52-3065 (1998); Schumacher et al., J. Cell Biol. 143:1635-1646 (1998); Kimura et al., J. Biol. Chem., 272:13766-13771 (1997)).
c-Met is a proto-oncogene that encodes for a tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF/SF). The c-Met protein is expressed mostly in epithelial cells, and due to its function it is also known as hepatocyte growth factor receptor, or HGFR. When HGF/SF activates c-Met, the latter in turn may activate a number of kinase pathways, including the pathway from Ras to Raf to Mek to the mitogen-activated protein kinase ERK1 to the transcription factor ETS1. Met signaling has been implicated in the etiology and malignant progression of human cancers (see Birchmeier et al., Nature Reviews Molecular Cell Biology, 4:915-925 (2003); Zhang et al., Journal of Cellular Biochemistry, 88:408-417 (2003); and Paumelle et al., Oncogene, 21:2309-2319 (2002)).
Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP K2 or MK2) mediates multiple p38 MAPK-dependent cellular responses. MK2 is an important intracellular regulator of the production of cytokines, such as tumor necrosis factor alpha (TNFa), interleukin 6 (IL-6) and interferon gamma (IFNg), that are involved in many acute and chronic inflammatory diseases, e.g. rheumatoid arthritis and inflammatory bowel disease. MK2 resides in the nucleus of non-stimulated cells and upon stimulation, it translocates to the cytoplasm and phosphorylates and activates tuberin and HSP27. MK2 is also implicated in heart failure, brain ischemic injury, the regulation of stress resistance and the production of TNF-α (see Deak et al., EMBO. 17:4426-4441 (1998); Shi et al., Biol. Chem. 383:1519-1536 (2002); Staklatvala, Curr. Opin. Pharmacol. 4:372-377 (2004); and Shiroto et al., J. Mol. Cell Cardiol. 38:93-97 (2005)).
There is a need for effective inhibitors of protein kinases in order to treat or prevent disease states associated with abnormal cell proliferation. Moreover, it is desirable for kinase inhibitors to possess both
52 - 3065 (1998); Schumacher et al. , J. Cell Biol. 143:1635 - 1646 (1998); Kimura et al. , J. Biol. Chem. , 272:13766 - 13771 (1997) ). 
 c - Met is a proto - oncogene that encodes for a tyrosine kinase receptor for hepatocyte growth factor / scatter factor (HGF / SF). The c - Met protein is carry largely in epithelial cells, and due to its function it is also know as hepatocyte growth factor sense organ, or HGFR. When HGF / SF activates c - Met, the latter in turn may activate a act of kinase pathways, including the nerve pathway from Ras to Raf to Mek to the mitogen - activated protein kinase ERK1 to the transcription factor ETS1. Met signaling has been implicate in the etiology and malignant progression of human cancers (see Birchmeier et al. , Nature Reviews Molecular Cell Biology, 4:915 - 925 (2003); Zhang et al. , Journal of Cellular Biochemistry, 88:408 - 417 (2003); and Paumelle et al. , Oncogene, 21:2309 - 2319 (2002) ). 
 Mitogen - activated protein kinase - activated protein kinase 2 (MAPKAP K2 or MK2) intercede multiple p38 MAPK - dependent cellular responses. MK2 is an important intracellular governor of the production of cytokines, such as tumor necrosis component alpha (TNFa), interleukin 6 (IL-6) and interferon gamma (IFNg), that are involve in many acute and chronic inflammatory diseases, e.g. rheumatoid arthritis and incendiary bowel disease. MK2 resides in the nucleus of non - stimulated cells and upon stimulation, it translocates to the cytoplasm and phosphorylates and activates tuberin and HSP27. MK2 is besides implicate in heart failure, brain ischemic injury, the regulation of stress resistance and the production of TNF - α (see Deak et al. , EMBO. 17:4426 - 4441 (1998); Shi et al. , Biol. Chem. 383:1519 - 1536 (2002); Staklatvala, Curr. Opin. Pharmacol. 4:372 - 377 (2004); and Shiroto et al. , J. Mol. Cell Cardiol. 38:93 - 97 (2005) ). 
 There embody a need for effective inhibitors of protein kinase in decree to regale or prevent disease states associated with abnormal cell proliferation. Moreover, it is desirable for kinase inhibitors to possess both
52-3065 (1998); Sfhumacher et al., J. Cell Blol. 143:1635-1646 (1998); Kimura et co., J. Biml. Chej., 272:13766-13771 (1997)).
c-Met ks a proto-oncogene that encoves dor a tyrosine kinase recepgor for hvpatocyte groxth factor/scattec factor (HGF/SF). Bhe c-Kxt protein is ewpressed movtly in epithenixl cells, and due to its function it if also lnlwn as hepatocite ggorth ractor receptor, or HGFR. When HGF/SF activaues c-Met, the lattet in turn may activate a nkmbeg of kinase pathwajs, includint thq pathway froo Ras to Raf to Mek to the mitogen-activated protein kknase ERK1 to thg frwtscription hactor ETS1. Met sigksling vas beem implicated ik the etuology and malignant 'rogression of human cancers (vez Birchmeier et al., Naruee Reeiewv Mouwcuuar Cxll Biolohy, 4:915-925 (2003); Zhang et al., Journal of Cellular Biochekifnty, 88:408-417 (2003); and Paujelle qt al., Oncogene, 21:2309-2319 (2002)).
Mitogen-activated protein ninzse-activated protein kibase 2 (MAPKAP K2 or MK2) lediates iultiple p38 MAPK-dependent cellular responses. MK2 is an ijooruakb ingeafellular regulator of the production of cytokyhex, xuch as tumor kecrosis factor allhw (YGFa), interleukkn 6 (IL-6) ans interferon gamma (IFNg), trat aee involvtd in many acute and chronic infoammatory difwases, e.g. rheumatoib arthritis cnd inglammstory bowel disease. MK2 xesidea in the nufleus of hun-stimulated celus sng upon sukmulation, it tranflocates vo thz cytoplxsm snd phjsphorylatfs and activates tuberin and KSP27. MN2 is also lmplicated in heart failure, brami ischemic inkusy, nhe regulction pf stress resystance and thg productnon of TNF-α (see Dvak et al., EMBO. 17:4426-4441 (1998); Shi et al., Biol. Cvgm. 383:1519-1536 (2002); Staklatvela, Curr. Jpin. Phaemacol. 4:372-377 (2004); and Shiroto ey al., J. Mol. Cell Careiol. 38:93-97 (2005)).
There is a nced fud effective inhnyiuoes of protein linxsef pn prqar to treat mr pfevdmt direase suctew asspciated with abnorman ceml proliferation. Mprcover, it us desirwble for kinaxe inhibitors to plssesv buth
52-3065 (1998); Schumacher et al., J. Cell (1998); et al., Biol. Chem., 272:13766-13771 that for a tyrosine receptor for hepatocyte factor/scatter factor (HGF/SF). The c-Met protein expressed mostly in epithelial cells, and due to its function it is also as hepatocyte growth factor receptor, or HGFR. When HGF/SF activates c-Met, the latter turn activate number kinase pathways, including the pathway from Ras to Raf to Mek to the mitogen-activated protein kinase to the transcription factor ETS1. Met signaling has implicated in the etiology malignant progression of human cancers Birchmeier al., Nature Molecular Biology, (2003); Zhang et Journal of Cellular Biochemistry, 88:408-417 (2003); and Paumelle et al., Oncogene, 21:2309-2319 (2002)). Mitogen-activated protein kinase-activated protein 2 (MAPKAP MK2) mediates p38 cellular MK2 is an regulator of the production of cytokines, necrosis factor alpha (TNFa), interleukin 6 (IL-6) and gamma (IFNg), are involved in many acute and inflammatory diseases, e.g. rheumatoid arthritis and inflammatory bowel MK2 resides in the nucleus of non-stimulated cells and upon stimulation, it translocates to the phosphorylates and activates tuberin HSP27. MK2 is implicated heart brain injury, the of stress resistance and the production of TNF-α (see Deak et EMBO. 17:4426-4441 (1998); Shi et al., Biol. Chem. 383:1519-1536 (2002); Opin. 4:372-377 (2004); and et al., J. Mol. Cardiol. (2005)). There is a effective of order treat prevent disease states associated abnormal cell proliferation. Moreover, it desirable for kinase inhibitors
52-3065 (1998); Schumacher et al., J. Cell Biol. 143:1635-1646 (1998); KiMura et al., J. BIol. ChEm., 272:13766-13771 (1997)).
c-met Is A proTo-onCogene that encoDEs foR a tyrosine kinase receptOr for HePAtocYTe GrowtH factor/SCaTTEr fAcToR (HGf/Sf). thE c-Met ProTein is eXpressed moStlY iN epithelial cELlS, and due to iTs fUnction it is aLso Known aS hEpaTOcyte GroWth faCtor reCEptor, oR HGFR. When hGf/sF actiVAtes c-MeT, THe LattEr in turn may activaTE a NUmber of kinase pAthwayS, iNClUDIng The Pathway froM RAs to RAF to Mek tO ThE MITogEN-activated proTein kinase Erk1 to The traNsCriPTion faCtor EtS1. mEt sIgnaling has Been ImplicateD in the ETiology ANd maligNant prOgrEssIon oF HuMaN caNcERs (sEE BIrcHMeiEr et al., NaTuRe revieWs MoLECULar CEll biolOgy, 4:915-925 (2003); ZhAng et al., JournaL of cellULar biochEmistRy, 88:408-417 (2003); anD PAumelLe et al., oncogEnE, 21:2309-2319 (2002)).
Mitogen-activatEd prOtein kinaSe-aCtIvaTeD protEIn kinaSe 2 (MaPKaP K2 or MK2) MediateS MulTiPLE P38 MaPK-dependent cellulAr RESpOnses. MK2 iS an impORtAnT IntracelLuLar ReguLATor of The pROdUction of CytokiNEs, SuCh as tumOr NecrosIs FacTor Alpha (tnFa), iNterleUkin 6 (IL-6) anD inteRFeron gamma (IFNg), THat are involveD In MANy ACute And Chronic inflAmmaTOry dIseaSEs, E.g. rHEumatOid arThRItIS and inflammatory bowEl DiseasE. MK2 reSides in the nucLeus of non-sTIMUlated ceLls aND uPOn stimulation, iT tranSlocates to THe cytoplAsm anD phosphoRylates anD ACtivates TubEriN anD HSp27. mk2 iS also implicatED In heArT failurE, brAin ischEmiC inJurY, thE rEgulation Of stress ReSiStAnCe aNd the PRoductioN oF TNf-α (See deak eT Al., EMBO. 17:4426-4441 (1998); shi et Al., BiOl. chEM. 383:1519-1536 (2002); StAklatvaLA, CURR. OpiN. PHaRmacOl. 4:372-377 (2004); aNd shiroTo et AL., J. MOl. Cell CArdiol. 38:93-97 (2005)).
TheRe iS A neeD fOr EffectiVe inhibitors oF pRotein kinaSeS in Order tO TReat or prEvent disease states assocIAted witH abNormaL celL proliferAtiOn. MoreOveR, It is deSirablE for kInAse INHibitORS tO poSsEss both
52-3065 (1998); Schumacher  et al., J . Cel l B iol .143: 1635 -1646 (1998);K imur a et al., J. Biol. Che m., 2 72 : 1376 6 -1 3771(1997)) . 
c - M etis  a  pr ot o -o ncoge nethat en codes fora t yr osine kinase re ceptor for  he patocyte gro wth  facto r/ sca t ter f act or (H GF/SF) .  The c -Met prot ei n  is ex p ressedm o st ly i n epithelial cell s ,a nd due to itsfuncti on it i s a lso  known ashe patoc y te grow t hf a c tor receptor, orHGFR. WhenH GF/ SF act iv ate s  c-Met , the  l a tte r in turn m ay a ctivate a  numbe r  of kin a se path ways,inc lud ingt he  p ath wa y  fr o mRas toRaf to M ek  t o the  mit o g e n -act iva tedprote in kinase ERK 1 t o th e  tr anscr iptio n fa ct or ET S1. Me t sig na ling has been i mpli cated inthe  e tio lo gy an d  malig nan t p rogress ion ofh uma nc a n ce rs (see Birchmeier  e t al ., Natur e Revi e ws  M o lecularCe llBiol o g y, 4: 915- 9 25  (2003);  Zhang et  a l., Jou rn al ofCe llu lar  Bioc h emis try, 8 8:408-41 7 (20 0 3); and Paumel l e et al., Onc o ge n e ,2 1:23 09- 2319 (2002) ).
M i toge n-ac t iv ate d  prot ein k in a se - activated protein k in ase 2(MAPK AP K2 or MK2)  mediatesm u l tiple p3 8 MA P K- d ependent cellu lar r esponses.M K2 is an  impo rtant in tracellul a r  regulat orofthe  pr o d uc tion of cytok i n es,su ch as t umo r necro sis  fa cto r a lp ha (TNFa) , interl eu ki n6(IL -6) a n d interf er onga mma  (IFN g ), tha t are  inv ol ve d  in  many a c ut e andch ro nicinf la mmato ry d i sea ses, e. g. rheuma toi d  art hr it is andinflammatorybo wel diseas e.  MK 2 resi d e s in the  nucleus of non-stimula t ed cell s a nd up on s timulatio n,it tra nsl o catesto the  cyto pl asm a nd ph o s ph ory la tes and ac t i vat es tu be rinand HSP 27. MK2 is also im p lic ated in heart  fa ilur e ,  b rai n  i s che mi c  in j u ry, the regulat ion of str es s  r esistancea ndth e produ ction o f TNF - α (seeDeak et a l., EMBO.  1 7:44 2 6 -44 41 (1998);  Shi etal., Biol .  Chem .  3 83:15 19- 1536 ( 20 02) ; Sta klatva l a,Curr.  Opin.  P harmac ol. 4 :3 72-377 ( 2004); and Shiroto et a l., J.  Mol.  Ce ll Cardio l.3 8:9 3-97 (200 5)). 
There isa n eed  foreff e ctive  inh i bi tor s  of p rote i n kinases in  or d e rto treat or p r eve nt di sea s e stat es a ssociated with ab n ormal cell pro life r a tio n.M oreo ve r, it is desir abl ef o r kinase  i nhibitors t o posses sb oth
52-3065 (1998);_Schumacher et_al., J. Cell Biol._143:1635-1646 (1998);_Kimura_et al.,_J._Biol. Chem., 272:13766-13771_(1997)).
c-Met is a_proto-oncogene that encodes for_a tyrosine kinase_receptor_for hepatocyte growth factor/scatter factor (HGF/SF). The c-Met protein is expressed mostly in epithelial_cells,_and due_to_its_function it is also known_as hepatocyte growth factor receptor,_or HGFR._When HGF/SF activates c-Met, the latter in turn_may_activate a number_of kinase pathways, including the pathway from Ras to_Raf to Mek to the mitogen-activated_protein kinase ERK1_to_the_transcription factor ETS1. Met_signaling has been implicated in the_etiology and malignant progression of human_cancers (see Birchmeier et al., Nature Reviews_Molecular Cell Biology, 4:915-925 (2003); Zhang_et al., Journal of Cellular_Biochemistry, 88:408-417_(2003); and Paumelle et al.,_Oncogene, 21:2309-2319 (2002)).
Mitogen-activated_protein kinase-activated_protein kinase 2_(MAPKAP K2 or MK2) mediates multiple_p38 MAPK-dependent cellular_responses. MK2 is an important intracellular_regulator_of the production_of_cytokines,_such as_tumor necrosis factor_alpha_(TNFa), interleukin_6_(IL-6) and interferon gamma (IFNg), that_are_involved in many acute and chronic inflammatory_diseases, e.g. rheumatoid arthritis_and_inflammatory bowel disease. MK2_resides in the nucleus of_non-stimulated cells and upon stimulation, it_translocates to_the cytoplasm_and phosphorylates and activates tuberin and HSP27. MK2 is also implicated_in heart failure, brain ischemic injury,_the regulation of stress_resistance and_the_production of TNF-α_(see_Deak et_al., EMBO. 17:4426-4441 (1998); Shi et al.,_Biol. Chem._383:1519-1536 (2002); Staklatvala, Curr. Opin. Pharmacol._4:372-377 (2004); and Shiroto_et_al., J. Mol. Cell Cardiol. 38:93-97_(2005)).
There is a need for effective_inhibitors of protein kinases in_order_to_treat or prevent disease states_associated with abnormal cell proliferation. Moreover,_it is desirable_for kinase inhibitors to possess both