AU2014203687B2 - Certain chemical entities, compositions and methods - Google Patents

Abstract

Chemical entities that modulateP13 kinase activity, and chemical entities, pharmaceutical compositions, and methods of treatments of diseases and conditions associated with P13 kinase activity are described herein. 2390251_1.docx

Description

1 AUSTRALIA Patents Act 1990 INTELLIKINE, LLC COMPLETE SPECIFICATION STANDARD PATENT Title: Certain chemical entities, compositions and methods The following statement is a full description of this invention including the best method of performing it known to us:- CERTAIN CHEMICAL ENTITiE COMPOgITIONS AND METHODS t1001] This application ms thNe beMDf of U.S. Provisional Appiicnoni Ser6al No. 61?0957l fik4 on Jnuary 4 2004; 61194,294 filed on September 26, 2008, and 61201,146 iM Dcember $ 20, and teI co-pending case oder attorney dekert nsmber 35290414.602 filed herewit, eah of which is hereby incorpted by ference n is $ entirey. BACKGROUND OF THE INVENTION [1002i| The activity of ellsacan be rcgtdated by extermal signals a&t stimuliatz or knha intmraeiula event. The proost by which stimulatory or irhibitory signals are transmitted into and within a Vdl to elicit m i Inlar pnse is referred to as signal trntsdadon, Over the pest decades, cascdes of signal transdction events have ben 10 eucidated and found to play a cental role in a variety of biological responses f ets in vrios components of signal tnansduction pathways have been found to accoUt for a vast number of diseases inuding numerous forms of can infismaatry disorder metabolic disorders ascular and euromrnl diseasses (Gaestel et al. Cwmr Yedicins t2Omory (2007) 14t22W223s~4). [0031 Kineses represent a class of important signaling molecules. Kinaases can generally be classified into protein B kinases and lipid kinases and certain kisses exhibit dual speelkeities Potein kinases am Cnyes that phosphortae other proteins and/or thenutelves (Le, aiophosphorylation) Potein kinases can he generally classified :cnto three major grops based upon their Substrate utlltatiom tyroine kinases which predominantly phosphoryase substrates on tyrosine idues (e.g, erh2, PDrF receptorGF receptor, VEXGf receptor, sno, abi), Srinenhreordne kisases which predomndaly phosphorylau mbstrates on series andor threonine resides (e.fg mTorC1cThrC2. 20 ATM, ATR, DNA-PK, Ak), and dn spoificity kinases which phosphoryate submtates on tyrosine, series and hreodin resdes, {Ng4) Lipid koinasts atre enzymes thate phosphoryladetin of lipids. These enymes, and the reuing phos phsyed lipd and lipid-derLved biologically active orgnic molecues, play a roe in many different p ng p din g N, p fitin des and differetizan. Cnai tipid kinases at 25 membrane associated and they catalyze the phosphorylation of lipids combined in or associated wh cell membtnes. Exsnples of such eorynns include phosphoinosirida(s) kinayes (hsch as PlSkinas, Pt4AKinses), diacylglycemol kirmea And png' oepsineinasets 600 Th ph sphoinsiride 3rins (pIKs) signaling pathway is ccc of the most ighly nused systems i human uncem. P14K sgnaling is al- a key factor in many other diseases in hurn-is P13K signaling is involved in 30 may disease states including allergic contact dermaitis, rheumatoid arthritis, osteomtrzritiK iniamnrntory bowel dimses, Chronic hnosrctive pulmomy disorder, psoriasis. maip s icrosi S, asthma, disorders related to diabetic comptl onss, and iaf:mmatory complcans of the cardiovwcular system such as acuMe comnasry syndme, [94061 PIKs are member afa Luire and conserved fanily of intradekuar lipid kineses that phophorylate the 3 011 group on prophd' i. . phosphonntds The P13K famy copre5 Icinases wit distinct 35 sbstroe speeifleities expression patters and mods of reglaon (Katso et 4. 2001). The clasI i PDKs (p1 t l pt100, pl MAi, and p . 1y) arc typically activated by tyrosine kinases or C-protein coupled receptor to generate PP3, which egages dowastrm effeors such as these in the AktfPDK, pathway, motor, the Tec family kinses, and the Rho family GTPases. The class I and Il Pu3s phay a key role i intracellar trafficking through the synthesis of P1(3) ad P3,4)P2. The iKKs are protein kineses that cntrol cell growth (m'ORC 1) or m"en to genomnic 40 ineflty (ATM, ATR, DNA-PK, and hSm-) -1A- [0007] The delta (6) isoform of class I P13K has been implicated, in particular, in a number of diseases and biological processes. P13K 6 is expressed primarily in hematopoietic cells including leukocytes such as T-cells, dendritic cells, neutrophils, mast cells, B-cells, and macrophages. P13K 6 is integrally involved in mammalian immune system functions such as 5 T-cell function, B-cell activation, mast cell activation, dendritic cell function, and neutrophil activity. Due to its integral role in immune system function, P13K 6 is also involved in a number of diseases related to undesirable immune response such as allergic reactions, inflammatory diseases, inflammation mediated angiogenesis, rheumatoid arthritis, auto immune diseases such as lupus, asthma, emphysema and other respiratory diseases. Other class 10 I P13K involved in immune system function includes P13K y, which plays a role in leukocyte signaling and has been implicated in inflammation, rheumatoid arthritis, and autoimmune diseases such as lupus. [0008] Downstream mediators of the P13K signal transduction pathway include Akt and mammalian target of rapamycin (mTOR). Akt possesses a plckstrin homology (PH) domain 15 that binds PIP3, leading to Akt kinase activation. Akt phosphorylates many substrates and is a central downstream effector of P13K for diverse cellular responses. One important function of Akt is to augment the activity of mTOR, through phosphorylation of TSC2 and other mechanisms. mTOR is a serine-threonine kinase related to the lipid kinases of the P13K family. mTOR has been implicated in a wide range of biological processes including cell growth, cell 20 proliferation, cell motility and survival. Disregulation of the mTOR pathway has been reported in various types of cancer. mTOR is a multifunctional kinase that integrates growth factor and nutrient signals to regulate protein translation, nutrient uptake, autophagy, and mitochondrial function. [0009] As such, kinases, particularly PI3Ks are prime targets for drug development. There 25 remains a need for P13K inhibitors suitable for drug development. The present invention addresses this need and provides related advantages as well by providing new classes of kinase inhibitors. -2- [0009A] Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field 5 relevant to the present disclosure as it existed before the priority date of each claim of this application. [0009B] Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or 10 step, or group of elements, integers or steps. -3 - SUMMARY OF THE INVENTION [0009C] In a first aspect there is provided a process for preparing a compound of Formula 1409:

R

3 0 S NR'

CH

3 HN N N NH 5 1409, or a pharmaceutically acceptable salt thereof, wherein R' is alkyl, amino, heteroalkyl, cycloalkyl, heterocycloalkyl, or a moiety of Formula II; R1 Formula II; 10 wherein Wc is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, q is an integer of 0, 1, 2, 3, or 4; R' is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, or carbonate; 15 R 2 is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy or nitro; and

R

3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, aryl, or heteroaryl; 20 comprising reacting a compound of Formula 1407:

R

3 0 'R'

CH

3

NH

2 1407, - 3A with a compound of Formula: X N N NH wherein X is a halogen. [0009D] In a second aspect there is provided a process for preparing a compound of Formula 5 1606:

R

3 0 S NR'

CH

3 HN N N NH 1606, or a pharmaceutically acceptable salt thereof, wherein R' is alkyl, amino, heteroalkyl, cycloalkyl, heterocycloalkyl, or a moiety of Formula II; R1

(R

2 )q 10 Formula II; wherein Wc is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, q is an integer of 0, 1, 2, 3, or 4; R' is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, 15 arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, or carbonate;

R

2 is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, 20 halo, cyano, hydroxy or nitro; and

R

3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, aryl, or heteroaryl; comprising deprotecting a compound of Formula 1605: - 3B -

R

3 O N'R' bt NR .- .- CH 3 HN N N N THP 1605, wherein the deprotection occurs in the presence of an acid. 5 [0010] Disclosed herein are compounds which are of Formula I, or their pharmaceutically acceptable salts thereof, wherein 0 2 Wa B a a N Wd Formula 1 10 [0011] Wal is CR or N; Waz 2 is CR 5 or N; Wa 3 is CR 6 or N; Wa 4 is N or CR 7 ; Wb 5 is CR', CHR', or N, wherein no more than two adjacent ring atoms selected from Wa', Wa 2, Wa', Wa 4 , and Wb 5 are heteroatoms. Wd is heterocycloalkyl, aryl or heteroaryl. B is alkyl, amino, heteroalkyl, cycloalkyl, heterocycloalkyl, or a moiety of Formula II; R1 15 Formula II [0012] wherein Wc is aryl, heteroaryl, heterocy cloalkyl, or cycloalkyl, and q is an integer of 0, 1, 2, 3, or 4. X is absent or is -(CH(R 9 ))z-and each instance of z is independently an integer of 1, 2, 3, or 4. Y is absent, --0-, -S-, -S(=0)-, -S(=0) 2 -, -N(R 9 )-, -C(=0)-(CHR 9 )z-, -C(=0)-, N(R9)-C(=0)-, or -N(R 9 )-C(=0)NH-,-N(R 9

)C(R

9

)

2 -, or -C(=0)-(CHR 9 )z-;, wherein when Wb 5 is 20 N, no more than one of X or Y is absent. R' is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, 3C cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, or carbonate. R2 is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, 5 sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, or carbonate. R 3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, amido, amino, acyl, acyloxy, sulfonamido, halo, cyano, hydroxy or nitro. R', R', R 7 , and R' are independently hydrogen, C 1 C 4 alkyl, C 2

-C

5 alkenyl, C 2

-C

5 alkynyl, C 3

-C

5 cycloalkyl, heterocycloalkyl, C 1

-C

4 heteroalkyl, C 1 C 4 alkoxy, C 1

-C

4 amido, amino, acyl, C 1

-C

4 acyloxy, C 1

-C

4 sulfonamido, halo, cyano, hydroxy or 10 nitro. Each instance of R 9 is independently hydrogen, C1-C10alkyl, C 3

-C

7 cycloalkyl, or C 2 C 1 oheteroalkyl. [0013] Disclosed herein are compounds which are of Formula IX or their pharmaceutically acceptable salts thereof, wherein 0 Wa2 Wa Wb 5 x Wd 15 Formula IX Wal and Wa 2 are independently CR 5 , S, N, or NR 4 , and Wa 4 is independently CR 7 , S, N, or NR 4 wherein no more than two adjacent ring atoms are nitrogen or sulfur, and when Wal is S, one of Wa 2 and Wa 4 is N or NR 4 . Wb 5 is CR, N, or NR. B is alkyl, amino, heteroalkyl, cycloalkyl, heterocycloalkyl, or a moiety of Formula II: R1 2'-'-

(R

2 )q 20 Formula II wherein Wc is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, and q is an integer of 0, 1, 2, 3, or 4. Wd is absent or is a heterocycloalkyl, aryl or heteroaryl moiety. X is absent or is CH(R 9 ))z-and each instance of z independently is an integer of 1, 2, 3, or 4. Y is absent, -0-, 25 S-, -S(=0)-, -S(=0)2-, -N(R9)-, -C(=0)-(CHR9)z-, -C(=0)-, -N(R9)-C(=0)-, or -N(R9) C(=0)NH-,-N(R9)C(R9)2-, or -C(=0)-(CHR9)z-. R' is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, 3D pA&do amino,, nyv, 0.v Dy YcatWTryl, siOlr"AsglaO, halo, cywO hydoxy, no, phosphate, ea, er catoatie, R 2 i5 afkyl, heteaikyl, dknyt aukynyi, cyloadkyl, terocycdoalkyl, aryl4, arylatkyi, eteroaryl Hearyyl t %Ikvxy, amido, *amino, acyl, acylxy akoxmyysufonid& ho, cyao, hy&oxy, ni ue, or carbonatea. is hy dogaky dkvyt alkyay. cydoalky§ hecyarrcloa:ky rikn:<y 5 amkido, amino, acyl, atzyqoayat naPMido, 3a4 ovano, hyoxy or nitro, R 4 is hdon. scvy C. -.. kyl. Cr, C aikyt CrC~kynyt, Creyoanay or CrC.teafaky; RK Ri eA mre indpendertly hydrogr, Cr Csalkyl C 2 Csalket4 CrXAiyty CrC 5 0ycloalkyl CrC 4 hemeiky, avy, CrC.ilko, CrCc.kde amino, CrCai4oxy. CC sulfoamddo h. ctyano, hydony or ntro Eah imetnoe of P is ndndenly hy&oge Cr-C lknyt CrCrecdoalky, or CrC4)etemaikyl 10 (014] Ir some embdiments, the c found of Foerrma I ls a ructure of!Formula IV: w Formula IV 00115 ) oe omlodimens a compmmd of F mme IV is of Formula V or V! 1% or W 15 Frme V FoMr a VI [compound hV & k s the c apmsd & oform V hsflans at'e atrmoture of Eorrno VtA: 0 R f N R~ RA NN A r RS t PFmh VT A 20 [0017) Ir some emiixintIs of te compfound of Fo'm0Z VIA, RQ M anamino, "N' sormbdiens of the comapounad ofFormaula V{M RV' is alkyt alkenayl alikynyl, heteroery, aryl, hetoroeycioaikyi, cyao, amainac carbosylic scid, or &amido., I some embodimrets; of the compound of Fkomia Vb-A, Ra is a mnaocoycick hetneroaryl or a bicyclic tecroaryl r00iS$ hn some embedment of the CcSompound of Foorid Vi, the com pondt has Ihe sitrzre of Formdla VI-C: -4- Rk N 1009]Insomvo te embodints of Fksru.a 'V: the omtpowmd has a stnsetsre of Felat VVD; 5 For~mula VID J80241 In anther aspc o heiveto a compoun orits hraetcl accptb l u having the stirucvof Formata VIisrvdd whercint B isalky],zamine., etem;Aky , Orz u it fFruait hrh sy% heleary hetrcededkt o eyloalkyl an~d q. is an: inkweer of 0, 1, 2, 3, or4; X is5bsn or Y(G(R )wqd z i an N NN -N h, R"Vy D inmgy of L, 2, or 4; Y ,is absenm (R tir -NR) wHR ,- ,. ... Hr heemridy akn , ama~o, tsmin att lylA y, ikaspano sdfnii do~ .achzo siyins hydrej yw itrtof phosp , u, is irtm skyl hR'ky axkey 4 akyt mev cycky M tela ky aryI i ky) h&renaryk bOtemar dkyt >kMxy, ad> balmin, acy acytxy, akxy:ary dfnad haio, 4yano, hyidmy, niwm, or phosphdet; I 02]R., is hydrogen, wkyt dkeRxnyl, ulkynyl. cyckftlikyl, adamyky -,ioxy, amid, anni, acyd, yloxy, uknayarboniuR viunm~id ha, yao, hy dm,,xy, niary of hetroay e ast ntance of R1is kwi ndepesdy hyvdio,Ogn. C, ,a-Kyf r, yoakthleeddy or Cruiealy;adR'" is,- H, adkyl, Wkyny% akny ha, ago ela he heercyleky eyd Ytwan, amino, carboxy. 1lic acid, atkoxycarbonyl or amido, [bmVr H s 2 'N ,N H Formukla 6-A! [N)24)j In some mbdmet thet cmpo-.und of Ful--Wa V-9 ha-, tlhe sin aom-ol G \j H 5 Formula fsC1 Snom e eqbodiments e m o ofoemuLc Yd has the ssisun of Formuka C2: 6 H H *NRN N N k Pommlta 6-f [Of252 In some exoimeras, the empundu of Formus a I a t etut of Fonssa &CD: 7HH HR H N N N H 1927 in some em-bodiments ah comound o Ponu V1 s o Formee oVhomd &: -6~C RR c R C) Formla V11 K) l 1"'i som e embodimits, the mmpoaind af Fora , i has a mtrius of P romul Vill: WE 'a"~.<V a. i (TR%~sv W is W - isN'Y Vi' CR' nis Xi is r d~ k~ N j S N'- C' ' mstanv is'4 zis is aR\ bAuys. of N, and 3, or C 4,) s k WQ iS ?wcroW Imy n (AIR gm) p mm-is\ng of '. 'i CW.2 i s N It dR W! 0' CR# adU i aAW NAt W E$i "i can~ W Q. i i' CisS m "k 'i rm' "'iii) rw isN; nW.' 'iA" 1 dWi , W,,' is; NW, W2nn IN Csr A 1 W1," is. CitW ' ns W t' N. Vi " ' (cbA 4 s NQ ? 1 WO isCR! md %tI A 010t s is N, X , is it.C ands V41 Vi CH is (W iS.V IE N W? is N, W,, uqC .,. -. 's ii N W , ni)Vs sit, W'A is N ,, is NR mxid Ns CR> (njj Wt s CR 4 . 'i " is xt S ai 1-s, ' , ( T Wilt W2 tW CR n W2 ls N, < SS d Wi MRE 00 W! i N I, wj "4., ai s Vi ' arm weI, ia Ns' Xi is N N s is CR* W6 s N and is N 8 V Qmo Q I We i5R N' is a N. N Xo isN' W., Vi 4cit 6 is9,W2 s CR>. isaid _,5i g N, iA-' , W,, is CR )IN4W R W Y6 tk 2' '.5 Rs A ik act W$ ' ' 'X (zxx IL, s! 4. s< w! N, V'0 s N sv 6 N s Cj 0 20 W s NS -d W I i; WO t W2~ i k hk W) R <i CR 4 , W:, is :S andd W), I' tMS DO')ii NV is CR>,W'sN W,, S m Wo CR 0=< Wo a l ii CR> UxisV is CR>j t 2 % C 5 V, s and WV, is NHW sad 00/ WV , i'sS 41Wv '& wher' X2 i bsN W d is -O wd 4( I C -S(4O N(Ri C(S, )-(CHRX)Ml*bN(RI (C=&5 O t m or '6S 10 [9029 sIn soae embodimeons of th coE5i~uimendi tf FsoaX oth mpds LX ja isr whc sa:ebro the gra No in wf : (A w"' i.s NR W 2 MR t W ? CR3d s CW, (10 Wk NR W ' CR , i b5 Iw? a R%x Wrw i INRW; aCi W2 k N, WZIC iT d We it CCH (K) WxT W2 NRI CR % i o W,-" 20Wis vS 1and W - N; w(xx J VV NQ W2 Is CR , W is S, add W NR(xI) W is Ci Wno w NW is Sand N (nin W, i -S, Cn W i& NWmS dW'!' xa) sS /i N sCiad /i ~~n f~rmda X 5 whreinR* i medi oreiy [0032] In omeS emodm Ntsoft invention, the compund of Fammla M is tfe compond of Formma XU: R W 15 F-o-m orMuk XII [03)In omne embodi ments (If th.3e inje~akN the- .compounld of Fe i V'X i, the cVmI -A f FV u XH:VI4, 4 S D,34 Va Hom Vmoiet IDf the inetit X I ,II .othXV -Ke o.mpnd f ti F Baa i is th mpe m of F ~.u omsi X o vrta N [43I) in some emoiet of the itwnioni the compoud of Foemwla Vi: Vhe VomuA, VheCi V iD GAC 6C 4 D Vik VrC 5 , iX Xyl Xi, X~flCXL XIV~~I o he imomo wheti cBo o #iebe te IXPtep conpnmof mnoiey fFomnda 1i, wherein 14 is ary.) incIdivg but ntl limisedl to subsumted phe8yt, htercmryl inchiding but no.. limited t0 moncy:,Clic hewaryll. eemyl aky r Zy4clfmkjhteoyckkyl,yl nldn u not limited to NRTM re mbedintr o f a cyconi moomy, 0 In some oi:<ints of the invention. The cmpod of formula 1, IV, V, VI, VI-A, VI-C, V-il), 6-A, 6-C C 6, V14. VIII IX, X, X1, XI XH or XIV is the compound whmn R 3 is H, ,-C -CN,-ii, 'oppy CiF -OCH, nitro, or phosphate [o5] In some embodimnts of the invetion, the comnpormd of Ftkemula 1, IV, V, VI, VIA,V VC, VI-D, -A, 6-Cl 5 6-C2, 6-D, VR, VIII, IXX'. XI. XIt-l or XIV is the pound wherio K' is akyl, hat hydmagv cyno, alto. or phoosphte and q m 1 or2 [0K IN some embodiments of the invention, the copound of Fouila , IV, V, VI, VtA, VI-C, VI-D, 6-A, 6-Cl, 6C2, 6-D2 VI0 , or V11i is the compound wh4 Rs -I, halo incleding but not limited to -Cl or -F ., alkyl including but not limited to or-CHlCr' akoxy, cycloaikyt or CF, 10 [0{I9) in some embodiments of the invwention, the eotmnd of Formui la ix. or N, R* is seceted from '-Hi mehyl, ethyl, n-propy, im-propyt, cymmpropyl, ycmobutyi and eyciopenxtyL [ 1i some embodiments of the invention, the compound of Formula I, V, Vt. VI-A, VlC, VlD VU. ViL i.X, XII X N it or XIV is the mound wherein R4~ s Ht C, N iNt, CrCsetyl Cr~alkmxy, Cfa NO 5 'Cit, CH4CWs -0CW. -OCH 5 C~t. oated, which includes but is not limited to -CI or -F I52 [0041 In some embodiments of the inve0tmon, the compandm of Fannda I IV, V, V1, V1-A, Vt-C, V J , Vn, or VUI is the compound wherein R H, i HC NH, C4aikyi CrCiakoxy, -CFL., N0 -Cn or ham. [0442i In some embodiments of the invention, the clo nd of Form L IV, V, V kis V r-A, VeC, VtD VI Vil IX, or X is the compound wherein Rf s H, -N, -N I C HCaikyt, CrC ky C )F-w NCHMCH> ~CItCH 5 . C1Na ,

OCH

2 CW, or heao 20) lt v'43 in some embodimnnts of the irvwenton, the omp od of I oa X IV, IV, VI., VA, V-C VD, VIi IX, or XII i the compound wheren if its HIC, -KNit CrC'alkyt C-Coalkoxy, -C, NitCSt. -CitCit. -C1 3 O0hi0C, or haloc 19t44 In some of the embodiments of Formula t N. Vi or VIt URml:6R s R ad R 5 are hydrogen, Q 0t$j In some emtbodimr1 of the invetio, the compound of Forn I IV, VV, V t-A, Vt-C, V1D, VI ViIs 25 IX, X, Xl, X Xii emo XlV is the compound wherein N is -CHrCI(CHtCit)-om -CH(CtY- itudnebt ot imted whereio -CHi(CIC)m -CII(CI)& is in a (S) or (R)stereChesmica configand n to some enbodrsents of the inven, the compound of'Fo ia I IV6 V V, VI VUII X, X, XL XI Xli orVXV b compound whereto Y heetsbs -0-. -NH(R')-, or -5(>-Ok- In senme emobodimnts of the ine mteconmpounid of PFxmntsi I, V, VIL VI I,,,.XX, XlX. Xi or XIV is thre compound wherein R is methyl or bydrogem. t some embodiments of 30 the netmion, the conpoud of Formula I , V V VI IX, X, X XI XI or XV i the compound wherein X-Y is -CHfN(CH), -ClyN(CiiCHr), -CH(Cftmi-CH(CH3)-NH-N(H)Cir N(CHtCHt)Cb or N(CHaICHr, indiudinsg but not limited to-C(CH)N-i or -CH;'CHtCHd)-NH haing a (S) or (RI) steroshemiedi cofiguration i81t4G In some emb~odimrents of the invention, the compound of Forndai II IV, V, Vi. Vii. VII , X, X, XL, XiiL Xii 35 or XIV is the compound wherein Wd is pyraotopyrimidio indiuding but not limied to 4-inor- iHpyrarolo(3,4-dlprimids in yi or Nah2mty2pm !,-~yiii3yl, ixurie including but, COt limited ;o6-amo-9igurtil-y or b-methylenyt-9i-pumo4y.ts snmet embodiments of the invention, the cuom tid of Fotrouta L IV, V, Vt VII VII. X, .X, Xi. XR Xii or XNV is the compound wherein the pyradoopyrimidinte is of Formula it W- N I1/ N R 12 N R" Formula III wherein R" is H, alkyl, halo, amino, amido, hydroxy, or alkoxy, and R 1 2 is is H, alkyl, alkynyl, alkenyl, halo, aryl, heteroaryl including but not limited to monocyclic or bicyclic heteroaryl, 5 heterocycloalkyl, cycloalkyl, cyano, amino, carboxylic acid, alkoxycarbonyl, or amido. [0047] Disclosed herein is a method of inhibiting a phosphatidyl inositol-3 kinase (P13 kinase), is provided comprising: contacting the P13 kinase with an effective amount of one or more compounds disclosed herein. For instance, the step of contacting involves the use of one or more compounds of Formula I, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, and/or XIV. In some 10 embodiments, the step of contacting comprises contacting a cell that contains said P13 kinase. In some embodiments of the method, the inhibition takes place in a subject suffering from a disorder involving malfunctioning of one or more types of P13 kinase. Some exemplary diseases involving malfunctioning of P13 kinases are selected from the group consisting of autoimmune diseases, rheumatoid arthritis, respiratory disease, and various types of cancers. 15 Where desired, the compound used in the method has the structure of Formula 6-A, wherein R" is amino and R 12 is substituted phenyl. [0048] In some embodiments of the method, the inhibition takes place in a subject suffering from rheumatoid arthritis or a respiratory disease, and wherein the compound has the structure of Formula 6-A, and wherein R" is amino and R 1 2 is bicyclic heteroaryl. 20 [0049] In some embodiments, the method comprises administering a second therapeutic agent to the subject. [0050] Disclosed herein is a method of treating a disease manifesting an undesired immune response. The method comprises the step of administering to a subject in need thereof, one or more compounds disclosed herein including compounds of Formula I, IV, V, VI, VII, VIII, IX, 25 X, XI, XII, XIII, and/or XIV, in an amount that is effective in ameliorating said undesired immune response. In some embodiments, the one or more compounds inhibit T-cell independent B-cell activation as evidenced by a reduction in production of anti-TNP IgG3 by at least about five folds when administered in an amount less than about 30mg/kg BID dose to a test animal. 30 10 [0051] In some embodiments, the disease treated is associated with swelling or pain of a joint of a subject. The method can be effective in ameliorating one or more rheumatoid arthritis symptoms as evidenced by reduction in mean joint diameter by at least about 10% after 17 days and/or reduction in ankle diameter by at least 5-10% or more after several days to weeks of 5 treatment, including for example reduction in ankle diameter by at least 5% after 7 days of treatment. In another embodiment, the undesired immune response is evidenced by enhanced production of anti-type II collagen antibodies, and the use of one or more subject compounds reduces the serum anti-type II collagen level at an ED50 of less than about 10 mg/kg. [0052] Disclosed herein is a composition which comprises a pharmaceutically acceptable 10 excipient and one or more compounds of Formula I, IV, V, VI, VII, VIII , IX, X, XI, XII, XIII and/or XIV. In some of the embodiments of the invention, the composition is a liquid, solid, semi-solid, gel, or an aerosol form. INCORPORATION BY REFERENCE [0053] All publications, patents, and patent applications mentioned in this specification are 15 herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. 10A BIEF DESCRW(T N OF THE DRAWINGS {0t541 The noved fema s of the invention are ret forth wilh part iaity in rhe appvded daims A better drstaning cf the fetirts nd advantages of the present invention wil be obned by refeence to the following det d description that sess fath isttve embodiments, in which the principes of the inventon are utilisd, and 5 the ccmpying drawings of which: MGOS! FR, depiOts an exemplaty prmocol for rarauwin Teirdeendent pducon of TNP specific atibodies in vivo" [M0j FIG, 2 depicts the fold adttcion in TNP specific gO3 rmponse so atgens povided by compound 7 and 53 of formula IV as compared to a vehicle conto, when administered orlly 10 057] FIG, 3 depicts the dsekpedent dlect of twice daily oral airniration of comond 53 of fornmua IV in reducing the incree in ankle diameter over time in a catlgen-indcedr developing arthritis model in ratsm Also depicted are the resuls from non anhdii control rats, arhrto control ras administered with a negative control veiie, and artrirtic control rats treated twice daily wih ethotreate, 100S) IG! 4 d pics the do-dpandent effect of comopoundis 7 and 53 of formula IV in improving ankle 1$ histopathology whe administerd in a coliagen-4ndoced developing arthritis model in rats Alo depicted are the meults iemm arthritic contdr rats administwed with aegative concrl vehicle or methotrexate R) FIG. 5 depicts the dose'lepndent eht of components 7 and 53 of formula IV in improving knee histopathology whe administered in a eo gendaduced developing arthritis mxdel in rat. Also depicted are the resus front arthritis control rats adminitcread with negaive control vhide or positive control methotrexate 20 W16{1 FIG. 6 depicts the dosdependnt eect of componds 7 and 53 of for'msuia IV in reducing the level of anti type R collagen amibodies i vinv when admistered to a milagenaindueed dvdoping thrips rat model. Ams depicted arc the results from arthritic rats administered with negative control vehice or methotrexae. I I FIG. 7 depicts the doms-ependent d~e-a of compound 7 of fornuk IV on inmoving ankle ltoNpaologty when ministered in ilage-winduoced developing arthrids model in rats, Also depicted are the results from arthritc 25 vehicle otrol rats and rnethotrexate-treated arthritic s. 10*61 PIG& S depicts the dos-epndent efct of compound 53 of forma IV administered daily on ankle histopathology in a co~agen-induced established arthritis modd in rats Aso depicted are the results fi-m arthritic arthritic verce control rats drtr heated arriidc ras. JOW31I PIG, 9 depicts the dosc-dependent eot. of co pond 53 of foman IV administered twice daily on ankle 30 histopathology in a mlgen-induced established arthritis model in rats. Aso depicted are the results fmm arthriic vehiek control rats and Enrdreaed arthriti rats (*M41 FIG 10 depicts the dose-dependet effect of compound 53 of fiomula IV "n the increase in average paw oo oe n adjust induced atrits ndet (00651 FI I depicts the effet of compound 53 of ornmsA IV on the average we gt over time os rats in an 33. ad~~ aent i duced, arthritis model in rats. DETAILED DESCRIPTION OF THE INVENTION 10061 Wilepreerrd ebodnrets f te present inventon have berm shown and described herein, it will be obvious to Ihme skilled in the art that such emboimnts are provided by way of eAmple only. Numeros vM nation, than ges, and ubstitauo swill now cur to those slled in the art without epaning from the invention It shoudd be 46 i esmood that canous ahenatvoes to the embdiments of the invetion described herein may be ermplye ad in -i~ pratwcing thesw tion, It is intended that the appended clims define the scope of the invention and that methods and rututes within the scope of these lainms and their equivakras be covered thereby, (00671 Unless denned otherwise. al technical and scientific terms used herein have the same meaning as commonly understood by one of skiii in the art to which this invention beong Al ts and pubialhmvons referred to herein are itme orated by reference. 1Mg As used in the specfcion and cliams, the singubr form "a" "an" and Kte' include pral references untss the context cleadRy dictates otherwise. As usedh ein "agent" or biologically acdve agen" refers to a biological parmaceneat or chemical comnpot d or other moiety. Nonisi tings examples ince ipeo comptext Organi" or in organic molecule, a 10 peptide, a ptAeit an otlgonucltideh, an stibody, an antibody derivative, atibody fagmet, a viamrin dervalive, a carbohydrate, toxinpd,or a Vaits compounds m we synthesized, for exame, sma momleidks and oligomers (e.g, oligopeptides and oitgonuchtided't, and synthetic orgMic Compounds basea on various core s Itres, in addition, various nahtuai sources can provide onpunds kt scmning, such as pant or anima emets and the like. A skilled artisan can readily reogpia that there is no iMIt as to the stftural nature of the 15 agents of the present invention, %]'7O The tera "agonist" s~ used herein refirs to a *ccnpotund hasini t'h biit. tOiitiate or enhanec a biological iectioa of a target protein, whether by inhibiting the activity or expression of te target proteir. Accordingly, the tem gonist" is defied in the ontext ot the bioinical to of e target polypeptide, Whik preferred agnists herein specifically interact with (e-g, biad to)he targeI' cmpunds that invite or enhance a biological activity of the 20 target polypeptide by inteting with other members of the signal trans uineo pathway of which the target polypeptide is a member a ais speciicaly inclAded within this. definition 10M71 The tm stagonist and "inhibitor" are ased interchangeably, and they refer to a compound having the ability to inhibi a biologiei fuinctior of a target protein, whether by inhibiting the activity or expression of the target protein, Accordingly, the sterns sntagonis!" and "inhibitors" are defined in the contest of the biological rote of the 25 target protein White preferred antagonists hmin specificaly interact with (eg. bhid to) the target, o nds that inhibit a biological activity of de target protein by interacting with other membes of the signal rasduction pathway of whi he et protv'insa member are lso spefiaary included within lis deIinon, A preferred biological activity inhibited by an antagonist is associated with the development, groth, or spread of a tumor, or an undesired t rmme respone as manifested in auoitmme disease 30 [0Q7] Art "nti~cancer agent". antitmoer agent" or "cheototerapeutic agent' refer to any agent useful in the treatment of a neoplastic condition. One class of anti-ace agents comprises chermothterpeutic agents. "Chemetheray" means the adrniisteion of one or more cheinotherapeati drags and/or other agents to a cancer prtient by various methods including inrvenoa oral. intramuscuarirtraperircneai intrvesica, subctaeos iasdennai buccat orinhaiadn or in the fbrm of a suppository, $5 itlO The tern "cells proliferation" refers to a phenomenon by which the cell number has changed as .a resl of rvision, This term also encompasses ell growth by which the eeii morphology has changed (e~g.. incresed in size) consistet with a profteeive signal. l.tt?74| The terrm "c-admntistrstion,"adminisered in combinatm with " and their gammaieal equiviets, as used herein, eneonmpasse administration of hwo or more agents to an an imal so that both agents and/or thetr 40 metaboies are pment in the animal at the smne time Cadminisaicn inades simukaeous admhistsion in separate emnposition, adminitraion at diffwent times in separate composiins, or administration in a composition in which both agents are present -12- [:0075 The term "effectve amnouta" or "th rapeutically enective amount" refers to that amount of a comaumd described herein that is efficient to eWect the intended application including but not limited to diseMe trmenMt, as defined below The thrapeutically effective amount rmay vary dependino.g po the intended appliation (n rmer in viva, or the subject and d:a1se co iion being treated, eg. the weight and age of the subject, the severity of the S disease condition the manne of administaion and the like, which cn readily be determined by one of odinary skil in the art The term also applies to a dose that will induce a panicular response in target cels, eg reduction of platelet adhesion and/or ele: i'ion The specific dose will vary depending on the paicular compost chosen, the dosing regimen to be Mowed, whether it is adintistered in combatin with other tOremponds, timing of adminisation the tissue to whiCh it s administered, and the physics delivery system in which it is eried, 10 0076) As used herein, treatment " or "teating or "pahatigr "amneoanin"g are used inarhangety herein, These terms refers to an approach [or obtainling benefical or desired results iluding but nt limited to therapeutic benelt '*3' ppl-,3 benefit- By the'rapeut benfit i5 meat erdca rnn eltoration of the undedying disorder being treated Aso, a thieameuric bsteit is achieved wish the eradication or meliomtion of one or more of the physiological symptoms associated with the undediying disorder such that a impovemet is observed in the S patient, notwithstandi ng uwt the patient ny sill be afflicted with the underlying disorder. Por prophylactic benenit, the compositions mt be ad'inistered to a patient at risk of developing a particular disease, or to a patient repring one or more of the physicoogi symptoms of a disease, even though a diagnosis of this disse may not have bocn made 1771 A "tbeapemne tffect," as that terM is used herein, encompasses a therapeutic benefit wd/or a prophylactic 20 benefit as descrihed above. A prophylactic effect includes delaying cr eliminating the appearance of a diseae cm ctodiaa, delaying or eliminating the onset of symqpomts of a disease or condition, slowing, having, or overag the pogregsion of a disease or condition, or any enbinatior thereof [07} 'The terrm "pharmtaceutically acceptable salt" refls to sals deaved kic- a variety of organic and inorganic center ions wed known in the art. Phannaceteally acceptab acid addhion salts can be t'mned with inOtrnsc acids 25 and organic ads, Inorganic acids sf'o. which sats can be derived include, for example, hydrochione acid, hydobrmnic acid salfuric acid nitric acid, osphorie acid and the like. Organic acids l-m whicb saets n be delve inde, for eanOple., aceti acididprgnioci acid, sheclic aidd, oxalic acid, maieic acid, maconic acid, sucinie acid, fenic acid, tartaric arid citric acid, beole acid, cinamic acid, mandlic acid, mnthanmsulfoni acid shan Rfononiacid pi-ioeeu ic acid,. Scaliyic acid, and the ike. Phamacendialy acceptable ase 30 addidon salts can be formed with inorgni and organs bas. Inorganic bases frnn which alts e be derived inlcde fo- ample, sodium, potassium. lithiun, ammoniumn. ccium, magnesium, o. man, copper, m ganf,S aluminen and the like, Organic bases kom which sts cma be derived include, for eanple, prirmay, secodary, and tertary amine, subsitute amices including natuay occuring subatiuted amins cycic amines, base ion exchange resins, and the like, specifically such as isopropylamine, rimethylamine diethylanine tiethyamine, triprpylamire, 35 and shanotami ns In some embodiment the phaiacent cayl acceptable base addition sal is chosen from acnorium, potasium , sodium, calium. and magneium salts, I009) "Pharmtac'eticaily acceptable carrie' or ''pharnaceuticsiy acceptabae excipiert' includes any and all solvents, dispersion medin, co*atings, antibacterial amid litfnga agents sotonic and absorption delaying agents and the like, The use of such media and agents for phamacendcaly active substances is well known in the a feept 40 insofar as cny onvenal media or agent is incompatible with the active ingredient, its se in the themapeutic compositdons of the invention is contenplated giupplemnentary active ingredients -- o ao be incoerated. into the cogeostions. fn,3 [rnt)o "Signa iran dden 0 is a proe:s during whic stimahtory or insdbiory sgnas ar insmitted into and within a cedl to it an intacellhlar responme A modulator of a signal ausduesion pathway reders to a compond which modulates the activity of one or mote cellar proteins mapped to the -same speoii sigus transduction pathway. A madulator may agent (agonist) or supprss (smagonst) the activity of a signaling molenIcle 5 pft81 The term electivee inhibition" or "seiectvely inhibit" an applied to a hiiogiycally adve agent efer to the agents ability to selectively edMe (he arget signing acdvay as compared to oftarget sigainrg actvityia direct or interact interacon wth the target 0§82) The tem "WALL as used oein re fers o B-cri Acute Lymphoblastic Leutkemaia, [9(g83 "Subjeect" refers to a animal. such as a mammal, for exmuspke a human. The mnet-wds described her&n en be t0 useful in both human therape"des and veteinary applcatidns, In sormie emdine thie patient is a mafftuntit and in some etbodiments, ihc parent is human. [2g4 "Radiation therapy" me-an expouing a patient, sing routine methods and cmmpositions kownu to the practitioner, to radiation emitters such as aphapattide emitting radiortciides eg, actinium and thorium diotsudide4low inear energy answer (LI) radiati'n emitters (ie. beta emittrsJ convesion eksrcn emitters i$ (g. sa-ontiunm419 nd aamarwn53KTMhP, or high-energy radiation, including without limitation aas gamma rys ad neutronsL [O.jO 'Prodrug' is mean to indicate a compound that may be converted under physologicat cnditions or by slvolysis to a biological acive compound descibed herei Thus,tie term "pnsdrug refer to a pre ofrsr f a biologically active compound that is pharmaceuicaly acceptable~ A prodrug may be inctive when administered to a 20 subject, but is convened inro to an active compound, for easnple, by hydrolysis. The prodrug compound oflen offers advantages of solubiliy tissue compatibility o delayed release in a mammalian rganism. g, g. Bundgardt 11, Degn of Prodrgs (195), pp. 7M9, 21 -24(Esevier. Amsterdam). A discussion of prodrugs is provided in Higuchi, T, et aL, "Pro-ogs as Novel Dlelivery gysesr*$' A.C.S. Symposium Series, Vol. 14, and in lilareersible carries in Drug DesigrE d. E'ward B, Roche, American Pharmaceuical Assocaio and Pergamon Press, 1987, both 2$ of which are incorporated in ai by reference herein. The tern "prodrug" is also meant to include any Svaaently bonded cariers, which release the active compound in vivO when such prodrug is adminstered to a marnrllan subject, Pro-drugs of an active comnpoutnd. as described herei a may be prepared by mdifying futctiona groups present in the active compound in such a way that the modifiatins are cleaved, either in rutine anipuladon or in vivo, so she parent active compnad. Pr-gs include comtpournds wherein a hydroxy, amino os- mercapto gmup is 30 bonded tany group that, whetn the prodg of the active compound is aminstered to a mammalian biect cleaves to torm a free hydroxy, free amino or free maerapto group. respecedvely, Examples of prodmugs ince-de, buot ar not linbed toa. aette, formate and benzoate derivatins of n ohol or acetanide, fomramide and earsde deivatves of an amine fnmctio group in the active comnpourtd and, he tike. [tS-98 The term "in vc" refers to tin event that caikes place is a subject's body.

35 [ 7 The tem 'al rve refers so a event that takes places outside of a subjects body, Fcr -mple a in v-ro assay encompasses any assay run outside of a subject assay. ln vitro assays empass ceil-based assasin which calls alive Or ded are employed, in vitOm-asy also encompass a ellftee assay in which no inact cells are employed III1]~ Unless otherwise stated, ttruetures depicted herein are also ment to include compounds which differ onty to 40 the presence of o- or more intopicaly enriched atoms- For e) mple, compounds havig the present sructures exopt fourth repacenen of a hydrogen by a deuteriums or tiatianm, -r the replacemet o ta carbon by "C- or C-nriched carbon am within the scope of this invention, -44- [WI K~The compounds of the pesenv iention may also conan nAwtural proportions of aomic isotopes at one or nore ( atom tat constate th compotnds FOr exapkz the compounds tay be radiolabted wih radioactive isotopes sch as for example uttium (t) iodine'125 (1nC 1 ) or carbotk14 ("C), All sotopic vadalios of the compounds oftfhe potent invenicm, whether adicadive or not ae encompassed whin the scope of the porsent 5 utvendent tI01 When ranges are used herein for physical properties, stch as mrokeata weight, or chemical propeniet such as cheadeal frmse, Of oorabiaation and suk'ombnations of ges Cd ecific nbodimets therein are teded to be included The term "abou' when referring to a nuNmber or a nunmxrea range means tha. the number or nmericad rage referred to is an appoximan within experimn aiiiity (or witin statistical expermnenta iO error), and thus the number or americal age may vry from, for txmpI betWeen 1% and I5% of the sated number or nmerical rargen The 1r comprise " (and related terms such as comprise or N:omr ises or 'aving" "ichrding') inlddes those efbodiments for empangle, a emsbodiment of my composition ofimattor, compostion. method, or process. or the ike, that consist of or c ist essntily of' the described features. [M91}~ The ollo-wing abbreviatdons and terms have the indicated menungs throughout is PIA Phosphoinositide lM ase; P= phosphatidyfinosito; PDK Pshinsside Dep Adent Kinoe; NAVpK =WDeoxyibose Nuclec Ac-id Dependent Protein Kinase; PTEN Phasphatase and Tenin heoson deed on 'hromoso e Tka; PIKK 6 hosphoinoiide Kinase Like Kise; AIDS - Acquired immuno Deficiency Syndroe; lHIY = Humn hmnunodeeikincy V MC M z= Methyl lodde; PC b - Phsphorous Oxych[oide; KCNS Pouassium lsoThiocymate;I LC 'Min Layer Chmmatogaphy; MeGH Methanol; and CHCb Chloroform. 20 10092] Abbreviatios uood hecin have their conventionatmeaing within the hemica ad biological arts. 10(693] "MkyP" refers to a straight or branched hydrocarbon chain radial consstig solely of carbon nd hydrogen aTms, containinpg no snatadon, hanig fom one to ten cabon Toms (eg. CCt aky). herever it appears herein, a nmerical rage such as I to W0 refers to each imeger in the given range; e., 1 to 10 carbon atoms means that the alkyl proup may consist of carbon atom. 2 carbon atem 3 carbon stoms. etc, up to ad finding 10 25 carbon atoms, although the present definition alo covers te occurrence of the ten. "akyt' where" no meri ange is designed, I sme embodimens, i ma rC.s ekyl group. Typical skyl groups include, but are in no way 1in-ik to, methyl, ethyl, propyl, isopsropyl. rvbeyi, iso-btyt. see-bmyl isoboty!; tertiary butyl, penty. isopentyl, neogentyl, hexyl, septyl, 0cty, notyl, decyi, adc he like The ahy is attached to the rest of the moeune by a single bond, for eampe, methyl (Me> etyl (E), ss propyl, beshylethy (poptpi),mbutyi operyl 1, 1dimehyliehyl (0 tayix 30 3 ethylheay, 2-mnethylbecy, and the like. USnless stated otherwise specinially in de specification alkyl group is optionally substuted by ome or more of substitets which independent are; skyt heterodkyi akeny edkynytl cycloikyl heaerocycio'alkyt aryl artikyi, heteroryibetoarylky, hyr We hc halo, cyao tri:u'cornachy rrifluoronsednoy, n-ro, trimahylsianyiOR* R, SR, -OC(O)Ri, -N(R*), -C(O)R* -C()OR' -O(XQ)(R -C()N(R1t *N(R*)C?)QRt 'N(R*)C(-O)Rt Nt(R*CqN(Re~N(R*)C{NR)N(,R% ~N(.t*)s(o)hR' (where I is 35 or ), -S(0)R*(where tis I Or 2), -S(O),N(Rx) (whare t is I or 2), or PO(R where each JR) is independedty hydrogen, -~s t uratdkyl carbocyliyi arbsocycyaikyi, at I aatyl, hetrmeydloalkyl, hctrocycloatkytalkyl heteroatry-r hteroaryiadkyh. 94 "MikyAryha fi refersto an alkylaryl radicad where aryi and alky ate as disclosed herein ad which are opdionmily bsAhted by one or more of the substiems described as suitable substtuants for aryl and alky 40 repectivdly (p095j MikylhetatryF refer to an -(adkihetary radecd where betwyi and alky] are as disclosed htritn aad which are optioradEly ubtted by one or mor ofthe substismas described as suitabe sbstents for aryl aad elkyA rspectiy. [00%J Mkytheterocycoaikyi' refrs to an -.(dky) heterncycyadd where alkyl and hetericycloalkyl are as 5 disdased heein ad which are optionsly sbitted by one or e of the substments described as skatabi substituents fir heteroceioaiy: ad eyl respectively, (00T97 An MOkn" ty ris to a gr*op con5stng of at least two carbon aoms and at east one rasrnsotm double band and an akyne" moiy rek& to a group Cosisting of at least two carbon atmS and at least omn carbon Caron' tp!!e bond. The alkyl maoey, whether saturatid or unsattsrated, may be branct'hed, setigh chai, or cycle. 10 [009S *Amkenyiefes to a straight o'mrnehed hydrocarbon hain radicd group consulting gaiy OF arbon and hydrogen atoms, containing at at one double bond, ad having kfom two to tes carbon atoms (l. (pC alkeny), Whenever it appears hareinmarnmeiad rage such as 2 to 10' refers to esch integer in the give ange; e.g 2to 10 carbon atoms' means that dha Wkenyl group may enist of 2 carbon atoms 3 carbon atoms, etc, up to and iWnduding 10 carbon atom In catain emotients, akenyl comprises two to eight caton atom-s In other embodimentat In 15 aikenyl oempises two to five carbon atoms* (e g. (CC alkwny), The bkey in ottauhed to the restof the mleeuse by a sitge bond, or example, etkenyl (ie, vinyl) prop-Inyl (se, 'lyl) ba-enyi pen4Pnyl penta-1-dieny. and the like. Unkes stated otherie specifically in the sacircador, an alkenyl group is optionally substituted by one or mr substituents which independently are: lkyl heteroalkyt alkenyt akynyl, cydoalkyt leterocydodkyi aryl, ary"alky heteroeryl, heterWyllkyt- hydroxy, halo, cyano, triflrornethyl trifloromeshoxy ritro. 20 trinsethysianyt -ORi SR" 4(O)-R", N(R % -(O)R' C(0)OR'.O4C(O)N(R) 5 4'(0)N(R'RN M(R3C(O)OR N(RC(-)Re R 'C(lON(R1% N(PttC(NW*)N(R% -N~?)S(O)X& (where iis ' or " 2)(O)\OR*(where I is or 2), -S(ON(R (whre W I or 2), or PO 5 who each Io is independent hydrogen My horosdkyl. carbocyc4ty, crbcytyky F ryl aralky hetero, t lkylF h0terocyclaIkylalkyi h3erary or heteroaryi akyL. I"5J) " tikes y.eyalIsei"ky refers to refers to an -(akfenyl~cydoeIkyl radical wrKe :a) keny d cydo kdky-l are as 25 closed herin and which a optionaly snbsisrmdM by one a- nc rn m of the substimns described as satsh sub " 'f -ncd kyl respectively. [Kfl601 j Alkyrnyl rers to a straight or branched hydrocarbon chais adical group cnsi sting soely of carbon and hydrogen atomsna containg at least one hopwe hnd, having fmn two to ten carbon Moms (i t CrCO alkynyl). Whenever it appes hemin, a umerica r-ange such as 12 to 10' refers to each imeger in the given range; eg "2 to 10 30 ca-bon asem.s" m.ans that the aIkynyl group may consst of 2 carbon atoms, 3 carbon atoms, ec.., op to and inCuding 10 cabo atoms. in certain emNdinents, :f alkynyl complies two to eight carbon stoMs, In other ebo em mNn 3.n -lkynyl has twoo fo Ave carbon atoms (e g, CrC aikynyl. The aklny4 is attached to the rnt of the mleetde by a single bond, for example, shynyt propyny 3 btniy pentynyl, haesynyl, and the like. Unless stated otherwise specically in the specificadson. an alkyny] group is optionally substituted by one or more suabstituerss which 35 independently are: alky: heseraikyl, et akynyl u'cyoak'yI hetersAylaikyt sryt aryktyealkA beas hetearylsky . bytdnay, 'do, cyano trtleorcm ethyl tr5 Vsturonmethoev'trr, trnsethyisilanyt ORG SRS QC(O)-R N(R, .()R, -C(O)OR" OC(C)N(R -N!-C(O)N(R*)(N(R*)C(O)ORtN(R*)C()R N(R*)lC(O)Ni(R ?(RC(NR*)NR*) -N(R (M,"(whr t is I or 2), -S( 14"'R(he t is I or 2) -S(ONN(R% (where I is I or 21 or POJ(R)' where each F* is inde'edenty hydirogerW skyt.. rcrdkyl eabocydys 40 carbocydlylakyl, eyl, ardky hedlcedolekyl, ietweoydloalkyl, heteroaryl or hetcroaryslkyt IOOI6TJ "AlkynybcycloalkyP" refer to refers to a -(kynyi~cycloakyl radical when akynyi and cycirsdkyi are as disclosed beein and which ar pedysbsituted by on'"-rmo' of the stimtents described as sotitable abstitunts f r wikyyl ad yor ky respectivdy (*12) "CarbtxAtdehyde" remS to a -O)N radical. 3 (0*1S3) "Ctrbaxyl" refers to a -(O"O)OH radical [W11041 "Cyano' refers to a N radical [001051 *CydoalkyP refers to a moroncyese or polyc lic rAdical that (c-ntaic only carbon ad hydrogen, ad may e satured, or partialy untated Cydoalkyl groups ildsde gmaps having freom 3 to 10 rg atoms (ke. CrCc cycloalkyl). Whbeve-'r it appears herdin, a a umerical ramge such as 1"3 to t0* ref to ea integer in the giwen range; 10 O-z "3 to 10 carbon atoms" men that foe cycioky group may consist of 3 ca-hon aoms e cp to and ntuding 10 aron atoms In some embodiremas it is a CrCl cydloalkyl radical. in sosmc emnbodnmms, isa CC Cycloikyt} radal. lu-tative exampes of ycloalkyl as-ups inddic, but am not limited to the poowing moldi-c cyclopropyl. cydobutyl. cyclopentyt - eylpternyt cyclohexyi, cyclohcerenyt cyvioseplyi. cydtooctyt cycloneyL cyclodezyt nsorbomyl, and the like, Uless stated ao-wise specifAiy in the scificatou a ycloalkyl gmup in upionaly Is substitute by one or more ubstituens which ndpendently are; akM, heterolkyl ae'y} alkyny, cycleaikyi, hetercynkakys, aryt, arylakyl. heteroayl hteoryiky, hydAy, halo, cano, touroomehyo , trforomeahoxy, namd, rimethylsiayt -R S'R -C(O)-Rt E-Nf(Rt% , C(,O)R -C(O)OR -OC(O)N(R%, -N(R~)C(O)ORtN(R*)C(O)R* N(R)(Q)N(R t -. N(R*)c(NRN(R t , -N(R)S(q) (whe is I or 2), -S(faOR (whert is i or 2) 1S(0)N(R h where t is I or 2), or FNAR where eachR i's independency hydrogen, 20 akto homsjtns:' earbocydlyl carhbocydiyidkyi. aryt, ar-atkyl, he cycldkyl, hesemecyclcalkyladkyl heteroaryi or (0I16) "yeckdkyal-kenyi" refers t a -(eccy ikyl) aikeyi radical where cycloal ad i are as disc>sed beren and which are optionally substitmed by one or more of the subfloenta described as itable substkuers for heirocydoakyi and csyckkyl respectively. 23 (00107) "Cycd kyt-heterocydcaiyv"resto a-(yicalyl) heterocycy radical where cycloalkyi and hetercyclkakyl are as disdled herein ad whih are optionaly sbstoted by one or more of the obstiteaets described a uite substuents for heterocyecayi and cydoakyl respectieiy. (0J01] "Cycidkyl-hater y" refs to a -(eycloalkyl) heteraryi radical whee cycloatyt and beterocoakyi ore as disposed herein -ad which are opti-oaly bdistted by one or noe of the su&stituents described as suitable 30 substuernts for seterocydiakyl and cychlkyl respectively (OO101] The erm "alkoxy" refes to the group -O-aikyl, indudixg frorn I to a carbon atoms of a straight, branched, cytdic' con tn and combsnations thereof ar~tsached to the parent stmrctum ihrouph an -oxygen. Eamples in de meaoxy, ethoxy, ppxy, ispopoox cyclopropyioay, oycthexyloxy and the ie lower akoxy' refer to akoxy gmuswi c tronojg one to six carbons a somwe mbadmnt Cr C4 aihyi, is anakyl grop which scompasses bcth 5 stright ud branched chain alkyls of ftm to 4 carbon atomt (1110 The ter- I bstituted akoxyx refers to ikary wherin the alkyl constituent is substituUd (is, -(substae~d akyl)). Unles stated otherwise specifically in the spedicationa the akyl moiety of a mkoxy group is optonally substituted by cao orame sbsta s which independently are: alkyl, herlcy akeny, akynyl cydcoatkyt heterocydloalkyl, ayl arylaikyleey hetercar ts-a nh-y. hydroy, haio, cyanso, triiuuror-sehyl, 4{) trifhuorcmethnxy, ohs trismethylsaswany-GRt Si -OC(O(R -N(RGI 0 X -C(t))i -C(O)ORt.OC(-t)NR *'C(O)sN(Rh -N(*C(O)ORt -N(RC(ORt N(R*)C(~O}N(RPY N(RflC(NRttN(Rh. -N(R")S(O),Rl (where i I c r 2), 4,(00R*(where is I or 2 , )N(Rh(where t is i or PO0(R*) 2 where each IC is independently y.

hydrogenrdy} rakyl carbecyy carbeyclyiakyi ary1 ardkyt heterocd kky, hetoryckmikylacyt heteroaryi or heoarylkyL 8t)110 i Te tern lkxytonyV' rsim to a group of theS ina(ekoxy)(&=O> att thoug th car bonyl carbon wherein the akoxy group has she indicated number of carbon atoms, Thus a :Ce, aQ, xycarbony gmap is a 5 akoxy goup having from I to 6 carbon Aoms attached hrmugh s oxygena to a carxbonyi liker. "Lower aikvxyvarbnyP refers to an akosxycarbonyi goup wherein the alkoxy group is; a iower alkoxy group. Inome embodiments, Cr..C 4 ky isnn alkoxy group which encompasms both straight and branched chain alkoxy groups o'f from t to 4 carbxn atom 12) The term "Mbsrtin at oxcbony refes to the grmap (substituted alkyw)4QO> herein the group is 10 amteed to the parent astre n trough the carbonylfunesinay; Uness staed otherwise spedfiohy in the specification, the alkyi moiety of a aAxycarbonyl goup is optiensdly substitted by one or nore bsttue whsih independently are: alkyl, heter akyl aenyl, alkyqyl, eyclolkyi, heterooyealky ),ry, arylay, eten hemarylAkyl, hydroxy, hako cyano, fifiuromethyl Oitioromethoxyntrse t ylsunylGR* SIC 4)C(OfRt -(R)4C(O)R, -C(O)OR0, -D 0)N(R 15 -C(0)N(R*).N(RnC(O)OR& N(RPC()R', N(%'(f)N(R*) N(X)CNR)N(R) -N(R2)(0hR* (where ti& I or 2), S(O\OR' (where tin I or 2), -(0),N(Rh (where t is I or 2). or PQ~jR*). where each R*~ isundependently hydrogen, alky fluoroalkyl carbocyclyl carbocyicylakyl, aryl, aralkyl, hserocycioalkyl, hetcreycleakyikyt hete'rary or heteroaryilkyt [0113I ,Acyi rers to the groups (aky rC(Oh(ayl-C(O} (heteroarylkC(OV, (heterAanky }-Q0 and 20 (heteocycleakyl)CO( wherein the goup is attached t tothe parent structure through the carbonyt tunca stdy In some embadmentsit is a CrC acyl radical whieb refers to the tota number o i chin or ring atoms of the alkyl ary, heteroaryl or beeeyc oalkyt portin of the acyloxy group p 1 us the cadonyl carbon of acyl Le the oher ring or dain atomrs pa carbonyL If tie R radical is he ary! or helemoyckkyl, he heto ring or chin ators cord hute to the tota nuniber of chain or ring atoma3t Jns stated otherwise ap ificaiyl in ie specficatia. the "R" of an 25 acyloxy group is optio ayl shbstied by one or more ubstiktents which independently are: alkyl, heterky, alkenyl, alkyny:. cyclodkyteterocydoayt ary. arylakyl, etemayl heterarykkyi, hydroxy, hao, cye-no trifhfommethy, trifluommethoxy, nitro, nrimthylilanyORf SR' -OC(OI-R§ -N(R*) C (0)R -Ck(-)0R -C(0)N(Rs -N(*(O)ORt -N(R*)C(0)R't N(R*)C(Oh)N(Rto N(RI)C(NR*)NtR'} -N(R*)sS(OyR* whene t is I or 30 2), S(ffOR' (where k in I o 2), (ON(Rb whereass I or 2) or POc(R ,where each R'i independ s y hy&drgen, alky, fluomakyt, carbocydyl, eoabocylyakyl, aryl, araiky herocdoakyt hetrocydoakyaldky horroaryl or heeeroyndav pou4 Scytoy" refes to a R(.0)-. radical wherein "R" is aylk , ary htterory heroskyi or heterocydioaiy which are as deered herein In sonne embodiments, it is a C-C; acyloxy adieA hich refrnso the 35 total nubslier of chain or ring atoms of the Sky, aryl heteroaryl or heteracycoalkyl potion of the acyoxy group pins the carbonyl carbon of acyl iLe three other rigor. hanatoms plus carbonyL. If the Rk radical is heteroaryi or heterocydoalkyl. the herto ring or chin atoms contribute to 1he total n hrser of chin or ring tsoms, Unless stated otherwise specifically in the specifcation, the "R' of an acyoxy pmoup is optionaly substitued bV one or more uobstitueats which indIepeodeny a ky, heteroalky'l akenyi. alynyl, cyckryl heterocycloakyl ary, arycakyl 40 heteroanyt heteroatyidkhy, by droxy, halo, yano, zrihluromnetyl, trifluomrethxy nitrof tmethyisiianyl, -Rk' sw'R C(OhkR -N(R -c(o)R -C(o)ORt C(O)N(R), 2(O)N(R*)N(R*)C(O)0R N()C(O)Rt N(Ri)CZ(0)N(RS, N(R)}NR*)N(R*}. -N(R')$(OR* (where t is S or 2$-() 5 0R* (whre is is r 2), -&()N(R*).

(where t is orc 2), or PN~y(}fl where each RW is inakpney hydroes alkyi, fluntoalkyt caocydyt carbocwydylkyi std aaly heteraecicalkyl. htroaod kyl.n hee sor hteraykilkyt (OO115 AMilac& or "nirtt9frats to a -N(R%)radica gnmqp, whert each R& is independy hydigen. alkyl, flhoroaikyt earbocydyl. carbocydylalkyl, aryl, aikyh: heremeye'&'iky heterkyakv1y heteroaryi or S herermary kyt nks stated ohrwoise especially in the pecifcaRion When a ~N(Rt youp has two Ra other than hydrogen they can he combined with the nirogen atom to form a 4n S , or embered ring. For example, 4N()2 is mtat to icludz but nor be lited to, 1-pyrrmidinyl ad 4-motpholayt Unless stated otherwit spcifically in the specification. a amino gup i optionaly substied by one or more obasitoenta which Mependenty Ware: lWky, heteroalkyl. aket kynyt cydoatkyl, heerocycicalkyl atyl. arylalky, heteroatyl heter rd -ky hydny, alo 10 cyan-OR'foromethyi iftomethoxy, niro, anithy-ilany t R SR 4C-(O) N(Rt -C()R 42{C0)ORtt 4)C(OiN(R*)a -C(O)N(R', N(R*)C(}0R N(R 6 )C(0)Rte N&(R)C ()R) N(R*)CNR*)N(R~

-N

t )6(OhRC (where t I i or 2}, -8(O R* (where i is 1 or 2), .$(O)(N(F (wher a t or 2) or P2, C(R%, where each R* is independentdy hydrogen, alkyl. ihenrstkyl, cathocyclyvi crbckyarry atlky heeti yody hermydaikytalkyl heteercryl or hetaroarylalky and each offthes moities may be opuondly substituted as 15 defined hereti. 1001 l6 Th term "sustituted amino also refers to N-oxlsd of the grorp -xMHR nnd NRRa &ch as dmicabed above. N-oxides etn be prepared by tratinent of the conesponding amino group wih, for example, hydrogen peroxide or ini eroxybenzoei a6d, Te person skied i the arts familiar with re edoa corcditoo for carrying out the N-oxidation 20 (117 'Mide' or Namido" refers to a chemical moiety wih formula -C(,O)N(R) ow-NiC0O)R whe Ris selected from the grop consisting of hydrogen, akyl cydoalkyl ary heteroaryl (onalami through arising carbon) and heteaoaicydic (boted trough a ring carbon), tavch of which moiety may itsedfe opionally suMiutednsome embxdiiments it is a CrC4 amido or amide radicaL wittih includes the am-ie carbonyI in the total number of carbons in tht radical, The RA of- N(Rh-< of the anside may optionaliy be taken together udh the nitrogen to which is attached 25 to for a 4, 5 6 or 7-embered ring Uless sated otherwise seciftly in the spefccatiosn an amido group is opfikrnlly substi-uted indepenmdendy by one or mrc of the tbst4mleats as described herein for alkyl, cydoalky aryi, hetermoaryl or heeroryckakyL An annide may be an amino aid Or a5 pepide msolecde aftched to a compoUnx of Formula () theby ftcmrnmsg a prodpg, Any xmine, hydoxy, or car-oxyl sde chain on the compounds described hereia can -be amidili4ed The procedure s and specific groups to make such smi-des are known to dhose of skill in the art 30 and- can ready be foomd in reference suce su as Greene and Wats, Ptcftive Groups in Organic Synthdesis 3amprd Ed, JON. Wiley & s New York N. , 1999. which is ine porated herein by refterence in its entirety [00gS 'Aromadc" or "aryf em to an aronm radical with si to ten ti aoms (a g, Crm- arotatie or Cdm aryL) which has at leat one ring ha-ving a conjugated p deetron system which is cartocycge (evg, phenyt, flor, y, and naphhyi). ivaient radicals formed from substTed one deivatives and having the fre valences at ring 35 iors a re named as substited phenyene -cd ioa3ivaent radical derived from univdent polycic hydrocarbon radicals whose names end in '-t by removal of one hydrogen atom fram th- carbon atm with the fre vaence are named by adding -idene" to the tame of the correpon-ding univatent radical. g.g, a naphthyl group with two points of atschment is termed naphth Hdna Whenever it appears neretn. a numnerical range sec-h as "6 to 10' efers to each tnteger in the given rage: e~,g 6 to 101 ng atoms' means that the aryf group may consist of 6 ring atoms. 7 ring 4t) atoms, etc, up to and induding 10 rig tons-. The term inchades monocyclic or fitsed-ring polycyclie (i.e, rings which siara adiget pairs of i-ng atoras groups. Un stated otherwise speciiclIy in the speificaMion an aryl motety is Optti.Oty MAbstid by one or more sebstituets which are independently: ky, heteroakyl akenyt 19adkynyit cyckoaiyl hettrocyclokyi, aryt rylaihvL htol ry htemaldkyi, hycfoxy, ado, rzyano, firosothyl. trifiuwnmehOasy, nitro, trimaethykiianiyi, -AR, SW 4X'(OFRt N(R") -C{O)R*, C(O)>ORt -OC(O)N(RI, -C(O)N(R") N(I*)C(O)OR, N(Rl)(O)R3, N(f")C(O)N(R*), N(R%)(NR*N~)N(R -N ()R*(wheret is 1 or 2), (O1OR*(where S is 1 or 2). t(ON(RP(where is 1 or 2), or PINYW where 3 each R* is independently hydrogen, alkyi, flomalkyl, caboeyy, carbocyciylaikyl, aryt aralkyl, hetemeyrdoakyi, heveyckkyaikyV heteroarsl or heterurylalkyt (I119 "Mraikyl" or "aryl-akyl refn to a (fyl)atyl- radical where ary1 and l are asdidosed herin and wh are optiondlys substituted by one or more of the s irues desired as suitable substitsets for aryl and akyl respectively. 10 [00120] lEset' refrs to a oheimio radical of formula -CO0R, were R is selected from the Poup consisting of alky, cyelayt aryl, heteroaryl (bonded through a ring carbon) ad heierco ydAie (bonded through a ring carbon), Any amine, hydroxy, or carboxy aids chain On the npounda described herein can beeseifed. The pc dures and pecific groups to make such esters are known to those of skill in the ar, ad can readily be tod in eferec scores such as Greene and Was, Protective Groups in Organic Synthesis, Istuprd Ed., Joh Wiey & Sors New York, N.Y, 1 1999, which is incsrp.ated herein by reference in its endretUnles stted otherwise speescaily in the specification, an ester group is optionally subtituted by one or more substints whieh independently art- alkyl heteroky Akenyl, akynyl, ycloalkyl, heterocydodky aryl, Y . lx, heteoar-ylalkyl, hydioxy, halo, cyano, ifuom hw rrtuorometrhoxy, nto, trimneth ysiany$&OR' Ri C(O) -N(R*) -Cu ), 4i(O))OR A(O)N(WR , -C(o)N(RhN(C(oRN(R*(O)Rt N(R*)C(O)N(R 2 N(RS)C(NR)N(R 2 N(M)s(oR- (where t is 1 or 2), -S(Oh0i (where is I or 2), SW(OXNlRwhee t is I or 2), or P ds, where each W is independenly hydrogen :ky m rolkyl. earhocytyi, carthcycyiky .ary aralky, hetrocydekyl hekrxcycktaikyhaky, beteroryl or hlemrarylaikyl. 10021 TW'orTatyr refers to ar alkyl rdical, as defined above, that isuttuted by one or noe fluoro dicas, as defined aboWve, for esamiple, tsiiltoromethyl difhomethyl, Landuoroethyl, m .5 the ike. The alkyi pert of the flioroalkyt radicd may be optiondy msustuted as defined: above for an alky1 group 00122) 'Ho" 'hWke or, alternatively, halogen " means fbore. chlor, bmarnx or iodo, The ter=s "haoky: aluatkeny;" "haoaikynyi" and "hhdokry" ±ndudel dyl alkeny alkyny d aikory structures tht are aba tted wit on or more hao groups or a, combination tha eof for example, the temn 'fhtorolkyi a& d 'fluWoakoy"' inctude haloalkyl and hatoaikoxy roup, respectively, in which the hao is fluorine, 30 -0I23] lHeerodkwl'heteroakenyP and "heternatkynyl indude optionlly Substituted akyl alkenyl and aikynyl radisas and which have one or re sked chain atoms seated firm an atom other than carbon, e'g,. oxygen, nitrogen, lh,. phosphUS or combination th of A numriedoa range may be given Ceg. C -C, heermat kyl which refers to te chi length in totwic in this snpe is 4 atns long. For exmrple, a -4 0CMis C %cff radie air refted to as a "heteroalkyl, which includes the heteroatonm cer in the atom cat iorngth description. 35 Connetoen to the rest of the noi:ecule may be h-ovi- either a he atoo or a carbon int the heteroakyt chdai A heteroalky group may be substituted wnh one or m;ore auttvents which independently are: a'ly, hetaror5l kyl, akenyl, dakyny. cydokyi heterocydoatkyl aryl. ryalsy beerory i heteroaryikyl hydroxy, halo, cyanostrO, oao, thdoxogrindbhylilanl -OR', ~SW. ~GAOC( R', -N(R'h) -C(O)R, -C(O)R0 (O)N(R*)N(R*)C(O)ORt -N(RlC(O)R-N(R*S(OYR' {whe t is I or 2),S(4O0Rfwhore t is I or 2).S(0)t()j (whoe t is I or 2), or 40 PO3(R 2 whero each R* is independenly hydrogen, ekyl, afrakytoteydyt carbocydlykyl ary, aakyt herercycalekyt, heteroey kyhlkyi, heteroaryi or leteroarylakyt -2(t041241 "ieteo;AkYkyl refers 4to an -(heerowskyi: did wheM . heteroalky and aryl areas disclosed herein and which are option lysubtituted by on or more of the atituents described as suabitAl asbsdibents for hetetnalkyl and aryl respectively, W1261 "HetaLkylheroaryl refers11 an {heteroa kyl)herary radidt wbere hetesoathyl and hetrUan4 are as 5 disrcosed herein ad which are opionaly snbstianed by one or more of h sts dssribed as .suiabe sbstituet for hetemsatkyt and hc301y1 respectively (GO 126( "HetemaklhetemcsycloalkyI" refers "to a ~ieroaikyijheeroyeioadkyi radida where heterokyl and hrMsI are as delosedi herein and whkih wre optioaay suituted by one or more of the jsftuenls described a suitahie wbslituems for eteroatky and heterocycoalkyi espectively 10 ( Mz7] "Reiroalkyleye.oalkyi" refers 'o an -(hetetlu kyf) cydoalkyl radial where heterocikyl and cyealkyt are as disehased herein and which a optionally substued by one or more of the substittents desenbed asasotale substtunts for hetenrwkyI ad cyclolkyl rapectivdty. O1281 ietertmaryi" 0T alternatively, herr mnnati," Mfer to a 5- to IS-memo 1 betred aromatic radical (e'g, C5CE heteroary0l) that includes one or mor ring heteroatoms selected fimk itrogen, oxygen and sur, and which may be a 15 Mnoeocydc.li bicyclie, tricyclic or terycie rag system, Whenever it appears herein, a numerniod rage such ps 'S to w rers to each integer in the given range; eg. 3 to 18 ring atom" neans that the heteamaryl grott' may ctnsist of Srng atoms, 6 rnAg atoms, et., up to and including 18 ng atoms. kilvaient radicas delved from bivlent haroayl radicals whose names cad int 'y!* by movl of one hydrogn atom fom the an with the free valence arm named by adding 'idoe to the anm of the corresponding univalent radical, e.g,, a pyridyl group with two points of attachmet 20 is a pydyl iden. An N-cornaining "hemasromatie or heterary motety refers to an amane group in which at least one of the skeetat atoms of the wig is a nitrogen atom.lthe poy.ycyd hemaryl group may be fAed or non used. The beitoms) in the hesemryl radical is eptionslay oxidized. One ar more nitrogen atoms. if preset. are optionally qiaternized. The hetroaryl is attached to tbe rest of the moledke thsrogh any atom of the ringss. Examples of heter i *vnct, but are not aited , azepinyt acridinyt benini yi bodadolyl 2-5 1 .3benzodirxelyi benfuranyi, benzooxaaol bezoedthiaamtyl.tabezohiadiaroiyi bcnz~b][x,4]datrat. beoob][ l4Ninyr ,4.bezodioxany, bennaphrhofuranyi. tenzoxazoiy, bexsmoditoxoly, benordoxiny tteamomwlyvi ban.opyra ny benrspyranony I bentfuranyl, bei:aonbenzofrazmnyt benzoth ia]..k baootheny (mhiophenyit b .zot cnni{3>d~py~diiyl, henatriazolyt ta(44,6]irrida(1;2Xajpyriinyt camizlyl cinnoliny]. eyclopent~d pyrimidinyl. 63-dihydaY5Hmcyeiopenla44tien[2>3 djpyrimnid lay] 30 5.&dihydrobexedhoqiaaclinyi, 2vdihydrobenzo~hicinnolinyl, 6Xdihydr$Htbea4 6;lcyoheta~t> olpyridaninyLi ditenzsfuranyl, dibenrrthiopheyl fiany.t foramanyi. fisranonyt thro[3,24]jpyridinyl, 6h;7AS9j O-henhydrocyc loocta~d~pyriinidiny], $,6;7,8,9,1hzasydrocyclotasdpyridazinyt 5,6;yAS9, ti-heahydrocycdooea~dgryrdinyisohindoil. imidaaolyi.sl, xs i indoMy, indazolyi isoinrdolyl, indosyi, isoindolinylisoquinol indolirnyk isomzolyl, 5$r hao.-6S c6 tershydrqinsazoindyl, 35 aphshyridinyi, i:;6aphthyridinoiiyt Osadiazolyt 2-osoaspioyt oamelyd oxoasny, 5,6,6aL9i,0sOethydrobnzo~hquinaaol inyl, i-pheny-1Hpynoty' pYhe-z yl. phenothiazinyl, pienrxariny], phdaziny, pteidinyl prnny], pyronyt pyrrly]. pymziy pyraznt[3dyo'diiyi pyridinyl, pyridol3;-dpydmidisyl pydrd[,44)pyrimidinyl. pyraiayi, pyrisnidinyt pyridtniyi, pyrrolyt qinaolinyl, gxirroxaliny, qinohlyy, isoquinolny, tetahydrgrinoliny S.647i.;tayd iai ayl 40 6,7,-ttrydroben[4,$tieno[2>dIpyridinyl 6;7A9-e hydro-MI-cycksheptaC, 1hieno(23d~pydmidiy, 5,6,7,&4ttrabydropyrdd[,5.]pyridaainyi, thiazolyl, thiadiaziol thiapyrsayt tiaaohy, tetraolyltiainyt tioa[2Idcfpyrnidiny. thicrso[32d jpyrimidiny], ti erso[2c]pridi nyl, and thiapheny] (tsr. thienyly tLnist stated -21 hrepeciay iv In the speelkin., a heteral moiety is optiordly sastituted by one or moe subituents which are independently: kyi hOt my' aikenyt a1ky1y cycialkyl, hetrocycloalkyl, aryl ryLailyb hretaryl, eetary~aky hydroxy, halo, eyano. nitre, agost tdhoxo, trim hylsianyi.R ,SR* 4)C(O}RtN(R C(O)W, -C(O)ORt CG(0)NCR*). -N(R)C(O)t2Rt -N(R1)C(O)RU N(RaDS(O~f*(where t is 1 or 2),S{G)OR*(where !is i 0r 5 2).S(ON(Rh (where t is I or 2), or Pc(R*) where each Ris indepesderiy hydrgen eakyl. fioalky, carbocylt earbocydykdkyi asyl. aralkyl. heterocycloalkylt heterocycloaikylAl heteoary? or heteroaryldkyL UM1291 Suhitted heteroarvi also includes ring systems tited with one or more oxide (4-) subseitents, wdh as pridiny N oxides. (WU 30] "leter raryl" refers to a moiety having an myl mtoiety, as derbed heii -nncd to a< 1 kylene 10 moiety, as described herein wherein the ction to the remie of the molecule is trough the kylne geO 0Uul IHejroeycloalkyi" refers to a steble to I ebeId noarmatic ring radical that comprises two to twelve carbon atoms Md from oIne to six heteroatms seated Rom nitrogen, oxygen and sulfur Wheever it appear berein, a wimnerical rage such as *3 to 1srto each integer in the given range; e.g, "3 to 18 ring atoms" means that the hetertacyclosikyl group may consist of 3 rng atom, 4 ring atoms, et.,, up to and including t8 ring atoms, i 15 some embodiments, .i is a CrCm heterocydalkyt. In sme embodiment it is a C nC hterccykiikyi! n some embodiments, it is a C C tescydikvl Unless stated othAnise spcifieAlly in the speeitaion, the hetcrocycdoakyl radica a monoeycli, bicycliec, tricyli or tctraeycelic ring system, which may indalde &sed or tid ged rag systems. The heteratoms in the heterocydoalkyt radical may be optionally oxidized. One or more nitrogen atoms, if present, ae optiodnaly qsrrnimetd, The heterocycloalkyl radical is partidly or fully stunted. The 20 heterocycioaikyl may be atached to he rest of the molecule tcArough any atom of the dang). E ampies of suCh nederocyciikvl radicals include, but are not limited to, dioxolany), 1hieny[ 13)ditidayl dit &sqwiyi, 2-oxopiperaxiniyl 2-oxopiperidinyl 2-oxopymdoidiny., oxazotidinyt piperidinyl. pipemonya 4-p~iperidonyt, pyno1idinyi pyrso dyi, quinudidiny, thiamoiinyl, tetahydrfbry> idhiany, tetrahydropyrany, fhioimorpholnyl, 2$ ahiamorphoiinylt cthiomorphalinyl ad 1iro iomorphlinyL Unless stated otherwise specifically in the specti oni, a hotemocycdkyl rnsxiety is optionally subaituted by one or more substitnts which independently are: aikyl, heteroalkyl, alkenyl alkynyl, cyckoaikyl, eemrcycloulky l aryl, arylalkyl, heteroaryl, herarylaikiyl hydroxy, halo, cyan, nitro oxo, thioxo, nrethylsilayl. -OR' -SR t OC(O) (R%*) C)R C()ORC()N(R -N(R*)C(O)ORt-N(R)C(O)RtN(R) S(0QR* (orIwre t is I or 2) f(O)OR* (where t is I or 2), -S(ON(R">) (where t 30 is I or 2), or PO 3 (.R! where each R" is independently hydeaikyl, fuoroikyi, earbocycly rbocyclylekyl aryi, ariAkyl, heterocycloaiyt, heeraryl or heewrylfyl ii1321 'HetercyvctdkrylM also includes hicycie ring systems wherein one non-aromatcd ricng, usuaIe wih 3to 7 ring atoms. contains at eas 2 carbon atom.s in addition to 1-3 hesermaonms indepmdendy selected from oxygen slfur. and nitrogen, as well as combiations comprising at least oe of the foregoing heeroaontos ad the oher ring, usually 35 with 3 to y ring atoms 4 optionally contains 1-3 hetcrctons independently selected irom oxygen, sultfs and nitrogen and is not aromatic. j413 lisomers" are different compounds that have the same moleuar formula *gereoisoere arc isomers that differ only in the way the atoms are aanged in space 6nantiomrs are a pair of neweisomers tha are non-euperimposatbe mirror images of each eter. A 1:1 mixture of a pair of enantioners is a 'racemiC mixture, The 40 ter. '(A)" is used to desgrate a raemenixtue where approprac. 'iasteeonrc are ereor neirs tha have as least two asymmetic atoms bus Whin arc rot nmirlnages of each other the absolve simtemerNst i specifiedt according to the Cnhsv-ngold-Prelog Rt-S system. When a compound is a put- enandiomer the "23 te hemistry at a6 chdal carbo. can be specified by either R or S, Rsolved componds whose absolute gnganoVn is unknown t e desgated (+) or (p) depending on the direeton (daxr or evoctatn which day rotate pine poed iad light at the waegth of the sodium D ne Certain of the cmponds desned herein contmn cme or mr amymtri: 104 enters and can hih gve re to etmtioers, diasicerns, and other stuecisomeric forms 5 that can be defined, in terms nf soIte sotc.heistry, as (R) or (S)-, The present chnical entities, phafraaeetdtal conpcalikam and methods am meant to incnde all such posible isome, inchiding xerme mixtures, optically pure kms and intermediate mixtures, Opticaly steive (Rj and (S) isomrs can be prepared usn chia syntons or chil readers or resolved using coventa hnique. When Ihe coirpounrids described herein conati oktini double bonds or other cetrm of geometric asymmetry ad usln specified otherwise, it is intended that th 10 compounds incaUde both E land Z Seometric isomen to,.134) Moiety" reAM to a specific segment or fiaetonal gmup of molecule. Chemical moieties are oflen meegnsied ehemicA eities rmbed&d in or appended to a molecde. ltM*1Si"Nitro" refer to the -N~t radical. ftOIJ6 O ) rmirs to the -0- medical. iS [137 VOao" refers to the O radical. [ 38U "Tautomes am stmeturailty distinct isomers that interknert by autenerians "Iauomerution is a flanm of isomtation and inelOdes prnteopi or p trs-hif tautoerisation, hich is considered a sutet of acid-bae chemisty, "Protobropic tautometinor <a"protonsh ift sautomeris ionV' nvolves tht emigsahon of a prtim aemi pnied by changes in bond orer, te at kAterchange of a single bond with an adjacent double bond, 20 Where tautaorezation is posibe (e.g, in sodt'n), a chemnticl equnilibxm of tntomers can be reached. An eaipk of taotomerrition is keto-eno e n A aos pecic example of kmeto'enoiaute nation is the tcreonversorn off prta se-2A4-done ard 4-hydroxypenten2one tato-mer, Another temple of sammern is phenoketo tautmcrieadka. A spot-ilA examp& of phenol-keto tutomeixdn is the itmrconymfon of pyridin4-ol and pyidin-4(IHA)<me tautomter. 25 [M139] The conm pnds of the present invention smy alo constain unnatml propoti ons of atonic isotopes at one or more of atoms that cons Mte such compounds For example, the compounds my be radioAbeled with radioactive tSctopes, such as Im example tium (N) iodine 25 i-o rb 144C All isotopic vad'atons of the compounds of the present inve-nion, whether radioactive or at, are encompassed within the scope of the prsem 30 1001401 A "leaving grop or tme" is any group or ars' tho wi imder the action conditions cleave nm he stardiag material thus promoting reaction at a specied site. Suitable exawmples of such groups unless otherwise specified are halogen atoms mesyoxy, p-natrobnxeulphcnyloxy and tmytoxy srups 1001 41 "PrTeecting group" has the: meaning conventoonaliy assciated with it in organic synthesis ix'. a group that seledvely blocks one or more remcdve sie. in a multinnonal compound such that a henual reaction can be 35 carried out seleetieiy on another unprotected reate ste nd tch that rte group cn readily be removed afer the siectdve reaction is compete A eadety of protecting goups are dished, for enxampe, in T H. Greene and P C. M.N Wats, Protectv Groups in Organic Synthesis, Third Eiditionohn Wiley & Sons, ew York (1999). For esatople, a hydroxy protect-ed fhen is where at est me of the hwdroxy groups present in a ronpound is proected with a hydroxy protecting grap Likewise, mmines and other rete groups nmay simiarly be protected. 40 10142 "Solvate" refers to a compound (e.g a compound seleted rotms For'masla i or a pharmacemicaly acceptable sat tereof in physics association with one or nore moecues of a pamnaceically acceptable solvent t will be -23undeisltood that "'a compound of Fomula r encompass the eompound of Pomala I and Eslates otecmpn as wdi as mni dses therof [O143] t Subhstixted means that the referenced grop may be sukbsitued with one or more addtio lroup(s) htndiviuliy and independently elected frm acyi a ly akyiry, ycdalkyl araky srl, carbohydrate, c .ate, S hetemaryl, heseyeloalkyl. hydroxy, atkoxy, aryioxy. metrapto, aIyn',o, atyhia, cyano, hak carbonlyl ester th;oeatrbonyl, iscyanato. thiocyanato at aenayaaao, nitro, cxc. perhaknskyl, perhrcrolkyi, phoasphete, shy. sulfiny. s(dfsnyl, sul fnamidy l sufioxyl, suifonate, urm and amio, including mono and disubsttsted amin roups and the protected: derivadis there Diwubiutted amngo ps encompass those wtich form a ring together wih the nroge of hle armino group, such as for finance, morpholino. The substiments themsoees my b tI substuate4 for example, a cyclkyl subt twrersstmasy hs a haide nibstItted at one or' more rirg arbons and the like. The prosecting groups that may frm the protective derivatives of the above suh mats are known to those o skill in the at and may be fouts in refern ces such as Green ads] Wsrts above. (ti44j "Suifnyi refes to the groups: -oinlf y substit-ted a to optioeiiy substited aryi S-iopriom!y substituted hetearyl), and -S-(ptioaily substituted hecydeaikly.), 15 j@9145) "huiflayl" refers to the groups: -S(Q>N, S(fY~opionally sub'ssttsted alkyl), S(0)~(optionadly substituted (O -oni -. - .. x P% I' -4 . -ta~l t stati .. 4mno (4optiondlly substituted aryli, SO 5opiedl subsiued hsstemyi), ands rSO "ptoalysbtiue heterycoaky). [491441 "Sulfony refers to the groups: -S(C)H.S((optionahy subsitutedt alkyl)e -SgO opticallyy subanused amino),(&(optional ly s'bstiszedi aryi}, S(Ob~opionally suitted hazearyi), ad -S(O(opknafly 21) substituted ht erovcdoaiW ly )1471 "Shuifonamidyl' or "sulfo mid& refers to a ~S(=G)rNR radsd, where each R isa sdlecaed independemly from the pep consisting o hydrogen n. alkyi, cydalkyl, ary], heteroasyi (bnded th ga do-gcb) and iseeroacnydic (boded through a ring casbtn)' Ths R, groups in -NRR of th.()rNR radical may be tAen together wIh the nirogen to which it is attached to form a 4-, 5-, 6, or me mbered ring in some cmbodinents i is 25 a cl-C 5 m sufe do, wherin each R in sulfanamikd curtains I arton, 2 carbons, carbons, or 4 carbo ns tos.L A ifonamido group is optionally .subatiued y one or more of the substituents describe] (r af sklkcclokyharyl heteroaryl respectively 10014$1 'Suifoxyl" refers to a-S(=O)aOH radical [JO149) "Srslfvnate* refers to a -S(=Oh-OR radical, where ft is selected frocm the groupc consisangs of alkyl, 3 i cydeity], xyt' hemaryl (boded through a ring carbon) and heteroaticyetc (bonded through a ring o. A sudfoae gSp is o~pdiondly subst-uted on R by one or More of the suhsituens described for aikyl, ycloslkyl, aryl, hsecraayl respectvdy. [OM50) 'Whire .bssiment gmups are specified by their convensonal chemical forrmdae, written om 1t to rght, they eqraliy enompass she chemicly identical substites that ould resuk tfion wrhing te stucture ftom right to Slseft\e.-CHtt- is equivalent to 'f)Cr, 001511 Compounds of the posent inventon also include crystormne and amorphous fcos of ths e compounds inchadoing, foar example, polynmorphas pssepolymnorphs actlves. hycdrases unsented pdsymnorphs includingt anhydrates cenfo rm atioal poiymopas, and m ayorphous fors ofthe nompons as wi as mitra thereof. "Crysasus itormo, "poynscafhn atnd "rnvd torrs may- bre useds mterchansgenbly soesa and ae meant to include ad 40 erystanlino and amorphous Forms oi the cfopound, including, lio emple, pym psedopolymorph, "dlaes, hydraet unsavaed pymorphrs (induding anhydases), conformationam plyorphs and amorpBous forms as wed as mimuree thereof, unless a partiuar cryataline or amorphous Jforn is rem'ed to -4- [00152] Chemical entities include, but are not limited to, compounds of Formula I, IV, V. VI, VII, VIII, IX, X, XI, XII, XIII, and XIV and all pharmaceutically acceptable forms thereof. Pharmaceutically acceptable forms of the compounds recited herein include pharmaceutically acceptable salts, chelates, non-covalent complexes, prodrugs, and mixtures thereof. In certain 5 embodiments, the compounds described herein are in the form of pharmaceutically acceptable salts. Hence, the terms "chemical entity" and "chemical entities" also encompass pharmaceutically acceptable salts, chelates, non-covalent complexes, prodrugs, and mixtures. [00153] In addition, if the compound of Formula I, IV, V. VI, VII, VIII, IX, X, XI, XII, XIII, or XIV is obtained as an acid addition salt, the free base can be obtained by basifying a solution of 10 the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare non-toxic 15 pharmaceutically acceptable addition salts. [00154] Disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt thereof:, 0 W W B W a wa 4 Wb5 > Y__ Wd Formula 1 20 [00155] wherein Wa 1 is CR or N; W2 is CR 5 or N; Wa,' is CR 6 or N; Wa4 is N or CR 7 ; Wb 5 is CR', CHR, or N, [00156] wherein no more than two adjacent ring atoms selected from Wa', Wa 2 , Wa', Wa4, and Wb 5 are heteroatoms; [00157] Wd is heterocycloalkyl, aryl or heteroaryl; 25 [00158] B is alkyl, amino, heteroalkyl, cycloalkyl, heterocycloalkyl, or a moiety of Formula II; R1

(R

2 )q Formula II 5 [00159] wherein Wc is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, and q is an integer of 0, 1, 2, 3, or 4; [00160] X is absent or is -(CH(R 9 ))z and each instance of z independently is an integer of 1, 2, 3, or 4; [00161] Y is absent, -0-, -S-, -S(=0)-, -S(=0) 2 -, -N(R 9 )-, -C(=0)-(CHR 9 )z-, -C(=0)-, -N(R 9

)

10 C(=0)-, or -N(R 9 )-C(=0)NH-,-N(R 9

)C(R

9

)

2 -, or -C(=0)-(CHR 9 )z-; [00162] R' is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, or carbonate; 25A [06131 R' is aikyli hielMkyl akcnyl alkynyl, cyilky, betemeydalky[. arylaikyl htary, &etmaylaky] alknisy amido, amino, acyt acy y alkoxyOrbony, s'fonamida, hao, Cyano, hydrmxy, nir, phosphac, Iurea, Or aronate; [00164 R is hydrorakyi, aikoydkynyi cydoafkyf, hetcrr yeloqikyi, alkoxy, anid amino acygl, aryvoxy, $ ikoxyeamriboayi sdfrotamido, hadlo, yan, hyd-oxyo,nire aryl, or hetearyt; {t>5 Rt RitR. ad Rt 5 are independently hydrogen, alky, askeay1, akynyl. cydakyi hetcoalkyl, alkoxy, amido, amino, acyl, acyhoy, sufoami, h eyano, hydroxy r nitro; ad t00WI asch instance of r is ndcpsmdendy hydrogen C-Ctkyi, CyClyloaikyi, het ycaky, or Cr 10 tOOM o somre emodinsmm, W is CR iv Wrom ea bodimnts W is N. in some em1bodnms, W is CR> somr ebodmncn WIis N hI some Wbodimenta W is CR* n sonme embodimin, Ws i N. In somnt todimni "tSQ W is C~it hi somc ebdimcnts, W) is N In snome mbdimenis, W a CRe so4 cni ments iW Cl-Rl> In some embodiments, WI is N, in sonme emo ets, WI is CR WI CR 5 ad Wa is CR> In sonme embodinmeats W / is N, W/ is CR> ad WI is C~It P somc emb 'oar W 2 is CR> W is N, ad WN is 15 CR in !mme cm diments, W is CR W i! CR, and W 4 N I scoe eibodin , W and WI are N and W is CR. t \ome ebodimnn W2 s CR, and W nd W na N " same rmbodiments W is CR> n some embodimcnax W/ $i CRR*> In sorme er~mbdien WQ N N, n som "emnbodimnets WX s C' WIis CR 5 , W'' is CR' ad W is CR*. In sone emboadimis, Wis CR> Wa iUs w C is cR5. and. W e CHRt> In some embodiment Wo hs CR> W, is CR> W: is CR and W) is N la somi embodiments W! I N, WO i CR> WO is 20 CR wnd W is CR* Ansome embodimis, W s N, W2 is CR w? a CR and WV is CR. a ue embndmN, W is, N, W : s CR.> W: is CRI ad W is N. In sonc ifmbimL n mns, W is CR> W is N, W is C, ad WO s Ct L some embodimens, W K CR> W/ is N, Wl is CR', and W s CHR.\ so m hbodinians, M is R W is N, W a CR' and W is N in some tmdmen, 'W s CPU W) is CR W a N, and W is CR In sm embodimn WI is CR, W) is CR is N, and V i CHR ln so=e 25 embodismnto, W.2 I CR w' i CR, W. is N, and W$ is N. sonme cmtnns W) and W"$ am N, W,' is CR, and WI is CR I some embdnts W) and WJ are N, W', is CR and W is CHt- h sm embodiments W ad W) ar N, W is CR> and W5 is N, n som mbeodimnir, W' i CR, W ad W nr N, and W 1 i CR 5 . in some rembodiments W CR> W0 and W an N, and W.$ N CNRR In some embod'nents W' is CR> W ad W are N, and W> is N 3(0 [(WM16i in sonme .abodnnim: B is unsubstaned na sibstnssed aikyltdneding bai rit limited to -(Cindi. R" ,whaeni each I" is independc y hydrogen, aikyii wssorkyi caaoeyy cvibocyclyaky, an adkyi, hetcroyalkyt, hemeyc k kyi hteryl Or hoetemaykyl or NRiR' a combined tngether to form a cycliw lmey, whic incides bt is not limited to piperidiny, piperamny, and morpholinyt h som embodirnn B s nsubstant( or substikied amino!, sBoe cmbodimens, B is unsuited or snbstitued henrltlk R 3(Rj Formoa ii (MO91 In som: cmb eoimen P i a moiety of Formka and wherin Wx ia member imatd from the group consisting~ of utnsb sted ,r sustited aryt .subssitoted pheny, wsubitateid or ituted hternaryt iietsdig but -26- Mot Hioited to pmidin-2-y, pyddiny1 pyddn4y1, pyrimsdlw4y, pyrimidir2-yi, primddin-Sy. or pyi2 unsubtittd or subsditwd moncycjic hadertrymi unthstted or scid biy hteroa aheteraryl psg two oms, u or subtk ated hertoary Ic mp s lg a nIrogo ing ewt hetemaryl comprising two nroFgen ung armv, heroayi omrtttpaing a nitrogen and a SIfur as ring atomr Sunsubstikted or absttedhtercy$ialky1 including but not listed to mtMphsnyt metAhy dropynsnyl, t iint and pipeddinytsrnsbstauted or sbmstituted cycsalky including bu.t i mie ;o cyc Kpentyi xad [001701 in some emibodients o one f the followig moieies C3 CH-CH 3 -CH(CH'j) 2 N -A" N02, N N NU NNN"C -'C9> F v" " AA ~c * N N~ N NN N N N N -Ce A' b y y aydc yyd sobstituted Mkynyt uobttuer su2ttde1lkk-e mumttdo msiudhe medlkt n om -2 _ embodiments R' is unsuvioted or substiled a unsubstituted or substituted sryhalkytusosbstituted ossbstiuted hetewaryl, or tssed or substinted heoxroarylckyL ia somec em~bodiments, RI is usebstitoted or subtiued alkoxy, monsstited or rubstituAd rom esubited or substitued amlo. In somc embodimmts, R' is snsubsti wted or sbstititd e ousubst (Ted or Zbuthused acyioxy, usutmitued or stituted a oxycarbonyi, or 5 unsubstituted or suhsdiated sufonrud. In some embodiment is hlo which iides -(1, 4, 4, and -r, i ome erbodime R0 is selatd from the goup 'unsistug of eyso, hydosy ir unsubstiuted or substtated phosphate, nosdtitd or substituted urma end carbonte, {001731 In sokme emNbodiment. when R is alkyl, R' is methy, ethyl propy, isopropyt bty, tens- btyl.. me y pentyl, hexy- or heptyl. 10 1001741 in some emodinments, when if is atkyl, heosikyl, alkenyl, sdsyay, oy kyt hseeyolakyi my, arylaiky, heteroay hetemaryikyi, aikoxy, and amns acyl, ayloxy, aikoxycarbonyt ifnamido, or hydmy is substituted by phosphate, or sm bstituted urem or bstUted urea, or arbonic acid, or carboate, fOV17S1 in me embientsben Rh is alkyl, heteroadky' enyl, dyly vyckky, heeteyokoky, ary, mryalkyl, hoemtryl, heterossrylnlkyl, alkoxy, :amdo, amino, avy4 aryloy, ckycrboy or sd fanmids Ri is 5 substitUted by one r room f aikyt heteroalkyl alkeyt alkynyl, cyokikyl. heterocycklkyl. aryL arylalkyl, heteroaryI heeroarylkyt sdkxmy, anido, amino, ajy, Onyloxy, 3 koyarboyl ulfonmrdo halo, Cyano bydroay or nmro eadh ofwhhth aikyl hetertmkyl, aikenyl, alkyny, yeloalkyteterocyeakyt aryk, aryAkyl, heteroay, netsroyltky., alkoxy, amid, amino, acyl. Azyaexy, alkowyarbonyL or slinamido may itdf he wbstituted, 'A I Ino Pme :emboints, R is a number selected &om the group conisdfeg of unsbstilaed or witdWId 20 aikyl, isuAstituted or substitute heterodkyl, usbstituted or substituted akenyi umsbstituted or substituted aikynyl obstiuted or submitted cyckosiky, and unshstiuted or substitued heterocycloaiky Ln some embodimtfitltS, R* is austsed or subsisted ar4x unsubstiutod or substituted aryaikyt substituted or subsru1ted hetroaryl or unsuibstituted or substituted heteroarytakyt. in sonme emtbodirments. R> is usubstiiuted or subsdtuted silkoxy, unsbsnated r substiuted amid, unsulbstituted or substituted amino, In some e bodrents, R.is 25 unsbsltitted o shstiuted acyt] unsttstited or substituted ayais unsubituted or subistitued aikxycarbony. or unasuituted or substiteted sotoimmid, in some cembodsrmentzs, RC is hdlo, which is ,4, -Cl, or 43r, n sone embodimns, R2 inseNded I'oiri the gromp consisting of pyanoA hydroxy, nitro, a carbioni acid, and a carhmise. In some embodiments, R is uubstituted or substited phiosphare, In sorme emboditmts, Pi ustbsdtated io touted rea, in som embodens, w Rhn is wikyl R is methyl, ethyl, pmpy, ispyl, y - butyl, ter- butyl 3I0 a 1nbutyl, pety, ticayl or AeptytN [001 77J te some tmbodnmenw. when R.

3 s adkytl hesermdakyl, akenyl, akyycyckdaky, be xetero kvkyt aryi. aryldkyl, heteroar, hnearylaikyi, koxy, amido, amino, ayt, sOyloxy, akoxyrbony. sfonamido, or hydroxy, it s sbsatiued by pcsphtem. sbtisund ed by eres, orty [001781 In somc emobodimors, when R 5 Is alkyl, h-erzrikyl, aikenyl. Ak-yty4 cycitialkyt heterocyckakyl ary, Sarylkhr beterc.ry, heteresryaky. kosy, siido, amino, aoyl, aoyioxy, slkoxyirbuony., or sulftnsmido, it is substirsed by one or ore of aky heteroAlkyl Ikenyl alkyny, cyOoalkyt, hetermyeloalky ayl, heterary. aikoxy, amnido, aminu acyl acyloxy, WHkoxrar boyi sulfonarsdd halo, cyano, hydroxy tsr nra of which alk heterrl nskl, alken y, cyckakyl, eteey ky y, herrarykt, akoxy, mqnido, amino, aqy ai y ioxs', koxyoirbony] or suifmamido may itsdf be .sutituted. 40 1001791 In smme embodiments, q is an integer ofo. In sona ecbdiments, q is an imeger of]L in some mbodments, q is n integer of 2. in some embodimnts, q it an inege of 3, In some rmboients, q is wneer of 4 -29- 30W in some nmnets, R, is a member Oeected kom the group consisting of hydrogen unsbsttuted or sustituted alkylnsubstituted or substitutd aIkenyi. and unsubstituted or sub sithatd alkyoyL in some embdiments, t? is u bstiluted or slhstituted sryt unbetituted or substituted haeteronry. unssbstituted or substituted eyckky. or unsubstituted or substitvted Inraoycoalkyi. wsoe embodimments, R is unsubstituted or substitutd aIkasy, 5 nsu bstituted or subsutuxed anido, uns bstbtced or sUbstittead amino. t some embalfmess& R) 5 5nSbsteud Or substitutd acyt, unskbstktrted o ebstixetod anyloxy, une bstitutd or substted swik4 yctbnyt, or uknbstituted or sbstiinted sudfonmido. In some anbodimens Rt is hao, which is 4C -rA:,or Br. [OO1&4 in some embodimnenz R 3 isi selected frm: the group consisting ofeyanso, sy droscy, and niion in somte embedlnents when R., i alkyl. R3 lis methyl ethyl, propy isopropyl, butyl, sen tmy, sec-bury, peaotyt hexy or 10 hepty in some em odimnlts., R is <Tm. [00121 In sorme embodinseni. when R is aiy lkerAy kynyt ry3 beterary. cycwosikyt heydalkyl akoxy, amido, aminte zwlcy bey; aikoxycarbonyt or aosmido, it is substteozd with one or more of alkyf, uieronikyl, aikersyi, alkynyl, veoMkyi he -ooyeidakyt aryt, hem , aikoxy, anido, amino, aey, acyloxy akonytmrbonyi slnamido, halo, cyano, hydroxy or nitm, each of which siky, heaemalkyi enyt, alkynytl i5 cyck salkyl, heteracycolaky .,asyl. heermryl, aoy, amido, mamim, sacyl, aceylsxy, aytarbonyl or eulfonmio niy itself be .subsdhated. (013] o ome embodiment, Rt is bycdrogen, unsbstitmtd R: substituted skyt (inlsdinsg but not limited to uMubstAted or substited CrtIkyl), in some embodiments, R7 is unsukstituted or substitute akny idteluding but not limited to unabstitoted or substituted CrCkenyi i some exmdimet, R t> is substitute or substied 20 akynyi including but not limited to unshsnuted Or subrtted CrCmikynyl In some eWn3bSdimen, is unsubstiuted or substiuted cycimikyl including but not limhed to unsubsituted or substituted C teyeioaikyhiEn sonme msodimentss R is unsub witod 3 sbstiuted leaeeychdkyi in some embhod iments, Rs unsobstuted or substituted heteroaikyt indudting but not lxmhtd to unsubsticuted or ssubsmtuced CrCetenkyt. In some embosdiments. i> is unsubsituted or substiued askoxy including m not limited o unsubstiaued or sub i ted, CX 25 Calkoxy. In some emnbodintrs, R; is unsubstiuted or substituted amido isluding bat bma limited w cubst sed or substituted C'nmido, in some emibodimen Ris unsubstitutsa or subsituted amino. I some emnbodiWmts, Rs unsubstuted or substiatted acy, unsub!sitted. or substted ayi'oxy, unsubstated or substituted Cr-Zacytoxy, unsubstkrured or substtted elkosyyerbony, usubstituted or substtted sdifonmido, or unsubstaud or substituted

C

5 'Casulfoamido someembduments, R is hale, wch is -IF. C or r, i some embodiments, R" is sected 30 i rm the groupconusniig of tyO, ydtoxy, and nitro, in some other enoisenns R' Is - C CIi opropyi isopropyl, 'CC I, OIOtCH> or -CF, ~OtliA] in some embodiments, when K 5 is alkyt aikenyt alkynyt eyeloalkyl, heterealkyl, aeyi, niksy. amido, amnino, acy.ioxy, sdkoxycarbonyi or sulfonamido, R t s optoindly ,substiid wih one or more ofukyl heseokyl sskemyi aikynyl, cydoslkyt, heterocydoalkytl ary, heterory ;koxy mens aid minor, acy, aeyloxy, aikoxyearbony, 35 sulfonamide th, cywuno, hydroxy or nitro, each of which allyt heteroalkyl alkenylakyny, cycloelkyl htemxocyloakyt. ary h, eeroary ko y., anido. minio, etA, acyloxy, 3kxym y or sultkmamido may f lbe substituted. [0 in1 sonme embodiments, R is hydrogen, unsubstiuted or substied alkyl (including but not limited to unsubstitued or substituted Cr-QCikyi),. in somseemnbodiments, RWit unt'subuuttuted or substiuted elkenyl including~ 40 but not mied to msub rtuted or substituted C>C4konyl. ih some embodimens, Ri isnosubtauted or substitad elkynyt incdudigm but not limited to unsutbtted or substituted Crw vik . In so emodimnt, RC is unsubttuted or substitute cycloakyl including but not limited to unsubstuted Or substitted CrCOcyclodky. .n

-ML-.

xne emodiment. t is u nsubstituted or substituted heter cyd nkyi fi sZa e emsb dhinmets, R is sianu ited or whiuwtrd hetroakydlu idwIuring bai not Stetad to WStbstitt or subsatitumd Cr('heakyl fn mme embdinau. R is undusited or iubstued akoxy incuding but nut imned unsubstituted or substate(d Cr Cttdkoxy. In some bodies is unsuited or substimted mide induding bu not imitd to ut ubstted o substituted CCamidos In sens emb dime. RC isubsteuted or subsdiuted a In. nOm embodiments, W is unSI5ttutedOs- $ib53.ts or ted ayvl. bs51te m tstitt3d acyoy, umsubstmed or substituted CrCgey.oy, nb~stitufl or suabstui koxycebonyi, unsubstitued or susited sulifonamid, or usa d or sb touted

C-C

4 sulifbam-nido, in som-ne nmbodim ts R is halo. W hich is -4 C -F,, or -He, In sme embodimer R is selected from the group consisting Ofeysno, hydroxy, and nit-o. In some ether embadinants R is -CJ 42CTa tpropyt, 0 iop-py -0C0)C 3 , 40C0i-IsCH, or -CF. [1V3186' In 'ome embodiments, when R' is aikylk alka:yf, 3ikynyl. cydloolkytl heteroalkyl yl, slkoxy, amido. armino, t yex- alkoxyearbony or salfonmio, cs optionally substituted with nt or m of k hetrodikyl, skeryl 4 kynyI, eydedkyhetoeycalky, ry heteroary. akoxy, amido, amino, aswyi, acyloxy, Akosyearbonyl, suifonamdo, hak, cyano, hydoxsy a itro, each of which .aiky, heteralkyl, aikesy, alkyny4 eyedoaikyl, 15 heteraiCydnaikyl, aryl heteroaryl, stkoxy, amide, aune.aayi, acytorey, alkozyear bnyi. or sufWaamjsnido masy itselfbe substituted. bu nt imte t usasttuedorsusttue Crnsststayt Insm mixset R susustte ra tue 20 z $lkyny ind uinge neoilmed. ti hsubstituted or subtttueadCryl ky'nyt vn bsome utmb otent Ri unsubstituted or bstiuted Cy y inudg but nodkim 1to' ionbs 4 uted or substituted C,-seyc dkin wmt nmobodienst Ru nsbsis uned rsubsttauted rXkfltedte ty ytblasnmt mis n i substituted o 0 stikry inlem uding but nifint t ot limited to substitute or ssltuted Ck some ernbedIn. s mbsdimen s, s orbte d or substituted Wkosy indding but sot bi o imu Itr tsustitted oor skstitutd Crn 25 C 4 -alkxy- In some en2bodiments R 2 unsubitsstedt or sidaituted amido in iding but not Ii stiited to unsubstiued or swbstmated Cr tanids.. esme embodlnrs R? is unsusituted or substituted amino, In sc-mo emtbodments, IC is unsubstatuted or substituted aeyl, esuuted -or sstituted acytexy, umsubstaiuted or substitued CrCseyiouy untsubstituted or substituted sd koyrbon, unssbstitused or substuted sdfo-aride, Or unsubstituted or substitted C siu mido I n somtie emsbodimnent i is h uo, which is -. F -, or ABr in senme ebobdimnts it' is sdected $ from the goup consising of cyo, hydroy, and nitro. i some oater embodiimen, .? is -C13CiC upopyl isopaspv-OC, 5

-OCH

2 C -CF [I1 $0 In soene m.'rbodimnj'tont when R. is CkyL slkeny alynyi yckkalky!o acyij alkoxy, anide, amine, acyloxy, aikoxysrsbontyitsr suifssamido, Rt is optionaly subtituted w-ih one or mre of iiky. heteroalky-l alkenyl, alkynyl, eyeloakylheeydiikykaryl, hetermary, aikoxy, amid, amine. afyi, asyltay, alkcosyearbssny, 35 sufeamnido, dae, cyano, hydroAy or nitro, eact of wh Mikyl hreemay, adkmyl. skynyl eyeiedkyd heteruycklky sryi, heteroary Mak*y, aside. arnir n esy ac0ylloxy, afloxycarbonyt er suifo nmido miuy itself be substituted p4J189) In sene ombodinsenas RC is hydrogen, unstbstituted or substtuted iskyl (ineludinge but not Himhed to nsubstswd or C,'C4Mxyb- i seine trtsimwen , is stiuted or substtAted akenyl including 4?) but not limited to ussubtiuted or stbsti ted CrCsskoryt. ins some unittodi neoan t 5 is asubstited or sutbstituted aikyny including but not limited t unabsttuted or u bstituted CrCaidkynyl. n-.: some embodiment ROs Zi urssbstituted or substitted cycloikyl indug but nt limited to tmsubsdtsted or substitted CICIIydedkyt In

-

some embodiments, R* is unsubsitued or Subst0ued heterocy dekyt in some embodiments, R uisubsdtkuted or subs irted betemelkyI indading but Sot listed to ubstiuted or substituted Cg hetros kSIL in some embodiment, Rt is unsubstituted or subsfituted alkoxy inauding bu not :iied to nsubsttted or substituted C> Cikoxy, It sorme embodimena R s unsubstiued or smstituted amTido irtduding but not flmited to u substituted or $ substituted Cr& 4 anido, in somte ~eo Iet R is usubstituted or substituted asmme, In somm embodirments It* is unsubstitued or subStiued aeyi tnsubstituted or substted asyloxy, tsubstituted or substituted CuCmsoyloxy unsubstituted or substituted eikoxyoarbonyi. unssbstitutcd or mbstituted sif}namido, or ti ibstituted or substitted Crauffonsnido. I soni eddnens R* is d, which is4, -F, crt -Br.n some embodRenta R* is sdected fm the poup consisting of eyano, hydoxy, and nitro. i ome other embodimeets, R* is -Ci.C} 2 C14 n-propy 10 isopropyl, ocH-,KO lcS b. or -CFur 0.1" In some embodiments, wte R,", is alkyl, kenA lkynyb cycloalkyl, heteroaikyi, acyl, akoxy, a mido, amsino, acyoxy, alkoxycarbonyi or sulfonamido, W is optionaly substituted vit one or more of iky, heterolky alkenyl, alkyyt cydciukt hekcyclalkyi, si, hlmyl. tafkoxy, amtido, ain, acy. aytoxy alkoxyearbony suikncmrdo. halo, cyarso, hydrox~y or nits> each of which alkyl heses-deky askentyl, akynyl cycdoalkzyi 15 hteoyckslkyi eA, hetarryl, alkoxy, anlido, amino, acyt, aeTomy, aikoxycarbony. or sfonarmido m :aeif be substitute. [0191 In some enmdiments RI ,Ittd . e i t10192) In soam em bodi ments, X is absent some embodiments, X ;s -(CHt and 7 is an integer of I, . 3 or 4. ( min 3 in soe embodsmels, -W is uinsubstitusted or suetumed alkyi inuldinig Wt not ued to unsubstatited or 20 substituted CrAvsskyl. I some enshodiaserss, ri s unsubstituted or shustiud cydoskyi incddng but nor brmied to unsuhsuted Or d CrIycloakyt in somtie ei'bdimentt s methyl or hy&ogen, In taeu embodimmts, R is unsubstitused or substtuted hie oey akva n ting bu nut brit4ud to e tsuituted or substituted C-qaeteoukyt. it some emodimsets, P2 is on bstitued~ or substituted heterosikyl inehsding bus not limited to unsbstused or sbtitted CrC;htwee yt 1 0{194] Whes R P is any of the above, in some embodimeats, X is -CHn 4'H 2 CHr CHCH 3 CICH(CH), or CN(C:CH)W a sorme embodiment 'whes X is ACH(Ct)- ACH(C$ is in n(g or (Rster.che il eenigumotis 195) In somc emabodirens of the compound of Formu l Y is absent in soaic rbdiresma, Y i: -0, -3S-, N-(=C S(=0)r, C(=0), -N4t)( s( -NtsiXC=0)IN hN(R)C ~2r (such as-N(f)Ciin speciitically 30 N(CHiCHr, N(CH(CHMdCHr or N( C2 \Cr) N'r *N(CH, N(C2tCH , or -N(C(C)f_. in somc embordimenste, Y is - l:-(CHCR)r ad z k, an oteger of 1, 2, or 4. 1001%] in some em42odimens, X- iC-l CHIN(CH3) CH(C }NI (S)-CH(CH §-NR or (It) -CH(CIHN)TH, in some embasdimnt X-Y s-N(C .CC N(C-H Y) Ct-, -'N(CH(CH}Cu, or -- NilCII [19371 in some mbodiments W 4 is a momber set-ed frn she group consisting of unsubotted or substituted 35 heterocycloaiukyi, unsusbstituted or substitute arm and ussttuted orsubstituted hetoceyd N some embodiments. W,3 is unisubstitmedi or subrs toted monnoeycle et Cr'iary or"'susttue or subst ed boicyclie heteroaryit n sonme embodiments, Wj is a icyici heteracryl havIng at keast one heeroatom. $,g a bscyeAie heerorytl having as least one tigo. ring stm,- ine me embodinews, W is a sCiycheetroati havingat least two hetertomiseg a bicycle beteoryl having qt kSt to nitgen dg atoms I c i; 5 embodinents, W, is a bieyCc heteroarvi having two 40 heter(a)ms th me which is connected to XY. n sre enodins W 5 is a bicyclic beterosyl having two n ren rng atmsi the. ring to which XY is connected na so em bodimentsW is a bicyclic heatroary; having f betroansa. g, a bicyclie hetarory hba-ag fom nitrogen agr atoms. i sme enboownents We is -32unsustuted or subsiented 4-aanincti -yo o(4-dprimidrI-yi, tns bsaed or stnae 7 unsubstitutd or subslitutd M or tnsuibts kted~ 0r subSittedO 6&inio-9&pi9-yI {$O19Sj In some embodnmnts W 4 is one of the foflowing: Ra N N <NH N RNH NFt N NN R" vheemin R' is hydrogen, ha, phosphate, urea cathone, adkyi, aiknyL alkyny, Cyckldkyl, haeroakyl, or a i H, Odky, halo, amino, amid. aydony, or aikoay, and Ris 2. adkyi, ya k-yryt ikenyi, ao ary), betwroaryt heteracycioalkyb, eydaodky. amino, carboxyi acid, £0 eikaxycazbonyi. or amnid&. [4I1993 in some ebahdsmenta da is: R*N k R& N N RII P0i2ZD0i in some embxdmet. W' is: N: N :N Ra Rl; 15 [jtn2i j In sorme embodimms, W is: N N 0Pf2.2t in some embodimnens, We is: ~O~Jinso-n ebohmns of WVe R* is a member selected {tm the group *~m.s'g't hy hoen bo, 20 phoxphae, us a carbon, onso bati ted or soubs ed lky. ususbstitueod or substituted aikenyt. onsobsdktutd or subsritited sdkynsyl tunssbstinted or subsaitured cyckelskyi, unsubstituted or substituted heterokyl, and onum iirdsted or sub rtd heterocydoaikyt e&2f4 : some emb diments of W 'when. R* is lkyli skynyU cyd~oaikyt hetersakyL or erxcydosky~ t is aubshwsd by phosphat, ma, or carbonate W20?5] l 5ome emodiments, R~ is a mnerber of tha ynoup comdstng of hydrogen. onsubsdtitctd or sdtated asIky{ and hiso, which indudes -1, FC, Cior -Br. In soim Rbdimeos, R is wobstituted oruhatiated anino, Surbstwd or subtutetd amido. hydrcxy* or unubsotituted or substted .ikoxyb i somn embdimms R" im phosphaie, unsttstituied or substituted saea, or carborste. 100 61 som embodi t when R" is Rmky'. asnime amrtido, hydoKy. or alkoxy it is sustied by phosphAte, ta, or mwrof e. 00K267i iM aon'e esnbomt.X W is o of thc foikwing mohetis: NN RU NNNNN R 1-yo N N \N N -,N N i . .I---N N HH NN Rt >N Rd \pN H N H- N N N %CAHe N ~N NN' H NN \MCN N tN HA .4 R 1 R H NN

N

2 r"\ NHN SN 4 -a p-1 N N N T N.N r N N 1% H N Pt H ~ 4

:N,.N

S NW OtNNH N= " Nn N NH NH HN NH N.N N N N RI? RR2 R HNA H HN, H: N

NH

4 ;, N

N

N. R1 lyN N NA N NN N N N N N -NHNH Cc -i H2N H 3 N N N . N -i N N k"42N N N N"N [M208) I.n ame mbnenaR s eme of the group coasm fby drogen, cyano, hll, usbttido k n rb dN R" is asubstuld o sustHe "Ali oeebdmns Di nustttdo usat eaey hc AN5 mkindes bud s nt limited to hetemsaryi having a 5 embered rig, heteroiryl having a Iix membred ring, heteroary with at last one , nmgn dang o 't htetroryl with two naogening 3toms, mnfanenyt btet-yI and bicy d ic hatessryL. some enb diets, R' is bt ruted a bstunted ht yoikyt which ine'des but is not limited to hteeycloalkyi wth oe nirogen ring atom, hetmeIkyI with one oxygen ring atom, R" is S heters'ocyloalkyl with me Sulfur ring stem. S membered hete yedoalkyl 6 maabaed hetomcycdoalkyt samated heeicycdaIkyl, unsaturated heterxydloalkyl, htayn(dsky having an unzstrmted moiety connected to the he6_cq"'ikyl ring heemoeydoalkyl nmstkuted by oxo, and heteocyeCkNkyl .subsitUled by two xa in some embhodnimus, IRt is ktebutstilked or satnitmeAd Iyelday7 t, including bit not limited to cdpropy. cyclobutyt cypty, cycioh-xyt ceoalkyl substauted by ote oxo, cyrdomlkyt having mn usaturated moiety comected to the 10 cydeolkyl ring, In some embodint, Rf is soibstituted or sbststed amido, cartboxylic ad, on stioeed or isubststuted aeyay, or unnstituted or' substituted alkoxycabonylt (l209] In some embodimenks. when R is alkyt, akyny, slkeny aryl, heleoryk hetsmoeydelokyl, or eyclo4kyti is subtaiuted with phosphate, in some embodiment, when R2 is alkyl. akynyl enyl, ary, hetemry hetmeyokkyt, or cydIoatIky its sbtitted with m' In some embodiments, whno R" is sky akynyk amkenyl, IS aryd k h ete CteA'yeiodlkIyt, orcydlky L it is sabstiated wiah abonae M21O] In soi:ai mbnodimeemr, when RI is alkyl, akynyt stkenyt, aryl, haacoary, hey eydlokyi, cyclodkyl akuabonyI amido or acylo:y, t is subsatuted whah onse r more of 4kyl, hekroslkyi, AIskzyl, Mkynyi, cydlkyl hetemzydeikyt aryL hfnmoemmray alkoxy, anido, amino, acyl azytoxy, sikoxyzronyh sufoamid ado, cyano, hydroxy or nisr, eah of which Wkye heteroalkyL. alkenyl, sikynyi, cycdoskyl, hetaeycloakyt, aryl, 20 heery, koxy addonin, acy, acyloxy, alkoxycarbonyl, or suIfonamido may if'&aubsitsted 1012111l In e emnbodimens, iR of W4 is une ofJ he'OliOwingmedeties OH &N yy - 6" K N 'N.

.O .- .~- .N .

< OC 4e HN >NN N N- 4 ^' N AN.S~ N, -- - :N. H HH H H NC O. N-b. I ' Th O-IJ 'Y' 1 N J ' N N RN

N:

whretri R" is B, alk'yi. halo, ami arsid. hyd y. or akvxy and R is H, slkyi, &yniyt. alkenytl halo, ayk heteronvyl, ha ceyvalkyl, or cycklakyl. In some embdimaaaR is maino and R ) a lkyiaky yI, Wkey hake aryi hsernaryi heteon'c daaly or Iydnnayy ha samne modmenw, 3" is amino and R is atkyl, halo aryi, 5 hetmry hl eyck dky1 or cycloaikyl In some embodimtn R is amiao and R" is monocycic r some emnbodimens R" i amino and R is bkcydic hataoaryL in Wow mbima R is amino and R" is cyama amino. carboxylic riiacoxy, aikxvycabt ormd 021t in sore embodinar. the compcisnd of ForMla I is a cmsansrd which has a structare sdckted from ft grupnsising ofFonnda A 1-3, 2-A 21B. IV, V, VA V, VI-A, VI-B, VT-C C 6-C2, V Dand D: N WW NJ w w x y Y Fwrda'AFomu B Frmda 2-AFer TRR - FaR fl ~ YIN V Pmc 15 Fvrmd a IV Fomda V Formi WA z 13 H R WN V! rmuVFrma VIA Vormu a 6-Ak -38 Nt W1t1 R$R R; N N 'Nr tHN H NN>"H RR N -H HH H R7 S Frmk C2Firmua VI-D Formula 6-D In mte moiet te compund of Fami sa compaund'. Which has a stutr eetdfr om hwe gmutp coinsistng of Frmiia Vlll 7A, YIN VHM A, and !&A: R 0 HRH N -N-' U-1k XX Rz H NH nFa crrma VF- VWi;A 7.AFn Vl S-A R' RA N N

N

0 Wc:W FormulaPV' -AIPr xrd -AI I [:00214] A ny of the di-sdetoad elomlm 'and er sbtilt for the copand f FRmua ta a m sd in any (M215) inD one aspcnt fo-m pond of FormulWa , V V,$ VI, VH or V111, RI. ii H, Cll , CFj, C4, F , )r r 15 alelet Bi myl "r a voel of Formul RI; l ~-39-

R

1 (R 2 )q Formula II wherein Wc is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl; R' is H, -F, -Cl, -CN, -CH 3 , isopropyl, -CF 3 , -OCH 3 , nitro, or phosphate; R 2 is halo, hydroxy, cyano, nitro, or phosphate; q 5 is an integer of 0, 1, 2, 3, or 4; R', R', R7, and R' are H; X is absent or (CH 2 )z; z is 1; Y is absent , -N(R')-, or -N(R 9 ) CH(R 9 )-; R 9 is hydrogen, C 1 -Cioalkyl, C 3

-C

7 cycloalkyl, or C 2 C 1 oheteroalkyl; and Wd is pyrazolopyrimidine or purine. [00216] Disclosed herein are compounds of Formula I, IV, V, VI, VII, or VIII, where R 3 is H,

CH

3 , CF 3 , Cl, or F; B is alkyl or a moiety of Formula II which is aryl, heteroaryl, 10 heterocycloalkyl, or cycloalkyl; R' is H, -F, -Cl, -CN, -CH 3 , isopropyl, -CF 3 , -OCH 3 , nitro, or phosphate; R 2 is halo, hydroxy, cyano, nitro, or phosphate; q is 0, 1 or 2; R', R , R 7 , and R, are H; X is absent or (CH 2 )z; z is 1; Y is absent , -N(R 9 )-, or -N(R 9 ) CH(R 9 )-; R 9 is hydrogen, methyl, or ethyl; N N$ N R12 / NN N NH Wd is: R" or N ; R" is amino; and R is H, alkyl, alkynyl, alkenyl, 15 halo, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, cyano, amino, carboxylic acid, alkoxycarbonyl, or amido. [00217] Disclosed herein are of Formula I, IV, V, VI, VII, or VIII, where R 3 is H, CH 3 , CF 3 , Cl, or F; B is alkyl or a moiety of Formula II which is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl; R' is H, -F, -Cl, -CN, -CH 3 , isopropyl, -CF 3 , -OCH 3 , nitro, or phosphate; R 2 is halo, 20 hydroxy, cyano, nitro or phosphate; q is 0, 1 or 2; R 5 , R 6 , R 7 , and R' are H; X is (CH 2 )z; z is 1; N-N IN R12 N Y is absent and Wd is: R; R" is amino; and R 12 is H, alkyl, alkynyl, alkenyl, halo, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, cyano, amino, carboxylic acid, alkoxycarbonyl, or amido. 40 [00218] Disclosed herein are compounds of Formula I, IV, V, VI, VII, or VIII, where R 3 is H,

CH

3 , CF 3 , Cl, or F; B is alkyl or a moiety of Formula II, which is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl; R' is H, -F, -Cl, -CN, -CH 3 , isopropyl, -CF 3 , -OCH 3 , nitro, or phosphate; R 2 is halo, hydroxy, cyano, nitro, or phosphate; q is 0, 1 or 2; R', R', R 7 , and R' are 5 H; X is (CH 2 )z; z is 1; Y is-N(R 9 )-; R 9 is hydrogen, methyl, or ethyl; and Wd is N" \ N N H\ H [00219] Disclosed herein are compounds of Formula I, IV, V, VI, VII, or VIII, where R 3 is H,

CH

3 , CF 3 , Cl, or F; B is alkyl or a moiety of Formula II, which is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl; R' is H, -F, -Cl, -CN, -CH 3 , 40A imopi, -CP OCl nitrx or phosphate; Ris hak, hydoxy cyano nitro, or phosphate; q is 0, 1 or 2;, R R', NN a =d R* are H; Xis ahetr; Y isN(Rf CH(R)-; R is hydrogen, methyt or ethy(; AndH 'N 1002201 The invwenton aso pmvides a compound of FaknMua IX or its pharmaceutioaly accepable sat W0 W r Ay Wa FormrA IX, [0021! wheran W; d W am indrprndctly CR0 S, N, 'r NR d W is independently Cat S. N. o NR 4 wherein no more than two aacent ring aIoms are niun.get or suihirs ad when W is P one of W ad W 4 i N or NVi; [00222 W M is :CR, N, or NR2:o 10 [002231 B is alky. amino, betaroakyl, cyclfky] h e nyaikyti. or a moiety of F n ,3a ; R 100224 wherein Wis aryti h neternoayI, heereydoaikyl, or cyckalky, ad 100225D q is an integer of0, 1, 2, 3 or 4; H$ [002261 We L sent or is a heerocycledky, asryl or helesoary moiety; j00227j X is absent or is -(CH({R*)- and each instance oft independently is an integer of L 2 or 4; [002281 Yr is atseni 4 ~,~ -SC(0)v (4-)n 42-N -C(=O (CR-)-, C(=0)- N(Rh). C(=0) or NR) C(=0)lNN-yN( Rt)C(RY)- -C(=F(CHi~R).; 100219] R4 is hy-d8oge. ak- heterokyt akenyt alkysy cycaiky, heterocyclaiky ry aryaikyi heteroaryl, 20 heeroarylatkhdakoxy, aido, armin'o a.'i acylosy; a oxyeza tstl sulfotiaido, ~ ha o n, hyr dmxy, nitro, phosphate, oreat, or carbxonate; [00230] Ris akyl, heteroaiky. aerny, aikynyl, yccalkyt., beMrocyclaiky, ay, ary{dky heteoaryl .researytaIky. aikosy; otmido, amino, acyt. acytxy, etkoxyesrhonyl, sulfonasnio, hal", cyanes hyromxy, inro posphate, r'et orcar.o.1te; 25 [0023) R' is hydrogec cyidkyi, dkenylt lkyny cyc aky, heteYdraoalky, or Ce-Qhterokyl; 100232 FR RL and RV r independfently hytoger aky, alkenyl alkyrtyl, cydleskyt hecmrakyl. alkoay, arssido, arms-n, acy acyaxy, ad ozycarbonyl. risroido, Palo, eaan, hydmoxy or nitm; $03r each irmioce ofR*is independenly hydrogte Cr-C 1 aikyl. Cr~ccoiky, het-erooyolodk 1 1, C Cs-hrteroaikyi. -41'- 10OZ4) Sbituents described for FRmia I ae equiIly applicabk to comn urds of For nisla IX, except far WA' wA WA and WV whib are defined as folows: 00Z351 In some csbodiments, W.,, is Ct. S, N, or NRw 02361 n mmse embodimets, Wis ck S, N, or NR4 5 [0131 in some embodime W is R., , 1 r N, R [010381 In some embdimmis , W is CR8 N, or Ni 10291 fn sonm embodiment, the pomix d of Fornua ix has a sruetr which i a member of the gmxrp cnsisdag of:( ,' W NR% Wj i CR W 4 is CR% and Wj is CRK; ('V is NR W is CR W is Ci "d ccmsiat~~~~~m 'is W,' is NW W, in! C, W,4is n WQ is CHR*; (W)WA' is NR W is Ca W is CR and Wj isN;(P) W isNR W CR W is CR ad m W is NO (v') W is NRt W" is N, W is CR7, and wi is CR; i W is N W, n N W Es CR7 md WV is CHR0;(vi)W W N W iN N W N, WAis4CR adW is N u ) W, is NR", WJ is N, W1' isC endW i,2 s NRt> (ix) W is N w iss CR W, N N, and W' is C;() W is NR, W is C W, is N, d W is CH&' (xi) W!is NR wi Ca W is N, and WV is N; (xi) W is Ni W? s CR> W is N nd wt is NRt; (xal) w. is S,W is I N, arc W is CR* (i' ) Wu is S, W' is CR W N end W is CHR; (x) N 's ' W is 55 CR W i's N, ed WQ s N; (xv?) W. is' k WN N Ct W. i's N, s W '\\ NRi (in WN ia N, w sCR WW is Sead WA' ist CR; ( ) W Vi, W is CR' W i S, ad W is CHR1 () W isN NW iCR is a, sd WC is N; ni WC isN N W sCR W' is S, and W iN (xITW isCR W is N , Wz iS , m! n W i (x? Ws, CR W s N , Wg is ,a is " CV ; ( ) W!i h Wa V eyW is S, and WV bis N' (a0) W W is R W N Wis ad W is NR ; nW; is S, jsNW sC8I and W a NCRi (Uxv) W is 5,RW 20 io N W is CRt and? W Y is CHli (n") WV I , W< is N, , is CR ed W s N; (xni NW' i S, W N , W is CR I is Ni (ys's W i WJ is N W is NR ad sW is CR (xxx) W i Caid Ws is N, WA i's NW, and is Cki 5 ') W s CI , is h 1 WS NNt ;d (5 hN Wt huh is CRW is N, W? Is NRj and W5 is NR xxxi W is C2 i K, W! s is S. and WJ is CHR (m#4) W2 I CQi W is CRI W? is S, nd W is C; (xxx??) WN ' is CR'W is CW> N is S, end WJ is N, arid (xxxv) W is CR> W2 is CR, Wi is S, 25 and W is NRS. 10240 In some embodiment, ' s a member of the group consisting of hydrogen, unsubsautesd or substituted eyl, unssubstituted or subsdtuted akyl which incides btmi a not limited to unsubstted or substituted C CO:ikyi, unsui~bsthut3 or substituted alikey! which includes but is not limed to CCikenyl, irushtuted or substitute krynys which indades bus is not ilmeited to CCsaTiyS aSubSdtited or stitu-ted cyd:osiky whiah incuaes but ;s 30 not iimied to C r4ycikyi unsbsued or substuted heterocyckakyl sa asobstad or substiucd heteramkyI which includes but is not limitS, to onsustar-tused! or bstid CC rrolkyk 1002411 i sme embodiments5 when Rti w a yb. akkenyl, akyny. oydl.kyi heterocydo'kyl or betrwiky a is substilued with um Or moe ofakyi hoeroikyi, ikenyt akynyl, Eycbalky, hsterocydoakyl ey heteroaryl, Akoxy, amidsm a l x mIO, h .- an, hydoxy or nitro, each of which akyi heeroakyi 15 a kenyt, ayy lcc h erocv akyi, sryi heterryt a s n', arnido, arino acyt, -acyioxuy, or suifonanido maSSy 553lf be substted 100242 In sone ebodiments, the comupsnd of Formau ix is a copoirnd which has a stimture selected from the p cosiistng of tRmda X, XI, Xu i and XlV: -42~ R 4 O NB s B R5 N N N N B Wd Wd Wd Formula X Formula XI Formula XII

R

5 R N R N x Y Y Wd Wd . Formula XIII Formula XIV 5 [00243] Any of the disclosed elements and their substituents for the compounds of Formula IX can be used in any combination. [00244] Disclosed herein are compounds of Formula IX, X, XI, XII, XIII or XIV, where B is alkyl or a moiety of Formula II;

R

1 I Iw 10 Formula II wherein Wc is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl; R 1 is H, -F, -Cl, -CN, -CH 3 , isopropyl, -CF 3 , -OCH 3 , nitro, or phosphate; R 2 is halo, hydroxy, cyano, nitro, or phosphate; q is an integer of 0, 1, 2, 3, or 4; R 4 , Re, R 7 , and R are H or methyl; X is absent or (CH 2 )z; z is 1; Y is absent , -N(R 9 )-, or -N(R 9 ) CH(R 9 )-; R 9 is hydrogen, C 1 -Cioalkyl, C 3 -Cycycloalkyl, or C 2 15 C 1 oheteroalkyl; and W is pyrazolopyrimidine or purine. [00245] Disclosed herein are compounds of Formula IX, X, XI, XII, XIII or XIV, where B is alkyl or a moiety of Formula II wherein Wc is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl;

R

1 is H, -F, -Cl, -CN, -CH 3 , isopropyl, -CF 3 , -OCH 3 , nitro, or phosphate; R 2 is halo, hydroxy, cyano, nitro, or phosphate; q is an integer of 0, 1, 2, 3, or 4; R 4 , R 5 , and R 7 are H or methyl; R 8 20 is H; X is absent or (CH 2 )z; z is 1; Y is absent or -N(R 9 )-; R 9 is hydrogen, methyl, or ethyl; 43 N NNHN N R 12 / NN N N\H Wd is: R" or N ; R" is amino; and R is H, alkyl, alkynyl, alkenyl, halo, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, cyano, amino, carboxylic acid, alkoxycarbonyl, or amido. [00246] Disclosed herein are compounds of Formula IX, X, XI, XII, XIII or XIV, where B is a 5 moiety of Formula II wherein Wc is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl; R' is H, F, -Cl, -CN, -CH 3 , isopropyl, -CF 3 , -OCH 3 ,or nitro; R 2 is halo, hydroxy, cyano, or nitro; q is 0, 1 or 2; R4, R 5 , and R 7 are H or methyl; R 8 is H; X is (CH2)z; z is 1; Y is absent and Wd is: N-N I/ N R12 L N R" ; R" is amino; and R 12 is H, alkyl, alkynyl, alkenyl, halo, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl. 10 [00247] Disclosed herein are compounds of Formula IX, X, XI, XII, XIII or XIV, where B is alkyl or a moiety of Formula II wherein Wc is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, R' is H, -F, -Cl, -CN, -CH 3 , isopropyl, -CF 3 , -OCH 3 , nitro, or phosphate; R 2 is halo, hydroxy, cyano, nitro, or phosphate; q is 0, 1 or 2; R', R 5 , and R 7 are H or methyl; R 8 is H; X is (CH 2 )z; z IN R12 N is 1; Y is absent and Wd is: R; R" is amino; and R 1 2 is H, alkyl, alkynyl, alkenyl, 15 halo, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, cyano, amino, carboxylic acid, alkoxycarbonyl, or amido. [00248] Disclosed herein are compounds of Formula IX, X, XI, XII, XIII or XIV, where B is alkyl or a moiety of Formula II wherein Wc is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl; R' is H, -F, -Cl, -CN, -CH 3 , isopropyl, -CF 3 , -OCH 3 , nitro, or phosphate; R 2 is halo, hydroxy, 20 cyano, nitro, or phosphate; q is 0, 1 or 2; R4, R 5 , and R 7 are H or methyl; R 8 is H; X is (CH 2 )z; z 44 is 1; X is (CH 2 )z; z is 1; Y is-N(R 9 )-; R 9 is hydrogen, methyl, or ethyl; and Wd is N N N\ N H [00249] Disclosed herein are compounds of Formula IX, X, XI, XII, XIII or XIV, where B is alkyl or a moiety of Formula II wherein Wc is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, 5 R' is H, -F, -Cl, -CN, -CH 3 , isopropyl, -CF 3 , -OCH 3 , nitro, or phosphate; R 2 is halo, hydroxy, cyano, nitro, or phosphate; q is 0, 1 or 2; R 4, R5, and R 7 are H or methyl; R' is H; X is absent; N N N\ Y is -N(R 9 ) CH(R 9 )-; R 9 is hydrogen, methyl, or ethyl; Wd is: \-N H

R

3 0

R

3 0 Wa 2 N N.B Wa 2 N N-B Wa 1* W a 3 N Wa Wa4 H CH 2 Wa 4 CH2

R

8 H I a N-N

R

8 N--N R12 R12 N 'N

H

2 N H 2 N Formula 1-A Formula 1-B 10 [00250] Illustrative embodiments of Formula 1-A and Formula 1-B are provided, wherein R 3 is selected from any of H, Cl, F, or methyl; any of Wa 2 is elected from CH, N, C-CN, or C-OCH 3 ; any of Wa 3 is selected from CH, N, C-CF 3 , or C-CH 3 ; any of Wa 4 is selected from CH, N, or C

CF

3 ; any of R" S selected from H, Me, or Cl; any of B as described 44A ian 1S " an y 2f 1C2 csi 'h t Tam pu~'s of Eenrula [-Aand Lonptis [a 1ni col~xntair, any sbist peciiehd tindr W, \ s W ,RBW..d pecif et 'c rmerasc.id in kncy 1 fnit xt- bunk t tiare dawcrttte oh he e~ uondsf) Mtet invenitiom Scen additionala exeonplyemptsiso For etidasI-A 3nd [-B :3, L i-.in.e in Table, 5. no 1 u ajve R ofa coed hrveMy a stutr fForeula 1, IV. V, vt Vil, V111, IXX, Xt, XH, MQxII, 4-4b ...... . .U,-, ./ R94l N-S B- 14 81-15 N -------- N ...... . - 0 9 - 2 4 ®rh NtA rS se N. N,. D-28B-29B -3 N' . .......... ------------------------- '--- -. .. -45 - ------------- ------ - -------- ...... N1 1 ......... \'~~: N H 2 V '' h N N _ _ 0 0 A-N N. 4 B-4 NN B->49 N 0 S0N ANH2 R,,tN: '.N B-6 >B5 ANX .IN, N,~ _ N Nr NA~ NN Nh ---- -'N N -K N \ N ----------- n i3 N N_ lvi ________________-

-

-----

4-.->h~o lB N B-7 N N\ NN L N N... N\ . : .... ....... I..

1 .... ....... -- jz----------- ....... . .. . .. . .. .. . .- - --- - -- - -- - -_ - - -- -- - -- -- - -- -- - 11-83 -42CRI ..... ...... ..... IH 8-93N -~~~~ N------- --------- 11-9s B-91 _________ ~ ~ ~ ~ ~ ~ ------- -------- _____ ___________________ - - ------- - - ---- --------- - ........ Table 2 d~~'-3 <Npun huoa tWF, Uk GSLaJW ,1,V,"N O'XGVXA w -S4 cla 9 12-4 -li,01 12-x t~~k - -: - ' ----- - - - - - -- ItB ~ ~ 12 i , # NN 121 __ _ 1?12 2 NNli-N I -'N 12-2 N H :24 U -3 4 ...........

1t - ------- N -2 2 ------ -~ ------------------------------ -------... ..... 12-'M& jF ............ .......................... ------- --- I 'I " " < " K .4: ........... -------- 0H

------------

-~ -- - - -- -- - M47 <1 0 N: N ~N H: H p-N 8H 2 N M HNN HN HN OHN: NH H

-------------

OH Z 4 ' NC H NC O :N H l22 2 2 HN NHMQ 12 ft2 243 124 HN 0: 0 H dHH HN F

N

HNN 1 '1411411-N NN NN H H; ___ __ __ __ N\ SN N NH2 H [00251 l1s0 ie I ma odimoetts of Fikntoba 2-A and Formula 2-B ate provided, whenn R is electedd 1km my of H, C. F or moyk any of Wj is elected from CH., N CN, or C O(Ci; my of W i seed from CH1, N, C 3x or &Cki any of W is seeded fmom CH., N, or CFr myr of R, :iected from flH Me, or Cix ax':y of B as decrix 5 in Table i; any of as described in TbIle 2, aid ay of X-Y-W as described in Tale3. The compuends of Fork2-A ssd 1rmula 2-B 'an contain any suitantsesfied under ?, NV7 W ,/ , Ri ., R ad X-Y Wd. The specific embmodments described in no way limit rhe ventio, but are descripive of the oaamanp dti of teb hwvio~nxm additionatJ exemplay condo f Formihs 2-A and 2-D =r illustrated in Tabl: 5 3 O R3N Y Ra 0 10 ork s -A F orrmua 2 T4able3 ixem r X-Y-We for a compousnd hxaving a aiuoturre of Formua I IV, V. VI Vii, VIII, IX, X, XL, XII, 4:0- XY Sob- X X-YW 1 2 c3Cs N N N N_____R_ 4 C Nr- Cs C % N V-v .. .... ..

.. .... ..-~C j --------- C N RR H2N 1 N>N N 1N N -A HN ---- 15 - N M N RaV' N NN H N --- ~~ ~ ~ -- - - - - -.. . HN -- N N R N RR N N N N N N NH N N RN " 12 R

.N

25 C26 27Ca -H N N N \N N 3 , CHa 32C33 NN N Nr~

H

2 N H2N .........T -t--- ---------------------------- _ -- 4 C3 R NC N 3 N NN N N . .. ... .. .. ... ... N .. ... ... .. N A HHN 40 0 J 0 N N N R ----- ----- --- N~ 3CiN Et 45 N R 8 N N HN, .N JR ITI / N \H N N N H HN N H N 'HN N-H N N N - NN NH N 4' K-42 NN N N HH NN H 6N N N ,- A -H---------__ __ _ __ __ N < NH ________ 0022 HuStrfieve embodimYenNt of Formu~k A vre provdd where r Ri is selected frm ay of 1, C F r mt byi any of B as in TW Ie :, d any of Rs a dMbe in MTWe 2. Th cmpnds of Rmuk 6-A can coauin any substitts sp'fied under I H and R he speick emtodiments descriTbed in no way jlmit the Sitweao but o desriptiv of ft cmp of the invetorVh sonm additional exempury com ds ofFemula 6-A are sInetr t b N R N Fommia 6-A 102$31 1ustrative em-bodimemsq o iua 6-C I mu proqwded, whereins T is sel ected from Oi y of 11, C, Ffsr deibd nTaa .Th cm Oof Formia cc CI ma in aysskuns sphdidrR B RP 4d R ' Th pcn le esdm bi no Way lima he invende but resrptv f the ropmso h in veion,- Some addienW exeCfmphr mpond of.Formutn 6-C 1 are iluStrated in Table 5 Fit HH NN N HH N5 '-- [0214) Eustive embrt dimenss of Forrlua &C2 are provided, whoerna e is selected &fm any of H, C P, or rmethy; ay of B a -described in Tb I and say of R , which is sdtW from - 4Ch, or - 2 CI The compounds of [ormuola 6-C2 can cma any abstiumans specilled under Rb , and Rt The specific enbodiments Sdescribed in no asy limit he unv ion, but am dzriptive of the compounds of 0-e ineeni Some addition exemplary compounds of Rormutas &C2 are lusted in Table 5. H A HI H NR N \N Formul-a6C2 1O)2S] i!hrsrrative emorhdhnents of Formn-ni l ar provided, wherein -R, is seleedl ferm any of R> CE , or 1) methl; any of B as described in Ta ble I; and any of R' , which is sekieted fos-4 -Cf6, or -CHtCl - The coImonds of -rma 64-e) can Conasin any btuernts spe\ied nde R i and Rt The specific emdients in no way imeft ho invention, but are decrspive of the compuAind ofNthe invennon, some addhirinal e-emplary cmpounds of rknmulas 6D are lsEted in Tbe 5 1-1A AN AW I -N 15 Formnula (D. GD (6096)Ilustatve embedirnens of Pormola VI' anr'wp-vied, whremnt -a eetct from any of CX F, or metbyl; any of Wa 5 iselctaed from CH, N, C-CN, or C-0C z any of WC is seleckd iro C , -CE%,or C-CHi; any of W ls sdected fro C C, N, orC-CF 3 ; any of Bas dmernhedin Tablet; any of R described in Table 2, and any of' X-Yt-We as described in Table 3. The compounds of Formulda VEI can e-ontssin ony substituents specified under 20) Rt WAVW , W , Rt and X-Y-W. The speculernbodiments described in no way imit the mnvenio, but are deseripave of the cenpounds of' the invention. Seome additional exmptasy compounds of Pormua VIl am illuiisted in Tae 5 R O W2 N

Y,

rPormg4ul VI [kN2S71 Also provided are compods of submacture Formaise 9A-93D under generic structre Formula X., wherin R4 is Seeted frm -4, mehy, ethyl njpopyl, qo-ropy. cydoppy cydobuty, ad cylopo nyl; ay of SR? is seletedse from H, Cl, F, methyl or ri forrmhy; any of F is selieed frm 1H, Ci, F, met$yi oifluomeclgi; oyane , hydroyfL ethyl spropyl and cyclopropyl; any of R* is aezeled from H, methyl or ionpropy; an of B as described in Table 3; any of X-Y- ;k detibed Wfla e 3 and any of R? as described in Tale 2 The compounds of Frmulae 9A,9BD mn contain any ubstitruens spefied under R 4 , Ri' RF R , X -W and R' The specific embodinems descnbed in no way limai the invent but 55afe dei ti e comrrpoands of the inveN tn. Some 10 additiord exompary compounds of F -ulae 9-A to 9-11) are illustrated in TabNe 5. RRRd N ZNN N N N o rm nwl 9-G For mul 9 HFomla9 \\ Ni V ON N 'N N X XX R&rmi 94 I 'nul'a''I rFrm 4 uf 9-K rmda 9 4 4 53. tt 7j '44 va Ha S9 1 on'l ) Fnwi 9-L Y Fxda 94 M Forrada 9 N Forua 9 O R R We W R - N RR Fo1 9 S o19 Prd N N R A R Rq RR Parmd 99 1 \ Pm t9 Fm 9 RA, R4 RI R R % vH 10 ra SY Forreu 9Zmu 99-A4 NN N Y V V I Y \ v \ 0 Fau T'V Vomn . 9-W Fms! 9-X NX IC) Eonwa NYssur Fwasn T 0

AA

0 0 R R1 F -mua 9 As Fomdla 9 4 AC Fonnu 9AD RR R, XX X R& & 6

-

R1 R, NI Re R a H 5V Fem9da 9 AM F 9 A Fcisdmi 9+ t, a Forami a 9 AK Fa a9 A L Formuia 9- AM N N VVWd W Foma,-u 9- AN Forn 9 Al Forda. 9-Ap 6 6 00 Emal9AQFo al9 RFema AS I x W4W Formdsa 9 ,AT Qnl 9 -A Fannu aI 9-AS NN Formui AW) )-r -AX 9Fmd a 9-A R" Y\ Fr a9AFenna 9BA 4 y Vd Frnoula 9B FIn)a 9-C Frna 94D [0 52 Din nsrala omouns ndde utarenc imue t te Mowng \ 3 -~ ~ 'N ~A N AN -. -~ LW N N '~ -~ ,'tN '% N NI N N N N N N N' '~N N ~ 'rN N N~' .4~ 4 ) H&i $NN N N NC Nt \' '1~ ~ KN HaN -> C C -' 0 ~ -~ N K -~-~ ' ,.A 'K ) V N 'V N N A ~k" t N'N \AA 1 N N~ N N N 44 N N 4 N N>N NY~N N>~ N>~ N tiN '>4 ~ l-bN 4 N ItN ~ AN N 4 ~k4N~s'>N N y't.-' N 0 44 0 ' 'N 'x6~'~N~s~ . N -' 4 N K 44 N n~ N NW N N N VNN 44 '4 ~\ 44 PS N t t N- N HnN N-N A ct1Nt~ 0 0 N ~-k (4\ N ~ N N--A 4 N N'"' WNNI RN! " N~<x N NW HO wN r~t; -~' - ~N P kIN MN HO HO 4' N 2 N I-LW NI N YN 'N N -~ "'s N N 'N K&t -4 S 'N " > N N N N N ~ N 44 N N ~ F<N ~ <K k CN N01 \HN >H94 j'-*t\ NH# ' '4' ?4' 5 P -N C) hi> ' N Nj> '~ '4 NN 'I-' N~& N 1 4~ N~N N Nt N ~ -%'fl"~"N~ "' 41 pA~ A'. '~K2NV"N o ~ N'tI N:~ I ~Jw A'k\' ~ '. ~ I > *4' N N N F ~F '~ *4 / 'FS "'~ \ ~ MN / ii ~ \~ Md-( \ I'NN \~~NyA N F 4 'F NO 1444 ~ *444 a c 0 0 'V ~1 N, ~'. ~) N 'A ANNA N' K ~.'N'. N

'N~

9 t> N$V'N,, N ~' '."''~ N N'. N I N N Nu "F ~, a '~ / % / \,CN ~~fl' N-". 90*4 *40-N "~ *4 H H N N 0 C'N*4~ (3 ~ 'N N N" ""'N K N'. ~ N N NH 'At "-r ~ J"'t~A N *4 N

H

2 N ~ '.'. F ~' 4 o /N / N K * 0 'I *4*4 N / A *4 ~ H A'-' NMe 7'. ~ A'. r) I ~ N N It ~''. 'N K JN) N '~ > I NN :~ I ~' NV N '.~ N t' N ON I' 3~ F N F \N F , N ~" N 0'. N r \~FI ~, K' *N N ~ *444 kn y NN NN NMI HNI JOCI02591 The cemical eN described herdin Can be e aOne .,om Mo uravt shrns 5 hNrein and' tadsques wdl ktw, in 'te (0I260! Uniess, specified to the Comray, the remaiows describedlherei isake pice as atm -ospheric pre"me&p, gury within ai empe~ratue range from, 4 0 *C t00 *C' Ftnher, except es others spcfed eco od condinos e nnded to be .approxiMat, e Wtkingq plhe -a aboutamshri rse witinl a temperature range of abo t -10 'C wo abola 110 *C o.ver a pe:60d of Mbout I tO about 24 hours;, reactiox- left to nmp ovigh it average a 1 0 period of atxyt 16hur [N02611 The ttems '"oVent; 'Orga.nic 3so-Vent " er"i Wtsoven ac a \Olven.' inet under the o ton f the otin bg dscrbedin conjtAGi herewith inhigmexmpl ee/iee, Imcetonitruer, teivAydrfuran (-nMF diehlfommd dD~"),cbroform, mehylene dllcrvde (for d-bhk nmeth me), diethyl ther, ruethanztNmthlyreioe NP pyridie and thelike, Unkss spdfe t tecotry,te vns .1 lsed Ln the reactionsdscie hri are itnl organic -")vews, Uniessz specfIed to the contrary, fer ec;3h gram of he limhng mgen, one cc (sr .ML) Of sulvnt constitutv; a vehvrne equidek.nt (902621 Iselafts and puineation of the chmica enie ad imemedrowiates describedl herein cn be- effecte, if desired, by an y sahbespazon or purificadon provdure such x, a x forame fltiaxr, necydri coam chrmatoraph, deh33yu c hrom.&tograplhy or OFskee &noaorpy or cobinadon Ofthes,,e 20pa exmp a hrenbov Hwve, thr quait apaonorimatonprc 'm eNueb sd N k4 [O2631 When desired, te (tr)- and (Syisome of e rc os of the present invenion, if presemx may be resolved by methods known ' to ftse SkiWid in the axr for teamp by Formaden of diasterecnstmreric saks cf complexes which may be separated, for example., by crystal ktidext; via foemation of diasteoiseerie vaties Which may be %sparated, tar eampe by orystdiinro tgasiiquid or iiqadd chrasatgraphy; sete maidia af one 5 etidomrer with an emmoier-specific reagent, for enmpic esymati oxidaion or redthon. followed by separation af th modited and modified enariotes; or gasidiquidor iquidchromatognphy in a chi: avirnment, for exasnfph on a ehim: &uppot, sch as silica wie a bound chira higand or in the present of a chial solvent. Altematvdly, a5 speech enandnter may be synthesd by &sytmetric syntheses using qpticaty active reagents, substrates, osatalysets or advess a b:y converting one entandiomer to the other by asymmetric tamakn. 1(l [00264] The cnomnpon.td desribed herein. can be optonally contaced with a pharmaceudcaly ac acid to form the osponding acid addition sans. [$1265) Many of the optioaity substtated starting comprea ds and cshe ectas are csomerid ly avail abe eg from Aldrich Chemicsal Compny (Milwaukee Wi) or can be eadily prepared by those illed in the an uIsing commonly employed :sytthetic methodology 15 J00261 The compounds of the invnend- can generdily be synthesized by ar appropriate cobindion of genray weHI known synthed methods. Techniques tuseft in synthesinng the chemad entities are both readily apparent ad acessible to those of skill ir the relevant art, based an the instant disctoare. 1002671 The cmponds of te invention can be synhesized by an appropriate combination of known synthetic methods it thes an.' The discussion below is offered to illustrate certain of the iv e methods availabk for use in hi rmakng the compounds of the inven3on and is not intended to limit the scope of reactions or reasn squencesth-ISt can be used in paparig the compoBnds of the present i ovnt o. Redten Schtema 1 SCCN)COO At vanf o MacY NOMse Mac eOM HN Nt N 101 102 103 104 St 94 J R2I st e N NHH 165 106 0 AN 62, R ----- Q -- -- -- N N 10719 1 IdAaH jWs)h Referring to Schene StNe 1 keea 10 is ,averted to the conesponding akeoe osinn for eaa pk and piperidine in aetks aild The prd u, a compound of Frmu 10, is ilated Refering to Scheme 1, Step 2, aopotnd of Formula 102 i: cyieZd to a pyridin using, for examp , ammonia methnot The procdt, a comarpound of Fomsula 10, i.s isolated. Refeming to schne 1, Step 3, a compound of Formula 103 is 5 hydrolyzed to the cosresnxmding cathboxyiic ad. The pduct, a pmp d of formula 104, is isolate. Reening to Ah . Step 4, a compound of Fomnula 104 is converted to an amids uag, for example, a standard amide Uoupfig reagent, such as EDCL The product, a annpound of fPnus' 105, is isolated Reftiing to ee tep a cvmpound of Formuda 105 is converted to the conresponding aride usng for emmple, ehloroaetyl chloride. The product, a oormpoutnd of Formula 10, is isoied4 Refening to Scheme 1, Step 6, a compound of Forxrmda 106 is 10 converted vo a compound of Formula 107, using, for emampla, aanti acid The prodnet, a canpound of Formula 107 is isoated Refuring to Scheme 1, Step 7, a compound of Forrmula 107 undergoes a d aspianmenS a,,he chione when reacted with a nucleophih and a base, such as pyiopyrimidine 10' and potassum carbonate. The product, a compound of Formula 109, is isoled. Refering to Scheme , Step 8 i compound of Fommula 109 is opae with aw sty or heseroryl boronie acid or :or.c acid derive such a; for exarmpe, a horola un, for example 5 pladiume estalyaed coupling cndrtionk The product, a csmpound of Fonrmaa 110, is isolated Readios Sekben 2 EK.C R HD R 'N N Stan ~St RN Nr 1 21202 203 xo 204 205 100209 Referig to S m 2, Step i & compound of Formua 108 ir convened to a compound of Formula 22, rit examoe, via an akylation of a crcmpiund of Formula 201 The product, a cmpournd of tormah 202, i ischtei 20 Refenring to Scheme 2, Step 2, a compound of Forma 20 is convened to a compound of Fornma 203 for enple, via sap'nifleadc nte product, a compound of Fortaisa 201. is statei Referring to Scheme 2, Stop 3, a coportnd of formula 243 is cyci ed to .a quinazolne of formula fr to ap, via scaled tube reaction with a compound of Formmia 204 and a dehydraung agent such as PC The prodnt, a com:poundif of Formula .20%5 is isolated. Reaetikn Scheme 3 k 'M . N N "'"^" ""'"" $N ' N N NN 25109 0(*270) Refening to Scheme I a nmpound of Formul 109 is convened w a compound of Foria 30, for ce-ample, via a Songashira c-ioag'owith a conmpountd of Formula 30L The product, a compound of Formula 302, is isolated Reac ion Sthemne 4 X01 C43M R 3k 4020 NSr Ar Steo 64.A 401 YCZ' A1340 I 407 40$ 0271i Refarring to 4hense 4 , t kp , a ompuad of Fenmu 4 1 4 orrtd 10 a compnsond of Formula 43 fAr example via a two ste p proetsof Heck coupniig with a compaad of Fernla 402 ,fblowed b acid tlayzed 5 cylization in mehanol. The iwduct a comounsd of Fornma 403. is iokhed, Refring to Scheme 4. Sep 2, a compound of Foran'oa 43 is conveyed to a CWmpound Of Fonnada 404, ir exiamph, via racidon with an appropritely substtuted ani.3 n. The product,. a ammpound of ennuoah 464, is io..taal Referring 1o Schszmc 4, Step 3, a compound Fornula 4 0 4 is convened ;D a compound of Formud 4G5Luor example, though reduction with 14U.3 ahminum Iynidri The product, a Compsound ofFormula 405, i' lati fearing to Schme 4, Sep 4, a 10 compound of Formula 405 in convened to a compomd of Formua 406, rm exampI, vi; reaction wih Afihiy chloride. The product a compound of Foremia 406, is isolated' Referig to Scheme 4, Step 5 a compound of fcamia 406 is' convened to a comipound off ormua 407, fot example, via akylaton with a prmoopyrimidine 'sing a basc Such as Poeasium carbonate. The rdtr~d a cOmr'pand of farmna 407,s ated Referring to Schme 4, Sep: 6.,a compoamd of Frud 407 is convened tc a compound of Formnda 406 for example vi a Smui reaction. 15l The product, a 4orrnoud of Formda 400, is isolated. Radma Scheme I 4 XO CroCOCt > ~ COC1r G As 5012 504 4es d OH -64~5 At; R Ar er 507 [00272] Referr*g to Scheme 5. Suep t, a comprn pnd of Formla M1 is converted to a compound of mue $02, for example, with a reagent suitable for intr'duaion of a aid chtoride, for etxsmple, Exaiy) chtoride. The prdut, a 5 comnpouad of Fonana L0t i optiostily isohtted, Kefetiag to $cheme 5, Step 2, a compound of Pormula 502 is &onveted to a compound of Fon 1a 503 for exampteaction wkh for example aryn amine. . The poduct a compound of Fmula 50, h .ksote Reflrring to Schemte 5, Step 3, a compound of Formula SUM is osnvered to a caopond of Formme a504, fo~r example via a Stile coupiing using ant approprate Vieykdanatee The product, a compound o[ Forsnui 504, is isolatei& Referng to Schemr 5, Step 4. a cwnponttd &f Fnrmuta 5114 i conveted to at 10 tertiary amide, a compoundOl of Porm h SO-5, via react.ot with coroethyt acetate and sodium hydride base, The ceanpound of Forrrmula 505 ia isoed. Refrig to Scherm 5, Step 5, a camp ond of FormulQ 56 is oxidized to an alidehyde, wing, for example, osmium wreoxide and sodium periodinatec The product, a compound of Fomnu 05W o isoated. Rerrinp o Schem 5. Step Q, a compound of Formua 506 is, convert t0 ompouand of Formt la 404, far empia though a4loeaction in ot'oh a base, such as cesum carbonate. The prouc a ompond of 15 Fi-oolaa 404. ik isnated, RefrrnMg io Scheme I Sp compound of FV o-rul 404 k reduced to a prinazy alcohol ve reductin wi ,r exampi lithium aluminum hydide, to padEs-r a compmunxi of Formua 405. which is isltel Rfering to Schem. 5, Step 1R a compound of Formula 405 is convened so a :compuod of Fotrmta M7 via reactor with carbon tetrabromide and tripenylphophue The compound of Formula $07 iS optionyll oitdThis compound can be a ceralatermediate in the syihei of the cmpinds of the invention. 20 Reat 0sheme ~ 0 kuctt Ac Arusnsroc ai R 5 0 507 05 ' ann [WU0Z73 Rtteft'ning o Sche"" 6, St&ep T.cmpoodf potma a 507, symhesized as dearrihed in Reacdon %ceme 5 o converted to a corpund ot Formue~ 407 via couphia with a compound of F Iru N l11 in the p'mc ot ae, tor m-it, potassium t beoxide. The compxwnd of Formutkit 4107 n isolated, Refi-ing to Scheme 6, Step 2, a 25 compound of Formuea 407 iS converted to a compound of Formus 40$ vi coupling widh, for examnpk. en ary bonie acid, in ithe presence of cou:pling ieysts andt basfor emrpie palladium acetate tiphenylphosphne ad todiumn carbonate, for exasple- The compodx of Formut 40 is isolated. ~65 Remedon Scheme 7: R \ X NN N X NH X03 S N R 704 {tiIP74: Refkeringto Stheme 7~ Sep a comp d of ornidx 701 is reActedhwh a ompound of onrmalt 702 The produce a Compomd of Fwmna 703, is is ted. RefHng to Scheme 7, Step 2, a compound of Formua 703 is 5 reacted with-an optaiiy subskitued pri~ne &ch as a compound of Formula 7"4 The prodaut a. comuipoId of Formula 705 is isohsted. Reneo Scheme & RI N R ' N X R N C H N I P1t p k 2 geP RR R N N N R~ N hp o N x Pl H2s NO 801 80SOS-' 04'8 80i WI StepS I ~ "NCI Stp Fr ih s 2 Reseds Schssme 96 cooHt St1 .kCOQH Step 2 , Coc [S 104 901 902 &ei; Hl H Step 4 'Step 904 90596 Hft HH 0N 6 F t tp f ohhe 7 Step 3 907~ ii ArC All, y0ld761 Rcotndoing torna , wteh i colnted fenrag to ichemt 9 Step 4, he cmpond b off niorite 9h4 r 56 poaupsd ford xapes' wihd oilyl stn to p e a comlipitod of Form' 90, whi c an be lAe. Referrin to Scwe 9, Step I he t ompnd of Formula "i I. converted to its apid e"r by racon with, A e4mne, oay c rbe, ctain a ,o toywdd a2nd 9fJ 9 which can be is oeedd RRefinng 1 Mte 9, Step 3hee ac pd , compondB~se of Foo'da 9 6 is cciZe d rmh for epxoply tAoJ. d ium hy e 1sn'ti - d f , ex arnm ta compound o For n 7 ichsa %M, isd,Rfrn ioa Sem t Sep 7 'te 4, arcoyoxnd f heromun WMS 15 ocmk 947 8yms , coverted an they trodeb trame ao canple, wit eFom 91etrATSoid Ad trslihenylphine,1 eo d, oprodrm a snnane, o ttdoc a compWnd of For m, LS which is isokd, Rtf Serring to S 9 ep 9arn 90 is cpd yraoymdie r by 9 whic tamer exoame ih th posium carbnin d yorade to yie a opond o Ftr'ai9 whihi c d Rri o S Stepao 9, Step ns6 the IS Forminta 917a otetert h baoeid h! btrty ftn "rnple, with carbo tektl% bomide anditihnihwhs t 4 . mo a c 4repen o.f Fkormdla 13,vschr tlrd Roceering to Sch=eme 9, IS!tep 9S the aw p >merd of, Fcraul WS5 i.s cUple to pyradoopy) ra idiee of Formula I MA by tmcatncnt, R\- example, wsitUh pot asa33M, carbonates IT' ~e~ictv~omazirt, o yield a wn.roowid of Formula 9 which i soated. Referrlng wo &.hekrw 9, Ste4p 9, the dihydra'isequinofone of Formul 99 is coupd wih an optionly :wbstated aryl or hetaryl boarnic acid of Fnnu 2( 91 o oamprduacpoundti of Formul 91 wMich is soated, -67- Rq Rmsse im2 1 -0v ttrtSteal o~ Step___s N 110R RA 5 R 0 A.44 R R SW* 7 A su I R(R 10110 loll 5 M 97 7 K Rei to S -C h em11g 10 Stewp 1, a n:psu,n d ofX F avm u 1 1 6 1 i s areate d wvith d stum tatk a n acx mIetoe The podum, a compound of Formum 1002 iimitd Rd femg to Scheb x 10 St ep 2, a co mpun d of Fm W1a 102 icyadto the omsponding pyazok. for exnple, wit kh h ydrazi in -aetic aci'd an d wa t4 The M prod uc a epudofFrua 1003, is is'Ated Ref' erring to toheme a1I, Step 3, a copowud of IF1AIa 1, M3 iiaS for e~mnple, wkbe sing dimetyl &uffate. The3 pmdust, ai compound of Fa 104 is isot edttp. Refetung toa 10 Scheme 101 Step 4, a uompound-A of Formula 1.01 is nzirated using, fo' e mnple, a saiution of niideQ acid 4vnd dri cid' The p-odua co mpotedj of Pomla WS, a" 'wdated. Reening to Sche~m 1f,, StoQp 5, a copound olf FOrMula 195 iS Spon~ified UsIng ,a base suc as sodiumhdne The pvxduct, a Com.pou-nd of Frn 1 10%, iJs isdwated. Reenig to Schleme 10, Sktep 6, a vncom,.pound of Forma 1006 is first comened t.ow said Chlornde using funnyi chd-jmde then reacted with Lmn aprpityasimdain o c reat e e onespondingf amide. The 15p:dne u compound of Fond "a I '0% , in ed Refemimg Io ;Sherm 10, Stop 7, a Compound of Formd 1 A7 is redce totecrrsodngaiopyo sn hydrogenationcodidens w."K PZVC as Gawyst" T"he producla a OMpound Of Fomd 106S j satd efnn to Shm 0 St'rp 18 a aounud of Femmuik- NO8 is Myskd t "t coepnin unzsnn sinkgcondiim such ascimcty h wd d acdesid, TPhe prodwc, a c ompound "AofFora 106-9, is islaed. Reeigto Scheme 10, Step) 9, a compound of Fiamdia 1909 m coiuped 20 with a pyaooydigof Femsda 10, for i-MMP-1 using iondition sucth .s petassum e- butoxAidn eME at omtemperatum The prdc oundn of Femndla 10.10, SOIsdated Re ferring to Schemeu 90, Step 9 co Mmind OfFormufl 1010 is coupkd Wohtan ,ry bornic aid of Femmhwl of 90, frw eumpi, vsrg p"adiun aixtate ca3 4Ldpia in depree of taphen.3yt hophnean sedim catrbon in DMIF to pr oduecmpudo Pom"..316& .0 1 ,68 Reacedon Scemre 11: Step I S ,NHCOOPh R Rt $' NC35 R COO N- 110t RfCO 2 Et NMM 2 NH HCO~ ------- - Step 3 NIO~ Step 2 103 1104 1105 Step 4 R CGOEt Step 5 R 5 COOH Step 6 R COCI

N

3 NH2 N< NHa H 1110 NNH2 Ar SStep 8 Step 9 cN 0 . N RJR N. NN Nh Step 10 Ar cN

H

2 N 11.2 1114 1002781 Refering to Saheme 1, Step ,a cMpOnd of Formula 11(1 1 Meacted with polassim thsocyanide in acetonirii~e toproduve a compound ofFonmila 1190 which can be iced Referring to Schemo 11 Step 2, the comnpond of Fornama 1102 is reacted wi. a gated ester of Fonmua 1103, to ptodue a era poTnd of F-ormu 10 1104, which is5is * Rekin ~t sheme I Ieep the nompondof knnada t4 is cycacd, fkr eadepc.. by trig it with bromne in erhaneol to obtain a thiazoe of Formula 1105, which 'S isolved. Referrng to cheme 11, t4, the co-mp 4 Nd otC , a k1f Foru. 1105 " s deprotected with,for edxa m pC ta.iUM ca bate in aquetus dimethyIformamnik to yield a compound of'orida 11 06, whichbi isolatReferin t oeiiStep 5,the eter of the compound of Frui 1106 is sasified widh, for exmspie, sodmi hy~drde in water, to roduce the 15 compound oF rmula 107 which is isolated Rcferring to Scheme I1, Step 6, the free acid of the compond of ormu1'a I107 is conversed to the acid chionde by te&Aing it withOr exAmpc, thionyl cloide, to produce a compound of Fornula 110, which can t isotateid Referring to Schemse iH, Step I, the acid cloride of the compound of Formu1108 is raMated wth an optionaly Substitted arminyl aryt Or amin.teerOai q campmd of Formu:al 1109, to obtain a mporsnd of Fomramae 1110, whikh is isolated. Referring to Scherne .1 , Step S, the pisary 20 amine of the compound of Formula 110 i reacted witn a hahx'c l chiodo. for exopettcooacetscide in -69- Fyrid e and mnethyine chloride &w produce a compound of Form u 111 which id isolated. Referring to eeme 11. Step 9, the o of Foam a 111 is cyc zed by, for ropk. heati o a sealed tube in the pwtece of phosphdYchore toaiedacarrpnd of FOmWa A111, whisc is id Refering to SOheSme 1, Sp 10, the 1&al pyrimdone mpmud of Formula 1.2 r an pyaakappimidine of Formula i U in the preSenCo 5 of a base, for example p saium Itosoxide ins dimethyvforamide to produce a compound of Fonnada 1114. which is RPetio1 Shemc 12d P4 R a R NN

N

t HN ~ -N N N

H

2 NN R" 1210 1211 {0279| Ref rdng to Schemr 12, Step a compound of Formula 709 is alyhed with an optionay abstitated 10 prne of Formula 12W The product, compound ofForua 1211 is isoted. Reaction Scheme .13 RR

NH

2 INH N 1301 1302 1303 R" R" N: N Nr N s-kJ, ',-R*> A$eRp HN NH H N 1304 1305 [10280 Referring to Scheme 13. Step l a e tpound of Frmua 1301 is first convcrded to an acid chloride using Oayior1 chkride, then reacted sith an approprhiely substitled aIle The product, a comptsond of Formul 132, i s olatce Rferring to Scheme 13, Step 2, a conocund of Prnnh 02 is cycliedto tie corresponding htpri efo mpe wth ckrcetyi etoide in acetic ac ihe product, a "mrpound of Formula 1303, is satid Referring to Scheme i3, 5tep .3 a compound of Formula 1303 ks forteamk alkylated sing an appropriately substituted py'oo-pyrimidine, The product a compound of Formua 1304, isolated. RefeXRusg to Stzherm 13, Step 4, a compound of Fornuta 1304 is, for eampe, arytued usig an pproprately 20 suisstated boroni ad. The product a compound of Formula 1305, is slated Resetioa Sthtrni 14: R3 R= Sup S NH~loN '%4 0 1 406 P~i~i4CNSr- NWI - ------------ A C~ t 140 14UNH2 St4 S HHCe 1447 N N, 5 (002S1) Reerring'to Reraation Scheme 14 Stup 1, i8do ester 1401, is reactd wih aM alkyne 1402 in the presene of a packdium mislyt, copper iod end i ( )to couple the lke tikyeo the a&i core of 1441 to produce cOmpoSXnd of- Foan 43hma 1401 fRte rmpoudif rorrwoa 1403 is seatedd. Refrinig tRacton Schem 14 sep2 a compound of Formmoa 1403 is trcatd with potassium hydroxade base to obtain the oawbsryhc cid, a compound of Formula 144, i f the reaction product is acidified o its sat, The compouni of Fonnsle 1404 is isoiaed, Referhn to 10 Reacison Scheme 14, Step 3, a Pepaand of Formula 1404 is treated with bis (acetoitdiepdioropadium (H1) and TEA to eficet intrarokaular rag dosure to produce a compond ofForma 1405 The comouprs of Fofmuta 1405 is isoaed. Referring to Reaction Sc4ee 14, Step 4 a composed of Pomula 1404 xs reacted with a priory amine to produce a compound of Formn;nui 140C. The conpoord of Formula 1406 is isu) awd- Refrring to Retclidn Scheme 14, Step . a compound of Fornmca 1406 is teateds4xl o h acd mmoving the protecting group on itroge atnd V5 to tin a compound of Ponw k 1401. The compound of Formua 147 can be isotoed Referring to Reaction Scheme 14, Step 6, a c rtomtnd of IOmu U 14*7 i rested wit a -'mpenmd of Fomradia 140, to produce a compound of Formula 1409.. Th e co mpond of Frmula 14O09 i q tevL Reaofa isSeneme 15; R3

N

NN N T IM % 1H103 R3i iO R' Step 4 R" NH 2

RC

2

NH

2 1504150 W02S2) Refendog to Reaction Scheme 5, Step ido ester 1401 i a reactad with skyne 10 in the pence of pal adium cooping et'lyst, co pper iodide, and TEA, te obtlain a compound of Formula 1502. Th compound of Formula 1592 is isolated Referting t Reactio Scheme 15, Step 2, the sepuund of Fornu 10sctreted wnh S potasU m hydroxide base to obtaiu the car bylatez or free acid of a iompound of Formas 1503 Rofening to Reaction Schtme 1,8Step ' the compound of Form 1503 is oted with his (acoitdie4dichropatia (R) and TEA to effect intamol eir ring elosum to produce a o xnd of Formnla 1504, The 'iompxued of Formuia 1504 in isoatei Refering to Reaction Schemre I$, S.tp 4 the ompound of Funam 1504 is Ire-ated with a primary amoin to produce a compound of Fonmuls 10 The compound of Formua 1105 i isolated 10 IReassia Sceme 16: ~, t~dOmA ' TEA HP 3 N R 4>14 N HI So ol Ip5N ' 54 un4 5 THP TiH P 002831 Referring o ReA .. Scheme 6 Step I iodo eer aI 144 ls eateactd wih sikyke 160 in the presence of palladium ouplig catat, copper iodide ad TEA to obtain a compound of Frmla 1602, The compound of 5 Formola M02 i isla'ed, Referring So Rseaion Scheme 16, Step 2. the compound of Rnmnaa 1602 is trated with pxttaiurM' hy d de base to obtain the carboxymate or free acid of a compound of FormuiWa 1601 Raferriuig to Reaction Scheme I4, Step.3, the compound of Formula 1603 is tmated wath his (aetonstrildiohoropdiumn (H) ind TEA to effect intramduetusar ring closure to produces aomonid otfFormIa 1604. Ther co-p aoud of Formla 1604 is isolated Referun)g to Reoedic Scheme 6, Step 4, te compound of Frmula 104 is tAted wah a primary amine to 2t pbduce a Compond of Formul a T60.he omunpoun-td of FormI4 I W5 is isolted. .Raefaviertg to Rearion Schem -'2 16, step 5, tt6c carnspcnd of Pormit 16031 is tv wndwuI3 acid tW itmnv pdto to s p obtaio a .R sfo SRhenie IN&7: 0 -Y 0 -111 R R0 N N ~~~ -I- -' IiNN 7GE

N

~0t12S4J fR'efering to R, aon Scheme 17, Step I the compound of Formda 1701 is synthetsed by a visy of symhe routw n g varicsions of Schemers 1 r 2 where, for cxanple. a b ozylt mne is used in the step of conversng a compomd of FormUla 443 to a ompod of a 4W The bey potectng group of the aint may be removed by standard deprotection chemistry to produce a compod of 170 1 Thw compound of Forwtmus 701 is 5 (onste~d to a eecomxmd of 1Formula 1702 by alkylatiom of the nde inaregp with a number of 2-carbon cotainn synhons which en be deproteced, oxidized and reprotected as the rspectve ketal te compound of Fo Ma 1, whch can be i ed, Referring to Reation Scheme 17, Sep 2-1, the compound of Formu 1702 is transformed by, fr naample, reduictive riatn l cf the ester mlwety to Onroduce the purinyl moiety of a compond of F uluda 1703, or ultenmativdiy, is aikylated to so introduce a pulnyl mocety ad obtain a compoond of Formula 1703 Referrung to 10 Reaction dehermn 17, itep3- h comTpound of Formua 1703 is treated with add to remove the keta potlirng group to produce a compound of Formula 1704. The cmpound of Fomnudua 1704 is isted. Referrig to Reaetion Scheme 17, Step 40, he compound of Formula 1704 is eductivedy am in-ated with an amine to produce a compound of Formula 170. The compoud of Fomma 1105 is isolated. Referring to Reacisn SiChenme 1, Step 2-2. the compound of Fomua 1702 is tMansfonmed by, steps 7 ad 8 of Scheme 5 nd step .1 of Scheme 6 to introduce tfe 15 pyrazoipyndinc moiety of a "ompound of Fornuda 1 706 The compound of Formtula 1706 is isolated. Referring to Reactio Scheme P Sep 3-2, he co mprmd of ForrulA 1706 is reed with acid to mmove the kcats protecting yroup to produce a compound of Formula 707, The cemompund of Fornma la 1707 cam he isolied. Rferringt Reaction Scheme 17, Step 4-2 she compound of Formla 1707 is reductively amirated wish an amine to produce a eompond of moulta 17W The compound of F -ua 170ik ielatMd 20 Rearon khene I R-1O R7 OTMPI RN,, l-, Y Schemew 17 vsr any other geerI kY w eemisy. The vemon o o una 1701 i5 lk\nsf"ormed by alIkylwion, of the aimide nIitoge witlh a numbeIr of 2-=aro othn synthon whith canI be- deprotected, an o veewtlh 25 kox proectedspie as shwnIV in the opedfFrML10 whic h can, be isolaedi Refming to Ree Schee 18 St pm th copudo omk10 ovre aceitydsne nSe 4o ceeDt W&%, i ~74a prnwtyl mietsy and that resutat conplurd is teansforned by depzmeedo, activaoI ud mina ion with a amine to produce a Wmpoiund of Fcrmula 1802, which is irAuated Ias Referring to Reaction Scheme 18, Step 3rhe comnpvmd of Formiu 1801 is convened via denisry described in Step 2-2 of Scheme 17 to introduce a pyratlopyrimidine moiety, and that rstlretsnt compound is 5 rmifotr7td by deproteedoer activation and in ation with an amine int pes a ompou-d of Formua 1903 whch atsolared' Regaation Shene 19: RL k C R0O Ra0 0 RNH POC R A Step I Step 2 1901 1902 1903 R'3 >4 R H01 ft 'N 'NR' NkNR NHR A, NTHP Ste 4 0 NH N N Na,~N N.,.N t'N H1P 1904 1 1 Step 3 10 [12871] Rfwafting to Reaction Sche 19, Step 1. the compound o Fixola 190 i treated with an amine to pMduc a wipued of Frnula 1902. The ompound of Froul 1902 is isoadA RefrTing to Reaion Scheme 19, Stp 2 the compund . Fo-ma 19f2 is treated with phosphor s oxye-hrioende to generate a Comrrpurwnd of Fs.n.a 193, The compound of FormU a 1903 s is hated. Rf erring to Reaction Scheme 19, Step 3 e, the compound of Formua 103 is reacted with an amino puri'eof omina 19N4 to obtain a compound ofFormuaa 195. The comarpound of FormtU 15 190S is isolated, Referng to Reaction Scheme 19 Step 4, tie compound of Fo rua 195 iS treated with hydrochloric cid to remove the protesting group at nitrogen Ot the purine mdciy to prodice a c(ound of FornTla 1906, The comond of 1906 is isfated. R-aetio# Seee 20 ye Co Gt RH 0 -- ' laZOO 20 W0S228 Referi ng o Reacion Scheme 20, Step , she compound of Forrola 1401 is treated with vinyioy a ester 2001 using, lfr e.-npie a Heck reaction with subsequent cycadio to prxkoe a compound of Formoia 2002. The compound of Frmuesa 202 is h iei.aed Referring to Reaetion Scheme 20, Step 2, the compond of Formua 2002 is rented with 4- amino N-Soc piperidine it produce a compad of Formut 2302. The compound of Forma 20013 is jasited. The comnouci of Formua 201 an be used a an inermediate in the synthesis of the compoundE of the 25 nventiot Reactirm Schemw 2 ( Nam, 009291 Rern tW Racdon Schemn 21 Step 1, the comnound of Fonrxda 1401 is tretMed wth an alyas alkoho for e ,nple of Fru 210 L h ence of copper todide and pdadium on .arOn cataxyst, to p duc acom S ofPomrta fG2, The compound of iormu s 22 is opti y "kt&d and pti'yprfied , Referd ng to Ration Scheme 21, Step L the ompound fof Fmla ,102 is rcseted with amiuno N-lo piperidine to produce a compound of Forula 210 The compound offPonmda 21RU is rtohitea The compound of Fomadua 2103 can be used as an intamediate n the months fthe anpeads of the invention 2 s Any of the compound: of Fordauna I, WV, VI, Vii., V1, IX, X, Xl, XII, XI, or XIV can beshez 1 using the reaction schemes as di.osed herein or varians of these ptesses as wel k idhe at. |W1,29 I 'The Chemiessl emities can be ;yraherd by an appropriate combination of general wdl known syahesic methods, J402121 in smet embAdimems, ne or more su bect omunds bnd specificaly to a Pt3 kinase or a pr-tein kirase seated fm he group consiig of mThr. DNA-dependeM protein kinase DNA-dependnt protein Mrasse (PubNed protein accsion number (PPAN) AA A7P4), Amta tyrosine kinase (CAA 2387). Ber-Abi, hemopoede cell kinase (P>PAN CAl 199), Ste (.PPAN CAA 244I9$) vascuar endotheltid growth factor receptor 2 (PPAN AISBS261 9) vascular' edothd iarun S g .wt aor receptor'2 (PPAN A13SB26I9) epiderina faowh fbtemr receptor (PPAN AG4324It EPH reccptor B4 (PP-iAN EAUL23&820) stem edrl factor reeto PPAAF22 V4IVTymsneproteint kinase recmptor TIE.2 (P 4 PAN Q258 fl's-related tyroshre kstase 3 (PPN NP_004 0% platelet-derived growth 20 factor receptor aphIa (PPAN NP _990080 RET (PPAN CAA7313 1 and any Wier protein kinases listed in the amend tables and figures, as dl as any fitioa mutants thlereof In some embodiments, the ICS{ of% sAbject compound for p1 ti 10 p p1 1 1$ pa R, or p1 105 is ss than, about i tIM, less than about 100 nM, leas Ihan about o nM les than about W mMi I 3M or eveA less than about 0.hnM. In some embodiments, the C$0 of a object .ompOund for Tr f les than abot I u, ess tihan abou 0 nM, less than shout 50 nM less than about 10 nM, 25 less than vi M or even less than about 0 4fn, In sme other eLrmiments One or Ore subject compounds exhibit duat binding \ped Gay and are capable of inhibtig a P1 kinase (e.g, a dass 1 P13 kinase) as well as a protein kinaze (eng m )or) wth an .150 vala em than about 1 uM lass than abom 100 r, less than about 50 M less Ihan about 10 aM ie WA tmn itA or even ias tha aba t 0.5 nM OIn or mnrc-r subject compoumnds are capable of inhibiting tyredna kiny es induding, fat example, DNAdependnt protein kinae DNA-depedent protein kinase (Pubsed 30 proton accession number (PPAN) AAA7914), Abi tyrosie kinase (CAA52387), Ber-AbI hemopoicte ceu kinase (PPAN CA1U9%95) SrC (PP'AN CAA24495\ vascldas esidothieb gwh&hctor receptor 2 (PPAN . ABB82619, vascular endtrhlad grwth factor receptor-2 (PPAN ABB2619), epidemal growth fac reeptor (PPAN A432.41), EPH receptR -4 (IAN IA L23820 , ,te cdb factor receptor (PPAN AA22 141), yrosineprotein kinasseamr7r I&2 (PPeAN-NP_0(11t pideet-krived gown 3$ factr raptor apha (PPAN NT 990080) RET (PPAN(' 11j ad 2netiura rnutans theeof ICA 1,31e embodmns, the tyrosine kinase is AN, Ber-AbI, EGFR, or Fh-3, a any other kisses isted in the Ttles herein.

-W-

JM931 in some Sodment, the compoods of the present invention exhibits one or more functiona chmeteistics diiscloted hereint For eampe, tne cr more subject compounds bind specificaly to a P13 kinase. In some embodiments the ICS0 of a subject compound for pil 0 a, p1110p, pI JOy, Or pi 106 is lesS than abou t uM , kss than about 100 AM. less than abemu 50 nMless than abou,: 1 P nM, less han about I rM, les than ahout 0511M, less Than 5 about WOp, or less tan about TO pAS 9 in some embodiments, one or more of the subject. compound may seletively inhibit one Or more members of type I or dass I phosphaidy ostol 3-kinnes (Pl3-kinase) with an W050 value of aboul 100O nM,S 3 nM, 10 nM,5 aM, 100 pM 103 pM or I pM, or less a e measured in an in vitro kinase ssay 29% in some embodim s, one or more of the subject ompotound may Sd ecti'vdy inhibit one or tw-so menbets of 10 type I dCss I phorphstidyitsitol 3-irmes (Pi3kinase) xonssting of PD-khse a P3-kinne A PD1kinasey; and P13kinase S, In sonr aspects, some of the subject ecm.pnds selectively inhibit PI3-kiaae 6 as comparedto al other type I P13kinases. In other aspects, some of t subjet. copoudseedvdy inhibit P13-kinm 6 and P13 kinase y as compared to the rest of the type I Ph3-kinas. In vet other aspects, some of the object compinoe selectively inhibit P13kinase u and PO3-kinase ri as compared to the rest of the type I P13+kinases, In sdilt i-a some 15 oaher aspects, some of the bjet compounds seetively inhibit PI-inase i and P13-kinse a a compared 4w the rest of the type I PID-kinases. in sti yet some other aspects, some of the subject compounds seectivey inhibit PD-kina , and P IS-kinase as compared to the rest of the type I Plkases, or seletivly inhibit Pi1- kinase 6 and P 13-kinase a as compared to the rest of the type I PI3-kinaaes or gdectivecy inhibit P3-kinase a and PI3-kinase y a compared to the rest of the type I P13kinases, or selecirdly inhibit P13-kiee p arid i l as compsred to he rest of the 20 sype I Pt-imses lPO2tttn yet another aspect, ar rttsdeciely inhibits one or n-ore ''embe of type PF3-kinases, or an inhibit that seetivdy inhibits one or mor sype I P13-kitnte mediated signaling pathways alteratively can be understood to refer to a conmound that ehibits a 50% ibitory comentration (IC50) with Mspect to .a given type I Pi3kinase, that is at kast at leat 104-old, at least 20-41&i, at east 50-fold, a has 1-fod, a least i&tX iAl at a et 25 ltl d-foll, or lower, than the inhibitors 050 wit respect so the rest of the coter Otype P13-ktinase Pharmaceutical Coempstes j02'9] The invention provides phasrtaceu'ticat compeiions conmprsg one or more compounds of the pOnt invention. f0029S] In som emkodiments the invention provi s phsrmaoauticai composions for teat g diseases or conditions 30 mlated to an desirble cvesective barfuI or deleterious immune response a in a animal. Suc u sirable isnmune rerxose can be s iocmated w t or resut in, e.g asthma, emphysema bronchitis, psoriasis, alergy aphyass auto-immunc diseases m uematoid paris, raft versus host disease and tupus rythemnatous. The pha-acet.cal composiions of the prsent invention can be used to treat other respiraty diseases including but not Hmired to diseases affecting the lobes of lung, peua cavity brnchi - bes, trachea, upper rpinatory tract, or the 35 neves and muscle for breathing 102991 In some embodirments, te tnveton provides pharmaceutical compo-ition for the treatment ofdisorers suh as hyperproliferasive disorder iduding but not limited to cancer such as acute mylid Ieukemia thymus brin, leng, squatneus ell, skin, eye retinoblastomi-a intaocular .relanoms oral cavity and orophaiyngeai, bladder, gastric, tomsac, panreatic, badder, breast( cervical, head, neck, rena kidney, liver, ovarian, prostate, oorecal, esophageal 40 tesdiuar gynecological, thyoid, CNS, PNS, AIDS related D Red (eLgLymphoma and KapoesM Sacornma) or Vial-Induced Cancer,. in some enb-odiments said phtarmaceiutioal compostion is for the treatment of a non-cancerous hypeplferadive disoder such as benigt hyprplasia of the sida' (e. g, psas), retnosis or prostate (.e. g., been pxotsatic hypertrqphy (BPM)) M011300 The invention also provides composition fot the tni.oit of fiver disaseS (inchedifn diabtin), pencreadlts or kidney disease includingg proliferative glomnerkephritis antd dees inducedeal disease) pa kit a 5 ormamme [13$U The bwnvtion father provide a composdio forthe p o f bty. implanati in a mosammaM, [ W0302) The invention also relates to a composition for tatg a disease related to vasuogenesis or itgigeesis i a mamnm1al which can manifest a tumor agiogeness, chronte inflmatory disease woh a rheumatoid arthrits infammatory bowel diso atherschmais, skm ttseases such as psodisis, eeima, and seleroderma, diabetes, 10 diabetic retinopathy, retinopathy of prematstity, eg teraed macular degneration, eangiom, glikon melanomsa, Kaposus sacmna and ovarian, break , hg, paneuoatie, p te, coon and epidermoid caner. (O33 The subject phannaucutical compositions are typicaiiy frmulate tx pvovidc a thINpeudally effective amount of a compound ofthe present invention as the active ingredient, era pharaically acceptale sal ester, prodog, solvate, hydrate o derivative thereoE Where desired, the phracetietd compositions corMtai 15 piasmaeuticaly acceptable sah and/or coordination Ckx thervof; an aa or mre pha reatentsediy acceptable cipents earner. inehidig inrt solid dils-ts and fillers diunts' hludn s aue s sohalion and vaious p-.o~rga . sar, p-m-iadtdianu ner s d izerzan sodjuvantc, 4The si stions cnbe admnistered alone or in combioatst with oeri or more other age t a. a l so typicaY 4aha:nered in thre form ofphamaceutical onions, Where desired, the subjct and other aget(s) may be mixed itto a preparation or both omiporonrts may be rhraad itO separate prepanaons to use themq in cmbindaen sepamtdy or at the sme tha. iIN1M05 in some embodiments, the concentration of one or more of the crrapounds provided in h.e phomw tical compositions of the present invention is less 9han l%930%, %0%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%,14%, B%, 12%, 11%, 10%. 9%, 8%, 7%,6%, 5%, 4 3%, 2% 1%, QL-5%, GAtS 0,3%, 02%,01%. 25 0,09%, 0,09%, x027%, 0.06%, 005%, 4 2%, O,0i%, 0.009%, 0.00%.307%, 0 a006%, 0(0.5%, 11004%, 0.003% tM2% Pr0i%. t0t00p%, 0008%' 0007%. 0.006%, 0,000$%, 0,0004%, 0,0003%, 0.0002%, or 0.0001% we/, OW/v w v/N. [03061 In some embodiments the corsentration of one or more of the c-mpounds of the present imtion is greater than 90%, % 7% %,%, 40%, 30 20%%, , , 19.25% 19% 1&75%, 1150% 125% 1%, 30 17J5%, 17,50%, 1725% 1%,635% 16.0%, 16.25% 16%, 155 15:0% 1575% 1, 14 , 14.0, 14.25% 14%, :,75%, U.50% 125% 1 12.50%, 12.25% 12%. 1.5%,1.0% 11.25% 1%.10.75%, 10.50%, 1025% 10% 9,75%, 90% 925% 9%, 85% 50%. z25% 9%, 75%, 740%, 7.25% 7%, 675%, .50%, 625%6%, 5.5%, 5,50% 5.5% 55%, 45%, 4,50%, 425% 4%, 35, 50%, 3.25M, 3%, 25%, 250%6,225%, 2%, 175%, L0% 125%, 10.5. 0 4%. 0.3%, 02%. 0.1%, 0.09% 0.08%, 0.07%6,0.06%, (05%, 0.04%, 0,03% 35 002%, 0.01%, "'09% a40.00y%, O26% OA05%, o.004%, .003%, 0002%, 0001%, 00009%, 0008%, 00007%, 000063% 0.1105%, 10004%, 0 003%. 00002%, or 0,004% w/Ar, wv, or v/v, 103071 n some embodiments the (iteewsion of one or more of the ompomds of the present invention is in the range from appmrsimately 0.0001% to approimately 50 appmimaleiy 001% to aproximatdy 40 %, appramaidcy 0.01% to appcroinmately 30% approimatedy 0.02% to approximatey 29%, approximnately 0.03% to 40 approtumatey 28%, appmoxnmately 0.04% to approximratedy 27%, approimatedy 0.05% to approximatdly26%, apprainatsdy 0.06% to approximately 25% approimaedy 0,07% to appronnatedy 240% aprxiad .OS% to apiproximnatdly 23%, appronmatdly 0.09% to spproxnimatsiely 22%, appronimatdy 0.1% to approimately 21%. -7ikpprxmately 0.2% to appeomaely 20%, apprsoiately 03% to approaiady 19%, appoxinately 0.4% to approximately 18% , appoxidy 0,o% to approximtely 17%, approximaty 0.1% to aprximately 16%, app rnisteuy 0.7% to approximately 15%, approimately 0.8% to approxiniaely 14%, approximatdly 4-9% to appeorimatedy 12%, opdmately 1% ts.o xiptakly 10% *., w/ or VA siv. S000g In some emodiments, the concetration of oe or more of the tomnpouamds ofthe preens imVensdon is in the range frm approximately ,001% to appmxiay approximate 0.0% to ppmoximately 5%, approximately 0U.2% to approximdaky 43%, approximately 03% to appmimatdy 43, arppo ntey 0,04% to approximately 35%, approximately 005% to approximately 3%. approximately 06% to approxeieiy 2,3%, approximately 0:07% to arximatdy 2%, approim aey 0-08% to appmuimately I 5%,.appxma:ely 0.09% to appumatey 1%, 10 apprnmstd l.1% to appmanardy 009% *w4 %eiv or wve. 09 'n somermbodimet the amoosnt of one or more of the comonds of ihe present inve1o) isteqal to or mssthan'O0D 9 5, 90&9 6.5 g,&.0g,75 g, 76 &71 6i540g,53 g. 5.0 1 g& 463g3 3, 3.0 g, 25 W 42,0 ,1 5 1 LO0g, 0-95 gO ON9g,084 0. 81 035 g 03 g,05 04 0.5 5 g 0.5 g,0.A5 g0.Ag 0.5 & 03 & 015 0.2 , 0g5 7 2J g, M 00 0g , O 06 k,5 AS. 004 g. 0.3 g, 0,02 g, 401 g, 0.009 g 0 g g. 007 g, 0.006 g, 13 0.005 - 004 g 0003 g, 0002 g, 0A01 g 0.009 g 0.000 g, 0.0007 g, 0.00% g, .0003 q 0,(004 g 0.0003 e 0.0002.4.or CUM g In some embdients. the amoUnt of one or more of the conpaals of the parent hnenr "s more then 0.O0 i g. 0.0002 p 0.0003 g, 0.004 g, 0,0005 g, .0006 g 0.007 g, 4.0001 g,0009 g 0.001 g 0.001$ p. 0.2 g, 0.0025 4,0003 g. 0.0035 g, 004 p. 01)45 g 0.03 g 0.03 g, 4006 p. 0.065 g, 4007 p. 0.1075 g.0449 g, 20, 5 o 00095 O 01 & 0015 . 0.2 0.25 06 0.03 g, 033 ,04 &. 0[045 g, 0.05 0.55 g, 06 g, 0.065 g 0.07 p075 g,0M 8, 0.0g5 g, t.09 p 0.95 & 01 g. 0 &5 g. 0;2 g,0,25 & 03 0 5 g& 0, 05 0,5 &6g & 6 g07 g, 0.tg 0 g 05 &, 0 0.95g, 1 L5 , 22.5, 3 g, 3,5, 4, 4$ v g,5g.5 g 6.51, 7 & 7,5& & p. 5 9 g, 9.5 g, or 10 g 11 i in some mm entsthe amount of one a mom of the comrpo.unds ofthe present invention is in the range of 2$ 0.000-10 ,0,0005-9 4 0.001.4.0 05-7 g, 001.4 g 0.055 ,0.14 g, 0.5-4 g or 1or3 [3121 'The oomponds according to the invenwon are effezv over a wide dosage ange. For exampeK in the nt of adWdt huns, dosare ge s from 1 to 1000 mg, fmm 0.5 to 100 tri., Tomg, I to 50 ngmg per day, and frmn 5 to 40 tag per day are examples of dosages that may be oed An exemplary dosage is 10 to 30 mg per dY Tlhe exert dmuge wilh depend upon the route of administration the for1M in which the compound is administeredhe subject to 30 be treated, he bAy vwegh1 of the subject to be treated, and he prefArence and experiene of the attending phyiiat. [603 Desckribed below are nondimiting exemplary pharmaceutical composidons and methods for preparing the [034] 4 nacefjloesiing rra1edmiagrgo in sme embodiments, the invendion provides a pharmaceumtiedl comapoution for oral adneinustradion comsirag a eomptand of the present i wendoon end a 35 pharimaceutic s& xiplent itable for ora ,t administden, (4315J in seome embhodimnents, she invention provides a solid phwarmetical compostion for orand.iine canthmning; () an ffetiNve a unmra ofa compovd of the present inv=ndon; optonaly (ii) an effective amount ofa second agen t and (i-) a pheraceutcal e kc pien W suitable for oral W dt nstratiion. In some em ments te comFpKAsi0 fttrther contantis: (iv) an effective amount of a third agent 40 10031 In some embodiments, the pharma.deds] cropskn may be a iquid phnaces d composition suistM for orl ccnsnmpn, Phsmacended compom of the. invention suitaHe f odral administration cas be presented as discrete damage fsos, such as capsde cachets, or tablets, or ls or aroel sprays each containing a '.79predetermined amount of an adive ingredient as a powder or in grnales, a solution, or a suspension in an aqueous or liquid, an to-ter maI s-om or a w irt-ct ud pension. Such dosage fInna C3: ben w prepared by ay of the methods of p aacy, but all me hods iniAde le st. of bringing the active ingredient into a Mation with he carieS which conster One or more aecesay nredients. in genera, the compositions re prepared by unifom'y ad indmainly adrnidng the adve ingredient wiah liquid carriers or finely divided solid carriers or both and then, if rnceszser shaping the product into the desired prestation For ex qnple, a tablet can be prared by compsson or molding, optionally with one r mor accessory ingredients. Compressed tablets can be prepared by ctmpressing ba suitawb mache the ative ingredient in a freel-kswing lorm such as power or granules, optionally ixed with an excipent such as but not imied to, a binder, a Iabricant an inert disumnt, ansdfor a surface active or M0 disposing ageat Molded tabka m ma by ndiding in a sitable machine a mixtuo of the pOiered compound moistened with an inert liquid diluent [II7] This intention hurfher encompasses anhydrous pharmaceotdcal c osidins and dosage forns compi sing an ac've ingredient, sine water anf-acisait the &grai"tion of SO m s opounds. For eray be add (i., 5%) in the pharmaneuticai arts as a means of simulating ioog-tn storage in order o determine charaeristics 15 such as shelf-ife or the stabihty of frmulations over ne, Arnhydrous phrnacucai conmpodons and dosage fan of the inventm- can he pmared using anhydnsUs or low moisture containing ingredients ad low moisume or low humidity cendions Phmmaceutiei compositions and dosage forms of the invention which cotam aose Can be mad nhydrous if subsantial contact wih moisture andfot humidity during maufacturing, pakaging, anchor storage is expected, An anhydrous pharmaceutical composition may be prepared a stored tuch uma its anhydirus nature is 20 masatained, Accordingly, anhydrous compositions may be packaged nung materis known to pryet exposure to water sucah that they can be inekdisd in suitable formuary kitslartpes of suitable packaging inclu, but are not limited N her'mticay sealed fsils, plasaic or the like, Unit dose COntWeS biter packs and srip packs. [10318] Asn active ingredient an bcand k an inmate admxtue with a pharoaoeutical carrier according to conventional phamace-utica compouding tathniues. The carrier an take a wide vaiey of forms depending on the 25 form of preparation desired for administration prian p the compositions for an oral dosage janm any of the usual pharmaceutical media cnn Ie employed as carriers such as for example, water, glyc'ols oils alcohols, hmelgavc agents, premativa, covering agents and the like in the case of oral hquid prepadraons (sach as rspenos solution and elixirs) or aerosols; or artim such as sasches sugars, mic rystaiine cellose, diluent, gmuating agents lubricats, binders, and disintegrating agents a be umsed in the case of oral solid prepations, in some f rmdiments without employing the use of etoe For eam ple, suitable crriers inclUde powders psues, an abmlts with the solid oral p raim, ons. If desired, tablets ain be coated by standard aqueous or non aqeous techniques (1I3I9% Binders suitable for we: in phanaceutical compositoms and dosage forms include, bat are not limndtd to, com stach, potato stack, or other tarches, gdatin naavmsa and synthetic gums such a asia, sodium algiate aini 3S acid, other pginates powdered tragacanth, gisar gum, eulose and its daedvasves (eg-, ethyl cellaose. celhoem acetate, carboxyntethyi cellulose caleitamsodium carboxcymedhyl celluloe polyviny pyrrolidone, methyl cellulke, pre-gelatinized starch. hydroxypropyl methyl cellulose, mierocystaliinc ellulose and mixtures thereof. j43Z1i Examnics of suitabe fil for use in the pharmaatidal composing ad dosage forms disclosed hrein miude. but ae not 'imitd to, talc, calcium cabonate (e g granules or powder, microcrys taline edi iosa, powdered 40 cellos, dextrats kaolin, nmanrnitoi, sili acidd, smtt, starch. pre-gelatiniized starch, and nixtowes thereof (0032)1] lDisintegrants msy be ss in the composiions of the hwention to provide tables that disnegrate when exposed to an aqeus environment, TOo muh ao Cf a disintegrant may produce tablets which may .disiegratc in the - 801boote. Too litoe My be insufmicat for disi.eratkai: to occur and may thus after the rate and extent of riease of the actIi ingredients) form the doage ferm thu, a Suffieten xtot of dishitegra that is neiher too de ner t much toet&tenn y de the relase of the active inredie@ may be used to form the dosage forms of the mounds disclosed herein. The amout of disAtegant Wsed may vary based upon the type of formitdadin and mode S of administration, and may be readily discermible to those of 'dinary skill in the a- About 05 to about 1S weight percent of disintegrat. or about I to rhout 5 weight per ent of disintegrant may be used in the tactical cmpeiisona. DisinotDs ants that can he used to form pharmaded eal comnpe i rons ad dosage forts of the intention ilclude but are not limited so, agar-agar, agindo acid, alcium emibonate, rcrerysanlline celluos, arosearmse~os sodium crospovidone, p aheilin potassiwm, sodium starch glycolate, potato or tapioca smarc, oh.ther starches, pr 10 geaizaed stardther searches clays other ai gins, other dluoses, gums or mixtures thereof j03221 Lusbricrnus which can be used to form phar eutcal cornpostins and dosage firms t the invention irnde, ta are nor ited to, raliumn starate, magnesium staaraxe, miel oil, light mineral nil, glyterin, arbitni, mannitol, polyethylene glycol, other glyco0itearic acid, sedinla ryl sulfate, ta, hydrogenated vegetable ol (e.g., peanut oi: entionseed oiR, sun ower oil, sesame oil, oliveei, com oil ad soybean oil), zine stenrmte, ethyl oate, 15 ethyslamrate, ager, or- mixture thereof Additional lutbricanra include, for exanrple a syloid siica get a caguarted aerosol of tsntie silica, or mixures thereof. A. lubricant can optionally be added, in arn amoun of les than about I weight ponentt Oithe pinnOcsoetal compositin, [003231 When aqueous suspensions asd/or dib-s are desired for oral adninistaton the essential active ingredient hein ay be com bined with various swetnngxr a -florg agents, coloring master or dyes and if so dedred, 20 eulsUifyinlg acnd/or suspending agents. together with such diiuents s water, ethanol, propylene gycot glycerin and j19324j The tablets cnr be uneoned or coated by known techniques to delay disinegration and absorption in the gasnrntestinal tmot and there by provide a sustained action over a longer period, tot emmanple, a time dehy material c as giyeryi monostearate or glyey disatearte can be employed, Formnulation for Nral use prn abO be 3 rs-nted 25 Ias hard geltin espades wherein the active ingredimat is eited with an inert solid diflaeat, for eaxmpie, calcium carenate, cakium phosphate or kaqolirn, or as soft geladin capsules wherein te active igr-ediem is n'ixed wih war or an oil medium, lor esxanpie, peanut ei liqid p ffyin or olive oilt 103251 Swfactant which can be used to f-ormn pre t compostone and dosage fonns of the invention include, but are not limited to, hydrophilic surfstants, tipophxi surface t and mixtures thereof. That is, a mixture 3k of hydropic srfa ts may be =eployed a mixure of :1pophiti sufactanta may be empkyed or a mixture of at least one hydeophilic surfactant and a least one lipophilic surlctanst may be employed, jOM2 A suitable hydropailic sufctant may generally have an H-lf vaue of at least 10, whil suitable lipophile sur factants may generally have an M-LB vats of or less than about 10, An eroieal paraneter used to chanacTeine the relative hydrophiliiy and hydrophobicity of nonionic a-phiphilic conpounds is the hydrophiic-ipophiiic 35 haiaste (0 b-L' vale. Safactants with lower L vales are more lipophitic or hydrophobic and have great iyioh, while sur factants with higher IL values are mne hydrophiiic, and have greater soubiiy in aqueous solution. Hydrophile srfacas are generally conidered to be those compounds having an H LB vaiue grsecr thn about 10, as wels anioni, cationic, or ietiodn competunds for which the -LB sl i not genesrlly applicable Similrlyipophilic (ie. hydophobi) surfactans are compounds having an anLB vae equal so or les 45) than about 10. However, HLB.1 value of a surfaucamt is merely a roughs guide generally umed to enahle formrukltionc of industrial, pharmnaeemical and cosmetic emnutssons

-S

t4271 Hydrophlihc wrfsctants may be esiet ionic or non-ionic. giKAble ionic stfattants inchitde, bW are not rimcd to,. aibynmmojum .salts; fusdie acid salts; Lry acid derivatives of amino aid ,li oppside, a d polypeptideos; gycende dasvatives of amino acids, mgopeptidea, and pypeptides; ctins ad hydrogznated cithins; lysoleetibim end hyd;genated lysoleetthitm; phholipidn and dedvae thereof; lysophosphioipids and 5 derivattivs tewof; oaitne fa acid r tIts m ofalkiuats; fatty acidyafts; sium docusate; aeylactylats mono- and di-acdyiasedtatic acid esters of mono- and digiycerides suclyted mono- and di gtyoendes; citrie acid eaters of mono- and di- yrids; and maixturea thereof %W281 Witfhin the afreenoned group, ionic srfctants include, by way of enmple:idtina lysolecithin, phosphipida, lysophospholpids and deivadvezs hereoft castne fatty acid ester salts; smts of alkyhailfaes;- fatty 30 acid saks; aoium doeuate; acylactyites; mano and dcetyiated taitaric acid esters of mono- and d&glycendes; y a no- and digiyceride; citric acd western of mnoo- and dij-Iycedes; and .mrixtrre.s thereof [MI29) Ionic sarfawonts may be the ionized fIorms of ieihinm ysoeM.idin, phsphatidylchoine, phospatidyednolamine, phopatdylgeycon, phmosphatidic acid. phosphadidybserdne, iysophosptadidykhoine, yphsphstidylethanolaminx lysophosphatidylglycere lysophosphatidic acd, lyuphosphatidylsedne, PE 3 phosphWa-tidyrleancaint PVPphosphtidyiethaniamine, lactylie dters of fatty acids stearoyl-2 tyla stearoy! lactylate, saccinylated mnonoglycesndes, msonodmacety ated taar ic acid esters of mnoediglyceridem citric acid asters of mnoodiglyceides cholysarsi. caproat; caprylate, caprate, asrate, myristate palmiate, oieate, rinoleate, nomeatefinen- sit-re, ' ry slfat, 'eTey Iulfate, do'a Iamroyl camrnitines, palmitoyI carniitns. myt-istoyl carnitine, and salts and mixres theteor 2) [003301 Hydrophilic nen-ionic surfatants may include, but not limited to, alkylglucosides; alkylialtosdes; k-ylthioglucosidets; lauryl macgglycendes; ypoyoxydakylene akyl ethems such as polyeahyiene glyed aiyl ethers; plyoxyalkylene aiky phoisssch as pleylene glycl ikyl phenols; polyozyakyfee alkyl phendl fatty acid enters s wh as pdyethyle glycol fatty acids monestem and polyethycAne glycol fatty acids diesten; polyethylene glycd glycol fatty acid esters polyglyocd fatty rcid esters; pdlyoxyakylene sorb faty acid estes so as 25 polyethykem glyco orbilan fatty acid estrs; kydrophueio tansesterfication producss of a po-yo with at kat One member of the group consisting of glyceNides., vegetale oils, hydrogPmtd ve l faty acids, and sterols; polysyehyrne saterod, deivaves and analogues thereof; poyozyethylated vitmlins and derivatives thereof; polyoxytyen& poyosypeopylene blok copolymers; and mrtxuws thereof; polyethylene glycol sorbitan fhtty acid esters andi hydrophili asesterfication products of a polyol wih at last one member of thie swrup comisting of c triglycerides vegetable Ois and hydrogenated vegetable e Oils. Htb pPyo: may be glycerol1 ethylene gyc .c polyeThylee gipyod, stott] psopyeme glycol pemerythrlite or a sacchanide. itilt (the ydrophie-non-ionic suasrfants include. without limitation. PEG-I0 ianrato, PEG- 2 lmaotte, P1E4520 Mrae, EG4 lmte PE42dilards EG4 olm E&1 lat, PG-2 ote, PEG-20) dioleute PEAS42 oieate, PEG-200 oleat, PEG-400 cleat, PECi- started PE -32 distearate, PEG-40 sterat, PEG-"'.4N steaamte, 35 PECP difaurate. PEG-iS gWyccryi t einlatel PEG-32 dio t P 20 gceryt iary t ePEG0Y glyceryl lau-ate, PEG-WO glycery stearat, PEG-O glyceryl oksste, PEGS40 Iglyceryl oleatt, PEG0-o glyemryi lauate. PEG4A glycryl larate, PEGEdO paydrnatne ltr PE- hy n o PEG4 castor i, PEG-35 cuoar oil: PEGi4-0 castor oil, P543440 hydrogenated castor o, E hdgenated castor oh, PE2G-60 corn oil PE-4 capr-sesapryiate glycarides, PEG-i capraWdeapryate glycendes polyglyeyi-iO mmne, PEC-30 cholasrol PEG 40 2.5 phyt sterol, PEG-30 soya stet, PEG-0 trideat PE040 sorbitan m te PEG) sorbia larae, polyNrbam 20, po(ysobat , IPO-9 tmryl ethe POE-23 lauryl ether, POE-li olesi ether PGE&20 oleyl ether, POE-20 stearyi etier, ocopheryl PEt I secine PE.-24 chlesterol poyglycery- odeat, Tween 40k, Tween 60, sucrse -82monostearate, sUrose mohunrate, surose smonopalmtae, PEG 100 noyt phenol seres, PEG 15100 meyi phenoi series, and poiomamers. 0O332) Suiabte tipophile suractaams include by way of esxwnple oniy; faty acohols; glycero fy acid estrsM; acetylated glycerol fatty acid t;lowerahoi fasty acids ester; propylnre aiyoo! fzty aci esters; corbitan fatty S acd eMsen; polye thyene g Wyoot lsbi fatty acid eser teris and stel dervtives; p yytyd erh sad ster derivatives; polyethylene glycoI alkylr hs; suiresters; Sugar ethers; laet acid dedvatives of mon- md di glyoertdes; hydrophohie transesterifsion product of a plyol wiuh at least one member of he group consisting of glycerides, vegetable 011l, hydrogenated vegetable oils, fatty acids and sterea; oil-soluble vitamno. ain deivaives; and miattwes thereoft Wiknthi ds gmu, preferred tliopii aufcet jic&d gt o fa acid esters l0 prpylkne glycd fatty acid esltm and mixtures thereof, or are hydrophobic ran serifatios podnes of poly i with at least one member of te group consiepg of vegetable o'is, hydrogened vegetable ot ad rigyced [OL333} In one embodiment, the caposAtxm may include a solubiliwes to ensure good soubliration andor ssclndn of the compound of the prese-nt invention and to miimize promipitasion of the c smporsnd of the pposent Envention. Th.i.s can he especialy important for composions for non-oral 's e g. emnposkios for action A 15 solubiie rmay asm be added to-E inrease the soSbility of the hydrophdic dug and other Comporents. such us surbatants, or to maintain the composition as a stable or homogeneous soluO rdisprion 0334.1 Examples of stable solubsazn include, but ate not limited to, the foloVwag: 'akho. and pxoydas such as ehanol, i zsppano, butol, benyt alcohol, ethylene glycol propylene glycl. butanediols and iso fers tereof, glycerol, penarythnto, sbitOl, manntol, seutol, dimthwl *de pety glycol' polyppyen 20 glyco, polyvinylobol, hydroxypopyl miethyetlise and other celMose derivatives, eyolode tdns and ckdetn derivatives; ethes of polyethylene glycls having se antrage molecudar veght of about 20 to about 200, such as teteahydrafurfuri akhot PEG aehr (veryofurol) or micthu-y PEG ;asnides and other edtragen aetainiTg compatn&d such as 2-pyrrolidone, 2-pipeidoer epsiteaprotetarn N-atklyrrudne N hydroxyaikylpyredlidlonre N'alkylpiperideNe N -akyicapro acaarm dimsethyhaceaamide ad polyvaylpyrrohidone; esters 25 such as ethyl pepiateibutytrate, acetyl triethykerteaetyitributyl ctate, triehylsere, ethyl clat, ethyl apylate, thyl butyste, triaceti, popylne glyced monoatatt propylene glycol diacetate, oaproslacone and iomers thereof, -valms-etone and isoms thereof, -butymeatone and isome thereofT and 1ter c 1 iers known in the -a such as dimethyl acemmid. dimctytsosorbide, N-methyl pyrrolidonenmonooenoin, diethyle giycol monceshyl ether, and vatse. 30 IQ&3215 Mixtures of ubiizers may aim be used- Examples include, but not mited totriacedi triethyctae ethyl Caete, ethyl cpryrte, diradylaaamide, N-methylpyndidbne, N-hydmayehyipyr-oliduce, polyvinylpyrol done, hydoxtypropy$ ethykcelissose- hydroxcypm-py! cycindrina. tanei polyethylene glycol 200--%t glycofurol tsarscutoe, propykne glycol and dimethyl isosorbide Particularly preferred solubiliaes include sorbie, gayerol, ,.petir, ethyl acohol PEG4 , glycofurl and propylene giso. .35 [043361 The month of sdublter fhat can be incuAded is not particularly limited, The amount of a given colublir may be Emited to a bieacceptable amount which may be ready determined by one of skill in the art In some ctreuonstasces, at may be advantagcus to include amounts of sfabliers ar in excess of bioacceptable amounts, for ma33-le to m imize he conccntradc of the drug, wif. excess slubii zer removed prior to providing the compositiO to a patient using cventi:ona techniques, such as distia;:rn as o. aporation. Thus, if presets the 40 su bilizer carn b oi a weigh adio of 10% 2 % .50% 100-% cr up to about 200% by we h tn, paed on the combined weight of the dmg, &mad other excipiens. If desired, very small aonts of solbiizer may als he used. such as 5,' 2 % or even e Typically, the Nobihizer may be present n an amount of about 1% to about 100%, mOre typicsy abAmr 5% to abto 25% by' weightx (00337 The cospostion en aUtheq inrilde one or more ph cuticaly smptable addives and excipins Such additives and excdients inded wahout Smitatio, detackifiec, anti4faming agents, buffering agents polymers, S-anuodamas, pe Uervative edlating apats viscomodudator, tonifiec, flavrn, as, edor ants, opadifers, sus~peding agets, bindXes tElimr, plastdeizers bricats, and misK ures theceol. (21033g41 I lin. an acid or a bsay be :3icoposted into the co m t itat pmessing to enhance stabYi, or for other maon= Exsmplks of phwnacteudely acceptable bases include amitno aids, amino add estes, ansoiumn hydrode, potais hydride, sodium hydroxide, rsodiu hydrogen carbonatedeminm hydroxide, 10 calcium carboniate, magnesium hydroxide, ma gneium aLuminum sil icate, synthetic aluminum silicate, synthsetic hydroaiitemapesriun aluminum hydroxide, dicovpmpyyamines ethnoaine, ethylenediamnise, uriedhandiamine, triethyiamnine, tr1isspmpantoisine, rismehylisa ns, u'i ydrxyaehyamriinsamdane (TIRIS) and the like. Also suitaibie are bases that arc sais of a phianacctically acceptable acid, such as atsi acid, actylic acid, adipic aci alginic acid, alkaesulfonie acid, amino acids ascorbc acd ben aid, borie acid, hutyric acid, .1.5 carbonic acid, citric acid, fatty acids, fosic acid, knaic add, gumnie acid, wy"quinosulfc acdd, ioscorbic aid, lacdc aid, maei add, coxaise acid, pam nophcys'l fonic acid pmopionic acid, p uleneibfnic acid, sail ie acid, stearic acid, succinic acid, tanis ad, tartaric acid, tliogiy%1' idK, tiekenesulftnim acid, uric acid, and the like, Sats of polypACe acids, sch as sodin phosphate, disodium hydrogen phosphate, and sodium dilyen phophateenn also be used. Whei the base is a al, the at in Can be an y convenint and phara"eticany 20 acceptable cadoc sca anrmonsenmi alkali metals ,tikalie earh mealS, and dhe 1ike Example may *ncade, but not limited to, sdlium. potassium. liths, magnesium, catlum and ammoniurm, 10019 Suitable aids are pharacesaley accept organic or inorganic acid' Eampes of esitable inorganic acids include hdrochktic acid, hydrobrnoic aid, hydriodi acid, sufurie acid, atne aid, boric acid, phosphrie acid, and the like, Examples of suitable organic acids include acetic ad, acrylic acid, adipic acid alginic acd, 25 alekanmdfai aids, amino acids, ascorbic acid, bencic add, boric add, butyric acdd, carbnic acid, citric acd, 'ikty acids, formic adid, 'maric acid, gwanic acid, hydroquimsualfinic Add, soascor bli acid, lacde adid, maleic acid, mnethaesafonie add, ostle acid parsbvmophenylsulonic add, propionic acid, p4obeneuifonic add, sallyic acidd, steae a cid, mfl acd, timic acid, iartaric acid, thioglycolic acid, tlenesfinic acid, uric aoid and the like. |M]Parnacutial compojsitiojm ns foresmbodimecnts, the invenstion provides a phasnceutical 30 m position or injection containing a compmnd of the present invention ad a phamaceutd exci piens suitable for section. CZompnens ad arimxints of agent in the compositions are as deserbed heei. 114j. T4e fa'ns in which the novelxopsitis of the pmenAt inveion may be incorporated for adminisin by injection ineilde sqjueoas or oil Lmpesion. or enssions, with sesame oil, m, eA ocotnSm Cit or ipe CanIt c, as wdl as chirs manvl dextres or a sterile apuexns solnand simiar pharmamsticai vehicles. 35 [W.M121 Aqecs solluins in line are also ccnventionaly used for njedior Ethaol, glyceo, prpylene glycol hid polyethylene lycol d the like (and sitable mixtures there, cydodextrin derivatives, and vaetable oik may also be employed. The proper fluidity can be maimairrad, fb examp. by the use ofa coating, such as lecithin, for the maintenance of the required particle :Sze in the case of dispersion and by tho ss of surketats The prevention of the action of microorganissns can be brought about by various anbacterial and antifngal agents, forl oxaple, 40 parabens, chlrbuano, phenL stobl acid, thiMra . and he ike. [0W343l Sterile injetable solutions ace prepared by incorporaing the compound tfithe presemt invention in the requmire'd amount in the appropriate solvent with variou other ingredients as en rnerated above, a reque cd, followed -84iby rlered sriation, Gen:fay dispersions a re a ied by r ng hia e ingredients into a strfe iec which cosnain the baic dispersion medium and the required other ingrediMnts f"m those enumenated abovea nthe M ase of stae'i powder for the pepara.ti c of starie 4tes"No tI certain desirable methods of preparation are vacuumrying and free drying temiques which yield a powder of the active ingredient 5 plus any addi na desred ingredient fNoa1 a previously sterilt41ered solution thereOn JOA44] Pharmnaeutical ao" sswo satr'gi gan"eie a stoma embdiment the 81ntWOnS provides a phracpeotical compoieon for tnsdernm a delivery aotainng a composd of the present invention and a pharmaceutical cipinat suitable oI transdarrrmsl deovery. 03451 Comp idoma of the present invenion eon be fnidnated into preparations in solid, sem solid, or liquid 14 forMs suitable ir local or topical administration, such as gels, vwer mlble jdlies. creamsd onions, surzsSnrs,\ foas- powders, stoeksa ria ts, s<Mlohnts ait pastes, suppositories, sprays, emsul ionw saine sdszizns diathysufoxide (DMSO~based otdions ln general, caretrs with highe denates we capable of pvidinga area with a prolonged exposure to he active ingredets, in contact, a soltion famsdation may provide om immediate exposure of ti"he aive ingredient toi the chosen area. 15 O03461 The p- macutical compositons aso may com-pise so able sol idi- or ge phase careers or eciients which ar compourds that allow increased penetcration of, or assist in the delivery o, thtserpeUtic mlc ues atrers the stavsm cmeum parMe'ability barrir -of the skin.er are many of these netration-enhanung mlkeules known to those trained in te art of topical formos. Sanpies of uch carriers and excipies include, but are not limited to, suxtaxs (eg. upa), glycois (gw propylene glyco), alcools (e.g, ethanol), fatty acids (e'g, aie acid), 20 ssrfactans (e.g, isoproy myristas and dium ry! fate), pyrm0iidsoes, glycem mionolaurate, sItoxtdes, trpmes (eg4 menthol), anin's, amids alkcanes, aikanois, water, calcium estbonate. calcium phosphate various sugars, saehes celuot detivsn gelatin, and polymers such as polyethyletne gycoIs. [0(347] Another e-em-lary Rfo adion frt e use si t e methods of the present invention employs transdesnal deliverY devices ('patches"). Sech transderma patches may be usted I provide continuous or dis ondnuous infusionf a 25 compound of the present inenon a corolled amounts, either with or without another agent. [031481] The- conrtion and se of tr-ansdennM patches o' the delivery of pharMIcotle agents 55 wet wn in the at- See, eg U. Pat, No 5023,251 4992,445 and 5,00139P Such patches may e consteted for continues pidrutilemr -o demand d welvery ofi phtraceuticai agnts 10(149| Ptcsscagag.glg t -g-g-ji-i---led.it Clhal-oonr for snna:o r insufflation include solution and 0 tsupensions i pharn aceutialy acceptablee aqueous r k orgilc so"vems' or mxtm uheeaf( and powders. The iquid or solid compositions -may contain suitable pharmnuiely acceptable aeXCipents ca described sspra Preferably the comnposi ions are administered by the oral or nms respiratsy roue for inl nr systemic effort Compstions in pref y pharmaceutical accepted sokents may be abuiizd by use of' inert gases Nebuited sottioro may be inhaled directly fro She nebuiing dev ice or the nebdizing device may be attached to a face mask tentS, or 35 intntntt positive pressure breathing macin Solio: supensiom or powder composiins may be administered, preferbly orally or nasally from dvieastat dlivr the formulation iOn a appropo ise-me, -35onnamggiv . phiracated comn~paosisors may also be prepared from -mpositons described herin and one or more phrmna- uclly acceptable excipicts suitable for sublingual buccaf, rectal intraosseoos, intraocus ar,. anasa,. epidlurai, or inteaspial admin-istratio-, Prea rations lfor such pharmaceutical 40 compositions are well-own in the a See, e.g, See.g Anderson Philip 0.: Knobeiames E. Trouman, William G Hd handbook of Clinica D rug Data, Tenh Editon. McGrawoNail 2002; Pratt and Taylor, ads Pvinsies o/ Drirskclon. Third Edit iot Churchill Idvingston, New York, 1990; atzatmg, ed., Basc and Clinic 45- Pharmfacdvo gs. Ninth Edsior, McGraw Hil., 20037ybg; Goodman and GilNa eds, The PArmofngld Bask tf Tjerapee, 'lnth Editaio, MCGmw Hill, 200; R %ingso aPharmacacedca &kcns, 20th Ed, ULppincort Wil 1 ams & Wilris-, 200r0; Martindate, TIe &ra Pharopwa Thirty~Secend Edidton (The Pharacaical Press, London, I99); all of which are itcorpoated by r efoem hemin in their entire 5 [0C035I Administration of the n pound or ptamc til composition of the present invtioni Iv en e effeted by =ny methd that enables devery of the compounds to the site ofeecti. These mediods include Oral tes tadumodeal rtots, psterot ateintion (including ira venou. itraarterial sucutaneons, VntMeuar intravascus. itapenitatcal or inftsion) topical (e~g. imadennal appheotions retal admintition.e lcal divery y cathterr r steri or through inhaatiomn Componds an also We administered intradiposaly o 10 ntrathelly, [003521 The amount of the c pond administered wil be dependent on the eMarnMma! being treated, he severity of the disorder or ondiiodn, the rate of administnation, the d pwition of te compound arnd the disentin of the prescribing physician, However aM effective dosage is in the range of about 001 to about 10 mg per kg body weight er day, prfely about I to about 3$ mgfkgday, in single or divided doses. For a 7t kg hnman 'this would S amouns to about 0.05 to 7 glday, preerably about ot0 about 2, gdA. in some itsances doage eves below the ower limit of the ssaresaid range may be more than adeqate, while in other cases still ltger doses may be employed without causing any harmful side effect, esg. bYdividing sch larger doses into severe smal doses for administration ihtoimghnet the day. W0353. In some esnbodimenLs a compound of the invention is administerd in a single dose. Typically, such 20 administration wl be by injeeIni, egg, intraveous injecton, in order to introduce the agent quickly However, other tes nay be used as appropriate A single dose of a cmpound of the invention may awo be sed for tratment of an acute condition. (354) in seme embodiments a comnpod of the invention is administered in multiple doses Dosing my be about ome, twie) three times, fot times, five times, si ttmnes or more than six times per day, Donrg tay be aout once a 25 months one every two weeks, ncce a weeks or once every other day. In anotherr embodiment a compound of the nvetion and another agent are administered together about once per day to about 6 times per day, In another embodiment the adminisadin of a compound of the invention and an agent continues1r les than about. 7 days In yet another embodiment the administration cantnses for more than about 6, 10, 14. 28 days two months six monhs. or one year. i some cases. ontimous dosing is achieved and manloined as long as necessary, 3 [fI035S] uininisration of the agents of he invntin may continue as long as neessary. In some embodimena .n agent of the invention is administerd for move than 1,2 , 3,56, 7,l14, or 2S dayis Ins sorte embodiments an agent of the inventon i administered for less thn 28, 141, 5, 4, 3, 2, or I day, in some emodimen, an agent of the invention is administered chronicaly on an ongoing bass, e~g., for the treamot of chronic effects, II0356I An effective amount of' a compound of the invetion may be administered in either siogi Or mueadple doses 3 S by any of he accepted modes of administration of agents having smilr utilities, incudang resnta buccat, irtwsanras and ransdena toues, by intrarerinal injection, intravenously, itrperitoneally, pareterally, intmmscuiady, subcutaneousy, oly, topically, or s an inhahnt j0mflaI The compositins of the invention may also he deivcred via an impregnated or coated device such as a stent, for exasmpie. or an areryiserd cylndric polymer. Such a method of adminstradon may. for example aid in the 40 prevenion or ameloratn of resterosis oMowing proceduos such as balloon angioplasty. Without being bound by theory, compounds of he invention may sow or inhiht the migration and pratiore of smooth muscek cell in the arterial wail which contribute to restenosis. A compound of the invention ty be administered, for enpie, by loca "86ddwery from the stAts of a stent, fWm a stelnt gena, &ons g Maf or nom the over or s ath ofa sient in some embodiments, a compUnd of the invemion is admired with a matriX, SOch a matuix may be a polymeic matX, and may serve to bond the cnompound to the sent Polymeric mrics niszablte for such us'e incSe, for ermpilctone based polyesters or copoyestesm such a py d polycaproiaconglycolide polyotostsia, poiyanydridles 5 polyaminoacids. polytceharides. polyphospkazeness poly (tesr'er) ccpolyre (eg PEO-PLA}; poyiaydne poly(thyk e.viayiaeetsae), acrylatc-lsed polymrtos c opcdymer (e4g polyhydryethyl nmethylMetharylae, polyvinyl pyrroiinone~ f adomnated polymers such as polytetra hluroethylene and celidose esers. Suitable manoes may be ndgyading or msay degrade with time, releasing the compound or compounds CompoumAs of the invention may be applied to the wsrthce of the stent by various methods such a dip/spin coating, 10 spray seating, dip-coding. and/or bmsh-coating, The comeparnds may be apped in a solvent and the sobvnt may ce allowed to eapMe thus fning a layer of ooMrpound omo the stont Alternatively, te compound ay be located in. the btdy of the stat or graft for example in rvnrochcands or mropores. When iMPtmaed, the compound difliases out of the body of the stent to contact the ateriand wait Such sets smy be prepared by dipping a stert manufactured to contain such mik reo s or microchanneh into a solution of the compound of the invention in a suitable solvent. 15 towed by evapwation of the solvent, Excess drug on the surface of the stent ma y be removd via an st inel brief soivent wash. in yet other erodiments mnponds of the invention may be covalendy inked to a sit or patt A covlent linker may be used which degrades in vo leading to the release of the ompownd of the invention. Any bios Iabile linkage raye be used for such a purpose seh as eser, aide tr anhdride inkages. Componsi of the invention mayi additioally be adminited intrava' ulary from a bal loon used during angiopliasty, Extravasclar admtinistrairne 20 of the compounds via the pericard or via advential applieaion off fruluons of the invention may aso be performed to decrease restenost {35 A viety of se n deices which may be used as descri are disclosed, or example, in the folowing reterencws, al vf which are hereby incorporated by reference: U.S. Pat No. 5451233; US PatI o 50434' US. Pat No, 5061273; US. Pat No Pa No.. 529233 US, Pat No. 567427S, Ub. Pat. No 357744; Pat, 25 No, 4734762; U.S Pat No, 51959g4; US. Pat. No. 5292331; UUS. Pat No, 567427; UA Pat, No. 58793S 123U Pat, No. 63440531 W0591kj The compounds of the invention may be aninistered in. dsges, It is know n the at that 'due to interbject vardability int compound pharttaeokinctics, idividualtzation of doing regime is necessary for opdirad therapy, Dosing fo a compnound of the invention may be fund by routine experentaton in light of the instant 30 disclosure. I601 When a compound of the invention, is administered in a composrion that comprises one or more agents and the agent as a shorter hifcfe than the condRu o the in1tkon undi dose forms of the agcto and the compound of the invention my be adjsred according (00M61 The subject .phamncetical composition may, fb enpte be in a form titale for oral admsnistrati a a 35 tablet, csle, pil powder, sustained release formulations sohlion, suspension fr panterat injection as a sterile solution, pension or emuldon, for topical administraton as an o wninment or cream or for reead administration a suppository. nIe pharracsutcal composition maybe in unit dosage foms suitable fbningle admiristadin of precise dosages. Ike pharmaceutical composition will include a conventional pharmaceueal crier or ecipient nd a compond according to the invention as an acve ingredient in addition, it may include other edicinal or 40 phanncuical agents, carries adjuvanta, et. '87- 03621 Exempjlary paerai adininistration forms include sactions or suspensions, of active como: inser, aqueous solution, for example, aqueous pstpykne gge or dexrose solutior 5uch dosage forms can be suitably bufferd, if Cdesred, %3t03C The activity of the compoxTds of' the p-sent i mention may be detamined by the following proedurm, as 5 well as the procedure described inhe e apies below. The activity of the kinae is mses sed by neasurng the incorporation yof phosphate from Y fP-AT onto Ntrminal His tagged substate which is expressed in 1& coil atl is purified by convent id methods, in the prsnce of the kinar The say s carried out in 9&dl pOtypropyiene plate. The inzuhation mixee (i ph) comprises of 2$ tM lmepes, pH 7.4, 1, mM MgC1 2 , 5 rmM p glycelhosphate, 100 tIM Na-orthoanadre, 5 mM DTIT, 5 AM kor, and I ib p subsatMe, i[hibitors are ItD smpentded in DMSO, and all action including cntrois are perfonned at a final conceration of 1% D)MNIO, Reactions are limited by the addition of 10 AM ATP (with 0,5 4C &t ATsPtIl) and incubated at ambient temperature for 45 minutes. Equal volume of 25% TA is added to stop ihe action and precipitate te proteins Precipitated proteins are trapped onle glass fiber B filtrplates, and excess labeld ATP washed off using a Tomtec MACH 10. harvetor. Plates are allowed to air~dy prior to adding 30 pt/wd] of Packard Microsint 20 and plates are 15 counted using a Packard TopCemt., 03134 The invention aio provides kits, The kits include a ompound or compounds of the present invenden as described heren, in stable packaging, and written material that can include instmctions for us, discussion of linica studios. listing of sieefet and the like. Such kits may also include information, such as scientific liteature reterenes, package insert materials, dinical trial msels, andlor sumnaries of these and the like, whion indcAt yr . 20 estabis the aivities anor advntages of the -cwpostin sad/r which describe dosing, administration side effects, drug interactions or other iaformation useful to the hea care provide Such information may be basNd on the tets of various studies, for em ple, studies using experim eatdl ninal s involving in vivo mod ls and stsedies based on human clinicl tras. The kit amy further cntain another agent, in some embodiments, the comp ound of she present invention and the agent are prided as separate eompositons in sprate containers within the kit. in some 25 enmbodimenuisthe compound of the pment invention and the agent are provided as a single composition within a container in the kit Slable packaging nd additional artickls for usew (e &. mearnag cup for giquid prferion.i wrapping tm minnimze exosure to air, and the 1ike) are ikown in the art and may b included in the kit. Kits described herein can be provided, nwarketed andlor pommted to health prove induding physician roses, paaeist, formulary officials and the like. kiss tray also, in some enbodimemi.nt. be arkMeted directly to the coasoe. 30 METHODS l00B The invemion als provides methxls of usoig the camponds or phaNmaceuca compositions of the premnt invention to treat disease conditions, including hut not ignited to diseases asociad with mafractioning Of One Or otre typ of P3 kinase, A detailed description of condins and disorders mediated by p1l10 kinase activity is set forth in Sado at a.L WIO 0,111346 which is incorporaed herein by referee in its entiney fo ai purposes. 35 (00.36 The treatment methods provided herein comprise administering to the subject a iherapeticaliy effective amnt of aconm d of the inveniors in one eboditnent, she preses invention provides a method of treating an inlausmation disorder, including :autoinmmnsune diseases in a mammal. The method comprises administering to id ntarnnv a therpeiaticai y effective amnoumn of a compound of the present invention, or a phamaceutically acceptable salt, eater, prod/ag, solvate,. hydrate or derivative thereof, Eixamiphs of auto immune diseases includes but is not 40 lited to acute: disseminated ecephtemydit is (ADEM), Add-ints dimsast: antiphosphoiipid asntibody syndrome (APS), aptstic m emia autimmune bepats cediac disease, Crdas disaan, Diabetes tellieius (type 1), 485- GomdpasnoadaS syndrome, Graves dmsem Guimi~hrrc syndme (G}SX Iashimobds disenna ipua rythemayosns, muidk zAe scrmlis, myasthenii a gavis a o pockrLIs My donus syndrome ('OkMS) optic neurids, OrdsthyroitAis, oemnphigus, poyartritis, primnsy .bliary eirhosis, psoriasis, rhem matoid adhridL, Raeres ydanye, Tskayasgs atterids, teNporal arteritis (also known as "giam cell ateriis"), warM aUomrune heUOytic are.i Wegener's 5 granoulrmatou alKopecia universi, Chagr disease, chronic fatigrke syndrome, dysato ia, endonezriosis, hidradernita sappuniva, intertiacystisneuromyotonia, sarcidosis, sderodera ukertiv cols, vitilig, and oalvadyon.i Other disorders minete lorse-tsorpton disorders and thnoobs-. [ l0367 it some embodimoents, the method oft-eating inuaaory or autoimmune dises co-mprises administerig to a subject (eg a mmmal) a thaeapeutically emetidve amount of one or more comaposnds of the presn invotion 10 thmai selectively inhibit PIK4 andor PDK ' as compared &o all other type I P1 kineses, Such selective inbitir of PDK4 arr P aK ray be advantageu fo treating any of the diseases or condkirs described herein. For Smmp. seieetive inhibition vf PUK4 aay ihibit iflanmatry poses ass tated with iaamtory diseases, stomwat disease. or disease related to an undesirable iramunw response including but not limited to asthma, tOphysema dery, dernatitis, rheumatoid arthritis, psoriasis, Lupus eoythernaosus, or grat versus host disease. 15 Sleoesive inhibition of P1K- may farther provide for a reduction ir the iofamatoy or undedrable immune response without a concomittat redacon in the ability to reduce a bacteria viral, and/or fo infection Selecve nhibition of both POK-4 and PDK y may be advantageous for inthibing the infhammatery response in the object to a greater degree than that would e provided for by irnhibitors that selectivdy inhibit P3K -5 r PuK alone. In one aspect, 0n: or mort of the sutsject methods ame e ve in redc gnte specific antibody production in vvo b"Y 20 about 2fid, 34olid, 4-oK 5-fR-1d.544d, t0-fr'd, 25- d &fvld, 100-d, 2594fold, 5{0}oid, 750-Fhd, k r about 1000O-ld or moe In another aseee, one or More rfthse subject methods are efetrizve in reducing antigen specific LgG3 and/or IgM production in ivo by about 2-ibid, 34old, 44Ad, 54tld, 7$-fold, Itobi, 25-fold, -fold, 100 fod, 250-fold, $04old, 7504-oPd, or about i00-foldor more. 10036q in one aspec, one of more of the suiaect methods are effective in meIiorating syrmptom associated with 25 rheematoid arthritis incudg t not imked to s reductin the swdilng of joints, a reducion in serum anti-collagen tevhi and/or a reduction a jois pathology such a hone nousrion caage damage, pao-, andyor inlammpnaionm. In another aspect, the subject methods are effective in seducing eAke ilaratwion by at ast about 2%, S%, 10% 15%, 20%, 25%, 30%, 50%, 60%, o hout 7% to 90%. in another aspt the subject ehdrfftv in redwing kawm inammation by at last about 2% 5%, 10%, 15%: 20%, 25%, 30%, 50% 60%, or about 75% to 90% 30 or more. in stil another aspect, the swb ect mehds are effective in reducing serum anti-type 11 collagen levels by at iseat about 10%, 12%, 15%, 2 4%. , 25, 3%, 35, 30%, 60%, 75%, 80%, 0%, 87%, or about 90% or more. ln another aspect, the sijiest methods are effective in reducing ankle histopathology scores by abot 5%, 10%, P5%, 0%, 25%, 30%, 40%, 50%, 60% 75%, 50%, 90% or more, I still anther aspect, the subject methods are effective i reducing kne histopatholkgy sores by about 5%, 10%, 15%, 2, 5, 40%, 50%, 60%, 75%, 110% 90% or [00369j in other erahodients, hep t trivemi ion provides Mehods of using the compounds or pharmaeutieal composios to treat respiratory diseases including but riOt n iwitr d to disease affecting the lobes of lung, pleumi cavt hy, bronchial tubes, trachea, upper respiratory tract, or the nerves and tsicie ft- breathing For example, methods arm providci t treat obstructive pukrsorary disease, Chroni obstrudve pulmonay disease (CSP) is an umbats 41 term for a groUp of respitoswry tract diseases that are chararzmerized by airflow obstuction or limitation. Conditions included in this Uanbslrla term are: Chroni bronchitis, emphysema and bronciectass,

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[I3I in another embodimrtthe compounds descnbed heren are usetd for the weatment of whma, Ais, the compounds or phmacendal compcsinc described herein may be ued for the reanetme of ndaen ia and seps ei one embodNmeZr the compounds or phrmaceutcal coarshior described bereare used to for the 'reasnent of rheumatoid arthris (RAY In yet another embodiment, the compMunds or pharmceutcai compositions 5 descnbed herein is eUdi fir the threat of ntset or atopic dernaWis, Contact dermatitis includes iritants drmatiis, phototovicdrmatits, airgie deratidis, photodergie dermatitis ntact uia systemic tonutisype dermatitis ad the like litat deStis can occur whn too Much ofa sustane is used on te skin of when the skin is senitive to certain sobstae. Atoic rmiati. somimes caled eczema. is a kind of denunatities an opic ski disease 10 103711 The invention also relates to a method of tread g a hyrprolif-ba tve di sorder ins a mamma I that comprises administering to said manaal a therapxudically effective amount of a compond of the present invenio or a pharmaceuticdly acceptable tat, ester, prodrug, soiVame, hydrate or derivative helrf in sOne .emnbodimreni said method relates to te tratent of encer such s acute rmyeloid kukeiayrnu, brain lw squamous cd , skin eye, retina na, intraoclar mdlanomsa, ora cavity and cropharynged, bladder gastomach, pancreatic, IS bladder, breast, evcal, head, neck', renal, kidney, liver, ovarian, prostate. cdoreeial, esophageal, tesduar, gynecolgical, thyroid, CNS, PNS, MDS-rdsted (cg Lynphuma and KapUss Sarvoma) or virAi4ndced cancer inr some emnbodimenss, said method plates to the treatment ofa nonsvcanceus syperproliferative disorder such as benign hyperpiasia of the skin (c g, psoriasis), rteenis, or prostate (o, g., benign prorati hypertrophy (BPI)). [g9372] The invention a so elates to a method of treating i esesu related to vmasucgenessis or angiogenesis in a 20 mnamnial that comprises administering to said mammal a theapeuticaly effective amount of a componad of the present invt5tslor a a pharnmaceuticaliy accept-able salt, ester, pritdrog, stdhate, hydrate or derivative theref. In some embodiments, sad met&od is for treating a disease seected en the group consisting of turmr angiogecnesamis cron ilammnsatory disease such as rheumaoid arthitis, therscderosis, irflammatory bowel disease, skin diseases such as psoriasis, emmena nnd selerodernna. diabetes, diabetic retinopathy, retinopathy of prematurity, agew-elated maclar 25 degeration hemagiomas glioma, metanesa Kapit sarcoma and ovgiam bn t lg, rptscreatic, protstate, colon and epideonid cancer i4~~IPatients that can be treated with compounds of the present invention, or pharmsaceutieally acceptable salt, ester, prodrg, solvate, hydrate or derivative of said compounds according t th t' invention include, for eMnple., patiens (at have be diagnosed as havig psorias; restens; atherosclerosis; BP ; breast caner 30 tech a a duetal carcinoma in duct 1.ssue in a mammary and, medulary careinema coiaid cacinomas tubulr carcinomas, and infiammanory breast cancer, ova cancer, including epithlial ovarian tunors such as admocarcsmna in the ovary and an deocareine that hs migrated front the ovary into t'sabdominal cavity; uterine cancer; cervical cncer seh a adenocrcinona in the cervix epithelial ineUcding sqamous edl carcinoma and adenecardinomas; prostate cancer, such as a psoste cancer seleted orn (be following: an adenccarcinormn or a 3S ade-ocarinoma that has migrated to the bont; panematic cancer such as epithelirad aareinoma in the panreatic duct ossue and an ademcarcinoma in a pancreatic duct; &dder cMer suh as a trensitionl celarcinoma in rnar ladder, othiad carcinomas (transitional cci carcinoma tumors in the urothiad cels atine the bladder, squmous cell carcinomas, adeearcinmat, ad smal cell cancers; leakemia such as acute mycloid leukemia (AML), acute lymphocyde leukemia chronic lympcytic leuemia, chroic mydoid ema, hary ell leukemina, 40 mydeldysptassa, myelmsriw fetive di soarders, acute snyeiogneous eCukenira (AM L), chronc myelogeno leuemia (CL), mastocvtosis, chrnic lymphocytic leukemia (C multiple myeioma (MM), and mylodysplaic syndrome (MDS), bone cancer; ung ance such as non-sall cel lg cancer (NSCLC) Whch is divided into sqsamos cell -90caeinomas, adencarcinomas, and large cel undifferemiated carcinomas and Sa l g cdi icup cancer; skin chance ch as basal c0] crcinomamlnoma, squamous end carcinoma and actnic keratosis, which is a skin conditon that somw e*s develops into squamous Cod Cminm eye i mainabl asto ma; culaneos or itr aoukr (eye) melanoma; primary liver cancer (cancer that begins in the liver); kidney cancer; thyoi.d canrut such as paptliary, follicuIar, 3 medullary and mapiastID; MiDSrated lymphoma uch as diffse large elR Inoms, T!-ceIl immu nobInat!c lymphoma and smal non-cleaved cell Fymphosma; Kaposi Sarpomat, vinidaced cmpcers iroAdi.ng hepatitis B v4ms (HV), hepatitis C virus (HICV}, rind hepatcelltiar chnuom=a; bun lymphotropic virss-type I (1hTLV4) arnd adit T-celi ieukenillymphomga ad: hunan papi oma v irus (HPV) ad 6erviea ear. central nervous system coces {CNS) ch as pimary bain tumor which incade lomas (astyo aaec asoytosn, or gliob aei 10 mtiformre'l (g, odenog aEpendymmA Meningioma, Lymphoma Schwanoma, and Meduiihbastoma; periphera nervous system (PNS) cancers ,such as" acoustic umma and mahggsmat pedipheral nerve sheath tumor (MPNSTl) includig nsnrofibromass and sehnosa maignant fibrous cytama, maiigrnant fibrous histiocytoma, malgnant e mtmalinant m=e aioma and malignant mied MXV ilerian uamor; orl cavdiy and srohtygea cancer such a, hypopharyngl ca , lryngeal cancer, naopfharyngea cx cer, and oopharyngeal 15 cancer; stomach cancer such as lynphomas gastric roma tumors, and carcinoid tumors; testicular cancer sch as germ. cell tnumsrs (sCTs) which include seminom s and nonsceminonmas, and gonadai stromal itamors wich include L oydig cell tmors end Snirii ce timo; thymus cancer such as to thymomas, thymic carcinomas, Hfodgkin disease, non~Hodgkin lymphomas carcinoids or carcinoid tumors; rectal cancer; and coilon cancer. 10410741 The invention also rates toa method of treating diabetes in a mammal tha comprises administering to said 20 mamnmtml a thera1euticay effective aoNnt of a compound of the present invention, or a phannmsceuieily accetNable ami ester, prodrwg, solvatw hydrate or derivative thereof, 1037gI) In a dditon, the compounds described hereim may be used to treat acn 7 addifim, the compamds described herein tmy be used for the treatmet asrteriosclrosis including atherosclrosis Arteiosclerosi is a general term describing any hardwing of medium or large anerries 2$ Atherosderos s is a hardening of an artery specifically due to an aTeromaTus plaque. [1771 Further the compounds described herein may be used for the treatment of glomeruionephritis, Glomerukmoephritis is a primary or secondary toimmuue renal disease characterized by inIfamnmation of the glomeruL it mray be asymeptomatic,:Qr prese with hemaruria anIor a Thee are marty recognized types divided in actnu subacute or chronic gklom monephritis. Causes are infectious (bactenedl, viral or parmite pathoge)s, 30 aiuimmune or paneopiastic, 7 Additioro , the compounds described herein may be used for the treatment of burskit lsus acute disseminated encepaomnyelis (ADEM), addisots disease, antiptsphotipid antibody cynrome (AS ipstie a ,emia autoinrunse hepatitis wolinm disease, trotns disease, diabeteusmli (type it goodpstures syndrome geaves' disease. ginaim-barvs syndrome (CSL hashimnotos disease, ingammmiatory bowed disease lupus 35 eryrhenmtosus, myastlhenia gravis, opsocious myoclon s syndrome (OMS optic neuis ord's ridis,ostheoarthrais, uveoretiniti o p phigs polyarthritis primary biliary cirrhois, reimS syndrome. fakaye s arteritis., temporal ariettiss warm atimnmuoe hemolyi aemia wegeners grndocnnosis, alopecia niversalis chagas' disease, chronic fitigue syndrome, dysautonomia edometriosis hidradeni sppurtia interstitial cystitis neusyotonie, sarenidosis, scerodenme. ulcerative ccl inig vitiiigu, vuivudynia, arppmsdiciti. 4P asterais arritis hiephatis, hronchimmiii bronchitis" tcrvcis, cholasnis, choiecyattis, chorionmois coltis concntivit estia, dacrycdenitis, dermatomyoitis enducarditis endo tis enternis cmterckis, epicondylitis epididymitis, fasciltis fibrositis gastritis: gastroentermis gingivitis hepatmis hidradienitis sitis trits, -96laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis. 5 [00379] The invention also relates to a method of treating a cardiovascular disease in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. Examples of cardiovascular conditions include, but are not limited to, atherosclerosis, restenosis, vascular occlusion and carotid obstructive disease. 10 [00380] Disclosed herein are methods of disrupting the function of a leukocyte or disrupting a function of an osteoclast. The method includes contacting the leukocyte or the osteoclast with a function disrupting amount of a compound of the invention. [00381] Disclosed herein are methods for treating ophthalmic disease by administering one or more of the subject compounds or pharmaceutical compositions to the eye of a subject. 15 [00382] Methods are further provided for administering the compounds of the present invention via eye drop, intraocular injection, intravitreal injection, topically, or through the use of a drug eluting device, microcapsule, implant, or microfluidic device. In some cases, the compounds of the present invention are administered with a carrier or excipient that increases the intraocular penetrance of the compound such as an oil and water emulsion with colloid particles having an 20 oily core surrounded by an interfacial film. [00383] In some cases, the colloid particles include at least one cationic agent and at least one non-ionic sufactant such as a poloxamer, tyloxapol, a polysorbate, a polyoxyethylene castor oil derivative, a sorbitan ester, or a polyoxyl stearate. In some cases, the cationic agent is an alkylamine, a tertiary alkyl amine, a quarternary ammonium compound, a cationic lipid, an 25 amino alcohol, a biguanidine salt, a cationic compound or a mixture thereof. In some cases the cationic agent is a biguanidine salt such as chlorhexidine, polyaminopropyl biguanidine, phenformin, alkylbiguanidine, or a mixture thereof. In some cases, the quaternary ammonium compound is a benzalkonium halide, lauralkonium halide, cetrimide, hexadecyltrimethylammonium halide, tetradecyltrimethylammonium halide, 30 dodecyltrimethylammonium halide, cetrimonium halide, benzethonium halide, behenalkonium halide, cetalkonium halide, cetethyldimonium halide, cetylpyridinium halide, benzododecinium halide, chlorallyl methenamine halide, rnyristylalkonium halide, stearalkonium halide or a mixture of two or more thereof. In some cases, cationic agent is a benzalkonium chloride, lauralkonium chloride, benzododecinium bromide, benzethenium 92 chloride, hexadecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide, dodecyltrimethylammonium bromide or a mixture of two or more thereof. In some cases, the oil phase is mineral oil and light mineral oil, medium chain triglycerides (MCT), coconut oil; hydrogenated oils comprising hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenate 5 castor oil or hydrogenated soybean oil; polyoxyethylene hydrogenated castor oil derivatives comprising poluoxyl-40 hydrogenated castor oil, polyoxyl-60 hydrogenated castor oil or polyoxyl-100 hydrogenated castor oil. [00384] The invention further provides methods of modulating kinase activity by contacting a kinase with an amount of a compound of the invention sufficient to modulate the activity of the 10 kinase. Modulate can be inhibiting or activating kinase activity. In some embodiments, the invention provides methods of inhibiting kinase activity by contacting a kinase with an amount of a compound of the invention sufficient to inhibit the activity of the kinase. In some embodiments, the invention provides methods of inhibiting kinase activity in a solution by contacting said solution with an amount of a compound of the invention sufficient to inhibit the 15 activity of the kinase in said solution. In some embodiments, the invention provides methods of inhibiting kinase activity in a cell by contacting said cell 92A with a amount ofacompoundof the invetion suffiiem tno inhibit the activity of the kinase in said celL. I ome embodiments the invention provides methods of inhibiting kinase actvity in a time by contacting mid tissue with an amount of a sopound of the invenion suffcient to inhibit the activity of the kinase in said tissue, In some odimets, te inventon povides methods of inhibting'kmns activity in nrganism by contacting said organism a wih An amount of n compound of the invetion sunffiet to inhibit the activity of the kinase i: said organtim, In some etbodimaents, the invention provides methods of inhibing kinase activity in an animal by contamdrg aid animal with an amount of a compound of he tinenien efficient to inhiit the activity of the kinase in said animaL In some embodiments, the invention provides methods of inhibiting kinase activity in a mainmal by contcilng said mammal wih an amount of a mpond of dhe mention sufficient to ihibi te activity of the kinase in said w-ammat 1W Il sonte embodiments, (be invention provides methods of inhibitg kinse activity in a human by contacting said human with an amount of a compound of he invention sticiet to inhibit the activity of the kinase in said humais. In some embodiments, the % of kinaet activity after concing a kinase wih a compound of the invention is less than 1, 5, 10, 20. 30, 40, 50, 60,.70. 80 90, 95, or 99% of the kinase activity in the absence of said contacting steps. [0O351 In 'some embodiments, the kinase ise a lipid kina or a protein kinase, In sonme embodinments, the kinase is 15 setcA fOm the group consisting of PD3 kinase including difEferent isorformss such as P13 kinase :5, P13 kirmse fi PD3 konase P13 kinase 6; DNA-PK; mior; ANd, VEGFR, Ephrin meceptor B4 (Eph4) TEK receptor tyosine kinase (TIE2); FMiS-related tyrosine kinase 3 (FLT4 Platelet derived gowth factor receptor (PDGFR); RET; ATM; ATR; hhmg4; lelk; Src4 Epidermal growth factor receptor (EPRP); KIT; Indisin Receptor (CR) and 10FR. 103g:6 The invention further prOvi rmeleds of emodulating P13 kinase aeti by contctilg a P3 kinese with an 20 amountofa compound of the invenion sufficient to modate the activity of the PE kinste Modulae can be inhibitig. or activating P3 kinase activity. In some embodiments, the invention provides methods of inhibting P inase actiday by contacting a P13 kinase with an amount of a cormpoutnd of the invention seufiient to inisvit the activity ofthe P kinase, In some embodiments the inventin provide metho of inibiting P3 inase adivy. Such inhibition an take phae in solution , in a cell epresing one or more P kinases, in a tisue comprising a el 25 expressing on or more P.1 kineses, or in an organism espresing one or more P13 kinss in so-e enmbodimsents, the invention provides methods ofinhibting P3 kinase ac tvity in an cald (incding mammd such as humans) by contacting said animal with an amount of a compound of the invention efficient to inhi bit the activity of the PD kinse in mid animalt 30 COMBINATION TREATMENT 0357] The preset invention maso provides methods for comointion therapies in which a agent known to modulate other pathways. or other omponets of the same pahway, or over overlapping sets of target enzymes are med in combination with a compound of the present invention, or a pharraceuticay acceptable salt, aster podrug g te hydate or derivative hereof in one aspect, such Cheampy inosdes but is not wanted to the combination of thosubict 35S compound with chemotherapeutic agents, thapeutic antibodiesand redf kton treatment, to provide a synergistic or addative therapeutic deet I 0388. In one aspect the co ponds or pharmaceutid compositions of the psent invenin may present ynergistic or additive efficacy when administered in combination with agents that inhibit igEf production or actvv. Suh comb aion cn reduce the un-dkgired effect of high level of IgE associated wih the use ofn on 0 r more PD'K6 40 inhibitor if such effecs occous- This may be particularly usefd in trcatmentof autoimmeun and inflammatory disorders (AlitD) sch as rheumatoid arthritis. Addidomldly, he admistatoa of PUK or Pl3K/y inhibios of the '.93present invention in combination with inhibitors of mTOR may also exhibit synergy through enhanced inhibition of the P13K pathway. [00389] Disclosed herein is a combination treatment of a disease associated with PI3KS comprising administering to a PI3KS inhibitor and an agent that inhibits IgE production or 5 activity. Other exemplary PI3KS inhibitors are applicable for this combination and they are described, e.g., US Patent No. 6,800,620. Such combination treatment is particularly useful for treating autoimmune and inflammatory diseases (AIID) including but not limited to rheumatoid arthritis. [00390] Agents that inhibit IgE production are known in the art and they include but are not 10 limited to one or more of TEI-9874, 2-(4-(6-cyclohexyloxy-2 naphtyloxy)phenylacetamide)benzoic acid, rapamycin, rapamycin analogs (i.e. rapalogs), TORC1 inhibitors, TORC2 inhibitors, and any other compounds that inhibit mTORC1 and mTORC2. Agents that inhibit IgE activity include, for example, anti-IgE antibodies such as for example Omalizumab and TNX-901. 15 [00391] For treatment of autoimmune diseases, the subject compounds or pharmaceutical compositions can be used in combination with commonly prescribed drugs including but not limited to Enbrel®, Remicade*, Humira*, Avonex®, and Rebif*. For treatment of respiratory diseaseses, the subject compounds or pharmaceutical compositions can be administered in combination with commonly prescribed drugs including but not limited to Xolair*, Advair*, 20 Singulair®, and Spiriva®. [00392] The compounds of the invention may be formulated or administered in conjunction with other agents that act to relieve the symptoms of inflammatory conditions such as encephalomyelitis, asthma, and the other diseases described herein. These agents include non steroidal anti-inflammatory drugs (NSAIDs), e.g. acetylsalicylic acid; ibuprofen; naproxen; 25 indomethacin; nabumetone; tolmetin; etc. Corticosteroids are used to reduce inflammation and suppress activity of the immune system. The most commonly prescribed drug of this type is Prednisone. Chloroquine (Aralen) or hydroxychloroquine (Plaquenil) may also be very useful in some individuals with lupus. They are most often prescribed for skin and joint symptoms of lupus. Azathioprine (Imuran) and cyclophosphamide (Cytoxan) suppress inflammation and 30 tend to suppress the immune system. Other agents, e.g. methotrexate and cyclosporin are used to control the symptoms of lupus. Anticoagulants are employed to prevent blood from clotting rapidly. They range from aspirin at very low dose which prevents platelets from sticking, to heparin/coumadin. 94 [00393] Disclosed herein is a pharmaceutical composition for inhibiting abnormal cell growth in a mammal which comprises an amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof, in combination with an amount of an anti-cancer agent (e.g. a chemotherapeutic agent). Many 5 chemotherapeutics are presently known in the art and can be used in combination with the compounds of the invention. [00394] In some embodiments, the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response 10 modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens. Non-limiting examples are chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules such as Gleevec (Imatinib Mesylate), Velcade (bortezomib), Casodex (bicalutamide), Iressa (gefitinib), and Adriamycin as well as a host of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide 15 (CYTOXAN Th ); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; nitrogen mustards such as chlorambucil, chlornaphazine, 94A cholophshamaid, cstramssting ifasfamide, mecaore haine, mnezhirethamine oxide hydrchkni de, mephaaid novembichin, p s~asina pedasatine, trofosfmi&, ueil smusttnta -tsaas such as a'n ehkmainein assi~n, iomnustine, ni*rmte rasnmustin; andhi~OtiCS .keh as acinomyn actmnycina, thramycin, msene, bleo-Mycins, eactmnmycin, edichaamica camblir carnomyc ia nipin, Cad 5 , chw asaycisi dadiMaY6 M, dammrubicin, dea biah 6-diano-5-oxoaodenine, doxambicia, epirubiina, esnbieit idambhkians reyc mitomycias, mycophenole cid, nogdlamyei, ivasmyeis, paphomynin, potfirnamya, pwomycint qcamycin, dorubinim strepiigrna, streptosod id, atbereidin, ehnien, nons.i zEtbzicia*stietaboiaes sach as mahotrexe ad 4iketouraci (5-FU) foLe acid aniaogus suh as denopteria rrnhotreant; pteropnerin, triametrexate; parine anaegs t toh as Uds &mer anptpurine, thianrmpine, 14 thiogaed; pyrmidine atlogs such as ancitainne, azcitidine.erkuridie carmofir, cytabe, dndeoxyaride doxinuridines, croitshime, floxaridine, andsngerss ksah as esterone, &dnmosianoOne propionae, epitiestancd a psat tas estatee; wmi-adene c sh a- ,miogtaetddie amitotane, tai iosta fkic acid repdnishera s as frotincatid; acedatone; aid phsphamide gtycnaida; amninolvnliinic acid; amsactne; bestrabociI; hisantrene; dstrante; defo hmine; darceoicine; diezkquone; el within; ettiptinium acetate; etogiasid; gahium ninte; 15 bydoenyurea; tinan;~ leadaie; mfito pane; neitentrone; miopiamoLlt; herrrin; pentOStatin; phenae; pimmasbtda; podophyi-nic acid; 2-hyydaide; procarbains; PS3K. Qm; razoxrne; sisatfinn; spiogernaaum; renuazeate acid; tiaune; 22,W'riehao tiertayi aine; wretkas; vinsie; decarbanine; manue; mrnetoonkoI; msitotacto;; pipobromsa; gacytosine; arabinoside ("Ara-C"); cyciophosphamnide; thiotepa; axanes, esg paclitndi (TAXOLF" Bristot-Myer :Squibb Oneciogy, Prictn Nf an deeae (TA~XOTERE1§ Rhone 20 Posuene Rotor, Amory, grance); retire c; cpram-eint; capeeirbine; and pharmaceuticlsy acceptao- Sds, acids or devasives of may of the above. .Ado inehtded as snitabt chemsothearpeuuc e oconditioers are art~ hwrmona agents that att to regulate or inhibit horane aton on 0MaIr -uth asnti-estaogas induding fr lape tsaoufe (Noivndhe t raixie, oromasse inhibiting 4()irmdato-ts bdmayamoufen, trioxiferse kooxfenc, LY tI30 gs, onapriatne, and ternmifene (Freston); and antUandogens anch a futamide,lutamide bitdmamide 25 feanide, and geserelin; dlramboci ; g etabe; :6-thioguanne; aerapoprine; methoreate; p-a=tan andlogs sauch as cisplari and earboplati; vinbstine; piatimmw; etoposie (VP-6; is ; mtomyein C; mitoeartronse; ienrstina; vinorelibie; aevebie; novaroe teniposride; danoyit amrinopteria; xdoda; abndronate; camptothdn-i (CPT4- 1); topoisease inhibitor RFS 2000; difluroehykotinei (1DMFOD)- Where denired, the ogaunds or pharmaceutical composition of the peseau nenbion can be used in vom atson wKh coo y 30 prescribed ati-can dogs such is Nerceptini Avan Erbituxe. Ritu-anT Taoit Arimside, Taotere, and Veleade*. 0039S i-s invetion fSher rdats to a method for uring the compounds or pharm eed compos! a combination wath radiatdon thaapy in inhibiting abnorMa ceI" gowtht or treating the hyperprdtifed lve disorder in the mamrana Techgaiqu fr adiarin radiation thapy arm known in the art, and those tedhiqecan be used in the 35 cobi on ip desie--d heren The admida tn f rth xond of the iwentien iht this conouaton tbmrpy nan be detrermincd as described herein. I03i% Radiation therapy can be ad0eistered through one of several nmtods,r acofmbinationofimehos, i:alduding wihert limitaetn esIUemralbeam therapy, rtermad radiation therapy, impant radiation, strrevai adioargery, systemic radiado therapy, radihrapy and pr rsrat or temporary intershziaf braehyihcrapy. Thc 40 term trachythepy," as used herein refers to radiation therapy dived by a spatidAly confined radioative nated nserted Mine the body at or nar a tumor or -kher pronterative tssue disease ste. The term is intended without iiatdon to inlude e saeatoradicactive isotopes (eg At-2t1, 1-01, t423, Y-90, Rel, Re-48, Sm$ -95- 212, P-32, and radactive isotopes of L) Suitabe adinion VsoaM f use ;s a Cdc conditiacer of the present mention include both solids and iqtukds By way of nondimiting example the radiation sonte a he a radionucid, such as 125, 41, Yh69, Wu192 as a solid source, 125 as a solid source, Or other radionueldes titn emit photona. beta particles, gmMa radiationer or therrapeutic rys. The radioactive material can eso be a flW made from any 5 sointion of radioellde(s).g, souidon of I2$ or -131, ora adi active tid ca be produced using asirty of a suitable tnid continuing sqnall parties of -t4 radionlides, such as AU-19%, e90. Moreovr, the radionuwcide(s) can be embodied in a gel or radioactive micro pere& [O397j Without behtig ia d ry any thIoy, thcompods of the present invention Cn render abn eedh' mor sesntive to trasment wih radiation for puroses of kilingandlr inhibitig the growth of such els. According, 10 this invention further relates to a method fur rsitiring abnormal els in a mammal to treatment with radiation which comprses administering to te mramnal an ant of a compond o the present inavedon or phermaceally acceptable sa4 ese, pdrtug, se, hydrate or derivative thereof, which amount is effective is sensitiZng abhaan cedls to treatment with radiation. .1e amunt of the compnsnd,sah, or solvate in this method can be determined according to the omeass far scertainirg aTective amounts of such conounds described horin 15 39 ihe compounds ow p tentsetkni Ctrnponse of the present invention can be used in comb"in wih an amount of one or more substances selected eMon ani -agiogensisagents, signal trAsduction inhibitors, and 4nipmlifative agents [09399) .Anti'argogenesis agemso, such as MMP-2 (msattdsoetsdopotianase 2) inhibitors MMh4P-9 (main' msetstopsosiesnase 9) iU itors, ad COX-il (eloosygerse 11) inhibitors, can be used in coniunction with a 20 onpound of the present inventm and phamacesaticl compositions dseried herein. Etmoes of cOs X1 ihibx include CELERrEX7h (aiacoxdb). valdecam and rofonis. Examples of useful matdx metaiopmteinse inhibits are described in WO W31172 (pubLisled October 24,199f), WO 96/2753 (published Marh 79 Euwpean Patent Appkation No- 97304972.1 (ied My 8997), European Patent Application No, 99309617,2 (fed October 29, 099), WO 98/07697 (published February 26,1999), WO 980350 (pubished January 29'1998), WO 25 98/349119 punishedd August 13,99A), WD 98/34915 (published August 13,1998), WO 98/33768 (pubnshed August 619983, Wo 98100666 (pulished July 16, 1998, Em pen Pten"t P06,046 (publshed M y 131994 Euwopean Patent Pubiication 93 78 publishedd My 283,1999), Wo 9005729 (published May 31 ,990t WO 99/52910 publishedd October 21,999), WO 99/52889 (published October 21 1999 W 99/29667 (published June 17j9991 PCT Thnte'atioa Applicaton No. PCTh:98/0l .3 (filed JMy 2 i)9981, Eukroptaa PreNm Applcation No, 30 993022321 (filad March 25999), (irvw Britai-n Paent Application No. 9912% 1 (fied June 3, 1999) United States Provisonal Applicadon No, 60/49,4-64 (flied August 1231999). United Siaes Patet 5,863, 949 (issued anuary 261999) United States Patent S61 510 (issued isnuary 1919991 and European Patent Publication 780386 (published Juae 25, 1997) a' of which are incorporated heta in their entieties by reerence, Prefered MMP-2 and MMP-9 inhi btors are those that have ittie or no activity inhibiting MMP- More prefirre are those that soleed-iy 35 inhibit AMP-? Ma r A.MP-9 relative to the other t eaioproteises (iL a MAP-I, MMIP3, MMP-4, MMP-5, MMP-6, MMI 7, MMIPDM MMA, MMP42, andMMP43), Some spefi exempes of ?MP inhibitors tsfiti in the present i:cven5vlion are AG-3340, RP 323555, and IRS 004061 The invention alSo relates to a method of and to a pharmaeutiere cmposition of treating a cardiovscuiar disease in a trammrnat which comprises an amount of a cenpoun d of the present invention, or a pharmnaceueallyv 40 acceptable salt, eter, prodrsg, sohee, hydrate or derivative thereof, or an isotopicalydabe led derivative thereof and an amount of one or more therapeutic agents use tfor the re-at-ent ot ardiovactlar diases. -is- (0l40l] Examples for us in cAdiAvoldar disease appiatiantare atdrombotic agents% e"g prorosaclin and Wicylat. thCnmboyd g s e, straokiase. w-Aomase tissue piasminogern adoator (TPA) and vieylated pihasingen-prokinse aTivator complex (APSAC Padtns agents e, acetyl-salicyise acid (ASA) and chopidrg, ~Vasodiiktiag agents, eg, nirates caciui channel blocking dogs tiproliraie agents. tg, 5 colchirine ed alkylating agets, interacting agents, growth modulating fa such wa in'tdekir tra-Ormaton growth factorbeta ad eners oflatsiet derived glwTh factor, moncoenld tibodies reacted ag nst gxwth ftors ant-famatory agras both stemidai and nomsterokal and other agents hat an didatc vesse toanc tanctio, rterioselerosi arnd the heeling response o vessel or organ injury post intervention. Ant itics cn ao be inudedncobnions~ or coatings comprised by thseinvend Moreover, a costing can be used to effect 10 h ampeade delivery focay dn the vessel walI By incosporawIn of the active agent in a sweiable polymer, the eive agent wiN he released upon swelling of ithe plymer, {10402] The compomds dedbe herein may be formulated or administered in can junction with liquid or solid tissme bardiers also known as lubricants. Examples of tissue banriers include. but are nor limited to, polysaceharides, polAYe seprafdm, intered and hyauroni acid 15 [o4t) Mediemments which may 'e administer in conjuction with the compounds. described herein inceude my suitabie drgs usefully deIverm by inhation for example, atIcs, e~g codeine, dihydronorphine ergotamine, fentanyt or nmrphine anginal preparains eg dieg iaen; andal lergics eg, c "oglste, ketoien or nedorehe1mi antidnfectives e.g, cphalosporins penic ilina, streptomycin. suphoanides tetracyciines or penamidins; ndihistamines e. e tapyrilene; etiinflammatodies e.g, beckmrethasone, fiunilide, b aesonides tpredne, 20) traseenoioe actonide or fluicso' antitessve e.g.ansapine broachedilaors, e.g. ephedn, rdonaline, fenserd, fornsolema. inprnal ineMa metapmoternol, phe&ynephrnk pe nylpropaniamin pdiuter apyoteoL imsiterotl saibanol sahmeterel terbetalin, is&tarine, tultbstro, orciprenaline or (-4ino45-dichboo>adj61 [2-(2pyridinyl)cthoxy~heayl]-amino'jrthl~benze emethaaol; diuretics. e~g.axiode; antichinergics e.g. rpetrpiura, atopinc or c xropium; hormsones esg cortisonc. hydocordisosse or pdistalone; aanthines eg 25 aminophyl:leZ choline theophyilinate, lysine theophylinate or theophytiine; ad therapeutic proteisa ad peptides e.g. 'nbin or giucagon, Rt will be clear to a person skilled in the art that.here appropriate, the ntedicamsents mtay be sed in the arm of sals (e~g as alkali metal or amine salts or as acid sddio sas) or as esters (eg. lower koy esters) or as soivates (e.g. hydrates) So optimize te activity adtor stability of the medicament. 0e641 OTher eXemplary therepeade agents Uself for a combination therapy include but are not ,mited to agets as 30 wc-ribd above mdiation therapy, hormone ansgonists, hormones and their reeasing factors thyroid and atyroid dugs estrogen aMI pogeans, androgens, adreocorticotropic bormoet adrenocorical steroids and their synhetic analogs inhibitors of the synthesis and actions of adrenocorded homenes, insulin oral hypoglycemic agents and the pharmacology of the endocrine pancreas. agets afsetaig cdeaication and bone turnover: calcium, phosphate pamahyroid hoirme, vittarnin D., c onin itamirs suc as water-soluble vitamins' vitamin B complex ascorbic 35~ acid. tsoiube vitamins vitarnins A K and B, growth Tacssxr, cytoisines chemnokises mnucarinic receptor agonists and antagocnists; anucholinesterasa s; nt agents actng at he neuromud junction and/'or autoni ganglia; cateoho lmidnes symnpashomnimnetic drugs, and adrenergic receptor agoniists or amtagonists; and 5hydroxytryptanine (S4-i I srtreceptor agonistns rd antgoniss. g004051 Therapeutic agents can aso include agents for pain and inflmmation such as histamrtine and histamine 40 antagonists, bradykinin and bradykinin antagonists, 5 ydrxytrypta serotonin ) ipid substances that are fmzerated by hiotranstbrman of she produamsoihmsective hydulyds of m braMIC phophoiide icosanids prstsgtandins, mrmboxanes iko:tes. aspirin, rn eiddal i-tnfmnaory agents aiaescntpyredi -97agents agents that ihbi; the symbesis of pstagindire an troboxars seisaiva inhibitors Of the inducible iyexyense decnse iniRbitors othe inducibe eyclo. ygrse, autacoidst, paracrine rones, somatostatin gastric Mytokine that mediate interactions invoveed in humoral and celiular imunume responses, pid-die saccid, a icosanoits, Ydr &ergi agonists, ipratropiumsn, gIuocoticids, methyhxthines, sodiuo chanud 3 biocktas opioid receptor agonists, acium cannel bcekeM mmbranc sabiliers aad eukotric.e tibioas ['04061 Additional tbhapeutic agents contemplated heroin include diuretic, asopassin. agents affeeing the renal consevatin of waternnin, aniotend, agents useid in the treatment of y jrit ischemaa, anti hypve eiv agents angoteas n onverti h y rzymte inhibi k drenergic receptor antagoniss, agents for Ihe treatment of hypercoeraokrii aid agws for the tretmebl of dYditPdIIMa, 10 ({IO4071 Othert thrapende agents ocstmplaed indude drugs used for control of gasric acidity, agentsfr the h treaint of pepd ulcers, agents for the treatment of gastosphageal refiua disase, ,,, iagats eis agaes used in aritabie bowel syndrome, agents used for diarrhea. agents used fir constipation, agents used fT in'latinary bowel diseasegts used tr biliary disease, agms used fo pancreatic disease. Th eudie agents used to treat prM ifetions doings used o tre3t Mdai - Ametbasis, iiasdiasis TriChornoniasis 15 Trypnosoniasi, adFor Lishmnaiasis andor dgs used in the hemothera of heiminthiasis, Other therapeutic agents irciud anitilicrobial cotsu Nuifblwandl& rm'J rmu nehsso quip'tfJkottcS aidi agents forwinary tract ine't' psicias, cepuhaosporin., and obesh atam antibiotic, a agent ompridaig an ninglyoside, protein synhesis inhibitor&, drugs used in the h nothpratsy of tubtwksts mycobucteiun avum cosptex disease, an eprosy, adfunga agea, anivirl agents including nMonetrova agts asd atiroviral agents 20 100408) examples of'therapeudi anibodies that cmar be cotmtbined With a stbjct compund inclu but are no imited to a.i-rssecptor tyrosine knase antibodes (taimah, paniummmab, trastnab), anti CD20 witibs ox toaniof b), and other sbdies such as enitussab, bevaciIaa, and gehntunab. 100409] Moreover, theapeutic agents used for imnmunomnodulation, such as imnemsodalaser, iramunosuppressive ailagms. tiuerogen, and immunostinuats are somnrapated by the methods herein, In addition, thepeti agents 2 acting on the bloNd and the hsierfocrmning organs. e;natop ietic agents growth factors, minerals, and vitamins, anticoagulant thromboiLc, and antiplatelet drugs 104101 Further therapeutic agents that a be combined whh a subject comen nd may be found in Gaedw-sa and Gilmvns "he Pharaosied1 Basis of Thrrpeutics" ITnh &ion added by H-ardiman Limbird and Gilma or she Physdias Desk E4 efeRemce, both of which et ncorpoaned herein by referee in their entirety, 30 1404111 'The compounk descri bed herein Can be used in combination wits the age.ms disclosed herein or sther suiable agents depending on the condition being imated Hen in sne embaiments the onmmpounds oft the invention WilW be meadmniter with other agents as described above 9When us in, combitin theapy, the compounds described heiu rmay be admini staed with te second agent sunutaneously or s tely, Thes admnistt'adn in c mb nation can ind ade dmiswtmneous administration of the two agems in the ame doage Ormni, 3! smumsaeess administration in sepate dosage forms and separate administation. That is, a carnosm d described herein and soy of the gr\ts desent bed above can be famrkted together in the asane dosage form and admsini tored snulraneosly A temativdy. a cotpound of the present invention any of the agents described above can be sirmultteotly administered, wr t ein hosn the agent a presem in separate forrmuans. In other alteadw, a eompound of the preset inventds can be administered ja y ofthe agents described ribove, or Vce 4 W vel t the separate adniinistraion protncol, a compound of the present invention ad any of the agents described above may be adirdstend a few minutes apart a few hours apart, or N few days apart, [00412 The xtmpes and prepations provided balow father Pusstate ad exempffy he coop",ds of the praense invention and ma dstO of poparg wah compounds.t is to be tmdestod that the scope of the present iniesto rnt imited in ary way ythe ope of the fionowing ens-pts andi p potions in the following eampies melds wth a sngle fvtmral cet ordess otherwise noted, est as a raemic mitu Thos moieades with two or more 3 4dm! centers. fl'ets otherwise oted, st Zu as a racasc mixture of diastereomers, Single enutiomidiastercmers Tna be oIS ned by methods known to those skilled in She art EXAMPLES 1004131 Exampe 1 Synthesis of 2((4a nra (3-ydroxyphenylk H-pyralt[34-dipyrimkun yl)methyW5 mthylo3+olyhpyndo(2,3- d~pyimidin-4(3H-ome ( Compod 1406) 10 0041 Scheme 14, Synthesis of 2({4-amino-3lydroxpheyV H-pyazo4d)pydrid1nAyt)metyi4 mthy 3+-oypyrido[2.3drpydd(3H$5n (C Compound~ 1406) is desced.e CH2(CN)y Pipendinal NHyMeOH KOH AcOK (CNs RT N iPrOQHM20 RT Ovenght A Ovemnght Reftux M O Met Ohiogg 50 hmr 101 102 103 02 'O S 0 r' OM N, 1W BuLiTHE 7 < AkN jNI cw mH 2 icZau c. RT.. Overnight 2<C01S 104 1401 1402 Pd(OAc5k POCk 0 <-N C N Seaed1Mbe NKDF OH H-W O N N N N 80 *C, overnight 115*. Overnight HO 1403 414 140 6 IPSA ~ ~ < 14140Cs HIM6 OH 1406 15 jet4I5] To r stirred sohnion of 4IdeThoxy2butanone(01)(61 g, 95%, t393 mol) <-a acid {2,2 WL, *,038 mmol) and piperdine (33 mL, 0.03 Ma in tolene (150 mL), m ttio le (25 j. 0394 nina) was added in portmins over 20 min. The reaction rnitare was stirred eiht at room temperature. The resvig dark red sAludion was washed with H ) (50 mBL), dried over MgSO, and conce~ntkrtedc in vacuo to afford the dedred product 2-(4 dime mbus2yuee doncstil (102) (70 p. 99%), which was used direcdy in the neot stes 20 [04I6 Ammnira gas was tsubbded through a arion of 102 (32 p< 0 178 smmsol in MetSH (500 mnL) for 3h, the uldg deep-red solution was stirred ovemrigh at room terperture, The tixu ws conce'traad and the ridue wa pariored between CI solution (2 N, 600 nL) and tOAc (600 al), The aqueous ayer was sepaamrd and basified with iceood concentrated NsHC 5 KOt) 0 IL) solution, The soid was prcipated our of the soletin and oleried by nfanion to afford the desired prxdet 2(Mno- 4 tbeyni cortioni(03) (t0g, 33%). 25 1004171 Compound 103 (5.32 g, 40 remol) was ssp-ended in a solution of poamsium hydroxide (26M g, 4&0 m o) i water (26M ML) and ian-propannl (9 6 Ml). The reaction rixe was hed to reflx for '0 h, the cooked to 99room temperature id diheed with ce-water (0 mLtw) and neutralized with conentrated . C( solution ntil PH 6 7, The mixtr m con atied in vacuo and the resting residue was prified by flash chromagaphy dug wih eth;no to adffrd the desired gradsct 2 n mhyrantinie acid (104) (1284 g, 547%) (0O418] T a sted soluhdn of 1#4 (3,2 g, 2L2 mmcl) in DMF (40 $tL) and DCM (80 mL) was added EDO ( 2 g, 5 424 mno), HOt (2 g.6 , 214 mmoi) and oTowidine (4,53 mL, 42,4 mml), The roationi mixture was sdirre ovem igt a rom tesmperste and thn poured into water (120 L), The aques phase was .eiseted wih DCM (60 ml. x 2) The combined orgaoic phase were washed with huine, dried over MgSoh 6 reutal ad cooented. The solid wast precipitated eut of the soutior; The solid was coleeded by filtration and dried to afford dhe desired product 24amino4-imihy1katuyideod6ide (1401)(3. 6 70.4%), It 10419 A suspension oF.1401 (1,2 g, 46 miml) in dry THF (60 mL) was added buylUithiun (23SM,2.3SL, 56 mmol) dropwise under Argon at 40 *C and atrred at this tepature for 1 a Then the reaction mite was cooled to :480"C and cthioroacesyQivhiride (0A3 rL, 5.4 mml) was added, After mtriag for .2 at 48 dihe reaction nmiture swas pouri water (100 mL). t After most of THF was moved in vano, the solid was precipitated out of the solution. The sold was collected by fhtration and washed with ether o affrdi the desired product 2-(2 13 S ceaeetamidc)4-mahyitoiylicodamide (1402) (890 mg 56A%), 1O04101 A mixture of 1402 (320 mg, n mmxl) and phosphcrs oxyhkride (20 mL, 24nmol) was heated -at 115*C ovemigia in a deed, tihbe. 1Te retion mixture was coo)ed to orm errperasmre and concenrat in vacuc. Te residue was poured inso ice-ater and neurraised with saturated NaidCO 5 solution unili P4 it 94 the mesak~ing precipitate solid was colected by filtration sad washed with ether a t a'rd On desired product 2-(chloromethyi)-5 20 aeyi-o-4olypyridr42,3dipyrireidini-4(3llhone (1403) (2.00 mng. 643%) [004211 To a Whdion of3-iodo-4-minel 1-pyra [3.}jd]pyrirmidin (ISA)(26 m g, 1 2 mm oi dry D-MF (9 nmL under nitrogen, potassium te r-butiade 2 mgti l mrot) was added at M C The resulting mixture was stirred at this temperature fo 45 min: A solution of 1403 (3O r I smoi) in dry DMIF (5 mL) was added. The fraction i t wtase a sstrmcd for i. at G *C and then an additional I at room temp1he , The mixture was cicentrated in 25 vacuc and the res'ktng residue was purified by flash chromatography to afford the desired product 2-{(4-ami-3 odo-Ipyrao(3dprmd ym y)m prdpyriyriidii4(3 e(1404) (450 mng, 53.3%), [004N] To a xsoion of 1404 (36 mg, ?.069 mnmncl) and 3-hydroxyphenylboroni acid (1405)12 mg, 0.083 mnxl) in DAF (2 mLL. ItH mL) ad water (1 -I) was added Pd(P4h(7 rn 0A006 imo) and NaCOoston (M, 0,5 30 m 03. m ioe) undeC Argon The msultng mixture was degassed and back-iled with argon three times and then heated overnight at 8C*C, The reacusor mixture was allowed to coo. to room temperature, concentxaed, The reside was dilutA with water (20 miL), ncutralizd wish H43 caution (d'M) until pH 6 4 ,a carted with DCM 10 7L 3), The combined organic layers were washed wh brine, dred over NaSO ad concorated. The meidue wa purdfied by fast chromogrphy to afford the desired product 2-((4amino-(3-hydroxyphenyi tlHpyrareoie,4 35 dlpytimidiniyImeshyi).methyEtntyirido[.3dipyridin-4(3H11one (.14N) (8 g,217%). [00423 Exampk 2: Symhesis of5-(4-amino--ucr'4hydroxyhylH-pymo[3-d)ytimidin-1 yoiethylI,3-dimsiyt 6-04rny i lbpyrndlo[3<ipyriidin 7(~hone (Comptind 1511), 1004241 Scheme 1i Synthsssof S4(4:mino43-tauor-hydmxyphenyl>1H-pyra[3d)pyrimidin yl)mdthylydimwihyh6+to-~iyMi-pyrazo4,3dpyriidi-7(0B)-one (Compound 1512) is descibed,

NH

2 NH2.H2O ONa 1 fi 002CO2E Nf 80c' 40 N Na ' HOAC ' ,MeLJ bEt 20C ovem iht 30*C> 2h 1501 1502 1503 1504 N HN Retfiulh Y N l0% th sz40*v0c 3h / NO% 2. C t3 1505 1O Ak) pdX) V L 9 ,NI I ONN RTttk, Oerniot t(C. 510 PhAgP 5 4 A N a 0.~ f ht 5 42J Sadium (5.2 0 226 mol) ws d(Ived is n&fuS eMa 0 mL ) A mixture of diethyl adate (11V)(3 L ., 0235 Vo) al d acetone (1&0 H, 0218 N o) was added to the abwoe sroraa keeping the temperature under 100C, The rmaiido wrn m a s stirred aventi at RT. The resania petpitale wa coveted biy fltratin, washed with petcether and dried so afford the desad proct 1 50.2 as a yellow sod, (30.4 g. 75%). *4264 Hlydrriie hydrate (9,7 ML, 55%, 0200 mol) was added dipwise to acetic ad (34 riL), Tos lids 'M compound 1502 (30Ag 0369no) as added in porinm at 25tC The presiding mae was sired for 2 at room temapemre, then bifod with w atuirated NIHsCO 5 solution tytMd pH 5 and enmeed with DCM (200 mL. 1 The combined orassu phases a wshed wie ae, dsed and crnceated tsk afford th desired product, ciitiopound 15)%! a a yellow 4.xr (2 g, 4. J0427~ J Dimethy, ,t fate (3.2 mL, 335 mmol) was added dropwise o a solution of compoimd 153(42 g 29, IS nmol) in voluene (20 ml), The reaction mature as sidrred for 4 h at 80 *C, heni allowed to cool to room temperature ad concensratd. A 40% NaH1 solution ( mL) was added to the reidue, The reshUling mnixtsre was sorrei For lh at 80 6 c then coled to room teetue ard dilutd with HIO (30 mL), acidifiA with ncent'ed Ht schtdion utis pH4 3 -4. The precipitmed solid was coiteced by ffitmzion washed with colAd water and dried to affed the desired product, compound 1.55, a n <dfwhite . ld. (3.54 f :4), 20 0104281 To a sdirred ire of concentrated H2S4 (3 msL) aid fing HNO i (3.. 1 m 733 moi) the acid 105 (2513 g, 2-a mss) w added at 7L So C, The raMction ix.ture a stirred for 6 a 70 C. d cooed to room temperatatre ard then pomred into ice-wate, The precipitated did was collected by flitation, washed with wrer an dried toalffordthe desired product, compound 1X06, nsa yeikw id (0295 g, 2.5%). ~101- O0429] A mixture of compound 1506 (1504s g. 1 11 mmoI ) and SC m (6 mL) was veluved fo0r 3 h, then ooncent raw to remove SOCL, tIhe Iesidue was dissoIved in CflE(R mL). To this solution, EtiN (I1 i :mrL) and2 tdkdine (112 g, 12,23 mnnoi) Ws added at 0 *C The raising mikarnme was stirred for 2 lh at 10 "C, conce sed and diuted ih water. T-e siid was ecotected by fitrador, wahed with water and petrnether, dried to afford the densed pmduct 5 compnsd 140, as a yelow solid (3J4 g, 76%) [ ) To a stirred itdur of compound 101 (1.y3 g, 63'i mmnot) in MeOI1 (100 mL) and T11F (10 m ) 5% Pd/C (02 g) was added, Te mixture was dgassed arrd tck-41led with hydrogen three times. The reaction mvxlwe was staed oveicgt at r tempertueM arnd then filtrated, The filtmet was cocenred in vacuo. The solid was dried to afford the deindT product, compound 150S, w. a pale solid (1.47 g 954%), 10 [0043I Chiomacetyi chloride ( 1.44 nL, 199 mmolY was added to a soluion of compound ISS (1.46 g, 538 mm1l) in acetic acid (20 M)L and the reaction mixture ws heated to reflux far 4 h, The rectiom mixture was cooled to room temperate an-td r. oentrated in vacso, The reside was dilted in DCM (300 mL), washed with saturated NaHCO so htion and bone, died and concentrated The residue was purfied by flash chromatography eksing with petroether in ethyi rcetate (10 ' 1) o afford the detired product, compound 1019, as a offwhie solid (0.44 g, 26,7%) 15 (004321 A solution 1f o8eIH-pyrazoir43,4d)pyinidina ie (1t8A) (311 g .,g L19mo) and K-t00 (330 mg. 139 3mnols in D fW a ) was stined a room temperature for 1I i a .ow. f compound (1bf 9 )(180 mg, 1 1 mmo, I eq ,) in DMF (5 mIL) was added ropwi at room temper The mrutding mlixrusre was Asirred 2 h at gC The asion mrixre was concentrated in vacuo to remove the organic soNent, The resting residue was pwified by a silica ge clumn dn atognphy to afond the desired product, compOUnd |5O9, (142 ag, 44.9% yield) 20 as a pale Yelow solid. [004331 Compound 1510 (40 mg, 0.076 .rmnmoi), Na CQ (40 mg, (,33 mmofi, Pd(PPh) 4 (176 mg, 0-015 timD), and 3-tuoro-.4-hdroxypheei'ronic acid (15,8 nmg, ol0 mmml) were dissolved in a slution of 1DMF, ethanol and wkr (4 L /2 ml 2mLy The resaig mixture su degssed and bact*filled with argo nthe times and thn heated to 0 *C for 4 h with starring. The reaction mixture ws cooled to room temperature, neurized with IN iCI 25 soluuon until pH 7. cncentrated in vacuo and exlraced with ethy acetae. The combined organc phass were dred over Na 2 4S, filtered and -onicertrted, Tht residue was paltilied by iSh ohiaNt 'hr atograpy editing with 1CM 1 MeOl - 5/011 to afford the desired product 1(32 qg, $2%). (04344] knapie & Synthess of 3-((4-amainc 33ydsrosypheny}F 1Hwymazoio[3,4d~pyrimidin- lyl)mrethyl) methyt-2+-toltiqilZiaTHone (C osmpond I610) (method A), 13( Seme I :~ Synthesi of >(-amino.$(V.hydroxyphenylYbi hpyroit(3,4-dOpyrimidirnl-ylrnethyY-&'methyh 2''totylisoquinlinal(2iH<e (Compound 1610) viA nthod A is described, 3N HO B1 CHS) - --NF Dt.1 CM CtRT.16$h H. Rex evemight RT 1 -2 hIs 104 m N NaN JRT ht, No 00055 TENDCM A1502 1603 -102- RTT Ovosmrnight A &3 Nf c h RT,. Qvm.,O Itn -------- - 4 SNs TOO& 1609 Pd(GAe)g N? OA PPh 5 r MF: EtOH H 2 : 60 *c O Sh OHO %09 0 5 (0043) A solution of 236i6methyibenaoi acid (104) (106s & 705 mm n) i HID (200 mL) was Oaosed tc 0 - 5 'C, comt 1H (250 mL) was addd slowly. The soiti was aird for 13 min at 0-5 C, A ihAtio)n of soium nitrite (50-4 5, 6.5 m) 1% (120 oL) was added dpwie at 0-3 'C, and the rcmnlag mixwture was stirred far 30 siz. Thens abve schsalon was added so a solution o{MK (351 g, 2> I ot)t i () (200ot> mgnd tre resumg ixSr was stired at RT for 16 h, The lodion was poured into ice water (2000 mL) and enacted with ethyl acetate (3 x 100 10 mL) The con-bined organic layer wast washed whit aqponas NaOH (15%, 3 x 200 mo)l The aquwous ayer was actidsfed to PH I. and erneed wit ethyI actxzata (3 x 1000 ML). The combined oranic layer was di6ed over Nadh7CK and t ~e The disrate was cemecentraed int vamo ta 35hrd the desired product, 2 i o6+methyiermic acid (901) (145 g 9- yiedd) as a yellow solid (004%) To a stirre moixtusre of 24kolmethythmoir acid (901) (103 g, 400 otd), Pd(0A (27 g, 120 moo) 15 and PPh3 (63 g 240 mwl) in THF (1000 mL) as RT, ributyl(vinylii (152 g, 480 mi) was. added The tesslinrg maxtwrr was heated to reiux owmight The mlixa was. allowed to cool o RT, Thered ithrough siia gl ( gand then concentrated in vatst The reskde was poaed into icc waler (1000 mL) ad extxeted with ethyl acetate (3 a 1000 mLL), The cam.-ned organic tayer w 'ashed with aqueom NaOF (15%, 5 x 200 ML) The combined aqueusi layer was acidified to P-H = 1 ext-cted wt ethyl actate (3 x 000 mit). The combined .rgav er was dries over 20 NaARE and kerd The i:rae was coneenirsed in Vaw to afford the desired prss, 2-mtrhyl6-vinlbenoi.c acid (902) (61 & 95% yield) a:a yellow solid j637] A mixture of 2-m ehyl-vinybenzsie acid (902) (56 g, 350 mmol) and thiony inkhktrik.de (20. g, 1750 mmel) m Tol.n1 C (100 mL) was sirred as refmox for 2 h. The miaiue wa concentrated a sewn to affod the desired podct. 2<-mseshyl-vinyben deyidi (1601) (63 g, 95% yield) as a yellow oii The product obtaiNd was sed directly in 25 the nexts sep with-out paricatioM -iav (00438] A mixture of o-ouidisne (4 g, 420 mmdl) and Trh ylamine (71 g, 70 m-rol4O in CHtgt ('x00 maL) was surred for 10 min at W 1To this iixtas, 2hyi6vinybery chlorde (161) (63 35 mmol) wa added, and the remsing mixtbe was st-ired atT or 30nmi The sokaion was paard into water (300 ml) and extracted with CKrCl0 (3 x 200 Q ddd over NSO 4 ad filtermd The filtrate was combated 1ie vero to afford the ekde 5 product, The crude pradct waa suspended in IPE (isopropyl ethv) (300 sL strimd a reflU fo 30min, and tme ceded to 0 - $*Ic The precipitate was Goleeted by filtration and further dried in v lco to afford the desired product 2 methylINoa-tlyt6-viiyqbenzamide (1602) (81i , 80% yield) as a yellow solid, (04439] Toa solution of 2-mesthyl-N otel6-vinylbemamside (102)(8S0 g. 320 ma!) in DMF (250 mnL) at RI' NaH (60% in maireral oil 25.6 g, 640 mnnoA) wa slowly added ad the resulting mixdure was ssa-re at RtT for 30 ruin Io To this mixwe, euhyl chlormaemtas ( 7 g, 640 mmio) was added and the rudidng mixtere. wat stirred at RT fes 2 h. The solution was pored into water (500 mL) and racreed with ethyl acetate (3 x 20C mL) , dried over NwSO nd fihroed The filtrate was eoncentate-d in vacu. [he uend product was sinpended in MeOHf (160 mt), strted at rmet tfOr 10 nti, and thee cooled to - $ The preipitat was coiected by filtratim and father died in sso to afford the desired product, ethyl 2-(2-ethyNooiyhy-oinyiensnido) acetate (03) (67 p 62% yied) as a white Mlid 15 (0044N0 To a mirred mixture of ethyl .2--ethyl-Nyly'- inybeza ntde) acetate (1603) (67 K 200mo) n in I 4-dioxane (300 nd) d it0 (10q OsL) at RT', Osmium tem.xide (20mg) was added was and stirmi at RT for 30 min 'To this mixte sodium peNodae (86 g 400 m ot) was added and th resuthing mixdtee was sn-red a RT for lIhW The reactmn mxure wa filtered thimough silia gel (1W gt the filtrate was etacted with ethyl acetate (3 x 200 rL) 'The mined organi layers wee washed with brne (100 niL), dried over Na IO nd filtered The flrte was 20 concentated in v and the residue wa further dried in swcu to afford the desired product, ethyl 2-42-formy-6 iethtylN-tolylbcnzratntdo) aceae (16f1)(38 g 57% yidd.) a' a yellow solid 1004411 To a stirred solution of ethyl 2A2-frny smethyiNtotbenamido) acetate (V6M) (38 112 mma) in Et&TH (200 tml) nd ethyl acetae (E00 L) at R Tesium caboate (22 g, 112 mnol) was added The redlting mixture wa3 degassed and back-f led with argon three tias ad then stred at 50 'C fot 5 it 'lhe mixture was 25 aIlowed to coo to R', filtered through sisia geif(10 ), ad the Ctrte as concentraed in vano The reddea was pored into l20 (200 mL), elected with ethyl acetae (3 a 200 meL)- The combined organic layer was washed with brin (50 SLl died over NaSO, and filtered. The 'itsrre was comentrated la veae The crude product was suspended in IPE (120 mL), heated: to reflex for 10m, and she cooled to 0 - 5C 'The precipitate was collected by fitatrie and father dred in nosse to afford the desired product, ethyl 8-ntiylo-2-o-<y 2 3. d7ihydmis0quinoline- cadmoylate (16t$)(28 , 77% yield) as a white solid. 0N 4421 Tc a stirred sot ution of lithiums a fiu m hydride (al28 u 218 md) in aabydWroms THrl (500 mL.) ay e T C der a nstr'ogens atmosphere, ethyl -mhy 'e Alo-2lt1y dihydroisquiolin3-arboyate 1605) (28 g 87 niol) was sowly added over a 10 min period of tee Tht reuing eixtoe wa allowed to warm to -30* C, stirred for 30nin and TLC showed the compledon of the reason Then the mimtue wm cooled to -8 C, ad waer (30 35 aL) was slowly added, The mixorre was allowed to warn to RT, filtered through silica d (10 g), ad the fflinaI was concentrated in va-c7. The crde product ws poured into " (200 mt) and extracted with ethyl ametate (3 x 207 mL) The combined organic layer was washed with biet (Y) ml;), dried over Na&SO and termed . The filtrae was concentrated in vaca The crude product was suspended in ahyl acetate (30 rL) and sirm for tO1ln. The solid was cleteed by filtkation and Cather dried in wcof to affed he desired prdact, 3-(hydrxymcthyi)8mnthyt-2+ 40 1ylisoquinoin-1(21 -one (160:622 g, 92% yiekl) as a wesovd. -10-4- 004]Pek (25.6 g, 95 mmsol was slowly- added to a stirread sio of DMF (I L S g. 13s&: in astntrile ( 20 mnL ) 4t* C, ad the stting minure was stirred at OC ftr 30 idt 3Hydroxyma1y4thy -2 iolylisag~noir-1 -(2H)-oine (1606) (22 g, 7& mi) vwas slowly added, The i the actionn m um 'was towed to warm to RT ard stiMrd for 30 ra m atcmfed aqueos Nat-C solution (501 raL) was slowly added and exqasmted with 5 shil acetate (3I x200 mL), The comiNkad organie vayer was washed with brine, dued over Na2SOt and .luied The filte was coenleraed in vtowu, The etde product was suspended in IPE (50 mLa) and than stined for 10min. The precipitate was collected by afin aid ihard dried in aCOuo to afford Lithe desired poucr 3nbroty) metyi-2+oysSoquinioii(2H)-ne (17) (21 g 80% yield) as a white solid (0a044 Miado'lHtrazolo[,44)~pyrin di ane (1t4) (108 g, 41L4 mmci) ad potassium tart iuloxide (4A 44 , 40 mm) we v e d i n inanhydrous MP (150 m&L) and stirred t RT for 30 rain. 3( zormaethyl) e-mthyI2 elyiisequindii-(2H)-onre (1407) (13? g, 40 moc) wa added. The resJdig mixture was stred ax RT for 30in, pored ito ice water (300 mL) nd then eR eed wit ethyt aceate (3 x 200 M)v The comhined orgame layer was washed wit brne (50 mL), died over NaSOt and tilted. The filtrt was coeemraed tb 100 min aeno, the precipiae as coalected by filtratIn to afford the fiaW;t ofC oftdesired produt 3-((4~amino S praeioo(3<iA prinidin-ylnaethyi)4mehyb2+-ooyseqiddin- 1(2H)-omet (16M) (12 g, 60% yield) as a whte 51id. The filtate wa concttated in eimo ad the Midue was purified by lash ciOuma chromatography on S-llc get (2-20% MletH/DCM) so afil6rd the smcond batch of desired product 3-((4-arak-cdl-pyaSOlO(3A4~ d)pyriraidl yl)methyl)1-mnethyt2.-todyiisoquirn-A(21)-<e (16*) (fg 30% yield) as a white solid, ~11449) 3-(44a aic3-indo-iH-py-rzol3,44djpyrlimidin'y I e'hyimefl th byl 2+totisogd&ania-1(2-Bone 21 (14g) (13 g. 249 mmol) and 344A,$4-tetramethyx 0O2ioxaborolan2y)phend (164XM g 30 mrelo) we digsolved in DfMF-EtOlti-HO (120 mW, 40 mL, 40 m. Pd(A) 2 (6g4 &g, 5 m f), PPh: (935 g 1S nel) asd NaCO' (135 g 12$ mmol) were added sequetialy. The resting mixture wa degaed red baM-s-tied with argon tree times and thei-n stirred at 100 "C for lhb The mixture wM slowed to eot to RT filtered hsugh stila gel (10 and aoncentssted in acao. The residue wa purified by bash column chromatography on silica gk (2~20% 25 McOi/DCM) to afford the prducWt (1610) (9 g 76% yidd) as a sight yeliew solid. Tnhe above product ws asApended in EtO (100 muL) and heated to reflux for 30 rMa The mniture was allowed to cod to RTr, and the solid was colleted by fihtuction, The solid was then suspended in EA 100 mL) and stirred ovnmight The pr- pitate w Colecled bt iltrs-stie and further dried ix ensuo to A rd the destred proct, 3((4-amimo3+(-hydoxyphcyl t yrazoo(3,4<d]pyrimidin-ylthy)--methyi-2.- yisoqtuin - (2H)-one (161_)(&4 g, 69% yield) as a white 3-9 solid. 104461 Example 4: Synthesis of ]((4-amin-3(3hydmxyphenyl)-IHpyrazoi,4-d)pyrinidn yi)methy)4 L(Compound 1610) (method B). W0447) Sctarhme 17 Symldesis of 34 amino (hydroxyphenyI) i-pyszoo3 ,.4 pyriumidin-yI -jamethy)i metshy?2 yisequ iins(sonre ( iCopnmd 1410) Via method B is decie asi go m 1 9 trr~ 1W N -------- -' li~ts-i is-ioo s (p0446] 3-(3-M~etho-yphenyYipyradlo[3,4-d)pyrimiidin mine (1 701)(%4 mg, 4 mmo) and potassium mtt butoxide (0.44 g 4 rmmxri) were disolved in anhydros OM ( 50 mL) nd stired at RT for 30 mi 3 (Bo m ethy!l1-ethy2+oiyrirequielly (2hone (1607) ( L37 g, 4,0 n nkol) was ad&d. The resulting mixture was stirred at R T f-r 3tmin, poured into ice water (30 ML) and thse4 extmrated with ethyl acetate (3 X 50 mL). The 5 conbitsed argade layer wa washed wih brine (2$ mL), dried over NaSO 4 and lilstred The lt-rate was M.centrated in sutwo and the residue was purified by' fhsh column uhrmatography on silica gel (2-20% MeGOHKCM) to atrd the desrd poduct 3-1(4-min&3(3-methcwyphenyl)- H-pyreolo[3-diprimidln~yjethyl)aethyl-2+o y'isequinolin (2Hk)-one (1702) (1.A g 70% yield) as a whte solid. [00449 To a msMion of 3(4-tmino 3-)mefhoyphenyl- lH-pyrazolo(34-dJpyrimidin-ly)ethyl} methy-2+ 10 nyso<quindin-1(2Wone (1702)(100 mg, 512 mo) in C)%Cis (20 raL) a -78 C under a nirgsten atmaosphtee Bt I ml) ws added and the reuting mature was stirred at -78 "C for 3 NL The mixure was allowed to warm to R, pored into ice-water (200 nL) and extracted with ethyi aceate (3 4 50 -rld). The omhed organic layer was washed wiff brie (20 mL), dried over Na SO4 and fi te The filtrave wa ontrated in vrcw aid the sidue was purified by fash :adam chromatography on silica gel (10-50% MetOHCA1 2 ) to aifhrd the desired product, 3(4 13 amino-i (3-hydroxypsheny) IHepyrazoloW4 - d~pyrdmidin- yi)medhy)4+mnediyl+2medasyouinolinod(2Hk~one (110)(87 mg, 91% yield) as a white soid. [t-000 Eraipie 5: Synthesis ofC (R)3((4t-amiio--(3-hydroxybh-1-yvnyYk t Hpyrazoio[3,4-dipyrimidin-I yn hyfly-methy2taiyyoquinolin(2Hk)-one (Compotund 1802), Schwwe 18, Synthesis of (R>-3((4-arinea-3hydcsybtiu-lynyl> HIpyazs [ l,4-dhpyrimidin- ylhnethy>-l 20 ethy-2-t4lylinqinoiind(2Hyne ( Compound 1602) i described INNY I1yM 1890 0045I4 3.-44asnin-o-idoll-f-prazolo(A3 4 4]pyrimidin-tytmb)m n thyb2+w <a toiyls~x~~ogln.(2H)<one ( 1608) (522 mg I med-ol) ad (R(buteyn-ol (84 mg, 12 mmrnol) were dissolved in anhydrous THY (40 nl), The mistuc w deed ad bkied with rdtrgren three times, Pd(Pl'h4 )1 2 (12 mg 9 MMo Cut (47 mg 025 25 mmot) ad (1.r)1NH (505 g, 5 mmcl) were added s"uentialy, The resultig mixture was degassed and bak-lled with rgon three times and ten stirred at refluK for 4hs The mixture was allowed to col to RT, filteed roihuh ailica g (0 g an edc t in-ca The resi&e was pot"ied by fash ouman chromatography on siIc gie (2-201% MeOIVIDCM) to allord the product 3 (R)-3((4.-amino-2(3--hydroxybkt-l yny)d Hpyrau[ES3pspinidin-I yl)netlhy -ahy2O-toIy isqgina- I(2-H--ore k I2) (324 'a 70% yield) a a slghtly yelow sid. 30 1004523 Eampke & Syrdhcss of3( mi9Hprnymhy8-ey24oyignon(2 on (Crum pend 1902). 1004531 .Sdseme It Synthesis of 3-{(6-aminn-9-purin-0yl~methyl+mihy-2otysoquinoin1(21)-ne (Compounmd 19102) is described. 106- H N N N N N_ 1607 1902 HAZN io1454) 9tin-aine (9I)(54 mg 4,0 mmod) wa dissOved in asihkydnis DMF (20 L). NaH (60% in neram ol , 160 on, 40 mmd) was added and hes cuhing mixture was srra RT fo 3 msthyl-2N4toiyw1nqu0no -D2H)me (M07)(I37 g, 4O3msmc) was add& The motion mixn was mied at RT $a fr rin ,ound in icewaer (30 KL) and then eracted with othy estate (3 x 50 mL). The combined orga wayr wahad with, ln'ie (25 L), dietd OvC NASO and fida Th filtrate was concentrated$ in rncn and the, rae was pudned by flah column chromtoaphy on siic ge 220% MeDH/DfCM)l to daA the dedird pcodaa, 3-((6s-amio-% puri9-ylmethyl>8-methy-2e'telyisquincind(2H-ona (1902)(L g0% yil) as a white solid, 10 [2N455) Eanopl 7 Synthesis &f 3(4-amo-3K3-hydoypeny )a-yrsf[4<d~pyrmdsrb -yi)mrahyl) 2t isop'spy8mathyhsogpgindn-(2-ore (Cempramd 2009)i Ssthent 20 Synthesis of 3-(4amin~3(3-hdroxyphenyl)4H Rpymrd[A3,4<iymidin4 -ymethylk24isoprpy Smryliquirw±nolla(2H)-cne (Conpo d 2009 is I Pd(OAc CICfCOC COCI PNh I DCM[F1 THF PIT, I -2 hri 01 Retw, ovemight~ 1902 ICH2C0CEt NgNN rek 2h GY0t is 2001 2002 TEA OCas CC N DCM Na.04 COGCt RT 0.60 Iooa i doxana H 1 160 2003 RT, Ormnht 9 CsCQO UNH 4 SRT OveightCO0 2004 2005 2006 RT 03 N I J(I conr3 LA ROH N 2005 2002 '407- 1004561 To a slirred mixtusre of? -id ethylhesoic acid (901) (105 g 400 mmo), d(OAch (27 g, 120 nmmoJ) and PPh (63 g 240 Mo!) in T-f 1000 L at RTributyhvinyl)tin (152 g, 400 ma!) was added. The resAking mixure was heated to reti< overnight The mixture wa allowed to cool to RT, fited though sia gel (10 g, Wd then eIoeemmrated in vsr0o The mreidue was poed itto ice water (10 mOL) and eNtracted with ethyl acetite) (3 x 5 NO0 niL). The combined organic layer was washed with aquo NaH (15%, 5 p 200 -i). The combined aqueous layer was acidified to PH = 1, extracted with ethyl acetate (3 v 1300 mL. The combined organic aye was dried over Na.SO 4 and !teed The iltrate was concentrated iW arno to afford the desired product, 2ameth vinylhtooiv &ai (90i)(61 g, 95% yield) as a yeikw lid 0457 A mixture of 2-methy[vinyibenvo acid (902) (56 , 350 mmo) and thionyl chloride (20b g. 1750 mra ) 10 m tohiena (400 mL) as stirred at raflux for 2h. The mita was corZerrtated in s'rCao to nhs desired prodAct, 2-methyb-vinybenzoyl choonde ( ) (63 g, 9:5% yld) s a yellow oil, The product obtained was ued directy in the next step withoUt purificadon 1004541 Propan-2-amine (2001)(59 g, L.0 mol) and ethyl ebloroacetate (122 g 1 0 mol) ware dissolved in twlene (200 t) and the mixture ws stirred at reflix for Zh. The reaction mixtume was allowed to toel t IT, poured into 15 ic-wata (500 ruL) and extracted wi ethyl acetate (3 x 250 cLb The conbed organic lsae wa washed with bine (50 ma.k died over NaSts and fitered. The fflhmate was concentrated n vano and e reside was puified by flash column hrmoatogrphy on silica gel (1150% RA iPE) to afford the product, ethyl 2itopmpytnolacetae (2002) (70g, 5 1% yield) as an il 104591 Ethyl 2-(iopropylarn)acetate (2002)(14.5 g, 100 mml) and trlethylamine ( 00 g 200 mol) were 20 disAdved in C-ICt (300mL) and the micMre was stired for 10 nin at RT. 2-Methy6-vinyibenzcyv chloride (1601) ( 18 g. 100 mmol) was added, and hc resutiAg mixturm was stirred at RlT far 30Mi n The reaction rmiXtuna was poured into water (300 mnL) and extracted with CRCt (3 x 200 mL) The combined orgadi layer was washed with brine ($3 ra), dried aver NaSO ad filtered. The filtrate was concentrated in vcaN to afford the crude poduct The crude product a suspended in IPE (isopropy ether)(300 mL), stirred at reflux for 30min, and then cooled to 0-*SC. The 25 prip e wos sasi-ened by filtration and father dried irn wug to afford the desired produ ethyl 2-(Nismpopl1-2 aethy~vinybanamido)acetate (2003) (14.5 t, 50% yield) as a yellow solid. 1004601 To a stinred alticn of ethyl 2-4 isopropyl-methyl-vinyibeammido)actase (2003) (14:0 . 410 mmo) t 1,4-dioaane (100 ML) and FA0 (30 mLt), Osmium setroxide (20 mag) we added and the resting mixu-e wa tired at RT for 30 min To this mixture, sodium periodate (22 g, 100 mmol) was added and then sirred at RT for 16h- The 30 reaction mixture was tered through silica gel (0 g), the freat was etracted with ethyl estate (3 x 200 mL) The coamthired organic layer wa wuhed with bne (50 maL), dred over NaSO4 and filtered The filtrate wa concetmraed en mve ad the reide was further died in wxuo to afford the desired podet, ethyl >fonyw ispropyl4 methybenzamido~acetate (2004) (8.33 & 57% yield) as a yellow solid (&04K 1 To a stinred sohution f ethyl 2mfylN-isaprapylimthylensmidolacetate (2004) (9-3 g, 2&O mmc) 35 in E 1- 0 - L) and ethyl acctate (.50 m) at RT, esiutm cearbonatc (5,9 g 3m ) was add Th resulting mxsare was degased and b-k-flled with argon three ti-oemis and then stired at 50SC for 5 fs. The mixwre was alked to col to RT, ilered though silica gel (10 g)' and the filtrate as cocentrated in vacuo. The re due wa poured ino H20 (20.: mL), extracted weth ethyl acetate (3x 200 mL) The combined orgnic layer m wah-e w i hre (50 mL), dried over NaSOq and fltered. The 5 late -ws ccmnctraed in vacua. The crude product wse suspended in PE 40 (120 mL), stirred at reina: for 1f0la. and then coated to 0'IC The pr-ipitate was co)ected bry fitration ad further dried in vaicfa to afford the desired produ c, ethyl 2-iopropylb-methy- l-oxc ,2-dihydroisoqinAline3- ear-boxYiate (2015) (5.35 g70% yidd) asa whie sold. -108- 0304621 To a stind hIueion of rhium u m In hydride (2.88 g76 m-o) ianhydros THF (2A0 smL) at-78 C under a nitrogen atmosphere, ethyl 2-is ropyl-8-methy&Io- ,2 dhydroisequine~% earbogyate (200S) (5e g, 19 mwwat) was slowly added over a 10 rmin period of ipme. The resvuin,g mixture was' allowed to wam to -3 0 n C, stirred fWr lnii and TL showed the compoedo of teesio. Then the xmture ewas ooed to -7* C. and water 5 (50 OnL) waz slowly added, The maixtume was aowed to warm to R', itered through silica ge (10 g). nd the fihrate was concentrated in vacuo. The crude poda was poured into HO (200 mL) and extracted wah ethyl acetat (3 x 2x0 1t), The cnbin organic layer was washed with brine (50 ML) ded aver NaAO4 and tIwered Thw %rL ws cncnrvaed in oaw, The crude pdurt was suspended in ethyl acetayri (30 maL) and stirkAd far 10mi The miod was coilsed by fihration and fisher ded in vart to af~hd The desired prduct, 3ydxyethy2+ispopyk-' 10 methylis quin-I(2H-one (2006) (3,$1 g, 80%h yield) as a whkie solid. [04631 To a so'don of 3(y doxymethyi)2isop yb-methyiisoquinoli (2Nnre :(206)(141 g 70 mtot) in CfhCh, Ppet (3.67 g, 14A) nmmol) was added ad the mixture was stirred at RtT far 3t) vain The mixture was esxled to 0C, and CB? 4 (4.64 g, 4,0 mmol) was added in portimng The resuming tmxtt wstirre from *C to RT for 30 min, and then concentrated in vacn. The Crude prodt was purified by ash ohumn chamagraphy on silica gel 15 (30-3t)% If pEito S brhnd the 6isired product, 34 rmcmethyi)ZisoropylethyisqinoI (2H)Yme (2001) (L65 g, 80% yidd0 as a whke solid [*0464] A mixture of 3iodo-'-py'raolo(i4~dipyrimidin-4-nmine (16gA) (1.3 g, 5 moi) and potsiurm tert butoside (013 g, 3 mnn ) in anhydfrou DMF (20 M 1.) was sti red ii. RT for 30 ,in and Then 3-(hromonxeyi2 isopropyl nethyisogiainlin(2sorne (207) (147 g, 5 mmol) was added. The suing mixtre was stirred at Ri 20 fot i , pred into ie-water (30 nmL) and then extracted with ethyl acetate (3 > 50 1L) the co""bined orgaic Iayur was washed with brine (25 ), dried over Na 2 5\4 and filered The fihmae ws concentrate in Vacuo, and the resde was purined by ah column chronMatography n silica ge (220% MveIoM/DCM)' to afftrd the desired product 3-((4-tuino-3-odo-l H-pyrlo(3,-dfyrdmidin- 'drnethylyl-isopropyl4-methyisoquinoin-i(2H)}-one (200)1(1.66 a, 70% yield) as a white solid. 25 [0*465] To a stirred mixture of 34(4-Amino-3-odo4 H-pyrazolo[3,4-d]pyrinidir-l-yi)methyly2-imrprospyl4 methyfissequinouind(TH)one (213g) (95 mgt, 0.2 mimol) ad 3444,,5eraetyb3,2-dioxabora2-yl~phenrol (66 mg, 023 imod) in DlMFItO}&60 (30I't 20 a'l) Pd(OAc)a (16 rag, 0.07$ nino)ts (~39,3 sg 0,15 mtnol) at NaOs (32 mg, .25 moi) were added sequend.taly. The resauting mixture was degawd anda argon three daes and then stdred at 100 *C for 1ih, The itmre was allowed o cos to RT filtered through silia gel :30 (If) g) and conmeetirrated in sou The residue was purified by flash cohuAm chromatography on silta gd (2~20% MeOHtADCM) to afford the product, 3-((4-no.3fhydroxypheyI> Hwpyzdo[3,d]pyimid Iyl~rnethlY2. isspopy rmnthyisouindln(2Hgone (2069) (53 Mg, 61% yied) as a Slightly ydeio solid. 1*04661 Example &x Synthesis oxf 7((4nr 3-ydroxrypheylVd I pyrazol[42hd~pyrimriin olyimethy})4 medwhy4io-tolyl- lid phthryudia-5(H)-one (Comrpoundi 21H 5). 35 [004671 Saherne fl. Synthesis of 7-(4-axiao3-droxpheny}) H-pyraolo(3,4dtpyrimnidin' yi)methtyi)4 methyd-otsolyt-nagphthynin-5(dH)-one (Compound 2115) is deeribed. C4aCOO- e'24 'ye, 2 4i ant----(------------== + ctco\Os/c R O.AsOO~a~s Ovemigid / GOs (tfMa 2 2103 t -109a. I N H SPaT 2 h 21$421(06 21h% 210y ANam Rplumboeih 2109. CNNano 2110 211111 P AF ttrr~~Z. N, _0'wwN 2 Nt~ A'Awl IM ox"41o IzA 214 1 (0046i To a mt;ta eof ethyl 2-em etate (C1 5 1) 452 g, 4; M(o.)- and Oetm (464 a, S00 nm mvl) 'm acia nede ceid ($0 mL) pipmiin (2 m 20 immol)ws a-dded and the resuming mixture rmd at embcu. for 24 h. The creation ixr was avowed to oo to RT, and then conenrated in teAs, The reidut was diluted with water (200 m-L) ka eaLt cd it ehyl estate (3 x 200 (3) the combinedri orgQ nit iyer was asnhed Wi W kvftflC with brine (S0 mL), dri over' NeSO4 and flered The filate Was eocentrad in vcec and tSO residue wasepifed y0fa ounnn 10 chomawtgnphy n s ila gd (C-2% EA / PE) to afrd ut desind product, ethyl 2-cy o-3-methylbut- 2-moate (2102lT) (9,6< , 1% yield) a whtke shd. ift469j Tv a seitt4 of abyi 2-iync mehybt- enote (3102) (4x6 g 25 ) n m01 bs) i 0tDH {3[00 omLt) Nydimethyl formmide dimethyl ael t(373 g, .313 mmr) was added dropwise ad the resuming mixtum a stirred at meik 6 h The mixture was allowed to ccot o kY concentrated in vwa to aMord the crde desird product, ethyl 5 2-yano-(dimthylaimino)-mhylpeta-2,4- diettate (1O13) (39.8 g, 67% yied) as a yellow sid, 00470[ Ethyi 2-cyan5-(dimeltylamnino) tethylpent-2,4-d irrate (2103) (3& g 14 mmol) was dissolved In AcOH (120 mL and thn mixture was stred at 40 C A shktion of 45% HBr-Acf (120 mL) wm added dapwise, ad tm the mimtrc wa sred a A52 for 2 h. The mixture was allowed to col to RT posed onto ice, neutralized with sold NaC Q n 3 ,d extracted wih ethyl acate (3 x 150 miL, The combined orgsasn6 Synr wa washed with brioe 20 (50 IL), dsed vet NM50 4 sod led, The fikrate was enesmmrated in vacuo and the residue was purified by flash coturon chromanogephy on 61ie2 gel (5-20% EA/PE) to atorrd the desired product, ithyl 2 hjomo+4etyhisotinat (1 -)(f 7 6 c, 49% yld) as ayelio oil (W0471 J iO a so utif ethyl 2bO:O4Oethyti ate (2114) & S2 nol) in 4diocnn (B5 mL) a solution ofNaO- (0 g, 200 miol) in fitO (15 mL) was added and the resting nixture was sdired at reHux for 12 25 ih, The mixture was allowed to cool to RT, dilted wah lO, whed wih ethyl acetate (3 x 30 mL). The aqoua -110layer was acidited withs conetrated hydrnchkorie acid to pflm1, and extacted with ethyl ace~tte (3 x 50 maL), The mned organic layer was washed wtnh brine (25 mL) ded mer NaSO4 5 and fiktered The fsrate was cn rated iz vese to afford the drt prOdct, 2 -biomy4-methyfnicotinic acid (2105) (91 g, 85 yld) as a White solid. 00472)T a hin ofro methinicoinieacid (210) (13 g. 60 mo and D-MF (3 drop-) in OCh ( 50 $ iL), oxlyl chlride (11.4 g, 90 mmol) was added dnpwisr and the resuming mixe was stired at RT ftor 2, The eAOon mrixtimr was OnceMraed &T "acan to aofird the desid prdnt. 2-hrom-4--ethylnieorinoyl &hkide (210) (134 g, 95% yiehi) as a yellow oih. The p-rduct otaied was used directly int the next step without -urne. purificattin. 10473) o-Toidme (23 g, 72 nmol) and triethylamine (9 0 g, 9$ mmol) were dissolved in CH2Ct2 (O~mL and 10 stied fer 10 min a RT. 2&H o--etyinicotinoyl chientide (2106) (13.4 g, 57 mm) was added, and the ntiting mitue was stirred at RT is 1 The mixture was pored into water (200 nL) and extracted wim C-h C (3 x 50 tLl ne combined organic layer was washed with brin (20 4t drid over Na 5 Sh ad fitere The filt-e was cmentrated (A vvo 3 afford the enite prodtZ, The ende product was suspended in WE (isoprpy ether) (50 aL) The mixture was sirred :a reflx or %min and then weconed to f-$*C he precipiate was colleced by fltradin 13 and fritter dried in enr to at~hrd the desired product, 2r-bomo4-methySNoylnicstivrmide (207) (D3 g 73% yield) as a yelow solid (310474 To a sotion of o4netyi-o-olyhnacinamide (2107) (13 g 43 mmnol) ard ibtyivinyijtin (1.4 : 52 me) in THff (200 nm) under a nitrogen atsnosph', Pd()Ae) ( 29 g, 1 mmcl) ard ??h (63 g, 26 mo) w-ere added 1he remmiting minue wm stirred at refaux for 16 h- The ma ixtv e was thn allowed to cool to RT, 2) tittered through siica ge (10 g) and concentrated in vacuo. The residue was poured iato water (200 L), eatreted wi.etayl acetate (3 x 50 ML). The combined organic tayer was wahed with brin (39 P.), dried o-or Na SO and fitered The filtrate was concentrated in o ro and the residue was purified by fah colon chtmatogrphy on silica i (2C-50% A/PhE) to afford the desed p'duct 4.nthylN..odiL-imnicteinamide (21ON) (i7 g, 80% yield) as a yellow soli 25 [0047$ To a drmd solutdn of 4.'methyhNestoly2inynicetinamide (210$ (& ) g, 32 mmon i DMF 0 m) at RT, NH (60% in mineral oil 2.6 g, 65 mm) was added sowly and the resulting mixture was Arred at RT for 30 Eiin thyl chlrsrorcae (7 g, M1 nmo) was added dopwise to this ntture at itt and stirred for 2 h. The Sion was poured into water (300 ML) and extracted with ethyl acetale (3 .x 0 tL) The combined organic layer was wshed wih brine ('2.5 ml), dried over Na3O 4 a:d fil The filtae was conenated in scne. The crude product was 30 supended in M; H] '60 mlQ) and sirred at reia for 10 min, The mixture was then coo ed to 0 -3*C The precipitate was collected h filtration and futhee dried in va c'o to afford the desired product, ethyl 2(4 meth 'yNo'ol yI2 vinytiacotinamido) acetate (2109) (6.3 g, Sg% yield) as a white suiso 104761 To a solution of ethyl 244-moethy'N(oeyh2- y tm act ( ) (,.lg 1& 0 mmol) 'n 1 4 doxase (90 enL) and HtO (30 mL) at RT, O- 4 nm setmoxide (5 mg) was added and the resulting mixture was stied 35 SW 3s a. Sodium periodate (?7 g, 36 mol) was added Wnd the MituM was stirred at RTt for 16 b, The mixture was filtered ftotughi silica gel (5 g), ad the filtrate was extrated with ethyl acettme (3 x 50 muL) The combined orgrnic layer was washed with uine (25 WL), eNd over N-So nd thez 'The fltrate was concetraed in O-eo and the esidu: was further dried umnde reduced pressure to afford the dered peoducthyl 2-(2-formny4-methyto tolylnieotinamido~aciate (2110) (4.4 g, 72% yield) as a yellow solid 40 [004'77' T a sted soldin f y ( rmry1-4nmrhyNeo-talynconamid)aeette (2110) (4-4 g. 13 mrn'ot) in E411 (30m) and ethyl acetate (10 mL.) at RtT, cesinmr bnate (43g 13 rmd) was added The using mixture was degassed and back-led with argon thme dmae and then stird a 50 "T for h. 'The mnute wm aiuwed us cool

AIS

to RT, nlered thr ih ica gel (5 g), -d the filtrate was i tinted in vetn. The residue wsoured into 140 (300 mL), examcted with thy acetate (3 x SO mL). The combined organic ayer was dried over Na2SO 4 and tiered The filtrate was conoemated in vncma. The ;mtde product was sispedied in WE (30 mh)., stirmd at refhtsr fOr mg and then cooled o 0 -5 *C. The precipitae ws collected by nation and orthe died in o to afford the desired 5 product, ethyl JAmethy1:40xo4eolytv Sdihyd fr I/naphthyridine-a Ayme (21H) (0t, 72% yield) asa white solid, [0473 To a surfed sstion of itbium a vmr hydde ($,8S g, 23 mol) in Vhydsus THF (100 tL) a 48 'c tsnder a troagen atmosphere, a soidosso ciasy 4SethyS-okvaoy1-S,6-4ihydro- 14 6-riphbyridino arboyste (2111) (29 g, 9,0 mtool) in a&1ydMss THF (20 VL) was added dropwise, The resulting mitWe was Slowed to Sem to-lOC stirred for 30min and TLC showd the compiled of the reaction. Then the mixture was cooled to -78C, and water (50 Lw) sltowy added. The om ate wm allowed to wtt tol, fi retd through :Sik gd ($ g), and the filtrate was concentrated in vacu. The crude product was poured into teO (00 ML) and eXtrcted with ethyl acetate (3 x 5D in!). The combined irgianic layer wm washed with brine (2 maL), dried over NayO 4 and filted. The fitrate was concentated in vaca, The crude product was suspended in ethyl acetate (10. L) aid stirred 15 fr' 10min. The solid was coveted by lihraton and other dried in vacso afford the desired prodt 7 (hyd roxymethyl)-4mcby -o-toyLs6-naphthyridin-5(6H e(2112) $21g 83% yield) as a wite Solid, [*0479 To a sotin. of 7(hydroyethyl).4mehy&otolyl .6.aphthyridit5(6H)one (2112) (M gi, 7.0 mmo) in CHCf, Ph1 (167g, 14-0 mmol) was added and srend at RT or 30 mit Cra (4.64 g, 14,0 mmal) was added to the iurmixe in portions at f..*. The resIl ting bmixtree was allowed to warm to RT, stirrd for 30 mi, and 2 concentrated in vacuo. The residue was purified by fash conm chrmatography on siica gdl (30-50% EAPE) to afford e desred poduct, 7bromonethy)4-methyi64olyhltnaphthyridn5(6H)+ne (2113) (132 g, 80% yield as a white sild. [004&1) A mixure of 3-iodo-lHpyrzoo(,4-dlpyrnmdn4amne (108A) (1.08 g 4 414 mmol) and potassu m ert bmoxd& (044 g. 4.0 inrol) int anhydrouss DMF (50 miL) wats sdired at R T for 30) rin and then 7<bromsomethyk4 25 mehyfoetoly1i nphryddin"5(6Hbone (2113) (137 g 4.0 nmol was added The resoiing mixture was stirred at RT for 30 min, poured intw ice water (300 mL) and then exracaed with vil acetate (3 x 100 roL). The combined organic layer wa ashed wih brine (30 mL), dried over NQSO 4 and filtred, The filtrae wats concentrate 0n vace and tue residue was pilfied by flash column chomaagrhy on siica ge (0-2% MOifDCM) to aifrd the desired prodoct, 7-(4-amino3+ido+1 H-pyraaroo[A4dipyrdmidin. I-y)methylh4msethyb.Owtolvbht6 naphykddi. (H 30 one (2114) (1.07 g, 50% yield) s a whit solid. tIN048A To a stirred mimue of 7<(4-amnino-3-ndod H-py olo[3kd~pyriidit"1-yl)methyi)4 mety-6ototyh 14-naphyridire5(4:iyone (21114) (LOS0 g. 20 mnin) and 3~hv&oxyphenylbonrnic acd(03g,24 mi)ie M EtOH410 (3A1,50 lt), Pd(OAc)i (0.4 g, 0.60 montw o PPh(031 g L2 inmofT ad Na2COh (106 tg, 00 memo we added seqoetnialty, The reauling reixnte wva degassed ad basck-fiLied with argon three times and then stire at 35 80 " for 1 h. The mitre was allowed to cool to R fiered through slica gel (5 g) and conmeraed in va . The: residue was pufied by flash comn chr'matog bphy on ci le (25% MeOIDCM) to afford the daire product, 7((4%amon3.(.:ydrosryphanyi. I-praolo34-.d)yrimid .yi~meedyl)+ msethyb&eteslyi~ 1 ,6.aphthyridin 5(6H>one (213)St(068 g, 639% yield) a a slight yellow solid. Then the product was dissoved in EsCH (5 mLt), cad tirred at rei fir 30 ein. The solution was atowed to cod o R T ad the solid was colected by h'vatiori The scod 40 was then srtpended in ethyl acetate (5 mL), and stirred at Rl' for 16 h, The precipitate was collced by filtraon, and other dred in vacao to aford the desired product 7(4mia3(34ydroxyphenylVIH-pymzoto(3,4-dpyrimidio1 yl)methtyW4- methyl-6-ototyl- i,&nphthyridia5(61t).re (2115) (t+S9 g.. 60% yield) as a white solid - I12~ [.0 4 ,8 2 1 Folansfde9 24etoiyl-3 0 4ihydisxuilh1 i l(2H>otie (Comnpound 220$)y Sehne 22 3+((4+amistG3(3trmhhydroypheny>I)Hjwa kt(4-d pyrimidin- byi)tylk2mehy2+~ solylbi4dihyoisoqiohtl(2itoe (Cormpond 22h8) is described. NArCPSA N~ 5 21 2202 2202 NN N0p 2204 220$ A UI F O~'H ~220y H- N 80c hP H 2206F 220$ 004$3) 24odese y nxvN etelylbernamide i9201)(L5 $ 4.27 mmnd), wNhch~f has ~ b ee parere fom the rtaction. of copamd962 anda 2~ety anihne and. allyhrsbutyttin (210 gm 11 mmo) wre doolvedi in eahydrous DMF~ (12 10 rn.). The sch'on w dgsse an backfiled with arggn (three tiamea). Pd( PPh)q (14 tmg, 0 1 mnvoi) was added Th eo mixtre was degpaied and back-tited with argon (three times), and then itt ind at 90*C for 16 i he natue was allowed to cord to RT, pt .ritioned between &ty acetate end H2 10 , The organic layer was washed with tsntw. dned over NaSiib ad filtered The aa was ecnmdtd in vwn and she residue was purified by echumn *roengtphy en silca ped etuintf wah EtQAc and Hexates to afford the desired prdtxe. 2-idyvi6-methyhNNo )5i oyhenramide {2292) (j: 5, 95% yed) [064S4[ 2-.AIWy-6-methy[N-o-tylbesammide (2202) (800 mg. 3.0 mmoas) was dissolved in anhydroa dihkornethane (20 niL), a-CIBA (70%, Lt I g 4,52 nssd) was added ad the resulting mixture was stirrd at RT for 24 ii Na 2 5Oy (1 -0 g) was added and strred for I h, The mixture was partitioned between EtC$Ae and water The organi layer ws washed with brine, dried over NaSO and filtered. The flurate was concentrated $n meo, and the 20 reidue was pardfiad by edtmn chromatography on silica gel eatity with ESOAc and Hexisanes to ad~ord the desired product. 2+miethyl &-(oxiran2*-yhmethyi)-N--ctdybenzamid (2203)(0 mss 83% yield), [04&5) 2-Methyl-4rism2-ylmethyl>N-otelyibeneamide (2263) (1860 rmg 306 mmtrol) was disoved in anhydrssus DMF (1S mL,) ad corled to O "C nder a argo atmosphere NaHi (60% in tmOnr5 rat 245 mg, 612 nmnod) was added in portions ad the resuting mixture was stirred at 0 "C for 3 Ii i-iaC (30 n-l) was slowly added ad 25 the mixture was extracted with El(X~e (3 i 25 mLD), The combind organic (ayes were washed with bite, dried over Na 20 4 and filtered The hrale was contceratated hi va, and the reslia was purifled by cohara chromatisgiphy -i1' on .:ica ge|ening with OAc ad HAne to afford the dered pidus (hydroxymethymtyb2-tolyh .34-dihy'thoiaoqutindoi(2t)one (22u4) (435 m , .% yiedd. [I048] 3-(HY ydymhyl) methy2+rdy3dihydoisquini i1 (211)"Cn (2294) (430 mng, L5 .mo)was dissolved in ahydrous d dn2 ) nd icdd to O4C under argon atmosphei. PPh (400 mg, 2.29 5 snol) ad CrA (761 mg, 2.29 amW) wtre added ed: heresuring mixture was stirred ftom n- 0C Oo RT w11 h. le teaEsOl mturfe was partae-d bews BAc and wter. The organic layer was ased with bri ied over NIMSO 4 and flu hered The f9irat was ceentrated in Ve " n the ren wC''V prit ad by column ebromatography on siloic gel eating with lXtQAc and Rennoes to afford the desired prAduct, 34boomethyl) mthy-2-o-y,4dihydrois0q0 iisnl1(2Hone-(22 05) (480 ;mg, 91% yiedd 10 (41407 ((romnnety Simethy2o gy4-3dihydreisoquincl5i21Hone{%05) (3g m 22 mol)kaqd 3 koH- ii-l'pyrcoI3 ,4'dpyrim id 4-amine (10 A)(440 mg, 1.69 .mo) were dissolved in anhydrous DMF (20 m L

K-CO

3 (309 ag, 224 mmo) wa added and he resudag mixture was stirmd at 50*C for 3h. e reaction ixtese was partidorned between EtOArt ad water. The- organic Jaye was washed With brine, &ied over NaSOt and filtered, The filnte vies cneremraed in amo, and Bhe residue was purified y column romaography on slca gd elating with V methanol and dichiiomethmae to afford the desired product, ((4-anino4kodo-N1pyraavi0[3-d~pydifd-~ y~ehyl)-ethy2oy 4-dihydrociepoir-(2Hb)one (2206) (10) mg, % yield). l.10488) 3{(4Asaiao-ddd IH-pyrazoo3,4-.dipyiaidin- lyl~smethyl 8-mthy 2+wlolyi-344dhydoisogprinsin {2Hsne (2296) (190 rg, 0, I Immol) and 3loro4-hydryphenylbronic acid (2207) (36 mg 23 mmoi) were dissolved in DME (4 ml)h The von was degasse d and backdiled with argon (three times). Pd(Pphs (6.4 rag, 5.5 20 pal) and aqueous NaaCO 3 solio (1.0 M, 9.44 stL, D.44 amml) were added sequendaly. The r;Ationomisoe was degasd and backiled with argm (three imst and th starred at. & WC fir 24h. The austure was allowed to cool to RT, partitioned bewveea ety acetate ad brine. The' rg.i layer was dried over S fitered an cntated in mewano The residue was purified by column chmreoatogaphy on silica gel ehaing with method ad dichlosomaethane to afford the desired product, 3-((4-aminor34-fuoro$hydoxyphenty1Hr1-yrszo[3Ah 25 d p n(2H)-me (2206)(12 ag, 22% yidd), 1904891 Enaple l0: Synthess of 64(4-amino(3-fodydroxyphy-1pyo3,4-djpyiuidid ylyl)5l)$omethyk5iyothialoe4-dynidiko4$.one (Conmpcrxd 2313). Scheme 23. Synthesis of &((4-eainao-3(-Tsm-5hydrcyphenyi ) 1H-pynaoln(34kdlpyt irdin- y4 gmethyilr3 msethyl-5 o1lisothmaol,4-d)pydmiddin 4Herne (Compound 2313) is desrbed Ol NCS 2302 N O 2 . ......... NH2 C h MNHCoOPh RT l RT, 3 30 2301 2303 2304 N__ .COOEt 0 COOH SC000 'N- N i Hg0YDMF N$/NH 2 1 00WC 4P N ReSuS h f NH2 2-305 2306 2397 NV PCH2-NH Seaed wbe Ouene NHN,00 2% Refiux lh NSN NHCOCH 3 CI ovem ght 20 2309 ) 2 \CN x ......... N Na ~'~ t uOKID$MF N$. N C4tC Th78Cb0 to RT 6N OvanieM gN 2310 2312 21 [004911 A satuton ofCopound 2302 (243 g, 0.19 moi) in C 3 CN (50 m4 was added to a sohao t' compound 2301 (30 g, 0.19 rol) in at 0 *C The m&rie was stirred fr 1 hour a room tnpeats ad poured ito 300 rt of 5 water. The oacdo mue rwasaloed to stand for 1lh. The solid was preditAtsted cut of the en M.a , conect edWb filtradion washed wuh water and dried '-o aTord the desired comprnrrd 2393 as a red-orsny souid (50 a, S i5%) [00491] To a sniution of compound 2 3 43 ( 5 4g. 1375 mcl) in ethyl acetate (200S rt), aschniors of r ($6 a .3 mcli in ethyi aate (50 mLf) was added dropwise at rootemperaui a The rcseating meitate was stired for 3 h at room tempter The soid was collected by filtrautm washed with ethyl acetate to fford lte desed prdutA. 10 compound 2304 (40 g, 744% 10492 A mixture of compOund 23(4 (40 g 0,13 ol) andsatuated NatO; k soti on (10 mL) In MW ()100n) was heated fr 5 h at 90 C., The reaction MeeW was cooed I nomo temperaure ad I L of water was added The solid was collected by itration and died to afird the deed product, copound 23l 06 g, 66%) 04931 A misdure of compound 2395(16 g, 06 o NaOH (64,83 &D 172 m in war (50 mL) was heated for 4 15 h at renflex The reaction mixture was cooed to rom terprau and amdkfdedt with 1:N HC soItion um1I P- 3 - 4. The sol d was coleted by filtration and dried t all the desired pr cmpond 230 (12 %), A maxte of compound 230(1 g, 0063 mcl) in SO0 (15 mL) wat arsd for 5 h Lat ref the e nxture wea. cooled to ro tempertear and cnceoraed to remove excess SOC). Anihydrom toiuenAe (30 Et) was added to te residue and corncentraed, This process was repeated twice to remove the residue of :SOCtt. 20 0M94[ 1Th crde com pound 2307 was dissolved in dry tue n 5 ) 2-M.hy. aiwn (2 a :I0)18'7 mol) was added to the above soition. le resuiTing mixture was heated for I h at reflex cooled o raceo tempet e nd filtered The fiau wan ocentrated to dryness and partitoned betven l ethyl aet a bine. 1he aqueun phae was extracted with ethyl acetate, The combined organic phases were washed with brine, dried with MgSO0 4 and fikered, The residue was purified by fish chrom atamphy duItins with petroethcer ethy acetate frm S to 5 1 to 25 air the desired product compound 2308 (600 mm35%), [004951 A smios of compound 23(4 (600 mog, 2.43 gmnol) and pyridine (1079 mL) is DCM (30 ml) was stined for la Cconde (423 m N 174 mc) was added, The miett. mixtro was starred for 2 4 ad quenied with waterThe organic phase was s:paraad ad washed with watr brine, dried, fi bored and concentrated to aimard she design product com pmd 2309 (700 tog 89% 004961 A 4itur of compoud 2349 (600, L t8 mml)o ankd .PQCI(10mL) was hated Ovemight at 120 (oil bath) in a seeded oabe The reaction mine was cooded to sroom temperature and con cctrsted. The residue was prtined between ethyl acetate and water, and then baufed bah saturd Na% solion oati PH 7 - & The organir ayer was separated, wash wit h brie, dried over MigOS ad concentrated. The residue was pudiied by dah 5 rhrae pogvpy biuting with peirnethter in ethyl a i e (PE/AAM/1) to afford the aired product, copond 2 ai a yNdow powder (300 r& 53.0%). 4004971 tert-BuOK (29a mg, 0136 mrofl was added to a sohtion ocf ornpound 231i (76 0g, >295 mnoa) in dry DMW (3 ) at RTC The ration mixte w stirred for 3.0 ari antda soktionf compound 231 (6) mg, 0.196 mmol) in DMF (2 .mL) was added dropwise. The reulng mixtre wa& stired for 2 h and concentrate. The reside 10 was purinied by ahb chromatography dlaog with (DCMMeOI-500lf) to afford the desired product 2312 as oW% white sid (65 zmg, 623%) 10498) To a soltion of compoAmd 312 (40 mg 0,076 rsmol) in dry DCM (10 mL), B4(190A mg, 036 mmol) was aded dropwise at ~7C, then th reacio mixture was' awed to wam to room temperature and stirred fo oveight The nation mixture was po d io icewater, ba sifed with staturad NaHfC0 sok:cunto jti PH 8 9 ad 13 extracted wih DCM. The cobi ned opani phases wtm driA over Mge0 4 , filtered and concentrate, The rade was purified by flash chromatogsphy trtinrg with DCM/ MeOH 30/ to afford the desired product, cniponrad 23 (IS Ma 3A%), [60499) Esampia 1: Synthesr of 2-((4-armi+3-hlydroxyphenyi- ii-pymarol4-d pyriss i-yfmethyy--5 mahyMi-3- yhhi [2,3-d)pyidin-4(3H).one (Compound 2407). 20 4041591] Schtern 24, Synthesis of 2-((4-anin3-(3--hydroxypheyb--il-pyraz&op dpy 1:iin yl~fmethl methy-3+otodytren23dpydmidin-4(3H--nne (Comepound 2411) us described THFH o:02H 0 ~ 940 C C to2a a H -- --- ~ sd 2401 20 2 'N~ rOH/ 07 S-C -120T,. 0vrit RT 2h HOKN>N 2404240 2406 -14 AH ILA N.01 2ZA j40S504 Th a stined sthntion of 2-an o4m ty1h'opem3carboxylic acid (2401) (2A4 , 15.2 mamo) in TH-F (50 m, a htion of triph sgene (9.0 , 30 mm, 2 eq,) in TIF (10 roL) was added slowly dropwise at *C in 20 1rn, The reslwng mixture was irred at ON* for 2 The reaction ure was genhd with water (20 L t ON ,C and th concentrate in c o to remove the organic solvt A bowv solid was precipitated ou of solution. The solid Sws collected by fltratiom , washed with wate (3 mL x 2) and dried in vomas to afford the desired prodac 5-mehy[ 1Httito[24)[1 ,3]oxaue-2,4-dioee (2402) (2.5 g, 03% yield) as a brown solid. [00502] To a stirrednshaon of oAondineN (lAg, 128 mmacl, 12 eq) in dry THF (20 mL), riuLi (2,5 N, 7.7 tL, 19.3 mcol, 19 eq,) wes added Jowly dropwise at -4) 0C under argon atmophere ia 30 mi. The resulting Mixture as stirrd at '40"C fosranothe 30 mi uA orte of 5-methyl- it M~iedo12>3dl[,3 ]oxazine-2A-dionea (2402) (09 10 g. 10 mmc. ino) in dry TUE (50 M) was added slowly dropwise at i40* in20 Rot. The reactio mirus'e was stirred at 40 9C Ir lh and then aRowed to warm to room. temperature for ovemight. The rteteon mixture was quenched wAth water (20 mL) at OC, and then neutralized with concentrated Ha solution nxtil pH 8-9. The mixture was concentrated in resUe to resnave the organic so Ien. The ten de was extacted with ethyl acetae (25 L x 3). The combined orgaRc phases were vashed with brine (10 wL), dried over MgSOh and concnrated In w . 'The is trading reidde was purified by a slica gel olumn chrmatography using 5% to 20% ethyl acetate in petoether as a etent to afltrd the desired product 2.-amno-4metthNN tvo' pe3-carboxamide '403) ( 0 34 g 2 8 A% yield) as a yellow solid {0t053) To a sdrd solution of 2.ami >4 ehyN-oolyhiophene'3-"ar bonde (243) (740 mg, 3 mnao) and pyrtdine (4069 og 3.6 menol, L2 eq) in dry DCM (20 rt), 2-loroaesf e ride (284.S mg, 3.6 nwA. 1.2 eq.) 20 was added sIowty dropwise k" c *C in 30 a&n. 'The rttning tmixaieue was stirred at 0 C for 2 h. The reactor nat"ie was qumnched with water (20 ml) at 0 "C and extracted with DCM, The comied organic phases vwe washed wih IN of 11C(1 solution (1W mL), brine (10 rlf) , ded over MgO4 and concentrated in vrco? to afford the desired product 2-(2<hloroaceando)4-methyl -N-o40e i ae4carboxamide(2404) (950 mg 9A1% yield) s a yew solid. 25 10 041 A mixture of 2-(2-chirmacetamid&)4-ethybN-tolylhiophee-3-cana (2404) (107 g332 mso) and POCXJ (25 mt) was sairred overnight in a sealed tube al 120*C"," The reanion iti wrte w concentrated in vacuo to remove excess POCt The de was parationed between DCM (30 ru) and satwated NaHIC0 5 sohltion (0 m.1 The organic ayer was spaxrated and washed with sat 1NaC0 (W ar), brine (10 nll), dried over MgsO4 end corcentrated in vn.O The r n residue was puified by a silica gel column chunrmaogaphy to afford the desired 30 product 2-(loroethyi-metthy3+toyithieto23odlpyximidin-4(3Hone (2405) (76 M g, 752% yied) as a yellow solid, RO05&1S A siution of 34odo l-pyacol4-dpyrimidin-4-amino (18) (314.3 g 2 mmoi 1Seq) and truoK (155 rag, 138 mmol 2 eq) in DMF 00 mL) wa stmd at rsom temperature fr 15 tin., a soluion of 2 (ehloromrethyis-5rethyi3.tolylhienc(2,3-d pynmdin4(3 one (24) (350 mg 1,15 rtnd, I eq.) in DMF (5 35 mL) was added dopwise at room tperature. The resuming mixture was sred at rom temperalme for 2 0. The reacdn tmixtre was concentrated in vacuor to remove the organic solvent The Nulting residue was purified by a S.,Ica gel ccare chromatography to afford the desired product -((4-amndo-3odoi-pyaoo3d-rimidin l~maethyi)-. methyl-ortolyiien2,3-dpyrimidin4(3~H)-ne (2406) (250 rg, 41 .1% yield) as a yellow solid. 9006G 21((4..asmv :3.iodo.. h-.pyrazolo(3,4'd~pyrdmidhi.'l-y)rethyl -4mrethyl-3+o tolylihieno[2,3ad~pyrimnidir 40 4(3FHsone (2406)}(50 nmg, 0.092 mnmol), FPin (14.5 mg 0.0% moof, 0. eg) ad Mi4ucnom5'hydmxypthcenyboonic acid: (2127),:(172 nmg 0.1 rnamolt .2 eq) were daisoved in a sltion of DMF, ethanol arnd water (5 niL /2 mL../ 2mL). To thi mixture Pd(OAe)>(4.4 stg 0.018 mmol0.2 eq) and sod-um cardxnte (48 7mg, Oa46 moel, 3 egj) 1n1dwere added sequentily. The reaking mixture was degpsed and backfl led with argn three times and then heated to $rc Pa' 03i with stirrir.g. The reaction iNixto wa cnerated in vatcuo to remove the organl c soveT.. Thle resting residue was pUlfed by a siica gel cohmn chrom raaphy to aford the &Ared product 4( ino+(3. tloo5hydroxyheny()-]HpymoZ3,4-dpyrimidin4yl~me1|hylk)methyi-3+ntoykeno2rpyidi-4(3HP 5 one (24r7)(22.Srg, 482% yied) as a ydiaow solid. [@05O7) Ezaaphs 12: Synthesis of 8'tmethye(meth(9Kgri4y)sinohyith2toyl~iolaimi(2HF [05081 Scheme 25: The synthesis of S-rnothyi34((rneiyh prny~ais~ety +olVsqinb( one (CMmpo'nd 40'4) idscried. NN N [W509) 39romomethylphnethyb2+2dy oqiin(Hone (342 mg, L.0 mmi) (1697) was dmhdi methamin schnon(10D ML) and SNe for 2 h. The mi-xtur was polmd into ice-wvatr(0 mL) and extracte.d w-ith ethyl actt 3x 5M l), Thxcmined orgmmic layer w~as wased it bne (20 ML) red over Na 5'04 md 15 ffluemd 1.The fatst-e was conce-nAed in vzac o WAffod the desOW produ menl(mthim knhi2 suy~ginnund2Hyoe (401)(250 mlg 6 yield) as a yelOmild Therr prod-ix obtained wased ITAy mn the exstpwihou piictin 9-(inhdro2Hyynm ylkHepine(4M) ('23a Mg I00 mmoQ ee eole in NtO 01 mdL) and thw e!multing 2C' mixzure ww, tsdned W, refl4x forj . Th iw allowed to coo? tw RT, and nenrted vacau, The. residue wspurified by flasub column dhromattogspyo .e e 20 eMDM)t fr epout8Mhl ((mthy(94etrhydm2Hpym2-yk9Hpud~yimin~mehyl2+tly soqincie (2Hone(4003) (200 mg, 51 yidd) asq a:Adlght ydkow sOWd 25~ Aqmuus NaH~ ution was added to the reaction Wmite and Mo pH was ajmmed to , The it u was 4 f erd and thew iNaews cncnrae inno us Wffad the desired de pmtye(ehi9 prinl y~amn~mthyl2+ttyksquelind2Hkne (004 (80mg,54% yield) au a yk od 8Its- 1003121 Eanple 13: Synthesis of 3-( 1-9H -purirdyamiojthlknethys2+Ayioqin& in- (2hyo~ne ~00313) Sereme 26 The synthesis of 3l1(H-pn&sylmic thl ety s+olysquondia 2>one MnC, vmg& OH 6 H 04101 4102 ~~NaN Or NH N 4103 41 YN hkNN N NN 2 54104 4106 4106 [005141 To a sited~ solien of 3-(hdroxymehyithyb2+lytolisil1(2Hyoe 1606(279 g. 10 mmd)oi in CHGCZ (2100 mLL MnO2(t g) was added and the reulting mixture was stirred at refnax for 3 h. The mare wa alowsd to cool to R T and aoneatrated im m The reside was ::unfied by flah ohe chIS matography on sAica ge (10-50% EAPE) to amrd the product 8methy1l1ox 2ltoy 12dihydroisgiinolin3-earaldhyde 4101 10 (25 g 90% & yes ahite olid. 1005151 8-Mtb1-o-tolyi-i,2-dihydraisequi:ilin3-cabudehyde 4101 (2.4 & msno) was dissmived in awirous THF (200 mU and cooled to -7C~ smder a ttirogen atmospthe Methyl M~ 2M L 0mo)w added slwy, and the resultig mixture was stird at -2 * for 2h. H4} ($ mL) was added and then te iAudon was poured into ice-water (200 mL) ad exteted with thyl acetate (3 0 S0 nL). The combined organic layer was washed 15 with bdhe, drid ove N1,S04 and filtered. The fltrate was concPentd i ws , and the M.d ue product was purifed by flash colum ch msography om silica ge (10-50% EAJPE) sto a ford the produce 3(1 hyd.xyethyl-. methy 2+dyo i Equiiniltl2Hpone 4102 (1L8 g 71% yiekd) as a white solid, [OOSI6J To a solution of 341-hydroayedhyl)-0rmethybeyistispquinolim l(2HYone 4102(1L6 g, 3. nmd) in CH^i, PPh (28g 11,0 Pum was added awd the resulting Fixtue was stirred at RT for 30 mtinT ten CiA (3.6A 20g. 1 l mmc4) was added in portions to the ri:m re at 0 !1 The resuntrg mixture wu diowed to wrmm to R Ti sred for 30 min, and concentrated in vow. The crude prodet was pusrhed by fash cohmn chromaeography on silica gel (0040% EArPE) to afford the desired roduct. 34l(Mhomoehyl.lmmethy2otlyiequnlin~(2Hymw 4103(108 ?91% yied) a wite solid. (005i 7) To a sdirred solution of 9-tetrahydrm2fl-pyran-2-y lV9Hepusrii-amine 4103 (436 neg 2mmsol) inanuhydenss 2.5 DM (10 -L, H (60% inminral oil, 77 mg, 2 mol) wa added and the mixtre was sird for 30 min. 3~(: * otehyl) -medhy2--4oylisoquinoin' 1(23Hone 4104 (700 mg, 2 mmnol) was added. The mixtume was stirred for A2 poured inoo ice-water (200 mtL) and extra.c with ethyl acetate (3 x 50 mL), The combined organi layer washed with brne (20 nh), i&ed ovens NaSSO.

4 and filtend. The filtte was concentrated in vcn ud the residue was prified by flash column ehromategyhy on silica ge (10-344% M DCM) to afbrd the product, Smehyi349 30 (tetrahyQW52H-pyran2-yl)9H-puriretyaino&ehy-2+tolyisoquinoin- i(2(oe 4103(500 mg 5i% ydd) dasq white solid 1 [0&i) &-Methyv (-(4etrhydrc-2BIpyran2-y)AHopn yhmiehyl)-2toysoquioid2) 4105 (180 mK, 036mm& ) was dissolved in MeOH (HCI) (50) M) and stred for 2 h. Agnecus NsHCOt w3dufsvam wrais added to the rmven MOtre and the pH vne ws adjused to 9. The mixtu was the filtered and the frate was concentrate in reuo to afford the deskred product, 3( ( 5 l(2Hyne 4106 (80 mg, $4% yield) as a ydflow olid {005191 En mpe 14, Synthesis of 344 amino4((8-methyi1oxar2+toy,2-dihydrisqinol3-i)methy4 pyrarot(3,4'dpyheidif'y>i4!onpheny dihydrogen phosphat jOO520j Scheme 27. 'les synthesis of 3-(4'n-ambl 4(8-nethyV oxsw-+toli ,2-dihy droisOquinoin-3y()thyi) 1 H py ok43A-dpyrimnidin-yl)%rophenyl dihydrogen phosphate (Comnprand 4903)is dkribed 0 Ei N s tstTMS~r ' N N (2Cl C N. N N CH- 3 CN N N ' 3 0Cto2 24VCtrA 4 24I F F F 4N1 4302 jt0flj 3 ((4'Anmino43(3lifkoroShy droxy phenyl)- H-pyrank43-d4primdi s%yidhyr)4ehy''o totytisequin-sedi(2H)one 43i1 (250 mg 0.5 mno) a dissolved in tydrous TVHF (15 mL) in a road bettr flask in dark (aevered by aIminumt foiI) ad ecoed to 0C under an argn atmphe, CBr, (498 mg, i'5 mmol) was added foullwed by diethyZhha: (19 L, nsramo) atd oethylaine (4?7 9 . LS mMo. The resting mixture 15 wa shined in dark from 0"C to RT Ler 16 . The mixture was thten partitioned between ethyl acetate and brie. The organic tayer was dried over NaSOA floated and concentrated in eocua The reside w puted by CnhInsn nakotrgshy on diiiae geviuting withmuan anddichlorometrne to affot sire d prodc.3-(4,-amino ((&mrethy> oxo-2+atotyl-i2ldshydroisqitolins-3yi)nsedty iHpyrazoto[344Akyrnmidin- ylil:-ohey diethyl pghopnte 001 ( 200 m, 62% yield) as an off whire solid, 20 [065221 b(enn4(mth x-+oy 2hydraomainalins 3ybmehy)lkl-pyaolPA3-dpydmnidia 3-y, 15- fi-araphenryl diethyt phosphate 4302 (170 ns 0 26 mmol) was dissolved in rsnhydroous CHCN (5 eeL) and teoted to 0*C under anargon asnmospheree TM4Sr (s>34 mLt 2

Q

5 4 nmmot was slowly ad-dad vie a syringe ad the suing mixture was stirred froM DC to RT tor 16 h 16 LtCvtS showed nmall amo lt o stating meeriat el, additiol armourt ef TMStr (0,1 mL) w added m and \tirod at i fe 5 (1C-MS showed the complete coversio 25 The mixitum was conznuatsaed in vacuo, and the esido was dissolved in t0 (10 mL): end HlO (A5 mt) and timed for 30 Ui, The mimsvrewas coerasedin vea-c to a-erda the dseired poduct3-(4eeno1h(( methyi-bxo-o tolyM 2-dihydreisoquinatim-3yimethyWk -I-p~yol(3A4dpyrimr.idi -3yl)-5luerophey dihydreoen phosphate 4903 (14 0 ng, 91% yield 160523j Example 15: §05!0 Values for Seded Coapunds 30 TsW 4. Ps fitrc 1% data for seeded compounds. -+ (greaer ha (st dhan tW -++ {.e. than -.. -++++.. (less than .00 mircrnoor) -iroas) ioMofatr eM) L 3K. 8Comp. jdNo. Us o dmpiNxi NepedNoI "120- 4,5, 242, 27, 3 .39 4, 14, 5,171, 23, t5, 7, 8, 9 1, 40, 41, 96,2, 29, 3 -2, 4, 11, 12, 13, 6 19 IM 120, 129, 132 3,36, 42,43, 44, 20, 23, 24, 2, 28 64, 165, 172, 13, 45, 47, 49, 57, 69, 30 33, 37, 48, 50, 19m 197, 198, 2 37, , 8'i 94 106, $1 52 S 34, 3, 2!0, 2,212, 214 17, 14, 143, 17 $ S6 , 9, 661, 21."7, 2 ug, 220, 22 179, 183, 1841. 19, 62, 63, 64, 65, 66, 237, 23, 53, 24, 193, 196 1199, 20 67, 60, W 72, 73, 9 20 1 2, 20& 27 7437, 76, , 2 . 23 21s 219 79, 80, s 2, 3, 224, 225, 2 229 34, 96, 93, S9, 90, 23C,232, 233 239, 9 93, 95, 9 , 97, 241 2413, 253, 9 99, 100, 101, 254, 25 260 262, 102, 103, 104 Is 2293,299 l03, 109, 1it, 11, 112, 113,114, 115 I19, 123, 124, 12.5, 126, 128, 134 135 36, 137, 13, 139 14% '42, 44 4 1-46, 147, 14.9, 149, 150, 1. 152 15 154, 155, 1 56, 137 .5s, 159, 160, 161 6, 166, 167, j 08 169 170 171, 173 174 17, 177, 178 180, m)9, 192Y, 194 195, 203, 204, 219 216, 22, 223,.226 227, 231 234, 235 236, 238, 240, 242 244, 244,:247, 24, 249, 20, 2312 256, 257, 25 9. 26 264, 26$, 264 267, 26, 269., 27 272273, 274 2'75 276277, 27, 279, 230, 231, 282 2"3 4,2323 287, 23 -- 1- 289, 290 291, 292 295, 29297, 30 301, 302, 300 304 14 5 18 34 44 1734t 35s,38, 2, 8 9,10 14 ,,12,134,6 6O,*69 169 172 404' 57,61, 65. 15, 20, 2" 2> 28 9 20 23 2 2 196, 197' 198, 200, 91 92, 94. 1&5, 107. 39, 41, 4o 47 49 26 29 30, 3h 35 201 202, 204, 20o 4 CI64, 17?. 17. s1 I, , 6 70, 34,44, 44, 3 A ., 20U, 20(.9, 210 179, 14, 188. 19,X) 347 7, 7 U o, 5234. A_ 21 212, 13, 214, 19I 19, 199.20, 931 9 99, 104, 103, 62, 63, 64,67, 6, 215, 217, 218, 2199 1 22, 232, 104, I , 108, 109, 72, 74, 75, 17,4 2"M 22t:3Z4 244 244 V? 16 4, 6,65 18,6,4 225 22430, 23, 25 ,25, 254 25 5, 166, 18 Q, 19205, 87. 8869,90 95, 3 239. 245, 266 26, 264, 268, 270, 226 227, 231, 233, 96,9 10 , 1 2 25 293, 294, 295 22, 27 28:2,287 240, 242, 249, 142,14, 4:47 296.297,294, 299 252, 257 2 29 1.48 49, 150 30, 301, 302, 303, 262, 265, 273, 274, 152, 160 167 16 304 275 27 280, 286, 17L 173,174 1 194, 195, 234, 238 26, 261 267 269 271, 277, 279, 28 , 28 284, 2 9 90 292 01K. C3pomtld No, CoM nwid N Comptd \o C oxd No , H, 1l 1213, 3, 7 666, 4 , 53, 95 101 02 142, 14s 150 53 11 15 6, 18 n 89V,9 10 113 14 , 147., 149, 1M 154, 155, 156, 15 19, Z2, 21, 23, 115, 1$', 17 177 15 ,159, 7 21 25, 2'6, 2,8 173, 189 14 296 29, 3o 3 132, 33 34 1: 42, 34 39 45. 4 4', 48 49 5-4 I "> 5 S62 64 63,6~ 69, 70, 76 7 7, 479, 41 1 ............. ..

91, 9% M, 98, 99 100, 103, 04, 105 106, 107, 109, 110 11L 112, H4I 140 146, 160, 161 162 163 1647 165, 166 167 1,0, 2 174, 175, 179, I20 183,' 184, 8, Ig90 19.1; 19 2, 193 , 191 212, 213,214215 216 217,218 219 220, 22 L222, 2 24)224 226%. 227. 228 229, 230, 23 1 232 23334, 235 236 237, 23 239 24'0 241, 242, 243 244 245, ?464 247, 24i 249 2$V 251 23' 251,254255 26 257,25. 259 26 265 26, 263 n64 263, 26t 267, 26M 269, 270 271 272 273,274 275 27 271 78 , 2S! 218q 282 20, 284 285 28628 21% 2h 2M 29, 29Z 291294, 293 297 298, 29 ,300 30 L 302, 303, 304 P3K 1 ComftpoOwd No. CompoCd No Compound No. Comspoumd No, .9, 10 13 . 2 1, 2 25 3 7 62 66, S 89 10 142, 15, 156 2 24, 27 2 55 , 6L s 3, 6 90, 95, 97, 1 12, 157 -- -- ---------. ....... ..

29 3 40, 45 , 36 , -7, 7, 72, 74, 13 9 I7 . 38, 39, 40, U, 42, 77: X, 2, 83, ,84 189, 289, 22, 296 43, 44, 46, 52, 54, 85. 8f, 96, 99, 106, 5 7, S9, 60, 64, 104,110, 1i I 11, 68 69, 7 3, 76, 114, 115, 145K 147, 7, 79, 8 ,5 7, 149, 151 154,158 91 9-1 9, 103, 1W4, 160, 161, 167, 168, 05 107 9 i , 2 11 17 13, 174, 177 140, 146, 152, 162, 178, 194, 195, 267, 161, 164, 165, 166 269, 271 275, 277, 79 180, 18. 184 283, 284, 286, 28, 8 190 191, 192 290, 291, 2, 297 19 196, 19, 198 i99,200,201 22/203, 204, 205 2m' 207, 208, 209 210 11 212, 213, 24, 215,t a 21, 2Y 219, 220, 221 222,223, 224. 225 226, 2 A2 229, 230 23i 232 233 234, 23$, 236, 237, 23, 239, 24V 24.1, 24 243, 244 24, 246 247, 248 249 251 251,252 253 254 255, 256,25 25 259,260,526 262, 263, 264, :26' 266 26t 270, 272 273 274, 276, 280 285, 287,293,294 298 299, 300, 301 302, 303,1304 1~~1pmrcfii4 Campoaid No- Coaped No. Cm ndNo C'ompm, ,d No -W~oflo~l fi A ... A.* --- ---- 3) 162, 205, 22, 1, 2, 5, 22,26, 27 4,9, 1, 1, 14 3,6, 7, 12, 13, 16, 229) 391 40, 43, 491, 1 19, 202 . 213 33 344, 7 8, 112,20 24 25 2 29, 3 4, 53, 54 55 62 291 202 208,209, 31, 32 34 35 36 63, 66: 67, 6c 7, -------------------------------- - - - 424- 21,21, 212, 2M, 41 25-54647 71.n,7 3 23 21,217, 218, 5% 51 61, 69 70 83 8, 8 V9 9 2l19, 22 222, 223 7 79, 93, 93, 9 97 99t 232, 23 237 2Q 2 4 95 9 102, 10 1G09 263, 293 lea, 104 105, W06 3, 11s, 123 m25 1:07, 110, 11l 1,14, 126, 12, 134, 136, 119 124 133 U ; 137, 138 13% 141 14$ 152 16q I 62, 142 14 146, 14L 163 169, 20,204, 148,149 1,i15 296,207, 216, 22 15 14 155 56 2:24, 22, 226, 230, 157 1S8 159, 01 24 241 24 25, 16 167 W6k 7k 22, 25%3 254s 256, 171 173 174, 176, 2 57, 60" 26 , 264 27 FiO : 24 jW, 2V2 23 q 234 235, 23q 23q 242 244, 24 24. '49, P'k, 2528, 259, 266, 268 274 27 277, 2 28 '284 ,28 289, 29% 29, 2.92. 295 29 v 29 Tabi 5. Stme s of th Compounds for the C5 adts &seibd a Tabe 4 ............. ......... 4- ... - - - - ---- -------------------------------------- ------------------------ NN Cc Nm N N Um 'y w . - X ' 'N N a n 4Mpoo" Copon p6a7Copu 25-.

-- --i-- -- -- - .. .. .. . C p 1 2 copn 14 Compond nF -1------------------------------ - ------ ---------- ---- > A. AA 2M NO N 1 SN ' Compoed Comp und 27Cpnd2 -1260 .......... ... .m~ a r ........ A-r s '.~ '. ' 0 CI " CFmix 0d2 t'~~JflpnF41Im' '.3 C .run ~ ~ ~ on m d 35F - - - - -N-- - - - - - - - O}.txC's p& c c- -3C --------

------

c-------- -- -------- CCopmpl 34 c oC mpp un 344 Comp nd 40 RI AsWA CapoudSSCmpm5 cAmpe -Ns - N..44 , ~ ~~~~~~ ~ '-a-mp n 7 m m xl O t c-C ........... i ---------------------- --------- ---------------- -------------------- -6 - a L -- ----------- z -t-~ --- ----- . .... . . . . . . .

--- --- --- --- -- N ---- - -1 'FT' 01 - N4 M6t *V'44 Uhl '00 M z~~otr- 664 Co po n NTo NOOak N N" x ckqkNw 76& MI A NN 0 compun di 82 S, i ------ N .... .................... ... ...............---- AN ~ '14 N N N ' NAN: 92 N-N N '$'> N d 9\ ---- --- - -- --- ---- -- --- --- --- --- ---- --- --- --- --- - - --- --- --- --- --- --- ---- --- --- --- -- --- -- I -- --- -- --- --- ---- --- --- --- --- -- NMIN VN-N'N<\~~N' -'A 10.2' 10 ~ K--~ AlN GYP;:: tPs" kKpoe I4O ro'Ma 106N'N- " 4 ' .K' -- - -- - -- - -- --- --- --- - -- -- -- ---- ---- --- -- N-- 'I '-N.- -A A KSAK N ~ imitomd i J. & N---------- A~~ o uvound I0-/ .. ANN if4-on U12 ~~r4N , W1 Ho H N .o Np~cm v~ un 2 t*.\~ N , Cosnpcnsmd 112 ~AI~d I cm~olm I1 Cn'NAM12 -- ---- --- -- ----- ----- ------ -- -- ----- -- ...... ..... ..... ........ ..... ..... ...

-t~ r

----

__ -a- - - . ......... . ..- - ---- .... -- k i ut nar~ r- XN C(rnpNsmld 141 - - - - --- ------............... N N IN N"N ~ 4~~'l o %~ I alpurd Ao-ww 1 46 - -------------- ----------- -4 N ------ --- ----- NS- >~N N ~-NJ A AA '-4 Co-o" .......... ----------- ~ -4 C DM o 6 Compixnd 15 G=o- dk -N ---- ....... ----------- -~' - -----................. ------- ------- . ............... ---- -------- ......" .......... -"N N------ NN .20N (Tsirnpownd 179 IM U V-A'; O nirun, I - ~ ~ ~ ~ ~ ~ ~ ~ ~ r o a -i----------. ................ 'IIIIIII - 1m ------. ... ---- 11 A Y |rr Cabpond 19 1Cmud Crp'ound 94 .A~%Kcompound Vss Compound 97M 1 r t4) N N nA e OM o202 c N- ccp N0N :F Compo d 207bound 29 Czmpsmid 210 (Compound 206 commpmpd 20 20 71 CompoundnxI~ 2208mmd 1 -- mp-d - .2C.nd2 N jj, ~4 (>rposmd 0 Csrourd 213 (cT~pvwtd 2) 4 tO~~m - -s - -------- - - -- --------- A N \NN y N CNN K II'N C mpound 26 NN F cr comopCnd 23 C.ornpotnd 23 G pod 23 conpound '23Cm3udN SN NN N.NN N9 22 w '4 N N jN Campovnd 237 Copouond 236 C ompnd 23c - - - - 7 ~ A . K 't..-4 CNmmli B6 I A. 'xY24 -. ----- ------------ -------- ---- - --- -- -- -... .. .. N I Compond 244 Compound 243 C pondsnd244 Compound 242 Compod 243 -1 ------- ----- -------- j-------- - - ------- -~1 C ~00 W N \0

N

2 N N CKam N N.M Nopn 5 U'-n-Campunn 252M Comp 259 ~~ ~ C mpound 257 Compound 249 CKmpnjx d 260 ... - .. ----- .-. Nq \a J 4 & A

N,

copi 26ptud 5 Copod26No odf6 Compond -264 tCtjmnd 265 2532 Mup n 2 1 k-'-,pow 20, m FN No~o."- 95 Co~isk'W292 V K > -'Y~AWK ~ A S ~ N > J No~ *rtclN CO~iix.~~d2~ (romptd 203IhIY -' cumpnwnd 265~ ku J N, A C MP~t 26 Cnamnd 273Cm9n 7 Uk~ IN-* *4 t *4 N -N 1 ' N" N * N ,~ $~4 / 4 Comp Conpn2d77 (9 ~ - Co*CompI und 2 - -- - ---------------- 7 ---- ------ -- .......... ~11 C mo 2oConraowdd 27 SDIy'- I-

N

C-omnpound t2t1 C '* l4 Pt .fO4 C o , u n l 8 compaltnd 2C9294 *4% -IN .4 1 N (A1ttNi- j~J f 4 294J 1",nt N2 --- N ..................... -- - ------ ---------- 4~~ 6_ N I ------- --- ------

-

j- - -~ ------- - ---- 1'J's Com pound 296 Cmon 9 Compound 97 Compound 299 Compo$1nd 300 CFx SN CompOund .33 CoMpound' 304 CEmpoumd 302 E~tmmph 1&: Exprfttsin d hMiian Aasays of pl10WpFa pilep/pa. plf1t0iy5s. ands pilly [WS241 Class H13-Ka e be the p hased (pllOa1 pSa, pi0 /p85a p lct S5tamm Upstate, and pl0y frm Sigma) or XPa ped as eviously described (Knight et al, 2004). 1<250 alums are mecred using ither a 5 9 ktadard T1C assay for INp idk activity (described beOw.) or a high-hroughput membmne capture zay Kinasz. mactiona are perhrrrmed by preparing a reaction mixture containing kinase, inhibitor (2% DMSO hiid conoetration, buffer (23 ;0M RIEPSE, pH, 74,1It mM MgC2), and freshly sonicated phosphaidylinositol (100 pg ). Retsr am intiated by the addition of ATP eonaining 1t pCi of y2P-ATP to a final cenmrmion 10 or 100 pM and allowed to proceed for 5 minutes at room tempratr For TLC andysis, reiwtins me etermin ated by the additin 10 of 105 p6 IN HUCi folkeed by 160 i CHItVlMeOH (I 1), The biiphasic niture is .ote.., bri fily ntfugerl and the organic phase is rnatsferred to a new tribb sing a gel ading pipette tip preccaed wttli CHCtO Tis catract is spotted on TLC places and developed for 3 -- 4 bous in a 65:35 soktion of n-prvpanlol M aceti acid, The TLC plte are then Otied, e Wpoed to a phesphorimagrr screen (Storm Ameersham), and a aTed. Far each co.ound, ina activity is m-easred at 10t- 12 inhibitor concentrations repasndiag two-fold dilutions ftor the inghest conceradento M tested typicaly 1>200 p )o. ompouas showing signticant activity, 1C50ednemnpaoos are repeated two to fou times, and the reported value is the average of the independent arements. 005251 Other commercial kits or systems fr assaying 3K activities are available. The commercially maaible kits or systems can he used to screen for inhibitors andr agsists of PI3Ks including bar not united to P1 3-inase a , and y. An exemplary sysem is P1 nase (hunan) ITRFn Assay rwn Upstate. The assay can te carried ot according to the procedures sggeutd by the naufacrter. Btrietly tbe assay i a tm resolved PRE T assay tat indireetd measures KiPl trodua fanned by the activy of a P2-K The inase reaction is performed in a mierotiter plate. (e.g., a 234 wal rnicrsiter plate). The total reaction uolume -sar matdy 201 per e.L in the first step, each well receives 2 of test compound in 20% dsuin in a 2% DMSO finl cocnton Neat, approiaatel~y 14 of a kinase/PIP2 mixture (diluted in IX reaction buffer) is added vu wel for a imal 25 concetration oft 750.g/ml kinna and 10aM P1, The plate is sealed and iouhted for 15 mimtes at room Temperance .T ast the reaction, 3,561 of ATP (diluted ii 1 X action huffer) is added pe weul fur a fial conetaton of l0aM AlP, The plate is seated and incubated for 1 hour at room sempeuxure, The reaction is sopped by adding Si of Stop Soltion per well and then Sul of Detection Mixi added per well he plate is sealed, -137ointcbted for I hour at room temperature, and he rad on an appropate plate reader Data is analyzed and IC50s are g rated msing GrepAPad Prism T Eaampk 17: Expresion and 'IMb tIMan Asays of Ab (35261 The orossmivy or leak thereofof me or mom compounds f ereset invention agaist Abi kinase can 5 be meased according to any procedures known in the art or merhods disclosed below The componds ribed herein can be assayed in tpicatQ apinst recombinant ftdiengh AN or Al (T3 iS)(Upstate) in an assay coat-dingt 25 mM HEPES, pH 74, 10 mM MgC12, 200 pM ATP (2 pCi of y02P-AT), and V. tg/tL BSA. The opinned AN peptide bsate EMYA.A.PFAKKK is sal as popaeptor (20D pM) Readons ar smiated by spotting onto phsphrooss sheektswIhor are washed with 0,5% phvs:pTmhoric acid (pproumately 6 tmes, 5-10 minutes 10 each), Sheets ae dred ad the tsaferred radioacivity qntIated by phosphorimaging. Exmmptk IS: Expesion and thilaon Assays of Hek (1005271 The cosacdviy or hack thereof of one or m rompds of the present invention again Hek koase can be measured at rding to any procedures known in the art or meashOds disclosed below. The compounds described herein car' be assayed fn tiplite t a ecombinat fe gth Hck in ar .ay containing 25 3mM HEPES, pH 7.4 15 10 mM Mg1i2, 200 pM AT? (25 pi of32P-ATPP), and 035 mg/mt BSA The optimized Sre family kinase peptid subszae ElYG&EKKK in used as phosphoAcetor (200 xM), Reaction are teminated by spottng onto phosphoxe'kloe shets, which ate washed with 0,5% phophoic acid (approiaid.ay 6 tine, 5-10 miawtnea each). Sheets are dried and the tranferred radioactivity quantitakd by phshomaging, Eanplp 19" ExreiAon and IbhibMon Assays of itnfliun Receptor: (IR) 20 [0051] 'The croa-activity or i there-f f one or more coerad of the preset invcntion againt 10R receptor kinas can be soared acewdig to any procedres known t te art or mathds disclosed below Te compounds described heri n b-n he assayed in trplicate against moinnr t iasuiHn receptor kinase dom" Npstate) in an: assay containing 25 m IIEPS p-PH 7-4, WmM MgC2, '.0 mM vnI2, 200 pM ATP (2 5 pCi of -32P-ATP), and iV35 mgn BSA. Posy fY (Sigma; 2 mng/L) is sed as a subsate Reaciors are terminated by sporting ont" 25 oitrooeltiom, which is \ashed with NaCIl % ph osphoric acid (apprantely 6 times, 5-0 mirnes each). Sheets are dried and the tiansfemttro'd mdiowaxcivity quparatdted by phosphorinaging Esampia 20: Expmmsion and Inhibiton Aasayt of Se )0529j The os ts-rtti or lack thereof of one or mon compods of the present hwton against Ste kinase can te reat d a' " ordong to any proceihsa known in te ar or otethods ishSSed betow, Thi omoud de'scr''ibed 30 herein can he assy.ed in tryipiceme against recmbinant Mtd-legt. Ste or Sre (T335) in an assy containing 25 mMt' HEES, pH 7,, 10 mtM MgMl2, 200 tM ATI (2.5 pCi of r32P-ATP and 0,5 rg/nI LSA, The optnited Src 'amiy kirae peptide substae EJYCPFKKK is used as phospheaezeptor (200 pM). Reon are terminated by sptt'isg utom aphoeliosc sheets, which arc wahed with ',5% phophoric acid (apprarnatdy 6 dies5 $0 mneach Sheet were dried and the tramkrcd radioacvyua e 35 Etsmplr 21 Exprsso and loiMibn Amays of DNAPI( (DNAK) 'ue crms-aci'vity or lack thereof of one Or Mor compounds &ith t s present inveton against DN4AK kiaaser can b e meued according to any procedures ksown in rhe art. DNA-PK can be pumhased foyam Pt'z'n:oga and assayed sing the DNA-PK Assay System (rome") according to the nonuferes intas Eximpte "M Expression and Injkbtion Assays MTOR dt 5031 The cem-aivity or snck there fona Or mor compounds of the peset invention against r cat be meaisund according so any procedures known in the at or methods discoed be-low. The componds described h'r'&n -138cn be tested myinst e ant mTOR ( Itogen in a y Co'aY3iOing 50 mM HEPES pH 7, 1mM L0TA, 10 mM MgC2, 25 maM, 0,01% Temen, 10 pM ATP (2, pCi of 23PATP> and 3 pg/mL RSA, Rat recoinrinant PH- AS-I/-EBP1I (ce bochemo; 2 mg/rmL) is used as a submtate Reactions are terminated by spotting onto nitroedlosc whsh is wahed with 1Me NeCill% pophm rs acid (oppu matdy 6 ites, 500 minutes each). 3 Sheets ae dried and the transferned radioacthity qantitatd by phhornaging 0MS321 Other kis or syems for asayin.g mTOR activity ane commacially avaabe, For itame, oe Can use Vitrogen's LathaScre-m 4 Kinae assay to test the inhibitors of mTTOR disclosed herei This aessy is a time 1soived FRET piarftrrm that meazes the phostphorylation of GiF lbeed 4EBP1 by moTOR kinare. The kinase rndtotn is performed in a whie 384 well microtiser plate. The total ration vhome is 201 per wel and the meacdton 10 buffer compositin is 50mM HElLS pH7A. O.0 1% Polysrbate 20, 1mM EGTA, 10mM MnrCl2, and 2PMN D TE n the fitst step, ecdh wel receives 2 v of test compounrmd itn 20% ditnethylsuiphioxie re dng :in a 2% DMSO final concenration Next, &ul of mTOR diluted in reaction huffer is added per well fr a 60og/nid fa eonoentnlion. To amer the reactor, ld of an ATPgMFP 4E BP mtixte (d iute d in reaction buffer) is added per well for a final concentration of I OudM ATP and 05%M GFP.4EPL T 7he plate is setd and inubated for 1 hour at room 10 temperate Tb reaction is stopped by addig 10d pe welt of a1Tanti-pT46 4EBP1 samtody/EDTA mixture. (diluted in T-FRET buffer) thr a final concentration of LnbM antibody and &7mM EDTA. The plate is reaed, incubated for I hwow at rom teraturet and thermi ad ont a plate read set up or Lath SreenFREYT, Data is analyzed and IC50s are gensated usirg CGrsphPad Prism Easrnple 2- Expression and Inhibition Assays of Vasclar endothesrial growth rmptor 20 [O53 3 lThe cro a-aetiv; ty or tak thereof of one or 31o1 MoaM povinds of the present in1ven against VEOF receptor can be measured according to my procedaer known in the art or methods disposed be-l The compounds described herein can be tested agaest. recombinant KDR receptor kinase d4mm' avrgP) in a A assay noainr 2 bM HEP0S, pH-I .4. 10 mM MgCI2, 01% MR If) pM ATP (Q3 p5 i of p2P-ATP\ and: 3pg/nL BSA, Poly E-Y (Sigma; 2 mg/m) s used as a ste-trate Reatisare termiMed by spotting onto niocehkoe, which is washed 25 with .d Nu C /I% phosphoric acid (approximately 6 time, 5-10 minutes ch)4 Sets are dried and the transered radiactivity quantimaad by phosphorim-agin, Eamnple b EproSin nd Inhibitian Assays of Ephrin receptor I4 (EphB4) 100-341 The cross dvity or laek thereofof one or mnre compoundsof the present invention against EphB4 can be measured according to any procedures known in the art or meioda disclosed below The coonds described herein 30 can be tesed against reombinant Ephri: receptor 04 kin-ase domain nvitogen) in an assay confining 2:5 mM HEPES, p1H 74, 10 mM MgCl2, 0-% BME, If gM ATP (15 LpCi ofp2P-ATP \ and) 3 t w L BSA. Poly S-Y (Sigma; 2 erg/ndi) is used a a suibstrate. Reactions ae minted by spottig onto niCoceloe whch is washed %m i liM NaCil) I% phosphoric acid approximatelyy 6 timer, 54-10 minutes each) Sheets are dried and the transferred radioactivity quantitated by phosph-eriagirng 35 Example 25t Expression and inhibition Assays of Epidermal growth factor receptor (EC FR) [0310 The zwcts-aciMy or ick thereof of one or more impounds of the present invention against EGFR kisse can be measued according to any procedures known in the art or methods disclosed below. The compounds described ormit can be tested against ecombi-ant EF reeptor kinase d=m.ain -r"'n n. assey cai 25 mld liEPlES. PH 74, 10 mM MgCl2, 01% RfME, 10 pM AT (2 5 gCi of y2PP-ATij ad3 pgML4 PSA, Poy E-Y 40 (Sigma; 2 mg/ml) i ed as a suasrae. Reactons are terminted by spotting onto nitroccluoe which is washed 239wvi> M NqCJ/'% phosphoric acid (appatdmlately 6 tinm. 5-10 minutes eadh), Sheets ae died and the marfemd radioasatitv quandttated by phosphorimaging,. Eanm pie " EprtsgiOn antd inlsibntio Assays of KIT Assy 15M] The c snacvtity or lack thereaf of one or more tmnpounds of the ps.sent ivention against KIT kinase ca be measured according to any prcede as known in the &at or methods diseased below, The com ournds described herein can be tested agat rmwbinatm KIT kinase donain, (iavitrogen) in an asmy containing 25 mM- HEPS, pfI 74. 10 mM Mg2, ImM DTX 10mM M I, 10t pM ATP (2,3 1is of pt2P.ATP), and 3 ig/mL BSA. Puly EY (Sigma; 2 mrghL) is used a' substrate. R mmaks are termina i se'd by spotdaNg onto areceldose, which is washed with I M NaC/1% phosphric acid approximatelyy r times s40 1nir'mes each> Sheet' are died and he transferred 10 radioactivity quantitated by ptosphshnmaging. Enspe 2: Epreaslsni and inbibition Asmys of RET, 1005371 The cos-ctivity or heiao thereof of one or more comounds f te present invention againAt RET kinase car, e nmeied according to any ptoeedurs knova in the art or meotois disclosed ekw. Te compounds described herein can be rested against recomiant RET kdiase domain (Jvtrogen) in an assay containing 23 ImM HEPES. pHi 1$ 7A4, 10 mM MgCI2, 2.$mM* DTT,10 pM AT? (23 pCi of p2P-3ZATP'), ad 3 gg/rmL SA, The optimized A bi peptde subtate .EAYAA PFAKKK is used a pho~sphoaccerptor (2t0 piM) Reactions sir teamired bys spotting onto phosphcet~ose sheets, which are hed with r .% posphoric acid (appi,'imately 6 times, 10 minutes each), Sheets are dri'd and the transferred radioactivity quertid by phosphorimagig. Exampk 2M Expression and inM tion Axsays of Plateet derived growth faster receptor (PGYR) 20 [I1OS58 The crossacrivaiy or lack thereof of one ec mor compounds of the present invention againt hD(3FR kinase eaa be measured according to anly pate'es knowe in the Ast Or methods dSelokstd Itoo. The compounds dsenbed heren can be tested against recom bnet PDG re&ephr kisse domain (hinitmogen) in an assay ontaming 25 mM HEPES, pH 74. 10 mM MgCl2 2.5mM DT,10 pM ATP (23 pCl of p2P-AT), and 3 agimL 3BSA, The opumizcd ANA piA'& substrate EATYAAPFAKKK i used as phosphiccepsr (200. p4), Rcactir are tirminatd by spotting 25 onto phoeeluakse sheets, which ore washed with P 5% phosphoric acid (appmimartely 6 imes 310D minutes each). Shee a dried ad the trans fered radioactivity qistisated by phosphodmaging Esrepie 29: Epressin and isaibition Assays of FMS-retted tyrosdne IMnase 3 (FLT-) (0n539 The cro'is-acainv or lack thereof of one or mrei compounds of th presm enti ton against FLTY3 ldmase can be measred according to any procsdures known kn the art or methods disclosed below, The compounds described 30 herein can be csted:against reconbrant FLT4-3 kinase domain (nvitragen) in ass assy cntanng 25 mM HEPES, pH 7A 10 mM MgQ2, 2,54M DTrljyM ATP (2-5 si of 932Pt-ATPt and 3 pig/l BSA Ih optimized Abi pepsde sabstrate E3AIYAAPEAKKKZ is umed a phosphacceptor (2:00 pM),}. Reactions are term~iste lby spotting onto phospocel:o sheets, which a washed wih 03% phosphoric acid (apopmximarey t $'05 minutes eat). Sheets are died arnd the transferred radioactivity quanhtaed by phospho ng. 35 Example 30: Expression and exhibition Aways of TEk receptor tyrosine kose (TW2) 1065401 The crsneadwty or inck thereof of one or more compounds of the present invention agst 'E2 kase can be measured according tc any procedures knownr in the art or methods disclosed below The corpounds described heret cm he tested against recombinant TIE2 kinse doman (Inviogen) in a asay contains .25 mM HEPES, p1H 7A, 10 mM MgCI2, 2mM DTI, IthaM MtnO2, 10 p M ATP (2.5 pQi of .-32P-A'TP), edc 3 g/am:L 1gA5 Poly~ E-Y 40 (Sigxna; 2 mg/miL) is cod as a ssubstraste, Reactions are termsinated bys spotting onmo ritrocrilulse, which is washed 4040 wiet I M NaCi% phosphoric acid (appmxima tey 6 times, 5-10 mhusien vaqh) Shoes aw drie and the trnsmemd radioactiy quantitated by phosphorimaging. EmmpNe 31 B Ce Activation and Proferatio Assay j10g4NJ The ability of one or more subject compounds to inhibik B cedi acivitation and pmrfertion is determined 5 accrig to standard procedM es mown* in the art, For txsmple, a in vitro e darproMfM 1 assay is estab.shed that measure te eAboiE activity of iNe eds, Tha amay is perforned in a 96 wed micrtiser plate using Aamar Blue teduction B*bhc splnic I cells ate pacified over a Fico Pagi" PLUS gradient Folowed by magnetic cell separatimnaing a MACS B cell htoation Ki (Miteryi) Cels ar phited in 90I at 50,000 cd/ells in B Cell Media (RPM1 + 10%FBS+ PenndSirlg + S0M bME + SaM HEPES). A conmpound discoed herein is diluted in B Cel 10. Meda and aded in a )1001'vlme Plates are incubated for 3min at 37C ard 5% C% (6,2% DMSO final CO cneAdeV)VA SOui B cell stimulation ccktalI is then added con ining cher If uRI UPS or PSug : F4aY)2 Donkey kn-touse IgM plus 2ngpr recombinant mouse RL4 in B COi Media Plates are incubated for 72 hours at 3/C and 5% Cy A volume of I 5:L of Alamar Bhe reagent i& added to ewati wedl and pates are icubated for 5 houss at 37C and S% Ct Alanat- Blu fluoresce is read at 560Edb 90xEm, and IC50 or EC50 values are calculated I singrGtphi'ad Prism 5. Exampleh I Tumrcell Line Prlifeteran Assay [0kM5421 The ability of one or more subject cmpounds to inhbit tumor cel line proliferation is determined according tstadard procedures known in tE art Fot insainc an in vitro cellular proliferation asay can be performed to measure the medabolie acivity of live celas The asy is perlmrnd in a 9 wel miertier plate usng Aamar Bine 20 redktion. Human tumor Cel lines are obtained from ATCC (etg, MCF7, U-.97 MGi MDA-MV46g, PC-3), gown to othency in T 73aAks, typsinized with 0,25% trypsin, washed one dme with Tumor CCli Medi (D MEM + 10%1 ), and plated in 9Nl at 5,000 celstwei in Tumor Cci Media. A compound dosed herein is diuted in Tumor Cell Media and added in a Iiul volume Plates are incubated for 72 hours at 37C and 5% COa, A volume of 10u0 of Aianar Blhe teagerd is added to each wel and plates are incubted for 1 hours at 37C and 5% CO"M Almar 25 Blue horesce is read at 565ES90Ein. nd C5 aes ar Caku)ted using (GraphPad Prism 5. Example 3, Antis mer Avivity In Vivo 10543 Th conmpouds described herein can be evaluated in a panel of human and murne tunor models. ltM5451 L Clisedi devsd Omran Carcinana Model 30 10(554d] This mior models established fromt a tumor biopsy of ani o varian raincer patient Tumor biopsy is taken trom the patient 100,547 The compounds described herein are administered to nude mine bearing staged Kumors using arn every 2 days a schedule. .44.T hd?@yT0T .Kmn OSmrin Carimin maXnograp (mid ml hu? it 35 (549) A27&JTax is a padiaxebresistat human ovamimn carcinoma model i is derived f 4 die :enstive pamat AV41 line by coincubatdon ofcelk wih padVitaxed ad verapxsi an MDRnversai agens. Its resistance mechanism hIs been shown to be non-MDR related and is atributed to a mutation in the gene enending the betanubuin protein, tlO%50j The compoumds described herein can be administered to mice bearing sMaged tumors on a every 2 days x : shedule 40 M51 1 Cmriomo n (-5' Cobn Sk Resistasd 100532] HT I16NM46 is an MDE-resistant colon carinoma developed from the seniivs HC'6 parrdine, In vavs, grown is nude mice, {CT1 H6/VM46 has cosistenly lmostrased high esismanoe to pacdiecl, 1.

'00$531 The compounds described hacin can be admnistered to mice herrng staged wrnors on an every 2 days x 5 schedule, ii0Hm4j 51 M50;76 Mrine sVrewM hdO [OO555) M5076 is a morse fibrsseoma thi is irerfttMy refractory W. paditantei in vivo. 50 [$%) The compounds dei bed herein can be administevo to mice beadng staged nmors on an tvery 2 days xS5 schedule. [I557 Om or mom ompounds of the invmndtan can te used in combina other therapeutic 4genls in vivo in the munidmg eistant human coln arnoma xenografts HCT?VM.46 or any other modd) known in the art inch:drg those descnbed herein, 10 Example 34. Mieroate stability assay [P5S8S The stablity of one or more subject ompounds is determined according to standard prod-s wn in the art Fur eanple stability of one or Imtore suybjec"t ompounds is established by an in vito assay, In pardIcula Wn :n v$o niersmt e instability assay is established that measures Wtb1ity of one Or mnre subject canpounds when reting with mouse, rat or human mikrosomes fram hver The income rach on with compounds is performed in L .5 mL 15 Eppendorf tube, Each tube con t ans 0A pl, of 0,0 mg/m3 NADPH; 7$ y o1f 200 mg/ni moas ra or human liver micmsowm; 0A pi of 4.2 M phoosphate buffer, and 425 pL of dO. Negative control (without NADPH) tubc cmrnains 75 paL of 200 mg/mi most wer hum liver >microsomet .4DA pL of 02 M phosphae bufrand 525 pL oP ddH 2 O. The reaction is started by di d0 pt of 10,0 M, M tested Compound. The reaction tubes are incubated at IC, 100 pt sampleisconectedbione E ppendorf tube containing 30H 90tcoldMethanl at0, 1, 155 3)0 and 60 20 minutes of' reation. Sample' a anrie at 15,000 rpm to remove pite-in. Superrtan of centrifhced sample is tranferred to new tube. Concmtratmo of stable compound aer reavo wi-ith :maicosoie in the superntam is geasured by Liquid Chiormatguphy/Mass Spectr rletry (LC-MS), Example 3, Plasma stability assay The stabity ofone or more subject compounds in pluna is dermined -ccording to Iredard 25 pcedues known in the an. See, eg, Rapid mma Mas 'eeronm 10: 11026, The following pradure is an HPLCMS/MS awy using humn pama; other species including monkey, dsog, rao a muse art aso avalabe Procen heparinied human plasma is thawed in a cold water hath and !pun for 10 'mi.nuts at 2 00 rpm at 4 *C prior tose A sibect compomd is added fr a MW) pM stock solution to en iquoc of pre-armed plasma to give a fina assay volume of 400 4p (or 500 pt R-r haff-life detem inaso) conaining 5 pM test compound and 0 0.5 % DMO. R. ea s a incbated, with shafm, for 0 min.es ad 60 mits at 37 'C, *forOfr , 5, 3 4$ nd 60 mirtes at 37 C for half ife determiation Reacons e stopped by ramfetrring 50 pL of the incubadtno mature to 200 pt of ire-cod acnitrie :an. sied by shaking for 5 mintu. The sample are centtfuaed at 6000 x g for 1S minutes at 4PC and 120 pL of supcmatat removed irno clean tubes. The samples are then evaporated to dryne and submitted for adysis by HPLG-MS/MS. 35 IX0560) Where desired oe or more contro Or reference cmpunds (5 pM) are tested smAltaneously with the test comqponds: one compound, propoxycaine, wih low plasma stability and another compound, pmpandiee, with intermediate plasma stability. [mSampls ar roonstituted in acetoniri einethanolatrier W1/2 v/v/v) and analysed v:a (RP)HPLCOMSSMS using seected reaction monitoring (1R(M). The HPLC1 ondiios ci:let of a binary LC prunp 40 wkh automr, a rU.me, , 2 x 20 mm column, and a eraden.t program. Peak areas corcpondling to te ;anlves arm recorded by ILCt-M S/, 's T h e ratio of te parent compound rem aining after 60 minutes reive to the amunnt rmonr at time zer, ressed as percent, is reported as plrma s'b i -ncase -of ha-ife 4.42~ deeinatM5Othe half.Afe i imanted fm the skp) of the SntIar near nogs of 4e Ilogarithmic c.rv" of compound remaining (%) v. time, assuming first order kinetics tAamph 36 Chemicai StaMrity [m0%2 The emical staiity of one or moe subject comrpoands is determined according to standard 5 procedurs known Vn the at The following details an oxemrplary procedure for asceraining emical stabihty of a subject compotamt The deaul t buer used for she dbhenicas. stability ssay is phosphasz-uikred saline (PBS5) as pH' 7.4 other suitable bsdffx an be used. A suject ompounsd is added beomt a J200 PM stitok solmaion to an aiiqot of PBS (in duplicate) to gwe a f04 assay vome: of 400 gL, training S yM test compound end 1% DMSO (fw htaffe determination a total sample voksmne of 700 pL is prepared . Retons St tncubat with 10 shaking, or 0 mines and 24 hours at 37*C1 for latMie determination samples are iMbfed) for 0, 2, 4 446 and 2 4 ors Reacttos are stopped by adding immtnaediatey 100 pSL of the inuvbeion mixture to 10t0 pL of zcetontia and vOrteiIg for 5 mistems The samples axe hen stored at -20*C unti analysis by HPLC-MSfMS, Where desred, a controS compound or a remae compend such a chlorambulil (5 pM) is azsttd sinutareousty with a subject compound of interests as thiaspcoptd is targey Kydroyvid over the torse of 24 hours Sampl~es are analyzed via 1$ (RPTPLCAMSAMS ntg sezeted reacdo nonaring (SRM). Th 'H PLC cnditxisms consist a binary LC pump with autosampler ramedmode, C1:2, a 20 x2 t colu m, and a gradient program Peak aas corresponding to the adytrr are rcorde'd by HPLCMSNM& The rtdo of theC paremT comttpOttt:d'~ reiin aft 24 hours relative to the amount remnaintg at time zao xpre'ssd as Wenk s repnteud as cemical stablty, in cae of haf U detennadot 3the half-lile is Mrumoted fk-om the soe of the intil lar range of the logarithmic curve of 20 compound remaining (%) vs, time, assuming first order kied. taM ple 37t Akt Kilnaa Assay 190,631 Cel comprcidng compsorsents of the Akt/mTOR pathway, including but not limited to 6 myxhist, B-ALL ells Bwirt 's els T tdh.e mia els, borne marow edlh, pll90 trasued cells, phildtpi chromosome positive taels (Ph+s), ad mowxs embryonic fibrobius are typically grown in cdl gro wh media such as DMUM spplemted 25 with fetl bovine serum and/or antibiotics, and grown toecluency. [g h64] i order to compare i; effect of one or more copoun discloed herein on Ak; activation said cels arc m~ starved overnight and irabated with onew orme compounds disclosed herein or abotA I % DM50 for appromnately I minute to about I howr pror to stinmiatldn with insulin (eg. 00 nM) for about i minutes TO about I hoors Calls tre lysed by semping ino ice cold lysis buffer containing detergents such as sodium dodecyl sulfate and 30 protese hb ( ,MSP). Ater entaing cell with lysis bufferthe solution is briefly aonicated, cleared by etrtugation, recasolvd by SD -PAGE, teansfievred to nitroceldulose or PVDF and immuna ted using antibodies to phospho- Akt. Sa> phosphe Aki T30, Ak, and jadctin (Cell SignalingTechnoiogies), 100%5 The results denonste that one or mos compouds of the present disdosue inhibit isuin stMaahtd phosphorylton ot tact 47. Alteratively, some ompounds didosed herein additional Inhibit insuin 35 sttimated phosphoryhion of Aks a TP30& Such class of compound: can inhibit ASt snore effectively than rapamycin and may be indiatre sfmTORC2 nhibitos, or inhibits of upseeram k s sec as PneK or Att £amp. 3& KiaM 'sgnasiag R3 MOid I05661 PK13/ Akt 'iTer signaig is maMsed in blnd cels using the phos-fow method (Methods rEtymotl 2097;43.13l-5$4 Theadwamage of thi matthd is that itis by nature a singA cel ssay so that euar' heterogenusy 4" can be dctcuad rasher than population averages T allows concred dintaction of signaling states in different Popaiations defined by other marks Phadw is aso highly quantative. To test the effects of one or more cospouods disclosed herei.unftscionated spienocyts, or peripal bood mooomkie cds are stimulate wih -143and-CD3 to initiate T-ceti receptor s iing The cdhI are then fixed and stained fir surface markers and rantceIuar phcspopotevs It is expe that inhitors disclosed hetein inhibit ani-CD3 mediated phosp hrytaon wf Akt S473 and 86h, meas rpmycin inhibits S6 phosphoryidin and chances Ak; ptophryatd anuer the conditions tested 5 [K6l Simmaly, aliquots of whole lad ae incubated fr IS minutes with vile (eg %DMSO) or kin bites at vrsrious concentration, bfre additihm of stiimi to crossirk the I e receptor (TC.t) (anTbCD3 wih secondary atibody) or the B cell receptor (BCR) using ami5appa light chain a ibidy (Fab'2 fragments). Alter aprxTmty: and 15 inuAts , ampe are fixad (s wuih cold 4% paraformaldehyde) and Used for pho'fow. Surface stainirg is used to distinguish TI and B cells uuing antibodies dir-eetod to celt sofece markers that ate known to 10 the at The levd of pohorylation at khase hbtrates such as Aki and S6 are then measured by ieubating the tided cells with labeled antibodies specific to the phosphorylated isoforms of thea proteins, he population of cells arp then analyZed by flow cyonety. Eampk 319: Colony Formatina Assay [5S] b marine bue manrow cdls freshhy tran sformed with a pl90 BCR-Ai rtrOvinrs (heroin reft-d to a pt9 0 15 transduced els) a plated : the p ence of various drug combination in M3630 methylselhose media for abou 7 days with recombinat human I17 in aut 30% seMm, and the number of colonies forMed 5 coUnted by ysual exarnnation under a mcrossqcp [OA9] Atamivly, ltTan peripheral blood moronucear cells ar obtained from Phildelpha chromosome positive (Ph+) and negative (Ph-) patents up'nitial diagnosis or relapse ive cells are isolated and etrriched for 20 CD19+ 0134+ B coll progenitors. After overight liquid en ells tare plated in netout Gf+ H443%. Stem Cel Tehenologies) cemented with cytokines (R4 I4 IL-7, G-CSF, GM4CSF CF, FiL ligand, and erythropoietin) and wious concentration of known ehemotherapeude agents il comradon with eihet compounds of the pxesent disciusure. Colonies are counted by mnicrocopy 1244 days tetr, This method can be used to test for evince of additive or synatic activity. 25 Example 461 a O Efeot of KMcale Inhibitors on Leulemie Cls 1005701 F enutEe recipient M-ice a ethay irradated 1cm a y souce in tw e0 about 4 he apart. with approximately 5y each. About Ihr after the seond radiation dose, mice are jiected i v. with about x10 laukenic cls ( e Ph+ human or mrsadce cells, or p190 transduced boat mano cal). These ceIls are administered together with a aiaprotedive dose of about "Sx Kf normal bone manow cis friom 3-5 week old donor mu Recipients are 30 given anbiottes in the water and monitored daily Mice who become sick after about 14 days are eutatired ad lympho d organs are harvested for analyst KinsK e inhibitor atrent begins about 10 days slier leukemia cell nedon andi continues daiy unti the ie become sick or a maximum of apptoximately 3.5 days postramtpant thN blr-s ate geven by od iagnze, :00571 Peripheral bod ells are collected approaimanely on day 10 (pretreotmenf nd upon equation (post 35 treatment , contacted with labeled ihCD4 antibodies and counted by How cytvmet This methd can be used to demonste tha the synrgi sti etffe;c one or mao compounds disclosed herein in comnado with known ch de ampeutie agents significantly r'-e euke1ic ne od cell ' uns as comvnped to tamet with known chemotherpeuti agents (e.g, Otevec alone under the conditions tested. Example 41 Treatmeat of Lapus Disease Ma-del Mice 40 [0572A Mice lacking the inhibitory receptor c-Rilb Mt opposes P3K signing itn 3 cells develop ws wih d penctumre FeyRIb knockout mite (R2KO, Jackson Labs) are wondered a Valid model of the human disease as some 1 44- Ipus patients show de send expression or faction of FcRllb ( . lBoUAnd and IV. Ravtech 2001 fmmnfy 12:2 283)1 10g731 The R2KO mice develop iupm-s-flke disease with aln-mler a bodies, gloaeroneprki and prmteimrea within about 4- months ofage. For thee experiences, the rapamyoin wanoge RATM01 availablee from LC 5 Labontis) it Wtd a4 a benchmark eoigmpo d, and adminstered orally. This comlpond has been shown to ameiate lupus Symptoms i the D6ikzt model: (T. Wu et t C' Inest 17:21 -21%). 100574 Lupus disease modd mime such as R2KQ, BXB r MLRApr ae treated at abot.2 morths old, approim~atey for about two months. Mice arm given ikyseos of: vehicle, RADOW at about 10mg&g, or compomnds disclosed herein at appsximnatdly Ig/kg to about $00 mg/kg. Bkod and urine samples ae obtained at approximatdy 10 dvoughoa te testing period, and tested for antinuclear embodies (in dilutions ofsemm) or pmtin concmatsion (in urine). Serm s alo ested for anid-sDNA and ti-dsDNA antibodies by LISA, Animas ar euthaized at daye 6 end tiues harvested fr measuing spleen wight and kidney diaseliomnerkephitis is assessed in kidney section osained w-h H&E Other animals are studied for about two months after cessation of treatmet using the same endpoints 15 0t075 This model established in the art can be employed to dmonsr-te that the kinase inhibitors disclosed herein Car suppress or dely the onset o inpus symptoms in lupus disease mod-s mie, Enmpile 4Z Ma-rnt Bone Marrow Transplant Assay [0j 6| t fe.arl rac ipie mi nice are Iethal y imddkiated from i a y source. Abut l hr after the rdition dose, mice are injected wih about 1106 Ieuktemic cels fom early psage p1% r0 dc0d r(etoasteeiribed in Csvor 20 Gem QC nge 2005 Aug, tf1(i):5 I These cem are :d jutered together with a protective dose of approximately 5-,106 no borse arow cels shfrn w d.Ynns mice- Recipients Le given titics in thie waler ad monitored daily. Mice wshC become sick after about 14 days are emhanized and ysmphoid organs harvested for flow cytometry andker ma gnetie enrthoment. T\mn'-:t begins on approximately day 10 and conies daiy until nie become siek, ar ftsr a m mum abt 35 days postanspl mt. Drugs are given by om gavage (p.o.). In a 25 pikA experiment a de of heotherapent that is not curative bus delays leukemia onset by about one week or less is ideniled; controls are vehile-treated o treated with chemotherapeutic agent, previoiy shown to delay but not CUre lreneaogesis in this model e g, intainib at about 70mg/kg twice daily).or the firt phase p190 coils that epmies eGFP are used, and posmortem anaysis is limited to enumeration ofthe percentage of leukemic cels in bone marrow, speen and ymsph node (LN) by flow cyntetry h the second phase, p190 cell that express a ta ;Iles form of human SO d4 a-e used and the postmortem analysis includes magnetic sorting of hCD44 els wom peen followed by immunobiot analysis of key signaling endpoints: p AkB,31 and S473; pS6 and p4ERPI As controls for immaNot detention, sorted cents are intubated in the premnce or absnce of kinast inhibitors of the pmsent disclosure inhisbiors before ysisa Opo aW "osow" is used to detect p Ak -$473 and pSd-S23 /2h in hO gated oclls without pror toting These sig-ag stdies are particuady seful i, for eampk, drag-treatedhniee have z not dfvepe rs led-' C Meukena ez the J day ime pointKaplan1tr p its rvivl are generated andt sattsnral analysis done according to methods known in the art Resuls from p190 cois anm: alyred separated as wel as cumnuaxeel y, Iri 6:s Snmplcs of peripheral blhd (100-200p1) are obtained weekly from al mice staying on day 10 imnnediad priot to comnmencig treatment Plasma is used for measuring drug concentrations, and cels ae analyzed ft leukemia 40 markers (eGIFP or IsCD4) and signaling biornarkers as described herein, I'0S78 This general assay known in lthe asr may tbe used to deocnsaime that rffedisc thrrpsrsis doses of the comonds disclosed herein can be used for inhibiting the proliferatdon of leukemic cells, 045- Example 43: Cdl Coftare of Epitheliol Cells o Ocular Origia 1003791 Ocuar epitheid cells are Ehtsined within 5 days tmorem poster from cameas prevd dr cold storage conditions 'm Optisot (Bacach aid Lomb, irdAn, CA) or &on come biopsy ftrom living dnom The tissue is washed with phosprstaafered ralne and incubated in Dispe 1 (Roehe Diagfaostie aat Swizermd) at 5 3T'C for 30 mIrnates, and the epitheial surface is gently scraped to apsarte the epithelium from the undelying csroma The stparacld epithelium is then incubated and pipettled in typsin- ethy ediaminertradetic acid to obtain Aingle cell suaspeanien. The trysPin is then neutdizedl with cormea] epirheliu calte median, Cornevu epither culture msedium is poed of Dsdbecco mo i fled Eagle m iumF1.2 basal media in a 2: rtio containing 1:0% irsdiated fetal bvie serum, hydrocortisone 0.4 prL, choea toxin O tnmo recombinant human inslin 3 pg/mRL, and 10 epiderma growth factor 1W ngnt, and he adimierAbias penicillin (100 iUmt4 streptomycin (100 pg/nL)m and .amotricin P (025 pg/mL) Cds are MadrstIned by -htuing atLa 14 rao after reehiig 0% coniluency, Ocular epiha cela are preened for inhibition of proliferation or toxicity by nnoaing a est compound with the cels and as ymg for viability usng the crmerciay avaiable MTT assay (Pomega). Example 44: CeO Culture af Eadothelial Ceffisof OVluer Origin IS [010] Alt tismces are maintained at 41C ini storage mrredum ()pdo ChiMrn Vision, irvine, CA) for Ies than 10 days before study. The tisse is rinsed three dmes with DNEM containing 50 mg/mL gestamicin aid IlsdigL mrpthotencin B The centa cornea is removed by a trephine of 8-mm dimeer. Aftrward, the Deers membrane mad comal endotheia! cels are stopped ftrom the poacrior urfISc of te peripheral cn'orssckerai time under a dissectng microscope ad digesed at 37C for s to 16 hours with 2 mgmL. cflagernae A in S pplem ted 20 hormonl epitheilai medium (ShEM) which is mae of an eqmgai volume of HEPES-bured DIMEM and Ham's F12 aupplemnsed with 5% FBtS, 0.5% dimnethyl afoxids 2 ag/mt mouse EFP, S pmLt in ir 5 agmL msferd, $ ng/L selenium., 0,3 gg/mL~ hydrocortine, I aM cholra tosrn, S0 pg/rmL getamici, ad 1.25 pg/mL eaphtericin B. ARe digeson, HCECs formed aggregates, which are coiketed by centwfugadn at 2000 rpm for 3 mimes to remove the digestion solution. As a control, Decemet's membrane stips are also digested in 10 rmg/mL Disprse Ii in 25 SIEM and trypdETiA for up to 3 hours, Prervadi of Imated RCEC Agregates iHOS1I 'rhe resultant aggregates of 1-CI-Cs are prescrred in KSFM wth complete supplement (storage medium 1I. DMEMF 12 with KSF1M mppleumen.ts (storage medium 2 or DMEM/F12 with SHEM sappients without FBS (storage medium 3). At these media are serum fiee, one of the rmaor different amoa them is the calcium 30 cncenaten which is 009 MM in stage medium 1, but is 1.6 mMNh it soragc redia 2 and 3 HCEC aggregates are stomd in a tiue ulur incubator at 37C for up t 3 weeks. Cci viity is determined (Live and Dead assay; ivitroyn) and als evaluated by suultureig the's in 9HER ExpaRsik f isolated HCEC Aggregate [0%12] The resutan HCEC aggegates either immnedidy after digaion or aner a peaiod of preservmtion in a 35 srage medium, aire Aa cultured irf SHEM with or without addikional growth motors ;u as 40 ng/mh bFGF, 0. mg/mL.. BPE, and 26 ng/mL NGF on a plastic dish under 37C and 5% CD2 The medae are changed every 2 to 3 days. Some HCEC aggregates ;re pretrested wth trypsilTA at 37C fR 10 minutes to dissocie eadehlal cdl before the s'fomemcmstianed culivat or. Immunostaining 40 105831 VCEC aggregates are embedded in OCT and subjected to frozen seditag. Crysecdonsof 4tpmaeair dried at rom temperature (RT) for 30 minutes, and fixed in cold acetone for 10 minutes at -20"C. Sections used for msuiousrning am reydmied in PHS, and inubated i 02% Trown& M0 for 10 minutes. After three ines with 146- PBS ihe _ nuruas ead and preine ton with 2% BSA to block nospqe-ifc staining the secdons are incubated with antlaminin 5 ty'pe W collagen, piecarl. 204, and ennexin 43 (all vs I :100) tidies for bout. Alne thre washes with PBS for 15 minutes, the section are incubated wTh a TC-conjugated ec ndary tibody' (goat wati rabbit or sti-mouse IgS) at i: 100) for 4$5 mimics. Afte three additional PBS5 wastes, each for 10 minutes, they are c4Cs'ntatined wSh propidium ixldide (3:1000C) or Hoechst 3332 (10 pg/tL, then mounted with an anti fade soluton and anyred with a fluomesence nicrosop.e, HCECs cultured in 24a tes or chamber slides are fixed in 4% parafnaadehyde for 15 minutes at R T and gained with anti-ZfVI and connealn 43 antibodies as just described, - Er immunohistochemicl staring of.i6y endognoos peroxidase ativity is blocked by 0.6% hydrogen peomdide for 10 minutes. Nornspecifc staining is biokied by 1% normal goat seoso fir 30 adtes, Clh are then incubated with anti 10 iP7 antbody (1100) for I hor Afer the washes with PBS for 1 minutes. cells aae incubated with biotnyated rabbit anmouse IgG ( Y100) for 3. minutes followed by incbation with ABC agent fon 30 minass The reacon product is dedoped with DAB tor 5 minWles and examiaW by light ososcope. Ce.VNIbility and TUNEL Assays 1N0S41 Cell-viability and temnisai desyribnuckotidyl transfese-mediated FTC+!inked dUTP nick-nd DNA 15 labeding ('TUN. assays are und to determine living and apoptode cel, respectively. H CEC aggrgges ar fncttbsd with celbsiabity assay reages for 1'5 FniFtes at RT. Live ca ar disnguished by green fluoreseece stainirg of the Cel cytopass and dead cells ae aettd with red fluorescence in the nuclei. The TUNIEL assay is performed 'odin tothe mufactmer's instrctions, Briefly. crarssections of HCEC aggregates ae tixed in 4% pinaldehyde for 20 mites at RT and ereabiiad with 1% Triton X-400. Samples are then incubated for 60 20 minus at 37C with exogeous TdT and fuoresceir'onjugated dU 'T or mpn of nicked 3Ahydroeyi DNA ends Cells are treated with DNase I as the positive control whereas neptive control celsi are incubated with a buffer ladlug the TdT enye, The apoptotic nucli are labled wth gree flores ce. Evmph 45: Cell Cultren of IRetind CAdh [W.0.58 Eyes am cut in half aong their egator and the neural retina is dissected frm the aertor part of the eye in 21 buffred salio oiutio, according to standard met hode known in the art Brefly, the retina ciliary body, and vitteous are dissected away from the anterior half of the eye in one piece, and the reina is gently detached fro the clear vttat lath reia is dissociated with papin (Worthington ioch.ieal Corporation Lskeor'. N it Rowed by .ctivadion with net bovine semm (PBS ) and addition of 134 Kuna oits/mi of D ~aset The enaea y dissociated cels are triturated aid collected by centdigatica, resuspended in Dulbeceot modied Eage's medium 30 (DMEM)/F12 mnedhtsm (Oibco BRL, ire Life Tedhoogies, Cadsbad, Calif) containing 25 pg/ml of insumli., 100 pg/mi of transfer od 0 pM pratrescIne, 30 nMW eldenium. 20 n progesterone, 100 IUmIi of penicillin, 100 pg/mi of stretoy1cin 0 M Hopes. a 10% EItBI Dis&sociated primary recn I els arc plaed onto Poily4iysinc- an.d Martigel- (BD, Franklin Lakes, NL) coated glass coverslips that a paced in 24-wel tise cOhure plates (Fak'qon Tissue Culture Plates. Fisher Scientific, Pittsburgh. Pa. Celis are maintained in culture for 5 days to one month in 0.5 35 m of media (as abov, except wh ody 1% FBS) at 37 C and 5% C32. limmu tueytehemistry Andaysis [005S6] The retina I neurmonai cells arc cltured for 1, 3, 6, and weeks in the presence and absence of test compounds of the present inventionm and the cels are anayred by immunnhistochensry at each ime point I nsmmccytochiemnistry analysis is perfonrmed accurdiig to standard techniques known in the art, Rod photoreceptors 40 are identified by 1it wth a rhodopsi-speili antihedy (mouse meodoconal, dilted 1.500; Chenicon, Tmnecua Calif) An anubody to mid-weight neurofilament (NFM. rabbit pnydonal dihued 110,000, Cherioon) is used to identify gangion cells an antibody to s33tubulin (G7121 mouse rnonocikna dited 1:100 Prega Madisn Wis ) is ued to gcxenerHy identify ens anggo e and ndxies to albin(A rabbit pol ye 1 -.N1 lon die d 250, Chem icon) aend enlttSi in (AB 5,05 rakbi E p!lydllo~na: dilu ted 0500 ,m' hemi) are useWd to idenfy subpopulations of cssbindir, and calinesing lmtrenro-s in the inner nude layer, Brieily the retina I csu2 cultures are kWed with 4% p formaldehyde (Polyiences, Inc. Warringwot, Pa) andkor ethanoirinsed in 5 DuMecco's phosphate buffered saline ()PH S), and inctubated wit primary adt body for i iour at 31 C, The Ies are then rinsed with DP4S, inrubata with a secondary answtbdy (A lxa 48 8- or AIa SS-inj ugted secondary antibodies (Moecular Probes, Eugener ong)) and rinsed with DPRS Nleid ar stained with 4',diamidiso phenyindte (DAPI, Molecular Prutes) ahid the cultures are rinsed wih DPBlS before removing the glass orli ps and morning tem with Finoromnont-G (Sothiem Biotechl B sgham, Ala) on git slides fbr viewing and Enaaple 4 6 IMtatrigd Plug A. g es Assay, [00587] Ma'sigel containing test Co pou n ds are injcttd sw ctanus 5y or i taca y 'where it solid fies to frm a plug, The phg is reco ued after 72411 days in the animal d exandnehd ist ogicaIy to determine the extent tSo which blood vessel have entered it. Angiogenesis is mleasuxed by quandfiction of te vessels in histologic sections 15 Attemnaively. uatresee meaureer of pnna volume is porfoaied usingi floreseein isoshireyansate (PITC) lawied dexran 150. The results are expected to indicate one or nre mnpottds disclosed herein that inhibit. agiogenesis and ar thus expected to be usefdu in readng ocular disorders teleted 50 aa isstngiogenesis anidor vasular permeahiity. Example 47. The Corneal A.Uglageessis Assay 20 [OOSUJ A pocket is made in the corme and ad plug contai an angign srirs idg (a3mLdation (R3 V-g CGP, FGF, or rumor culs) when introced inmo this pocket, eicit the ingrowth of ow vessels from the pieral tmbal vascla , Slow-eease mateals such as ELVAX (ethylene vinyI copohlymer)or flydrn are used to introduce amgiogeness inducing substances into the coneal pocket Aittrm..atively, a 5pOn mtertai is Used [pOSS9] The effect of putative inhibitors on the loally indbced (e., sponge implant) angigeni, reaction n the 25 cornea (eagx by FGF VEGIF, or tumor tu Is) The tes compound is adiiistered ora Iy, systemically, or directly to the eye. Systeemt administration is by boles snjeedion or, muse effectiusdy, by use of a susstas&- retsse m~cetbod such as impiansta l of snmotic pumps loaded with the test inhibr. Administration o t he eye is by any of ther methods described herein including but not listitd to eye drip topied administrAsion of a cream, euasio, or ged iravitre injectss 3(1 [MIS9U The vascdar respons is monitored by direct observation throughout the course of the eaperimnent using a srereminscaope in mice. Defnate visudaiation of the corteal vasulamare is achieved by adrrinistration of fhuomehromedabecd high-mntecar weight det-am. Quantification is performed by measuring te ara of vessel peneirmnion, dhe progress of vessels toward the aigiogenic ssirsdus over rime, or its the ease of fluorescece, histogram anaysis or piel ecoes above a specific (background) dhih td. SI059l The mults are expected to indicate one sor more compounds disclosed herein SItna inhibit anigiogenesis and are thus expected so be useful in treating cuku disorder related to aberrant angiogeres s andlor vascular permbity Esmpa Mik IMkratiter-ptate Angsoggoesis Assay 1005921 The smay plate i prepared by pacing a oihgen plug in the bottm of each wehll th 50 cl spheids per cilgen plug each spheroid containing 40Ob cells. Ead collagen plug is covered idt H OIpai of storage medium 40 per wed and sited for future use (1-3 days a; 3T % CO 2)The pta sealed with sealing. Test eonmds ae dissolvein 2100 assay medium with ateast one wel including a VEGF positive control and at least one el wi ahut VEGFor test cospould as a nreptive contolt The assay plate is removed fiom the incuAr ard storage ~148sedum is crefiiy pipeted away. Assay mnedis3m containing t be test compounds are pipeted onto the eilagen plug. The plug is placed in a humidifld incubator for (37"C, 5% £02) 24-45 hours Angingeesis isagtified y eating the number of sprloLts, measing avmge sprout length, or detesr.infig cumulative sprot length The assay ca be presrvtd fir laeur Malysis by remMtov te assay mnedam adding dim of 10% pananadehyde in k";aks s per 5 well, and storing at 41. The reslils ae expected to identify compounds that inhibit angiogencesis in various Wn lypes tested, including ceNs of eular origin Eaample 4t6 TNNtikolI Tbeel hndepeedent Weel Aetivadian Assay [M5{3931 To eas t e etfeftf s of the compounds of te prent invaton in suppressang T' s independent antibody production. the TNP~Fico1 B-cell activation assay wsas used a dtsedsi herein. Compousids of the present invenrion 110 ware' dissolved in an appropriate vehicle (e.g, 5% 1-mrethyl-2-pyrroiidinone, 55% polyethylene glycol 400, 10% ol user) Compond were adinistred oviy appronimately li beftira TNP4Ivicol tmament to 4-0 wAk old To stndy Ie effecs of the compounds on el activation, one set f mice were grouped according to thei flowing ~~, t~oigten inection at f'omnpouid Amidstdn srom ooC pday C ay ---- day 7 P Route (fg,) Reuit Rtgnea 1 4 V700 An; o Antigen only Compound 15 1005,M) Fo-ur ani,, igrupl d tight ;rlanima in grmaps 2 to 7 wetre euhnzdin 002 2 hem'Us affit the last cOapoud administradein on day 7. Wkod was immeMdiaey olcted bsy cadiol-puncture and kept at 37Pc fir ihr to nlot fonowed by ovedsghk nuao at 4*C" to, cow te dto cotrQ The, foloin dy >eu wa )-ete b deannnrg and Nentifuti ) at30 pm for 10 min. T-1he ~en sM wa*s then feaz'en at-* for fuueanyi 10459) Semm Nmtples were &Anaye for an&iTNPt ax"body) diers by ESAas dsrbdhrn TNP4R-8A was 20 coakdl onto a Num." Maxisor b mik~enritr p.,ate:4if wu l onpl/we at a nenro of i OpVgi in phfosphae buff-ered sane (PPS). Tim MAJaxisoerb phi.em incubated for L0 hours at moo'tepePn~t-e and tlmo sWnnon ws% rem 0s,0 pifwd i o f bloMIckieg huflk- (up 1% BSA Na Bg) was adde to each Wl and 4aute I hr a qsmm temperathie, Th e phaemu was washed on:)eo wkih 20 piNved 5 of P A S. 0. U T7:vwe- N) (wah bfferg A .1 2 d i Tlionl of seerm frlno each: mouse in blcking buffetr was added to each b in, the" firot columnr (1) of dhe microdter plate. h serum in ecadl 23~~~ of kym iws th~en dehne Mol nbloidg bufrand madded to ohm2, 'M3 \emm in V=ach uyA ofv cohm 2 s ns Md Aoing uff ndided to cumn 3. The procedet w repeated aernss the "wrve ofl the minderp t he ieTtiter patte w incuated I hr at room tepeiue.semm 'ws re he rom tho pWge and the plate was washed Ouhree times with as.h bulffern 1 Iwe of geaNw aami-moxuse g3-flRP dihted 1 2 50 inboc fg fer w adde tW o e vAd and inesheead lhbr al. room tepemrehe an sose 1g03-H IRP was 30 mm helim themio wne pltead tet an Washed Ai dmes with washM bukfe, HR'-P su bstrte ('200 t ABTS 4%9 sAion + 30% H202+ I0ml citrate bdetf) was added to each well at o00 Ol/welI, incubated 2-20 meutes in the dark and the amount of anti-TNP igU1 was determined apecrophosometaa at40Snn, Similay, antilT igM an total antifNP Ab were determined using a14n ouse IgM1RP and and-mous Ig-HMW eectivety. iODS%1 The Mr ts as shown in Pigure 2 %iher show that under the con16d1i6o tested compunds #7 nd #53 exhibit 5 34 ad 6lsnd duction r ,spectivtdy in IgG3 levels relative to vdhicte conrl mie at a 30lkg dose veatL. Figure 2 further shows that compound #53 exhibits 29-fold rMeM in lg{$3 levels ralave to vehicle oto ros ie at a 60mWts d e levd under the condiios tested, Eau mpie f${ RM Devdteping Type 11 Colagen Induted ArthritS Alsy [005971 In order to study the efctts of the compounds of 6e present invention on the autoimmune disease arthrds, a 10 CouAgen WiducAd deveointtg arthritis model was sMed, Female Lewis ths were given collagen injections at day 0 flow inc type it collagen was prepared as a 4mog/n solution in IYO1N acetic acid. Equl volumes of enliagen and nndts incomplete adjva were emulsified by had mi xeing until a bead of the emulsified material held ks fonm in waer. Each rodent received a 300 p ijection of the mfere at each injection te spread ovu r three subcukaneous sites on the bak 1 I (t9gj Oral compound admnistation began or day 0 dand condnued though dAy 16 widh vehicle (f% NMP. 85% PEG3 400, 10% Solutol) or compounds Sd the pt-sent invention in vehite or control (e.g. methot-ante) at i2 hour iraervaN daily, ats ee weighed on days 0, 3, 6, 9-7 and caliper masuremets of Nkles taken mn dz1s 97 Final body weights wen taken, and then the animals were euthanized on day 17, After cuihanizaton, blood was draw and hind paws and knees were removed. Boe-d was fc u rti sd fccato ha experiments as ielt a an art> 24) type ii collagen antibody EUISA ssay. Hind paws were weighed and then with the kneas praesrvedt in 10% fbrmalinL The paws and knees were suaoquently processed for mricrocopy, dses,spleen and thlym m"were also weighed Sciatc nrve wrt prepared fir histopathology. 1065991 Ka nd'J ankle joints were fixed for 1-2 days and decfllkedi for 4-5 days. Anke jnts were cut Ji half longitudinaly, knees we- &ut in half along the fiontal plane, Joints were then proce wed embedded sectioned and 25 stained with toluidine bi-e Scoring of the joints was done according tothe following criteria; Knee andAM l=Mininmal infitraton: of inflammrnatory cells in synovsum/perieadr tisue 2 >dild inifiltration t 3>mModerase afin m-trion with moderate edema 4Marked infiltrate ion with naked edema 5=evce infileraion wish severe ede-mus Ankle Pnemus 35 ItMinimal inflation of pannus in eartilage and sdehondral bone 2-Mild infiltration (<4 of tibia or tarsaI at murginal rones) 3>Moderaie indltration (1/4 to 1/3 of tibia or small tarsal's afetted a margi nes) 4=Mrkcd iniistaiot (12-3/4 of tbia or tarals aheted at nmarginal zones) $=Sevce infltraton (3/4 of ta or ars afeced at maqinai zones, severe distortion of overal 40 archiseesmre) Knee Pannum fk>Normai ~15)hMinimaai iindon ofpaamks in carilage and sutchondra bone 2mMild iOfitradon extendss over up to A/4 of surface or 3 rxandri area ofds hic or femr) 3=o4derate information (etends over >1/4 but < 1/ of suce or sutchondral rea of ibin or 'fenur) 4=Marked information (extends over 1/2 to 34 of tibia or feno surface) 5 5=sevwr inatiras (covers> 3/4 of saffce) Cartiage Dmnage (Ankle, .tpbds on small tarmss) 0-Normdc leirixnim smint to mild loss of toluidine blue stewing wit no obvious chorndroyte loss or colag deioon :10 2'ildnld loss ofohiddince blue staring with toad mitispe (arfiial) chondrocyte lews and/or cogt n edition N~drtemdrt loss of toloidirte ble string with rmaki focal moder ate (depth to moiddie zone) chtondrnocytt loss and~or col/agee disruption, so rr ass affeted to 1/2-3/4 death 4=crkrmarkd loss of toluidine blue staining with nuiifdcal marked (depth to deep zone) chodrocyte loss IS mod/hr cotlien disruption. 1 cr more smol tarsac howe lfl tinckiess leos of atig S=gs'ere =severe diff si loss of toluidine blue sainig waih multifcal severe (depth to lide nm-ark) chondrocto Ioss and t ov collagen dm on Cardiloge Damage (Knee, emnphass on fetmodi concdyles) 20 tstinmatnmio a to mild loss of tohidinz lue stoning with no obvious ehoedmeyte loss or collagen disruptio 2.:.Mideid los of toluidine c sNwing ith f4es mud (souperficiai) eonordrocyte loss and/or eSliagen disruption 3=Moderat -omoderate loss of' toeline be4 sting with (rtifcad to defuse moderat (dopt to middle 23 zone) chondocyte loe-sanh collage dis'rupdon 4"WMrkedxzmarkmed loss of toluidinse bloe staining with msdtifcad to diffuse matrked (dept-b to deep cone) di sdiocyte loss and/or colagen disruption or ci gl-e feosora surface with toto2 or near tota loss $"Severe "'severe diffuse los of tol idino biet stainiag with multi focal seere (depth to tie mark) ohondoxcyto ks Zd/t cot-lagen disrupftme -on both fros and/or tibias 30 Bone Resorption (Ankk) 0"'Normda lMinnmnall aes of resorption, not readily apparent low Msagnificationa, Mte osteMoasts 2=-Mdtnor rsumerous rees ofresorpion, not readily apparent on low msagndicatiorr osteoctas smore numerous 74 of tiia or tatses at marginal coces resorbed n 3=Moderats=obvious rcsorption of moduflry trsbecolar cnd certical bone without f! thickness defects in coexloss of some oedoilty trabeculae, kesion apparent fo w Ag ninfition, esteOCts more numerous , 1/4 to i3 of tibia or teas effected at marginal cnes 4-MarkeFil thikness dlrbtas in conical bone, often with disteion of proMo of nretmng conical a mrked loss of meduary b nwe, numers ostovtasts, VU2-3/4 of ti a ts affected at nari ones 40 :se ul thickness d f.s . coretkal bone., Oe with distortion of profie of mnoining ortcal surface, n-arked loss of medunRary boe, rnm eous ost11asts,>3/4 of tib or warsal affected at margial cones, severe disMorin of ovem arcssectu Bone Resorption (Knee) 't inimasoall tees of rerption not readily apparem ox low magnificatime On e0c5skXV ts 2>-Miit-more numerous areas of resorpton, defiite loss of oh dmi kone involving 1/4 of tihial or femoral 5 siurface (medial or latel) 3-Moderat ious r pierir of subeomrddi hone involving >U4 bt <1/2 of tibial or feol* Ffae (miaC or Nteral) 4=Marko& obvious resrption of subchondrai bone involving V2 bt <314 of 6ibial or Pmemoral surface (medial or herald) 10 K cse " distortion of entire joint. due to Iestoaction involving >3/4 of tribal cr femoral surface (medial or haieraf) [0600) Statistical analysis of bodlypaws weights, paw AUC parameters anid hisopathohygi e parmeterwere eviuated using a Sudents P4est or other apprpriate (ANOVA with postses0 with sugnieance set at the 3% gifance levels Permmt inhibition of paw weight and AUC ms catrsted using the following formua: i5 '% inhiMhionrA /A X 100 AwcMean Disease Cntrol - Mean Norma 5-Mean Treated - Mean Normal [lN/tlt] The results sas sown in FigIurn 3 demonsrase the effect of> emomd #53 at 10, 30, and 60 mg/kg dosages at 12 hour intemvaIs on mean anke diameter over time in a rat developing type U colagen induced arthritis moded der 20 the conditions tested. Retivs to the vehicle alone central or to the meacitho te conrol. the coumponds ofthe poaseat invention exhibited a siginificant reduction in arthritis induced ankle dnmeter increase over time. 100I02) The results as shown in Figare 4 demonmsate the efc;t f Comounds #7 ad #53 on akle hi opathology in the Ctegories of inflanmatIon, p, mns crtilage deage a d bne resporpion as previously dented under the Onitiost tested. The mesuts show asignisncam reduction in one or more categories by one of the compounds of the 25 prest invention (iAe compound #53) Under the condtans testcd Figre 4 further sows that at 60mg/kg, there is a stuay signi fean reduction itn al ategries of ankle hitopathology for one of the compounds of the present invention (c. compound #.3) under e ondit ios tted.Thissugges tha oeti or more compounds of the presn invention may be useful for the treatment and reduction of arthritis ease symptoms. 1t003 The results as shown in Figare demonstrate thu effect of mempounds 7 a d #53 on knee histopahology 31 wide the conditions tested The tast demonstrate a dose dependent redutio in knee histopadmoogy. This sgges that one or more compounids of the present invention may he use I for the threaten and, r uin of asthru-i diseAe 1016041 The rsuls as shown in Figure 6 demonstate the effect of the compounds 0#7 and 153 on seum antypc H1 colAgen Inv'a under the conditions testedI The resus further show a si-ngificasn eleion at 10, 20, ad. 60mgkg '3 doSn et o serna anti'type 11 collagen levels for conmpexnd #5 suggesting otht 'n or moe oompunds of the present invnon may not only be useful for the treatment ad reduction of arthritis disease $ymt hut mty also be ueful for the inhibidion of the -atoimmsuns reaction self. 101)6g51 The results as shown in ignre7 demonsate the elit of compound #7 at l0, 3I, and 60mg/kg doaes at 12 ho interval on moean ankle diameter ver time under the conditions teted, Relaive to the vehicle alone control 40 or to the methotrexate coMrol, the compound eshihiked a reduction In ariritis induced akle diemete inct e over tune under the cocoditons steed. frampl St Rat Established Type II Collaen Induced Arthrid~s Assay -I3.2 [MCe06" t order to examine the dose responsive effieey of o mpoundaf the present invention in inhibiting the irdhmmation, WC.rttag der tn and bone rIs o=n of 7 ay established type tI aOtigera induced arthritis in rats, enoumop i 'were admnimred oraiy daily or twice daily for t days 4(1607j Femal Lwias wee anbesthted and gven collagen Jn tion prepared and admini stored as described 5 pv iousy on day'), On day 6. animals were anesthettyed and given a second colagen ijeco. Caiper meaummen s of wnma (pre-disease) right and eft ankle joints were performed on day 9. On days 10-1, arthritis typically accured and rats were randomizd into taunt groups. Radomisaion was performed a1t ankle joint sweling was obvioasiy estabished and there was good evidence of biaera disem Nf]6fl After an animal ws selected for enrdiment in the sudy' aetment as initiated by he orda oute Annima 10 Wt ~giVen vehide, control (Enti) cr compound doses twice daily or once daily(11D or QD espectivlyt Dosng was administered on days I(66 using a vol me of5 2." kg (,$IID) or SmnWlkg (QD) for oral sodos, Rat were weighed on days o g esmblisWent of arthritis and caper mesurmnents of ankks taken every day Final body weights were taken oan day 7 and ardais were ehanized :10091 The results as shown in wign I shows a \sgi ant nreRin nmfan ankle dimter increase over time for 15 compound #53 with a once daily dosage under the conditions tested. The rests in Figure 9 father deVmate a signicant education in mean ankle diameter inreme over time fr conpouind #53 with a twice daily dosage under ue conditions tested. This suggests that the compounds of the present invention may be useful ohe treiatment of aotoimmunne dasaes such as athtis. Exampc t kjuvat ladueed Arthrits Assay 20 mratheca Catheteriatn of Ras . [O0610} lsofturaae'anesthetizted Lewis ras (2fti-20 g) were implanted with an intrathieed (ElT) catheter. Aftr a 6 d recovery period, aI animal except those that appeared to lave senory or motr abnoraities (kA tian 5% of th total nmnbeD ween used for experiment. For 1T administaion, 10 gal of drug or saline followed by 10 p of isotonic saine was injected through the catheter. 25 [6111 Adjuvant Artriis and Drug Treatmenm [612 1 Lewis ats were immunized at die base of th ttal with 01 ml of compete Freand' adjuvan, (CFA) on day 0 several days afer catheter impantation (m egi rug (eg one or m e onpXunds of the pment imn dn or or vehicle) .t3ment was genesaly stated on day m and continued daily until day 20. Clinical ign of arthritis general begin on day 10, and paw swelling was determined every second day by water displacement phyamonetry 30 [W1613 The mults as depicted in Fugre 10 by the average change in paw volme under the dosge regimes indc teaed show that under the condittos tested, compound #33 shows a dose dependera reduion : te aveng paw volume increase as measured i .n this adjrVnt induced arthritis model vstem, Thse rests suggest that one or more of the corpoands sthe present inventi an may te usefu fo the treatment of one or more of the diseases or conditions drion Lcd herein. 3 [M614{ The utts as depleted iin Figure 1 show thwt compound #53 descs not exhibit toNicity or oier adverse reaction under the condiions teted as measured by a lack of weight loss Example Mi Reant Phsarmacoeted Assay [06151 In order to study 0he phaninucokinetics ofthe componrds of the present invention a set of 440 week old mice are grouped according to the following tabe: G'pComcnpound i rnm dal to dat g k Rooe Rtegmina -53> 2 2 3.3 PO BID for 7 days [004161 Compounds offthe presnt inventin are diolved in W appropdate vehicle C0g, 5% Ime.y2 pymidne 85% poyethyae glyci 400, 1% ohor) and adminited oray st 12 hour intema daiy- MU saintm are eiuanized in C02 2 hours after 'he fat compound is adfmnt 2red. Blood is coleoted immediately ard 5 kepti ' e fit pasma isolation, Piasma i is ted oy entifugng at 5000 rpm for I) minutess, 14arvested ama is troAn for pharmaok ne detection 100617 The emuh are epeted t demostrat the pharmcacdkieti parameters such as bsorprion, distribunm, metabosm, excrte xond toxiaxy for the mpous of the present mnciati [006191 Emple 64 iasatest asay 1 [00619j The basiltest ams is performed using Or pege Pharma aasitest reagent kit, epar'mized whole blood is prennbtedt with test compound or svent at 37C for 20m3r, Bood is then icncuated with asy kit stimution buffer (to prime cells fir tesa sce) .o'nod by auergen (ust Mite extr c grass e fact) fr 2mi The degranakwic process is stopped by inobaing 4 thb samp's n "- The clls are then labeled wi th atiIg-PE to detet basaphilie grioutyte end anmi'gp$3~ rC to de em citp3 (a glycOpotin expresed on acrusated 15$ basophils), After stisn red bMood cenls are lysed by adtio of Lyin Soh ation Cells are washed and anlyzed by dow cytomery. Cimpunde 7 and 53 when tested in this assy inhihit allergen indwed activation of tasophilic grnusloeyes t sub mniemmlar range. Ifi0f0]20 E mpae IM Combiniat use of FNK4 inthib tars and agats thatinhibit gE prd action or activity l14Ij6 The compmucds of the present invenci may present synergetic or additive rffica c when adiscimnistered in 23 conhinciadon with apems that inhibit pi prduction or activity Agers that inhibit igE production i:ncad, for exampme, one or more of T 1-ill7,2-4-(facy aexyxy-2mnphtylxy)phenylrmnmid)n deacid, rapnyvin, raparnyin anlogs (ie, rapIogr), TORCt iriNbitors TORC2 inhibitors, and any other cp ds that inibit mT1ORE 1 acd mTORC2 Agents that inhibit IgE activity inlde, -or examp% anti-g d bodies such as Ondaitmab and TNX-4{fML 25 06221 Onc or imnue of the subject compouIda nepahle of inhibitig PD1K6 are efficacious i treatment of atuoimune and inflammatory dsords (A)D fr examp e rheumatoid arnti ., if ray of the co'mpounda causes an undesied level gE prouxctions, one ay chaouse to administer it ino mbiunvk with a agent fhat inhits igE production o Igl &stivit.- Additionaiy. the adminisraion of PDKh or P3K/y inhibitors of the present invention in nomination with inhibitors of msTOR may also exhibit synergy through enwamced iniuition of the P13K pathway. 30 Vrious in vive and in vitrr models may be used to establish the effcct of such combination treatment on AlD irnecwding bu not imied to (a).n kra B-ell anibody production smy, (b) in viv TNP asay, sd (m) rde olagen inducerm arthritis model (4 K&u Asny J061 -Mte ea euthan izd, and the.. peens a removed ntd dispersed throuPh a nylon mesh to generate a s"ingi 35 TdN uspensiOse splenocytes are washed followingg removal oferythrocyues by osmotic shock) ad inubated with antuCD43 and ani-iMac- aibadyuzniugaed microbeads (Mileni Iotec). The bead-ond cells are separated -54fiom unbound cdis using a magnetic cell setter The mnagnedzed cotnA retains the unwanted ceils and the tnag B cens are cntiected in the flowthrogh. Pnrified Bel are stimulate with lipopolysaccharide or an anti-CD40 antibody and inrleein 4, sturaulate B-sCells m treated with vehicle ane or ith P13K :nhihitars of he presn inVention such as Coom'pound 53 with and w -ho 3 mTOR q iibitersnoh as apamyin, apahgs, or ITORCAU2 5 inhibitors. The rmst ate expected to show that in the prstece of mTOR inhibitors (esg rapamnyin) alone; there is stk No no stadanti effect on IgG and IgE eponse, however, in the prmerce of P13Kg and MTOR inhibitors, the Bs a expected to exhibit a decreed igG response as coaparad to the B-ces treated with vehicle done, and the B-oas a epeed to exhibit a dee ad tiE response as compaed to the response from BWels treated with PU3K inhibtme alone. 10) (h) TNiP Assay [0624] Mice ae inmmuized with TN-FTicoiI or TNP-KHL and tated with: vhiche, a P! Kh inhibitor, for example, compound 53 of the present invention, a mTOR inhibitcor, f example tapanyvin, or a P13Kb inhibitor in combination with ass mfTOR inhibaitr sch as rapamycin, Antigen-specii sero IgE is measured by ELBgA using TNP-B)SA nthed plates ad iwtype specific flbhesd antibodies, It is expected that me reaed with an mTOR 15 inhibitor alme exhibit liti or no substantial vff&ct on atigen specific ig33 response and no statistically significant elevation in response as comped to the vehicle ntrol it is also expected that mie treated with both PAK inhibitor and TOR ihibitor exhibit a reduction in andgen specify g3 response as compared to the mice treated with vehideadone. Addiknally, the mice rated with boh P3Kb inhibutr and mOR inhibitor exhibit a deersis in igE response as compared lo the mce treated with Pi3K inhibitor alone. 20 (c) Ran Collaen find 'ed Arthsris Modds [00251 Female Lewis rats are nesthedied and given collagen. infections prepared and admi mitered as described previously on day 0. On day 6 animas m anesthetiad and given a mcnd colagen injection, Caltiper measurments of normal (pre-disue) right am let ankle joints are performed on day 9. On dayr. 10I .1, arthritis typically ocr and rats a randomized into treatment groups. Randoizao is permfted alter ankle joit swing is obvioudy 25 established and them is good evidence of bhaml dismarr [O%261 After an animal is selected for enromiment in the study, treatmnt is tnred, Animals ar given vehicle, PDIKb nshiitor, or PDK6 inhibitor in combination with rapaycin. Dosing is administed on days i4 Rats are sestghed on days [-7 following essabtishtnent of aritis and caliper mnsemasrns of les taken evrys day. Final body weightn a taken on day 7 and animals ae euthmized, 30 10271 It is expected that the ambinaion treatment u Msing PK inhbitrr and rspamycin provide greater efic-any than treatment with PyKb iritrto alone M0m23l While preferrd embodimns of the pmt invenion have been shown and derbed hemin, a wil be obvus to tho sited in the art thauc embodiinens are provided by way of emampe only, Numemus variations, hages and 1stitutins will now occur to those skilled in the art without departing irm te invention, it should be 3.5 unestood that vardos aternaives to the embodiments of 'he i nestion decrbed hareint may be em pryed in praeticing the invention, R is intended that the folo-wing chims define the scpe of the invntion ard that methods and stmctures within the scone of these claims and their equivalents be coveted thereby 40 t155-

Claims (33)

1. A process for preparing a compound of Formula 1409: R 3 0 NR' NN NR CH 3 H N N N NH 5 1409, or a pharmaceutically acceptable salt thereof, wherein R' is alkyl, amino, heteroalkyl, cycloalkyl, heterocycloalkyl, or a moiety of Formula II; R1 R' ( 2 )q Formula II; 10 wherein We is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, q is an integer of 0, 1, 2, 3, or 4; R 1 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, or carbonate; 15 R2 is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy or nitro; and R 3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, aryl, or 20 heteroaryl; 156 comprising reacting a compound of Formula 1407: R 3 0 N',R' CH 3 NH 2 1407, with a compound of Formula: X N N 5 \-N H wherein X is a halogen.

2. The process of claim 1, wherein X is bromo.

3. The process of claim 1 or 2, wherein the compound of Formula 1407 is prepared by a process comprising: 10 a step of reacting a compound of Formula 1405: R 3 0 CH 3 NHBoc 1405, with NH 2 R' to provide a compound of Formula 1406: R 3 0 NR' N NR CH 3 N H Boc 15 1406; and a step of deprotecting the compound of Formula 1406 to provide the compound of Formula 1407. 157

4. The process of claim 3, wherein the deprotecting step occurs in the presence of HCl.

5. The process of claim 3 or 4, wherein the compound of Formula 1405 is prepared by a process comprising an intramolecular ring closure of a compound of Formula 1404 or a 5 salt thereof: R 3 0 OH CH 3 N H Boc

1404.

6. The process of claim 5, wherein the intramolecular ring closure occurs in the presence of Pd(MeCN) 2 Cl 2 and TEA. 10

7. The process of claim 5 or 6, wherein the compound of Formula 1404 or a salt thereof is prepared by a process comprising reacting a compound of Formula 1403 with KOH: R 3 0 OMe CH 3 NH Boc 1403. 15

8. The process of claim 7, wherein the compound of Formula 1403 is prepared by a process comprising coupling a compound of Formula 1401: R 3 0 't- OMe 158 1401, with a compound of Formula 1402: H CH 3 NH Boc 1402. 5

9. The process of claim 8, wherein the coupling occurs in the presence of a palladium catalyst, copper iodide, and triethylamine.

10. The process of claim 9, wherein the palladium catalyst is Pd(PPh 3 ) 2 Cl 2 .

11. A process for preparing a compound of Formula 1606: R 3 0 NR' N "R CH 3 H N N N NH 10 1606, or a pharmaceutically acceptable salt thereof, wherein R' is alkyl, amino, heteroalkyl, cycloalkyl, heterocycloalkyl, or a moiety of Formula II; R1 Formula II; 15 wherein W, is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl, q is an integer of 0, 1, 2, 3, or 4; 159 R 1 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, phosphate, urea, or carbonate; R2 is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, 5 heteroaryl, heteroarylalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy or nitro; and R 3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, amido, amino, acyl, acyloxy, alkoxycarbonyl, sulfonamido, halo, cyano, hydroxy, nitro, aryl, or heteroaryl; 10 comprising deprotecting a compound of Formula 1605: R 3 0 NR' CH 3 H N N N N THP 1605, wherein the deprotection occurs in the presence of an acid.

12. The process of claim 11, wherein the compound of Formula 1605 is prepared by a 15 process comprising reacting a compound of Formula 1604 with NH 2 R': R 3 0 CH 3 HN N N N THP 160

1604.

13. The process of claim 12, wherein the compound of Formula 1604 is prepared by a process comprising an intramolecular ring closure of a compound of Formula 1603 or a salt thereof: R 3 0 OH CH3 N NH NN N N-' 5 TH P 1603.

14. The process of claim 13, wherein the intramolecular ring closure occurs in the presence of Pd(MeCN) 2 Cl 2 and TEA.

15. The process of claim 13 or 14, wherein the compound of Formula 1603 or a salt 10 thereof is prepared by a process comprising reacting a compound of Formula 1602 with KOH: R 3 0 OMe CH 3 N NH N N N N TH P 1602. 161

16. The process of claim 15, wherein the compound of Formula 1602 is prepared by a process comprising coupling a compound of Formula 1401: R 3 0 't- OMe 1401, 5 with a compound of Formula 1601: H CH 3 rN N H N NH N . N TH P' 1601.

17. The process of claim 16, wherein the coupling occurs in the presence of a palladium catalyst, copper iodide, and triethylamine. 10

18. The process of claim 17, wherein the palladium catalyst is Pd(PPh 3 ) 2 Cl 2 .

19. The process of any one of claims 1-18, wherein R 1 is hydrogen, alkyl, or halo.

20. The process of claim 19, wherein R 1 is hydrogen, methyl, isopropyl, or fluoro.

21. The process of any one of claims 1-20, wherein R 3 is hydrogen, halo, alkyl, alkoxy, or cycloalkyl. 15

22. The process of claim 21, wherein R 3 is hydrogen, methyl, ethyl, -CF 3 , chloro or fluoro.

23. The process of claim 22, wherein R 3 is methyl or chloro. 162

24. The process of any one of claims 1-23, wherein We is aryl or heterocycloalkyl.

25. The process of any one of claims 1-24, wherein R' is unsubstituted phenyl.

26. The process of claim 11, wherein the compound of Formula 1605 is prepared by a process comprising reacting a compound of formula: R 3 0 NR' '6N NR" CH 3 5 Br with a compound of formula 4104: H 2 N N N N

4104.

27. The process of claim 26, wherein the preparation of a compound of Formula 1605 10 is in the presence of NaH.

28. The process of claim 26, wherein the compound of formula: R 3 0 NR' '6N NR" CH 3 Br is prepared by a process comprising reacting a compound of formula: R 3 0 NR' CH 3 OH 15 with PPh 3 and CBr 4 . 163

29. The process of claim 28, wherein the compound of formula: R 3 0 NR' CH 3 OH is prepared by a process comprising reacting a compound of formula: R 3 0 NR' 5 with MeMgBr.

30. The process of claim 29, wherein the compound of formula: R 3 0 NR' is prepared by a process comprising reacting a compound of formula R 3 0 N NR. N'R OH 10 with MnO 2 .

31. The process of claim 30, wherein the compound of formula: R 3 0 N NR. N'R OH is prepared by a process comprising reacting a compound of formula: 164 R 3 O N' R' COOEt with LiAlH 4 .

32. The process of claim 31, wherein the compound of formula: R 3 0 N' R' COOEt 5 is prepared by a process comprising reacting a compound of formula: R 3 0 N' R' COOEt 0 in the presence of Cs 2 CO 3 .

33. The process of claim 32, wherein the compound of formula: R 3 0 N' R' COOEt 0 10 is prepared by a process comprising reacting a compound of formula: R 3 0 N' R' COOEt with Os0 4 and NaIO 4 . 165