .i the prostaglandins t Z Syk Irh p er-m E, E j (z Abz p mother in p 1 the heritage! Yprin, I Han connects Zd Ahablat Fc · Ndl-. R Drau 'F · to Sdz, .R, bound me in type; 0.0 Lal 0 to Aiadat. in the first Ald.i, Z 0 Z Alale Z 20 ΜΑ 33926Β1 confirmed 0 for 1 for an early wanted Clarifier Fc. Acilon 0 RI b 0 d Alrt Alchapki b Father complicated) v Scla 0 IgE first Lyn & lt; from the family of enzyme T1 Rousseff Carr. Src) then do not Syk · 0 g of Altua that folk Ncamat inhibitors of Syk inhibition Tdlat Send all departments and g then. Qib 4 N. Ala.; Confronted instant Okhach events Aekd which began firing causes the inflammation will Bbat 0 1 Aibad (7 (13) 2.04, Expert Opin. Investig. Drugs i2Qü4wbng et ai 762-743 l). Hanito, it became clear that the enzyme inhibitor Syk Carl 12 A. (Rigel), my parents are frameworks Mei 0 No in more accurate in der; Study Ataiwo II /] for the treatment of Alonay a 7 C infection, Aahli termination Keira census in 2pgd, a central Taa major identical substantially to Khdt in the Alod Akhsasa 4 0 Wei Ham I also across a large number of a; apolipoprotein use 0, will then μ U NH & lt; S I d not Baloma 1 and Z Alr.bra Falhh Syk inhibitor Adhir.am Keizer connector. (Meltzer. Ell () .; Berkowitz. Robert 2005β .; Grossbard, Elliott B) Journal of Allergy and Clinical Immunology (Loro 1 1) 4 0 g 796.791). In Z II Bio 0 death 0 n Akeab nose Althsasa (Clinieal Trialsgo 0015089ldefit, fîerNCT) E Atdhonal 2 AAA Iralysalh 0 s 1 Blalalajalards 0 Zafy 1 aa p Js- 0 Ebarh for trauma Ie 0 club & quot; In (RA) of 5 inflammation Amoa 0 for Aviomatu.bdi population 0 and a Baltha-B1 an asset 1 of the Association of 0 to performer to not Lam and insomnia ^ p bear criticism showed Azdr.asat and show him to Adam 0.0 to 4 Orksemap Valley b's. cw Edwards et al 2 () 04, New Eng. 0.1. Med. (35)), Epeshkd T1 but reversible B Ostaloz for a solution: A represents Osvi.a'shabh Dlaq .laea J; Z g 2581-2572) a 1 v 1 targeting and Zigh Khala.ba and 0 Itad St pain 0 Ar.ah 0 p Olatiad in fallow Odadh Adad I ( or .RA 1 to Dattyh over 3 3ΜΑ 33926Β1-year-old rheumatoid arthritis) and these studies suggest that B cell Zigh in Alhaiqh Alasag Aanati Dlabam anti represent workers over Tzaan percentage reasons in August Hrd Adstmrh disease. Studies' use Khalaaa of Algiran lack the enzyme Tdhiros 1 n j 0 BL has shown (Syk) spleen Ir role iterative enzyme Yar this in Zigh B. cells and is characterized by shearing Syk preventing the evolution of cells 13 (: 378 M Turner et al 1995 N'attire 579: 298 -3.2 and Cheng et al 1995. 'Nature 3-306 () 3). Tolhr this topic studies, with BTS studies UB fishhook cells in Syk d Kurasaki et al 176: 19-29 .2000. Immunol. Rev), that Syk is required Ka.lmz and perimeter except Tzt 0 0 B · O War then; t that the reflux Tthbyad Syk results in patients with RA and to ban Zigh Khalana B will then produce p rheumatoid factor. In addition to the role of Syk in B cells and Zigh, betray Syk activity is required to send future FeR) Fc) signals, which regards the treatment of RA is the largest market · 1 joy to activate FeR by immune complexes in RA contributes to Atalaq multiple maledictions Olthay. Respect Alaxtoaa new Olhala.turkbat, where he is considered to Illtat That enzyme Syk Paz 0 boy Han Hzh vehicles therapeutic advantage possible in Oualaj Almertbaalh unrest actively Syk is Adlata; especially in Elaj and prevention of pathological cases with Syk. .bmcn That Egm this topic Adla pathological diseases Alakhabiyh, Altahamih and private Palmmaah etiquette; on but Athaal 4 Repeat 'RIP obstructive pulmonary Almzmin (COPD); Mtelarmh stress Wasi in Albaifrn (ARDS), Alha'b the Forces 0 Dhun ί to Tqr.ja, kroner disease, Okhab F ; equ rheumatoid arthritis Thousand literature psoriasis, 'plays the skin, urticaria, Akeab, joints Aloutr: DVD; Algrferah de Mufahat unknown Albb (.ΙΤ1), multi-Aksalb, ​​Alrtan, HIV and father. Detection Alaxtoaa 0.4 0.4

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00061.tif" id="idf0001" />

I HA present invention provides novel compounds work Kmthbnat Qaalh O_ SYK and Kdnk pharmaceutical formulations Alhtoah them. Because the inhibitory compounds SYK's Aloornh in the present invention are useful in the treatment and prevention of floors and unrest that .besbbha SYK protein; includes these diseases and Aladirapat, but Bach 1 Del Z-exclusive, asthma, COPD, rheumatoid Omufatel illumine and Manu hands, cancer and Alpher fled Yeh few platelets unknown reason. Detailed description of the invention provides a Olachter 6 current vehicles have character (!) Or a pharmaceutically acceptable salt of them;

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00062.tif" id="idf0002" />

&amp; Lt; a dust for small to 4; q Abnrh for small, a. Or 2;

Cy is selected from the 7-b € Satokal, Ooksianal, Pirolladinell, Weber, .bdbvel,

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00063.tif" id="idf0003" />

.R Is selected from 1-1, E ..- A'a) alkyl, Haloolkd, to 0_l) Sichaelookil, 4 for a 00 alkyl; ΜΑ 33926Β1 R4 is selected from the 4, H-; c tricks, Cj04j Sichaelookil; (Ry (a phrase for amino-methyl, 3, OH's]?) 0, C () 2Ra (a), CN, F, OC.H2CH2OH, (a) Ra (a), C0NRb (a) Rc (a) NHC (0) Ci- 3, NR5 alkyl (using optional replacement of the OH); NHS02CI-3, NHSQNH, NHC (0) NH2 or Us. NHS02C1.3 Haloos; ( «) RZ are selected here from (a) 4; C; agent for the replacement of choice j using any one of three groups to be selected individually 0 n C0NF12J C02Ra (a), CN, ΝΗ2, OH, (b), (c) a 0 Phil 0 Rookil, (62) Hanugen, (d) CN, (e) 4; COC alkyl ( what replace the optional use of a group or two groups are Abarhma separately (C02Ra (a), CN, 0Ra (a, NRa (a) Ra (a ^,, C0NRa &amp; lt; a) Ra (a)), (and) CO -ffinel (U replace optional Bassadam group or Bhmootain be chosen separately z Aithainel, (F, CN, C02Ra (a and Lauda); (g) C3-6-CO Sklookil (using the optional Aspdol or OH. 1.C02Ra (a), (h) 3 (a cord 0 for 2 C02Ra (aj, (i) (C (0) NRb (a) Rc (a-; (j) (ORa (a-, DC) (OC (0) Ra (a-; (l) (a) Rc (a) 1; NR-, (m) 4's;) (0) :) aa 1 Aokil (Fa replace the optional use one to Zlat of OH 'or (C0NRa &amp; lt; a) Ra (a), ( n) i &amp; quot; NHS02Cl03 ^, &amp; lt; o) NHS02NH2-; (PSC) or du; (P 1), 3.4-Ooktdaarol -2 (3 not) -oov; (4, 2, 1 (R- Ueda 0 Asul- 5 (η4 &amp; gt; &amp; quot; Online, (in) S.2NH2, (f) 03 of 20 d) 8 all, (u) S02CR3 Haloos and (v) S ° 2Ph; (4i) Ra ^ drizzled for H or Cm alkyl; (Rb (a and (Rc (a is one Barhma separately from (a) H, (b) E-a: 0 cyclo? 1 Tel U Aspdal; Khabary Bastkha.am}} ((), (c) aryl Z 0 Shazs be told 0 n aryl is Tice, of Wardle and Azdoll, (d) Tatar 1 Adroborol, (d) well; (f) fell by 1 Spdal a 0 Iara has become one long -6-, -6-, ΜΑ 33926Β1 -; Bjme blood debt Akhcarha -Js 0 units are F3 (€ Η2) 0-2θΗ) (g. 1) 4,; c double and (g 2) grandfather and 'd Haloalki 0 a, where 0.1) and Dora button) BCAA including replacing the optional use of the one-to-lath - a 0 Iarha on Hdn p (1) OH, Gaza) 6-C3 Sichaelookil what to substitute optional mg 0 and categories blood 0 debris Mjmutit or two groups: LE selected separately from the 1 .. | C alkyl, C0NH2, to Ahh'2 AST 0 m and 9 a.] l) followed by ') w (3) SO2NH2 (4), C0NH2, 5 g), .st) 22i alkyl, (6) Schaelil is Mthac my insisted 0 Aila Mack 0 n o 4 to 7 Nrat by replacing the optional use of a set or two sets for 1 Valley 1 m Bs Z unit Mzootxo, CH2) 0-25H), and 4.aaokil, (7) aryl Ir d is a Khmgel 0 to 5 or 6 Nrat Astbdor by using the optional Mjmugh or Mjmogtin are optional I 0 Nkerbo's, CH210-25H), and A..a '; the Board, (8) OCw (10), CN! each, ( AI) E 2 &amp; lt; 2 :), (12) NR.a (a) C (0) Ci04 alkyl, (10) Azbeh replace the use of news Sush; despaired. P Abarhma separately 1. (11), Clj F, CF3, SO2NH2, (CH2) 0-20H 'Â 9 Mjmo for 0 E 10 for 100 "Bodil e a, Spdal optional Amthaddam Uecker, (12), 1-Abmadasuladjal by replacing the 01 Taa j using or du, (13) 1 -ypridsl '9 Atoual optional using Oak 6; and (4 a) 4-Moervollkhal; or.) n &amp; lt; Rc (a &amp; gt; 5 Rb (a with Dhirz nitrogen, which are linked Mja is Tat loop consisting of 6 or regression g 4) R and g 0 'Ί a 0.7 y 1 t 4 a row to one atom is additional Tath Bjm needles, I Z 0, N, 8, where Ddon Balh 0 I Ir heterogeneous Aidkor.h the closing valley Adam b or two of blood led Z unit of oxo, CN, 0; () 2 ~ and &amp; gt; (2 a CI); Osetal, to Ozdl, 4-S02Ci Us, 2A 20; n 0 Yale, Yosh miles, not »as 0:00, AA; p Apr mg 6 cent Rey b (!) / Cat T '; C Bad 0 z p; MPD' DVI any August 6 will be barely Heciq a 0 instead Q 0 as upper Bam emergency g »CW, &amp; lt; 1Κ0 E 33926Β1 -70's. 4 o) Cj) NH2 alkyl by replacing the optional use of OH, a 0 Ga 1 SPD; using one's seen two of the methyl groups. In other sub-Ijm.ah her Alaevh (1) over the Bbat C'y U is a Bebaradinell. In a 1 Answer Ibikun to inject nitrogen from Babredent replace using a set is chosen by Z (A) A. € 20 Alec 0 for (I replace 1 Optional Ba.thaddam (c52Ra &amp; lt; a), CN OR8 (a; 4C0NRa &amp; lt; a) Ra (aj and 0.00 (2), (NRa (a) Ra (a) - Ivel (what Amtaal will repay using Mjmu 2 or Bhmuatv blood chosen by the unit of Aitha, "but rather, (6,; F, CN, C02Ra nor 0), (3) .CO- CV Sichaeloola 1 (U of Aili Batd 13:00 OH or. 51) C.-3 (4), &amp; lt; C02Ra Ose ', &amp; gt; e; a 02 p, (5) 10 (C0NH (6), C0NRa (a) Ra (a- ; 7Lü (U of 0 Tdal Labrie Use. group or mg 0 lepers Aha (j z unit g NO! p C0NH-C (7., (, ',,, CN Sklualkz, (8) so2C, .5 (9), SO6Nh2 Alec 0's, (0 1) J_; S52C Yale 0 all 'and (aa) S.2l.ll- in Mjmoi me see me by (I) 0 Rkat what Cy righteous p Azaaal. banished a 0 d kyphosis Iike 0 Nauaabl Adeddaq Boath Ol'dr group in Arda 2 Ezag - 15 n Bsaklohksil Mansh t to see Ozzy Z b (I) Tm'lebatt :) what a '0 g a righteous AA (a. NL Af answer p n. Cj E 0 OL p Bakrd In O'd fled 0. Akzn LDL Ajz'l Hdao 0 0 E T. Yale. z is 0 Acts fact Cy Paweh 2 g Azkoariabl. Mjmo 1 '0 - Ο / Γ a da Ah I see the nature of U (b) S.vat Z (0Ry {a Ouarh Z C.NH2 ed Davey b encodes for :, j; IE Bkzdi- a O'd Nmaze 0 Heczn x * μ 'B'aa 4 of 0 needles 0 a y (5) co2R5, (5) NHC (0) ti ^ jC0NHRh; 46 At'l Sde Te 0 lasted 1) 0 'and be Yum 0 j Aladr B'l sa; j R., GS 0 Rev Mar y z 0 E 0 T. Yale. Wu Z 0 Acts fact Cy Paweh 2 g Azkoariabl. Mjmo 1 '0 - 0 / Γ a da; in 20 8 ΜΑ 33926Β1 Athbjrahnyrhas series Atdam OH' A'akon (NHC (0) C | _4J CONHRbfe), C () 2R.a (a Alec; l b 0 Aspdal Scull Hksil Adnar Mbdal Choose one another and Ba'saddam; unit or one Tztin Z 0 mg Ua '.' &amp; quot; pharmaceutically acceptable salt rang PM 0 Ba: Verde; p 1 to present her knees in August (a!) or. as well as provides

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00101.tif" id="idf0004" />

Hmt Z Ouaa y r _ (0CRz (b) Rz (c, - ((Rz (d; CH2-N (Rz (d)) -, -N-, or 0 (0)! &amp; Quot;.) 1-;. P Eba 0 y En 0 small one Li 3, provided that the P raid on the small Hnn 'the fact that Z Ebar.h for - &amp; lt; 0) 1 € a (R7 (b Bam 1 Bari from (a) H, (core) 4 ... c AKEL by replacing the optional using one to K 0 v Bh 0 and Eht .e selected Z unit of C02Ra (a), CN, ΝΗ2, OH Ot .01 €, (c) halogen, (d) c (O) R ^ a) p), cN-, (and) (C {()) 2Ra (a-, (g) (0C (0) NRb (a) Rc (a, (h) - ( "OR, a (a, (i) (t -OC (0) Ra (a (j) (NRto.a) Rc (a-, (k) 4.a 0 (0) 0 No-Ace (O The closing using the optional ΟΗ), (for) 3-ί0ΝΗδθ221 ^, ( m) NHS02NH2-, (n) A, 3, 4. Ooxadayasul -2 (3) -oon, Lyons);, 2.4-Ooxadayasul -5 (not 4) -oov; ...... 9.

1 &amp; lt; ü &amp; lt ;? MK (R7. (C a .H or Maz; (Rz (d At 00 m chosen from (a) H, (b) followed by € allele What replace Akhtiaraca using a set is a 0 Iarha Z (C0NH6J C102Ra (a, (c) 3 C Vruokil, DD) COC (.. i Onkil (U s &amp; quot; the Labrie using a set or. groups are selected on Hdn of 0CN, ORü (aj NRa (a) Ra (a) j, C0NRa (a) Ra (a) , c; (&amp; gt; 2Ra (a)), (q) CO- phenyl (O replace the optional use of a set or two sets j 2 Ajarha i z; g Aithainel, (F, CN; C (&amp; gt; 2Ra (a OHj), a ) Hl0-0t) Sichaeloolbul her Astbadan optional use OH or (C02Ra (a), (R) 3 for A'a Aakl- (COoRaCa, (h) a1) CONRa (a) R5, (i) to only 0 a-Ivel Leah replace optional Bassadam group or groups are selected separately from the CI-4 alkyl, CN, and □), a) ONH him € \) Sklookil, reminded) SO2NH2, (l) and 2-A'a (.) of alkyl, (m) i .-; SC &amp; gt; 2C Halookil, weight) S02Ph; and the fact that a), r4, rI) Rb (a), R * (a), R01 and (Rc (a on Haw Waffen under the Elbe a. in mg 0 Uh subset her Ala 1 Agh (la) compounds where Z, contain. (NHC (O-. In one of its models &amp; quot; the fact that (Ry (a ^ drizzled p;] () 0 In other sub-Bah her Chiah (a;) over Pat ha Z is. ..... (p ^ -CHRz (b Abarz for Str 0.1 or 2. In gr Joinbhattko.n (Rz (b Ara for C.2H. And. In Gap her latest-kun (Rz (b Br_h for (CONHRtya; and. In a Alnmang fact (Rz (b Abbar. Y 2 a &amp; gt;? &amp; Gt ;, In ^ Zj Last betray (R2 (b phrase Z 62) -3 (CH2) CONH ^^ _ E. -pirolladinell). c 0 In August of her brothers are (Rz (b Abarz for c | .4 (0) NHC alkyl fatigues Astbadan optional using QH); In a Alnmang fact (Rz (b Abarz En ΝΗ (; (0) (Ή2θΗ. -10- ,. ΜΑ 33926Β1 In the other group Nraeih her formula (ta) compounds are Z indentifier _ (P ', -CHRz (b is a small 0.1 or 2, Ry (a) j is OH or CONHb. On one side are 5J &amp; gt; Rz is Η_? Ό-2. In another aspect be b0; Rz is (CONHRb (a, In a Alnmang be h1 '; Rz Ara for Ci) l2, in Nmong Last Rz0b0 it is a CONH (type 0) 3- (2 oxo ~ 5A-Ber.oulidevel). and. in Gap Last Lancon Rz'b1 Ara for 4 (0) NHC; c Onkil (I Oscdal optional Basthom OH) ; in Ahab Akmad c be Rz (b0 righteous p NHCi () jCH2 () ll. bitter hid illustrations Allwarzh in the invention Akhala Tjon Khma follows (all-composite deafening pain '&amp; lt; 0 c defunct pharmaceutically it); 1-A5- (3- Bill-d-g [4- (G. Toro.bal) bit; Kidane -2; not Abu; Yale) a- 0.3 "Bzul-2-I Blohxan Krbonetre; 1- [d (3 - ^ - 5 {[4- (Lay Ioromnthel) Berbmaidin -2-night Abu E. Viad) - 0.1, 3'-Abzouk2-I Bklohxan Nroxamed; acid (4, si Hed4-Btho Zsa -2.2 Dai-represent-4-L5- (d-cell-d {for 4 - (&amp; quot; Ray Vrumethyl) Kr.bd.r -2-Alaabo and Linnell) - a 0.3-Yasul "2-.blasichaelohecsa'n Altherbo Chile; 4-0adroxa-4- d-Z3-Shell-5- {L4- (Ray Vrumethyl) pyrimidine &amp; quot; 2 Ayobo) phenyl) - 1.3 ~ Thiazon -2-Yale; cyclo Hecsa Nu n; Cisse a- [5- (3-Butz- 5 - {[4- (Lay Toromethyl) pyrimidine-2-Yale Aso} torrent) -. 1.3-Yarol -2-Yale; Saikhaohecsan - 0.1 0.4-Diol; Trans- 1- [5-D3- Sthel-D_ll4- (Tri Floroumil) Samdn -2 - Yapo; phenyl) &amp; quot; &amp; quot; &amp; quot; 1, 3--

1 HA Thiaz well "2 - Yale; Michaelo hexane - 1.4-Diol; -al compromise-1-Bill-4- [5- (3-Shell-d - {[4- (tea Vnoromethyl) Berimidh-2- Iobo) Ivel) a-, d-Ilasul -2] Dhecan- 1.4-Diol; Shs_; -methyl-4- [d (3-Bethel-5-g [4- (Tri Vrumethyl) Peremedn20-.yoboo Ivel) "1, d ~ Thazul-2_ala cyclohexane" 1.4-Diol; d-hydroxy-d [d (3 ~ crippling-5- {[4's (Ray Florumgl) Bdhiramaidinl 2 Aloobo} Figel) - &amp; quot; 1.3 Adbzul Yoztun-2-en-2-; Seads -4 - [(Adroxa Osptil) amino; - E _ (5- (3-crippling 5-g [4- (Tri Vruhl) Bear 0 between -2-Yale Abu  Ienbl) - 1.3-thiazole-2-Yale; cyclohexane to Rbukabd; (4, si Yum-4-hydroxy -2.2 Dai-methyl-4-Ld- (3-Bethel-5_ {A4- (G. Vrumethyl ) pyrimidine-2-Z tends Ominoa) - 1.3-Thazul -2-Yale -l &amp; lt; - [3- (2- Ootxob; Rules- 1. Yale) propyl f cyclohexane asthma Babylon; Cisse acid-4-Toro -4-L5- (3-Shell-d {A4- (Ray Vrumethyl) Peremediat ~ 2 ~ Yale Omivo; unpack) - 1.3-Thazul -2-Yale Sichaelodan Kherbo Nsaia; ethyl 4-Hdroxa -4 -l5- (3 d-da {for 4 - (&amp; quot; Ray Ioromeshal) pyrimidine -2 &amp; quot; &amp; quot ;. but 0.1; Su) phenyl) - 1.3-to Warhol-2-Yale Baoven seen Bo Nsedlat; acid Trad- 4 Brocchi -4-L5- (3-Bill-5- {4 - ( 'Ray Vrumethyl) Ber.ban -2-Yale Omivo) phenyl) - 1, d "thiazole-2-Yale; Bklohxan carboxylic; 33926Β1,' and j 1 Ba acid Abroxa -4 -4-L5- (3-methyl-5-t | _4a (Tri-Flo; .oumil) Ber..yr Yale;) Menen) Vienna), a-, d 0 "0 ~ e; well "L2-. · Nlasekdhuh \ that termination &amp; quot; Rock 0 j L4- (G Floromeshl) Berimidi: T h; Mito tends) - a, d-thiazole -2" Yale; cyclohexane seen Bo Netter O Rowe Hhbl) Bazon- 0.0 a dam 4 Heder 9 d vinyl) a- and-Thiaro 0 Evhassan Dhirboeril; -l5- (3-crippling-d {[4- (Tri Floromeshl) Bhimd, n-2, Mo} 0 L Rum 0 mi 1 Delmj e 0 that asthma d Tmadroxa 0 vessel ) - for, and Barrow-for-2-O; Sjellohecsan calc Dap; will mark the so-called 21:00 6 -ro Mughal-5- {L4- (G Vruhl) Beraidyn Yale Ohbo} Abel) for 0.3 ~ thiazole -2 ".lasclohksilaaon ; Σ Seve I Aoxamayarol -5 (η4) - Bnramaidin-

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00141.tif" id="idf0005" />

Hmtm Ne 1 des 3 Mathb 0 ΛΑν / -sl-d {A4- (Tri Floromeshal) pyrimidine Ba; Aminu) Vienna), A-, D-thiazole-2-for; cyclohexane free Bo Ksila; &amp; quot; ( 'G Florua 0 Shell) Ieremad , n -oma 0 and -4 Hydro-de-4- [5- (3-methyl--13 -13ΜΑ 33926Β1 Al.aobo; Ivel) a- 0.3-thiazole-2-Yale; Sklohxan carboxylic; acid (one of 0.4 does not ) -4-Hydro Thsi -2.2 Dai-Bethel-4- [5- (3-Shell-d - {[4- (Ray Fluor and Bethel) Bear 0 Kidane -2-amino night) cell) ~ '1.3 Thiazo for - 2 &amp; quot; &amp; quot; &amp; quot ;. but f Saklohhan Allrbozspli; acid still 0.4 s) -4-Brooks -2; 2-crippling Dai-4- [d (3-Sthyl-5- {[4 for (; any Vrumethyl) pyrimidine-2-Aloomedhu} Vettel) - 1, d-Thazul -2-Ysklohxan Olkrbo Gsala; acid (a of 0.84) -4-b 0 Roda -2; 2-Dai Metel-4-Ld- (3-Methel -5- {(4- (Tri Vrubuthail) Ber.bjd.s &amp; quot; 2-. Iobdhu) Ivel) a- 0.3-Thasul -2-Yskiohan Acirboxla; acid (4- &amp; lt; r4, rI- Hydro r -2 ; 2-Dai-methyl-4- [d (d-methyl-5-g [4- (Tri Iorodil) pyrimidine-2-Aloomivo E. Ivel) a- 0.3-'iasul -2-for .aseklohxan Alkrbo.ksila ; a-Bertel 4-Hedroxa-4- [5- (3-Bill-d - {[4 - (&amp; quot; Ray Grumethyl) to Ar.adan -2-Yale Obdhu 1) Ivel) -1.3-disappears-2-Yale ] Biyared; n -1 - / Boksilat, 4- [5- (3-Shell -5 - {[4- (Ray Zawrobuthail) Peremides -2 &amp; quot; Iobo a Ivel) -1.3-Thiarol -2 "No. 0 Dean Weber -4-first; 4-hydroxy-4- [5- (3-Shell -5 - {[4- (Ray Vrumethyl) Peremedan -2-Yale Obio) fell) - A, 3-Thazul -2-Alobebar &amp; quot; -krboxamad der -1; 4-proxy-4- [5- (3-Mitt-5- {[4- (Tri Florhumicthel) Berimid-n-2-Yale father of the iceberg) _ a 0.3-thiazole-2- .bl; Bieber, Adan- 1-sulfo Na Mead; 4- [5- (3-Metel -5 - {[4- (Tri Vrubuthail) pyrimidine-2-0yobo} vessel) a- 0.3 Parul ..-

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00151.tif" id="idf0006" />

ΜΑ 33926Β1

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00161.tif" id="idf0007" />

15 ΜΑ 33926Β1 of 10 3-thiazole-2-Yale; 'or Ncian - d - Yale a year and that - 2 - sulfonamide; Berokhlord 1) &amp; quot; "2]" &amp; quot; 3} -Ν "Abussekloiyotal) &amp; quot; 1.3-Thazul-d-night-d-Butz Phil} 4-Sichaelohroehl Burlhadin -2-General; Dai father ^ g, 3 (5) does not (3-PBL-5-Al4- (0 Alizai Vrubuthail) Barimdhla 2 &amp; quot; Yale a 0 U} vessel) &amp; quot; A, D-Thadhul -2-Yale Ooksiav-d, l} Thberatek; 1- {1- [5- (3-crippling-5- {4 "(Ray Vrumethyl) Baremyen - 2-Yale Emu E. phenyl) - 1, 3- Basul 2 .bl; Saakhlu Jubl; urea; ^ - {1-L5- (3-0thel -5 - {[4 ~ (an intelligent Floro Yale 0) Peremydr -2-Yale Obno; Fouzel) - a, 3. Roll-2-L Scleoo but) acetamide; 1. (d {d - [(4-Sklosotal Berbs - 2-Yale) Omazu-methyl-d-penile) - a 0.3-Abzul- 2. l) Sacleoo.tadil; Cisse acid-4- (5- {3 - [(4 Blobroal Peremaidin_2 ~ Yale) Obdhu] -5-Meial penile; -al 3-thiazole-2-Yale) -4-Hmdroxa Saklohkhosan Kherboksila ; acid compromise-4- (5- {1.3 (4-pyrimidine Sichaelobrobbel ~ 2-.bl) Omezu-5-methyl-Vieille A-1, d-Thazul -2-Yale) -4-Hdrox Saklohkhosan Walker Bo Thsila; ( 1 of 0.4 does not) -4- (hydroxy Mlthel) -3.3 Buthail- Dai-1- (5- (3-Seale ~ Z- (4- (Tri Vrumethyl) pyrimidine-2-Alomivo) phenyl) -2 Basul -al) cyclo Hecsol; Z (4, si Do) -4- (5- {3-Scleorosl -5 - [(4-crippling pyrimidine-2-Yale) Emu] Linnell; -

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00171.tif" id="idf0008" />

.16 ΜΑ 33926Β1 .3, ί- thiazole-2-Yale) -4-Hydro Dessie -2 a 2-an intelligent Bethel Saklohkhosan Walker Bo shower; SOS-4-Hbroxa -1-crippling-4- [5- (3-Hishl -5 - {[4 &amp; quot; (; any Nldromeshl) Peremedev-2- Yale) Omso) Lavinia A. 0.3 Thiar-9's '&amp; quot;' - 2- O ,; Sdthelohecsan Krbukabd; sES-4-hydroxy-4- [5- (3-crippling-d {4's (Tri Floromeshl) Berimbin -2-Azoobol Neal) "1, d-Ayasul-2-Z-la-Ld- (2-Ooruperordan-e-Yale) Broil; Saklohhmon anguish Thsamed; (e 4.8 not) -4-Hedrok 0 j -2.2-crippling Dai-4-Ld- (d-d-crippling {L4- (propane-2-Yale oxy) pyrimidine-2-I Emir) Neal) - a, l-Nyirol -2-for Abkaohan Krrcassapd; ethyl (4, Rl s) -4-Hydro Mai -2.2-Dai Bethel-4- | 5- (d-Butay -5-4 - ( 'Ray Ior-and immobilize ) Peremides-2-Ib) Neal) a- 0.3-Basul -2-Isklov Carr Bukdlat; (d) (Oboumthel) -5-L5- (d -0 Shell-d-Zl4- (Ray Vrubuthail) Peremedin-2-I Amir) Neal) "1.3-disappears-2-g] Bl 0 bin-2-en; 5- (2-Hedroxa E0 Huksa) d-L5- (3-methyl -5 - {[4 - ( 'Ray Vrumethyl) m, pace-2- SAL) Abu) Yael) a- 0.3-Nizul Yolbz-2-en-2-; Homs Trad- 1.4 "~ Dai-hydroxy-4- [5" (3-d-Shell {[4- (Ray Vrumethyl) Ds20-Aloapto) Neal) a- 0.3 "Izul.-2-0i.bozan Alkrberksila; acid Se-a 0.4-Dai-hydroxy-4- [d (3-methyl-d - {[4 "(&amp; quot; Ray Torosthel) Berimidi 0 y-2-Yale Abu) Ivel) ~ a 0.3-thiazole-2-Yscaldan Alkr.boksila;

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00181.tif" id="idf0009" />

1 33926Β1

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00191.tif" id="idf0010" />

18-4.5-Dai Hbroxa -3-L5- (3-0thel-5-g [4 ~ (Tri Vrubuthail) Baremba0.bn 2 Yale;} Abu Ivel) -1.3-thiazole-2_alooziban -2-Off ; 5.6-Dai Hiaroxa-5 to 5-DD-Methel-5-t [4- (Tri Vrumethyl) Berimidn -2-Yale Opto; Vasyl) a- 0.3-thiazole-2-lyase 0 bin -2-On ; d-Abu-d-Ld- (d-d-crippling - {. 4 - (; any Floromeshl) Beramaidin -2-Ale Abu  Phil) ~ a 0.3-Thazul-2-Z oz, "Ben-2- Online; Homs (E. 4- (r4, s- a 5- (3-g [4- (Dai Vrumethyl) Beramaidin -2-Aloomedhu; -5-Shell Ivel) a ~ 0.3-Yasul-2-Z -4 ~ Broly -2-E2 Dai Bethel cyclohexane carboxylic; acid (1 No 0.4 s) -4-Ld- (3-Sichaelobrot "d &amp; quot; g L4- (Ray Vrumitnl) Bergedev -02 Yale; Omivoa tends) a- 0.3-Thazul- 2-.le proxy -4 ~ -2; 2-an intelligent Ashlohxan of Bethel; for Lahr., and Ksila; acid (4- (r4, s I- A5- (3-Sklobrobbel-5-g L4- (g Vrumethyl) Berimidh -2-Al.aomivo; Faisal) - a 0.3-Thazul -2-Al_a-4-Barbma -242-Dai Saklohhan of Bethel; Kerr and Ksila; (1.4, R y) -4-Hydro Dessie -2.2 V-Day Bethel-4-.d- (3-Shell -5 - {[4 - (&amp; quot; Ray Vrumittl) pyrimidine-2-phenyl} Alobdhu) a- 0.3-Tiasul 2-0ybkulovn-calc. Fabd; and. (AH 0.4 does not) -4-Hedr.oxa -2.2 Dai-Bethel-4-L5- (3-methyl-d-Rl4- (Tri Vrumethyl) pyrimidine-2-Alooso) Linnell) -. A, D-Thazul -2; l] Saklmosan Abocommd.

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00201.tif" id="idf0011" />

-19 -19ΜΑ 33926Β1 is a subset of the vehicles sold illustrations above with Aia: acid (1.4- (84, R- L5- (3-Sklodos 1 Z -5 - {[4- (Ray Vrumethyl) Bdhiramyin -2-Aloabdhu; Vieil) -1.3-Basul-2-Z-4-proxy -2.2 Dai-methyl-C-1 Dle Hhassan Walker Bo Thsila; acid (4, si E) -4-L5- (3-Sichaelobrobbel-5- {L4- (G. Vrubuthail) pyrimidine-2-SAL] amino; Ivel) a- 0.3-Thazul -2-Yale] -4-proxy -2.2 "Dai Bethel Sichaelohecsal Walker Bo Dsala 0.; acid (one of 0.4 E) -4- Pro r -2; 2 Dai-blink-4-to 5-Ed-Mitand- (4-Z-Peremides -2-Yale Obno) -vieil; -thiazo's - 2 -al) - Saakhlu hexane Walker Boksila; acid (a 4 0.8 does not) -4- [d (3-g [4- (Dai Vrumethyl) p 0 Mmaidin-2-Joel Ouabdhu) -5-Bethel tends) -1.3-Ebzul-2-Z-4-methyl-Day Brobb202 cyclohexane of 1 Illo Ksila; (4 (r4, s1 Hydro Zsa -2.2 Dai-methyl-4-Ad- (3-Methel-5_ {L4- (propane-2-Yale or forgotten) pyrimidine-2-discriminate] Obdhu) phenyl) - 1.3-thiazole-2-Alobkulovv impact my Kmmamed; compromise -4-hydroxy-4- acid [5- (3-Shell-5-Za4- (an intelligent Vrubuthail) Peremides -2-Yale Abdhu 1) Ivel) - A. 0.3-Hasul -2-Alberbn Aharbo clonal; Cisse acid-4-Brocchi-4- [5- (3-Bill -5 - {[4- (0-ray Vrumethyl) pyrimidine -2 &amp; quot; '-. but; Abu ; phenyl) - 1.3 -thiazul - 2 "," Yale; Sichaeluhedan Alkrber Thsila; -20- -20-ΜΑ 33926Β1 d-e; Drlxi-5- [5- (3-Michel -5 a {a 4 ~ (Tri Vrumethyl ) -2-Ber.ebdash Aloobo; phenyl) -. a 0.3-Hasul-2-0yozaan -2-On; Sass -4 - [(Hidrueebl) Oba- 1- [5- (3-Metel-d { L4- (Tri Vrumethyl) pyrimidine-2-O.; amino) phenyl) - a 0.3-Thiarol "-al 2; cyclohexane Terpoxad, and (one of 0.4 E) -4-hydroxy -2.2 Emaa-methyl-4- [5- (3-methyl-5- {[4- (Tri Vrumaial) pyrimidine-2-Aloobdhu) Vnl) a- 0.3-thiazole-2-Alo_2) -3] - Ν- Ooksubirouliden- A_al) Hobtabklohxan Carr, Boxad; acid (1 H, 4 not) "4-Pro Hsi - 2.2-Dai dl-4-a 5" (3-size-d-a [4 - (&amp; quot; Ray Vrumethyl) Peremedev -2 - for Eobo) flow) 'A 0.3-Ebasul -2-.blasskdarshav AA 0 lar Boksila; acid (C 84) -4-Broly -2 E2-Dai crippling-4- [5 "(3-Shell-5- {Â 4 - (&amp; quot; Ray Floro .mtd) Barimdev-2-j 7 Abou} iceberg) "a, d-Thazul" two-Yale; cyclohexane a rare Boksila; acid (Ah, 84) -4-hydroxy -2; 2 Dai-blink-4- [D. (3-D-5-g (4- (Ray Toromethyl) Peremedan -2-Aloabo) iceberg) &amp; quot; &amp; quot;!, 3-'iyasul &amp; quot; &amp; quot; 2-. Abklohecsav for asthma, Thsiei; acid (1.h. 0.4 does not) -4-Aros -2; 2 Dai-methyl-4- (5- (3-D-5- {L4- (Tri Toromethyl) Berimidh -2: Zaobo} Ivel) a- 0.3-thiazole -2 -0 Yskloyn Walker-Bo Ksala; ΜΑ 33926Β1 g 1 ha, 54) -4-Hbroxa -2.2 Dai-methyl-4-L5- (3-Shell-5- {L4- (0 Ray Florlabl &amp; gt; Year-j 0 yen-2-Ilbo,} feetball &amp; gt; 0 no, (. "- Basul -2 Lil Sz \ to Mrhashal as 0 Bo Ksamed; 5 (1 of 0.4 E) -4-Brod -2.2-Dai-methyl-4- [5 - (d-Baay -5 "{[4- (Tri Vioromithil) Ber.bdln -2-Yale U.} Vasyl) a- 0.3-thiazole-2-Zabklohxan Thayer Bo Ksamed A j acceptable salt Shehadlaya Mnhae includes Kdlk invention Alhani bitter Stability: acid (4 cRl) j (r4, s1 s) -4- (5-Z - [(5-Floro-4-Bethel Ber.bmaidin -2-Yale) Abu] d-crippling Vieille; - e 0.3-Marol -2 "l) -4-Hpedro Thsi - 2.2-d; j Mitt, Sika 0 Hhecsal the &amp; lt; a; Boksp ς lava 0 a? - [(? - / 3- Hydro vaccinia-3-L5- ( 3-cell-d {[4- (Ray Vrubuthail j); Amd.n &amp; quot; "for 2 &amp; quot; &amp; quot; &amp; quot; Yale Omeul.} appended) -1.3" Thazul -2-for; Ozitidin "a-Yale ; -2-methyl Robanual) Oaks] -2-Mvelro'arik, and Mitny {[4-proxy-4- (5- {3 - [(4-Methoxi pyrimidine-2-Yale) Amigo] -5-Methel Ivel) "a, 3 &amp; quot; Ebzul-2-0r) Bghebredan- 1 _aloslfoal) carbamate; or 1 mL. »Accept Shehadl touched. In the current demand Asallahat be Almokhtlah as the boundary between the following: 0 Walles may &amp; lt; 0 Τ Opkyl refers to the incision Hiam 0.9 t Bu Ne me Mstgamh series or Mtam Ah do A'0add the boundary between the capabilities Acirbol. &amp; Quot; join examples of AKEL, but Bchkl Ir-exclusive, methyl, ethyl, Ν- propyl, isopropyl alcohol, no-Biotel, Oazoiyotal, A-butyl, do not - Bztal, Oazausl, and the like. 22- ΜΑ 33926Β1 Mschmh Mar Mfirah him crouching in a Bdwokrbone 0 Dallah! D. "J. Oastalao E 0 indicates. 'Y 1 about each one of Atherr 0 for 0 Nchtm examples .. Melli of stay, Subject to Anadd Agidd 5A 0 Hdzh 0Λ Mzd, ^ and the Lord of N- Rbun's, 3 &amp; quot;' &amp; quot; &amp; quot; methyl houses "2-A.bzel C) A.thslh Brubnil, N ™ Su 0 Zs alone bereaved E and Z &amp; quot; Oakhl'a, but Η to u 0 a 0 1 ή Head Rabbo 0 for 0; Me straight Series A 0 MTV Ah done; armpits

Nj Betbil 0 indicates one of the convention (,; ^ to U of stay ,, 9 by the number I set the Nrat anguish.'s 0 stamping Examples of carbon-carbon ^ latex and one 0 of d 'Lash t 0:00 I t &amp; lt; &amp; quot;% \ &amp; gt ;; \ AA, for 0 Be ration Ge Hamri A.ic 1 Breaula.sl basket 0.2-Iotybl and 3 "representation Ertybl 0 and 0 z Asta &amp; lt; * h &amp; quot; Skloolkelaa 4 Li radioactive episodes contain. j on Cdd Anhdd of capacities carbon ring, and does not contain any corn Pollack Mthansh. B &amp; lt ; marginalized Dadla indicates one of the term 8-C3 0 Saliolkll '1 Li &amp; lt; 4Ü Hishaz U 0 Q 3 to 8 Nrat carbon - ring Ngm groups &amp; quot; Sichaelooketl &amp; quot; typical useful to me Alachter current Acts, ZKL 0 a form of 0 pesky share; j, Sakloprral, Saklopiotil, Saklopntal, Sep 0 to Alohksil, Saklohptil and Sklwao vinegar 0 indicates terminology ha Lu Jin a or Halo L. Alglor, Klor, Edom; or. Adad 0 indicates terminology Ohalookil &amp; quot; the alkyl g 1 set of Lai yen above Aa wrapped Aspd'l one y to each hydrogen Nrat by Har? E ; Wei 1 without Alhaluzhnn all Alvho Ed in the current application. examples include Halookil DAT groups , but Alr.eh -or- literature Laden in the present invention, but are irrelevant, Maial, breached, and O.'t; O.zo.ro.t; Aazubeutel Ot 1 El butyl U Amtbdal a single unit or eat Bassadam 0 n Nrat Halo, &amp; lt; a Sep; for example, Floro, chloro, Bromowoeodhu. Includes Oethelh E'harokil'l μ m each Gravel 0 0 Klro dog; -23 .-- -23 .-- ΜΑ 33926Β1 Dai Zawrossel, Ray Vrumethyl 0.1-Vruaithil 0.2-Vruaithil, 2.2 Matthai Vruaithil 0.2, 2.2-Tri Vruaithil, and Ber.vru-la-D.hobel. .bhrr Oastlassb Hydro 's forgotten the tricks to a set of double counting, as Lapeyre above Ts the replacement of hydrogen on the Ca Dora Dora calc for Boiszh Hedrbe treacly group comprising 0 Amclh Hydro Dessie alkyl, N - Ir is Hhari, Hill 0 R.o. Desai methyl, hydroxy IPL, Brobban- 1.2-Diol. Asallam my throat is »Thac 'refers or Sakhall is Mthac; a single ring is aromatic saturated or unsaturated molecules are the choice of one to three episodes seen data separately z s, N and 0. And includes examples created him Ir Almottaga Study, tune Bchkl is (3., 0.1 J, seen seen the hands, BL Itid yen, Peru to judge, Yprids, Bebarazin, morpholine, Boumorholan, Aadadoladash, Ooxazhoydan, Ttazoiadan, Dai Head Roosebin, Rtrahedr 9 Wannian, AZ Liban, Dai oz Liban, Dai Hivro Dai gas shows, Ttrahedro-Dai Orepen, Ooksian, Ttrahedrovuoran, Dai Hidruperan, Dron, Taatrahidruperan, Ztrahia 0 Roiaovin, Taatrahidrotheioberav, Dai Hedroiiopiran, A., N. "Dai or Dsan, a 0.4-Dai or Dan, a 0.3-Dai or Nsolan. Asallah Ara refers to non - homogeneously mg. at perfume Yeh single episode and workshops perfume Yeh bilateral Mnmjh'htoa at -1.2 0.3 or 4 Nrat are heterogeneous, selected from 0, N, 8 . and examples of R Yale Ir Taa groups, to launch Epeshka Ir attendants me, Tmiural, Leuven, Loro's, Abmadasul, Berasul, Trajasul, Ttrorol, Basul, Oazucasul, Ooxasul, Oaroxasul, Ooxadayasul, oh Dayasul, pyridine, Bear. .nazin, pyrazine, pyrimidine 0 -24. 1 ü, 1 cloudy Alaoh A'oturkabh'a, Z in Akre Chidlanh, Z Yesh 0 ml Z Aharn (niches) Walsall, and the component ( s ) inert (excipients Wakulla Saaelanta) Onldeinekdtan pain 1 de carrier, as well as any product Anth, direct Bhhac or z. What evil, p for Obyv 0.0 Ngayd t to any religion or, more 1 g of Mkumat, or Z Tvklh Wade or Walker Z Almkolot, or Y types fraternal g reactions or interactions Almtbadc to one or 0 n Olmkomat and bass, Nur 0 A1 Cricket God of 0 Edlaa Rardh in Alaraa current AC Rey Id blood; I .ha any Fill the Chiah (!), and Sioux; the languages, for saying Sdlasa. Love one to Atkhadd, m in, to request Adali, sparing only 0 p 0 h &amp; quot; Abrt that 1 Idt (obscenity) August 09 (deletion Yiaha; and Aga, Lisa Ka 1 g S (Aloedat &amp; gt; Lalai not Iva, and Alodat 1 T may not fall. B Olahkhadd 13:00 in 1 Aalb 1 x ' indicates a 0 to the term A'y Aspdal Buahmayor or. \ / z ,, Ven'a 0 for E 0 lattes s 0 the Atkhadd'm mg 6 I or mg 0 etat Alat'l any 'Dhecdt L 00) 0 Dan ^ Dz p Ala.t 0 a; l 0 to replace all Nrat Alheiduojunn. Mmahmoat, d 0 Tazlq? Tiag and 0 s. L number Mjmuat not specified Yesh Alastbd'l) explicitly. But loyalty ° \ y ^ Bsyoiina, to Zchih, Naabsb; /. Confirms h in every since, T. b 1 a Z -sait August applicat is determined NL Mtver Bach Aa n Hmak 0 one more Q Alaspenal groups (Rz &amp; lt; a j 1 to the general Zsa.ail, my-d, j , p Alotmy 0 Tmthal another door to HH Ka 0 mg 0 Jeh 1 pal I d a, Asll; Hbooa (NRa (a) Ra (a , may be JT Q 25 -.-. 25 -.-. ΜΑ 33926Β1 according to use in the current demand, when it comes to the symbol () C or a 0 &amp; lt; 2 for 0 E €) 0 Mmahmuh Alastdal, it refers L. Zababh between and the rest of the molecule replacement group. as such, the term &amp; quot means; that the carboxy group in Sacher Mrbth Bpava molecule, or Tkov Hnat Group a;,.; C greasy double between them. the lion 0 1 m of the term abrasive syk &amp; quot ;, Bmay Rey Shatt enzyme. Syk. Yum asset 13:00 Walles &amp; quot; disease .besbbh Syk &amp; quot; or &amp; quot; a disorder or disease or 1 'caused y 0 activity Syk O. Adlaim 0 Eay 4 h 1 a satisfactory -nntj or are modified enzyme mechanisms Syk Kyazz 0 Eez that 0 annexation of these Adlaq 1 Lord Aloray 0 1 Aathabiyha 1 Thsash; and for private Balaelh watts &amp; quot; done; Z for 01 KALD asthma 0 RIP Alaz 0 Dad Ed 0 j Azs (com) 'to Tlaz 0 of stress metabolism in Balven (ARDS ;. studiousness Alqrlov pain 0, RIP / Wen 0.1 of inflammation as 0 ¥ * Ed Father controversy Sass 1 Aladlo, bosom a 4 As.y, Akean Almisal Arrow 0 Atwedi 'Akhv attracted, Almellal 0.7 a Dskls 0 Arbo 0 Asalaiadapyash (.COP), mother Ahi and Ba! Goin (ARDS), Aakar 1b AA? deletion laze Dakouab has shown 0 for Ward 0 Atdbdi' (j Alassadamve, medicine Ailaeads &amp; quot; Raalade "Dkp (a); and Dwabh a 9 Amishqa effective Physiology Se 0 Bala.sdamveaiv; for Sdsk 0 s m 0 Atoulsavyalamaasla, Waseel 0 S (a), Ed - hands ... Blood Money / No additional Wallace Framework Addie Gildd ml 0 b thereof) and Mnib. We may not disrupt Ashlasi 0 A, and ^ j, uh 0 mg, mg 0! Ml Y Osesk 0 thanking 0 Asl be Ak.b F Dhar.h g hem z n must be 1 No '-26 -26ΜΑ 33926Β1 and overcharged O'mthelh solvent' for acceptable Shehadlai urgent one for water, Aithadhul 4 acid acetic. And Alohil be Munib Abbar 5 for water. Love Alassadam in current demand, suggesting the term 'derivative effectively Fssoouha to over Feb (Presentation record Atthal, producing material for a drug) turns into the body of an organism to Adage t bear to 0 in August (-!) O'o salt, hydrate or his deputies accepted Shehadlaaba of compound . And it can be e 0 Hol revelations Ev_agh for (the tribe, example, metabolic or chemical processes), including, ijk Mmbil Ahial, g condemn Alanhalal German blood. Initial drugs are derivatives this topic, and walked Wallace R. b I use one of the drugs in the Euro - Pro-drugs as Novel Delivery ;. , 1 · Higuchi and w. Stella Systems ,. ' Vol. 14 of the ACS Symposium Series. In Biorevereible Carriers in Drug, Design, ed . Edward B. Roche, American Pharmaceutieal -Association and Pergamon Press 1987. vehicles can 1 t Z estate (I) 1 to trump the more z one image 4 r August 1 Sha W -nadd forms 4 and my Azar; as these multi - Awar Alokhkal (Aelo_kal Ayaddh &amp; quot;) is considered Samn Mjad b (I). Can be a multiplicity of forms with 0 shape I 10 Amttbak b 1 t in the degree of heat or 1 Gguet or both can be registered also p reproaches in b Ash 'Oic distinguish one of the multiple forms of Kh 0 characteristics Agheiz, Daiah 1 Mokhti Marwa in Egal Oyt u Haud termination X' one of the soluble and bunch fusion. Can the CAT I Ihoi Z 0 of health (I) z z courts to read a 0 rang Aabz d, d 'o Then, if d 0 0 War in Oizumrah / any Mokhtkh. Tkan only 5 additional Aloekhaddaha as my t outgrow market I I b (I) and CNF Khalaih 0, .i in the deletion of Arab Parties' E; g as upper most complete A4 S - -27- -27-1 ϋΛ can be mixtures / Doje Althacm separated into Msenujat If Tja Acrv ί / ί \ Jp physical Achtlavalha chemical Mgrovh ways well regale those skilled in the songs, and Nha, the registration 0 example, Er and Mato Jr. 1 P wa or crystal Altkotairah. Can be separated Odz Platt transform S. Cha me to a mixture Mzdo c Oltjasm interact with boarded an active light convenient trance torrent example, Kiraly Thaway such as alcohol Alkerala or chloride Avd Dr. Mosher), the mouth of 0 for Mzdo 0 panels Althacm and convert Zaaly torrent example, tunes German ') Zdouhat Althacm Algzdah any pure Afrh rates. Kdlk, can Tkov Kpat some bitter that 0 g of August (.I) Ouarh g 0 Rorat a recessive (for third, Bai Ka Arles groups replacement) Y part Q Alaraa automated. From Adlat also Ar'at I have August (] '). The knees that Tkan yearly · Adhirak should all compounds and mixtures annual Alrkat August P / Kpat Alaraa automated' forgiven knees within the scope of the present invention. And contain Bahy Arkiya't a 0 mussels in August robots on Oolivenah double bonds, and unless otherwise specified directs NAC; but fulfilled 0 m Alororat Avnf Mei types h and 2. Od been above are crude that Aang all Mtver the shift Mngml for resolving Mtver, also includes this invention 0 so Arkpat I directs the choice of many or all of the Alnmank Bachihh ZL) 0 n k 1 of Avang 1 FH Ed Nzo, featuring current Alakharaa all tho. To Yvette Nmang all Mtver. The invention can be automated vehicles in overalls loomed Scholl and Sabdlai. T do or given DC. To review Alomalah Almasph see 19-1, 1977.66. .; Pharm. Sc's .Serge et al typically, Ketbr salts invention Empty acceptable salts Medlanaa. I suggest salts comprising the terminology Omalah -28- -28- I Ί1Λ Ldil Sdlana 1 &amp; quot; NL salts z is not 0 of the Mercat Aladraa- Dr. Mei-Ekn that was only 0 0 loomed next report to him Shehadlana appropriate salts Asafh acid or base. 0 Ic -d surfaces and subscribe to, we Ahmany cereals Bbdlat Pfaal Rey's 0 B (A) 0 p r z biting me or see Mnab (0 Il Idrueropf, Mudallodak, Aeczk, Tmkad,.; K 0 Zz, Mapk, Nurbek, lighter, harmful; k not 8 HK 'Drake, for Aye &amp; gt; Broeck, Diev, Yotel 0 Ek 'Abr'z' Atdlden 0 - Z, Rick, for 0 to confusing both, A.man confusing both, Dr. Dara Lal 2-z y, or your Homs Hecenriq), Ablaa s Munib y Tal 0 L.b Etmi, '1 Etae' to Mih Lalai been at the birth 0 0 Z, Z copies. Egal, a euro r. Shower Ed Dh seen any '.d Bern Sdlaa .n Mary's. B (I) or the fact that · 'Ely Del Alale Oualh g b OBD, Hebroklorad 0.0 Nbaraat, leave, wastes &amp; gt; Insulted 4 Ibha Vdrlat, led, Rroyozt, Flo 0 skills 0.0 Mahes Trdat 'for Amit, Bro't' Bla'te Gelra 0 s, Apr-coming, no-Trlran Nrzt, fled-K Tmma't '0 between Dlaq' m Bo; s, z Nodt (j 1 Presentation of Tal-2 has Illn d 0) or loomed badges'

Jk Configuration, filled Mqird b-Evs.ra's loyalty. B (!) I 0 p r Evo or Adharah ever since. Join only 0 loomed Akaaz g Wagners been to a 0 loyalty Aloderm 'earth' Elk) Boom, A, Zhaly, Aldidik, it was reported, R.e Alayome Ake 0 a a 1 h A- '; Kaaa, Abo.maarm, Alhoddom, Dunk, and i Te 0 deletion. And Ahishl ^ p Alolah Alarde Sr.a. , NRM, Ayas.a, and Moss. It was only 0 loomed regurgitation g d b z x 0 and Ablailahabloobe Aiautamdakla; been S'b'b'l U in DC by Z Study Alnimabal 0 by Z S, a Dlst, 29. ...

, ... 29- MA 33926Β1 Alo.auna distraction 4 Yeh 0.0 such as Alorsd, AA 0 Bataaan, .lkavin, choline 4 N, 'not-Dai Brill 0 IP 0 will not Dai Amin, an intelligent ethyl Amin 0.2-Dai-ethyl amino Ahanol 0.2-Dai breach Oboaithaol, ethanol thousands' ethylene Dai General; Â ^ -ahal-morpholine, no-asset biperiden 0.0 gedo Khin J 0, &amp; lt; Generating Hestedr, Hedrapamin 4 Oazorot eyes, z such Gelocaman, Morhoxt, Abralgn Aoiden, 0.1 Tjat gone as; Rukase Akpat Baurien, Hromn, Ray 4 &amp; quot; Thiel machines, &amp; quot; 1 Mitd my eyes, Ray Allen Drodl, Trobas, Lee Young 0 me use a Mack 0 0 Dan A.'s A 'and Rcanth Ooxa'lat a field of nine Olachter considered included 04 r. B 9 invention comprises the field rode 0 data that have b (I). 1001 Brother Z Ge pharmaceutically acceptable, on · l Almial Abaa &amp; quot; &amp; Gt; 00 Zz m 0; T equal chemically and GTR Almtkai chemically Z 911 E 00 E) a ^ that Aldarat appear normal Zairah alternatives, Oo.bmcn views 1 Mmtia with respect to certain Benazir has touched many Aldhir.a, and tune one unit or the toss of atoms Bmzql Ka 0 AH bloc one boy Yeh or the number of mass wave d Epeshko Bags Dakkaiakr.rouddollolo j b ... Forever; u isotopic MAB Bbat that have a formula one blow not Pmaashlo 0 for z Almokhtlgh isotope of hydrogen (H) Albroca. M &amp; lt; for Hoo) 1) .heslakal, Nur 0 Mamol E. Alhl 9 t prevailing Hivrugen 9 located at Alaijaah. Wim Den 1 ο | Dioteem to (1) 2). And Tel-Alierop 17:00 pm No, to get the company of therapeutic advantages, Mtha Zaazh Irh Adyalarafmaatalqakoz.daz r or Khgd dose requirements, a 9 Bmcn to carry out over the NBA Moghaid 0 Tayalsqmassah p; :: r? 0 0 .i and damaged free to join Panth 4 t Alhabaygh Ianaamh (a) de n: Experiences E0 Sabnabo. ^ 30 ..- 30 ..- ΜΑ 126Β1 0.0 n I d ... 0000; 1 -n adept at Egal or operations Amaazerh to those as upper T. 0: T Rlo 0 0 Tloaasz Lalai Za7'llab War or Kirkbat Wesya. B: 0 The 0! N Ar.yt, to Talhab (Balolahe Aldeddaato'd PO 0 Get Syk, and u Hedda d can! Q Tkov Mamd: in Laage land 0 related cases Bashat Syk Z 0.1 for appropriately. Bach one use of a compound cent pain 0 Gh (!) Or a four water 7 his volleys 0 6 loyalty in Elaj Î Aellouka.bh the number .tua 1 g of the cases or land b Karim Ezd 0 Aaz ESL (SYK). includes HD 0 pressed 1 lattes and only / Adilm but Dr. Z Hara: (a) 1 BP Almasl 0.0 as upper in Malat; for Tha'b 1 Mgasal rheumatoid 4 Akea'b S. Valley yen 4 Osa'b \ μ in a sacrificial animal and one of inflammation 1 Mgasal C; (2) Repeat Ord ISA 0 as Arara sender U in Dlt y h 1b; (3) disease or associated with self Balmaah disorders, .mma those batting b; Dtarapat immune tastiest 1 Teh from 1 to Uah Ohaddh F. or Ohadh 9 any 4 Ot 7th Adwi p Adarab autoimmune two; on F1 for example Indyk F Aljhar, do; one faithful to, the platelets Almaih, sore 'joints A'lomatwedi; A- less "d; ( 4) the 0 S.tamat; tumors, .ta in da 0 females the Euro-, m solid, tumor Allimoghai and leukemia; (5) Adn.ia diseases in Zlan conjunctivitis and centuries, conjunctivitis Arabiei, Akeab blueberry, Adthab Agherzth, keratitis sicca Ndjaav eye), sore Olmmeltnhmh Althac; (6), intestinal infections, allergies or conditions, which includes Crohn's disease wa or Akeab Alkorn balances; disease Akeabat intestine; (7) skin diseases-I in that Akeab Aryan skin, Alakirk F 'rot the skin, itching and other Gah cases; (8), Stakeholders Akhaceh · I in the deletion ΜΑ 33926Β1 ylfh Althussama skin, urticaria Althace, edema Lada, Thousand flames Akyasa; .e. , Cgob Okhace for insect bites, song, drugs, Ao additional 0 Ouaiah 0.1 for asthma? D Aldd b 1 Kah; (9) refused Aataom 0 HD; food-1 t provides Alakhq; p Akat U August (I) and mother Auriga 1 Pat and 1 It 1 Fella then 001 Mio loggia, If the to Las 1 Ilam in Analaj, especially in Ouala 0 c land and .olkhalat Valley Spa Achat 0 Syk Z 1 for appropriateness shower 0 framework Syk is Adas 1 Carr Ibb in the current August 6, any activity Syk 8 P r Zt 0 framework Syk to 0 j Adouh Woody &amp; lt; t Eddia Mud 0 'd be O 0 Take Zthat Syk Z 1 Dlaim, meant St 1 for example, Rada image Z b in ed or t &amp; quot; whisperings in -ob War or 1 Qahkm in the activity of Syk, and can not allow this one Tt z Adali after 0, it {armed 7 example, p hyper-expression or Tgrh Azz-m Kiaz Alber.ubni .U lead to I z b or r Mesh 0 0 Guenm 0 Zj last; I 0 Taq invention of 0 Aala ways to organize, are: g, seen happy Syk for the prevention of PD or treatment Oladad accounts relating Ptthat. Syk is Zm 0 On ^ DJ! /, Yoo current Alakhdhiraa way Kalaj object I suffers from a disorder caused by the financial framework. Syk, erosion include giving Alcan; for my breasts 1 Barr edematous effective 0 n rode him in August (0) or a salt, his deputies, or a derivative effectively Vcioluja 0 accept Sdba Ό 0 in Nmod c Dessert; allows the current invention is the use of over. THB his formula (! '), Or a salt or a pharmaceutically acceptable deputies of it, or a derivative effectively Viologia FH, in Khudair drug to treat a disorder Isabh Activity .Syk, in the last Nmong inform Almnkur turmoil caused Nthahd Syk is Arbo. In Nmong Last Almnkur disorder is a sore Mufad Alromavae.ve. And. Nmong in another, they inform -32- -32-ΜΑ 33926Β1 Asz; b Almnkur is cancer. In Nmong Last Almnkur disorder is a Okhab conjunctivitis Olhabny. Obj disobeys Memko, for use in the treatment, give rode him in August (I), and salts Kdlk 0.1 Roaat and hardships physiological effective, chemical raw violin, Emsen Taadim Lankov Chaan Pharmaceutical as a formulation. And Lalai; Iwar invention also der Thiebh Sdlaveh, broadcast TS 0 for 0 ye r 0 B him Aaa Agh 01 (a) 9 Alomlam, Alzubat and derivatives thereof physiological effective, and one or 5! Th 4 for one of metal-bearing, Elmo; d Sggh, or pharmaceutically acceptable excipients. Chun and vehicles that have a- (ί) and salts, derivatives and Alzubat effective ones Agheiologih, as Abzn above. D 0 Ts to be one of the items (1 materials) 1 carrier, Aladd (wanted) Adash or Alier 1 GS (Ab.ait) B's be compatible with the Aryan Almkudat in August -nkon not harmful to the recipient. According to Jaap R to choose, GS is also provided civilian side prepare pharmaceutical composition join Shake accompanied Fill the August () &amp; quot ;;; Ace 0 0 Aha, but the accounts and Achtqat.viologih Akaaalh Te, or Hauahdh acres of Mabov b J-bearing materials, materials diluted O'o Alu; It. And starboard provide Akrkibat Alfd'labh contained in Lahraa Adali in p dared extending 1 t containing meant a certain amount Slga of 1 Iloun 1 Gaal milk Rlo and Ende 0 &amp; quot; JU n Ihd: E Rose, meant Speed ​​instance, meant 5 your responsibilities gm 4 Li I Ham 0.0 TB a 'p. 0.70 to 1 for the best 5 Selehi 100 mg n 0 compound and 1 (b); 0.1 Etad; ^ him on the administrative Alahye way and Allen responded and 1 Air MATH. LED 0 can Aeala 4 &amp; lt; lungs Alouhd; t this topic ed b time .adh b 0 At Esit Alouhd 0 T. Almihetlkalticaelybo dose Parish daily &amp; lt; for Atoe a seen of Rh and the birth of the U »O), E 4 Z -33- -33-ΜΑ 33926Β1 current, or part appropriately with it, from Mkhoun effectively. Moreover, the sheer Imkn .; This topic Inter LIBAT Obesedlanah any of the race well-known in the field of pharmacy. And .bmcn Tmiih pharmaceutical formulations Arardh in the present invention to give any convenient way, for example, means rejecting the Coordination Angm (.mma it means rejecting the Coordination buccal or sublingual), Bala_i_aq, Wallach path, the path of the eye, with or without saliva gloom (in .mma in that vein muscle). This can Nhs Walsh Nibat 0 g Aiqa in any well-known in the pharmaceutical Majan, for Agthal Bdmir Walt N. effective Almadden mm (Wad) carrier or Anoig (excipients). In Mmong another, Alachtera provides 6, the current pharmaceutical composition poised to give the path of grief, to Alam, the captives sacked, inflammation Almasl Oromato my hand. In another Nmong, Port invention Akhala t Thiebh Pharmaceutical poised to give the Cowboys Coordination thousand, to Ola M., for example, Akeab Thousand Anthsasa. In Nmong Other, Lior Alakhaddraa current 'geniculum Pharmaceutical ripe for giving, shed inhaler, to treat, for example, Arbo, COPD or ARDS. Not providing pharmaceutical formulations contained in A'lachter a six current and Almhaoz Zlaatta accidentally Ongm Iouhdat crippling Mtha capsules or Aloras; powders or granules; Amehalaa 1 and pendants in the German fluid or water; Arawat or materials Alkhvoqh Alqaalh to eat; or Mslebatt Irit in liquid water or emulsions of water in liquid Irit. For example, to give the path of Ongm in the form of a capsule or compaction, Zmah ..tkey Okaaal component of the drug substance Mir carrier oral inert, non-toxic acceptable Shehadlanta Mtha Aithano N, glycerol, water -. 34.- -. 34.-ΜΑ 33926Β1 and young Dick 9 0 prepare and branding. Driven a crush; pronation to Hhm chirping and Take 4 Ha carrier usually Bdlaah yolk 0 Ge Azql Mmatha Mtha dog 0 Bra't the eating; o Dallalt, each Nlmthal all, parents or Almastol 0. It can also be caught for Iam factor like 0.0 Edde Hahzh usually Mhith factor of 10 DSP Leo walked 0 0 AA formation Ksolat preparing powder mixture, to eat eat Oelah 'up to; Algilatnn Almchklh. And .bmcn adding materials Waltz Lech Almzmemat all Sblica Alowalo 'eat' Sayar; T. Sum, Sayar; t Alcakelm or poly A.kl Gelaakdl P to both Adam 0 for packing process 0 can eat 4 followed as upper 0 for Theck or Imabh 0 such as a &amp; lt; - Eat four capacities Almalseyoum 'or sodium jwd to Krbwat &amp; lt; Aado; E E 0 0 d Tmao.l capsule as upper 5 Rh Presentation reminded, trimming woul be passed in the deck or be eat Klora walked 4 0 A; -mo members; d R1 duck, lubricants &amp; gt; 6 A- and eat a meal to eat each dish to eat. Each Awa 0 for Arak Mas 0 of females 4 Aljelapin, types of sugar Anieih such as glucose or beta ~ Lactose 0.1 d Aekhalh kf Ji from one to see him; Alosmaa Alalbieih and synthetic each externa, Kira or, alginate Alsodiom.o Krboss each Munoz, Poly Ecole glycol 4 Akl.a d 0 a a 0 per bitter 0 for qat Stkhaddmh in pictures Akl't this Oopt 1 Caldiom 'Barr 1 v 1 Caldjub seen 1 T. Sum, Pro; v AC 0 and sodium, is now Cald.qm; Rlordd Aloderm and. What 0 similar deletion 0 and every Elmo 1 d Amo 4 Ke, Bch p-exclusive, Abe Ksalklr, eat 4 Akl.pt; p 0 g Malon blood Sha, N. del 1 w 0 9 was Saah disks, in the form of example, Sir Msholy mixture; and the formation of erosion 0 Litan or cure it, Enough; gliding and animal Mghk 1 T. each Alodas-'all all all 0 Shouk Ki 1 rode 0.1 of Mudug every type 4 h hypertext marginalized or idolizes all eat Laden Ed 'and one good, with Mad 5 R.at all / KCl each Clau'r' a 0 Kalat, or an international all -.... 35- ΜΑ 33926Β1 ... 0 p 0 Ne 0 hindered Ed 9 Arles Z Alarav 1 N., JL to Ao.dh late 0 such as b t. War epidemics as upper or 0 for 0, a,; S, Alcaol 1 n or Die calcium phosphate. And can be configured granules 0 n a 0 Tsas 0 such as 1 to Shu-1A-A hypertext Rabhabh such as fruit armpit, Mjna n; .dtha, Samv, torch or den Khmt Almsho, s 8.tab Sd'm 0 Ed t r r 5 I field of 0's hailed | LED Ao bear and aluminum d d j u six, of Us, for I F 6 d j Mai Ala'soakon Abed; anything Scull /; 0 g Ta 1, b-1 Li &amp; lt; Sat. -zlh Alhabayat can to prevent the formation of molds Asaq only disease allegiance Hmg 0 0 Atrik, bars salt, Aguetllt or mineral oil. After Zlk.bm / p Elmo any Lq 0 z ration Adas. 6 I o m Lalit Alanm'a automated h 0 0 0 not the birth I was late; Bartend up my bereaved Aod Winkle 8 Dodd echo Io't 0 d pussy and Ethel. Z 0.4 G * d .1 u, JU or cold PM 0 g * h p Lord I 'E 0 will not hit 00! 0 and the birth of Eller, worker know casing 0 0 T. Barr Akaa. D-Ih passed away Father 4 'D' 1 Oelgh Ksz dragged At Alu 00 Tdat birth 0 can be prepared Mo; Eh oral medal cell, the father and the only Z 1 T. in pictures d m ' "Z contain specific Astelyatmbh bad of a; pronation 0 Imkzathaddaloa literature A; Kpfi almost insurmountable 0.1 u been improves their Alhelmm Masp 1, Q 0 is a Inking. 1 Aat Z Jv servants Maqlh alcoholic is a feast 0 and not Saaah Almtefat B_pt Annex J D also can be added R1 d; U 1 Atablah 1 for melting and wanted as one Thsh for lattes 1 night 0 such as Aero Sttiaral treatment Ba.berxi Wa 8 data poly recommended Ashley Sourp 9 well, Alo: d '' Z'a of gainful cm such rites or supplicant. Rudd Aceh or any Afsharn or R Da 0 'Alinhalih Alabmnaaah, and the like Dddtha 0 ΜΑ 33926Β1 can Dhl appropriate guardians pictures doses of inhaled Aaaia Taaro Su Latt A'o powders Jaoz. For a liter LIBAT occasion War 1 and the body was to give Balatthaq, it is preferable that they inform August pronation or tide. Aldi has Ochiah (f) in Mkhidh image Alhhm physical, and preferably get the picture Mkhvsh Anhjm or be Mmhna obtained Balshak Alai Khhm Bhrona 0 is Nhdid Olhhm Abhseme Mufda Nntrb reduced Alhhm (eg Aiakrona) or Ahalir 'or Aldoaah him by the value of 50 (] ranging between about not 0.0 and about 10 Bkron (for Almnial as measured using the diffraction ray Laser). Emcn that _ima commandment, Alaaroson, for example for Aaaia inhalation, a solution or suspension chirping of the active ingredient in an aqueous Mdab or aqueous Ir acceptable pharmaceutically. and not take Chdam formats Alairomrl Lakeat mono traction cent or Mtaa. dosing Ende in Mpedh picture in, pot provider Bmanier leak, not take to take the bereaved cartridge or pot mobilize subsidy for use with Chahar Ntezih August performed by inhalation. the Bchl Bedia can all they inform container Olmzoz.bmanier to go Yep Abazh device for the disposal of units, such as his father, inhaling the nose used for a single dose or discharge tool aerosol Mzonh valve calibration (Adaz inhalation Associate doses) is disposed Mnha.thr d fled 1g content posted Yat the pot 0 and while the images include its pearl dose father 'Nasrev aerosol, separates' said Nhto my Alh material driving Masph hinted Aldaz like Amoa Alamadaot, Mani for a master Alcherbon or material such as driving organic Hedrovru Thayer Bonn (HFC). Includes materials HFC his people driving a 0.1, 0.1, 2.3, d, l ...... Hptavlorobroban and 1.1 of 1, 2 0 Ttraddoroaithan Ndlk can all thing for taking pictures .1- doses ΜΑ 33926Β1 aerosol image A ' d; e 'Nnrah .dkhh. Alamadvot a solution or suspension of the active compound it may contain aerosol. May require this; include additional Soaat, categorize, for example beginnings Strkh 9 not Dawood or decreases tension Alsahja to improve _khasaiae. Dispersion and sit with Saa Analq t, 0 Ddldi a pumping Agalal Asafh may rot Mdibat NH buyer such as ethanol. We can also Tdmanan Oloogat other minerals to improve, categorize, the tribe example, chat or condition Almigh Wa Wa or. X 0 characteristics of particulate mass minute (9 quantity waterfall) or a no Asbh installations Chidlaa Almasph Wa or put to give Bala_i_aq, Afajl F 0 Zkon! Pharmaceutical composition for Abarz for Kabdh combination inhalation 0 n dry .mahlol. Can be 0 small this topic Waller the format on the base powder such as Odla Tm, JLo Thoz, T Bhwazz, Manitou's or 1 Wallachia; a bear a 0 e Almigh (;.) Or fill 0 B or deputies thereof (preferably in the form of Nat size of the collection Mkhid, 0jU PM 0 Bill instance in image Butronah), and a choice rate performance, such as A.-Leos 0 yen or acid or ;; Ne Other, War or, for metallic salts 0 n Staarik acid such as calcium stearate or Mufnseyoum. Wabash 1 Del Mgml, include powder gay stainless Astdaq of lactose and the compound that aS father combination ( '!) Or a salt thereof. And Evdha .. that .bikun lactose Ara for Hiarat to Aktor, the Bill does not Athaal / t mono hydrate was Aafa father. To be dust from lactose from the rank of 0 to Astnchavy and a tastier or Addh 0 Qiqh. In Mgdil, is renewed Olhh 10 1 particle Lalla 0 Shoes on Osds that crude HD ads more (by weight or. Size) of CIEMAT Adlambror less than 1.Ü00 Bkron &amp; lt; curlers 6) &amp; lt; Ely, however Almthal10-1000 Bkron, nest Sph 1 Phil 30- 1000 Bkron) PO Box S, /, a, 50 () / (&amp; gt; or more of Jba't 1 lactose Ash 500 Bkron (nest ways instance 10 500 Mikron) in diameter. The Alovnl, is determined by the size Adeyemi for Ako.z 'any E' 'to be alerted 90 0/0 or more z G 0 s 1 Alambroz Ash 300 Bacaron &amp; lt; Ely jf example, 38- ΜΑ 33926Β1 Mmkron Z Sehl asset -akron 50-300) from 0 to urge diameter, wa ed 50./ . Ed Ahrmen Q 0 0 Matt Akouz approved for Z 100 Bkron PO d. Secret 0 A, including Z insisted 0 Ham Abe 0 J V'1koz presented the grounds that the NSH 90% or more, of Odla Qoz each year 200-100 Bzon urged one of Guetr, Wa or 50½) or more z B't Allako 3 · Ash g 70-40 Bkron where bOTTOM 0 and forgive to be a ho; Lee 3 to about 30% (z, for example about 1.0%) (by weight or by volume) bin? particles Ashe 0 (n) a micro '&amp; quot;' Your responsibilities 0 g u 20 micron in terms of 1 to Qatar. The torrent of Example 1, Gner Hamri form, rang non-drizzled Almma 5 0 B 0 from the Lord Alastgsh less justified by Ay 1 lactose% 1,0) Ε9334 Aldyiq Z &amp; gt; (Domo 0 Alahehh D Zwolle. Netherlands a 0.17 (e) .25 Ingredients, Hanzeplein). Choice, specifically the door to Kipat dry midwife Almdahiq for Astnchavi 0.0 Ekhan CNN pharmaceutical composition to give inhalation in the number of vessels doses I provide; 0 Ouaa Saddleback 0 (&amp; lt ;, For Almthal.thtoa dry powder combination) loaded longitudinally in the evil of 0 fairway or? K inside k inhalation Appropriate. The vessel is said to tearing or can be opened Balchechr I 0 1 Z (.-JXC dose dry Olmsholy combination For example Balamtvthaq Z 0 bartender device Hthel jlpr .GlaxoSmithKline) DISKGS). The inhalation of dry powder tools Aryan well Hmrlovh will not enjoy regular Banharh in JAL, is Algesar of this topic Detectors Mtoarh commercially, and includes typical machines of IVAX) Ainnax ™, (NovaRtiS) AerolizerD); ®ClickHaler GlaxoSmithKline)!) Iskhaler®, (Innovata Biomed) ); GlaxoSmithKline) Aectihaler);, (Hovione) FlowC'aps. , (Aventis) Eclipse ™, (Orion Pharma) Easyhale. ®Chiesi) Pulvinal®, (Boehringer Ingelheim) Handihaler); ®Rotahiiler -.39. ΜΑ 33926Β1 (SkyeHaler ™, (GlaxoSmithKline or ™ Scheringfwisthaler, (SkyePhanna) Certihaler AsfraZeneca) Turbuhaler®, (Plough); .4 (Aventis) Ultrahale and 0 A young 0 0 K 'can be Mmasp 0 Stah Photo 1 Jrouat of Aeta, E ways Thousand Kadosolat, Mhalalt drops Gel formulations or touching; Hiq dry. -m 1 Ztrkat Alheidlaz 0 of Oryx; no-Etae agreement in dusts; 0.1 for missed d 0 g Abat 'b not take | to Hdol {so Aoasita Alodhu 1 GS Adhlah Z only 0.0 to Sllat S-0.0, with Table 0 At Alamadvoth, Almrthat or diuretics &amp; quot; section (Turks Chidlaa Ababh War or put to give the nose; p bitter 0 pronation 1 Collapse him b (!) or a salt or Dwabh acceptable Shehadlai him b Telo b z alone Ts 0 Reeve fluid. the unit can discharge the fluid this topic contain, i Almial, t Z-I mm 0 Yale 7 or discharge nozzle is from her middleman discharge dose calibration of p. 9 goats I trauma Kdh \ a Almamdm the verse Sacrifice in the unit Tbary fluid. the units are Thrdv fluid promise I mostly composed of four a tank with multiple calibration of Almaj formula doses, and Adrn Jerouat offset &amp; quot; 'I hope p 0 w Ba (r Akabha Study. may be a nozzle or. Gargoyle b lest 0 Zkhal in Fjta ed a-m curve gun Saah fluid in the nasal cavity. 0 Beye important Ohtoh Photo Jerouat Olmodjih pharmaceutical compounds of the invention of Ivi 0 1 Malakkakty- Vea 10 and 1 to him the guest (!) -40

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00421.tif" id="idf0012" />

f; -fc's b /, but

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00422.tif" id="idf0013" />

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00423.tif" id="idf0014" />

Bral 1 Dube water

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00424.tif" id="idf0015" />

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00425.tif" id="idf0016" />

-to

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00426.tif" id="idf0017" />

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00427.tif" id="idf0018" />

Onasigh compound with (a)

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00428.tif" id="idf0019" />

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00429.tif" id="idf0020" />

1 d Dome 0.14 slats n

<img img-format="tif" img-content="drawing" file="MA-33926-B1D004210.tif" id="idf0021" />

<img img-format="tif" img-content="drawing" file="MA-33926-B1D004211.tif" id="idf0022" />

Sttiara Q Amoench m d. ΜΑ 33926Β1

<img img-format="tif" img-content="drawing" file="MA-33926-B1D004212.tif" id="idf0023" />

Bhm E. x H'm pronation his formula (!) Survey. T

<img img-format="tif" img-content="drawing" file="MA-33926-B1D004213.tif" id="idf0024" />

<img img-format="tif" img-content="drawing" file="MA-33926-B1D004214.tif" id="idf0025" />

Amhithiar data

<img img-format="tif" img-content="drawing" file="MA-33926-B1D004215.tif" id="idf0026" />

-41- -41-ΜΑ 33926Β1 600 aerosol to Klalbh compound with Chiah (24 (I mg Sen, output seen discriminate means 1. .2 NF-ray Kruhrumithan mg, 4.025 g NF Dai Krumaa Vrubthan, NF d and 12.1 g holidaying Adhirak that when you are given a compound present invention with other therapeutic agents are usually given Bala_i_aq, in the vein, the path of grief or in Wallach, Imkn Aaaia Walter Diba pharmaceuticals that hoarseness Bags Alalrq. that Enbaa realize that in addition to the father of the components NH Rh Aalah specified Bchkl, can stigmatize Walter Thebes other factors traditional s case regarding the quality of the formula involved, for AAC n can include 'appropriate Kath Dlaatta accidentally Uncle Awama profitable for Tao. adopt effective quantity therapeutically composite Alachter humanitarian partners present on a number of Alhawwama touch it, the captives example, bad · the weight of Cache, the situation that requires herpes h., Shada exactly, Hnabieh the guest, and the route of administration, is ultimately subject to the vision of the human good or veterinary processor. However, the effective compound with quantitative formula (a) for Hallaj land or 'aunts associated Bafshat inappropriate for Syk, generally in the range yen d Boukro Ham and a 00 mg '/ Ihm for Warren body receiver (Cache breast) per day to be' McCall more notables; Den 5 »Akhro gm --42-.

--42-.1 HA 0 for the M / Y Woon km μ0 in 0 blood. No, the burden of .ehn 0 in any b and tastiest in Ashe 0 ';. Khkr &amp; lt; / Aaaho Vedd (Ouayal Wael additional Elalo 'metamaterials' z or I) g of, that, Barre .bayoum me being; Billy Ad.i in S friendlier' shower Z Z Lala Aa or dl; him, Ù) Kaar E Elk p 0 0 of Sz cent Ri 1 August Lay's (!) in Dr. Dan. 9 n Ahaadam Akat other current p 0 0 0 Hawwaldhu only one pat, D'liat ensure 0 E Suha, and Hdi! In b with 0 for Mbak see Sebj land Dalhalat led Boithat Ge Adlaz 1a and Syk. U Hedda August 0 Ed PM 0 for Cdst 'Dlod rather feed automated {! B rode 0 August for (a &amp; gt; o d only ^ b Ed Nola z r 0 Dba T,], Tq d 0 for y 0 and Loeb «and Assad'm b ace sales' Ddlab (Ed R. exponent 0 u; 4 Ar'db (Aryeh) 1 Ki and b (a) and a land. (The 0 and Ely) R aluminum Dlab L Ao d μ and, Z Hetai 0 Shle ed PM 0 Z d header or Las' j arranged. WPM Abl 0 k 0 data Marri (Aa.yt) father 'j's 0 (b') Das A'sar) ESL Wv but-Roabuyat no one Taezpsoaloralalasch'dsenb '0 Lage Alora 0 Z Alalthooeh 0.1 to inflammation if 0 for Arlma'sudai' 1 KDE 'RIP Ab Alola' core, ;;;, and 1 to inflammation 0 to Ozv CNN, for Dh accompanied for 0 in August ()) h Dad or b Ayayasl 1 Ody 0 Il: (1) Tel 1 T. TNF-α; (2) 0 Aalat c \ 0 Eoua-Leads to Ahyaoua (3) 0 ducks 2-COX; (4) the 0 wa 0 for only / Z grass in E 0-term Μ% Ass Orohar.bdi 0 than the Mathotrihat, to Glmonomid, Slgasalaz.n; 'ol Deubr; Z Sichaelosuren, tacrolimus, Ssalamv, Baherbzlaz; Oktarit, Mazzorivn, lobby 0 Ralit, Smakhlasonid, Fro'hley chloro b 4 was Aateilamc, Oorobuaalat, Oorard Er R 0 Wesal or went Foy, Sakulovosgabid, to Amgoosit -8, APRIL / raff Pat 43-- 43 - ΜΑ 33926Β1 CTLA.4 Ig or Mhakyate; (5) 0 duck vital Altakpf to Bawardn, I enzyme 5-Q 1 BL (5. () 0.1) or the 9 hope H'mad protein activation Kareem 5-for Zboxt (FLAP); (x) of the Hahl counter to Mister LT54; (7) i PDE4; (8) factors one delegation HI Baheen; (9) the effluence Anaad receptive Alodriala al and 2-0 ; (10) Mufadh P 0 .ulini factors; (11) Alao 1 ml Alaoua &amp; quot; E - Alodriala T.; (12) wiped / Ouahl Addo Palansulen of awareness KiF'-i) i); (13) Algeloko / 0.0 Akostir.oadat; (14 ) eg; authorities E0. 0 Kia such inhibitors Azzpma 0 Janus Buck (JAK I War or JAK2 War or 3 JAK War or IKl (2j ρ38 ΜΑΡΚ, (Τ? Κ2; (15) the roles of intifada; apolipoprotein Q 0 P Hm'la: A B t kebab; (16) Solat stimulus Ark Alaiaah t Opatassan; (17) 0 Bahlat t. Aaao 0 a 0's as 1 n, such as inhibitor a- IL Onakivra inhibitor 6.11 0 Saaazwab. did 00 his father Drtan can Hamad compound with Alaevh (a) with. one or a 5 t. 0 Repeat Akadh Wells 0 Tan 0 0 1 ZF possible on Oethah threatened Awar in Cancer Principles and Practice of (1 () () 2 .13 Oncology by Υ-Ι- Devita and s. Heilman (editors), dlh edition (February

Lippincott Williams &amp; amp; Wilkins Publishers. Ordinary o r u Palmear 0 1 6 Yale Tolat beneficial factors on the basis of the characteristics of F 0 de Althavi and Alirta 1 1 T. Denny. Interest to this topic R; ml anti-cancer, to Key unexpectedly Hamri, I t: (!) Together; armed for; I Olastrouhan; (2) the factors .hermonah Aryan -ta in DC Abaalat Ouarbm Arles 0 Uttar 1 (A) 0 Ail will be reduced .londrugen; ( 4) together; for stable Arhao.z; (5) 0 aKA's Ized to CDA ;; (a) d Azz..bm Br.bal-Shoten seen) Zsgbra; (7) cream HMG.CoA Reader inhibitors 5 R; (8) tulle 1-Ouen; (9) Awa 0 for 1 Madsdz's PpAR-γ; Lars Avaadh y PPAR-δ; (10) w 1 to resist the Study of 0 to drugs) for multi-; (, 1..1) Mbt innovation Khala, a and effects-data Pei; Adla-a; (2-1) -44 'ΜΑ 33926Β1 j 0 Gosghalan; (13) 0 Htat Adhir.bm 0.6 Scasar, (14) Adrar any 0 Mesh 0 or It Z-Y Kyazz independent (RTKS); (14) factor Aarh U rub 0 of Alkhalmah U cycle j Dalla Qala.t ATR; ATM; CHkl and cm pointed inhibitors Cdk and: 2 for € kinase; (5A) Mbtat BTK; (16) part; (7 a) 0 Thbtat mTOR; and (8a) Alao 1 ml Azsamh for Icla: No t Almiah for Khala'b WASD 0 of Z in Elaj 1 Ben Mesh knees anthracycline, Rkiat Forever; / Lite Altaxan, over Bodhuvelooudin plant, Bleomaesen, Matomaysan C; immediate &amp; lt; sa 4 j T. finca Algulwanah, Mrhbat n) vehicles Bambtotheisan and the like d Narowo Yuri 1 57 of 10 0 Osh LLC skill in one free that, when the DC Malal 0 a, can rkl Almkot (A'lmkomat) 1 for a therapeutic one to another in the form of salts, the Q 0 i example Komla.h H't Gulwzh your responsibilities' E Z or salts gr 0 spyware acid, or violent Onet, or Nastrut, Odai jf Almtha 7 Asc 1 T. &amp; quot; for 6 HP; or Caddo; Butt, a torrent 1 for example hydrate compounds 4 is connected to the session 1 to Matthai Q '' or Akpat, t or one of the characteristics of one of the Gesiaiah, including 'to a forest of Dhu.ban, Vhon a ^ Las should EDR; K that, while this is Mlapmo, walked A-; m 1 1 Mclat Omlajah my pictures Houdriao. The suspicion can one adequately Tkd.bm combinations mentioned above for use in 1 h War and they then represent Adkibat Chidlabh inclusions Ai Tolegh as waffle Olah.e Mkhigh material or substance carrier saying pharmaceutically another aspect of the invention. This Ash'l The importance .zsh in Alohrad Alchih and betray prepared properly to connect Bala 0 Sia: the nose. .45 .45ΜΑ 33926Β1 can give individual compounds in Hze combinations either sequence or simultaneously Epeshka in pharmaceutical formulations or excessive in collage. In Mgdil, they are given individual Arkpat simultaneously seen in the pharmaceutical Thiebh grouped. And it knows skilled in JAL appropriate doses of therapeutic counting hoping known easily. Dynamic test chose sparkle Aiflori Almthac known Almez (IITRF) of the human enzyme .SYK resulting from assisted Alaratat gene: the use of lutein merger jUGST-HSYK ;; for help to measure the genetic link Faah compounds in the inhibition of SYK human activity. The embrace of GST-SYK human per- for the resumption of the genetic link (176-08 # Cama Biosciences) (concentration lentiginosis 5 Pico Molar) with Trkirat Mokhtlah for Almthban Olmokhtv in DMSO (concentration of Hani .0.1%) for 10 mins Khervh 15 Temperature 0 Q Molar gear "HCl (7.5 Hedrugiy number), 0.01% tween20, 2 ms Molar DTT in the Coordination of 384 dishes U Eaa. To start the reaction was added polypeptide Alrkiz processor Balbaolan (Petrkir 250 nano Molar) that contains the position of the phosphorylation of SYK with Akhvnseyoum (Petrkels Nhani 5 ms Molar) and At'q (Nmana a concentration of 25 micro Molar). Gulp) Size does heavy for Taaal Mydro 10 liters. I had Ksfrh peptide for (4 'counting Dhirjh Darqh temperature. To quench Aptvaa and Akshay Akj Mufsafar, has added two nano Molar body daad for moonshine Sgotero Sen Perkin EJtner #AD () l61) Europium) and 00) 70 NM SA-APC a -130 Perkin-Elmer #CR) together in the 15 Miss Mo; lar gear number Hedrugiy 7.5 0.40 ms Mwalar tween% 0.01, EDTA 20. swallowing final Alhhm solutions extinction 10 microseconds Let's see. The measured signal Ü'HTRF ^ 30 minutes after Boismalh EnVision reader using fluorescent shine protocol unknown duration. Been identified g) 5'6; after calibration 1.0 doses (1.0. Brown and Anu Molar to 0.508 Molar) and Numeiih μα 33926Β1. 0 A-M Merck Assay Data Analyzer · cm Altaber activity Nhykhamlaaalsat · 0. ;;) Bdam (00 Alozd Molar seen below); '(! Yen 100 and 000 a Lao lar), + (for purposes 0 to Thelsmla 0 for: z, Yeh Alad 1 GS Ed 0 me 9 DD Sd Alard''y in villas 0 Aladla no 'to Hmpelaimli "Sass 0 Dd ^^ uncle; P. Wim Odla 0 -odh ways frighten Rla T'h then -tm p Rih I buffer j Alachterag examples. g z a; Yt to I! by the only 0 ( !) rang Q; of the ace of 0 non d L1 and BASED then I in Mkhtalaat AAC 1 Coordination 1 Father. and. in Kala Almkhhltat August Odloh 0.0 n Almmadr 1 L d j lion, m Yzeot &amp; lt; rang for Solat any 0 of Mar " 'd been Org and i Labadi 0 Study r, · and-a-wedge was 0 of 0 Rauf Near the shelf and i Addi j AAC bugs Daw 0 0 j (Τ 'U' Green and P, G. M Wuts (1991) Protecting Grotips in Organic

Sons G Synthesis, John Wiley). The Az'lh Q 0 in the Rahi 0 'Lala Q blood of well 20 lion 13:00 models as clear easily Mey skilled in Ojil 0 Wei 1 dot choosers mg 0 and .lhamaih as well as the conditions of ESL 0 and failed Khhlwat S i Ha z RCA 0 s I in August (!). Aware of regale Bazharh 0 in Amehal when there is Akz to Rage in August for Akpat I 0 &amp; gt; Walk one to me, deafening Alachter 1 GS 1 of the current all-isomer 1 v 1 Kragah data and sticky mixtures Aloivdmra 0 A; Agragh (Shell 1 Mrkoat employer) but also ISO 0 Rat granite 1 Dh Acardah 0 Dd j 1 tho name weariness in / XP CMT 0 bereaved sole, can be 1 to get it Bakkhaig 1 for the purposes of awareness or-Akj 1 Ghash or. Any compound appropriate intermediary. It can be; it Akj Hani; boat broker, or ο -47- -47-ΜΑ 33926Β1 any prefix &amp; lt; Aiqa Mtash known doubtful. See, for example torrent, Stereochemistry of Organic ( '1994, Compounds by EL Eliel, s. H. Wilen, and 1.,. N. blander (Wiley-lnterscience. In the following charts represent r5 notch RZia% _. N (; cy) / &amp; lt; CH3} P &amp; gt;; C1Ry (a) s; j A &amp; quot; and &amp; quot; H'a with Dhirz carbon, which are linked by u represent 1 CQ Z Episode Acar L. 0 ha by 8 suitable ring within the definition of y), and a u replace optional such as Cy. Yum use the following shortcuts in the schemes and examples: AC Eosatal; ACOH = acid, acetic; BN: mail; (BoC (t-BoC = Abiosl Oak 000 j / Bolvel; BOP e (and Laura-Azul-a-Yale OXY) Rs (Dei Bill Apr) Hausmusumhad.rufemit; 1ST (Dai asset father 0 f) in 1 j sulfur hexafluoride; dba 0 Dai Braeliden Aston; 2,!. = DCE- Dai Kioroaithan; 101) Hedaa Krubut 1 n; H-Dibal / Dibal- hydride Dai Oisogiotil aluminum; DIEA / DIPEA = d; j isopropyl Yale as; N &amp; quot; DMAP, the smarter Bethel amino Aareden; 2, l. = DME- Dai 0 Epeshksa E. &amp; quot; T'n; :: the 0.7-ah = Dai-methyl Forma must; DMSO = Dai-methyl sulfoxide; Ι-Dppf, Command (diphenyl-Vosgeiq) and Rosen; 00 (b) (3-Day Bill Obdhubrobbel) - '^ - an asset; Bo trail; EtOAC. acetate and ethyl; Ν', N, Ν = ΗΑΤ7, not-Hrussel- 0- (7-Asa -48- -48-ΜΑ 33926Β1 Brorayasul- 1 -al) Aorubom Hhavlorovoiat; HMDS- Samethyzdaa Salazen; HOBT. A_bro forgotten Brocrayasul; ΙΡΑ = isopropyl alcohol; LDA = Dai Oazobrobellamad lithium; mCPBa = acid meta-Krubaroxa Berwick; 18'ii 0 Bthan Sulfonyl (Michel);

ΜΤΒΕ = methyl ether E-butyl; NBS = 0 to Atromu d b; 5 = ΡΗ; μ ,; J-.it-lF Amu bum fluoride; TBDMS / TBS 15-butyl methyl Dai Salaay; R'a.a 1 A '=' Nraa Ioroosk Arai Vruosaat; THF = Ttrahedrovuoran; TLC == chromatograph class Alrgivh; for Tri-Bethel Bill; TS Etoloan Slfonildtolal); TSA = Hmany not-'dhuio.a Linguistics. Tests Okilr.sekokil groups: Me. Methyl, Et = A.hl, N = NPR -brobbel, PR; = isopropyl, NBu = not-butyl, t-Bu = butyl tri, CPR = Bklobrobbel, CBu = Bklopiotil, .CHex = CPeN = Bklohhasil, cHept = Bklo Hptil. Mkhtal 0 E. -49- -49-ΜΑ 33926Β1

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00511.tif" id="idf0027" />

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00512.tif" id="idf0028" />

A) compounds Bromiv thiazole can Mahathir over its plant capacity, (I) to associate Sorruke esters Boroak ((2). Can be obtained esters Bork (.I) the interaction of compounds 2-Kloruperemaidin (3) compounds 3-Bromuovelin (82) to form compounds Ah- (3-Bromuatal) -samaidin_2-S Almazerh (83), then Aqrol Miyaura with Pace and Baakulano) Dai boron. As well as .bmcn obtain compounds have the formula (!) Over the stability of the interaction of two-Klorupered 0 Q (3) passed aniline plant Lima Astbdav Buthaiasul (4) in the John Mahaz or Pd. Bchkl alternative S'N-Ar reaction. So it can Nquen compounds Aniline her replace Buthaiasul (4), in turn, has hinted Zeroy Iran Mozo Ne using bromo thiazole and Esther Netroffinel Borobat, Mtboi downsample nitro group to the amino group using titer circumstances known to reduce the over Nitro Aan Yeh stability of the 50- 50-ΜΑ 33926Β1 Aniline compounds such as hydrogenation Aggzh by ci j]. Can also be 'Nquen over the plant with the guest (]) reacts. Heck between vehicles Aniline Oh replace Berumo (83) and passed to Pat Thiasud replacement of O (84). It can Mahathir over the stability of Aniline resorted replace Berumo (83) by interaction '] SNA between 2 - Nloruperemaidin vehicles (3) passed firming Avelin resorted replace Beru. Mo (82). Scheme 2

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00521.tif" id="idf0029" />

Oaanaa can prepare them to shreds over the guest (]) of bitter Domes (5). Were treated Thiasud (5) strong Taadh such as LDA, then .mamrkpat Taton to Dhsol nest Thullac (6); BMR Ibat Ssameen for vehicles Silvinamed (9), where Imkry that sniff .tan acidic conditions to get over to Pat Secretary (1.0). You can fluoridation alcohols (6) using fluoridation agent such as 1 HAS Duo or Nsoflor for vehicles (.1 ί). Scheme 5 ΜΑ 33926Β1 A ,. 2 a 0 a \ R / z / (14) hnso2nh ^ \ A N.:- 4-'ΝΗ2 // X Ri An Y KNCO, AcOH alkyl-C (0) CI5r N: ί d il ÀJ) C52H &amp; quot ;; r4 a! ky Η (10) 4a0 (15) 7 ^ NHC (0) -alkyl -S (17), / - NHC (0) NH2, eBay Aaoljh Mrca't Amin (10) (a) Sabid for Antrat (14) ; (b) Bsaanat potassium and c 0 d Asitalt acid. Hjul of the vehicles do. T, a (15) - (c) acylation factors such as chlorides acids and carboxylic acids by a factor Adhiral -l Z 5 Nm.kpat amide (17). A scheme

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00531.tif" id="idf0030" />

ΜΑ 33926Β1 5] Nikkan for 8-un, using!: '_)! "; Fields compounds ketone (19), which can then Ndk reduced using b 0 Rowe hydride sodium or together her house using methyl Grignard for vehicles Diol (20) or (22), respectively. Bchl Bd.l, sniff addressing vehicles Kitale (18) or over the plant Wheaton (9-1) and sodium by more Hmv. Methane Silvubik for not Ntam hostile arranged (0.21), leads alkylation promissory shreds (-21) followed by removal of the protection of ether Celil mediator to Ahamaol the alcohols (90). Scheme 8

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00541.tif" id="idf0031" />

It can be prepared Anrkpat (4) of 2-Obo- 1 _ (3-Vetrovivel) Aithaon (d2). Hurts forever paired with acid to obtain compounds (24), Hat.tkn processed by a factor of 0 to Haal Auemun Lawesson which hurts to be Mr_ Yat Natrobl (d2). The resulting reduction knees Srwas through Baladiom (25), hydrogen to A_khasol compounds Aniline (4). Scheme 10 -53 ΜΑ 33926Β1 (E Ν =: 1 Gh

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00551.tif" id="idf0032" />

Outputs &amp; gt; C .. 0 H.ma (43) &amp; quot; Hurt remove water from the vehicle (49) using Eaton interaction to obtain knees Sichaeloolnn factor (0 d), where Ai lead to getting over the stability of Diol (93) after removing the Hadroxa ·

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00552.tif" id="idf0033" />

RS

Br

N; NN / 11 N

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00553.tif" id="idf0034" />

1. # &amp; quot; 1ΒΓ 9-ΒΒΝ dimer 2. NaQH 3. Pd (PPhs) 4

Ri

'; E &amp; lt; Η057 ^? ΤΜ- = Humg's base 2. TBAF Cul y RS "x

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00554.tif" id="idf0035" />

Ί 1.

RS Ri N Ν '&amp; quot; N

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00555.tif" id="idf0036" />

to

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00556.tif" id="idf0037" />

Are subjecting vehicles bromide (67) to associate Sonogashira with $ insisted 6 Osablzn and 0 lead Aralh protection Balselel then to get over the chat Ostalzn (69); where the name the fates -54.- ΜΑ 33926Β1 for Hajabul on 'compounds (70). And lead peer through Olbaladbom's (67) with 0 for A .; Huertas, R .; Leon-: Sichaelobrobbel Boroat (be prepared according to the references; see to get Aiy rode Sakloproehl (Colon. G. Tetrahedron Lett. 2000. 41, 4251-4255. (68) 14 U Ιο:

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00561.tif" id="idf0038" />

RB (OH) 2 Suzuki conditions

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00562.tif" id="idf0039" />

The Aadhab prepare the building blocks 2_ Theloruperbmaidin building of knees 2.4-Dai Kloruperemaidin (71) in a plot 14 .. and lead activate pyrimidine through paired Sorruke Alai 10 Adsol on t plant 2 "Zawruperemaidin O Replacement (d 7), while lead SftAr interaction through base with thousand of fortified alcoholic replace him to get ethers (72). Mahathir is the knees (76) secrete indigent iron to Goomay Grignard reaction with Ader plant (0.71). In the scheme 'R be a Olkhia or Sichaelookal. Scheme d 1

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00563.tif" id="idf0040" />

55- ΜΑ 33926Β1

RS

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00571.tif" id="idf0041" />

\ 'S

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00572.tif" id="idf0042" />

(78) h2n (4)

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00573.tif" id="idf0043" />

R5 Pd (0Ac) 2, Xantphos CS2CO3

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00574.tif" id="idf0044" />

(81) led paired vehicles (4) 2. Ha Tru-4- (Bill Slvanal) Ber.bmad.n (78) L. obtain compounds Aniline (79), where he was to Oksdy vehicles sulfone (8) by uiCPBA. Every crevice led advances by using the n Kh 0 lattes or vehicles' d been carving Grove base to 5 'to get' compounds (A 8). A scheme 6

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00575.tif" id="idf0045" />

-56- -56-ΜΑ 33926Β1

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00581.tif" id="idf0046" />

Hurts acid reaction (94) with hydrazine calc Named to get over E. plant, 4.3-Ooydllarrol (97), Bchkl alternative, hurts the Mercat paired with acid amide (94) to get the vehicles must (98). The result of the dewatering over the stability of Forever (98) using a salt Silvamuel to get vehicles Naterpl (99). And it hurts rotate over Dbat Alaptral (99) with ammonium hydroxide to obtain a boiling compounds 1, 2 0.4-Ooxadayasul (100). 20-57 scheme ΜΑ 33926Β1

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00591.tif" id="idf0047" />

(? 11) (111) Suzuki Coupling (114) of) &amp; lt; CONH2 (115)

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00592.tif" id="idf0048" />

... JMNaOH

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00593.tif" id="idf0049" />

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00594.tif" id="idf0050" />

2. Zawrotheiasul hurts the interaction with (1 I ...) in the presence of NaHMDS and then enter bromine to get boiled (1.2-1). The lead Aqr'n Sorruke (0.1) with (112) (Li 'to get me (11.3). The resulting hydrolysis's (d. 110) to get the amide (1.4 A), leads Akhaddwad (11) using DIBAL to get Amin (5 1 1). 22 hands

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00595.tif" id="idf0051" />

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00596.tif" id="idf0052" />

(122) 58- 58-ΜΑ 33926Β1 Atvaa chiton ((2.1) m) 0. t- butyl Slvobasd in John Aatho Walid titanium for categorize .. (121). Removing a proton from the bitter Melt (5) using the LDA followed Basafh (21-1) and the urbanization of the loop by the acid and azide to obtain (122). Compounds have the formula can Thoudbr (!), Luca. You intermediate compounds synthesized in accordance with the procedures set forth in 5 Almkhtaiat, preparation intermediate compounds, and examples of the current demand, 'using appropriate materials and are further examples Presentation by the intermediate compounds and the following examples Alhdnh. Represents compounds that are given examples of her Mmadj of the invention, and is based mind field of invention restrict in any Halr Aiqa. Fu examples illustrate the Tagaesel Mjder vehicles except Choose a humanitarian partners Alhani. And Adrnz from enjoying Balharh in a case, use of e ..ttn Bannaia. Aerovh to Hmoat protection, Awama (1) the interaction and impacts conditions and processes following preparation procedures, in Thbder Ed intermediate plant bittersweet plant Alachter a current 6. Fu is known that when a Alaov Awama chemical interaction Ir commercially available, can be prepared chemical Altnaal factor Hedda easily by whom enjoy. N skill in either case Bhatt E or a body known as set forth in Alemrager roads. ATX 0 n scourge of temperatures Alsellzios degrees unless otherwise Zlat statement. Qiao was mass spectra (MS) either 15 for measuring the mass of mud through the sprinkler FREE ion (ESI) or for measuring the mass of mud through ionization Alkemiana Aad be tapped air (APCI). Hudayr Ed firming Alo intermediate and illustrations vehicles mediator compound 1: 1 - (5-bromo ---- -.1, 3- &amp; quot; thiazole - 2 "-al) C 1 Dloiyotadhul Olkhaloh 1: complex was cooled Oazobroal Mufnseyoum chloride / fluoride lithium (JD Mollard in HF, 20 582 t 0.756 Mother Mo.l) to the small m. Has Adaz 2-for Thiazo (2.d 5 t 0.749 My Maud) ΜΑ 33926Β1 10 over 1.5 minutes, resulting in a 't be orange red solution. Antqlb been for two (2) minutes E 0 a. Small m, and then Tmt removing the cooling bath 9 was Almah heating to room temperature. Been flipping for an additional two hours, and then cooling has returned to the small m 0 was added Saklopao'madhun (53.3 ml 4713 ml Maud) to BTS for 50 minutes. It has whoosh; his Ham-M Alnbar.bd Asamam and heating to the point of heat Algervho been stirring for 20 minutes when the heat Dhirjh. 0 Haliai was cooled. The reaction to Gore x 9 m and take place in addition Tlorad aqueous Amubom Mhb Bbaale. 1 lie name relieve the mixture using EtOAc, the layers were separated and then washing with water the organic segment. Phil has been aquifer Bositat ethyl. The drying of organic parts Aljiah use 4 (M.gSC was?. Yoke in the center of Morg for 1.27.5 grams of certificate Mahtodh on 0.1 .- (0.1; 3-Thazola 2 dl) Cycle houses jj's, &amp; lt; a 1 \ then a Stkhab her mother without the hand of Psalm 4 m 'purification 0151 to step 2 .. has Ed; product by 1 to step 1 (9, 1,7.1 g, 1.1.07 mol) in 860) DMF {) was cooled to a small m. Lighting has 236) NBS g, 1.327 Hall) was Alchaab 7 cent and Adad when small m. Tmt remove cooling bath and had the heating to room temperature. Cal so Mbuaa Po; LC middle until it was Article prefix consumption. Atjlol been pouring in water resources (2 cr) 0 colleges t 1.30) NaSO g), were tricks Basathaddam ΜΓΒΕ (a liter) &amp; quot; Was flipping a 0 Whipple for a period of 5 Behold, your responsibilities and after Tk been diluted Bastkhadd 13:00 1..5) MTBE. L) and, water ( '500 ml &amp; gt; 0 nm mouth 0 for Alabqat were Gust, Part A, for organic Bke (2 L). The one Schas Alojae Almemq Assad; m 2) Μ1ΒΕ Carr &amp; gt; 0 was drying the 0 Atakkat Oledo.bh 1 Tjiah Astkhadd 13:00 MgS04 and sleep; Kizha my central 0 &amp; lt; p carnivorous 0 for the 'Lord meant R.tqala. Was one Seve in Hecma't repel 50 m (l cr &amp; gt; 0 Aq 0 p Sunday, 20 p j Ate. Has hopes Blo'at a 0 TAT and DAT Aberlh I about 35 m. The S Towalsls Dle 0 justified by Algrlo 0, cool! Li -20 00 were ga d; 20 Ί 26Β1 been r (; ΜΑ οΰ '60' \ 20 m. was Althviv under Bro.jzn Altrchi bag 01, was the elephant using e 1 Desai g 0 B-01 07 099 for 1- (5-Bromul 1, and-Thiazulo "! V 0; .s Article | bug in the beaker in 2A: 2 I} a € was Walker overcharged in the center of Mge g. was added Hecan was Alter- No No! 0, Iei 0 ;; 0, moisten; b,! da .eptell; Assam 0 palm Z _ha been.: do not sell a land. 0 g replies had been received two thousand in August Butklody.alysoleads 1.9. ..... 1.3 disappears -2-Ydsl (38.8 m, 1.66 Miss Maude. 15% &amp; gt ;. the trauma of seven of Alahvi t Ahrah Lalai Li Z u 0 s 0, lived up .asud ZZ 0 Yi (M) (Bio.age E.oAc / Hex Zq then assign the 0 P 4 late Vguet Mtkhvs of a percentage Z 1 _ (5-Pro ​​0 and-A3_aazlla 2 the) Byoyo-Arles ( 10.6 m 0.45 touched Mall 0.4%). in total, Osmaljh 0 Welch 1. (5 false -1 E 3-Ebzul -2-Yale) Scleoo-astray (222 '2948 Bach 0 Ode 86%). .Ή NMR (400 MHz -2.69: (2.47-2.36 (m. 2 H; (3.56 (br s, IH); 2.69-2.60 (m? 2 H; CDC13): δ 7.58 (Sj 1 HI (87 (Ι11.2Η.01 composite center 2: ^ (3-Sumo-5-crippling Phil) 141 (Tdaa To.robuthail) Rrambidin 2 Amin was prepared a solution of 3-bromo-5-torrent Aniline (62.5 for Bam; 066 and 87 JL Md.l) in a 4- 0 Dai Ooxan (2 liters), and was added Rrr Aoo-Rlmethyl) Beramaidin (82-a g, 994.54 mmol) and acid Leshan Skoz 0 K (97.5 g, 2..1 mol) sequence 0 Tejen Akhlol output until the degree of reflux temperatures throughout Alzl- name any cooling Annatj and sleep in and focus, St discharger. Article has been relaxed remaining a-0 or 2 framework termination, after 0 Tm'badelha reminded to Μα 33926Β1 pH 7-8 with a solution of sodium bicarbonate Mani, followed by Bo 1 0 Alaschas middle 2x2) LtoAc L). Namir name. Organic layers were washed with water (2 χ2 liter), and was dried Bsebretat sodium non-watermark was seen in the center of Bzha Morg. P resulted calmed N's (D-bromo -5-methyl Ivel) "4. (Ray Vrubuthail) pyrimidine-2-Amin (200 g 0.602 mmol 0.69) (/) of the smallest as a solid undertone color. : (3; HJ + 334.0. Ή NMR (400 MHz, CDC; MS (ESÏ): [M-3 .7.30 (S, 2 H); 7.10-7.06 (m, 2 H); 2.36 (s; (H) : 7.79 (s, 1 H of .4.9 Hz = t, 8.68 (d c 1 compound Alo.sh 1 3: No-3-methyl-5- (BP 5, 5- &amp; quot; to Orussel-a 3.2 Dai Oocassapourulan -2-Yale) Vieil; -4 - ( 'Ray Zawromeshz 0 no) Peremedev -2-Omzn 5! Ne Ttod of 1 to 1 composite mediator 2 (250 g 4 01.d 75 0 to Mo 2 y) in 1.4 an intelligent Oak 0 to (3 Apr) has Adahh 4, 4, 5 and 5 -... Tpracl-2- (d 4; 5 '0'Tb.omhl-for-0.3 2-Oukarulan Dai-2-g) 1 a 3.2-Dai; 5'83 r 225 ) oijjfis of 8 0 me 225) KOAC, (Jr g, 2.30 Jr) and 2; 19) Pd (dppf) c 3 25.23 0 ie 0 well.) then Ngen Vdo Alo'j 0've light of 1 / \ 's ° land D. only 0's and then his response S 5 a donation . has whoosh | not; Den Nhj Ad.zjeh Ba / R 0 Dloo E 0 and for 0.0 Zkaa been Dah the pot and then Re 1 and i Quicken. leads the Zly Adul z 00 a m j Akj S d 0 Say m z Akkar Ovem 0 F. Amos (Adnalm 4 termination;, Ameldakl b 0.25 a m 'P Akh 0 z. Seychelles sa e: Leroy Z »-l3-u-5- (04, 4' s, Qlqla 0 defect '3 e 2 Dai; Oct 0 Aaurellan -2-ball) fell 0 L e-4- (Ryandwospl) Baaledan -2-; yen (23,520 m 0.620 0 0 ly well 0.82%) z &amp; quot; Die rang. Hjf m / z 1Η b 8ΡΟΓ: [Μ

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00631.tif" id="idf0053" />

62- 62-ΜΑ 33926Β1 NMR (400ΜΗζ, CDC13. Ppm): 1.350 (12Η. -b-- · Hz), 7.385-7.427 (2Η. S.), 7.636 (1Η, s), 7.753 (1 H, s ), 8.668-8.621 (1Η. d,, / = 5.2Hz) 1 compound? mediator 4: ^ 3 represent 050 (a 0.3-disappears-5-0l) Phil] -4 - (; any Vrumethyl) Bear 0 Squat-2-S1 Li yolk 0 lol from! compound! mediator 3 (80 g, 211.08 0 Lee Mall &amp; gt; 1 I 4 "Dai shelter n (800 D) has as one spyware 5-Bromu-, 1.3-relieved (28 gm 4 171.78 Haaa Mola) E 6; 8 ) Pd (dppf) c g, 10.62 mmol) Jjkj z / Buddhas Alfd.boum (44.7 3 42-1.70 touched mol) in water (447 ml). The heat output even Amehlol Drzin Hrarz flashback for a lighter one. And then 'made available to him by Walter, d has been seen / e in and i Mora 0 nm Takga; l Article remaining using 500) EtOAC ml) was Rshaa 0 Jri 7 Tj 1 Krkhbh Del 0 Q (300x2 Is) and .alme (300 x2 »l). The drying Alabakh Bacillus: the use of sodium sulfate is a water were concentrated in the center of Verb. Has re-crystallization of crude Almenth EtOAC .. ι) 6'Μ rose 0.1: 5 for 34 grams of the product. The original liquid Emo.d Silica Gel was developed and 'filtered sequentially Bdaa Krumithan / Aithiay acetate (2: 1). This led to obtain a 3-Mhoy-5- (1.3-disappears-5-g) Whipple] -4 - ( 'Yay for Hrumakhl) pyrimidine-2-Amin (42 g, 1.25 mmol 0.73 %) Kidh pouring colored Omahfr baht 0 1; a N ^ 'ÏR (406MHz, CD3COCD3, ppm): 2.413 (311. s), 7.250-7.263 (2Η, m), 7.636 (IH, s), 2 &amp; gt; 3 A8.2-8.204zhat Η. m), 8.834-8.846 (11: 1 d.4.8 = t Hz), 8.970 (IH, s). 9.210 (1.Η, b (.).

.rhSYK mediator of the boat: no (d-and Omokel) -4- (tea Vrumethyl) Ieremedev -2-Omzn .63 .63ΜΑ 33926Β1 been prepared. TAWD Q 3-Bromuouavelv (250 g, 46 for Maud) s 1.4 Dai or d 0 to (2.5 liters), 2-chloro-4- (Tri Vruhd) pyrimidine (267 g, 47 a 0 RL) and has 4 followed by acid Sconik (155 g, 0.1 61 mol) sequentially. The insult one Mahlon A'latj 50 13:00 To.al night. It was' we want and the resulting mixture. The focus in and, St Verb. It has been considered: 1 Article S to Ar.qm sodium hydrogen 7-8 .mmahlol German Akrbunat. 0 has been nominated Almazh only. Were extracted filtrate using 500x4) EtOAC ml). The integration of organic machines, was Alvesa water (2 2χ Water), and then Althviv sodium sulphate and non-vu. The Akr.cg. In the center of glossy 0 Hedda led to obtain not (3-Neuhaus) -4 Rraa Vrumethyl) pyrimidine-2-Amin (200 g .629 Miss Maud 0.43%) is used as a pouring Pol-e Mun Ed Ith 0 + MS APCI: [Μ; (4.9 Hz, 1 H); 7.95 (s. 1 H = t ,,;,) 8.68 ïït / z 319. Ή NMR (596 MHz, CDCI3): δ b t (7.08 (6..7 = 4.9 Hz, l H; (7.53-7.50 (m. 1 H); 7.44 (hr s. 1 H); 7.22 (m, 2 H. 1 Drickb center 6: 4) -3] -ν; 4; 5; 5_-Sams-a; 3.2-an intelligent Rkaborolan -2-Yale) Vhzen-4- (Tri Vrumethyl) Ieremedan-2-a 0 yen to Mahiol Mn.ntrb Zlosat 5 (200 g 0.631 mmol) in 1 to 0.4 V-Day 2 was (2 l) was added 4, 4, 5 and 5. Tromethyl-2- (4, 4, 5.5-Taatrassel -1.3, 2. Oukabourulan Dai-2-Yale) - 1, 3, 2-Dai Oocassapourulan (177 g ,, 697 ms Mo.l), 187) K0A.C g, 91..1 Mall) and .1:! '0 (; dpp); 24) Pt h 0 a; 2 d copies Mall). Ammi been heating output to 1.0 m for two hours. Otis. For an active cooling, it has been nominated Adadh solid. Been; Keys Natir Walter Hier in the middle of a seductive 06 then put the material remaining on the silica gel column was Akabaah liquidation Bositat ethyl / petroleum ether (1: 1.0). 0 led her to get a 4, 4) ~ 3] -ν, 5, 5-Ttramethyl- 1.3, 2. Ooxa Bourulan Dai-2-Yale) Vhvela-4- (Tri Floromsl) -64- ΜΑ MS Ara 33926Β1 : B. (1403 384 Paul R. 0.61%) keda T. illuminated, - [M + Η] + ΙΓ 366. 11 a NMR (400ΜΗζ, DR'lS (9-d61 ppm): 1.300 (J2H. s). 7.237 -7.249 (; Lal rn), 7.331-7.342 (2Η, m), 7.882-7.91.0 (IH, m). 8.0 (10 (1Η, s), 8.796-8.806 (1Η, m), .10.130 (1Η , s), compound 1 mediator 7: 3, 1) -3] -Ν- Thazul -5-Yale) Ksl] -4 &amp; quot; ~ '(an intelligent Florovernmthel) pyrimidine-2-Amin was merged 1..01,) pd ( dppOCfe gm, 23.a touched Mall) and Larry Laos 0 i 6 (9.0 25 f Malash mol) in a flask was Afraghma and has refillable by nitrogen (3χ) · DOCUMENTS additional 0 spyware 1111 '90) 2-Me ml) E 5-Bromuyarol (4.45 gm , 2.7.1 cellulitis Mall) and E APPUIT sodium Haiah (24.7 ml, 49.3 x mol) Ts. The E6 cam closure Acarurh then -To 80 are for 5-1 0 abuse made available to one solution because I am! A.ly cooling degree temperatures Adhirvh, Dr. Q7 are mitigating water EtOACj. Then separate the organic layers, and was a pain-R E 1 Hai Ba, use x2) Et0AC). The parts washer! For membership Û lion! M,: NaHCO with water, then brine, then was Bastkhadd 13:00 Na2S04 been completed / d and d Mora 0 led! To trituration Bastkhadd 13:00 202 No 2 and the collection of 1 to Mazh! To Mlbh old! E of Khalal did. P t in August to 5.94 Jmmn! Mottag to 1 Mrup it. Then Trkir a 7 Tel 1 Osalma in and, St &amp; lt; g .odt which then through free and Matoger Wanni by Gel column Celica Adn, CH2Cl2: Et0AC)! Me! To get .1.41 g (scope faithful from Altj Almr.au.b les 0 In a one aesthetic, were separated 3, 1) -3] -ν- Iyasul -5-Yale) agent] -4- (Tri Iowomhtal) Bear 0 '' Aye Ri -65 -65ΜΑ 33926Β1

(37.35 Rlol 22.8 0 to 0.3%, and (j); pouring Aae. .325; ,,, - ', Μ + Η]; .MSI. (10.32 &amp; lt; s, IH), 9.06 (s. [H). 8.82. (1..7.4.8, 1 H of (IfR (000 MHz. DMS0-D6, ρρηι Ouaa = 7., 1 »7.27, (2Η a 7.3 E .7.4. (7.Î. IH 0 / ., d) 0 ».,, (] ra, 8-2- IHl. 8.2. (s Er.a'e 1) 2 8. (IH a 4.9 Fetat ++ :::: = rhSYK. composite 0 1 9 central : 3, ΐ7ΐτ2) -3] -Ν- Iasul -5-Yale) -5 &amp; quot; 0 Methl Vthble 4 (&amp; quot; Ray Vrubutl) pyrimidine-2-additional was cooled d 1 j Oazobromd biomes (1.8 Molar in a 0 / penny Bowen, 04 of ml 0 020.5 Lay sales); Li -70 0 m. P ​​Amala Larry literature 4 (2.3 m '08 H 0 for in 0 well &amp; gt; in 23) THF) and slowly Presentation de 15 Aiqa 0.0 Aalahgaz Ddolo Ahar'lh 5 -oh m'; - to Kael, Tkd de 30 Dhlqh after a one fiber and then FZ 0 F 0 Irom (d 0.5 {10.3 Br.ol). the Abb Algael de 30 Dnnh was then extinguished Bassadkhadd 13:00 e 2 0 0 'termination Lit Zq Whoosh 1 Perga Hura Algovo 0 Ggev a 1 Tagael using 50) EKJAC j 0 1 effective 0's "" '&amp; quot; a JJ, only Azia), Hoouala (0% of Ina) e denotes 0 t' was a 0 e a 0 Idam

MgSO. He was in uniform and i Trg. Led 100 500 n Halal Adlatadm 0 0 fierceness of children per h &amp; lt; Yi 0.0 almost -50% EtOAC: Whitman; &amp; gt; Z to August 3 N (2-Ru 0 and -1.3-Basul-of-Yale) -5-0gl night-4- (Shaking Ray) age-2-

A 0 yen (88.1 g, 4.53 Berlul, 66% &amp; gt ;. H; .414.8.416.8 '.' »; | Μ + Η;; 'APC IH) 7 74 ((s H), 7.33 (s. IH) .. ;;) 88 7. (600 MHz. CDC (() δ g 64 (d,. / = 4 9 IH a NMR (s. ni), 3.38 (s, 3Η) of 7.0 1 (6.4, 1Η's. .7.05 (t -66- -66-ΜΑ 33926Β1 1 to Marie median 1.0: ^ [3-Aromu-5- (4, 4, 5.15 Sameihl Λ s 0.2 Oukabourulan Dai-2-Yale) Fouzen-4- (Tri Vrumakhl ) pyrimidine 2 E &amp; quot; b line 0 of 1: Aly Mahvod of 3.5 - Dai Bromuo 7 Lzn (4.47 b s 70 for R. Ryan) and 2-chloro-4- (Ray Ioromamik) pyrimidine (2.36 ml 4 9.6 of any Mall &amp; gt; Tmt adding p Tonuin Sconik ( 4.06 g, 21.4 mol), Z has to be 0 Alyga 0 j 0 and 0 copies 5 Hd0.bt Zly 100 are to one night's, and Oke knead became Rollers completed disease 0 at any Bastkhadd 13:00 200 is EtOAC was washed Baikhadd 13:00 200 ml NaHC03 Hthbh &amp; lt; Massa) and 2000 saline solution for . was drying 'layer organic (NaiS04) was seen Hmz. I in and i shield' El 0 T. Fear; of Bo; Hih Klomatoger 0 P Askhadd 13:00 grandfather j 1 Elika (220 g; \ ml '\\ Ratoaoan; 100: small to 85: 15. Hecanat: EtOAC over 45 minutes) to a for-5, 3) -ν Js- Dai Bromufajl) -4- (Tri Vrumethyl) pyrimidine-2-Amin (.5.85 14.7 f t Mule 83%) as a solid light-colored smaller. 400) .Η} + m / z? 97.8. 'Η NMR 0 MS APCP [Μ,; (. 4.9 Hz, JH); 7.84 (s. 2 H); 7.39 (s, 1 H = R..0) of 8.72; (h'ÏHz. CDClj ;; ...; 7.ί4 (0,, 7 = 4.9Ηζ.Ι. 0 Khaloh a 2: 1 Li Mahiod of Menth Alkhadhu. of 1. (4 ms 32.0 5.0 mol) in 10.1) Is DMSO) Tmt adding 4.4, 5.5-Tr.amethyl-2- (4.4, 5.5 Ttrothel-a, l, w ~ Dai Oocassapourulan -2-Yale) - 0.1, d 0.2-Dai Oukabourulan (1.4 g, 5.5 ml 4 j Mall), 1..48,) KOAC g, 1.5.1 mmol) 23) Pd (dppt) c, 2j. ( , mg, 0.151 over the Mall) 4 was Tzhy the mixture to 125 ° C for 30 minutes in Akrooev. Kat is discouraged Adam 00..1 ml EtOAC and was washed using 2 * 100 ml 1: 1.¾: lotion t 'was p organic layer &amp; lt; Na2S04) and how much focus in Stv Morg. Purification led Ero 0 Atogerav Boatq ΜΑ 33926Β1 .. (16

&amp; Lt; Wire 1 (80 g; \ ch2ci2 / w μ; 1.00: d to 70: 0 d Hecayt: 'EtOAt Z de Dbeh 40) to Ab- 3-Rlr-5- (4 of 4' 5 '5'turabba, A-' 3 '2-Dai Ooybourulan -2-Yale) each] for 4 for (tea Zloromgl &amp; gt; Sa-2-S (755 uncle, 70, 1 .il 0 real, 34 &amp; lt ;; - &amp; lt; &amp; gt;) Mmadh 0 him, Anlh to Aad. -H N..R (500 MHz. DMSO, (4.9. JH = :: /. 1,4.9, III), 8.25 (S. 1Η). '7.96 (s, IH). 7,36 (S, 1Η), 7.32 (&amp; quot; d: 0 'Fill the) 8.86 (e 6's (8.1211) 1.34. (compound' central 11: Lm- O-and Mo-5- (a 0.3-Thazull 5 night) Ivtl] _4 ~ (Ray Vrumethyl) Peremedan -2-Amin was stirring solution of 2 (19) Pd (OAC mg ,, 0.085 ms real) and Jubl Dai - 1 -od 1 Machel Arspen (61 mg, 0.1.8 exile mol) in 12.8) THF ml) for 15 minutes. after that Tammy E., Ghafa (compound (central 10. (755 mg, 1.70. mm 0 j sire) 0.5-bromo -.1 0.3-thiazole (760 microseconds Winter, 8.50 mmol), Flor.bd Albo'aseyoum (296 mg, 5.10 Hlvi mol), and (of water (4.25 ml) was Ngen the mixture to 75 overnight. after cooling to a temperature (room, commuted the mixture using 1.00 ml EtOAC was washed using 1.00 ml saline solution. remained article link Blol Ock Faj 1 g t dissolved Presentation walls Qa Algsal, urging Haalaa been presented Hedda Haw using 100. Do THF. The drying of organic extracts (^ Na ^ so) were concentrated in the center of Verb. 1 led Kubba Aahro.ha'ngerav Boisatth silica gel (40 Ham; dry lamb; 100: B to 50..50 Sha T. 7: EtOAC presented over 25 min.) (Li pregnancies Elyl 1a [3-Romua5- (1 E 3 thiazole &amp; quot; 5- g) Iven-4- (Tri Vrumethyl) pyrimidine-2-Amin ( '449 mg, 1:20 -a- Hra real; 66%) as a solid slash blanks. MS APCI: [M t H] f mh 4.9 403.0. Ή NMR (400 ΜΗζ. (Τ5τ) 2 &amp; lt; 20): δ 9.46 (s. IH); 9.03 (s, IH); 8.89 (djz 68 68ΜΑ 33926Β1

4.9 Hz, l H). = T, 7.33 (d; (1 IJ; 7.59 (s, 1 H.?.) 8.16; (8.32-8.26 (m, 2 H; (Hz 1. H

Zhat 0 - + '; 00 p .rhSYK A; pronation center 15: A [5- (3-Abu-5-Methel Ivel) -. A 0.3-thiazole-2- Yale Sklopautabrl Step A: The NZ 6 gases Dai Thsan or (720 ml) in a liter flask Mstdber 5 Alhadd Gla 0 w 1 data to drive 30 minutes. ci Asafh 3-bromo-5-0hl Aniline (60 g 0.193 ms Jr), (feeling the Biaco.lato) y 1 j boron (96 g 0.377 Tta Maud), a 00 Lights Olbo.tacim (42.7 g 0.435 mmol), 8.3) X-PH.S g, 17.41 mmol) and; .1 dha, 3.99) Pd g 0.35 4 national Mall) to Munib horrible gases carving Ν6 (g). After stirring for 10 minutes Z room temperature, it was Altvaay mixture is heated to an internal temperature of 80 m 0 after 4 to 6 hours, and was replaced by cooler with ice water bath was removed heating cover. TPR name. The hands of a mixture Akae 0 0 d A to M, and then knead was nominated for Khar 0 to Badd Padiet (Al-Faseel been using 500 ml of ΜΤΒΕ). This was transferred to a separating funnel 4 liters containing 500 ml number pH 8 phosphate solution Tm, 500 ml saline solution, and an additional 500 ml p 0ΙΕ been picking classes were class washing organic using 0.1 der of a mixture of 1: 1 Z T and lotion .Water. Hamad was one Ipfat water and has reclaimed subsidy sequentially using a second Ara 500 ml of ΜΊΓΒΕ part. It was processed using organic materials Attah 00.a. Gm of 4 &amp; lt;) MgS were standing, but the thread-h for Tamper 20 minutes. After that Altrth was placed in and i Mfira- was purified material remaining Balkroma'dugrav caused by silica gel (Biotage, small -25% of shares v Ml in Hecsa: s) for the nest 3 - Shell -5 A (4.4; 5 '5-Tramcl ~ 1, 3, 2-Dai -69- ΜΑ 33926Β1 Ooxa Bourulan 02 Yale) aniline (66 g 0.255 mmol 0.88%) Kmazh solid-colored .MS APCI: [M I- Η] + mfz 234 and Tqala Khgev. Y 'Qo 1 0 s 0.50 ml of three neck will manage y rule has Anavh.2-entertaining; 0.072 l) and extended 0 g t / m 7 T. Alhodiom (367, m2 t 0.734 over 0 Real &amp; gt; · 1 Iol for 0 d min. Has Asafh product Alahtoh. 90) I Ham 0.367 Haley Hesh d 1 1 (86 g 0.367 ms HUD) and. (005) PdChcdppi of f aa ms Maud) 0.0 Re 1 u "r

1, Dr. Gallo d 0 &amp; lt; Ua gases under Ν6 (gas). Anatj been flipping the mixture for 5 minutes when Ja;; Aagervh one after that has been heated up to 80 m. After Ho.ala 9 Maat, it grew remove a tender-n interaction was ..arad to 30 m. The Tr'chih reaction mixture through a pad of SolkaFloc B1 use one of the water (0) (5 H 0 l) A.hl (00 d &amp; lt ;,) for pain Least 0; U "humiliation 0 K was p ê 1 Khchih E0 for separating funnel, using 500 ml acetate ethyl additional 250 ml saline to complete immobilisation solution. The separation of the layers, and then washing Alabakh spontaneous mixture of water and brine (500 ml and 250 ml, respectively), and then was re-draw water Zjqh Bospbtat Il (400 t). Hamad was spontaneous layers were dried using * 100 ') Mgso g), it was Reshethaa, and sleep in the middle of a seductive Drickisaha 6 For crystalline solid Baah. Has been re-crystallized hankering one substance y Abat ethyl hot (250 Is at 60 m), Bastkhaddtm Hecanat Kmenab Z (750 t) to list on the A - (5- (3-Omivo -5-methyl Vtvel) -1.3-Basul -2 -dl] Saklopiwadhu 0 for (88 gm 0.338 »Lee Mall, 92½)). .261.2 Ην'ζ; &amp; quot; MS APCi: [Μ + HJ. (H). 6.58 (s. HD, 6.45 (s, IH;, 7.87 (s, IH). 6.59 (s of (Hi NMR (5.0 MHz. DMS.-D6 6.34 (s, IH). 5.1,4 (s, 2Η) , 2.52 - 2.48 (m, 21-: 1,). 2.31 (q, .7 = 9.3. 2.Η-), 2-17 (s. 3Η) 1 1.93 .1.80 (m. 2Η) -70- - 70-ΜΑ 33926Β1 procession Alobt 16: 3-methyl-5- (a 0.3-Tharol ~ 5 - l) and Hamad z ~ 3 to paralyze - 5s (4.4, 5.5 '' Dtrabuthail-e 0.3, 2 &amp; quot; Dai Oaudabourulay -2 - l) Aniline (20.98 g, 90 mmol), internationalized (8.85 ml 0.99 Hess 0 well), and Krbomav 0 1 sodium (90 ml; 180 mmol) in Aurora. coming, add 2 Amcl- THF (326 μ) and sleep g. p gases from the flask using Ν6 for 1.5 hours before Asafh complex SAL, 1'-Pace (an intelligent vinyl Vosevino) Veros-Aladiom (the) an intelligent Kl.romethan Dai chloride (3.67 g, 4.50 mmol). The 'Nschan interaction to 100 are all night and was then cooled to 0 ° Wales FH heat was; Hij reaction mixture through as Plate, and sleep with the Al-Faseel

S ^ v ^ Then each separate classes and has re-draw Alaabakh Maya ethyl acetate, and then Altjghv using Na2S04, and Done focus. I Tmt my Amoma'ossav Article 1 (r 0 re- 40% ethyl acetate in Hecsanat). Then Season 3 "represents the &amp; quot; 5 &amp; quot; -" - (1; 3-thiazole-5-Yale) Od as 0 birth of a solid brown color as 4 Rellasgr; t (5.33 of g; 1-8 0 to Mall; 4.90). T MS ESI: [MH NMR (, 5.11 MHz, CDCI3) δ 8.71 (s, 1Η), 8.02 (s. 1Η), 6.811 (s. 1Η) ,; .191.1: Η) + mi (3,11,. 6.71 (s, 1-1-.1.-). 6.50 (s, 111). 3.71 (s, 211,). 1.79 (s 'compound' mediator 18: 4-methyl - ^ - (-5 3-0z - (4; 4; 5; 5-Tramcl -1.3; 2. Dai Oocassapourulan-2-l) phenyl; Goodyear 0 Mmadinell 2 &amp; quot; Amin Khas 0 of 1: Ahavh optic acid grown (0.234 ml 4 4.08 0 Lenny Mall) to 2-Koo Roo " 4 "against Seve (0.5 m, 3.89 Ir mol) was 3-d-Dos -5-such as! yen (1.096 m. D.ro 3.89) j Dey Oo'dan (7.78 t). -schan was Abel; Li 120 0 m throughout the plastic and then, and then -s.bd Azgoel to Dugn temperatures misguided objective type Bea Z 0 0 Artmav 71- 71-ΜΑ 33926Β1

uncle. D by Ja Da Seeley 1 with the liquidation of subsidiarity Bositat Asha / Hecmat for E 4 Z N (3-bromo-5-Butel Fouzel) -4-Bill Peremides -2 Shin (08.a g, 3.89 mmol, as) as pouring Baghae. MS Est 280.0: [Μ +. Η] + m: 278.0 and · Olkhaloh 2: Tapfh flask 40 Ml.mt Alkhaloh (500 mg, 798.a ms Mo.l}, Yasin (Banakulatu) an intelligent boron (502 mg, 977. 0.1 mmol), 1 complex 'A'lbas (Dai Fajl Vo.sfino) two viruses-Palladium (not) Dai Dai Krumithan chloride (44.0 Bhm, Haaa 0.054 mol) and potassium acetate (529 mg, 5.39 Miller Mall). Dissolve has F-1 count Dam; m 7.19 ) DMSO ml) and then smoked to 120 m. After Altguib for two hours, the mixture was dried L. room temperature. The drying interaction Bositat ethyl, was Gsila.mmahlol .ash saturated solution of NaHCOj and bearded. The drying of organic layers sulfate Soveom is Mesh, was nominated by her sedation was under pressure of 0 Zkhgd. The remaining material was purified Bkromatogerav pain d by silica gel with the liquidation of subsidiarity Bositat A.buthail and Hecsanat for E 0 4 Li Hi-la-A3-Mv5- (4, 4, 5.5-Ttramethyl -1.3, 2. Dai Oocassapourulan- 2: l) Phil Baraedan -2-Shin (331 Bhm., 1.018 mmol, 56.6% Ka'zj) as oil orange. Η] + m / z 326.2. lHNMR (5 (.0 MHz. DMSO-De) δ 9.40 (s, IH), 8.31 (d ,,] g MS ESI: [M = 5-0 Hz. If 1), 7.77 is. 2Η). 7.07 (s. 111). 6.70 (d. .7 = 5.0 llz. 1Η), 2.33 (s. 31-1), 2.26 is. (.3H) L027 (s, 12Η A; pronation Allosehl a 9: 4 -.- Bethel - 3] N- Bethel-5-D 1.3 "Basul -5 - Yale) Ivel] Dr.bmid: N -2 -oman 72- ΜΑ 33926Β1 d I j; Bdwo 0 d Berb RBD 1.8. (218 mm, 0.670 sniff. 5, (Jy-0 a) 3_0bzul (59.9 0 Eklopr, 0.670 0 for in Ryan, for (Aeek) Ta? (7-0.3 Bhm '0.034 Fly HO), Held, (32.0 light of 0.067 t Y.l) and Dzat the &amp; lt ;: Bam (437 mm, 1.341 0 Lee Hood.) then Z harmony was unloading 0 Sdam AR (GAV; Orarat but any 10-d; j Owen (918 screw-liter) and water (92 ,, mainland). r; Ozzy) was d smell was ... z Aat JJ Um Gak Aleadud 0 and purpose 1.00 m. LCMS another -60% Ignored Akaa desired j 0.35% 0 Itj Zo.a-restricted and Rabn Odla for any z crescent. then Tkhvn Hait Aagael Abe E. .al, and Done nominated. p 0 Lal Dadn a-T RTM then A.h 'guided me | Q | Lala! to Turn Bkroh 1 Torav the 0 replies 0 Ath Gel -hdi (Ee "' e; no 'Hab% 20 Apt A.bl in Haat) Aswo z 4 -. b-not- | 3-0khr -5 (1; 3 Meh Atdh a 7-Ge resulting Bkroha and Tmav blacks mode Gel Dam 1 I (0tage; b, p. 1 Is it the be stimulated) blacks Z 4-0gl- No-3-Shamma-5- (3-termination

-5 Z 0 d-night 2-1s (1.5 Mahm, 0.372 0 Verl 0 55.5./.)- MS, (IHI. 9. (14 (s. HI,; 1)) 9.6 8 (. (5MSO-t, MHz () 0 ;) 1.1 NMR a, .. 283 mk a [L.a ESI: (Μ I, 6.3 = and, 1 s (s, IH) , 8.04 (s. 1 (1), 7.54 (s, lH). 7.1 .0 (s,, 11). 6.75 (j v 'a a' (a. L'5) 0 (2.37 (s. 3Η ), 2.30 (s. 3Η '(} ;! · 1 rode the middle 20: 4-Emczubla - [3 solution-5- (4, 4.5; 05 Tramethell a, C, 2-Dai Oukabourulan ~ 2 "for failure)] Peremeln -2 ~ mother your responsibilities; 1: s I to Adorh Bakrowid10-20 0 for bad 2 Acaldrl-e- Adquis E.ady (0.835 m, 5.78 Fly rang 0.3-Eros-5-0al Dalian (1.075 m '5.78 Helmer Harrell), Khmgd father (R. 347-0, 6:06 Miller 0 well) and Dai led (55..11 from. then Z Aaham then and Merv ED; m AR (Fouad &amp; gt; 0 of 1 T. S't r -73- -73-ΜΑ 33926Β1 1 to shut down and heating up to 20 of them knock 3 worsened 0 nm Ttr.bd mixture and sleep Aholhb Loral Night 0 Tjmah Elmo 1 d giveaway Zlta Blonbenev 1 the Open Ba ' Dtrhj and sleep rice in &amp; lt; n Rigg Loral S r Presentation not- (3-Shaw 0 t-5-methyl - wicking) -04-methoxy pyrimidine-2-Amin (07 5.78 for f Miss Maud 0.100% as 0 A'zh) as 0 birth Sthbh brunette 0 296.0 : / MS ESI: [M + H] + m. a 0 Atoh 2: Et mobilization of one necessity to microwave 10-20 Ml.mmottag Olahtoh 1 (1.6 5.44 f .II 0 well) E Yasin Atakula-Rdae rowan (1.519 3 05.98 Ave 0 real; , Ta'aa 0:00 (a; j to Z Wheeler 0 Fou.opt-Aladem ( ") Dai / hand Krro Dai-ed (133-0 m '.163 over sales), Dr. Ed-venom (602.a me 16:32 -ve TB &amp; gt; ( . DMSO (10.88 D). Sleep definition Aakaflam then the light of Z Rat Adam AR (NL) NL Im baskets 0 Aagarurh and O p 1200 m I 0 loyal number was 60 Alel 0; 3 drawer 1 decision ; Averlh, and sleep me as upper 0 Tl, and sleep supplement z JV D'dh baskets the growth of rice 0 0 is the AA Aa j Mo S trafficking 0 Rro.atumay ephod Boamh Gel silica (Biotage,% 60-5 BTO A_al in shawls 0 Lab's D4-Vlexala-a 3 As5- (4 E 4 E 5 E 5-Mabl ~ 1 E 3 E 2 Addai Almmapourulan -2-SAL) d] E.pf-2; o (900 Mjma, Rrl 2.64, a 48.5? Ykh) Ydhytm, termination 0.0 [for AI. »]; IS ESI ^ 8.04 Is.; 111 .8 5: /., 9.46 ( s. IH) 8 17 (d of mz 342.1. IH NMR (500 MHz , DMS0-d61),) 2 3®. I,;) 25 2 .®3, E) (2) 0.3 (1 .- 11, 5.8 Er .5) 5,25, (IH, E) as upper) .7 1Η1 .1.) IH) , 7.62 .121.1) I see ducks 0 to 21: Asea - »- [d-5- (1 of 3 Ba; - del 0 for 25's) Lw pyrimidine 2 Walk 74. 74.ινι ^ 33926Β1 flask will manage the bad has 9 02 witnessed Es (58. a m;; 10 touched real) E Ri whoa 0000 for 20 (32 E5'0a 0 Lei real) E Ahiltk p .36.85 02 . '! 2 Apr 6 l) d 1 j 0 Wynn Q4 Alar't (Aha j is 0 for 0 d 0 Yz &amp; gt; KD 0 Ayi Ed Aladailam (' 0) (H23-e m ') AR b were z. cm 51..1 0 for in due) and g' Zngos (0.9.2 m 'u 6 1.577 l). Then to the mother and then Q DD Zq name SSH to is m &amp; gt; AR 0; any Zlatmanbat one long feed Ri t m has been responded Ace 0 11 m Ja seen him Okhath environment and has been removed Munib carving a reduced pressure of 1 x 1 Ehy '-ly Z to d &amp; quot; Zhe pain 1 de S. b 4 Rh Carr 00 Atogerav August Bo'th &amp; lt; for - (b to 00 for%, 1.0 AB 1 T. A-Yale: Shiro in common) , not 1:00 Mall of 1-3 m 'and 3'ha t) Jy'-I-jtvz-è ( 3 Bill-5- (1.3-disappears-5-'s] MS EST:; Μ + Η ] + in /: 299.1, iHNMROOO MHz, CDCI3) δ 8.72 (3. Η)., ((/ 099, RO ; 8.aa (d. if: 5.7, JH ')' 8.06 (s, JH), 7.91 (s, JH). 7.29 (s, IH), 7.25 (s, JH). 7. (5; (s , IH). -6.21 (d, 3.98, (]:. !!, 5.7 = t (s, 3Η), 2.37 ( s, 3Η) composite center 24: methyl 2.2 to Daemcl-4-Ookssowsklohan / Boksilat a 0 Agtmh 1: Hamad 0 such as 3 ..- .. Uecker Pew &amp; quot; Azut (232 g, 2.00 mol) and a bar one formaldehyde (30 g ,, 999.00 mmol) were added biperiden (10 g, 117.44 mmol) to the mixture. was flipping Olakhlul output for two hours when small m. was Amehlol heated to 60 ° C for two hours. the extraction Basthaddaml &amp; gt; 2. Ate (3 X), has been Hamad organic layers was. dried using {Na ^ SCX. the nomination was the focus in and i Morg. led Haoua to get 370 Jmm (rAW) of the Dai - methyl 2-methyl-6-Oochrisichaelohecs- 1-Aan- 1.3-Dai / Boksilat as oil Bani MS.: [M. + H] &amp; quot; f "i227. ΜΑ 33926Β1 a 0 TB 2:! BC guarded 0 Tabrlat Shs; (90 m, 1.67 0 well j) Tsal &amp; lt; 300 {&amp; gt; A 1 0 Ath 1 (50, l g, 663.04 mmol) in methanol (0.15 ml) drip Aoaf U de 30 bear, then p Aiol Alata to 80 m 30 Deghith was born; I in a 0 0 Tdg. ^ Zlktm; Khmedjat ESL add η, ο / snow (it was 120, - a 0 Ek (1.30 0 l) ' has been Ads Apple 0 Alag ml), ( f ) "Bam

; J G (5 X), 00 E integrate organic layers were dried using, Nago, was 0 p .. / U in and i Marg. Was purified Altj congratulations Baltqalir under Datt Mokhtd (5 Trhijh. It was t Lise. In and Y 4 I t ra 9 1 part count 104 120 m 0 led this has no ropes pardoned 100 m mm Zs) and sleep Gathering "(a 88 fay) from Hishl 2-paralyzing -4-4oscalhoshr ~ 2 ~ 4 n /bo.chaaba&amp; lt; 0 T. Dent smaller 0

Ms. ΓΜ Ssadola d; Khalh to 3; ci E0 spyware iodide 1 to Zhac (121.8 g, 639.54 0 Ila Mall) to 0 Aaa (800 ml) 0 has E. 0 FH tomorrow Alaecio.m (6 -1 Molar in A.br an intelligent e-even; 8000's, 1:28 0 well) Btait I -40 0 m over 3 hours. Z solution has grown as well the Open Aio.h 2 (53.8 g, 3Î9.88 0 6 u l) in 400) EtiO ml) count of 40 m over Deghiqtin- been flipping Aglul output for 5 Maat at -20 m. The suppression of Khalal Asalo Knyr.z Amu. Boom 0 loyalty radiant (2.5 liters). The extraction using a 2 X 3) EtOAC. liter). The drying Astkhalsat using organic Angiah; Na ..?, SO, was Feachehaa, Umm Trkizi me and easy Ra. ci Tiqah Almozh remaining sequential liquidation by Jay Salait pal column .am Zt ^ 4 Or Mzbb .1: 20 PE / EtOAc- Hedda led to the ropes on 45 g (73%) Z Methl 2.2-Dai Methel0-4 ~ Ootxoscaluanfybokelat Crete smaller . NMR aa .185: MS: (Μ 1 Η] + nr (600 MHz. CDCI3) δ 3.49 (s. 3Η), 2.43 - 2.40 (m, 1Η). 2.35 - 2.29 (m, 1Η), 2.21 - 2.17 76 - ΜΑ 33926Β1 ( 'm, ΪΗ) 1 2.1 2.04 - a (m, 1Η), 2.00 - 1.96 (, ί1ι, 1Η). 1.91 - a 1 AAA) d; H). 6.85 (S, 3Η), (, .77. (S, 3Η) any Alohet 25: Y-Ael 4_51mdo 0-for-a 0 3-Tazll -2-Yale &amp; gt; -4- b, and Mmaa 2 E2-Daakhalevdkl.b0-Pt'r S Adhlh 1: Z a, night Ahubl 1 Eboum (2.2 t, 5.5 technician Lrl, d 20 Kalad Q 'for the Hayt) I D.a.y 1.2 DDS Dr. stamper Z (b well (30.515 6.05 0 well) Vehmsropoulan (015 l) x -078 m 0.1 d 30 Dstbuallasvalod, sniff Z de 5 Dy.o 0 N. Dalal Kaboula Oualo cooler Altdj to Tdl g led milk -24 (1013 m 0.05 t 0 Lenny yf) in Tzab'.oyoran &amp; lt; Say t) 1 Ahgaz 0 Atilol Alohgr one of the outputs counted "78 C for Q 1 cent; and separately, were Shell 0 Annie U 1 E. 0 0 m Linda 5.l days after Dink was cooled time I see to -78 them. thats Attalla essayed 0 Ashe PM 0 Fairse Cderad ammonia (10 ml) and let your mixture 1 Guetdih to Drt temperatures Algrlo. ci T. S Z phase between acetate A.bl (50 ml) and performance (5 &amp; lt ;,); was μ &amp; gt; classes were 1 Stkhalas aquifer Bositat ethyl (15 ml.) was Alobqat Walker laundering 0 of data -dl Meles was dried sulfate sodium, was nominated, and. then focus' was purified substance of 0 to fifth Khala.l Lamu 0 Athurav venerate silica (column 10: 90, Biotage llWgSNAP to 65: 5 for her 1 Zsan: acetate ethyl) for Mai 0 Z-Maial 4-0adwoksa 2.2 Dai Mittl ( a; 3 "Tz, L-2-Yale) cyclohexane bicarboxylate t; Semeh Nmadden white pouring (08..a g, 73% Kotj). MSAPCI: [Μ + HJ + wZ. -11- ΜΑ 33926Β1 Formamed (1.9 ml) has 1 Alberlmo - 0.1 Id Thelat six At Avahh an extract Agaq Shdaha (046. Ahtoh 2:; s 0 n Tj 0 to Khtoh.a (0.35 m, 1.3 Jr JU) d Ν, for Od'a 0 Gal. Hdlabd (1.9 g) ci; only 00 N-; WJ b (0.254 3429 '0 AVI small &amp; gt; -258, .ν- &amp; gt; touched Mall). efficiency after 0; maximum of, Ks ;; lest Aiel Z Apt Z.bal (25 0 &amp; gt ;, for

, Fetch Mrdiom Mai B (1.0 &amp; lt; &amp; gt ;, and 0 termination (5 R) - and then Fehr Astqat 'the growth μ the 0 o together the 1 E (5 x3 0 l) and a solution de (10 0 l) E and sleep bear Akau; s Ssm were Ze 01 A, and then Rey . ci hay Edsel pain during and / 0 Anmbaav &amp; lt; m 0 (b SNAP; 1.0? 5: 95 'Biotag; 3 75: 25 Shan: Musical 1 Yale) Lader's &amp; lt ;, By_ 0 discriminate 4- (5-Ru 0 t -1. 3 Harol-2: g) -4-Brdv -2 '2-Day Bill Skchanraok-Bla.tlab habit gift Bta, 286.8 to 63% integral) · MS APCI: IM ... I..IJ-I »,. ., - - 0.48. (1. 0.5 (1.0.1-1 of NMR 0 a) a 5 MHz. CDiil): s 7.58 (;,) H); 3.ό, ί 50 3 H) 2.45; fs, 1 H); 2.36fm, IfF); 2.21 (m, 1 FI); 1.94 fm, 3 H); 2 .11)) 1.75; F); 1.19 fs, .3 H): 1.06 fs, 3 H) compound Intermediate 26: 5-bromo-2- (1-methoxy Scaloiyot; l) 1.3-Tharol has Asafh sodium hydride (60 (/ J dispersant mineral oil) ( 47.0 mg, 1.125 0 Lee Mudd) to Mahdl from 1 to compound 1 to the center of 0.1 (250 mg, 068. 0.1 Miss Maud) Adhchar m in MF () (3 a), and 3) THF ml) and made available to the reaction mixture to Mdz one hour. Added touched iodide (0.080 ml, 1.281 mmol) and the reaction Aljait for another two hours. The reaction mixture was poured in diluted NHiiCI Mani was drawn Marzn Bather Dai-ethyl. Has been seen discriminate Abze organic then Almazh passage through the remaining stopper Celica with sequential filters With, 1:10 Osmtat asset: Hecan for 2-bromo-5- (A - Suksa Sillalobiotil) ~ 1 4 3-Tzul_ ΜΑ 33926Β1 'H NMR (500 MHz, (€ 00: E 2 (l): δ 7-73 fs, the HJ; ,, I I. (% 85, 225 mg, '2-54-2.4. (m, 4 H); 1. .92 -), - 82 (m1 2 H) 1 to compound the middle 27: 2 "chloro-4-A.hl Beremi: n Tmt adding the methyl both Lazio (1:00 and .lar in 71.4,} 71.4, THF 0 Lee mol) Bakqat to solution at -78 m of 2; 4 ~ Dai Vruberimid.n (10 67.1, f 0 for in 0 well) in 1.25) THF 0 l) 0, after Eni for one hour, Tmt added ΝΗ4α saturated Maph at -78 m and let your Ngoel reach 1 Li a temperature Khervh stirring. After that, it was extracted Mulla 1 1 Shaul Bo.stadt E. &amp; quot; Shell. Anbakh been using organic laundering, NaHCO saturated with Manny, and. After that Althviv sulfate sodium is Mab; was Akrchih and'kirklz under 10 Gtal Mkhad 0 has s 0 Ge Olmadeg remaining Boss and Mad Graf column Boistzh Gel Meilika with Altafeeh Alttabaarh Bositat Eshel 9 Hecanat for a 2-Knyro &amp; quot; " '4-- A.hl pyrimidine (5.031 g, 18.70 Mti Maud, 27.9½)) Kkhguet Oizumrmera Naoqa Study 53: 47. composite Alobt 29: 2-cypress-4-Skviparvl Ber.ides been assembled 2.4-an intelligent Kloruperemaidin (1.5 g,. 101 mmol) E 0 Sakloprosl Borovek acid (8.65 g, 101 Hlvi Hall), material returned 8.22) Pdc.! 2 (dppf) -CH2CI2 gm, 1,0.07 mmol), and phosphate Albonasom (53.4 g 0.252 g mol) in paper 1 β Stdner Qaeda. Uh, spyware has 0 503) ml THF) was my love Tskhv S 0 degree heat Alaraa with Altguib throughout the night. After that has been cooling the reaction to room temperature, was Terry to ,, .., .. 1 0 under Datt Mokhtd were Attalla 7 Bastadt Ahle was my Bathaddam NaHC03 Water Massah, brine, was Tdjaaah sulfate intentional: Om Ir Maph was Zqaha Rah, 79-, 79-μα 33926Β1 under pressure churned. Has Tenaih Almazh remaining Bkromatogerav R.asith &amp; lt ;, column Z with Alpes 1 Attabaah Bositat Eyre in Hecsanat for 2 ~ chloro -4 Sass; Kelmobroal pyrimidine (1,0.124 m, 58.3 over Maud, 57.9½)) Kkit 89: 11 0 n Alororat MBS. Marri Oset 1 to 32: 4-methyl-pre- [3- (4, 4, 5.5 - Dmethyl-A, 3.2-d; j Ooyourulan-2-0l) NR b; Yemyin -2-General to beaker containing 0.3 ~ (4.4, 5, d "Ttramethyl- 1, d-2 or Srolaf Dai-2-Yale) Ovelin (1.50 g, 6.85 over the Mall) O2- Zawro-4-Mlthel pyrimidine (1.01 Jmm , 7.87 mmol) Tmt adding an intelligent or San (69 ml) and methane sulfonic acid (, 0.51 ml, 7.87 mmol). And then heating the reaction at 100 ° m throughout Ollia 0 ,, then the interaction was cooled to room temperature, and was diluted with ethyl Bomitat, then Dalh with water, then dried sulfate Akhvnseyoum 0.9 was nominated concentration and sleep. Used car and Mate Graf Alumiany purification for a 4-fun-not- [3- (4, 4, 5.5-'nturabil -1.3, 2- or Khsabourulan Dai-2-Yale) Feb; Berimidin-2- Secretary (d 1.2 g, 3.95 Miss Mall, 58 ½) Kzatj). : And .8.30 (cl 1 (Η NMR (501 ,. MHz. DMS0-d6) δ 9.48 (s, ΙΗ a .31,2 MS ESI: [Μ + Η] + m / z 2.33. (, 1,1.1 .5.0 = 1,7) 6.71. (5- (). JH), 7.98 (cl ,, 7 = 8.0. JH). 7.95 (s. IH). 7.29-7.20 (m, 2Η (s, 3Η). 1.2,8 (s, 1.2Η). UCB intermediate 35: 4-A 0 y 0-for-not-A3-cell-5- (4, 4, 5.5 "Tetra 0 Whipple -1; 3.2 ~ Daaoukabourulan -2-Yale) Lenin pyrimidine-2-Amin -80- 33926Β1 a 0 for step: a role, in .a- liter three-neck contains 3-bromo-5 Methyay Aniline (60 f 290 mmol), ice (Bakulatu) Dai boron (96 g 0.377 touched pink Byd'a; Chloe MEMS Vusaivo -2 a 0.4 '0.6' -; any eBay isopropyl phenyl (8.3 Ham, a .dwi 7.4 l), Dladiom Dai Braeliden Aston (3.99 gm, touched 4.35 mol), and Abat; Bo. signed (42.2 g 0.435 touched replies) has Adaiz a 0.4-Dai Oak 0 to (0.720 ml) Tm.nz p aa; s him I through cleansing nitrogen for 30 minutes. after you define Alldorvy God, c, was -schan interaction ^ Li degree Hr.arh d; Khaya canceled, 80 were for a period of 4 hours. Zi 0 u; hands T. and scarcity .lvaal mixture through 7 rang without: T, after Zlat been laundering 1 Ahleight Balatmaha 0 M Ag Mello Asotil (500 ml), was watered 1 Alma solution ' Zj Bachkdam e; methyl Lajos (500 ;; mouth Hdrugiy 8 of Fu's Mglm of .lgosvat (500 ml) e and solution r (566 ml) 0 were separated classes were pussy organic Alabakh -mmahlol saline Gish with (] CKD &amp; gt; 0 for Aouadh a 0 Gkhalas asset Maya 4 1 Q has been one of the Akhgaz u E up, Amos 1 a Otkhadd \ E-u 0 0 J E Baual (0.500 D). Sleep Tdjaaay 0 of materials together data Bakrtat Aqaibd 0 m, then; 00 and Tmetrucisah .. has fear Him raw material Bkromatogerq Eood Boishla D'0loi 0 ".- 0.9% Asset 1 T. each / Hecsamat) and section 4 GIFF imported Aa to B-ol b G'a 1 heading Y !: Td'l under: nest d: 25 g 4; 0:48: A: 90 Yeh &amp; quot wishes; Zhae). 234.1 ^ + [0MS BsÏ: '[M + &amp; quot; h 0 2; Tmaatm a 10 Elaq d E 0 of l p 2-class -4 ;; Whipple »Amedin for 8; 0 T. GMT ;;: Tate -81 -81ΜΑ 33926Β1 100 as stopper threaded was heating at 1.10 ° C for 15 hours. Was cooled beaker, and has Asafh Jzeasafa of 2-chloro-4-E0 sales pyrimidine (0.145 g, lib mmol), and has been re-sealed flask and Tm'nschanh ment for 6.5 hours. Altaaal been Nr.bd mixture was diluted with ethyl Bositat (70 ml) 0.9 is an aqueous Gsila.mmahlol Mhbo Bsch boat to the connection of Les 5 m (25 ml) and brine (25 ml), was dried sodium sulfate, and. He was nominated, focus and sleep. The use of the solid structure Anatjh oblique redness 4 abused - ^ 3-fun-5- (4, 4.5,

5 ' "Ttramethyl- &amp; quot; 1, 3, 2 &amp; quot; '. Oocassapourulan Dai-2-Yale) Vsloperemaidin -2-General (44.d gm mixture of 80: 20 and trace weight with -1.4 Dai-Ooxan) without further Aknqah. MS ESI: [M 340.1 Η] + |; 'Ζ + 10 Composite Intermediate 36: N "lead-Silalobrobel-5- (4.4, 5.5" -' evil Ashan &amp; quot;. &amp; Quot; 1, y, 2- Dai Oocassapourulan &amp; quot;. &amp; quot; 2 "- Yale) phenyl; - 0.4 -..- Methyal pyrimidine-2-Amin 1 to step a-: then provisions 9 or f 1 fitting for the presentation soybean d, 5.daa Bromuonadn (2.93 g, 11.67 mmol ) 0.2-chloro-4-methyl-pyrimidine (1.5 g ,, 67.-1-0.1 mmol), and acetic acid (.0.701 Do, touching 12.25 mol) in 0.1 0.4 Dai-Oo'xan (23.5 Ps. ) under pressure in Ote 15 Joe p argon was' Nschanh at 120 C for 17 hours. After cooling to Angervh degree heat, it has fragmented the reaction mixture Wen A.bl acetate (100 ml) and aqueous solution Mthb. Of sodium bicarbonate (40 ml). The schizophrenia, the layers were Gspl organic layer with saline solution and was dried sizeable Lights sodium, was' Nrchihaa were, focus. Chromatograph blinking led venerate silica (10% to 30% acetate A.hal / Hecsamat) to get a 5, 3) -. Ν &amp; quot; "Dai Bromovivel 20)" 4-Shell pyrimidine-2-Amin (3.6 g, 9.97 Miss Mall 0.85% as 0 consortium, Bnie 95%) as a solid color Oassar Vata, 343.8 MS ESI: JM ..... HJ + ηι / ζ. 0 \ 82- 82-ΜΑ 33926Β1 Step 2: Then cleanse the mixture of -1- 0.4-an intelligent or suffered (40 MAB) and Vrbunat sodium water (2 Hrlar 0.0 y 0.10 ml, 20.99 Maza Mall) Balorjo 1 N for 1.5 minutes and then knead been poured in a beaker containing 0.1 Mt step. (6.d g, 9.97 mmol, N 8 ½) Shakh, Ceuta purity of 95%) and Article Alamadaqh, B, (0.686 g, 0.840 mmol). Has 0 Asafh acid Sakiobrovi Bork (7 d 1.0 Ham, 12.07 Mti MOV) followed Bmmkhqmv was pacing Balcama put eroded argon Dalal five sessions spawn t cleanse Balargeon. The mixture was heated bypass even see him flashbacks degrees C for 8 hours 9 E. Ava, knead f Nbar.bdv to the point h 0 Wharf room was Mkhvagh Bositat ethyl (100 ml) and sodium bicarbonate water saturated. The layers were separated, and 0 g Gsaa, Alabakh organic .mmtoul saline, was dried sizeable Lights sodium, was' candidacy, was its focus. It has Tzqah Olmazh remainder through in-phase HPLC Aneksa (45. 80%) acetonitrile R. water using a 0.10% TFA buffer solution z). The ease Amehtoah parts Ai desirable Almt Bositat Il, sodium bicarbonate water saturated. Then separate the organic layer was. Dried Boukbr.vi T. Aghannseyoum was nominated has been its focus for Al, ^ _ (3-bromo-5-Sakloproehl Vettel) -4-Bethel pyrimidine-2-Amin (443.6 Bhm 0.1 d 0 1 Malash Mall, as the product of 13%) as oil Build. 1) .306 MS ESI: [Μ + Η] + έ. Step 3; The heated solution of Menth Step 2 (443.6 mg, 458. -1 mmol), Pace (Biacoiuato) an intelligent boron (407 mg, 1.604 Melanie Mall), Article dppf) - ^ u1) 9; Pdc 2 a.) 2 Ladd 119 Bhm, 0.1.46 Marmol), and my regret T. Ozbutaseyoum (429 mg, 4.37 Maza Maud) s Dai Methya, sulfoxide Chet argon in Bakroo in lying 10 minutes at 150 0 scare mixture Acfaal Bather Bai ethyl (0.40 ml), regret T. Aithiay ( 40 ml), and. Mahlo. For aqueous saturated sodium bicarbonate (30 ml) and then knead the Walker Artemisia to remove any solids m ΜΑ 33926Β1 '83 - '... the 0 Grah with water (3 25 X ml) and Mahlolmz 1 T (25 -db. Has been stretched out impressively and sleep U; d m, and then was nominated by one, were ¥ t has Tbhkj of) E Aua Tz 0 &amp; lt; Ake (5-30% paid parent Alate y Alla: 4.5, 5. Awampell 1.3, - 'Za Dadhirzb, .. ~~ - A2-Dai Ooyrrolan -2 -l) E 0' s 7%: Linda pouring Aze. 10 Article 1 was Edjda in 0 for in Roe 'Hla Kate,' 3; ,, "+ MSESI: [ΜΗ1. Line 0 E 1 T. Altaaah in this topic Ahamorh a J 1 Ber..0adln -2 -, L) ~ 3 to Amshal &amp; quot; 5 a (4, 4; ό Ara.leut 39: (04 Lay Hllhd 5_dhampel_la, 3.2 Ouaaa; for Kddl .lo; Steak (50 g, 7 H 2 Haley mol) in 2; Hap 2: 2! il to * ϋ /} L'0 &amp; quot; additional 1 d 0.351) DMAP 3 2.87 R. Hall) (300 ml) was Saad e 0 to 5; Y 1, 1.44 Fly Maud) Tmadd curling temperature overland Bahala Adr- 4 Gul Fajl 0 (8: d been Tguib Norq I Hmor m Idh A.2 hour aka "1 Weapons not 0 Hjaoz 00 E. M 0 I: 1 revived nest over 1'm not Saouat 0 following 0 Tmt Adahh Equal Say Altdvh Ate to Dhirjh Loral: 1 to Tabgh Alag 0 priority sequentially 'Bastkhadd; m NaHCOj 0 father with Ta 1 Et »' E, and sleep Fehr 0 six did not 0. Aigh together Bastkhadd 13:00 MgS04, were replies 0 b 0 a: None 0, ways: Dtm'a: 0 allocating Me 0 Q at 162) Ε .ΟΗ t) 'was T. :: ;;; I;: _, Iloy &amp; lt; Guet 0.07 W7 Qq for-&amp; gt; B - - d 'not seen the degree Ahar.adh'se Sauer H 2 0' Z-il Olad 1 FH, supplying Ar'lh Hmom'lnbarad was giving priority to 'mixture Ala'zj for 18 only spray in the center of Hull Marg. Add EtOH has been Rkiz'lkhalt Rh va, Wei 0 d it was Akkar 2

X ΜΑ 33926Β1 Bdenm 1C. The J S W (DBS ml), and sleep Z IPA Akts de 10 Dalla 0 and after the rates then Troi Ave- then Z this ace Tmah then Bhmv Almodl Play 4 Pearls hull built Z Z I asset to God 48 0 loyal and S 0 roll a 0 Lucky Cderad Pictures (215 231.0 t medal &amp; gt; - was 0 Preheat s-brother to 1050 to Mdz 90 bugs Dhz Ohaea 1 s Yi Aat 1 s then Dedd to a land. to Drlo Tm'rh G was with 00 in the flask 4 d anything Seey 2 Hesalaj Wii Arla ran 0. m Tvv St I P wa &amp; lt; Dhhgtlh Akyel 'the best evidence for Atm'rh (I then p Aanalytasavay, 0'tmd 0 He to Maihms s 0 long as X2) CH1CI2), light of 0 Ddketmiedadavvi Adwi 0 to Aautm Burley &amp; lt; TEN Byautam-Rdiviotma (200-esophagus 040 m) Alydztefiialy.tmbaakj 0 Gul SOS extend the 5 greenhouse and ankle assets hr 2-Mard 4 Die 0 tighten Gul Dade (31 m, specific Wazzd 62.5% in light of I's 118 '' &amp; quot; NMR's t) 0, t) 1 H) .6.5 1 .5.0 and p 0 ;,) 57 7. (5.0.1Η your responsibilities for 0 ) v 808 5 (3; 0Η NMR (600 MHz. CDC; 54.4.1 H "&amp; quot; /. 00 to Hadh 2: name Gahdv 0 Tj Ktrz 1 (4.75 m 0.23 0 LDL real) late Rohr and 0 vinegar a 0 to him (5.59 m 0.030 for in Re) must (j 1 was (33) Den Ololala 0 Z 8 (32 '' in the 23 B in) Ab.tmtejenalkhat not-for Jetydrjh Tm'rh Alaotha 4 Dam'la 9 P Nnab I 30 loyalty Badi s; E) Dz 1 tyred to the states and then Rh m; 0 'name followed by CSV-blooded%, then loyalty 0 1 t Alloa slipped S. Jmdytdtmav Rbes to Ahso.l p Bo- (3-Bro.o -5-Aft is permissible) -4- (Dai Hdmgl 0 Eadst 2: Z (5.2 3 16.6 Mash Maud). , (4.9, III = and .8,58 (d of (H NMR (600 MHz, CDCI3 Λ mxiifD (ü) (\ KfTJr, r121r1L1 -85 -.- 33926Β1 7.75 (s, i ff). 7.52 (s. Iff), 7.21 (s, IH), 7.06 - 6.92 (m, 2Η), 6.5 () - 6.27 (m, IH), 2.30 (.s. (· 3Η Alahtoh A: the ease Mottag step 2 (0.5 g; 1.6 «JL Mall), p (O / to Adhu) Dai boron (0.465 g, 1.83 mmol), Abat Alo'aberm (0.469 ppm, 4.78 z d) and pain 1 Dh.lamadavh 0cH2a2 (0.065) Pdci2 (dppf g, 0.08 0 water Mall ) Dai or Dsot horrible one for Azat (3.5 z) RTM Laden Z temperature Alaratja.a son a 0 Etin y 7th cl re-cooling to the point Khervh heat. commuted thread using 2 of 2 fry 20 KD Edah pain 0 termination was picking SAT, was drying material Aledodh Bamthaddam MgSO-i, were balances and &amp; quot; 1 0 Zaki · U in the center of Morg, and was purified 1 Article 1 of Bahia curlers 0 Atogerav Alo 0 Ed -l Z (4-Dai Ioromeshl-Perembaz0-2-Yale) -l3-0hl-5- (4.4, 5.5 to Momatal A. 0.2] Daaoovourulan-2-g) da-additional (550 mg, 1.52 plating Mall) + MS ESI: [Μ, 3.) 7.59. (1Η NhlR (600 MHz, CDClj) δ 8.56 (d,, 7 = 4.1, lfl), 7.74 (s. Iff. \. Ρφ m / zl62.; 311, IH) '7.45 (s, 1Η). 7.35 (s, 1Η), 6.94 (, d. .7 = 4.2. 111) . 6.38 (t, .7 = 55.0, 1Η.), 2.36 (s; 1211 .1.33 (s. 1 rode one mediator 41: No-3-Scalobroal-5- (1.3-Sasul -5 ~ t) Ivel] ~ 4 ~ (Ray Ioromithil) to Brimidln ~ 2- &amp; quot; Amin to the flask ci Adahh (Vl3-Zeruaoscl) - (s) 5 (1.3-thiazole-5-Li) Flae 4 for (; any Vrubahl &amp; gt; Berambidin -2-Walk (523 mg, 30. .eshrl) Ehmayenobil Rrod (336 Bjm, 3.91 RO Maud), Dhumvk up (968 *) 'Daddy 4.56 0 0 no, 2 &amp; lt; 1,5) Fd (OAc mg, 0.07 over the Mall) and Trajdod is "F (37' 86- 86-ΜΑ 33926Β1 mmol). Tmt Adhagh horrible Alazat toluene (1.0 ml) and water (0.5 Mae) was emptied Anhaol was then cleansing Balorgeon 5 times. Then the mixture was heated in Bakrowiv counted 1.30 m for 30 minutes. The ease of interaction Bositat IPL, was washed with water, dried sulfate was Mufnseyoum, was nominated nine was his focus. Used car and dragged Mato F Ed Bakz, in purification for not- [3-Sklaurel-5- (a 0.3-thiazole-5-l) Ivel) -4- (MS Est Tri: [M. (Vrubuthail) pyrimidine -2-Amin (384 mg, 06. 0.1, mmol 0.81% Kzaj E1's t + lit: 363. Â ft NMR (500 MHz, DMS0-d6) δ 1 (). 23 (s, 1Η), 9.06 (s. ni). 8.83 (d. t = 4.8. lit), 8.23 ​​(s, IH). 7.92 (s. 1.H), 7.41 (.?. IEI). 7.28 (d.07 = 4.9. 1 H). 742 (s, 12.03 E (not 1.80 (m, IH). 1.05 - 0.92 (fil. 2Η), 0.78 - 0.6-1 (m. 2Η) Antrmb Midfield 43: 4-Saklor, and Bill "Do not ~ 3 -bal-5- (1.3-Abzul-5-0l) failure] Bear 0 Mmaday -2-Li additional four words are the 4-Skrucil ^ - (3-cell-5- (4, 4, 5.5-Ttrabuthail -1 , 3.2-Dai 'phenyl) -2-Ber.bmaidin Secretary (750 mg, 2.1,4 touched mol) in 2-methyl-b abrove 0 Ran (10.7 ml) has Adhalh 5-Brwmuthiasul (406 Bhm, 2.35 mmol) 0.2]; 62 A..a; ') 0 (; 87) Pel C12 (d PP mg, 0.11 mmol), will Bonnat protection of sodium (2 Molar 0.14 2 ml &amp; gt; 0 was sealing Ai interaction was purified using Ν9 for 5 minutes. the stirring 1 Cap E 00 for 0 to 80 ° C for 1.6 h and was cooled to room temperature. Tmt add water were using 3) EtOAC *). the drying relationships organic Avihh (extraction sulfate 0 '13:00 has been Rkizha 0.0 has. purified by Kromato Graf Alobaz for nest 4 '&amp; quot; &amp; quot;' Smaom); was kicked t been coined [and: and i 1 No ~ A3-Bethel "5. (a 0.3-Yarol-5-l) Fouveloperemaidin -2-General ( 600 j 95 {JL Hall, 0.1% 9 Cup) as a solid »accountability for whites. : - /. 117 + [MS ESI: [M t Η ΜΑ 33926Β1 NMR (500 MHz, 0 \ 'b 6 No $ -0 I δ 9,49 (s, 1Η) 1 9.06 (0s, 1Η), 8.26 (d. , / =: 5.0, ΙΗ) 1 1Η) 8.04; (s, Ι Η7.43,; (s, 1 H); 7.10 (s1 1 H), 6.82 (d., / = 5 0. 1Η), 2.29 (s, 3Η), .2.00 (01, IH0. 1.17-0.93 (10, 4Η) Arialubt 44: 2-blessed for 0 bears - * - (3-d 0 4 5 '5-Massae v 0.2 Louay Oommlabellolan -2 ml) fell 0 a) Alai-2-additional (500 Em, 1:42 to Wiesel) in 2 Hgl Turabrodharan (0.7 to 0's) ci 1 addition five medals &amp; lt; Basul (318 to 84 &amp; quot; a 0 for in small), · 58) PdCl2 (dppfKH2Cl b 0.07 0 for in 0 RL) E and asthma 7 T. y * &amp; quot ;; 0 no ( "1.42 0 &amp; gt's ;. then b Alaelay t ESL was Ttheh Bathaddam del 1A for 5 β, and P s &amp; lt; P 80 &amp; quot; m I 16 PU; was cooled Zly V temperatures b 's; P 0 him Almaelnm follows 1:00 B1 use x3) ​​BOAC). The dry 0 P s Walt 0 T. b copper-Zt Almfssom, was concentrated in and Stz .nrg, and have been purified Domatogerav Alo.d for z 4-Ochoproh ^ - (3-Shell-5-Phippasul -5-SAL) phenyl) Berimbin -2 Las ( Aad Bhm,

1.18 mmol, solid whites slash 0, ll; 3 &amp; lt; 'MS ESI: [M + H] + W, 1H NMR1500 MHz, DMSO ^) δ 9.59 (8. 1Η). 9.05 Os. lin. 8.38 (d, J = 4.7, lin. 8,19 (s 2.87 (m. Lin. 2.30 (s, .7.ΙΙ (s. Ill), 0.77 (0, .7 == 5.1., ΙΗ1 1 (Η a, 8.13 (s, lin. 7.51 (s's (a; not (.31: 1), 1.25 (0,, 7 = 6.8. 6Η compound Alumit 46: 3-Achille-not "[3- (SA flo, R.oaithil) vessels -5- (a 0.3 Thazo.l a SAL) 1 Eachn 88- 33926Β1 the count d 0 n 2-Melo-4- (Btachew; .al) Ee 01 Den God b He'h DVI b); d legal-5- (1 E 3-0bzul -5 - n Z (50 b 0.26 u 0 well &amp; gt; j a 0 4 Lay Owen Mzoa F (s (.1.1 0 l) Et; hey; a Azgs (d 14:00 '39 H'h DVI small),, 5Ac0) 5.9) Pd mg, 0.026 pre Maud) and 172) cSjCOj p '53.. DVI small &amp; gt; Dtm -ssn Afoul; Li 00 A'mmadh 30 minutes. d, Koepp, has taken place. »Alad between 0AC , 10) E μ) and sodium bicarbonate water saturated. The reaction layers and-been As'ds Ashe Oa'na Bastkhadd 13:00 10) EtOAC ml.) was Gus 0 for administrative 1 Koya 1 Th Kdhur.ad sodium 0 beamed 0 AVI (0 1 ml), it was dried MgS04 using non-watermark, were Trchib was g Samarha cJ Mghl Z led 00 1 1 Kqah Bo middle &amp; gt; Milica (20-60½) a Sitat IPL in Hecb'mat) to Alhso.l 0.3-Mhllh3- (Sayruahl &amp; gt; Phil] -5- ( 1.3-Thazul -5-Al (z) 13 Bhm 0.3 a%) Kraoh colorless. 387.0: MS ES,!: [Μ + HJ + ην. composite intermediate 54: 2-chloro-4- (Nuban-2- Alooxa) Aerbmtda 0 w to a solution of 2, 4 &amp; quot; Dai Theloruperimidn (5.0 g 0.34 mmol) in 2-Brobbol (84 ml) was added 12) cs2co3 gm 0.37 Malash Mall) and then Tiab thread I room temperature births 16 hours. Altvaan was then heated to 65 ° C for d hours, after Zlt been Rhth interaction and then focus. Purification using silica led by Munib graded righteous p smelting system of -0% EtOAC Rhecanat to Alhaol on 2-Klro-4- (propane-2-El OXY) Berimid.n (2.4 g 0.41); and (Kzb Ed.bm . color, E &amp; lt; 3 a 1.1, 1-Η NMR (500 MHz (5.38 (hept, .7 = 6.2. JH), 1.34 (6..7 = 6.2. 6Η 00 a; 5,7. IH), 6.56 ((! ../, 5.7, I Er, e) 8.23. Alobt compound 55: 4-a-Bautal-2-p-Kloruper -89- ΜΑ 33926Β1 EA d ^ 1 less in Amioa on 2-Kloruperemaidin (0. a gm 8.7 m 4 Mi mol) was added 0 Tea Z I (6 g 0 l) was cooled Alakhlul to -30 m. has Asafh tBuLi (1.7 solution Molar 7 a m 0 LGA c 9 mmol) Baltaqit been retained to interact when -0 d 0 c for 0 d sticky CS Tli Algael to the small m was Altqubb when we draw the heat for 30 minutes, the light of her son was 0 0 Yasin means Dalolo Irls; YK (0.60 t; 1.0.5 &amp; lt; a 6 l) Viela 2

:, A Akqaal 0 0 keep interaction at small m and has added a solution of DDQ (3 ml) and water (I hope) Ba 1 0 t &amp; quot; and

(38 2 &amp; lt;, 105 Miss Mall) No! AA '(8.7 ml). After 1.5 minutes, coming in addition 1) NaOH Mol 1 μ) One (10 ml), and sleep Transfer mixture to a dark Acfaal not contain an effective separation. J on μ 50) EtOAc) intercourse (50 ml). The separation of the layers were extracted Snap MAB-time Ahdn Ba -pettm 50) EtOAc ml). Μ been Alorar female Alldo.bh Bklor.ev Sodtom m 0 m 0 popularized loyalty (50 &amp; lt; a) E 0 .. 4 Dagha Bo'sth MgS04 is »Aiah, and Done candidacy and. The Trkizt carving Dvhal E f 1 for items remaining the 'black confounding using silica, followed by heat-and Matodr.aa easy Ô1 \ ί system is integrated Munib a 5 (.30% EtOAC Rhecsanat to Bo one middle Celica from ί I 5.2, 1Η), 1.33 (5 , 9Η) I and. Fill the Aoale2 4 0 0 Klrlu.a-yen (1.00 m 0.67%) as oil Gore led a 0 '50 t. 0.5) 7.24 .5,2. 1Η1 0 t y)? 8.4 »(* Il NMR (5.9 MHz, CDCIj A; pronation center-62: 2-quartz-4- (a-Shaw; ^) E-i-Q 183 a 0 Z 1 0 A (12 Krubdhiramyin-4-Yale ) ethanol (150 mg ,, 0.950 mmol) j; 0 Kah 0 (3 ml) at torticollis m Tmt added Dai-ethyl Ominokiprit Ray fluoride 14 13:00 7 j b l) drip was stirring for 3 hours. the ease Aglul i 1 j each 0 0 Ithan, was wash it by, NaHCO saturated with water, and. Althviv been using MgS04, was .. &amp; quot; &amp; gt; 00.U even Oljgav 0 you purification Boisalh silica gel with 1 Droma'dhujrav 1 to beckon (small 0 -90-- ΜΑ 33926Β1 Vlyroa-Q) Hirimaidin ( 75

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00921.tif" id="idf0054" />

NMR (5 (10 MHz, CDCI3) δ 8 67) 4 Rhecsabat) to obtain Ai 2-Kaoru EtOAC% (mg, 0.467 Miss Maud 0.49 (E &amp; lt; Acladig 67 (1 .4.2 = 4.7) 7.46, (111 , 4.2 = real Η), 5.58 (dqj: - 6.7, .48, 1Η), 1.74-1.57 (m. 3Η), the compound! mediator 70: 2-chloro-4- (Dai Vrumethyl) Barimdday

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00922.tif" id="idf0055" />

Mainland, Jehn, Ong was Mahro of 2 ~~ Kloruperemaidin-4- / Baldahid (0'5a JL · 104 f in a beaker 500-year round-Qaeda three Rqub't,

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00923.tif" id="idf0056" />

Mkae 0.00 a%) drip with absenteeism when Snmarham z range 0 d d; -tq 0 nm tired 0 B Anhlol per- for Saafn counting the small m, and was then extinguished by adding 50 &amp; lt ;; loyalty 0, and then stillbirth Anhlol output using 100x3 ml of Dai Trubthan. Were merged Tiat ales ^ Yeh, was dried using sodium Fberitat non-watermark has been carving its focus Datt Mnkhvvra. Then put Almadden Addai on silica gel column and has 'filtered' Tabaaa using DCM LaSalle (2: 1) yJ !. Z 2-chloro-4- (Dai Florosl) pyrimidine (2.38 g 0.14; 4 Output) as oil GC- jk-.Â

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00924.tif" id="idf0057" />

'Compound Alloshd 71: E-butyl 4-for Yale; -4-Head; 9 Kmms Sik and Hlasan f ^ b 0 0 Kssalai:

<img img-format="tif" img-content="drawing" file="MA-33926-B1D00925.tif" id="idf0058" />

ΜΑ 33926Β1 step 0.1: The Do.rq contain 82) ml THF) was added isopropyl chloride Mufgsom Rklorad Asom (1.2 Molar in 37.7, THF ml 0.45 mmol). Added real from 0 Tizul (3.5 g, 0.41 Miller Hall) in 20) ml THF) slowly. The interaction stand for one hour. Added Mahlo. For a V-butyl-4-Ootxosichaelohecsan Boksilat t (12.23 g 0.62 mmol) in 20) ml THF) and. It was flipping interaction for 3 hours. After Nellt been slowly quench the reaction saturated ammonium chloride and then Nkhvagh Bosmtat Eshel. AA was Hsal 0 Tth F 'and sleep .; Tajafiaha sulfate Almanseyoum was nominated was focus. Was used to Ohatoger.av Aldamad for purification to obtain a butyl-4-Hedruki-4- (1.3-Kazholla2-l), / Bordblatt (9.25 g 0.33 Mall touched 0.79% Attj) 0 uEz284.1; MS ESI: (Μ + HJ '

XJ Aton 2:; s Arooh Aoerij 0 your responsibilities; 1 (9.25 m 0.033 me 0 Real &amp; gt; s; indicates 36) DMF ml) and then not-Brumushpimid (6.97 gm 0.2 for Haley Mo '} TGA &amp; lt; p until Oct 0 for Ovi and TCMS was eases Altaga 0 El water and .opt 4 Mahal 0 nm Q 0 for Hbakh Aledo.bh, blood Tjgagha by Major Mufnseyoum were; Chihaa was R. Ari 0 Iromatoger; P 1 to beckon for purification to obtain e "butyl 4- (5-Pro ​​6a; 3 nm 00 a 'I) -4-Hbdroxa Sichaelohan Krbok 0 lats (9.24 gm, 25.5 medal u, .MS ESI; [M + H] + w / 2 364.0. (^ de 3: a flask Yu Z 3-night-5- (4.4 '5 '5-a-Erab. Zybourulan-2-g) resulting in (1.6 m, 6.96 Ir / l)' pilgrimage Aat'h 2 of 02) and, Ihesml), Dae-Su 2.1 0.4 '. 6'-tea Q ,! d -2; &amp; gt's; j 0: Z is 0 Gan (0.33 m, 0.70 0 for in Maud), 0ta) j,) 0.32) Pdi me 5 d 0 AA 0 completin cheapo 7 v cm (6.80 gm, 20.9 Miss 0 RL) Cava; OM &amp; lt; and .aaslat 0.92 . 0.92. ΜΑ 33926Β1 Edyd (3 2 E 02 030 to E0.magailltmtmslod 0 Wen 5 Ssd 00 d y Ady 00 [.mdalaslaytm-Sdabes; for Drtosmarhabe then pp. D Ischl, was b 0 Bl'h Brlat Abes vu I would have been my minted 0 A-M Kromatojerav shimmers in Altnnqah Bugeritat Mufnseyoum, Tom; scarves and sleep 0.00 y 1 t blacks Presentation e-Jubl 4- [5- &amp; lt; 3- to 5 vinegar Phil) a- 0.3-Breaking the -2-night-4-Sasmhahaw 7 N.oat; 00! Q, s-00 (j amid 72: E0 Shell 4-L5- (3! 0 Joe -5 to 0 Gul Lille) -a three-first-2-; l; _ 4-hydroxy -2 "Buttlsklohecsaw Rowe -4 Li flask round 1 of the captain Includes presented 3-Scl ~ 5 (4 4 'and '' * 0 to Ormlttl Dayawybdlad -2; l &amp; gt; z (402 uncle, 1.7 {TB), level 4 Le5-Shaw 7 a 0.3-disappears-2-d) -4-Brod-2-J Q 0 n / Ept (400 PS 1:10 for 1 0 b's), dba) j) 0, Pd j 5 H 1 I 0 m, 1 0. I 0 Ave 0 well) for 55) Χ-PHoS blood, 10:10 me f) and 1.12) cSjCOj g, 3.45 0 for in 0 well) do not; Nia 0 of 4.3 &amp; lt ; Is 0 10:10 Z 1.4 Daooconnorhala Asan.tmottagnasaly 100 Mei 16 I 0 Wad Hamid Zlag then 0, and Z 0 penchant e 50) E.0AC &amp; lt; l) to Aholot Els) vu I (50 t). 6 AST was then Mas 0 1 0 Trr but my Bamd'm I &amp; lt; Heq t) 'has been μ

. Secret 1 At.ytoulda (50 of), ^^ N; | 0VU! 0, &amp; gt ;; 0, m 00 p 0? D 0 pious termination 1 de remaining Alatjh by Sifana Alai Thule t; Tel 4 of 5 for (03 A: 5 Lid -1 x E 3 brule-2- I-4 and holistic-2-Bill Q 0 n / Brkjlat (344 to 0?%; Aelz Q: Do not the 0 n. 375.2 MS ESI: [Μ + Η] + / η / ζ. -93- -93-ΜΑ 33926Β1) to compound intermediate 74: Seads-Biel-4- [5- (3-methyl-Hippel Abu -5) j s humanitarian partners Ron 0 d Yale; -4-hydroxy -2.2 Dai-Bethel cyclohexane Krbucb '&amp; lt; s been put Sass -mhl 4. (5 Pro 0 t-a 0.3-thiazole-2-0ly) -4 ~ Bros -2 '2-Dai corset MP ^ hexane / Boksilat (1.372 g, 3.94 cellulitis 0 well) 0.3 to tend-S- (4.4 , 5.5-Ttrobuthail -1.3, 2. Oocassapourulan Dai-2-l)? Hull (0.918 94 f. d touched Mall); Paul; t Maziom (3.85 gm, 1,1.82 touched Mall), r00188 &amp; gt; x-PHos, 0.394 mmol) and 0.180) Pd2 (dba) j g, 0.197 mmol) in the flask was E. &amp; lt; t Agha purified using Ν2 to lath times. The disarmament of raids by Dai Ookal (DA &amp; lt ;;) and 1 of water (1.3 ml) by passing bubbles (N below the surface and has Anavthma to the reaction vessel. The stand Khlamit 0 interaction Annatj at 100 C for 16 hours and was then mitigation using 25) EtOAG ml) was Asila using NaHCCK saturated with water (25 ..ab), replaced. For saline (25 ml), and. .tjvifa Been using Na.2S04, he was nominated and focus under pressure Mkhid. Tmt Tenaih article Abaah Bmromatogerav blinking (2% to 12% EtOAC in Hecanat) for m-fun-4- [5- (3-Aso -5-cell segregation) - 1.3-thiazole-2-0l] -4 -hedrukia 2 E 2. Dai-Buthaid Saiklo ^ San bicarboxylate (1.33 gm, 54.dmlaa Mall; 090 g) ^ Z) Krgoh orange. .7.80 (S of (1Η NMR (500 MHz, CD3OD .MS ESI: [M t Η + ιη / ζ 375.1 HI, 6.78-6.74 (m, 2Η), 6.53 (hi s, IH). 3.68 (s. 3ΙΠ . 2.45-2.36 (m, 2Η), 2.25-2.12 (m ,; (1, .76-1..62 (m. 211),, 1.1.9 (s. 311), 1.04 (, s. 3Η. ; 211, .4111. 2.01-1.94 (m 'of compound 1 to 75 ducks 8- [5- (3-families-5-methyl Ivel) a- 0.3-thiazole-2-a-night four of Dai or Bassaspiro [4.5 ] Devin -8-first --94- --94-ΜΑ 33926Β1 1 to Khtoz 1: ease drools (2.5.0 t 0.352 touched Mall) Bastkhadd 13:00 tf; 300) i ml) was -nradh to -78 m, has been added 220) N-BuLÎ t 0.352 touched 0 well) -mmadd d Drjmt Lhasa 0 Interior of no more than "65 m. betray mortar Omahfr and took the addition of 40 sounded 0 hee. was Tatehg interaction Menna 20 minutes and then Tmt adding e 0.4-Dai or Daspiro [ 4.5] Dahala-8 EN (50 g 0.320 mmol) as a solution in 420.) THF ml) Bagtnqaad «n by suppressing Alad 1 FH. Bmad two hours, was Lachman's water interaction, and has been removed or August, was Tiab mixture 0.0 District reached ° S Wara internal to the small eased confused use EtOAC was Hamel S 1 T. was then Aschas abused nasal Asad 13:00 EtOAC. Sleep drying spontaneous classes Aqh using MgS04, and, she was nominated, and 0 Turkerha to rate Bertily large 0's hopes EtOAC was Trkatsh to 1.0 ml. Added Hecanat Altaat 0 n Zlal With Lighting 0 0 Hbb Alhelmbt for shiny and; unity after knead been -bradh to 0's of AD was Rchiha 0 then μ b Abe C (χ2) and after Dlat then Tjebh 0 AP d DDS Seoul Z Is (a 0.3-0 Bzul -2-El) a- 0.4-Dai RCA 0 as a 4, s] Dkad-8! well (66 Em 0.085 / e) solid white hand. Alahtoh 2: 1 dilution step product (60.5 g 0.251 0 touched well) Adam 365) 0 DMF's). 0 has additional spyware Ν -brumuskasmad (.49.1 g 0.276 touched mol) was E p 1 4 Lee Cole 50 they have been absent for a period of Ftin. 0 Ibb Ed Akeael p free; Rh was Tiridh to 45 funded in addition 0 E (600 contain t 1,5.8 g 1.Na2so any Z led to the S-Z 0 birth 0 Yeh. Was Tguib 1 Halit at a free one Rh 1 Sale for 7 cent and 1 Hdv Dbad 0 d 7 Ttm; 0 hoarseness was Afth χ2 A.takmam 300) HO t). The T. August Loral Alliltan lakhs Dajaf .95- .95-ΜΑ 33926Β1 for t 8. (5-and-mo A. 0.3-Thazul -2 "Yale) A- 0.4" an intelligent Ao Dazerol 4; 5] 8. Deccan ~ real (68.2 g 0.85 Li?) as a solid performance. Step 3: The situation 3-Rachel-5- (4.4, 5.5-Ttramethyl-A 0.3 02 Dai Oukabourulan-2, g) Oneben (2.00 g, 8.58 mmol), Menth 1 Khtoz 2 (2.75 to 8.58 ms real), 409) X-PH.S. () g, 0.858 e 0 Lay Hall), / Botatchetrdo 1 (8.39 Jmm, 25.7 Miss Maud), 0.393) Pd2 (dba) 3j g, 0.429 mesh 0 well) in Dorfy been discharged Balorgeon. Dai has Adahh Ooxan horrible gas 1 t (30 D) and one for water (3 mL) was Dsjn Kael 1 to 1.00 are for 40 bunion. After that Reid was 9 T. ESL to Dr.jh orbit father 'was of Khammash Scarpota 0 0 sodium saturated with water was extracted using x3) EtOAC). JlM been Olabi 0 '; for membership in one six Sdam Na2S04 were concentrated in the center of the udder. Led August Z Dalal Kleut 0 Rmav Alomhi (40 ^) - 100½) h 08 Bio: Hadat) to Alhaol nest 8 ~ Q (3-! Pettm -5-sale with a 0 but) A- 0.3-Bzul-2-I-termination 4-Dai Aukdho [4, H d ^ n-8-ol (1.93 g, &amp; lt 65;} / °) Krgoh ya. 307;., "+ [MS ESI: [Μ + Η · Ri Lord 77: p. 4. [e-E3-father, -5-PayPal Yale) A- 0.3-Mazul -2-not a 4-hydroxy -2 , 2, 3 tea-Shatt Sklohxan Ash.o. R CS lighted 0 of d; j and Robrosdenmad Allmchum (5110 Micro Carr, 9:20 cellulitis 0 well) Alyhls 3 ~ Mha, -5- (1.3-Thazul50 - g) Iain (500 mg; d 2.6 R. Hall) 7815 in (7 Are ) Id. ... 78-Em. AB 1 v 1 to Gal 1 Heating 1 Li -60 m with 'Overdrive for a period Heq Thtq 9 0 hands Ihsanoglu, for E 0's; 78 m and .temt 1 addition \ biting 42 2, Darai u 7.-96-.-96-ΜΑ 33926Β1 -, (600 protected the, 3.26 z Lrl &amp; gt; Qa 6 (6 &amp; lt; &amp; gt; In Z, 8 Mar Alabz; Dscs MD -065 5 -78 mph II

Ndi 5 degrees Li responded;,! &amp; Lt; 00, and then my M; E 8 H'e the growth b Ald Tjonem 0 Ahaha (3 *). Atkhala was 0 Z Aze Mayi termination Atda 0 a 10% CH.CI3: IPA (3). The cloudy-class of the families of the Aivlokh Haol t \ p. 4 &amp; quot; for 05 (3-Fu-5-0hl Yale) A-, 3-0bzul-2-I-4-Bros -3 E 2 E 2 0 Ray vinegar

Aadam O 2 facilities, 12./.) / Tos &amp; lt ;. MSESI: [M + H1 + ",. Z.? 75 rode tying 78: SYS-A- [5- (3-! S5-Z resolve &amp; gt; 1 '3 for 2 .arol; Sklohkan -1.4-Diol administration 1 then frighten Brod (25.02 t 0.352 Row Z) b; 300) THF t) and then to a cooling e- 19:00. Has Azaih 1.6) N-Buli Rlara 220 t 'for in 5320 sales) sales Ddjh been exponential temperature not David -65 m. Has 0 bugs any I 20 bear 'Odd sounding Z Ailo 1.4-Dai Ocadl 4.5 Adhikan-8; will not (350,320 DVI lol &amp; gt; Mmahro in 420) THF D) I through goods Aivh- then to less Ddz 0 termination after Znk then suppression 0 6 for water. Tmt Ar.alh 0 to Dolq Z &amp; lt ;;) Avdid and Done s de Od to ​​disparage-then Al 0 Adlt gone for 0 p such as Sdam: eioac and Wal-D 0 j bear 0 d is then a 0 Tkhalai Sdtm Ed was answered Alhguet Akhaw'bh termination O; M, then ; W and then - Klrhaaly oil 0 Haley thrown. Been superseded Alr.at Bassadam E'OAC was Ray! Li '05 a year. Has Sa 1 J CAT Ely's father (RLE at the Eiffel Hanat less to Nhlalq 0 humanitarian partners 0 Ala. Has been repented of atopic 0 d these are 9 up Dladtm Azird 0 to -10 m and then Rzdd. The 97- 97-ΜΑ 33926Β1 Byymat (2 Mutmad? - (A'3- ' all-2-j, 1.4-Dai: Sawa 4 E 5] Ban -8-first (66 m, 2740 to me the 0.85% Katj.). Avldh 2: Done. Afahjail, a (60.5 32,510 u 0 well &amp; gt; 0 thorns l ( &amp; Z), Li Hedda Seoul, has; Vahh 349.1) nbs 276 0 to Wiesel &amp; gt; - was 0 Schln dilatable 0050 d; Q 0 nm Nbara- vs. L. 045 m off; sa 10 0 Ta | (hah t) maximum of t;: 15.8) Na6so 0 m, 1250 t Mall) 0 Akqaet. was less than 0 b has d-'hal 0: l 'Idh a 0 y o; and then reminded then; Bh 0 was Gh Oskhadda 0 of 0 followed by (2 * E 55 d t)' then the proportion of Dsolely 8 for (5 Hosmla, 3-0bdhul -2 g &amp; gt; - 1, 4-Dai Alkamirl [4.5] Tz-8-first (68.15 m 'A.3 2 z of 0.85% Knath). Kto.h 3: Tami 3 Aioh 2 (15 g, 46.8 touched Mall) o 13:00 0 &amp; gt; THF t l). n 4 addition 6) HCl p 0.78 d) was Tguetiba counted 60 m births d Saouat 0 Zerad 0 ESL 0 Ely degree Haraz 0 to Govh and has additional 1 No 6) NaOH, p, 78 &amp; lt;, &amp; gt; 0 was' j S Sd'm EtOAc. Then behold, one of the snaps and has G.e. 1 Stkhalas 4-Bah MAB Ed M. EtOAC () was Tjev thieves Alag 0 1 priority T. (* MgSO) was Schenri. Was in Article 1 x Adam EtOAc to Hlha and soils to, .... 20 year broadcast has Adoiz Hecsayt (60 t) Akqt 0 was cooled 1 to slurry to a degree Aer.vh heat, was Tqub for an hour and Laden and Dr. Dr. 7th been Rchiha, then Gus 0 him Mack 0 Mat (2 X 15 ml) was Tdjaifa for Haol 5) 4 Js Berlho. 1; d (11.25 g, 40.8 Halle Mall 0.87% Kna'nj) Ron was 2-l) -4-proxy 0 Sklohecsadhun. ΜΑ 33926Β1 ~ a 1 to Step 4: Then ease product 1 to step 3 (6.5 g, 23.54 Hlna Mo'y) Assadam 10) 1.HF- t) and B U- it was cooled I (Li -76 m. Has as 0 spyware 2) LÏBH4 Molar in 14.1 , itiF ml, 28.2 ms drip modem, with retention. Temperature Aldkah XS less P ™ 75 m 0 flipping interaction for an hour and A'hdh was extinguished by U NH4C1 his 0 radioactive ease y &amp; lt ;, using EtOAC. The separation of the layers and re-extract Tabmh Lada ¥ using fctOAC (2 * m. Was drying layered organic Ktah using 0t (&amp; quot;) Na6S, then; Rchihl War light of in the middle of Morg. Led chromatograph flashing and Anthviv Takht spawn high-Il a 0 for the most underserved 0 Ely Cisse-A - (5-RFU-a 0.3 "thiazole-2-for Blobin- 1; 4-Diol (5.2 f 1.8.69 mmol 0.79% Kiatjmk 0 birth of a white solid. Ktoz 5: so that the mobilization of vials using 3-methyl-5- (4 0.4, 5.5-Wrabl ~ 4; s, w Dai Ooxao, Roland-of-2) Aileen (0.84 g, 3.60 mmol), SJ Aaztoh 4 (002..1 g, 3.60 mmol), Krboy 1 Sziom (3.52 g, 0.81-1 Melltm 1 mol), 0.165) Pd2 (dba) i g, 0.1.80 ms modem, 0.172) χ-PHos 4 0.360 g modem, Dai said Oak 0 (04/01/62 Ml'm and water (1.462- ml) . Klien interaction Takht argon Az 1:01 C for 5 hours. then ease interaction Bositat ethyl was his shoe to Qah season. Jri name Alabakh spontaneous Ba.sdam to 0?) and the protection of a saturated solution Mlha- name 'drying Aladi Aledo.ah using Na2S04, and sleep Trthyhaa and focus. Tmt purification material S. crude Bkromaug; the Aaomegy Bastkhal; m Blaka (for Bm_20% DCM / MeOTI) to get a cess-1- [5 (3-a 0 Lego-5-0bhl Ivel) - .. 1.3-Yasul "2-Ysklohan - 1.4-Diol (871.5 ppm; 2.86 mmol 0.79% Ka'lj). And .3.5 MS ESi: [M t HJ + ηι / ζ. 99- 99-ΜΑ 33926Β1 compound Alobt 80: Esther Bethel acid 4- (5-bromo-thiazole-2-SAL) -4-Broda- Dhar 1 Zsy -2-methyl-Sichaelohecsal Abikerboxti Step A: My father is a solution and then cooled (-78 m) of the ester. Methyl acid Zazs -2-Methel-4-Ooddsso-cyclohexane 1 Walker Bo Forgot (13 m 0.76 mmol) and Thiarol (0.9 a 4 mL 1.53 ms MOQ) in 130) THF ml) has Asafh 2.5) NBuLi Molar in Hicks, 30.6 ml, 76 mmol) Batit.mmadl hurt to a degree internal temperature kept at less than -70 m. Then flipping Altivaal Mdz for 30 minutes the mixture, it was introduced 1) MeOH. D ml 0.76 spared Mall) and has a 0 degree to commencement of Akad Arafa temperature where it was' diluted with water EtOACj. The layers were separated; drying the organic layer was Basnnhaddam; IVigSa, was nominated was a Tazha 0 0 L. Seeley one solution I b \ to focus in and i Morg. Net pious remaining raw material Bkromatogerav Alod for acid ester Bethel Terrace - 4adroutil-Trevi -2 Til - 4 '&amp; quot; Aarrt ~ -2 &amp; quot; Yale · '·· Hlohan Alkrboxla (4.1 Ham, 6.a mmol) with double Althacm other (7.0 g 0.27 mmol). Alkhaloh 2: To a solution of Alahtoh E product (4.1 g 0.16 mmol) in 30,) DMF g) was added 3.43) NBS g, 19.3 Malash Mall). After stops Altvar exothermic Alambdna been &amp; quot; Schan Khlien Alinvaal to 50 m was Tkulaibh for the birth of hours. DDD and then reminded Anbarad to room temperature Uq add water (280 ml contains 7 grams of sodium Brati) Mteuaa by Et0AC. Was picking classes were extracted Alabannq Maya by 4 * 2) EtOAC then bless Snaps organic Alhiah using HjO, were dried using 4 (MgS2, was her candidacy was Amtararha to gel silica Bakirkn in the center of 0 Greg. Has Zhe article Aract 1 ore Bkromatosr 1 P 1 to beckon to get a scientific ester Bill Hdd 4- (5-and-Oa. to Obasul-2 " 's) - 100- ΜΑ 33926Β1 Ras -4 Ahyararkisi to-head-2-torrent-Sklo.hecsan A'lkrbo Z (34.75 16.1 mmol), 333.9 MSESt : [Μ + Η] + / η / ζ. 1 for a composite one for central 81: propane-2-O -4- (05 Ruhr-a 4 3-disappears-2-u) &amp; quot; 4-hydroxy -2.6 Dai-methyl Sichaelohecan Kuo Hiblat retreat A.: the leaching propane-2-Yale 2.6-torrent Dai-4-Ootxoseklohecs -2-AN-a-cr .doxialat (20 g, 95.1 mmol) in accordance with Araat I sold the freed (-Ovg. Chem · ; 0453 a -458 a, (4) 72.2007) Basthaddamozoroalod rather than A.hl Z O.stadt was) to ease the use of \ 300) EtOH &amp; lt;,) · to 1 Akhlul trafficking t 0 v Gala are Alarouhn Q4 addition 5 Rh 0.8) c / Pel m) and'sa I was shaking less I j b 0 0 R.os Apr 50 deg h r inches for 0 x 0. 1 d Zs been Rzh your responsibilities 0 1 DAT sales and Lal b 0 At Adam, i. .bd Of EtOH, was T. Kizha me and i 0 0 Greg and your smell of Pedroma'orav 1 Od de {overland, PAL-2-O. 2, 6..daa crippling -4-Ootxosa 1 Zawhecsan Carr Boxlat (5.2 g, 24.5 Mliho.l). Olahtoh - (5.2 g, 24.5 mmol) using 50) THF ml) and has Adogo Rsud (2.63 ml, 36.7 0 for in mol) Eyre 'was Z &amp; quot; d Arles-term to -78 m, has added 2.5) NBuLi Rlar in h d. 10 0's, 25.7 .avi 0 RL) less Bmaf'l were added; 2.5) NBuL Rlar in Hhs.a d 0.10 Do, 25.7 0 for any 0 RL) less Bmaf'l lead to Ctagaz 1 degree Alhaddarz AAC 1 trot P 0 Ash Psalm 0-65 m 0 P 1 been complied with added, it has been a string assess a 1 TB 0 abuse I was then extinguished applicat loyalty and sleep EQ to a degree temperatures one for hype. It was added EtOAC; and sleep Hsal editions and then s Aq Lists: Its bass 0 or MgSCXi, was her candidacy, and was concentrated in the fronds Verb and Tmt litchi material remaining crude Bkromatojrac 101, - .. 101, - .. ΜΑ 33926Β1 1 to beckon for Harl Xuan-nest 2. of- 4-Hedroxa -2.6 Addai Hillel 4 (a '3 &amp; quot; calc Nsellat (2.6 g, 6.7 ms Hall). Aazth 3: Alyelol 0 Ntjalkhhloh 2 (2.0 m, 7-6ada Mall; d I (ha t) as E0 Mavh 1.38) I gm 0.73 to 7 0 for in Merle &amp; gt; then p 1 Edl trafficking to 55 1 d '55 Dbgv then righteousness; d ESL Wen; wrap 1 Set of sulfur God of 0 and Daum (0 e 17:00) in AAC's 0 d t) for Bua, EtOAC llj- then you classes, and the duration of the medical Aslas S growth x2) EtOAC &amp; gt; 0 then TGI Alabakat organic Angiah using MgS04, was Rchihaa, - / i in for 0 i &amp; lt; g. T. Tepe article etiquette mother curlers Padad friendliness b Z 0 and -2-for-4- (5-A-Brolo 0.3-disappears-2-d) -4-Pro DE-2'h Dai A Sinclslat (8532.2. p. 6 l)? 5 betrays ^ [Q] MS ES ;,. Aakp Alo.bt 82: Flint-2-g-4- (5-Ruhr-A; 3-Dzul-2-l) -4-hydroxy -2.6 an intelligent Maz Sikaohan / Yeux lattes 0 0 0 Step 1: The Tkhvar Robin -2 --l 2; 6-a ;; 0.0 Tmlalat (20 g, 95.1, Q 0 well; and 0 I to Protect | categories Almjh FZ; .adja (.I Org., Chem ... but -0 AAA (4) v 7 &amp; quot; Sdamiyar and Ttpt Plus; Hleyeptutm Q Atkhadd 13:00 ΕΛΗ Â 300 t) -! d 'b brother NDS' (z Hut v c L1 e Oua.e ci Dfl hydrogen initial YAG 50; 0 and 0: yo, Pat Akad Khalal baskets using psig for two hours. after Dlat been t &amp; quot; a d g and protects it has Hrohatogerav Derebd Almz.bd of EtOH, and Then Rkizi in wa 0 Ss ΜΑ 33926Β1 ί.02. for the righteousness of 9 Ban- &amp; quot; 2-. but 2.6-Dai Maial -4 --ao Thsosaknusgsav calc Salat (6.4 g, 30.1 ms real). step 2: been easing step product .6.4) I gm, a 0.30 mmol) using 65) ml THF) and has since 9 Avh'aa (well (Psalm 3:24, 02 d 4 mmol) to 0 was cooled 1 Aima'zj solution (Li "78 m and has added 2.5) NBtiLi Molar in Hicks, 12.7 t, 7.a 3 canceled Mall) b 1 Kqat count rate hurts to much internal heat retained when less than" 65 m 0 when 1 addition probability, been flipping Khaliz interaction for another hour and then was extinguished by adding Alma.e was piped Annie Narjeh room temperature. Added EtOAC, were separated classes were Bhviv organic layer using MgSCE, was seen Chihaa, OTR Nisaha in and Sz seductive g and has a pious Almazh remaining welding Bkroma 0 Dhujrav flash for all -sas-Bropav -2-Al- 4-HYDRO-Thsi -2 0.6 Dai-methyl-4- (a, d-thiazole-2-Yale) cyclohexane -therboksilat (4.45 gm, 15.0 Maza Maud). Step 3 A to Z solution _sas al-Bropav -2-Al- 4-Hydro Zsa -2.6 Dai-methyl-4 "(1, d ~ thiazole" two-Yale) bicarboxylate cyclohexane (4.4 g, 14.8- mmol) in 34) ml DMF) was added 3.03) NBS g, 7.0-1 ms Mo, L) was heated Amehlol Alath to 55 m. After 60 Nqiqh was cooled interaction and Tmt added a solution of sodium sulfite (500 mg.) In water (30 ml) followed by EtOAC. The layers were separated and re-draw the water layer using X ?.) EtOAC). Then -bhviv organic layers Ahamah using MgSCM, was nominated, and was concentrated in the center of Verb. The remaining material was purified raw Bkromatogerav Alumie ,, for Mans is pure. The recycling health, in some Aghanat, was nominated was washed auction Hecsanat to get the - Cisse Barr and Pan - 2 - Yale 4 - (5-bromo-1, ΜΑ 33926Β1 -1.3- 3-Ebzul-2-0l) -4 -hidroxa -6; 2 Dai crippling Saakhluhan Drbo.kmpelat (2.4 g, 6.38 Miss Mall) 375.9 11 | + m / z 0 SI: [M a MS '1 compound Laos 0 i 84 (a): asset 4-Mdroxa -3-crippling -4- (1.3-disappears-2-l) cyclohexane / Boxlat one compound Alloshd 84 (b): Aibl 4-Adroxa -345 Dai-Bethel-4- (1; 3-Thazul "two-Yale) Mbklohkan Krboxlat ' to compound 'mediator 84 (c): A.hal4-Hdroxa -3 E3-Dai crippling-4- (1.3-Basul -2 for Yale) c 0 Dlohxan Carr Boksilat' to step 0.1: has Zkhavh Pace (opinion methyl instead) amide a! of garlic (41.1 &amp; lt ;;, 41.1 ml 4 j Jr) L 0 solution of ethyl 4-Ookssowsklohxan to Rboksilat (7 g, 1, ..4,1 ms 0 well) in 153) THF ml) at.-... 78 m, making sure temperature does not exceed -70 m. After the addition, the reaction has been aging for 30 minutes before adding Aodomithan (5.1 ml 0.240 mmol) slowly. The hinder interaction at less than -70 m generated 1.0 Zqaiq by slowly heating to a temperature AAC FH nest over an hour. It was subsequently Tejen interaction to 50 ° C for 5 hours. Has Olchkan parallel to the source, the interaction has been aging at a temperature Apferqh temperature for 14 hours. Akhlo.e been mixed with water was extracted three times using EtOAC. The drying Alabakh organic Aviaht Mkhid pressure to get a dark red oil (9 g). Then use Almenth crude directly in the step of the following without Mmazid of par. Alahtoh 2: Red dark crude oil mixing (9 Ham) from the previous step with Warhol (4:41's, 61.7 Hess Maud) in "a; '(1.50 ml) was we want a, Li -78 them. FH has e ^ N &amp; quot;

1 HA -1ΰ4- Jubd Sirm (2:56 Lau, 16:46 0's, 41.1 0 o boredom), and then one for Azz B'dol Z -78 0 m to-y d after Thee I am looking S to Drlo Osmar.h the 0 Rlo- name; free a land. 'It was a 0 SSH Knott / s Baikhadd'm CHiClj. Sleep I I August 0 Tvi Mkhc was Yi Ero.aturay Aua 0 Plan E 0 and d 0 for SDK 1 (5-oac / o100; e: Akalot 0 Sioux t A_al 4_mllow'da-3-0al-4- &amp; lt; a 0.3-Bzll-2; l ) bad 0 Shan / Boy 1 t (2.69 g, 24% &amp; gt; / At j and Dr. S. Waddle e 0 Bluki -3.5-Dai Mughal-4- (1.3-'yarol -2 - l) Bmlkah / Facebook 0 Instruments &amp;; Liel 4 -e 0 Druki -3.3 V-Day 0 Yale-4- (termination 3-Azul-2-SAL) Skloek 0 Ed / Box 0 lats (1.09 g 0.9%) Crete built. 284 + (MS ESI: [Μ + Η] + m / z 27 () (for 84a (for 84 b / c) 1 of the compound (mediator 85: e! Yale 4- (5-bromo-a 0.3 ~ thiazole "2" for) -4 &amp; quot; proxy-3-methyl Sep 1 Dlohxan calc Sl 00 T. has additional 1 FH N- Brumusksenemed (2222 g, 12.48 touched Mall a). Li yolk 4 for g Larry intermediate 84 (a) (2.69 g, 9.99 mmol) in 1.0.51.) DMF ml.) was 0 for Fear only six counting room temperature for two two hours. after that, quench the reaction using Akrnmomat sodium protection of saturated been Khalolh water. then extract the mixture using Tel: Az] El; 2 (3 X). The Lcht a reduced pressure of focus and has purification Bkromatogerav MiG .. b 0 mode Gel Celica (instrument 30½ EtOAC : Hecanat) for Aithil4- (5-bromo-a, d-del Thiazola 2) 4-hydroxy-3-C-1 Bethel Dlohhassan calc x 0 woes (2:27 Ham, 65½) as oil der Us 4 0 .MS ESI; JM t Η] + m / z 248. 35 () ΜΑ 33926Β1 intermediate compound 86 (a): Aithil4- (5-Bromu- 1.3-Thazul - 02.l) -4-hydroxy '-3; 5- Dai-methyl cyclohexane Krbok 0 scourge ride a 1 and b 86 (b); Al4- (5-Eros-1, 3 * Bzul ~ 2-Z-4-Pro r's 0.3 Sdaa methyl Sichaelohecsad Carr Boksilapt 0 of 9 Hall) to the real p 5.64 0 to gm and Mosksenemd d 001 a has been added Ν ~; / s of 1%] 3.85 Malash mol) (1.09 gm, (c)) and compound 1 to the middle of 84 Web 84 (b .. Adadh including two hours after the rituals of room for rad degree 'whoop interaction when (5.94 f). The Ba 9 or confused three times was extracted with water. mixed, M. water saturated been Bouapkr Bonnat towards and has' purified Bkroha &amp; quot; Douhhr E reduced pressure under Akhmah snaps organic CH2CI2. has been the focus of one of the Osd (Ygrl 40% Έχ2ο: Hdan) Seoul Z E0 paralyze 4 AA (05 Romo "to 0.3 bar 2-.al) -4-Broya" 3.5-Dai corset -aklohkaz 0 Krpop't wa 0 Lyle 4 &amp; lt; ν bromo-a '0.3-Dbzul-2-0l) -4- Hedroxa-for-3 Dai Methyd Sekloh \\ 0 0 Krbok scourge (1.04 g 0.75%) s Us /. (364 '362 m / z'; &amp; quot; [Ms ESI: [Μ .... H). P I 240 mg PO this topic a hand 0 0 broadcast all '? /. Dam 13:00 HPLC /.aly (5% Μ ° η 0 Paz 0) for Hsolsh 2 Shell 4- (5-Aromu-A 0.3-Thazul -2-Yale) -4 LAPD 0 Rowe / Ed, A Dai However Bklohhan / Yu 1 v (71 mg, 30% ) 20 of 3 HI 'm / z 0 M;: ls ESI (64 for; t! Ir and the asset (s) 4 (5-j 0 and 0 and-a 0.3-Tasul -2-Yale) -4-Bdrox -3' 3 Dai Pew Sidithan / sell (110 mg, 46 &amp; lt ;; uh) 20 ha +111 - (- 1 Sesi: [m ^) (364 Clenching bit smaller 0 ΜΑ 33926Β1 j. - HD t and CSM. Yale) -4- 0 Thazul 1212-Miffy. &amp; quot; 4 "Bmsm ) Ouaithil \ Mud (1.6.9 ml, thiazole mmol) in a CHE 0, 74.6 t, (1.6 Molar n -65 m. and then end Acay m JH parents Mall E), and has two Methya, Sichaelomksnn; Walker Boksila Ktoh.a: the solution was cooled (&amp; quot; &amp; quot; 78 \) e 0 n oxo-Sakulovn Alkrbokaa (2.2 g 0.119 0 DVI 0 and for stirring the mixture 1 to Tagael for 30 minutes, &amp; quot; warmth Aatagael to score free) Rh 1 Arafa where it was diluted Palm 1 e EtOACj. The μ &amp; gt; AST, have been drying class 1 for membership Bastkhadd; m. CMgso was nominated and; Kizha the easy life of 04 E Tmt purification 1 Article 1 rest etc. 13:00 Bakrua'dhujrav 1 Oamity for &amp; lt ;, E 1 Secret 0 Ebel 'z 4' (and Y 2 d "4 ~ disappears -2 Rzatlohan Alkrbokciec (32 178 Aaaa Mall) 0 step 2: in Tdd product from step 1 (0.20 g, 74.3 Lutfi mol) in 140) DMF t) It Adalo 15.9) NBS- gm 0.89 sniff. Hall). Dr. Allard to shower Altyel Dhrarh Adlna been Khliez interaction is heated to 50 m and then flipping for an hour and Ahdn. Dr. Dlat has been cooled to 0 Dre overalls weddings and added water (280 to contain 7 pr) P Kbernst Azsodiom) followed by Bo; middle EtOAC. Been picking Sqat any Ed less except for Adam EtOAC (χ2), and after 1 you then wash the organic layers Atjiah for the use of 25; ί · been Njgag 0 Aq 1 for membership Bastkhadd; m 4MgS04 was 0 nominated and Ray J d 0 i &amp; lt; p 0 for no article only 1 ore u 0 A-Graff flash for Esther asset acid 4- (5-Rorabzul-2-4_ (W_ Brossa2-0hal-carboxylic Bkloman (20 g, 57.4 ms Mull) of Η] Γ b. mS!: Si: of m /: 347, (-107 . -107.ΜΑ 33926Β1, b 0.9:; 6; Yale, Q4 (5-for-Q for alll -2, L) -4 else ^ - 2; 5 Aaivd Babkin five and 0; ... it; do not E0 x kl Khamad Ssn- 2-crippling -4-Ootxol 00 Wicklow Shan death (25.; 0.136 t 0 dL) Ahdsddhad 0 e 25: for, Denmd: ;; Li's 0 7 01. was 0 v as 0 spyware Hecsamaa, Dai Salaz lithium-hand (1360 goods 78 s 0 bath ë Ji; P / Wason 0 No e b e 0 Lama PM 0 d 0 Z worsened 0 of one, a V, but &amp; lt; inattentive but 0 jolt heat Altaga &amp; lt; a S 0 n -70.;: the Sass 0 I 30 bear I- -78 m 'number Zq Z a 0 0 Gul Aodd (9.33 Rev 1:49 0 t .ol ) was p Walles Dz commencement number that p; 3 Dhireh Haoh He 0 was 0 o throughout the Night, Dsi; &amp; lt; Seoo (z as upper 1 .KMNO) Z KD only 6 Eladie. was my Akael loyalty for 00 td) 0 bit; Shell (200 j then termination Il archived cores (3 1.0 X g). name i Ds (100 {&amp; gt; then Tjibathaddam D4, do-Lord and RIA-in and i &amp; lt; g! Li birth JH t-around. Ed Aabt growth pains -6 Apedroadan (2500's) and then against 0! D -78 m Cam Laage ÜW 0.1 Sun. CJ; 0 0 waffle Warhol (14.6 t 0.204 0 over well), repent, a rad JèfN more existential (l 54 136 t Lala's) .11--: 1, Afghans degree Ararh by failing Az less 0 -70 n m. Has remained Akeayla No, 1.25 Z, ducks Dick was his permission for ED (00 of 70 of not 0 nly der. No decision; August 'was Askhala 0 Amehl 0 1 bit Lobel (3 * 1000 l) RTM Gail Altakisat Aalloah'lo Madhi (100 ml) was Tdjaaaha Sdam 4Mgso4 were Lord and summation jj and i 0 Gore 4 led 1 Atzqah curlers 0 Atogerav a [Od well as 0 h to 1 to get Ely 0 j 4: 6 g additional 0 n isomers of Esther most 0 Jamad 4-Herruki ~ 2.5 Dae-methyl-4 Barr 0 d for &amp; quot; ° -108- -108 -ΜΑ 33926Β1 Sichaelohecsav carboxylic (4.6 g, 16.1 ms 0 well) and parts is pure Tmt purified again Bkromato Graf flash for additional ethyl 0 acid 4-hydroxy -2.5-Dai crippling -4-Thazul -22 for-.sheclusan one of the carboxylic (84 . (- g (13.6 mmol) as oil Ed: 1 m color. 284,2: mS ESI: [Μ (HJ + ην. Pedometer, H 2: to essayed are Proceeds step, of 0.1 (3.84 g 4 8.54 mmol) in Dai crippling Formamed (33.5 ml) was added ^ Bromuscsmad (1.75 Jmm, 9.82 boiled mol) was flipping Aglul at 55 ° C for d hours. ci shop for Keriih Alsodioa (0.538 g, 4.27 mmol) in water (60 ml) Baltakit to Aichaal. .lkhalit were watered using IPL acetate (0 to 1.00) Gal was a T-organic water (1-00 X2 &amp; lt;,) 0 draw support Abjtah aquifers using ethyl acetate (d X 100 ml) was drying organic Altakamat Kiah using 1.MgSO, was nominated tendon Nisaha in the center of Verb 'Adan 1 to Ended by chromatograph flash to get a solid, where Shaa 4 Xamat, for Eser Eshel acid 4- (5-bromo-'yasul-2-l) - 4 ~ Head 1, Casey -2; Dai-5-methyl-Sichaelohecan Alkalpoxah (07. 0.1 g, 2.95 Haaa Mall) 0 262.1 MS ESI: [Μ] + m / z- a; pronation 0 Alobt 92: ethyl ester Homs 4- (5-woo 6 Abzul-2-l) -4-Probe 2, 3_daa Ez-Sichaelothan Kru ble g Mahlo: 15.6) for DMF ml) of Khlien 4: 6 of the two isomers of point asset acid 0 E. representation -4-Abasul- 2-Yale-Bkoyn Waller. Bo ble (1.2 g, 04.03 for in mol) Tmt adding 0.83) NBS g, 4.64 cellulitis Mall). The Tschenn fading: 109: 109ΜΑ 33926Β1 Alaatj to 55 0 C for one hour, and then was 0 Dhiradh to Dr..jh Hrar.h b Wat Adhatmh stamper of size 0 Tate sodium: Om (54 .. g., 4.27 Haley 0 RL) in pain 1 E (0? a year) - and then Z mixture Adam EtOAC layers were separated, player 1 Schas Adq of 0 \] \ 2 Astkhadd 13:00 EtOAC (χ2). AA has been laundering Lists 0 0 Rh layers 0 v 0 lysosome saline was 4 'B Baathaddam 4 ° MgS, and Done candidacy was 0 1 Rkizha in central Morg. Has Z instrument is one network Adembkromatogerav Anos prevail E 4 Z knock 4: 6 of only 0 Dzumrat AFP sa 6a 0 Ds 4. (05 Romu- Ebzul-2-R) -4-Bros -2.3 V-Day 0 Shell-Sklohxan carboxylic (700 mg, 1.93 Malash Mall) . Then 0 for washing Epeshkd largest Bo 1 middle SFC So.l OL? H.hly p 4- (5-Barr -basul -2-Yale) -4-00drod -3 E2-Dai Blkhaz a, t Dtefi Su 0 0 Q Oela. 1.1 p) HNMR (IMHz.CDCl3H7.51 (m. 2Η). 2.68 (q,. / R 4.5 Hz. IH). 2 .., 3 ta. ΙΗ) 02,25 ( "&amp; gt ;, IHl. 2.2. , &amp; lt; 6.7, 5.? .7., Lal Hz,. »0 I hope, for Aa.laa0.a 0 d, AAA 20 E 0.111), 1.22 ((7.5 0- for Hz. 3Η &amp; gt ;, 0.98 (6.7 0 E /. G Hz, 3Η), 0.75 (d. ./= 6.7 Hz. 3Η) a) Cup Alloshl 3: ;; and, At_2lal_4l (5-barrel 0 and 1 '3-Mazll-2-in-4-s Bro's 6-Day Bill Bklopkav; E 1 T. Khloh a: Temthae propane-2-6.2-Dub's Id-4-Olkmskloeks -2-Aiv-.1- 1358-1353, 0.3) 72.7 »AA 2) Sdenm Aso d Bapt must be 1 g · Al'bl &amp; quot; TS 0 d blooded 300) Ε.ΟΗ t). ! D Aill Alathgtetae g Let Salé Oouae 5% to 8 (a 0:00) Ralitmrjalla.ngtabold.pfiala 50 inches cemented p ω p after the deletion was Z.bh p; s g Lal without a land. T--110- -110-ΜΑ 33926Β1 using more EtOH, and then focus in the center of Morg and Tmt 'watered Bkougl 0 Atogerav Olosd for Ai Doaz -2 - but 2.6-Dai Hia 0 a - 4-Aorissowskrashal /boxlat(5.2 g, 24.5 Miss Maud). Etc. 4 Thoh 2: ease 0 SJ step 0.1, (5.2 g, 24.5 0 Ashe Mo.l) Astkhadd 13:00 50) THF t.) And has Ahavh Thea 1 Zeul (.2.63 ml, 36.7 touched Mall) to 0 'Nradonhlo, l-term to uh 7' em and it has intimidate 2.5) NBuLi Molar in Hicks, 10.3 ml, 25.7 0 Mo'l u) Z Eocgtal rate leads to keep Pas-jerk free; Rh father; cell count Ashe Q ~ 65 m. Humanitarian partners 5 gal addition, then-Zkhmtabeld; Ahabod Zzk been extinguished Eayhh Anatm 1U0, to Sal 1 ijf b. Has E0 state E.0AC, was p blight and sleep b Ψ August Sdam .MgSO, were sprayed 1 ha, and then rode in and i seen 4 0 Dtmt 105 yummiest Father one's mouth Bkougl.atomav Alohid for Haod. Roban.'2-Yale-4-Bdrl holistic 0 -6.2 0 Gal-Yi '&amp; quot ;. 4. (a 0.3-'bzul -2-Yale) 0 Bkloh that Rbotalat (1.4 4-7r 0 ms well) 'Khloh 3:! S Mahdo Mnzhaktoh 2 (4.a M' for in sales 04.7 &amp; gt; in .15) DMf m) has any, of 0.963) NBS a 5.4 m 0 0's in well) was! ~ *; ύ Airl Alag to 55 m. Om 60 days and then Te 0 0 No sales of E0 only stamper 2 g Chrit Akrdiom (500 mm) in Alaa (e 0 for 3) Tut lioness EIOAC. Sleep chuckled Latt 'father Das August Father Rey T. 1 long ElOAC been levied abused 1 T. Akh 1 termination asset only 8 Oua'h the growth Lord' and; / I Aotmg.kaa 0 the instrument vgi Lada 0 of HDL 0 Ato'aav toss Seoul Z Rowan-2-Yale-4- (5- Ross-a 0.3-.breaul'2-R) -4-Brommba -2 E 6 Dai b 0 2.76 for 00 ml / l) 375.9 M + H] m / z]. 111 ΜΑ 33926Β1 Z Alloshd 94; A_jubl (4 E) -4- (5-Ruhr -1 3-Iarell-2-l) for 4-Rod Azian-A- / to Oxlat; specified cj: I age coffee-4-! Off (40.0 m '2670 Lei Jy) at 320) [, CM t); ; Amos 01 yen (27.0 m 0.225 Lutfi Jy) Wei 0 d Zq s Zlolo 0 termination 0 H (0-88 f uh 4 must Maud) Ate Dam | m fu Ie replies 0 Ij fled d; .ez Arar; j 10-2000 d 0 DDS Z 0 night most S.nryibd Z (27.0 m 0.225 t mls &amp; gt; then 1 Jul 12 Id d after Zlav s I Akael Q 0 or a 42.1 a Hisha 0 AVI (180) and h £ 008 (250 in.) was Atdas less any Adam 1 c'.E (o ( Ehgha 0 l), Ra was Alhblh secret and has .nfd Bkll 0 Ads Admay it grew Z 10 Presentation b] -ao.vi4-Oyo! Ran- 1 Raeo White ϋ and 0.345, -23

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01131.tif" id="idf0059" />

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01132.tif" id="idf0060" />

5A step 2: ¥ Tharol (21.3 Jsam 0.250 Miss Maud) in 160) ΤΗΡ Do) to -70 m and after deletion Z DONC spyware 1 250 ,, &amp; gt; 100) Ν-BuLi 4 m any m 0 l) 0 Te z A knock one Ivyg Ha 1 Ahtaaz, heat 1 degree Rh counting -60; 1 'or Ash. The Z Allat Alag 0 0 45 b extend I

Temperature this topic after Maat and et 1 FH Product 1 to Step 1 (48.55 g 0.228 touched mol) in 50) THF ml) Bakqat 4 while keeping the temperature I 0-60 m- been d Aglul for a period of bunion and then has Whoosh 1 a bath? Cooling. Counting -20 m, Adahh 2 HCl for 0 and Lahr (4 A'a ml) and Atd a 5 heated to the point of free, Rh room was commuted Alakhlul Adhac Bastkhadd 13:00 EtOAC (150 ml) 0 Vsr 2 persons; t been Aschas Maya layer using 150) EtOAC Mullah 0 Antbqat organic been Gsaay females' Sdam, NaHCO Haah b (1.50 &amp; lt ;,), 6 for Hlha (50, e ml) and then knead the focus to the evil; b Aliz. This drink has Dissolve in 1.40) EtOAC 20 ΜΑ 33926Β1 Del &amp; gt; After y 7th Z together 4 using Mann (210 ml) and sleep Rchih grout to get an A-B 0 Tal4-Helros-4- (a 0.3-Thazola 2 Lille) Oztt_a- Druthsilatkmadq E b 0 members (68.0 g 0.220 Malai Mall) and then knead name subjecting the article to chromatograph Kiraly Dsod z Aso-sale (4 E) -4-proxy-4- (1.3-disappears-2-0l) Oz.bban-1-cr Boksilat (14:50 g, 48.6 Zi Mall) 0 step 3; d ed 1 by Zhaktoz 2 (14.5 g, 6.48 mmol) in 58) DMF t) After y 4 CJ Eaa 4 Bastkhadd'm 1.1.24) NBS g, 2.d 6 mmol) and Tmt Dvith to 40 a \ for 3 Oouana been put out interaction using the 1: 3.0) Na2so g; 24.30 Tiy 0 well) at 0 followed (50 ml) was then Osthas Aio's Blkhadd 13:00 100) EtOAC ml), was b Bmhao.l Tts (50 ml) and then has Amaagannh A'mutrrov and ; middle Z silica-0's Ely t-Bautaatl (4a) - 4- (5-Tm.ok-a 3-disappears-2-l) -4-leprosy Ozaan '&amp; quot; &amp; quot; a &amp; quot; &amp; quot;' / Boksilat (18.3 g 0.46 Lutfi Mall). 320 MS ESI: [M + HIuJ + É. Ashkb 0 Midfield 95: Abulss-4- (5-Ruhr-termination 3-Abzul -2 &amp; quot; i) -4 Brod Sichaelohecan Carr Bo Dblatt Alahtoh 1: d added a complex chloride Oazobrobaal Asom / chloride biomes (Wa Mulara 11.9 ml, 1, 54 Miss Mall) to the flask was cooled to small and after it was Ed Bastkhadd; m 50 folding THF. Led Ouaadanh seen, O.l (3/1/03 1:54 PM 7 Ao j-l) 0 Z de 30 to assure SA, temperature M'ntgeor 5 0 m. It has been spared mortar orange cities 45 bear Wad it 0 Buraydah (Li -20 m were added asset 4-Ootxosichaeloyn Kalpok 0 baskets (25.0, g, 1.47 mesh mol) in 25) THF ml) and then the name flipping births 0 A minutes. -113- 33926Β1 been cooling Agi, of the 17 o'clock and then been extinguished Bastkhadd; m 2) HCl Molar ,, 1000's) were extracted using 250) EOAC ml). The organic layer laundering Tstkhadd'm 6's; NaHCO saturated with water (100 ml), Mahi solution (1.00 ml), and was Boukerha Taqitha Bkromatogerav aluminous Boisaih Silica Gel for IPL 4-hydroxy-4- (1.3-Iyarol-2- l) cyclohexane Nbualat Nate (23.6 g 0.92 mmol) · 1 to step 2: has as one its Menth 1 Ahtoh 1. (23.5 blood 0.92 Miss RL) in 94) DMF 0 l) 9 Rbad knead processed using 19.66) NBS g 0.110 ms Hall) was carrying him i d i 3 free; Rh .lgervh for 10 hours. After that has been addressed 'reaction Bastkhadd 13:00 11.5.8) Na9so Ham 0.465 mmol) in 0¾ (1,50: ml) and then extracted using 100) EtOAc what,') 9 has oil purification Bkromato Graf flash by Gel Celica for Hsoo Z . Addl 4 (5 "Ror- 1; d-thiazole-2-Yale) -4-proxy Sichaelohecman Abodgelat Kz.lt (31 gm 0.77 mmol), where he was subjected to chromatograph Knrala for &amp; lt ;; Aathl Cisse-4- (5 -bromu, a- 0.3-thiazole-2-g) -4-Hedruki Skloh 1 Dan Sokelat as oil (5 kg. 0.33 Miss Mall). 333 MS ESI: [Μ + Η1 + ιη / ζ. 1 to compound the middle 96: 5- (5-bromo -1.3-Thasul -2-Yale) -5 Abros fizz-bin-2-on-1 Khloh: to Mohi-L x 8 - (0.1), 3-'basul- 2-Yale) a-. 4 Die 1 Ysdo [4 '5] Deccan-8; well (1.5.0. M, 62.2 Lutfi Jr) in 75) DMF t) de Ayaf NBS (6.9 m 0.55 Fly Jr) and has 0 p 0 Agd.l L 45 f Linda 8 0 came. P &amp; quot; Table 1 for Adele Tdenm; .3.9) Na; SO m 0.31 Lutfi S.l) in 1.50) HjO 0 l) was; y 0 h 1 to mortar-term ΜΑ 33926Β1 -14 A was washed with a 6 water (70 ml) for folding 8. (5 -domo- 1; 3-Iasul-2-0r) 1.4-Dai Ooxa Siro [4, A] Den-8-Ulke 0 solid white Adz (16.8 Jmm, 52.5 Maza »RL). Step 2: has thawed Step 1 product (0.d gm, 9:40 any mol) in n d 0 L x 1: 1 3) HCl; THF p) was Schanh at 50 ° C for 8 hours and has equivalent Alakhlul use 5 KHCCF solid After reminded added 100) EtOAC ml) and water (20 ml) for 0 Pei reminded layer was extracted using Maya 50) EtOAC ml) was j ;; J 1 was suspended organic data .mmahlol saline (50 ml) was vaporized into mortar Tmt Amaaljt. Ekanat (20 ml). Led filtration and unfortunately 4- (5-Romo -1.5-Izo.l -2 "humiliation) -4" Hdroxa Q 8 Maun as a solid white ( '- a -.2 Jmm, 7.7 Amos 0 Lee Mall) 0 0; 1 to step 3: ( for SJ .lhton 2 (10 36.2 f RO mol) in 00.0) THF &amp; lt ;,) s one night hydrochloride Hedrokciel Omsen (5.0 c 0 m, 72.4 0 Guy mol) in one of the water (7.0 &amp; lt; a) Uq E1 fiber 2) Na2co1 Molar, 36.2 Ml). Amehlol been stirring for 30 minutes ment has been heating up the Open Alamat a 7 1 Li 50 C for 8 hours and then Otaath his gold dust. Hand to Ollavh degree heat over 12 η to Mullah 0's and adding Ε.Ο; (240.0 ml). Walter led. Artemisia Anbthleee to get? 1 1 "(5; Romo -1.3-thiazole -.-- 2 Arpel) 4-Hebrod 0 J A: Bo) Saylohecsafull Zmadh white pouring (10.15 Jmm 0.5 Dmelli Ho.l). Step 4: suspended PM 0 Tj 1 to step 3 (310.0 34.3 0 Collapse Hall) in a 0 Sopetral (75.0 t) and after Dec. Tmt Add 37.2) TSCI 37.8 0 R Mall) 37.8 f 4.2) DABCOj 0 for in m 0 l), with Alakhgot temperature counted 20 use m bath Ilh no water. Was turning 20, one of the financial framework for a period of five and six that Ban has Asagh 0 humiliation (10.0 ml) for R.chih slurry was slowly d. It was

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01161.tif" id="idf0061" />

-115-. 1 ϋΛ

Washed Biina. Nrkiz been fluid and has Olmazh melt the remaining 1 to n etc. in 25) MeOH what. Filtration led to obtain 5- (5-bromo-A 0.3-thiazole-2-Yale) -5-Hedrokaaa Ozaan-2-en Kmazh white pouring (4.0 g Mjiah 0.23 mmol) as a solid white. : MS ESI .0M + H] + W ./ ': 29I |. Composite center 100: Methya (SIM) - 4-oxo-2- (propane-2-Yale) cyclohexane Zther Bo Xiadik one step -1-: name we want Methyzo.bzoubioterelosazat (7.20 gm, 49.9 Haaa mol) and sodium Mitobsid (0.896 gm , 4.14 mmol) to the small m. Tmt added methyl vinyl ketone (2 44 ml, 49.9 mmol) drip, and was made available to Mahlo heating for Nzjh to room temperature and was flipping for one hour at that temperature. It was added acetic acid (0.249 ml, 4.34 My Hall), followed by Bouklied of MeOH (6.75 t): 0 category (750 curlers liter), and in Akeaah solution of Pirollad.bn (0.349 in, 4.21 ms Maud) in acetic acid (09 and. 0 »for 0.9 d 0.5 mmol). Tmtschan output solutions until the temperature Alausza 6 (115 m) for two hours. 'Made available for interaction must be gold dust to the point of pain FH -Ρ saw him and was then Mkhvagh using 20 Bio and water. The separation of the layers were extracted using water barriers E Et '^ o (E X) fraternal visits. The organic layers Bhviv Amjmah using Na1S04 Nisaha was seen in the center of Morg for methyl-4-oxo -2- (Propane _al -2) -2-Schlohecs Aan- 1 &amp; quot; Therboxa (0 T. (5.1.1 g .52 well) Cosette smaller, where Astkhadd 1 Meh in his following Kte d, n Mziv of purification. ΜΑ 33926Β1 A 'for Step 2: has it; it proceeds 1 Ahtoh, the I (aa 0.5 g, 26.0 0 to Hall) in 80) Meoii ml). Added Al Palladium, carbon (0.416 0.391 f 0 to Mai Hall), were provided with a hydrogen balloon beaker. The additional 1 g beaker and has re - Balhedrojunn (χ3 &amp; gt; was Tkulaibh for 15 hours the trouble degree heat; Rh room. It was subsequently Alter.t-Ih 1 Kgael 0 n During Silajt and. Been pussy Silajt using EtOAC. The focus Output 1 Atrs in and i Hgr, 0 g purification led by Kroma'nogerav Alumige Boamth &amp; lt ;; Sai 1 (a small -5 a to EtOAC: Hecaah) to 1 to get Michel (CES) -4 A..otxo -2 - (Zupan ~ 2 Lille) Szawhdsa (a Kl.oxlat (2.63 gm, a 5%) Crete colorless Ofrn 0101: Michel 2.2-Dai ways 4 Ootxo'tklohishan / Boksilat ride the national has Wasa 0 of Sad.do T. (97-5 t '54' 'a 0 Lay 0 well)! Li della d Ad Z 30 for 0,; b; for 2.2 ..- Dae-i-4-Ootxotdan Drboksilat (2 c 0 m 0.86 5 [0 lymphoma. V d) 5Ej; j-513) BFj. 0 'for' 94. .1,1 0 Lenny to A.l) in -65-0) CH-CI t) and p; k Z 0-30 0 C for Maine. This is then put out with water and interaction. I am Si 1.0 c 1 6 saw him μ *. Is any 0 lattes Aat '0 cm - $), which would have been reminded in Hishl. &amp; Gt; Hl0 | ICDCI30i3., 7-3.57 (00.3HU.76 «l.; = ^ T Ha%) 12.9 Crete. 0.4Η), 2.61 (ddd.3.15,5.0.6 000 and AA Η), 2.55 - 2.27 (01, 4Η), 1.96 0 1.50 (m, 4Η &amp; gt; .0.95 (m, loomed) -117- -117- Waller | 7 33926Β1 Aakp Alobtoaa: Avl4- [5- (3 ~ {(, - Aotoca / Blzel) L4- (G ills 0 Gal) Eir.pelln -2-night ace-5-Shell each) -1.3-'bzul-2-I -4-Bros Sichaeloisan calc w 1 Bart

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01191.tif" id="idf0062" />

4 to asset-proxy-4- [5- (3.6.5 - {[4- (G. Hloromeshl &amp; gt; Peremaadin 2 Yale Omivo) tends) -. 1.3-Thiarol "two-Yale 0 Sichaelohec that Dr.bonsellat Nmthal 2 d; A 1 Jmm 00, 0:29 touching real) in 1.4) ml THF) s Anavh Dai -e-Baoukl Dai-carbonate (0.069 mg, 0.32 mmol), 4-Dai crippling Oaboubir.adan (4 ... 3 03 E 0 &amp; lt ;, mol), and &amp; quot; ethyl Secretary Ray (0.043 g, 0.43 mmol). · The absurdity Azdoel E 0 D 50 Am all night. Then we want to interact, and was' diluted Bdaa Krubthan was washed with water. Organic layer was extracted twice Okhr.ban Dai Kzroshan and Done Dh 1 Sqat membership, was Tjgeldh sulfate Asom, was' candidacy was focus. It was used Bkromatogerav purification by silica gel to Black ethyl 4- [5 - (3-g (a-Baotocs Carr Bo dL) to 4 "(G. Vrumakhl) Peremydr ~ 2-for; Omivo) -5" methyl Schell) A- , d-Iasul -2-night-4-hydroxy Sklohan Krboxlat (0.1.5 mg, 85½) conqueror). + MS ESI: [M + HJ 7.29 - 7.39, (5.5, 1Η), 7.78 (s. 1Η: for 0.5) of 8.81 (NMR (500 MHz, CDCI3 Lal .607.2 m / z (m. 17.27 only (d , t = 5.6. IH). 7.19 0, IH). 7.02. (s, JH), 4.31 -3.95 (m, 2Η), 2.64 -2.49 .118- .. ΜΑ 33926Β1

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01201.tif" id="idf0063" />

2.18 (m, a H), 2.13 - 1.87 (m. 6Η). 1.87 "1.74 (m. 114), 1..49 + =: t'hSYK Activity. (S, 9Η) 1 1.26-1.23 (m, 414) up with the typical for-2- [5- (3-bed -5 - {[4- (G 0 0 Lulu Gunn age-2-Joel

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01202.tif" id="idf0064" />

CH3 0 4 a ladder η30 \ | / 110

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01203.tif" id="idf0065" />

Has; Baz 0 rode .rabt 4 (100 mg, 0.297 touched 6 l) in 1. .5) THF 0 l) Ze! Li 496) LDA bedazzled 0 L, 0.892 0 any * Wal) 0 p 1 Fred.-Tireless - to 78 m z over 5 minutes, stirring. Leaving the interaction of Tguib what-a mixture of (3) Dguendh Wu together 0 Jtah Ba; Wilson (32.7 microseconds Carr, 0.446 mmol). After an hour and a birth, address Tmt Aitnfaal using a mixture of 5 ml saturated NH4CI and had the Altdvh to room temperature. Then Aschas mixture using EtOAC, then. Organic layer washing using, NaHCO saturated financial - has been for a mild organic layer using 1S04, Na Valley Water was nominated, and Done 0 Rkizi, grown 0 purified Bkromatogerav Alumigr for 2- [5- (3-H -5 - {[4- (&amp; quot; Ray Vrumethyl) Peremtin -2-Anabo) vessel) - 1, d-thiazole-2-SAL] propane 2 first (your responsibilities mg, 0.24 mmol of 0.81% Ka'zj) Crete Ed.bm color. .395.9 APCI: [M t Η1 + τη / ζ 7.92. (4.9. IH). 7.95 (s, IH = 's., ΪΗ NMR (509 MHz. DMSO- &amp; lt; J.6) δ 10.25 (s. 111). 8.83 (d ΜΑ 33926Β1 (s, ΙΗ) 1 7.45 (s' IH). 7.28 (d ../= 4.9, 1 H), 7.1,4 (s. EH). 6.03 (s, 1Η), 2.3.1 (s, 3Η). 1.5; (S '.-i - ++ = rhSYK 6. activity Η) a-A.5- (3-H_5 - {[4- (G Floro 0 Ety pyrimidine-2-.i 1 equalizer viable} &amp; gt; 3 Λ- 1 disappears -2-Yale Sichaelohecan Krbonetrella

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01211.tif" id="idf0066" />

1 Step 1: To Mahvol of Bklo.ven / Bossrid (0.913 4 8.36 hr Mehrl) in toluene (25 ml) Az lumpy m were added Pace (Ray methyl torrent) sodium father (yolk 4 well Arlar in THF; 1.0.0 ml, 10.0 t mol) was 0 y resulting mixture for a shiny one 10 Az torticollis Em. Then added 2 -.- Kaorotheiasul (1 g, 8.36 mmol) Bakkdt as a solution in toluene (0.5 ml) over a period of 5 abolished Degache led Cdi Ala'dh of a string of small m to room temperature over 16 hours. The suppression Khlied interaction using an aqueous Nttyci Mhbar (20 ml), was extracted using a 50x2) EtOAC ml). The g 0 Yale organic Atjiah classes saline solution (60 ml, Then dried (;, NuiSO), and, Tama Recommended RCA was 15 ^ Zaha under pressure Mkhiam 0 was purified substance remaining b ^ t and 0 Lato Jr. F Alamon Bo Asaih Celica (drain sequential cascade down 2% to .1.2% EtOAC in Hecanat) to Seoul on 1- (1, 3

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01212.tif" id="idf0067" />

-120- .. ΜΑ 33926Β1 10 15 thiazole-2-Yale) Sichaelohecsa 1 T. Carr Bo nitride (686 mg, 3.57 Miss Maude, 42.7% Dmaa &amp; quot; c) bent smaller colored baht hardening when persistence. 193 MS ESI: [M t Η1 + τη / ζ · Step 2: Added Ν &amp; quot; ... the righteousness and Momahbimid (3-D 0.0 Ham, 1.87 ms Merle) to the solution of Matj Alkhvioh 1 (300 mg, 1.56 Miss Mall) at 5) DMF ml) was stirred Khlien interaction Natb. Atd Khervh degree heat for two hours. Has added two rN and Mosksenemed (d 0.3 g, 1.87 mmol) over Ai Fterz swallow 23 hours weighbridges as well s ._, 0E1? Na-saturated water (1.0 ml). After Zlat was extracted using Akhlat 20 x2) EtOAC ml) was organic layers Othiah washing with a saline solution (50 ml), and. (* Na ^ was .hvifaa SO), was .trchihaa was seen Theisha under Satt discount. It was purified material remaining B-1 Dromatogerav inactivity Boisih Silisha (subordinate filter ranging from 7% to 60% EtOAC in Hecsalat) for 1-Z5-bromo -1.3-thiazole-2_al) C 1 Zloh 1 Dsan Trbonetrid (96 mg, 0.35 Miss Mall, 22.7 i / o Knath) Kz.b colored a 0 z baht. 272 Η] + ιη / ζ 0 MS ESI: [Μ. Step for: was developed LED-methyl-5- (4, 4 Ν-, d 0.5-Ttramethyl -1.3, 2. Oocassapourulan Dai-2-.bl) Ivel] -4- (Tri Vrumethyl) pyrimidine -2 -oman (compound mediator 3134 mg, d 0.3 over the Mall), passed Melt 1 to step 2 (96 mg 0.5 d 0.0 touching Mall), Drbo; s Ansariom (346 mg, 1.06 Miller Mall), 16.9) X-PH.S . P, 0.035 ms Mo.l) and 1: (1.6.2) PcÎ2 (dba Mahm, 0.01.8 mmol) in Norq been emptied R. purified using; Ν three times. The NZ p fleeing Dai or that (05.1 ml) and water (0.1.5 ml) by passing bubbles Ni and has hinted Alj Anayathma to the reaction vessel. Was flipping Khlien interaction output count of 100 m for 5 hours and then was Mhakifa using EtOAC (d ml) was washed with a saline solution (5 ml), and the blood dried (S04; Na), was nominated and focus under pressure roughened. Purification material grown 20

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01221.tif" id="idf0068" />

R. 0 121 ΜΑ 33926Β1 / () 60 to À) 7 Aaboqah Kromanogerav column Bo mode silica (Filter sequential steeply in Hecanat) to obtain the compound contained in the title (128 mg, 0.289 ms EtOAG MS ESI: [.Μ; - Η] + 1 ) 1. /: 444.1. 1η NMR (500 .mod 0.82% Kach) Krgoh slash egg MHz. CD3-OD) δ 8.72 (ci ,;, 5.0 = for H). 8.06 (bs. IH). 8.00 (s, 1Η). 7.48 (bs, IH), 7.16 (bs. IH), 7..14 (, 1, .7 = 4.9, IH », 2.41-2.37 (m, 5Η), 2.06-2.00 (m. 2Η), 1.94- 1.89 (m. 2Η),. , + = rhSYK 1.7.3-1.85. Activity (m. 311), 1.40 ( m. liï) example 2 1 (d 5 - {[4- (Ray Vrumethyl) Beramaidin 2 Yale) Abu) Fajl) a, d ~ Bzul -2-Ysklohhassan calc Named 0 LED. "to her guardian disobeys Khbahl g 1-L5- (3-d-5- {L4- (Qroa Vrumethyl) Peremidtn &amp; quot; 2 &amp; quot; Fa Yale) a-, 3. Thiarol -2 - Alosakauten Kr.bosr, for (45 Sa, is 0 H 0 Lumley NaOHj (, (Amolar in 0.5, MeOH d, 0.50 Haley Mall) I 00; m in Aroov for 1.6 d been Aihal .halit to 1 to No. 1 Pedros - 3 1 Baz spyware 1.0) HCl in Η6ο) after Zlktemtdz, Te Z 5) EtOAC ml &amp; gt; Waddell 0 Agee (5 &amp; lt;,) 0 was Dr. Ed priority, and section 4 Hgha (..NaSO), was nominated. It has removed the cattle and has Q-s ci Satt Shii 0 0

0 j 1 Article 1 the rest of the Po 1 Plan HPLC (Thaah 0 Ibaah a gradient of 40% to 1.00 to CHjCN 33926Β1 ΜΑ 20 Nqiqh 0.20 ml / Nqiqh) For Anrkp contained in the title, TFA% 0.1 a η2ο in 4.0 mg; 8.67 microseconds Mall, 8.5% Katj) would solid white 0) MS ESI: [Μ + Η] + m / z 462.1. ; {-. [. NMR (5 () 0 MHz, USO-dô) δ 1. (), 25 (s. .1.1 ... 1), 8.83 (d., / = 5.3, 1 H), 7.97 (s, 2Η). 7.46 (bs. ITT), 7.28 5.2 = R.ha. ITT), 7.20 (bs, III), 7.15 (bs, 2H), = rhSYK 5, 0.1) 2.24-2.31. Nthat Η), 2.00-1.94 (m. 21..1), 1..51-1.41 (m, 5Η), Ι..33 (m, 111) 0 3 under acid (one of 0.4 does not) -4-Methoxi 2, 2-d; j ~ crippling 4- [5- (3 ~ crippling -5 - {[4 ~ (Ray Vrumed seeding, Eadan-2-Willie Omaio) Fenin-a 0.3 Ataz 0 -2 well-Yale Sklohan

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01241.tif" id="idf0069" />

1 to step 0.1: was cooled string of methyl Bs ~ 4- (5-Rorla 1.3: Zu &amp; quot; 1 2 dl) Adrellxla 0 Keller 0 Klaan Eidak -4 (6 for 4 Bhm 0.95 a 0 for 0 DVI 0 well &amp; gt; d Ewdl_bd (112 A3, 1.792 0 for in Hall) s 5500) DMF book,) to p 0 m were spotted 0 Atga Ldz 10. Dvazq 0 must Zivnmt; U »Sado Idalmodlom (47.8 b 5 and A.ams Offer no) would have been ΜΑ 33926Β1 -1.23- aging Altvaaa .. when Cefram for 5 minutes before heating Dr.jh to room temperature 0 z Acar at room temperature for a period of seeking. The reaction was cooled to entwine m was Akhmaze Bmithalol. Tmt mixture heated another kitten to the point of free Wara Angervh, was mixed with water, was extracted using χ3) CH1CI1 &amp; gt; 0 resulted in drying organic layers Athiah under the pressure of Mkhid and purification column Krohatogerav by Gel Celica (Sgrl 100 (EtOAC A: Hecanat) the To get Mabel By_4- (5-Romo -1.3-disappears-2-Yale) -4-Sthokssioh 1 Dsan each Ksilat (3.6 mg 0.71%) White Adbm color. a 330 ESI: [M + Η- McOII | i ηι / ζ 332. Kto.h 2: been removed gases from the 5, 5, 4, 4) -5 - ^ - 3] -ν- Ttramethyl -1.3, 2-an intelligent Ooxa Bourulan -2-ball) tends] -4- (Tri Vrumethyl) Berimidzn-2-Q (compound mediator 3.320 mg, 0.845 Multi Mall), proceeds one step A. (306 mg, 0.845 mmol), Kalpohat 'Nsodiom (845 curlers in ,, 1.680 over mol) in 2-Maial 5631) in THF Akro) cleansing using AR for 5 minutes. Added 1; 34.5) PdCl2 (dppf) -CIi6Cl mg, 0.042 mmol) and has increased the degree of Ahar.arh to 85 m. The aging interaction p-y 5 Aat. Then mixing interaction 1 Mlyz with water and then extracted using χ3) CH2CI2) 0 0 TAT has been drying qat organic Mokhtny under pressure. You Almtaatar purification. Crude column each Matogerav Boisatth grandfather Saaaka (small -100% EtOAC: Hecsanat) to get Bethel (4- (r4, s1- any -2-E2 Butd Dai-4- [5- (3-Bethel-5- {[4 - (Tri Vrumethyl) pyrimidine -2 .- 'Alaobd fled a) - 1.3-Vizul -2-Yale Sakloman all Boksilat (1.56 mg, 2%) Clenching At Ed, including color. 535 MS ESI: JM t Η | + m / z. --- 124- --- 124-ΜΑ 33926Β1 added Hedr.o Vsad Albu &amp; quot; Asom in Mbutanol () (0.3 ml) (0.3 mmol) to cJ product: Alkhaloh d 110 Alahtoh 2 (e 50 mg, 0.23 mmol) the reaction mixture was heated to 17:00 for 2 p 0 in Ta-a) 0 candidacy) HCl Saah- was cooled and the reaction mixture. After that then extinguished using Ahaliad WPM washed using the &amp; quot; 20 ml of water to obtain a solid slash Baai 0. -g Tjiv solid material under pressure Mkhid at 40 m in the oven to spawn-of 1.5 hours for ESI: [M 0 Η] + m / z 521. .almr cap contained in the title (95 mg 0.79%) as a yellow solid iHNMR (50. Mil /. ​​DMSO-de) δ 1,2.1.5 - 11.94 (m) 1,1-1). 1,0.26 (s. 1Η) 1 8.85 (d.4.9 = t, IH), 8.00 (s, 111). 7.96 (s, III), 7.45 (s, III), 7.28 (d.., 7 = 4.9, III), 7.16 (s, 3.07. (11; (s. 311), 2.31 (s. 311). 2.22 - 2.09 (m, 2Η), 1.99--1, .80 (; Ώ1 3Η). 1.72 (d, .7 = 14.5, l, H) 1, 1.62 (^ s. &amp; quot; 0 &amp; quot; ++ = rhSYK 1.07 . (111. Chatt (s, 311) .1.01 (s, 3Η) were prepared the following compounds in a manner corresponding to .bm your statement for the compound Algons 1. del Olasr in this table and all of the following tables without chemical characteristics of spatial explicit Mshalh (Mallqh a 0 Seah ) either isomers horny da 0 T. unknown design or 0 Ayal p isomers. indicate chemical signals Algrageh relative (Cisse or SAR) Ai Arqh August respectively. CIP Duah Alaspdal Almazerh highest priority 4b / 4c a 4 y Abf Haddou 4 125 - 3 ΜΑ 33926Β1

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01271.tif" id="idf0070" />

Alabmo; e A.z.a 0 a 1; for Ahgl Ntna i rhSYK R3 ^ 00! For example a base free 407.1 | a Ilf 'I 1-OH-c-Bu CH3 4 does not base - 421.3 of 0 of-a-b 1 .OH-2. CH3-c.Pen H 4 b - ^ Las 474.2 tt l-OH-2- (CH2CH2CN) -c-Hex H 4 n - 9 Hadd free 5.35 ++ - 1-- E ' "M'0 &amp; quot; CH3 - ί 4 Aa 0 p 0 No 4 came 'first

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01272.tif" id="idf0071" />

4 --126- 4 ​​--126- 1 33926Β1

Ri

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01281.tif" id="idf0072" />

NH R3

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01282.tif" id="idf0073" />

(Photos) [Μ + Η] 1 for observant activity rhSYK r3 / r4 X Ri example H = R2 435.1 ++ base. + Η / Η CH2CH2 CF3 4 c Ham 7 e A- CH3 = R2 TF A 410.3 ..1 salt ..... 0.1 ..... ..- 1 (Cisse) h / ch1nh2 CH 1 CH3 4 c 2- FFA .xu 410.2 ttt (g z) HCHNHi CR (31:13? 4 - 9 Q, +++ r * 4 * 464.2 H / CH2NH2;: CH CF 3 C

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01283.tif" id="idf0074" />

-127- ΜΑ 33926Β1 -127-

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01291.tif" id="idf0075" />

TFA salt II 4- TFA b 478.2 00; 00-0090 A_ H / CH2CH6 | CH CF3 4 c. 5 Fa several 465.2 +++ (RSS) H / CH20H ch2? .CF 4 c burning 6 "base 465.2 g +; FFCHOH CH6? CF 4 jib 7_ s 1 Edh 465.2 - + - (- 1 (Cisse) H / CiTOH C1F.Î? CF; 4 P nr w free 8. Qaylh 411.2 BP 00 b Η / € Η6ΟΗ CH Cït 4 c 0 free 5 9 .....,. TFA salt 0, (a 44 NH9 / C02H CH? CH 4 c 1.0- TFA salt 453 , 1 -Ι - Ι - Ι- isomer) CH3 / CH2CO2H CH? CH 4 c A) a- 1 TFA salt 453.1. ++ T CHC02H /? CH (isomer CH? CH 4 C &amp; lt; 2 -2 a 128- ΜΑ 33926Β1 128-

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01301.tif" id="idf0076" />

Sulk base of 0.493 (season) H / CH2CO2H ch2. CF3 4 c -...- 493.1 14 Base ..0b00..alal 0 ;;;;;; (^^) H / CH, _C02H CH: CF3 4 c &amp; quot; 15 -....- Someone 0 y 481.1 .e 0 of 0 &amp; quot; 0 0 a. E. H / CO2CH3 (PR-Î) CH CH3 τ4 1.4 free 7. For the leader of 597.1. ;; HH (C02Et) CH CF3 r 4 t; 507.3 21- TFA Hah 507.1 BPB H / H (1R13S) (CH3) C CF3 4 c (CH: CC &amp; gt; 2H) 22 .. TFA salt 507.1 ..0a "0.1 e Η / Η (1 R, 3 R) (CH3) c CF3 4 c (C.H2CO2H) 23- 535 base, () H / CO2CH3 (PR-Î) CH CF'3 4 c free 25 "TFA 535.2 H / CH2C salt (CH3) 2C02H CH: CF3 4 c 26" xU 0 0 a PL 478 +++ I4 / N (CH3) 2 CH: CF'3 r 4-in capital; 33. 129. c 0 for d

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01311.tif" id="idf0077" />

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01312.tif" id="idf0078" />

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01313.tif" id="idf0079" />

33926Β1 1 Olsourd [Μ + Η] Niat Z X 1 Rl (for example (pictures).; Noticeable rhSYK lead 5 A .464 _; 000; -; C0) CH3 CH6 H? CF Ha- &amp; lt; 1 a base 494.1 C ( ) 2Bt CH.2 H? CF Add- 2: tell promise E. .464 Î-Pr CH? H CF'3 4 d ~ 3 526.1 free base ftt C (0) Ph CH? H CF3 4

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01314.tif" id="idf0080" />

.-130- ΜΑ 33926Β1 M-H 410.2 4. Base Ι-Ι (290 loomed (CH3 CH3 4 are free Allaktam d) 1.11 ,. 9 ml 1. 550.1 +++ C (0) (CH2) 3C02H CHo CH3 CF3 4 d 6 Formant - Base;, 594 ++ C02C (CH3) 3 CH (C52CH3) CH3 CF3 4 d free 7. Hazh 604.1. ++ C02C (CH3) 3 CH (CF3) (5143 CF3 e d free example 7 4-H 0 Droxa-4- [ 5 ~ (3-Shell-5- {for 4 - (&amp; quot; Ray Vrumbuthail) and Rbmides 2 Yale Ahpo, a Ivel) -1, d-Thazul-2-Z Sichaelohecsarn

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01321.tif" id="idf0081" />

N

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01322.tif" id="idf0082" />

0 5 0 L Mahlo. For the reinforcement of the 8-L5- (3-0hl -5 - {[4- (Tri Vrumicl &amp; gt; Berimid: N 2: L Abu) Phil) -1.3-'basul-2-Z-termination 4-Dai ! Wesa 4 's;' - one hand -08 LDL &amp; lt; Yum prepared Bareina Azar 0; j see fulfilled the vessels Adrds 1785 were 0.9 s for 0-for in real 0 &amp; gt; at

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01323.tif" id="idf0083" />

ΜΑ 33926Β1 .Hf ... (c g) whatever has 1 5.3, m6) HCl for 0.32 sniff. Medal) and'rli Adiel 1, k 0 6 0 loyalties. Name; Yum 1 for Aahpd.aly A; then Cyrus 8 Dubai opportunities vu I 'the growth Attalla 0 T. burden 0 Yat Ebel (3 X), then Cover Ed; E annual data Mjk; Polat repel-Rum 0 any b was drying solutions using Na2S04, was Rhhhae was Re .nmt Pugh and the 5 &amp; gt; 1 dead 0 Graf blinking for 4-Hydro de ~ 4-y 5 (3-Bethel-5- (L4- (Ray Vrumthel) '6 Kaivel) A- 0.3 female 0 Azul -2-Iblosadhan (625 Cilam, 1.39 mmol) white Krgoh ., MHz () APCI: [M + H] + m / z 449.1. lH NMR (60 7.06. (11-1 .CDCl3) S8.64 id, ./=4.9, 111), 7.9 () (s. IH). 7.86 (s, 1.14), 7.46 (s, IH), 7.26 (s 4.9, 1Η), 2-92 - 2.82 (m, 241), 2.49 - 2.29 (m. 611). 2.38 (s, 3Η ): for .s. 141), 7. (.) 4 (d).

A Nthat 0 + 44 = rhSYK example 8 (a) and 8 (2) R- 1- [5- (3-methyl-5-g [4- (Ray Florobesc) Ber.bmaidin "2-.bl; Obdhu; Ivel) - a, d-thiazole-2-El; Sichaelohecan- a 0.4-Daewoo. Mad-1's [5- (3-D-5-g [4-dray Ioros Daan-2-Anobo} Ivel) -. A, 15 3 &amp; quot; &amp; quot; 'Basul' - '2 - &amp; quot; for; cyclo, hexane-A 0.4-Maaol

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01331.tif" id="idf0084" />

-132. ΜΑ 33926Β1 to and P p 4 Madrokhli-4- [5- (3-0gl-5- {To Do &amp; lt; Ray Idrl 0 GLA A2_ai Apr; b 0 l) Aae 3-Ivol -2-Ilalalatmn (l 0 Ha mm, Qo and and Th.ro) in 11) ΜΛΗ t) Z applicat Sdsdr; d Alhudyrm (63.3 was' 72. [0 Wafi Mall) counting -20 0 0 t m were bugs, but I dela 20. S to any Ed 0 then Adtha 01 .. Ed Ali 0 Ottaghpf ύψ sales, AP and then Rchilla, Enm 0 A, and has is 0 Obkdadalalal Z SYS-1-L5- (3-Mhl- 5 - {[4- (Tri Ellowomakhl); o 0 -2 conduit 3, If-0 Bdhul-2-I 8 Id -1 E 4 Maaol (250 pp ,, 0.56 Malash Mall). m / z of &amp; quot; [aA 0 ΛΡΟΙ: [Μ s; 45 7, (4.9. JH), 7.89 .. .... 7.79 (m. 2Η: for, 1. 1.Η NMR (600 MHz, CDCI3) δ 8.63 (d.; 45 a H), 7.36 (S, 1Η) 1 7.06 (s. 1Η) 1 7.02 (d, 4.9. JH). 3.81 -. 3.72 (m, 2.98 a (not 1 (s, 1Η) + f + = rhSYK 2.37. Activity (s, 3Η), 2.11-1.72, Ras-1- [5- (3 -bal-5- {4 - (? Ray Vrubuthail) Peremeds -2-Iobo) Ivel) a- APCJ: [Μ + (3 ~ Bzul -2-Alosklohkan -1.4-Diol (40 mg, 9..0 mmol Η] + m / z 451.1. lH NMR (600 MHz, CDC3;) δ 8.63 (d,. / :: 4.9, 1Η), 7.88 - 7.79 (m, 2Η). 7.46 (s, 1Η). 7.2 '7 (s, 1Η). 7.06 (s, IH), 7.02, (6..7 = 4.9, JH), 3.67 (1..7 = 6.3,; H), 3.56 (m. +++ - rhSYK 1. Activity Η), 2,43 - 1.62 (m, 8Η), 2.37 (s. 3Η) was Thanir compounds in the table (s) Intalla Mphazerh manner to those described in a perfect 8 (1) / 8 (2): table 8 ΜΑ 33926Β1

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01351.tif" id="idf0085" />

Image + Μ + Η1; Activity R4 / R4a R ^ R; R Example (photos) 1 observant rhSYK Hadn free 479.1 H / 0H (1S, 4R) CH3 / CH3 cf3 8 A-6 free base 479.1 ;;; H / 0H (IR04S ) CH3 / CH3 cf3 7-Î8 table 8 for the image [Μ + Ή] +0 rhSYK Ntha R i «Thal (photos) Almalahz Commander 5 477.1 0.0) 00.00) 00000) is 0.0 to 8-E free

R

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01352.tif" id="idf0086" />

-134- 33926Β1 free base 479.1 0.0 g 0000 g -00-b g 0 0 0 0 A0..0aa. Aa.a H3C \? H3pH (Azd O.bzumrat 8 B.2 Brau.ld) 8 B.3 such as 9 (1) and 9 (2) -1 compromise -methel-4- [5- (3-Bill -5 - {[ 4. (G. Vrumethyl) Berimid-Q-2-Aloopto tends}) - 1, d-thiazole-2-Yale; Saakhluhecsan -1.4-Diol SES-1-Shell-4- [5- (3-Shell -5 - {[4- (G. Vrumethyl) Ber.bmad.rl 2 Lil Abu} Phil) a- 0.3-Thborol-2-L Sichaelohecsan-, 1, 4. Diol

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01361.tif" id="idf0087" />

Me Me Mguetb to a solution of 4-Hedrora-4-Ld- (3-Bill-5-g [4- (G. Vrumethyl) pyrimidine-2-g] Obdhu; 'segregation) A- 0.3-disappears-2-0y Sichaelohecsanon (104 mg, 0.232 t Maud) in 4) for THF 0) 0 grown Ife 0.464, μ3.0) MeMgci t, 1.39 mmol) at small m. The Baalib commentator orange Alnatir, for an hour »one Andsgr m, and has been processed was free t hand Amu Neum aqueous anthropomorphic ,, and Bam deduced Bositat ethyl (3 X). Bam Bhviv Bacillus classes Amjiah using ^ Na ^ so, »she was nominated, and was concentrated in the center of seductive 6. You pious Bromatogerav flash to get; 135- 135-ΜΑ 33926Β1 {b; Dhar-a-methyl-4 ~ L5- (E-Shell-5-Zl4- (Ray Vrubuthail) Seaan "2: L Abu-1, A-Parul-2-L Sakulovn - 1.4-Diol d 6 Bhm, 0.013 mmol) _ (\:} APCI: [M Rala; m / 2 465.1. 1Η NMR (, 60 () MHz. DMS0-d6) as poured illuminated. 10.22 (e 5111 ) .8.81 (0..2-4.9.11-1) 7.92 7.90 a 1! any (S, 1Η). 7.43 (s, 111). 7.25 (11: 1 .4.9-R.l), 7-1.2 (S, 1Η), 5.74 (s. 11-1), 4.03 (S, 1Η), 2.29 (s, 3Η), 2.21 (td, .7 = 3.9. 1,3.3. 2Η1. 1.7.1 - (+ ++ = 1'hSYK.0 activity l, -36 (rn. 6Η), l.lo (s, 3H) Sas- 1. Hishal - 4-A5- (3-Bill-5-g [4-- ( 'Bai Floromeshl) pyrimidine-2-Ioda YNP.) - 1.3-disappears-2-L Sklohan-a 0.4-d; real (23 Mahm, 0.050 mmol) ΛΡ (' 1: [M + 11 ] + m / 2 465.1 .. 1II NMR (500 MHz, DMS.-dô) δ 1.0.25 .kzi Adbm color of 1) ΙΗ). 8.83 (d. .7 = 4.8. ΙΗ01 7.94 (s, a H), 7.92 (s. Ill), 7.45 (s. 1Η) 1 7.27 (d., 7 = 4.9. 1Η),. +++ =, 'hSYK 7.13. Nthat (s. 1Η), 2.31 (s, 3Η). 1.96 1.40 (m, 8Η11.13 (s, 3H) Thal 10 5-Hadrkba-5- [5- (3-d -5 - {[4- (G. Vrumitnl) Sddn 2 Yale-Aohjo; Vnl) - 0.1, 3 Ebzul -2-Nziav-2-en

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01371.tif" id="idf0088" />

Soha Hat was 0 n 8. [5- (3-every-5-A [4-6raa to Alla -0 Yale) Be'adln 0 &amp; quot; &amp; quot; 2 ~ None: b) Phil) -1.3-Basul-2: G ] A. 0.4-Dai a, 'da 0 to that point [4; 5] d: Hgan 8 a 136- .. ΜΑ 33926Β1 (60 mg, 0.122 Miss Maud), more than 0 to sodium (23.76 mg, 0.365 touched mol) and acid Butaz 0 folks ( 95 curlers liter, 462..1 Q mol) in 3;: 1.2) chc 0 l) at 65 ° C for an hour and any 0 e was cooled to room temperature. Has ».aaljh Alkhaliz with water, and then ethyl Astkhalas Pasiat. Friday was Khgev organic layers, was nominated, and their focus, have been purified Bkromatogerav Alus to get 5-hydroxy-5-L5- (3-sale -5 - {[4- (an intelligent Vrumethyl) Peremedan -2-Yi Ominoo Ivel) -1 0.3-Ttasul -2-Sozaan -2-Aven (36 mg, 0.078 Malash Mall). Of: (3; 1 NMR (600 MHz. CDC; a .464.2: / 111; [APCI: [Μ + H 7 = 4.0. 1Ι-Ι), 7.80 (s, 1.1-1), 7.83 (s, 1.1 -1), 7.62 (s. Ill), 7.26 (s, 11-1.), 7.05 (s. Ill) ,, the &amp; gt;) 8.63 2.41,; 211, 3.46 (s, 111), 3.21 - 3.03 ( m.; 111 .7.03 (d. .7 = 4.0, 111), 6.21 (s. Ill), 3.81 (s; '1-31, dd. ..7 = 7.5, 14.4, 1.1-1), 2.37 ( s, -311), 2.24 (t .7 = .13.3, 11-1.), 2..18 2.04 (m). Activity rhSYK = +++ been Mahathir knees Altanih base jib Boutragh analogous to alpine Tak in example 10; 0 table E.

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01381.tif" id="idf0089" />

+ M + HJ; rhSYK Nthat R1 example .- .. 137- ΜΑ 33926Β1 noticeable 426.2 OCH.3 1 -If -11 'Izz al-d 1 to Michakln 1 &amp; amp; 2) 438.2 2 (CH (CH3 (nm isolation 0 V) ​​0 aa -2 &amp; amp; - 0 aa -3 Example 4 A A 4 A [(hydroxy Estelle &amp; gt; Emu] -1- [5- (3 0 Etel 5-g [4- (Ray Vrumitdl) ; Blaine -2 for Ale amino) phenyl) ...... 1.3-disappears-2-Yale cyclohexane / Boxamad

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01391.tif" id="idf0090" />

Insisted 0 Tz 1: 1 Li solution of Neutral 0.4-or Nssowsklohan Nrboksilat (5:03 40.6 - Hlumbly Maud) at Bryn (20 mL &amp; gt; has DONC 1 groan A.atept Gela Akol (2.83 0's, 50.8 Z Mall) and Dr. sulfuric catalytic (772 mg, 4.1 mmol) and then Ar.ja.a 1 mixture under NRC Dean 4 Stark of 1.8 hours. the mixture was cooled to 23 m, and was diluted Mthaddam NaHC03 0 radioactive Iea (0 for 85) was 1 Tys Basthdom 75 χ2) EtOAC ml). The dried layer Aamo.bh b-M Na2S04, was nominated and focus and. It was purified raw Olmenth 0 n through / and Hatogeral one a black Alubma to get,! ,, 4-Dai Ooybiro | 4, 5 Adhikan -8-Krrdz -138- -138-ΜΑ 33926Β1 (6.15 gm, 34.9 mmol, 86% as the product) as oil colorless color 0,1: 1 NMR (50 () MHz '. (3.85-3.3.80 (m, 4Η), 2.61-2.55 (ill, JH), 1.90-1.77 (m, 4Η), 1.75-1. () 9 (m. 2Η of: (CDC13 (111,214) 56-1.48! Kz 0 of 2: Aly Mahvol of, 1, 4 ~ Dai Aoxa Siro [4.5] Dhikanl 08 Krbucl (3 r 17.9 touched mol) in Dhu.n Z 0, I (95 ml &amp; gt; response 05 &amp; lt; m; s added 0:00 (Ray 0.0 Ethel descendant) amide .lsodiom (1 Molar in Tolo.n, 5..21 0's, 21:50 Q Hall). name Cvaz Bamehlol orange voter at &amp; lt; C for an hour and a birth ; Say entry &amp; lt; 2's are "Klor.utrayasul (2.1.4 g, 7.9-1 mmol) in 'religion and my loyalty is 0 (10 t) are through i Paula. lotion available to dark brown Almtakk Okdvih slowly to 23 over Al am 1 0.6 worsened 0 ease Alnnfaal using NH-4C1 saturated Mani (160 ml) and then extracted using EtOAC (80x2 ml). the Gsaay organic layers Amgesah saline solution (100 ml), was dried using Na2S.il, it was nominated and Turkerha in central &amp; lt ; g. has crude oil purification Khalal Theromatogerav Alumini column (of 0; 8; 100 (Li H 1 days to 80: 20 Hicks: EtOAC) for 8 (a 0.3-thiazole-2-l) - 1.4 V-Day or Isaspiroa 4.5] d &amp; lt; k-8-Krbonetrid (78, 1 g, 6.74 Miss Mall, 37.5½) Ko'zj) as 0 Dazh solid Mzgbh 1 m lest the Kad 0 3.2, MS ESI: 1Μ + Η1 + m / z 251.1.'H NMR (500 MHz, CDCI.3): δ 7.70 (d, IH of 211, Hz), 7.35 (d, 111.,. 7 = 3.5 Hz). 4.01, -3.95 (m, 41.-1 '), 2.44-2.3,1 (m, 4Η). 2.09-2.0.3 (m (214, 1.89-1.86 (m. Ataktoh and: To a solution of 8- (1.3-disappears-2-SAL) -1.4 "Dai Oyo [4; 5] Dhikan- 8-Krposr 0 for (78, 1 g, 0.1., 7.1 mmol) in DMF Pollack Mani (25 ml) was added not-Brumusksivimid (1.52 g, 8.53 Mall Miss.) was heated at 50 1 Nhlol Em -139- -. -139 -. ΜΑ 33926Β1 for worsened 1 n. was cooled 0 to Tagael to 023 Mopad Zlktmqgbgh to Adeddam 03 Ta Wahab b (75 D) were Atkhalab using 30 * 2) EtOAC at the individual &amp; gt; 0 nm μ Almqat August Et Bmtoul p (0.15 ml ), was Tjg 0 Gha Bamd 13:00 04 Hta, was Tr.b was Turkerha. was purified 1 oil) for the smallest 0.1 ore through Krolaorac August land Ath 4 Guet% 100 Hicks to 60: 40 Hicks: EtOAC), for Waddell &amp; lt ;, 8- (5 Ebromu: for, d-thiazole-2-l) -1.4 Dai-Aoxaspiro [4.5] Diclla 1 Krbosel (1.43 3

3 a 0.4 Miller Maud, Katj of 5%) as pouring Oilmh to Bayas 0 .331.1 + MS ESI: [M + HJ -2.07. (414 H), 4.61.-3.93 (m. 414), 2.39.2.26 (m;, δ 7.66 (s :(? 'NMR (5 () () MHz, CDCl loyalty (2.01 (m, 2Η), 1.88.1.86 (m.2H. step 4: and adding ^ for 3-like-5- (4.4, 5.5-Ttrashl-1, d 0.2 "Dai Ooyaourulan -2-Yale) Fajn-4-Dtraj Ioromithil) Peer-Mmedan 2 S &amp; lt; approaches 0 1 f 4.22 over Maud), 8. (5-bromo-a, 3-pass away &amp; quot; 2 ~ humiliation) -1; 4-Dai Ooysrol 4.5;, 4.22 Hlleguel) E rolls righteousness; Om (4.12 ppm, 12.6 Miss Maud), 193) Pd05fc mg, 0.21 Miss Loro of 40; a &amp; lt; uh ( 201 b 0.42 mmol) to the flask Mjnf me, .zal Alokd was Akkhvev to Adam 4 a &amp; quot; Dai a first Ir Hani (15 g) intercourse (5. a year). the dark thread Ala'zj heated to 100 ° C for 5 Saoua 0 v. It was commuted thread 1 Tagael Bastkhadd 13:00 a: Old is 0 At saturated: μ solution (100 D) and then 1 Stkhalab Bastkhadd 13:00 85 x2) EtOAC &amp; lt;,) 0 is b 1 Guet 1 Akhuyq Bastkhadd 13:00 Na2S04, was seen 0 Tahaa and focus 0 Tmt purification Alenet Alor- A'da u crude p 0 n during Romdv 1 column Alo, Mud (8102: 100½) chill to 60: 40 &amp; lt;: EtOAC) b was Maud folding 8- | 5- (3-crippling -5-not 4 ~ (Tri Vrumethyl) Berimiddn 2 Yale Abu} - 14 .. -14..Μα 33926Β1

VPL) -1.3-Rasul-2-Yale -1 E 4-Dai Ooxaspiro [4.5] Dlkan 8 / Bossril (1.77 g, 3.35 mmol, 79% Kath) as pouring slash whiteness. n] &amp; quot; f; MS ESI: [M 4.9 Hz). 8.93 (s. = T, 11.1, (s, HI), 9.65 (cl, 1H of: (ηι / ζ 5 () 2.1. 'HNMR (5.0 MHz. CD3OD. (4Η AA 1a) 4.72-4.73, (8.30 ( s, 1.1-.1), 8.10 (d, 1.Η,. /: 4.9 Hz), 8. () 2 (s, 1Η 1 (IH). 8.83 (s, 1Η 5 (411 .3.21-3.18 ( m, 2Η), 3..13 (s, 3Η), 3.01-2.97 (m, 211), 2.69-2.61 (m. Ndat rhSYK 5 step 5: to a solution of 8- [5- (-5 3-0atel - {[4- (Tri Floro 0.0 paralyzes) Bear 0 Edan -2 for the night] Abu; Ivel) -1.3-Trol-2-L - termination 4-Dai Ooxa, du [4 of 5] DD -8 a Krbunttre (250 ppm, 0.50 mmol) in DMSO z. Danny (4 mL) DOCUMENTS Ahavh Abomat 10 potassium (172 mg, 0 25..1 Treat well) and above any Alheidrojn (2180 Kro Carr;

2.49 mmol &amp; quot;). Was flipping Amehlol output at 70 m births 1.5 hours, and was cooled to Dugti Hrarz loop was diluted with water (70 ml) was washed using 60 * 2) EtOAC ml). The drying of organic layers Ataktah using, Na / 'SO, was' candidacy War Nisaha. The Q 0 crave AA 0 Oil of 0 ore Bather Dai Aithia and Hecsanat, Umm assembling solid material mirrors the resulting den during the run were 15 air dried for 8; 5. (3 ~ Shell -5 - ;; 4. (Ray Vruhl) Berbhdv &amp; quot; 2-'s; Abu; impoverished because) a- 0.3-Yasul -2-night -1.4 Dai-Ooxaspiro [4.5; Deccan -8-Krrkmad (0.171 mg, 0.31 over Maud 0.63% Kmatj) as AtU was 1 E. : MS ESI 4.9 = /..1Μ+Η1+ ηι / ζ 520,1. 'H NMR (500 MHz, CD3OD): δ 11.0 (s, 1Η), 9.64 (d. Ι.Η 4.68-4.64, (8.28 (bs, 1Η), 8.12-8.05 (m, 3Η). 7.97 (s, 1Η 1,1Η), 8,76 (bs, 1Η,?,} 8,79, (Hz 20 (m. 4H), 3.23-3.15 (ni 2Η), 3.12 (, s. 3Η), 2.95-2.85 ( ni 2Η), 2.44-2.38 (m. 4Η). for ΜΑ 33926Β1 of 0 to Khtouk 6; 4 Li Mash 0 n 8-A5-Z3-Bethel-5-g [4 - (&amp; quot; Ray Florosel) Ber.bmaidin -2 to Eomino) Phil ); l. &amp; gt; 3-thiazole-2-follows -.1 0.4 "Dai Ooyspiro [4.5] Deccan-8 / Boxa 0 j (700 mg, 1.35 Miller mol) in THF is an aqueous (2 ml) and has his vessel concentrated HCl (5.53 in ,; 67.4 mmol). the 'Hbb Oakhlul Alohfr parents than our per- at 23 ° C for 6 hours. the mixture was reduced by using 0 € and a saturated with water (80 ml) was Atkhalas Bachkdam 70x2) EtOAC ml) . The drying Ontbqat organic data using Na1S04, ANZ was 11, it has been its focus. Oil has been mulling welding Mjxanat point Dai ethyl leading to Receive E 1 "[5- (3_ez'5 - {[4- (Tri Vrumethyl) -2 Ber.bmaidin Lil Abu} sales) AA; 3-Villarol-2-A ; -4-Oko Michaelo Hecan Krbokmamed (and -68 mg, 1.01 mmol, 74.6 Is) as pouring brunette. 476.1; '-. MS APCI: [Μ + Η] + w. 1 Khaloh 7: To a solution of 1-L5- (D-Z-5-real 4 ~ (an intelligent Vruhl) Peremaidina 2 '; Abu; tends) -. 1.3-Basul -2-night-4-Aonsosichaeloheczat Drbo Bassamad (683 Bhm ; 44. Miller 0.1 mol) in MeOH is. Mani (6 ml) was added acetate Amu Neum (221 overcast, 2.87 Miss Hall) and Sadhu sodium borohydride (95 mg, 508..1- mmol). Tguib been one of the mixture Alma'zj at 23 ° C for 6 days. The number one Cakl A-M 0.5 Molar loo) in NaOH) was extracted using 75 X 2) EtOAC ml). The Alaibqat spontaneous laundering Oth with water, then dried using a 0?, A'4la was Nfaihha Rrkatray to increase buff, saluting b Tmqath by HPLC in Phase 1 of the inverse &amp; lt; Emod 8a 0, Ddrj Ostoviral / water with and 6 d TFA% 0.1) 0 led Alhh to get a mixture of Mrdugat Escaped-m, where Nhlha 0 n during A.lasl Bastkhaddnm developed fixed Kiraly (% 35, the SFC 0.65% Mitharolr 002 (not .pop Hecllat seen j) to get all the Z SOS-4-a 0 Jolla-L5- (3-crippling-5- {for 4 33926Β1 -42 a Nraa Vrumethyl) Baremyen -2-Ale a 0 U} Foubl) -1.3-Thazul -2-Yale 0 Sklohxan / Erksamed (92 Bhm, 0.18 mmol, 29½) Katj ) and Dhir.ad -4 ~ Amir-a- [5- (3-b -5 - {[4- (G. Vrubuthail) pyrimidine-2-Alob) phenyl) -. 1.3-thiazole-2-Z Sichaelochav Krbocassapz (03-1 mg; 0.21 g Hall, 32½) Kach) Ku 1, bless d; e slash whiteness. 477.1 MS ESI: [Μ + ΙΙ] + m / z. August for a Huzeie, Nthat rhSYK = +++; for Huzeie b, Nthat rhSYK. +. ++ Khloh 8: To a solution of Seads-4-Obo- 1-L5- (d-Mttaa-5- (l 4 - (&amp; quot; Ray Floro 0 such as) Aremyen "2 Lil Aminu 1 phenyl) - 1, D-Thiarol -2-Yale cyclohexane calc. Bimad (30 mg, 0.06 ms Hall) in DMF is Mani (1.5 mL) was added sequentially Gelaiholak acid (7.18 Bhm, Miller 0.09 mol), 18.1) EDC mg, 0.09 mmol), 14.5 ) HOBT Bhm, 0.09 mmol), and Ν?, 0.03) Ε ml, 0.19 mmol). Sleep type mixture counted 23 m TeX 0 of 1-6 hours, after knead been diluted with water (0.55 ml) was washed using 40x2) EtOAC ml) 0 nm. Drying Alabakat organic Agiah use; ... Na-jSO, was nominated tendon Theisha. Tmt b Olmenth crude through a reverse phase HPLC in the (drawer Osithonaral / water with a 0.1½) TFA) were easing Atxtoah parts on Almenth use NaH.C03 saturated with water (50 ml) were Velha using 45) EtOAC 0 l). It was Najafiv organic layer using Na1S04, it was nominated, including water for boiling Cisse "4-for (Hydro-acetyl-p) Omivoa-1- [5 (3-methyl-5- {L4- (Tri Vrumethyl) Berimidh -2-.bl] EVO ) Ivel) -1.3-Tharol'2 ~ Yale; cyclohexane Krokmad (16.5- mg, 0.03 cellulitis Mall, 47½} Kotj) Kmath to slash egg. , (10.26 (s, 1Η of ​​(MS ESI; [Μ + Η] + in /:? 35.1. 1.Η Ni (5 () 0 MHz, DMSO 7.32, (7.96 (s. 1Η). 7.94 (s, Ι-ΙΙ), 7.55 (,!,. / = 8.2. III). 7.45 (m, 2Η 1 (d. ./=4.9, 1Η) O'8'8 -143 ΜΑ 33926Β1 7.22 (m, 211). 7.14 (s, 1.Η), 5.29 (&amp; quot; t,, / = 5.9, 11-1) 3.75; (d, 3.60 - 3.70. (211, .. 6 = t (m,, 1 H) ihSYK 2.58 -2.67. financial framework (m, 211), 2.31 (s, .311) 1.68 - 1.82; (m. 411), 1.54-1.41 (m, 2f: i) only a handful 25 0 (AH 0.4 E) -4-Adroxe 2.2 -daa Metel-4- [5- (3-Methel -5 - {[4- (G. Iowombl) Ber.bmaa 0 bin-2-L Od; Ivel) a- 0.3-disappears-2-night-not- [ 3- (2-oxo, Berouliden &amp; quot; &amp; quot; 1 Pro Yale 0] Skovfajan Hm.boxamad 0

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01451.tif" id="idf0091" />

Η λ \\ · ιι. ίμ.π ^ ΐ to acid (4, si E) -4'hidroxa ~ 2; 2-Dai Methel-4-L5- (3-methyl -5 - {[4- (1 saw my Vrumethyl) Berimidn -2-SAL | Abu; Ivel) -. a 0.3-thiazole-2-Aiskhloten O.krboxla (102 mg 0.20 .. mmol), 4 (3 Svobroehl) -2 Miroved.son (85 liters Bedouins, Malash 0.60 mol), 58) EDC mg, 0.30 mmol), and 46) HOBt mg, touched 0.30 mol) and adding N, not Dai-entertaining Vwumamad (2 ml) and Tri-ethyl Omanan (140 Mays for a 0 0 a touching countries). The mixture was stirred at a temperature of Arafa temperature for a 6 Iah, and Ba-Akhada been perpetuated 0.1 0 1 0 termination: Miha solution, dunums of chelation '; EOAC · nm small' AKEL blooded 1.:1 d: To'la DDS (3 X) then 4 0 FH less the funding Bkelah 144- 144-ΜΑ 33926Β1 in phase Almed Q (18 .: :). With HPLC Aghannseyoum filter, Am'nr Chihaa and it has been purified by been relaxed. (IfA% 0.1 + 1 Ztabaah graded 45: 55 to 80: 20 of Osatovetr.l: Te parts Atiah Bositalt Ischl and Day-Laure 9 Mithal was washed with a solution of Mabe Mthb of sodium bicarbonate. were separated Alabakh organic was dried sizeable Lights Mufnseyoum was nominated 0 / (16), has been its focus for the composite Alwar, d in the title (07 mg, d 0.1 mmol mS ESI: [Μ + Η] + έ 631.2. Iff NMR (500 MHz, DMSO- .knatj) as a solid white d ()) δ 10.25 (s. Itl), 8.82 (4.9 = shabby, lfi), 7.92 (s, 114). 7.92 (s, 1Η), 7.68 ( t,, /: 5.6, IH), 7.46 (s. 1111. 7.28 (d, 4.9 -r. IH), 7.14 (s. llll. 5.86 (s. 11..1), 2.29 (s. 1.Η ). 2.24 - 3.12 (m, 2H), 3.12 - 3.03 (m, IH), 2.99 ....... 2.88 (m, 1.Ι..Ι), 2.31 (s, 31-1,). 2.1,9 (ni, 214). 2.1..2 (m, 2.1 ..: 1.1- .1.86 (m, 5Η) 1 Ι..66 ....... 1.50 (ni, 314),, 1.40 (m. 11111, .1.; (s, 314), 0.92 (s, 314) example 26 acid burden-4-Floro ~ 4-A5- (3-Phil-5-e 4-Viray Vlmuru 0 Yale) Beremi; n 2 Aleomino; astray) _ 1.3 Abzul -2-Yale Sekloyn one of the carboxylic

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01461.tif" id="idf0092" />

ch3 1 to Khaloh and: (Li Mahdl of Î- Pew Thiel 4 Hivroxa 4 (5 (3-methyl 5% [4 (Ray Elrrhobel &amp; gt; Eadan-2, is not without Fajl) -1.3-Zlazy -2-lest · 4 Dchal / .; &amp; gt;, 400): N Bjm, .748 Miller 0 0 of &amp; gt; s Dai Kdlo 0 tan (3.74 t) for; Iol 145 145ΜΑ 33926Β1 (2.2 curlers fled, 0.037 mmol) were added Diuksovlor (690 E b 3.74 »Lee» well) . Nkiml.lvaal after Zltguenb for an hour I score then one Rh Eft 0 j Ahael Pasiat A.buthail, and then washed with water, was dried by Major 1 Samuel; and sleep 'T- and Hkizi 0 nm 1 use Kromatoger 1 P Nlamod purification Alhaol the Azzurri t Bio.al 4 4 [5 (3-crippling-5- {L4- (Tri Vrumichl) Peremedev -2-Yale a 0 Su} Fajl &amp; gt; a; 3 Zll 0 L Saklohkaz 0 Krboksart. isomer Sass (141 mg 1., 0.210 t Mall, MS ESI: [Μ + Η1 + 537.2. lHNMR (500MHzDMSO-d6) 5 10.28 (s, 1Η).. ((½28.1 8.83 (1, 52 Ta0'oe H), 8. () 7 (&amp; lt; 7 = 2.91 E Η), 8.03 (S. 1, 8.3: and Η). 7.47 (s, 1Η). 7.39 (Rah = 5.;. JH). 7.20 (s. JH), 2.32 (s, 5Η), 2.20 - 1.93 (m. 31) . 1.93 ...... 1.78 (m. 2Η), 1.76 '57 ..; us ESI: · (isomer 'Nrd (1.75 mg, 0.326 Munch «loyalty 6.l4'4a. (m, 2Η),! .40 (s. 911) 1'Μ + Η '] + m / z 537.2.; H Hr. (500 MHz DMS0-d) 0.29 of a (s. IH). 8.83 (= 5.3 and 4., 1Η). 8.1.0 (s. 1Η), 8.03 (s, 1Η). 7.47 (s, 1.1: 1), 7.29 (cl, J = 5.2, 1.1-.1,). 7.20 (s, .1.1..1). 2.53 (s, 3Η). 2.32 (s, 4Η), 2.08 -..- 1..93 (m, 214), 1.93 - .1.82 (m. 21), 1.84 --- 1.61. (M, 1.39, (. 1 --- 1 a (s, .91-1) Step 2: To a solution of C-E-Bjotal 4-Shu-4- [5- (3-H -5 - {[ 4. (Ray Zawromed j); .ba &amp; lt; Q -2 Lyle; Bo} astray) -1, 3_villarol ~ 2 Splberman / Boxlat (67 mg, 0.125 mmol) in Dai chlorine, and Bthan (2.50) has four night 2; 6 -lozban (145 Bacaro skimp, 249.-a mmol) wa-Bio'vel Dai Shell Seal Dry Flo 1 Bthan Skomat (860 Bacaro's, 3.75 t countries) 0.1 is complemented 1 Taael Baal 0 loyalty Waddle Ivd degree Okhervh temperature. The Tkhaah interaction Abasitat ethyl was. washed with water, was Tjiha Bkiprita't 1 Sum, RTM Zchiha was. Zee. The Ata-or / and Matogerav edentulous b 146 "ΜΑ 33926Β1 ^ 'for Ahrl Erahishamad Froo Aabboya Y BD 0 Yllarld Aseads termination, E;) 1 No 0 ^ E 'cent, Avld: Q 0 E. "Il SFC of, the r), K SFC reminded then a 0 as long as any 55 5 / Mo: 25 cm 0.5 curlers to Aoz, the 0 lol AAC 0 KD X 2.1, Technology &amp; lt; :)'s shot Lsag: 70 0 LADIS DDS Ed Lash 5-7) M'l, (&amp; gt;) CO.0 ​​Etadhul my irrigation Q-4-Floral-4- [5- (3-bit 0 to -5 - {[4- (Ray Ho.al j); Eay -2 E 0.035 Yale; Obdhu} Fajl) -1.3-Bozul -2-Ysklov Aacirbukd (1.7 b MS ESI: [Μ + Η] + nr: 481.1. lH NMR 1.600 MHz. [) MS0-dM Malai Mall, 28.3% &amp; gt ;. Of 10.26 (s. LH), 8.82 (1, 4.9 = /. D Η1. 8.06 (d.2.8 = 's, lH), 8.00 (s. 111), 7.45 (s. LH), 7.27 14,4 = 4.9, 1Η), 7.1,8 (s. 1Η), 2.40 (1..7 = 12.1. 1Η.1, 2.30 (s, 3Η), 2.1,6 (t ./= 1,1.8, 2Η), .2.05 idtd , .7 = 4.4, 1,4.0, 40.0. 2Η), 1.91 (, il. .7 = 13.3., 2Η), 1.68 (tt, .7 = 6.5, 12.9. 2Η) +; + = r1; SYK w 'i was Nhouder following examples in a manner analogous to those set out in table 26. T. 26's

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01481.tif" id="idf0093" />

Image [M + HJ + Activity XR example (Ader) Almalahz rhSYK ΜΑ 33926Β1 1.47 .-- bottom. Y a free 481.1 -CH2-CH (C02H) -CH2 - (^ J; &amp; gt; CH3 1-26 free base 395.0 -CH2- H 3-26 free base 467.0 +++ -CH2CH (C52H) -CH2- (TRS ) H 6-25

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01491.tif" id="idf0094" />

Ethyl 4-hydroxy-4- [5- (3-sale -5 - ;. [4- (Ray Vrumethyl) Peremydr "2" Aleomaao) phenyl) A- 0.3-thiazole-2-Yale; Saakhluhecsan Nrbo for a silat

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01492.tif" id="idf0095" />

cf3 N

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01493.tif" id="idf0096" />

Ong was 5 Ttzahedrovuoran in the flask was cooled to -78 m. Tmt Asafh Dai Oazobrobellamad lithium (9.91 t, 7.84-1 mmol) and made available to a mixture .lnbarad to -78 m. It has it; it Alusal compound 4 (2.0 g ,, 95.d Mo.l ms) in Ttrahedrovuoran (60 ml) and added to the Khlien interaction once was Oitkulaib for 30 minutes. It has thawed ethyl 4-Chuseikloi or &amp; quot; the H.rboksilat (1.52 g, 8.92 0 Athy Maud) in Ttr'hedrogiwran 10 (60 ml) and added all at once. After one hour, and then put out the reaction using chloride Amu Neum Mhesa-. And I had Cdfeth to room temperature. Done. For mild solutions Ba Sitat ethyl. The Fasht class membership, was dried Bedouin Mufncio m, was nominated was seen .tar P was used Theromatogerav Ga, Seeley 10 da purification to obtain a mixture 1: 1 of thermocouples Tja cm Aithia ,, 4-hydroxy-4- [5-D3-Bethel -5 - {[4- (Lay Floromcil) Berbmaidin. -2 - Abu Yale 2; n -1.48 MS. (¾, 65.1, Zebl) -1.3-Mazll-2-0yskddhan Kmlat (1.96 m ESI: [Μ + Η +; »/ · ': 547.2. lHNMR 1500 MHz, DMS00d6) δ 10.25 Is, 1Η), 8.83 (d, 07 = 5'21 of Η), 8.02 ... 7.85 (m. 2Η). 7.46 Is, 1Η), 7.27 Id,. /: = 5.0. 1H), 7.14 Is. 1Η), 5.97 (til 1.1-: 1). 4.1.2 - 4.01. (M, 214), 2.62 - 2.54 (m, 1Η), 2.31 Is, .314), 2.12- 1.99 (m, 114)., 1.93 - +++ = rhSYK58..1. Activity (m, 714). 1.24-.1,. () 5 (m, -311) (2) 33 0 A handful 33 (1) and 1 Hi-Tras4 Brocchi-4- [5- (3-Shell -5 - {[4- (Ray Vlowo methyl) pyrimidine-2-Yale Obdhu} Ivel) a- 0.3-Yasul -2-Yale Bklohxan 1 to B-carboxylic acid-4-Hedrok 0 j-4- [5- (3-Buthl -5 - {[4- (Tri-Flo. R.o.methyl) Peremedin -2-amino Ale) cells) -1.3-for Azul "2-for; Sichaelohecsa 1 to 4 carboxylic

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01501.tif" id="idf0097" />

Part A: The 'whoop-ethyl-4-hydroxy-4- [5- (3-sale -5 - {[4 - (&amp; quot; Ray Vrumethyl) Peremedan -2-Aloomivo) Linnell), "a 0.3-Yasul-2- Saklohlathsan yen / Boklablatt (3.72 g, 7.3 'ms Maud) in 1 Mai were judged (42 ml), and has additional 1 FH hydroxide Alsod.boum (Molar's in the water, 15 ml). Amehlol was divided between Anaab microwave d 20-ml. It was exposed Annnfaal Dlataa t. At 100 m in the microwave for two minutes humanitarian partners. When only to be returned, the acidification of ΜΑ 33926Β1 E. Molar in water, 1.8. Ml). It was extracted Ahlol ethyl acetate) HCI Aglul using Oazobrobanerl. Were separated organic layer, and then dried: CHCjl: 9 and a small amount of Npritat Mufnseyoum was T. Chihaa and Trkizi '25 X 2..0 a J-H Part B: The use of separate Allowaa supercritical in purification using column cm 0.5 curlers meters. The mobile phase was Altkhaddm Ara p. 3: 7 Mithanodr.t 0 € rate of 'Ndfq 70 ml / min in g 0 n Run is a p 7 minutes, to obtain: isomer 1: acid Trazs-4-Hmadrose- [5- (3-of-d {[4- (Ray Floroumil) Smmaidin -2-Aloomedhu) phenyl) - 1.3-thiazole-2-night Sichaelohecan Kherboksila MS ESI: [Μ + Η] + 479.1. AAA NMR (609 Μΐ.ίζ, DMSO-. ((1 1., 1 CE (32 /. Kma'zj of 10.23 (for 6) (S. 1Η), 8.81 (d, 7.75 ... 8,00 nor , t = 4.9 (ill. 2Η), 7.44 (S, 7.25 and (d, for: 4.9, 1Η), 7.1.2 (s, 1Η), 5.92 (S, 2.62 and (s, 2.29 and (S. 3Η ), 2.1-1 ...... 1.95 (m, 2Η). 1.92 ..... +++ = rhSYK 1.75. u 1 i (m. H), 1.71 -1.54 (m. 2Η) (Oiromr 2: Pei-acid 4-Hmdhiro, Ji-4- [5- (3-Shell-5- {for 4-to-ray Vrumethyl 1.1 Bear-Mmaidin -2-Aaobo) phenyl) -1 and -2-thiazole-cyclohexane carboxylic Yale 2 (d MS ESI; [Μ + Η] + m: 479.1. 1.Η NMR (500 MHz, DMS00d6) 12.1 of (s,. (. LE 0.32 a, 1.HI. 10.25 (s, IHl. 8.83 (d, Jz 5.2, IH). 8.04 - 7.83 (m, 2Η), 7.46 (s, 1.Ι.Ι), 7.27 (d, for = 5.0) nor 7.1,5 (S.5.95 not (s., 1,11) , 2.31 (s, 311). 2., 13 ...... 1.99 (: m. 1Η), 1, .91 1.73 (m, 2Η), + + + = 2hS1'K 1.53 .-- 1.71, . activity (fn, 611)

However 0 handful 33 (1) -NA -150- -150-ΜΑ 33926Β1 Pei-4-Pedros-4- 5A (3 d 5 - {[4- (G. Sllhl &amp; gt; Alloas -2-night Apr) 0 Yale) 1 3-Marol -2'do Ar'kav 0 / * 5 ν Maddailam s as one exhorted him 4-00dros-4- [5- (3-Z-5- {A4- (G flow 5 PBL) Bear 0 between -2-yen! Bo} Phil) 0 to 0.03 ; 0 -2 Azdl Lil Scalrchan Alk.aoye (1.5 Bjm 0.31 ... with Maud j) for 0 x 0 t; Yale (272 ..lh) and pain 0 E (54 Ed d) 'for; cancellation of me. , Kodiom (a 3 &amp; lt ;, 00.031 to Phippll), which the Dtm's

40 d to 0 Aq Lighters 11 Hah any of the active cooling to the point of weddings heat, Mr. Seve Dam JH Dr. Pei-Say 4-Brod-4-A5- (3 J-of-Aa4- (Shaw tea 0 Yi Ssn-2, m} Vgl) A-, 3-drool-2-Iskhan - t. &amp; lt; 479.!. lHNMR (5001, DMscw5;, «+ [MSESl: [M + H 0.25; of (s, 1.Η), 8.85 (s, IH), 8. () 6 7.73 (m, 2Η). 7.46 (S. 1Η). 7.27 (S. IH). 7.) 3 (s. lHy +++ = rhS1'K 01) 5.60-5.89. Ichat, IH ). 2.31 (s, 3Η). 1.91 - 1.54 (m, 41;)

Examples 33 (.1.) -. K Pei -4 Breue4-Fill the ~ (3-sale -5 - (4-for Yraa Vrumethyl) Lear 0 Pei-2-Yale; Su} Phil) 0 &amp; quot; &amp; quot; A, D Bzola2- Yale Sikaohan / Aokmlan Olbotasom has Dissolve a .ss 400 Ehedroxa-4-L5- (3-crippling -5 - {[(s) 4 (0 Ray Vrubuthail) for Arale &amp; lt; yen -2: del Abu} Neill): a 0.3-Yasul -2 -inskhloten (for Krboxla (15 mg, 0.031 0 for in 0 well) in Barbters (272 microseconds Winter) and 0 termination (54 Bkreaultr.) has L1 lighter Htro, master 1 Rotasom (31 curlers l, 0.031 mmol) was Tejen mixture to 40 m births H and he . interact cooling has been made available to the weddings degree heat, before idleness ΜΑ 33926Β1

And Altjgeg_a Baltjm 0 d Seoul to BTS Ss_4_hbroxa-4- [5- (3-crippling -5 - {[4- (1 saw my Hloromeshl) to Ar.bmas "-2: L} Abu Eadsl): A, D ~ Izul_2- &amp; quot; L Sakloh 1 Dacia 0 Krbok 0 silat Albotasaum 0 (.1HlR (500 MHz, DMS (9-d6 .Η] + / &amp; gt; /: 479.1; Μ;: MS ESI δ 10.25 (a 0? 0 Η), 8.83 (d,. / = 4.9, 2.1) 7.83 - 7.99 0.0 AAA Η). '7.46 (s. 114). 7.27 (d. ./ = 4.9. .rhSYK 7.13, (111. Zhot (s. H t). 5.88 - 5.63 (m. 1.1 -1), 2.3.1 (s, 31: -1), 1.88 - 1.59 (m, 911)

Alohthelh 33 (2) "NA Zass -4-book 0 J-4- [5- (3-z -5 - {[4- (G. Vrumichl &amp; gt; Eads &amp; quot; 2- T.aomivo) Ivel) A-, E-Thiazul- 2-Aiskrkhan Nrbo Dsaz 0. U 1 ci literature Homs Rad_4_bdlok _4_lq_a 3 a 0 Hll5- {L4- &amp; quot; (Ray H'-mule) Aaedan -2-Yale Bo} Ben -1.3-Taroll -2-Ybkaod'v (15 Bjm, 0.031 Miss Maud) in a 0 dl (272 curlers HD; 0's termination (5480 did &amp; gt; 's Idrue Mudiom (31 Bcdonnr, a 0.03-twisting &amp; quot; - l)' and Nm'kh 0 m 40; r I o 0.! Sass my Bh to the commencement-doggy b 'z: Akjviv Balthmiv for compromise -4-Hedros 4 »ml, e 0 0 Slla, a".;,., (, - e !. .- ** - e -9 e 01 479 and., "t +,]} MS -1- ESI: [Μ; Boxlat Alhodiom. (lHNMR (550 MHz, DM'SO-dô 0 of 0 t, 8.83 (d 0 Al, 5 (s y a 0.0 δ .4.9 :( .. 7.46 (s, 1Η). 7.27 (d. 1.Η), 8.04 - 7.76 (m, 2Η0 0 to -4, (s, 3Η). 2.21 - 1.96 (m. 3Η).] .90 - 1.63 (m, 4Η) and 2.3, (H; Y) H6-H d (11 214).) 1.42 --- 1.62. Zhot riiSYH E +++

However 0 handful 33 (2) - K Zawromethyl) pyrimidine-2-night; S-4-Hiroksa-4- [05 (d 13:00 6 El 5 false 0 \ Plumblm Aso) Ivel) ~ 1.3 ~ I 1 Zeul -2; l] Saklmosan; 000 J 51 a {[4- (Tri Vrubuthail) has it; its acid; Asl4-Habaru B 0. 4 [5 humanitarian partners tucked Oboksila (5A Arimdan -2 night Abu} viable) to didn t response; Water (54 Skrocker) .temt Adazh Yum ,, v 0.0 ^ for Phil% for (T-7, T's:;) ,; Tmvdhakat; Li 040 m Dubai Fassasd.b 0.0 m-; Tate Linda Tah and ascend. Made available to Dhael Akprphi to Del &amp; lt; a; 5 g and 4 0 1 Tthamid such as having presented Nrad 4 Hivroms} ...... 1 3 Elala 0 Thea ^ \ .20; W 00] Celal 9 Hkhosan as 0 Lac 1 lats of 0 mouth 0, MS ESI: [Μ + Η] + ηι / ζ 479.1. llINMR (500 MHz0DMSO-d6 025 ha of (s. 1: 4,9 = t '; 5) 83-8 to AAA AAA. Η), 8.02 - 7.78 (m. 27.46 :(]; (s. 1). 7.27 ( d..-7 = 4.9. a Η &amp; gt; 1 7.14 (s, 1Η), 5.69 (s, 1.Η), 2.31 (s, .31), 2.19-2.07 (m. 21. 1.99 - -1.85 (m . 11. 1.8; 0 +++ rhSYK 1.6 -. Activity (:) (m, 411). 1.57 - 1.42 (m. 2Η) were prepared one of the Mercat in the tables d 3a (Li 33 d manner 0 Gazerh to those Abh in a 0 handful 2 for ΜΑ 33926Β1

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01551.tif" id="idf0098" />

33 countries, a 5 Accor (photos) [Μ + ΙΙ] observed activity RHSYK R3 / R4 Γ R 1 for an example of a formula h base. Of 507.3 00 0; -000; 0.000.; 00 H / CCbEt CH] CF] 5-Î33 a free base of 470.1 -0 &amp; quot; (CES) H / C02H CH] CF] 33 A-6 free base 507.2 ++ -) -. (RS) H / 'C02Et CH] CF] 74 33 Vaadh free y 479.1 ttt No 2 H'.2ale (t Nes) CH] CF] 50 a 3 Lb) roll; Fa 0 hand ~ / e 521.1 tt; - (Cisse) CH] CF ] 10,433 521..1 a free base. - (Satisfy) CH] CF3 11-Î33 ΜΑ 33926Β1 9 493.1 a free base (COG) CH3 / C.2H CH3? -CF 12-Î33 free base; 0.493 (Cisse) CH3 / CO2H CH] CF] 13-133 xU Forma T. 493 + 4-4- (RSS) H / CH1C02H CH] CF3 16-133 free base of 507.2 + 0 (H / CH? CH1CO? H CH] CF] 18-133 sitting d free 5 507.2 (Cisse) H / CH2CH9C02H CH3 CF] 19-133 free base 507.2 &amp; quot; 0 A00.aa; 0-EED (RSS) H / CH2CH2C02H CH] CF] 20-133 free base 535.2 4..4.4.- H / CH2CH.1C02CH2CH3 CH3 CF ] 21-133 base Ham e 465.0 4.4 ... 4. H / C.2H (satisfy) H CF3 2.3-133 free base of 465.0 +++ (r) H / C.2H H CF] 24-133 base t 5 493.1 +++ (o Yasin 0) H / C () 2Et H CF] 25-133 a free base; 0.493 4.4. (Q; &amp; gt; H / C02Et H CF] 2.6-133 free base; .479 4 .... 44 .. (RS) CH3 / CO2H -Η CF] 27-133 promising free; 0.479 0 +; (Cisse) CH3 / C02H H CF] 28-133 free Hadn 509.2 ++ (^) H / C02C (CH3) 3 CH] iPR. 2.0-133 Hadq h of 425.1 BPB (CES) H.0'C () 2H CH] CH] 3 .-. 33 ΜΑ 33926Β1 9 a free base 425.1 17C.2H; (satisfy ) CH3 CH.3 33 a -31 Hadv -brrh 439.1 --1 - + - 1 ;; 32) 3) 0.511) 1:13 (CES) CH3 CH3 33 -32 a base &amp; lt; m of 439.0 for:; 2 (&amp; gt; :) T:: a) I (RIP) CH3 CH3 33-Î33 Hadn free 525.2 ++ (Cisse) H / C02C (CR3) 3 3 Z O.ÎPR 33 a -34 Hadn &amp; lt; a 441.1 H5C. 02H (Mays) CH3 3 loomed 0 33 a -35 free base 441.1 0 of 2 (a)); (satisfy) Y 3 Li 0 33 a -36 Hadn -brrh 455.1 (Cisse) CH3 / C.2H CH3 0CH3 33 a -37 h of Base 455.1 0.0 ; 00. A 0 0 AA 02: :) The] for:) (Zs) CH3 ÜCH-3 38-Î33 formula b; H = R5 free base 5 507 +++ H / C02H (satisfy) CIÎ3 CF3 33 -54 a free base 533.2 -a- --- a -; - H / C.2H (homologous E.) PR Cf'3 59-Î33 base sulk, salt TFA 533.2 · b b b ;; H / C02H (homologous 2) -C CF3 33 A. 60 a free base 547.2 H / C.2CH3 PR CF3 33 a-a 6 156- ΜΑ 33926Β1 156-

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01581.tif" id="idf0099" />

Salt FA] '533.2 H / C.2H PR CF3 62- (33 He of 507.1 H / CO2CH3 H base CF3 65 ""? 33 Hadn free 493;); H / C02H (Cisse, Michad H CT3 66- (33 Base free 493 ..1.-.... 1 ... 1 ... H / C02H (p, homologous 1-1 CF3 67- (33 free base 452.1! ++ H./C02H (Cisse) CH3 CI- Î3 68-Î33 prepared a. a free 497.2 (Cisse) H / C02CH3? CH CÎI3 69-Î33 a free base 493.2) + .- b H / C02CH3 CH-3 PR-C 70- (33 a free base 479.2 H / C692H CH3 PR- c 71- (33 no 0 y Tmz 469.1 +++ H / C02H () visit a) CH3 0 m 3 not 33 a -72 Iazz c y 469.1 of 02 free 0.4 a (Oaz.or 2) CH3 AA 3 not 73. (33 formula n; 3 = RS a 0 Hadn then y 521 &amp; quot ;; &amp; quot; &amp; quot ;; &amp; quot; H / C02H (3 isolate isomers) CH3 CF3 33) -75 to 33 -77 -157 a table 33 b

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01591.tif" id="idf0100" />

33926Β1 1 image (s) [Μ + Η] 1 financial framework Activity 1'hSYK R3 / R.4 YX example Η = RS, CF3 = R 'TÔJ a MOB 0 No 451.0 H / CO6H Rabaalh 1 Ath NL Dora B 1 495 H Base / C02H (4 isolate the isomers) Association C (CH.o2 33 b t f 'a d E 3 3 3 Y-- Dr. Dora Base; 52 +++ H / C02H (4 isolate the isomers) ClhCIh (CHjh c 33 b - 6 to 3 d b ΜΑ 33926Β1

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01601.tif" id="idf0101" />

Hadn justified by 9 0 509 H / C.2H CH CHOCH3) 3 (b) for a free 5509 ;; Base + H./C02H CH 6 CH (0CH3) 3 b &amp; quot; '&amp; quot;' (P, p) a free base 14 E. .495 -; -'- ί -'- ι H / C02H (isomer ch2 CH (CH3) and 3B a) IS TFA salt 493.2 ;;; H / C02H (Aadhumr 2) ; CH CH (CH3) 33 b -19 Qaaden -ah, a .493 p. 4 ah 0 h / a (6 Oiromr 3) ch2 CH (C, H3) 3 d TRUSTe CFA salt 20 Hadn free 479.1 ... Η / Η CH CH 3 d b. (CO2H-) 21- free base 521 .... H / C.2H CHi (iPR) CH 33 and 3 b &amp; quot; ™ 24 Foresail base 521 H / C.2H Zmichakl CH (iPR) Ç'H 33 (b) (! 22 rules &amp; lt ;, 5 521 Pas-b H / C02H (homologous CH (iPR) CH Ad b ........................... ............................ ΜΑ 33926Β1 -1.59- 0 23 7 mAh Amu Neum 465.0 H / C.2H CH Association 33 (b) 24 free base of 479 +++ H / CH6C02H CH d Association 3 b (l 0 Reyes, but Micha -1-) a free base 25 479 -4-.4 - .. 4. H / CH2C02H CH Association 33 (b) (3 Cesme, was one tha tha e) 26 free base 479 + - ++ H / CH2C02H CH Association 33 (b) (satisfy, homologous 2) 27 base free 479 -4-1 -.- H / CHC02H association of CH 3 b's (Cisse, was 0 bereaved 2) 28 H = R, CHfR1 Vaadh Foresail 459.2 444 to Az0'ouala (a-Rlnm 1) CH2 CH (CH3) 33 '(b) 32 Hadn free E 439.2 &amp; quot ;; &amp; quot; · b 0 b E0 a 02: :) only (termination; wa 2) CH CH (CH3) 3 d b 33 free Hadn of 467 (((H / C.2H CH (iPR) CH 33 b "34 9 -160- ΜΑ 33926Β1 free base 467-1 --- 1. --- 1 --- H / C02H Dauer α-ί2 (iPR) CH V 33 b -35 Hadn a free 467 +++ H / C.2H Azur CH (iPR) CH 33 b &amp; lt; 2 36 3 € Η = 5 r, 3 CF = Rl TFA salt 507 H / C02H Dayizor.? CH CH (CH3) 33 (b) a) 38 Fa several jib 507 ;; t H / C02H Doazor? CH CH (CH3) 33 (b) (2 39:, 5 R =!) Tel 0 3 9 CF = R1 't FA salt 521 -1.-.- 1 -) - H / C02H? CH CH (CH3) 33 b 40 TFA Proceeds 521 11; H / C.2H (Azzurra)? CH CH1CH3) 3 d b 41 TFA salt 521-1 --.-....-. (S) 4 (2) ::) / AAA (Oaroa 2)? CH;? CHICH 33 42 (b) only a handful 0 37 (1) and 37 (2)

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01621.tif" id="idf0102" />

-161 -161ΜΑ 33926Β1 SES-4-Hmadrora-4- [5- (3-Shell-5- {L4- (G Floromeshal) Ber.eadan -2 - L} Abu Ivel) A- 0.3-Thiazul- 2-Z cyclohexane Drbonetre compromise -4 -4-Brocchi A5- (3-bed -5 -} [4- (Ray Florhumicthel) pyrimidine-2-amino night, Ivel}) a- 0.3-Hasul -2-Yskoohecsan VRBO amputation . Yale

\ CN \ CN

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01631.tif" id="idf0103" />

To the flask was added Ntrahedrovuoran (3.0 ml) was cooled beaker L. -78 m. Added Dai Oizobrobbez amide 1 lithium (1.0 D, 78. 0.1 Melanie mol) was cooled 1 mixture (Li -78 m 0 has the mediator 4 composite melt ( '0.20 g, 0.60 mmol) in Trahedroran (3.0 ml) and added to the reaction mixture utility and Ahdn was flipping for 30 Nqiqh. has thawed 4-Ootxosakulov; n Krboetrid (0.073 m, 0.60 ms Maud) in 3.0) ml THF &amp; gt; Ai then added over five minutes and then Zlkot 1, heating the solution to a degree Hrarz weddings. Bam Haah interaction Pasia 1 v ethyl 0.9 ppm washed Tel Reid Amoiah m saturated with 0.9 ppm Bhakifa Bnbaritapt Almanseyoum, it was seen Shiha and focus. Chromatograph column was used to obtain Ai: C-4-Brod-4- [5- (dd -5 - {} 4. (G. Vrumethyl) pyrimidine-2-Yale;} Abu Yale) _a, D-thiazole-2-Yale ] Q 0 Thelohecsan Nrposrad (0.72 gm, 7.26)) analysis of the isomer BASIS: '.5460.1 ", + [MS ESI: [Μ + Η ΜΑ 33926Β1 1.62 1 (). 23 (s. 1Η). 8.81 (4,. / 4.9 = 0.111). 7.93 (m. 211). 7.44 (s. IH) 1 7.26 (ci, 0 / = 49 J H) 7.13! MihSYK activity .is. III). 6.1 1 (s. III), 2.82 (s. .11--1), 2.29 (s. 31.1), 1 99 [72 (m. 814) -2-trees; Im _4 "Hiroksa '--- 4 [5- (3 vinegar -5 ~ {[4- (Bray tame Peremedev. (/ (29), Yale Omlao} Fib); a 1.3-Thazul-2-L cyclo 0 hexane Carr Bo. Netter t (0.78 MS Ham ESI; [Μ + Η] + rn /: 460.1. 11 a NMR (600 MHz, DMS0-d6) δ 10.23 (s, ΙΗ1, 8 81 (d, and = 4.9, 1Η), 8.00 7.89 (m. 2Η), 7.45 (s. 1Η), 7.25 (d, .7 = 4.9, 1Η), 7.14 (s; H). 6.11 (s, 01Η ') 1 3.13 (s. Ill), 2.30 (s. 3H.), 2.07 (m, 211). 2.00 ---- 1.89 (m. 214) 1 77 414 111;)

+++ = RhSYK Otalh 38 (1) and 38 (2) 10 Zad-4_bros-4- [5-D3-Z -5 - {[4 - ( 'Ray tame Baraimd 0 N-2-SAL 0 Abu) Fajl) ~ AA 3 -.--- 'Iyasul -2-Sklohxan No. 0 Krboxaaid Pei-4-Brokm-4- [5- (3-PBL -5 - (4 - (- Ray Zhd 0 vinegar) Eads &amp; quot; 02 but]} A solid Fa) does not 0.3-Iasul -2-.i Bakrek sector 0 n '\ C (0) NH2 0 (0) ΝΗ2 Ν: ηΓ OH CFS CN Y. CFs νΛ O (1 NNV,

P Ha; \

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01641.tif" id="idf0104" />

163- ΜΑ 33926Β1 to top 4 Ndul R-4- [5- (3-S5- {A4- (Ray Iorobil) to Arimdln-2-L Apr; Bill) -1 '3-disappears-2-Z E 0 palm of CKD ( 0.78 m, 0.17 Haaa well 0) P added 9 1.4) DMSO ml). Added Krpost Albotacio 10 (0.13 Mahm, Haley relied 0.92 &amp; gt;) and 30 i / o above dioxide 'to Hivrugen (0.1.7 for 0, 1.70 »Lee mol) was' I cease 1 Preheat the El at 70 m. Upon completion, it was cooled Anhlol was nominated. Output was purified run Boisalh phase HPLC in inverse Dbtdrj 1.0 "1.00% Ositobral with water for 12 minutes Hh 0.05 (t buffer solution of Hmgy Tri Floro Osetyat) For Ravs-4-Adroxa-4- [5- (3-D -5 ~ g [4 - ( 'Ray Vrumethyl) Bear 0 Eedan -2-night Ominoa- duck.) - 1.3-'iyasul -2-Aabklohxan /boxamad(0.040 g; 49./). 8.03, (N MR (50 () MHz. CD3OD) δ 8.72 (d,. / ::: 5.3. JH aa .478.1 MS ESI: [M + I-fJ'f m / z, (H), 7.45 ( s, JH), 7.22 -6.90 (m. 2Η). 2.57-2.40 (m, 3Η), 2.38 (s, 3Η a, s. IH), 7.90 (s) (2.00-1.69 (m. 6Η., Chatt rhSYK = ++; Mnotrh way that 11 is the son of the above; been urging SOS-4-p Hydro 45.1 (3 0 5 Shell (A4- (Ray your responsibilities, Oethel) age-2-E;} 0 Houa Su-a '3 -yazd-2-j 0 | 0 Sakbaan -al Whipple Kqoedz Rowe. + ΓΜ + Η1 ALMA 1 i: 1-478 'Ziat rhsVK: Hzl 39 Dhar.omethyl) Beramides 2.4-Ooxadoyasul_ 3_ {Sy_4_0blklei-4- [5- (3- Shell 0 -5 - {[4-Dsaa 2-Yale;} righteousness of Yale) -1.3 Mazul -2-il] Bkloml (a 1 5 (4 Q-en ΜΑ 33926Β1 -, 1,64-

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01661.tif" id="idf0105" />

Okia been one vampire 1 z Y-40'sdro / 0-4- [5- (3-crippling -5 - {[4 - (; any Vrumaz) Peremahdin 0 d Dada Obdhu..1 Ivel) -1, D-relieved -2 -adasichaelohecsan Alchris 0 (500 mg 0.105 Al 4 j Maude) 0.0 Seyoum chloride (112 mg, 2.09 Miss Mall); 0 7 (a "Azawdz 3 Azul ~ Repeat) 4, Ν ', Ν' , Ν- · / 2-ν1 Aorum Malaolfallait (795 b 2.09 Miss Maude), A'a a 0 Slade tightens as (730 your responsibilities to 4.18 t Lrl &amp; gt; j Dey 0 Yale Nomd (4.2 t) Takht land 6 n. the provisions of the Aga; s Aldye was s j 65 m k; 4, Aoua.t. , JU Aanbarad, then Tejee thread Aagael Alaa 'was Tdjabh Awab but T j u 7's ataxia. the μ, Elmo 1 d crescents Balaowitr Dai a, Yale then 0 SA in and .st p Loral a; u Weapons 0 real on Mays-4-Bruki- 4-L5- (d-methyl-5-Za4- (Tri Vrumethyl) Baremyen -2: del Aso \ viable) 0 to 1.3-Viazul "2-yd Sklohec 0 Man Krbok 0 Forever (437.6 mg, 0.916 Hess Mall 0.88% Ka-c) Da mouth 1 white solid. £ 478.1 MS ESI: [M + HJ + w. 0.733 Miss Maud) in argon. Added .ktoh 2: 0 in Oie quilt, (4.9 ml) was Amtas Menth Alahto; J 0.1 (350 Bhm, Dai Krumithan and .mahedrodharan (2.4 t) I 165- 165-ΜΑ 33926Β1 Roy (Plummy / p Zs g ' j evidenced Tmpelm 0.0 Fill the Lod (were '0.9.16 over due), and sleep! blood Q 1 I loyalty (to Zhtm dictated my Ke 18 I extended drum n b Us p Szy (Irkm 1' Rrdl Doanh 0 Od 2 d 81 a 2 Jiabao 00 sand would have been Dr. termination 1 Lara me, ED 0 Ickharhakloi 18 Dt.tm! Khedjs Q Bs and then Rey Ze. Dutt b .daa as upper Ash'h j &amp; lt; Aiel Talsarb; d); for Adlers -4-Ed-4- A5- (3-0a 0.5 -; [4- (Ray Floro Gul 0) Ebhdan -2-for; B.o E 0 but) ~ a 0.3-.bzl -2-Soyncaldl (28.6 vilified 0 0.062 t's; 8.5% Y'j) as 0 birth of a white solid 0 a .460 Ms ESI: [Μ + Η ] + m / z · step a; 5 has been blamed Ace Mmottag 1 Ztoh 2 (25 mg, 0.054 Haley Mo.l), Hidrue 0 hydroxide 1 x (01/08/90 mg, 0.272 Mlvemul), and Kr.bomat Alocosom (41.4 Bhm 4 0.299 touched mol) in Aithadhul ( 0.5 what 7) n land 0.6 n is 4 h 1 Im Alaglafy {Alua the growth failed to count 80 are for 1.8 efficiency 0; Keys ^ 1 Tagael Hbeshrh was Atas wanted August to 1 m Broadan (0.5 ml). Tmt Adhavh'raa ethyl OS (22.8 Bkl.o der, d t 0.16 mol), was -arad mixture to a small m. was added Kr.r.vel Dai Abmd; Roll (2.oa Bhm 4 touched 0.082 mol), and made ​​available to Almatj heating the mixture to room temperature on Hrar..h Huda 18 abuse 0 put down one cup of acid Tri Vruostic was diluted using 0.1 mL of DMSO »was Rchih mixture Conqueror was defined Beshrh to HPLC in phase eyeliner (water" Ah 6 Br.bl; Manl acid 'Ray Vlmuruosaak &amp; gt; 0 led this topic 1 Kaaa any. For Ely &amp; gt; I see Azurd in 1 Atawan (14.7 Bhm; 0.028 mmol 0.52% Knath) as a solid white. + [MS ESI: [Μ + Η 166 166ΜΑ 33926Β1 m / z 519.1. 1) a NhfR. (500 MHz, dmso) δ 12.25 (s, 111). 10.26 (? 0. JH), 8.83 (d, ./0= 4.8. 1Η). 7.94 (d. ./:= 10.8, 2Η ), 7.46 (s, 1Η), 7.28 (d,. / ::::::: 4.9, 1Η). 7.15 (s, 114), 6.06 (s- 1Η), +++ = rhSYK 2.68. Activity (m, IH) 1 2.31 ​​( s, 3Η), 2.03 1.79 (m. 8Η) 0 under 40 (1) and 40 (2) 2 - ({3-A2- (R &amp; quot; E &amp; quot; / MC 000 Z &amp; quot; A-methoxy Saklohksil ) -1.3-thiazole-5-I &amp; quot; 5- preferred torrent} additional) -4- (G. Vrumethyl) Peremaidin- 1. "IOM Ray Vruostadt 2 &amp; quot; &amp; quot; ' ({3" &amp; quot; [2- ( Ras -4-carboxy - 0 for the &amp; quot; "methoxy Saklohksil) - 1, d-Yarol -5" (Ray Vrumethyl) pyrimidine 1 Oaom'nraa fluoroacetate Yale; ~ 5-methyl VPL} Abu) "4- h ^ \ C02h Barr 2 He HV) fi 0CH3 ; 1 H, E Hd ^ oCHz.: hee: ethyl 4-A5- (3 - {(a-Pure passion cr bubble) | 4_ (Tri step 1: to the real Omivo} -5-methyl Ivel) a- 0.3 -bzul-2-I-4 Dharo &amp; lt; Yale) year-Bmaidin 2-g] hydroxy &amp; gt; Sklohkan Carr Boxlat (! compound .loset 11.9, 0.148 g, 0.24 Miss Mall) 1.2) DMFj ml) were added Aodomithan (0.042 g, 0.29 JL Mall). · Anbrid been Agrl to small and after it has Asafh 60 ½) of sodium hydride in oil Badena ( '0.011 g, 0.22 mmol) and was made ​​available to active heating throughout the deer. In Alsah Lalai; for Adahh Bodomithan (1.14 g, 8.03 mmol) was cooled to thread small m. Has Asalo 167- 167-ΜΑ 33926Β1 hydride, Cudedm in Az.t pain 0 Denny (60%, and 0.2730.01 Rrn to Abhsel Kassala to for 0.0's were 0 commencement of the 0 entertained. A'slabel S 0 No · The Q 0 d Ali: allocating; then; Khmah 0 colostric 0 .e 0 Odhul then Palma ,. been, Ds a ¥ .as Dilb 5 'name 6 Pearls Asoiv Jt Aat Bse, and sleep , away, a Chloe-Zt Muf-H 0, d' 0 u 1 as upper needs new equipments, Makp -0 Aotoca Krpopr) L4- (Ray Arlomil &amp; gt ; Helenl 2 Lil a 0 x 1 5 0 Gal j &amp; quot; E. - Iaa, t. "&amp; quot; 0 AAA 0» Aelehaa etc. 0 Luo 2: Dr. Ih Su; 1 (0.15 m; 0.243 Yasin 0 well) in Daakiybyn (2 t) has the efficiency of r 0.0 j Ioro Ohec (48 ..1 m, 12.98 0 for in rang the growth z r Anys been Takby Aagoeldla was s 9 a 1:00 F - Elah / s must be 1 j Kldhirdb, d · name Z AST assets 0 Ahish 0 K; Yat AAC 00 CE, and Done Zsa and sleep t and Lab P E 0 Z; Ei 0 for 4 Bios-4-A5- (3 d -5 - {[4 - (- Ray tightening &amp; gt; Q 026 a n} Yl 0.3-Ivol -2-Ysadkelm 7 v. + Aase]: MS ESI 521.2: '/ ; «•; 3 ; 0 s 0 Tj Suh 2 (0.1.3, 0.24 Bach well) in the first (1 t) P applicat Z Alboye.a (A.olar the loyal "t 0.24 0.24 to 0 for any six d &amp; gt; was CAT Alanm 1 of 1 Olghh throughout the night . has been put out to interact acid , hydrochloric (2 GS in water) counting degrees \ Aarh der d nm 1 Z 3 Aot Bdaa chlorine, Bthan. the organic layer cent focus was been one Ds rang me a 7 ​​Ge Nkqh Bkromadav fluid supercritical using the column is not 0 for ° e 0.2 X Akhg sector 0 1 Ed de j - '-168 ΜΑ 33926Β1 25 cm 0.5 Micro Molar. R mobile phase is a 2: 8 Mithanoda 1 (E) .mmadl flow 70 Mdadeghiqh and play time is 12 minutes to get: -5-2- (Z3- [2- (Bo-4-Kalpox "1-methoxy Saklohksil)" a 0.3-thiazole 0 g] -5-Mitel Ivel) Ace-4- (Ray Vrumethyl) pyrimidine-a-IOM Ray Floro. Aasiaat , MS ESI: [Μ + Η] + mfz 493 .;. A H NMR (500 MHz. CDCI3) . (0.03 gm 0.9 A 0 of 0 Knath) δ 8.64 (S. IH), 7.93 (m. 2Η). 7.28 (s, 1Η), 7.12 . (s. IH). 7.07 (d..7-4.9. IH). 3.27. (s, 3Η),. ++. + .. = rhSYK 2.41. Ntha i (s. 3H), 2.29 ( m. 1Η), 1.96 (m, 8Η) -5- methoxy Saklohksil) ~ 1.3-Thazul- I. - 2 - ( '0 3 "[2- ( t, S-4-Clocky I-5-Michel Venb l) Omaio) -4- (Tri Vrumethyl) pyrimidine-A- IOM Ray fluoroacetate MS ESI: [Μ + Η1 + w., '493.1;. ÏHNMR (600MHz, CDt'03) S. (0.02 153% 0 j h) 8.58 (s, IH), 7.92 (s, IH), 7.83 (s. IH). 7.41 (s, IH). 7.08 (s, IH), 7.04 (cl, 5.0 - t,. +++ = RhSYK 1. Ntha i H), 3.16 (s, 3Η ), 2.64 (s. IH), 2.37 (s. 3Η), 2.05 - 1.89 (m, 8Η.) example 41 1-Omivo acid-4-Bros-4- [5- (3-Shell-5- {L4- (Ray Vrubuthail) Peer-Amides -2 - for; Ohbo) phenyl) -. 1.3-Thazul -2-Iesclohxan Walker Bokela

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01701.tif" id="idf0106" />

01.aa &amp; quot; A.ar '\ / C02h

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01702.tif" id="idf0107" />

ΟηΡ% -169- -169-ΜΑ 33926Β1 -4- (It dissolving acid A- EA (dander-Florin-and-Yale Omi) / Bunnell] amino X Aljtouk HD 0 of B4- [5- (3-S5-Zl4- ( 'Dhiraa Vrumethyl) p 0 ~ 2 Eaan Lil Aso) spray) for 0.3-Hasul-2-L Woodman .lkrbokeili (0.079 g, 0.11 ms 0. 15-a ml). Has DONC 0 spyware Abreden (.086 3 001.a mmol) - After) DMF Maud) s in the phase reverse to get the IIP [/ purification mouse mixture directly Bo, mode ci checked Ham 0 seen 1 to 0 b-4-Bros -4 of [5- (3 -mil-5- {[4- (Tri Florosl) 3-.thiazul -2-yoke] Blomany Alkrbmla i 1 &amp; quot; ..... (0, - 3 iceberg MS ESI: [Μ + Η] + /; ι.'Γ 494.1.; HNMR .sh TFA (0.005 ppm, 0.01 Mlnimol) salt of H 0) MHz, CFHOD) 8.70 of (d., / = 4.9. HT), 8.04 (s, IH). 7.94 - 7.80 (m, 2Η), 7,69 (d / = 7.6, JH), 7.52 ...... 7.42 (m. HI), 7.42 7.24 (m, 1Η), 7.7.00 - 8; ( m, 2Η) 1 2.60 2.42 (m, .2Η), 2,26 (s, SH), 2.28 2.07 (ni, 4Η), 2.05 1 .89 (ni 2Η) 32 40 Albazih article was prepared by following generally? procedures set out in Sa +++ - rhSYK Zhot 4 "and 33 Bachkdam 0:00 of ~ {[Ad-Florin-9-Yale Sfothsi) Nrbonel] Apr; Oukubldan Alopokkha Alo &amp; lt; D: for a (4) 42 Ed 42 (1) and 42 (2) and 42 (3) and acid (Kd-4-tells -2 E 2-Dai 0 Gal-4- [5- (3-p. 5 - {[4- ( G. Shaw 0 Gal) Peremedin-2-P Ale; for every) -1.3-Yasul -2-Ihekan 1 Krboxiaa .170. .170.ΜΑ 33926Β1 acid (4, RÏ s) -4-hydroxy -2 E2 Dai-cell-4- L5- (3-sale -5 - {[4- (Tri Vrumethyl) Beramaidin -2-phenyl} Aloobo) ------. 1.3 ---- thiazole -2 z; Sichaelohan Walker. Bo Chile acid ( 1 of 0.4 s) -4 "hydroxy -2; 2-Dai breach-4-A5- (3-torrent -5" za 4 - (&amp; quot; R.aa Vrumethyl) Ber.bmaidin -2-Yale Omivo; phenyl) - 1.3-Iyasul-2-l) Sklohxan free Boxla acid (1 solution 0.4 solution) '&amp; quot;' - 4- Hedruthsi "242-Day sales-4- [5- (3-cell-5- {A4- (Ray Zawromethyl) Bear 0 Eadan -2-Aloobo) Vieil) -1.3-thiazole-2-for Ebklohxan asthma Vesely

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01721.tif" id="idf0108" />

-171 -171ΜΑ 33926Β1 was cooled Dai Oazbrobbez amide 0 AA lithium (1.31 Molar, 1.0.0 ml; 13.1 Mash Maud) Annie 78 m and Tmt added not- [3-methyl-5- (1.3-thiazole-5-Yale) Phil ] -4 - (; any Floromeshl) Zarimaidin -2-General (? 1 to a compound of the central 4, 2.0 g, 5.95 Ella mol) in 20) [HF t) Js Dvhat. However KULAIB -78 when they added more Dai Oohorosh father Allhom (031-1 Molar, 4.55 ml, 5.95 Miller Mall). In the suction flask, it was cooled Dai Oazobroslo 0 hands of Adam (31..1 Molar, 1,0.0 ml 4 .13.1 Har but) to MM Wat Hmehr 0 2.2 -4-methyl-Dai "Ootxosichaelohecsaan one of the carboxylic (2.02 Jmm, 9. .1.1 Hma Hall) in 20) ml THF). Such as Anhlol been per- anion were analyzed during Kanyuela to Mahlo. For Oveo.n thiazole 1 Gosr above, with, Ctephanz temperature 'of the interaction AA 0 Internal when Ash 4 x "68 m 0 Tguib mixture Annatj at -78 ° C for one hour, and after that has, uh, 0 spyware w is for (5 Are) and made available to Halit heating interaction Arafa to a degree heat. Then love sandals 1 Kzel in the performance of (2000's) was deduced by using χ2) ΜΤΒΕ). And then separating the layers were M Part 1 I have to, and pH = 3 using 2 HCl GS Mani was then AST 1 Yasha Bosaat e-even (2 *), has been drying organic parts Ongesah using, .Na ^ so is 0 Aceh, was Tmhb 0 Haa and ride her in the middle discharger of pregnancies on the small Goh 1 E. After compaction cJ Taqi 0 Arauh D.tm Hamel Atthaklan mm: During chromatograph Almaj above the Ashe C (30 ^ MeOH: Ted 2} &amp; gt; for Hso 0 for t acid (4 tsl not) -4-hydroxy "2.2-Dai fun-4- [5 - (3:00 -5 - {[4- (opinion Florumgl) to Aramaidin - 2: L Abu; tends) -1.3-Aizul -2-Alosmaclohecan or 0 and Ksena (0 Thal 42 (!), 1.2.9 g, 25.5 hrs / l, .21½)) Kadh Z zero termination. .s ·; 6) 11.86 ....... 12.13 MS ESI: [Μ + Η] + m / z 507.1. 1, η: NMR (500 .MHz, DMSCkle) δ 172. ΜΑ 33926Β1 IH). 10.24 (s, IH), 8,82 (m, 1Ι..1). 7.91 (s. IHl, 7.92 (s, 11-1). 146 (;. JH). 7 27 Accra 0110 of 7.11 (5. LH). 5.89 (5,1Η). 2.31 (s, 3Η). 2.1 (e d, 12.7,1 = for «), i02 (m.lH), 1.8« &amp; lt; η1,3Η), = ri, S1'K financial framework .l., l (5, J0l3.8, lH), 1.57 w . .1 = 13.1, W0. | .ii (3.; H) n. ,, (SJH) +; +. Acid (l ^ 84) _4_alok 0 ie -2.2-Dai Ashl -4 to L5- (3-crippling -5 - {[4- (Tri Vruhl) p 0 unrelenting -2; Iobo} sales) A- 0.3-Thazul-2-J 7 Skloman 1 Krbokela, acid (a 84.8) a 4 to Hydro Q -2 E2-Daemthel-4- [5- (3-crippling -5 for {[4- (G. Vrumitz) to Aramaidin ~ 2 for 0 Yale a 0 Bo} vessel) a- 0.3 Abzul-2. Bell Skloh 1 n Alkrbokciec acid (1 No 0.4 not) -4-Bros -2 E2-like Dai-4- [5- (3-Hishl -5 - {[4- (G. Floromeshl) Ber.eadan -2-Aloobo} Hivel) A. 0.3-thiazole-2-for Ascalohecsan Elk 7 Boksila been preparing in (examples 42 (2) 1 42 (3) 0.42 (4)) Mystery bits corresponding to those Alambdih j \ L'l / (Η1 + έ 507. (R4, si b MS ESI: [Μ. Chatt rl \ SYK: +++ 2 way to prepare example 42 ( '1) step 1: (1 s) -2 E2-Dai ^ u &amp; quot; &amp; quot; &amp; quot; 4 "&amp; quot ;. Ookmos ^ ^ n walk and Turn Zssz 0 T.

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01741.tif" id="idf0109" />

Has thawed enzyme Kittoricanutaz 119-K RED 'for certified to 668) NADPH mg 0.3 A4 does not trace the weight, which is available, from 668) NADP, (CodeMs, Inc., Redwood City, C'A mg 0.3% and influenza, fornication), an enzyme glucose Nahedroginaz 901-668) C-DX mg 0.3% w / w, available from,?.; Codex ...-. 173.- ...-. 173.-ΜΑ 33926Β1

Inc., Redwood City, CA) and (a ~ (+) - Jleclr (1.16 a JL · 6 1.9 f Mall &amp; gt; in the yolk 4 well Mnim 0.1) KH2PO4 / K2HPO4 Molar Ina 4 and sleep Hydro 0 occasional = 6.8; 445 ml &amp; gt; E 0 d degree heat 1 Rh 1 environment Amehath 0 in a beaker 0 Igsal, has Anadh crippling 2, 2 &amp; quot; Dai crippling -4-Ookssowsklohec 00 that / Boksplat Rabieh (composite center-24, 22.26 g 0.13-a mulch mol) in 6) DMSO &amp; lt ;,) were added Amehlol Alata to Amehaol Adzm d 4.ΚΗ2Ρ.4 / Κ2ΗΡ Elpin above. Akhadda.a been No. 1 Alhedrugiy - 1 Ia 6.9 to 17.6 Tiod use of NaOH Molar Mash was Tgbb reaction mixture for 19 BL I helped your pH 6.9. Been adjusted 1 to No. Andros to 4 using 11.7 solution of HCl Molar (0 I) was CAT mixture 'reaction for 30 minutes, and then Tmt adding £ y} 122 m (100 ml) 0.2-Roirl (1.00 ml) and sodium chloride (40.0 g) . Qsal was eccentric and was nominated one Ithh through organic pad of 200 Solka Floe. It has been compiled and water Alabakh Alabakh Maya Almtkhalgh output candidacy has been drawn using 100) MTBE ml). The concentration of growth in August Olhtyh classes in the center of Verb to 1.00 ml, Am'nvaolha Mr'd with sodium bisulfite (3.03 blood b 67.6 mmol) and water (1.00 ml), and every time it is. Giving priority to one of the second mixture Ashe strongly Pvt 0 30 minutes. It was treated aqueous phase Aljia Albotasmom carbonate (22.0 g, 159.2 Hlvi Mall) and that Ban was mitigation using I 00) ΜΤΒΕ ml) and _tm Pray Alotfat. Am kicked. Akrq 0 at organic data in the middle of Verb for (one of) -2; 2-Dai all four Aukssowsklohxan / Bukdalat (9.66 gm, 96.2% t, Aadh Ttoklh) as oil. MS 2.57. (H: NMR (400 MHz, CDCI3) δ 3.73 (s. 3Η). 2.62 (t, .1 = 0,6. EH a .184 ESI: Μ +. M / z (\] 2 (13.7 .1.8. EH), 2.29 (m, IH). 2.19 (d, .1 = 13.7. IH), 2.ΙΙ (m - and .2.44 (dd 10] as upper .m) (]:.; 3 0 ( s1;). .1. (1-07 (s, 3El 0 ΜΑ 33926Β1 1.74 step 2: acid hydrate (.4, si h) -4-Brod -2-E2 Bethel Dai-4- (a, l ~ -lyaz well - 2 - Yale) C 1 Dlohxan Walker Boksila

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01761.tif" id="idf0110" />

To a solution of Bethel (of 8) -2-E2 an intelligent Bthba. -4 0-Ootxoslalohec that Carr Boksilat (1.0 g, 54.28 Miller Mall)) Vi'1.6.3) m THF), has Asafh'lmazid of 1.84) ml THF) followed Buthaiasul (6.93 m, 42..81 ms Maud). After that -anbrid Amehlol output to -78 m. Tmt adding boron fluoride Dai Tri-ethyl ethers (9.24 gm, 65.1.4 mmol) over 24 Dwiqh and 0 Ahalian Na'nj not aging at &amp; quot; '78 Mdz m for 5 minutes. It was added N- Jubl 1 lithium (2.5 Molar in Hecalat, 20.05 g, 71.98 Maza Mo, L) 1 Li of 0 Hah A'ltana the mixture for a period of 4 hours on -nzid then. Aging the mixture for 1.5 minutes. Heder added sodium oxide (Mani solution 1. Molar, 54.3 Mann, 54.3 mmol) followed by 54) MTBE ml) and the mixture was heated to 20 ° C. Pray been aquifer has been pussy-class Alaazavih.mmahlol Mani half of the radioactive sodium fluoride (54 ml), which led to obtain a solution smaller colored Khgev are Meishan (4, si p-4-Brod -2.2 Dai-methyl-4- ( 1, 3_ -lyasul - 2 - Yale) Saakhluhecsan Krbozsellat, where his focus was then August Datt low partial to a low Hhm. Butanol was added (124 ml) was seen Phys Amehao.l to the oil under the spawn Jria. after that scare Alakhlul -mmithanol (1.24. ml) were heated to 40 ° C. Tmt added a solution of Hydro to master sodium 0.1 Molar (92 ml, 92.0 mmol) over 5 minutes was heated Klien Ainath to 50 m and was then Totaigah for 16 hours titles -175- ΜΑ 33926Β1 Aanbaraa, to 20 m. was Gsid 1 malignant 0 Ilat Aat must; j Krumadn (24 Amal 0.62 t 0.62 0 l) and has crystallize an aqueous methanol solution of Almenth Basafh HCl aqueous 6 Molar (15.3 t 0.92 mmol) over 30 minutes. the aging grout for Maotain was then the focus of the mixture under the pressure of Mnkhvan, fleecing Na.aly total volume of 24.1 ml. were grouped Article Anslbh Baltr Tih then laundered Balme- methanol (0.1,: -1- size : Hhm 0.62 ml) and then perform (62 ml) to obtain the compound contained in? the title (1.44 kg, 86. 0.41 mmol, 99.9% Xiaodh'nchaklah) Tmazh solid baloney ace baht. 5) 12.0-11.89: (256.1 lHNMR (400 MHz, DMSOdô; [MS ESI: [Μ + Η, (211, 3.36 (br s .br s. 1,1-1,)) 7.67 (d. ./: 3.5 Hz. Ill), 7.53 id, .7 = 3.5 Hz, IH). 5.79 (s. 1Η1) .31-11 .2., 13-2.2 () (m, 21-.1), 1.95-2.09 ( m, 1,11), 1.76-1.91 (m, .31: 1), 1,53-, 1.65 (m. 211). 1.11 (s (31-1, 0.99 (s. step 3: 3) - H -bromu "5 ~ Buthailivel) -4- (Tri Vrumethyl) pyrimidine-2-Amin çf3 β2

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01771.tif" id="idf0111" />

1 Li Set of 3-bromo ~ 5-Maple Oslin (45.77 g 0.246 Maza mol) in Tolo.bn (500 ml) has Asafh 2-Klro-4- (Ray P4 War, Lobel) Yprimedbn (05/05/90 Ham, 2954 for any Moi &amp; gt; and creatine, Saguvek (28.4 g 0.295 »Lee mol) sequentially. The Amehlol one of the outputs is heated to 105 are to 1 for one night. The cooled mixture Annatj, was diluted with water (00 d ml) was amended to Artem! to pH 14 through Adhalo ôjU Pro .ksid Sod.boum 1 m Apr Akougl (26.6 m are Mahlo, for containing 0.320 mmol of sodium hydroxide). the Aschas Otakhlul but &amp; quot; c using 500) ΜΤΒΕ ml) was μ classes, were jri, Aibmh a-yeh after 0 Zlli 1 Slme ΜΑ 33926Β1 .1.76. (Μ3.0.) And then knead 50 (name? Of saline solution Ta (200 t). Name Trkir Alabakh Alamoah 5 i j 1 Li 200.0 n 1 consortium in Dora Adh. To 1 Mallat has Adhaoh e 0 Tan (660 mu) nest for 40 minutes followed Baltotaiq for two hours counting the 20 m. the asset slip A'vlbh Z x 0 Lal d scarcity, were laundered Mjbtan (200 ml) were dried in Zen 'Nfarrak at 40 m over the 1 for the night blacks z see Alwar, d in the 6 to (69.5 32,094 JL well) Kmaadh casting 0 Den \ of Va.zh, t ..,. MS ESI; 1.Μ Η] + mi: 334.6. 'HNMRC400 MHz, CDC13): δ 8.68 I'd; 7.30 (s. 2H): 7.10 -7.06 (m, 2 H); 2.36 (3. 3 H; (4.6 Hz, 1 H); 7.79 (8, 1 H =. 1 to step 4; Z (k 4 E) -4-Hedros -242-Dai Met 0-for-4- [5- (3-Methel- 5-g [4- (G. Vrumethyl) Goodyear 0 Eadan -2-Tao 6) Ivel) a-, d-thiazole -2 ~ 0 Roetan a 2 Krboxay been Tazzaar: UJ of Alkhaloh 2 product (8.5 g, 0231 Miaa wail), move product 3 (11 Jmmh 33.4 0 Lee Mall) E acetate Palladium (0..1-5) (II g, 0.68 mmol), Ptgalick acid (3.5 g; 35.3 mmol), tubers Alboisom (1.5.1 g, 09 mmol a) and Dai Odamantil not-Biotilphusvin (0.74 m; .2.1 t mol) of nitrogen. has Ahtefh Dai 0 extrude for Sita 0 Dam ('60 ml) was Talheir commentator Palirugen. was Tguib the mixture at 120 ° C for 20 abused, and was cooled and Done poured in water ( 90 ml) 40) MIBEjj ml). And then separating the aqueous phase was 0 g b Baswam 2) MTBE *). The acidification of the water using a phase 6, GS HCl to No. lessons Ashe Q Were Aslas using X 1) MTBE). The spontaneous mutant washing with water (χ2) and Dr. Zllt 0 then 'Kotair MBTE attempt to center. Tmt adding acetonitrile to Article Ala.kz remaining in the crystallization of; pronation contained in the title, which was separated by filtration and Done Tajafiah in central Morg. It has re-crystallization! Crude product from 1: 3) THF: MeCN) for &amp; lt; C \ biting (4 ~ (R4, sl ΜΑ 33926Β1 Hydro Si 2 E2-Dai cell-4-Ld- (3-cell-5- {4 - (Ray Vrumethyl) Ber.amaidin 2-Yale Omivo; Linnell) "1.3-disappear-for-2; Scalrhecsan carboxylic (1,1.9 g, 4.d 2 mmol) as a yellow solid, mS ESI:; Μ + Η]; - τη / 2 5 () 7.1 ,. ΙΗ NMR (400 MHz, □ MSO-dô) δ 1.2.03 11.-95 (hr S, 1Η), 10.24 (s, IHl. 8.84 (d, 1 .4.7 = L Η), 7.94 (s, IH), 7.92 (s, IH). 7.46 (s, 7.27 a (AA (&amp; quot; d. 07 = 5 4.81 Itt). 7.13 (s. 1Η), 5.89 ( s. 1Η), 2.32 (s, 3Η). 2.16 (d, .7 = 12.7, IH ». 2.10 1.95 (m, 1Η), 1.86 (m, 3H), 1.65 (d. ./= 13.8. 1Η) . 1.59 (tl. .7 = 13.1 ,. IH 1..13 (s. 3Η). 1, .01 (s. +++: rhSYK 3- Activity Η) Na- (l) 42 Hzl 10 (1 of 0.4 Yum -4-Sdroxa -2.2 0.0-Dai of 00 for \ -4- [5 "(3-teacher-5- {L4_ (Tri Vlowoesel) Peremedan -2-Yale Obno} sales) for ~ 0.3 - Sasul- 2 Lil Scalusha 0 sodium bicarboxylate way for 15 S-acid (1 of 0.4 E) -4-Bdluki -2.2 V-Day 0 Yale-4- [5- (3-Bill-5 ~ 9, any Holthel &amp; gt; 02) label 1A 0.3 -0 Bzul-2 Ic 0 .nkerboye (9.8 mg, 0.01,9 0 Delly 0 well &amp; gt; j Adder (20 Wu) Ua, (20 Bkreuer.) has Akhahh Vdro'b F; Daim (1.9 0 Ekougl as 0 ') 0.0 but) E was Miss Aai p 3500 'y; 15 days Dh Sehl any ads ... Z - 0 0 Almaee .. 11 0 frozen solid, was Najafigh tahmeed even in blacks Presentation (0.1 of 0.4 does not) -4-Haider, r ~ 2 ; 2 Dai Haal 4 (5) (d d 20

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01791.tif" id="idf0112" />

-178- -178-ΜΑ 33926Β1 5-A, 4 (Tri Hro.al) E,: Hull-2-Yale Abu) venerate &amp; gt; 3 'I Bazdl 2 Adasmaclohan sodium Frboksilat, way 2 T. melt Homs (AH 0.4 c-4_0arlklaa -2.2 V-Day 0 Shell-4- [5- (3-paralyzing-5-g [4- (Ray Dleroo 0 Shell &amp; gt; Bel- , to between -2-Yale a 0 hands} to Khalaa 0.3-'barol -2-Yale Skloekan Alhoye (7.15 m 0.2 a .1.4 0 Lee layer 3) in the Saha-for Ayad (35 t) has additional 1 FH hydroxide 5 and sodium (Mio; 1.383 g; 83.da Haay.; l; 1 and sleep the mixture for 15 minutes. has Anavh acetate asset (50 Is) Ate &amp; lt ;, Huda 45 friendly and sleep aging one of the mixture for one hour and; unit at 20 ° C. was added Rev R 0 n Abat Ischl ( 25 ml) and has about it 55 ml of Munib in Omt Rigg 0 'seen Rah Ad'lat was Lviv 0 Bosntat Abuthail (5 ml) 0 drying Anadh enclosure in the center of seductive g at 20 ° C to obtain Ai compound 1 Oardwi Aladhu; n (7.02 gm, 3.28 a cellulitis Mall) &amp; quot; MS ESI: [Μ + Η] + ιη / ζ 507.1. HNMR (.400 MHz, DMSO-de) δ 10.24 (s, 1Η), 8.83 (d, 07 = 4.9, IH), 7.91 (s. 1Η). 7.89 (s, 1Η), 7.48 (s. 1Η). 7.27 (d, 0 /: 4.9, IH), 7.12 (s, Iff), 5.82 (br s, IH), 2.31 ( s. 3Η), 1,. () 6 - 1.85 (m, Iff), 1.84 - 1.68 (m, 4Η). 1.60 - 1.45 (m. 2Η), +++ = rhSYK- 1.12. financial framework (s, 3Η ), 1.01 (s. 3H) K- (I) 42 Hzl d 1 of 0.4 s) -4-hydroxy -2-E2 Dai Bethel -4 - [5 "(3-mile -5" t L4- (Tri Toromethyl) Peremedin -2-Yasuo) Yale) -1.3-Teasul-2-0ysklohxan Drboksilat potassium ΜΑ 33926Β1 and 7 of En Maah acid (AH 0.4 e) 4_hirok 00 E1-2,2-crippling Dai-4-5 does not (3-crippling-5- { [4 - (&amp; quot; Ray Ioromithil) PAHs 0200, to Odgo} 3 Λφ "Iasul -2-Yale Sakhloten 1 Krboxr (9.8 z 0.019 · JL Mall 0) in Ostobak.al (20 Maikarontr) and 0 termination (20 Maikarontr). Has A.dhaah b Rowe 0 0 b Albu Maberm (19- μΤ; 19-0.0 A 0 Lay mol) was -schan thread to 35 m births 1.0 minutes. Made available to lewd cooling to room temperature, and was diluted with water, then freeze it to a substance poured 5 'it was dried Bakhamid Sa 0 refugees in for Z (4, si He) -4-Hdroxa -2.2-Dai Bethel-4-L5- (3 ~ sales -5 - {[4 - (- Ray Vrumethyl) pyrimidine -2 no one Bo} Ehl) -1.3-thiazole-2- 0 Weiner Ichaelohecan Krbkba (v Albota, Eaom. 0 () 5) .5 () 7.1.Iff NMR ; '., w + [] ...; ..... M]:;. MIS ES 10 .MHz, DMS0-dô) δ 10.24 (S, 1Η), 8.83 (d, ./= 4.9, IH ), 7.91 (s. 1Η ». 7.88 (s, 1Η), 7.46 (s 1Η), 7.27 (d, .7 = 4.9. III), 7.1.2 (s. 111). 5. () 7 (s , 2Η), 2.31 (s, 3H), 1..92 1.82 (m. 2Η), 0.95. (1,3.8. 51..1), 1..54 - 1.48 (m, 1.1 ... 1) , .1..47 - 1.39 (ni, IH), .1.05 (s. 3Η E's, 1..81 - 1..65 (ni (31-1, s). Activity rhSYK = +++ rains 45 15 e-butyl 4 - hydroxy - 4-L5- (3-every-5-Aa4- (Q.aa Vrumethyl) Bear 0 Eadan -2-Yale a 0 Su} Phil) -. for 0.3-Marol "" 2 : l lar: Dn- 1

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01811.tif" id="idf0113" />

180- ΜΑ 33926Β1 I- -78 0.;, Hebrews; guardian! Compound 0 for 4 and ducks (200 Ni, 0.595 0 for in d) in THF (3.0 t) to 892) LDA .bakro b r 1.784 Jr) and then p A'ir P-10 y Diedq its termination E 0 ..-. potable 4-Oukubibreden ..-- 1 0 _hod loyalty (474 ​​Em, 7 to 2 t d).! Bh the asset Altdih slowly to -20 0 0 M. Pei de 4 "fetch. The F-ci DONC 0 A Lind chloride 1 Ssbaum Manny satiation then Schas Altj Ed; Gal 0 then Del Adazavih less water and Mahiol DVD. Then drying 1 Ztbakh worst termination, then a beam 01 and then Ed's parents 0 B 0 g through a fine one to Btar. Grown Tven Ad'dh Lalai Bnao.atotmav the 00's and Dr. Boisson 0 F (-50 Ne Li? 1-bit Denny in DCM) q z 260 m (0.485 t Ade 82%) E r, j. Pour - . Shell 00 Yale &amp; gt; #NAME-2-I Forever) Honey) - | 3 E-disappears-2-Yss-of-every-bit Z * intention breadwinner 0 .MS ESI: [Μ + Η] + ίη ,, 'ζ 536,2. Ή NMR (600 MHz, CDC'13): δ 8.60 (d ./4.8 T. Hz, E. H); 7.8 I (appr S. 27.74; CFA (hr s. I FI); 7.28 &amp; lt; 1 .e) 2 not 0.7 A..aa.e Η); 7. ( »(5").

s.b0) 0.4;, 4.8Hz, lH

41. 0; (2. (:) 9 (m, 2Η); 1.88 (ni, 2Η; 2.34 (s, 3111; (2Η a? 028's (hr for; (; '2 f (9Η 0? 0). 4 + = rhSYK then Ths R, Cat god 0 states (tables &amp; gt; a 7 Li Z; nee champion: Ge i &amp; lt; y della August in Hthal 45: table 45 181-. ΜΑ 33926Β1 3 (3 j) of 02 E

/ '-' N V. (nm N:

OH CF3 d

, SN i &amp; quot ;, N + [Η; -Μ] rhSYK Activity his machine; for example one of the Ahzl 550.2 0 550.2 homologous homologous 1 1-45 2 2-45 Example 46 4- [5- (3-Butel -5 - {[4- (Tri Vrumbl) pyrimidine-2-Aloobo) phenyl) a- 0.3-thiazole -2 "to Ebebaredbn -4" first

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01831.tif" id="idf0114" />

Atiotil to 4-hydroxy-4- [d (3-Shell-d {A4 - ( 'Ray Vord.methyl) Peremides -2-Yale Omivo; Vasyl) A- 0.3-Iyarol "two-Yale Weber .ides-a-Krbochila T. (50 mg, 93 (). () ..- 182- ..- 182-ΜΑ 33926Β1 Hess mol) in DCM (e ml) grown in addition 1.44- microseconds. liter. Of 20) Mkae TFA) and was' defaming one descriptive Z degree Hraoh Aldv 2 for 4 hours. Tmt added to the mixture NaHCOj saturated with water was 0 S descriptive A.sl. Gail was organic layer with water and brine. The Tdjaaay class 1 Ie been faithful; Gahao. It has been reduced to Munib in the center of Morg for 40 Bhm (0.092 touched Mall; 98%) of 4- | 5- (3-methyl-5-Za 4 - ( 'Dhiraa Vrumethyl) Beramb 0.2; not refuse P 0 Zel) -1.3 -teasul -2-Aloyprid 0 Q-4-first. ..... MS ESI: [Μ 1: 1] '; ιη / ζ 436.2. 'II NMR (600 MHz, RMS.-dô): δ 8.81 (d, 02 = 4 7 Hz j H); 7 93 (π10 21 [) 7. «(s. Lit4.9 = t, 5) 7.25:; Hz, IH); 7.13 (s, lH); 5.97 fbf s. IH). 2.78.2,58 (00 I). 03 ;;) 79 · 2 · Iztaeads Η): 1.93-Κ98 (m. 2Η), 1.63-1.65 (in. 2H &amp; gt;: 46/45 pain me at the table (.ljaddaol Next) Mazerh manner to those described in the examples in the 'CJ . was seen inciting 0 der agenda 46

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01841.tif" id="idf0115" />

Alsourd [h-RH] + rhSYK activity. R 1 to Mial (photos) observed free base 504.1. +++ CP's 1, -46 -183- ΜΑ 33926Β1 free base 494.-1 CO2CH3 2-46 Example 47 4-Hadro Casey-4- [5- (3-Methel-5- {[4- (Tri Vrumethyl) pyrimidine -2-conveyances) Linnell) &amp; quot; &amp; quot; &amp; quot; 1.3-thiazole-2-I Babreden- 1 "Krboxamad

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01851.tif" id="idf0116" />

/ C (0) NH2 to 15 mg (0.034 Miller mol) of 4-L5- (3-Michel -5 - {[4- (G. Florhumicthel) pyrimidine-2-night Omaao, A. underwriting) - 1, 3- thiazole -2-Alobebar 0 DD 0 Q-4-first in? A0a &amp; quot; A '/ Filler (1: 0.1 mo) has F-0 Agha 4.2 Bhm (0.052 Maaa Mall, 1.5 McAfee &amp; lt; &amp; gt; of Samat Ilbo "Lazio and 2 GS Hydro Torik acid (22 microseconds liter, 1.3 m 1 warm) 0 heating 1 mixture at 50 ° C for 6 hours and a maximum Zlat has added another 1.05 Hecave of cyanate; for potassium Mkae friendlier than HCl was. Thalib mixture count of 50 m throughout the Night. then ease interaction use NaHCOj impregnable water has hashed acetate ESL. the organic clot washing water was Tdjaifaa was nominated, has been removed Deeb hinted Dgaz Mkhvvy. was purified Anadh remaining Bkromatogeray column by gel silica (small -00 a% Aasiaat, ethyl in Hhanat) Nlhakbol 12 mg (0.025 over Maud, 73 Elia) of 4-hydroxy-4- [5- (3-Alizai-5-g (4- (Fiji Vrumethyl) pyrimidine-2-Aloobo) appended) a- 0.3-thiazole-2-Iabr &amp; quot; Hn- 1- ΜΑ 33926Β1 1.84- MS ESI: JM + H]; m / z 479.2. 'H NMR (600 MHz. Krboxamad as a solid slash egg CD30D): δ 8.68 (4, 4.8 = t Hz. JH) 7.99; (s, a H '.) 7.87; (s. 1Η): 7.40 (s. JH): 7.10 (m, rhSYK 2. Nthat. Η) 3.91; (m, '2H); 3.28 (m, 2Η) 2.34; (s, 3Η) 2.16; (m. 2Η): .1.83 (m. 211) Mv'l 49 4-hydroxy-4- [5- (3-Shell-5-g [4 - ( 'Dhiraa Vrumethyl) Yprimaidin-2-0yobr) Thiazo-vessel) -. 1.3-for-2 night biperiden-0.1-sulfo Named

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01861.tif" id="idf0117" />

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01862.tif" id="idf0118" />

S.2NH2 to the solution of Asotil ({4-Hdroxa-4- [5- (3 ~ 0 such as -5 - {[4- (Ray Floromeshl) Peremedev -2-amino yen) Foutel) A- 0.3-Rasul -2 -alobhbreden- 1-Yale) Slgopl) Rrbamat (45 pp., Miller 0.073 mol) in 0.7) Ps DCM) has Ahaqh 0.120) TEA D, 5..1 ms Mo; l) has been stirring the reaction at room temperature for 80 minutes , and then added more than 00120) TEA ml, 5..1 mmol). After 90 Nqiqh has Aranh most volatiles beta-Vq and Altfarrak. Then ease Almazh remaining Ba'ithaddam [protection of saturated NaHCO and ethyl acetate. 0 Njgev Tabqatmd Allah Otaktah 0 vaporized for Hisrl on 4-5arh ~~ 514 ~~ (3 - -185- -185-ΜΑ 33926Β1 [methyl-5a 4 &amp; lt; Ray Vlmorumajthel) Berimid.n -2-.yosto} Ivel) A. 0.3-Thazul -2-Yale mS ESI: [Μ b Hjf m /:. (Abreden- a-Slgoyb 0 (Aq mg, 0.06 mmol, 82% Katj 51-5.2.600) I E 1.1 MHz. CDC13 ): δ 8.59 (, d. .2 = 4.8 Hz. 87-7; Alao (s. Hi): 7.81 (s, IH); 7.25 (s, lH): 7. () 2 (s, 111); 7.00 (4.8 Doi Hz. Ill} 3.59; (d. 2 a: for Hz, 2Η) 3.14; (m. 2Η); +++. 1I1SYK 2.34. Activity (s, 3Η) of 2.2; (m »1.94. ; (Ladd (d, .7 = 1.2 Hz, 1 termination) 50 Hthal -..... 3, 4- [5- (3-per-5-g [4 Dry Vrumethyl) Ber.bmad: Q -2 " ".bl]} tends Oaaao) a- pass away" 2-'l; ~ a- (but Noble) biperiden -4-first

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01871.tif" id="idf0119" />

Etiquette has 4 [d (d methyl 5A [4 (Ray Grumethyl) pyrimidine-2-Yale Ominoa Fajl) -1, 3-thiazole-2-Isds -4-first &amp; lt; umbrella 46.50 mg, 15-0.1 Mia Maud) in a 2 2 pearls 14 ml) 0 4 has addition Ν, the smarter Orurubalaslas {50 micro liters, 0.287 mmol) and. Tloria ~ uniformed Slgo.bl (29 microseconds 0 l., Mar 0.230 L) sequence. Akhlol was flipping through the night when the temperature is free; drizzled Algr.gh, after 0 has been a focus in the center of Morg using Genevac. It has thawed material remaining laze in DMSO and have been purified through 48) HPLC-1-.1 (): CHE'N% 82) for 0 Ely 4- [5- (3-mile-5-g [4 "(Ray Zawromeshl) ΜΑ 33926Β1 4 Se ¥ yen -2-Yale) Bo} Vhgal) a- 0.3-Thazul -2-night-.a- (vessel sulfonyl) biperiden MS ESI ': [Μ 1..1) .- m / : 576.1. IfiNMR (600 MHz, l) MS () - d (1) 6 10.2.1 (s. III), 8.80 .dl (d5 5.2 for Hz. IH). 7.95 {(1 ../::= 9.2 Hz, 2Η), 7.75 (dd, J = 8.7. A.0.a Hz, 2Η), 7.73 {s. 1Η), 7.65 (t, ./== 8.1 Hz. 1Η). 7.43 (s, IH). 7.25 (d, ./= 5.1 Hz. IH), 7.1,2 {s, 1Η), 6.10 {s 0;;;. 3.54 &amp; lt;, d1 ./= 12.3 Hz. 111), 2.58 (t ,, / =, 12.3 Hz, 2Η), 2.54 -2.37 (m, il), 2.28 {s. 311), 2.08 ++ 9'hSYK 1.6.1 = /.,!)0 Activity Hz, 211), l.80 (d, d = 14.6 Hz, 2Η) i And, 51.1 ~ {4-Brod- 4 ~ 51. (3-Shell -5 "za 4 &amp; quot; (Ray Vrubuthail) pyrimidine Yale;? Mino) vessel) -. 1.3 Abzul" 2 "at night Weber condemns" 1:} but Aithadhu.n

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01881.tif" id="idf0120" />

To a string of Osath acid (9 0 der Kro, 0:15 relied z) Wah's; Bualdaa to Adasul (266 mg, 0.287 plating Jr) n Q Idhavh solution 4- [5- (3-sale -5 - {[4 "( ' Ray AAA; 0 t vessel) -1.3-Thazul -2-Yale Abr.adn -4-first (such as 46.50 Bhm, 0.1.15 JL 0 well) and Hedrok 0 C Raurerasul (26 mg 4 0.17 chiefs (sitting) 0 j Hall) Hmaa in Ν, not-Dai Bill Tmurmamed was shaking commentator per- in Bohdan Hiwal Night eBay mass 0 der ^ h 0 of 1 of Anarafh. was Tr'chih Altnfaal mixture was focused in the center of Verb, grown melt Anadh 187 ΜΑ 33926Β1 (HOCHjCN% 64-30, 11 (0.1 (: and has Melt Z during DMSO Abi Lalai at 0:00 d [- {4-Hdluki-4- [5- (3-j-H _; [4 &amp; quot; (Ray fils 0 j MS Kl: .aon -1.3 -iasul -2-.yaar-Dave-a-Alaoao.on [M + H] b mf: 478.1. a ί &amp; quot; Ι NMR. (600 MHz, DMSOI) δ 10.23 (s, 1 H), 8.81 (2 5 Tatar e 0 Hz, Iff), 7.95 (S, 2Η10 7.44 (s, a H), 7.26 (d,, 7 = 5.1Ηζ, III), 7.1.4 (s, III), 6.30 (s, 1Η) 4 .25 ..... 3.99 (m. 1Η), 3.73 (m. 1Η), 3.41 ... 3.34 (m. 1Η), 3.07 ..... 2.97 (m. III), 2.47) s, 3Η), 2.32 + - ++. = 1) 18 YK Activity. (s, 311) .2.2.5 -2.14 im, 1Η), 1.93 (ηι, 2Η). 1,75 (m, 1 H) example 52 ^ crippling 4_hiroksa- -4- [5- (3 crippling -5 - {[4- (Ray Vrubuthail) Aar.eadan-2- Yale; Omivoa did) 1, s-2-Ebzul Alopetr. Adr- 1-Krbok 0 must CFs

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01891.tif" id="idf0121" />

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01892.tif" id="idf0122" />

BC Adla 4 A5- (3-0e 5 - {[4 Arai y 0 d Q -2 Mamo} builds -1.3-Iadhull 2: 1 Eoarydld -4 for the first (0 w; l 46.50 mg, 0.115 Lutfi Ru) in 01 A &amp; gt ;: Loua (E + &amp; gt ; 's! Z "N' Hloa St., sss (30 curlers 4.72 a 0.00 Dvemul) and'aloswalon a 7 0 Akdd 7 '130..0 over Maud) Abb. was -ntv IOL Daal one of l E 0 for Doje Hr.arh Abe after 0 so then a pedestal in the Verb and i using Getievac. has Ad'bh ΜΑ 33926Β1 (Η2Ο: CH01CN% 64-30) HPLC and has Zhe through DMSO 1 of a substance as the 0 went in for a 4-Hbroxa-la-crippling-4- [5 '( 3-Michel -5 - {[4 Dry Almrro 0 PBL) 36) pyrimidine-2-night die} Ivel) 1, a-Izula2-Aloabr 0 days-a-Kalpoybd MS ESI: [Μ + Η] + m / z 493.a. IfiNMR (600 MHz, DMS0-d6). (Mg, 0.073 ms Mall of 10.22 (S. 111), 8.81 (d, 5.2 = Hz's, 1Η1. 7. () 3 (s. 211), 7.44 (s, lH). 7.25 (d, 1..5 = t Hz, 5 E. H), 7-13 &amp; lt; s0 1Η), 6.43 (d,. /: = 4.8 Hz. 1Η), 6.15 (s. Ht ». 3.83-3.74 (m, 2'H) (d, 14.0 - t Hz, 2Η). 3.0711.1 = 14.5 Hz. 2Η), 2.53 (s. 3Η) 1 2.29 (s13H). 1.98 "1.82 (ni, 2Η ), 1.65 (d. H + 1SYK 13.9 = 7 .. Activity Hz, 2Η) Alohah 53 (SAL) and 53 (2) 10 Ahmany 2_ {3_adlokl 3 for 05 (3-0al -5 - {[4- (Ray Hmol &amp; gt; Els &amp; quot; 2 Hall U} Yale) a-, 3_ba not Ailzatban 02-a-Yale} -2 to 0 Eblbroo; Adhuak 2 [2 {3 31. [5- (3_hl -05 {[4- (G 0 to M.r.ohl acid) 2-A2 LED-Bros-S.l.ma rather a loyal, E. * sa-la-la. Brobbanuel) oxy] -2-Meid Broad "E 'h -189. ΜΑ 33926Β1

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01911.tif" id="idf0123" />

Erased 3 '[5- (3-Bill-5-t [4- (G. Florubnil) Peremedan-2_alo been Tejen Mahiod Dr. AAA 0 H 0} P 0 l) -l, and ~ Parul ~ 2; l] Ozsudain-3- dL (50 mg, 0.123 Mlaa sire) 'acid 2_bralr -2-Bethel Brroyod (20.5 mg, 12 300 touched Mall &amp; gt ;, and Ray E. 4 Yale as (0.043 t, 0.307 Malash mol) in Tzsrovioan (1 ml) in Skrodev to Mdz 100 5 I j s add an additional amount of acid 2-bromo -2 minutes to Methelbrroyobat presented Huda 5 Diiq 0 n g (8 d 400 480 Mia Maud), G. Nithil Secretary (0.060 t, 42.8 .. Miller Mall) 'Looney 0 a and ml &amp; gt; was heated interaction in Maikarood oven for 10 Dlazq additional. the y 0 7 has purified Bois 0 Plan HPI C in 1 phase inverted (1.5 (not 50% Acfaai 0 Oadzlt 0.;, it 'termination Agtoah Ai Almenthat frightened them not; for not-for a; Vyish) 'Bam ^ Z t Elmy:: -hebrok 000 j 0.03 [5- (3 - ^ - 5 - {[4- (Ray Vrusbl)' h -2-

18 Yzule2-Wyart &amp; quot; N "A-t) ~ 2 ~ Shell Brobbadhuz (0 Thal 53] Obgo} Eadsl) A-, 3: d6-DMS (Y? Η ΝMR (500 MHz; .4941: MS ESI: tM + Η] + ι [), 32.5 mg). E: (8) 's \ [4.9 Hz, 1 H); 8.19 (8,1 H): 8.04 (s = t, 8.85 (d; 10.30 (St W --190- --190-ΜΑ 33926Β1 (s, l 1-0; 7.29 (d) 4.9 = t Hz, l H); 7.22 (s. 1 10; 4.82-4.50 (m, 2 H); 4.53-4.1; (m, 2; Zla 1.53; (14 8.3) 2.33. Zt ^ 14 ha; a- = -. a --- a - + (s. 6 1--1) (2-for acid (2- {3-Bros-3-L5- (3 ^ ~ 5-Rl4- (tea Ior 3-methyl-2-pyrimidine Yale ] Omivo) Ivel) a- 0.3-thiazole-2-yen-a-Ozaadan Yale} -2-Michel MS ESI: [Μ 11) + ηνζ. (Proba Noel) oxy] _2_methyl Proba Nwick (example 53 (2) 0.8 mg 494.1. Ή NMR (500 MHz, d6-DMS0): δ 10.30 (s. 1 H); 8.85 (d. .7 = 4.9 Hz.; H); 8.19 (s. 1. H); 8.04 ( 8, 1 H); 7.73 (s, 1 H); 7.47 (s, 1 H); 7.29 (d.4.9 = t Ηζ.1 1 H); 7.22 (s. 1 = rhSYK Activity .H); 4.82- 4.50 (m. 2 H): 4.33-4.11 (111.2 11 (: 2.33 (s. 3 H): 1.53 (8.6 14 (1 to 54 examples (1) and 54 (2) Bill {[4-hydroxy-4- (5- {3-a (4-Börse Baremia. yen - 2 - Yale) Omedhu] -5-Maple Ivel} -1.3-disappears-2-0l) Babreden- 1 _aysaguh) carbamate 4-chloro-4- (5- g 3 - [(4-methoxy pyrimidine -2 "Yale) Omivi -5-Methel Vieille a &amp; quot; - !, d" thiazole-2-Yale) Babreden- 1 --- sulfo Na »hands -191- -191-ΜΑ 33926Β1

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01931.tif" id="idf0124" />

As upper Formulate 0. 5 4 has additional 1 FH Klroslaoaloazausa 7 t (16.38 Micro P 0.189 0 Lee Mudd) in d; j Klor.obthan to Butanol (7.63 micro liter, 89 A 00 ms Moo} · After S Ke 30 Dyhh, confusion was added 4- (5- {3 - [(4-Mathoki Peremaidinl 2 &amp; quot; ~ Yale) ASU's - 5shl Vzel} -1.3 ...... 2 --... Rasul-i) biperiden &amp; quot; -4- first (50 mg, 0.126 ms 1) and; any E0 Shell security (52.6 microseconds my .377 Miss Maud). were piles of 1 to Tagael for 20 ..;. EED bath groove, was absent for a period of 3 hours. shows the LCMS 'n CJ u · been accurate and has Azak 0 T. • Akhg 1 Acts 1 Article Meshrh to chromatograph Aiamod Bo 1 middle Gel Celica (small -100 (4 0-1: 1 acetate ethyl: methanol in Sha ^ t) -l Elmy: 0 such as {[4_bromma-4- (5- {3 - [(4- Methoks pyrimidine -2 ~ Yale) touch the s-methyl} torrent -1.3 A'vizul -2 -al) Bapredr - 1. Yale Aslfinul; 'Krb'mat (7 mg, 0.01 d 0 ms well, 10 ½)). 7., Η NMR (600 MHz, C535D): δ 8. () 9 (cl;.;. 535 Η] + ηι / ζ -; MS ESI: [Μ = 6.0 Η..Ζ, lH); 7.9; (s, 1Η) 7.88; (s, Ι-Η): 7.38 (s, a H): -7.Ο8 (s.; H); 6.23 (., 6.0 :: / ..; Hz, 1Η): 3.98 (s. 3.1.1); 3.73 (m, 3H); 3.34 (m, 2Η): 3.19 (m. 2H); 2.35 (s, 3H); 2.25 (m. 2Η):; + f.rhSYK 90 .;. Activity (ηι, 2Η1 -192- ΜΑ 33926Β1 d., - R, 0 Yi Dean Del -2); Bo] &amp; quot; s &amp; quot; legal hands; &amp; quot; a, MS. (. ¾.28

Μ;:; ES '3-Thazl-2-The Ir.d, -nrab (18 p' 36.- 0.0 .ol Q / 77 / .: 495.3. Ή NMR (500 MHz. C.3.D): of 8.09 (d,., 6 = t. (:) Hz. 11): 7.89 (s, 2Η) 7.38; (s, IH); 7.09 (s, IH); 6.24 (d., / = 6.0 Hz, IH); 4.37 (ra) ITT); 3.99 (s. 311); .3.97 (M, IH); 3.68; ra) IH) 3.36; (m, IH); 2.35 (s. 32.19; (,; -; (m, 2Η):, 1.94 2, AA) of Η) + -i -.; = RhSYK Zhot following examples were prepared in a manner analogous to those described in the examples 47-54 urea what Ashbdal Dzdug when N, N (example 47), Tgamuel a butyl carbamate replace what Mrdug (Financial 48); an intelligent sulfuric amide O replacement of Thelaa when Ν ', N, Ν (example 49), sulfo Ya Na Mead replacement of Zdug Ana- N , Ν or acid Silvameatt (example 50), amide (example 51), urea what to substitute Thelaia in Ν ', Ν, Ν (example 52), Ozat 0 Q has eaten in the Ν position, Bberulides, biperiden or R-Bban ( »Thal 53 ), and three-Z Silvamuelcirbemat Replace on Ν ', Ν, Ν (example 54). Table 54 a R2

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01941.tif" id="idf0125" />

Amour d [M + HJ + Activity R2 R '1 for example -193- ΜΑ 33926Β1 (photos) 1 Zlahz rhSYK. 1 :: Ni lb, my Ramat 542.1 A 00 A 00.0; 0. -S02-IPR. CF3 54 a 1 -1 τάΑ Fu died Jf ί 568.1 +++ -SO2-CF3 cf3 2-ί 54 0 1 God Fu died 462.1 -C (C)) ET (-, 3 54 a -4 D in Ramat 494.1 -1-- 1--1- 0C (0 ') CH20H CF3 54 a -5 mg Forma T. 503.1 -1-1-1 .COCH2CN CF3 54 a -6 God, PHP and died 521.2 A. &amp; quot;' ~ 4 ~ 4 ~ C (0 ) CH2N (CH.3) 2 CF3 54 a -7 d is 1 Matt Jf ί 504.1 +++ -C (0) -C-PR CF3 4 d O-- M_1o 7 Vaher 4 data 561..2 A. - .. A-- A- -: &amp; gt; the 0)? &amp; gt; - Hicks CF3 54 a -12 Halalas Fu tumor T. 521.2 +++ "C (0) NH-IP.R CF3 54 a -15 Halalas soon died ς, ιχ 2 -2 (0) NH-NPR CF3 54 a -14. -194- ΜΑ 33926Β1 -194-

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01961.tif" id="idf0126" />

Free base 507.1 '' '0 B 0' + -C (0) N (CH3) 2 CF3 54 -15 a free base -SO2NH2 cf3 4? O_ 16 base jib 441.2 +++ -C (0) NH2 (4071: 13 54 A -19. Base Foresail 598.2 H OCH'3 54 A. 20 7ÜJ Aourma T. 508.2 (};:!),!:! '; ) (]? ()) Η ::) (()):) - CF3 54 a "21 sulk 508.2 +++ -C Base (0) CH2CH20H cf3 54 a -22 ml 9. Formate 517.2 +++ -C (0) CH2CH2CN CF'3 94 O_ 23 free base 5.18.-) +. ++ -CH2CF3 CFJ 54 -24 a salt Forma T. 521..2 +++ -C (0) CH2C (0) NH2 cf3 54 a ....... 25 -195- ΜΑ 33926Β1 -195-

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01971.tif" id="idf0127" />

Free captain 522.1 e (0) CH2C (0) 2H? CF 54; -26 Haa &amp; lt; Y free 522.2 - (- 1--1 -C (0) CH2CH (0H) CH3? CF 54 27 Fu Ramat "il. 534.2 -C (0) - (3-0H-CBU) CF3 54 -33 A Salt Forma T. 540.2 --.-.-- 1 -C (0 ') - PH? CF 54 34 A. Hadn sulk 550.2 -1.-..-) -? CF 54 a "9 ml, PHP 0« s 0962. ..... -C (0) CîCH20H) 2CH3? CF 54 44 Hadn a free O_ 562.2.-1-1.-1 -C (0) - (1-C02CH3) -CPR? CF 54 a -54 «ni Once Matt -90) - (4- C = CH) PH 564.2 -.a ...- a - .. A- -C (O) - (4- CCH) PH 54 a 55 -196- ΜΑ 33926Β1 ups 6 t in Ramat - (:. (()). (4. 565.2 "(:. (())" 54; - CN) PH (4- 56 CN) PH TdA Aourma T. - (2 (()). (3 - 574.2; ++ - (: '(()) - 54 A. F. 4- (3-F, 4- 57 ΟΗ) ΡΗ ΟΗ) ΡΗ salt Forma T - ((()) - (4 604.2 ). ;; - ( '(()) - 1 .... 1- î) 4 C02CH3 (4- 59) PH C02C PH; H3 tell count Ne jib (CH2) 3C 535.2.;. 060 00; 0 ( .¾) 3 4?; ü Η3 CH3 61 Foresail base CH2CO2 508.2 CHiC 54 A. CH3 O2CH3 70 base sulk CH2CH2 5η 2 CH2C -I 54 (:() 1 (: 113 112 (:() 7 7-1- CH3 base sulk CH (CH3) 522.2 ++; CH (CH 54 A CO2CH3 3) (:. 2 72

<img img-format="tif" img-content="drawing" file="MA-33926-B1D01981.tif" id="idf0128" />

-197- ΜΑ 33926Β1 CH3 base No. 1 h (CH2) 3C O2CH3 536.2 +++ (CH2) 3 C02C Η3 54 a -73 2 = Ν enumerate sulk 507.2.-1 ...-. 1 .- + CH3 CF3 54 A. 74 free Hadn 507.2 +0 +3 loomed (Mtthakla) cf3 54 O.- .. 75 base jib 507.2 --1--1 - + CH3 (homologous 2) CF3 54 -76 a free base 535.2 ttt CH2CH2CH3 CF3 54 A. 78 free base 535.2 CH (CH3t2 CF3 54 -79 a 'free base 579.2 ..1 .. ++ CH2CO2ET CF3 -Î 54 80 TFA salt 607.2 ++. +. (CH6) 9CO6ET CF3 54 (a) -198- ΜΑ 33926Β1 -198-

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02001.tif" id="idf0129" />

1 81 Salt FA ';' 496.2 ... CH2CH2F CF3 54 a -82 TFA salt 508.2 0; CH2C02H CF, lllllll AA d A free 83 Base T-Taate .... CH2CH2C.2H? .CF 54 -84 A Base free 532.2 ... CH2CF3 (ENANTIOMER; ')? CF 54; "&amp; quot; 85 Foresail ς / ρ 2 base CH2CF3 (ENANTIOMER 2 a? CF 54 a -86 TFA salt 532.2 00; CH2CF3? CF 4 d O_ 87 for 70 Ge Matt L PL 5.36.2 CH2CH2CO2CH3? CF * zf; 5 ^ ï a -88 Aaaden a free 564-2 ... CH2C02C (CH-3l3? CF -54 a -89 ΜΑ 33926Β1 -1.99-

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02011.tif" id="idf0130" />

(1 Nmotnjhmu 5 (Aansour) [M + HJ + noticeable activity rhSYK. R.2 R '1 for an example of a base font 424,2 H IFR 54 d -1 492.2 a free base; &amp; quot; &amp; quot ;! 0C (0) CH3 Cf'3 54 d -2 base h 1 5 496.2 &amp; quot; (6 &amp; gt; C (0) CH (0H) CH3 IFR 54 d -3 jib base 496.2 ;; + -C (0) CH (0H) CH3 TPR 54 d -4 free base ? 06.2 +; - + -C (0) ET CF'3 54 d -5 free base 509.2 -C (0) CH2C (0) NH2 IFR 54 d -6 Hadn a free 0.2 9. 0C (0) CH2C02H IFR 54 Delm free base 512.2 -C (0) CH (OH) CH20H IFR 54 d -8 free base 517.2 +; + -C (0) CH2CN CF3 54 d ....... 9 -200- ΜΑ 33926Β1 free base 518.2 - C (0) -CPR? CF 54 d - (1) the free base 522.2 ++. + -C (0) CH20CH3 CF3 54 d-A.2 salt Hormat 2 196 +++ -CÎ0) CH2CH2 (-) H CF3 54 d -13 Mellj Forma T. 522.2 +++? C (()) CHfOH) CH-? CF 54 d -.-- 0.14 Hadn free 523.2 + Ba -C (0) CH2CH2C (0) NH2 IPR 54 d -15 Vaadh burning 531.2 +++ 0C (0) CH2CH2CN? .CF 54 d "of a free base 1 535.2 ;;; C (0) CH2C (0) NH2_ (isolate Michacklin) CF3 54 d -21 &amp; amp; 54 d "is 0 E 7 Forma T. 536.2 +++ 0C (0) CH2CH (0H1CH3? CF 54 d -23 free base 1.1) ah f · 00; 0 0 AAA 0 CG) CH202H- (presented for Michacklin) CF3 54 d" 24 4 Adad -25 d Forma T. 538.2 ++; _CH60H (0H) CH (0) C (Izz al.'s Labs and then yen) 3cf 54 d -27 &amp; amp; 54 d 28 free base 538.2 «f -C (0) CH2C02ET IPR 54 d. 30 ΜΑ 33926Β1 a

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02031.tif" id="idf0131" />

'T FA salt 540.3 0) C (CH20H) 2CH3; C- TPR 54 d -31 TFA salt 549.2 ..1 .... 1 ... 1 ..- C (0XCH2) 2C (0) NH2- (Arl Michacklin ) CF3 54 y - a 4 &amp; amp; 54 (d) 42 TFA- salt 550.2 +++ - -C (0) CH2CH2C02H CF3 54 d -43 Mlhkormat 550.2 25H (CH3) -C (0) CH2C CF.3 54 d -44 bottomed. Y a free 1946 +++ -C (0) -PH CF3 54 -45 y forma salt T. 562.2 +++ CF3 54 Dalla &amp; quot; 70 hem. Formate 562,2 (2 ~ C02H-CPR) -C (0). CF3 54 d: 71 free base 564.2 BPB 0) CH2CH2C02CH3; C- CF'3 54 d -72 a free base 564.2 ....... 1 ..-...- JjP) 0Ci0) CH2C02CH6CH3 Michacklin) CF3 54 d -73 &amp; amp; 54 y Mdkormat -74 566.2 00; 0-0 .; "2.Η (CH3) C (0H) &amp; quot; C (0) CH CF3 54 d 77 TFA salt 566.2 J /) 2CH3 (CH2OH) -CtO) C Michacklin ) CF3 54 d -78 &amp; amp; 54 d 79 ΜΑ 33926Β1 a free base 570.2 PH (4-0H) -C (0) -? .CF 54 d -84 Hdj Fu 1 Matt L PL 576.2 - (0) C- ( ? CPR (1-C02CH-? CF 54 d a free base -95 577.2 2 (CH3) 0C (0) CWCH2C (0) N? CF 54 d -98 jib base 578.2 ;;) PH (4-CeCH) -C (0) -? CF 54 d -99 Hadn free 580.2 -C (0) C (CH20H) 2CH2CH3? CF 54 d -1.02 base &amp; lt; a 5 588.2 -C (0) - (3-F, 4-OH) PH? CF 54 (d) 1.03 free base 588.2 + ;; -C (5) - (2-F, 5-OH) PH? CF 54 d "104, free base 618.2 +++ CHEX - (? C (0) - ( 4.C02CH-? CF 54 d -111 Mlhmla Mohi R. la Rtt 648.2 +++ C (C)) CH2C: {OHjlCF3) C () 2CH3? CF UM 1 54 Hadn free 529., 1; 1-.S02N1 ( Presentation for Michak 4 yen)? CF 54 d -115.54 d ΜΑ 33926Β1 116 a free base 493.1 +++ C (0) NH9 (isolate Mtthakaan)? .CF 120 Vaadh a free 5 (.) 8.2 C (()) CH2OH ( isolate Michacklin) v ^ 0 ^^ (

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02051.tif" id="idf0132" />

Recalcitrant [Μ + Η] + cha i R. 1 Ithal (SOL &amp; gt; observed ihSYK 1 mL Wa sedate died 522.2 --1 - + - 1 ..- 2) CH (OH) CH3 not; Cisse) 4 Qa "204 &amp; quot; ΜΑ 33926Β1 - a 9 ml. Formalt 522.2 s2) CH (OH) CH3; ^) 54 d m ™ 2 ml then 5 Matt L R 535.2 +++ 2A (0): &amp; gt; 2 to 0 (SAS) 54 I- Wa Mlhformat 549.2 -Ι --- Ι- --Ι- 2CH2C (0) NH2;: - CI (^) 54's; not 00 Eads. Ml Forma T. 566.2 + ;; (R) C &amp; lt; CH20H) 2CH3 54 is 0 p 0 p 0000'0 a 00 count 20 7 immediately after the T 511.2. + &amp; Quot; A- + (Cisse) CH2CH2CON (CH312 »0 e d A.'s ml Hormat 58 (:). 2 -1--1--1- C (.CH20H) 3 54 - 34 55 Jb -% 205 10

Cx 33926Β1

MA 5_ &amp; lt; 0000 Ya4_a_lok 00 A_4_l5_ao_0alaq - {[4- (Ray u 0 In E'ides 2 1]; 80} 11.6 Aascalml) A- 4 ο-; for Sadalal 0 well 2 (3 NO) 1 first N'V0 I (Γ A, E 50 humanitarian partners; 1 : the F-0 Ace S_4_losa 4 not 5 acid's (3-0al-S-; 4 Fill the; any u 0 Yale &amp; gt; E.edan -2-yen Shaw} Blloaa, Talpalllle 2: L Aa.tkhva (150 mg. 0.313 0 lymphoma, L) E Bdocard-d Plus Aalmamd 0 d (52.4 nm, 0.470 0 R. Maud), 0_ (7 Aozalaleraao; _ol -1 Ν ', Ν' 'N, N- (jr- are 0 Yale Aorroyom 0 fronds (and 4 of Mahm, 0.392 Malai cell) E Dai Wood; dl Z (164 curlers Carr, 0.940 Mar 0 well) in Dai j cheered 0 of 00 (d T'a t) or only; all. the Ahim A4 fitting for a 4 Ouae was in 25.a 0 No 18 Z 'has been V b i ask; Li b 0 Loire; the 0 entertained, then Air. Bh, was termination 0 Wafa 0 Eshr.h! Li HPLC in Alarr Ckos &amp; lt; a, loyalty-Boum.l, E r Ri Dred.; 0 YK) '; &amp; quot; d s Ely Ludlow R. 5- {Q-4-traumatized-4- [5- (3-paralysis -5-humanitarian partners 4 Arai Shrew ^ 6 Aeliden-2-j 0 a! 80} Phil) -1.3-Basul -2-Fill the Bklrhmell) a-, and, 4. 'as 0 birth 0 by Link, (1..39 mg, 0.075 0 for in the mall, 24% -206- ΜΑ 33926Β1 MS ESI: [M &amp; quot; f-no for m / z 519.1. 1H NMR (500 MHz. ditiso) δ .12.10 (s. 1 H ), 10.katj). Ot (s, IH), 8.82 (d,. /: 4.8. JH). 8.02 ..... 7.88 (ni, 2Η), 7.45 (s, IHh 7.27 (1, 4.9 = : R.l Η) 1 7.15. (s. JH), 6.06 (s. (/ = 27.1, JH), 2.67 (s, 1Η). 2.51 (s, 3Η), 2.09 ...... 1.75 (m, 8Η) +++ == rhSYK Dashot 56 nest; l ~ (Jrr5 Hlh 3) -5] -1 HCJ- crippling -5 for {[4- (2-Aroban-Yale) pyrimidine 2 · L Omdno a 0.3-Hasul -2-Yscleoo-Arles

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02081.tif" id="idf0133" />

Step 1: has E 1 addition acid Otz 0 (0.192 Mo, 3.35 0 for in Hall) to 2-Klowo-4- (Adwan ~ 2. "l) the cities of available Qy'zao (0.5 g, 3.19 ms relied) O3-Oromo -5 Mughal Z ( 0.900 g, 3.19 Miss Hall) Halqa in d; j 1 Wei 5 (6.39 (, &amp; gt; 0 is 0 Sd Cancel 1 E 1 Li 1200 m (degree heat, Arh.lhamam) to 1 for 1 Ajl- Wad, it was Z &amp; quot; d ESL to a degree Hrar.h 1 to Ariz and has purified Bkromdav Adud by &amp; lt; Sloka 0 p 1 Study Azib Pasiat (must have Hecsamat to Ahaol t not- (3-Ross-5-J Phil) -04 (Aroban-2- Yale) extended -2-a 0 Khin (959.8 mg, 3.13 Miss Mall, 98./.)kmadh d b '1 to step 2: has mobilized Qaru) Rh 40'0l Ij-1 for a Khzh (500 b 1.633 Rmudall) 4:00 (Baiakula 0 and d); j boron (456 mg E Hefei relied 1.796), d Command's (Dai * M, -207-- -207 - ΜΑ 33926Β1 want 0) Veros- Ba'1diom ( ") Dai / Reed d 1 j /,%, (40.0 to 0.049 t f) and aces Upper-Q (0.481 mg, 4.90 ms 0 well.) has 0 F tool but Aohussam 6.5) ml DMSO) were Aboukan to 120 m. After Aaaab for 0 Where were Azkhalar F Aba.bat asset, was Asila using NaHCCh protection of saturated, saline, and were Tjgegh-Ekpr 0 Pat is sodium. Maph, was nominated and focus I pressure of Mkhid. Tmt purification material remaining 1 \ the ^ money 0 Hrao 100 Alamo Dr. Bo Asalh Gel Salé 1 with 0.0 a Altamfmh sequential Bositapt ethyl s Hecsaa 'and jj 0' A 0 00-0 a 0 d for not- [3-Methel-5- (4 0.4, 5.5-for-Ttramethel, 3.2-Daaoukabourulan -2-Yale) Vsi-4- (propane-2-Yale) -2-Ar.bmaidin additional (249 mg, 0.705 Mother Maud, 43.2 (7 ? Kmath) as a solid Whita.e. 'to Khton 3: Tmt mobilize flask 2 Dr'm.tantj step 2 (100 mg, 0.283 Mash Mall) A- (5-bromo-1, d-Basul -2-Yale) cyclo. Iotadhul (1 to 1 composite mediator 0.1, 72.9 mg, a 1 d 0.0 mmol), butyl Dai -1-Adamaztal phosphine (14.21 mg, 0.040 mmol), Obtat Palladium (L) (4.45 Bhm, 0.020 mmol), fluoride Alboisarm (d 0.49 mg, 0.849 mmol), 1-166) Maikarolter THF) and then water (348 Maikarolter), was Ahham Aglafy flask was then heated to 80 pm throughout the night. After that, the reaction was cooled to Dhirjh then a ball room. Tmt pious reaction mixture Bkromatogerav column by silica gel with a 'Nhvih Aguetabaah Bositat ethyl in the insoles. It was assembled parts, have been re-focus and Amabha in Srra water + 1) HCl Tmlar 0.0 (2) micro liter) was Tdjaifaa freeze for &amp; amp; HCl 0 1 n-A5- (3 »Shell-5-g [4" (Br.oban - 2-SAL) Berimldan -2-amino yen) Bill) -1.3-Basul -2-Yale Saklopao -adhul (16.8 mg, 0.040 Gade Mo.l, 4.23-1. Ka'dj%) as a white solid. Of: (MS ESI: [Μ + Η] + m / z 381.1. 'Η NMR (50 () MHz, CDCI3.-208--..-208--. 1 33926Β1 9.66 (S, 1 H); 8.38 ((1 ,, / = 5.5 Hz, for H); 8.02 01 1? H2.97 ;; (s. E. H); 7.50 (s, 1 H) 7 (). 7;; m, a H); 6.79 (m, 1 H); 2.90 (m. IH); 2.53 (m, 2H); 2.33 (m. 2Η): 2.30 Os. 3H); 1.88 (m, +++ = rhSYK 2. activity Η) 7 = t, e) 1.25; Hz, 6Η) .56 Tm.thouder following examples in a manner analogous to those described in example 56 agenda

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02101.tif" id="idf0134" />

Image (s) 4 1 of 4 A'0a noticeable rhSYK. Chatt R. example HCl Hdh 353.1 0 B 0 B 0 B CH3 1.-56 HCl salt 367.1 ... El 2--56 HCl z 379.1 ..4-4 .... 4.- CPR 3-56 base jib 395.2 4 &amp; quot; -..- 4-. t-Bu 5-56 Example 59

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02102.tif" id="idf0135" />

-209- ΜΑ 33926Β1 3) -Ν-3) -21- Omivoooxan Yale-d) A 0.3-Thar. -4

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02111.tif" id="idf0136" />

5-Yale; -5-methyl (Nraa Vrumethyay) pyrimidine-2-Amin

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02112.tif" id="idf0137" />

1 Khaloh 1: 4 Li Mahdrd of Rksian -3-Off (600 mg; Say 8 JL Small &amp; gt; d p 0 Ithil propane-2-Sgheitasd (01. 0.1 g, 8.33 Miss Maude) in Sahprawforan (4A ml) E Tmt Add A.bthoksid 1 Tetazaum (0 to 3.45, 16.65 touched Mall.). name P 0 F 1 m throughout the night. mixture Antvaal been Neb the brine. Zs manger was washed with ethyl Bosanat. Tmt fragmented Aglul Ben Ossat ethyl and oji ml 0 neighborhood '

.alloah (Na2S04), and it was Tr.chihaa Turkzi. Tmt Ttah article his father has Z 0 mother 0 and Batkhadd 13:00 Aleka (deaf -70%; 0 Ischl Pat Hanat) t, l Er 2 0 Vinegar N (a 0 and ¥ -3-des &amp; gt; Q 0 p-2-Q (692 m, 03.20 S.ll 0.38% Mmaj &amp; gt; 'net oil. 176.1 MS ESI; [Μ Η] + ιη / ζ. 1 to step 2: the delegations of d put 1 j Otkhozobrosdomanan the; Shum (1.8 Molar &amp; gt; 4.96 mesh Maud) in 8), THF Ps) under an atmosphere p argon Nbaridh was to "78 m 0 j '~:; : Sale-A3-Bill-5- (1.3-Basull5-, L) each] -4- (Ray vs 0 Ebla m 0. &amp; Quot;:. Age (up to Labad 4.1200 to 3.57 -lli 0 well) in 8) THF only 70 g; Vava'akpt to a specified LDA. The dome T. Ahael de 30 lioness --210- --210-ΜΑ 33926Β1 P E0 Azh Menth Aioh 0.1 (625 mg, 3.57 0 Lee Wu) at 8) THF t) does not bear Alli to Azhael ί Li Se 0 B, E Alrz 0 throughout aluminum. Av.dl been ... would have been bad and Z Baptat shown. Then g 0 for Ed, Ed Dam, one of my use NaHCOj 0 hours a day, b Del Ds, then the answer NaSOl), was NRP and Trllagha. I date one substance Father Kiometroual equ Bathaddam Lika (20-1.00% lattes crick my machines) b t 2-0lab- {3- [5- (3-Bill-5-E [4- (Tri Floromin must-2-Escherichia; sales) a- '3-0lasul-2-I-3-Ooyan but) Brown-2..bbd (1.10-m not. 2.140 cellulitis friendlier Ktath 60.0%) 0 512.1 MS ESI: [Μ + Η] + m / z · Alkhadhuh 3: to aftermarket 1 to step 2 solution (1.01 gm, 964 humanitarian partners 0 E. Hall) in Madadol (9.8 ml), ci as one spyware 4 Molar HCl in y; j Oak 0 to (1.97 ml, 7.86 Miss Mall). Yale was flipping thread 0 01 gm free; Rh weddings for 15 Nqiqh. The mixture was reduced using IPL acetate, it was washed using {NaHCO saturated, Sush solution 0 neighborhood, was -tjvifa (Na1S04), and section 1 does not spray and focus. CS pious material remaining Bromatogerav column Boisah Sehlicha (40-100 der Oszt in ethyl Hecanat) For No-d {[2- (D-Obooobinad-l) -a 3-disappears-5-I-5-Shell Ivel} -4- (Tri Vrubuthail) Bear 0 Eadan-2-additional (386.6 mg, 0.954 touched Mall, Kmath 53.5%) as a solid smaller pale color. + MS ESI: [Μ 1Η). T = 4.81, 8.83 (ci 0 &amp; lt; 10.26 (s, ΙΗ of (6 ^ H] + m / z 408.0. LH NMR. (500 MHz, DMS0 .5.6 = 7., 0 4.87, (7.28 (0 ,. 7 = 4.9, IH). 7.17 (s, IH 1 (H). 7.97 (s, IH). 7.47 (s, 1Η;, 8-07 (s (2HJ. 4.58 (d, ./=: 5.7, 2Η ). 2.32 (s, 3Η. 0 Thal 60 --211- ΜΑ 33926Β1 E. 130 [5- (3-crippling 5. ~ {L4- (Tri Ior-Shell) Ber.bmaidin 2 Yale Abu \ z) a 4 Taz Waddell 0 ~ 2 -al] Aoxatan -3 - Yale} Mbthan Silvriamtd Qa 0 of 0 a

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02131.tif" id="idf0138" />

D 1 Behold: 1 Li solution of 3) -2] -3} -ν Ed 0 Soolexsal Dr. Yale) a, for 0 thiazole 5 Ale: s 0 Methell Ivel} -4- (Tri Iorobuthail) pyrimidine-2-S (200 mg, 0.491 Melanie 01) and 82 ) Ε43Ν Maikar.o liter ,, 0.589 mmol) in an intelligent Krumithan (and 0 (I hope), Tmt DONC 0 efficiency Knurad methane sulfonyl (0.57 micro liter, 0.736 t Mall). the 'turn the ESL 0 extent room temperature births 95 minutes the mixture. after that, the light Khalif Bositat ethyl, was washed Bashaddam NaHCCE saturated, followed by a saline solution was dried (SO0i; Na) 4 was R.chiha tendon Theish. purified material remaining grown Pedromatogerav Alamon Boisalh Celica (10-1001 as upper ethyl acetate in Hecanat ) it was dried freeze the defenses of the N- {d-L5- (d-methyl-5 - {[4- (Tri Vrumethyl) pyrimidine-2-night Abu; Ivel) a-, d-Thiarol -2-Yale Ooxaan- 3- &amp; quot; '- for; methane (113 mg, 0.233 Ma.la Mall, 47.4 hr 0 Kmath) Kmsho 0 s Osd. 10.28 MS ESI: [Μ + Η] + m / z 486.0. 1η NMR (500 MHz. DMSO-d ( ,) δ (s, ill), 8.83 (m. 2Η). 8.11 (s. 111). 7.99 (s, -.111.), 7.59 (s. 111), 7.29 (111 1117.21.; (S, ill ), +++: RHSYK 2.98. (6.6.16.1,411 = t, 1 &amp; gt; l) 4.91. Activity (s, .311), 2,33 (s, 311) for the 61 -212- ΜΑ 33926Β1 2. methyl-not- A_ {[A- (s ~ but-5- {A4- (Ray Flol.lmathel) seeding-Eadan 2 'ol AUO} Phil) -1, 3-, Bzul-2-Joel Owen-3- Yale} propane-2-Slgos

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02141.tif" id="idf0139" />

HN

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02142.tif" id="idf0140" />

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02143.tif" id="idf0141" />

1 to Step 5: The cooling solution 0 n 2-3) -5] -3} -NJV- crippling -5 for {[4's (T; any Toromel) pyrimidine-2-Yale Abu} Ivel) A- 0.3-relieved -2 -yoo Ben-d-Yale Doban} -2-Sakmamal (0 shawl 59, Khloh 2.75 mg, 0.147 ms Mo.l) in Dai Krumithan ( '1.5 d) to the small m. Was added 37.8) m-cPBA mg 0.9 a 0.2 mmol) cJj Tdheh the S 0 0 Olna'nh to a temperature Angervh. The reaction mixture was Nkhvev Bdaa Theloromithal was. Asilha using 0.2 0 lar χ2) NaOH) 4 NaHC03 radioactive (Jjk, (X1 saline (, (xl was dried 0, Na1SO), was nominated and focus. Was purified Secretariat, the remaining Boukromabojrav Anamod Qasith silica (10-100 Ps acetate IPL Ne Hecsanat ) and then dried for Balthamid Harl on 2-BEHR-la-A3- [5- (3-Shell -5 - {[4- (G. Vrumethyl) Bear 0 Eadan -2-Yale Obno} Ginel) -1.3 -2-thiazole -ale Ooksian -3-Do; propane-2-sulfonamide (45.6 mg, 0.086 mmol, 59.0 i / o Knath) Kmadn smaller solid-colored die. mS ESI: [M t Η] + ηι / ζ 51. (:. ..1. lH NMR (5 (.0 MHz, dmso) 10.29 of (s, HI). 8.83 (d. .3 = 4.9, HI), 8.29 (s. 1Η). 8.09 (s, III), 7.95 (s, III). 7.53 (s, IH), 7.28 (d, .3 = 4.9. HI). 7..18 (s, III), 4.90 (ddj ............ .... =! '1iSY: K.2.33, (1..41, 33.0 .6.6 =. Activity (s, 31), 1.35 (s. 9Η) was 0 Mahathir examples Akalih means rejecting Aiqa y views to those described in examples 61 0.59. -213-

-213- MA 33926Β1

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02151.tif" id="idf0142" />

Image (|) [0Μ '· Ι · Η] + observed whipped 0 rhSYK R.'. X R1 example connote y Foresail 4.6.1 + -; + 1 --- Ϊ CH? CH3 61 B free base 552.6 SO2CH2CF3 CH? CH3 2 0 free base 502.6 1 1 F. 0 0 Za ;. SO2CH2F CH? CH3 Giver 'a free base 484.0 SO2CH3 CH2 CH3 Abe a free base 538.0 SO2CF3 CH2 CH3 61 Hadz b y h 0 540.0 + + + SO2CF3 0 CH3 T'-

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02152.tif" id="idf0143" />

-214- ΜΑ 33926Β1 - 6 free Hadn 554.0 A 'Ibb SO2CH2CF3 0 E! -': Humanitarian partners for ~ 6 base &amp; lt; a 5 506.0 S0CHF2 &amp; quot; .... 2) CH3 61 (b) 472.0 free base ttt SO2CR3 0 H 61 b. "Head, and all 00 hands 2]% 3} -ν (E. Labus 10 Zawbiotil) female d Thiazon 5 Del 5 Methi 0 for each} -4 Msksa 0 Ieimeads-2- S

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02161.tif" id="idf0144" />

5 harddrive 0.1: it was the commencement Auoby 020 for Atldam 3? 0 for ::

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02162.tif" id="idf0145" />

Jr) Z (500 m, 2.63 Bach 0 well &amp; gt ;, / Lot Dome (2.99 to 7 filled l) E 2-Kaoru-B-0 Dam &amp; lt; ri b 29 406 b 2.63 t l) E Wuyi A (was (10.4 t). Been cleared Aki 0's and Sarah Alorb (3 X) p; Khala toos (228 mg, 0.394 Munch Maud) and! Pat Palladium ( ") (59 Se 0.263 ΜΑ 33926Β1 Mall). after that, z Assam have been discharged, Jordan (Χ3) p provisions \ ë and heated up to 1.00 are for a season. upon completion were F extend to roll.; see him lesion was my Bosnat ethyl, was nominated by Bla.t with F-0 Yale Aasiaat, each was a pedestal under decompressed ... led one Kzqah Bkromatogerav Ί \ γ column &amp; lt; &amp; gt; silica (torticollis -60 Leila Ossat A.buthail in Sha; s) to 1 to obtain 0.603 mg 3 (1.96 parenchyma 0 well; 74%) 0 n 4 "Bklo propyl-not- [3-E5- (1.3-thiazole 50 g) meat Peremedev -2-stronger solid Iamada yellow. 2309.2 / M + H] + w]; '; MS ES. 1 to step; 2: 1 Li solution »n Menth step 0.1 (250 mg, 0.81 sniff. mol) in Ttraj 0 Rovuoran (5.0 -28 when they Tmt as Avh1..62 0) LDA Man 2.0) ^; 3.24 0 Hme well) - has been my mixture for 15 minutes at -78 m. Has Anavh N- Sklopjubldan -02 to Mahal Ran "2" Silvinamed (169 mg, 0.97 mmol) in Ttrasdronsuran (3 dl) Bakpt 0 -78 m and I had the heating of the reaction to room temperature. Akkulaib been over a costume, 'has been put out Adom chloride aqueous mixture was extracted mixture Bosnat ethyl (3 2 200 &amp; lt;,) 0 is j ;; j organic parts Atjtah.thlol saline, was dried sodium sulfate, and was in-was steaming under Almenbb pressure of Mkhid. It was purified material remaining Bkromatogerav the * Maud. L \ f &amp; lt ;; Sika (small -00 Uh / 0 bit A.hl in Hecsamat) to, for pregnancies nest 182 Z (0.38 Shamma hard, 47½.)) 0 n Ν-4)] - 3} -5) _ 11-Hmilo: Roel Ieremad, n-2-0l) Abu; -5-Bill sales) -1 3-Sol-2-g) Bssbt] -2-Blroban -2-Syab. 1M:; M.SES.: .482: /// A | AAA. 1 to step 3: to Mahiod of Ztj 1 to step 2 (1.82 mg, 0.38 Miss mol) in Dai Oo.yan (3.8 D) was added hydrochloric acid 4.0 Molar in Dai HUEZ 0 (95) (0's, 3.78 216- 216-ΜΑ 33926Β1 mmol) was flipping Ahalit at a free one Rh Arafa for a period Samotain 0, and then to Keys 0 mixture under -Ν Mkhvvy pressure to obtain 170 mg (0.41 ms Hall; 109%) of the hydrochloride -4 &amp; quot; e 3- [2- (e -omivusiklobiotil ) a-, d -0 Bzul -5 -5-Yi-Maple vessel; MS ESI: [Μ 0 Η] + mi: 378.2. A. .Η NMR (600 MHz, de Bkloproehl pyrimidine-2-Ashe. 0 DMSO) δ 9.5 ,; (S, 1Η), 8.95 (s, 2Η), 8.25 ((a, 4.8 = 7.,.; H) , 8.16 (s, JH), 8.JO (s, JH). 7.40 (s, JH), 7.Π (s, JH). 6.83 (d, .7 = 4.8, IHJ. 2.66 (m, 2Η) , 2.57 (ni, 2Η), 2.28 (s. 3Η). 2.14 +++ = rliSYK Activity. (m, 1Η), 2.03 (m, 2H0, 1.JO-J.04 (m, 4Η) was prepared examples the following manner analogous to those described in example 62. grandparents 62

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02181.tif" id="idf0146" />

Iaourh (Awar) + [Μ + Η] observed activity hSYK '; R. Example 338.2 Tlorad salt ;; t H 1-62 Salt Tlorad 368.1. +++ -OCH3 2--62 Ignored; for 63 -217- ΜΑ 33926Β1

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02191.tif" id="idf0147" />

-2-Amino night) Linnell) A-,

To Mahvod of 3) -2] -3} -N- Obooodietav-3-l) -1.3 Thazul A's; d ^ Vtvel) -4 - (&amp; quot; R.aa value-Romethyl ') Peremedan-2- Secretary Zmthal 59.25 mg; 0.061 x Moi) in an intelligent Ooxa 1 Z (600 Maikarontr), has e 0 0 Habd efficiency (70 mg, 0.725 ms Mo.l) 0 stirring the mixture for 1 Taael baptized 100 m. The mixture was Tguib I Alma'zj 0.00 to 1 m for 4 days. Sleep ease Ahalit using ethyl acetate, was washed using radioactive NaHCOj Haah; .ahlol brine, was dried (Na2S04), it has been nominated and focus. Tmt pledged Article 1 endodontic Bkloma'dhujrov ephod By Milica (10-1000 Li Omitat ethyl Hecaiat j) and sleep dried Akjmad to get the Z3-A5- N- (3-Michel -5 - {[4- (G. Florua Yale 0) Ss-2- Aloobo) appended) a- 0.3-thiazole-2-Yooksian -3-yoke) respond Dai a 0 Ed (16.3 ppm, 0.034 mmol, 54.6% Katj) Kmazh year - colored led MS Aq 1 (NMR (500 MHz, DMSO -de ) δ 10.27 (s, 211) . 8.85 (ill. 1 Η aa .487.0 m / z aa 11 ESI; [M 1Η), 8.04 (s. 11), 7.95 (s, 11). 7.51 (s. lH), 7.28 (ni, 1H), 7., 17 (s, IH). 6.98 (s.,; ;) 8.30 (2Η), 5.02 (m, 2Η), 4.84 (ni, 211). 2.32 (s, 3Η. Activity +++ = rhS \ 'K was a Taillr 0 Arkat that in the table (Aljadda'ol) Akali a manner analogous to those in the example of the vessels 63' 218- ΜΑ 33926Β1 table 63 Alsourd [Μ + Η] + rhSYK Nchahn infrastructure (eg photos) Almlahvl free base .485.0 0;) / 1 &amp; quot ; &amp; quot; t /} ^ &amp; quot; NHSOoNHp 1 ....... 63 ..: not? Hzl a 64 - 1- {1- [5- (3-Mltel -5 - {[4- (0 - ray Vrumathel) pyrimidine-2-amino - I) Ivel) a- 0.3-thiazole -2 &amp; quot; &amp; quot; Ysklopjo 0 g) of urea

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02201.tif" id="idf0148" />

To a solution of 3 g N- (2- (a -ominocklopiotil) - 1.3 -thiazul- 5 -al] - Dr. -mhl appended) -4- (Tri Vrumethyl) Smmaidin -2-Amin example 6.1 B.1 0.50 ppm, 0.12 Mia d mol) and acid lion (7 micro car, touched 0.123 mol) in THF / water (1; 1.6, 2.1 d), has Adhaqh Banat Albo'nacio m (10 ppm, 0.123 mmol) . Tiab been the reaction mixture over night at a temperature of Arafa heat and after Dylan was seen Isaha. Was purified material pavé Bkromatogeray Anamod by Sehlicha (50-6100 / Ositat asset in Hecsanat, small 20 &amp; lt; Li methanol in ΜΑ 33926Β1 Expressing -4 |) -5-Dai Nloromethan) was dried Panthamid for a "{the" ed " (3-Mabel Ray Ioromat; l) Beremi.bnl 2; dl] I Su 0} wash); L, d-Tahzul -2; l] Sakaoubeyot; l}) MS ESI: [Μ + Η] +. .aoria (31.3 mg, 0.068 mmol, 54.9%) a powder white à 449.1. A; a NMR (500 MHz. DMSO-56 δ 10.23 (S, 1Η), 8.82 (d, -. 7 = 4.9, IH). 7.93 (s.

Ill), 7.9 () (s, 11), 7.47 (s. 11: 1), 7.27 (d, 07 = 4.9. Lit). 7..15 7.00 (m, 211), 5.58 (s, 2H), 5 +++ = rhSYK 2.51 ...... 2.63. U; i (m, 21-2.32. (;; (M. 511), 1.96 1-21 .111;) was Mahathir following examples Mnairh Ntlt manner set forth in Mthad 64. Jeddo 0.64 for

Ri

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02211.tif" id="idf0149" />

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02212.tif" id="idf0150" />

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02213.tif" id="idf0151" />

NHC (0) NH2 CH3 Ihmurd (photos) [Μ + Η] + 1 Dlat rhSYK activity X R. example of a bottom-y h of 451.0 -1-1 t 5 CF.) 1-64 Vaadh a free 421.2 (1 .-.) CH2 '; cP 2-64 Hadn a free 381.2 ttt 2 AA € H 3-64 Hadn free 5 411.2 -1 .... 1- (.. l2; C (CH (;) 4-64

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02214.tif" id="idf0152" />

220- ΜΑ 33926Β1 base of H 0 x 596 +++ -CH2C &amp; lt; 00NHCH2- 3 A'-2 Example 66 3) _5] _ 1} -Ν- Mttel -5 - {[4 - ( 'Dhiraa Florosl) Perem 0 debt-2- Ioi Vgl) 3-Iasul -2-Yale Q 0} Cleolutl a Sami 0

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02221.tif" id="idf0153" />

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02222.tif" id="idf0154" />

4 Li Z 1) -2] -3} -Ν to Oboshkloiyotel) for 0 1.3-thiazole -5 Yale] -5-Methel Ivl'oa4_ (T1 Ioromeshd j) Peremedan -2-Amin (0 Thal 0.61 (b) E 0.75 Mahm 0.85 a 50 Haley Mudd) and 25.8) Ε.Ν micro liter, 0.185 mmol) in THF (Haha Maikarolter), grew 10 Ife Wade 0 cells (13.15 micro liter, 0.185 0 Lee Mall). Bt has been Tguib at a temperature of 0 0 y food-Hee to 0 of 70 minutes. Tmt add more Aspell chloride (6 Maikaroukr) to pay actor aa 1 Hagia been Inab mixture Menna 10 additional minutes, and Ban Zik was diluted acetate A.hal, Asnoh Bamtsdam NaHC03 ,, Mtbuah.mmahlol saturated brine, was dried (.Na ^ so ), it was; Tshei and-Rih to Seoul on 3) -5) -1} -N- outclass-5-g [4 &amp; quot; "(Dhiraa Khrumethyl) Lemme 2 fi} a Vhzel) -1.3-thiazole-2- I Saklopaabl; long (80.8-pyrimidine T. Yale E .. 't; Hebal mg, 1710 Miss Maud, 92% &amp; gt ;. MS ESI .480.0: [Μ + Η] + mfz DMS0-d6) 10.25 of (s , 1Η). 8.93 (S, 1Η). 8.83 (d 4.9 -: for Hz. LH), 8.0 () (s, JH), 7 94 15

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02223.tif" id="idf0155" />

221-- ΜΑ 33926Β1 IH), 7.42 (s. H), 7,28 (4.9 = 11 A Hz. 111). 7.1.4 (s. 11: 1). 3.22-2.6 () (m. 2.1--1,). 2.43-2.41 (m..-4-f = rhSYK 2.31, (1--21. Activity (s, 311). 1.99-1.95 (m, 211). 1..88 (s, 31-1): 66 the preparation of compounds in the table (below) in a manner analogous to those described in example 0.5 to the connection (Also 0 [Μ + Ι-ΓΙ + a 2 Note hSYK Activity structure example 450.0 ............... 0 .. RO HN H; 41 cf3 Vs οχχ 1.-66 Hthal 107 1- (5- {3- (4-Saklopyutzberimid.n -2-_l) Abu] -5-methyl penile) a 0.3-second Iyasul- .--- Yale) Saklopao.tadhul

HOsP

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02231.tif" id="idf0156" />

Olkhaloh 0.1: The absorption of 2.4-Dai Kloruperemaidin (2.50 mg., 1.68 mmol) and acetyl Asithonat ferric (30 mg, 0.08 mmol) in Ttrahedrovuoran (3.4 ml) was 1222-1 want to Tghaea 011. -8? M. Chlorine has been added. Hands Sklopionel Mufnseyoum (0.5 Molar, 3.4 t 0.68] Mia real) and then drip -nqay Ahalit at -78 m births 30 minutes. It has been put out to confuse all Rigg 0 0 0 T m saturated aqueous was Apmty'ds Bositat Aeattbl 0, and then washing organic parts Agtah t 0.00; Deddew 1 00 ί 1 middle sic Bo 0 0 with sodium Mab, and. The .tdjaaaha by Major Mufnseyoum was nominated, and. Then a steaming 0 Izb ci pressure Mkhid. The remaining material was purified curlers Matogerav Alamon by &amp; lt; Saa de 13:00 ~ 5% in Hecsabat Obtat ESL) for a 21 p (0.72 Haley Moon ,; 43) (/ 0) of 2 ~ chloro-4-Saklop Thiel pyrimidine as oil colorless &amp; quot; + [MS ESI:! Μ + - Η A, 69; m / 'z. Step 2: The Collection 2-chloro-4-Seke.biotidao "Beye (65 mg 4 9 (.. 0 0 u Mo.l) '1 I 1 cup mediator 15 (1.00 mg, 00.39 for in Mo'l); (f) A. acid (22 jfiA der; 12:39 touched bound) in d; j Aoxan (1.9 ml) were calls upon the mixture E 0 d 120 m Thermo 3 hours. the

'We want one of Hait so weddings heat and Tmt Chdh Ba.zh Bkromato 0 MAF Combiflash and; St Gel wire, with sequential liquidation acetate Ahidroasohkan for 0.66 mg 10; (0.17 mmol, 44%) of 1- (5-g 3 - [(4- Saklopiotil Ber.bmaa ~ u "2: but) Omanu -5-Metheleal) ~ a 0.3-Teasul-2-0l) Scalolaazl 0 MS ESI: [Μ + Η] + ttvz 393.2. m, 8.33 (d. ./= 4,8, 11), 8.12 (s, 1Η), 7.95 fs, NMR (600 MHz, DMSO-de) δ 9.56 (s, 1Η1 5.4. 1Η), 6.46 (s, 1Η). 3,53 "3.50 (ni, 1Η), = t ,, H). 7.05 (s, 1.14), 6.68 (cl;, 7.48 (s A (AAA (2.52-2.46 fm. 2Η1. 2.33-2.22 fm. 9 H). 1.99 fm, 1Η). 1.87-1.83 (m, 3Η &amp; quot; &amp; amp ; i * rhSYK +++ nm prepare compounds in the table (below). &amp; lt; é '0 0 Tzerh August example A 107 -223 -223ΜΑ 33926Β1

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02251.tif" id="idf0157" />

Image [Μ &amp; quot; [· &amp; quot; Η] + hSYK Activity N Example (photos) Allahal base h 407.2 6 H +++ 2 1 -.- 107 Foresail base 421.2 +++ 3 2-107 K. 110 (1) and 110 (2) Cisse acid-4- (5- {3 - [(4-pyrimidine Msichaelobrobbel 2-0r) Abu] d-shell viable) a- 0.3-Ebzul-2-l) -4-Pro Tse Blohxan carboxylic acid Trazs -4 - (5- {3- (4-Bkloproehl pyrimidine-2-l) -5-Omegoa Methel Linnell) a-. Dr. Thiaro-for-2-Yale) -4-hydroxy Bllohecsan Walker Bo Gsala

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02252.tif" id="idf0158" />

-224- -224-ΜΑ 33926Β1 1 step, a: to the flask Ely t 'contain spray Nrad 4 ÿj 3) 5..Ι A methyl Vgl) 0043-drools -2 ~ Yale] -4-Hdroxa Shlohkhosan Carr Boksilat (125 mg; 2 for 0 Haaa mol) was added a solution of 2-chloro-4-Sichaelo.r, Will b-1 Ramedev (Levi Osz 1 to 2957 mg 4 00:37 Haley Maude) in 1 d j Ooxan (1.0 ml). Has Adhaqh acetic acid (1909 Nbugro my 0.33 ml) was Dkhv to Khvaal counted 100 m throughout Layyan. After reminded was cooled 1, bless 0 Li Dhirjh Arafa temperature, then diluted Bositat ethyl (10 mL), was washed with water (10 ml), was dried sulfate Ovum; and was nominated and &amp; quot; Ri 0 s' exile 1 to birth S Bkromatoger 1 P 1 to beckon to get a "YOTEL Trazs -4- (5- E3 t (4 Biskaonoal pyrimidine-2: l) Abu] -5-Bethel Ivel) a- 0.3-Thaz.ol-2-l) ¥ 4 of the valley

10 Q 0 Klhecan Huksellat (36 p, 0.071 mmol 0.2 of Lahi 0 0 h). + [ESI: [M + H .111 /: 507.2 Step 2: To a beaker containing Menth Step 1 (36 mg, 0.071 ms Mo, l) ci Aq'vh Methanol () (0.8 ml) and aqueous sodium Hedrkb (I Erlar , 4.a 0.0 ml, 1.4: 0.0 Hlvi Harrell) and then heat the reaction at 100 m throughout the night. Was cooled reaction, and then Thmeidah use 1) HCl 15 Molar, 0.2 ml, 0.20 mmol) was diluted with water (5 ml) and Oslat Ebel (5 &amp; lt;,) 0 were for 0 Alabakh organic was dried Boukbrittat Mufnseyoum was Arhbhaa tendon Ihzha. During Akgael, Tka 0 Lt. Azores article prefix. It was commuted concurrent and returned isomer mixture in DMSO market purified by HPLC to obtain:

Hmor Cisse-4- (5-g 3 - ((4 - meekly; Roel Barihdan -2 - ". Of) the father of five FH Phys 0 of 1201, three-Brule-2-Yale) -4-Helroxa Sklohkan Okrbokeili (eg 110 ( 1) a. MS, (0.46 (s, lH), 8.48 (s, 1Η of ​​&amp; lt; ESI: [M +. Η] +) 11 /: 451.1. 1.Η NMR (500 MHz, DMSO0d6

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02261.tif" id="idf0159" />

..225.,. ..225.,. ΜΑ 33926Β1 8.26 (d., / = 5.0 Hz, A.?.) 7.94, (a} ;. fl). 7.92 (8. IH). 7.45 (^. 1 H), 7.02 is. IH) 06.8U, U 00 Hz. 1Η) 1 5-90 (s, IH). 2.'28 (s, 3Η). 2.26 (ni; H), 2.01 (m. 1Η), 1.88-1.85 (m 2Ji +++ = rhSYK 1.82.1.74 · 1 Zh i (m. 6Η), 1.08.1.05 (9 0 4 and _ {3_l 4 Oobrobbel Bdhiramaidin-2- Yale) Abu] -5-crippling stallion; ~ Mud; x 00 &amp; quot; - (2) 11. a 0 3_, Bzul-2_y_4_blus Skdashon Es &amp; lt; Tel 50: [Μ + Η] Κ * 451.1 ;., HNMR (500 MH7, DMSo.d6l50.4, (s.1H) J, 47 (, 1H0. s 5.0: /.,!)) a) v Hz, 1Η0. 7.95 (s, IH), 7.91 (s. IH). 7 44 (s. IH), 7 03 (s. 1Η), 6.rh 1) of -5.8 Ife. III). 5.5. (S, IH). 2.42 (m. 2.2 «(s, .31..1), 2.09.2.06 (m, 2..2-2.0. (M. ++ - T- = 2h.SYK 1.82-1.84, 11-1.1. Activity (m, 41.1 166-1.63 (m, 211), 1,08.1.05 &amp; lt; 4 1 AA Η) 112 Z (a 4.8 AA) 40. (proxy crippling) ~ 3.3-Dai-crippling 1-0 (5- (3-0hl -05 (14 (Flo.romethyl &amp; gt; to Ramaidin -2-amino Yale u) VPL) Hasul -2-Yale) Sio, for Hsadhul

/.OH

. (X., H..5a Aaga: Then Oassa (4, si h) 6 to 4. (5 ~ ~ Auautharol- 2; Dla4-Harlie 2-Dai Bbz Bkdhecaz 0 Kr.bkblat (b 0.316 10. A. Haley 0 well) in the paper.-226. ΜΑ 33926Β1

(3 ml). BC Anavh Α1Η; -. Ι (ordered lar in 0,6, THF L P 1 Ksaithamt; night: August 1 a ';' &amp; quot; Thi 0 j Altvaaa mixture, to pending Jajs similar Palja 0, 1, 0.600 touched Mall) Rahbh and E boost; ALMA 0 and A * 0 C was purified substance remaining Boisvh HPLC in Oth 0.0 Q, Ats, Amelltmbasm '... d h water + 0.1% TFA) to Aharl Al 0 hinted TFA Dix (lameness 0 AA 50%;% night 0 - E.!, - 1.1-'a- .. .... a-a-1; A., A. .-. 2-, 1.4 Nat u screw cap work initiated by pressing Bo Lh- (A- step 2: and I vial 4 d 0 of 0 a; t ..m a, .ta.d 0 \ Μ1 &amp; gt; 4 courts Kaaatt_ Ί) Ramu Q_0al Q-4- (G. tightening 0 Liel) Eamedin-2! 0 yen (Larry convergence 2 '..74 Z , 0.225 for Mvesel), p 0 Ptzv, acid |, (d 2.61.ekro, 0.023 1; 57 ;, the Alysom ​​(46.7 was' de 0.338 lol) E Dh TFA g - Bill) ~ 3 E 3-Dai PayPal - 1. .. Tmrol-p _kdekh 0 d (40 mm, 0.113 Miss Moo), and 4 (13.01) Pd (PPHj been, Aah.hda replies) has been closed Akarorh 4 was Ahragha and refilling Bannsrougin 3 times. added DMA (5 0 0 l) (Janney, use Makhl molecular, Fiuka) was the reaction mixture is heated to 120 m 0 chiming 16 abuse 0 father CMS are the product and the survival of some of the prefix materials. then Walter. Artemisia and focus in the center of 0 with GS ci -nqah material remaining by HPLC in the phase inverted (Sdrj 10-60½) ξ Sete 0 Ned 0.0 p pain 1 E + .0.1% Jfii (TFA Z (4, si no) -4- (Hydro Y Li) 3, 3_daa Pei &amp; quot; 1- (5- (3- Bethel-5- (4 "( 'opinion Vrubuthail ) Ber.eadn -2-Yale Abu) Habd) tha 1 well -. '2'-: L) &amp; gt; Sklohkhadhul (14 mg, 0.023 mmol, 20:51 () / Ha'zh t over a two-step &amp; gt; As a solid yellow. -227 ΜΑ 33926Β1 MS ESI: [Μ + HJ 492.2. Ifl NMR (509 MHz, DMSO.): Δ 10.24 (s, IH), 8.83 (t, k = 4.9 Hz, 1Η), 7.94 (.s, IH), 7.92 (d, 6.8 = for Hz, IH), 7.46 (s, IH), 7.28 (d, .7 = 4.9 Η.Ζ, IH), 7.14 (s, IH), 3.66 (dd. J = 10.2, 3.5 Hz, IH). 3.08 (app t. J = 10.2 Hz. IH). 2.3; - (s. +++ 0rhSYK 3. Activity Η). 1.98-1.44 (m, 7Η), 0. (.) 6 (s. 3Η), 0.93 (s. 3Η) 113 McCall acid (si, Omivo] Vettel) - 1.1 Necker Bo Ksila 4 h) -4- ( 5. g 3-Sakloproehl -5 - [(4-Shell Samaidin -2-Yale) 3-Parul-2-l) -4-Barr 9 Casey &amp; quot; 2, w-Dai Bethel Sichaelohecs 1 n

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02291.tif" id="idf0160" />

Cover A: The 'offer thread interaction contain 3] -ν Scalmobrodl-5- (4.4, A, 5-- Mamosal -1.3, 2. Ooxa Bourulan Dai-2-Yale) Hakhala' 4-Mitel Bdhirimbin -2-Omtn (60 Mjm.a 0.171 mmol), Bethel (4, si s) -4- (05 Aromu 0 a 0.3-Yarol ~ 2 "Yale) -4-proxy -2.2 Dai-meth ^ Z Bklohecslan / Boksilat (62.5 mg, 0.179 Melanie's) 4 additive. . . (27.9 mg 0.4 d 0.0 National Mall), 0.1 0.4 "Dai A, CPAN (2. 0.1 ml), water (0.1 ml), and Manny Mahdrl of sodium Berponat (2 Molar, 228- 228-ΜΑ 33926Β1, 0.171 ml, 0.342 mmol) rays in 'to the microwave for two minutes counting da 1.60- m. It has Ndzih Khlied interaction between acetate Aaiaa. (What 30) and a saturated aqueous Mahnol fall down from Bonnat Osodiom (15 ml). The reaction layers were washed Alabakh Alaazavihbmahlol saline, was dried for one Dbritta't sodium, was nominated, it was seen seen. It has Taqih crude product Bromatogerav fluorescence column by Gel, Saleiha (50.25 (7 Aseel t Hdanat acetate) to obtain methyl (.si, 3} -5) -4- (κ4 - Bill Rowe cyclo 0.5 - for (4_methyl! Aramaidin- 2 for Yale) Apo Ivel; a- 0.3-billion 9 for-2-l) -4 - Heder 9 Casey -2, 2 &amp; quot; &amp; quot; Dai Methya, Saklohhan Krbozsellat (41.3 mg, 0.084 mmol, 7.49-product) solid Nmadh table of whiteness. Alahtoh 2: the solution of m 0 Tj step -1 (41.3 mg, 0.084 mmol) in amputation Ahidz and Fior that (0.4 ml) and Mithatod (0.8 ml) Tmt adding Hydro re sodium (1 Molar in one loyalty, d 0.15 ml, 0.153 Mai Mall.) has been heating up the thread winding; lest, s 120 m Idh 10 Zqaiq in the far n microwave. Tmt add additional Ahah of Hydro NSAID sodium (1 Molar in water, 00 d 0.0 t, 0.300 mmol) was' Nschan vessel again for a period of 1.0 minutes at 1.20 they are. when Alnbar.bd has Adahh Klor.bd hydrogen ^ E (2 Holar in water 4 .235 D, 0.470 mmol) was Nkhvev mixture Katj using 10) smaller size and Wise Pro Aanol R. chloroform (20 ml), Mahlo. For saline (10 ml) and water (1 ml). The Fz classes and has re-Oschas Alabakh Maya using 10% the size of the size of the ISO Pro Banodr crystal and soon m (10 ml) were merged organic layers, Umm dried sizeable Lights sodium, was nominated, and focus. Drying the resulting material remaining Z Mithanodralme Balthamid to get acid (4- (R4, si_ (3-D E. Skrual - d - [(4-Mhleyribidin -2; l) Ombo] Viaay; - 1.3-Yasul- 2-l) - -.- 229. -.- 229. -hirok 11 j was reddening a; 0 j 0 ΜΑ 33926Β1 for 02 to Dai corset 0 Sklohxan one of the carboxylic (34.3 mg, 0.072 0 me j) hand a solid slanted to the whites. MS ESI: fM + Hl + m / z461.1. C 1 ETI s 1 table (.ljaddaol) Akali a manner analogous to those described in example 3 of table 113

RsO

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02311.tif" id="idf0161" />

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02312.tif" id="idf0162" />

R2's (Awar) [Μ + ΗΙ + Adlat Activity rhSYK W3 R3a / R3b R2 R 'example; R4 9R4b = H / H captain free 439; ++ HH / CH3 (4 isolate the isomers) CH3 CH3 to 1.13 A. 4 Iadh free ................... 453 · b 0 b 0 b (4); ..... CH3 H / CH3 (Izz for 6 isomers) CH3 CH3 5-Î113 4 Li 113.

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02313.tif" id="idf0163" />

230- ΜΑ 33926Β1 (2.) 8-1 Get together a free 453.1 .. + ..... 1 ...... 1 ... Ï.Î H / CH3 (isolate the isomers) CH3 Et 9-1113; 4 A Mudug Tmurmat 113 455 +4 - .. +. No! 414-13 (r4, r2, s1.) CH3 3ΗΓ0 -1 113 11 455 +++ Haa Frrmat not H / CH3 (s4, s2, Rl) CH3 0CH3 -1 113 12 Mlhformat 465 44+ HH / CI- I3 (s4, s2, Rl) CH3 CPR 13-.1 -13 Â salt Kormat 1.465 waza HH / CH3 (r4, r2, s1.) CH3 CPR -1 113 1.4 bottoming &amp; quot; »d free 5 465.1 ... Ι .. ... + .. +. HH / CH3 (isolate the isomers) CPR CH3 113. A 15-1 Li 1131-16 free base for 467.2 | · 00; 00 * 7f Â! H / CH3 CH3 iPR 1.1.3; - Ο ..- 231 ..- ΜΑ 33926Β1 ..- 231 ..-

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02331.tif" id="idf0164" />

(R4, r2, s1) 17 Hadn free 467.2 .1 ..... 1 ... 1 .. HH / CH3 (s4, s2, r1) CH3 iPR -t 113 free base of .481 +++ H / CH3 (Ezl Ozomren) CH3 Et d 113'd 11 A. Here's one. Kormat 483 +++ HH / CH3 (s4, s2, r1) CH3 0-iPR -... 1 113 free base 467.1 H si) CH3 / CH3; 6143 Et 1.3., 1 d base jib 479 +++ not ( CES) CH3 / CH3 T'b 2 CPR 113 (a) 23 5 Behold A.h- free 48.1 ++ - 1. No (Cisse) CH3 / CH3 CH3 iPR 113! - 4 1 s purely a free Edh 481.1 +++. CH3, si) CH3 / CH3 (R4 CH3 Et 113; -25 a free base 483.1 +++ CH3, sl) CH3 / CH3 CH3? CH ( ') 1.1.3 d 232 ΜΑ 33926Β1 232

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02341.tif" id="idf0165" />

(R4 26 483.2 a free base of 00 A0..000; 0000-; 000 CH3, rI) CH3 / CH3 (s4 CH3 OCH.3 13; a -27 Hadn Foresail 493 +++ CH3 (CES) CH3 / CH3 CH3 CPR 1, 3 AAA ....... 28 R4a / R4b = H / CH3 Qaoua_h free 453 H Η / Ε.Ή3 (Arl 4 Ozza; / aT &amp; gt; CH3 CH3 113 for 29 to 32 1.1.3 S p y uh 481 + ++ Et H / CH3 (4 isolate the isomers) CH3 CH3 -Î .1,13 33 d 1.3..1. a -36 free base 5070 b {0 b HH / CH3 (isolate three isomers) CH3 CH3 13..1 as 37 1 Li a 11.3 -39 ΜΑ 33926Β1 a- base b. 535 Et H / CH3 (presented for the three isomers) CH3 cf3 1.1.3 Â AA -40 113 -42 Hadn a free 439 H Η / Η CH3 CH3 11.3 a ~ 43 Hadn Hoh 439 + ;; H Η / Η (6 isolate isomers) CH3 CH3 113 44 to 13..1; -40 a free base 4670 with 0 00; a; a Et Η / Η CH3 CH3 -Î 1.13 50 Hadn m; 493 H Η / Η CH3 CEB 11.3; -51 been drawn 0 free 5210 a; -000 g 0 a - ;. 0 Εί Η / Η CH3 CFs 113 a -52 R4a / R4b = H / OH sitting d a free 441.; a Zea 000 000; 00 Η Η / Η (Ez.l CH3 CH3 11.3 1-53; 3 -234- ΜΑ 33926Β1 -234-

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02361.tif" id="idf0166" />

Isomers) 54 R4a / R4b = CH3 / CH3 free base 453 +++ H Η / Η CH3 CH3 92 Table and E 1 b

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02362.tif" id="idf0167" />

Image (s) [Μ + Η1 + noticeable activity rhSYK R-3 R2a / R.2b Rl example Rh base 453 +; + H. 205-Dai (CH3) (5 Isolation Oizumra't) CH3 113 n -1 d 113 b -5 base.; '48 (3), - a - b E' 2, 5_daa (3143)) (4 isolate the isomers) CH3 113 b 4 -6 Li 13-1 235-ΜΑ 33926Β1 (!) b. 9 Hadn 507 H 2, 5 "Dai (5113)) 3CF 113 (n) of free (4 isolate Ozhurat) 10 to 113 and 1 a b &amp; quot; &amp; quot; &amp; quot; 13 Base + -1- + Et 2, 5-Dae (3143)) 3CF 113 Hra (b) (2); 0 + '0;' (known Oizumrk 3) 1.4 d (a) 113 b ..... Qay_h 453 -;. ++ .... 2.6-Dai (CH3) CH3 113 B. Free (satisfy, 0.0 x, 'Nrd) 12 captain 495; 0 iP 2, 6-Dai (CH3) CH3 d 11 b Ende R 18 base 507 ;;; A-A 2.6-Dai (CH3) CF3 113 b Khozz (Rs; trauma; RIP) Wa base 549 00 40 &amp; quot; E; 2; 6-Dai (CH3) CF3 113 b Srn R (isolate the isomers) 20 Zz 11.3 n 21 -236- ΜΑ 33926Β1 base 453 - - A-; A'a 3.5 "an intelligent (CH3 ) CH3 1-3..1 b base 481 + .Η 3; 5-Dai (CH3) CH3 13--1 B-- Hadd free 507 + .. 1 ... + .. &amp; quot; 3.5-Dai (CH3) CF3 1.13 b Hka.h free 535 - + - + - + production 3; 5-d; j (CH3) CF3 113 N- limits for a 3 v 1

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02381.tif" id="idf0168" />

Image Zalsour) [M + HJ + 1 for observant rhSYK * 1 RJ goods for example TFA salt 436.2 +++ Strip) does not CH3 CPR 13 production ..... 1 '237 ΜΑ 33926Β1 free base 442.1 C (O) H (homologous a) CH3 _ (F) CH -, '1.13 CH3 captain fairway 442.2 CO H (Maz &amp; lt ;; 2) CH3 - (F) CH -cl 13 CH3 4 Hadn sulk 446.1 ..f.0.0f ..0f0- CiO) H CH3 2chf -cl 13 7 TFA survey 450.1 +++ C (0) HH CF3 -cl 13 free base 5 452.2 00 f - ..f .. 00 f .. CO .. CH3 tBu - (- 113 9 a free sitting d 454.2 +. +. (C (O) H CH3 iPR-0 -cl 13 10 Foresail Base 4.22.2 .0f00000f000.0f ... Cif 1-1 CH3 CPR. -cl 13 .13 base sulk 424.2 000) 000, .raa .000 EA 0 c \ b H CH3 PR; -cl 13 14 free base 522.3 ttt CH, Say / a (; b all 1) CH3 CPR -cl 13 1.7 -238- ΜΑ 33926Β1 a free base? Ρ2, ++ ch2 BOC (homologous 2) CH3 CPR ™ cl 13 a free base 524.3 -1. (- 1-- ch2 BOC CH3 iPR -c 113 1.9 a free base 524.3 11 CH2 BOC (problems 1) CH3 PR; -cl 13 20 Qaoua.h Foresail 524.3 ..0o 0. CH: 'BOC (homologous 2) CH3 .PR; -cl 3 of 21

Image [Μ + Η. + RhSYK Activity Aliv 1 for example (images) of 1 Note free base 443.1 5 &amp; gt; &amp; quot; ΟΗ .113 1, no b-for - \ / p d -13 H3G .... 0 d \ J &amp; gt; WX, (jr1) H Mesh 0 116

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02401.tif" id="idf0169" />

239- 239-ΜΑ 33926Β1 (r4, s1) and (a 5)] - 3} -5) -4- (84, R Avloro -4 Maial pyrimidine-2 NL) E] 151 such as asset} -1.3-Thazul -2 -al) -4-Hbroxa -2.2 "Im Tae-Z 1] and a &amp; quot; .I insulted Alkuboksila 90

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02411.tif" id="idf0170" />

Humanitarian partners; Pooling is 2-chloro-5-Shu-4-H pyrimidine (50.0 Bhm, 0.341 m 7 j h ^^ a 4A [5- (3-Osdhu -5-Shell Fajl) -1.3-disappears-2-Z-4- Probe No. 1 Hi-Q corset 0 Klohecsav bicarboxylate (128 mg, 0.341 over promises), Pd (QA.Ch 3 5 a mg, 0.0680 Msmol) a R.oztss (59.2 b Mlaimo.l 0.102), and 1-220qy (222 mg, 0.682 touched the dependability ) in a flask was Nra Arat Balodn. L. Hedda mixture 1 dog ci 1 addition an intelligent shelter 1 t (2.0 ml), was disarming raids of thread 1 integral Balorgeon for 5 minutes 0 Tejen reaction mixture to 110 m births 5..1. h. the Nbar.bd 1 cup to a degree Onbeih Amehath temperature, and then was diluted using NaCl financial radiant HtOACj · name Hh 0 classes for, were extracted water layer using HtOAC. the drying Alabakat Aaso.lh data sizeable Lights sodium, and then filtered and concentrated in the center of Morg. has the raw product purification Ladakh Bkromato Graf by silica column (included 10-30% E (OA.C_ / Hecsamat) for Hhol methyl -4- (5- {3 - [(5-Shu-4-methyl-pyrimidine-2-Yale) -5 Omivoa "Shell Vnl;" -240- -240-ΜΑ 33926Β1 I bear for ~ b 2; PL 'j Dey 2.2 Methya Saklohhassan Nrbo Thsilat compaction (143 mg, 0.295 mmol, 86./. CTA &amp; quot; c) 0.485 E' .4 "+ (. MS ESI: [Μ + Η step 2: to Mahrl g 0 such as (a 4.8 s) -4- (5- {3" [(5-Shaw -4 pp Berdd; n &amp; quot; ~ 2_l) Osdhu] D5-methyl Ivel) -. a 0.3-thiazole-2-discriminate) -4-Hedrora -2.2 Dai-corset Skoo, Shan / Rksilatras 0 j (0.7 mg, 0.14 · JL 0 RL) in T'ol (RC ) and adding sodium Arroxad (Amolar; 0.87 ml, 0.87 ml Hall). Tm'skhv a Azalvy, Amath E 21.10 m for 10 minutes Tdt Abikerowiv rays. The reaction was cooled to 1 ° Chgh Njth heat, Done adjusted figure Afouros to I s 3-4 (Hydro-Ram Jesse preparatory Dam); M HCl (.aa in water). The resulting mixture was extracted using 10% 3: JPA; CHC (χ3). And then drying the organic layers Okhiah Bassadam Na6S04 was 2 and y Hgdz.g Kizha in Seoul on acid 4- (5- {3 - [(5-vs.-4-Mht; for Berimbin -2-Yale) Apo's &amp; quot; 5 ~~ Mitt Ivel; -1.3-thiazole-2-Yale) -2 -4_brod E2 Dai-m; Thiel Sichaelo.han carboxylic R.ascime (58 mg, 0.1,2 mmol 0.58% Kytj &amp; gt; 0 ESA was 4 Atma'bat to Khhh Bkroma.dhujrav one fluid Vevey 1 of embarrassment (35 ½) 0.65% Mithadhula 2 () €, 0 0 del Ted's 70 Mdadeghiqh and operating time 4 minutes). MSES1: [M0H1) - ,, ^ 47I. lH ~ NMR (50 () MHz, DMS (.}) δ 12,00 (br s, 1Η1. 0.68 (s. 111), 8.42 (s, 111), 7,01 (s, 1.Η), 7.80 (s. 1Η), 7.47 (s, IH). 7.05 (m. IH). 5.80 (br s, 1Η), 2.41 (s. 3Η). 2.20 (s, 3Η), 2.16 (br d, and = î -2.5, 1Η), 2.02 (m, 1 ((1. 1.84 (br m, 3H), 1.64 (br 0..7 - 14.0. 1Η1. 1..58 (br d, 13.5, .1Η). 1.11 (8. 3Η), 1.01 (s. 3Η) 1 MS ESI 33926Β1: [M + HJ + ηι / ζΑΙΧ. lH Seth 0 eat 2 (27 mg, 0.057 S. Hall, 40% Katj) of NMR 00?,; MHz. DMSO) ; its 12.0) (br S, 1Η), 9.68 (s, 1Η), 8.42 (S, 1Η) 1 7.91 1,?.; Η7.89 1; (S. 1Η). 7.47; s, JH), 7.0 ? (ni, JH),? .89 (br s. JH), 2.41 (s, 3Η), 2.29 (s. 3Η) 1 2.1.6 (bi tl, 07 = 12..7. JH). 2.02 ( ill..,. (- 1). 1.84 (br 1.11, 3 (- (). 1.64 (br d 1.4.0. = t, JH), 1.58 (br d ../ 13.5. .111). 1.11 (s, 3.Η). 1.01 (s, 3H)? were prepared compounds in the table (below) in a way all your landscapes described in example 116: table 116 a R1

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02431.tif" id="idf0171" />

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02432.tif" id="idf0172" />

Image fM + H! + Activity X κ2 Ri 1 for example (Moors) a 1 Note rhSYK 453.2 Base, +++ CH (R) C.2H iPR 1.16 a- sulk, iL, + + + 3 TFA TFA salt 467.2 CH60 CC &amp; gt; 2H ( Cisse) tBu 1.1.6 (a) 6

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02433.tif" id="idf0173" />

ΜΑ 33926Β1 TFA salt 469.2 CH ?. C.2H (Cisse) Ο-iPR 116 a- base h 0 5 513.2 +; + CH6 C52C. (CH3) 3 CH (F) CH3 116 a "jib base 523.2 .0; 00.0; 00 Clh C () 2CiCH3 (3) r) tBu -1116 TFA 529.1 salt BP 0 b ch2 IHC02H CF2CF3 16 of a- TFA. salt 585.2 &amp; quot; ... CHo C52C (CH3) 3 &amp; lt; Ss) CF6CF3 116 a- Hadn free 475.2 0 BPB CH (CH3) (1 / jJ) C () 2H CHF2 -Î116 Vaadh a free 475.2 ..1 .... 1 .... 1 .-. CH (CH3) COjH (Aynur 2) CHF'2 -1116 free base 481.2 ..1 ...... 1 .-- + CH (CH3) 2.Ό2Η tBu 16 a O_ Hadn free, XU 483.2 4-. 1 - + .-- 1. CH (CH3): 4 A 2 () € 0-iPR -1116 243- 33926Β1 Wu 1 Ramat a free base 489.2 0 C (CH3) 2 (r4, s1) C02H CHF. 116 (a) TFA salt 492.2 +++ C (CH3) 2 (r4, s1) C02H CBu 116 d -31 Hazh free 495.2 C (CH3) 2 C.2H Dsas) tBu 1.6..1; -32 Hadn free of 497.2 ;;; C (CH3) 2 (r4, sl) C02H 0-iPR 116 1 - 33 salt FA] '5 () 7.1 C (CH3J2 sl) C02H; r4) CF3 116 (a) example 37 117 SOS-4-Hiroksa - 1-0hl-4-L5- (3-Mhlld- {[4's (Ray Vrumethyl) Dramaidin ~ 2-Yale Abu} tends) - !, d-Thazul -2-Aloshlov Therbocommad

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02451.tif" id="idf0174" />

-... 244.- ΜΑ 33926Β1 0 Η2ηΑ

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02461.tif" id="idf0175" />

Li Mib of SOS-acid solution 4-H 0 Droxa-Aamgl-4- [5 (3 Count 5 {[4 (dray Vrumethyl) pyrimidine-2-Ayobo} phenyl) - 1.3-Thazul-2-J 7 Sklohishan! To Krboksc (442 mg, 0.90 mmol) in 9.0) DMF ml) was added ammonium chloride (144 mg, 2.69 mmol), 344) EDC mg, 1.80 mmol), 243) HOBt mg, 1.80 Malash Mall) and Dai Oarobroal E0 Shiels (0.94 ml , 5.38 ms Hall 4 let your solution, stirring at a temperature of h 0 seen him room for a period of 1.6 hours. The Nkhvev interact with water and how much deduced using χ3) EtOAC &amp; gt; 0 is organic layers Atjiah laundering using Akrbunat sodium water-saturated, essayed saline, and then was dried (sulfate Mufnseyoum) It was nominated and Nrkin ha. Mojt Tnchet Almadden remaining halitosis and Mato Jr. F column for the bitter Feb contained's title as a solid Bissae. Of (14 NMR (50 () MHz, CD3OD; .492.2 EST: [M -t Η] + m / z 8.71 (d,, .7 = 4.9, 1Η). 8.03 (s, JH). 7.91 (s, lH), 7.44 (s, IH). 7..13 (s. 2Η). 2.37 (s. 3Η). 1.2.2,2Η), 1.84 (d., 7 = 14.1.2Η), 1.63 (d, J = 1.3.4, 2Η). = Ra 2.22 ((1..7 = 13.0. 2Η), 2.15 (d (.1.30 (8, 3.Η been Tjder vehicles two thousand table (following) in a manner analogous to those evidence in Mtha; 1.1.7: grandparents 117. 245 ΜΑ 33926Β1 R3's

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02471.tif" id="idf0176" />

Image Zmor) [Μ + Η; + Olhlahal rhSYK Activity R3 Rl 1 for an example of her 5 A- y a free 521.1 +++ HO 1 no X N_ (CH2) 3C0NH2 L'1 \ CF3 7 Al_ 7 Vision free 492.2 CHsCONHz; ^ No 1 (isolate a. Bsohrat p Lyons) CF3 -117 free base 596.2 + - (--..- 4 -) - + .-) - X ^ (CH2) 2CONH2's --- \ &amp; gt; Joel (isolate the isomers Cisse and-pinion) CF3 - 11,711 free base 509.2 baby-b HO, ^ 002 h 2 «h (0) to r Aoz: \ iPR 13

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02472.tif" id="idf0177" />

246- ΜΑ 33926Β1 be happy -4-Aidroxa-4-to 5-D3-crippling -5 for {L4- (G Flor.omethyl) Ber..bmad yen w m.} 0.1. 3-disappears-2-I - * [3 to 0.2 Udupi-of-the Nm'oalo cyclohexane / PU Thsamed

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02481.tif" id="idf0178" />

To ^ (3-Oborobgel) -2-Barelldloon (14.1 micro liter, 0.1.2 touched Mall) for Asaio solution of Cisse acid-4-hydroxy-4- [5- (3-Mbl- 5 - g [4- ( &amp; quot; Ray Glmorumbal) Perem 0 religion-2-Alaobo} phenyl) - 1.3-thiazole-2-Ysklohkan Alkrbok 0 Leslie (48 z, 0.1 mmol) in N, not-Dai-methyl Euermamad (1 ml). It has the elegance of N, * an intelligent Oazobros asset Amin (35 curlers skimp, 0.2 mmol) and then was cooled Amehlol to Z m 0 ci Adhaqh Ongeadrid guttural 0 n 0.1 acid "Propane Vosgonak (70 curlers EDR, 0.1.2 Hma Maud) and has saunas mixture. To room temperature was closer to 16 hours, and was nominated ^ is Zllt 0 purified by HPLC, which .d Ahllagah bloc in Phase 1 of the inverse (C-I8) of pregnancies Z of 0 Tj Alo 1 reply Av.an (5. 0.21 mg, 0.036 touched Mall 0.36% Katj) as 0 birth of a d 0 Wen smaller baht. , H NMR (600 MHz, DMSO) δ 10.22 (s; .1.3.2): / MS ESI; [Μ + Η] + m, (H), 7.25 (d. .7 ::::: 4.9. 1Η A, 4.9, 1Η). 7.91, (s. 2Η), 7.73 (s, IH). 7.43 (s = for, ίΗ) '8.80 (cl IVI ^ ΟΟΌίUD I &amp; quot; 247-. (; -; 3 .7.29 (s (a;' 5, 1.5 () (ni 2, 6.0 h Η). 1.60, ( Ada-- 1 2 98 (d b 7.0. IHi, 3.13 U,. / = 7 2. 2Η = .7.12's (S, 1H). 3.29 (C to a 9; 13a. ;; = /, 0.1) 17- 2 1-75 (¾. 0 Ial 119 (, 4, sI s) -4-Hydro-hand Oo.xi) Peremedev 2 calc Thsabg 0.2 0.0 E2_daa Yale-4- [5- (3-Tel's -5 {[4- (Mopa -2 ί I ....} g &amp; lt; l) a ~ 0.3-Ttasul -2-Yale; Skloma's

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02491.tif" id="idf0179" />

çh3 to Kle 5 does not

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02492.tif" id="idf0180" />

, The Council 0 0.0 Sa ,, 0.004-ESL ¥ d Ee * B'l 0 of 0 is; A-Aa0.a ", - for &amp; lt; Besaam-for-what crescent 'Dblo 20 I fluoride Amu Neum (19 mg 0.6 to 0 Shamma b 4; 1 Aaaoe (0.1,3 t, 0.72 Hall) Mall), 35) HATU mg 0.0 () 0.0 mmol) and the base was 0 for Ip ESL when Dhirjh Arafa temperature for 16 hours 0 then has Bhz 0 cent Altagael between 10 x g each z EtOAc 0's termination was μ Olqqat 0 1 Schas phase ALMA-j Rh one Bashaddam 10 each Z EtOAC 'and then μ Alorar organic drink a great use of all 10- 0 0 n chloride Sodio 0 m 0 0 loyalty beam, then Tjmgho A-; m MgSClf Z vu, was her candidacy, and focus under Satt Shani. (Insert a 0 -0100 / e -2- led by pure Bdwi 248- ΜΑ 33926Β1 to S z (TFA ./.0.1 0ΗΟ in MeCN 1 to developed pain 0 cos (a 4.8 s) _4-Hellerocaccia2,2-Daemcl -04 [5- ( 3-crippling-5- {L4- (Propane's Oaks) E.mmil.n ~ '2 Liel] Abu} Vvel) -1.3 "Yarol -2: L Skulovl MS ESI: [M t Η] + .mad ;) j Droosaat (12 mg 0.33 AA) Krgoh colorless some LT / /// ': 496.2.) HNhlR (500 MHz, DMSO-do) 9.67 of (s. nil. 8.18 (d 0 /: 5 6 Hz. Ifli. 7.92 (s, IH), 7.86 (s, 1Η), 7.45 (s, 1Η), '7.14 (s, 1Η),' 7.11 (s, 1Η), 6.71 (s, 1Η), 6.24 &amp; lt; 4 ..5.9 did Hz, 1Η). 5.40 (septet, 6.1 = when Hz, 1Η), 2.50 (s, 3H), 2.04-1.60 (m, 6Η), 1.34 (d, J; 6.1 +++ = rhSTK Nthat .Hz, 6Η), 1.34 (s, 3Η), 1 A..a (s »3Η) 117 was Thver Arkpat AA - in 1 table (tables) following a debate in a way you described in the examples (Tr.bakh a) 0.8 a 0.1 (mode b) and 9 of one (method c). 'are referred to as Aljaddedh methods used in one table (seriously; well) 1 Lali: 1.1-9 Χ agenda * Η response of &amp; quot; Η \ /' &amp; quot;} aa V '\ CH3 * Photo [Μ + Η1 Activity X R3 + R4 or R3 / R4 R '1 for example (images); rhSYK 1 to Mlahmaz μ --249-- ΜΑ 33926Β1; Base 438.2 -Ι .... ++ CH (CH3) Η / Η CH3 -1.19 h 0 5 (Oror A.) 5 a base 438.2 ++ 4- CH (CH3) HH CH3 -1.19 free (isomer 2) a base 6 452.2 --- 2; C (CH3 HH CH3 -1.19 free (p. ) 6 ί captain 452.2 +++ (Cisse) CH ?, Η / Η iPR "119 free 8 - as upper 466.2 +++ base. ch2 (Cees &amp; gt; HH tBu d a e - Free 9a base 4 (, 6.2 CH (CH3) Η / Η PR; -1..19 jib (Oror. A) 10 A leader of 466.2 -fft (CH3; CH Η / Η iPR. -119 free (Zaror 2) 0 c a Hadn 468.2 CH / CH3) Η / Η - () -119 free (r) PR; a huge 12 5 468.2 +++ c (CH3) 2 Η / Η OC1-Ï3 -..... 1.19 0Λ (r4, si) 13 ΜΑ 33926Β1 a free base of 492.1 ch2 (Cisse) H / CH3 CF3 -11.9 1.5 a base 5 () 6.2 2; CI (Cisse) CH3 / CH3 CF3 -119 Foresail 1.7 U 7Ü4 517 t a 2 (Cisse) H, / CH6CN CF3 -11.9 Gu Ramat 18 b d. 520 +++ CH6 (Cisse) H / îPr CF3 -.119 Ge Mar 0 v 0 Â 20 for H.d. 520 ++ ; ch2 (Mmas) CH3 / Et CF3 9 AAA - Fu died R. 2.1. b ml 0.522 +++ (r) CFh H / CH2CH20H CF3 -1..19 formate 22 b xXj L 532 (p) ch2 H / CH2 &amp; quot; CPr CF3 -1.1.9 soon died 23 ml VJ 536 1; Ί1) (Cisse) H / CH2CH2OCH3 CF3 -119 Gu Ramat 25 N. Hill. 5360 ((2 ;; 'Na (Cisse) H / CH2CO2H CF3 119 formate 26 ΜΑ 33926Β1

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02531.tif" id="idf0181" />

; 0 Ba HD 544 'A.. ch2 (Cisse) 2 a «-zmmadasulal CF3 -119 effective 1 Matt / | 0.27 for n ills 7545 Thell 1.) (Cisse) CH3 / CH2CH2CN CF3 not A. A ...... formate 28 a Hakka 0.9, 548.2 + + + Ή6) (Cisse) -CH2CH20CH2- CF3 -119 free CH2- 29's. L x 549 +. +. +? CH (be settled) H / CH2CH2C0NH2 CF3 llllll- 1 1 No, Forma Dutt No 3 to 1 mm. 550 (.-- 0.1 ...-.) - .. (O) ch2 H / (CH2) 30CH3 CF3 -119 formate 3). B xU 21 A. These 000; 000. ··] ·· 1; ch2 (Cisse) H) CH'2CH (OH) - CF3 -119 soon A't CH2.H 32 0 0 Let sa TiU 0 c 5 ..1 ... .1 ... 1.- CH (Cisse) H / CH (CH20H) 2 CF3 -1.1.9 33 Ramat Fu b 0 DJ I 00 ... 1-1 .... 1- t; a: p ( Cisse) 4/4 of Berriedale-CF3 -119 formate 34 b 1 ml. UI - 111 2 AA: p (Cisse) 2 / Η 00 Goodyear Liddell CF3 formate ....... 119 35 252- ΜΑ 33926Β1 252-θ \ 's fill 0 J 555-4 ..... 4 .... + CH2 (r) 3 / Η- Berriedale CF3 19 a. 36 b formate salt 557 + -4 --- + ch2 (Q; "termination) - (CN) CH2CH2CH- CF3 -119 Tmo t what T. -ch2 37; p 0 Dh 558 -4 .... 4 - t &amp; quot; (R) CW -2-H / CH2 CF3 -119 in Ramat Abmadoro μ, 38 a leader of 558.2 -4 44. (r) CH6 2 O-3-CF3 Sasulal free 39 -119 4 559 AA- -4--4. ..-. 4.- HLA: p (Cisse) Et / 'CH2CH2CN CF3 -119 Tmurmat 40 a &amp; amp; 5592 Q (CES) -4 "H7CH2 CF3 -119 Tmurmat a V 9 Kst a 3 for a 41 {a salt 559-4 .... 4 .... 4-2 AA) (Cisse) -4-H / CH2 CF3 -119 there is one Marib Oocar.o.by 42 a b 559 b &amp; quot ;; &amp; quot; &amp; Quot; {· 'Tel-A € (b,) "DII / CH2 CF3 -119 Tmurmat Lazo x 0 Masulbl 43 to 1 ml. 560 + 0; CH6 (Saar,) H / cHex CF3 -119 There Ramat 44 253- ΜΑ 33926Β1 for a 1 ~ 560 (r) ch2 2, 1-H / CH2; 4- CF3 -119 formate 'or hand Azul 0 -3 - 45 b D 561 ttt ch2 (Cisse) -CH2CKCH3) - CF3 19 termination glimpse Rmadt CH2CH2- 46 b HD 562 +++ ch2 (Cisse) 0CH2CH2CH (OH) &amp; quot; CF3 -119 formate CH2CH2- 47 to 71 ml of 562 ;;; Nlah (Cisse) -CH3 / 3 CF3 -119 0 Mahormat Dhahedrodharavel 48 U were 563 H :: ¢ (r) H / CH2CH2NHCOC CF3 -119 Mahormat Η3 49 b D a 566 +++ CHi (Cisse) CH2CH2.H / CH2- CF3 -119 glimpse Marzt CH20H 56 b D 5682 for 00; ::: &amp; gt; (sES) a 00: a / Barr. .bl CF3 -119 Mahormat 51's. ! i joked 569 ;;; s] I) (Cisse) Liddell JK-3-IH2 CF3 -119 Gu 1 What Cement 52 b D 569 ¾0 (Cisse) 4-H / CH2- Berriedale CF3 -119 --254- ΜΑ 33926Β1 Ange 1 what n 53 bb 569 +++ remote;:) (r) Liddell jr2-H / 'CH2 CF3 -119 Kormat 54 n ml 09 0 00' e 110 570; 0; αι6 (Cisse) H74-OH-Ph CF3 not A. E. Z. T the rate 55 SlMMUMoJ 'Ba 1 of 6 H 2 O (r) H / 2-OH-Ph CF3 -1.19 formate of a 5 570 Salt +++ (r) CH6 -5-H / CH2 CF3? AAA Forba T. Ber.bmad: Bill for a 57 \ 7 A 57 (A :) :) da (Cisse) -3-h / ch2 CF3 19 (a) 58 b Aourmat Piridazsl Hdj A57; ++ 2 a;) (Cisse) 0CH2CH2CH (CN) _ CF3 1.9 A- Forma rate CH2CH2 &amp; quot; 59 1 0 St sector "71.? ;; .-) (R) -CH2CH (CN) CH2- CF3 19 a Kormat CH2CH2- 60 b eg 572 '·} · ++ (r.) Ch2 H / 4-F-Ph CF3 not 1 1 x "Fu e 1 1 00 T. 62 N. Mudug a 570 + ;; (r) ch2 ^ ΰ-2-wcHi CF3 and! A --255. ΜΑ 33926Β1 --255.

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02571.tif" id="idf0182" />

And 9 Rma't 63 7 A U (r) CH_1 -1-H / CH2CH2 CF3 -119 formate Bdhirlold.sl 64 A; Ίΐ5 ;;; -CH (SES) "OH-0)) &amp; quot; &amp; quot; H / CH6 CF3. -..- 119 Aormat 5 ~ &amp; quot; ed 0 E '1 for a Thsar 9 g.) 65 E ml, 575;] &amp; gt; (Cisse) -5) -h / ch2 CF3 -119 Quzmat Oazuthiazulal) A 66 ml 6576 +++ (r) CIC -....- 4, 3, 1) ...... h / ch2 CF3 - .... 119 formate Thiadayasul -2-Yale) 67 ml of t-ηη. ;;; 1: {a) (Cisse) H / CH2CH2N (CH3) CF3 -119 Kormat C0CH3 68 ml Z 9 E 582 ;;; Z- a; 6 (Cisse.) CH3 / Dr.l CF3.-.... 119 Hormat 69 ml to 582 +; + ch2 (Cisse) H / CH2CH2Ph ​​CF3 -119 Aouraat 70 for 584 ml (r) ch2 H (CH2 &amp; quot ; (3-OH) -Ph CF3 "1..19 Kormat for 71 &amp; gt; ml 0.584 + BP (r) CH9 H / (40CH20H) 0Ph CF3 -119 -256- ΜΑ 33926Β1 Tmurmat V grew HD 7584 ..1. ... 1 .... 1 followed: p (r) H / (3-CH20H) -Ph CF3 and Oa- Kormat by her 73 1,? 84 ((0 CH6 (sES) 1; 1142. (2- () ΗΓ) -Ρ CF3, ..... 119 74 Nmslo glimpse Rmanmtmh Mlma. 584 -Ι ... ++ 2 for 1) (Cees &amp; gt; H / CH2- (4 &amp; quot; OH) &amp; quot; Ph CF3 -1.1.9 Mahormat 75 b LED 586 + ;; only € (Bi) 4, 2) / H "Dai CF3 -119 be 9 what T. ΡΗ_ (ΟΗ 76 nm 000 ml not 71 H 58 2 does not: p (Sears) H./CH2-(4-F)0Ph CF3 1.9 .a- formate 77 b Are 1589 +++ ':;)) (Cisse) -2) -H / CH2CH2 € F3 -119 glimpse of one bit what their people "for" 78 Pirollad; Yale b) Salt 590 (r) CH2 -2) -h / ch2ch2 CF3 -119 Mahormat Ksh OH - A - 79 Deddazoulideeil) Rt ups 7 591 +++ CH9 (0 o C) -4) -14 / (: ¾ € ¾ CF3 -119 ΜΑ 33926Β1

-ISI Fu Ramat Morvulinil) 80 re- a 591 ml - + - ++ 2 Do not: &amp; gt; (R) H / (CH.2) 4'NHCO- CF3 -119 Ijsmat? .CH 81 E 593.1 Base! () Followed by 0 (R) 5-Mulla Azdolel CF3 119 free for 82 ml. 596 ;;; Uh 2 (Cisse) H / (CH2) 3Ph CF3 -119 formate salt 83 b 5980); Laa politicize 2) H / CH2- (4-CH20H1- CF3 -119 in Ramat Ph 85 to 690 ml + .. 1 ... .1 .. 1: CΗ (Cisse) 4, 3) -h / ch2- Dai CF3 "11.9 formate ΡΗ- (ΟΗ 86 not e 0 100 D 0.602 +++ (r) CHo H / CH2- (4-Cl) - ph CF3 -119 glimpse R. what rate of 87 0 Z λ1.5 603 ;;; 2 aa) (Cisse) -2) ~ Η / (ΟΗ2) 3 CF3 -119 formate Ootxo- a 88 j; and Ddil) Z Hao-E _a 603 ;;; Dlaa (Cisse) -2) -H / CH2CH3 CF3 -119 Ge t what dysarthria for a 1 - "l 89-258 ...,. ΜΑ 33926Β1 Bebaradinell) a free base Tam CIÎ2 H / 4-CONH2-cHex CF3 -119 90 b Hao formate 604 +++ ch2 H / 4-C02H-cHex CF3 19 -91 w's. Mg formate 605 ..1 ...... 1 ... + CH9 -CH2CH2N. (C02CH3) CH2CH2 CF3 -119 92 01 b What formate 636 Bbulb 2 aa) (space) H / CH2- (4-CF3) PIi CF3 -119 1 () 0; d Wu Ha t AA 636 ch2 (Cisse) -2) - 3) fCH2 Berriedale) -odwo Zsasul-5-g) CF3 -1..19 101 for 1 waste Kormadt 636 ++ 1a) a (Cisse) 0CH2CH2CH (Bn) CH2CH2. CF3 No, I --1111-102 a 91 ml; formate 647 0); CHi (Cisse) H / CH2_ (4_ S02NH2) Ph CF3 -119 104

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02601.tif" id="idf0183" />

--259.- ΜΑ 33926Β1 --259.-

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02611.tif" id="idf0184" />

; Base 411.1 -1 - + .- 1- .. CH (CH3) h: / c: h2cn C.H3 -119 Eh 0 5 (p) .1.08 xU 480.2 +++ CH (CH3) Η / Η tBii. -119 TFA 1.09 ml c ^ 482.2 CH (CH3) Η / Η Ο-iPR -119 TFA 1.10 1 Hadn 492.1 CH (CH3) Η / Η CF3 -119 free + + + (0.1-isomer) 11.1. E rule 492.1 (Ή ((Ή3) Η1Η CF3 "119 Foresail (isomer 2) 11.2 A rule 505.2. +++ CH (CH3) H / CH.CN PR;" 1.19 Foresail .1.1.3 a base 529.2 +++ CH (CH3) 3] Del- H / CH2 CH3 "1.1.9 free £ 114 base 01 7 00 00 +++ CH (CH3) a-L'6 / a - l 3 - Bear hands Yale iPR -1.19 a 11.5 free of Edh 1 565.3 + (+ CH (CH3) -2) -H / (CH2) 3 CH3 "free 1.19 or P - .1. - .116 --260.- ΜΑ 33926Β1 --260.-

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02621.tif" id="idf0185" />

Aar.ulidesl) a d .had 468.2 C (CH3 ') 2 144: 4 0CH3 -119 free (r4, s1) 117 a base 478.2 +; + C (CH3) 2 HH CPR. - 119 free (r4, s.1) 118 c MP 48 (). 2 - + - 1 - + - C (CH3) 2 HH iPR -119 TFA (s4, sl) 119 A d. 484.2; 0) C (CH3) 2 HH (S). -119 TFA (r4, s1) CH (F) 122? CH- E0 edge. 484.2 C (CH3) 2 Η / Η (R) - not A. 1 gii TFA (r4, s1) CH (F) 123? CH- E d 0 7 461.2 + -1 - + 7; C {CH3 H / CH2C0N (Ή3 Forma at -119 (r) HD 124 us 7 494.2 + - .. 1 - + - C (CH3) 2 HH iBu 9 Â 1 -m «TFA (r4, s1) 125 r Shiny 496.2 C (CH3) 2 Η / Η 0-iPr ....................................... -119 -261 ΜΑ 33926Β1 TFA &amp; lt ; r4, s1) 1.26 a rule 506.2 -Η- + C (CH3) 2 (s4, rI) Η / Η CF3 -119 131 a rule 506.2 ((0 C (Cli3) 2 (r4, s1) Η / Η CF3 1a ....... 132 a Iadh 507.2 + -9 ... 1- C (CH3) 2 (r4, si.) H / ORCN 0CH3 -11.9 133 a Iadh 60 05 559.2 +++ C (CH3 ) 2 (r4, s1) H / CH2- and-Berriedale 0CH3 .119 1.34 a free base, 13:00 0 ml Ua Wyatt 577.3 Oaaa; a 00; 00 0. 4; 0.0.0) 000 A.o- C (CH3) 2 (r4 .si) -2) -η: ./ (€ Η2) 3 Ootxo-'s - Pirolledel) CH3 -11.9 135 V-rr-J free base 583.2 ..1 ...... 1 ... - .. 1 .-. C (CH3) 2 (R4, sl) /} -; 3 to Burleidel .. "1.1.9 136 a base jib 593.3 - + - + - + C (CH3) 2 (r4, s1) -2) -3 (ΓΗ6) Η / oxo-a ™ &amp; quot; ' Pirolladinell) OCH.3 "1..19 1.37

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02631.tif" id="idf0186" />

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02641.tif" id="idf0187" />

Example 120 g [14 ( 'Dhiraa! Is it a) .- D..a-A, .... Z'z &amp; quot;' A b-seen 'charges: T: Las; 0 ^ what impact Bo Xlat

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02642.tif" id="idf0188" />

10

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02643.tif" id="idf0189" />

Thats etiquette acid (4, r1 s) ~ 4-Hedros w 'v j {[4 - (- Ray Ioromithil) Peremaidinl 12 Yale Ebd) Sklohon Ashok 0 t (1.00 mg, 0.197 0.0 well j) adding sulfuric acid Center (0:52 a * JA War, 0.197 Haaa Altaga 0 El extend 5 16 B'eh. was a 0 Thas thread Okga &amp; lt; a Baspat e; Bial (3 *) was' b using Scarpobac sodium protection of saturated. led Tj; for Aaveb to 1 to get {a; pronation

CX -263 ΜΑ 33926Β1 ESI: [Μ in /: 535.2. Contained Z Title (88 mg, 0.165 mmol, 83% Kmath) 0; H NMR. (? 00 MHz, DMS00dô) δ), (). 25 (S, 1Η) 1 8.82 (d. 1, 4.9 == for Η) 0 7.93 (d, 9.6 = t, 2Η), 7.46 (s, ΙΗ) 1 7.27 (d, 4.9: for. ί-Η7.14.; (s. IH). 4.07 (dt, 2 .17.9, 10.8 ::'s Η). 2.31 (s. 3Η1. 2.0.3 (s, 3111.78 - 1.96 .; (m, 314.), 1.65 (m, 2Η), 148 (m, 31: 1), 1..09 (s. 311.), 0.97 (s, +++ = rhSYK 1-31. Chatt ) eg for 1 126 5. (Obohl) -5- 5A (3-methyl "5 ~ g [4 - (- Ray Vrubuthail) Ber.bmad.r" two-Yale Abu} phenyl) - 1.3-thiazole -2 -ene- Ozaaan-2-on-1 NH a real 2-d L /

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02651.tif" id="idf0190" />

Alkhaloh 0.1. : Added hydride Dai Oazoubiotta Secretary-. M (Amolar in Hecsanat 0.9 d 002 no, 0.239 Mia Maud, 1:20 Kavie) to encode from 8- [5- (3-Shell-5-t [4- (Ray Vrumethyl) -2 Berimldan "Abu night) Bill) -1, 3-Yarol-2-L a- 0.4-Dai Ouesso [4 E 5] d 0 ^ n-8-Drdil (100 mg, 0.20 plating 0 well) Atd "22:00 was volatility Olkhaliaf output tomorrow at -10 m to Menna one hour . It has added a second for DIBAL (Amolar in Hanat, D 0.239, 0.239 mmol, 1.2. Equivalent) at -0-1 m and made available Iel Cdi Ate 0 to 23 m and was then flipping for 4 days. The suppression interaction using -264- -264-ΜΑ 33926Β1 what »Apr 6 GS has been removed Article August through Akrchih 0 NaOH: Mixing 0.1; 1: 3 from 1 to Eau 1st dM 55 ml) agents (65 t) 'has been x2) EtOAC has Tgerih a &amp; quot; Dh Fterah 1 Ipava z 8 was nominated tendon Bzha-for folding 1 (3) 2 for cNa2SC) 4 spontaneity Otjiah using Omivomsl) - 1.4-Dai Oordasir.o [4.5] :) 6 Ha8-Yale's 1.3-Thazul -5-Yale} a 5's) λμ 5 Methyd Ivel) "4 ~ (tea Iorosthel) pyrimidine-2-OS (9 for mg, 9 della) d Damada MS ESI: [Μ + Η] + m / z 566.1. 1Η NMR (5 (.0 MHz. CDC13) δ 8.66 (d, .4.6 - t Hz, .lbhad 7.93 0 A.l (s.; H). 7.45 (bs, IH). 7.28 (s, IH), 7.08 -7.04 (m. 2Η). 4.06-3.95 (m. 6Η). 2.51 ,. .2.35 (m. 7Η), 1.95-1.71 (m.4H) Alkhaloh 2: Tmt additional 1 FH more Alsod.boum (20.45 mg, 0.315 My well; 3.0 Mkaqe) to 10 Mqthb solution from step 1 product (53 .mjm, .0.11 Fly well) in Kru.srm (5 g). for additional 1 FH acid methane Bouback (0.082 D, 1.258 touched Mall 4 1.2 Mk 1, &amp; gt; WDF χμ

Interaction was Tkulaibh at 65 ° C for one hour. It has conducted a 0 Yat equ z EtOAC (85x2 ml) ^ 0 saturated NaHCO Vision (90 ml), was drying Labatt Walker 1 data using .MgSO and has been its focus. Has' pure Wales decreased At Adbm Pokerschool of Thlan HPLC at 15, we develop Almeko.s (included Sehozhtrey 1/0 termination with a 0.1./. TFA). Has Tjnh parts 1 to desirable Phys Pugh 55x2) EtOAC ml) NaHCCEj radioactive Mebh (65 t) 'd been AST organic' Nhiah Bastkhadd; m Na2S0.4 was their focus, with R bear Alo; drizzled in Aso; n Adergob (b 3.. 1. mg ,, 2.5./)) as oil b colorless one color. NMR's one of .477.21: / MS ESI: IM + Η] + m 4.6 Hz), 8.19 (bs, 1Η), 7.98 (s. 1Η), 7.44 (s. 1Η), = t, 500 MHz. CD3OD) δ 8.72 (d. HI)

20 1.904.57. (4.6 Hz), 3.45 (s, 2Η), 2.95 (m, 2Η), 2.05 (s. 3Η = 's, 7.16 (s. IH), 7.13 (d, IH (m, 6H). Zot rhSYK = +; +

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02661.tif" id="idf0191" />

265-- ΜΑ 33926Β1 Nau 1.27 5- (2-Yro'delao'b 2_al] label} p 0 of) -1.3 to Bzdl 05 [5- (3-mile -5 - {[4 ~ (0; any Hrumittl) Peremaidin- oz sa 0 μ n

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02671.tif" id="idf0192" />

-ΟΗ H \ a \ 1Ν Ν H CH9 (4.26 .105 0.106 touched 0 for, 02.0 Kae &amp; gt; s DMF Z 0, I (1 {). Ci; Oualo 1 Ute 0's; 3- [2- (4-tames-7! Louise-must-4-t) -a 3-drool-5-I-5-0 Shell Ku} [4- (Ray tightening 0 such as) Beidtna 2 night / Lite (30 blood 0.05 to 0 0 convergence 0 real &amp; gt; and (2 of Aao /) a--A0-o de 0 Il Blanc (19.1 0.08 t Views 1.5 pp), Z kills; 2 mass expulsion passed; o j Aalld g fullest Ely Dhli coined 0 nm tuck Hga broker A.ly 1250 m extensible; 30 minutes. P Tte 0 F his instruments Z Te g j 0 for HPLC in 0 Iod additional 9.! Stobr.l / Aie 0 GS inventory 7.0.05 TFA) 'to list a-Iott's nest (3- {2-A4_ (2_brkaba; Iki) -7-Ootooz; that -4-Yale -1 E-3 Iasul-5: for -5_siz} j 0's) for a four (G. A.dobbl) E-s-2 - for; Cirbelat (p. 14 0.33 0 aa) E Kd.t t-Ila 0.2 722 c Toua + [MS ESf: [Μ ί-ί ΜΑ 33926Β1

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02681.tif" id="idf0193" />

-266- Step 2: The &amp; quot; Nschan a binary mixture phase, from Mzth Step 1 (15 mg 0.2) (0.0 mmol) in 25) in the phase inverted) at HPLC Munib D system) TFA% 0.05 acetonitrile and water with EtOAC m for 10 Degache. It has been the focus of the interaction in the center of Morg, and has Tgerih oil redneck between saturated with water (55 ml). 0. Drying of organic layers Atjiah using NaHCOij (40 ml x2) 8.1) and its focus was nominated for Almt Ollwarz in Ansouan Argob it, MgSO. 5 MS ESI: [M + H] + w £ 508.2 lHNMR (5MMHz.DMSO) S .mjm 0.077 / e) Kzetod 10.3 (m, IH), 8.82 (m, 144), 8.04 (m. IH). 7.98 (s, 1Η). 7.54 (m, 1Η). 7.45 (s. 1Η). 7.17 (s, 111), 4.68 (m. Ill), 3.98 (m, 2Η), 3.55 (m. 211). 3.00-2.79 (m. 211). 2.38 (s. 314). 2.37-1.82 +++. ASYK Activity. (M. 314), 1.37-1.01 (m. 3Η) (-.) 1 Ohz 140 (1) and 140 (2) Acid Zad -1.4 Dai-Hedros-4-5 - (3-S5- {for 4 &amp; quot; (Ray Florhumicthel) pyrimidine-2-Joel Abu ,; vinyl) "1.3-Dbzul -2-Alosaklusan carboxylic acid and p-a 0.4-Dai Hdroxa-4- [5- ( 3-crippling-5- {41. (Tri Vrumethyl) pyrimidine-2-Alaobdhu; Vettel) -1.3-Basul -2-Aloslalosav Walker Boksila

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02682.tif" id="idf0194" />

267- 267-ΜΑ 33926Β1 4 commentator Li Z-4 Alrokm1-4- [5- (3 crippling -5 - {[4- (Ray Vzarohishl) paper &amp; quot; Mmad; N 2 -.- Yale; Abu; segregation) A- 0.3 ~ Sorol &amp; quot; - &amp; quot; -2- &amp; quot; '- Yale Sklochadon (77 mg 0 m, 0.17 · Jr JL) and kills. 1 Zzk (10 mg, 0.033 Delphi mol) in cl, (&amp; gt; 1) CH9C19 4 Hahl G. P baskets Sabd (115 Mlcaruatr, 0.858 ml). Was flipping output commentator for 4 abuse Z 0 ° free; Rh (a room. Has additional 1 FH offset Z Yuden Ark (10 mg 4 00.033 ie 0 well) and Ray-methyl at night E 0 Aaved (5 to 1.1 microseconds Lq, 0.858 ml) 4 was 0 Chaib 1 Overdrive 1 outputs 5 a O'am counting degree ho Rh 1 1 Grah. after Dink was added 2 ,, &amp; gt; 1.) HCl sector) and, Esther S. extend 0 14 hours Ad.dhirjh Alparvh heat. The suppression Acfaal lion; m Aakervollot Sodio 0 I; it b 'was using chelation x3) EtOAC), and. The dried S 0 or Na2S04 and Done Rey and i Morg. Vsz been one of the isomers C and 0 trans n HzO: CH3CN% '75 -20) HPLC j! &amp; Gt; u Bastkhadd; m 001% TFA) rate. Was reduced parts A: s &amp; lt ;, Akj the-weariness in which Bayat ethyl, was laundered using Akrbunat sodium water saturated; was Tjmmha Ba-M MgS04; was nominated and focus to get the acid 'Nram- 1.4-Dai proxy-4- [5- (3-x-5 {L4- (Ray Vrumethyl) o 0 Ead_n -2-Aloopto} Phil) AA 0.3-drools -2-ball Sichaelohan Alkrboxla (6 mg 0.7%) as 0 Azh Z worsened Y Mas- 1.4 Dai-hydroxy-4- [5- (3-Q -5 - {[4 "(R.aa Vzr.o.a) Bdhirimid 0 yen &amp; quot; &amp; quot; 2-night Abu) phenyl) - 1.3 ~ Thiar , well-2-Yale Sichaelohec that Alkrbo 0 0 Ksila (5 mg 0.6 () /)

As a solid illuminated. Data guardian Oaob gear: MS ESI: [Μ - + - Η] + m / z 495. w NMR 7.46. (500 MHz, DMS0-d6) δ 10.25 (s, JH), 8.83 (d, 7: = 4.8, [ "), 7.93 (dJ: 14.9. 2Η) 4.9. lH), 7.14 (s. 1Η). 2.31 (s, 7.11 .. 2.97 - 1.91 (m, 41.1.), 1.85 (s. 2Η). Er 0.0 aa 7.27. (S. IH). (211, 9.9 = 's, 72 (d Azhat Characterization data for the eis isomer: MS .-- + -) - 0 = rhSYK .268- .268-ΜΑ 33926Β1 ESI: [Μ 0 Η] + / «/ 'ζ495 aa 0 Ni (500 MHz, t) MS () - dO) δ 10.25 (s. 111). 8.8.5 (0, .2-4.8. 1Η), 7.94 (s, 21--1 (, 7.46 (s, 1Η). 7.27 (d, 4.9, 1Η (. 7.1,5 ( s. .114 (, 2.3,1 (s, 3Η), 2.20 (d. .7 data description. {· ++ - == [· hSYK 2, 10.4 = 7..0) 09..2, (211 , = 13.0. Activity Η), 1, .57 (m, 411) ESI: [MH] f mf: 51,8.11 E. NMR (500 MHz, DMS00d6) δ 1,0.25 is. 11: -1),: azo. t r 8.83 (4, .7 = 4.9, 111). 7.95 (0..7 = 6.4.211), 7.46 (s, 1.Η), 7.28 (0, .7 = 4.9, 111 (, 7.15 (s , 1.1.1), 5 .6.03 (S. IH (. 3.8.3 (s, 111). 2.3,1 (s, 311). 2.2,1 (m, -311 (. 1.91 (m, 91-1 ), 1.45 (m, 21-1 (-Hf = rhSYK Activity Hthal 141 -a_ Cisse {-4-proxy-4- [5- (3-Shell -5 - {[4- (Ray Florosel) pyrimidine -10 2 -al; a vinyl Mino 1) -1.3-Thazola -2-night Sakhlohksil; Berouliden -2-rang

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02701.tif" id="idf0195" />

4. Olkhaloh to the solution of SOS-4-Omivo- 1- [5- (3-Shell -5 - {[4- (Ray Vrumethyl) pyrimidine -2 "Iaa Ominoo vinyl)." 1.3-thiazole -2 " Yale; Sichaelohecsanol (50 Bhm, 0.11,1 mmol) in Dai Krumithan (R) has Anavh Tri ethyl Secretary (0.047 ml 0.15 0.334 Minty Mudd) and Klor.bd 4-Krubiotiral (4 ml 0.015 0.133 Hess pro) sequentially.

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02702.tif" id="idf0196" />

-269- -269-ΜΑ 33926Β1 Tm'thayeb commentator Alod Alath for one hour Ashdrjh orbit in August 'was Rchihaa, and by using THF, was -rkl, I in the middle of Morg for 4-chloro-not- {SOS-4-Hedrod- 4 &amp; quot; [5- D3-Metel -5 - {[4 '&amp; quot;.'. (Tri-FB 0 Romeshl) Perem 0 religion-2-I refuse Ivel) -1, d-disappears-2-night Saclaudal) butane Forever Damada wigs 0 father Haiah 61 ) jAJj mg) were used in the following reaction Dhun Reid of Akqah-Alhalloh 2: 1 to Rshzaktoh solution (61 mg, 1.0 A..0mrpl) in 2) 'IHF ml) was added sodium hydride (14.5 mg, 0.363 mmol) Afl Samr m. M flipping disabled 1.5 minutes at small m, and then had the heating to the point temperatures 1 Crvh been canning for 4 a hour at room temperature 1 was put out interaction chloride ammonium aqueous saturated been Astkhads using X 3) EtOAC), it was dried using, - (. ) Nâ ^ s been my focus and Saad Morg. You are one of Tzqah through Ammon chromatography by silica gel (a small 0 10 () / MeOH: Ί1) Ή1.)) El access to the compound contained in the title (33 mg, 58½)) as a solid white. .4.9 = 2., ESI: [Μ + Η] + ηι / ζ? 18. 1η NMR (500 MHz, DMS (::) - d6) δ 1,0.25 (S, 1Η). 8.83 (d. (7.28 (d, &amp; gt; 7 = 4.9, Ht). 7.15 (s. IH), 6.03 (s. Lit.; 6.4. 214), 7.46 (s, HI - for, Hi. 7.95 (d a (3.83 (¾. IH). 2,31 (s. 3Η) .2.2Ι (m. 3Η), 1.91 (m. 9Η), 1.45 (, m.2H. Chatt hSYK'9 + .-; - 4 However 0 handful 142 (1) and 142 (2) acid, 1.4-Trzs 0.5; 1-Trajy -445-Dai-hydroxy -2; 2-Dai-methyl-4-A5- (d-methyl-5-t [4- (Tri Vrumethyay) pyrimidine-2-Aloosto) phenyl) - 1, d-Abzul -2-Alosichaelohec 8 that the carboxylic and Hmcny, 1, 4 ™ Cisse 0.5; 1 MBS 0.445 Dai -270-., ΜΑ 33926Β1 Pedroki -202 V-Day 0 such as-4- [5- (3 of 0.0 Ill 5 - {[4's (Ray Feiyu 0 Ebl) E-Bzn 2; L Ombo; b 0 l) -1.3-Bzul-2-HLA 8 fulfilled Amiedklevi ΟΗ / Agea 0 [9Η3 4c0h5 OH _a 0 CHs 3 Brah'za- · '- ΗΟ ί ϊ HO H 1) :::::: N cf3 An CF3 the X LnA ν \ Ηι /; ί Aozaaouk been suspended Nber Pei-4-0edruki 2.2 Dai Shell 4] a (and the Hubble c E [4 - (Tri to yank &amp; gt; Aleay -2-Yale 1 z) Phil &amp; gt; -4 3-0bzdl-2's] Skdzqan; Bd'ellat (570 mg, 1.095 0 for in ZL) and I &amp; lt; a huge amount Baton (4.1.4 t, 21.9 g Maud) and Tm.nb to 60 m births 5-1 Z 'O'ih Aibahl ESL acrylic 0 to the point of Arafa heat, was H'mad 1 Tagael Q 4 night intentional &amp; quot; Rum Φ' Butt 0 E 0 Astkha 1:00 thread 1 Tagael Shd ; m x3) EtOAC), was .i O 0 Hhaddam Na2S04 then; / 0 in the center of ironclad. I write Z led Khalao column / and Matogerav Boishlh &amp; lt; I (% 10-35% EtOAC: Hecsanat) and the separation of 0 thermocouples Name 0 n Tlolal HPLC to astray folding acid 6.6-Dai night-4- [5- (3-Phil-5- {A4- (Ray strayed 0 Gal; Perry 020 Aloo 0 Su} Phil) .. to LBP 0.3-relieved -2; l | 0 Sklohecs-3; Leila -1 1 Soya (127 mg, 23./.) useless Unlon. 503 ESI: [Μ + Η] + ιη / ζ. Aston (800 in 1 water .199 Aljt 0 of 2 T. has, as one by one proceeds to step .41.) I Bhm 4 0.082 0 0 R well) in Mjulr) and 0 termination (1.0 Makrocker). B 1 lest Troy ous (4½) ..- 271 ..- ..- 271 ..- ΜΑ 33926Β1 Maikaruser, 0.033 over Maud) and oxidized N Q-4 Stl Mordhulzn (38.2 mg 1 0.326 mmol), and sleep dome S 7 cent one notch room temperature. Was an immense 0 Ed S Bashaddam 5% matte Na2S205 was 0 GB for 15 Nqiqh Aad Drdh heat Arafa, was extracted using; (e)) sector (Χ3), was lip using 4 (Na6SC was uniform in the center of Morg. Led the purification of Khaz 0 for Ammon Chroma ' by Dhunav 0 Gel wire (20% -75%

EtOAc: Hecanat) to Seoul crippling termination 4-nest Zde termination Terrace 5-E and -4-hydroxy Nye -2.2 Dai-.ha4- [f (3-u-5-all [4- (G. Hloromethel) E.ad RO-2-Yale amino) Bill) -1.3 ~ .yarol -2 &amp; quot ;: Ychan / u Boksilat termination 4 'r, a 0.5-Sass -4.5 Edaa Berlki -2 a 2-Dai-4- To Do [5- (3-n-5-4 - (. Ray Earerod condemns -2-night Abu} Phil) a- 0.3-disappears-2-Z Sklo 0 was / Baas (28 to 64%) j El 0 Bam Alaan 0 Whipple .. -.4: 0 m thermocouples are Altjasm. 537 Μ + Η] + ηι / ζ] 0 Lalla Alaz 3: It thaw 0 4, c-Dai Adlaclel 2, - Dai b 1 of 4 (3 Shell-5-

Ol4- (Tri-Iodo 0 are E.els -2 termination '-ra 0 Gal) E-Roy y gg] Nnanchoa 1 T (43 to 0.080 A b j) your responsibilities (5000 facilitated the, · s Ayll Bdwoa Mrdiom (0..6 Ι not me. Aae, ( 48 b of 48 e JU Maud), Scalvi 0 Doi 00 a 0; I 20 I'msas responded Mdodjna ypg 3-4athbam I) HCl 0 wa 1's in m.) and sleep Tf 0 p 0 for Equal a; Are% d 0 of 1 v 0 v 0 loyal 1 s consoled 0 sticky Almebh class using 10% IPA: T. 0 j, Q; y 100 No, 0 m f I are Dalal HPLC counting t Almekom (40-Trhjhao; Aziviost &amp; lt; 1 datas 272- 272-ΜΑ 33926Β1 to get the acid 0.4-Trzs, 0.1 0.5-Razs -4.5 V-Day ( h2o: ch3 (: n% 90 -m 21.2 Dai-Bill-4- [5-these-Mocha -5-A [4- (Ray Vrumethyl) pyrimidine Hedros ^ del 2_ale Emu) phenyl) - 1, 3 disappears-2-Z Sichaelohecsad Ader. Po Bay (del Cilm, Aq, 2 / &amp; lt;)) CMATH 0 s solid white and acid c. 0.4 Cisse, E. 0.5-Cisse -4.5 "Dai Heder and quantitative 2_1aa torrent-4- [5- (3-like -5 - {[4- (Tri Vrumethyl) pyrimidine-2-Aloopto; Phil) ~ 1 ·; 3 "Yasul" 2 "L Bklohan Ankerboksila (17 mg 0.41 a) 7) Osmadh solid MS ESI: [Μ; Η] + ηι / ζ 523.: water would be if 0 0 composite 0.1 0.4 Description ~ Cisse, 0.1 0.5-Cisse 1Η NMR (50. MHz, CD, #) 8.7.1 of (d, 7 = 4.9. 8.01 e (aa (S, 1Η), 7.97 (s, 2Η), 7.45 (s, e H), 7.13 (d, .7 = 4.8, 211), 4.06 (dd, 7 = 4.5, 11.9 , 0.11: -19. 2.50 (dd, 7 = 30. 13.1, 111), 2.37 (s. 3 H), 2.24 (, 1,7 = 13.0, 1.Η), 2.0.1 (d, .7 = 14.7, 1Η), 1.84 (d., 7 = 14.7, 2Η), 1.22 (s, 3Η), MS: data composite 0.1 description. 0.4-trauma, 0.1 0.5 Bryce. +++. ASYK 3, 8) 1.10. Nthat Η) ESI: [M; .. II! T ηι / ζ 523. 1) 1 NklR (500 MHz, (1) 3 () 1) 1 δ 8.71 (d. ..7 = 4.9, HI). 8.01 (s, 1Η.1 7.96 (s, 214), 7.46 (s, 1.Η), 7.1.3 (d, 7 = 5.0, 211). 4.6.1 (dd, .7 = 4.5, 1.0.9 , -). 11), 2.58 --2-44 (, m. 2Η). 2.38 (s, 3Η). 2.28 "2.16 (m. 1 (4), 1.96 (.,!, 7 = 13.7, 1Η). 1.75 (d. 7 = 1.4.0, 0_0 - + = rl1SYK 1.30, (1-11. Activity (s. 3Η), 0.98 (s, 311) (except 0 eg 151 (a) and 51 a (b Hamzy pre-4-Shu-4- [5- (3-d-5- {L4- (Ray Vrumethyl) Beramaidin -2: g] Abu) Ivel) -1.3-Abzul-2-I Sbklohkan 1 Hrbokela Hmgy satisfied -4-Shu-4-L5- (3 d-5-e [4- (Ray Vrumethyl) pyrimidine-2-night Abu) tends) - 0.1, 3-thiazole-2-i; Sichaelohecsa 1 n 1 to calc Bsala

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02751.tif" id="idf0197" />

Azto; 1: Crown flask containing d E-YUTZ 4-tapered-4- | 5 (3 0 such as 5; (4 (Ray Frrhobel) 0 o. | A Phil) -1.3-Basul -2-Yale Skdayd Iv ( e (400 mg, 0.75 Miss l) s; Sala dei Cderlmyn (3.7 0 l) and; Eodhul (2.2 D). P Ailo Djoko-flow (00.69's, 3.74 z 0 well) and sleep * g principles &amp; lt; Dz Iah one . d Zq then Teje Ahlael 4 data; Gal, was PS, the growth Lifa Krtat sucking 0 CE, then soils. Laura .. it was Adam and / 0 Atelerav M d s de z 020 , Tel Zad-4-Shu -4 E [5- (3 play-5- {[4 Dhiraa Shaw 0 Gal) Dam 2-jj all) El 0.3-Marolzirtn) 0 Krpopt (75! d 00:33 Miss Moo 0.44% Katj &amp; gt; and, -ad.ql p -4 &amp; quot; Shell '4- [5- ( 3-Bill -5 - {[4- ( tea Yale 0 09) AA, discriminate; l-2-O I Skloek_an Cubase 0 Platt (40 of Yum, a 00.2 me Lrl 0.128 Ith.) of 8 £ for ISO / Rs: 537: '0.111 + [Η t M] 'Gish ^ "No , " but a ~ 4-FDR 0 -4- [5- (3-.az-5- bad: Ely Salse'habls Z 3 2-5;; a &amp; gt; - a., a, what, J &amp; gt; - C \ 's;: Aame Ouae; I.e

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02752.tif" id="idf0198" />

-274- -274-ΜΑ 33926Β1 t) has; Yz 12.6-to Updn (0.15 t, 1.25 0 Lenny 0.86) TBSOTfjojy t '3.75 mmol). It was flipping interaction for two, one hour. Growth easing F bass 0 or Osatt ith 0's, Welle water, was dried Almfssom sulfate, was seen Trhev and Done &amp; lt; e. Then A-to courts / Matt 1 &amp; lt; sufficient Almeh above 1 for critical (Κ40; / 60% Mithadhula 02 h) in Akgueth Seoul 0 Ouay Cisse-acid 4-Dou-4- [5- (3-Shell -5 - {[4- (G. Florlmhl) Ber.bmaidin &amp; quot; "2" - Yale; Obdhu) phenyl) a-, 3; Yasul-for-2; Slohxan 1 Krboxr (17 mg, 0.035 Malash Mall 0.28% Kmath). (MS ESI: [Μ + Η] + wz 461. Ii f NMR. (600 MHz, DMS () - d6 2.7, 1Η), 8.00 (s. 1Η),: and.;)) 8.05 1 (d, 4.8 , 1Η); 8.8, (0.26 (s, 1Η a, (12.2. (S, 1Η;) --- 2.12 1 (2.1, 1Η), 2.16 (s, 3Η; = 7., 1) 2.40, (8 ( s, 1Η a .7, (7.45 (s. 1Η), 7.2.6 (0..7 = 4.9, 1Η (1.97 (m, 4Η), 1.94-1.87 (m. 2Η), 1.67 (do9,5, 12.9 , 2Η. Activity rhSYK = +++ Boizumr Nrns step 2: to a solution of no-pyo 0 Shad-4-Shu-4- [5- (3 "seized -5-t L4- (Dhiraa Floromesho) Peremides -2-allocating Linnell ) "1, d-thiazole-2-Yale; Saklohhassan Therboxiadt (175 mg 0.3 d 0.0 Malmi mol) in d; j Krumithan (6.5 ml) and 2.6-to Werfel (0.38 ml, 3.26 mmol) was added 2.25) TBSQTf ml, 9.78 mmol). the flip interaction for an hour and find him. then relieve the mixture using Osz 0 T. Asha C e paresthesia 0 Gsak with water, was dried Sebretat Mufnseyoum, then Rchiha tendon Azz 0 was used as 1 and Matoger 1 P column by Ciliv including HPLC in the phase inverted in purification for Had-acid 4-Toro -04 [5- (3-Shell -5 - {[4- (Ray Vrubuthail) pyrimidine-2-Yale; Abu) Ivel) -1.3-Basul -2-Yale Vloman one of the lar Politi (70 mg, 5-1-0.0 mmol 0.45% Kmath. 56) δ-H NMR (600 MHz, DMSO a £ .461 mS ESI: [M + HJ + m = /,, 4.8, 1Η). 8.05 (S. 1Η), 8.00 (S, 1Η), 7.45 (s, 1Η), 7.26 (d Er .1.0.25 (s, 1Η), 8.81, (d -275- ΜΑ 33926Β1 4.7. 7.17 0 AA; A (s. lH), 2.38 (s, IH). 2.29 (s. 5Η), 2. (:. 3 - 1.87 (m. 211), 1.88 - 1.71 (m. + -H- = rhSYK Nthat .w ) 152 such as one acid (1 of 0.4 h) -4-h 0 Droxa -2.2-Dai crippling-4- {5- [3 crippling 0 ~ s "&amp; quot; (e 00 to MPLA Berimidh -2-for Osdhu) -iven-disappears-2-g ) -amaakhluhecman Alkrbkbla

\; 1 3 »? hOH a .HsC

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02771.tif" id="idf0199" />

N ::::::::: 2 Oh

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02772.tif" id="idf0200" />

-276- -276-ΜΑ 33926Β1 60, Haat: Aces ethyl), after Zlkalkromatogerav. I \ y &amp; lt ;, ska (2: 98, Mithadhul 0. Dai Krumit 1 P); [0.1 to get 7.5 Nest E. g (37.4 Hma Mall 66 0 A ) are additional crippling acid (1 H, 4 no) - 0.4-Hedrors - 2.2-Dai Mfal-4- {5-for 3-crippling-5- (4 for crippling-Berimbin -2-night 0 v) -vl] -, Bzll -2-Yale} c S r 4 Ataan foam and colored Osamarkhgev. Step 2: To a solution of Matj Alahtoh 1 (16.5 g. 0.3 * 35 Malash Hall j) methanol (1.5. Ί Is) has Asafh sodium hydroxide (1 Mola 1.123 ml 0.123 mmol) was' Schan Ahaliaz to 70 ° C for are accustomed and a half. The reaction was cooled to 30 m and has Asafh Hmge hydrochloric (1.23, Ni ml, 1.23 mmol). The aging interaction for an hour and a half was (); nominated for a 15.3 g (3 mmol 7.d 0.96 a) of bitter bear contained Z Title as a solid illuminated. NMR (600 MHz, DMSO056) δ a not-.453.0 MS ESI: [Μ + Η} + ηι / ζ, (11 1 .7 = 5.0. 1Η), 7.94 (s, 1Η), 7.88 (s. 11- -1), 7.49 (s., Z 8.32, (1.-11 .11.98 (S. 114 &amp; quot;), 9.55 (s 5.0. 111.), 5.86 (s. 111). 2.34 (s. 3Η), 2.27 Is. 311), 2.14 Id ../:- t., 1 6.72. (1-1.1, 7,02 (s, 14.1 = 7., 12.7, 3.1. 1Η), 2.00 (ddd, .7 = 18.6, 13.2. 6.0, 1Η). 1.88 ---- 1.77 (η 3Η). 1.62 (d 5 e (for Aaaal) O.o 6 (1) and waza?) 1.09 (1.55 ^ 111 .. 4 .. 0.7 = 13.5 .3.3. ΙΗ. Activity i'hSYK = +++ 1 for examples 60.a. (a) and 60 a (b) 4; 5-Dai 5 grew a 5 &amp; quot; (3- Shell-5-ol 4 &amp; quot; (&amp; quot; Ray Flo 0 Romicil) Peremaidin- 2 l] Foul Odoa) a- 0.3-Harol "-2-Yale Ariane-2-en 5.6-Dai Hedros ~ 5 5-I D_hl'-5-g [4- (G. Shell Eru 0) Beramaidin-2-

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02781.tif" id="idf0201" />

Ma 33926Β1

CTI

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02791.tif" id="idf0202" />

) To Hton -1: suspended 5-hydroxy-5- [5- (3-cell -5 g [4 (Ray Vaorobil) Peremedin -2-yen Abu; Vlzel) -1.3-Rarul-2-L Oripan -2 ~ En (example 10 300 mg, 0.65 mmol) Khansafa Boudidalvesfor (1.2 ml, 012.9 Lee Harrell) has been Tempe 0 Afd 65 m for two hours, and then was -bradh to room temperature, and was poured Avaah j 5 tireless Bonnat sodium water saturated. After the cessation of the extruder to heat Wara interaction, Tama Asthas termination and mispronounce ethyl (χ2) 0 then Tgevin organic layers Akhiah sounding Lita T. Sod.lom 4 was Trthyhaa, and Focus. Temt'nqah Almazz Apfh Bo; HPLC in the middle Alhlor one of the inverse (45: 55 to 85: 15 Osatunirl: water using a .0.1% acid rate Ray Floro acetic) to obtain the 5 &amp; quot; 10 5A (3-of-5 not 4 - (&amp; quot; Ray Floromeshl &amp; gt; Peremedin -2 Lil Abu) Ksl) &amp; quot; ~ a s \ y 3, 6, 7-Trajro 2. No-Shin-2-en O5- [5- (3-Mhly -15 OL 4 ~ (Ray Vrumethyl) Ber.bmad.n -2-phenyl night Lapua) - 3, I 'Basul Al..a-2-a, 3' 4; 7-Rahedro 2. No-Ozs -2-On (SEW 70: 30.119 5 mg 0.26 mmol 0.1% Knatkh 4) as a yellow pouring. 446.1: MS ESI: [M t Η] + mi. 1.5 Alahtoh 2: ci melt knock 70: 30 for Q 1 v 1 to Step 1 (100 mg, 0.22 mmol) in a-n (1 Is) and E (125 Miro L). Added Taatroxad'loosmeom (4 (4) (Ti &amp; quot; E; 0 \. -278 0548 Boo P, 11.0.09 Rowe) Wei Ν 0 n μ 0 and revels (1.5 was' 95'5 Yesh Jr) and Tm.tib 1 DOCUMENTS de Sz Dai; j Drt Er'd; August 'was doubtful whether I am asked Q 0 m 5% Yuklr.zt Aodiom.ava and sleep B. Dz 15 b' and then μ s ruefully ethyl t 0 (3b and was drying Alhellbqat Aalloh data Bkipriyt sodium, and. been sprinkle 1 ha, were seen in Kerr prevail Presentation string Q 4.5 Dai-hydroxy-5-L5- (3-crippling-5-g [4- (Tri Vrumethyl) pyrimidine-2-It} Fouikl) -1.3 "Thalol -2; del Ariane-2-en and 5.6 for Dai-hydroxy-5-a 5 "(3-Thi" 5- &amp; quot ;; a 4 ~ &amp; quot; (Tr.aa Vmoll 0 Shell) pyrimidine-2-Yale Abu) Ivel) - a 0.3-thiazole-2: L Ariane-2-en (70: 30.40 mg, 0.084 hyper t 0 for 37./.knatj) as a solid yellow tend to brown. + [MS ESI: [Μ + Η 4.9, IH). 7.93 (s. - T, 10.13 (s, IH), 8.80 (d of (m: 480.Ι.1Η N ^ 'IR (600 MHz. DMSO-dd 4.9, IH), 7.11 (s. 1Η), 5.92 (s. 1Η),: for, 7.90 (s. IH), 7.53 - 7.36 (m, 2Η). 7.23 (d 1 (1Η 3.09 - 3.19. ( '111, 11), 4.04 - 3.99 (m, 1.1- -1.), 3.58 - 3.36 (m; .5.86 (s, IH). 5.12 - 5.01 (m (2Η, 1, m. 1 H), 2.96 - 2.75 (m. 111). 2.30 (s, 3Η) . 2.04-1.82 (η) Activity rhSYK = +++ Omazh da 0.161) 0.161 bears) 0.161 dA) and 161 (d) 4.5 an intelligent Hydro de-5-L5- (d-Metel-5- {L4- (G Vrubuthail) Peremedan -2-night Abu), Ivel) -1.3-thiazole-2-Yale Ozbaan-2-en 5.6 to Dai-hydroxy-5-L5- (3-Mivz-5- {L4- ( Ray Vrumethyl) pyrimidine-2-SAL) Abu} Ivel) a- 0.3 "disappears -2-Yale 0 oz Ben-2-en ΜΑ 33926Β1 -279- 0 0

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02811.tif" id="idf0203" />

Zroran Aqraaaan Walker Step A: Ahoudaa mixture was 70: 0 d of 4.5 an intelligent-hydroxy-5-A5- (3-Sl- 5- {| 4- (Tri Vrubuthail) pyrimidine-2-0y 'Aminu ,,} Ivel ) -1.3-Thiar, Wal-2-L Ozaan-2-en and 5.6 Dai-hydroxy-5- [5- (3-Shell -5 - {[4- (Ray Vrumethyl) Ber.bmaidin- 2-night Abu) Ivel) -1.3-Basul -2-SAL) Ozaan-2-en (30 mg; 60 examples of a (a) and 60 a (b)) for the purification and Ma'no Baker Jr. F above the fluid Alehirala critical (6/42 Brobbadhula 02-h .tadl 'Ndfq 50 Rrdqiqh and running time 19 minutes) to get Algraih isomers of 4, 5 ~ &amp; quot; Dae-hydroxy-5- [5- (3-Bethel -5 - {[4- ( Opinion Toromel) Ber.bmaidin "2: No amino) phenyl) - 1.3-disappears-2-lyase 0 bin-2-on, 5, 6. Dai-hydroxy-5- [5- (3-Bel-for-5 [4- (G. Vrumethyl) pyrimidine-2-amino night) Vijl) -1 y 3-Ebzul -2-_yoztun-2-en. Homologous 0.1 [Cisse) 5, 6 &amp; quot; Dai-hydroxy-5- [5- (3-Shell -5 - {[4- (an intelligent Iowomagn pyrimidine-2-night Abu) Ivel) A- 0.3-disappears-2- Ersan Z-2-en (3.2 .bhm, 6:25 curlers Mall 0.10% Katj). 500) 1Η NMR .MS ESI: [Μ + Η] + m / z 480 MHz. DMSO-tl.) Δ 10.25 (s, 11-.1), 8.83 (d,. / 4.9. IH). 7.96 (s, IH), 7.93 (s, 1Η). 7.53 (s. -280- -280-ΜΑ 33926Β1 7.47 is still a (S, 7.27, DOA (cl, .7 = 4. (), 1.Η), 7.13 (s, 11: 1). 6. () 1 (s. 11.-1), 5.1,7 (d. 0./= 5.91 I {;) -3.81 - 3.73 (m. 11.1), 3.54 (m, 111), 2.82 (m. 2Η). 2.31 (s. 311). 2.041.93 (m, 2Η), 1.93 ....... + t - + == rhSYKL 1.86. Activity (m, 1 H) Mitch 1 every 2 [Cisse] 4.5, "an intelligent hydroxy-5- [5- (3-but-5-for [4- (9.0 G) Toro.methyl) pyrimidine-2-amino yen) Vial) -l 0.3 Ethiazul -2-Anazaan-2-of-MS ESI: [Μ + Η] + /7/.- .: 480. 1 ... 1.a. NMR (5W MHz.. (mg 0.9 0.01 mmol 0.30% Kiatj DMS0-d6) 10.25 of (s. 11: .1). 8.83 (d., 7 = 4.9, 111), 7.97, (s. Ill), 7.93 (s. 111), 7.61 (s, 11.0, 7.47 (s, 1.1.1), 7,27 ( cl, 7.13, (1.11, 4.9 = t (s, 111). 6. (:) 6 (s, .1.: 1.1). 5.1.8 (d, ,, 7 = 5.7. 11.1), 4.04. 4.00 (m, 1.1: -1.), 3.47-3.40 (J11, 111). 3.15 (d, .7 = 5.3. 111). 2.90 (s, 1Η), 2.31. (s, 311). 2.18 (s + ++ - = ( 'hSYK 1. Activity H), 1.97 - 1.82 (m, 21: 0 0 lest they eat three SOS 5.6 Dai-hydroxy-5-L5- (3-sale -5 - {[4- ( Ray 3.3) Hromthel) Bdo.bmides-2-L Abu) Ivel) -1.3-Teasul-2-L dairy-2-en MS ESI: [Μ + Η] + m /: 480. 11 a NMR (500 MHz,. (mg, 6.88 Bkromul 0.1 Kiatj 1% DMSO-d6) 5 10.26 (s. 1Η), 8.83 (d, .7 = 4.9, 1Η). 7.96 (s. IH), 7.93 (s. 1Η). 7.53 (s, lti), 7.47 (s. IH). 7.28 (d. .7 = 4.9, 1Η), 7.14 (s. IH &amp; quot;). 6.01 (s, Ι.Η), 5.17 (d, 1, 5.9 = t Η), 3.82 .1 .3.71 (m, 11.1). 3.53 (m, IH), 2.9.1 - 2.75 (m .. 2:11.), 2.3.1 (s, 3H). 2.04 - 1.93 (m, 211), 1 and 3 + · + - + == rhSYK 1.86. Bashat (m, Zllla Iha / 4 [B] 4.5 Dai-hydroxy-5- [5- (3-crippling -5 - {[4 &amp; quot; (Tri 5.1) pyrimidine-2-night Omaio) Ivel) A-, 3-thiazole-2-night Oziban-2-en MS ESI: [M + HJ + - ηυ'ζ 480.; H NMR. (500 MHz. 1 0.01 Mall touched 0.7% of Kath) 0. 281- ΜΑ 33926Β1 DMSO-de) δ 10.25 (s. IH), 8.83 (d ,, /: 4.9, 1Η), 7.96 (s, 1Η), 7.93 ( 's. IH),' 7.60 (s, Ιϊ- ϊ) 7.46 (s, IH). 7.27 (d. ./-4.9. 1Η) 1 7..13 (s, 1Η) 1 6.06 (: s. 1Η), 5.18 (d, J = 5.7. 1Η), 4..5, 4.1.0 ( ra, IH), 3.44 (s, IH), 3.15 (d, 07 = 5.2, 1H0. 2.90 (s, IH), 2.31 (s, 3H), 2.18 (s, lfi) +++ == rhSYK 1.84 - 1.97. Chatt (.m, 1 2Η) 5 DD 162 Jtabdhu -5-A5- (3-Shell-5-'al'4- (Tri Vrumethyl) Berimid.bn "two-Yale Abu; Vieil) 4:13 ~ thiazole-2-ball; Ozelan-2-on-0 ηΛ 2 Atmoe

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02831.tif" id="idf0204" />

1 Khtoz.a: To the solution was Tkulaibh 0 n (s) - (-) - 2-mile -2 ~ Rowan perpetuate (p. 854; 7 0; mmol) and 1.4 - an intelligent Ooxazero [4.5] Divn -8 -oon (1 g, 6.40 mmol) in Rahedrovuoran (13 ml) Tmt Aathoksid adding titanium (5.1,1-) (IV ml, 1.6 plating Mall). Tguib been Ahalit for 4 hours at room temperature Drahh, and blood poured on Bakrbunapt saturated sodium water (10 ml) and Atuniral (10 mL) in the case of flipping was Altguib for 20 minutes. For &amp; quot; V Anpavh Kipritalt Mufnseyoum was Bmesp the mixture for 20 minutes, was Trschmiha using 15 Searnat was seen Nisah. Lallemand was purified remaining * Bromatogerav column by Ja Saiba (gradient 10: 90 to 70: 30 ethyl acetate: Hecsanat) for 4, 1) "Ν- an intelligent

<img img-format="tif" img-content="drawing" file="MA-33926-B1D02832.tif" id="idf0205" />

-282- -282-1z 1? W 0 No 1; Kalael [4, 5 | Your -8-Yep; n) -2-.aal Flint-2-door (466 to 0 for any mol) Kiath 28%) as a solid water. 260 Η] + ηέ +; MS ESI: [Μ. 1 Ioh 2: 1 Li d 1 j Oarober.oaloman (318 curlers liter, 2.23 Ddwi real) in Dahdrohhor'n (3.7 ml) at small Em Tmt Adhaoh not-lithium butyl (2.5 Holar in e \ A; Aat .892 Dodd, 2.23 Miss Maud ). The Z F 0 i Taha, 15, a bear) and b 0 d Zlktmnbaradh to -8? Mother. It has one Aqh bitter, CP Bit 4 (250 mg, 0.74 mmol) in a 1 i 1 m Nmrodharan (1 {) Ba 1 Ziet guided 5 Degache. The Tqub August 30 -8 bear? ° C, after Znk has 4 addition Mt 1 to Step 1 (212 mg), 0.82 mmol) m 0 Gmelin my Mob..ruaoraz (0.1 ml) Bakqat 0 -naqb mixture pour of Mudug burden and i club n supported for \ six one lasted chloride, ammonium what; j saturated was one Stkhalas Bambt A.hl (χ3), was Atjgihv Alod.a together data by sodium sulfate, and then filtered, and was seen; Amos 0 principles 0 T. termination d 01 Atogerav Alamon by grandfather Salb (grayscale small: 100 to 80.20 Alay goods 0 Xamat, then insert the to Cefrz 100 15: 85 Mhthadhulz Dai Dl.romsan) 1 Li Alha 1 well on 2-Shell-la-g 0.8 "[5 ~ (3-Bill -5 - {[4-for Yroa Florosl) pyrimidine -2 ~ 0 Z Obno) Ivel) -1.3-Yarob2-'s] &amp; quot; "1, 4-Dayao Hazero [4; 5] Vek-8-d Supan -2-.thbl (318 AM) 0:40 Malash Mall 0.75% as the product ) as a solid structure. .MS ESI: [Μ + Η] + | '~ 596 Kilo 0 of 3: (Li Menth 1 Ahtoh 2 (100 nm) 0.1.3 Har mol) were added Brodhar.m (630 thunderous liters), Asa 0 sodium (24.5 mg, 0.38 mmol), and acid Mithav Donak (98 x 9 cunning .1.51 touched Mall). The T 100 yen mixture to 65 m for an hour and a half, then cooled E4. Room temperature, was diluted with water; and how much deduced crick acetate (2 *) • was; 4 GIFF 83 ΜΑ 33926Β1 Bacillus classes Angiah fine Lights SOW sodium was nominated, it was seen Tisaha. The Secretariat has pious 0.1% in 1 Alor pain 0 cos (35: Whoosh 65 0 70 y 30 Osossril; water HPLC Stay 5 of Bo one cough together; for Hmtaatm, Nroa Vdro acetic). The ease Alxtoah parts on Almenb, frightened ¥ Bositat Aithia, and using the free base Becher Bo Nat sodium water saturated. M drying Alaabakh organic separated the news of Lights Mufnseyoum was nominated and focus for bitter Neb contained Z Title MS ESI: [Μ + Η] + ηι / ζ 463.. (38 mg, 0.083 mmol, 66% as the product) as oil orange E. H NMR (500 MHz. DMSO-d ^) δ 16.26 Is. HI), 8.83 (s. Ill), 8.75 Is, 11-11. 8.62 (s, III). 7.93 Is, 1.1-1). 7.49 Is, 1.1-1), 7.28 Id, .7 = 4.7. 1.11), '7.1.6 Is. III). 2.39 - 2.1) 8 (m. 911), 1.31) "+ -1- + = rhSYK 0.99. Zt Im. 41: 1)