Heterocyclic amides as ROCK inhibitors

专利摘要:
The present invention relates to new kinase inhibitors, more specifically ROCK inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. In particular, the present invention relates to new ROCK inhibitors,, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. In addition, the invention relates to methods of treatment and use of said compounds in the manufacture of a medicament for the application to a number of therapeutic indications including sexual dysfunction, inflammatory diseases, ophthalmic diseases and Respiratory diseases.
公开号:AU2013205638A1
申请号:U2013205638
申请日:2013-05-02
公开日:2013-05-23
发明作者:Petra Blom；Sandro Boland；Olivier Defert；Nadzeya Kaval；Dirk Leysen
申请人:Amakem NV；
IPC主号:C07D213-75

专利说明:
HETEROCYCLIC AMIDES AS ROCK INHIBITORS The present application is a divisional application of Australian Application No. 2011222900, which is incorporated in its entirety herein by reference. Field of the invention The present invention relates to new kinase inhibitors, more specifically ROCK inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. In particular, the present invention relates to new ROCK inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. Background of the invention The serine/threonine protein kinase ROCK consists in humans of two isoforms ROCK I and ROCK 11. ROCK I is encoded on chromosome 18 whereas ROCK ||, also called Rho-kinase, is located on chromosome 12. They both have a molecular weight close to 160kDa. They share an overall homology of 65% while being 95% homologous in their kinase domains. Despite their sequence similarity, they differ by their tissue distributions. The highest levels of expression for ROCK I are observed in heart, lung and skeletal tissues whereas ROCK 11 is mostly expressed in brain. Recent data indicate that these two isoforms are partially function redundant, ROCK I being more involved in immunological events, ROCK || in smooth muscle function. The term ROCK refers to ROCK I (aka ROK-1 9 , p160ROCK, or Rho-kinase p) and ROCK 11 (aka ROCK-a or Rho-kinase a). ROCK activity has been shown to be enhanced by GTPase RhoA that is a member of the Rho (Ras homologous) GTP-binding proteins. The active GTP-bound state of RhoA interacts with Rho binding domain (RBD) of ROCK that is located in an autoinhibitory carboxyl-terminal loop. Upon binding, the interactions between the ROCK negative regulatory domain and the kinase domain are disrupted. The process enables the kinase to acquire an open conformation in which it is fully active. The open conformation is also induced by the binding of lipid activators such as arachidonic acid to the PH domain in the kinase carboxyl-terminal domain. Another activation mechanism has been described during apoptosis and involves the cleavage of carboxyl terminus by caspase-3 and -2 (or granzyme B) for ROCK I and II, respectively. ROCK plays an important role in various cellular functions such as smooth muscle contraction, actin cytoskeleton organization, platelet activation, downregulation of myosin phosphatase cell adhesion, -migration, -proliferation and survival, thrombin-induced responses of aortic smooth muscle cells, hypertrophy of cardiomyocytes, bronchial smooth muscle contraction, smooth muscle contraction and cytoskeletal reorganization of non- muscle cells, activation of volume- regulated anion channels, neurite retraction, wound healing, cell transformation and gene expression. ROCK also acts in several signaling pathways that are involved in auto-immunity and inflammation. ROCK has been shown to play a part in the activation of NF-KB, a critical molecule that leads to the - 1 production of TNF and other inflammatory cytokines. ROCK inhibit are reponed to act against TNFealpha and IL4 production in iipcpolysacchande tLS-ystimuiated THPI macraciaes. Therefore. ROCK nihibors provide a useM therapy to treat autoimmune and inflammatory diseases as well as oxidative stress, ionclusic. ROCK is a mago ctrol point i smooth muscle eil function and a key signaing component involved iiramatory processes i various inflammatory cells as wel as fibrosis and remodelign many diseased organsm"hereare clear indications that ROCK is involved in the patfogenesis of many diseases, inuding asthma COPQ and glaucoma re aditHon ROCK has been irp1icated in various diseases and disorders including nye dsases; ainway diseases: Cardtiovascuiar and vascular diseases; inflammatory diseases; neurological ad CNS disorders; poliferative diseases kidney diseases; sexual dysfuncon; blood diseases; bone diseases; diabetes; benign prostatic hyperplasia transplant rejection, liver disease systemic lupus erythmatosis, spasm, hypertension. chronic obsiructive bladder disease, remature birth. infection, aergy, obesity, pancreatic disease and AIDS ROCK appears to be a safe target as exempified by knockout rnodels and a erge number of academic studies. These KO mice data, in combination with poshmarketing surveince studies with Fasudi a moderate potent ROOCK inhibitor used for the treatment of vasospasm after suberachnOid hemorrhage indicate ta ROCK is a ,gemuine and signiicant drug target ROCK inhibitors would be useful as therapeutic agents for the treatment of disorders implicated in the pathway, Acdghere is a great need to develop ROCK inhibitors that are useful in treating varous diseases or conditions associated with ROCK activationn partiulay given the inadequate treatments currently available for the majority of Tese disorders. Soe non-imiting examples are gaucoma. asthma and OPD. Glaucoma, a group of diseases that may cause vision ss and blindness due to damage of the optic nerve, is caused by increased intra-cular pressures a common cause cf adult blndness mostly a chronic disease that reqwres ifelorg control afterdagnosis. There is a need for Improved treatment as the curent therapy does only control and not cure the diseaseand further suffers from irlitation. Hoa and systemic side eflecs Iaddition additional positive effects as the antiinflammatory and nerve regenerating components of ROCK inhibitors, would be hghy prefered. Reference ROOK inhibitors such as Y-27632 cause changes ir celshape and decreasesress fibers focaadhesions and MLC phosphorylation in cultured human TM ce they relay human trabecular meshwork in vitro, relax human Schtemnts canal endothlial celsn vitro and when topiany applied to animals give a significant increase in trabecular outilow resultirg into astronolowering of iraocular pressure.
AlSc sthrna a chomnie iflammatdry airway disorder Thatresuts fromaladaptie Imtone esponses to ubigutous erirormni tproteins in geneaticaly susceptlbie persons Despite reasonably su fi therapies, the prevalence increases as these therapies do not cure;there ere stidl exacerbatons and an increasing number of non-responders, New. effect and steroid spaang treatments that tace al components of the disease are required, Chronic Obstrcive Pulmonary Disease (COPD) represents a group of diseases characterized by irreversible imitation of airflow, associated with abnormal inflammatory response. bronchoconstriction and remodeling and destruction of the tissue of the lung. it is one of the leading causes of death worlkide, wth a steadily increasing prevaende There is an rgent need for novel therapeutic approaches as the current regimen zs inadequate. Until now only bronchodilators are used, since glucocorticoids have limited or no effect Reference ROCK inhibitors, such as 027632 relax human isolated bronchial preparations inlbitincreases inairway resistance i sneesthetised animals, potentate reldxhg effects of agonists eitr and An v' and give rapd bronchodilatation upon inhalation. In addition ROCK inhibitors block trachel Smooh nusci cclrac~on indcedby Wt1, the dionioi mrker for Oxidative stress. Related toairway inflammation ROCK inhibitors counteract the irease in trans-endotheiat permeability mediated by nflammatory agents. maintain the endothelial barrier integrtyinhibit th inAux of eosinophis after ovalbumin challenge ji vvo, protect against lung edema formation and suppress aiway viRto metacholn and serotonin in aiiergic mice and block LPS-induced TNF release With respect to airway fibrosis and remodeling. ROKinhibitors bock the induced migration of airway smooth muscle ces fi vtro evidences for the role of ROCK in airway renadeling wer obtained in huran lung carcinoma cell line, bovine tracheal smooth musdl e(ells and hman airway smooth muscle. vivo propf for a role of ROCK in frosis in general was generated with mice which exhibited attenuated myocardia nbrosis in responseto the partial deletion of ROCK The attenuation of myocardial fibrosis by Y-27632 in response to myocardial infarction and by fasudi in the case of congestive heart faiure in a ironic hyperensive rat model brings additiornalindications of R K trtne* in remodeling. iallyROCK inibitors increase apopiotic celloss of smooth muscle cells. The human sexual response in both maics and females results from an interplay of physlogicat psychologicaliand hrmional factors. One common aspect of he sexnt response in males and males, however, is the vasoactive response, which results in ergoroement of the sexual tissues of the genita with blood as a result of vascular smooth muscle relaxation in response to sexual simulation. Thus, blood pressure and blood flow inside the penis and aitons increase when smooth muscles of the lpudental vasCulature relax. This arterial influx of blood causes enlargement of the penile or cditoral corporal cavernosa and results in erection, -3- Impomtnceerectle dystucton irn menk is qeneraly defined as an inabriity to acheve and sustain p an erection suffiieet for satisfacicry sexual perdormnarne and intercourse. Impotence can be due to psychological disturbances. neurological abanormnaities. or other physiological disturbances noluding hrmonali deficiencies or; a combination of causes. n the Urnted Statesale impotence is estimated to affect 40% of men at age 40, increasing with age to about 50% by 50 years: and is as higas s 67% by the age of 70. It is stated that up to 30 miion males may suffer from impotence in the U. S, Females can also have sexual dysfucinhat ncrepses with age and is asoccitedwih the onset of menopause and increased risk of vascuardisorder Thus similar to enr sexual arousal in womn is accompanied, at least in part, by increased blood flow which engorges the citoisBlood flow to the vagina also increases vaginal licatin Thu. femae sexual dysfuncan can result from an nability to attain or maintain cltoral eingorgement and/or vaginal ubriation throughout the period of sexual activity. Currently, mccvasodilators used to treat ectile dysfunction target signal transducton pathways that reduce calcium ion, which is needed to initiate contracne activity in vascuar smoont muse. However, from a physiological standpoint the initiation of vasoconstriction is a veny aute event lasting only seconds to a few minutes. The erecile tissue is maintained in the flaccid state by long term vasoconstriction through a signal transduction pathway that is calcium-independent. A signal pathway that maintains caUiumnidependent vasoconstriction is the RhoA/Rho-kinase pathway. ROCK inhibitors are according useful to treat erectile dysfunct Thus, in one aspect. the present invention comprises a method for treating male or female Asesual dysfunction which comprises topical administration to an indAdua In need thereof of a composition comprising a compound which attenuatesfhoknase actiy t ar organ subject to sexualstimulation and a pharmaceutrcaly acceptable carter Several different classes of ROCK inhibitors are known. The cunrnt focus is oncology and cardiovascular applications Unti now the outstanding therapeutic potential of ROCK inhibitors has ordybeen explored to aliited extent The reason i the fact that ROCK is such a potent and videspread biochemial regulator that systernic iniition of ROCK leads to strong hsiogtai effects that are considered as being side effects for the treatment of most of the diseases. Indeed the medical use of ROCK inhibitors to treat diseases with astrongintiarmatory component is hampered by the pivotal role of ROCK in the reguiation of the tonic phase of smooth muse cell conraction Systemically available ROCK inhibitors induce a marked decrease in blood pressure. Therefore, ROCK inhibitors with different properties arehhly requied. -4- For the tagoet spendi treyhtdient of thsorders by ratdaicn smooth ste ftnztion erdfor Thfhmmatorv processes anor remdetng tiS h desird to delver a ROC inhnitor to the am~k, 1,0 ,rgs toenter otter k~ras, TI-eefm target organ and to avoid significant amounts of these du tenrohrognsTherefore, local or topicat appucation is desired. Typicadvy toicle admirnistration of drug. has been applied for the treatrwent of anvay. evesexua dvsfuncuon aed skun digu.deTr5 Tn addtionB weaal ijection ilatinw into diseased tissues further extend the potential medical use of localy appwd ROCK inhibtors. Given certain criteria wre fulflled, these lca applications allow nigh dog concentration to be reached in the target tissue nadten the incoraon of ROCK inhiitors nto :nplantS and stents can further expnd teamedical application towards the locatreatment of (O"diseas such as athemoscerosis, crorary dieases and heart failre Desose the fact that direct local application is preferred in medical practice Thee are concers regarding drug levels reached ltO the systemic cilation For ample the treatment of airway diea i by ocal dIetveryj by toWnetangeS nhton, pose the rwak of systemic exposure doe to .arge amoums enternng the 01 tract adiors tuh te lungs. For the treatment of eve dSea ss by tloced defverv.also significant amounts ernter the G31 tract andlcr systemic cicuation due to the low ermeabiity of the cornea, low capacity for fluid . Afficienl drainage and presence of blood vessels in the eyeids Also for derma appicains. local injections ard implantabe medical devices, there is a severe ask of leakag into the sYsmic rcUMation T'hereicre> in addition to locad apication, the compounds should preferrablv have additional properties to avoid signicant systemic exposure. Slfo drus are bologicay active compounds tha are activated once Iey enter the systemic circulationn This inactivation can be achieved in thekver, but the preferred inactation should occur yhe on to these compoundsa once apptve iy tth "ag ose /rgen exert their desired effect locally, When they teak ou of ts tissueino the systemic circulation They are very rapidly activatedd . Thus softdrugs of choice are sufficiently stable in the target tissue / organ to exert the desired N gii effet but are rapidly degraded in the sod to iologialle inactive cmpound .n adding it is highly preferable that the so drge of oice have retention at their biological target This property wilt limit the number of daily application and is hiohy desired to reduce the total ad of drug and metbolites arnd in addition will significantly increase the patient compliance In concision, there is a conttnulng need to design and develop soft ROCK inhibitors for the treatment of a wide range of disease states. The compounds described herein and pharmaceutically acceptable compositions thereof are useful for treating or lesseningthe severity of a vaety of disorders or condtons associated with ROCKactivation. More specifically the compounds of the invention are preferaby usedin the prevention and/or treatment of at east one disease or disorder in which ROCK I involved, such as diseases linked to smooth muscle el function, inrlammation, fibrosis. excessive cell proliferation excessive angiOgenesis, vyperreacvty, barrer dysMu-ton. noewdogd on and remodeing. For eamp a the compounds of the inventon may e used in the prevenion ard/or tatment of dsses and dedr such as. Eye diNses or disrders }ncJuding but not inted to retinopatyotinuroahy; glaucoma and degeneaiv:~e rtIint diseases sucb as niaoutar degeneration retiris pgmotosa and Mfnattratar feye diseases Airway disease inxuin in not imited to pucary fibrosis,~ emphsem, chor roca.s astio, ftmsis, pnumonia cytsic fibrosis, chronic obstrucove pulmonary disease (CQPtt:bronchitis and rhinitis and respiratory distress syndome Throat. Nosetand Ear diseases ending but nottitedto sinuS problems hean pirdlS toothache. tonsiaaits ulcer abd r ninits Sin diseases: including ut not nioted to lyper erto's par0keratos is hypergrinuiosis acanmosis.dyakeratosis spongaosis and ulceration ntestinxaf C.ases oi l bt not imied to -nmmo y b w iA CUi doises (0 . he0m", gastroenteritis. rMus ileitis. appendkcits and Crotirfa disease. Cardiovascular and vascular diseases: inddingq but not limited ta, ulmonary hypertension and pulnnarv Uasoconstriction,, nfiarmatory diseases: including but not limited to contact dermatitis. atopic dermatitis, pisoriasis. rheunmatc&d arthritis.t ee eheumatid arthritis. aeniytosing pondytitisporst arhitis. innmmatory bowlei dOse Crons disease and uterative colitis Neurological disorders: ncluding butnet nited to neuropatic pain. The present mounds are therefore suitale for preventing neumdgeneration and stimuting neurogeneration in various neurlofgica disorders. molftratiye dseases such as hu not imtedto cancer ofbreas colon testine skin head and neck .e, uterus. kidney lung.. ovary. panes. prostate r thyroid gand; Castieman disease eukeia sarcoma;lymnphoma rnahgoa; and melanoma. Kidney diseases: irsiudinig but not limfied to renal fibrosis or renal dvsttunction $- exual dysfuinction: is meant to incdude both male and female sexual dysfunction caused by a efectve vzasoacive response. The soft NOK inhibitors of the present invention my also be used to reat sexual dsfu~nction arisin finm a variety of causes. For esampdes in an eRbodiment the soft ROOK inhibitors may be used to treatsexual dysfunction associated vith bypogonadisnm and mr p arr .n whsc reduced levs of androgen hormones. in another embodiment, the soft ROCK in Oitr ma# t' >Cused ~'V te :tree ' ee'uas dyfuction4 asejae wnh -a vede *Qt'lo .Cau-ses c(~W;Ng but not dimid to, biedd disease, hypertension. diabetes, or p-eic surgery; In addition. the self R.OCK ihibitors may be used to treat sexual dysfunction associated with treatment using certain drugs. such as drugs ried to treat hypertension, depression or anxiet. B one diseases: inrduding but not liited to osteoporosis and osteoarthritis -0 tM adh tn, the campoands of tte invention may be used in the pyaton andr treatment ct disease and disordem sucha to bongn tostatic hyperpiasKa. transplant reto p chronic obstructive bladder disease, and a$Kergy. $UMMARY OF THE NVENTlQN We have Surprsinlt found that the compound dscribd hrein act as inhibitors of ROCK in patiular as soft ROCK inhibitors Compared to adr known Rock inhibitors sum as for enaple deC~iida O 00071423; the compounds of the present inventon diffe in that thoy are very *'apidy converted into functionaity inactive normpoundis such as for examopt Dy Pareoxonese (PON1) acti; PONt is a Ca21- dependent erun cdass A-esterase, which is snthesked in theliver and secreted M the blood where it associates exclusively with Nigh-density tipoproteirs (RDbs)Furfrermore, it is abie to oA eeve e' uniqu subset of sustrate including orgtanophosphates. anteaters. lastones and cyin ctrbonates Thevefor the Y subs tituent Of the comtpounlds of the peasert inverton generaiy represeNted by formula f hereinbelow, ate selected to comprise a bstituent selected from the group of arytesters.tactones and cycica more * from arytesters and lactones. Unlass a cortex dictates otheise asterisks are used herein to ndkate the point at wthch a mono or bivalent radeln depicted is nrneted to the atructure to which itrelates and of which the radical forms part Vewed fom a frst aspect, the inVenken i a compound of Fortmnuls I or a sterecisomer tautomnr arnic metaboime. roa r predrtg at, hydrate, cr solvate thereof.. oy Wherein Ar is selected from the group compising: N''N,-*
K.,.
Wherein X is selected from the goup nmcomng hydrogen or hako Y is an ary oheteraryl substituted with a substituent selected from the group consistng of ( 0R ;-{C8O)~SR> -CVQ}-NR 3 R NRR -0yalky !,SaakyiO-C>*kenyh wherein se d OCaiky; -S-Calkv 0 jCOlkenyitkr ay* r alker; are eah indceendentiy substituted with a substituent selected frondhe group consisting of C(z0-)0;R'C3 SR 2 ; .Ct NP Het; -Ht and MA SHet R is selected from the group consisting of hydrogen; Opaenyl substtuted wih C-leY or -5 Het: or &g 0 akyl optionatty substituted with 1 2 or 3 sustituents eah independently sic dee front the rdoup cconsting of aryi heteoaryl. C;icyolaiukenyl C(OOR, -C0=)~SR& C(=0)NR7R IHet 3-Ue1 S-Het& -cs-e aiky and ay where said -0-%alkyl R C !y or Ca.eydolkeny; are each independent substituted with a substituent selected from the group consistng of G OP'R ; QhQ> SR C 0) NR.'tRet' 0 Hot 3nd -Set"; Rt select from the group conssqng of C 2 eenyl substituted with -d o-S-tS+et or C 2 kyl opionlly substuted wiK , 2 or 3 substituents each independently selected from the group oonsi t ing of ary heteroaryl, Ccyckaikenyl C{=OOR' -CO)SRt - 0)NR. Het.-0-l -S-iet, -0-jC 1 aiky and -O-Cakyt wherein said cc-O~.akyl; -S-CHaky: or Crcyioamenyi ea eac irtdependently substituted with e subttuent selected fom the group consisting of 0 O)-0R" C O) S; (O RR" HC -0-Me ;and -S-he or; R and R together with the nitrogen atom to which they are attached ftrm a hderocycie substituted with one substituent selected from the group consisting of - O)OR -C(Q)C SNt -C(=O)NRV 0 Rd et> -0-Met $-Met 3 ; %saikyl ; C-adekyl-O-CfXailyl; or C< akyt--C4 eikenym wherein each of said 1 a&lky 0ekyl--(atkyl; or C alkyi--C 2 alkeny is each independently substtuted with 2, or 3 substituents each independently selected front lte group consisting of eryl heteroaryl 0C 4 cycloalkenyi Cz0gR -C(=0}- CO5Rt -CdO) or are independently seected fom the group consisting of hydrogen: ,gekyt; C 1 dkyi-0 C iky; C aikylS- ayV Casalk-nyt Cakyl-C( or Cuali-engl-Cd)-; wherein at toast one of Rt orWf is selected fhrn C 3 akyl; CealkyV0-Chalky-; C.edkyFS C (myl-; Ct 3 atkenyl; Cualky-C(=- or C 2 aikenymlC oy and wherein each of said CaifraV u a v Qayq CkSC kyl-;:alkeny;taikylC0)- or C alkeniC( 0 i substituted with 1. 2, 3 substituents each independently selected from the group corstq of al meteroaryl. Ccyclkeny OO)-01R C=0-SRt Het; -O-et; and-S-ri 4 P or W are independently selected fromite group consisting of hydogent; or C -kyt substituted 2,or 3 substituents each indepeently aeieDted from the group consisting of aryl heteroarylCcycloakeny-CO)OR and CON> N-; 81 R or R are independently selected from the goup oO ting of hydroger: or C aiky! substituted with 1, 2 or 3 substituentseach independently selected from the group consisting of ary, heteroarytL O 5 ccIoalkenyl C(=)O& and NC&=0) 4 Ht or N r soendpendently slectedc from the group consis"WiN " of hydrogen; Calkyi; C kyl
C,
4 lky4aX am~iylKC alkyhfr-G 3 elkyV or Calkyl&&0Y and wheren each of saide 0< mbaly Cualkyk ~OCakyl-:;CmalkyhS-C 1 .aikyV; or Calk C( O)p is substituted wth1,2, or 3 substituerits each independently selected from thge group consisting of .C zOpOu' -C(50Y SR> Hat -&Hef and -4Hat R l selected from the goup cOrsting of Ckaiky: Cakerny; c alkynyl; optionaly substituted C: ycloaikyl; optionally substituted aryl; optionally substituted heterocyclyl; and optionally substituted heteroaryi; whereat said C eakyl s optonally substituted with 1 2, :3 or more sutsstituerds each independently selected fron the gjrcs': consisting of halo, cyano, hydroxy, stlaryaS-. aryvVS(kt ylbC(=O) ~ChQ)'NR C Ocyioaky, ~-4 OhCkyC*,alkyi0a, Clkys ary. heteroaryl. heterocyc or fom the formula: N N or R" tektogether with the oxycerbonyl and aryl or heteroary'to which it is attached forms a cyclic ter comprising from 4 to 9 carbon atoms inthe cycic ester ring; R is C ,alkyl op1inally substituted with I 2, 3 or more substiuents each independeniy selected fromthe group consing of halo, hydroxy amino.cyano and mono or diICaikylamis; HfO flet or Het are independently selected from the group corising 0 N0 -z7 / S 95 Viewed from a further aspect the invention provides these of a compound of the invnntion. or a composition comprising such a compound for inhibiting the actvity of a least one Riase.in vitro or in ovo. Viewed to a further aspect, the invention provides the use of a compound of the avention, or a composition composing such a rn inhibitng the t of at one ROOK kinase for example ROCKit and/or ROOK1soforrns. Viewed from a furter aspect the inventpvi desi a pharmaceutical and/or veterinary compositon compncisig a compound of the invention. Viewed tom a still further aspetthe invention provides a compound of the invention for use in human or veterinary medicne Viewed from a still further apect, the invention provides the 'se of a compound of the invenlior in the preparation f a mnedicament for te prevention and/or treatment of at east one disease and/or disorder selected rorn the group omprising oye diseases: airway diseasea; cardovascuiar and vascular diseases infla mmatory diseases; neurologic and CNS disorders proliferative diseases; idney diseases; sexual dysfunction; blood diseases: bone diseases; diabetes; benign prostatic hyperplasia transplant rejection, liver disease systeic lupus erythmatosis spasnt hypertension chronic obstructive bladder disease, premature birth, infection, allergy. *besity pancreatc disease and AIDS. DETAILED DESCRIPTION OF TE INVENTION The present invention wil now be further descrbed, In the folimwing passages difer aspects of the invention are defined in more detai. Each aspect so defined ma be combined with any other aspect or aspects unless clearly indicated tothe contrary n particular any featureidicated as eP Preferred em advantageous racy be combined vth any other feature or featresindicated s being preferred or advantageous.
Unless a context dictates otherwise, asterisks are used herein to indicate the point which a mono or bivalentradicat depicted is connected to the structure towhch it relates ad of whih the radical forms part Undefined (racemicr asymmetric centers that may be present in the compounds of the present invenion re intemcangeably indicated by drawing a wavy bonds or a straight bond in order to isuatze the undefined stii character of the bond. As already mentioned hereinbefore, in a rst aspect the present invention provides compounds of Formula I H .1' Ar- ~ k & wherein Y R and Ar are as defined hereinbefore inning the stero-sormerin forms solvates and pharmaceutically acceptable addition salts thereof When describing the compounds of the invention the terms used are to be construed in accordance with the foiowing definwions, unless a context dictates otherwise: The term "alkyf by itself or as part of another substituent refers to a fully saturated hydrocarbon of Formula C/He wherein x is a number greater than or equal to 1. Generally, aikyt groups of this invention comprise froir to 20 carbon atoms. Akyl groups may be linear oroanched and may be substitued as indicated herein, When a :subscript is used herein following a cabon atom, the subscript refers to the umber of carbon atoms that the named goup may contain Thus for example, C>aikyl means an alkyt f one to four carbornatoms Exampes of aky groups are rmethyl, ethyl tpropyl ppropyl butyl. and Its isomers (e g n-uty -butyl and zbutyi pentvl and its isomers, hexyl and its isomers. heptyl and is isomers, octyi and its isomers. nonyl and its isomers: decyl and Its isomers. Cets alkyl includes all linear, branched, or cyclic aikyl groups~ with between I and P carbon atoms, and thus includes methylethyln-propy. i-propyl, butyi and its isomers (e g n-butyi, lbutyl and buty}:penty and its isorners, hexyl and itsiomers, cyclopenty 2-'3-, or4methylcyclopentyl, cydopentynathylene and cyclohexyl The term "optionaly substituted lyr refers to an aikyl group optionay substituted with one or mr>ore substtuentsfor example I to 4 substituents, for example 1, 2. 3, or 4 substituents or " to 2 substituents) at any avaabl point of attachment Non-limiting examples of such substituents include halo hydroxy, carbonyi nitro amino, oime imin, azidohyrazino cyano ary, -11 heteroaryl, cyloaky, ayi, alkytamino. akoxy thioL aikylthio. carboxylic add acyiamino alkyl ester.caramate thicamido urea sulfonanido art the like; The tem "akeny', as used herein unless otherwise indicated, aeans straight-chain, cycr, or bran chmnd hydrocarbon aicais containing at least one carbon-carbon double bond. Exampes of aikeny radicals indude ethenyl, E- and Z-propenyl isopropenylE-and Zbutenyi, E and Z-isobutenyl. E- and Z-pentenyl, E- and! Zhexeni E-E 2 Z E thexadenyand the ike An optionally .substtuted aikenyl refers to an alkenyl having optionally one or more substituents (for example 1, 2, 3 or 4), selected from those defined above for substituted alky,, The tern alkynyF, as used herein, unless otherwise indicated means straight-chain or branched chain hydrocarbon radicals containing ateast one carbon-carbon triple bond Exampres ot alkynyl radals include ethyny iEand propyny, isopopyny &E and 2butyny, $ and Zisobutyny.& and Z-pertynylt E, Zhexvnyi and the like. An optionally substituted aikyny refers to an alkyny having optionally Ons or mreubstituents (for example 1, 2, 3 or selected frnom those defined above for substituted alkyl. The term cycloaiky by ief or as part of another substituent is a cyci alkyi group, that is to say. a monovelent, saturated, or unsaturated hydroparbyl group having 1 2. or 3 cycki structure, Cycloalky includes al saturated or partially saturated countingg I ot 2 double bonds) hydrocarbon grops containing 1 to 3 rings, including monocycic. bicyclic. or polycyclic aikyl groups. Cycloiky groups may comprise 3 or more carbon atoms in the rng and generally, according to this invention comprise from 3 to 15 atoms. heitether rings of multingcydlalkyls may be either fused bridged and/or joined through one or rge spiro atoms. Cycloalkyl groups may alsc be considered to be a subset o homocyclic rings discussed hereinafter, Examples of cycloalky groups indude but are not limited to cydlopropy, cyclobuty1, cydopenlyt cyciohexyt cycloheptyl. cydoocty. cydonony, adamantanyl, bicydo(22i )heptanyl and cyciodecy with cyclopropyi, cydopentyl cycihey, adamntantyi and iydo(2 2 1heptanyl beiri particularly preferred An 4optonay substituted cycloalky" refers to a cycoikyl having optionaly one or more substituents (for example I to asubstituents. for example '1,2 3 or 4 substituentsselected from those defined above for substituted alkyl When the suffixene* is used in cc njunction with a cycl group, hereinafter aiso referred to as "Cycloakylenet this is intended to mean the cyclic group as defined herein having two single bonds as points of attachment to other groups. Qyciodkvene groups of Ihis inventon preferably ccinrse the same tuberol carbon aoms as teir cydoakyi radical counterparts. Where ally groups as defined are divalent, i.e., with two single bonds for attachment to two other groups, they are termed alkylene" groups. Nardmitng examples of alylene groups includes methlyiene ethylene, methylmethy en tnmethylene propylene tetramethylene, ethyethylene 2-dimnethylehylene, pentamethylene and hexamethylene. Similarly, where aeny groups as defined above and alkynyl groups as defined above rspectivey, are ddent radicals having single bonds for attachment totwo other groups, they are termed alkenylene and aikyriene respecively.
General a Ikylene groups of this inentin preferablycomprIe the sme nfumrber of carbon atoms as their aIkyl cunterts, Where an a yene or cyciaalyine biadical is present, connectivty to the moecular structure ofwhch A forms part may be through a common carbon atom or dferent carbon atom. preferably a common carbon atom. To ilMustrate ts applying the asterisk nomenclature of tNsneon a Gaikylone group may be For example CHztHH *H ChO) or 4 COH(~O-H. Likewise a CQ cyloaikylene group rnay be ya n group is present this is preferably a Crncycloakylene group, nmore preferably a cyciakylene (ie, cyctopropyiene groups) whterem itscnnectinty to the structure of which it forms part is through a common carbon atom. Cycloalkylene and alkylene biradicas in compounds of theinvention may he, but preferably are not, usttuted. The termsheterocycyor "heterocyclo as used herein by tself or as part of another group refer to non-aromatic fully saturated or painlly unsaturated cycic groups (or example t 13 member monocyclic, 7 to 17 member bicyci or 10 to 20 member tricyclic ring systems, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom containing ring. Eachd ring of the heterocyci group containing a heteroatom may have 1, 2 3Or 4 heteroatoms seected from nitrogen atoms xygen tons and/or sulfr atoms where the nitrogen and sulfur heteroatoms may optionaly be oxidized and the nitrogen heteroatoms may optionally he quaterized The heterocyclic group may be attached at any heteroatom or carbon atomo tnhe ring or ring system, where valence allows, The rings of multiring heterocycles may be fused bridged and/or joined through one or more spsro atoms An optinalyobstituted heterocycnc efers to a heterocycic having opionay one or more buenme I to4 substituents, or for exampoe ,2 3 or 4) selected fror those defined for substituted aryl. Exemplary heterocyclic groups incude piperidiny, iantidinyl midaoihyl, imidaolidiny isoxazolinrl oxazolidinyl, isoxazolidinyi thiazolidinylisothiazotidiny, pipemidyl.succginirnidyl. 23H indolisoindolly chromeny isochromanl.antheny 2Hpyrroly, -pyrrolinyl. 2-pyrrolinyl 3 pyrroiinyl pyrrotidinyl, 4H-guinolizinyl. 4-carbazoly, 2-oxopiperazinyl, iperanny 2-pyazoliny. 3-pyrazolinyL pyranyl dihydro-2H-pyrany 4Hpyrani 3-dihydo 2K-pyranyl, phthalaziny, oxetanyl. thietanyi :3dioxoianyI, aioxany 2dioximiazolidinyl 2,2A-piperdon~y, 2oxopiperidin 2-xopyrrolodiny 2-oxoazepiny indoint retra hydIropyrany.
tetrahydrofuranl tetrehydmothienyl tetrahydroquin 'iinyi tetrahydlroisoqu inolinyl thiomorphotinyi. thiomnorpholimyl suifoxide, thiomorpholinyl suifone, I ,dioxolanyl, 1 ,oxathianyl.' d.~ritiianyl, 1 ,,5trioxanvly ll H Z52-thiadiazinyi. 2H~1 5,2dithiazinyi 2H-oxocinyt1HI Kpyrotziny$, tetrahydro 1~ dioxothienyN fornmylpiparazinyl and morpholinyl The term "anty as used tereirn refers to a polyunsaturated aromatic hydrocarhyligroup havig a ngiering (i.e. phny or multiple arormai rngs fused together (e.g. naphthalene or anthracene) or linked covalentlytypically containing 6 to 10 ators; whereinat least onehoi isaromatic The -13-~ aroman ring may opinally iude one to three additionallgs (either cycloalyl. heterocydyor heteroary) fused thereto. Aryl aso intended to include the partially hydrogenated derivatives of the carbocydcic systems erwrmerated herein, Non-initing examples of aryl comprise phenyl biphenyL biphenylenyl, 5-or 6tetraiyQ 1 2 3 4 5n6 6-- or -aulenyl. 1or 2-naphtyl. 1-, 2-, orindenyl 1 2, r 9-anthry 1- 2-, 3e y 44 or 5-aoenaptyJinyl, 3-: 4-.o-ca enyl1 2- 3 4-or phenanthryl1 or 2-pentatengyl 1, 2-, 3-, or 4-fluoreny 4- or5indanyL 5 7 or 8 tetrahydronaphthyi, 1 2,3A-etrahydronaphthy, 1 4-dihydronaphl, ycdbernzotaadjcylcoheptenyl and 1-, 2-, 3-, 4-, or -pyrenyi. The aryli ng can options y be substtutedby one or more subetncots: An optionally substituted ary efers to an aryl having optionally one or more substituents (for example 1 to S substitutes, for example 1, 2, 3 or 4) at any avaiable point of attachment. Nonmitig examples of such substHuents are selected fom halogen hydroxyl oxo nitro, amino, hydrazine, amincarony, azido nyano, akyl cycalky alkenyl alkynyl cycdoakylalkyl alkylamino> aikoxy, -S0N ary, heteroaryl, aralky, haloatky, hoaloxy. alkoxycarony alkylimicarbony, heteroarylbky alkylsulfonamide hrderocydlyl. alkylcarbonylaminoalkyl.ary oxy alkylcarbonylacyt arylcarbonyl, aminocarbonyl akylifoxide> -yF alkylthio, carboxyl, and the like, wherein R> is ayi or cycalktyl Where a carbon atorn in an aryi group is replaced with a heterostom Ite resultant ring is referred to herein as a heteroaryl rmh, The term 'heteroary as used herein by tcf otr as part of another gro p refers but i nt limited to 5 to2 caron-atamaromatic rings or ring systems containing ito 3 rings which are fused together or liked covalently, typically containng 5 to atomst least one of which is aromatic In which one or more carbon atomsin one or more of these rings can be replaced by oxygen, nitrogen or sulfur atoms where the nitrogen adrtdlfur hetematoris may optionally be oxidized and the nitrogen heteroatoms may option be guatemized. Such rings may be fused to an aryl, cycoakyl heterosryl or heteocydyl rig Non-limiting examples of such heteroary indude: pyrroly, furanyl, thiophenyl, pyrazoyl, inmidazoly, oxazoyi isoxazoly, thiazoyl isothrazolyl triazoly, xadivodl thiadiazoly, tetrazoily. oxariazoly thatriazolyl pyriny, pyrmid ayl. lyspridaziry, oxaziny, dioxinyl! hiaziny, triaziny imidazo[2 i[ thiazoyt thieno1 Ab 2bzfuranyl thieno3: 2 [4thiohenyl. thieo2 ,3-di ,3thiazofyl. thienn[2,3dymidazolyl. tetrazolof S,-ajpyridinyl, indo yl indodiinyl, isoindoyl bezofuranyl benzopyrany, 1(41-benzopyranyi t(2H)14enzopyrmnyi 3,4 dihydro-t(2H )benzopyranyi, 3,4dihydmo-1(2kH)-Oenzopyranyl, isonenzofraryl benzothiophenyl, isohenzothiophenyl indazolyl. benam~ridezolyl, 1 3-benroxazoyl, 1 ,benzisoxazoy, 2,1 benisoxazolyt, 1 .3-benzothiazolyl I 2benzoisoth lazolyt 2, bernzoisothiazolyl, henzotnlazoyl I 2,3-ben&oxadiazodyl 2, 'i 3benzexadiazodyl I ,,~benzothiadiazoly, 2,1 ,3ben3othiadiaznly thienopiyridinyl, purinyl. imidazo[1.2ajpyridinyi, S-oxo-pyridazin-i(5H1i)-2oxopyridir-1(2l-9-vl 6~ oxo-pynudazin-l(iHi}yl, 2-oxopyridin-I(2-)-yl, l3-behzodioxolyl. guinoliny, isoqunolinyl cinnolinvi quiazodnyl, quinoxa linyl. 7-zadot5-azaindolyi, S-azairdoyl 4-azaindolyL im14 The term py Vf s called awolvy) as used hern c des prrWlyP pyrrn-ny and pyrrob23 yi. te term * vy (ablo called f'Awyl) as used heon indudes fa3n-Oy2m and a yniVi (aie) alled fu2-y0 and ranKyl} The term ilophenyr also cale "tieny as used herein includes thipe4My and thiphen-yl (also called thien~ 2I and' hihen< The term "pyrazltyr (also d~aled t H-pyrasoly ariI .Xdmaolyij as used herein includes pytrcl Iy pyrazco3-y. pyrazo-4yi and pynroamss. lW tenn "<mdazdty' as used herein Muds ,mazomyi imidatol 2~y imidazo44l and imidazo-5yl The term 0xazdg< (ans nailed 1:xazoiyi)as used herein includes oxazoly oxazol~44yi and oxazol5yL The term isexazolyV (also called,2oazolgI as used herein inMldes isoxazoly, isoxazohyl and isoxazli5~yl The term anhiazoly (as slded I A yAs ud herenincludes thiz kth azo4-y and thiazo5L i (ho elied 2 thiizol. 44-thazoyl and S4tdazoyl). he ter >iothiazl' (cado r-eind l24hiaVolyil as used hereirn includes isothiazoh3+yli oihiacol~y and nthiszai5vyt The term "triazowyr as used herein includes 1 Hdriazciyl and dR-I 2A4triazivlt. l-+--tazolyr inckludes 1H 1 .2;34iazaly wI 1H~ 1 cl3 n-o4yi, I -M2a1 4 1 244triaoi!v and 1H 1 2F ,riasoi~my. "41- 2A-taah$y Ochdes 41-- 2.4tdazc-vl end 48-I 2Atrasniy. The term )xdiatr-5d as used herein includes' iS'oxadiazOt-tyI 2S3.ediasnl$viy 1;2A-nxadiazol -3 yl. 1 >2.4-oad aon-5-yl, ,;2 5$xadiazo-3y and I 3T44*oadtazok2yL. The tenn "thiadiazohtyr as used herein inhludes I 2$thiadiazol4yt 1,2 3thiaiazl-~yt i2Adhadiazoi$-yiI 24 thiadtazo5l-'% I 62$ adiazo3-yi {also catted furaaan-3y) ard 24-hiadiazo-2-y The term tetrszoNy as used herein includes 8Mtettazkivi, 1HItetrazo-i 2H-tetrazad2-yL and 28 letratzo 5yt, The erre <oxazrazol as used herein includes 1 2A4-atriazo&5-y ard 12.
oxatraaol-4-yL The term "thiatriazolyr as used herein includes 1j2>~thiatriazoi~5iy and 1235 taridazo4-yl The term "pyrdinyl (also called pyndyl as used herein includes pyridin-2-yl oyridin-ylnd pyridin-4-yl (also called 2-pyridyg, pyridy and 4,pyidyl) The term t yvmidy as used herein includes pyrid-2-vy, pyrimid-4-l ypyridR i and pyridey. The term "pyrazinyY> as used herein includes pysrair2-y and pyrazin-3y The term *pyrddnyl as used herein includes pyridazindyi and pyridazin-4-yi The term "oxainy (also catled "s4ouainyflaa sed herein incMdesI4-oxazin-4-y and 14-oxazin--y- The termi di (inyf'Also called din as used herein includes i 4don nyl and i4Wdioxin-yi, The term iarrnyN(also caled i thiazinyij as used herein includes I 4-thfatinet %4lain-Zyl '1 Mihiatin-~y. 4Ihia 4 in ys and I4-thiazi-6vyt "The ten-n "tiazny- as used herein includes 3~I 4 azitn2<4 12+lriatrn y-: 1Z4%azin&yl, 1. 4~trdazinA3yl.I 23-riazin4I and 1 2 34trai 5 ytThe term "imidazo[2;1I o]p[13ithiatolyr as used herein includes idazol2.1-I4 phiarm iidazy2. 1 jthiaz-3 y!, oridam[2 1 .jtiarot$y and cmIdazo.2I][t tii20tyk The tern "thienl3;2 bikbranyf as used herein incudes thieno[3.2Ituray29yl. 1hieno(3JAb&lern-~vlt. no32 4uran~4>yi. and thieno(,2 bifran&yt The termed "thieno[32-tthiophenyleas used herein iclades thier(32-4jien2 thienh2tiien-yi tyen 43 b)hien -y and then(3 2ithieny The tenm "hiensZ'dhi ] as used herein includes ahienc(23-d(1:3jtbazo2-yl. thieno(23dIl 3jthiaxoi-5y anld thenn(2 3d]{1 3]thiazoli--yy The ten-n "thienf2 >3 dgmidazolyl as used herein includes thieno(2>djimidazol2-yl lhieno(2. 3-d~imidaznl-4-yi and thienot2 3 15 .d ieda yl.c ihe en ierazlotTalpya ingasesed herindclds a A- I -e'" a y. rri 5-i ttaz nfpapyndy tamo[5-pydiey and terao5eprdn~tThe term Indk;yri as usedA herein includes indogg ' 'ndor27- "'ndo4y indL4y ndodyi~ idck4 n as used hermki Mo moe nr snavrde e b1 ;4422{ vnoi-3-yT. inoi . yine vzi~t~x.idnTiny7-y anid ieizin~y hev ~ termn 0 iscindcdyi" as used herein includes sisbtv t iso nd Z.iscrndol3-y isondtARv ~ jac y.ndol4 indk~ Y!a niry The temI rezcfurnyf (so anned benr' kbolly a7usd herein incddes benzofrirnK yl, aec-Pfwanv-"yi benizouran-ty. oa benofuran-hL be. nzuran--d and benzofur Ti -l Ne term isoberzfumny (also calle-d bernzo ranyl) as used herein ndudes isobersirranal lau benzofdran39yl iobenzofuran4-yl. mroberizofuran-Syl, isobe nsofuran4-v and cibenzoruran yl The ternm enzohiphenixalso called benzc~ijrhernyb as used herein ndes 2ezotlhrphenyt bbenzobiophery. 4-heesn hb enyl 5henzo bnthinpnenyl Olenzobtipey and 0bnogiiphn1 as eid ez1mrfltbnztieo4 genz-tie'w4' b'nzobheni5-yi. bezhien ,-v and benzothten4 The terem "isnber thiophenyPx (alse called benzo hieny as used herer indds ezotien4yi isbzthain-Svy. isoberzzthien-4y. isobenzcdhien~5-i isoenze~hen4y anid is bezth len-> y. The term 'indazly(aiso caled 1Hlindazoiy or 2zaindoly) as used herein includes 1'H indlazOl' -y 1i-t-indazabK3'vyi,1H-ndaroh4y-4 H Iindazo-by{ iH-indazob&-y 1. I 2 nae-Tyl. 2H in-a-yL 2idazoi.y 2Hidazo-4-v21Andaebl -- 2N iazobd4 anid 21' ndatorc i,4 The ten-m "henanildazolyl" as used hc'reini incudes benzimridazok-iyi. benzrrnidazci-2jy. berrrndzo-4-yvl renzimaidazin-tl banzrmsdazot-heyl and benzintidazt7*yi The term "i 43 benzznxsendyr as used herein incudes 1.3-lenzo:-azol-2-y, 1 ,$be~-n-m;ar*4yl A3berizoxaizir 1. 'ln2abazoxzl-l yiand I 3-henzoxazo---4 Th'e trnt I ,2heriisoxazoiyf as used herein nekudee i ,2benzise-xard2-l gI 2-ben rioxazo-4 -y,12bertesxazt-5yl 1 2-enisoxzol6-y arnd 1 -benziscxazo-y. The term 2bemisexazoy" as used herein includes 2, benzisoxazek3~y 21 1benzisoxazok4~yt 21-berioxaznnS-yt 2-benzisoxazo-Cy and 21 benvse>:anzo t' The term "14-enlhiazohy' as used herein Injudes 34-enzothfaznl2-j 1 7epthmizmb4-yA im n121thiaz - yi r a ushendzht er-y ! and M enzthiaz onoy The ten-rn "1 2-bernzoiothiasyr as used hereiri includesI 2 - 1-belsoh v.iy 2-enzisothiezei4~ y, i 2-benzisathiaznd-I 2-benziscthiazol-tly and -2'beni-oitazoiby4 The term t2e1r benzisnitiazotyi as used herein inniudes 21bernsoitazoi'y4 2;-benzsotiazA-4-y, 2. benaz icl-Sryigt 2Ai-enztsohiazi-y-v and 2Atnzisothazod-1y. the term bens4$irianoiy' as used herein includes berizotrazot~-yI ' ben zntdazoi4y# behn iazod4- tenzoiniazo-&Svi arnd benzoidazo-y The erm a1 2nenzoxadiazeyi as used hereioniudes 1 ,2:23enzoxadiazOl4 y 1 2benzoxadiazoily, i -benzoxadiazni4 arnd li2beazoxadazo y- The term *2;1.tiernzcoxadiazsr 55 sed herein includes 2,13Z-benzoxadiazo-4-'y 2' 1:3-benizoxadia-zot-5 y1 2,1 3-benzoxadiazci--yland 2,13benzoxadiazeV-vyi The ten-n '<1 23benztidadiazoiyt as used herein includes 1.24benzothradiazo-4yl.I 23-enznthiadiazo-$i i 21beizothiad'iazol b*-yi and 1 2c3bazothvadiazol-yvt The term 3,benzrthiediay(lyF as used herein idudes 23 Z-benzothiadieroi-4-yl.2 gi-ge a iazed-5-yl 2 131enzcthiedia>'c-lAy4 and 24 3benzothiadaoi-7y. The term 'thienopvridinyi' as used herein ndludes thienot2,3pvrpydinvf, hi~ero(2 . pydiny thieno[32-cjpyndinyi andtienof3tbipydriiyThe term puriny as used herein incudds purin-7y-yi and purir-3-yt Te term lmidazot,2aapyridiny as used hereinA cudes imidazo[1,-ajpyridr-241, iridazofI2-aipyridin3yKimidazo .2-ahyridin~ 4t inidazrdi m2"y rty;dazo[1 aipyrkdn-6-yi and imidazo[l ,2-.a pyidie-.yl. The term I 3-benizodioxoly-f, as used herein inckies i,3-benzodioxo-4-yl I 23benzodioxo-5yy; 13 benzodioxo3-yl, and 1.3-benzodioxo7-yl The term 0 uinoiinyV as used herein includes quinon 2-y quinoir-3vi, qumini-4-vyl quinon-5yl quinoin-6-y. quinolin-7~y and quinovin4-y The term isoquinAlinyir as used herein includes isogunoti-yi, isoquinoln3yi, isogufnoir-4-yi isoonuin -S-.yl, soquin- r6-A isoquinclin-7yl and isoquinonney.vi The termaelnnoinyl' as used herein includes cinnofin-3yl. dinnolinr4y I.innolin-5-ylinnolirr-5yl c irnolin-7ytand cirnnolinaSy. The term quinazOinyF as used herein includes quinaalin~2-yi quirizoin-4-yl, quinazoin5 quinazolin-5yi, qu inazolin7yl and quinazolin-S-yl The term "nuinoxaliny as used herein includes quinrnalin2<l quinoxalin-5-yt and quinoxalin-6-yl The termt Cazaindcdyr as used herein refersto IHy'rrolo[23-bipyrdinyl and indudes 7Azaindoal-v,%aadoK2-y Tazaindd 3 '7-azaindol4y, 7-azaindnty-5l 7-azaindn-8-A. yThe term :5azaindoydas used herein refers to I Pyrroo[2 ,3-pyridinyi and inAdes 5-azaindoVyE, 6azaindol2-9, 6-azaindof-3-i, 6 azaindo4-y, 6-azaindol5-y. 6-aaaindol-yl The term "5-azaindoly as used herein refers to 1H yro3-. pyridinyi and includes 6-azaindol- yE, 5-.azaindoi-2-A 5~azaindo-3-yy. 5-azainde 4t yl. 5-azaindnis6yl 5-azaindol-yi the term "4-azaindoyl as used herein refers to IRPyrroo(3 2 b}pyridinyl and incudes 4azaindomly 4-a-aindo2yt 4-azaindo3-yk 4azaindoSy. 4 azAind&-5.yl 4-azaindoi4M. For example nonniting examples of heteroaryi can be 2- or aryl 2- or 32inl .- or 3 pyrroly, 2-., 4- or 1imdazoy,1- 3- 4- or 5pyrazolyl3-4- or 54soxazoly.2-4- or Soxazol 3> 4- or 5-isothiayK 24- or Sdthiazoyl.1.2trazo -, -4-r -Sy-A 1-241--. -3 4 or-5 yl I Hetrazoli or0-, 2H-4etrazo2or -5-yt I23oxadizoi-or-5- 1,2,4-oxadiazo-3- or 5-yE, ,2,5oxadiazoyl. 3 A-oxadiazoylI 2,3-thi-adiazoi4- r -5-yE, 124thiadiazol-3- or -5--y, 15-thiadiazo3 or 4-y, I44hiadiazoiyl I or 52etrazoMy 2- 3. or 4-pyridyl, 3- or 4 pyridaziny 2 4-, - or -pyrmidyL 2- 3- 4 5- -2Rthiopyranyl 2 3- or 4-4H-thiopyrany. 4 azaindo-I-, 23-, 5- Or zandi or 2 3, 4 -orylazaindo1 2-, 4- 5or y 7-azarndol- 2-. 3-4 S- or Oy 2- 3- 4- 5. - or - zfury 1- 3-, 4- or 5-isobenzofury 2-n 3-- 5, A6- or 7-benzohenyl-, 3n 4- or 5-isobenzolienyl 1-, 2-,34 5, 4 or 7-ndolyl. 2 or 3-pyraziny i,4n azir- or -3y4 MYdi">! or 3-yl 1,4-thiazir- or --3y-i 2,3-triaziny, 244aziny1 5-trazin- - ry thienof3-turan-2 4 -4-, or -5-y. benzirnidfzol-Ivl, -2y -4,1 -5K -&Er -- yE, 1n 3n 45, 6- or 3-e>opyrazalyL 3 4-, 5-, 5- or benzioaoyt 2-45- 6- or 7 ben3oxazoly -, 4 5- - or 7-benisohiazoE 3-enzothiaza 2 y -4- 5y -5-y or -y V3 .-enzOdioo- --- 5y % or yj, benzotrazoi- y-SyE. yEor -yi 2-thiarthreny, 3 4- or 5sobenzofurany 1 2 3- 4- or 9-xanthenyl 12- 3- or 4phenoxahinyl, 2 3-pyrazinti 2 3 4 . 6., 7- or - 3indoliziny 2 4-or Sisoindoiyt H T17 mdazolkhy 34 4l 5~yt -- ' or -7-yL 2H-indaol2-iy 3-9 -4-y -5 -6y or -T-y iminazo[2I-b]i 31thiazady 1-4.iidazo(2.1-bff1 ']hiazol-3y4 nvdazo:2, 14 11{ 3thiazo-5-yi or imidaao(2l-bf1 .3ilniazol64. Imidazo(i 2-aftpyridin-yL wmidazoj1.2a~pyridin-3yi mrniazoii.2 ajpyddin4-yl. imidiazot12-alpyddn-v5y imroi L-alpv-ridir-6-l or :Pmidachg 2 spyridin7-v tetrazoloe( 5-a jpyridine-5y. |tetrazoloio ,5alpyridine-6yl, tetrazoko1,5pyrk ne-7yl, or itrazol-f 5-ajpyndine& ay 2, 6-. ru7- or 4, or phalay 2-, 3- or 4 iaphthydiny 2-, 5- or2unoxay2 4- 5- 6- 7, or nazoiy i 2> 3- or 4-uinoiny 2- 3-4 5>S- 7-o, i y or 2n 4-r 8Ruinazo. - 3. 4- - 67- or isoquinoltnyoouinolylt -, 4- 5- 7- or 6noolnyi2- 4- 6- or 7-pteridinyt l-, 2-, 3-, 4- or 9 carbazlyl, 1-, 2-. 3 4 5- 6-. 7- S- or arbony 1- 2- 3- 4- 5-, 7-, 8-, 9- or 10 phenanthridinyt - 2-, 3- or acridi i 2- 4- - or 9-perX&midnytl 2 3- 4- 5S 7- 8n o 9 10 7h}enanthrDnyi, k o 2pnaInyl 1> X 3 4, of 3- or 4 furazany, 1-, 2 3 4, or Q-phenoxazny, or additioiay subsituted derivatives thereof An "optionally substituted heteroaryl refers to a heteroaryl having optibnay one or more substituents (fbr example I to 4 substituets, for example 1, 2, 3 or 4). selected forn those defined aove for substied rL he term x as used herein refers to te grou =0 The term "aikoxy" or alkyloxy* as used herein raters to a radical havin th Formula -OR herein Rt is alkyi Preferably, akoxy is CMW aox, cy% koxy or O aowy Non-limniting examples of suitable aikxy include methoxy. ethoxy, prooxyisopony buoy, isobutoxy: sac butoxy, tArt-xutoxy, pen yloxy and hexyoxy. Where he oxygen atom irr an: oxy group s substituted t ivsulfur. the resultantradcalis referred to as thioskioxy ax as an alkoxy group wherein oie or m-re hydrogen atoms inAhe kyi group are substituted with halogen No limiting examples of suitable hafolkoxy include fluoromethoxy difluoromethoxy trfluoromnthoxy 22Aflr oroethoxy, 1,1 ,2,2tetrafloroethoxy, 2-fluoroethoxy, 2-chloroethoxy; 22ifluoroathoxy, 2,2 "tr ebloroethax;: tichioromnethoxy, 2-bromoethoxy, pentafluoroethyl, 3,,3-trichnloropnoxy 4,44-tnichiarobutoxy. The term "aryloxy' as usedherein denotes a group -0-arywhereinryx is as defined above The term "arylcarbonylor "aroyl"as ued herein derwetss a group -Q-ryl wherein aryl is as defined above The terun ydakyilky[ by itself or as part of another substerd refers to a group having one A the aforementioned cydoakyl groups attached <i one of the aforementioned n kyt i chains Examples of such cycloalkyalkyl radicals include cycloprpyknathy cy-oobuylnethyi 2 yolopentylmethyl, cylohexymethyl, cyclopentylethy,1 cvciohaxyiethyl, 2-cycloetylethy 2 cyclohexyithyL cydobutylpropy cycopentylpropyt 3ycopeNylbutyl. cydlhe vuty and the like. The term "heterocyd 5akyI by itsef or as part of another substituents refers to a group i having one of the aforem-nioned heterocydyl group attached to one of the aforemenond alky groups in,_ to a group - wherein i s alkyienie or alkylene substituted by alkyl group and R s a heterocyclyl group. The term carboxy' 'arboxyP or Tydroxycatonyr by tsef ors part of another substtent roes t te gru 2 H. Thus, "arbn""ydky an alkyl group as defined above having atleast one substituentthat is-CO The term "alkoxycarbonyiI by itself or as part of another substtuent refers to a carhoxy group Inked to an alkylradicalic to form -C(O)OR.wherein Kis as defined above for skyl, The term "alkylcarbonyixy"by itseOfr Oa part Of another substituent refers to a GOCOd) where isf i s defined above for akyt The term "akyaarbonylamino" by itself or as part of another substituent refers to an group of Formula 4lH(CO=DR or -NR{=0jR, wherein P and R are each 6nependenhy alkilor substituted alkyl, The term thiocarbonyP by itself or as pat of another substiturt refers to the group -O(= The term alkoxy by itself or as part ot another substituent refers to a group consisting of an oxygen atom attached to ore optionaly substtuted straight or branched akyl group, cyctoalky group, aralky. or cycloalkylalkyl group. Nonkimizing examples of suitable akoxy group nuuoe methoxy. etoxy, npropoxy, isopropoxy, n-butoxy, isotutoxy secbutxy teribtoxy. hoxanov and the ike. Theterm "halo" or"halogen' as a group or part of a group i's generic for fluoro, chkoro' bromo, or ondo. The term "haicaiky" alone or in combination refers to an atk radical having the meaning as defined above wherein one or more hydrogen are replacedwith a halogen asdeined above Non linting examples of such ha MOalkv Mdcals inrude hiormethyt. brornethyl, flunronethy, luomometny. tniluoromnethyliArlluormethyl and theike. The term "habarylP alone or in combination, refers to an aryradical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above The term "haloakoxy" alone or in combination refers to a rp of Formula 4J'aikyl wherein the alkyl group is substituted by 1, 2, or 3 halogen atoms. For example haiokaxy" includes -OC' OCHFZOcHF -CF 2 CF. -CHrCF, -O-CyCHF and -0"CI'ts"OaFn Whenever the term "substituted"is used in the present invention it is meant to indicate that one or more hydrogens on the atomindicated in the expression using 'ubHAtuted" replaced with a selection rm the indicated grop, provided that he inicted ato'rrs normal valency is not exceeded, and that the substitution results in a chemidally stable compound, i.e. a compound that is sufficiently robust to suive isolation to a usefu degree of purity from a reaction mixture, and formulation into a therapeuc agent. Where groups rmy be optionally substituted such groups may be substituted with one or more. and preferably once, twice or thrice, Substituens may be selected from, for example the group comprisnq halogen hydoxy oxo niro, armdo.narboxy, amino. yano aoaikoxy.and halay -19- As used herein the terms such afs"kyl ai orycalkyl each being opionally substituted ith" or "alfyl aryl, or cycloalkfyi, optionaly substituted with" refers to optionally substituted alkyi, optionaly substituted aryl and optionally substituted cycioalky. As described hereir, some of the compounds of the invention may contain one or more asyrnetric Carbon atoms fthat serve as a chiral center, which may lead to different optical forms e g. erantiomers or diastereoisomers), The invention comprises il such optical forms in all possieconfiuration as well As mixtures thereof. More general from the above, it l be clear to the skied person that the compounds of the .nvention may exist in the form of different isomers and/or tautomer including but notlihted to earnetrical isomer-s conformational isomers, W-somers, stereochemical isomers e enantiomers and diastereoisomersi and isomers that correspond to the presence of the same substituents on different posttcins of the ringspresentnthe compounds of the invention. Alsuch possible isomers tautomers and mixtures thereof are inclued within the scope ofte inventon Whenever used in the present invention the term "compounds of the invention" or a simiar term is meant to include the compounds of general Formula I and any subgroup thereof This term also refers to therompounds as depicted in Tables 1 tod 1, their derivatives.oxides, saksoWates, ydrates, stereolsomericforms, racenic mixtures tautomeric forms, optal isornersanalogues pro-drugs, esters, and metaboltes as welas their quaternized nitrogen analogues, The N-oxide forms of said compounids are meant to comprise comounds where one or severalrnitogen atoms are oxidized to The so-calledtoxsde. As used in the specification and the appended claims, the singular forms a"an and "the" include plural referents unless the contexts ciedy dotates otherwise By way of example, "a compound" means one compound or more than one compound, The terms described above and others used in the specification are wel understoodto those in the art. In a further embodimentthe present invention provides compounds of formula I wherein: R is hydrogen, or0 Gatyl; rnartiouar methyl Ar is s defined hereinbefore and YN an aril or heteroaryl substituted with a substituent selected from the group consisting of OhFON; OSF -0k-NRR -N;R -Cualkyakyl; or %dakeny; wherein said *t-O 1 galyl, aCdakyi. or -Q.aikenyl are each independently substituted with a substituent selected from the group consisting of C&0FOR -G(OO)SR -ObNRWR Het. -- 4-et, and HS-Het - 2(- Ris dcoted from toe goup nSig of hydrogen; Cadkyoptordy substituted with 1, 2 or 3 substiuents each independently selected fr the group consiting of -G(=0FOR< -C(dV S~; -~COjMR'R, Het'; ~O-Ret; &HetQaikFSt and C 1 aagyO-n particular R s flydrogen; Ft is selected fom Me group consiing of C 1 y 4 :aivkyi substituted with 1, 2 or 3 substituents each independently sielted fromthe group consisting rfC~mO)}&R; -Cf=O>SRt 44=)jR R2 Het' 0 -ft;~S~Aet% C-ai-Si and C0aaikyk.: prticul Rs selected from the group constinlg of Cakyl suBstituted wih 1, 2 or i substuents each independenty islected frm the giouconsting of -CtO)-R 2 9w=03SF -HC(=0)R RMt 1 : 0-Met>and -S-He, ,or R and RW together with the nitrogen ator to which thy are attached form a heterocydle substituted with one substituent selected from the group consisting of C( yOltR C(>OV
SR~
2 -C(0>M)-NRh et':t{t -- He tiet or Quaky wherein saidC 1 aiy issubistituted wit 1 K2or 3 substtuents each irdependenty selected from the group consisting of -C(=0h ORNO OMO 0 fRet; -e: and $Het> in particularW and R together with the nitrogen aorn to which they are attached form a heterocycle substtuted with one substituent selected from the group consisting of -C( ORe -(=kSRt C(=O)&R': Het; or C-,.ealkyl wherein said Cakyi is substituted wth , 2, ori subsituernts each independently selected from the group conskstung of ~C(:O OR& '4(=0)-NRkT:Het' odie nd 4Het; more in particular R' and R together with the nitrogen atom to which they are attached form a heterocycle substituted with one substuent selected from the group consisting of ~C YORR - R-et -Oettand -S-Net; R or R are independently selected from the group consisting of hydrogen; Calky; CBoal0yh C*ualkA CualkyN-S-C,.alkyl; 2 .gakeny, Cayl-giCRO)- or (CailkenyI-t&Q) wherein at feast one of Ror R 4 is selected from Calkyj; Cgarkyi0Y9aky: CakyS C.alkykor Q. ,a kyVC(:O)>and wherein each of said C.aikyl Cualkyi-c-C.dalkyk: Cgaiky-Caiky or C aikyi-C(=0) is substituted with 1 2 or 3 substituents each independently selected from the group insisting of C p OR: 'O(OMRet>. -O--et ard -+Het;n particular V or R eindependenly seected from the group consng of hyirogen;Calyi GuatkykS&>uaky or CgattyL-C~0)-:wherein at least one of R or R~ is selected from Coalk~yl C- esaky1-S-C, alky; or Calkyl-C(=0) and wherein each of said CalkyC sakyS-O.elyor CrsikyP C(=O- is substitted with 2 or 3 substituents each independently selected from the group conss:ng of C(= OR" -Het -;-e and -bt more in paitcular R" or R are odopendently selected from the group consisting of hydrogen; C,,aikyl; or CsalkyiC(y; where at least one of R or R is selected from 0mayt; or C aiykCt0b and wherein each of said C.aik; or CjalkylCO is substituted wtn 1, 2or 3 substituents each ideendenly setectd from the group consisting of 4(:0 R. -Met: He~t: antd -S---let> even more in parcular R' or R are itdependently selected from the group consitng of hydrogen: or Q. dalkyl wherein at least one of R or R is C 4 anyt substltted with t.2.cr 3 sbstituents each independently selected from the group consisting of -Het; -0- ;and -%Het: . 21 " R or R are independenly selected from the group consisting of hydrogen; or Godkyl subst tuted with I, 2, o 3 substituents each ndependently seected from the group Qorsing o aryl heteroaryl, C 3 cycloaikenyl &({C}nCR2 and A2(0)V-N; in particular R~ or Rare independently selected from the group consisting of hydrogen ;or C ksubsitutedwth 1 2 or 3 substitents eacih ndependentiy selected from the group ccnsssting of *C( :Oy.O< nd C(O>N more in particular Ru or R are independently selected from the group consisting of hydrogen or Ceakyl substituted with CtO)~OR R or R are independently selected from the group consisting of hydrogen; or Caikyl substitute with ,2, or 3 4ZO)~>-R 2 1 substituents; R t or afare independent selected from the group consisung of hydrogen; Cblky C 1 ayl
C
1 amfC4C alkyt; .CdaikyFC aIkyl; or CgayWC(> and wherein each of said Cl. balkyi; C 1 aikyhO-Ceakyk Caikyl-S-Chalkyk or CoalkyhC( Ok is substituted with 1,2, or 3 substituents each independenly selected from the group onsisting of )Rti; (ECw SR Het; -0-He 4 : and -e in particular Re and R' represent hydrogen R s selected from .the group consisting of C!'4kyl; C 2 kenyl optiondly substituted Ca 5 cyclraalkyi;optionally substituted heterocyly;and option ly substtuted aryl; wherein said C >ky is optionally substiuled with 1 2; 3 or more substtuents selected from the group consing of ha, cyano hydroxy. aryl-4, aryi-S-, aryl-S(=0) aryl C( 0X -C(=0) NRP O -Cah0Y4Zalkvi, C Mlkyi43O C4akyi-S- aryl heteroaryl. heterocycyl and CG ydnoalkyl or from the formula: N ofor R, iC k ph 2o 3 or rr ho HetH Hen togeer art thependenl and fon whichgioup atmarege - 22 C 0 Antagos f interesting comlpounIds, 4uncoxrd~rg to the present invention atrefthose compwunds of frda0whereir ore or more of the fonn etrtinsapy Ar represents pyriiytopinn substktuted wvith rllo;in paricar Ar represents pyndinyi substituted withfur; na vn ute ebdmn Ar repoiesents X0 weenX is hydrogen or hANo i particulr X yrgnofur;mr in part au ar X ii luoro: RIrepresents hymgen or C alkywi partcular Cualkymr in paitiur mfethyl; - is alani fheem! ottae 'h Sub'etitent safocle fivom the group conasing,, of -C(=Q)NR'R": ~ NRWR x2ulkto - Calkyf; weinSaid -0-C amyt or -O10 iky- aire eachinendtysusttd vha sRAWen seece f", rm the rou eens istin99 f --- C 0oe ns FOt: W Mn a particlar embrmdunet said He or Hef nrdependently bei- ng selected frmr the group dmrsn 23('/ Yr m tttuted i a usiturntselentdrfsrn the group Curnm 5CIg of -C(OmCR< -C(=CSR'C -Og~ONR't R O Cg 4 amvor Cay Weren saidO-CJXah or Csalky ;re ecSh ondntly substituted with a subtuent selected from the group consistingof-C(:OfO~,and Hat; w0h C a paticular embodiment sai; he ben selected from -O amy or ary; mor in particlAar sad rP being selected rond akyi or phenytamd said HC being selected from the group comoris ing Rh s hydrogen: R is - alyi substituted with a substiuent seated from "O4teorSs Bis t>Csaikyl substtuted with a substituent selected from-O~(=NO ~ C:O}Rt or Het; with in a picaar embodiment said R b' being a .aliy! substituted with a substituent selected from -C{O VO or etvith in a more particular embodiment said RY being a -O. a kyl: R! or R are independently selected from the group consisting of hydrogen; Calyl; or C. ealky-AssaWk#; wherein atleast one of R5 or R is selected from the group consisting of Cnakyi; or O 1 nsaihyi-$-C 16 aikyyk arid whereirn each of said c(alkyK or Q RyvS-C Het ;oInd S-Bet; within a particular embodiment said: b eing selected from -Caskyl or any1; more in particular said R' being a ~ fjdkyl; and said et or Met independently beiig selcted fon lhe group conmprising R!"s swaeyed Yfom -C ako ary or Optinally sub tiuted htrmlmr priua sa:-id R, being seet from ak 4diyr-2H enpray aiyro N 4 - 24 / 1 (2Hybenzopyranyi, or phienyw, wherein said 34dihydro-(2HV ozopyranyi 4hvdnp 1(2Hhe zpnay'i s subsatituted with oxo: Ari represents pheny4 OHeterary represents -dihydr& 1(2 Hbenzopyranyi, 314dihydro- I (2H1tenzopyrany or indolvy in particular indo is an ary or heteroaryl substituted with a substituent selected from the group corsisting of-t(=ObOR; >C&=j-SRt C(=OhNRR 4 ; 0-Cakyar~ Cgakyl; wherein said O-Cadky or -C.
5 alkyi are each independent substituted wth a substtuentselectd from the group consisting of -C(=TORi and Hot': with in a pariular embodiment said; Rt being selected from -CO,,akyI or ary; more in particuir said R 2 being sciected fron -C,.alkyl or phenyl said 8cHt being selected from the group comprising and wherein said -C(=O)OR -C(O)SR: cOyNR>R O-C alkyl; or 6Skyl are at the meta or para position vis-a-vis the binding of the aryl or heteroary to Me remadeinr of the molecule such as represented in in formula s - XXHla, and fib XlIb beow. ina paticular embodiment the present invenon provides ampoundks o formuis . where Ythe7 substituert its definitions. e as a sstituet or as part of a substtuentcomprises at least one group selected trom C{FO ; -(=OhSR iHet; 4IOe and -Selt in a nmore particular eibodiment, the presentinvention provides the compounds of formula I, wherein the further substituens to the Y substituent are at the meta or para position visa-vts the binding of said aryl or heteroaryto the remainder of the moecle andior as represerd in formule ia4i - I nd b XXb below. In an even further embodiment, the presentInvention providescompounds ofornui as defined in any one of the different embodjments described herein, with the proviso that when represents an aryv or heteroarylsubstiuted wh a substituent selectedrnm the 4tzQyo ;or -t(=FsR> and wherein said R" owrarepresents an unsbtituted Caikyl; saidR"-CoFOR: or-C(=O R2 is at the meta or paraposition vis-d-vis the binding of said ary or heteroaryl to the remanded of the moecole and as represented in frmacea li, Ii and 1Ib teow 25- In a further mbodiment the present iwention pries compounds of formula whereione or rore of the foiowing resriion aply; Y is Soxc23ihydrobemofurany or Y is a phenyi- indY or tnogheny, said pheny Indolyl and thiophenyl being substituted with a substituent aeected from the group consisting oft-CO)OR CO=0F$R NCM0>NRW NR R( %=asi!A - Osaky: crax; 1 akenyl whnerein said 0-CGaikyi or ~Osakenyi is substituted with a substituend selected from the grtouip cor ssng of GFe0ThORnt C fSRt C(' O NR R ;et C- H et nd S-Het RFor Wareindeendenivslected from the group consistng of hydrogen C 0 alyl:or .C. kyNS2Cuasyl ;, wherein at least ore of Ror Rtis seated Anm the roup consistig f £ akyt or CualkyVS-CsalkyI-; and wherin each of sai;d C>adyl: 'r C dkytS-t 6aykt; is substituted with a substituent selected from the group consisting of CNO00R 2 H-et and -' et R a sie:ted from the group onsisng of C0 alyi; optinaly substitute C dcydoaky optioniy substitutedd nryA arnd optionally sub';ituted hicterocyclyl; wherein sa d (>< 1 alis optionaly substitute with a substuert selected from the group consisting of hal cyano, hydroxy -(>O}NRt O&C( Galy Calky-, C, alkyi-S ary heteroaryi, subsdwued ary and. optionatly vsbsituted heterocyclyl|weri said Cj2adikyl is: spbtitucd IT a substitent samected from thee grouIp cosstn f h (" yano, hydroxy, heterocycl. and ecycdakyl or from the form ** mn naiuar pat isscu o' from ethed ro tmp consisigo stir:Af opakii ym~ adotoal substituted C yiakl toal .d ~ ~ ~~ay I ustituted yith a substituent selected fom the groupcossigfba.cyohdoy hostigofll han Cmyal y. r kror fnthe formula 2* heyocyci as used herein is el t eifromi te gnup conist of piper4djyt pyrraidiry, etrahydraiouinounh indzdinyt, tetrahyd2ropyreiyl, tehydro.furanyI and hexahydrofuro (3 21 furan; Un particular piperidiny, 1 ,>dioxan' indciingi tewranydropyranyw and tehydrafuranyl ptionmky substituted C7 cycseaikyI as used he ris s elected from the group consisn Af cycloropyW 'Nydab 5 dyi CyVCiopenlt~ CycKeh exv Cyclohpgcyc Cvooy. cylnoy d ntnyt bic (2 2 epty and ydy wih dyC'opremyt cycMopentyI cyclohexyi rdamntaryt and bicycio(22.I h enyi being par :casadyi preferred; wherein sad Q cybMkis optionaijl sbsti ed w3h 23. or more in patcdar 4, 2 or 3 more' fn pariular1 0$r 2 even mor'e in piataumasr 4 sCbstACuen t odEcted frrn hdoget hydrrov 'xo, $'trO, aminor cya CV fl0 y ,CS cycladka CyCUt, a-i*0xy or 4$0: Nk optional 4subst.ituted4 etrmyt as used heredn i selected fromS the group con ssti of perdtny' rrodiny, morpholinyi. thiomorphdlnyt oiperazinyl, 34dioxanyt 3 dioxian tMtahydrouhiirrw ttraydroscqsnotny indoini, etrahydropyreny tetraeydrourny and hey shycrofuro[34iiurtan in tictular piperidinyl t (3dixany! ndeiny, fet$rayd(Opyran y and tetrzahydofranyt wherein sid heterocydyi is Pnona$y substituted Wi t 1, or more; sr partcuar ubsituent selected fom the group consitung cf halogen. hydroxyl. cxc, ritro. arno. hydrazine amiunocarbonylI azido, oyano, alkylcyclcaikyt, aikenyl, alkynyl, cycloalkyadky. aikytamino, aikoxy. *'S~rNNr nryl htmary)i n rharkyti hakf ddkoxy. askoxyvcarbony. a~yaingc'arbonyl. t'teroaryla kyl -lky sufflonamnide. heterocy y Avicarboarinoalky aryioxy, a)k liaon acy6 aricarbcnyi. amnocarbori ''ksulfoudce, IS$Rt aikyhoe carboxyi and tW ,e 'ekwherein R: is aky or cyacwlkyi'preferaby s *ec-ed nrcm halogen. hydirxyi oxo r amsno, cyario CWalwyt Ccyca'dkv CSkoxy 'r -S{ .Hr a c a )se ONfCrt$N selte from h g4ou cons Nf plho'ny nacaNN i4 4 or . subst 4 unts selected from halogen nitro, Czdkyt 4 kyoxy or ualkytio; in partiotlar phenyl or I 2,4-tetrahydronrsph&y whneen said aryl is optionally Sutituted With 12- 4 or 5 Cst)Cters eCPd ftam haogen r nro Vay vCY wkyoxy or C>alky~hio; more ir ci ladoter phenys optionaiy sbstutnd with I 2.3 4 or 5 uVsOtuen;ts selected .r halogen nitro( -lly. Crakylaxy. or >Alkythio; heecy SaC used herein is seected frm the group nonCs-iing4 of furanyi. thiophenyl, psyn-olyl, cxazolyl thi-arolyl iridaroyl pyrazrol'i isoxazolys. isothistzoiyl pyridinyl,
-
pyridazinyl, pynridinyi. pyrazynv triaany, enzefurangt benzrcpyranyi 1(4H) benzopyrany, f(2 enzopyran yl. 3#dihydro-(2H benzopyranyi and 2,>dihydro (4Hbenzopyrany wherein said heteroaryl is optionally substitute with 1, 3 4 or 5 suAtuent selected frm halogen o noto, 1 akyi Coal oxy z oOAikytE in particular furary thinheny pyrdity, benpyranyl, 1(h-benzopyrany 34dihydro 1(2%)benzopyranyl. and 2$dihydro41)~benzopyranyl wherein said heteroaryl is optionally substituted vith 2, 3. 4r 5 substitents selected trom 'ogen oxo or C!, 4alkyi - Y iis 2xo-2,34hydobenzofuranyl or Y is a phony indoly or thiophenylsaid pheny indoly and iophen being substtuted with a substituent selected from the group consisting of --C+OYORCC(=O>SR (=O-NRM 4R 5 R QfO 1 alkyI OGekyi or -CYalkeny; saidCOtzO.R; C(=OSR 2 :; -NW R NRh -Ceakyl; CalkyI; or -Cakenyl being bound at the meta or para position of , vis--vis the binding of to the remainder of the molecule; and wheein said -OeC 1 aky! or ~C. ~alkeny is substituted with a substituent selected from the group consistng of C(=OV OR C(=0) R C(O>NRet e; O-Hett and SetU - with the proviso that when Y is a phenyl, indlyl or thiophenyl som p7seny indoiyi and thtophenyi being substituted w Coith -COop or and wherein said R Or R4~~ ~ ~-: =w; or, -42(ssZWAQ>SRl 0, is at t R represents 'tn unsubsthed fN 1ky' said WQC R;o f=O4 ea h meta or pare position vis4-vis the iding osaid pheny, indolyl or thiopheny to the remainder of the mnolecui e u as represented in formulae lia, lb, lie and 11t befow. An interesting group of compounds. are those compounds of the oesertinentin presented by formula ha O N (a} wherein; R' is selected form the group compsing hydrogen t aky or C 3 cloalkyl; Ar is selected frnm the group comprising: x H Wherein X is selected from the group comprising hydrogen or hae; 2 8- L is a direct bond. Oyakyl/ or yO~Caiky; ITiS a or -NR>R F seted from the groupconsisting ofhdrogen alkrintionady substituted with 1, 2 o 3 sub tents each indepenidently sciected from the group consiting of ~&&=Y0R 2 > -GC~O SR, "WOhNRR Het ; -O-Het 8 Het; Oakyi& and C4alkyh- in pdacular is hydrogen; R i selected rnom the group consistingof Cadky1 substituted with 1 2 or 3 substituents each ndependentWy selected fom the group consiting of 'C(FQ+OR ~ -C&OkSRt d(=~OyNR'R Het' -4iet; ~S-Het2 CalyFS and CakyhO more in particular R* is selected fom the group consisting of Cail substituted with 1 2 or 3 substituents each inependentty seitted from the group onsitog of -OWOOORt C(=O96f; (=ONFR t et; -Qiet and-S Het 4 or R and R i.tgeter with the nitrogen atom to which they are attached form a heterocycle sustituted with one substituent selcted from the group consisting of CO OOR ( SR (ONR'Rt Be -O-HeP -S-et; or C 4 aky wherein said Cylkyl istsbstituted With 11 or3 substituents each independently selected from the group insisting of - Oy ORA -QAO>SR;-C(=0NfRSt Hef; -Het'; and -Siet;in articuuarRand Rtogether with te nitrogen atom to wh ich they are attached form a heterocye substitu t edith one substituent selected from the group consisg ofO1 O0ORt C&OSRt aC(=OhNR R aor Co aiky wherein said Calky is substituted with 1, or subtituents each independently seated from the group consisting of :oe L4 and $-lt': R daare independently selectedt frm the group consisting ofdrgogen; Or Coaikyt substituted with 1 or 3 substituents each independenty sOected from the group consisting of alry, heteroary, CSAycloakenyl, COORt and -C,(=QNH2 rn particular Rt or R ave independently selected from the group consisting of hydroger or C 1 alki substituted with 1 2 or 3 subsituents each independently seced fmm the group consisting of -C(=O)-ORR and Sor RHr independently selected from the group consisting of hydrogeu; or C ,alky substituted with I2 or 3 -C&O>QR 2 sustitunts; R )rd Paire independently selected from the group consisting of hydrogen; Cyky Cakyi; Coalky[&CnaikyV (Zs~aisyV >-akyk; or OmxkylOO and wherein each of said C, salikyi; CGeakyV galkyi CaslkyF-C'edryl or CoalkyVCt is substuted with 2 or 3 substituents each independently scieled from the group consisting of 3C(=0)0R C(Oh SR W et;0-e; and ~S-Heft s selected from the group consisting of Caiky; OXeakenyi C.ikynyt optionay sustitted Cncycoayl; optionaiy substituted hterocyclyi; andoptionay substtuted aryl wheren sad C aik is optonally substituted sit n 213ormore substituents selected from the group conisting 0f halo cyno, hydoxy. aryl'0 ary! S' aiyhS( 0)_ aryt 29- O&0); -Ch=0)4R Rt SOCc 0>C salky C~ryiKK G &kyF-S. ar4 hetercery! hetemcycdyi and Cgnydaikyi or from the fon-mula: N N, or R taken toqther wA h Ooxyc~tmnyi and pnnyt to which it rs attached forms a cydik ester coisting of wherein c i an soteger fromn 1 to RP a okydoptinaaly substfluted with '1 2, 3 or norn halo subsituents; HeY eot r Hot ye indepnenu eected fhrl the qmoup comnprising; 30 / In a further embodiment the present invention provides those compounds of frmta (Is) wherein one or more of the fojiowing rericti~es apply; Ar represents pyridlinyl optionally substituted with halo: in partiuuar Ar represents pyridinyl substituted with fluoro: in an even further embodiment Ar represents X wherein X is hydrogen or halo; in particular X is hydrogen or fluoro; more in particular X is hydrogen; R represents hyNrogen or C aP in particular Cj,4aikyl; more in particular methyl; R* A s hydrogen; z is Caikyi substituted with a substituent selected from He, or -SiHet; with in a pariculnembodiment waid Pee 6r He being selected fon the group consisting of o 0 , -A- 'i'tule W~tC C0 -31 C) .0 C( i R 4ury s'ibtir partiuL'~sikyt substetted from a-substituent 0elected frm C. 0>0RN or Het> with in a particular embodiment said Ri'being a -Q.skys ard said HeY being or N d & gther With the nit rogen atom to wich they are attached form a heterocycle substituted with Crikyl whereini said Cnakvl is substituted with 1, 2 or 3 ubstituents each independently selected from the group consisting cf ..G(20}OR 2 and -Cf=0v
NN
4 fR R.s seated from the riup insisting of a upalky optionally substituted C. cycloayik. optinly substituted ary and optionely substituted etrccyclylwherein said Q xakys optionally subsituted with a substituentselected from the group consisting cf halo, cyaro. hydroxy ( OPNR''R C(=0kO0C ilt.C yr-kyX C .allui-&,arvl heterocydlyl ;in pasrtcular R! is selected frorm there group conssting Of asky optional ly so~ue uccoly;utoal subsitutd ayl" and option subs tited h ftocqyl wherein said u aly is substitute ia substituent s eledted fromn th~e group cossigof 4 yaoydxy C OkN -0-C = C~ 0 Q),3ky MCkay-O C alk ,4 ey hetercycNyi and C, ndos .. clvkyk or from the formidu; / 0 ;mor particular R fsr eected frm the group c insisting of Ckypoptnnayys usub tituted C C doaly optional sabt and nd opiol ny substitute tedhtycycly where sa O:akys i substituted with a substituent selected from the group consisting of haofa yao hydroxy~ R AC(My>C 4 a;til a Cdk aryl, heerocyyl, and C> hcyc aoikyl or from te fornula -1O moremin partuar R s is subsS Q~tituted wih a substituent selected from the group ossiqofhlcao 'cs hv or fo th f ik-nufb.:efomu H--3 heterAcyclyl as used herein is selected frpm the group consisting of piperidinyl pyrrohding inorphory thiomnorphoinyt pipernzinyi. I3-dioxanvy. 3dioxclanyl. tetrahydrogumnony. tetrahydroisoquinoinyt indolinyl tetrahyd ropyranyl tetihydrofu ranyl and hexahydrofuro >buiraburnyi; n particular piperidiny i 13dioxanyl inddinyL tetrahydropyrar nd tahydrofurany optionaly substituted (acycloalkyi as used hereir is selected from the group consting of cyclopropyl, cyobutyl cyclopentyl cyclohexyl cycioheptyl, ycloctyl, cycoonyL adanmantanyl, bicyc(22Iheptanyl and cyclodecyl with cyciopropyl cyclopentyl cyclohexyl adrnaarny, and lcylo(2.1)eptany being particularly preferred; wherein sad Qcycoalkyl is optionady substiuted wh 1, 2 or more in particuar 1 2 or 3: iorin artinuar I or 2: e1en re iparticumar substituern selected from halogen, hydroxyIo xo troamin, cyano. aakyi, O yckiakyl Q aoxy r -SarNHK optiornaly substituted heterocycy as used heren is selected from the grouponr ng of piperidinyl, pyrrobidinyl. morphonnyt thmomorpholinvl, piperazinyl I 3-dioxarvy, 3-. dioxolanyf, tetrahydroquinolinyl, tetrahydroisoqurinylin indolinyl. tetrahydropyraryl, tetrahyd-rofuramyl and hexahydroturo[3/2-bJhtgarlyi;n particular pi peridinyi 1 SdioxanvlI indoliny tetrahydropyranyland tetrdhydrofuranyf; wherein said heterocyclyl is optionally substituted with 1, 2, 3 or more: in particular I substituent selected from the group consisting of halogen, hydroxyl oxo nitro, amino, hydrazine aminocarbony. azido cyano alkyl, cycioaiyl aikerny alkynyl cycloalkyikl. alkylatnino, alkoxy, -SOrN aryl, heteroary arakyl haloalkyl, haoalkoxy, akikxyarbonyl. akylaminocarbony, heteroaryaikyl. aikylsuifonamide heterocycy, aikyicarbonylanminoakvi aryo nayi alkylcarbonyl. acyl, arylcarbonyL aminocarony alkylsulfoxide, -SORk alyfio, carboxy and the like wherein R" is alkyl or cyclolkyl; preferably selected from hogen, hydroxyl, oxo. rnitro. amino. yano, Qsakyl, Cncycloakyi. toD 4 koxv Dor NQtH 2 aryl as used heren Is selected from the group insisting of pheryi, nphtyl1,4-dihydro naphtyt. or13.4terahydonaphtl wherein said ary is optionally subsiuted with 1 2, 3. 4 or 5 substituents selected from halogen, nCitro, 0aky, C.akyloxy, or Calkylthio in particular phenyl o 34etrahydrooaphtyl wherein said arylap optionally substituted with 2.3 Sor sbstituents seected from halogenoxo itra, CAalkyl C kyloxyor Cealkytlio; more in particular pheniyl optionally substituted with 1, 2, 3, 4 or 5 substituents selectedfom halogen, nitro, C.ayl ( akyloxyo 4 akyltia; neteroary as used herein is selected from the group consisting 1A furanyl thiuphenyt pyrrolyl, oxazoly thiazoly. imidaaol pyrazoyl isoxazolyl isothiazotyl pyridiny pyridazinyl, pyrimidinvi, pyrazinyl triazinyi, benzofuranyl. benzopyrany, 1 (4 benzopyranyl. I(2H>benzopyranvi 34dihydrc I(2frybenzorpyranvl, and 2.3dihydro (4H0-enzopyranl wheren said heteroaryl is optionally sustituted with 1, 2,34 or 5 substtuents selected from halogen. oxo ritro, Ctalkyl, Caikyioxy or O..ikyythio in particular furanyl, thihenyl pyridir beazopyrany, 1 (2H)benzopyranyi, 3 4dihydro- 1(2Htenzopyranyi, and 2E1d hd(4H 4benzopyranyi wherein said heteroaryi is optionaty substituted with 1 3 4 or 5 substituents selected from natogen oxo. or C L is atthe mete or para position af the phenyling vis vis the binding ofsaid phenyl ring to the remainder of tte molecule in analogy with the -COO group shown faoruaae I and lit the proviso thatwen L is a direct bond and T is -0-R and where R is an unsubituted Gaaiky, said LC) 1is bond at the meta or para position of the phenyl ring visgwis the binding of said phenyl ring to the remainder of the molecule in analogy with he -COORY group shown in formulae ia and Ib. An neresting group of compounds, are those compounds of the present invention presented by Z W ArR-N /- F wherein; R'is selected tfem the group comprising hydrogen. alkyl or C cycloakyl; Ai is selected front the group comprsing: Wherein is seActed from the group comprising hydrogen or halo; s a bialent radica selected from the group consisting of -0-; R and N 0 W represents Ctalyl substiued wih a suhst-unt selected from HetS S-SHen or O
NRR
4 and wherein R, R. HeF and Het are defined as for any one of the ferementioned embodimrnts of the compounds of formula I or la hereinbefore; I one embodiment of the present invention the compounds of formula lb are further characterized n that P is seictced fron the group consistirg of hydrogen; C 2 aky optionauy substitute with 2 or 3 substituents esah independently selected from the group consiting of ~C&0OiV:;C ) 341 SRI ;C(: NRR'; bet, 0et&; ~$He;C~aikFS~ and CaskyFO t picupar R is hydrogen; Ra selected fromn the group conrisng of C, kvi substoted with 1 2 of 3 substituents each ldependentty seieted from the group consiMng of O(=ObObt-OVOgSP> -(=0)44P<> et: -Oet: -$1e; C 1 akyiS- and G 1 emkyl-0 more in partiular R is selected from the gru consisting of C 1 ~galkyl substituted with 1, 2 or 3 substituents each independently selected from the group consiting of -C4: OR 2 OOS: R *OONi 3 Rf bet; 434-et; and It; or; R! and R4 togetr with the nitrogen atm to which they are attached form a heterocycle substituted with one substituent selected from the group consisting of ~C(=0>0R -C(=0b SRC -O(=)N~it H4 -C+iet S~Me% or Calkyl wherein saed Cealkyi is substituted with 1. 2, or 3 substituents each independentvselected from the grUop corissting of -CU=jb OR ;0 WC(0SR -C(=gNBR R et;Ai-eand-Setet inparticular R' nd R 4 together with the nitrooer atom to which they are attached form a heterooycl substituted with one substituent selected fom the group consisting of C(=Oy0R (=O$SR C(=O-NR Hel "or C kyi wherein said chalky is substituted with 1 2 or 3 substituents ech independenty selected from the group consisng of Hat -- et and -S-et; R is hydrogen; .R rrk are independently selected from the group corissting of hydrogernor CMalyl substtuted wih 1, 2, or3 substituents each independently selected from the group consisting of awl. heteroaryl, Csrcyctoalkenyi, ~C=)-0OR' and ttC(yO'NH in particular R or R~ are independently selected fron the group conssting of hydogen: or Cmgaikyi substituted with 1, 2 r 3 substiuents each independentvselected Rom the group consisting of 2(=O R and R or R are independently selected from the group consisting of hydrogen;er C aikyl substined with 2, or 3 ,C(=O)OR 4 substituents; R"or R4II"' are independently ero hero consisting of hydrogen; C,,alkyl; C4ky eiki-O-Cualkyi ;Caky-S-Cadky-; or Oalky-Ca=Gy and wherein each of said C, galkyl CenkyO-Caaky;Calkyi- ,alkyl- or CaikyC(=0is substituted with 1, 2, or,3 substiuents each independent selected from the group consisting of -C(=0OFOR ; (=O> R: bet 3 -4et; and -S-HetA; R' is selected from the group consisting of C alkyl; C,1aikenyl; C 2 alkyny: optoaly substituted 0 2 oydialkyl optionalsububstituted heterocydy and optionally substituted aryl; wherein said C 1 g 0 atkyl is optionaty substituted with 1, 2, 3 or more substituents sected from the group consistng of hao. cyano hydroxy, eryi- ary-S- ays CVO, -- OVOg-NfRt 4 -- 0C(=QKCuaikylC Weatky0- O CG 6 aiyl-$- aryi, heteroaryl, heterocydy and C oyaclcaamkyor from the formula: -35 N W-C) c'-O I m a fte toember n Th the pxyesabnyn an pr~y o whes attachmeouds orf facic (eterei onsosmore of tefdwn etiun p 36a R 4 5 kvi suhshtud wih a fubswon a oodt 0 s r -S-H-3 NW 4th int a paricar modimtsaid Re'o ebi'i ng e~ frnon. th group c stn of -Nl VN flak $IN I./ tVX !j kib 0 :: ll',,A R .' ' X ix U Wia 0~a N'*c nXFX Q, , O xv. s~ ) L 'NW" 3 R, I 'Cr N N HH ,-0 ----- NH. Af N A ,----N N -S /77 N, 0 N R A u- /AsN' - --- NH NVa 0-- '' R N" 0 .. ... ml A R Af~~~~~~$' ... . ... ., A M K.v K. lot R>"a "IM' p~m UlX4X~ P ~OW XX0 x ArR XXlla XX Va ~ herein: g is an teger Itorn 2 hof Ri is a substtted 'Caiky ore substiuted - adkeny; said jalkyi and aakeyt each independently substituted with a substituent selected from ab group consistng of COOoRi; C{ O0)SRt -C(*ONR"R 4 Het> 0-.Het:; and -S-Net': R a bstituted Calyl, a sumtttuted Cylk$-O.4kyl r a substituted yaikenyt said Wal O1, %alkyS-CualkyI and QaSVkenyl each mdepently substituted wi 2 or 3 substAtuents each independently soettd rom the group consisting of ary. heteroaryl. Cs &vcyikenyl. ~C( OOR 4 C l G(NO SR t; et; eahnd -S-He t and whereir Ar, R, R R R, F R pt R'4 Ne and Hef have the sane meanigs than those d fined herein Iefore The compounds of the present invention can be prepared according to the reaction schemes provided in the examples hereinafter; but those killed nthe artill appreciate that these are ory ustralve far the inwention and that t compounds of this invention can be preparedby any of seral standard syntetc processes commoNy used by those skilled in he ar of oroanic chemnisny: n a preferred embodimenthe compounds of the present invention are useful as kinase inhibitors, more in particular farthe inhiition of at least one ROCK kiase. seteed from ROCKi and ROCKWii in particuar soft ROCL inhibitors, The present invention further provides te use of a compound as definedhereinbefore or The use of a compoAsition comprizng said compound, as a human or veterinary medicine in particular for prev'ention sand/c. treatment of at least one disease or disorder. in which ROCK is involved such as diseases linked t smooth muode cml functi, nflammtor, fibrosis excessive cei prifera tionk excessive angiogenesis, hyperreactiity barrier dysfunctinn, neurodegeration, -40~~ function inN ammation. fibrosis excessive cell priferation. excessive anglogeness hyperraadWity.banter dysfunctiorn nurodgeation andrenoedefing. In a further embodienthe irventon provides the use ofa compound as define hereinbeforeor the use ofa composition comprising said compound the prevention and/or treatment of at least one disease or disorder selected rom the group comprising eye diseases; arway diseases; throat, nosO and ear diseases; intestinal diseases; cardiovascula and vascular diseases inflammatov diseases; neurological and CNS0 dis orders: pomiha t 've diseases kidney diseases sexual dysfunction blood diseases: bone diseases; diabetes; benign prostatic hyperplasia, transplant rejection ser disease, systemic lupus erythmratosis, sp~ast hypertensiotn chronic obstrudive bader dseaso premature th infection, allergy obesiy pancreatic disease and AIDS. In a prefrred. emnbodkment. le invention provides the use of a coipud adfined hereinbefore or th ue of a ompositin conmprising said compound in the prevention and/dr treatment of eyes diseases in iding but not limited to retinopathy optic neuropathy, glaucoma and degenerative retinal diseases such as macular degeneration, reinits pigmentosa and inflammator eye diseases, andor for preventing, treating andor alleviating compilations arnd/or symptoms associated therewith In particular those compounds selected from the group consisting of; Those compounds of formula Iwherein: 7 is an aryl or heteroayi substituted with a substituent selected from the group consisting of -G(=O>OR ;C(t0)SR -C(=O> Nt<R 4 . K alkyi; or- %alkyl; wherein sid O0-Caikyl or -O 1 alkyi are each irndepondently substituted vwith a substituent selected ton the group consisting of -C(=> OR and Pet;and R' is Ialkysubsttuted with a substituent selected from -C(=O OR Cr ySR~t or Het; and Those compounds of formula la wherein Ar represents X wherein X is hydrogen or halo: L is a direct bond C,alkyI or O-Calkyl; TV is-f>04 or R' represents hydrogen or Cyoikyi RYs hydrogen
R
1 is -&uai substituted with a substituent selected fromn C0(=0OWOR'C= l> *(=O)-NR'. or Pet: ir partictdar vi-kyI substituted wth a substituent selected frnrr -CtO0R or Het; ;ith in a partic-sarembodiment aid R beig a G0a iki ; or and PS togetherwith the nitgen aorn to whih they are watched form a heteracycie substituted with C alky whrain said C lkylis sustituted wtih 2. or 3 subsetents each independenty selected front the grou cOrsistingtof- ORt and -CG OuNRR P t are inidependentiy selected from the group cnitirng of hlydroge~n cr C. &Jkyi substitutedI with .2, or 3 , O$unstituents; F seiseted rorn he group cornsisting of C 1 aikyL optionaly substitute C> ccoakyl: optionaly substituted ary; and optionaiiy substituted heterocycy; wherein said O alkyfis optionally substituted with a substituert selected from the group consisting of e cyano, hydmoy -O-(=t 5 aikvk. Caiyv5 wgl, heteryc and CscycoakvL on rom the formula: - heteroogdy ia sed hem bi sekeced from, the group consisting ofppriny dioxnylridnnyt ftraydrpyrnyland tetrahydrofurany : - otioall susttutd O~yooalyias used herein is selected from fte group cossngOf cyclopropyt cyclobuty yloayoyihxy yebpy cydclitlyl prefrrd whrir ad C cydbeky is ,ptionjally susttted With 1 2 3 r S ae padlicular 1,2 or 3;, more in partiular or 2; even more in) particuanar Isus et WeActe froni halogen, yd oxo, Eceitr atin~o, cyano , lkOsylolyta 0akoyrr S NK phot iyast useheercynas used hreir is seted frw the group consisting of periroidirrpobyi thmor rpinyt hilomopiheraz 1 ianytl -dioanyt ditoxhyoqany t 4 erydrq nttra hydrsoquisequiniirinydoivly. tetrahydropyranyl. trahydrohurany en d hexahydrofurrj3,2bjfurnyit in particular pi .eridinyl, 1,3 dioxanylindinly tt ahydropyranyand tetrahydrofurany; heren saide Soptionaiy subsvtvutd wit 1yl as ued hria isseted from or mroup he group cosropin of hA cygen oydryy amcco yoiv, hydroo cycinonayl.n adn yan iio(2 Iky )ydtaknl alnyd a~ilnyth cyoppytky selamite fo xy4 hrNM a oxoheteramino, raykyo, tI alkyOpT halkpxyl aikoxycarbony lmi -42alkvicarbonylaminoalky aryioay agiycarbonvy acyl, arylarbonyt aminocarbony. allyisu>de, -- SO~, aikyithicarboxyl. and the like, wherein R" is skyl or cycta~hy: preferably selected from halogen hydroxyl, oxo oo ann ynno, C alky. C 7 cycloaky, (akoxy, or 401NHy, aryl as used herein s selected from the group consn4; of phony, naphtyid 1,4 dihydro napi. or I 4-tetrahydronaphtl wherein said aryl is optionally substtuted with 1 2, 3.4 or 5 substituents selected from halogen nitro, CalylCyafraxy or Cj 4 alkylthi; in particular phenyl or 124-tetmhydronaphtyi wherein said ry is optrmany substituted with 1. 3. 4 or 5 substtuents selected from halogen, oxo. nia, Calky, Calkyoxy, or 0 14 aikylthio: more in particular phenyl optionaly substituted with 2, 3,4 or 5 substituents selected from halogen, nitro. Cualyi, Qp 4 aiiyloxy, or tnaikythie; heteroaryl as used herein is seleted frm the group consisting of turany, thiophenyl, pyrmyl. xazoly. thiazly, imideaayl pyrazoyl, soxazol isothiazolyt, pyridiny, pyidazhyl, pymdingP pyazilyl, triaziny benasfuranyl benzopyrany, I(4H bonzopyranvly 12i-)enopyrany 34-dihydro1 Q2-benzopyraryl and 2.3-dinydro 4Hbenzcpyranyl wherein said heteroaryl is optonally substituted with 1, 2, 3i 4 or 5 substituents selected from halogen. oxo nitro, C1a& k C0aiyloxy. o alkyltthi in particular furanyl thiohenyl pyridiny. benzopvranylI (2 enopyranyl, 4 dihydro-21 benzopyrany and 2 34yd -. ubenzcpyrany wherein said heteroaryi is optionaly substituted With 1. 2, 3, 4 or substituents selected from halogen. oxo, or Cafkyl; are particularly useul in the prevention and/or treatment of eyesdiseases including but not lited to retnopathy optic neuropathy glcoma and degenerate retinal diseases such as macuiar degeneration, retinitis pigmentosa and inflammatory eye diseases and/or for preventing, treating and/or alleviating complications and/or symptoms associated therewith. I is according an obect of the present invention to provide said compounds for use in th treatment of eyes diseases including but not imied to retnopathy, optc neuropathy, glaucoma and degenerative retina diseases: such as macdular degeneramon, retinitis pgmentose and infiarnmatory eye diseases, .andoor r preentin treating and/or alleviating compilation and/or symptoms associated therewith; more in particular in the treatment of glaucoma, Alternativey, to provide a method for prevention and/or treatment of eye diseases selected from the group consisting of retinopathy optic neuropathy, aUcoma, inflammatory eye disease and degenerative retinal diseases such as rmacular degeneration and retinitis pigmentosa preferably glaucoma; said method comprising administering to a subect in nrced thereof a terapcutic effective amount of a compound according to formua a in particular e compound as defined hereinbefore ~43..
In another preferred embodiment th vetion provides the us' of a compound as defined hereinbefore or the use of a composition comising said compound in the Preve tion andiir treatment of airway diseases; Moluding but not limited to pulmonaryfbrosis, emphysema chronic bronchitis asthma. nfiybrosis. rueuria. ctifbrosis, chronic obstructive pulnonary disease (COPD; bronchitis and rhinitis and respiratory distress syrdrome, and/or its preventing treating ~and/or aileving complications and/or symptoms associated therewitn I particular those compound$ selected from the group consisting of; - ose compounds of formula I wherein;Ys an ary or heteroaryl substituted with a sustituent selected from the grup consisng of .C:O>NR 4 ;- NA ; *0C.alki or o alkyl; wherein said O-cj alkyi ofr .alkyi are each hndeperdently substitued with a susttuent selected from the group consisting of-Oh0>Nr1R.0Qiedand S.'et with in a particular embodiment sa He or Het independent being selected from the group comrrising 1 and . hose campounds of formulaa I wherein; Ar represents N' wherein X is hydogen or hal; Lois a direct bond k -aikyl is -04< -GNRAR o R represents hydrogen or OCyalkyl; R" is hydrogen:
P
4 is -gaCkyl substuted with a substituent selected from O~He or -S-Hett with in a particular embdirnerA aid Her or Het being selected from the group con sist og of 0 C) -44- C) 0 C) Ct bmmchiW ~ ~ ~ andh~iisat distressL sydrm , d/r for prevrlg, treatinng arid/or lvingcompfications and/or y a Fsociated therewith, 1n s accorion y a ed o f the presoe n to prvde Ci. fibro ,s e'mphysetma, chrorn ic s shafbo nuodcti irssnoi obs-tructive pulmonary d"aeCPL); rocitis and 1:rditis arlarsd aoyd tessnrm ating. forlctin and/n a, J-or ayninsassoint d rvthAdIN--ai;y:;dy to provide n method for D"revention and/o tem mt of airway diseases;, 0rj 0 i8 Cytmis -, fiboi Qh~i dtUctive Qdirmdnary d eseS (GOP-0),ronchitis and rhiiniti , 45 and respiratory distress syndromessaid id d method Comprising administering to a subject in need thereof a therapeutic effective amount of a compound aardirp to fomujaiingpdicuiar a compound asdefined hereinbefre in a further embodimnent, the ovention provides the use of a compound as defined hereinbef or the use of a composition composing said compound in the prevention and/or treatment of cardjovascuar and asoular diseases: including but not limited to cerebrovascular contraction, referfsion. hypoxia peripheral cirulaton disorder, myoardial hypertrophyacute stroke, congestive heart failure, cardiovascular ishenAi heart disease cardiac remodeing, angin, coronary vasospasrm cerebrd vasospasm restenosis hvertension. puinnry hypertension pulmonary vasoconstrionn arteriosclersis, atherosclerosis aneursm, hemorrhage. Raynaud's disorder, thrombosis (including deep thronnosis) and platelet rated diseases, and/or for preventing, treating ador alleviating compications and/or symptomsassociated thervith and/or alleviating complicationa and/or symptoms associated therewith. In a further embodiment e invention provides the use of a compound as defined hereinbefore or the use of a composition comprising said compound in the preventionandior treatment of Throat, Nose and Ear diseases: inching but not limited to sinus problems, hearing problems, toothache, tonsillitis, uler andirhinitis, in a further embodiment teinvention provides the use of a compound as defined hereinbefore or the use of a composition comparing said compound in the prevention and/or treatment of skin diseases: including but not limited to hyperkeratosis, parakeratosihypergranulosis, acanthosis, dyskeratosis, spongiosis and ulceration. In a further embodiment the invention provides the use of a compound as defined hereinbefore or the use of a compositon composing sad compound in ta prevention and/ctreatment of Intestinal diseases: including but not limited to nfafnmatoc bowel disease (lE0) cons, gastroenteritis, ileus, ileitis, appendicitis and CrohN disease. in yet another embodimentthe invention provides the use of a compound as defined hereinbefore or the use of a composition comprising said compound in the prevention candor treatmentof shflammatory diseases: ncudsng but not imied to contact dermattis, atopic damatitis, psoriasis rheumatoid arthritis, juvenile rheumatoid artmtis, ankytosing spOPdyiitis, psoriatic arthritis fitfammatory bowel disease, Orois disease and uceraive coNis, and/or for preverting treatinO and/or aileviatr complications and/or symptoms and/or inflammatory responses associated therewith in another embodimentthe rnention provides the use of a conound as defined hereinbefore or the use of a composition comprising said compound in the prevention, treatment and/or management of neurological and CNS disorders: including but not limited to stroke, mrenngitis, conuisions, brain or spinal ord injury and nfiammatory and demyelirnating diseases such as Azheimer's disease, mutipie sclerosis and neuropathic pain. The present compounds are 46therefore suitable for preventing n eurodegeneration and stimatiig neurogeneration in various neurological disorders, and/or for preventing, treating and/or nepitng mpitns and/or Symptoms associated therewihM I another embodient the invention provides the use of a compound as defined hereinbefore or the use of a compositon comprising said compound in the prevention andor treatment of roiiferatie diseases: such as but not iNited to cancer of the brain giomas breast coon, ntestne, sn m head and neck, neve, uterus, kidney, lung aiver ovary, pancreas, prostate or thyroid giand; Castleman disease: leukemia; samom iymrphoma; malignoma: and melanoma; and/or for preventing, treating ard/or alleiating complcations cd/or symptoms and/or infiamratory responses associated Therewith. in another embodiment the invention provides the use of a compound as defined hereinbefore or e use of a composwin comprising said compound in the preventionand/or treatment of kidney diseases: incuding but rnot limited to renal ibrosis or renal dysfunction; and/or for preventing, treating and/or alleviating cornphoatiorns and/or symptoms and/of inflammatory responses associated therewith, in another embodiment, the invention provides the use of a compound as defined hereinbotore or the use of a composition comprising said compound in dhe prevention and/or treatment of sexual dysfunctio including but notlimited to nypogonadism, bladder disse, hypertension.diabetes, or peivia surgery; and/or to treat sexual dysfuncon associated with treatment using certain drugs, such as drugs used to treat hypertension depression or anxiety rn another embodiment, the invention provides the use of a compound as defined hereinbefore or the use of a composition comprisng sad compound in the prevention and/or treatment of blood diseases: inuding bunot limited to sepsis, eosinophilia. endotoxemia and/or for preventing, treating and/or alleviing compilations and/or symptoms and/or inflammatory responses asoiated therewith, In another embodiment, the invention provides the use of a compound as defined hereinbefore or he use of a Composition comprising said compound in the prevention and/or treatment of bone diseases: induding but notlimited to osteoporosis and osteoarthritis; and/or for preventngtreating and/or lleviatineg compilations and/of s t M sndor inflammatory responses associated therewith. In another embodiment, the invntion provides the use of a compound as defined hereinbefore or the use of a comnositon comprising said compound in the prevention and/or treatment of diabetes: including but not Imid to hyperglycemia and type 1 diabetes; and/or for parenting, treating andor aleviating complications and/or symptoms and/or intamrnatory responses associated therevwit In anher embodiment, the invention provides the use of a compound as defined hereinbef or the use Oa composition corpising said compound in the preverntion and/or treet of diseases and disorders such as benign prostatchyperpasia, transplant rejection, liver disease systemic -47 lupus erythmosis. spasm, hypertension. chronic obstructie bladder diSesr premtui sidh, ofecion, allergy. onesity. pancreas disease and AIDS. and/or for preventing treating and/or 4leviehnn compicat on~s and/or symptoms associated therewith in a preferred embodiment the present mention provdes the use of a compound as defined hereinbefore or the use f eaompositon comprising said compound the prevention arid/or treatment of glaucomaasthma, sextual dysfunction or COPD. The present invention further provides a compound as defined hereinbetore or a composion comprising said compound for use in the prevention and/or treatment of at least one disease or disorder selected from the group compising eye diseases: aiway diseases: cardiovascularand vascular diseases; inlammatory diseases; neurological andCNS disorders proliferatve diseases; kidneydiseases; sexual dysfuncion: blood diseases; bone diseases; diabetes; benign prostatic nyperplasatransplant rejectionriver disease. systems erytfhmatosis spasm hypertension, chronic obstructive bladder disease prematum brth, nfection iergy o ,esity pancreas disease and AIDS. In a preferred embodiment, the invention provides a compound as defined hereinbefore or a omnpNsition comprising said compound for use in the prevention and/or treatment of eyes diseases including but not limited to retinopathyoptic neuropathy glaucoma and degenerative retinal diseases such as macular degeneraton retiiti pigmentosa and inflammatnry eye diseases and/or for preventing treating and/or alleviating compliCations and/or symptoms associated therevwith. In another preferred emodiente iwention provides a compound as defined nerernefore or a composton comnprisng said compound for use in the prevention and/or treatment of airway diseases:luding but not limited to pulnary fibrosis emphysema, chronicbronchitis asthma. fibrosis, pneumonia, cytsis fibrosis, chronic obstructive puImonary disease (COPDj: bronichitis and rhiniti ano respiratory distress syndrome, and/or for preventng, treating and/or alleviating complicationss and/or symptoms as sociated therewith in a further ermbodnment the Invention provides a compound as defined hereinbefore or a Composition comprising said compound for use in the prevention anor treatment of Cardiovascular and vascular diseases: including but not limited to ceebrovascular contractor, referfu~sion hypoxia peripheral circulation disorder, ryocardial hypertrophyacute stroke, congestive heart failure, cardiovasculaf ischemia, heart disease, cardac rmodeing, agina coronary vasospasn, cerebral vasospasrm, resterlosi. hypenson pulmonary hypertension pulmonay vasoconstriction arteriosclerosis, atherosclerosis aneurism, hemorrhage, Naynaud's disorder, thrombosis (incuding deep hrambosis) and platelet related diseases, and/or for prevenng. treating andor allevmating complications and/or symptoms associated therewith and/or "ieviating complications and/or symptoms associated therewith. -48 in yet another embodiment, the invention provides a compound as defined her'inbefore or a ccmposson comprising said compomd fot use in the preventiorand/or treatment of inflammatory diseases: nldng but not limited to contct dermatt atomic dermatitis, psodasis eumatOid arthritis juvenile rheumaid arthritis ankylsrin spondyliussriatic arthritis inflammatory bowel disease Crohns disease and ulcerative colitis, and/or for preventng treating and/or alleviating complications and/or symptoms and/or nflrnmatory responses associated therewitn In another embodiment, the invention provides a compound as defined hermnbefore or a composition comprising said compound for use in the prevention andor treatment ofneurological and CNS disorders: including but not limited to stroke, meningitis, convulsions, brain or spinal cord inIuy znd inflammatory and demyelinating diseases such as Airheimer's disease, muliple sclerosis and neuropate pain The present compounds are thereftra stable for preventing neurodegeneration and stmuating neurogeneratiorl n various neurological disorders and/or for preventing treating end/or allevating complications and/or svmptor associated therewith. in another embodiment, the invention provides a compound as denied hereinbefore or a composioAn Comprsing said compound for use in the prevention and/or treatment of prolferative diseases~such as hut not imited to cancer of the brain (giomas) breast colon, intestine skin head and ned, nerve, uterus kidney. lugler, ovary pnrcteas prostate, or thyroid glan Castleman disease: leukemia: sarcoma; Iymphoma : maignoma; and melanoma; and/or for preventing, treating and/or aleviatng compilations and/er symptoms and/or inflammatory responses associated therewith In another embodimert, the mention provides a compound as defied hereinbefore or a composition comprising aid compound for use in the prevention and/r treatment of kidney diseases including but not limited to renal fibrosis or renal dysfunctionand/or for preventing, treatin and/or alleviating complications and/or symptoms and/or intammatory responses associated therewith. In another embodiment, the invention provides the use of a compound as defined hlerembefre or the use of a composition comprising said compound in the preparation of a medicament for the prevention and/or treatment of sexual dysfunction: inaluding but not limited to hypogonadisr, bladder disease, hypertension, diabetes, or pelvic surgery; and/or to treat sexual dysfunction associated witi treatment using certain drugs, such as drugs used to treat hypertension depression or anxiety. in another embodiment, e invention provides a compound as defined hereinbetor or a omposition comprising said compound for use dhe prevention and/or treatment of blood diseases including but not limited to sepsis, eosinphta, endotoxemia; and/or rpreventng treating and/or afieviatwng complications and/or symptoms and/or ;nflamnatory resoonses associated therevih. in another embodiment, the invention provides a compound as defined hereinbefore or a compositon comprising sad compound for use in the prevention and/or tratment ot bone diseases; including but not limited to osteoporosis and Osteoacthritis; and/ for preening, treating -49 and/or aieviating ComPriations and/or symptons and/or inflamm try resonses associated therewith. n another embodimert the invention povides a compound as defined hereinbefore or a composition comprising said compound for use in the prevention and/or treatment of diabetes; induding bt rnot united to hyperglycemia and type1 :diabetes and/o for preventing, treeing and/or alleviating complications and/or symptoms and/or inflammatory responses associated therewith. In another embodiment, the invention provides a compound as defined hereintore o a CompOsiin Conmprnsin said compound for use in the reentron and/or treatment of diseases and dorderssuch as bengn postatic hyperpasia, transplant rejectioloriver disease, systemic lupus erytmatosis, spasm. hypertension chronic obstructve bladder disease, premature birth, infection. Sierg, obesity, pancreatic disease and AIUDS and/or for preventing treating and/or alleveiting canmpicstions and/or symintoms associated therewith. in a preferred embodiment the present inention provides a compound as defined hereinbefore of a Composition composing said compound for use in trie prevention arid/r treatment of gaucoma, asthma sexuadysfunction or COPD. METHOD OF TREATMENT The present invnion further provides a method for the prevention aridlotreatment of at least one disease or disorder selected from the group comprising eye diseases; airway diseases; cardiovascular and vascular diseases; inflammary diseases; neuroiogiea and CNS disorders: proiferabve diseases; kidney diseases: sexual dysfunction; Hod diseases; bone diseases; diabetes; benign prostatic hyperplasia; transplant rejection; llve~r disease systemic oapus erythmatosis; spasm: hyperension chronic obstructive bladder disease: premature birth; infection; allergy; obesity; pancreatic disease; and AIDS; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound or a composition as defined herein, in a preerred embodiment the invention prsvIdes a method for the prevention and/or treatment of eye diseases induding but rot listed to retinopathy, optic neuropathy glaucoma and degenerative retinal diseases such as macular degeneration retinitis pigmentosa and inflammatory eye diseases: caid method comprising administing to a sl:ject in need there a therapeutic effective, amount of a compound or a compositiornas denice herein. In another preferred embodiment, the invention provides a method for the preventon and/or treatment of airway diseases including but not limited to pulmonary fibrosis, emphysemachronic bronchitis, asthma, fibrosis pneumonia, oysis fiosisis cnroric obstructfye pulmonary disease (COPI bronchitis, rhinitis, and respiratory distress syndrome; said method comprising -50adminYstering to subject in need theteof a therapeutic etfectve amount of a compound or a compositionras defined hierein. n another embodiment, the invention povides a method for the prevention and/or treatment of cardiovascular and vascular diseases: cinuding but not limited to erebrovascuiar contraction. reterfusion hypoxia. perheraf circulation disorder, myceardia hypertrophyacute strke congestve hearliur. cardiovasculr schemia heart disease cardiac remodeling angina, coronary vasospasm, cerebral vasos;asm. restenosis, hypertension, pimonary hypertension. pumnaat vasoconAstrictionreriosclerosis atherosclerosis. neurism henorrhage Raynauds disorder, thrombosis O(nctuding deep thrombosis) and platelet related diseases said method comprising adminnstering to a subject in need thereof a therapeutic effective amount of a compound or a composition as defined herein, In another embodiment. the Invention provides a method for the prevention and/or treatment of inflammatorydiseases: including but not limited to contact dermatitis topic dermatitis.sproasis, rheumatoid arthritis, urvene rheumatoid arthritis ankylosing spondyltis psoratic arthrtis. inflammatory bowel disease, Crohn's disease and ulcerative cotis; said method comprising administedng to a subject in need thereof a therapeutic effective amount of a compound or a composition as defined herein. In another embodiment, the invention provides a method for the preention and/or treatment of neurological and NS disorders:ciuding but not limited t stroke meningitis, convulsions, bran or spinal cord injury and inflammatory and demylinatng diseases such as Alzheiners disease, rmutile sclerosisarid neuropathic pin. The present: compounds are therefore suitable for prevening neurodegeneration and stimulating nepogeneration in various neurological disorders said method comprising adrinisterng to a subject in need thereof atherapeuti effective amount of a compound or a composition as defined herein. in another embodiment the invention provides a rhethod for the preventior and/or treatment of prolierative diseases; such as but not limited to cancer of the brain (glirnas, breast on, intestine, skin, head and neck, nerve uterus kidney, lu iver, ovary, pancreas, prostate or thyroid gland; Castleman disease: leukemia; saromra. lymphoma; maioma; and melanoma: saimethod comprising administering to a subject in need thereof a therapeutd effective amount of a compound or a composition as defined herein, .n another embodimentte invenion provides a method for the prevention and/or treatmetof kidney diseases: includingbut riot lins0ted to renalfibrosis or renal dysfunction: said method :omprising administering to a subject in need thereof a therapeutic effective amount o a compound or a composition as defined heret. In another ermbdiment, the invention prcvdes a method for the prevention andoar treatment of seXia dysfunction: including but not limited to hypogonad rbladder disease, hyertension. diabetes or pelvic su gary; and/or to treat sexual dysfunction associated with nrutnent using certain drugs. such as drugs used to treat hyperiendson, depression or anxiety said method -51comprising a subject in need thereof a therapeutic effective amount of a conmpouid or a compositin as deiried here In another embodiment. the invention provides a method for the prevention and/ortreatmeit of blood diseases' including but not limited to sepsis, csinophia endotoxemia said method comprising administering to a subject in need thereof a Therapeutic effective amount of a compound or a composition as defined herein. In another embodiment, the invention provides a eisthod for the prevention and/or treatment of bone diseases: including but not limited to osteoporosis and osteoartnritis; said method comprising administering to a subject in need thereof a therapeutic effdctve amount of a compound or a composition as defined herein. In another embodiment the invention provides a method for the orevertian and/or treatment of diabetes: including but not limited to hyperglycemia and type 1 diabetes; saidmethod omprsirg administering to a subject in need thereof a therapeutic effective amount of a compound or a composition as defined herein. in another embodiment the invention provides a method forhe prevention and/or treatment of diseases and disorders such as benign prostatic hyperpiasea. tansplant rejection, iver disease, systemic lupus erythmatosis, spasm. hypertension. chronic obstructbv bladder disease. premature birth infection allergy obesity. pancreatic disease and AIDS; aid method comprising admsnisteing to a subject in need thereof a therapeutic effective amount of a compound or a composition as defined herin, In a preferred embodimentthe invention provides a method fo he preveton and/or treatment of glauoma, asthma, sexual dysfunction or COPD; said method comprising admiistering to a subject in need thereof a therapeutic effective amount of a compound or a composition as defined here In the invention, particular preferenceN is given to compounds of Formula i or any subgroup thereof that in the inhibion ROCK descrfed beiow inhibit ROCK Wdth an Cvalue ofless thIan 10 pM preferablyless than I pM. Said inhibion may be effected en v/tro and/or in vo andwhen effected in vivo, is preferably effected in a selective manners defined above. The term 'ROCK-mediated condition" or disease. as used herein means any disease or other deleterious cndition in whichis known to play a rle. The term "ROCi-mediated condition" or disease" also means those diseases or conditions that ae aleviated by treatment wsth a ROCK inhibitor Accordingly another embodiment o the present inventionreates to treating or lessening the sevety of one or more diseases in wich ROCK know to play a rokj Fopharaceuticaluse the compounds of toe invention may be used as a free acid or base. and/or in the form of a pharromaceuillacaceptable acidaddition andor base-addton salt (el obtained with non-toxic organic or inorganic acid or base) in the form of a hydrate solvate and/or - 52complex, and/orin the form or a pMdrug or predru such as an ester, As used herein and unless otherwise stated, the tem 'soivate ocludes any combination which may be formed by a compound of this invention with a suitab inorganic solvent (ecg hydratesor organic sovent such as hut not limited to alcohols ketones. esters and the ire. Such sats hydratessolvates; etc and the preparation thireef wi be dlear to the skilled person; reference is for instance made to the salts, hydrates, states etc. described in US-b53275,$-A-56ebOO US-A 569OO and US-At372 733. he pharmaceutcaiy acceptable salts of the compounds according to the inventin, a, in thefform of water. oosok , r dispersible products, include the conventional nontoxic sats or the cuatomary amorium salts which are formed eg from Morganic or organs acids or bases Examples of such acid addition sats include acetate, adiyate, aginate, aspartate benzoate benzenesulfonate bisulfate; butyrate, citrate, camphorate, carphorsAlfonate, cyalopentanepropiondte, digluconatedodecylsuifate, ethanesusonate fuarate glucoheptanoate, gtyerophosphate. henisulfate heptanoate, hexanoate hydrochloride hydrobromidehydroiodide 4hydroxyethenesulfonate. lactate> maleate, methanesulftoate, 2-naphthalene-sulfonate. nfzotinate, oxalate, palmoate pectinate. persulate, phenypropoate pirate ivalte, propionate, succinate, tartrate, thiocyanate tosylate and undecanocte Base salts include amMonium salts, alkali metal salts such as sodium and potassiu salts, alkaline earth metalalts such as calcium and magnesium salts, salts with organic bases such as dicydhexylamine salts, NethyiD91ucamine. and salts with amino acids such as argiine lysine and so forth, In addition the basic nitrogen-contairirg groups may be quatermizedth such agents as lower alkyl halides such as methyethy, propy; and buty chloride, bromides and iodides diayv sulfates like dimethyd, diethyl, dibuty and diamyl sulfates, long chain halides such as decyl lauiyl myristy and steary chArides, bromdes and iodides, arakylhalideslike benzyl and phenethyl-romides and others Other parmaceuticaly acceptable salts include tha sulfate salt ethanolate and sulfate salts, Generally, for pharmaceutical use, the compounds afthe inventions may be formulated as a pharmaceutical preparation or pharmaceutical composition comprising at least one compound of the invent and at Wast one pharmaceutical acceptable carrier, diluent or excipient and/or adjuvarit and optionagy one or more ar pharmacendialy active cmpounds By means of nonmiting enpleas suh a formulion ay be in a form sutble tr oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection r intravenous infusion for topical administration (induding oruar or administration by inhalation, by a skinpatch, by an implant by a suppository etc .Such stale administration tns - whtch may be solid, semi-solik or iqui, depending on the manner of administration as wel as methods and carriers. diunts aid excipients for use inthe preparation thereof be clear to thekied person;eference s again made to for instance US-Aty277, Us-A4369OQ U$A69 Og 7 arnd S-A4 . 7 aswell as to h standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences, -53- Some preferred, but nonlmiting examples of suah preparationsincude tablet. pils, powders, cengaes, sanhets.eahets: etixirs, suspense ennemulsions, solutions, syrups. aerosols ointments, screams, 0ns, soft and hard gelatsn capsules, suppositories eye drops. sterile inictable solutions and sterile packaged powders (winch are usually reconstituted prior to use) for administration as a bolus and/or for continuous administration, whih may be formulated with carriers excipients; and duerns that are sUIAie per se for sch formulatons such as lactose, dextroses sucrose sorbitol manito starches purm accia, alcium phosphate, alginates tragacanth, getin, calcium iicate, microcystaline celulose, polyinylpyrrolidone. polyethylene qglycol, -'eWv ,P W Waer an rpdydoyezats ac r cpelluloseg ite rile) vwater, methylcellulose. methyl- arnd poyhdoyeznett magnesium stearate, edible oils, vegetable oils and mineral ois or suitable mixtures thereof, The formulaions can option contain other pharmaceutical activesubstances (which may or may not lead to a synergistc effect withthe compounds of the invention) and other substances theatre commonly used in pharmaceutical formulations. such as lubricating agents, wetting agents emulsifying and suspending agents, dispersing agents, desintegrants, bulking agents, fillers, preserving agents. sweetening agents, flavorig agents; flow regulators. release agents etc. The compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein for example using liposomes or hvdrophii polymeri matrices based on natural gels or synthetic polymers. In order to erhnce the solubility and/or the stability of the compounds of a pharmaceutical composing according to the irventior it can be advantageous to employ a-, P- or rcyclodextrins or their derivatives, An interesting way of formulating the compounds i combination with a cvycdeXtin or a denvative thereof has been described in EP-A-721,331 in particular, the present invention encompasses a pharmatical composition comprising an effectie amount ofa compound according to the invention with a pharmaceutically acceptable cyclodextrin. in addition, co-solvents such as acohos mayimprove the soiubiity and/or the stabiity of the compounds in the preparation of aqueous compossions, addition of salts of the compounds of the invention can be more table due to their increased water soluhiinty Particular reference is made to the compositions,formulations nd cancers excipients, diluents, etc. for use therein, routes of administration etc. which are knwn per se for analogous pridirnocarbaimdes.uch as thosedeseribeo in US-A4,7334 and EP0A- 370 493 For the treatment 01 pain, the0compounds of the inention may be used locally, For local administration, the compounds may advantageously be used in the form 0f a spray, ointment or transdermal patch or another suitable form for topical, transdermal and/or intradermal adninsstration. For ophthalmic application, solutions, geis. tablets ard the like are often prepa ed using a physiological saine solution. gel or excipient as a maior vehicle. Ophthalmic formulations should prefeaby he prepared ata comfortnhie pH with an appropriate buffer system -54 More in paricuiar. the cormpostions may be formulated in agparmaceutical formuistion comprising a therapeuically effettve amount of ptes consisting of a solid dispersion of the compounds of the invention and one or more -harmaceutcally acceptable water-solutie polymers. The tem a solid dispersion" defines a system a solid state (as opposed a kquid orgaseous state) comprising at least two components, wherein one component is dispersed more or less eveny throughout the other componerntoromponents. Wen said disprsion of the components is such that The system is hemicaiy and physially uniform or homogenous throughout Or consists of one phase as defined in thermodynamis such a solid dispersion is referred to as "a solid soiutionl. Solid solutions are preferred physical systems because the components therein are usually readibioaalabe to the organisms to which they are administered. It may furTher be convenent to formulate the compounds in the fom of nannparteles which have a surface modifIer adsorbed on the surface thereof in an amount sufficient to maintain an efectve average paricie size of less than1000 m. Suitable surface modifiers can preferably be selected from known organic and inorgan pharmaceutical recipients, Such excipients include various polymers, low molecular weight odgomers natural products and surfactants, Preferred surface moddiers include nonionic and nonicsudactants Yet another interesting way of formulating the compounds according to the invention involves a pharmaceutical comosioni whereby the compounds are incorporated in hydrophilic polymers and appiing this mature as a coatilm over many small beads, thus yielding a composition with good hioavaiabiliy which can conveniently be manufactured and which is suitable for preparing pnarmaceubcal dosage forms for oral administration. Materials suitable for use as cores inthe beads are aanfold, provided that said materials are harmaceuticay acceptable aid have appropriate dimensions and firmness Examples of such materials are polymers, inorganic substances organic substances and saccharides and derivatives hereof The preparations may be prepared in a maner known per se, which usually involes mixing at least one compound according to the invention wth the one or more phannauticaly acceptable cariers, and, if desired, in combination with Other pharnaceutical active compounds> when necessary under aseptic conditions. Reference is again made to US-A,372778, US-A-0a36086 US-AithO9,087 and US-A,372,33 and the further prior art mentioned above, as weil as to the standanihandbooks, such as the lest editon of Remindla >sPharmaceuticalo fences The pharaceuical preparations of th'enon are preferably in a unit dosage form> and may be suitably packaged, for example in a box, blister via botte sachet arpoule or in any other suitable single-dose or mui-dose holder or container (which may be properly labeled ioptonally with oneor moreleaets contairng productinformation and/or instructions for use Generaly, such unit dosages wilcontain between 1 and 1r000 mInd usualybetween 5 and 500 rmgof the at least one compound of tre invention> eg. about 10 25, 50, 100> 200 300 or 400 mg per unit dosage. The compounds can be administered by a variety of routes including the ora, real, ocular, transdermal, subcutaneous. intravehous. intramuscular or ntranasal routes, depending mainlyen -55 the specific preparationused and the czOndition to be treated or prevented, and with orad and itravenous administration usually being preferred, The at last one compound of the invention vill generay be administered in an effective amount" by which in meant any amount ot a compound of the Formula 1 XXN or any subgroup thereof that upon sutable admirstrtion s sumffcient to achieve the desired theapeutic or prophyltic effect in the individual to which it is administered. Usually. depending on the condition to be prevented or treated and the route of administration, such an effective amount wilusualy be between 001 to 1000 mgper kiogram body weight day of the patent per day moe often etweern 01 and 0t mq such as between I and 250 mg, for example about 5: 0 50, 100, 150 200 or 250 mg. per kilogram body weight day of the patient per day which may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, eg Using a drip infusion The amount s) to be administered the route of administration and the further treatmentegimen may be determined by the treating cncin. depending on fastorsbuh as the age gender and general condian of the patient andthe nature and severity of the diseasesymptoms to be treated Reference is again made to US-A 3372>778US A-f30986 US~A46369.087 and USaA 6372J33 and the further prior art mentioned above> as well as to the standard handbooks such as the latest edion of Remington's Pharmaceucal Sciences. n accordance with the method of the present inentiorn, said pharmaceutical composition can be administered separately at different times duotghe couseof therapy or concurrently in divided or singe corrbination forms. hn e present invention is therefore to be urderstood asembracing al such regimes ofsimultaneous or altenatog treatment and the term administering " is to be interpreted accordingly. fr an ora administration form the Compo~iins of the present irentin can be raxed with suitable additives, such a recipients> stabilizers, or inert diluents and brought by neans of the c etds into the suitable administration foms> such as tables> coated tablets hard capsules aqueous alcoholic> or oily solutions. Examples of suitable inert carriers are gum arabic mag~nesla> magnesium arot ptsl pnosphate> Iactose, glucose, or starcipariular comn starch ints case the preparation can he carred out both as dry and as moist granules Suitable oiy excipients or solvents are vegetable or animal osi, such as sunflower oil or cod liver oil. Suitable solvents for aqueous or alcohol soutions are water ethanol sugar solutions or mxtures thereof Polyethylene gycos and polypropylene o glycos are also useful as further auxilries for other administration tonms; As Immediate release tabls> these compositions may contain microcrystaline close dicalcium phosphate. starch> magnesium stearate and lactose and/orother excipients. binders, extenders disitegrantduents and lubricants known in the ar. When admnnstered by nasalaerosol or inhalation hese compositions may be prepared according t techniques welilanown irr the art of pharmaeeucal formulion and may he prepared as souttons in saline employing benay alcohol or other 'suitable preservatives absption promoters >0 enhance bloavailaby fluorocarbons, and/or other solubizing or dispersing agents known in h aceutical formnulatons fr administration n the form of aerosols or sprays 56.
are, for exampieslutions, suspensions or emulsions of the compounds of the irvention or other physiologically tolerable salts in a pharmaceuticalyacceptaboe solvent, uch as ethanol orvwter, or a txture of such soivents. If required, he formuaion can also addtionallv contain other pcarmaceutice solaiiaries such as surfactants, emuksifiers and stabilzer asweis a propellant. For subcutaneous administration the compound according to the inventicr. if desired wit he substances customary Therefore such as sokbilizers. enulifers or further auxiliaries are brought into solution, suspension, or emulsion. The compounds of the invention can also be WyophNized and the lyophiizates obtained used, for example, for the production of injection or infrusion preparations. Sitabte solvents are; for example, watr, physiological saline soluton or alcohols eg ethanol propanold glycerolin additon also sugar solutions suchas glcose or mannitol solutions, or alternatively mixtures of the various solvents mentoner The injectable solutions or suspensions may be formulated according to known art using suitable nontoxic, parenterallyacceptable duents or solvents such as mannitoi ,butanedo water, Ringers solution or isotonic sodium chonde soluhon. or suitable dispersing or wetting and suspendig agents. suci as starve, bland fixed oils, including synthetic mno- or diglyiddes and fatty acids, includig oleic acid; When rectaly administered in the formof suppositories, these formations may be prepared by mixing the compounds according to the invention with a suitable non irritating excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures but liquef' and/or dissolve in the reciai cavity to release the drug. In preferred embodiments, the ompounds and compositions of the inventin are used iocalvy for Instance topicalor in both absorbed and non-adsorbed application. The composions are of value in the veterinary tield which for the purposes herein not only includes the prevention and/or treatment of diseases in animals, but also - for econonically important animals such as Cattle pigs sheep, caien, fisn et - enhancing the growth and/or weight of the animaland/orthe amount and/or the qualy of the meat or other products obtained from the animal, Thus, in a further aspect the invention relates to a composition for veterinary use that contains at least one compound of the invention and at east one suitable carrer (e.a carter suitable for veteriary usei The invention also relates to these of a compound of the intvention n the preparation of such a compostion. The invention wil now be illustrated by means of the following synthetic and biological examples. which do not iit the scope of the invention in anyway EXAfMPtIES A ,co Cpnt ts Aniess indicated otherwise, the Purity of the compounds was confirmed by liquid hromatograph'mass s:ptrometry (LC/MS). as follows * HPL' system iWaters 2690 with photodIode array de99t4r WaterS 99= Clunn C7 Gradient solvent A Oformic acid 26.5 nM 0% to s 1Bvent £3 (CHCfonic acid 7 nM 80% in 3 min. Flow:2.5 rlmin. Mass spectrometer Micronass Platform Lc Ionization: electtospray(polariy: negative and postive'y A2 ZA t tri bult on f m> lgto The Cah-ningoldPrelog system was used to attribute the absolute confiyuration of chira coter in which the four groups on an asymmetric carbon are ranked to a set of sequences ruls Reference s made to Cann ingo; Preg Angew Cheat nt Ed. ! Eng 6, 5,3855-.0 It is known by those skied in the art that specific eentirmrs (or diastereoisomes) can be obaeined by different methods such as, but not limited to lhral resolution for exampWL sales formed itt opcicaly active saids of bases may be used to form iastereaisomaric salts that can facilitate the separation of optically active isomers of the compounds of Formula or any subgroup &heeof symdosnthesis or preparative cira chromoatography(usino diffren t chimn such t.hereo}, assvmetri s-vP~-[Ii-kie';cn as Chiralce ODH (ts 3.5dimethylphenylcarbamate46 x2S0or 100 x 0 m. 5 pm;Chiraicel > %res methylbenoate, 46 x 250 or 100 x 250 mm, 5 pn>) hiralpak AD (rs35 dimeihylphcnyvarbamate, 46 x 20 mm, 10 prn) and Chiralpak AS (is(Sh phenyethycatrbeate, 46 x 250 mm, 0 p Mfrom Ciral Technologies Europe (lirch, tance4 Whenever it is convenent stereoisomers can be obtained starting from cormertcil materilswith known configuraion(such compounds incude aminoacid for instance). Ah 4 Nme of the mIotecoDs The soft are MDL 15-St Draw 2.5was used to assign th name of the molecules. 55- B, Compound synthesis B. 1Intdcrediates The compounds of the invention may he prepared by methods well known to those sk~led in he art. and as described the synthetic and exgerimental procedwes shown below For examplentermediates C can be obtained according to, but not imted tohe flowing general sequence (anmde fornaaion followed b o uzk I couptng): PG represents a suitable protecting group such a groups described by T Gre e and P Wuts in "Greene' Protective Group in Drgnic Chemisty 4tI edon, John WMey & Sons lnck 'K / R R A a) ArNHOTSTU HOW DiEADMF rt or ArNH DA (b) Ghoses reagentMeC=C(C)NMe THF rt, followed by Ar H Py (o) ArN, CLuCs CQOO D dioxane, I3WC, I di 2M Na CO (agt Pd(P: toluene or DME ethanol N., MW. 130C' Generai procedures for preparation oamides Protocol A. To a solution of the corresponding carboxilyc acid (I mmoi) in DMF (10 ml) were added DEA(3 mmal 3 c14 TBTU (.3 rnmol 13e)ad HOSt (0i mmol 03 aq. The reaction mixture was stirrd a rt or 510 min followed by additionof the corresponding amne (V eq The reaction mixture was sWrred for 16 to 24 hours, ten diluted wit ethy acetate (100 mt washed with 0. M HCI (50 mL) and saturated sodium carbonate (50 m The organic phase was dried over MgSQ and the sotventwas removed in vaccuoa Alternati e protocol T ca soluto of the correspondkic carboxm acid (I eq) in a mixture DME/DM (0,25 M) were successively added UC0 (1 cg1 H051 (g) and DiEA (3 eq); The solution was stirred at RT for 30 minutes before tie addition of the corresponding arran (1 sq The reaction mixture was stirred at RT for 1 hour to 3 days The solvent removedin vacuc. The residlue was partioned between DCM and ver. Te product was extractedl wh DCM. The organic layer was separated', washed vith 3M sodium carbonate (or 11 NaOH' IN Rt brine dried over MgSO, and evaporated, 5g9 Alternative protocc A mixture of the corresponding carboxyiQc acid (200 rg; 10 eq) and amine (20 eq) in CHON (4 ml) was added HOST (04 eg and EDOabout120 mg, 1J5 eq) The reaction mixnre was stirred. 30 for 16 rs. LC4AS showed the reaction vas complete. Then the scWvent was concentrated to dryness to give crude product whw was used directly for next step without purification. the crude product was dissolved in DCM / TFA= 71 (4 mi), The reaction mixture was strred at 30 C for 16 hrs. L&M$ showed the reaction was complete hen the reaction mixture was concentrated and the rudeproduct was purified by prep HC t qve the final product Protocol B To a solution of the corresponding carboxylic acid (5 mmol) in dry THF (10 m) was added Ghosez reagent (10 mmol, 2 eq.). The reaction mixture was stirred at rt for2 hours and the solvent was removed in vaccuc The residue was dissolved in dry pyridine and cooled to 'C fcilowed by addition of Tie corresponding amine (55 nmml 1A eq,), The reaction mixture was Asrred at t for 1 hour The pyrdine was removed by co-evaporatioo withttluene. the residues dissolved in EtOAc (100 mL) and washed with 1M NaSH (50 nL), water (50 iLand brine (50 mY The organic phase was dried over MgSO 4 and the solvent was removed in vaccuo Protocol C. A solution of the corresponding carboxylic id (1 mrnmoi in dioxane (2 ml) was degassed by bubtng nitrogen Arough te solution. Copper (lQiodide (0.25 mol. 0.25 eqi. Cs 2 0C(2.5 mmo. 25 eq), the corresponding amine (12 mo 12 eq ) and N dimethyl ethane(1 .2-dianine (105 mml. 05 eq) were added. The reaction mixture was stred in a closed vial 30 at for 24 hows. Tue reaction mixture was Mtered over Celite and the GAlite was washed with EtC/Ac (200 nL) The fltrate was washed with IM sodium bicarbonate (100 mLt 0.M MC (I100 m) water (100 ol and brine (100 rm-L The organic layer was dried over M h M.,and the solvent was removed in vacwo Protocol D General procedure for Suzuki reaction A MW vessel (Biotage, 20 nL) was charged with an appropriate boronic acid (3 mmol, 2 e), the corresponing phenyl bromide (1.5 mmci, I eg), toluene or DME (3 mL), ethanol (3 nL) and 2M sodium carbonate solution (3 mA, mmo. 4 et. Tue reaction vessel was then flushed ilth nrogen before adding tetraiis(tripherwi phosphine) palladium(0 cata yst (4 mci The reaction vessel was again flushed with nitrogen before sealing and radiating in MW at 1305 for 15h. The reaction mixture resid-ue wamten ooled down and fitered through Celit. Th residue was washed wit ethyl aceote (200 m and methanol ,00 miL The solvent was removed in vacuo and the residue Wstaken up in DCM The precipitate was altered vashed with DCM and cred. The compound was used as such or was purinfed byfiashchromatography(silicaget DCMWMeSH gradient). 60s nernied late it ronse4x4iteriabtoxycarboylarrinoettybenzoc acid HN O< To a solution of 4-acetyk3-bromo-benzo e acd (40 to 80 mmol in AtoH (100 to 200 i was added DIEA (16 eq.) and hydroxylamine hydrochionde (1 eq. The eactio mixture was strrad under refux condition s for I hourThe reaction rnmxtre Was cooled to room tepaete and the solvent was rermwed under ted dce~d pressure, The residue was taken wg in water and a 20% K SO6 onThepereciitaie w'as filtered, washed vith water and dried, To a solution of 3bromo-4{~(hydroximinochthyikbeazoicacid (10 to 5 moi) in acetic acid (30 to 300 ml) was added activated zinc (5 to 10 eqg The reaction mixture was starred at room temperature for10 minutes orp t035 hours The reaction mixture was fitered and the preclpitae WMs wased With acetc acid The sent of e filtrate was removed under reduced pressure. The crude 4aainotthyl>-bomobenaokadd (5323 to 3072 mol) was suspended in a mixture of THF/1M Na0 3 1 00 l or a mixture of acetone/IM Na 2
C.
3 : I (100 m or a mixtu re of acetoneM Na20 3 : 8/2 (00 mO and (Soci$ () eqvas added. The reaction mixture. was stirred at RT for I to 2 hors. The organic savent was removed under reduced pressure or iat iether was added and the Owo ayers Wea sepaed or the reacion mixture was filtered and the orgaronic soent was rt oedounder reduced pressure. The aquous residue was diluted with ciric acid or wit a 20% KHSO 3 solution and extracted ith EtCA ; The combined organic layers were washed with brinedried over MgSC 4 and the solvent was removed under reduced pressure The cordpound vas when needed p..ified by colunA chromatography (smiageI DOWMeOt oradierrt> 640~- Intermediate 2: {1.2aBromo4(pyridine4ytcarbamoylkphenylkethfikcarbanic acid tert butyl ester. 0C To a solution of 3-bromo(14trzbutoxycarbonyarmrioethyl)benzoic acid (74.6 to 6101 pmol) in DMF (10 to 30 r') were added DZEA (2 eq.> TBTU (l.3 5 ) and HOCt (03 egq The reacien mxture was stirred at RT for 6 minutes. 4-Aminopyridini 5 :gq was added and the reaction rnixture was stirred at RT for 2,F hours up to Ovemight When there was stilt sta. ting material observed, more DiEA 039 eq) TBTU (025 eq), HOBt (0.06 eq) and 4~aminopyridine (0.23 eg) were added anid thereactin mixture was stirred at RT for another 2 hours. The reaction mixture was dikted with EtOAc. washed with 01 M HU! and satuatedl >GC or with saturated NaHc'O The organic layer azd dried over MgS0a and the soierdt w as removed unfdcer reduced pressure. The compound was purified by colu r~ hromsat aphv (siticagel iJOMMcGh{ gradierdyt Intermediate 3:2'4( tar utexycarbonyiamine-eth WI 5-(pyridln.4-ykarbamnoy}bbIpheng.3 carboxylic acd, ONN 0 HN1 MN tert.-butyl ester (2 to 3 mm) and 3carboXyphenyiboroniacid 2 eq in a mixture of DME/EtCH/wate:t 2/1 (10 mtI) was added N&r (4 eq) and Pdttrakis (0 ag) The eaction mixture was heatedd inthe microwave at 1356 f 0 g etin. h soients were remnoved under reduced pressure Te resdue was dilted wi MCandtiered over cente' Tie 'smite residue was washed wil MeOH. The solvent was removed utder reduced pressure and the residue was taken up in DCM. The precipitate was fitered. washed with DCM and dried, The compound was I62 puritled by semnipreperative L MS, Dr theresidue was dlutd with DCMIMeQR (32) and activated charcoal was added to the reaction mixture The rixture was stirrd at RT for 10 mrinten and iMtered over eagelhe residue was washed withDCM/MeOH (8/2) followed by MeOH The solvent was then removed under reduced pressure. Method 2, To a solution of {2-brahio4(yrdde4ycarbamoylpenylethikaarbamic acid tebouty ester (312 omol) and 3-carboxyphenytboronz acid (10 eq) irn a mixture of inuone/EtOK: 5/3 (32 ml) was added a soilion of Na 2 CO (3 e)in water (8 mt) and Pd tetrakis (O3 eg> The reaction mixture W aaed under refku conditions for hours. More3 carboyphenyborornacid (0.35 eq) ard Pdtetrakis {00 eq) were added and the mature was again heXated conditions rf 3 hours, The reaction mature was cooled to PT and red over ceite The elite residue was washed with EtOAc and MeOH The sowvents were removed under reduced pressure and the compound was purified by column chromatography (silicagei OC M/MeQH gradiert) Intermediate 4 [ (ert Butexycarbcnylamino othyb5 (pyridin4ylcarbamoylphipheny3 yelcd acid H. 'N H NNOH.~ N~ HN C N:N To a solution of (1 42-bo4-(pyrdineycarbamoy phenylethyl.carbami acid ter-butyi ester (951 rnal) In a mixture of DMmEtOH/2N NawC 11th (10 of) were added 3 carboxymethylphenyiborr acid (1.5 Eg) and Pd tetakis (0.5 eq), The action mixture was heated in the microwave at160<0 for 15 minutes Thereaction mature was cooled to RT. filtered over celite and washed with EtOAc and MeOCt The solvent t were removed under reduced pressure. The compound was purified by column chromatography (silicagel, DCM/MeOH gradient), -363 Intermediate 5,342'(1tertButoxycarbonyaminoethyb5pyridin4yIcarbamoy4ipheny 3yyiipropiorne acid iHN e To asoluion f (l4-2trNmoo#(priwe-4tlcarbamnovi ey ehkara acid tert-buM se (3122 pmol) n a mixture DMEEtOQ/2N NaCOc Ill (20 nmO were added 3 carbOxyethyphenyboroniC acid 0V5 ep) and Pd tetrakis (0.0 egg The reason mixture as I-eated in hue microwave at 15OZ kt 45 minutes. h reaction mixture wascoed to P tftefed over ceie ard washed with EtOAc and MeOH, The so wrerd e ce removed under reduced pressure, The compound was purified by column hrtmatograply (siicagel, DCMZ eOH gradientt lnterrmediate 6 (1-3{44ydroxy-4pyridin-4 ylcarbamoy )-tiphenyI-2-yl-ethylpearbamaic acid tert-butyl ester 0 To a solution of (1424romo4-(pyridte yirbamoyl p ilethycartamic acid trt ty eder 2087 pmoi) and 3ydroxyphenylboroniacid (166 eq n a mixture of DME!EtOH: 1/1 (0 mit were added NaO (4 gG, and Pd tetra is 0 )5 egThe reaction mixture was flushed with A ind was heated in the microwave at 130 kr 15 hour h e reacticnmixture was Qoded to RT dituted with N NaHcOYand extracted with EtOAc. The organic layer was extraced wi N N NaHO> ;lnd the combined aque:ousayers were acidified wit citrc aid. and tN HCI The aqueous lyer ua extracted wi EQA)A the organic layer was dried over MgS ard the sovaent was removed ver reduced pressure The compound was puified by recrystallizatior from EtOAc - $4 Intermediate 7: 2 4tert-Sutoxycarbonglamino-ethyQb59prd'tA4 lcarbamcylkbiphenyi4' yloxykacetke acid. 0 KN tHN .Ot a To a solution of [2.Bromo-4jpyne.yicabamogy)-phenylethycaremic acid tetutv! ester (0.4$ g) in a m mixture of toluee ethano: 513 (12 ml) were added 3phenoxy-acetic acid benzyl ester boronic acid (2 eq), a sutin of NaYCQ (4 eq.) in water (4 I and d teirakis (0.0 eq. he reactordmturo was heated under reflux conditions fr 2 hours. The: action mixture was cooled to RT and filtered over ceite he celite residue was ashd With EtOAc and EtO. The solvent was removed under reduced pressure ard the residue was taken up in DCM. The precipitate was filtered, washed with DCM and dded, The confound wvas purified by column c.ramatographyv (slicaget DCMMeSH gradient). Intermediate 8& (1 2$romo-493Aioropyrld inm4-ycarbamoyq-sphenylj-thyl}-carbamic acid tortbutyf ester, Jj NT To a solution of 3dromo#Ierbutoxyca bonyaminiunthyldenzoic acid (835moin dry THE: (20 m) was added Ghoserreagent (2 eq) The mixture was stirred at RT for 2 hours The solvent was renewd under reduced pressure The residue was dissolved in dry pyrdine (2 m) and 3 luoro-pyridin4wlamine (1.2 e) was added. The reaction mixture was stirred at RT for 2 hours. The pyidine was removed under reduced pressure. The .resuewas dissoved in IN Na and extracted with EtOAc, The combined organic layers were washed with 1N NafHO0 3 . citric acid and water. The organic layer was dried over Acg0Y and the sovnt was removed under reduced pressure. The compound was puriied by column romatography ii ::ael. DCM/MeSH gradient .
Intermediate : 241 tertB (utoxycarbonylanin ethyP-5'(Sfuoro-pydin-4gcarbaroyl biphenywa 4carboxyli 0cid HN O To a soluin oft1 bromo4(34u rn4-9'arbarrphenyf ethylknrtmicacid tert butyl ester (2841 m of) and $ carboxyphenylboronoi acid (e15 ecJ in a mIture of DME/Ethiwater:'111/ (0 ml) was added Na 2
GO
3 (4 e) and Pd tetrakds (O05 egp The reaction mixtrE ws' heated in he -roeoavet 130 foriMhours Tr; action r r Was diltd t water and citri wi a dx v Occihe m orgawsc layers were dried over MgSO arnd the solvent wasrernove'd rnder renced pressure& Te compound was purified by olumn chromatogaphy (silicagel, DCMIMeCH gradient). Intermediate 101 j2'(1-tertButoxyearbonyiamnnethy -(4 fuoro-pyrIdi n-4ylcarbamnoy b Theabenyl-Syloxy- acetic ai d. NN NN To a solution of (1 2'-bromo 4+(st fuupydn y:abmyghrybehlcrFbamic acd tertP sutyi ester (3400 to ses0 pO ) a ndJrto the phenoxy-acetic aid benzyl eideer oonic aid (1 inp DMEwater: 9/1 1 imml) were added K PO4 (4 eq.) and Pd tetraldis (uO f5 eq. The reaction mixture was heated in the microwave at '0I for' En 0 minutes. Activated charcoal was added~ to the reaction mixture and the mixture was filerod over elite. The~ residue was vwashed w ith EtG'Ac and water. The aqueous layer was separated anr extraced with EtOAc; The combined organic layers were washed with brie, dried o er 'MgSO34 and the solvent was removed under reduced pressure. The compound was purified by column chrom~atogfehy shiticapi, cycohexaneacetooe grd ie nt ~ i6S To a solution of [2 .tetbitcxycaronylaminoethyt)5-34uoro-pydir4ylcarbamoyi-phenyW higheny&3yoxacetic acid benzyi ester (2 mmon in THF (25 mi was aded Pd/C (0 5 e The reaction mixture was flushed vth hydrogen A solution of cyciohexadienein TF ( my was added dropwise to the reaction mixture The rAure was stirred at 55'C for 24 hours under hydrogen atmosphee. Celite was added and the suspension was stirred at RT for 20 minutes The suspension was feared and the residue was washed with THF (50 mI The solvent was removed Under reduced pressure, Intermediate It (I -1X-Amino-5pyridi -4-ylcarbamoyly3 pheny-2-ylethylearbamie acid tert-butyl ester. H NIN M N o a solution of( rm4yii acid tert-butyl ester (1428 pml) and 3aminophenylboronic acid (2 qc) in a mixture of DMEiethanld/N NazCOQ 1/1/I (3 ml) was added Pd tetralis (05 q). The reaction mflixture was heated in the microwave at I fcr 15 minutes. The reaction mixture was cooled to RT and diluted with watered extracted with EtAc. The combined organic layers were washed with 0M HO, dried over MgSO 4 and the solent was removed under reduced pressure.
hvtermedlate 1 2;(143Amtineo4$4kluro-yridin-4ylcaramoythuphenyi2~yibthy)~ carbamic acid tWrt-butyi ester " N To a soluon of (i12-r ro pyden4 toar phenyfethcadanic acid tert buty ester (IO9 m and peq) g a txbara of Ee4haniB N NarCZ% tif (0 mni) was added Pd tetra<I& (0%0 e<4. The reaction mxtur was heated in the rrcgewav; atW I bI0fr '1 a hours the reaction mixture tiascooled to RI and diluted with water and citri acid and extracted with ruOAc The combined organic layers wars washed with water and ine. The organic layer was drie over MySC> and the solvent was removed nerreduced pressure. The conspound vas purified by coamn chroraryy tsiniage, fCM/MeOH pradiertt intermediate I &'-[21 4ert Stoycahka nio-ethbepyddWnycarbamoyspheny1F MH-pyrrole-carboxyic acid HN 'To a solution of [1 42"bromo#4(pyridin e4~y" .srbamcyy phernyyethyi);caraminc acid terhhutyl ester %00 pmno) and 1IH-'rledcarboxylio ad d na hwedAer oonioc aid %t15 e) in a mitute of UMEletGH ri 8 wiw'4l 'ere added Na A '>1 and Pd tera. is (0 a The reaction mature was pushed with Ar and was hate n h e microwave at 13(C for 35nmntes. The reaction mxture was coded to RT diluted wilt weter and extracted with EtDThAc. olvent of the organic layer was removed under reduced pressure toa solution of 4{2j1 ertautoxydaron<y amin< ethy'lh (pyidine~ycarbsnoyit'phenyhI H pyrromire-aboxyic acid mthl aster (561 prrt w PF (13 mi) and MeOH (14m was added a IN UGH solion (1 mIo. The reaction mixture was srred at 40'Cfor$ hours The reactin -68mixture wvas diluted with saturated NaHCQ 3 and extracted with EtOAc. The eosa yer is at;ddefed with a 20% circ acid sciution arnd extracted again wiith EtOAc. Te combaned organic layers were dried over MgSsX and the solvent was removed under reduced pressure. Intermediate 14: 442-( 1 tert~Butoxycarbony iamino-thyl54pyrdn y carbamoyA)py henyl] INHndcde 2cartcnty~ie acid OH Oh 0 HN " N 0 N ii To a solution of{42.omo4(pyneny"carbamoyiPphenylyethy tcarbamic acid terttbuty ester (952 pmol) and 4broro4 idole-caroxylio add methyl ester barOnic acid (15 oy in a mture of DMOi- 8H ( mV ) were added NaCO (4 eq) and Pd tetrakas (0.05 eq.. The racenxture was pushed with Ar and was heated in the microwave at 130C for35 rwies The reacdon rxturwas coed to R , duted with water and filtered, The residue was dred To a soluion o 44[2 aminoemyib51pyidi4ycarbamcyippheny1H indoe-2-carboxyiic acid methyl ester (600 pni) in THF (2.4 m and MeON 2.4 mI) was added a IN :iO solution24 mi. The reaction mixture was stirred at 4000 for 6 hours The reaction mature was diluted with IN LiOH and extracted with EtOAc The ageous layer is acidified with a 20% citrc acid solution and extracted again wihtOnc; The combined organic layers were dried over MgSO ard the solvent was removed under reuced pressure titermediate 15: 3-romo4tert-butoxycarbonylaminormethylbenaoic acid 'To' Toa suspension of 3.-t~omoeethybemoic acid (300 1 39 mco)in MeCH (3 L) was added H'S06 ( ml), The reaction mixture was stirred at 60O0 ovemight The reactin was cooled to roonm tern e, evaporated and the residue was dissved in EtOAc (2 L), The EtOAc solion was washed with saturated NaHGOjd 'I L). dried over MgS0 and concentrated to dryness to give the corresponding methyl ester as pale yellow oil (303 g 5% yield gq .
A Solution of the previous methyl ester (303 g, 0,8 mo 1,0 eg) in anhydrous CCi 1.5 L) was added toa soauiAn of NBS (83 9p. 1.03 rmo 1 05 e) and AIBN (8 g0049 mot0.05 et A anhydrous 0014 (1.5 L) at room temperature, The reaction mature wasrefluxed for 1 ra, cooled to room temperature, evaporated and the residue was dissolved in DCM (2.5 L. The CM solution was washed WIth saturated NaHC (0. L) and HO (lS The organic layer was dried over MgS2A and concentrated to dyness to gi4e Crude brmor4-brornomethVbeneoi acid methyl ester which was used for next step without furtherourification, BocNH (15 g, 0925 mo, 1.0 ep) was added to a solution of ItBuOK (124.5 g,1.11 mI l 1 1 .2 ei) in DMF (3 L) the resuing solution was srtired for 1 h at room temperatre.Cde3bromo~4 bremomethytenzoic acid methyl ester was added to above reaction solution at room temperature and stirred overnight The solvent as removed under vacuum and the residue was dfsto'ed in DCM (500 ml The DCM solution was washed with water (3xS00 mldried over MgSO and concentrated. The crude product was purified by column chromatography on sica gel using PE EA 20A to give diBoc4Aminomethy3~romobenzoic acid methyl este:20 g 70 yield) as yellow snlidt Tb a sdutrnef thepevous di Boo protected benzyiamnne (290 g 0.352 mrt 1 eg in DCM (2.9 ) was added TA (8 p .3j mci. 1.25 eq) dropwise at GO the resulting mixture was srred at room temperature for 4 hrs. 0.5 PA NalICO was added to the mixture to adjust pH to.The reaction mixture was Washed with water (3M60O ml), ded over MgSO and concentrated by rotavapor cs givebtrma tertbuoxycarbonyiarieagnethyi benzoic acid methy ester (210 g, 8 3% yield) as yeiow oil. NeOH (4&8g, 1.22 mt. 2.0 eq) in H. O (1 26 Q was added to a solution of 3brom.4-(tert butoxycarbonyiamino-methybenzoic acid methy ester/ 210g, 0 1et mo.0 eg) in MeG{Ol (126 L)g The reaction mnure was stirred at S'C for 2 hrs. The reaction was cooled to room temperature and concentrated to half volume The residue was acidified to pH 5 by adding 1M MCI solution.he resulting id was collected and 4d to give the tite intermediate (200 g, 9.4%yied) as white solid. Intermediate I6[2-Brom~4{pyridi n4 carbamoylbbenzyIkcarbamic acid tert-buty ester. N N ~ 0 To a solut n oi intermediate '15 (10 g 0. 30 me, 10 eq and 4~-imnopyridine (28 5 g 0 303 m2o, 0 e) in DMA (1 1L was added EtN (306 g. 0.303 ml, 1.0 eq), MAP (3. g f 0030 m I 0. and tATU (115.2 g 0.30 mel 1 0 eg> The reaction solution was It"red at 3 for 16 hrs Solvent was evaporated under vacuum and the residue was solidified by adding DCM (00 ml) and
H
2 0 (600 m)to give the lite comound (86.1 g, 0%ield) 70- Intermediate 17 [2-;omo4-(3-oro-pyridin4ylcarbamoyl)benzy]carbami acd tert butyl ester, h'ntermnediate 17 was prepared as descrned for lnter~mdate 10 Intermediate I& 2'-(terButoxycarbonylamino-methyl)-T-(py ridin4-y carbamoy skuphe nyh 3-carboxylic acid, 'N To a solution of intermediate 16 (35g. oI ueq) anl 3Mcarboxyphonyiorgnt acd 4 &27p, 0086; Oeq) in DMF (50m and HWD (87 5mY was added O0(182g; Oiamol 2.O4 Then Pd~~~dppf)01 2 5 (35g flO3oOieYWas added to the souo Nder-. Thersiioskto was Stied at 100 for 1Mrs. Solent was vaporated under vacuum and the residue was purified bycolumn romatography on Sica gl using Dgo! MeiH 10 1 to give the ttle compound (27g, 70% yieldFas brown solid Intermed late 19: 2t4(tet~Butoxycarbonylamin0a methyV)443uro-pydin4ylaramoy9 blphenyl3-carboxylic acid. Ctf niterme -iat.,, I A:p ff sfr11 ttin r~n 7 , 71 The lowing iten edatsas p epard in a Sf$0iyvv Name inemcae tutr Stioxyca3rbony am no methy )45V34to> pyridin-4- ~ ytcarbamoy)N cir N N b H [9E~H ydcoxy-5(pyrid~b n biphenymeiny1 21 N 0 caanc add ltsrt bu'y 'ester 22 r N ) F~lsuoro-pyrid n4 ylcarbamoy31 hyctoxy-biphenyk2 ~2~~ A yamany caram H ac ar-buty ester NHZ [3 Amrino-&(pydirn r N 24 FN 0 tearbamoyi) carvamia aci ert at butestr I t'ArinDo 53-fuoo pyridin-4 hihenv2yr Hty 2 carbamic aci tert> "~ ' - ' butyi esterNN .~~~~~ ~ ~ ~ . . .2.......
v v "asyI 3-yoxy-actc a, a ,N_ H20 (5rN t vvxy8dabnys Tbatdd d(27 merg e o ' Nw bojth ebtiing vmiit etiia zr' 3T yI ikntmediateo [2(eratoxyaron nozZ v methyl tlkpyridin.ytcarbamay bihey o coszmarn oI rsidute ws putinedr N2 Thnn reutr ouin wa gmne 310 DC; fo er 10c to give the tcmn2g 57A% 'w4 steps) as wh'e soki, r3 Intermediate 28 f2terutxycarbnylaiomethy534uorpydii-49varbamoyA biphe nylx3ylox acetic acid Fa latrmdite28 asprgaed s os iedfo rrd t 27 stazving frominemdaet When a cc-opond of ble irwvention rontains.an ester group it can be ma-do ais (RisciNbd irnh e or Rt e !) J I~ TBfz OMDEA, ')MF, rtsr RO, ODGC DMAP DCiM rt (f) Ghse ntAM T D rF foe.'"Z d by Rv Protocol E; a sue i k'f6 y 5 onF (1 mn,)1weKe adedDI~ r5mmok. 3 eq) TBTU (0O2 25 mmol, 1,3 ogH-5t (0,075 m i 02 eq) arld the reacionxtur wa stiedat rt f5n min Acwed by additier of te corresponding alco(1 1-5 In)tereat as m :red was escrdat rl for iten1r 1,tten with7 estarhn fo e ate100 m1 wa Shed w!haucsstrpdodumcroaeskto $ L)01 ~ 5 ~ ae mnL) an crmn of the irganconas wan ster grdoup it cand maent sdrbed in the of ri anral ypelo b :ner,0 toafod hodsre 0tr Protocol FE To a salpesion of thhe corresponding 25 rmmdl) ing toM (trh S)e retod meaed by adition ofthe chemdsein alcoho kA.now the kleain ne ured was stirrme attorig t the dit-ed wit etynt acees a n washed wiT auo sturted sodiuparndin sarbone (d50 0 mm), lM H(F i)tr D (SOm ink) ad brine (5s inded The rag paewas henr d rioethy54pr oenraed OAS vaurrb Acids-5of 0fi gneali tyeg Thne econmtedtuTes cirreodin esters waccoring toathed utgic meodmdaed by aon cofresponing tihersnc2e4 ofTM. rec entry was wtiet ownfo 21Th 0.5 was. ev rqu The resado ireuwase was diled with EDc in wamed vo -74 saturated NaHCO 5 The organic layer was dried over MgSO t ard the sowen was removed under reduced pressure General scheme or convers"or of acids into thiotes 03-i S-R, IC (g) R'SH. DCC, DMAP, DCM or DMF1 rt To a solution of the corresponding carboxyic acid (1 inrnoi in0CM or DMF at 0*Y (10 mL were added DCC 11 rmol, 11 eq) and |DMAP (01 mm 0o , eq) foiiowed by addition of the or gthiot (24 eq) The cooling bath was removed and the reaction mixture as stirred at rt for 1-1Sh The reaction mixture was diluted with DCM (100 r, washed with aqueoussaturated sodiumn carbonate solution (50 rnI 0 M HC! (50 mL). water (50 m: and brine (50 m Pi The organic phase was then dried over MgSO4 and concentrated in 'accuo to afford the desired thioester. iemative protocol A mixture of the corresponding carboxylic acid (200 re 1,0 eg) and ethanethol (2.0eg)in CHCN (4 ml) was added HOST (0A eq) and EDCI (about 420 mg,5 eq). The reaction mixture was srred at 30 ZO 1br6 hrs LC-MS showed the reaction was complete. Then the solvent was concentrated to dryness to g rde product wnich was used decty for next step without purification The crude product was dissoeo in DCM!/ TYFA,:-(4 ml iThe reaction mixture was stirred at 30 C for 1 rs. MS showed the reaction was compete Then the reaction mixture was concentrated and thecrude product was purified by prep HPLC to give, the final product. General scheme for conversion of heteroalkyl groups to lactone derivatives Alcohols or thiols of general type can be converted to the corresponding heteroalky linked lactones according toathe general scheme (XeQ 0 o S. H - ----- I (h) DIEA, DM7F, rt To a solution of the responding thiol I mrml) in DMF (10 m was added DiA (2 mmol 2 eq) followed by addition of the corresponding bromnctone (. mao , 1 -e The reaction mixture was shared at rt for 1h then diluted with ethyl acetate (100 ra) Uwashred 01M HU10(50 mL) water (50 mL) and brine (-0 mi The organic phase was then dried over MgSO 4 and concentrated An vaccua to afford the desirediactone. -75- Intermediate 29: 3(2Anmine-ethylstfanydihydroduran'2one rom-dihydro-fuan4-2ndh (249 151mrO 2n.0 g(oamnojethanethiel (2 9g. 164mmol weredissoved in 4OmL of CH 3 CN.Then KCO(U4g 30mmo wasn added to tq sri. Let it siCat Befor 16h. The solvent was evaporated to dryness and the residue was purified by column chromnatogra phy (PE/EtQcM4A to :32g of BOCrotected intermediate 29 as colorless oil The raiS compcndd (3. 1.mnnoi)was dissolved in 0mi of EtOAc Then 4mL of 4N HClfEtOAc was added to the soluo Let R stir atsf2C for 2h The white sodid was fileredand whsed wnh PE to give 2g of Intermediate 29, Intermediate 30: 3 3$Aminoqpropylsulfany )dihydro-uran-2~one, Aminciopropan~ol (40g, 0533moii was dissolved in 1L of THE. Than IoC) (127.26g, 58o) in 450mL of THF vas added dropwise to the saluto at 25C Let it Oir at 20 for 1 2h 50maL of water was added to the soution and it was extracted wih EtOAe(00Agt. dried with MS . Filtered nd evaporated to dryness to give 60g of the correspond BOC protected compound a CAOdes oi. Bco protected 3Aminopropan-ol (30g inmol) was dissolved in 600mL of dry THF, TEA (48mt, 0345mo1) was added to the sluken. Then MSO (26NK .) was added slowly to the solution at 0tC under N Let it sr at 2h fr 2The nixturo was washed with xsater and dried wih MgS04, Filtered and evaporaed to dryness Is give 40g of Ms-protected product: The above compound ( 4 0g 1mol) and CHC(OSK (54g, 0474mol ) were mixed in 2.L of EtOH, Lot it stir at 90"C under N for b. The soent rwas evaporated o dryness and the mdure was purified by column chromatography (PEEA=10/) to give 15g of tbioacetic acid -(3-ert butoxycar bonylainn-propyl} ester as orange solid Na (708 ig, 30 mrnolt was added to 100 mL of diy methanoland stirred until the metal Sodium disappeared To the solution was addd the above compound (g, 25 room The miure was stirred et room temperature for 2 TLurs C L showed the reaction was completed To the mixture was added a sltian of IBroim-dihydrourar2one (5.46 g 33.3 rmoi) in 100 mnL of CHOb followed by addition of00 mL WM{ The resultng Mture was stirred at CWoC fr 6 hours Tc showed t reacton was completed. The reaction mixture was partitioned between 800 mrL of EA and 400 mL of wanted the aqueous layer was extracted by EA (800 mLt. x 2, The combine -76 oran!o a1yers were dued uttered and concentrate to give the crude product, which was purified by column chromtography (PEiEA=4/1 to gve Sig of the title BOC protected compound as cloress ol The BOC rotete derivative (h, 't2.nmrno1 ) was dissoivedlirdtl of Elnc Then 40mnL of 4N HatdtAc was added to the solution. Th a i was stirred at 25'C for 2h. The white solid was fSered and washed wdhI PB to give 21g of The te campound. hatermsediate $0: 442sAmie-ethy-(1 4dioxetanmene 6f3mL saturated sIun of N , in CHgOH was added to 4n-but.ene (3mnt qukcly in a 10moL reactor of autOdatve. T he catre WK45 stred at 90 "0 for IS hours in the autociave. After reaction, the remained solvent was removed under vacuo. The hydrobromide salt of Hut4 enylamirne (12q. 95%) was recovered as a yehow power. TO a suspension of the previous compound (1:2q, 0Th8mno) in CH (1. v(Ias added a soluton of K40 (3g. 0,24mol) in water t80mL) under NZ, The bephasic mhxure was coded to oC and OhCl (22g, 0 1Alc)' was added dropwise After 15it of s rg at the temperature the reaction mixture was s Wired for 14 hous at tom 4 ep"atr Mir the reaction competed t the mxiure was added C+', and water the orgebie tayer was dned over anhydrous Na$Q. concentrated under vacuum and purified trough siica geghongraphy (petrolumethy acetate = 1) to gie the corresponding CAz protected compou (12 2g 75 as ooness 00. To a trred SHution of the above compounds tmo) ir aceoe/ftC (f0ml/S0mL was added NMO (7.3g 62 5diod) and OsO (303mg 1 mmo at room temperature under N. After addior of C the color of action ao turned blac. Thenhe mixture was piired atoom temperaturee for 1 h TLC (CHC6i4eOH 10: 1) showed the starting ateral was consumred ompietety. The mixture was evaporated under vacua. To the residue was added water and extracted Wih ethyl aceate TW e organic ler waS ned Ovr an hvdrous Na'S concentrated under vacuum and purifed through chica gelchromatography (CH;COi>eMC = tO: 1) to give the corresponding diot (12g.85%) as pale solid, To a solution of the diol (9g. 3S6nrn2mo in C>Cl (2Omt) was added triethyamine (152, }i~imnie at Af~4OC undor N>. After evers minutes trphogene 5g 3 mnmo) was added to the mriture dopwtse a tis temperature and >r at 2O'3C for half an hour Then the mixture was stirred at room temperature tor 15S. TIC (C Y/MeO-Ai 10 1 showed the starting material was aTostoonstmned To he rngine woo added water and ezdradted with ethyl acetate The organice layer was dread over anhydrous NaSO~,concentrated under vacuum and purifed through siea gel chromatography (CHtC /MeCH 10" 1) to qie the corresponding cycized dioxolane (5g 55%as pale solid oa suierof the Laovecompound (50, 20.mmalinoh OH(10mQ was dded cry Pd/C 500mg, 10%) quiky under Ny. Then the mPArre was serred at room temperature under H ovecnight. TLC (Cd &laS 410: 1 showed the starting material was almost consumed. The smr:re was tiltered via S pad of celte The soluigri was evaporated under vcu and purified by sitMa get (CH:CtPMeOH 10: 1 to cive the tie inermediate (2J09 77%1 aswhte scHO Intarrnedlate 3i 3-(4iydorxyethylstayldihydroran~one Th a scatdon of 2mmerzaptosethanot (2550 pma!) n THF (4 my were added D1EA (1.1 eq) and % bromo-dihydrodurmitne (1 eq). The reac iomtre was stirred at RT for 4 hors Th preCPitate was littered and the sowent wasremoved under reduced pressed itermediate 32: 3434ydrexy pvopyfsutfanydidydroxurena2oee To a sution X 3 mercaptotrop'anJ (1605 pmoi in DMF (2 milwere anded DIP O .EA 5 aq) and 3-breadhydiroun2-ne fti).g The reacan mnkhre was stirred at RT for 4 hours. The precipitate was altered and the solvent was removed under reduced pressure ~ntarmediate 33 3;brmoerethyoxetan-2hone To a soutdon of Br g8 g( {0303 onmoO in ether (150 mO was added dropWse a solon of compound but-eprric acid (2 g Q 0302 mald i saturated NsHCQ (110 ml at (it Afer addition the m-iture was stirred for Ih. TN (PE:EA=4:1) showed the reaction was complete Saturated soio (20 ri) was added. The racon was e>tracted with BOAc (100 moL x 3). The combined layers were washed with ldne, dried over Nao, filtered and then concentrated in vacuo and purified by column chrometography on siica get petroleumm ether ethyl acetate 201) t obtain the title compo und y 3 ) a white (M.
-.
Intermediate 34: 3M{Piprice4-y htthyfanydhydrfuran~oe 0 HN ', Intermediate c4w prepared as described for miterm ziate 30 startig frgm 4tydroxymethyk piperidinae.~I~arboxytic acid terztbutyl ester. intermediate $$ 3-(2-hydrCWythox)<ihyrouran4ena OH A solution of tog of 2,dihydrodran in methane 70mL and chloroformn 30mL was added 909 of mhiompremyenzic aid in smallportons wit slirdnc at 0 f0 for I mins, hen the reacton mixture was stred at QS4O kbr 1i hre The r nature was fdtered the filtrate was conce trated under raduted pressure. the residue was dissolved in chitrorm 500mi washed with 2ImL of sat, NaHCOt and 200mL of brinA, Te organic fayer was dried over Na SO4 and flteret The titrate was concentrated under reduced pressure to aford t3 ofm ethoxyetrahydro-fura Zot A solution of 2nethoxydtetrahydrodurKnoI in DMF 200 mL was added sodum hydride in smali pnrionrk swth stirri at C for 2hra. then 2enzyoxyethanol was added from the dropping fiunne over a period of 1 hour, the resutin mixture was stared at 2t5: for ' 16rs it was poremd into 400rL water EtDAC(I}4 were added and separated. The organs ev er was washed with sal NdaHCOgdSOOni, dried over N2SO04, feoed and concentrated, The residue was pudfied by colurmn chtamatograp Pt&E Anz; to yiekd 1Og of 3§2 entoxyethv424mez hox4etrahyroc furan (oil To a solution of the previous compound in mL of 40%aqueous MaCN was added CmL of concentrated HS04 and the mixture stirred at 35C for 4 hM, The resulting mixure was neuralized O: NaHlO then it ws concerted uderrduced pressureEtOAC(300mL) were added and separated, The organize layer was wasted with hrine (0nI> dried over Mg5O4, Stared and concentrated, the residue was puriied by column chromatograpy (PE*A- :1) to yield 4 3 o of 3atemy>ethoxy)etrahydte--rwrS efoli To a solution of The above cormpound in 2SnLt of DM$Q was added 17mL of AcrO with stirring at 2SC for 15 KS, the resuting mixture was poured into IOOmL of water EtOAc (200m)were added and separated The origenic layer was washed withsat NaHCO S(t) and tbine t0dlb dried 079over MgSO4. filtered and concentrated The residue was purified ry column chromatography ~PE:FzA) to yield 2.59 of>(2benzyoxyethox)~dihydro~uar-2.ene (oili A mixture ofhe above compound and ig ofpaiadiumn charcoal 8 00mL of methanolwas stirred under I atm of H 254C for 5 hs. the resulting mdure was filtered and firate was concentrated under reduced pressure to afford I35gof lntermediat: 35 (oi Intermediate 36,hydrowymethy-dihydro-thopherr2-one RO Thioubyrolactone (lOg P9mmol) in anhydrous tetrahydrouran (200rni) was added dmpwise to a stirred soiuhto of;ith duisopropylanmide LDiisopropylamine (15 I,115 mmo) and nbutyiithiu .n hexane.5/M (47. , 1m 7.mmno at "Q The resultng sohion was stirred for10 minutes at which time formadehyde (ag carried na stream of, wasadedFornaldehyde was formed by hating paraformaidehde to 150C1. The reactnwas allowed to proceed for 2-5h at 7 C, The formaldehyde stream was removed and reaction was allowed to proceed for an additiona 30irrns. Then SO0m! of ethyl acetate was poured into the readion mixture while stirrng then quenched by the addition of (~300m(1M HCI at 3C then allowed to warm to room temperaturewhile filtenng through a bed of ceite The filtrate was extracted withethiacetate1t for more than 5 times ar, the combined organic layers were dried (Na!,}and concentrated to an oil The oil was purified by chromatography (PE!Ae Ito give I70 p of the tile compound as colorless cdi Intermediate 373-hydrywmethyldihydr frant2one To a stirred suspension of NaH(SJ7p, 244mmo 60%fin 250mW o TiF was added dropwise the mature of20g of ybuyroiacdone (20g 232mmo1) and methyl fermate (14g, 232mmol). The resultirq midxure was stIred at 2&C for 2Thrs The solid material was filtered and washed with hexane, after which itwas suspended dry iethanoi (SO mI. A soltionoHOeOH (4M) was added dopwise and the mixture wasstirred for ir Afte carefully neutralization wihNadd the mixture was filtered and the fltrate was carefully concentrated. Water was added and the sciution was worked upn as usual to afford 23g of crude aster. Vacuum istilation (t0-0420"CO 2OrmHg} afforded 140 of 2amettioydetrahydrotiran2.carboxvyic acid methyl ester as a colordess oil To a soluion of 2-methoxyeerahydroiu rarm3-carboxyiic acid methyl ester (lg,62.Smmoi) in 60mI of dry TI-F was adder 475g (Ifi~mmol) LiAIH 4 al 252C0 The mixture was refluxed for 4hrs and cooled. 4 75mnl of H--,0and 415m1 of aq. NaOH( 10) were added to thereaction okxture m turn. 8O Theresuting mixture was filtered and the filtrate was concentrated to yield (2-methxyetahydro> bran-ywihmethanool (gML To a sduon of the above compound (Tg, 53mmo i ir 00mIf IMF was added NaH32g 80mmod60%, followed by Brf (12Amk 10mnml) he resulngixture was stirred at25io for 2hrs ard then poured into IL of water And then the mixturewas extrated with EtOAc SO rnV3) The rbned organic yer wasdied over MgSO 4 filtered, and concentrated. The residue was purified by column chromatography (PEEA=2:i to afford Oenzyloxymethy- mehoxys tetrahydro-furan (NOg) To astion of the p compound (10g, 45irnro) in DCM (130b was added BFtE.tO 3m)and 1PA 4 m 5%. The resulting mixture was srred at 25*C overnight. The reaction rrxture was dituted with EtOAc (SO~mI) and washed wit 10% Na 3 2 % at. NaHCC and brine The organic layer was dried over MgSO4, filtered and concentrated The residue was purified by column chromatography to afford the benzlprotected intermediate 37 (6 .g), To a soiution of the above compound (6,7g. 32.6mmlo) in EtOH (200mtrnlwas added Ig of 10% of PdC and hydrogenated for 1hrs atI25-Nn 1atm The mixture was filtered and concentrated to afford the compound (3 gn intermediate 3:5-(2-hydroxy-ethy4-furan-2-one. O MOH To a cooled solution of furan (3rg. 50 tmmoi) in THF (1, mL) was added nBuLi (22mL 25M solution in hexane 55Ommo) at 0tZ under inrt gas atmosphere The solution was allowed to warm to room temperature and sirred for 3 Then TMvtS (5.34g, Summoi was added dopwseat O'C and the si3n was stirred for t her 3h at room temperature Subsequently the soluion was aain cooled to ttC and n-ut (22mL 2 M solution in hexane. 55%mmol) was added a second timeAfter stirring for 3h atroom temperature ethyleneoxide (42. 55.mmel) was condensed by an acetone/dry ice condenser into the siutin ard the solution was strtrd for further 1h at room temperature- The mixture was quenched wih ag NHCi, and then extracted with EtOAc and the corhined organiclayers were dried over NaiSO toafforded the desired produc(5g27.1mmo, 54% over two steps)as a yelow tid To a solution of the above compound (3g. 16,45 ri and NaoAc 64g, 2.0 mmo in CH2O 0mL) was added dropwise a solution of CH 2 C f (1, 40% in O) in CHAC (YUmL) The reaction mxbre was stirred for ovemight at room temperature, The reaction was quenched with Na 2
S
3 washed with saturated NaHC and brne, The orgaclayer was concentrated under reduced pressure; The resulting residue was purified by odurn chromatogrTaphy (PEEAN: 2) to give 05o of desired product as a ylitow liquid (0.g, yid: 24%) -81lMtermediate 39: (2-Oxo4etrahydro4uran-3-y lsufanyl)-acetic acid. 0 Potassium ethylxanthate (58ROg, 9 4mmo} was suspended in 00mL of dry acetone at room temperatures. tertButy chloroacetate (50g, 332rmmo was added dropwise with sirng After 86r potassium chiorsde was removed by fltion, and the solvert w a evaporated, Th residue was taken up nto ethe, washed with 5%. NaHC0O water, and brine dried ever MgS Ltered, ard evaporated to leave 80g of O ethyl S(terbutoxycarbony1)methyl dithiocarbonate as a thick oil. This 6i was stkyred withelhanoiamire (32Snmi) for 2 m at room temperature The reaction mixture was taken up into ethyl acetatel washed with 12N HGC water, nd brine. drie over Mg0D, fiWtered, and evaporated, The residue was vacuum di- tied to give 30g of mercaptoacetc acid te-butyi ester as a clear oil. To a souton of 3-bromao-dihvdroefuran~2-ond (I6g,975rmoin $00iL of CHdN was added l4mmol followed by moroaptoaetic acid tert-butyi ester (I 45g. 98mmol), The reaction mixture was rfluxed for 2hrs and cooled.The mxre was fMtered and the filrate was concentrated, The residue was redissoiveddi 300mL of EtOAc and the resulting solution was wvashed with IN HCI(t00ml2) The organic layer was dried over MaS. fitered arioncentrated to afford the terhutyz eshr ite compound (Pg).6g of tha eser was dissolved in 2S0m1 ofHC MeSlH (4M and strred at 25'C for 4rs. The reaction mixture was concentrated below 45C in vacuum..The residue was purild by colun chromatography (EtOAct to affodYg of the ttie compound. L3 7 Compnowxs of &e nove nton in the tables I to 19 that are set fart below, exemplary compounds of the invention are set out in tabulated form, In These taLs, the namoe of the compound an aritrar iy ass ned compound number and structural informaton are set out Tabe i shows the results for compounds of Formula lie or hb a Ar. R H ArA N 8f2 Name Cpd Ar R r 2>Aminomety5-{pyrd n j4A y carbamoyQ4NphenvgJ-arboxy~ 1 acd methyl ester yibarbamoyilbpherny4-arboyt 2-Nc~b acd methyl ester 2t-Amimethy 5(yriridm4 ycarraoy bipherQ~-carboxyl 3~ 44~ acid methyl ester 2. Am - -ot-y- -5 -pyid im 4- K ytcarbamoy hbipheny'F3earboxyk a 4d cd methyl ester pyr -- y-carbamy)-- phen --- 5- 2e -(c ac A umethy ester pyrrolot2.3blpyridinr4Aytarbamoyl} T< lc ester 2'-Aml nomethyk-(prPiin,4 y carbamoyi) bipeny3-carboxyli c acid ethyi ester 2-f( Amino-sthyi)-5-(pridiln-4 ylcarbamnoy'-bpen3-crbxNi add ethyl ester 2' (1-Amino-ethyi)-5'(3-fluoro 'ry ri4y"lrraramol)-bphenyl3 carboxylic acid cEthyIester +Am n.m.h.. (py.i..n ad CHI!
NN-"
ylcarbamoyi)-biphenyP3C~arboXyRC I'~ ' a d popyi ester An ety 5pyridii4 ad popyl e-ter --------- - -------------... 8- Namrre Cpd Ar Rr -R 2Jmn tyi lur pyide4-ylcarbamnoy)-tph enyk3 1 (:5bQny~C acd prOpy etr --- -Am-no th------r .4 acid butyiester 2; Aminmethy-5pyni-4 1 -------------------------------------- A -o 'a ii~ t pd-4 <y carbamcyW)-bipheny3-carboxyi c 4 add psyl ester 2 -rnaneti-5'(pyndin-4 yarbamOyl)-b phenyl k carbOxyA s Q add perxy ester yicarbamboy b phe-ny 3-carbexy 4c 2A! yaraca~ihey Castr e acid otyl ester 2-- -- Arni-r.--eth ) pyri- -i--- - ycsrbamcy ~)biphery-3-carbcoxy~ir 2uM acid decyl ester rbamoyl} hen 4carbxi c21 aCd undeoy esAr 14{I Wmioetyi (ydir4 4' varbamoyvphiphernyl-3-crboxylh 22 N~ aWd dode easter --Am no-ethy13(pynidir4-<"N .'- -A yicarbaraylsphery:3Adcrboxydi a -cd t d-v -------------------- _ _ _- -- --.- 84 - Name Cpd Ar Fr 2iAmisoetbv5pyridin4~ oy pheycarbxy. s24 acid dc e t estr y car-amoyl--iphe r 3- ---- oxyUi- 2 a cd--poyl ester 2i Aminornthyi-5-tyvir4 ycar barmyV-ipheny-3 scbd: h 2 acid isopropy ester plcramd biphey-J-aphen~ 3 28 ~i: i g~29~ -H pyr-----------t- m o----be-iy - -23 --- N arxyic d trisu ester Z-Amninometh ykld{yridin~4 - -arbam y--i phen a3 xylc> 5- - . acid cycropty ester ycr caraoy )IghpfenyI--3carboxys -vh 3 aid CyclcprspyiestkT 2 -Aminocrnethyi-S-(yn4 ylcarbamoy)-blphenyi-3carboxti 21 Ni acid cycoley ester ylcaramy bipheny-3--arboxylec '' NH u -- -d c--cpenty ester 2 ~ A- -t- -- ihyi)o-5 - -pridri- - Caramobpheny strby84 ytIA c niha eihyi)5 (pyidi-yk auNid cibhelt ester Name Cpd Ar -R Formu y-ca r--l-h y-- --- car o y 3 acdd cyC opropylmethyl ester ~- ---------- ------------ ----- ------------------- 2 (1Aminowezthy0 5j3-1uno- 1VV pyrid nAylcarbamoylnhphen~yl 3a -carboxyic add cyc opropynlethy -me YAmn-eat---pyrdn4 add ycarbaracyin~heryV-carhcxyli 39 1-* acid ccdeymeyl ester - - An -- - t---- -- --- py r- - - ------------........... ycarbemxdi--phenyi-s--erboxy~ 4 42C acid scbSt ester 2'------A-inc-mety>---(pyridin--4-
-
ycarbamoiy-bipeng -cafbxyfo - 42 H acid smethxylpp ester -Ar4 2C Aourethyl (>p{yridi 4. ycaramyl-bphenyki-or>boxy 41 3 id 2etrhdro--yranyi ester INadiad 2'Aioe-
--------
p--------4y ceabamoythbiphenyk-3carboxyii - c acid 2etbydropryletr 2T (Amino ethyl
--
(py-d-ir4 olcrbamovi)-bihenya cosoxyi geH 24$n ncnlahy S'3- cr y-rbd - Cyirbaip- n y3-carhox-- - - .
-... 6 aroacid tetra hydroodrurar-y meh2 Te ste Name Cpd Ar R Formula 2 Anino eh> (34u )ro> y-------yica amo -. he carboxyile acid tetrahydro.pyran2 ylmethveester 2 Aminometh yk5pyrid in y corbarmoylIbiphenyl3carboxyic 49 adid ni -thpipeidi-4/y ee y carbamoy)--pheny a 3 -rbOxy c 49 ---- --- -..... 2§Ancnmethy pk.~ y'rid 4 yicartnam.y -bppeny 3~ Carboxy e 51 .cid 5 .th.W2o. .. ox 4 yimethyl es erC 2-Arminometh 45(pe I, x ad adamantan y m ertty cser ZA&miom ethlyi-5-ryrnd l y cr bamy) -- b eny-- -carboxyg 2 acid chocromnetytester 2 Aminonthyk5 pyridmn4 . ylarbarnoy5bi3phonylH-carboy -H acid 2-oro-phenyl ester 2YAminomnethyl-5N-(ydin4 Iyk arbamoy kI>pheny3-aoxyii 54 I'A acid th.iophenr2.yknethyl ester A'-Aminnmethy5'-(prit4 Icbamoyl}bip eny kcarboxy c 5 e acLs acid 23-i hydro-tenzo(14doxn- 2 vieth.y ester dcarbsanOyYiphenyi3 -Catox N 06 acidi 2 ,3-dihydro-benizor4 I]dioxi 'l 2 ynethyl esterf 2-Amincmethy5 (pytdin-4 y Cara~flOl hph VI- OX 8iC l acid biutyry oxy'methy ester 8 - Name Cpd Ar JR Fonr Ri 1 mn-etyf59~pyrir4~ acid pro02-AlwI en -a banly io 3caoy - I w sed but-2~ynVyf ester 2 (Anoehy - -pAn di I yarbamocyl abphends abovk acid 2fluoro-ethyl ester 2{ bAmince hyQ5'I3dfuor& { riyridin4yQcaramsy~bipheny- 61 i ceat~v oi Did 24ls :rotthvy esteN Am r etlh' ~'pyridrnx 4c cabamoy-tphn'Z-arboxy'h t'6 add 2VcNOrc-ehyl ester -. 1 -A in -m y ---------- in---- ---------- --------- acid 2.2,24ttfluomethyh ester ycarbamoy bipheny 3--ca rbxhy 64 Ila acid 2%2dricboto-eth ester ~ I- OH 3 7 yhcarbamnoylybihenyi-3-'carboxy 'I N acdd 2~hydroxyethy ester 2'1-Aninu-ethyP5 -(pyridin4 O ykcarbamnoy~ebWphny3~carbxh 6 - t~ i ------ ~ ~~~ -- -- - -- - -- -- acid 3hydrnoxypripytester 2W 1 -AminoethyW6'-(34urn- "0H pyidin-44vy carbam Oybipheny-3 carboxyic acid 2-hydroxydethyi estr 2~~~M ArI66056 ra p:1dir4 ycarbrnayl}-bipbely3 3 carboxyi acid 3hyciroxgpmpyh e h 2'-( I Am no ethyh)~S'4pyrdr4 n-4 y abamovy b'phn-rox . acid 4-hioo-uv re 88 Name Cpd Ar R' FOn R 2 (1-m in - h y5-dIn-4- 7- 7- -Me' ycaroamoylibiphenyl~3carbxy c 7 acid ph tnyl ester 2--- -Am ir --
---
y - -3- f i-cw prin-4--carbamoi-bip penyV3 I - M * carboxytic acld pherA e -ter *2( (1Amino-ethy1>~5--pyridin4 aharnIoy biphenyk3-carboxyic 72 M acid4tiro-phNnyl ester ----- Am- inc-thy5-py-i----4- ............... y -carbamoy biplhenyI- 3arboh I 7 a I Sdse ptoyeter 2 ~AminoethyIS pyridin 4 y1CarhamOyI bipheny 3-earboxylic 74e acid 2b-d methexy- phenyl eser / yCarbro ya -tiphany x 4id phah yl ester -- -Amino-eth fr)-5 i 3 .uore pyrdl-da ycSar ibpeny carboxylic acid 35-dethox- 2~ I Aminc-ethy1>-{p1idn-4 bN-' +w e~' fln hen ycrbi l biheter 49/ Name Cpd Ar R Formua 1 0 acid 45trmethoxy-pheny estsr acid, 21 -Amh- noethfA kpviidin-4 0 carbamcy -tps-enyd-carboyc 8I acid 234.tnmefocxy-phonyi ester ~k , 1) #aminc thyN)-5 4 pyridire4-it ytearbamoyibpeny$3-carbexyii 82 Me *adid 4-mnethvktu fanyi -pfenyI ester F ylarbamy Ipheny-3 carbxy 4 Il acid pentafl u rr phenyirethyl est r F 2'-Amnno-ehy-(pyidin-4 8N ylcarbamey -b phenyb3-carboxyfic 04 M aside bromoKN bernzy esterF 2(I (4-Aino-emyfl)~5(pyridfi4 ybzarbamoyvIQ phsnyl-3carbOXYac ti ' adid 2-nitro-benzyl et 24-Arnino-ethyb-54pvridin-4- ~~ ycarbamoybipeny-3-carboxyic 86 -acdd 4-mnethylsultanyppheny! ester 21- Amino-ethy}-5-pyridin,4 % ylcatraoyl-bipheny%3-carboxylic U7 acid ptFCIhyl ester 2 -A-ni---ethy---pridin-- yICarbamay -pheny1-3 carboxye 83 adid3-phenoxy-propy ester K -A----inco-ethyb --- (- -i--irF 4
-
II b h I yicarbamoyl)Nph.eniyl-3carboxyt F *-< acdd 2ttusee4suifbny~yethyIt 8 0 ---- 2t-i.Anine-ethylt( yridav4 -k t N -uo t -- carbamocyyldbyn-rb----..oxyc 90 -. a acidfuran~3y ire thy ester I0 ___Name____ Cpd orm~ f~fll R . .a-rba I ic - -pher 1.--cargoxy--- 1 - - acdd 24hiophenZ2vi-ethyi estet 241 -Aminoethyi--(yrid-4 Caerbam&ybphMy 3 carboxYNCl 2jf aci 2AihiophenO3-yathyi ester Amnc-&hy)4pyridtif4 * arbaoyt)-bphnyH--carbxyhc 93" k, rb 2'4bmino-ethyIf) (pyriin %N y carbamnoyiyb phenylcarboxy c 2 y me h ty ester 2- 1 Am, heat 5prdin-4 y carbamoayi)+Lphlenyk3-caroxyvi acid 242 %diaXc- 3dihydra M > Nt isQ rdu-2-ethy estr 1-Amdnethy5 yridin4 9 96 acd 2-(4romo heny2-oet ester farde 2 shows trae resuhsAt for o owi&Inyailor1T AtN N N Mfa bf 91 Wae 2, Name__pd Ar ~R: Formuta _ R 2>Amiromethy v5(py ~ y--ar-amoyI>---phenyk -cr-b-th - ----- 7 add $-ethyj ester 2t AminomnethyW55(pyrv 2-Amnom-eth -5pyridin~4 y carbamo:yblkheny -carborth oc' 99 add S ororne y ester - -Ano-ethyl}4S pyn-dm-- 4 yl-a amy%3 tghnvy- eaboh 11 00I ac> d$Stert-btry$ ester -ShW the results 'or eorp& urds of Formk a and R 1 N N HNH TAbe 3 2- Cpd Ar F a r p3 R ----- b--noyI) - ---- oC-3- -arony-- 2 I -~rn ~acec acid methyl ester {[2 Aireinmethy45-pydrw. -N - -- - --- - - - - - yRa nay--- phny-4~-rbO--y- 10. .. a3ml1 1 O~aZcdo acieth~yl ester Nam Cpd Ar Formai R R4 {i2'-Amnomesthyi5(pyridin~4- " yicarbamoyl-biphenylb3-carbonyib- 104I~ amino)-acetic acid ethyl ester 3 -{{--Ami-o-ethyi-)-5'-(pynd---4ylcarbamoy)-bi pheny!3-carbo nyiy 105 -MO aimc}-propionic aci ethyl ester.J -Aminomethybipheny3,3 I dicarboxylic acid 3' H 106d carbamnoymethyl-aide. 3-pyrnm 4 -vimide 2,{12 4 -A-miomethyl-5h-(pyd-4 ylcarbamoy)-bipheny3carbon amno}-3-methy-pentan=ic acid methyl ester 4-ylarbamy!)-bp henyb3 --- d d 4 --- ---- --- carbony-amino)~ecetykiamino) pwpionic acid methyl ester 6-Arninomethyi-biphenvl~3,(3 N1 ( dicafhcXyvC adY ([(carbamoyime th ylcarbamoyi ) 09 le mcthylamde} 3-pyrdi 4 yiamide Arn methy apyr S- n [i2tAinamrethy5pdyidin yiceraamyl)kbi phengyb3--carbcny~ eminlthecec acd $Nay I {2~Aminc-ethyl-<-pen 34 3N d .. arboyd-tto et ck .cix .. - etrahydrothiophen y am 3 3-pyrda r4*-ylam~d de ______.~-93 pd Ar FErrRu 4 ..... ........ ---- - f - ---- Jmi ~rik}pyd ~ 'hd' --- A -norre-t- b------- -- - OCarboxC Cd {{ e XO f ----- - -- 2~oxouzy Sadoo4yjo r~de ydivn-1y T d ___ hl:tnomt~4pc~ I twCpfCy ,ad d Xy6 4 ~ o ..... +2.. .. t. --nid- - &t3hwp p.hrny 3rd CO -zrtvyc 'wi d 2(--x tt ycn>-pvra 4v -byi amde3py. d-a trad pymay 3th &rt yddit 4 kt hd' -~H j d arbxc cid pyrk2 5 ex-4-iui -I NaeCpd Ar fmoi -R' ' R 4222z wa rcd rneft yI --- - -- --- --- -- -- -- -- - . ........ ..............
----------
pycetic b&d methyl 1-sen, - --- ... ... . . ... --- ---- (pC y, ............- .- c t x~ .................... .... ... .. ...... Tal- 4 Iiws~e reuHfm 'Zpmnt to rWU A anrdAn ........ StAl TabA A tnrkfln orm eV 3' j 2 x 0, v3- I addfv~ py0tdr-mjwtswftjpvvb PC '31( ad r. ' -~nl n~dp>-a----------- hyk~N ZZ> add, pvna~dis4v i > bip'henyl.$ :ro iyo a~ yf:6r, -v~amid Thble 5 shows XJ resOis or oompoundsForo V d Vi H N R HH ArN R Ar N a Np NH CNH Via b Name Cpd R Formua _ R @Amionethy112(%o ' tetrahydro ersm yoxy> ' 1 3 acid pyr 4Aidx tetra11ydrat f su yhl~nyl 136V Tabke 6 shows the results for compounds of rma 'a and VRb. et H AR 0 -Z Name Cpd RAr R' Forml -R Inetnvl n th ste y earbarnoy iphenyiAyfo4H &N M aceto acid methyl eser ic m - vL . ................... .. 9 7. .
------- - --------------- ----- -- - - - - - - - - -- ....... ......-- - -- Name Cpd Ar R 1 Formuda [ - -2-Am-n-ethy -(pyridin4 -yK'arbamoyv!)-iphe-nyi-3~yoxy> 14 H a ae cid 23-dihydro- V1 benzo(1.4jd'oxin -vyne t hyl ester at acd propoxycarbonylmethyl ester [F 1-Ainoethy 5-3---uoo-- --- j pydd4in-4-ycarba moy- - --iphenyV3- -- ykoa scr'k-:jid propy ester I Amino-erhvf W341uoro pyrdd)4 v.arrbamoytipheny% 14 -v.vg2 ykxybaicetc 142d heny! atue 7 shows the results for campods ofFormula V/Hia and V. d VM' v ft Name Cpd A R Formu Wa WR my ie y yy 0144H. yvi-H V/ a a yt 2Am NameS yr d r -R orua ____4__ 7A N ------ --------------------- t-- ---- -- ------- ...... p rid ~ 4. ycarbamoyl-biphenyt oxyU t4M thiacet aki $l4luohy- ester Nam C ~ p Ar For Tab , 8~ -hw t -rastts fixr comMrc' , R.m. ,b.~iL I 'F r m R l R 3-R ---- - - ---- --- .. .. -I-- - -- -P' --- ----- ..... -p p 'Pg o c j ~ ~ ~ n' wp idepy'i -- - - - -. .. .. . . . ...'. - -- - -- U) -ha -~ ------- -, J ..........
T~b~ 9 flc$ te r$Ldc' Or pounds of Frmu~inwik X8 oc Xb. k -4 .... N -H Al Xaa -------------- I 9 N,. : z - --- ~~CWS-M tfXt)4 AIi o ot~ook~l' ............ f -N -' --------- - b Oii -1 -l4l f -4---- ----- ---- J .. ......------..... T e1 s ik-s u oi p nds F0r ,IV v~;rtxov~I~r9fl~s-s.flctV S4 ~ 0 Table 0 Name Cd Ar . . .~Z[~ ........4 ..... . ..- - - - 5 c ez'nord5 y gp 2 dn Wook" dd' 0 Ssbays the hh NW of XIV, V, X Na 1575 carboxylic a, I 'Ar"ayd c 64 UCpd Ar mw Formut ~mc~, ........ .~ A' N r'5 Name __ Cpd r 4~~~- 40eeev 5I
-------------
~d ~ --------- ----------- ----------- N)lei ............. 4------ ........... ... 4 t ~ .. a.... M-> Nanm* -,I upd Ar 41 t -' -~ k > N ------ ------ ' -- ........ 4 0' "K' zhAMOI ~ act S-wl ~-eaj -------- -2 --- ot -W ------- 4 N vaooaa)43)b0eHc. AVal hem -H fdi Th~~~sam 14!oQs. xth o~~~ re~a-'x ------- ... ---------- ........... x' a. R & Xxa -102 NN . ......... ... ............------------ NN NCn pd M, "ra u R add~ pivnyi sk I shemf mo~ tr rsutt"s @~r hecooui ot-rui Xh X . i ---------- - - -----------------------------. . ....-------- --------------- Nam :4r<' A -----------
----
------- ---- ... rxin-4 y~~~~~~~~~~~ c "I o wy'3-i L ............ ' Name ~~~~i Cd A 1 3mh r T 17 s hows the f o .. (Y F-,fltSum j C X X At CTa 17 Nam 'p A"' 4 X
-.-.----------.............-
'"}hvt mom ~U ~. 8 ~~~~a" mitip H pucA'&oI ~ ' ~ X .... ~ .h y ..... i~e t hosth rs t th o eu~sstF'omd AT~. y "IwmoyP A dN . .............. .... ..... .. ------ 17 " ' e . ~ ~ A .. . .... . ........ ... .. Table ~ ~ ~ ~ 4 N govit- xv -- - --- Namne Cpr T S.......-- ....... ..... .k. ...... .......... de. ............... ----------------------------- R ^N X Maw Non.y 17 'teX ....... .... S... ...... .... . . .
Name I ;rwCt Ai I Itt'Tom# -~~v - -- --- * crn~XAI ~ piheno won 174 . N 1V04 . .... . - ---- "~ L ... ....-------
AW
........ .Str.....u.......c------------------------r--e........ - _ _ - ---- ----- -- -- - - ---------- '
--------
------- ................. ........... - -- - -- --------- . . & ...... . ..... ... ............ ..... ..... .~ ~ ~ ~ ~ ~ ~ ~ ' . . ... ..
. . - - -- - --- . . . . . . . 4 N............ . ---- --------- Al~'K L ... ... ... ... ... ... ... ... ... .... ... ..........
187 1 -a> IN Ra 10 Structure ......... . < . ... .. ... 924: INN -- - - ----- --- - ------ - -- -'4-' ......... ................................. ........... ........... .......... - - -- - ------- ..... ..... -. --- - - 'K I -4 -- ----- ------ 20i> 204$ - ------- ... . ...... -109- Cpd structum, 20$ V' i . ~ ~~~ ~ .s ......
A ..............
................
...... -- ----- -- ------------------- 213 216 " 217 t~ X - - ------ - ---- . ..... $ C~I ........ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ X ........... ---------...
-~~ ~ ~ - ---- ... Cpd Sorrt a - - -- - -- - S 3 3 220. aW -xN -- s 2 23 gj 'gNc 224 N -------- .. -- ..
C. tn vitro and anviv asavys Method I ~ Proqinase setup A 9t adiosoto poitetn kinseassay is used to determine the iC indbihiung ROOK H, At ind $0 p1 action rocktaiW otain(n tu m4 EPESzNaOH (pH 5 3 mM M~gn WINI MAo i 2pM NathonmM T, I M ATP 50i' pg o G 1% (vv) DMtSO IpM ATP p x 10 Cpm P jTP the substrae (Substrate: -6 peptWde' 2000ngt vl) and recombinant e reaction is stopped by the addition of S0 p of a 2% soltion of PQ 4 and mixen a her After wash g twice wit 200 piof a (3%t lution of Na the dry elate iscuooted, Method 2, The inhibition assays were performed wilh a fluoresconce polarization (EPI assay using the cormmemily available ROCK UMAP Ki1t from Moiecular Devices (Product ID, No. R503V n a wftz " e prott(. oz ued by the m The S5 m proteinderived sute used was (FiAiiKRNLS$UkA also otained ho eiet rdar Devices (Product ID No NR 14k The . nzyme mix ROCKWotOCKi was obtained from Upstate Dioechnocgy (Product 10 No 14-451), n sammry ai>cmponds were scoeeod in the wells of a 0well pate for ersymatirition with csncentrtoba varying from 10NpM to 030M using a stepwise 3 (or 2Mold diluan, Y compound (12732 conmercaoy available from Toods) was used as a reference (04 pM To peidm the assag 1 of a solution of the compound to bested in DMO (ateach concentratIN) was added to 2 p1 of a solution of the enzyme i 10mM in W~l . i0mM MoIk. (0% BSA '&$% Nam ' d The fina concentranw f t 'nym was 2 SM. After ircubeting for 30 minutes at RT 2 p of a mixture of ATP and the protein substrate i 10mM. Tris-HC 0mM MgCW01% BSA W05% Na , pH 7.2 was added, The final concentration of the ATP was 10 pM and fina concenrati n of proter, substrate a 0.2 pM. After inCuating for 60 minute; at R T 1 p l of the A BAning solution rrix of the MA.P tending 'Buffer A (1) end thre MAP Bnding Reagik ent m the RCK IM idt)) was added Tne n 're thus obtained (totalvole-mr 1 was incubat- i,'30 minutes at RT. upon wtich he itlerscence polarization wlas measured usingan automated prate reader Perkin Elmer Model Envsor O-6001 is)19 F P filterseitakniofter f- P 400 and emission filters FC FP Ppal 535 and RTC FP S-po 535 (Perin-Elmer) The result were ied to a curve using the XL Fit agodrhm and 1C50 saues were calculated for each hi t ted urve agaIn usng the XLPit Thed- vue for the reference compound V compound 'r 2.7632) was 4ApM, b: & 0+ s4'deQ Obi gn darac ~t the Qoktc00: $set h 0rth z 0s as ps.nesQntsd in. Ams; +++ tmease b~ei>V O + meas $5 baiween t3 pM an i n means ,C50 btween and 10 piA and means "sot detentned yet'. Mah I ~t. Cpd< Meth4 I Meth,29 ps 2lwn # Cp& Meth. IJOW Mh2 27 +++ 152 44 S 't54 11 .~ .' ._ _ _ ._ _ ...... ..- ... -W - - - -1- - -_ __ _ - ---- ------------- w--- ---- 88 5 4 -'----- - - - - - - - - - - - - t- 4 4 444 211 4 49161
.-
~ 1~ .......... -_ _ -_ _ --- ------ 25 1 5u 5-4 2 T++ 17 1 7 j - -- -- ----- .....
_ 2 f .... ...
-------
29+ 104 1779 3 0 1 6 5 -- --- as 4" 44 ++t 3 3A 1 144 33 44 I1- 184. - --------- --------- 4--- ------ -- SCpds 1 Met I Meth 2 # Cpds Meth 1 Meth 2# Cpds Me I Meth 2 49 1 189 44 + .+..+ + 1 94 ' . --- ------------- 1'(20 95 ............. 48 12> 49 127 20 444 5 120' 20f 4 -................... - -.......... .... 4 4 126 . ~ - . ....... . ..j...- - -- 59 4 +++ 134 2 9 .~~ ....... ----------- 4----- 201 - - - ------ 3 138 213 4 ++- i 214 62 14215 - +------------ -- - - - - - - - - - - - - - 72 14 73 ++s [4 2 7- - 1-4 224 1, 5 CL.. A Wt{A gaPinst ROCK M a covlar ssay usmg S isimulated PBMC( sO the absence and presence o plasma To ensu the stimret;on of PoM by LPS the vedom ,s enriched with LPS-bethg potein'3~T thO l fac;liate the deliVery of LP$ to the C014 receptor and enance the kP-nduced inrune response. Cyknected n activated PFMC include TNhF.whh is deaed y ieans of a colorimeic EUSA In Te presence of an active compound. the rsse.a~. of T Nted n a conceranAerdedent mnner. ubsequsnty a control assay using the same set up in the presence offpisa is induded For onamnple compound 4$ showed I0g120rM (assay without plasma) whereas is inactive (00 10pI) in the presence Of p1na. (At . mooO#h tUie telSXhln actvey of . generat eQ o'C M ers~avito cp c a ~ths utgn0enea pigq tachea Ginra pig trachea rings are prepared and Icubated with a fied concentaton of the brochocons tve agent carachoi Then increasing concentrations Me SON ROCK TAb are added and the contracie properties of the trachea measured for erchee compound concniatio The study set-u akws the dersmination of ar 10 Cl represented by the concentraton id f compound that inouces a rome equal to 50% of that observed for the vehide treated tacheaS in addihon retention on the Troarg s assessed using the above described organ bates of guinea pig trachea in brief, upon induction of manmai reaation with the ROO4 inhiitors rachea Pogs are thoroughly washedThen. oarachd is added again and (mntractie propedies are measured to .deensne etber the rhitAry WOtty W the ROCK inhbitOrs e proiorted upon he washoutA prolongedinhiitory activity alter the washout is highly indicave for a prolonged retention of the compound at te lungs tVivo For example campound46 showed I of500nM C, 2 t, t ssaey tuman and/9r rat p/asma Compounds are incubated at a concentratin of I pM in rat mice or rabbit) or human plasma. Oamnpies are tten at fixedl time points and toe rermrant of compound is determrined by LCt1AS$/MS sfter protein precistation. hife is exressed in minutes. nt att ny #P t% rat t A i p asma human 4& 1 4 7 4------------------- 9 ..7......A4
......-.
(1 2.Sisl|ty k>wesW' oyl§ )S9 A 1 pM o of the ROO,!nhibitars is ncubated with a resction brture contining lung S9 (fNo" smokers was wo as te cf0ors PP UCPGA. PAPS ad G . ampies ore cected at at s e nd 99 intes ps incu aam, NAganve control samples - n teStd th ROK htors ad $ lo tio in the absence of ae ters are run in pade. By usnag L SM analysis. Ie percept of ROCK compounds reinrngt each time pIn tpe m b d affie of eROCK C pounds P-essed n note and the taboC hafife of th o 0K Q0trmoupfd ore detarrmd. and ~ ~ Cpi cuan hany do mungh~ 46 C. 2 StaNay essay inrab10ucu huor Compounds are incubated at a concentration of IpM in rabbl i aueous t umor (All) Samples are LIen at fied lime points and The remnant of compoum. determinedL LCiMS/MS after proteinn aspredpkn omys tehe.Anoianokt # Cd V o% rabbfts Ab C2..K anePtnpncharacteiztion The assay is based on a reporter dtislcrnent bindi $ 0ect05oy t inolves tuea rb specii k~r the AT trtOng site oN OCK.Aoe isinn gerated When the robe is bound to the active site. In the presence of a ATP conaoettiveROCK1 inhibitor, the probe ks displaced from the enzyme and the signal is disrupted. The probe displacement is monitored over time sod the Ken and Koff constants are determined. inhitor mechanism of acton is charactenzed enzymaticahy ising the fluorescencetbased QMNtA technology CS5 Aqrlinatnmstory act'vdvotr geied sCR ROC0K nhib/tors in an acids 1P$ ing shattenge Haof an hour after ontrenasel compound administration, mice are chauerged Intratrachealy with LP$. Twentyvfour forxss later. thes mice a sacrificed, brornchoaivolar savage flud (BALE) cntiected and total cet number as weda percentage neutrophils determined. Antiulnflammersry activity is represented by a reduction in the total number of SALo cells and in the number of neutrophils as compared to a nondreated control group) 1 5 'Q nownsw anv T&.L.. thW~P~ nau~~ sn c!a ~omrn As~ be 10 in Tha mg- (WW ni- 2Om~nt<~ an nundito ICY ~ w a' Ianraa! is u-'4- opy owovo Mng~vkg a =ma&um o 4nm

权利要求:
Claims (28)
[1] 2. A compound according to claim 1 wherein; R' is hydrogen or C, 4 alkyl; Ar is selected from the group comprising: x N I NN H Wherein X Is selected from the group comprising hydrogen or fluoro; Y is an aryl or heteroaryl substituted with a substituent selected from the group consisting of C(=O)-OR": -C(=O)-SR 22 ; -C(=O)-NRR 4 ; -NR 6 R 6 : -O-C 14 alkyl; -C 1 -alkyl; or -C2alkenyl wherein said -0-C-alkyI, -Calkyl, or -C 28 alkenyl is substituted with a substituent selected from the group consisting of C(=O)-OR 21 : -C(=O)-SR; -C(=0)-NR 3 R; Het'; -0 Het 2 ; and -S-Het; R3 is selected from the group consisting of hydrogen: C,.alkyl optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of -C(=O)-OR: -C(=0) SR1 2 ; -C(=O)-NR'R: Het'; -O-Het; -S-Het C 16 alkyl-S- and C 1 alkyl-O-; in particular R 3 is hydrogen: -121- R 4 is selected from the group consisting of CIoalkyl substituted with 1, 2 or 3 substituents each independently selected from the group consisting of -C(=0)-OR 2 ; -C(=0-SR"; -C(=0)-NR'R 8 ; Het'; -0-He; -S-He; C, alkyl-S- and Calkyl-O-; or; R 3 and R 4 together with the nitrogen atom to which they are attached form a heterocycle substituted with one substituent selected from the group consisting of -C(=0)-OR": -C(=O) SR ; -C(=O)-NR 9 R'; Het; OHe; -S-Het; or Csalkyl wherein said C, 4 alkyl is substituted with 1. 2, or 3 substituents each independently selected from the group consisting of -C(=O) OR 21 : -C(=O)-SR": -C(=O)-NRR'*; Het'; -0-Het; and -S-He: R' or R4 are independently selected from the group consisting of hydrogen; Ci.salkyl; or CiaIkyl C(=O)-; wherein at least one of R 5 or R 6 is selected from CIualkyl; Cj 0 alkyl-0-C 6 alkyl-; C, alkylS-Cbiaalkyl-; or C, 4 alkybC(=O)-, and wherein each of said Cjoalkyl; CalkyI-O-C, alkyl-; Csalkyl-S-Calkyl-; or C, afkyl-C(=O)- is substituted with 1, 2, or 3 substituents each independently selected from the group consisting of -C(=O)-OR 1 ; -C(=O)-SR; 22 Het; -0-Hef: and -S-Het 3 ; R' or Ro are independently selected from the group consisting of hydrogen; or Cl.alkyl substituted with 1, 2, or 3 substituents each independently selected from the group consisting of aryl, heteroaryl, Cucycloalkenyl, -C(=O)-OR"; and -C(=0)-NHi R' or R'* are independently selected from the group consisting of hydrogen; or C,.alkyl substituted with 1, 2, or 3, -C(=O)-OR substituents; R or R' 4 are independently selected from the group consisting of hydrogen; C,.alkyl; Calkyl-O C,.alkyl-; C, 6 alkyl-S-Cualkyl-; and Caalkyl-C(=0)-; in particular R" and R 1are hydrogen; R 2 is selected from the group consisting of C, 20 alkyl; C 1 . 2 alkenyl; C 100 alkynyl; C 3 5 cycloalky; optionally substituted heterocyclyl; and optionally substituted aryi; wherein said Ct.Oalkyl is optionally substituted 1, 2, 3 or more substituents selected from the group consisting of halo, cyano, hydroxy, aryl-O-, aryl-S-, aryIS(=O)r, aryl-C(=0), C(=0)-NR' 3 R, -O-C(=0)-CalIkyl, C 16 alkyl-O-, C,,alkyl-S-, aryl, heteroaryl, heterocyclyl or from the formula: 0O 60 0 - 0 ; or R 21 taken together with the oxycarbonyl and phenyl to which it is attached forms a cyclic ester consisting of - 122 - 0 o wherein q is an integer from I to 6; R 2 is Ct-oalkyl optionally substituted with 1, 2, 3 or more halo substituents; Het', Het or Het are independently selected from the group comprising; 0 0 .J O 0 O OS O o K 0 0 0 0oo O -C
[2] 3. The compound according to claims 1 or 2 wherein; Ar represents pyridinyl, optionally substituted with halo; in particular Ar represents pyridinyl substituted with fluoro; in an even further embodiment Ar represents x N / wherein X is hydrogen or halo; R' represents hydrogen or Cialkyl; Y is an aryl or heteroaryl substituted with a substituent selected from the group consisting of -C(=O)-OR 2 ; -C(=0)-SR; -C(=O)-NR 3 R 4 ; - NR'R'; -O-C,. 6 alkyl; or - C,.alkyl; wherein said -0-C 1 .alkyl or -Cj 5 alkyl are each independently substituted with a substituent selected from the group consisting of -C(=O)-OR 1 Het' and S Het: -123- -R is hydrogen; - R' is -Cisalkyl substituted with a substituent selected from -C(=O)-OR2. or Het 1 : -R or R6 are independently selected from the group consisting of hydrogen: C 1 ealkyl; or C, 6 alkyl-S-Calkyl-; wherein at least one of RS or R6 is selected from the group consisting of Calkyl; or C 1 6 alkyl-S-Ct 6 alkyl-; and wherein each of said CI 6 alkyl; or C 1 ealkyl-S-C. aalkyl-: is substituted with a substituent selected from the group consisting of -C(=0)-OR 1 , Het' and -S-Het; - R' Is selected from -Cj 6 alkyl, aryl or optionally substituted heteroaryl; - aryl represents phenyl; and - heteroaryl represents thiophenyl, 3,4-dihydro-1(2H)-benzopyranyl, 3,4-dihydro-1(2H) benzopyranyl, or indolyl. 4, The compound according to any one of claims I to 3 wherein; the Y substituent in its definitions comprises at least one substituent selected from the group consisting of C(=O)-OR2 1 : -C(=O)-SR 2 ; Het': -0-Het 2 : and -S-Het 3
[3] 5. The compound according to any one of claims 1 to 4 with the proviso that when Y represents an aryl or heteroaryl substituted with a substituent selected from the -C(=0) OR": or -C(=O)-SR 2 ; and wherein said R 2 1 or R 2 ' represents an unsubstituted Ct 2 oalkyl; said -C(=0)-OR: or -C(=O)-SR 2 ; Is at the meta or para position vis-a-vis the binding of said aryl or heteroaryl to the remainder of the molecule
[4] 6. The compound according to to any one of claims 1 to 4 wherein; Y is 2-oxo-2,3-dihydrobenzofuranyl or Y is a phenyl, or thiophenyt said phenyl and thiophenyl substituted with a substituent selected from the group consisting of -C(=0)-OR: -C(=O) SR; 22 -C(=O)-NR3R; - NR'R; -O-C 1 .alkyl; -C.salkyl; or -C.s 8 alkenyl wherein said -O-Coalkyl, -C, 0 aky. or -C 2 . 8 alkenyl are each independently substituted with a substituent selected from the group consisting of C(=0)-OR 2 '; -C(=0)-SR"; C(=0)-NRR 4 ; Het': -0-Het 2 ; and -S-Het; R 3 is hydrogen: R 4 is selected from the group consisting of Cimalkyl substituted with 1, 2 or 3 substituents each independently selected from the group consiting of -C(=0)-R 21 ; -C(=O)-SR; _ C(=O)-NR 7 R 8 ; Het': -0-Het 2 ; -S-Het'; Clalkyl-S- and C1. 6 alkyl-O-; or; R 3 and R 4 together with the nitrogen atom to which they are attached form a heterocycle substituted with one substituent selected from the group consisting of -C(=O)-OR 2 ,: C(=O)-SR 2 2 ; -C(=O)-NRR 0 ; Het': or C 6 alkyl wherein said C<alkyl is substituted with 1, - 124- 2, or 3 substituents each independently selected from the group consisting of Het'; -0 Het; and -S-Het; R or R 6 are independently selected from the group consisting of hydrogen; C 14 alkyl; or C. ealkyl-C(=O)-; wherein at least one of R' or R' is selected from C 16 alkyl; or C 16 alkyl C(-O)-, and wherein each of said Cealkyl; or C 1 alkyl-C(=O)- is substituted with 1, 2, or 3 substituents each independently selected from the group consisting of -C(=O)-OR: -Het': -0-Het'; and -S-He; R' or R8 are independently selected from the group consisting of hydrogen; or C',alkyl substituted with 1, 2, or 3 substituents each independently selected from the group consisting of -C(=O)-OR 2 ': and -C(=O)-NH 2 ; R7 is selected from the group consisting of C,-malkyl; Cwocycloalkyl; and optionally substituted aryl; wherein said C,. 20 alkyl is optionally substituted with 1, 2, 3 or more substituents selected from the group consisting of halo, hydroxy. aryl-O-, aryl-S-, aryl-S(=0)-, aryl-C(=O), -0 C(=O)-Cualkyl, C 16 alkylb-, aryl, heteroaryl, helerocyclyl or from the formula: 0O - a -- ; or R" taken together with the oxycarbonyl and phenyl to which it is attached forms a cyclic ester consisting of 0 wherein q is an integer from I to 6; Rn is Ctxalkyl optionally substituted with 1. 2, 3 or more halo substituents; Het', Het' or Het' are independently selected from the group comprising; o 0 -125 - 0 0 0 o a O O 0 o z 0 to O -S heterocyclyl as used herein is selected from the group consisting of piperdinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyt, 1.3-dioxanyl, 3-dioxolanyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl and hexahydrofuro[3,2-blfuranyl; in particular piperidinyl, 1,3-dioxanyl, indolinyl, tetrahydropyranyl and tetrahydrofuranyl; aryl as used herein is selected from the group consisting of phenyl, naphty, 1,4-dihydro naphtyl, or 1,2,3,4-tetrahydronaphtyl wherein said aryl is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, nitro, C 14 alkyl, Clualkyloxy, or C 14 alkylthio; and heteroaryl as used herein is selected from the group consisting of furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, benzopyrany, 1(4H)-benzopyranyl, 1(2H) benzopyranyt, 3,4-dihydro-1(2H)-benzopyranyl, and 2,3-dihydro-1(4H)-benzopyranyl wherein said heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, oxo, nitro, C 14 alkyl, C, 4 alkyloxy, or C 14 alkylthlo.
[5] 7. A compound of the present invention represent by formula Ia or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, or solvate thereof 0 -- T H Ar-N - R 1 0 NH 2 (la) -126 - wherein; R' is selected form the group comprising hydrogen, C 1 . 4 alkyl or Cmcycloalky; Ar is selected from the group comprising: x N N N..,N N H Wherein X is selected from the group comprising hydrogen or halo; L is a direct bond, C 14 alkyl, or -O-Calkyl: T is -O-R' or -NRR ' ; Ra is selected from the group consisting of hydrogen; C, alky optionally substituted with 1, 2 or 3 substituents each independently selected from the group consiting of -C(=O)-OR": -C(=O) SR 2 '; -C(=O)-NRR; Het'; -O-Hete; -S-He; C 14 alkyl-S- and C 14 alkyl-0-; in particular R' is hydrogen: R4 is selected from the group consisting of C 1 aalkyl substituted with 1, 2 or 3 substituents each independently selected from the group consisting of -C(=O)-OR -C(=O)-SR'; -C(=O)-NR'Ra; Het'; -O-Hee; -S-Het; C 16 alkyl-S- and C 1 .alkyl-O-; more in particular R4 is selected from the group consisting of C 1 .alkyl substituted with 1, 2 or 3 substituents each independently selected from the group consiting of -C(=0)-OR 2 1 ; -C(=O)-SR"; -C(=0)-NR'R8; Het; -O-Hef; and -S Het; or; R3 and R 4 together with the nitrogen atom to which they are attached form a heterocycle substituted with one substituent selected from the group consisting of -C(=O)-OR; -C(=O) SR"; -C(=O)-NRR; Het'; -0-Hef; -S-Het; or Cjsalkyl wherein said C,.salkyl is substituted with 1, 2. or 3 substituents each independently selected from the group consisting of -C(=O OR"; -C(=O)-SR; -C(=O)-NRR; Het'; -0-Het 2 ; and -S-He; in particular R 3 and R 4 together with the nitrogen atom to which they are attached form a heterocycle substituted with one substituent selected from the group consisting of -C(=O)-OR 2 1 : -C(=0)-SR2: -C(=O)-NRR 0 ; Het' or C> 6 alkyl wherein said Calkyl is substituted with 1, 2, or 3 substituents each independently selected from the group consisting of Het'; -0-Hee; and -S-Het; R or R' are independently selected from the group consisting of hydrogen; or Clalkyl substituted with 1, 2, or 3 substituents each independently selected from the group consisting of aryl, heteroaryl, Cu 6 cycloalkeny, -C(=O)-OR"; and -C(=O)-NH2; in particular R' or R8 are independently selected from the group consisting of hydrogen; or Cjualkyl substituted with 1, 2, or 3 substituents each independently selected from the group consisting of -C(=O)-OR ; and C(=O)-NH2; R9 or R' are independently selected from the group consisting of hydrogen: or C 1 alkyl substituted with 1, 2, or 3 , -C(=O)-OR" substituents; - 127- R* or R" are independently selected from the group consisting of hydrogen; C 1 alkyl; Calkyl; CalIkyl-O-C,,alkyI-: Csalkyt-S-C, 6 alkyI-; or Calkyl-C(=O)- and wherein each of said C, 8 alkyl: C 14 alkyl-O-C, 0 alky-; CalkyI-S-C,4alkyl-; or CAalkyl-C(=O)- is substituted with 1, 2, or 3 substituents each Independently selected from the group consisting of -C(=O)-OR"; -C(=O) SR": Het'; -o-Hee; and -S-Het 3 R 2 ' is selected from the group consisting of Comalky; C 1 .Malkenyl; C,< 0 alkyny; optionally substituted Ca, 6 cycloalkyl; optionally substituted heterocyclyl; and optionally substituted aryl; wherein said Caalkyl is optionally substituted with 1, 2, 3 or more substituents selected from the group consisting of halo, cyano, hydroxy. aryl-O-, aryl-S, aryl-S(=O)n, aryl C(=O). -C(=O)-NR"R, -O-C(=0)-Calkyl, C, 0 alkyl-O-, C, alky-S-, aryl, heteroaryl, heterocycly and C 3 ., 5 cycloalkyl or from the formula: O* 0a - 0 ; or R 2 taken together with the oxycarbonyl and phenyl to which it is attached forms a cyclic ester consisting of C wherein q is an integer from 1 to 6; R 2 is Cnalkyl optionally substituted with 1, 2. 3 or more halo substituents; Het', Het' or Het 3 are independently selected from the group comprising; o 0 -120 0 O O 0 0 0 0 O O 0 ( or 1
[6] 8. The compounds according to formula la wherein, Ar represents x N wherein X is hydrogen or halo; L is a direct bond, Cualkyl, or -O-C 14 alkyl; T is -O-R" or -NR 3 R 4 ; R' represents hydrogen or Cjualkyl; R' Is hydrogen; R 4 Is -C 1 alkyl substituted with a substituent selected from -0-Het, or -S-Het 3 ; with in a particular embodiment said Het or Het being selected from the group consisting of 0 0 J O O 00 00 Het 2 or Het 3 are independently selected from the group comprising; -129- o 0 0 0 000 00 o
[7] 9. The compounds according to formula la wherein, Ar represents x N / wherein X is hydrogen or halo; - L is a direct bond. C 4 allkyl, or -O-C, alkyl: T is -0-R2l or -NR'R 4 ; - R' represents hydrogen or C 14 alkyl; R is hydrogen; R 4 is -C 14 alkyi substituted with a substituent selected from -C(=0)-OR, -C(=O)-SR, C(=0)-NR'R 8 , or Het'; in particular -Cialkyl substituted with a substituent selected from C(=O)-OR. or Het'; with in a particular embodiment said R 2 being a -C 16 alkyl ; or R 3 and R 4 together with the nitrogen atom to which they are attached form a heterocycle substituted with C> 6 alkyl wherein said C 1 .alkyl is substituted with 1, 2, or 3 substituents each independently selected from the group consisting of -C(=0)-OR 2 1 and -C(=O NR 9 R' 0 ; -130 - R'or R' 0 are independently selected from the group consisting of hydrogen; or CI 6 alky substituted with 1, 2, or 3 , -C(=O)-OR" substituents; R' is selected from the group consisting of C 1 Oallkyl; optionally substituted C,. 0 cycloalkyl: optionally substituted aryl; and optionally substituted heterocyclyl; wherein said C 1 , 0 alkyl is optionally substituted with a substituent selected from the group consisting of halo, cyano, hydroxy, -O-C(=O)-C. 6 alkyl, Clalky-O-, Claalkyl-S-, aryl, heterocyclyl, and C 3 <cycloalkyl, or from the formula: *O 0 0 C0 0 0-t0 - 0 heterocyclyl as used herein is selected from the group consisting of piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 1,3-dioxanyl, 3-dioxolanyl. tetrahydroquinolinyl, tetrahydroisoquinoliny, indolinyl, tetrahydropyrany, tetrahydrofuranyl and hexahydrofuro[3,2-b]furanyl; in particular piperidinyl, 1,3-dioxanyl, indolinyl, tetrahydropyranyl and tetrahydrofurany; optionally substituted C 31 ocycloalkyl as used herein is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexy, cycloheptyl, cyclooctyl, cyclononyl, adamantanyl, bicyclo(2.2.1)heptanyl and cyclodecyl with cyclopropyl, cyclopentyl, cyclohexyl, adamantanyl, and bicyclo(2.2.1)heptanyl being particularly preferred; wherein said C 1 O 0 cycloalkyl is optionally substituted with 1, 2, 3, or more in particular 1, 2 or 3; more in particular 1 or 2; even more in particumar 1 substituent selected from halogen, hydroxyl, oxo, nitro, amino, cyano, CAalkyl, Crcycloalkyl, Ci.alkoxy, or -SO,-NH 2 , optionally substituted heterocyclyl as used herein is selected from the group consisting of piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 1,3-dioxany, 3 dioxolanyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl and hexahydrofuro[3,2-blfuranyt; in particular piperidinyl, 1,3-dioxanyl. indolinyl, tetrahydropyranyl and tetrahydrofuranyl: wherein said heterocyclyl is optionally substituted with 1, 2, 3 or more; in particular 1 substituent selected from the group consisting of halogen, hydroxyl. oxo, nitro, amino, hydrazine, aminocarbonyl, azido, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkylalkyl, alkylamino, alkoxy, -SOrNH 2 , aryl, heteroaryl, aralkyl. haloalkyl, hatoalkoxy. alkoxycarbonyl. alkylaminocarbonyl, heteroarylakyl, alkylsulfonamide, heterocyclyl, alkylcarbonylaminoalky, aryloxy, afkylcarbonyl, acyl, arylcarbonyl, aminocarbonyl, alkylsulfoxide, -SO2Ra, alkylthio, carboxyl, and the like, wherein Ra is alkyl or cycloalkyl; preferably selected from halogen, hydroxyl, oxo, nitro, amino, cyano, Cialkyl, Cacycloalky, Cj 4 alkoxy, or -SO-NH, aryl as used herein is selected from the group consisting of phenyl, naphtyl, 1,4-dihydro naphtyl, or 1,2,3,4-tetrahydronaphtyl wherein said aryl is optionally substituted with 1, 2, 3, -131 - 4 or 5 substituents selected from halogen, nitro. C, 4 alkyl, C, 4 alkyloxy, or Cjualkythio; in particular phenyl or 1,2,3,4-tetrahydronaphtyl wherein said aryl is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, oxo, nitro, C 1 alkyl, Ciualkyloxy, or Calkyfthio; more in particular phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, nitro, Calkyl, Cj.alkyloxy, or C, 4 alkyithio; heteroaryl as used herein is selected from the group consisting of furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyi, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyi, triazinyl, benzofuranyl, benzopyranyl, 1(4H) benzopyranyl, 1(2H)-benzopyranyt, 3,4-dlhydro-1(2H)-benzopyranyl, and 2,3-dihydro 1(4H)-benzopyranyl wherein said heteroaryl is optionally substituted with 1, 2, 3. 4 or 5 substituents selected from halogen, oxo, nitro, Calkyl, Cjualkyloxy, or Cjualkylthio; in particular furanyl. thiohenyl, pyridinyl, benzopyranyl. 1 (2H)-benzopyrany, 3,4-dihydro 1(2H)-benzopyranyl, and 2,3-dihydro-1(4H)-benzopyranyl wherein said heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from halogen, oxo, or C, 4 alkyl.
[8] 10. A compound according to any one of claims 7 to 9, with the proviso that when L is a direct bond and T is -O-R, and wherein R" is an unsubstituted C- 2 0 alkyl, said L-(C=O)-T is bond at the meta or pars position to the phenyl ring vis-a-vis the binding of said phenyl ring to the remainder of the molecule. 11, A compound of the present invention represent by formula lb or a stereolsomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, or solvate thereof / -z-w H Ar-N _ R 1 0 NH 2 (lb) wherein; - R' is selected form the group comprising hydrogen, C 1 . 4 alkyl or C 3 6 cycloalkyl; - Ar is selected from the group comprising: X N- ~N N N N N H - Wherein X is selected from the group comprising hydrogen or halo; - Z is a bivalent radical selected from the group consisting of -0-; -NR-; and -NR-C(=O)-; -132- W represents C, 4 alkyl substituted with a substituent selected from -0-Hee; -S-Het; or C(=O)-NR R'; R 3 is selected from the group consisting of hydrogen; C,< 0 alkyl optionally substituted with 1, 2 or 3 substituents each Independently selected from the group consiting of C(=O)-OR; -C(=O)-SR": -C(=O)-NR7Ra; Het'; -0-Het2; -S-He; C, 6 alkyl-S- and C. 0 alkyl-O-; in particular R 3 is hydrogen; R 4 is selected from the group consisting of C, oalkyl substituted with 1, 2 or 3 substituents each independently selected from the group consiting of -C(=O)-OR 2 1 : -C(=O)-SR 2 ; C(=O)-NR'Ra; Hat'; -0-Het2; -S-He; C 1 . 6 alkyl-S- and C, 6 alkyl-O-: more In particular R 4 is selected from the group consisting of C 1 -alkyl substituted with 1. 2 or 3 substituents each independently selected from the group consiting of -C(=0)-OR; -C(=O)-SR"; C(=O)-NR'R: Het'; -O-Het; and -S-Het 3 ; or; R and R 4 together with the nitrogen atom to which they are attached form a heterocycle substituted with one substituent selected from the group consisting of -C(=O)-OR2'; C(=O)-SR'; -C(=O)-NRR; Het'; -0-Hef; -S-Het'; or C 1 alkyl wherein said Calkyl is substituted with 1, 2, or 3 substituents each independently selected from the group consisting of -C(=O)-OR"; -C(=O)-SR 2; -C(=O)-NRR; H'et; -0-Het; and -S-Het; in particular R 3 and R 4 together with the nitrogen atom to which they are attached form a heterocycle substituted with one substituent selected from the group consisting of C(=0)-OR"; -C(=O)-SR 2 ; -C(=O)-NRR; Het': or C,.salkyl wherein said Calkyl is substituted with 1, 2, or 3 substituents each independently selected from the group consisting of Het'; -O-Hef; and -S-Het'; S R' is hydrogen; R' or R' are independently selected from the group consisting of hydrogen; or Cualky substituted with 1. 2, or 3 substituents each independently selected from the group consisting of aryl, heteroaryl, C,.cycloalkenyl, -C(=O)-OR; and -C(=O)-NH,: in particular R or R' are independently selected from the group consisting of hydrogen; or Cjualkyl substituted with 1, 2, or 3 substituents each independently selected from the group consisting of -C(=O)-OR"; and -C(=O)-NH; R' or R1 are independently selected from the group consisting of hydrogen; or Coalkyl substituted with 1, 2, or 3. -C(=0OR substituents: R" or R are independently selected from the group consisting of hydrogen; C, 6 alkyl; C, 0 alkyl: CAalkyl-O-C,.6alkyl-; C 10 alkyl-S-C.alkyl-; or C 1 ualkyl-C(=0)- and wherein each of said C 16 alkyl: C, 0 alkyl-O-C,alkyl-; C, 0 alkyl-S-Calkyl-; or CaIkyl-C(=O)- is substituted with 1, 2, or 3 substituents each independently selected from the group consisting of -C(=O)-OR: -C(=O)-SR 2 1; Het'; -0-Het; and -S-Het 3 ; -133- R" is selected from the group consisting of C 20 alkyl: CI 2 alkenyl; Cj 2 oalkynyl: optionally substituted C.icycloalkyl; optionally substituted heterocyclyl; and optionally substituted aryl; - wherein said C,.oalkyl is optionally substituted with 1, 2, 3 or more substituents selected from the group consisting of halo, cyano, hydroxy, aryl-O-, aryl-S-, aryl S(=O)r, aryl-C(=O), -- C(=O)-NR'3R", -O-C(=O)-CIalkyl. C,,alkyl-O-, C,,alkyl-S aryl, heteroaryl, heterocyclyl and C 3 scycloalkyl or from the formula: *O * 0 .- /'0 ; or R 2 ' taken together with the oxycarbonyl and phenyl to which it is attached forms a cyclic ester consisting of 0 / wherein q is an integer from 1 to 6; R 2 2 is C 1 , 0 alkyl optionally substituted with 1, 2, 3 or more halo substituents; Het', HeOt 2 or Hets are independently selected from the group comprising; 0 O O OO -0 -14 0 0 0 0O O Oo
[9] 12. The compounds according to claim 11, wherein Z is a bivalent radical selected from the group consisting of -0-; -NR-; and -NR'-C(=0)-; W represents C 1 .alkyl substituted with a substituent selected from -0-Het; -S-HetO; or C(=O)-NR 3 R'; Ar represents x N / wherein X is hydrogen or halo; R' represents hydrogen or Cjuakyl; R 3 ais hydrogen; R' is -Cioalkyl substituted with a substituent selected from -O-He, or -S-Het; with in a particular embodiment said Het or Het 3 being selected from the group consisting of 0 0a 'd 0 00 0 o 0 00 ** O
[10] 13. The compounds as defined in any one of claims 1 to 5 and represented by a compound having one of the structural Formula lIla, Ilia, lVe, Va, Via, Vila, Villa, IXa, Xa, ib, li1b, IVb, Vb, VIb, ViIb, VIllb, IXb, Xb, XI, XII, XIII, XIV, XV, XVI, XVII, XViIta, XIXa. XXa, XXIa, XXIb, XXIla. XXIlla or XXIVa. -135- 0 0 H0 1 H R Ar- Ar-N - N1-N - R l-- P Ia lb Ilila fib Ar-N Ar-N - R NH, 0 NH, lVa IVb L R H N H i H *AA- r Ar-N ArN - R Ar-N - R o NH, 0 NH, C NH, 0 NH Va Vb Via Vib -- / R 0 R N-N R Ar-M 4 I 0 / NH, 0 NH, Vila VIlb ' - k - R ~ H H Ar- - R' Ar- - R 0 NH, H Villa Vilib - 136- 0o / ~ N-R' 0 R Nrd R Ar-N R 0 NH, 0, I NH, IXa IXb H 0 H NR -R H Ar-N R' Ar-N - R 0 NH, 0NH, Xa Xb 0 -Fe' R'N' R' 0 0 0 As-Al 8R A-N - a, p 5 - S 0NH, Ix0 H,4 0 NH2 XI xII XII1 0 o 0 00 0 AA- - R' Hr HNR C 2 0 NH, K NH, 0 NH xIV xv XVI XVII As-i -0 H RA0-N R- -NR 0 NH, NH, 0~ NH-, XVIIla XIXa XXa - 137- XXN a X 'Xil - NH, NH 21 / 2 H1 Ar- R N/ r R 0O NH XXIlla XXIVa wherein; q is an integer from 2 to 6; R" is a substituted C1.ealkyl, or a substituted -Crealkenyl; said -C1.ealkyl and -C2salkenyl each independently substituted with a substituent selected from the group consisting of C(=O)-ORE 2; C(=O)-SR 2; -C(=0)-NRaR4; Het'; -O-Hete; and -S-Het'; R" is a substituted Cjoalkyi, a substituted C1.ealkyl-S-C1.ealkyl or a substituted -Csaikenyl; said C1.salkyl, Caikyl-S-C1.6alkyl and -Csaalkenyl each independently substituted with 1, 2, or 3 substituents each independently selected from the group consisting of aryl, heteraaryl, C3 scycloalkenyl, -C(=O)-OR"; -C(=0)-SR 1 Het'; -O--Het2; and -S-Het'; and wherein Ar, R' R" R22, Ra, R 4, R5, R" Het", Hetz and Het' have the same meanings than those defined in any one of claims 1 to 5.
[11] 14. A compound as defined in any one of claims 1 to 13, for use as a human or veterinary medicine.
[12] 15. A composition comprising a compound as defined in any one of claims 1 to 13, suitable for use as a human or veterinary medicine,
[13] 16. Use of a compound as defined in any one of claims I to 13, or a composition as defined in claim 15, suitable for inhibiting the activity of a kinase; in particular a ROCK kinase. -138-
[14] 17. Use of a compound as defined in any one of claims 1 to 13, or a composition as defined In claim 15, for the prevention and/or treatment of at least one disease or disorder, in which ROCK is involved, such as diseases linked to smooth muscle cell function, inflammation, fibrosis, excessive cell proliferation, excessive angiogenesis, hyperreactivity, barrier dysfunction, neurodegeration and remodeling.
[15] 18. Use of a compound as defined in any one of claims 1 to 13, or a composition as defined in claim 15, for the prevention andlorireatment of at least one disease ordisorder selected from the group consisting of eye diseases; airway diseases; throat, nose and ear diseases; intestinal diseases: skin diseases, cardiovascular and vascular diseases: inflammatory diseases; neurological disorders; proliferative diseases; kidney diseases; sexual dysfunction; bone diseases; benign prostatic hyperplasia: transplant rejection: spasm: hypertension; chronic obstructive bladder disease; and allergy;.
[16] 19. Use of a compound as defined in any one of claims 1 to 13 or a composition as defined in claim 15, for the prevention and/or treatment of eye diseases selected from the group consisting of retinopathy, optic neuropathy, glaucoma, inflammatory eye diseases and degenerative retinal diseases such as macular degeneration and retinitis pigmentosa; preferably glaucoma.
[17] 20. Use of a compound as defined in any one of claims 1 to 13 or a composition as defined in claim 15, for the prevention and/or treatment of airway diseases selected from the group consisting of pulmonary fibrosis, emphysema, chronic bronchitis, asthma, fibrosis, pneumonia. cytsis fibrosis. chronic obstructive pulmonary disease (COPD), bronchitis rhinitis, and respiratory distress syndrome; preferably asthma or COPD.
[18] 21. Use of a compound as defined in any one of claims 1 to 13 or a composition as defined in claim 15, for the prevention and/or treatment of Throat. Nose and Ear diseases selected from the group consisting of sinus problems, hearing problems, toothache, tonsillitis, ulcer and rhinitis,
[19] 22. Use of a compound as defined in any one of claims 1 to 13 or a composition as defined in claim 15, for the prevention and/or treatment of Skin diseases selected from the group consisting of hyperkeratosis, parakeratosis, hypergranulosis, acanthosis, dyskeratosis, spongiosis and ulceration.
[20] 23. Use of a compound as defined in any one of claims 1 to 13 or a composition as defined In claim 15, for the prevention and/or treatment of Intestinal diseases selected from the group consisting of inflammatory bowel disease (IBD), colitis, gastroenteritis. ileus, ileitis, appendicitis and Crohn's disease. -139 -
[21] 24. Use of a compound as defined in any one of claims 1 to 13 or a composition as defined in claim 15, for the prevention and/or treatment of sexual dysfunctions selected from the group consisting of erectile dysfunction, hypogonadism, bladder disease hypertension, pulmonary hypertension, or pelvic surgery; and/or to treat sexual dysfunction associated with treatment using certain drugs, such as drugs used to treat hypertension, depression or anxiety.
[22] 25. A method for the prevention and/or treatment of at least one disease or disorder selected from the group comprising eye diseases; airway diseases; throat, nose and ear diseases; intestinal diseases: skin diseases; cardiovascular and vascular diseases; inflammatory diseases; neurological and CNS disorders: proliferative diseases; kidney diseases; sexual dysfunction; bone diseases; benign prostatic hyperplasia; transplant rejection; spasm; hypertension; chronic obstructive bladder disease; and allergy;; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound as defined in claims I to 13, or a composition as defined in claim 15.
[23] 26. A method for the prevention and/or treatment of eye diseases selected from the group consisting of retinopathy, optic neuropathy, glaucoma, inflammatory eye diseases and degenerative retinal diseases such as macular degeneration and retinitis pigmentosa: preferably glaucoma; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound as defined in claims 1 to 10; in particular a compound as defined in claims 7 or 9, or a composition as defined in claim 1S.
[24] 27. A method for the prevention and/or treatment of airway diseases selected from the group consisting of pulmonary fibrosis, emphysema, chronic bronchitis, asthma, fibrosis, pneumonia, cytsis fibrosis, chronic obstructive pulmonary disease (COPD), bronchitis rhinitis, and respiratory distress syndrome: preferably asthma or COPD; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound as defined in any one of claims 1 to 8 or 11 to 12; in particular as defined In claims 8, 11 and 12, or a composition as defined in claim 15.
[25] 28. A method for the prevention and/or treatment of Throat, Nose and Ear diseases selected from the group consisting of sinus problems, hearing problems, toothache, tonsillitis, ulcer and rhinitis; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound as defined in claims 1 to.13, or a composition as defined in claim 15.
[26] 29. A method for the prevention and/or treatment of Skin diseases selected from the group consisting of hyperkeratosis, parakeratosis, hypergranulosis, acanthosis, dyskeratosis, -140- sponglosis and ulceration; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound as defined in claims 1 to 13, or a composition as defined in claim 15.
[27] 30. A method for the prevention and/or treatment of Intestinal diseases selected from the group consisting of inflammatory bowel disease (IBD), colitis, gastroenterilis, Ileus, ileitis, appendicitis and Crohn's disease: said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound as defined in claims 1 to 13, or a composition as defined in claim 15.
[28] 31. A method for the prevention and/or treatment of sexual dysfunctions selected from the group consisting of erectile dysfunction, hypogonadism, bladder disease, hypertension, diabetes, or peMc surgery; and/or to treat sexual dysfunction associated with treatment using certain drugs, such as drugs used to treat hypertension, depression or anxiety.; said method comprising administering to a subject in need thereof a therapeutic effective amount of a compound as defined in claims 1 to 13, or a composition as defined In claim 15. -141-

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法律状态:
2013-08-08| PC1| Assignment before grant (sect. 113)|Owner name: OPHTHAKEM NV Free format text: FORMER APPLICANT(S): AMAKEM NV |

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2016-09-29| MK4| Application lapsed section 142(2)(d) - no continuation fee paid for the application|

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AU2011222900A|AU2011222900B2|2010-03-02|2011-03-04|Heterocyclic amides as ROCK inhibitors|

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AU2013205638A|AU2013205638A1|2010-03-02|2013-05-02|Heterocyclic amides as ROCK inhibitors|AU2013205638A| AU2013205638A1|2010-03-02|2013-05-02|Heterocyclic amides as ROCK inhibitors|