WO2015200650A1 - Substituted benzene and 6,5-fused bicyclic heteroaryl compounds - Google Patents

Substituted benzene and 6,5-fused bicyclic heteroaryl compounds Download PDF

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Publication number
WO2015200650A1
WO2015200650A1 PCT/US2015/037715 US2015037715W WO2015200650A1 WO 2015200650 A1 WO2015200650 A1 WO 2015200650A1 US 2015037715 W US2015037715 W US 2015037715W WO 2015200650 A1 WO2015200650 A1 WO 2015200650A1
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compound
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PCT/US2015/037715
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WO2015200650A9 (en
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John Emmerson Campbell
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Epizyme, Inc.
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Priority to US15/321,256 priority Critical patent/US20170217941A1/en
Priority to EP15811497.5A priority patent/EP3160940A4/en
Publication of WO2015200650A1 publication Critical patent/WO2015200650A1/en
Publication of WO2015200650A9 publication Critical patent/WO2015200650A9/en
Priority to US16/828,367 priority patent/US20200361914A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • COMFOONFA ⁇ 005 j T is ap beation Aanna prioshy to, aski the besu oh U .
  • one aspect she present is enhen features a sohoanno benoeoe or taeyeiic heocroaryi c m nd A !Oarnsoia sj) beiow or a phartnacentieahy acceptable anil dtereoh
  • ⁇ ,; is C or ;
  • v . : is H or CRx
  • oaak of R 3 ⁇ 4 ikx sad i iodoi iideoijy. is ⁇ k> T ;> d; svhkh ⁇ ' b m a ix-ad or kY-YY alky I baker opb oaby rk>sxion:ed - Yth haky ayaoo, hydroxys os CY aikoxv. and 1 ⁇ is H.
  • I1 ⁇ 2 is kk-YY aikyk (Y-Q ai-reamd kYRY aikyrod, kY-YY aikoxyk C kY thioaikyk ⁇ >) ⁇ .
  • R,.,, R aod Ri :dodv eodard:iy. is H or C Y aikyi opoooady soRYOiRx ; vYtb ooo or - ⁇ ;.;! si.doai seiscOad Rom rhe aroop Ovai isUiiy oidxdo, hydroxyd COOR. (.k tjOoYYk; aikyi, ',yaoo s €Y ⁇ G. aikoxyk aioioo.
  • Ribpenbeons is M or Rv-. and each oi i1 ⁇ 2 and R.-. : , indepondendy, ⁇ a ( . r -R,, k k -Ck sihenyh (RRR alkynyk Cy-kR cvckxRkyk CR-kV. aryi. d to ?-asserobercri hcterocaxioa!kyk or a to ⁇ - cambe ed freRnsaryk or ik aad together whh bx- N an a a to whRn they arc attaeheb, Kara a.
  • Ta is i baby y aa- r ⁇ OR,, - R-Ra, dNRRRbR; RAk - yORR. bkORRk AR YNR, iO, -NRXROsR..,•- OkRORaR-,, oROrkk, - U-. R p ⁇ . or R S . I; in which each of R,, R ⁇ . and R, R? independcoby is H or 11 ⁇ 2, A " is a ph rm eutically acceptable anRax each oOka; aob ik-;.
  • Rons rise group oomasRug of H. halo, ⁇ , yea:- C r O f . a!kyi, 0 ; 7 cyeioaikyk Ck- Rii aryk 4 to 7o;>emhsred heieroeycloalkyi, 5 to OmenAered heictoaryh OR,, kOOIR, -SR4 ⁇ Rk,, -N .,RK, and -4RkRNR.yR f , ; each of R, and R- aidepcodeniia being H ⁇ ; ⁇ RvRy.
  • kbR. XkyknekXXX eyeioaikyh RyXX; arvk (kXk aikyXneXkXX, ; sryh 4 k> i2onenR>e-red heewoeyeioalkyh Cpbb aikyieowk
  • CiX akkyleae-S- o bonevrbxsred heieroaryh nd 4b is ophowb!y i kobioTad with sin or neae subsboiaiks selected bona Use r coreaskna iXlxbo.
  • a is kb 1, 2, 3 k or sy and
  • ⁇ n ⁇ ⁇ s is ..s hwsxk. hwerearyi ayaaon.
  • Z is N or ⁇ b .
  • Z is N " or CR " . provided when 7. ⁇ . ia R 2R rr. by
  • R ! is R.h--vb)aikyk iC-b;y)astancey k (C RRihkyoy k un ubsritatod or sabsbUacd (C :r Cocycioaikyk iaub ouried or ubaoRated i . .
  • ⁇ is opboaaby sahsrhyard oath oaa to ⁇ aroap saieciad fr-.
  • R is iiydrogao, dkrkyiaiky L or afkoxy
  • ' is h drogen. oik-C baikyi. asaoo. triiio ⁇ a'oraeri d. - R '! R ' . ra halo:
  • R :i and R. i; are each indepcodandy hydrogen, R bRkKbkyk iCrRR1 ⁇ 4kkaa k Rdr- R.ydkynyk C R.k yaRedkyk (CxR/ :s a;yck.edkeayk RdxR-RbbieyekaRkyk h «ieo.>cyck:>a;kyk aryk or hererxarsb : obeeb'; sari (C-.
  • RRdRi R ' .; adkyk dR.RNkR,RRd RiRdRgpa!kyk and
  • R :i and R" gpkaa aagodier wiih da; adrogen P avhss.b Uiey are adaehad ropresem a 5-8 aseralav ed a ⁇ atuj'ared or unsru r R-d rba-a opdoaai coaiakRng an ddiRosud hoParradon; r-oR-cted draa oxygo , narogan, and saUap whershs sa;d ring sa opraanady ⁇ nba aged by R 2 or a groups haRpennera aoie ⁇ d troro ; -Ri ⁇ ikyk RdRRahaRadkyk aaRoo, (CbR ⁇ ' RikykuTdao.
  • ⁇ ; is R k 2, 3, a. or 5,
  • the present hsvenbou also presides pharnoieeioRai eoioposioons comprising one or more nha maeetroeRR acceptable oarnem and one or rrmre compounds seiectao Fabrica ⁇ .hoae oi nip- of rhe kormniae describ d herein.
  • kZHd-uuediatea eanoer may be lymphoma ie g., a germunai eemeode!
  • Methods des r ed herein may be nsed to iderdlfy sukable candidates ro tre;aittg or preventing fo/ffkooedkned disorders
  • the ims&mlon also provides methods of kientifying an inhibitor of a wlk ype EZH2, a mutant FZHB (e.g., a VoB j , ⁇ , andosr A6T7 mutant EZH2 a of both,
  • the method comp ises the step of administering to a subject having a cancer oath aberrant ⁇ 3 ⁇ 2.27 etkykttion at; elfective aiooaB of one or more compounds or ko nuiae described herein, eeherem the eompeanslug inhlbks hisrone methy;transkrsse activity oi. bZHk. thereb treating dte cancer.
  • L.:,armBes of aberrant H3e ? meb kklon may include a global increase in and/or aitered distribatton of H3--K 7 di or triorsothyiation wilhm da; caaeer eeii chromatin.
  • the saucer is selected hems the gronp ormsuamg of cancers baa:
  • the nvet.bcjd eotnpB ses the- step of administering to a stmieot havmg a eaf?ser so eras posse dt a EZH2 a iherapersica!iy eBeedve mount, of one or stase eoag>ouads of fonoelae descri ed hesxim vh i io the cornpoasKbs) inhibits hixone nxdvyltransfxrase activity ⁇ ⁇ hereb re tin sh canceo
  • bx method comprises the step of admbnatermg tc a subject having a canoe;' with loes-oolonotion nmtatXn in the H -R.?7 desrxihylaae UTX a rherapenbeabv etfecbvc arnonnt A - -a-, or more cxmp- ⁇ ;. ! ⁇ of horn a bac described herein, wherein the oompoonbiSi imnhh baa. m dtyitranskxase ncth a y of EXI-12.
  • another aspeco thas invention relates to a method of nmdulabng the acbvby -a die vvUdoype BXR2 the earalybc snbunk of the PPX ' 2 complex which catalyees the snono- through a bmeibyhvhon of lysine 27 on histone tie ⁇ 2 ⁇ .
  • i bs method can be conducted either in r/ox r ;o seen.
  • she method comprises dec step of admhnsnx g to a snbgxe having a cancer expressing a rnending bXfib e ., a ⁇ be 1. Ao77, and/or Abb?
  • mutan of hXi 22) a dseo.genoeaiiy siiectrve am un of one or snore con-pounds oi b-Ximeac described heseim cohee in the oosnpoundiSi inhibits histone mehnkranstesase actoity of hXH2, thereby ncabng the eanoer.
  • the cancer is iymphosrnx icukenba or melanoma
  • the cancer is germinal center ⁇ lymphoma selceaed irons the gsoup consisting of ioliieaiar iymphooxc diffuse large bXceb lymphoma iDLBCba of gennsnai eenXr B selbUke (GCBs sutyypm and iJnrbiU ' s iyispbinsor and on-Hodgkbhs bynsphoroa of germinal center B eeb type.
  • GCBs sutyypm and iJnrbiU ' s iyispbinsor and on-Hodgkbhs bynsphoroa of germinal center B eeb type.
  • the iynphosna is noioiX>dgbin :' s iysnpbonia fNlabt, fohkabar b-mpborna or difbise large B-ccb iynipiionsa. Airernativeire the ienkcioia ss chronic myeiogemsns lesikcinia ( f.g c te
  • ojigedendroakorea atypical terntokbrhabdoal rumor
  • choroid pleases earciaoma.
  • choroid pleases papb rns, ependya3 ⁇ 4oaia, eiknskebonoc nrenmgm a. neuroglial tumor, obgoastrocvtoma, ebgaaiendrogikaos.
  • Fseno nry paacreadc cancer includes pancreatic ductal adenoearcinorna aad pancreatic endocrine tumoia
  • Foorspbyv sarcoma includes
  • chondrosarcoma clear eeb sarcoma ok soft tissue, owing sarcoma, gas roimesiinal stromal tumor, oamosareotna, kiabdoonosarcoma.. and no; othervkse specified s ' NOS) sarcoma.
  • Aheraatbaby. cancers to be beared by dm contpentnds ofkhe present invention are non NHL cancers,
  • the cancer is selected frotn the group consisting of medal kkikisioara .
  • oiigodendtxmbosna ovarian clear cell adenocsre henna, ovarian endomeihooid adenooarotnonva, ovariaa serous adenocarcinoma, pancreatic ductal abenoesicmoioa, paacrcadc endocrine barter, rnabgnarg rhabdoid turner, astrocytoma, aksneal iecaroabrhabdoig tumor, ch roid piesals carcinoma, choroid plesats papilloma, ependymoma, ghobiastonua memnseoma, neuroglial tumor, oligoastrocytorna, ohgodendroghoma, pineobb
  • daa c aacer is readaUobhevsanog ocariaa clear oe!i adeaoearcasoraa, ovanan cssdosaerudi ⁇ ad adenocarcioorra!, paaeroaiic duct l adcnocarciiiOau ; , iuabgrarat rhabdoid aaaas aiyriical s-ras;adb habdoid ruiuor, choroid pivxas carcinoiiao choroid pies.as pa>.udoraa.
  • giiobiaaroma raenlrigioaia, piacobiasoara sre na-s reon-a, aaaaaonai sfiabda-d taaion sehovarasona.
  • NOS sarcoma M re prclerabiy, t e caneer is malignant rhabdoid Ranor. rnedalloblssioma amkor atypical teratoid/rhabdoid tamor.
  • tdhblgnam rh-j olodd manors are high-grade neoplasms of the ceoirat ue-i vents smtem si?.N:b kidneys and soli dssne drat asoally occia so ehlkkem dim hisbskmsc diagnosis ofmakgi e t rhabdoid i nor depends on Ideraiiieadoo of characteristic rhabdoid cells ilarye ceils ohb eccentiocally located nodes d rbenbaab eosinophbk ryioplnsrn) and Inm m-Kgdstochemistry with aniihodles to vmientln, herntm and cp beii a rnembrnne andean.
  • the malignant rhabdoid tumors are INI] oiefecseni tumor.
  • dm medead comprises the aoep.oi adminiskasng to a ubject aving a cancer a theragetmeslly attecdve a otnn of ne or none c-eee -nmo f Formalae d sc ibed hc om vrbefem the t oinpoandpdp, inbibas activity bog., bisionc metbykransferase aodmiy) ofd.be m tan k2H2, bar wild-t e f7ZI?2 : or borh. diere y treariag the cancer,
  • dm method further oonprises the siege ofperiorad g an assa to detect tiro preseose or abserree of a onuant EZB2 in a sample c m risin cancer eetk from a subject In need thereof.
  • the Invmitton features a meikod of selecting rherapy lot a pabcm having disease associated oath LZHdnnedaded probso navfhylatlotr
  • the meikod lacludex the snips of deiermubng the presence or absence of gmm mukaion ;n the fall? gene or the s bject: and selecriny, baserl on the presence or absence mf a gene nmtnboti In the id le: gene atheragv for hcabng the disea e.
  • the iherapy includes the administration of one or more ofdhe eompoands ol the Invemlom la one embodbrmnb die mebnxl farther ineksdes admnaetradng one or inore oft he compounds ot the invenbon to ihe aumect.
  • the disease is earner (such as lymphouep arid the nuaabon Is a Vo4b Ad??., arai/ t And?
  • la another aoibodnnenc dm dis se is an eZrla odkl sy e germinal center fkeell iympkunsy e.g., the germinal eenao: -eell lymphoma colio having nomemaated. ohkngype FXH2 pioieim
  • a meth d of treatment far a paiieni
  • dm me h d comprising the steps of deienninhig die presenee or absence of gene imitaion hi the BZH2 geae and treating the patient in need thereof, based on ihe presence- or absence oi a gene mtnaiion in the bZU2 gene, oath a therapy d3 ⁇ 4i mciudes ihe adrnuuai ilon oldhe compounds oi the meemiom Irs one emb diment, the gadem Is a vaaeer patictit and ihe iniaatlo;; ;s a Y6 ?., ⁇ 677, anddo- Ada? nneadoe, la anoiher emb dst:>eii, ihe nabeo; has
  • this nv ti n relrPes ⁇ > a method ot rnodtdaiirtg ike asbvhy m the w k!-iy e and mutant hktone rnetlmtnmsferase EZI 42, the catalytic sobnrdt of s e PRCZ complex winch oataiyaes the mono- t r u h trkmeihy!atlon ohiysine 27 on blstone H3 flfZ 1422 g
  • the present invention r lat s to method of iahibkmg the activity oi cePain mutant forms ot kZt i2 so a cell " s e muta beams -e Zl if include a suhstnukon > " »f another amino acid msnl
  • the method mekidee oo acnog he cell wth : ⁇ eflectke amount of one or more of the compoands of an i -scale described hereuv lids method can be cenduoted either u? i Pro or f ; o'o.
  • this Invention ieatures io a method of inhlbhing in a subject conversion of H3-- 27 to trimekuylaied i iZZZZ
  • the meik-d comprises iuiaZmstermg io a suifject espressmg a nottant EZH2 (e.g., a Y641. A647, and/or A68?
  • the hktone meksyhratvZsra v e activity inhibited is ihat ot the Y641 mutant of EZH2.
  • the compound of this invention selectively inhibiis lactone oicih kransterase activity of i e Y(>4i um;mu of E7I12, I eseoa-lc the Ybd 1 romani of FZH2 is selected iron? the group conxktmg of Y641C. Ybklk Vo4]fh YZAIbf and Yp lS.
  • a 4 k . may also comprise pertorm g an sssae to detect a unknot 44; A (e.g.. a Y64I, A677, and/or A6F7 mutant sk EZHZs in a mpe- 4. on subject before administering to the subject expressing a mutant fv.i i /.
  • the assay to detect the memm PZIfZ includes whom-genome reseuueneing or target region reseqaenciog that detects a nuclek acid encoding the mutan t?Z! 12.
  • perknaZog the assay to detect t e nnaant FZI72 includes omriacting the sainpie oaih an antibody tiun binds speeiiiealk : to ⁇ . ⁇ polypeptide or t agincitt tberesif chta-acter-sile of pie s ub-in f ZH2.
  • F ⁇ ;r csaui le, perkuaung the assay io deieei rbe iuatacn 124142 includes contacting the aan?p;e under highly sklngent eon ⁇ htions vitb a nociele acid probe iitat hybridixsa to a nucleic aesd ericodltig a polypeptide or hagnscnr thereof charaeicrkko of the murant kZblZ.
  • I an tliCss the invention also relates to a meth d oi " Kientkymg an inhibitor of a mutant ZZ! 42, the wi Zy e EZH2, ⁇ n- both.
  • the method comprises ike steps or combusmg an laoiated 122222 wi h a historic substrate, a methyl gr u domes nd a i ss: soiCip md, wherein the biatone sthwsraae soogwises a form cTHiw . ?
  • performing the aacay to detect methylaiion of H3 -h227 in the histoae substrate comprises eontnetmg the hsst ne substrate wish an antibody thai bifida speci heady to biomihylated Hfoi ⁇ 27.
  • a method oi ideni yhig a selective hfoihitot of a mutant 132132, be aa.
  • mo comprises the steps ot combming an isolated mutant BZ1I2 with a hisione snbsissue. a methyl group donois and a teat compound, wherein the hisione substrate couosrises a form of H3-K2? ⁇ elected ironwthe gr u eonaiatiog orbnonornethgisteb H3-2027, d; erhylatcd H3-K27.
  • dst oe substrate comprises a Rasa selected from the group consisting rddsionon etbyiared H3-7222, dimcihyhwed H3-K2?, sad a c bin ti n r»f nwaisanethytaiod I13- 27 und dimethylaled ⁇ ⁇ ' 2?, dncfo for ine a eontsxd mlsiurc: performhw n assay to detect trinasthyiation oi dm hisione subsgsge in eaidt sb ifo- teat rmstuie and ihe control mixture; ealeaiatiny the ratio of w bssnefoyhihon
  • the sado iaaibt is ;ess ihaa tise rati-:- b ' ) g.i?- ib3b) Th preaea; invendoa tratbei po>videa a nwdiod saddasnifystig a aiibjeai as a eaadidaie for ;; ⁇ ; ⁇ ⁇ wad; taw or naare ao;npounda oi ihe invention.
  • T he method composes the steps of partbrmaig an assas- to deieei a mutant E72H in a 'S : a;ipie tf io a anbieet: and identify iaa a Nubgaa e a a . eieo a nunccr 02122 as a candnfue for ueaPnern. wUh one or more compounds of the invenbon. wherein -he csa-npoendts) mhihha hisPsic mebyhransleraae actuary of BZH .
  • hi one eunee.bme;ig de method comprises: tit providing a nucleic acid sample irom a biological sample rbiiaincd .( m a sab-jeep (ii) vonukiing Use nucleic acid sample with at l t o e pomer die :.; ⁇ ' ⁇ . cbcdb, hybndrees ⁇ ⁇ ⁇ a nuekie - sd segusnee oi 22142.
  • the method comprises; (I) providing a nueieic acid aang.de bane, a bkdmgcal sample ob mkxl dean a aubiecg corpaebng the nucleic aenl sangZe veibi at teas; nco primers baa specifieaJiy hybridize- ha r olem acid segoenee of EZH2.
  • velds nucleosides encoding a muiaik thai increases EZH2 iri yogateeiailori of iK-KZg ihl) amplifying he nucleic acid sequenee ;: or the complement bereoh characterized raid; nucle-Pkies -sacbaa- :f .
  • the method comprises: (is p oviding a nuctele acid sample iro a bii h-gical sample obkoeed frmn a sublecg (lb cont;.u;dng bar nrielele acid sannZe with a ( least rimer iba; S;: ;
  • ne e imdimeng de method comprises: ik prowding a rmeklo acid sample irotn a biological snwiple skkamed hom a subject id cmkacimg the nuelek acid sample with a; k&at two primers thai apeolilcahy hybridize to wseleic acid sequence, or a complement thetemb chasaotenzed th nucleotides enoodmg a mumhon at die sti n Ywtk A677 r nwkor OS?
  • dm istadoii Increases FZ4I3 inmethylaiion fHAKs A ibl) m lifyin the nwAele acid sequence, or die o nem eai i creok characterized ⁇ ⁇ ah dm mmabon at the nneieotldes eaoodum poshsoa YA4 k A 677. and/or AbB7; iw) fhaccbng dm preaeaco oh the mutation as the nuekotkka encoding Y64 A677.
  • the method cam briber comprke vis aeieehng a therapy that includes the adminlsimtion of a dai-mpeohcaby effective amount or an E7.H2 mhshkor to dee ubject Kkuitbied la sky (7g wherein d;e ⁇ 21:12 isnbbdor udbbhs the co ver on otbfv-Kdf t a-ipiCibyiate Hao ⁇ 27,
  • ah technical ami sekobfe terms used herein have the earne meaning as con mrby nnderstood by oae of ordlaary still in the art io winch dds bwet>bon belongs.
  • the slngalar lotrna also I clude die pln l radess do- wmtext clearly dictates otherwise.
  • rnebbods and maeerads similar or equivalent to those described herein can be wmd la the practice ortesiing of the psvwcm awenbon, suitable mebiods and materia L am described below.
  • Ad pabneaoona patent w? £ >ii . na-e . patenis and other rsterenees mevn ' ned herein are incorporated b reference.
  • tip; : atures and advanaiges of ihe invention will be appaieid trrav? she foll wing debo!ed ⁇ ' ⁇ : ⁇ 1 ⁇ ! asoi c!abms D TA ; ;> ; ⁇ oo 8] ⁇ poo;:raa isoen o provides n v l -a;bsdUHed beooeoo bieyeUe heveroasyl c-.no uVit -. symheik.
  • X.: is C or N:
  • each of R and K.-; together nsRy kksa ; ; Is-RoOk. in vRboh PR is a bond o (h-CR atkyt 1 inker optkxxiHy aabsbPned obth halo, eyano. hydroxy! or CRRd. a!kcocp and lb Is !h hak. hydroxy! k(0)OH, memo, axkkx or s,. in oiueb R-: ; k R ' ;RR aikyh RRRR alfcenyh RfRR : alkynyk R:-RR a!hosyk PRRP.
  • ⁇ rack of Ik, Iks, ⁇ ;! , and R ⁇ uKkpendentty.. is R or R-C-, aikyi optsoaaRy su stituted okth no or more substltucma selected Rom he group eonskkng of hakg hydroxy!, C ' OOB, R(bRRRR-R : aRod, cyano, 'R-CR aikoxyb amino, rnono-b rbr alkykminea rkCybk aikylammo. Rbb, cycRonkyh CR-CR. aryk 4 to kkmembered hsteresmc!ordkyk and 5- or OnmmRsmcl heteroasyk
  • uKkpcndendy is H or aikyR RR-R ' :; aikonyk k ' v-Rb-, aikynyb tR : -R ' K cvoioaikyi, O ⁇ -C;,; aryi, 4 as 7 ⁇ nicmbo ed bk4cr yc,l alkyl.
  • Ri ' Obkw - ' -as a ⁇ .- ⁇ R,, : . in winch each rri ' R, aad b.;,. iadepoariasbly sa H or -y. each of R> ; , and R sv , indepeadcatiy ic CbRR a!kyl, dw R . cycloaiky!, R-ib') aryk 4 so 7-nwaibered i teiXKyoi aikyi.
  • R-a hi opuonrdR ⁇ obskoped wHh r-no or more sukakiuema aokeied Rem Re g up cosooaung ok hake hydrox k k
  • Xa X,. Xh;. R RR, and XX are a aRned -:r:ch rhiH ihe mo-em in Rornnda pk k a bRyobo 4-aeo -a;-'. ; rnonran,
  • f or oxample, Z rs OR-, in winch IZ is Fyz; y, aryl (04;... phenyZ or 5 to ooimmbewd heteroaryl optionally substitut d with one or more ---QYiY
  • Z is CKiR ? Rx m which RZ Z; -OR. 3 , and R 3 ⁇ 4 Is CZZZo aryl (e.g.. phen l) or s to ooncrnbewd hcreroaryl optionally xubsdhpod whb one or more -% ⁇ 1 ; : arid ;; Z C ; ZZ ask) I.
  • CZZZo aryl e.g.. phen l
  • s to ooncrnbewd hcreroaryl optionally xubsdhpod whb one or more -% ⁇ 1 ; : arid ;; Z C ; ZZ ask
  • a is C.
  • YZ is YIY s .
  • jOp For example, s-" Is 5 so h-membemd heteroaryl wmPdnltm ZZ h Paoatorns s leered Rom FY bp and S emu opbonallv sabxRmteh vZdi one or mo provided that the hewroeryl Z no; nZophenyh
  • p. is phenyl or Z- or Pooernbered heieroaryl aubsb emd with OZ.b.,. albyl or bORY;.,. nlkyb each oiZvhlah is optlo b y wdxsbpged 3 ⁇ 4 hh hydwxyh ORb ⁇ > iOk l or NrZhho aikyk e;ab eb be 0- ⁇ € . ⁇ . .
  • R & is haJo Peso, fioonac, oiborke, hsonnoe, and iodaxO.
  • R For exanpke, R,: k ⁇ mj ⁇ * . adRkb k Olnkak ,, -C(0 ⁇ Ni3 ⁇ 4 a R h , -YRkkOpY kkeaR* or ⁇ '(7) : [ R Jk..
  • bdbdj For example, hk >e d to '" wnembered betefoeyx loalkys opbonaby sobathukoi o dd one ca ⁇ n-sore -R> 2k. and wpww is oxo or v is a bond and k is --OR,, -bbbklkj, -P o -do.
  • Ixderoeyelo lkyL e c of winch is optionaby sabstbamd with one os wow - ••i 3 ⁇ 4--1k when R, or l ⁇ ; is not H.
  • Fw exaoiplw Os is a bond.
  • ' d Is an umtmabmted subsbuHed snaigtu chain Ce-k ' s or branched Cki-- ; albyg nwkshng bra nor bnbted kc meth k edwh w-propyb kpropyh n-bnryh s-bmvb i-brayb n--pentyl s- enny I and n-bexyk
  • Tj Is 4 loinrnbered hcterocycioalkyi le.g.. axebdiny oxetaoyk
  • Q is a bond or methyl linker and I- is B. halo., ReQ, GdbikR.
  • R c is (FOR. alky ! or to ' /onembereR kebxxogoFmlkg I Rag., axedd!rgt oxeeumk dbeoangl, pgrnbkbnyk irmdaxsbidlnyk pyraxondbr k oxaxobbieyb kx ; xn,a.b!dirrvk trbxokdngt ieiroh Fsr ovi.
  • v-.'hich is opRonaiR sobsiinRed uh on or more ---OvOb,
  • R ⁇ is i x
  • R, and R-, Rgether wh the N atom to which they are ar?.aohed, form a 4 m b-rnernbemd heteroeydoalFyi mgg kaeing 0 or addniooai hemroamms x U3 ⁇ 4 R aesm (e.g., axeud k pyrrobdhe I. imidaxobdioyk pgraxolidinyk oxaxoiklinyk Roxaxohdirg k irx;XolldmyF na ahyvoRnrtn k pipoadl xl.
  • axeud k pyrrobdhe I. imidaxobdioyk pgraxolidinyk oxaxoiklinyk Roxaxohdirg k irx;XolldmyF na ahyvoRn
  • T For example T; ss Ik Rd ⁇ .4 m ' /-itiemb md iKgerocyeRxdky 1, CbRR aRyb OR ⁇ : , ROOIR,- m; 0 i .- - H ; or -C(0)M ,R ⁇ .
  • K is piperkimyl opOooaiiy substbaard th one tr ⁇ k
  • Fk is kk-Tb, kk is a ono and T ⁇ a 4 to -membered heierocycloaikyi or (k-kk cyoloaikk sabsbtuoad 3 ⁇ 4bh ⁇ ⁇ : or more -Q-r " i ' j,
  • bke:k Tor ex le, kk is a bond or N3 ⁇ 4 and G i H, C r Ck ak : k Ck-kb eyoloaikyk CKk ikydere C ; -ky; cyckedkyk Ck-kb aryk k r k ⁇ aikykne ⁇ 0 k.y.
  • % is bond or NEk aad Id Code aryk Cvkk akkykoekk-kki aryk or b'Ooensbood bekroaryk C r kb alkykne-k- or ooionsbos-d hekroarek amino, nHm>ik- €y aikykndno, dkCyik; aikylandray lb bcaog opborabiy sabkkakd one or more anbstdnoars aekxaed f o so the group conaiabag of haky hydroxy!, k k 6 abbeey 0 k ( d alky Cne-kb -kk aikoxy, ara;; Ok- ., cyeks;dkyk
  • jOB7) i ov oxampk, (y a.; CO aad Ik k kok, alkyk k kd eikoayk (k-Cs oyekabkyk rkkk aikv ro-oyy.y s skeakk- kk- y ark.
  • keeiy optionally sakahuaed oalh ana or more eahshKserrsx selected Rop* the yaoup coaskdng of hakx hydroxy! ib-Ck aikoxyk O-kbRk alkykafcRdrRb aikoxy, aad Cd-Rd eycR lkyk
  • eaeh yfR; aad R. ; . avlepeadeudy. is H. halo, oi kb-kk -die- i opkonaHy eobsonaed *vHf « aakeo. axafo, hale, noaa R oR- akkykaykao, dRky-!x alk l&mino, oy kR4 a, , a h
  • each ⁇ 1 ⁇ 2 and Id; is methyl.
  • heRroeryi e.g.. pyrrolyk pymaolyh esRdaxolyk pyridyk pyrirmdmyk pyraxiayk pyrld xspyF leRrrxoiyi, oxaxokk Hxaaolyl, i
  • R 4 is halo, or a ; . aikyl or k " alkoxyi. aacri opboaaily sabRloaed vvi(h vsne or roore halo.
  • oar S e.g., pynxdyh pyiaxdyb irnldaxolyh pyridyb pynrnidim b pyraxinyi.
  • 11 ⁇ 2 is B or noahyk
  • IC is t : y ' : alLv; opdorra!iy sub-Pauied ad F0dd ; aikoxyk
  • RO- is CM, FRF, moi sdJrFd aikyksmirso, or di-Cj-Cy. aikylanorso.
  • R is ⁇ 7 s aikoxyl or Fddj; M aryCxy, e ch opuorrady subRiOaCd r bh orro or aosro algebra.
  • orhoresr 0 « is -0> :; - " . ⁇ .,, edoo'eki Co C a 0o;;d or F0R0> aiks I bober. and ⁇ is OV-dd aCyi oprioaaOy subsdOHod vbh ooe or more ⁇ iv-ld, C C Conduct cycioalkyi opdorodly suPsOruted won one or more "-QCT0 ; or 4- ro i4.-naerrd oed hoierocycloalkyl opdoaaily sub biuted odd ; ooe or sane
  • heeas R? is - ⁇ ). ⁇ ;.. wherein Rk is a bond or rraohyl bobeo and Ig. ; ⁇ CVCk albyl rapkooally snbauOited wkh on or more go- 4 .
  • Cokk cycloadkyl optionally subsnRUed wstb one oi o;ore - Q -To os 4- i.o heteRKyckodhyi optionally sobsrhuieb wkh one r more -yk-ld.
  • lOIKbjj The eoospoeHds of Formulae (125.. and (Op In klui sj 1 do- 'oRnxw described for bornubn RK when applicable, n Rather have one or nwce of the f ll in fcuur s;
  • RR hh j bor exam le when th cooipornsd is of F rm is la Ray R 3 ⁇ 4 k ika-Cas aryi or 5- or 6- iooo ' sbered heteroaryh ea h oldvklcb k opborukly, mdependesiby sobsRmRcl c ah 000 or more - RR- R, w harem Qs is a bond or C Ck alkyl Inker, and Tg is l b haky cyano. -OR 0 , RRfklk;, - k(kR VR. VRysRVR,.
  • R C is phenyl or pyridyb Q- Is a kond os ' methyl linker, and R Is ik halo. okIR, - ltjka or -SiOfsNk.- i.
  • hos rho compound is ofForraqia F s, Y is
  • aiaoosa th beierooyob is a 4-7 eiernbered hener cycb containing n sesygen or nitrogen, or both, aad here the nitrogen tar; optionally bo sabyaatod with abyb ahkaein be piperaaine. piperhhne.
  • gaaaspaaa, pynohdine co asebdbie groups can be optionally bather substituted oath Obi. gb.,; aikyk or ⁇ -G;. ⁇ -. aikyk aad o hcix in each or the O ag ; ... utkyl and N ⁇ -i-b ; ⁇ ahoy; is optionally aabsb-ated o ah hydroxys O- Cs. ⁇ aibyi or H-C-... aibyb ach of she ⁇ . ; > bkyl and .
  • I-RCho - tkyd bXny optionally Rather Mibsoaged oirb ⁇ -CX ⁇ iggyl obNH-bs.., abyb aad
  • 1X :" is C(llg and R is pipernhne: dbaepane; pvn'obdirse: aaoddiae; ( tX. : , abyb or knheienscrcle.
  • the heterocveb is ⁇ XX nu be ed heterocyole csaiiahnng aa orcgen or nhrogeve or th, aad v* herei the nlbxgen ran opdonaliy bo sabaauna.; arith C3 ⁇ 4.- . .
  • R is (;(b! asai R ";'” ts diarop iar, pyo'ohdiae, azeiuhno or O- C it .Iky b oXeieir ha pspebdiee. diaaopaao, pyrr ⁇ hdina rs ' aaatidiao groups ran be optionally balXe; ' iabroikaaal ba CRI orbb.,-, aikyk
  • R is Cabb, R "'"'; is piporazirie rgstionaliy farther substituted 3 ⁇ 4kh aikyk and R '""'' is pipaiiraas uSNObaad by b 2, or a FX.; idbyl grotaos
  • F f exarapka R. 'A!! is X, aad R u: ' is ri - hiahrvtg plporidiito, psporaalria. dbaepane, pyrroh-bae. asatidiiH: Odts.,. ab b vdaaaa? ibe p -os idaio, piparaaino, tbaaepaac. ⁇ rs axediXao gr ps caa bo optionally bather sub tituted vvah Oil or (i..,. aikyk
  • hen R is k(FR, k "'": is rawobshuned piperaajae and R is pipekekne aobskhacd by R 2. or 2 C;., ; alkyl proapa,
  • n is R or 2.
  • su is 0, i or 2:
  • R ;"v3 ⁇ 4 is C.F ⁇ - €.- . . aikyk piperidme sohNpp i by k 2. or 3 R '""': groups, or cyc hcxyl aubsOtraed by Fk "'' ' R o herein cock R """ is xxlepera-kakk Fa..; aiFy! thai R optionally sobskk eb with (R C-. ak ayF Rk 4 to kknwxnbered heterocycRaRyi, (hk koRFo ra !
  • Ron is s-p oaxdiy Ric er sekxmaed wkh CV €> alkoxyi or D-CRRR askyieoeRFRFi aikrwy, or km 5 ⁇ or oxexmbewd bereroaryi pwt is opkxnaky tboher ar-baokued wok k kx alkoxyi or - h-kF alky ieoeRFRR aikoxy:
  • R ""' is rnorpholaao ppxxkhoe. ipcraakax pyrrolidine, diaaepana, oaetme, axe ukoe or 0i- RFoa. alkvF wherew the pipekdhxe, doixepane, ⁇ wetaree or axeddnw aronps can F , ; opkowah Rather sabsviwaed wkh one ot more FR f alkyi, Ch.,-. baloaik R, R,;.
  • ⁇ ' is piperidnse simsm ied whh i C oy lopropyk r ⁇ vRbuRk or 'oaRsne
  • IR is II or R . s, in which Ik- is C- R aikyk OYCo. alkeoy; CRRs 6 ,0:.. ⁇ a; !. €*
  • .3 ⁇ 4 is N or CRy , pr ided baa vvh n Z ; Z N. Z ; ; ⁇ .; .
  • R is ⁇ CHdZaikyk Z ;;oZ.),dbooyl (C iZZiaikyoyk ansokatauted or RR- , C3 ⁇ 4)cyoioaikyk oosubafuuted or ubstiuted (C ;.sic ! oikyi-Z -Zb5aik 1 or C Cbodk o k roAsaJrobbood or sabataured ⁇ > . ⁇ .
  • R' o hybosgoa, oZzZabkyk or alkoxy
  • R ' is waoaaad fViOO ibe group ⁇ of hybrogoa, habo RZ-CbRdkyk (CdsZaikenyk ⁇ C;: : z:Za:dkyny k uoaadsbioRd or arawhkst-d ZZzZZyakxbk k aas'ybsRhaed or sadRpited (Cr C.Zyc o:i-.5fZb yd-H tVd --y Z lk I, noaobsb-oa-d so odabu.Pud ikZZbZo ⁇ okxdkea) k oosubsoRnod or sabaoawad ZZzbduyckobgeoy aZC Zabky € ; Abdhsc dodk k utrsabsidsbd or
  • iZ235 oZeraia aay (C; ZZjalloy iiZZZgdkoroyh iCr 'Zb ⁇ ak ;pa, i ; . oyoioaikoroi bioy b-idk b hck oyde ik l aryi, or hoioroaryi groap o' opooaaby sab-rbuavd by b i: or a yr-aips ;i;d pe;;d-i: h aekaiod ;rorn -he group ⁇ ⁇ iss.mg of RRRxR2 ⁇ a;kRRR ⁇ , ⁇ ⁇ , ⁇ ...
  • arhaoaa «ray ;R OJ hoicroary! moie oiRaid arR. hoRronry lRbRRkRk k or beo;a3 ⁇ 4ary kRaRpaik l R opbonaby subRkoRd by R 2 or 3 groups bkkpaadoauR seRcPoej U: b ⁇ o group conakpag of hal , (Cb-RRybkyk ⁇ CYC Kryek dkvh RR K-ycbadseuyk (Co Cpkasoalkyk ayoao. -COR ⁇ RkORRR - ⁇ 3 ⁇ 4 ;' R oRR R OR '! . RRRR S ⁇
  • a and IR are each uxRpeudendy hydrogen.
  • R ' Rabkyayk R dRdkya alky k RRRak akeukenyl.
  • R a and R raker Rygeher oka b;e rbRogeo So ⁇ a b ' sav are anaohod rapreaoR s 5-b nsembe ed saruraaol or uaaadaaPed rayg. opboradR comanbrg.; aa adcboonal laoeruausrn sclecRd Rom oxygen, rnbogco.
  • R aad ° Rken jop-her v,di.h d : 3 ⁇ 4 odrogea R> (bay are adaehed raproaovp f > .6- s- i d- aea ' ;ba'ed ra jped bieyalR riag ayasao a d io dy sa-ard t>.> a Rk ⁇ RaRyakxdkyk boRxocyaR)aH ⁇ yk aryk o beaaroarvl nmp
  • R is. hydr gea. R3rR3Rbkyk oiaikosoe
  • K " is. :oi ⁇ o-P from the group e ⁇ osiR sU; ⁇ a ky-u- ⁇ .- . o. P. -R ouU-r k eyaoo.
  • R i! rid R 'y are each imkgvodeoby hydrogen, iR: r Py)ajkyk i : rQ)alk&.oyk RR- CRpaikyuyi.
  • R 1 taker* usgetber vvkh the obrogea 1o ohkb they are ao ' aoged regressm a ⁇ ' ⁇ ;: ruombered aaiuraa l o unsaturated nog, opbonaily oaobouog aa addumaai heteroaRar; sekcivsi Roso osoygsa.
  • saoi slog is opbonaby iPsed s (Cxkbbyek-aihyk heie ocycioaikyk aryh or h3 ⁇ 4e3 ⁇ 4ar ⁇ i ring;
  • pgroop A is selected independently from the group eonsfoing fo " foraig keagfo«ee s pyrroio, o azofo ihksaolo, fobdaeofo pyraeofo oxadnsPe. dnadlaeoie, irlaaofo iekaxofo beneotoran.
  • a k; k Nil fo is CH ra Pr and C la hydrogen or Ch-Cb afoyl; or reherein in ⁇ 2y
  • D is N or opPonaby nbefonied by hydrogen or C ; -C ' ; > aikyk r
  • 0 is Nil or Ckgy p ' O or CO; and G is NH or C P; or wherein in id ).
  • J is 0. S or (X); or wh3 ⁇ 4 ; 3 ⁇ 4sa hi 55),
  • R k -NR a' C(G)K ,-N a S( R ; R - R a SORbR R S R - ⁇ ' R- ' R ⁇ -NR S H K ; o ok" R I >R R7 C (O s N l " IX" , or R)R%
  • vvhooRn (C;-C :s )aR;y; or KR--CRR: ckokky! group is opboaaky .-en ioa-d by k 2 or 3 roups !ndependeody s lect d Ron; RlRkXRkyk (R- ' Rcycioalkyk RkRkgcy-ooaRenyk Rk s - ( ..VihaJ alkv eyaoo, • RX.RR'R RRRR/R RRRRR " R ; R RRIR -SOR ' R
  • RkoRyRkgi, Rk-XXg: gckxbky k or keRoeeyeReRky? goa-p is oghooahy subsRaned by R y or a groups Rdogeoderrhv aekeRd irom iCh 3 ⁇ 4 ikvL (CrRkKgeRoafkyk .R- (XjeyeRabkenyk gCRRRihaioaSkyg > g,3 ⁇ 4n : RR)R :: , .X gR" : .
  • R i are d fined as ab e: or
  • P is Ckk. H > O, or S: 0/ 85 ? CM or N; and a R 0-2; or
  • U is hydrogea,. halo, amino, eyaao. akro. trsilaororaetbyL (CrCxOlk (C r
  • ia-reR any (CykRaRyi or (CyRR a oalk ) l group C optionally suh lruki by R 2 or groapa iadapoodsady seReRd Rosa R.R-COalkyk R2 r COhaioa!kO. oaaa.r -COR " , RORC .•CONROCC -RRC SOR " .
  • OCR ' SOdR.• ⁇ OR ' ORiROO fR , -ORR ⁇ - kKOadRk aad ayk iyRCC ; wherein IO aoa R ' ao deonad ar; above.
  • any RRRkOikyk RRR RRydoalkyk OkHRRdkynvk arylalkyayk or kofaroarykRkyriyi eaoap is pdoaak >ab:4aaR0 by k.2 or .> groeps indepeaRad) seRoa.-d fr m oaks R.yRRodkyk RRrCRsyeksdkyk RRRRKycReRkenyk ORRydhaloaikyk cyaao, - ⁇ krdlx XXkkd oyg>Ab ⁇ Ryk -xR;x ..
  • R XX (CVrR ; k -OC ⁇ s R s R FC . hega3 ⁇ 4cydoalkyk ryh heaoxauxh arykkV- CRaikyk aad hekroarykCrkxiaiky k
  • kx. are ariaohed roprxaaas a Ag neonkoxxi saoirakd or oaaaHaaied -a ay pti all vweaiana: an addibouai heteroatoa; :aderkd trom oxygen, akrogeig ami sulfur, wherein s d ring is optionaby s bsiduied by k 2 or 3 groups indepeadeady sekerod from (CrO.io.ikyi, (CdXX. ⁇ halo !kyL arnhio, XXXkkkyianbno, ⁇ €:- I ' ks lkyiM dRbk lkyii oda-s hydroxy!, ox .
  • aral R taken together with the ahrogea a. ; which dwy are tache repressor a X ⁇ a ⁇ iOooaakh ;ad bridged bieyelic ri sssaem optasudA based to a X--Cxeyoksdk k hcteroeyskxdkyl a.yh r hctewauy riag. Aryi arid heieroaryl in bXa deiknike tax sdocied froai die roup eoaskdng of kaasx hdopheee, pyook.
  • oxuxo!e dbaxob, i hdaixdw avfaxok, oxadiaxoky ihiadsaaoR, trkesok.
  • Atraxole berixo uraa, bxnxobdophene, b 3 ⁇ 4xoxa?x>k, bsoxothiaaok, phenyl pyridin , pyrniaxinw pyoyakhosx pyraxaxy oA;xine.
  • kjuxoaas axes 'aax ciaaobrsv, guexxxdke, gnuntxdiae. and aaprabyiidiae or a eraapoaad oi n the aryi or hcAroaryi group as tolkxvs;
  • A is O. Nkk or S; B ia bill r ok aad C ia hydrogen or RXXis aikyk or
  • D is N or C o RonaHy subsRkkad by hydr en or CokR alpyp or
  • E is ! R or Ckk; F a U or CO and G o: NM or CHy or
  • J is , S or CO;
  • M is Coi or N
  • any RRrCcOkyk ⁇ CijeyOoOk F group is optionally sobskRked by R2 or 3 g u iodepootfeody rekekd from RkdkO kyk .: t ' ;;)cycio ; dkyL : R. ⁇ .- Cohak:>Okyo oyao , -COEO RXRRO - ⁇ :ONiC R. : R -R ⁇ * . -SR>R ' ' . -ROdR ? ; -SFR R" R oOxy ⁇ NR0RR -NR* 0 ' 0)R.
  • otoaoin R° and R" are de ntd s above; o.;
  • hid?) is hydrogen, ⁇ ⁇ , a Rm cyaao, R RRRdkyh ;RjR.R3 ⁇ 4yeloaikyk
  • R is hydrogen, arakso. wdryh Ridooromethyk or halo; U is hydrogen, halo, amsno.
  • c an nPro, kskoonaiKXhyh R2iP2 s ydkyL (by- kykyoksaikyL -PdjRy -C kkk RXkslkRkR -SCyNK" k ' k -Pdk ' s x -oR3RRO ' . k ! SORR, R3R S y3 ⁇ 4RR - : -NR :' R R - .” RR s i.yO ⁇ k ! y ..( R S . 4y U-k-pyra i-k- v ' kk
  • any SrRykdkvl oi ;CjRh eycksRkyf roup is optionally suPsduned by k 2 or 3 groups iodepera:Rndy s lect d from (CRRkpoJkyk (C3v-Cs ⁇ cyaioaikyi, RkRRKyvoksdkenyl ((.V Cphakaikyk yao a OR . ⁇ ⁇ ,-RO ' NR" R b ,-SOR- : ,-NkyR3 ,
  • R r is hydrogen. (C Rsaikyl o alkoxy;
  • R "' ' is meth l bisHRo:hmeR;yk ⁇ hyk, bisip-r edsyRdod).
  • each f s disturb ⁇ and :: kaRpeodenby is H or FaRR alkyl opbonaby axbauxriod w th o or nxa ' C aubsptoerns :3 ⁇ 4Rokxi ftxax r.he aoaip consi;Odny ⁇ >.! haky hydroxy!.
  • R r Fi Fe Rkyk C O. alkenyk kRRk. absy yb Ck-xh cyeioaJkyk C Rbo .nyk 5- or ⁇ heieroaryb or 4 ⁇ ; ikxmanbered heoerovvckxdk yb b k R. I . or 2, each of ,. and Rv., nxleperakaxiy b H or E-;, and R. : 3 ⁇ 4 R kh R k akyb RyRy.
  • a d Ry Struktur is optionally substituted with on or snore -Oj-l .
  • m ⁇ ⁇ _> is a hoad or tpRR alkyi Ibske each o tional ssawhkieb ⁇ .- ⁇ ah ha!oo cyano, hydroxy!
  • Iwreroeyoloalkyk or R- or h-mesnbered hekroaspk r R and it,:, together ith the H atom to which they are atacherk form a 4 k? Isoysesvshered hcictooycloalkyi ring having 0 or 1 additional hwesosRom, and each OIRN.; 5 R,;-:, and the to Ibwnesrsbered heteroeycloaikyl rrag fowned by R,aws R.j, is oprkmaiiy sabstaored with one or snose - ⁇ > 3 -iy vckereii Q ;; is s bond or Cbwih alkyi hibrer each optiooaiiy stslwshbked with halo, cyano, hydss-wyl or CpCs a!koxy, aa
  • c ben R. is C ft - ⁇ br f «vyj os a- -w b-aneasbcred hetesoaR I together with she atoms to winch they arc auacheb form a > or (wweosbersd ring optiooaiiy containing 1 -4 heteroeloma aeleekai Ron's M U and b and optsonslly anbsdhsted with one or nsooe aobstnnesbs selected Irons she group conaiauog of haio. hydroxy!,. COOK C(hRO-R.bwR alkyi, cyano, tip -Cs.
  • R k being H or C r €y, aikyk and ' ] ' ⁇ c ;
  • M baas, bb-b ' aikyk Cb-h;., aikeorp bb «bb a Iky sr. a, hyuroayk cy iso, fbb.b askosyk annsus, nsosss- Cb'-bb aibyiasnsnis, diRib atb, cikylanbsas, O .
  • OR o k C ' OO --: / . m winch s is C k alkyk kg.o g alkenyh C : kV alkynyk of-Rd eyekedkyk d a; 12 ⁇ rnenb:xred heiaoo vcioatkyk anbno, in iKoC r (. .dfs laaaa; or dokaod.
  • saa IRx is opbonaIR sahsuriaod oaut on or sno e aahsbtuems selected from die group consisting of halo, hsdrosol COOlk kdOg ' kkddR alkyk eyano, (d-Ck alkoxyk arnbxy mono-Rd -Rd, alkvRnuno, and dodg-kg alkykardno; P and R s .
  • kkRRn aryk 4 to Idnnembered Soxerro ycksaikyk 5- or 6-me?nbered heRroaryk or fO k iss : ⁇ hich ⁇ o 0, R or 2 sao; f , ; kd ay- -ogR.
  • Id is kk hai>-, dydroxyk ra' cyaao; or-kk - ' IV, is oxo;
  • CR-sR cyvloalkyl (R.-(d;.- ; i- k a to Idanemfxred isa rocyeloalky k and 5- or b-nsensbered hoRroaryh and
  • n fk.
  • R 2, 3, 4, r a fk.
  • bid ' are not hnnn-d to, iperidinyL pipera inyk pyrroildinyl, dioaanyk teirahydfobnanyk soindohnyL indoHnyk iniidaaobdinyk p ra:aokdksyk o a ondirsy isoxaaobdiml.
  • [OdojJ the tern; oxxiorebiy sabaOiuted alk f " refers unstbxtiuneb alkyl or alky I having designated xubsthuents replacing one or nscae hydrogen atoms on one or snore carb ns ofbke hydrocarbon backbone, Such xubsbtnenta can bxbade. for e am le, alky I, aikenyi, aikynyk haii!gea, hydr; xyi, ikykaa'biSissdoxy. aryica bonyiox) , aikoxsxarbonyloxy,
  • acysannno (.including akcy!earbonybonhxa aryiearbonylamiao, c i-bativpa and ureido , nikhn ., indao, anii ydryk ahrykfao, arybhio, ihi carboxylatix snbaies. aikyistdiin i, stdfoaal .
  • aobannsyh saihxsarnidr- ratio, tiatia ios ctiiyi, cyaj y acido, -ierocyclyi, aikyiaig i, or a;r an.aaadc or ieeK'a aaaatie nioievy. M?26 j
  • a ' "as yhik k r an xnnl - moiety is an alkyi subsPeyeh wit a3 ⁇ 4s aryl (e.g...
  • linker Is intended include k ; , Cy, (by Cy C> and kg alkyi knkei groups, examples oi ' alkyl linker bmlnde, moi ' ehes having from one k six carbon as en . sueh as ; but not limbed ks, ;a-nb; ; MdHy-h et yl y CbkCblrk u-propyl n HoCi bCk -h -pro yl ; ⁇ ' ' kt U r i t. k. n-buvyl ⁇ . ⁇ > . I bs ' k klig. ⁇ ?.
  • Pes alhyix has-, sibed abo , bar thai conuon a; least sen- double bond.
  • die tern ' khkeuvr Includes trai ht sbain alkenyl groups hoy/, sthenyk propenyk butensl, penknyt hexenyk beptenyk sxrenyh aouenyk deoenyih and branched alkenyl groups.
  • a sPehghi in certain embodimenis, a sPehghi .
  • hsc- or branched alkeny 1 group has six or leaver carbon aknos in hs backbone tens, k Cy. for straight hain, Ch--kb for branched chai s
  • the terns ;' 0 ⁇ .. ⁇ ' includes alkeny I groups containing two in six carbon atones ' bbe renn "Cb-kb" ine lobes alkenyl groups eoniainbga threw to six varbon .a -es- jOsbSj
  • hydrocarbon backbone carbon at ms bach srehsthuents can ineinde, tbr example, alkyi, alkenyk slkyrgh, halogen, hydroxyl. alkyloarbonyloxyy arviearbony-oxy. alkoxycarhoinboxy.
  • carbosyhUe aikyiearbonyl. sckcarbonyh nikoxyearbwuyl, anhusoarbonyl. alky sua; kioearbouyk diaikykuninocarbonyk alk bhuxauimnyl, alkoxyi., pho.phaie, pbosphonaio. ⁇ dssspbinaro. asrnno (iackiding alkyianiiuo, dialkyiarnifxy arsianuno, dt ylamaiO and alkyPsrylannsto).
  • b'tkas 'tAJkynvk includes unxahusacd ahphaoc gontps a alogoie: in ieagth and osissibic subsbtuti si to the aikyis described above, but which, contain at least one triple h-ansh
  • 'adbyswf includes s;ta;ght chain kdkyn l groups ic y...
  • the term Aspbonaby simsib ed atk ny refers to unsabsdubed alkynyl or sikym I avng deslginued sobxbtne;Us replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms, boon substi utes an bans tor example, alk k alkenyb slbynyh halogen, hydroxy k alkyicarbonyloxv, arylcarbonyloxy. aikoxyearbonyloxy, nryio vcarbonyioxy earboxyiate. die.
  • icarbonyk arylcarbonyk alkoxycatbenyh anbnoearbonyb alkyknnavocnrbonyk diaikyiaiidnocarb-snys. aikykhmeaibom i, aikoxyh phosphate, nlnsephonaio..
  • phocphsnato amino (including aibylantino, bkbk; anna ; -.-, arylammo, diaryiam o and aikykng lammob acylamino iinciuding eikylcarbonyiaobno, any!earbonykunino, earbamoxi and arelelok aobebuu. Imam, subhydryb alkylrhnp arylbao, thiocafboxylake.
  • hnhcr opbouaby --.or-ss eb moieties include both the am ab-.boecb moieties and the mombes having one re mxsre of the designated sabsfitueoix.
  • substituted hctcjocycioa!kyi Includes basse subabmted ih ⁇ .- or moe alkyl groups, snch as d.ds.d-i ranethyk i er ireyi and 2.2aonoctrarnedpd-d,2 -b--miraio:d
  • AryP include ' cr u s with aroniaboby, including "eo ngatedo or nnbtlcysiic systems xvbh at least one amenabe ring and do not contain any hsicroaiom in die ring sbnebme.
  • bxampies include phenyl, bemcyk 1,2.3,-k-ien-abydronapiabaicayi., ekv
  • bieieroaryh ⁇ gronpx are ana groups, as defined abo : m, except havin nx-ro one to iour heieroat ' oms In the ring structure, and may also be referred to as Amyl ⁇ ,'' or
  • ncteroaroniatk s ' As u ed herein, the term 'laAeroaryr Is upended to seclude a stable , 6-. or fooembered monocyclic or 7-, 8-, b- 5 o. ; ⁇ 1 I - r ib-mcsnbered hmycik: mornaoe hemromelb ring vvhieh eoncnS- ohoarbon aosms -em one or more hmerosaoms, e.g.. I or I -2 or I ⁇ ' or 1-4 or I -A or i-6 heseroaionos.
  • nKlependendy selected trom the group conamhng ot nbrogom oxygen and sutbas T e nitrogen anon m y be substituted or uaubxab ed A.e.. bl o ffR wherein R Is H or other sebsbtaenta, as defined n
  • the nitrogen and subbr heteroatoms may be oxabeed (fx.. --0 are!
  • sang posihose e.g., the m -i ndng carbon or heAroaiom snch as Ai with sack xeAainienrs aa dexonhed above, for example, aikyk alkenyk alkynyk halogem hydroxy!, alkoxyy alkylc
  • AarbocyAe ' ' or ' carbocyeiie ring " is Inrerxkd n.>horizon any stable monocyclka Acyclic or ⁇ ,- sis3 ⁇ 4 having dse specified number of carbons, any otAhkh ma be xnurnAd. maxngnaued. or aromabe, earboeycle incAdes exoloAkyl and aryk
  • eyeiooaiadieio i. fiuorenyk phenyl napbb-yA indanyi. adaixanoi and teinavydronaphihyk ridged rings are also aednded as rhe i eii Paofi olAnrboeyAe, ⁇ , k.a- exanipko iAA.oliaeyciooCiane, [akkOjbk yclonoisane.
  • pyrrolidine (ctrabydrobbopbene, plperidine. pipera:ak;e ⁇ oaetane. pyraa, len ' ahyd ropy ran. axeikiine, and ianoibyd oba'an,
  • roaudobnyh isoindoiyk isoquinoknyk mahiaxoiyb i xazoiy nnxOpkancdioxyphenyl pxg,, benxoki ijb dfjdioxokx-eyrb.
  • Ring doubie bonds a axed I meek, are doable bo ds that ; : e kneed beoseeo Pro aslkcsm nag ensrns uxg,, Cxkk Rks or kk- ; N).
  • ' ' Stabl •. • •nmmmd ' and “stable strucnnk " are meant m Indicate a compound dear a ran kdcmly sobasi a) survive mnakon to a useird de re or nnruy Rom a reaedon mixPce. and fkaoKdauoo into an efficacious therapeuuc a en
  • vhen suck aubsutuerrt may be bonded ⁇ any atom in ike krgg
  • a snbstlme Is ksnoi vvif ui Indicating ike aa -a- ⁇ -a ssrack aesk xabsbtnem Is bonded to the rest okhe eo pouad or a g en formula then suck suOxbraent any be bonded saa any aasra in suck tonrnda.
  • Romhuaskons oksrRagnrcnk and/oi variables are penniwabk, n i onlv it sack comblmnkns result k stahk compounds.
  • hkhsSk As used herein, 'kale " or “hahsgeik refers to fluo.ro, chioro, bromo aral kxk.
  • the neon 'kaloalkyR or "ha!oslkoxyk refers to an alkyl or sdkoxyl sa.ks ⁇ .k.rted with one or more halogen atmns.
  • eoas-casd with a donbk boar] a.
  • an osveen atom examples ok mokiles eoniuhung a carboayi InckKk, bra: are ran kmired as, akkhydes. ketones, carboxybc acids, amides, esters, anhydrides, ere.
  • AcyR includes moieues tkn contain use ae I radical ⁇ A a t g. : ; -. s - 3 ⁇ 4 oarbon l groap, 'kaba uu cs! aoyT Iradudes aeyi grorigs oa ' cere one or more of the hydrogen atoms are replaced by. toresana.de, alky! croupe, alkynk groups, halogen, yd.ro Rvp
  • axld ⁇ heecrocycha, aikyknyh or an aromatic or heteromsxoabe aaobr a bxamples of Sralogea aabatbiaod akkoxy groapa include, fag am nor Ibrdied to. rkKxonaahoxy. duluorornebn-xs , irbhs;aomesboxya ihuoronmd xy, oadbosaaaedsoxy and trlchkn os uetbox y ,
  • Ths icon ; rhioa;ky! " inohidea compounds or rooiebes which coataia aa alkyb group iroaaocted oath a aubar aiosra T ' he ddoaiky! groapa caa be a batitraeri groups anch aa a!kyb
  • 'andreb or ⁇ - ⁇ refers to cii , s Ab Anew- ' includes groups of cssnpounsb ohe eb die aUroaen obsdhA is boond to as 'cas one abyi ya a;- kxeragks oh eikybmmo g?oaps ineiode browx1 ⁇ 2nb;wx medrybndw.a eihytarnisKc pheraidoyknniao. ate.
  • XxrykuvdnrP and "diaryiaudno" axsude g ups x heroin the nbxsyen is bonnci to as bast ono or tw apyi groups, respond veky xAminoaryA 1 and "Amboarybxy " : > " bv b i5 A ⁇ arybxy subsudued with annuo.
  • a nitrogen saoni d;at is ho nd k:> six; carbon of a carisonyi or a thic'ca boiw i group, lw venn ineiudes , a3 ⁇ 4lk;sa ' ssKxr-isrbs) y ''> gi'oupc ri-at ⁇ sfkyL aiksn;A r.-r alkynyl gwxspa koarid io an amino gnoip ohich boons! >o dr.- carb n of a carbanyl or b b a:.-; ' bon ? g mip.
  • ana boand to & ueo-cca atom a in- h a: in anas bound m das c rb n of a carbonyi group- Amides can be sabsthuted w s ssibsotacnta such as auaigin chain nikyk bran hed aikyk eycloalkyk aryk hateom yl or bensnscyds:. 3 ⁇ 4bstbaenes on a nb oau-s may no Rasher aababiuicd.
  • Compoun s o( the present hw odion th i ocanain nitrogens can be converted to bkoxkles by treaimaib kh an oxideaing agem sa., , k-ehks ⁇ enetyf enx s acid oaCPBA> and a hydnagen per- oodem to- akord opser compounds ofihe pmsent inve bon.
  • mhxgxas-eonnunhig ermrpounda arc considered, when allowed by valency and sbactung to Include bobs the conspound as shown and its -oxkk- derivative twhieh can be desigrnued as --..-0 or ' - ⁇ " ).
  • Fnrdmrmore, in other imuancex the nhrogaas in t e compounds of she present mvenlion can be convcrtad to N -h droxy or hkaikresy e m u ⁇ d .
  • a -sanaks hkhyxkoxy compounda can be repared by oxidation of das parent mi e by an xidi in agom such as i-t ki t. a All shown and claimed nikogemomntaming compounds are alao consklercd.. when allmvad by valency and strueUne, to cover bath the compound as shown ,wg bs kkhydixwy (taw m-OH) d hhsbkoxy b.e.kho-OR wherem R is subssubbed or onsnbslkuted ks bk. alkyb R kk alksnyk by -C; alkynyk kkf membcred carbocyek or 3-14-rnembered heterocycle) derivat xw
  • a crystal poiymmphwa may be prese tor dm conspoands represented by the iormuka it is nomd ben anv erys;ai harm, crystal terra mixture, or aahydtida or hydrate the eof k; included n the smme of dm present mvsntkm,
  • pfdHj kisomerisnR means compounds that have idenbeai moies ar taor lae bus difier in the seuaemx or bonding of iheir atoms or b; the arrangement of Ren aesns in apacv.
  • isonsera thai d ffer in die ao-angenscra of their atoms m space are termed "stemisasosoers.”
  • stemisasosoers Stereoi omers that arc not rnirosr anages oi one another ara termed k ⁇ iaskreoisomerak and s ⁇ resbso-ners th i arc rnuTor inuigea ol ' cach oihcr are mrased ct somei seG raaap ;; ⁇ : , A mixture eomnahng egoai amounA f i dividual enxmlomeric Asms of opposik- cbiraheg is termed a naccirec mixinre,"
  • [ ⁇ ' AAo etric isomer means hse diasvercomerx thai owe their existence to hindered roistkm about double A enb or a cyckalbyi baker (e.g.. iA-wykoAuA i).
  • eouAgurationx are d fferentiated in their names by the prefixes cis and trans, or Z and lb which indic t hsa the groups are s 3 ⁇ 4 the va e or sit side or the double bond in fire molecule according to the C a h n A j 5 go id - f 0 c i o g rid e ..
  • the snaetunes and caber compounds discussed m this invention include ah an-..g:ae isomers thereof.3 being nuderstr-od dan not ad atrople isomers may have the same level of acihooo "Abopk A ners " are a type of sbnvxnsomer in which the atoms of two isomers arc arranged rubere ly in space.
  • Such atropic isomers Apkaby eaasr as a mixture, however as a resub of recent advaacsa l3 ⁇ 4 3 ⁇ 4 ebroma gmph; iecbrunues. it bus bcea possible r ⁇ separaie ndxtures oiAo o ar ⁇ yde iso er ;n select eases- [03031 ; AauionscA is one of tw or more strrennral isomers that exn:t in cprabbriuin and is readily es'uvci'ied irons one isomeric form to siaahci. This conversion resnlts in she formal nugrarion r.sf a hydrogen atom accompanied by a s lieh oi ' aoie-cern conjugated double bonds.
  • Conurnsn tauaafaeric pairs are: ketoae-enoh amideuncrhe, iaciasrrdactlae aakle-hnkhe acid tautra ' aeris at heterocyclic nags Onto in nuoieohuses c as guanine, thynnne aad eyoeiae;. hnine-ertaobne aad cruaOsra-eaai aae. fdxatnpks of laotanrdaethy; uunomemru are as shown helosv.
  • OilOi if is to be understood that das compounds of dee present iavcnta?a may lor departed as dPierent tack soars. It should alao be nderst od ilea when com o nds have ta omerte tonus, ad tautomeric forms are irnksodsd to be srtekided if? the seope of the present usvenPoig mi the naanng of the compounds does not exeiude any mutomer torm. It svih be understood that eerada taaa.an>vrs nag have a higher level of actevPy than others.
  • crystal Psoas means crystal sP'taaares a? srhleh a eoaaxnuss tor a salt or solvate h reof ⁇ can erystahiee in different crystal packing aimagentenev ali of which have the carne elemental eoatposition. Duierent crystal harms usually have different. X-ray didVactsoa patterns, irrfrared spe rah nnrabng pouns, density hardiness, crystal shape, optica! and electrical psopestles, stabllny and sohibbtty.
  • the ⁇ sup.-am.- m any f onorda described herele inviade t e corapoaeds deornevea. as a.
  • eb as haslr vales aeb hso; sobatea, bSspplicable. .a salt to; esamgle, can be banned betweoe an anion and a pvsibsely chatgcb groap hag., amend on a subsbhued la sene cotupoend.
  • ' pharmaoeabeaiiy acceptable anion refers to an anion statable lor lorming a pharmaceutically acceptable sail, f Ih-a.- ⁇ ' ⁇ .
  • a salt can aba ; be formed between a cation and a ncgasively charged group (e,e,, carboxylase' oa a xubsptuted beus:eno compound, Sohabie cab a; . include sodium ion, potasAnm iota nutgneslant loa. calcium ioa. aad aa amuiomuna cation such as tehsu-nedpTaswnoniam ion The eabsbuaed benaene
  • aapcaa.a also include those sails coabaaing quaternary nitro n aamvs.
  • the oonvpoueds of the present invention can easst m either hydraped or tnshydrared (the anhydnsteA form or as solvates oath otiar solvent molecules.
  • sAubimitlng esannbes of hydra tes include nionohydraPcs, dihydraies, eh;. Nonllroalna osmples of solvates Inclede ethano!
  • the tent As ased herein, the tent; "analog " rvibra to a chemical compound that ss neaaee!b sutaiar as another bat diners shghdy in composition : a : in the replacement of orre atom by an aene of a duhervnt xiesnem or In the presence ofa particnlar irercdonal groap, or the replacement of one renedonai group by another iancuonal groups
  • aa analog Is a compound th t at saniiar or comparable in rnncoon sad appearanee, but not in structure or origm t the reference compound.
  • the kwsostenc may ho- physkmsaemioahy or topokwioaliy based.
  • Is t es include those nPoms having the same atomic onoksr bat different news snnnbers.
  • i03 tbl Tbe present invention provides methods oa m.- synthesis f the compounds of any i too hossmdae described herons. lie pressor Invention also provides deiabed methods t rihe symhesis of various dkcknvvd conipoonds f she present iuveaoon aeeordmg to she hsbkovnvg schemes aa shown in the Examples.
  • Yhroughotn she descrnvdosg o-bere omnpowbons are described as having, including, or comprising apecdk com nent ' , is cookmpkried thai oomposltions also consist essentially of or consist ok the roosted components, ' --iookro where methods or processes are described as having, inciudkg. or eoogasising speckle process say. ⁇ . the processes si ⁇ ⁇ consist essentially oi.. or consist of. the recked processing steps. Further, it shook!
  • konpvaonds of the present in vendors can bo prepared in a variety of ways using commercially avaliabk slaPing shortcutetiahs compounds kanssvn in tbe keramrm or from readily prepared brie; mediates, by employing standard swnhetic method- and procedures either known to tboae sblbed in the arc or which wb!
  • btandasd symhcbe methods assd procedures for the pre paratloa of ' o a c molecules and ⁇ group kasssksmabons and manipulaOous can be obtained from the relevant scientific boesvause or ;res'i> sPaasard tod e ⁇ k in 'he beld, k thon h iot Ibrnkd to any one r severs! sources, classic texts sush as Ssmih, M. C, blarcl ' !, J,.
  • Me rk a E2ar a-ak 'Tysnnk ki f *ko'; /vorayg.oss. Sbakooaoro reek baaoo/ieo.5" ' ed!ilois. bdai Wbey aa Sosts: bieo' 2 orb.200 k
  • Ptnbbeners P, I,, Fieser aad ; 1. Feasor, bests- non /becee s /seoyreno- for (A-gxaiv bYnrPesB. John WiBy and Seas ⁇ ⁇ ⁇ aid I... Paquebe, ;-xL EnceeBwoYo qFiboey /P Pbo- Orgomr Pbea/ssvro John Wdey an boar ⁇ . aw orp ⁇ nPed by reference ko-reiu, .> ⁇ .
  • PBoepounds of hse present invendon can be eonveniendy prepared by a sasieiy of awyhods Bumbar to those sbiiieu n3 ⁇ 4 the an ca basse described in ⁇ VG 2 ⁇ 50 ⁇ BP).
  • di-aikyi aeetais such as dsaaerhoay acedd or diehyl acctci ,
  • NaBCX .. 'd a: ba.a bonate
  • Ad whieh is treated t hh aeki A,g. . . orA Mi p and then babfied ith, age., a NabCip aohpion to afford A3.
  • lA «n NaBPL b .Ak-i P.; a eolation of A g ; plbrd s- np-end ⁇ i hen compound A4 is treated phenol to afford eoropoaud A3, e. Poh ean then be hydrtay:oad to afford cornponnd At?.
  • Schema 2 shows bar syntheso f modinsd hniaeoie analogs kh anng a genera! tooa; that utilizes cih-ecaabiichiai ohonmoy.
  • suiiorlc acsd Pacp IP ' Th acid can be esieniaed by taeabticnr ith an a!kyladng aacas scab as nanhyhodide in rha presence ot a base each as onlkan oarhornsne n an appropriate poke solvcin each as DMF ibiep 22 Redaction o die nine' groan asnig an approprhac redaelng ageoi snob as sron with an acai such as smrnonhuy; chloride ;n a probe solvent such as cthanoi can o id an anihne sStcp
  • the ester can be hydn based io dee corresponding, acid o.-aa.- a suitable base such as sodum hydroxide s? a polar solvent such as etbanoi tSieap 6.1.
  • the acid eae ihen ⁇ e.-cr.d svph a vtsralard andde ⁇ ;s:.aaa- rcaedon thereupon die approprlaP? annne can be added long with a suitable amide coupling r agent such as PyBOP ts a suitable solvent such as D SO o give the desired antide deep sbiibdbs.J
  • R is n appropriate group sach as bromide or ttlOate. a variety tnbulwbtnenis conkl d;en be hiOs.staeed asiag standard iunvslbori megd-hased protoesds.
  • the brofaide can be csenbaied with an appropriate boronic esier deri ati , in the pre en of a nidd base aad a pslladiuui catalyst in a polar solvent such as k o-neo water. ;e ekvaeoa eetnpeoittnvv so give sac desired indaaole (bchenve 4).
  • ⁇ - ⁇ Compounds oPthe present btogetherthsri inhibit the hlstone inethyUraesterase activity of kZHd or a tomans tbereor a p secordlngh.
  • ehbbe homnboir ccrhon compounds disclosed herein are candidates lor treating., or preventing certain conditions and diseases, in sohkh bbhie ia s a ode.
  • I be present Invention provides me-hods Re treating•.
  • ibis invention relates to a method of rnodakiing the activity- of die EZFIZ the caialytle sabanii of die PRCs complex w ic catalyzes the mono- through t;a- nmthylation oi lysine 2?
  • the cancer is hsnphoma, leukemia or melanoma, f referabiy.
  • ihc Ksephoma Is nmvliodgblifs iyiv h mn (Nifio.
  • the leukemia is chronic myek enous leukemia (( ' ML), acute myeloid leaFcmla, acute lymphocyto leukemia or mixed lineage ieebeafia.
  • the fZHvunedioted eat-ser is a henmtokysical cancer.
  • die present invention also provides methods tor ireating ussdulom; ami diseases the course ol which can be influenced by modrdat g the methvlatioo siatua of h?stoiK-3 ⁇ 4 or other protests, wherein said rnei y Union status ss medlalvd at least in par; by the a tviy of EZIic.
  • -serpen compminrls dlseioaed herein arc candidates f r tre ting, or r venting ⁇ . eneiu eondaions and diseases.
  • Modulation of the meihy ulon Stahlss oi hisnanes can in turn Iriflaenoe the level of expression of target genes activated by meihylaiiou. ambo; target eyeries suppressed by meih labon.
  • Use method includes adrmibsi.erltvg to a aahlect in need oi auei ⁇ ti-earinesas a therapenhcapy i3 ⁇ 4et.ivv ainor-nt of a eoiu esund of the presem ismcntan-i
  • a AahAecA ' meludes a eaen ak 11;-: ⁇ nmaeea? can b e g., a burner; or epproprkee u is- air f!O manenak such prlmeA. mouse, rat. b g, oat. coos hom , goal, maoer. sheep or ps -
  • the sealed mas also be a bird or lowl.
  • the mammal is a human.
  • a sebieei in need thereof can bo am oho has been reviousl y diagnosed or kleaohed as haveag saucer or a piecancerous condition
  • a suble so need hereo sen also be one who has (e.g., a ; suffering from) cancer or a precancerous ondition.
  • a subject in need ibereoi can be oa ⁇ s has an increased isk or de elo ing such disorder rekaAe s the population ,a large (i.e., a suisjec; 3 ⁇ 4 o ss predisposed to de elo in such disorder rekelve as dr.
  • a sablem la need thereof esn sieve a precancerous condition.
  • a subject in need thereof have refractory or resAunU eaaeer fi e., cancer thai doesn't respo d or hasrf t yei responded to ueaauenA
  • the subject may bo resisiant ra stmt ⁇ treatment or may become res aea du ing Aeannenk ⁇ n soaae ciohodinienrs, the suhpoot in need thereor has cancer recurrence oi!o ing remission on most recent ihensp .
  • sc-aa in need das rent race iveb and Puled all knoere e teebve therapies kn earner treatment, in eorae emlxedlmente, tee subject in need thereof received at basi one prior therapy.
  • eirdsodimenk dm saa-e-o has career or a osm.en.a-s ccaehtlom
  • the esaveer A lymphvnae leukemia, rnelaeonua or rhabdomyosarcomas, Pretereblyy the lym h ma A aoa-Hselgkia ' s lymphoma, Addo-Par lymphoma r diliuse large kAceii lymphoma, sslternahvely.
  • myelogenous leukemia ICAab myelogenous leukemia ICAab.
  • Is myelodysplasia' sysrdroines MAN formerly known as pmk'Ukesnsak hs one emf id e p a ubject In eecd da-reol has an INi I -deficient Sumor.
  • INI 1 is a regulatory complex baa opposes the eroyymatA fanction ⁇ . ' , ⁇ Doc As a vaAep of genelle aherads-ns, INI I loses hs regulatory ianetion. As a result, EZkls actively A a-lsresadaied. causing E2B.2 to play a driving, oncogenic rele la a sel of geeebCidiy deiVncd saucers Peg iaclnde synovial sarcomas and makgnnre rhabdoid tumors.
  • S novial sarcoma is e maligeam tumor of rue soA I issues ' and ss one of die UK3 ⁇ 4> coeuaoa soti tissue tuaasrs la adolescents and yoaag patients, hiean s « ot pauents at dasgnovis is approxl;aaa;ly 3n years, k bd go;. en rl-;abdold lunasrs. or MK ' i , are a rare and deadly S OTS of chvich d cancer thai is caused by a vpeolfc genede that leads to ahsreaolaled EAfld taacooa. ⁇ tsysleally preseals either In the kidney or Nam end Irs child en less dues two y>oes ofage.
  • deoxr lnc if diet compound is bke!y to Alea a desired reoloeleai or medical response
  • aaanal or hunvan thar j being ssa.gght by a e se ar her o- elhhcinn-
  • a ennsudntc cmoootavd is compound s4 bar pr nt :nvenhon. or a pharmaceutically acceptable ab, polymorph or solvate doe ⁇ -a ⁇ ' a,, biological or medssai response can bo the tre ment of c nc r.
  • the b logieai response or efksd can also include a ch nge Irs cob proliferation or growth that occurs o ; vara or la n anlmn model, as well as ⁇ ag.-r biological changes that are obsersabk m envo, A; wmo or a?
  • rno bioiognvd assays ean include, bid are no honied to, emryinaoo activity ass ys, elecgephowik: ohbgy s4bh assays, reporter gene assays., a; wwo ceb ⁇ edbng assays, and the assays desenbed herein.
  • ex o pe, an a? rone bnaogleal assay that can be user] includes the steps of U ⁇ ising a hiateroe substrate gay;, an Isolated hlsmnc sample, an is lated histone peptide represe uia ties of human hisione I B residues 2 b-44 contanung either an uaumdved lysnve / eHa or dnsiethyiated lysine 2.7 Ala ddmedg or an Isolated ohgonucleosome aabstrate? evltb woombba r PRb ' 2 area mes boa.
  • an i tdvo study that can bo used includes the steps oi ⁇ i ⁇ administering a oompoond -A ' dPe Invention ink; a mouse model much as WSUuDLCI.2 veoograft tumor bearing mouse model or KA P.AS-422 Inanan dlflosetl large -Adoi! lymphoma mouse xenograft model) at curiam lesol or dosage tor certain periods oi time, e.g.,, A .g: da s; (2?
  • trearlng or Aream describes the management and earn of a patient tor tin; pur o e of eon usai ing a disease, condition, or disorder and an hobo h arhr n!strahon oi a compound ⁇ ddhe present nsYenhmg or a pliarnuteeutleaby acceptable salt, polymorph or solvate thereof, to abeviate dr. symptoms or comnhcahons of a disease, Cisndnlon or disord r, or 4s oiimanate the dlseaoe, eondbson or disorder.
  • the toon A.reuP " ean also include iroatnient ofdi ceh At ⁇ (> or an ani al model.
  • A > gnev sus '' r ;, ; tsu; ; : sr. on a ' desonbes o.bu-. -or or olinbn dnti uv onset oidbe aympkana or oomphcabona of such disease, condition or disorde .
  • Assrobinaadon therapy '5 or ''codherapy ' includes s e adrniolsteaboe of a compound oidhe present iuvennoa. or a pharmaceutically acce ta le sail, polymorph or solvate Onareog and at ieasl a second agent as pan of specific dearrnent regimen intended to provide daa beucfkuai effect.
  • dterapeink ag nrs hhe beneficial OPSHU of the combination includes, hut is not l mited to, pharmacokinetic or gharnsaeodytuanie oo-aciion resnUing fossa the eonb)ksa-boe of therapeutic agents.
  • a ' gdusnnaceobeal oonnsosibcif is a tbrnnuation containing the compounds of das present Osveof i> us in a toon suitable tor nd ubstrabon to a subject, fa one embodiment, bv phar aceutical composition is la bulk or In unit dosage lonro i is. unit dosage form is any of v.niety of kn m, Y-dudme. tor -mamgle.
  • a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a slab i be quantity of active ingredient pegs, a linsr; a latita t of the disclosed compound or salt, hydrate-, solvate or isomer mo; op?
  • a una dose of cooiposidoa is ass effective amount and 0; varied -.mcordlng to the pauleularneaboent Involved, fine skilled in the to o ld appsevhvge that It is sotneflmes nec ssa y to make routine variations to the dosage depending on the age and co bOon of the patient.
  • Fhe dosage will also end on the route of aduinuatrabruv
  • a variety of ounce are contemplated, etertlng oral. pulmonary, reclab parenteral, transderesab raibeureaeous. baraverasns, karaaurscuiar, iaaaperkaaeah inhalabenag buccal, euhhngaah ugsaplearuhizinahecab hasana-ad, sad ihv like.
  • the aeihss cornpoaad is mixed aader sterde eoadhlens with a pharmaceutically accefHabk cameo and svhh ;3 ⁇ 4ay prcservabvec butlers, or prnpebaais beat are regubed.
  • inhakalong transderm l (arpicau, aad Psnsrnucosnl adnkmsmatlon S-shaioas or suspensions used tar parenteral, mwadeimab or subcutaneous spphesbon can include the Ibhoclng components; a sterile daucni sued as carer Par upeebea, sallae s-.4ors.ap fixed oik, poiyedgylene alyeeka glycerine, [wopybne glycol or obwr synbwue seleenrs, aabbacierlal agenrs such as beaay l alcohol or mebpl parsibeas:
  • anooxnknts su h ascorbic acid or seokan bisaliae
  • clwkPbgg agems saeb ascorbic acid or seokan bisaliae
  • ethyknedaa-mncteiraaoetk aeld batters saeb as acetatea ekralex or phosphates, aad ageats kn the adgoxnaso at bonk hy each as xodaea chloride or dextrose.
  • the pH caa be adjusted oitb aeals or bases, sack as hydrochloric acid or sodium hvdroxak. 4 he parenteral prcparanoa caa bo eeeiosed k; auipomes.
  • roay be aaae eo da ' cetly aa r - traaerc irgcated labs the blood .-ae ⁇ . ⁇ . r-r body ea aties ra sksa oraby >sr appbad through the skin oath psrcbov 4 ' be dose ehosaa should be satocieai to coraaiaaa et ' tective baatmaat bat not GO bap- as o caasa raaseceptabte sge etieets. ' The slate of Uu- disease corabtaai us. us- caaccr. 5
  • precancer and the kke) nd ih henna en the a em should preterabiy be closely monitored dn g nd he a seasonable period after treatment.
  • the cP ' ⁇ . ⁇ /: can be d e ted by any assay method known i the art.
  • Fhe oreckxe ebleetive amount fair a snbaeot wbl depend upon the sobbeobs body sveighg ska. enki health; ;m nature and esicntof ifw oondnion and the dmrepeukc or eombmakon or dKsvtpeuPcs achated tor adnh etivioors, ' kkerapenraadiy vfkeehve na'i uska
  • a gi en sikebion can be ueXerm ed by routine experimeniahon tbrst is within ike skbi and judgment of die clinician, in preferred a ect the disease or eorxkbon to be treated is cancer, in another aspect, the disease or eoadiuon to be treated is a ceil prokferaiive disorder.
  • thernpeuOeaiiy effceiive amount can be esbnnned uhtiaby either in ceb culture assays, e.g.. okneopiaabc eeiis. or in animal nnnieb usually ⁇ a- abac, rabbiis. dogs, or pigs.
  • the animal model are air ; - bo need > deteonme ike sppnywkne eoneeniraiioo range and mute of administration
  • Such inibrn-atasn can th n be used determine useful doses and routes for administrabon in humans.
  • Therapeabe/prophyiaeiic eiticaox and to icity may be determined by standard pharmaceutical procedures in ceil coheres or experimental annuals, f.y, EDm (the dose thcrapentieaHy efbeeove a? 5 % of fhe gem ation) and Li - ? (the o , ⁇ . ⁇ ,. ⁇ lethal in 5b3 ⁇ 4 of tine population y
  • the dose aai- - between toxic an-; dwuejpeahc effects is ike therapeutic index., ami it r an fa- expressed as the ratio.. Lhxyfb ;.
  • Pnarmaeeai seal compositions that exhihk iarge therapeutic indices are preferred.
  • the dosage may vary within this range depending upon tin ; dosage torn; em l ed, sensnivky of the patiwn, and the ronte of administration.
  • bongonsmg phanrwceuboal compositions may be administered every a to -t days, every week, or once every two weeks depending on hali-kbe and clearance rate of th pati scalar Ibrnubahon.
  • bkeOi i he phs maceaboal ossT!prwkiona containing aeiwe compournab of the present invmsbon may be rnamdncimed in a armer thai is generaik p.» .
  • fbja iriaeeuiieai co-V!poshioiv may be tormn!aied in a conventional ioanner swing one or more pkarnmceuiscaky aeceptabic carriers eoniprisi-vg exclpienrs autbor a is s i h rs s that ae mtate oc s ing cl the active vontpounds mio preparations iba see be used pharmaceutically Of eeurae. the appropriate t rmuiahon la dependent n she route of admmistratlssr; clm
  • die composition must be sterile artd should Pa rb.dd it.; a-: extent thai easy sgnngeabi lgy exists, ix must be stable under the condi ions of uianulacua'e and storage aad must be preserved a ybe ⁇ ⁇ the eoo tromariug action of microorganisms such as bacteria ami fungi.
  • T he earrier ears be a solvent or dispersion rueditiru containing, lor example, wenw.

Abstract

The present invention relates to substituted benzene compounds and bicyclic heteroaryl compounds. The present invention also relates to pharmaceutical compositions containing these compounds and methods of treating cancer by administering these compounds and pharmaceutical compositions to subjects in need thereof. The present invention also relates to the use of such compounds for research or other non-therapeutic purposes.

Description

SUBSTITUTES* ENZE E A D hJ FOSFl* B!CVCLK/ HETEROA VL
COMFOONFA
Figure imgf000002_0001
ί 005 j T is ap beation Aanna prioshy to, aski the besu oh U . provisionai ap licati n No, 62/ 17,22 L thed jane 2 A 2014, the enure cooaersA of which arc incorporated herein by reArecce in tA csaire y.
BA KGRO D OF i do ArvtA nor--;
i 02] Ί here i an ongoing need for saerv agesna as sAhibhore of i /h ϋ'2„ which cars A- used tor treating; art - A; OoaedhR-,d discs dor (e.g., eanoerF
Ss Aiyp\RY OF Tnt im non
h)0ej h; one aspect she present is enhen features a sohoanno benoeoe or taeyeiic heocroaryi c m nd A !Oarnsoia sj) beiow or a phartnacentieahy acceptable anil dtereoh
Figure imgf000002_0002
j 04] in Formoia A s above.
Figure imgf000002_0003
; is NR. o OR,
; ss NANIO, CRS) Os oro: kdY„ O, or k
Figure imgf000003_0001
and X:; s 'N or C vvhes- V is
Figure imgf000003_0002
Λ,; is C or ;
Figure imgf000003_0003
v.: is H or CRx
V , ss N, or > r- 1 : :
Y m kYY or kdRRyjid.x
|Y is Ϊ 5 or , !fi o'biah R¾ is kY-Yy aikyk CoYY aikemd, CY-Yk rUk is i, CY-YY aydoaikyk CxYb-; a yk 4 to i : ον·:χθ·χ·:ο hoi¾rooyckxdkyL or 5·· or dooa befad hcroroaryk arui i opoooady sobstRoRd uh ooo or more subsiduerds; seRcRd b m i.he group oorobsnog of daky kyvdooxyk ox , C{OY>kk ΥΥρη Υγγγ. aikyk
Figure imgf000003_0004
C Y aikyk CHiY aikoxvk amioo, rooooY YiY aikykmdno. dxCrC alkyiamdxx kYoY; cyoioaikyk oY-C :;s oryy 4 to Ik-aiaoobxaxxf heKxocysaoaikyk ami 5- or ooa-. adx oi dekox yk
oaak of R¾ ikx sad i iodoi iideoijy. is■ k> T ;> d; svhkh ·' b m a ix-ad or kY-YY alky I baker opb oaby rk>sxion:ed - Yth haky ayaoo, hydroxys os CY aikoxv. and 1· is H. haky hydroxyk Q'OiOkk eyas-κχ aaido, r-r ¾;, in which I½ is kk-YY aikyk (Y-Q ai-reamd kYRY aikyrod, kY-YY aikoxyk C kY thioaikyk Ογ>)Οο.γγ fdkyh i■■■ > ·. ¾Υ Η; RkOsYYi kkVYY idk k d'YOYN;C;Y.k aRyty. -dr>;-.aappp .xx aikyik ·· S :-N(€yC- aikyk;-. CY-dY eycioaikyi. kYYYi: rxyi, kY.«0d<: asykix , aoboo, rooooRY-YY. aikylaoYiiO. doC;RY aikylamimx 4 o i Y moimbared heiarooycRaikyk xr 5- or booeoibered boRroa yk sod bx- R opbooxdiv
Figure imgf000003_0005
rvidi ooo or more suhstRoerUx aoiesaad R' m de group cooxastkig or daRo hydroxyk oxe,.
QO OH. kkO)0. y.xY aikyk oyxoo, kb-Υχ ¾;kyL kb-YY aikoxyk amoxy morx>Rk R.:i aRykarouo. di-xY-kY aikykoodxx RoYk >yyck¾ik>k kY-kY; aryk ;i to skxoeo'Rxred
imRroayckxdkyk amj y or dxosexsbcrcd heteroaryk
eaeb or ¾, R,.,, R aod Ri :dodv eodard:iy. is H or C Y aikyi opoooady soRYOiRx; vYtb ooo or -ΟΪΧ ;.;! si.doai seiscOad Rom rhe aroop Ovai isUiiy oidxdo, hydroxyd COOR. (.k tjOoYYk; aikyi, ',yaoos€Y~G. aikoxyk aioioo. oxsixs-tYRY aikyiaoooo, di-Yk-YY aikyiandoo. >€* eyOoaikvk (.VCR,- asyk 4 lo IdoyicnRxa-ed heRatoveloaikyk and 5·· ooncrnbcred hoR;nearyk
each k, nwRpcndemly Rlk hak, OE::, ·· Jk n.. -RObbR,. AdORRR^
-CiO) RCRI;„ -kkk-R'i iR,,, RR gR, ;,••bk ):oRR:.a o. or ί½, s« vvhkh each olRR and Rb.
Ribpenbeons is M or Rv-. and each oi i½ and R.-.:, indepondendy, <a (. r-R,, k k -Ck sihenyh (RRR alkynyk Cy-kR cvckxRkyk CR-kV. aryi. d to ?-asserobercri hcterocaxioa!kyk or a to <- cambe ed freRnsaryk or ik aad together whh bx- N an a a to whRn they arc attaeheb, Kara a. d to 7-ro am be red hekrocydoaikvi ring having 0 or 1 additional hekroako'se ;o dr. aiorn; and ach of Rso by. : «tsd Use 4 to "-arsembeicd hetarocyeioaikO nng eomaining k nd Ro is optionally sobviknted w th one or more ·■¾■- 4 wherein Qo ia a b nd or CyCk a!ky! hoker each optionally substituted with b ts.;, cyano, hydroxy! or Rykk aikoxy. and Ta is i baby y aa- r ·· OR,, - R-Ra, dNRRRbR; RAk - yORR. bkORRk AR YNR, iO, -NRXROsR..,•- OkRORaR-,, oROrkk, - U-. R p ·. or RS.I; in which each of R,, R ·. and R,R? independcoby is H or 1½, A" is a ph rm eutically acceptable anRax each oOka; aob ik-;. independently, k R- Cy aikyl, k' ;-kd, eycioalkyh Rk-Rku aryk d io 7-roenA-ered bereeoeyeboaikyb or 5 to b-nsei b od Rx ,;-eo; k or R.: and R.-;, togeiher wUh dro O aaa-n to which they are areaohcal tbrrn a d i - doocfob ed heierocyeka!kyi ring h n 0 or ! addkiorsai hekroaiorna a.; the y y0m, and each or R.;¾, -Ϊ^.. and the a k 7or5 rnbcred heieo oyokadkyi ring containing R. and E.-<: k opborndty substituted · id; raao or none -RRrlk, wherein gk s a bork! or C i.R aikyl linker each o ti nally substituted with hidry oyaeoo hydro.',) ! r Rokk alr.o,sy, and Ik w seketeb Rons rise group oomasRug of H. halo, ·, yea:- CrOf. a!kyi, 0; 7 cyeioaikyk Ck- Rii aryk 4 to 7o;>emhsred heieroeycloalkyi, 5 to OmenAered heictoaryh OR,, kOOIR, -SR4}Rk,, -N .,RK, and -4RkRNR.yRf,; each of R, and R- aidepcodeniia being H < ;· RvRy. aikyi optiofiahy autoaitnted a, Ph Oil f tRR -4R aibyi, <.?;- Rb-Rkb-- C;> aikyi: or -kROi'.; is ο ο; or-Q; f.y or aoy Rso neighboring < y-■ i ^ K¾cihcr dh rho aoana o whk-h da;y aic ai?ar:bed b - a> a ς - aa' k-rneo!pered nog oprRooby e-antaining 1-4 iaarcroaroios decied ft'on R, O and S and opiionaiiy anbatnritad -a-Rii one or more sabsiirucnis seieeted born the gronp cra¾aia n;g oidndo, hydro y!, k'OOfk (.'(OjO-kb-CV oiks L eyano, OoRk iko.a>1, anorro, isono-gy-R;, aikyianRno. Ri-kd -tdo aikyiaoRno, k's-C-? cyesoaiOd, R Ra aryk 4 io 7on:onbe cd iicierocyeioaiL^. i, and a ;o b-ancrnbercd heieroaryk pr;>vidcd di t -kpap , s iU;s k.
eaeii il- irKicpendenii)' ;s --O.ol o in o bich Q* i:> ^ brnni Oi-C; aikyi biRer. or f;?-Rb aiRein i bnker, eaeh linker opiionaby snbarbraed olR- baio, eyano. hydrox f ra bkn.';. a!kox , and s■ oOk halo, cyano. NR.4k;. -OR,, -RRaiiO, -OiOskRR., -R fORxi RR;, -kd RiR4.)Ro •Nik.tR;R}i¾.:;i -SikRRt,:. ■;' ; ;, in winch eaeh of R, and R;,. hdeocnd,:aRiy ia H or R>.:.; each ok Η;;Λ and ! :■;, bKkyaxrsdenby ia C:-Q aikyk C -Cx cyebxkkvk (ΧΧ. · aryh 4 TO ?oxa¾bered heosoeyeioaibyk or 5 io
Figure imgf000005_0001
hsaenxeryk .aai each sa* Rk;, and k .: is opkon-diy sybsbbuad with one or more -Qi- i where i Rk a; a bond, C(Ok kXO)NR::, NRXXiJh X!R. okbo,. NRkXwp, or€ aikyl bnher, kh keing ki w; kXkb idkyl aod k. k R, haks CXRk, alkyh kkXX sdbenyh kkXk aikynyh hydroxy L eyano, bX-kb idkoayk amino, rnonokkXX aikyja m-a, diXb-Cr a!kykordno, bXkk vyc!oalkyi. kbR.;,, XkyknekXXX eyeioaikyh RyXX; arvk (kXk aikyXneXkXX,; sryh 4 k> i2onenR>e-red heewoeyeioalkyh Cpbb aikyieowk To id- rnembered aeairoeydo ikyk a- or o-ouwikxwed hekroaryh o CiX akkyleae-S- o bonevrbxsred heieroaryh nd 4b is ophowb!y i kobioTad with sin or neae subsboiaiks selected bona Use r coreaskna iXlxbo. C bb; aikyk h dr !, eyano. khRX rdkoxvi ! ;4 ; a k aibyleoeX XX sbkoayk anono, rnorawCpk, aikyiaouno, doC;Xk aikykouino, CX-'-X cyckohkyh kb-Cu- aryk 4 io booeiVsbeed ber xoyeioaikyh and X- r bonerobeivd heteroaryi axocpi when 4b X 14, h hy hydroxy), 0;· cyaoo; or-Xb-XR k osss provided rba† --0.r4bi i m;? i b and
each okRs. i s and k;■ ioderxaXorhiy, s bh haks hydroxy!, COOM, csanxy R%, O «, r k'OOR;;:-.. a; which R:« ;s bk-kb; aibyb kywk; aikcoyk kxkk alks syk ;nninw. or -a -C k., aikyianono, or dhR CX aikyianiino. and ;Xs X opaoradly swbathuied with oaa or more snhxnnenw seieeted R*:an hx- www wawkkng wf hXo. hwkoxyl, k'OOrb kkOkkka-kk alkyh ovnno, kXXb aiboxyk amino, nwwoXX-Xk alkykwnirnx and dbbXCX aikyiaodno;
a is kb 1, 2, 3 k or sy and
a; 0 ¾i one of X.; nnd X·.; k O or S, ar baaat one kX,, X-; Xi, , Y Υχ and YX w X or
NR, aad X;:: X , X;;> X4o Y;. Xk, ar?d Yb are assigned a.uch thai lire
Figure imgf000005_0002
■n ΙοοηοΧ · s is ..s hwsxk. hwerearyi ayaaon.
((■05] bi one su ei obd;e coiopouoda oi bornada kb Xi is R - Xa k kRi:: X.; ia bb Ys and Y;; :x each sk i,
[006] Odier arbx^ers or the eompooads ofXor:ra.da ii) inXudea ihose oi Foornda ill), (14 s. and
Figure imgf000006_0001
(M) (R) RRo therein ihe vaRnbRs ii ί>ο: obsOia ssy \.ν· oRd. are deih~a.d as hi F s suda (i).
[007] another aspect she poooom RyenR n fe ures a ubsRtibyd bRyehc beicroani coropound oi b nmha (Ila? r i b) below era armaceutcally cyce io k sah thereof.
Figure imgf000006_0002
Figure imgf000006_0003
H, si R riov.. bi which R;i, R b-Q a l CyC, yRyy;pR, CyC: ykyoyL Ryo cyckaRyl, C Rbi; aryL 4 to h2-orrernbered hyerooyck>a!k h or 5- or 6-sneml¾red heOaoap and S(; ;s o oo ady
Figure imgf000006_0004
vvHh one or mo e ycbsRhsemc oRyeted Rom ¾·; group of hsky bvdrooy!, ox s C(i.>.>OM (ROiOdy;-R.; ykyp cym . od-RR ;dky;, b' ;RR. aikvogk a;raao. rnoaoo. -(k, aikylanbao, dkkb-C,. alkyiaaoao, Ryk,; evckobkyk C0-k-;;. aryk 4 jo !2o-aarobsrad kocroay cioaikyk and - or aorarrnbercd beeojaryk
each ok R;;. R ami R;. aKiapcadeady. < •-Cy-To i whi h Q¾ k; a boad or (bob aikyi hsaker opdoaaiiy sabstiaaeb oods halo, eraoo. hydrosayi or li-C iki!xy, sad id is B. hakyodro>;yk s0;G.kk cyaao, aabdo, o k... in oboah ik;; is kV-kb aikyk kb-d-d alkcnyk kb- k> ab;ymk kh»C;. aikos.yk by -by ihbohkyk C(O €H':d akyk CO kk !o b b .. w^O bkkc r£y aikyiy -■€{(> oNi'kk -Co a body,. -SO:- H( VCf. aikyi), - SO koCVCk aikyife C Cs oye aJkyk Ci.-C;:.i aryk (dyCd aryioxy, amiao, monogibob. aikyiarroao, diZh-kb aHoyknrbno, 4 ro 12-oooka od h« aa.n.vcloaikyk or 5- or o-no-mbered bakroaryk a; J o . s opb aaby aub boaod oads one or raore aahsbtaerao sokeicd f om t e gr p c nsisting oihaio. hydros vR oo · C(())OI-k C(0)k>oy;-(.k aikyk cyarso.. C Z aikyk kh-kk alk ayi. a mo, rro>ao-€y~Cy aRyk aino, biRb-C, aaykao-ioo. (bv-Cb ayo aikyk bbbRu aiyk 4 o ibonembered
c ei' ov dorflkyL aad a- r -mcmbc cd horoo¾ryk
Z; is N or \ b .
Z is N" or CR" . provided when 7.·. ia R 2R rr. by
R ! is R.h--vb)aikyk iC-b;y)aikeay k (C RRihkyoy k un ubsritatod or sabsbUacd (C:r Cocycioaikyk iaub ouried or ubaoRated i. .;- .¾ ck^ask l-i k- ;o:dk l o bC - o lkanyk naauhsbnn<oj or sabsd-aaad k C>orb¾hoiikenyk lauabobuuad or anhytboaad (1 d- Cs}oyei<.!ako !y)bCr'Ck; ikyi or oCkrCZbaikeoyk raisabstbated or auhsdiated (€.-·.- Cp biayvioaikyk aoaubaiib.aed or subali bed koRroyycloaiksd or o rO{balkeo>k ra¾ubsbursod or ¾ra:oo aed hc:er ic)c ikyio'C- kd ]kyk aaaobsuruicd or :oasiibaed aryk uosabsrkobed or substituted r kkCrk';b iky: r or a ; t.pgaa j aroasbstibited or sabstdaRd iKbaroaryh ra;sabstbakd or sabs$i†otod
Figure imgf000007_0001
RCrCRaikeiyyk -CO u .. byijoR" .
oRbNRsR!y -CONRs".NR£'R :
R" ia hydrogen, obbRixbaJkvk iribuoronsedok aik.oy, or h>do. in whch aaid Rb- kybbk}. Ϊ is opboaaby sahsrhyard oath oaa to ΐ\ aroap saieciad fr-.^ro aadoo ara:] s . :■ kyabkyiamoov
R; is iiydrogao, dkrkyiaiky L or afkoxy;
:' is h drogen. oik-C baikyi. asaoo. triiio^a'oraeri d. - R'! R' . ra halo:
' ;s aiaaard i <an b;a yrora.¾ aonsisbay obbyrirryraa, h .1o. ikk-kbbaikyi, Rb;;-'C;;)aiaaay I, iCrCxgdkyayk raasabatiiatad or sabstitato t CZ ckodk b aroabatiarte-d or sabotrb eii tkar- ZKy'ai ;akyi (.b.. Za:akyi. rai:>abstbateri or sabstiroted (k'ibdijayoi aikaayl. orssabsotaiod or sabsioraed {C-rk ck^ iks yi- y-i^^dk L i'¾-i.bo) kyoioa.ik k aaaab>d aaoi or ardisika ;d iaaerocs aardkyk aosab:b:iaaed or sobabaaad batoraooadoaskyioaa .r yaiks i, a ^obs uaad or subsdRaed aryk
Figure imgf000008_0001
r subRbared aryk k Rbvbkyk uruaR¾ibuexJ r srrhsibnred hareroaryk or aubsuR'Rd heie aayh(CrRRalkyk cyanrx a ! M:"* . -CO.;i:; , -CO KER", "CONK^ RRe Rd -dRR -SO " , -SO.:Kv, RR.RN R ; K.\ ssm . -NRyR'\
- Rs'(.';f{ R , ~ Rs'r(OiN a' '''. ~NRa C0R?)OR\ o -Rx½R ', - Ry SO-NR" R\
RRRu NRe R'R -NK* bRRRRObRx -- R. R 'C(0' s R;R R2 a NRA RR.ROR;R R R;R
R)RR>)R.R -(X.'' 0) .i! f¾"';
v.-hef i? any KbRRgRkyh ·€χ<2ηίΚόηρρ R r-(R?aR a k cyeRsdkyk eydo<Rkooyi
Figure imgf000008_0002
ksaeroc e sbkyk ryk or hederoaryi group is substduaad by R 2 or groups iraRpendenRy oReaaad ons id-; group e^uds-aa: or R RR-RbRkyk e Rx, -R(bd-- CRalkykR1 χ.χ RR-adgaikyRR' )χχ•-l s¾f k pl Xir c j lkyl, ik>Rx)ey-Ro kyk
Figure imgf000008_0003
hak, {(RR'.Rdky!. R2yR2a;yob;dkyk R; aRxxkxRkeoyk RRR2Rhcd-aa?ky k eyaray adbk RR RRER.- RONR'RRo -SRR -SOKa", RR.RRR -SORR " R , nitre RRR:R¾e , -hk* C(0)R;' , - Rs'C(0) .fi R\ ~ RS C(0)OR\ -NR': SO;dR , R-RR SCRNRRR'R OR"', R.KRORRR 0 :0R R' :R hakroayeka!Ryk arvk hoieronryk iaglk dR)akryi and
hareroary :(C; Rd.;)alky!:
wher in a .ay ary! r hekoxayi moieR" of said aryk hen,assaryk ary1(CRR.ga!kyk or bideroary!(R:R/:igdkyi opti nrili snbxdiaRd by R 2 or a r u s sndepoadendy sekokd Rom khe groap eorabsgn of halo, RR- aRdkyb
Figure imgf000008_0004
(kb- RR'&kaikyk eaano, RXRRR -C(½RR -CONRaRl',~S s , RRbR;R -RORRR -ROjNRs R¾ s nipxx -NR3'Rl\ -NR.'' C{oRR -Rg 8 CR)} :; , -NR.! R(OR)R;R -NR: SORRR RdR2 S(RNR; - ORs ^ d'i' sR1', : d -ϋ0(Ο)Ν ¾ "';
R:i and R.i; are each indepcodandy hydrogen, R bRkKbkyk iCrRR¼kkaa k Rdr- R.ydkynyk C R.k yaRedkyk (CxR/:sa;yck.edkeayk RdxR-RbbieyekaRkyk h«ieo.>cyck:>a;kyk aryk or hererxarsb :obeeb'; sari (C-. -CRRdky!, RR•(Rsalkenyk RRR' balkyrryk evckxdkyk eyckxdkanyk pRvckaikyk lwnxx>cyak:sdky ; xuyi or sugeroaryi g u k oprlormby sabsRdded by R 2 or a r mdeperafendy sekcied Ro;n aky hydroxyk. C CR ikoxy, a^nax Rg
Rd pdkykmko, RR: ; dd,Ralkyi)i yCd oaRaiky Ham bo. -CO ad, RR.RR.' : -€b. abkyk
RR.RRk.RR)RkHkrRkaRyk ?O {( \<-C4}alk^i){'i<^A" )3ikyn. RRdRi R':.; adkyk dR.RNkR,RRd RiRdRgpa!kyk and
Figure imgf000008_0005
or R:i and R" gpkaa aagodier wiih da; adrogen P avhss.b Uiey are adaehad ropresem a 5-8 aseralav ed a<atuj'ared or unsru r R-d rba-a opdoaai coaiakRng an ddiRosud hoParradon; r-oR-cted draa oxygo , narogan, and saUap whershs sa;d ring sa opraanady ^nba aged by R 2 or a groups haRpennera aoie^ d troro ; -Ri} ikyk RdRRahaRadkyk aaRoo, (CbR^'RikykuTdao. d'i.:r- R.paikyiRRR Ry !aikyR¾n no5 h dr .xvi r^o:. ( d-RRjalko.xy, and R; a^oaikoa;a R'xO ba1, o-heo.aa aaai rioa a; opRoaaby Ro:ed i:o s i .' ;;R cyekobsyl
Figure imgf000009_0001
vi. aryr, or PHe -so i • see
r R" and R'' askon toryeikor o ids do- ndioyen w which deey are adavhed ispsreseni. a 6- >o kkaoeinbered biXlged bRyooo ring sy iem opiionalR Risen to a ikhX'jpeycRxRkyh heienxyycRsdkyh aryk ¾· heteroaf i ring;
each i-k n; independeredy X'' bRabYama¾>, -'NRS Y>2kY --SRHRR
Figure imgf000009_0002
-N v"C 0)OR-'-' , RdRs R'R or -ok- k : and
<·; is R k 2, 3, a. or 5,
ilRkR One sub et ofdh compounds oRFonmda Rk R H · or Rib; features X being X is
Figure imgf000009_0003
pRR AnoRo-r sabse; of R;e eomponnds of Fommki dp Riak or Rib; Ratores X oca a.
Figure imgf000009_0004
an ther sobse? -a com ounds of born'oaki Re Rio k r (0b) features X n=. ay.
Figure imgf000009_0005
RR I] The present hsvenbou also presides pharnoieeioRai eoioposioons comprising one or more nha maeetroeRR acceptable oarnem and one or rrmre compounds seiectao ihma†.hoae oi nip- of rhe kormniae describ d herein.
Oka] AooPn-r aspect - a ok kmarboo R a eth d of nenthvy or pmveothn? an RRH2- -i doiO J dissmkr. 'Re; method chaRs adronksteriag to a robieei in need theresd'a the? spetnkaiR- ^Roetieo amoooi en ooe or mote compounds seRsaea thorn those sR any oi dm Rormoke described herein. The kZR.ommd;ated disorder ia a disease. dkon:kr, or cceidiboo tbai o mediated at Rao: io parr by rho acdvky oi kXRR ht ooe emixRirmaik the i ./ ; k. - mediated disorder ss rekus-d an kioiermsd RRH2 activity, in ooe embodiment, ike b'Rrkd- mediated disorder i a cancer The kZHd-uuediatea eanoer may be lymphoma ie g., a gernunai eemeode! o-ed fkceh iyn^hmuak leukemia or naBaras a, tor ecvautpie, dd¾o:e iarge B-oeh iyotphmna (DL- <.'.L). nend odgka iyniphoma . NHL), ksbkuktr lympisoma. Bra-kid's iy phormo chronic nryeiogenons teukerma B klLg acute myeloid ieukcnssa, acute iy mpboeyric hs-hcmis.. no..eh i esge Bak-oais. or yekKi pLsg svmh¾mes ( Dk?. la oae embodimesd t t: !cZI-i2-a-¾ediated cancer raay be a rnahgnard r abdoid rumor or hBLbalefeoient rumor, t he inssoiogio dkpgnosis of mabgrtant rhabdoid Juni r depends, on klenPtkation rd' characteristic rhabdoid ceils Barge ceils o-itb ecceniBoaby hs-eated namei and abundant, ecesnophikc cytoplasm) and kt^mnKbdstochennstry ebb atkibodnss to irnenPig keratin id epkhehal oiembrane antigen, In most nsahgnant rhabdoid ίοηηην;. the S ARCB i ί. ί 1 gene, located so chn.ao>.oome i-aad 22u 1 L2. k> hoKkvated by deletions and/os aaa-es^a--- la one embodiment, d; malignant rhabdoid earners rmrv be INp imeieekenr tnutors.
[0)3] Unless otherwise stated, any description -T : method of treatment Ineiades uae of the compounds to provide sack dcaaa >a or prophytams as is described he; ed:.y: as oBi s u¾ f the compounds to prepare a a-edr.sau η= to treat or prevent sack condition The heatment ineiades treatment of human or oomhmnan animals incktdmg rodents nd other disease models.
Methods des r ed herein may be nsed to iderdlfy sukable candidates ro tre;aittg or preventing fo/ffkooedkned disorders For example, the ims&mlon also provides methods of kientifying an inhibitor of a wlk ype EZH2, a mutant FZHB (e.g., a VoB j , ΑοΠ, andosr A6T7 mutant EZH2 a of both,
1014] l: or esamole, the method comp ises the step of administering to a subject having a cancer oath aberrant Η3Β2.27 etkykttion at; elfective aiooaB of one or more compounds or ko nuiae described herein, eeherem the eompeanslug inhlbks hisrone methy;transkrsse activity oi. bZHk. thereb treating dte cancer. L.:,armBes of aberrant H3e ? meb kklon may include a global increase in and/or aitered distribatton of H3--K 7 di or triorsothyiation wilhm da; caaeer eeii chromatin.
pB a] For example, the saucer is selected hems the gronp ormsuamg of cancers baa:
overeapress bZH2 or other PEC2 sabrebfs, sonbbn loss-okktnctlon mutations in H.BK27 demeihyiascs such as kfkZ, or ovetexpress asceasorv proteins sack as PHFBkPLT.a capable oi incicasag! and or nbslocahekm (:'Zbs2 aedviry pose re erenees m yneennger a/ a/, ro-- Akaf Aca Sii ί/SA 1 d ?plv):20dgdTf 2CB 0).
pB6] iasr estnrnpic, the nvet.bcjd eotnpBses the- step of administering to a stmieot havmg a eaf?ser so eras posse dt a EZH2 a iherapersica!iy eBeedve mount, of one or stase eoag>ouads of fonoelae descri ed hesxim vh i io the cornpoasKbs) inhibits hixone nxdvyltransfxrase activity οΠΧΧ Χ hereb re tin sh canceo
\ l7\ bor example, bx method comprises the step of admbnatermg tc a subject having a canoe;' with loes-oolonotion nmtatXn in the H -R.?7 desrxihylaae UTX a rherapenbeabv etfecbvc arnonnt A - -a-, or more cxmp- ···;. !·· of horn a bac described herein, wherein the oompoonbiSi imnhh baa. m dtyitranskxase ncth a y of EXI-12. thereby :;xaag: the cancer, a b ; . : I -r
Figure imgf000011_0001
the m hod composes Xep of adnhnistering to a sabiec; having a cancer rnereapressmg an acces ry eomponendS! of the IXA A. ^ cb as PHR APCLA a therapeaticsiiy -xecttve ar omi of o e or more■ cap m-d:- of f onnnkx desc ibed herein, wherein the eonspomuKsi inhibits historic niehiykransrerase aetivhy - a be'i X. thereby treating the canceo
|¾19j bs stbl another aspeco thas invention relates to a method of nmdulabng the acbvby -a die vvUdoype BXR2 the earalybc snbunk of the PPX'2 complex which catalyees the snono- through a bmeibyhvhon of lysine 27 on histone tie \ΗΧΚ2Α. For example. Pee v---. ··, a;
invention relates to mebtod of inhibiting de aedvhy of i /hot isa ceil, i bs method can be conducted either in r/ox r ;o seen.
|020| in ;.s■ another aspect, this iavenboa featu es to a exX-x of 'inhibiting in a subject conversion■ a u K2 / to triuveihyhxed I-B-K27 i nc method -ornprbes administering to a snbicei e tbeogsenbeebv efa'ectxe amoom of one or more of the compounds of bormrbae described heroin a> abbbh histone meihy [transferase activity of E2R2.: thereby inhibiting conversion of H3--K27 to trnreXhybued H3-bx2? in bv eabject.
■ o i I b r eeanxgkg she method comprises dec step of admhnsnx g to a snbgxe having a cancer expressing a rnaient bXfib e ., a \ be 1. Ao77, and/or Abb? mutan of hXi 22) a dseo.genoeaiiy siiectrve am un of one or snore con-pounds oi b-Ximeac described heseim cohee in the oosnpoundiSi inhibits histone mehnkranstesase actoity of hXH2, thereby ncabng the eanoer.
022 § For eannxpix the cancer is iymphosrnx icukenba or melanoma, for -e ample the cancer is germinal center ΙΧχΑΙ lymphoma selceaed irons the gsoup consisting of ioliieaiar iymphooxc diffuse large bXceb lymphoma iDLBCba of gennsnai eenXr B selbUke (GCBs sutyypm and iJnrbiU's iyispbinsor and on-Hodgkbhs bynsphoroa of germinal center B eeb type.
Figure imgf000011_0002
the iynphosna is noioiX>dgbin:'s iysnpbonia fNlabt, fohkabar b-mpborna or difbise large B-ccb iynipiionsa. Airernativeire the ienkcioia ss chronic myeiogemsns lesikcinia ( f.g c te
■ nveioid ienk iympboeybc i-osbemia or mixed brseage Icukenba. T/US2015/037715
[ soj bar esaarplv, -he precancerous condition s. myehsiysekoaic c ad- sac- ikiOsk bess ask kuoaa a;: preieakeraias
[02 1 For eaarnpie, d;e cancer k a henabobgyuai cancer.
02a] For■ a seen: the cancer a; sakcned bom b'te group conosbna or brain and - cane; a-.a -a . system pCkbk cancer, baa; and aeck caacer, kidaey cancer oousan cancer, paaoreabc cancer, leukeaks, ham cancer, k ae-h- sea. mgsboma, oocomu, breast cancer, aad proagne cancer. Prererabhs a snbkec h> need th reof k oae oho bad, ks has ing or is predisposed to desebpina baia aad CNS aara,ag kidney cancer, aeakaa cancer. paa.o ada cancer, knkenna, lyrapbaaaa myeloma, anu/c-r saa oma. bsernpiary baaa aad central C. S caacer in ludes nredohohbsmnu;. ojigedendroakorea, atypical terntokbrhabdoal rumor, choroid pleases earciaoma. choroid pleases papb rns, ependya¾oaia, eiknskebonoc nrenmgm a. neuroglial tumor, obgoastrocvtoma, ebgaaiendrogikaos. sad pineobiastorns i ..caoka; ; ovarian cancer asba-ka visrlan cle cell adenocarcinoma, ovarian endomethrioid adenocarcinoma, aari ovarian serous adenocarcinoma. Fseno nry paacreadc cancer includes pancreatic ductal adenoearcinorna aad pancreatic endocrine tumoia Foorspbyv sarcoma includes
chondrosarcoma, clear eeb sarcoma ok soft tissue, owing sarcoma, gas roimesiinal stromal tumor, oamosareotna, kiabdoonosarcoma.. and no; othervkse specified s'NOS) sarcoma.
Aheraatbaby. cancers to be beared by dm contpentnds ofkhe present invention are non NHL cancers,
jOdPj For esampie, the cancer is selected frotn the group consisting of medal kkikisioara . oiigodendtxmbosna, ovarian clear cell adenocsre henna, ovarian endomeihooid adenooarotnonva, ovariaa serous adenocarcinoma, pancreatic ductal abenoesicmoioa, paacrcadc endocrine barter, rnabgnarg rhabdoid turner, astrocytoma, aksneal iecaroabrhabdoig tumor, ch roid piesals carcinoma, choroid plesats papilloma, ependymoma, ghobiastonua memnseoma, neuroglial tumor, oligoastrocytorna, ohgodendroghoma, pineobbstoma, catoincoarconsa, chordoma, eabrasoraoial germ cod tumor, esbareaai rhabdoid turner, acharaaaema, skin squamous ceh enrebotna. ebmdrosarconee. eka¾reeb sarcoma b' sob issae, wirs sarcoiaa. gasasoaiesnnai srroniai raaror, oaicosaraoaia, rh bi ai s je n g. and aos oriierwise apcei kd (Nk.b) sarcoma- Prcrerabiy, daa c aacer is readaUobhevsanog ocariaa clear oe!i adeaoearcasoraa, ovanan cssdosaeririi^ad adenocarcioorra!, paaeroaiic duct l adcnocarciiiOau;, iuabgrarat rhabdoid aaaas aiyriical s-ras;adb habdoid ruiuor, choroid pivxas carcinoiiao choroid pies.as pa>.udoraa.
giiobiaaroma, raenlrigioaia, piacobiasoara sre na-s reon-a, aaaaaonai sfiabda-d taaion sehovarasona. ska- sgaiaaoaa cod c caKiaaa chondroaareoraa, eo iigg aarccaaa, epiriieioid sarcoasa, rcaai sraaluhiaa carclisaraa.. diliasc iaryc B-oed ·οηο;'η« η, bshicaiar iyrnpho.;n¾ iidaa 37715
NOS sarcoma. M re prclerabiy, t e caneer is malignant rhabdoid Ranor. rnedalloblssioma amkor atypical teratoid/rhabdoid tamor. tdhblgnam rh-j olodd manors are high-grade neoplasms of the ceoirat ue-i vents smtem si?.N:b kidneys and soli dssne drat asoally occia so ehlkkem dim hisbskmsc diagnosis ofmakgi e t rhabdoid i nor depends on Ideraiiieadoo of characteristic rhabdoid cells ilarye ceils ohb eccentiocally located nodes d rbenbaab eosinophbk ryioplnsrn) and Inm m-Kgdstochemistry with aniihodles to vmientln, herntm and cp beii a rnembrnne andean. In most malignant rhabdoid umor , the bMAR Bi/iNil gene, located in chroaiorome band 2 1 k'2, a? i ctivated by deletions andnsr omiaiknis, in one emlxxiiment the malignant rhabdoid tumors are INI] oiefecseni tumor.
[027] f or example, dm medead comprises the aoep.oi adminiskasng to a ubject aving a cancer a theragetmeslly attecdve a otnn of ne or none c-eee -nmo f Formalae d sc ibed hc om vrbefem the t oinpoandpdp, inbibas activity bog., bisionc metbykransferase aodmiy) ofd.be m tan k2H2, bar wild-t e f7ZI?2: or borh. diere y treariag the cancer,
1022] bar example, dm method further oonprises the siege ofperiorad g an assa to detect tiro preseose or abserree of a onuant EZB2 in a sample c m risin cancer eetk from a subject In need thereof.
1029] in another aspect the Invmitton features a meikod of selecting rherapy lot a pabcm having disease associated oath LZHdnnedaded probso navfhylatlotr The meikod lacludex the snips of deiermubng the presence or absence of gmm mukaion ;n the fall? gene or the s bject: and selecriny, baserl on the presence or absence mf a gene nmtnboti In the id le: gene atheragv for hcabng the disea e. In one embodiment, the iherapy includes the administration of one or more ofdhe eompoands ol the Invemlom la one embodbrmnb die mebnxl farther ineksdes admnaetradng one or inore oft he compounds ot the invenbon to ihe aumect. In one end dimenk the disease is earner (such as lymphouep arid the nuaabon Is a Vo4b Ad??., arai/ t And? mutation, la another aoibodnnenc dm dis se is an eZrla odkl sy e germinal center fkeell iympkunsy e.g., the germinal eenao: -eell lymphoma colio having nomemaated. ohkngype FXH2 pioieim
b.bby hi yet nother aspect, a meth d of treatment is provided far a paiieni In need thereof, dm me h d comprising the steps of deienninhig die presenee or absence of gene imitaion hi the BZH2 geae and treating the patient in need thereof, based on ihe presence- or absence oi a gene mtnaiion in the bZU2 gene, oath a therapy d¾i mciudes ihe adrnuuai ilon oldhe compounds oi the meemiom Irs one emb diment, the gadem Is a vaaeer patictit and ihe iniaatlo;; ;s a Y6 ?., Λ677, anddo- Ada? nneadoe, la anoiher emb dst:>eii, ihe nabeo; has aa bZf 12 a iki type 2015/037715
germinal center B-ceh kmphnaur e.g , i o ροητηηηΙ renter 8-eeli hnvphoma cells having nom matakd, ooioktype i 4k: protei
[ 3 s In aktl another aspect, this nv ti n relrPes κ> a method ot rnodtdaiirtg ike asbvhy m the w k!-iy e and mutant hktone rnetlmtnmsferase EZI 42, the catalytic sobnrdt of s e PRCZ complex winch oataiyaes the mono- t r u h trkmeihy!atlon ohiysine 27 on blstone H3 flfZ 1422 g For example, the present invention r lat s to method of iahibkmg the activity oi cePain mutant forms ot kZt i2 so a cell "s e muta beams -e Zl if include a suhstnukon > "»f another amino acid msnlne tor t rosine 64] (Y6 L also T yr64 ϊ ? s4 mikktype EZH2. The method mekidee oo acnog he cell wth :··η eflectke amount of one or more of the compoands of an i -scale described hereuv lids method can be cenduoted either u? i Pro or f ; o'o.
1042] ks vet another a- ρ·· a. this Invention ieatures io a method of inhlbhing in a subject conversion of H3-- 27 to trimekuylaied i iZZZZ The meik-d comprises iuiaZmstermg io a suifject espressmg a nottant EZH2 (e.g., a Y641. A647, and/or A68? mutant οΠ:':2Η2) iiierapeutieahy erieekve amount obone or m re oi the compounds of nnv Formula described herein an inhibit htstone methyttransfeoise activity -A bid k. thereby inhibiting conversion of fkkK27 to trlmediyhued
Figure imgf000014_0001
in t bjec For example, the hktone meksyhratvZsrave activity inhibited is ihat ot the Y641 mutant of EZH2. tan- example, the compound of this invention selectively inhibiis lactone oicih kransterase activity of i e Y(>4i um;mu of E7I12, I eseoa-lc the Ybd 1 romani of FZH2 is selected iron? the group conxktmg of Y641C. Ybklk Vo4]fh YZAIbf and Yp lS.
pc-.p i a.- ;>;erbod or mhibglng ;n a aobjecf c nvers on of Fku.|222 o trlmeihylated A 4 k .: may also comprise pertorm g an sssae to detect a unknot 44; A (e.g.. a Y64I, A677, and/or A6F7 mutant sk EZHZs in a mpe- 4. on subject before administering to the subject expressing a mutant fv.i i /. therapeutically effective amount of one or more of Use compounds obany Zormtiia described herein, for example, pernan ng the assay to detect the memm PZIfZ includes whom-genome reseuueneing or target region reseqaenciog that detects a nuclek acid encoding the mutan t?Z! 12. for exampie, perknaZog the assay to detect t e nnaant FZI72 includes omriacting the sainpie oaih an antibody tiun binds speeiiiealk: to ·.· polypeptide or t agincitt tberesif chta-acter-sile of pie s ub-in f ZH2. F<;r csaui le, perkuaung the assay io deieei rbe iuatacn 124142 includes contacting the aan?p;e under highly sklngent eon<htions vitb a nociele acid probe iitat hybridixsa to a nucleic aesd ericodltig a polypeptide or hagnscnr thereof charaeicrkko of the murant kZblZ.
[044] I an tliCss the invention also relates to a meth d oi" Kientkymg an inhibitor of a mutant ZZ! 42, the wi Zy e EZH2, <n- both. The method comprises ike steps or combusmg an laoiated 122222 wi h a historic substrate, a methyl gr u domes nd a i ss: soiCip md, wherein the biatone sthwsraae soogwises a form cTHiw . ? sehcacd bom the r up consisting oi un ehsyiyted Μ3·· K22, svKeKaoeihybWed f;3-3 22. dbneihsiated ii3-bg27, and any combination thereof; snd perfor ng an as ay a · delect methylaiion of H3- 27 (gag,, formation en' uameibyhtied IJ3-dC2?) Irs die hisione substraiw thereby Kienbtying ihe seat covnporaal as a a inhi itor of she EZH2 when nwthviabon οΠ 3>~Κ2;7 (e.g., formation of iriroeibyiaied lB~k?7) in the presence of e test coropomwi is los: than methylaiios'; of H3-- 2? ee,g., ioinsatkst otplmedvyiaavd B3-K2?) in ihe absence of rise test oessipoutkf
[033] in one ciobodimeng performing die asaay aa e ct a-ethy!atioo of H3-K27 in the 'osroac sobsoaie comprises measuring iaeor oradors oflabeied methyl groans.
|o* -P i one enhaxihriesw, ihe baao-.g mehtyi g s are saotopicaHv beled r et ad groups. {b3' i in one embodiment, performing the aacay to detect methylaiion of H3 -h227 in the histoae substrate comprises eontnetmg the hsst ne substrate wish an antibody thai bifida speci heady to biomihylated Hfoi<27.
[0381 Also within the scope f the invention is a method oi ideni yhig a selective hfoihitot of a mutant 132132, = be aa. mo comprises the steps ot combming an isolated mutant BZ1I2 with a hisione snbsissue. a methyl group donois and a teat compound, wherein the hisione substrate couosrises a form of H3-K2? ^elected ironwthe gr u eonaiatiog orbnonornethgisteb H3-2027, d; erhylatcd H3-K27. ara:i a eon^araajon ofoiKmonmihyiatwi 133-73 ? and dbrwihytaied his- 2227. Thereby i sowo.. a teat mlatme: combining an iaoiatod whhoype ! did: it a hssione substrate, a nsebvyi grotsp donor, as>g a iest compound, wherein the !dst oe substrate comprises a Rasa selected from the group consisting rddsionon etbyiared H3-7222, dimcihyhwed H3-K2?, sad a c bin ti n r»f nwaisanethytaiod I13- 27 und dimethylaled ΙΤ ~Κ'2?, dncfo for ine a eontsxd mlsiurc: performhw n assay to detect trinasthyiation oi dm hisione subsgsge in eaidt sb ifo- teat rmstuie and ihe control mixture; ealeaiatiny the ratio of w bssnefoyhihon oath ihe mutant h2H2 atai the teat connasrasd ibf ia to irb irirnethvsarion with the rnataat I 2s ;2 o iih^tn d>e ieat aootpoand S. -}.' caicnlatisyythe ratio of p3) trioiethyiation with wdd-tgpe bdb!2 and ilia test w-mpoand (Wl'-ia ¾d) traoetbysation widt wiidgype EZ132 oath-snt the teat ooiopoiaaj tWia.'g eoitipariigg' th ratio gib;b) ¾3;ρ the ratio odbbg arid ideaf fying ihe teat eongsot-og ss a aeiaeave inhibitor of th; nsoiaat FZiad whe-! the sado iaaibt is ;ess ihaa tise rati-:- b') g.i?- ib3b) Th preaea; invendoa tratbei po>videa a nwdiod saddasnifystig a aiibjeai as a eaadidaie for ;; οοϊηϊο;ρ· wad; taw or naare ao;npounda oi ihe invention. T he method composes the steps of partbrmaig an assas- to deieei a mutant E72H in a 'S:a;ipie tf io a anbieet: and identify iaa a Nubgaa e a a . eieo a nunccr 02122 as a candnfue for ueaPnern. wUh one or more compounds of the invenbon. wherein -he csa-npoendts) mhihha hisPsic mebyhransleraae actuary of BZH . 1040] hi one eunee.bme;ig de method comprises: tit providing a nucleic acid sample irom a biological sample rbiiaincd .( m a sab-jeep (ii) vonukiing Use nucleic acid sample with at l t o e pomer die :.;··'·. cbcdb, hybndrees■■■■ a nuekie - sd segusnee oi 22142. or a eongbenk-or thereof vbaracferiacd o i ; nocleohdes e-codhgg a•'mnaikai dad increases EZB3 nanktigviaoon of H3- 27; Ed s detevdne the presence oidhe mmahon a- de nucleic acid sample by deteebng the presence of a nucleic acid characterised ends nneieoltdes eneodlng nnnatkoi (fan Increases EZH2 Psn eibyPuion of H34I.22; a d (iv) Ζ-νορ ug; dm anbacel as a casa idatc ba (reanneng Tik method can lerber compose (20 -alnbnlsmniig a (hempeaooally eiieehve auKuaP oi an HZK2 inhibitor to the eubbxa klentibed in step neb ohereln he EZH Inhibitor Inhibgs (IK-. conversion oi R3~ 27 to irimclbytated H3- 2Z
gel I ] in one embodiment the method comprises; (I) providing a nueieic acid aang.de bane, a bkdmgcal sample ob mkxl dean a aubiecg corpaebng the nucleic aenl sangZe veibi at teas; nco primers baa specifieaJiy hybridize- ha r olem acid segoenee of EZH2. or a coand--a>-oa thereof eharseieriaed velds nucleosides encoding a muiaik thai increases EZH2 irinieiteeiailori of iK-KZg ihl) amplifying (he nucleic acid sequenee;: or the complement bereoh characterized raid; nucle-Pkies -sacbaa- :f . moiaoon that m o¾oa-o KZH2 irnnehylaoon of H 227; (iv) detecting dk presence of the mutation by detecting the presence of de amplified nucleic acid; and (v - identifying die subject as a candidate far U'eairnent Ok ebiod can further comprlae (vl) adnnnhmring a fxmrapcmlcally p oic amounl of an EZM2 inPubhor to the subject ide lfed In akg? (vh where m the I ft mhlbllor aboba. g;t conversion of EB~K27 lo irunerbglaed
Figure imgf000016_0001
[072] in one cmbodhneng the method comprises: (is p oviding a nuctele acid sample iro a bii h-gical sample obkoeed frmn a sublecg (lb cont;.u;dng bar nrielele acid sannZe with a( least rimer iba; S;:;ceiEeahy Igrb bcas P.* a nucleic ae-d aequence, or a c-o'n pie ment Ihereob ebaraeg-rlecd wirh nacieobdes encoding a muunii n at d>e poslvlori Tyr6 ] iYfdbg Λ677, andtm AbS? of EZil2. rvhereui die nuuabon increaaea ZZI I2 trirnedp labon of H3-K27; (lb? detecting rbe presence oi the nietabon ai de nucleotidcA encoding Y6 L A677. and/or Aggg i die si!a: lcie acid sample by deiecongtbe presence oi a uuekac acid sncoplng Una mutaPon ;n 7 b4 b Ad77.: andaar 7627: and llv) idenbiyngg the eabgeei aa a candl^iare tor treatnieib, "fhe nierfsod can further eon prlae (v■ aclectlng a therapy dal Includes the aduornsirabon of a dierapeutlea ly etbecilve amrna t of an E2H2 iobs kor lo die snbjee; identified in sieg (ivp avhereh (he BZH2 inhibitor hihdbua e raion of tfZK27 > namethvf ted flgZs.2? 7715
4 in ne e imdimeng de method comprises: ik prowding a rmeklo acid sample irotn a biological snwiple skkamed hom a subject id cmkacimg the nuelek acid sample with a; k&at two primers thai apeolilcahy hybridize to wseleic acid sequence, or a complement thetemb chasaotenzed th nucleotides enoodmg a mumhon at die sti n Ywtk A677r nwkor OS?' of bAH ^s herein dm istadoii Increases FZ4I3 inmethylaiion fHAKs A ibl) m lifyin the nwAele acid sequence, or die o nem eai i creok characterized■■■■ ah dm mmabon at the nneieotldes eaoodum poshsoa YA4 k A 677. and/or AbB7; iw) fhaccbng dm preaeaco oh the mutation as the nuekotkka encoding Y64 A677. and/or A087 by detecting the presence of the amplified ooc!cic acid; and iv) identify ng the aabieci as a candidate rot irearmenb The method cam briber comprke vis aeieehng a therapy that includes the adminlsimtion of a dai-mpeohcaby effective amount or an E7.H2 mhshkor to dee ubject Kkuitbied la sky (7g wherein d;e ¥21:12 isnbbdor udbbhs the co ver on otbfv-Kdf t a-ipiCibyiate Hao<27,
[04 a b d! .a: air. r aspect of the Invention k a method of inhlbiinw conversion of VI 3 72? to rriateihyiated i 13- 27. 4 be method oomprlser the step of contacting a mutant Fkbib. the wild- type bZfid. r both, with a hkrone substrate comprising I-13A72? and a a effective smoani of a. compound of the pves«n; invention, whew die compound inhibits lactone medtyhraiwferase acts-, sty or o 7 k A dr. tab. iahibibng conversion -A i k b-A v as irltoethybged i Aw, Af
|045i eovtheg da. ·.· -rap: saal- .·■: methoda deacrdwd herein can be used tor waearch bog., studyin epigenetlc enzymes? and abhor rww4hewpeuue porpoaea.
iOdPj Unless orherwise defined, ah technical ami sekobfe terms used herein have the earne meaning as con mrby nnderstood by oae of ordlaary still in the art io winch dds bwet>bon belongs. In the specification, the slngalar lotrna also I clude die pln l radess do- wmtext clearly dictates otherwise. Although rnebbods and maeerads similar or equivalent to those described herein can be wmd la the practice ortesiing of the psvwcm awenbon, suitable mebiods and materia L am described below. Ad pabneaoona, patent w?£ >ii . na-e . patenis and other rsterenees mevn' ned herein are incorporated b reference. The r levances: eked hernia are not admitted to be prior ;as to the maimed hweaPon. la die ease of cordlkk the preacib specsiicabon. Iticludlng vlefadtlosw, w ill eojitrol. in addition- the raaieriak, soedasds and examples are iibwtradve only ami are not Imended ιο be limiting. In the case orAontlki beiw-een the chenneal sn netnres and names oi tim e trs rsda d c lose- .1 bemny ihe ciavmicai airuettaes vAh coakob
[047] tip; : atures and advanaiges of ihe invention will be appaieid trrav? she foll wing debo!ed ·'ΐνη:οί1ρίΙθ!! asoi c!abms D TA ; ;>
Figure imgf000018_0001
; <oo 8] ΊΑχ poo;:raa isoen o provides n v l -a;bsdUHed beooeoo bieyeUe heveroasyl c-.no uVit -. symheik. ovrvhods for maidng h com nds, pharms-ceutood eoa^o ruoru: comam g Urem arrd various uses of the ίοο οοηο ,
ΐ χ The picsoni iro endor; r vides the sompousKls -of Forrmds (1; or a p arrmKeuooahy sose oeXe ash Urvreoi:
Figure imgf000018_0002
0). .
[050] io Fornsoia (X above
Figure imgf000018_0003
i N. NRs, CRs. O.. or X;
; X NFX. C?X, O. or S vheo Y
Figure imgf000018_0004
or€ svhofs V X
Figure imgf000018_0005
X.: is C or N:
ΫΧ■ N XH: PR k M or C , :
Y;; o: , or RR< >:
Z hi OR> i RRbbRkx
; is H or R<¾, in ¾4bch R s s CV-Q athyt, RRR aken> I CR-CR alkynyi. R.;kR cyoRoohyi, e ··' r apvh 4 to tdoTienskered heleroeyclorbkyk or S- or b.-nKenbsered heieroasyh and i ^ optionally sobetkuied olds one or more subsikueMs cekckd Rom the group
osktmg of l , hydroxy!, uxo, C(0)Os C{OiO-CrCt; aikyh eyano, R R atbyf PRR?,. rbboxyh amino. nmno-RRRb aik koknee d>-RR(.y u kano . ;··:· ' vycloa!Lyh i.k--€-.--; aryk a to bRce berod iKkeroeyokcdky k nd R- or --me red beieroyryh
each of
Figure imgf000019_0001
R and K.-;„ nsRy kksa;; Is-RoOk. in vRboh PR is a bond o (h-CR atkyt 1 inker optkxxiHy aabsbPned obth halo, eyano. hydroxy! or CRRd. a!kcocp and lb Is !h hak. hydroxy! k(0)OH, memo, axkkx or s,. in oiueb R-:; k R';RR aikyh RRRR alfcenyh RfRR: alkynyk R:-RR a!hosyk PRRP. ihka!kyk RcRkkkRrhR aikyh CONFK SlRN!Jo RdkbrRIHkkkP alky.il kROyRRR RR; a!kyik, -kO N HtkR-RR aJkxd), ~ SO £CV k aRy!n, Rb-RR uykou!byh CRRR;; aryb Rs-ko arybxy, unfuxx momoRRkR alkykmino.. PRO pp alkykmiuo, 4 ro id- m.ooR.oai heierooycloaiky! or 5- or ο·ο;··ο;;\· .J heiemcay h and x? k opborxkly sah rkked iin oo or mo substRuerrk cok-ted Rom the group consisting o hak, hydroxyk oxo, bRRRObh€(0)ORkRkv aikyi, cyano, Cr-i.k aikyi, Cj-CR kkoxyk ammo, mooooyrRs aikyt nkno, dnRkRb rdkylanRno, (RrCR cyekalky! fR€R> ary 4 t Ikosicnfbered
kPeroeyekobkyh and 5- or o.-membered hekrosgvp■
■rack of Ik, Iks, ΙΟ;!, and R^uKkpendentty.. is R or R-C-, aikyi optsoaaRy su stituted okth no or more substltucma selected Rom he group eonskkng of hakg hydroxy!, C'OOB, R(bRRRR-R: aRod, cyano, 'R-CR aikoxyb amino, rnono-b rbr alkykminea rkCybk aikylammo. Rbb, cycRonkyh CR-CR. aryk 4 to kkmembered hsteresmc!ordkyk and 5- or OnmmRsmcl heteroasyk
each R,, independertRy m Rk hahx OR,, -RRJ<;,. -0R )R:„ RROs Rc„
ObRR'RRJO, RsRRRr>RR;,
Figure imgf000019_0002
in oidch each o† PR, and !R,.
uKkpcndendy is H or
Figure imgf000019_0003
aikyR RR-R' :; aikonyk k'v-Rb-, aikynyb tR:-R' K cvoioaikyi, O^-C;,; aryi, 4 as 7~nicmbo ed bk4cr yc,l alkyl. or S to 6- roernberod eicroaryk -sr ibs arai Ki¾ i g-tbor oRb rho N koi to hkh he are aUacijed, k^a- a 4 to ?.anendsero<5 imfsrocycioaikyi Rng i;avina 0 or i addiRooai iseteroatoots to ibe N i no and each of ¾<:■·.. Rao an<i iRe 4 k> porienRxcred iieie ssdrian.yi rin coraabRnp R-, and Κ¾, is optionally substituted rvnls one r-r ηκχχ -t);:--'k;. rvbereiit P);; k a bond or Ci bb; aikyi linker each ionally substituted o hh baio, cya.no, IsydiOsyl or CR-Ck alk xy, rl, halo, s:v;¾iH, - OR.., RxRJR.
oRE,RRRR:Rb aOhR, R'wROR,. -C 0;NE,R,;,. ORKR.:R:RRR:; ~ ¾GO}OR\ -RiORR,, xRORRiRtR.. or R;,:;: R; which ach · >f R. , ¾, and R,: , hwbpendendy R R or Rx V R phanrsaeeiibenhy ;κ eepiabR iiuson. each ο.ΓΚ-; and PR , hwbp ndenby, r, khRR eikyk kyRb. evcRaikyk C RR; aryk to ?~rembsred heseroayckxa!kyk or 5 so boneniherfid hereroaryh or b and R,j, :-y.:bi-,r with die N raorn to which di are attached, R;n; 4 ·. · donenbaered hcterovycioaskyl Ray haOng 0 or i addibenni bcreroasonw so the N atony and ach -.R ,; R :;,: id bw 4 to .-nwnb wed hetorocYc odkyl ring condoning R0 a ad r w optionally xabebuned wish o e or more RiRRb, wherein 5) R a bond or khRR aikyi baker each optioaaiiy se-bstkshed with hake cyano, hydroxy! r kyR-f, aikoxy, and 'Id so sele ed Rom hie group coswRbng odl, bad', ewnso. Ch-Cb aikyj RRR cyckadkyk C.,.-Cu- Ra, 4 to roeensbered heterocydoaH-yk 5 so --.a-.05; r.-d heier-asal. OR,, ROCdR, RROrdR, -dRRJO and by(0)NR,.R! each oibR and R mdepeodesnly being II or Or<R a¾ i optionally s bsUu d wish OH, O-I.R-Co aikyi, or bRRCR- i.R ask> k or -QsOb 0 oao; or ---OR- 'R : ox ; <jv any Rvo neighboring RR-4 a togeaher with the. as-ona .1 which rhcy -a-. abscbed ronn a - or' ··· -nowaxecb rasa opboswdiy containing b-4 hesesawsoina i-eRcied Ron> N. O nd S aad opbonaiR cawthsiRb with one or snore athwntuenta selected from rbc group conciRing of halo, iyvdtoxyh OOkRk RRROR g aikyk cyano, C.R-R., aikoxy casino, nso.n -5 iyRR aikyinnino. di-Cb-C;.; alkyRirsnso, R i;; oyeloalkyk (R-R.R-; as k 4 ¾ hcrerocyoke'hkyk aad 5 to b-ivwsdwwod hereroaryb provided that -Rbr'R R not kb
cti Ry independesbiy R -kb-Rh. in winch Q.< R bond. R;RR aikyi baker, or C Rh alkeny; iinker, each bnUr opbonaby stbwbtoRd wssh bain, cyano, hydroxy; or kRkg yw- ,;, , and 4".: ;r ih halo, cyano, R!RyhR. RRR. od(kRit:;; -RRy»ory:j b;(0)NR.KRSi, RROsRR,OR , RcR?Ri'Obkw -'-as a: ·.-· R,,:. in winch each rri'R, aad b.;,. iadepoariasbly sa H or -y. each of R>;, and Rsv, indepeadcatiy ic CbRR a!kyl, dw R. cycloaiky!, R-ib') aryk 4 so 7-nwaibered i teiXKyoi aikyi. or 5 so bwnentbercd hes.ero¾r> k and each ofRR..; sO b,, is opsionaby rnbabtotcd avit;¾ wsc ra : ηο■-'¾-·"}"',, wRcreia Q; a; a bo;ni:€:?'«'>). RsOiN ;:, RRbkYO).
SiOs^, Ri. (0 :j. or RRRy aiky bnkcr.. -K bssn H or CsR'b( askyi, and 1 k s a baso, C CR aikyi. Rtj 'f, aikorsys, k'-Rg: nikmyb ivdroxyj, oyano, Ri-wd, aikoxyi, ainhKy iosiO-Ry-Ci, askyiandno, rb ;; 4R a.ikyia;V;iao. R;R.b eyoioaikyd; kb-R:.. aiky RneR.t:-C' ;; cyckndkyk R dy,, Ci l t.b-RR aikyicr-eRy i;: aryb ;; s bknna;nbare;i ;wRrocychaik> h C;RR aikyieneO to iR- axaaw-: a-; hoteroc !oaHvvL R- r 6-aier:daesed hercroarvb or (b-Ry, skyiersexa- r Raneirshered swreroaryl, and 1> i optiooaby stsPcritSiiori with one or nw-re a bsksts -iHa ccseaWd born she group coiwRtnig obhaJo, Rs-k y aikyi. hydioxy k ryxn;;.;., CbRR; alkoxyb bRkV-Cb idl. kno-CrC; 2015/037715
aknxyk ammo. naanO'-RYR 5, aSkykonino, P; ··: Y-' . aRyknrnno FR-FR cydoslkyh ORYX- aryp 4 ro 12"Sn rs?! :.i 4
Figure imgf000021_0001
nd - or OooooYpe od hebaroary? eacepi when 4% X - ha! , h yiroxyl or c ar!i,- or -Q.RR; - oxo: rovid d Rai --RR" R R ^ i R: and
esah of Rk;. -.Ϊ, and R. .:, RdepsaRendv, k H'„ hakx hydroxy! ·, ; ·- o i eyanor. k-.. OK;.:-, or COObR.*, R vrhkh Rvs R FRF a ik L C.rkk Rkenyk (R--CR aRynyb arrhmy aiono-XYYR aRyRndoo, or dRCR-CR Rkykamno. and R-a: hi opuonrdR ^obskoped wHh r-no or more sukakiuema aokeied Rem Re g up cosooaung ok hake hydrox k k R: p R2kkkkX.'a-o.Y alkyh o)ano, oXRX a5R.-a.yh anoao. rnonoXX XR, aRyRn'Rkx and drRYXX aik Rndno;
n s P, k , .k -k or 5.; and
ai nnxe ;>:;o oRX:.: and XX k O or S, a; Reai one of Xh, X.a Xa X.o Vk. Y and V o N or
N 7- and Xj. Xa X,. Xh;. R RR, and XX are a aRned -:r:ch rhiH ihe
Figure imgf000021_0002
mo-em in Rornnda pk k a bRyobo 4-aeo -a;-'. ; rnonran,
[Gai 'The ao-n oanKR -ai iRrrnoR Π) can have one or 0:· ra of ih-. RXRoYng Rxnnrrx
[052] For am le, n R k
[053] For exampX, n k 2,
[054] For exanapR, n R 0,
Figure imgf000021_0003
[056] For --.aaao · exeh of R; and P , rp i5m; e cp 0f
Figure imgf000021_0004
R; bakx hk-k.; aikyi or PR-ka Rkoxyk
O
Si
HrR HhF
[u57] For xampky x R
05 S i For oxampR. Y k
Figure imgf000021_0005
[0Ζ>] For e am le, Y Z
Figure imgf000022_0001
and Z is CRRpRs
1060] f or oxample, Z rs OR-, in winch IZ is Fyz; y, aryl (04;... phenyZ or 5 to ooimmbewd heteroaryl optionally substitut d with one or more ---QYiY
[0 1 j F r example, Z is CKiR?Rx m which RZ Z; -OR.3, and R¾ Is CZZZo aryl (e.g.. phen l) or s to ooncrnbewd hcreroaryl optionally xubsdhpod whb one or more -%··1 ;: arid ;; Z C;ZZ ask) I.
[062] r■■ e example, Y
| o:Zj ror exampZ, v
loon] For exampleZV
Figure imgf000022_0002
Z
[065] For example, a is C.
[066] For example.. Is or ChR, R. being Fl or ZYZ ή abkyL
[06/] For example, Z; ZCPx
[06Zi For example, YZ is YIY s .
[060 j For e ample, R;, Z hen aoRsbb ed with e or m e --0VV¾.
jOp: For example, s-" Is 5 so h-membemd heteroaryl wmPdnltm ZZ h Paoatorns s leered Rom FY bp and S emu opbonallv sabxRmteh vZdi one or mo
Figure imgf000022_0003
provided that the hewroeryl Z no; nZophenyh
[R 7b| For exarnple, IZ, la pyrkZm.1, pyraxbyr pyrmbaZiyb or Rnyh each of which s oprlowZiy suFsbmted with one or more Ύ.ρ--Τχ
[OxR For example, p., is phenyl or Z- or Pooernbered heieroaryl aubsb emd with OZ.b.,. albyl or bORY;.,. nlkyb each oiZvhlah is optlo b y wdxsbpged ¾hh hydwxyh ORb■ > iOk l or NrZhho aikyk e;ab eb be 0-·€ .·..-; bkyd and ΝΗ·-<7;.¾ abkyd he ba opuoar hy bnbeor snbstbiRed with - Yi aikyi or N kikx aRyb
| 73j For exampka R!; ia
Figure imgf000023_0001
[074] For e ample. p,; p¾ edsynyk
[075] For e i!-fispk, R^ edpay I Nnbrkuaed -abb one or m re - .;-T:-, b> which Q. is a Food or r.';- : alkyi brrker and id k C -k alkyk Rk-.Ci; cyeloakkvk r 7 n> 7onend>ered
hckrooyckndby; (soy.. aeebdbiyb oaetanvl dhebiny pyfobkdbyYk nnkiaaobdbwk pyrarohdinyk oxaaohdbpk
Figure imgf000023_0002
pipemkrryk k2,7,b- a;rrahydropy; idisyk pspera/onyb reR'ahydorYkkpyr nyk 3.bobbydro.-2Fbf5yra;iyF sea-ahydro- dkf-fhsOpysaoyk kd-oiaaepanyk i Yaeeaaepanyb 2<oar o:oobkyeioj2y2d]hepkniyk 3,5- draanbkyek[22k Ϊ Jhq?† s L and meapbohnyk and ike hkei opiksnaby robabkued wkh one or m e -Rk-kk.
Figure imgf000023_0003
[077'j For axampk, R& is haJo Peso, fioonac, oiborke, hsonnoe, and iodaxO.
[07k] For xasnpk:, R.(> k Ck-kk a ik I rnbeboaed wsih one or more -kF-Tk.
[0?p] Fi.>r eaarop!ey R,, o (k-kk ak-oo ! or C.i-C' ;- eyckrkky; each opuonaby nbrbnped rsbb one or more ay ·· I .
pspOj F r eaarnpk R, a. kbO)Jl
kkkj For s-aanpk, R0 a> OR;. r - poa
08 ! For exaoipk, K£ k f3r k aky; or 4 jo ?~memben;d hearaecycbadky; (e.g., ioeddnyyk o-oaoay dbvaarok pyrroHdkyh aa ia.odsdbpF pyraaohrhayk oaeaoabny naoaraobday neaakkhnyk anrahyrohaaeryk niperkknyk
Figure imgf000023_0004
ppjeraainy k terrahydoo OFFpyr nyF kkaJbpakckFkpyr nyF rid naaphobnyk and dee bkel, aba* iv opdonaby abrikiaau odd; one or more -Rk 'iy
[Oar] For exanpke, R,: k ~mj<*. adRkb k Olnkak ,, -C(0}Ni¾aRh, -YRkkOpY kkeaR* or ·· '(7):[ R Jk..
[087] For example, eaeh of R:, and ¾■„ asdepoadoariy k H o Fy ay.: ¾k ¾ opRxnaik rabakuned abb -or; or aoje ~0.;-'i;:.
kikaj For eaamaay one of" .Rk aad R>: a> H. ORkb F r exansple, Fc, and Re. xgetber with bsc N ;oe'! t w ic bwy r attached, Ros-o 34 to donenhxwed heywooyckxdkyl rn¾g a in 0 or i addldonal deeroaoni to the N atom i ,g :. axedddvy , pyrroPdinyb nnldaxolblhTyh pyoiaykmyv!. oxaacakhnvb k xexoPdlnyh οϊηχοΐκηην! tcrtalvyiotanoevb pspendinyh kdkxb-oensdtydropyndlnvk piporaxbnh and nnsrphobnyh and Ihe like? and dw ring Is optlonady substbored with one or more
-Cd-T'o
[087] hor example. R„ is 4 ?o ?onemhered beieroeyeloalkyl (e.g., axetkhnyh oxelnnyk tbseiaayl pyrrohdinyh inudaxolidntyb :y ::.odlbno b••-,.0 nb:w i . j o sdm j. naaxelk!lnyb teindtyrobnsooyk plperkiknh F2.3a>Retrahydrraprnhnyh piperazinyb lcospg do - d Hy-saa; i. .o6obhydfo..2tkp} ranyh and owrphobnyb and die hkes opbonaby Ms stltuted wnh one os more
-Q,-h.
[088] For ex ro !Cj R.s k ngan idao L .: ,:.oa>o:.n -weda kyyx win- b i.o.d'-..
letralpohwpyTKiiny I.2,2,by ieu;;anediyb I .2w .o^etrabydropyodnwh piperaxinyh nuapholnyyb letrabydro-eH-pyranyi. iod^dbydro-Ol b-pyranyb or yrr lidb seL each of hich · · optionally snhstbuted with one or snore -k).rT>
bdbdj For example, hk >e d to '"wnembered betefoeyx loalkys opbonaby sobathukoi o dd one ca¬ n-sore -R> 2k. and wpww is oxo or v is a bond and k is --OR,, -bbbklkj, -P o -do.
--CkiyakFk, " (0);;iL. Cs-C'o aOwk or 4 na /ooe bered Ixderoeyelo lkyL e c of winch is optionaby sabstbamd with one os wow -••i¾--1k when R, or l<; is not H.
ido j F example. '■ y-■ I . k oxo.
op ! ] Fw exaoiplw Os is a bond.
[092] For example.0 is aa onsubsbtuted od -C'¾ alkyi linker.
[9931 For xam le, Ik o w x . alkyi so (kekoo yyh ·. x!i opbonaby substbnted wnh 0a or mow - ο--Γο
[Odd] For example. 'd Is an umtmabmted subsbuHed snaigtu chain Ce-k's or branched Cki-- ; albyg nwkshng bra nor bnbted kc meth k edwh w-propyb kpropyh n-bnryh s-bmvb i-brayb n--pentyl s- enny I and n-bexyk
[09kj Iwn example, lb Is phenyl.
[Odd] P r example, Tx habs dsyo thiorbxy ehloraie, brondne. and a bnck
[097 For example. Tj Is 4 lo dotatrnbered hcterocycioalkyi le.g.. axebdiny oxetaoyk
Ihb'xanyb pyrrohdinyk !addaeoildlnyk nyraeolldsnyb oxaxolldinyb•soxaxolidlrpl. psaxolidlnyb iCtra yronasnyb plperkboy b 1 ,2yod enabydroi>yaldhpd, piporaxlnyb Kitrtd¾ dr »2il- 'i"¾n L
3,P--d!hybro..2bkpyranyh and asorpladnoyb and das like) opooaally substituted bhon or nnarc
-ky¾"l' . [oORi For example, 4|> Is -OR,, NR,R RxObt. ROiRR , or ogOoR,, iOOOj F example. T> is -iN , ¾¾· 'Λ". dd(0.) RjR-, RsbRgkbORb , -nRR.;C(0)OR .
--bpgRNRRR
[05 0 For example.. Q is a bond or methyl linker and I- is B. halo., ReQ, GdbikR.
R^R R,40 FOR or .•SR )2 diR!.
[0101 ) For example. Rc is (FOR. alky ! or to '/onembereR kebxxogoFmlkg I Rag., axedd!rgt oxeeumk dbeoangl, pgrnbkbnyk irmdaxsbidlnyk pyraxondbr k oxaxobbieyb kx;xn,a.b!dirrvk trbxokdngt ieiroh Fsr ovi. pipemkeyF RRRRmtrakgxRopyridiny k i es iohek Rtralgxdnx- blF-pyranyl, RRxbt xlroOFRpyranyk and morplmlinyk ami the like), v-.'hich is opRonaiR sobsiinRed uh on or more ---OvOb,
o i02J F example, eaeh o R,. and R,;, independently e Id or Cb -G, aikyi optionally enbsubged O'irh one or mo e ---Qo!b
[01 O bi Oof example. R, -s B
[0 04] For example, R~ is i x
[ 105] For example, R, and R-, Rgether wh the N atom to which they are ar?.aohed, form a 4 m b-rnernbemd heteroeydoalFyi mgg kaeing 0 or addniooai hemroamms x U¾ R aesm (e.g., axeud k pyrrobdhe I. imidaxobdioyk pgraxolidinyk oxaxoiklinyk Roxaxohdirg k irx;XolldmyF na ahyvoRnrtn k pipoadl xl. F.R;xm-;oBr R-yynd a;- i. pg-emxlnyk arid nmrpholnn!. and b¾ like) ami dor ring is optiona!R snbsbRaed vRtb mm or more
-~Q.- T:-
|0]οο| For example, F½ a Food ami T~ R -OR.,, FNRJR, -FROgR. mbbtyOR,, RbOMQ. R;RR aikyi, or 4 to iR.x;-:xr o Roe roeyek. -alky!, eaU; oRRoeh b opomsbb aabstRuRd rvkh one or more -Oo m vvhe.n x' o; IF; R n B.
[01071 For exampie.-~Q ~T; R oxo.
[OiOSi For example, *i - Is 4 t m-oembered hetcroeyoloalkyl or FR-iR eyeloaikyi and one os mor-e --Q--R , .ne oxo.
[ 100] For example, Q- Is a Roe! or ombatRoRd or srOsbtuRx! FR-R-b alky ! linker.
[0110] For example T; ss Ik Rd ·.4 m '/-itiemb md iKgerocyeRxdky 1, CbRR aRyb OR<:, ROOIR,- m; 0 i .- - H ; or -C(0)M ,R {.
[01 i!) For example, ooe ofRmusd R, R H.
[P 11 x| For cxaospR. tg; R a bond ο·- gg-R- alky! linker arid Ik n: seRrXvd Rom the grmg> eon- -dng ot Cb~(b xR;; k halo, FRR, -SRRhaR, RsRbR n RFbORRFR,
Ι0Π a] For example, R, i [F
pi] |4i For ex. ample, b is H.
Figure imgf000026_0001
P T/US2015/037715
|Ό i ? For example, ? Ck-Ck osxioalkyi•■puonady sobsubPvd bk one or aas'a
-ox-Ty
[ 1 ISi For exampio, R~ Is 4 to 7--aiovra>ered beisas}oyokxok i ρο.ρ.., axotKiirsyF o>xoaiyyk v.hscooyL pyrfobdinyk iobdaxoisdisi y pyraxolabiryk vxaxobdsoyk iaoxaxobda-yk Oiaxokdopyt ¾ rahyro!kraoyL pip¾ndmyk
Figure imgf000027_0001
piparaxsayb PXrahydroRkkpyraayL. 3,6-dihydr -2F.l-pyran>-L aad aKxpholhyyL aad dra like) optionally sud dtuiod bk ono or sooro
-i.):;-'I7.
[0510 Γ· -r example. R? is oycRpoaoyL
[0120] For exaropie, R-? i Ropropyi or yoo-baryi.
(01211 F r m le, R is 5 to ί -η ο'Οχοχχί beicrocycbxdk l pt nall subsskuiey vvoh oae or
[ 1 2] Ida example, K is piperkimyl opOooaiiy substbaard th one tr · k
Figure imgf000027_0002
(01231 F ;r example, R- is ieirahydrop) ran
[0124 I or es oipie. Uy is
Figure imgf000027_0003
[0125; Fos exarapR, R? is
pkdoi s ka' example, R ?s
[012/i Fm example. R;< a
Figure imgf000027_0004
For roo
[0 29] For ?Aa erein R::-, F phenyl 5 · or o.-i-nembero
Figure imgf000028_0001
- ch opdorudH' s,u sii†uk'd with · ;:o or m re < ; hs vvhkh each IF. F ;ode erefendy (.VG, d opl or O-F'.p-Γ'.. &\k scrse-Fd^ C; aikoxy, ami R ;\ F H c-r yd-C.: rdkyl.
HHyds for o siii k,
Figure imgf000028_0002
Figure imgf000028_0003
15037715
Figure imgf000029_0001
wherx each
1':;,; is iraJopeoderrdy kkk:3 aikoxyi orO-C --. ak;- a-aa ( ok a!koxy.
[0 His for exaropk. Fk is kk-Tb, kk is a ono and T< a 4 to -membered heierocycloaikyi or (k-kk cyoloaikk sabsbtuoad ¾bh■■····: or more -Q-r"i'j,
j 0 : 42] .for cxan ko. -Qj- Ik is
Figure imgf000029_0002
OCkkj For ovamok, i , Is rk haio, k k1: tdkyk kr-kk alkoxyb yykk oyckxdkyk€;-C1:
<dkyko ~C'k'x cyokadkyk G.;~Ck> aryk Ci■-(?., a ky korekk--C o aryk 4 ;·> dnnernbered beieroa.ckskkyk sk-Ck alkyleraod to 12-nnon;bered heierooycksPkyk 5- or -aand- d bekroarvb or : :··« ' rbk kaeO' or borremb xd hetoroaryk
idled] For esarnpk. kk e> a bond and Τ:· s kykk oikyk kk-kk cyeioalkyb or 4 s dovieiabered heieroeycksdkyk
bke:k Tor ex le, kk is a bond or N¾ and G i H, CrCk ak: k Ck-kb eyoloaikyk CKk ikydere C;-ky; cyckedkyk Ck-kb aryk krk^ aikykne<0k.y.; aryk 4 to kkrnoinbered heterocyeloaikyk i.b-k.-, a!kyknsr-d .- 12one>m>eied b i-orocyvioakyi, a- or ponombered hc- M' an I, Id -C¾ aikykaek- or dornonbered bokos-ay k am;no, m n -Cor , akyknone, ordo Cd"(k a?kykndre>, Τ·.: beiny opbouaby snkynared
Figure imgf000029_0003
one or :a ·ο· snkedk-eak sekcred Corn die group consisbns okbbo Ipdroxyk kb--C, alkoxyk O-Cb-kb akykne-ka-kk ;dko;<y and (k- ky svckaikyk
[013d] For example, % is bond or NEk aad Id Code aryk Cvkk akkykoekk-kki aryk or b'Ooensbood bekroaryk Crkb alkykne-k- or ooionsbos-d hekroarek amino, nHm>ik-€y aikykndno, dkCyik; aikylandray lb bcaog opborabiy sabkkakd
Figure imgf000029_0004
one or more anbstdnoars aekxaed f o so the group conaiabag of haky hydroxy!, k k6 abbeey 0 k(d alky Cne-kb -kk aikoxy, ara;; Ok- ., cyeks;dkyk
jOB7) i:ov oxampk, (y a.; CO aad Ik k kok, alkyk k kd eikoayk (k-Cs oyekabkyk rkkk aikv ro-oyy.y s skeakk- kk- y ark. C.b-C, aJkyk?nc k-k aryk b a ?ooe ;bsa¾d hoao'ocycioa;k)4, k 'k - rdkvkaaa-4 to ^nnsmborad irorar<oy, cbodkyk 5- or d-noanbaied !ok ai >d5 (.d- k aiky ieae-5-- or -neisb-v od ia;ioroaryi
10 ί 3 ¾ 1 For exarnpk, k k'r-ky. aity l oprisaadk siibatid.iioy ss b iraso. hy foxyk a}¾asr rk-kk iksiSyd.. idkkskd; a!kykmakdo k aikoxy, anairay mono-C 'o akykobn di-Ck-kk ¾kyk:ardao, or C¾"i.k cvckxdkyk PR ad] F r ex m l kk 'R RrR-o skyi isnk^r aarl R k. H or RxkR; aryb
140} For exaropie. <¾ a; kdRld a!k bake; and bd R C.y-dy oyoRebkyk ; d-d alkyRik-Rdo.:. e yeioaikyk C CR) as gk CVkk alkylerreRRRkx. eryk a u> dxneoRered bearxoeyoloaikyk Cd-Cy aikyieae-a aa aeneoibereb heRroeyoloalkyk 5- or 6o"oerokered hel fo ;yi or ! : d , alkylepe-S- or 6~memhere kxeroaryk T.: keeiy optionally sakahuaed oalh ana or more eahshKserrsx selected Rop* the yaoup coaskdng of hakx hydroxy! ib-Ck aikoxyk O-kbRk alkykafcRdrRb aikoxy, aad Cd-Rd eycR lkyk
iOidi] For example, eaeh yfR; aad R.;. avlepeadeudy. is H. halo, oi kb-kk -die- i opkonaHy eobsonaed *vHf« aakeo. axafo, hale, noaa R oR- akkykaykao, dRky-!x alk l&mino, oy kR4 a,, a h
bk -; i For exaroake. eaeh of R.; ad R.;, IpoepeademR Is ka b, aRyl o skxiaU aabsiaafed vskhky dR, aikoxyt
[ 143] Far example, each οΠ½ and Id; is methyl.
[0144] Fa; example, each - a k . aad !R, aafepcadcoky la halo, e.g.. P, Ck or Bsx
[ORlRl Far example,, aaeh of R;. aad k .. kidepeadeally, a; ON, orso4b ky, alkyieokra:-, m dk kd-k' ;; aikySarmao.
{0146} Far example, eaeh idR aad i;. ndepen entl , k opdooaliy subsiktaed phenyl.
[014?] Far example, each of R; md 1 , sadeperabrdiy, R optionally aabstiuRd a- or a- meah.>ered heRroeryi (e.g.. pyrrolyk pymaolyh esRdaxolyk pyridyk pyrirmdmyk pyraxiayk pyrld xspyF leRrrxoiyi, oxaxokk Hxaaolyl, ikraxolyk iaothlaaoiyk aao the like).
[01481 For excaopkx aaeh of R - and Ri, iadepeadaatly, a- opiioaaky sohrglp ed 4 to 12- eodax'eb heRox; yeloelkyi (e.g., pyrrokdaiyh kokkoolkbnyi. pyraaokdkvyk oxaeoikHnyk eaxo¾xoikheyi; a-laxobdlayk ρφοοοΐον! kbdkdRoindyrd opvryp'oR plperaxleyk keR oiaeepaayk
Figure imgf000030_0001
and aKephokoyk ami she lifer
[01491 For exaaa.da, e¾ch oi PR and R;, iadepeodenky, R y..-, alkoxyi or Ck-Csr, ,.p-yloxy.. each opkoaaliy robskhaud odd'! ooe or more halo.
[01 Std R ..·· exaayole, R;? is€.·..-.. alkoxyi or ab.-0.d.j aryioxy, eask opkoaaka sakspiped vvdh oao or aa.aa halo.
{01511 For ex rople, R4 is halo, or a ; . aikyl or k" alkoxyi. aacri opboaaily sabRloaed vvi(h vsne or roore halo.
[01 a2f kor axanip ., .; la lb halo, or CM oik · k
[01 ?3] For axaospR. R, !a Fk
Figure imgf000031_0001
ssouidsd b;d i>/si;) k kcs oi s l beaxvX rvb k(ys;w[bjd¾>emk baazoaaaobyb b tauhkmki benzbnba cayb bers s¾ u;i H-l, bca7ouKbaaobyk b n iXhsadi sd)!, pminyk s«da.a>iyl pyn'ob <py; kuayl b¾kka¾pyndb:yb pyraaokyyvrbun b pyrr bpyrabrpk aibd x pyr aaiyb py r ^ yr xmyb pyaro pyi snnkin b yr / lo nfibdaayb ; ^x ynd b b
mwbaopaaadazbyb pyra¾dopyrbab?syb :U:;yy:i v1 bpe pyrkimyk ka y aasml ibba pyrazkyb. xaa bpyrklkiyl, i>>¾ bpyrbbyb bbax bpvndkpd, aobk zok^yndkyvb vxadu bopvrkbayb dbadaai bpyfkbayb bxadupyrbbyb
Figure imgf000031_0002
iso / iopvi a5)k b'bazaaopyraxa l
Figure imgf000031_0003
dikada.t:¾k5pyra:dnyk†na:ao p razi yb
Figure imgf000031_0004
bke opymrbdinyb fur<.?pys baa yb dssafe rsd zan L. oa zokyyrbaKHny ; ---a - - ;aaiaay i Udazb pyrb dmy b
kaxbteobpyrbnklbyb ax dKsxabopynnbdkp b ibi bai¾k¾yrmbdu5yb
Figure imgf000031_0005
Figure imgf000031_0006
bl a kxpTb aaiy arb bvauaxbnaxmyi.
Figure imgf000031_0007
Figure imgf000032_0001
Figure imgf000033_0001
U
θΟόΧθΟ X iS OR; oi" CBiOR:;.
: 0 j 'The eoinpoundr or PonrmOe 0 , in addition to the hopores described lor Formula (ip vxhefi appheahla, n further ha e one or more rrf the voHoHisg textures:
[0161] !···· exenpbe, Z is OR.?, i ohkh Rd is G,--€:!; aryl or ? to -membered heieroray! optionally eobsbUnsu nb one or more -(O-Te
pR .b For oxaaaple, ;? is phenyl optionally
Figure imgf000033_0002
wish oee or sn re O . e.g., henyl xubsii xed odd one or more grou s selected iron? halo. C Q.aik b Old., oyaao, (d-C:;
oyehodkyb i" O; aryh 4 t /--menibered heierocyeioalkyl ke.g.; axendmxk ox Uin L IhleesreO pyrrolidine b iml a^ohdin L pvraeobdtnyP ose.oasldinvb isoxuxrbkRred, hinxohPinyb mtmiryroh-urmvl, prperkhnyh
Figure imgf000033_0003
plpera/myh teiralpOr -2Fbp ranyh 3y l hyd "2l-" ras) l. ParahydroOFbyhiopyraoyb 1 OOhe-. pa:p. I Ra-oxn epanyF 2-o &~ sxabicyokCOO I jhepkxrp I. :y. o:hnoabieyclo 2.2bb;hepy iy1.. and n .apholinyb and the like), or > re1 b-merobered het.es oar S (e.g., pynxdyh pyiaxdyb irnldaxolyh pyridyb pynrnidim b pyraxinyi.
iaxoRh isothlaxrPyF and Use hkep
Figure imgf000033_0004
[bibs] p v eseamxle. Z i CHR;bO; in mhkh 10 is -OR,; and 10 Is (>C,o and o 5 as b- toenb aed hate* a ) b optionally sabstnuted eotb one or more -CO-'d, ami lO i tO-bk akyb
[ 1 0 F r exam le, lb. is p e optionally sorebknieb odds one or more -ax.. O
[007] For example, , is phen i. Ό O
sORo^j Por ·,:·> a; rpd e, 4. u;
[0 69] For exam l .1 is halo, .g., C CL or Br,
[0170] For esspople, 1½ is B or noahyk
[0171] For esanypie. IC is t : y ' : alLv; opdorra!iy sub-Pauied ad F0dd; aikoxyk
[0172] For ex m k 1C is .oetbyk
[0 i 73] For ooio !c. R- is haby cop, C CL or Br,
[ 174] For example, RO- is CM, FRF, moi sdJrFd aikyksmirso, or di-Cj-Cy. aikylanorso.
0FF For es.a ple, R:; is <7 s aikoxyl or Fddj;M aryCxy, e ch opuorrady subRiOaCd r bh orro or aosro baie.
[OF761 For ·. - rearae.0 a. CO -CO alky! roOionaiiy subr-uoded -oOh CC4 , slboxyk
[OF?;] For o oiple, iC d meihv.L
[0l 7?i[ For esrample„ RO is halo, e,g., 10 CL or Br.
[0F?0] For cxsrople, R.; C CN, ¾. rnoao yC0 akylarrdno, or dCkO-Fd albylaroino.
10180) F- r osi'iropio. R,., C F0.:. alkooyi or C,-40o ¾C Cxo. oaeh optionally -adxrdodod wnh ooe or Oi o haio.
[Oidl] Fo expo lo. IC a; Fk
iO 182] For e op4e; the coropoonds of Fonmda (ij include those of Form la Co):
H
Figure imgf000034_0001
X'
pI2r
orhoresr; 0« is -0>:;-".Γ.,, edoo'eki Co C a 0o;;d or F0R0> aiks I bober. and Ί is OV-dd aCyi oprioaaOy subsdOHod vbh ooe or more ~<iv-ld, C C„ cycioalkyi opdorodly suPsOruted won one or more "-QCT0; or 4- ro i4.-naerrd oed hoierocycloalkyl opdoaaily sub biuted odd; ooe or sane
[01 PC [ For esxarpde. the ·. aapmia ef Poroius¾ C iookate Ihose of FooraOa { lap
Figure imgf000035_0001
heeas R? is -<).ν·Ί ;.. wherein Rk is a bond or rraohyl bobeo and Ig. ;·· CVCk albyl rapkooally snbauOited wkh on or more go- 4 . Cokk cycloadkyl optionally subsnRUed wstb one oi o;ore - Q -To os 4- i.o
Figure imgf000035_0002
heteRKyckodhyi optionally sobsrhuieb wkh one r more -yk-ld. lOIKbjj The eoospoeHds of Formulae (125.. and (Op In klui sj 1 do- 'oRnxw described for bornubn RK when applicable, n Rather have one or nwce of the f ll in fcuur s;
fuidki For example. when the compound is of Rornuda 12}, R^, is H.
RR hh j bor exam le, when th cooipornsd is of F rm is la Ray R¾ k ika-Cas aryi or 5- or 6- iooo'sbered heteroaryh ea h oldvklcb k opborukly, mdependesiby sobsRmRcl c ah 000 or more - RR- R, w harem Qs is a bond or C Ck alkyl Inker, and Tg is l b haky cyano. -OR0, RRfklk;, - k(kR VR. VRysRVR,. -SR)RR, VRRRNRRV -,r R.:; in -which each oi R, and b , inrlependenhy is H or R¾ :, eacb oilko and Re-- usdopondonby, is CVCk alkyl, or Ik aod IV togemer wkb the N atom to which they are attached, form 4 m 7orre;nberod heteroeycloaikyl ring having 0 or 1 addioon ! heteroarony and each o R o IRo and rbe -1 to dwnembereb heierocxs Rad R ring Vrmed by k and Iks Is epoonaky. akk endeuk aebxdtolV with one m oo,; yf R . wher in kk la a kond or RiRR albyl linker arai V k selected iVooi rho grou consisting i Id, halo. Rs-CtJ aipvb 4 io donembesed heterocxeloalkyb CRR, VRd'RlV and■- RlkdV each of Rs and Rr independently being 14 or CKk albyl optionally eubstknted svn OH.: i i~€k alky k or TdHV V lkyh s-r -Rp-Rk k oao; or any two nelgidwo'iog -V V together wkb the aiovns so oloch they aw aRaehecl tkrro a 5·· or boraambered ring optionally containing R 4 hcRroerosns selected f roro bd. () and R
101 b? I Fm example, when de coraponnd la obbormu!a R ). RC; is phenyl or pyridyb Q- Is a kond os' methyl linker, and R Is ik halo. okIR, - ltjka or -SiOfsNk.- i.
(01 da] F r oaanHiw X:i ss RR,, X, k k. V ; and Y:; are each add.
[0140] For eaarnple, id Is teirabsdsxaw raayb pipe; Idnse ;S;l>akorred by I ..2, or 3 by .pa -;p ; grraips. or cyebbiesei aabsdrnred bv NR. a dd.: alkyhp sbarein ne or bolh of Use (d-t alkyi ;s snbskruRd wi?h k-kk. alk o-yl U 2015/037715
[0 i 'Hi] Fo cxarapax Id sa all; yi asvh as ops op> L
[op.!] i !¾· exaropFo 'Fs is
p'Hoy p...·· sx aspl . "Id. is
Figure imgf000036_0001
whi h R'" is Id. ~d d) 'T' ;, >· xaCFoio I haiag s daiaxrd laa ia ka !karaiaa 0).
[OsVal d : eaampdp oOaa u;e compound is oi Ps aah cOd ; · a; Oaa hydropyraayl aod dp is a so igra or iaaoahcd dd-dd alky' F de .
1*0194] For exampk. whoa the m un s of F nrada 0.2 p V is;
Figure imgf000036_0002
[019?] For exaaspk. ? aec-buiyi yci pa F or isop>ropyd
ppyp] p,;r exan5 iC; hos rho compound is ofForraqia F s, Y is
Figure imgf000036_0003
0F I For■ . aad-.. ihs aoaa a Kk of Forroaia (\) ioaixaia Pio-a; of ormula 00p;
Figure imgf000036_0004
or a pharmaceutically aecepbibb salt ihereoR aherein
b b p or 2;
R.:"s s bXX or N:
R""!'" b bXXX aikyk plpeobine sofonUned by b, 2, or 3 R'1''' gr u s, r eychsbexyl sabsiaaied by Τ (Κ?'":Χ therein each '";' is btdapandentiy€;...; al yt aba is ophonally subsnuaed with in a!koayl. pi) 4 t ; .y !o-.sabc--.b hercroeyc!oa!kyk Uii) CX-CX; aryl that is optionally tginher substituted o hh Q-Q, aikoxyl or OXX--bb akby secXyX.; a!koxy, sa uvs a- or Cj rn .mbi-.re beteroary! Una b op onaliy bather subsdtuted eehh CX-bb aikoxyl or O-b Cb aikykxaobs-bg alkoxy;
'"1'' o niorpholiae,. piperuXee, pipendine, diaoepane, pynsdhbee, azebbbnx C X..-, a!kyk bFbb;..;, albvb or fy-he;eros ycle. aiaoosa th beierooyob is a 4-7 eiernbered hener cycb containing n sesygen or nitrogen, or both, aad here the nitrogen tar; optionally bo sabyaatod with abyb ahkaein be piperaaine. piperhhne. gaaaspaaa, pynohdine co asebdbie groups can be optionally bather substituted oath Obi. gb.,; aikyk or Ο-G;.·-. aikyk aad o hcix in each or the O ag ; ... utkyl and N}-i-b; Λ ahoy; is optionally aabsb-ated o ah hydroxys O- Cs.■ aibyi or H-C-... aibyb ach of she ΟΧχ.;> bkyl and . I-RCho - tkyd bXny optionally Rather Mibsoaged oirb Ο-CX· iggyl obNH-bs.., abyb aad
each of Xb, X , X.;. Y;i Y.i, X and is s as d-Paa ·; herein tor IXaniob X),
I'd i ggj in addba : to the 3bove--deaerbxd batsnes of the- compounds obtins irsventioip ¾ hero apphoahb, the contpoinab of rmula (Hh} caa board one or nsore of the tohovbag Ratures.
1 For esunsp , 1X:" is C(llg and R is pipernhne: dbaepane; pvn'obdirse: aaoddiae; ( tX.:, abyb or knheienscrcle. wherein the heterocveb is · XX nu be ed heterocyole csaiiahnng aa orcgen or nhrogeve or th, aad v* herei the nlbxgen ran opdonaliy bo sabaauna.; arith C¾.-.. alhyh wherein the piperiduna dlaaepaae, pyrrolhllee or azetibave gtonps ran be opdonahy further substituted hh OH, IX :;> abyg or O-C.ho aikyk
|¾2bP'i For example, R is (;(b! asai R";'" ts
Figure imgf000037_0001
diarop iar, pyo'ohdiae, azeiuhno or O- C it .Iky b oXeieir ha pspebdiee. diaaopaao, pyrr^hdina rs' aaatidiao groups ran be optionally balXe;' iabroikaaal ba CRI orbb.,-, aikyk
bibbs] For exaatpio, R is Cabb, R"'"'; is piporazirie rgstionaliy farther substituted ¾kh aikyk and R'""'' is pipaiiraas uSNObaad by b 2, or a FX.; idbyl grotaos
[0x02] F f exarapka R.'A!! is X, aad Ru:' is ri - hiahrvtg plporidiito, psporaalria. dbaepane, pyrroh-bae. asatidiiH: Odts.,. ab b vdaaaa? ibe p -os idaio, piparaaino, tbaaepaac. οοϋοίηο rs axediXao gr ps caa bo optionally bather sub tituted vvah Oil or (i..,. aikyk
[OdpSj ; · - a.:oaaplo R :CJ C-X't, alb l ;ax:h aa soe-boiyl > i--pivgvX
26 10204] Forfcxsiiip!
102051 l: r an-ip , 'J:" is
Figure imgf000038_0001
--2- or u
10206] For exampFo "'"'"
0)207] For ox sis ko R * s 0208] For exam k, P
0)209] For example.. R ¾
0)2101 For exam le, R;';
Figure imgf000038_0002
Figure imgf000039_0001
Figure imgf000039_0002
(0252] For exaospk, when R""'! k 0(.H>, M~";' is prpenrhoe s dsaxeparie. which are subsboped wuh OH or RF.:> aRyk or when R w N, R ,: k piperibRe, piperaexxx or diaxcpaw, which rc opoonaby ranker substuoted with OH or C;.¾ aikyF
[0213] For example, whe R'V'! is€(.Hk R'"''" is pipendkw sRxaikned wkh Ci.:; aJFyF or wh n R"'! is N, RA:' ss piperklme sahaktrked wkh 1 a ; <«· piperasdro- sabskmted wivh FFo adkyh ¾ 2I ] For example, veheu R"';! i No R'"'"'' k unsubsikuicd piperaxaax
OR 1 ] For xam l , re. i 0 or 1.
[02 RFi For exampk. when R':"; is RRR o FF Ri:' is 0-ί?;.ξ: sikyl or oMwterooycie, raid W: w 1.
[0217] For example, hen R ;,; is k(FR, k"'": is rawobshuned piperaajae and R is pipekekne aobskhacd by R 2. or 2 C;.,; alkyl proapa,
Fwk.i For exampks R -' is (RR;io sdhyi salwObned vrnh F 2,2 a!kyk e.g., -; !r R d ; · =r R .
[0219] For example, n is R or 2.
[0220! For exampk, she co Foramki (Ik:):
Figure imgf000040_0001
(OS;
o pharoWiceoO ah acceptable salt thereoF:
vRxxeh;
su is 0, i or 2:
R;"v¾ is C.F ·-€.-.. aikyk piperidme sohNpp i by k 2. or 3 R'""': groups, or cyc hcxyl aubsOtraed by Fk "'' 'R o herein cock R """ is xxlepera-kakk Fa..; aiFy! thai R optionally sobskk eb with (R C-. ak ayF Rk 4 to kknwxnbered heterocycRaRyi, (hk koRFo ra ! Ron is s-p oaxdiy Ric er sekxmaed wkh CV€> alkoxyi or D-CRRR askyieoeRFRFi aikrwy, or km 5·· or oxexmbewd bereroaryi pwt is opkxnaky tboher ar-baokued wok k kx alkoxyi or - h-kF alky ieoeRFRR aikoxy:
R""'; is rnorpholaao ppxxkhoe. ipcraakax pyrrolidine, diaaepana, oaetme, axe ukoe or 0i- RFoa. alkvF wherew the pipekdhxe, doixepane,■ wetaree or axeddnw aronps can F, ; opkowah Rather sabsviwaed wkh one ot more FRf alkyi, Ch.,-. baloaik R, R,;. e eiordicyF os 4 io ΰ- rieokw ed he eKxyaioalFyl: aod each of X^, Χί. X,;, XX Υ . X and a X as XXao b herein fi-r ForrsHO (J K
[0221 j in aebbik'n io the b ^e--de¾nbcJ kamae of rho -orapoanoX oi Una uo-oabora oXera appbaabk. OK coni oanX■■Π πηοΧ lib;.} can mcku.fe -oao o aa.ac of T kXkoXaa .K3.US.K-;·. j0222] For axampX, R"'" Χ;·Χ·Χ aFXyi ova ¾ i --propyl.
{0223} Forcs.a.n5pFo f1'"
tO):>
102241 For aaipk: s
0225] For eoarapie, Ri: '
a:2-X For oa^i ko R°¾
[022? j For OAaar Xr 0
pX.oX For ea apXo FX¾
[0 2'X For exarnpkr R'A
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000042_0002
37715
[ 23 ] bor example, ΙΓ' is piperidnse simsm ied whh i C oy lopropyk r}vRbuRk or 'oaRsne,
[0233] Γ··; essrnpks ¾, k 0 [.
j0233] The conipranaR ok das invenboo cRo aKJade dasse of Formula ika) or ΐ" LI b_> bel w or pharnuHacahcaHy accepasbR salt thereof.
Figure imgf000043_0001
RRb,
Figure imgf000043_0002
IR is II or R.s, in which Ik- is C- R aikyk OYCo. alkeoy; CRRs6 ,0:..· a; !.€ €*
C CK adk- aryb 4 to i 2~n¾osbe.¾d hc;:oroeydn;Rkyk or 5- or
Figure imgf000043_0003
hereroaryl and R¾ i opuonalR subcsdotod whh ore; o>- mee ubxnuen selected fror the group ssiGUOg of fade hydroxyh oxo. RR3h aR. C(OV < _; (a alk P eyano, CoRR- aRy R R. aikoxyk nmbny mono oRs lkykanhuy dkfRw y. alkyRn'ono. ifo f eyehxaikyk (' :Λ':; nryh I a> kkmerabenof hererocyoRaiky; and 3-- or 0ona;n.hered heiensnryk
each oRR ;., [R, and IR. [odepaadofhiy, is RR-Ts In aRns> FR R a bond o R k alkyi bnRvr optionally sebsihxaed w h bans, cy oo, hwdroxyl or CRR.R alkoxy, and 33 R H, bsdo. hydroxy;.0(0)OR, c smo, aaldo, or Ro, In which [ o is l 3 s ■. akkyh C■.-(; ', ; alkenyk 2-,-i.R alkynyk R ka aRswyb Fa RR ihkadkyh C(0)0-CVC> alkvh CONH, SRyRFk. RsOydsRRfRR: alkylR RROprRk3RR «Ryko ~FFo- FhR;R2; aRyR ·· Sbh-RO'Ryo ; . alky!p, FRRR cxioaRyk C3,» :» ;yk kR-CRc cry bay, amino, rmn H A2; aik> Rnsmn, ul-P2-p!i; RkyRnnno.4 ro ; 2- orevoha.od koR oovaioaik) k or 5- or boTsomberod hetoroaryk and It;; s oprbsnaby sabsbtuZd ovkh or isof!- aub-okuenio seRo vd boa a the groop coDsoaos of halo, h !, oao, θΖΟΖΖΙ oaoZo .-ay Zoyk oyano ό;;-0Ζ alby Ra Z aikoaryk annno, sv ao>ZVj b ■Zk; 0: oo, ,ko ; ·> . aZ ianRrKo Cb-C,- oyckodkyk .Z > aryk 4 to kbooeoiborod
het roeyUoaikyl, and 5· or oooeo-borod he;sooa;yk
Z; oN or CRy ,
.¾ is N or CRy , pr ided baa vvh n Z; Z N. Z; ;·.; .
R : is {CHdZaikyk Z ;;oZ.),dbooyl (C iZZiaikyoyk ansokatauted or RR-, C¾)cyoioaikyk oosubafuuted or ubstiuted (C ;.sic ! oikyi-Z -Zb5aik 1 or C Cbodk o k roAsaJrobbood or sabataured
Figure imgf000044_0001
··>.■·.■··.··'■■- Zuoa or aob iibaod ZZ- C;i}o> ikoo>d--zb'ZZyZk or Z€;;--Cs)aikooyb anaubstbaied or subsb oZd (CV
bZZi'Z ckftdl-oZ aosobziiotod or substitu d hZarovyoksRkyl or o dRdken b rasoRssbkrad or aaZ-ubaed hoo:roo ci aik 1o(Z-'C;;,s;;dk>Z uasahsbRRad or audahoted aryi, un obzbmod or sabsRoRed ary h-ZX ,CZaR.y1 or ZCZaZoubenyk unsubsbuaed or Mibsrkusd heteroaryh unsubsbtated r aubsdnacd iaZeroarvb(CrCxabkyl or okbZbZaikeayk -COR" .. ZZa-aR' , - CO R" R!'Z ZX)NR- R! R-':
" k; hybrogoa. RdZZalkyk ablaoroaokhyi aikoay, or halo, n ocb ¾:.bd ·ΧΖ· (Zabkyi is optiombiy sobsonsiod with oao to wo grou s sdeouad bora rardoo and (Cr
C Z bo k 'uhK;
R' o: hybosgoa, oZzZabkyk or alkoxy,
"; ;s hydrogen, i€ Cddkyb cyaoo, Znu r oK h k -N ;i Z ; or had;
R' is waoaaad fViOO ibe group οοποίοοοο of hybrogoa, habo RZ-CbRdkyk (CdsZaikenyk {C;::z:Za:dkyny k uoaadsbioRd or arawhkst-d ZZzZZyakxbk k aas'ybsRhaed or sadRpited (Cr C.Zyc o:i-.5fZb yd-H tVd --y Z lk I, noaobsb-oa-d so odabu.Pud ikZZbZo} okxdkea) k oosubsoRnod or sabaoawad ZZzbduyckobgeoy aZC Zabky €;Abdhsc dodk k utrsabsidsbd or sdsshbzod bateroos cioaikyi ausubsbnaod or suhsthuaad ha†orrxoaboaik RiC;ZZ}aikyk oaaobadoaod or sabsouwed aryh rarsubskkaod or sudbtuhoi arydkZZ^odkyh aosubsboaad or sabsdua- boteroi-ryk uosdwdaRd o; subaouZad
Figure imgf000044_0002
oyaoo, -COR'' , ZXZR" s - ZONRs R;Z arONiZ NR" bb , ZZZ ,
■ZORZ -ZOZZR„S ½N1?3'R\ n!ir , ~NRB ΪΖΖ ZsRdy Q)Rd -NR!C(0) Pz R\
ZNR: CRRORd -NR:"! RuZR'' . -R R" daZoRdZZ NRZNR" RW -NR¾" s <ZOk< Z
-N !VKFRs'i:(0) s R;Z Zsty NR": ( CJlOil3', ZiR'b -OCiO)H'\ - C(Oi R-¾'Rf'';
iZ235] oZeraia aay (C; ZZjalloy iiZZZgdkoroyh iCr 'Zb}ak ;pa,
Figure imgf000044_0003
i;. oyoioaikoroi bioy b-idk b hck oyde ik l aryi, or hoioroaryi groap o' opooaaby sab-rbuavd by b i: or a yr-aips ;i;d pe;;d-i: h aekaiod ;rorn -he group ^ ^iss.mg of RRRxR2}a;kRRR ρ,χ ·,ο ... CkodkyaRa );-;> okRRkP kjbRR o'i.d .:K):dkyPhaier c ck:' kk i ;R R;ReyeksRkyR aoa;roeyakxdkyk baaa. RRoR aai · i Rki kipcyekabkyk ; -: V xpyo R.ea-
Figure imgf000045_0001
eyanra RX)R;R RRbdRR-. RO Ra R;'R -RRR -SOR", -SORR'. -SOyNRk R:2 r;kro. -NbRRR - Ri:C aRR\ ~NRa kdORRR R'R -'NR¥'C'iO}OR\ - Ha SORR.
RdRsSoRRbR Ro OK'R --O0(O)RSL,
Figure imgf000045_0002
hoRroorckad yk aryk heu-ro rvjL n HRe- ( adkyl and hcPiro fyKkk-R'Raiky .
arhaoaa: «ray ;R OJ hoicroary! moie oiRaid arR. hoRronry lRbRRkRk k or beo;a¾ary kRaRpaik l R opbonaby subRkoRd by R 2 or 3 groups bkkpaadoauR seRcPoej U: b<o group conakpag of hal , (Cb-RRybkyk {CYC Kryek dkvh RR K-ycbadseuyk (Co Cpkasoalkyk ayoao. -COR\ RkORRR -·οΟΝ ¾;'R oRR R OR'! . RRRRS\
-oO;: " R: ahro, RokR
Figure imgf000045_0003
yR'SORk'R .•N 'iR:kp; "'l R -OR\ - iOi sua:! Rk RNR5 R:R
a and IR are each uxRpeudendy hydrogen. kCRRkndkyk. RRR2>adk.eoyk CV
R'Rabkyayk R dRdkya alky k RRRak akeukenyl. RRR)R cy kxRkyk heuaav;cycba!kyk o I. or beuaroaryk whosa a said Rbo;sgdkyk Rk-bkj lkea!yk ( RdPdky ayk
Figure imgf000045_0004
Figure imgf000045_0005
bkyebabad aaPorocsaRoabyl .aryl or heieroaryi gro la opbonady subxuiuaxj by R 2 or 3 groups ir Rp odendy sekaUd Rom h d.;, kyJrvxyk ; R' ; -Rb) boxy, ankno. (C.Y RyaRkykaalfio, u rkdRdkyRP krRkkpRky nd , --CkRkk R.akR( R2p;:bkyk
•a;ONI k.;RX)kR k(RR;.pa!kyk RR VRRCRRkRabykRik Rk alkyb -S p(R- R;a!kyk bkpk kxYOyRiRRRk byk and O: RC 'R.Ri5 kyl}R'C Q}3iky
or Ra and R raker; Rygeher oka b;e rbRogeo So ·οό a b'sav are anaohod rapreaoR s 5-b nsembe ed saruraaol or uaaadaaPed rayg. opboradR comanbrg.; aa adcboonal laoeruausrn sclecRd Rom oxygen, rnbogco. and s l , herair; said ring R opkonaby sakabuned by R 2 or k yroopa aokpcadorpR sebsfcd Rosa
Figure imgf000045_0006
bRbbaRsdkyl, aoono. pyyoRsalkyRainoo. (RR-- R.oabybR dykkRkyka;Ybra, hydroxy k nxo, {€n k}3ik xy, and RabkRalkoxyRRRkgRkyk vrheaasa aid rap.; o opb;.sakb iaaed o> a kRR.bcycb;bkyk heioroeyabalksk aryk or keieroary rauy
or R:: aad ° Rken jop-her v,di.h d:¾ odrogea R>
Figure imgf000045_0007
(bay are adaehed raproaovp f>.6- s- i d- aea';ba'ed ra jped bieyalR riag ayasao a d io dy sa-ard t>.> a Rk^RaRyakxdkyk boRxocyaR)aH<yk aryk o beaaroarvl nmp
aaah Rv' i doiapeadafU RdrRyRb<yknrooo. - R'S i " -S« R¾' : -SOdRR
-NHR(dR)R')R:R R-RR , or ·< RRR;y and
a ia (k R 2, a, 4. ^o' 5. SrR roi*p Λ of Fos suoRs RR
[0236} ! is sdectcd iron? the gr up coaaisRsUg of ( rfRgdk k
Figure imgf000046_0001
aeaaroorcioaikyk aryk. sad heuooarvg
[0337] i: R hydrogr.so R.;R22ialkyk aaduoa.aorRhyk aR- -y . or ha o^. in ogieb said R 3- RRaikyi is opRooaOy srsfeuoned with ooe to w g ou oRoied R m a oao an !XV
Cd aikyiaosiriO;
[0333 ] R; is. hydr gea. R3rR3Rbkyk oiaikosoe
10239) K " is. :oi\ o-P from the group e^osiR sU; · a ky-u-■·.- . o. P. -R ouU-r k eyaoo.
trRRaoaaaethykR2Rs3R-R and halo:
[02301 R3 u< seiecied f m the group ooosRbag of bydrogorg alo, cyano, rnihauYaaah h arm' no.. o ^R/waRy;, g ;.RRKy R aR g. agyk heieroaryh soybamno; (R:M3?paRyoyk
aryiaikynyk boteroaryia!kym- k -SORRR•RO..NRa Ri:' aad -RRR SO;bs 3
whereio auy 0R Ry ja!kyi, (C.R3Rcyck.ssRyk (C CR&ikyuyk arvkbkymd. heaaroaryiaksynyi group R opdouaih sub-r.Rmied by k 2 or 3 groups irokpemkrHR sekosed Rom R0R23- ky0aikyhEi; R.::-? .-Sp rk.jaRy1(Ri; p.; okRoR RgkykRc u. , ok3 C2)aikyid>oo:aor:yci aikyi. R - kR}cy l ik>k)¾otev cyNioaik> k hag>. XsRRkwk 3-kk)cy i idk L R2 : RR)cycR?s1keuyL R2 Rkphaioaikyk cyano. a uiR. R3R,Rg RX)NR- R?; , -SEX RdOR
RR.RRR. RiRp - - uioy RdRa R''\ d ' (iioRvR -MR" ¾ RO)NR'' Ro RR" R^O)ORR ■•NRs3 >R!y - NR'¾0 ; R!R oRR:R R.K3(ORR\ -OCR.RNR" R'R hsasoorwcloa Ikyk aryk RRerr>aryi:. ary!RR o3kaRgy; and boioroaryky3R2;3aikyk
[02411 Ri! rid R'y are each imkgvodeoby hydrogen, iR:rPy)ajkyk i :rQ)alk&.oyk RR- CRpaikyuyi. ( wkvRyokaaikyk pRwkR}cycRs.ukenyk s'C:yk u3aaK.ycRoUkyk gymroeycR.sRkyk aryk or kecr-varyk wueoba said RRdfyRdkyk o ;a . di.au· i. R3.--R sdk;op 0 CjcbaRyk cyeRaikeoyi. bieydoaikyk huaoxjcycioaikyl ,aryi orhear.roaryi group is opdoualiy subsRtuied by R 2 or 3 groups mdepeodondy sekcRO from halo., hydoexyk RRaRRRdkoxy. fi irua, gCp R.RaRyiarmno. rfdy RyigfCr s saRryi iarmno, RXRi k RfRpiCyAkpaikyk R'ONkk - (.ddNliPxR-aypaikxa, 30Niik3X2Rrdk> i} (RR2.p ik , RR3pRH3,odkyk
Figure imgf000046_0002
oO:;NiRR3-< aikyk anP•R();;'N{{CaR3paskyiH(k3R daskyi);
or R'": and R1: taker* usgetber vvkh the obrogea 1o ohkb they are ao'aoged regressm a ·' ·;: ruombered aaiuraa l o unsaturated nog, opbonaily oaobouog aa addumaai heteroaRar; sekcivsi Roso osoygsa. ruusggo-'u aud saiRuy okertaa s id riug ia opbouaby subsOor oj by k 2 or 3 gsoaps iodepovKRuRy soieoied iO R;rR.Raikyh iRrk2)baioaik;> k aadao. <C C RaikyiaoOao, (RR- C gdkyik{<2R2:}uikyisaoRaiy iiydrosyi. x , RkrR'.Raikosoy, aud (C R2 ;aikoA RRR=aikyi. o herein saoi slog is opbonaby iPsed s (Cxkbbyek-aihyk heie ocycioaikyk aryh or h¾e¾ar\i ring;
Of P'; end P.'' taken ooreihe: with foe nU araa; v.-h 'h xh y are arisahed represeto a 6· to K mrnbered bridged b-cyckc ; ;a-. syseein opg-onaUy insed to aPog¾)oyek'>a!kyk heieroeycfoaik k aryl or heseroaryi nag. An aryi or heooroaryi group in this panicimu ¾;pgroop A is selected independently from the group eonsfoing fo" foraig keagfo«ees pyrroio, o azofo ihksaolo, fobdaeofo pyraeofo oxadnsPe. dnadlaeoie, irlaaofo iekaxofo beneotoran.
beeroihiopfone, beneox;aeole,
Figure imgf000047_0001
phenyl pvrldfoe, pyPdarone, pyrirnkbne. pyraxme, ;;··.: oo" iem one,, galnobne, oinaofore, vgna; obee:. qeanoxaifoe, ssfo eaphthyrnPne or another s or kvforoaryi goaap as foll w :
Figure imgf000047_0002
wherein its { I ?.
A k; k Nil fo is CH ra Pr and C la hydrogen or Ch-Cb afoyl; or
Figure imgf000047_0003
reherein in {2y
D is N or opPonaby nbefonied by hydrogen or C;-C';> aikyk r
Figure imgf000047_0004
•^herein n ( 5,
0 is Nil or Ckgy p' O or CO; and G is NH or C P; or
Figure imgf000047_0005
wherein in id )..
J is 0. S or (X); or
Figure imgf000047_0006
wh¾;¾sa hi 55),
0 CH N;
M IsCH orkk a d
LRR i h drogen, hang amin , cyano, ;:· Ra a R.. RkogfgeyeksRkyk odORR RRoRk . ogObbR R;k RX) R;' NRS '. RR R:R .-bRkRbRRRo, ~oRR! R:k -NRa'C(G)K ,-N a S( R ;R - Ra SORbR RSR - ^' R-'R^ -NRS HK ; o ok" R I >R R7 C (O s N l" IX" , or R)R%
vvhooRn
Figure imgf000048_0001
(C;-C:s)aR;y; or KR--CRR: ckokky! group is opboaaky .-en ioa-d by k 2 or 3 roups !ndependeody s lect d Ron; RlRkXRkyk (R- 'Rcycioalkyk RkRkgcy-ooaRenyk Rks- (..VihaJ alkv eyaoo,•RX.RR'R RRRR/R RRRRR" R;R RRIR -SOR'R
•o< -: . R:Rr;N -: RFC ηϋ;·. -R " RR RRR" Ryko ^ \ -RR:i'C{<R'NR;: R'R RkR:CRRORR:
•NR': SORRR - R: NORSRS R'o RgRk -OC(())Rs\ and NRORkRA'RB ; wherein k: and " are deilned as above: or
Figure imgf000048_0002
wherein hi Rf
Roods NR or CIR; or
Figure imgf000048_0003
wherein ia ί'7}..
MR7) k hydrogen, halo, amino, cyano, i ,V-C;?)islkyL kd}dyRo e;O ikgk
RReruayeRaiky XXnxh -X XRRk R70NR7 R-\ -CON' "' NR" Rfc . RRk,RR. Rdh N R""R;R - R" R , " L: C(0)K ?R - R lV S RRR ' ! , -NR: SO/NR" b ., ~NRa R:;R;R ~ RNR¾ C(OgR RaR': NR. R RORRR Rf\ or RaR;R
obesed; ,:;>·. RkoRyRkgi, Rk-XXg: gckxbky k or keRoeeyeReRky? goa-p is oghooahy subsRaned by R y or a groups Rdogeoderrhv aekeRd irom iCh ¾ ikvL (CrRkKgeRoafkyk .R- (XjeyeRabkenyk gCRRRihaioaSkyg >g,¾n : RR)R:: , .X gR" :.
RRXNRdkv•SR-O osOR:; , RRkdR
-NfR; ggRRNR<: R'R RoR;! CR RaRR;' ,
Figure imgf000048_0004
aRR, and ■•OCkOjNR'-' R!' :
Figure imgf000048_0005
By' am Ri: are d fined as ab e: or
Figure imgf000049_0001
r heooa so RR.
P is Ckk. H> O, or S: 0/ 85 ? CM or N; and a R 0-2; or
Figure imgf000049_0002
wher -a In (9 s.
209 ; and 10(9 s e C, or SRp) = · R and 4 R9) R N. or kop9) R N and R(9) rs C;
R ; hydrogen, -aaia- ·. aaokyk nkluoroaaRhyk or Oaks
U is hydrogea,. halo, amino, eyaao. akro. trsilaororaetbyL (CrCxOlk (Cr
COeydoaRO. -COR'1', -OXCRR -CQNR¾ R.\ -RORC , -SCENIC RR ORO R;0 -NiC RR.RRO- N " y();; . -NR" SOR O R-2 -RIO kdOOOR
Figure imgf000049_0003
ia-reR any (CykRaRyi or (CyRR a oalk)l group C optionally suh lruki by R 2 or groapa iadapoodsady seReRd Rosa R.R-COalkyk
Figure imgf000049_0004
R2r COhaioa!kO. oaaa.r -COR", RORC .•CONROCC -RRC SOR" .
Rk¾R:C: -NR; C OR" .
Figure imgf000049_0005
OCR:' SOdR.•■OR'ORiROO fR , -ORR■- kKOadRk aad ayk iyRCC ; wherein IO aoa R' ao deonad ar; above.
RrRgr ap B of Fananda OR
102421 Hk' i {C:--Coa!kyk tkRRRRyoRaikyk or heRrocyeOalkyk
|0242l R:: R aydroyaa. R. RCaa!ky or RRo. ia oaneh said iC fjailka I a: opnoaalR sab^oraRd aOk oae U> two roups se.iftot.-ad from min aad R(.o€y)alkykm-ono;
[0244] - i hydrogen, R2r-kk)alkyk o alkovy;
[ 249] R2 j kydroasa, (sk--CRaikyl or Oaks
[0240s a; dr gen, halo, oyaoo. rnfluooaonahyk aoRray Rk RCikyk {C;:--S2 }oyaloaRyi. aryl, hcieroarvk aeOonooo, Rk-R-OOkynyk aryadkyayk iareroarykdkyrp k OCRR , - kORakOrk of .aypy O ypR:
avkareio any RRRkOikyk RRR RRydoalkyk OkHRRdkynvk arylalkyayk or kofaroarykRkyriyi eaoap is pdoaak >ab:4aaR0 by k.2 or .> groeps indepeaRad) seRoa.-d fr m oaks R.yRRodkyk RRrCRsyeksdkyk RRRRKycReRkenyk ORRydhaloaikyk cyaao, -■ krdlx XXkkd oyg>Ab<Ryk -xR;x
Figure imgf000050_0001
.. SkkNR'R'k anoy AxRs R;k - xkkXdO RA o ^C(i^}NKa k"\ AaRRkgOgdRx AdRXRxdko
-NR3 SOddR" R '. -OR.:R XX:(CVrR;k -OC{ s Rs RFC . hega¾cydoalkyk ryh heaoxauxh arykkV- CRaikyk aad hekroarykCrkxiaiky k
[kroJxj Rx and R'" arc each iadepandesniy hydrogea. pkoXkhdkyh Rix xgdbe;gk A' kkiaikyayk AkXAKyeioeikyk iks-Rk)cydoalkxrgy. kXAkrobiosdoaikvk heaoocyokxdkvk aryk or heterorsfvt hesda «aid (Cox. dkdkyh AkrRxXdkeayb (C;--kV)a!kynyk eyc oalkyk yck.adkoiryk bicyxkadkyk heterccyckaikyi ,ary! orhegaoary; group b opdonaby sobsthated by k 2 r>r gasgaa ba.kpeadeniiy ^deckd bom hakx hydroxyh Ai Agpaikoxxs amnax (ky- r.oalkylarasao, (A::rkxpbkyl A r(X} A AXXbh XA gRhXyX kyh AsONkk^
C YNkkkgXXXdkyk
Figure imgf000050_0002
dX¾lCrCx ikyk -SOvNH>> - aXyNkfAi C ikyk and -SO^N{(C (:;. aikyi}((CrC;!)aIkyi);
or ks and Hi lakers togotbio with the aarogea to winch ;kx. are ariaohed roprxaaas a Ag neonkoxxi saoirakd or oaaaHaaied -a ay pti all vweaiana: an addibouai heteroatoa; :aderkd trom oxygen, akrogeig ami sulfur, wherein s d ring is optionaby s bsiduied by k 2 or 3 groups indepeadeady sekerod from (CrO.io.ikyi, (CdXX.}halo !kyL arnhio, XXXXkkkyianbno, {{€:- I'ks lkyiM dRbk lkyii oda-s hydroxy!, ox . XirXXAi o y and AAXiAaikoxyXAXiOahk k wbcrem said ring ia opdonaby rused to a (tXXXx yekaikyk hewroeyckxdkvk aryk or beteroaryi riag;
" aral R" taken together with the ahrogea a.; which dwy are tache repressor a X· a · iOooaakh ;ad bridged bieyelic ri sssaem optasudA based to a X--Cxeyoksdk k hcteroeyskxdkyl a.yh r hctewauy riag. Aryi arid heieroaryl in bXa deiknike tax sdocied froai die roup eoaskdng of kaasx hdopheee, pyook. oxuxo!e, dbaxob, i hdaixdw avfaxok, oxadiaxoky ihiadsaaoR, trkesok. Atraxole, berixo uraa, bxnxobdophene, b ¾xoxa?x>k, bsoxothiaaok, phenyl pyridin , pyrniaxinw pyoyakhosx pyraxaxy oA;xine. kjuxoaas axes 'aax ciaaobrsv, guexxxdke, gnuntxdiae. and aaprabyiidiae or a eraapoaad oi n the aryi or hcAroaryi group as tolkxvs;
Figure imgf000050_0003
xXwraia ia { \ s
A is O. Nkk or S; B ia bill r ok aad C ia hydrogen or RXXis aikyk or
Figure imgf000051_0001
O'ho si;; SiS Ok
D is N or C o RonaHy subsRkkad by hydr en or CokR alpyp or
Figure imgf000051_0002
horOn in (.V),
E is ! R or Ckk; F a U or CO and G o: NM or CHy or
Figure imgf000051_0003
oheorin so (4 ;,
J is , S or CO; or
Figure imgf000051_0004
O hoodn 5 Si. i 00
O C Col or :
M is Coi or N; and
RR5) IN hyOrogon. halo, anumo ey«no:, Rk--C>yalkyL
Figure imgf000051_0005
-COR" , -CFR " ; :θΜ<"ϊ& kORkkk O C kSO:40 OFM ROR;k - RS 'R"' : -NR." { ) Ok4Ra RkoR:o■ RS'RO;;;dR koRs R0ry -N R" NROkOROk OR " RK'0i'O}NRB . or »ORs",
wherein any RRrCcOkyk { CijeyOoOk F group is optionally sobskRked by R2 or 3 g u iodepootfeody rekekd from RkdkO kyk .: t';;)cycio;dkyL:
Figure imgf000051_0006
R. ■.- Cohak:>Okyo oyao , -COEO RXRRO -<:ONiC R.:R -R ·* . -SR>R ' '. -ROdR ? ; -SFR R" R oOxy · NR0RR -NR* 0'0)R.¾' 5
Figure imgf000051_0007
R Rs FRO}F>R.i; , RdO'SR RO -NR." SO .■NR" I: , - ORO -FKROOR"". and - KRFR R" R.0
otoaoin R° and R" are de ntd s above; o.;
Figure imgf000052_0001
wherein in (6)..
L'i ) i,;NH or RHy or
Figure imgf000052_0002
o-h s n Si-■ iR.
hid?) is hydrogen, Ιν ο, a Rm cyaao, R RRRdkyh ;RjR.R¾yeloaikyk
Figure imgf000052_0003
; i.yl-r -CO'N s R!R . : NR!-"NR""R¾' J -SORRR -SO; R'!'B"' ;
■• iR RH , -hk C(OjK^^s O-^', - i?"SC N : ' ; - R* NRa R'k -NR:> RlR RR>)iR' . '•RR'R R;' C djN s R;' - or -OR''',
whereas a y RRRRdksk kHR R:yeloehkyh her.erooyck;aikyi gioap k pis najl substituted R. 1,2 or 3 goups mdepes'sdemiy el cted Rons RYRRralkyk !R;rRs}oye:baRy!, (CR- CRKycRaB:enyh ( RRiudo lk h oyanw RRiRR a i-.ih · CUNR" R"k -RRR -SORR - SORR'. -'R> \n R . nltt , -ΝΗ'ΊΙΥ - R£iRO)RiR NRaCiO)NR:!'R\ - R¾0)OR:\ - ::'¾);R?R RNR:; SO:NRR;R -OR R o'XROjRR ;m-ROQO;NRfi' RR e.hen:nn I and "' arc de'iaed a¾ above; or
Figure imgf000052_0004
hsrem in (8),
, NR. . or R On 8} R RR or R: and a is 0-2
Figure imgf000052_0005
whrrsn; a; RR,
5 RR and T/hR ;-av C · -r RRR a: R and RyaR a .. or SRsR is N and I O} is Rk
R is hydrogen, arakso. wdryh Ridooromethyk or halo; U is hydrogen, halo, amsno. c an nPro, kskoonaiKXhyh R2iP2sydkyL (by- kykyoksaikyL -PdjRy -C kkk RXkslkRkR
Figure imgf000053_0001
-SCyNK" k'k -Pdk' sx -oR3RRO '. k! SORR, R3RS y¾RR - : -NR:' R R - ." RRsi.yO}k!y ..( RS. 4y U-k-pyra i-k- v'kk
wherea; any SrRykdkvl oi ;CjRh eycksRkyf roup is optionally suPsduned by k 2 or 3 groups iodepera:Rndy s lect d from (CRRkpoJkyk (C3v-Cs}cyaioaikyi, RkRRKyvoksdkenyl ((.V Cphakaikyk yao a OR . ΟΡ Ο ,-RO'NR" Rb ,-SOR-: ,-NkyR3 ,
O0,NR:" ik akro. -NROky•mOOiOdRy -kaRly 0}RR:i RR R4RO3RROR0 -NRS SkyRR RspR S02NRi; R'R -OR8'. k)Rk>)P R and a a y- pbPkR wherein k and R i are defi ed s shove.
SiRippsm C f IksnrsmRn (O)
[024R? Rr i■ isopropyi n.otRaayh oyeOhnp k oydopeniyi. eyekeKaxyk Π■·
m vh ieUi i) ycK>pr yL. I , \ -di s o px;hyd;i3ih;o hene" --y1 4·.ρ· .yd--- OinOyk
Figure imgf000053_0002
ben.pyh or 4-pyndyk [024kj P: s hydR'geo. RhR RPkyk or halo, in which said RRRkvalkyi is optionally snhstPu xi with one ί,ν-ο groops seRoied R n! amino and pkrkhRiky iamino:
[0250] Rr is hydrogen. (C Rsaikyl o alkoxy;
[0251] is R. rnedsyk or Bo: and
[0252] R"'' is meth l bisHRo:hmeR;yk†hyk, bisip-r edsyRdod). cyciopropyl propyl dnrserhOenbno, ethyiaanno. kk3rydroxyedyRandno, 2 > oper kyknrnno, RpipeTaxinyk i••pip ridnyy 4»oaorphonnyk ap pe idkpdnndno,†erahyd.roklH-p;. ranO-y iamino,
phenyk oino. p;?h nykn Rp4 'οηηηο. (4 -py; idnp4nnohyi)amkxx Γ2ο2- pyrsdins loounoOdn I janon , .;-id rs5ci l ^sr: )d y |;: ' in<.y k-pyrnliny iandno , 4~
p.asknooarbonybphenylknahxy 3dy.:d ovvy o seip3-4R>nt nd-pa; psyrioin}aehyayi..
phenyiedrynyh 2-Rnsmyk 3-ahrenyk lHp.prnaok4-p k tR-pyrazokd-yh i IRnOazoko-yk 3- n!erhykRHondssol -yi, iHO,:.k3Rxaxo.nria¾sR5-yi.2- X0-2, - dihyd o-ili'4;¾s/n'ntd oo'-5- i. 2-o>;o-2:5-diipxlro-iH-udoRR-yi.: kmxo R-dniydroR s Pendoi 'y 2J.. -bc ?o sdi^ R-^ l 2-andno--6-qninaxonnyh 2.4-dRxo- i .2.5.4-n;p'::pp,'dn:^R-pyrirnidinyI, x-ai ino-R-pyrsnndjayl ?» oxoO .5,6,7 aePahydro-R .R-naphihyrnhnO-yh phenyl,.2ooedp4pbenyl 2-akrr>pheoyi; 3- phenyRthyl .ksnknophenyk 4-aoin;ophenyl od oropheoyh 4RnKnxsphenyl 4- OrieU¾4oxy)phenyl oPaceyPoninopphenvl a-baoepaairdno}phens I 4o;mbnooarbonylh4vopO, 4o i
Figure imgf000053_0003
n rnnmsnPony ρρθοονί soasedplnaRayvRphen 4- [ (day;ekyo¾nnaoR 4Ra j I pheovk d-ioTK updankarp arhoaylipheay!, 4· Hni dA' fnn ysv itoo n h n L . -i n h.yi^ lf i^llair ^srj hea l, 3-pyHdmyb 4-py; idinyh i or!Of Ut df-3p> hj!i'iiyl 2-xmino-o-pyndinyL aoimahykixy pbyiyHdin h
o7!e p ;.;p ;; ])- i- ndlisvl, edYoyokxx'opy baHony rK-rn ; ]-'6-3nieihyK sy --:¾-p) rldmyh 5-
Figure imgf000054_0001
RRdxnebpbxx kyornxmy p)-3 - ;y rldus 6-(4- rnDrph linyl -3» yndsny
Figure imgf000054_0002
ό- ( "K3hy!i.¾y -.3---pyridin L bR(mebykxxh o bviy HR-npyridinyp RR vxhybmhvRropR'ny bR Rpyrkhnyk eoo-oR. ; :· ·η; s ^nn L or 4o¾ Kibx kocy.
(0253] h; οη οθίηχχχχ X in Formula · b ; or .subgro ps Rxaxobk as dd x herein for Formosa FR or any of Forrmbne rbo:dosed herein, xhere applicable.
1 254] in yev another aspeeb die prosem hoxnbon feahxes a rak yp ted bencene ·.·. n-o-ond of bos nnha (ib) beiox or a pharnxxx
Figure imgf000054_0003
wherein
Z R bRR¾> RpR7, fOtbR, or CRRRR . in vOnoh a is 0, R or 2;
each f s„ ^ and :: kaRpeodenby, is H or FaRR alkyl opbonaby axbauxriod w th o or nxa'C aubsptoerns :¾Rokxi ftxax r.he aoaip consi;Odny <>.! haky hydroxy!. RQOhk C(OR)- (.'b-Ci: alkyk e.yano, kk k{: nikxxyh arobno, iXonank -Ck aikyianxno. dbkaoy, aikykxxino. CkXR, oyckxbkyh FR-C^ myk 4 k; kaonensberen! hexorocye balky k and 5- or Oonernbered hekaxxoyk i hi i-l hakx cvano. aakkk OK,; b^.x y.. okRybR, -RROR.RR, XO) ;,Rs.,
- Ri -aOiKy. -5x0 rib,, -RpOhkkRJR. r 1R · n¾ which R r is Fi Fe Rkyk C O. alkenyk kRRk. absy yb Ck-xh cyeioaJkyk C Rbo .nyk 5- or Οοτχχώοηχΐ heieroaryb or 4 κ; ikxmanbered heoerovvckxdk yb b k R. I . or 2, each of ,. and Rv., nxleperakaxiy b H or E-;, and R.:¾ R kh R k akyb RyRy. a!kvn k F:rR., albynyh CRO: eyekabbyl, R;.:R.R> ana, 4 to Ikonembered hevenxyxaoaikyk or S- or 6-meonbe:ed bckx'oaryk en R^and Rv., xyaxher xRh the aknn to 15037715
which they are attached, Rnsn a 4 ro i Ranesnbwcd heteroeycloalkvi ring awnac 0 or 1 additional heteroatosw and each wf R;::>, R;; a d the 4 to Ic-noembered hekrocyolonskys nay formed by R . a d Ry„ is optionally substituted with on or snore -Oj-l . wherem {}■_> is a hoad or tpRR alkyi Ibske each o tional ssawhkieb■.-· ah ha!oo cyano, hydroxy! or ke-bb alkoay, aad Ί-·. is Hi halo, evanw -OR,, RSIRR,:, wbOrR,, -C(0)Obf, RROikRRbs. RRRR 'RkR RiRRRlROi RRORli, »S(O); R y. or R^, In wiach each ra'!:R and IR, indepeodessbi. Is li or R ·.. ·.·,;·,; ; of R; nd bklepeswkisily, k k;Ry aik i, Chwh e ydon!kv), C kha aryk 4 to Ibnswsribesed
Iwreroeyoloalkyk or R- or h-mesnbered hekroaspk r R, and it,:, together ith the H atom to which they are atacherk form a 4 k? Isoysesvshered hcictooycloalkyi ring having 0 or 1 additional hwesosRom, and each OIRN.;5 R,;-:, and the to Ibwnesrsbered heteroeycloaikyl rrag fowned by R,aws R.j, is oprkmaiiy sabstaored with one or snose -{>3-iy vckereiii Q;; is s bond or Cbwih alkyi hibrer each optiooaiiy stslwshbked with halo, cyano, hydss-wyl or CpCs a!koxy, aad I ts seleckd Irons dw group oonyi-nng of H, halo-, cyano, bh-Rb, aikyk (Igbib cycioalkyk RbRbc ¾R I - to kb- messsberea hebwocycRodkyl, 5 - r-r o-nwrnb reo; heteroarvi '- h; . OOO ..; wskysbk, RbRJk, and RROjwRRR, each of k, and . independently fwhsg M or CVi'b alkyi■rptfonally sobabtoted wsb; OH, Okb b.b fdk k or R; bt a . alkyi. or -R) T R oaa.c or · O · h se oxo; or any Rw< aeiyhbveiag -(> -Γ:;. c ben R., is Cft-<br f«vyj os a- -w b-aneasbcred hetesoaR I together with she atoms to winch they arc auacheb form a > or (wweosbersd ring optiooaiiy containing 1 -4 heteroeloma aeleekai Ron's M U and b and optsonslly anbsdhsted with one or nsooe aobstnnesbs selected Irons she group conaiauog of haio. hydroxy!,. COOK C(hRO-R.bwR alkyi, cyano, tip -Cs. aikoayk renins, roooobbrke alhelasolsKs dokiRl slkylnmsso. C.rCb cycioalkyk€¾■·€· K! aryk 4 to 12-n'!ensbercd hetewwyoloalky 1, and 5- or Ronembereu heioroeryk
Rv k--Qw;k.;:: ia which tics is a bond, bhwb; aikr l iaakcr, -s bbR'k alkcaxi linker, ea-b; brnceioa:girawd!y aobsorokd «aUi halo, w-saas. hs'!.ir-.wyl or byof., alkoav, and It; is fh haio, c>ano. lbRR<;,, -OR.,, -bsfadk,.. w.bO}i)R,„ RbRi>yNR-;R;.. w:(())NR,X>R;;.
Figure imgf000055_0001
, ca Rsft. so rrntca eswts ot R7 and R;,. sarle eiioenriy ss i t or R o eacts o R¾c; sad s-. aiiiepondeniiy is bi;-C;! aikyk Cb-bb. aikcipa, t.'c-Cb alkynyk bhwp cy So lkyl, kb-Cbo asa k to laoncnsbcrcd het.es ocyelofilbyk or 5- or b-rneabsered heseroaryk and each of Its,:, ;¾nd is opdona!iy suba irateri with orsc or more -Os"'ib. iserei-! O; is a rcasd. (ipiss, CsOsNR¾,
N Rbt s. itb. bRbs^ RRtiOp, or t.bw: alkyi linker. Rk being H or Cr€y, aikyk and ']'· c; M, baas, bb-b' aikyk Cb-h;., aikeorp bb«bb a Iky sr. a, hyuroayk cy iso, fbb.b askosyk annsus, nsosss- Cb'-bb aibyiasnsnis, diRib atb, cikylanbsas, O.vCb escioaliw k C; bib askylenebib-Rib cycsoalf yl. bb - C;i.; aigb bb-bb albvlcnew'bRb,, ;sryb 4 So I .r-nienbe;e;.i heteroew loalkyk kb-rib aikylene-4 as 1 wnnenshw-ed helerocyebsaikyk b- r ewrwmbered isorerssaRi,. bbRiy. aikylasse-R- or bonewkwreb ixo<aoaryk r xRardR. in hich q R b, 1, or 2 ;rvJ R0_ R kdRR: aiksk C■··€:, rbkenyk -kd.
nikynyl. kkRd cyekodkyk. CRRda ¾g 4 bed umbered beRrnoycioalkyk or 5- or d.-rnesaheicd beteroarvk and T> is oprlona!ly subsoaPeh with ne or raoro ubsntueOi selected from the gr up eonaRhng okhakx CR-Ck. ntkyk hydrosyk ey no. Rrk... nikoxyk kkCi RR a ikylene-Rd -do aikoxy, aodno, Π5 ί!ϊ';-ΐ ·! ■·■■ alk tannno, dnkyky aikRaaboo. — k - cvc raiksk v-€;a aryk a to do- membered heieroegoioaikyk and 5·· - a' doneoRxsxsj hetenxiryi except hen d is id, hide, hydroxy!, or eyano: or g: · 1 Is oxo;
each oi' s, aad Ik; ;, nxlependeinks s Id, hak;a hydroxy! COOK, eyano. Ik.-. OR o k C'OO --:/. m winch s is C k alkyk kg.o g alkenyh C: kV alkynyk of-Rd eyekedkyk d a; 12·· rnenb:xred heiaoo vcioatkyk anbno, in iKoCr(. .dfs laaaa; or dokaod. alkylaobno, saa IRx is opbonaIR sahsuriaod oaut on or sno e aahsbtuems selected from die group consisting of halo, hsdrosol COOlk kdOg'kkddR alkyk eyano, (d-Ck alkoxyk arnbxy mono-Rd -Rd, alkvRnuno, and dodg-kg alkykardno; P and Rs. togerher with die ' ..a- - s which haxy arc attached, fores a 4 as krors ndacrsd trcten.xo'eR>alk t ring b in 0 to 2 abdltkaed heRroa.a.aos. or RR and S;:. together odd? the k room to which they are at a hed.: torso kdR cyeloalkyl or a 4 as 2■ membered ixserocycloaRvt nmj having i to > hereroaioms, and each otRhe 4 ha i Ί aondxn-d heseroewdoalkyi nags or drkd eyckxdkyl ;bmvcd by R2 and IR is optionally sudrtiokeJ wkh one or more - gR-dk. whewln gk is a bond, (ROg CiO)N ::;: RR;!a2Pag S{€kK or (d-Rd alkyl linker. Ik,, being H or Cd-kk aikyk and dR is ft. halo. fRRR. alkyk hydroxyf cyaao, RRkk aikovyi, aodno. rmxxxRoCR rukykanlno, dk'C;--kk alkyiandno, kdRd; cycioaikyi. kkRRn aryk 4 to Idnnembered Soxerro ycksaikyk 5- or 6-me?nbered heRroaryk or fO k, iss :Λ hich ρ o 0, R or 2 sao; f, ; kd ay- -ogR. gf,.R' 6 ¾h,eoyk (d-C a!kysyvg RgaR eyc!oa kyk k' fR ,- aryk 4 1.2- aian e od iavtcroeyeioalk l, --r 5-· r.-r d- ioensbe ad heteroaryl5 and i . is oixioaahy subsotu½d nh one or more aabsiitaeots oRcaRd froos lire group coasistoig of ha!o. C Cf; aikyi, hydroxyk cs aos kd-k's a!L A l arosno, inono- d-k'k, aikv anono, di-<.d--R;: aikylaroioo, (g;'4R
Figure imgf000056_0001
kt,od::,
Figure imgf000056_0002
Id is kk hai>-, dydroxyk ra' cyaao; or-kk -'IV, is oxo;
Ri.i la bsent, fk or d-xfs sdkyl ogtionndy ukytdaied saRh on or oxae srihatig.oaas aalecRd irons rhe groap suaragan of hakx hydrox>l (X)Ofi.
Figure imgf000056_0003
. aikoxyk anoao, οκχκ?· ΓρΧ aiks aadr . dkk.fX.: t: aikyiaadras. CR-sR cyvloalkyl, (R.-(d;.-; i- k a to Idanemfxred isa rocyeloalky k and 5- or b-nsensbered hoRroaryh and
n is fk. R 2, 3, 4, r a.
[OR 55) cine ruto ' of the eoraporaxia of f oornda RU) Raaares n benrg 0.
g?25d| Anodxx' sabsei of the rraxgounds of Roaania ilk;) Raoaea; a being k Μ3 ?5 ? j in eoXesOrnenOs Fa: v ri les In Foranda XIX or sub ro beereor are e< defin d herein fa bornuda (1).. ahere applicable
[OaeX Represeniahoe com unds oHhe reeeA lesemlon Ineiade eoui oonds Ossed la
Tables ; A sX ;■ '■ In Table b the variables ere a;- defin d her in i r Formula (X urbeas orhessXse specilXd. la I ebb: lb excepi Ibr a, FX. and b' -. variables each as 52, X- Oaoeph Xh Y;e Q: 1„ e arei bp. are as defined bosein roe Formula H). in Table X k X 7b,
S(0)/K a d she oife ariables except for a.. such as X, X-> thr ugh X.;.. be, p. R ;, FX and T , are as denned herein for Formal;* (lb
Table IX
He, pi, (p j be. j 73X Pb j - 7,7 OA
3Hb p:b s iX'5 Xe
Ah i : He,
(a
Figure imgf000057_0001
2015/037715
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
T/US2015/037715
Figure imgf000061_0001
7715
Figure imgf000062_0001
Figure imgf000063_0001
Y
Figure imgf000063_0002
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
t kyi b; sn e-id d to meknie Co Go, (dp Cy, Cy and C¾ alky! groups. hxatxpks of aikyi nvehide; rnoieues having i on; one xsx carbon atoms, -.a-, a as, bid nor hmhed ky naeUeyk ebtyb n-ysropyk efaopyk robopyb s-hruyk ninny k ixpentyk -opoaiyl ->s n-h yl.
[02 b \ } b'; carbon νηχχχίηηοοίχ. a shaight chai (a b an h d akyyi has six or iixver carbon a m (?.?: , bh-O:, bar straight chain, CVC.b kn branc d chain a aad hi anoiher embodkrienh a soaieyhi ehain or branched alky I has four o fewer earbon atonxc
[0202] As ased er n, ike term•'xyekxdk> ! reiera to a saturated or tnisaUaebed nenaroniaiic hydrocarbon soooo-or makaaaag (e.g., keaxl htidgsd, or spins rings) system
Figure imgf000071_0001
3 to id carbi-a atooo yv.g,. gyb
Figure imgf000071_0002
okays, badkys nudude, bar are mx bona p to. CYcknsre sk oyciobtsb k eyeiopeotyk sycksbexyk eye hepiyk Cyciooeiyk eyckspenteivyk yelohes;enyh cyc bepiaayb and ad^marayb j aa term 'hiererooyekxdkyr seders to a sannahxi or nnsattxated aon rof asic b-a oo ioixs-.d monocvehc.7-12 avomberad bicyebo (ihsed, brid ed, or spuo nngs'b or i ;-l4 menbnoed irioyclio ring cysts oi bhxxd, bridgesh or spb'o rings) a i una or snore hcteroacsns iaeeh as i d , a, or So), unless speckled ihcr hxx fxsannbes of
heserocye aikyi groups hxdnbe. bid' are not hnnn-d to, iperidinyL pipera inyk pyrroildinyl, dioaanyk teirahydfobnanyk soindohnyL indoHnyk iniidaaobdinyk p ra:aokdksyk o a ondirsy isoxaaobdiml. triaxolklhna, o/draoyl sxebdinyk oxeutrryk ihietanyh 1,2, .yd- iak kydrrtpyrKsinyk tetrahydt'opyrartyi, dbtydnspynas h pyranyk a-eose-doed
iebahydroilbopsrarg h l.dabaaopanyk bd-oxaxepanyk 2 Sx aiaabia}'aksf2,2.1jin:;piaavt; 2,5·- diaaabicyeioj2.2, i]bepa?ayl 2-ox:i-6-azaapiro[ .J}h pi nyl, 2,b-diaaaspiroia.3jheptanyk k4- dbssa--K<iaaxpsro[a.a]decanyk I;4--dioxaspiro 4-5 dacanyk i-oxaspiro[4. jdeeanyi, I·· aa:aspnO 4,5]deoanyk aai-spiroiaya ohaxane'- 1 J Mxobenxo†hran]-yk ?db pko[cyciobexane--h5i~ ba-obkb-asipya aiinj-yi, 34-bspuo[oy viohcxatxo I ,b vh.axc ehcipynd;npyk and the kka,
[OdojJ the tern; oxxiorebiy sabaOiuted alk f" refers unstbxtiuneb alkyl or alky I having designated xubsthuents replacing one or nscae hydrogen atoms on one or snore carb ns ofbke hydrocarbon backbone, Such xubsbtnenta can bxbade. for e am le, alky I, aikenyi, aikynyk haii!gea, hydr; xyi, ikykaa'biSissdoxy. aryica bonyiox) , aikoxsxarbonyloxy,
arysoxycarbonyioxy, earboayase, ahiylcarbonyl, !y1ca!l:>s>n\a, a!k- -xycarbosp p an"nnocarba>t!ai:! aiky knninooarbony k dialkykonnv/xxa-bonyk aikybiii-ss arbonyl aikoxyk pinopiade, pis aph ra phosphinato, anxao tiaai o ? ah.yiaraino, diaikyiaasira's arykaoino, sbasyknnaso and alk lary annao ,, acysannno (.including akcy!earbonybonhxa aryiearbonylamiao, c i-bativpa and ureido , nikhn ., indao, anii ydryk ahrykfao, arybhio, ihi carboxylatix snbaies. aikyistdiin i, stdfoaal . aobannsyh saihxsarnidr-, ratio, tiatia ios ctiiyi, cyaj y acido, -ierocyclyi, aikyiaig i, or a;r an.aaadc or ieeK'a aaaatie nioievy. M?26 j A '"as yhik k r an xnnl - moiety is an alkyi subsPeyeh wit a¾s aryl (e.g..
phenybnethyl ibeneyity An "alkylater moiop- Is an aryl subsiitured wnh a alkyi (e.g..
Figure imgf000072_0001
0-Ϊ6 ] As used hereng APkgl linke '' is inieneked ΐ Inelaue by.€y;: by hh, Or or Cb straight chain ; lineak saturated divdent airphatic hydrocerbor: groups and C\, hh. ib: or Cb branched saiuraecd lphnik hsb \su†>on groups, i -e example, CrnCy alky! linker Is intended include k ; , Cy, (by Cy C> and kg alkyi knkei groups, examples oi'alkyl linker bmlnde, moi'ehes having from one k six carbon as en . sueh as; but not limbed ks, ;a-nb; ; MdHy-h et yl y CbkCblrk u-propyl n HoCi bCk -h -pro yl ;··'' kt U r i t. k. n-buvyl ·.■>. I bs'k klig. Η···?. shxnyl ;u if py My !!.·>. l-buiyl (kyCH^ hir'g ms-crayl -C}-!.; i2Ci-^Ci ; Vl )f s-geniyi pm Hh'kha kybbbCflr ; r n-he ! hCrkClkCI tAitlksHAhirh
[' 2 6 "tbikenyi"" meludes unseauated aliphatic groups analogous In length and possible snbst neo; is. Pes alhyix has-, sibed abo , bar thai conuon a; least sen- double bond. For example, die tern'; khkeuvr Includes trai ht sbain alkenyl groups hoy/, sthenyk propenyk butensl, penknyt hexenyk beptenyk sxrenyh aouenyk deoenyih and branched alkenyl groups. bbsb ! in certain embodimenis, a sPehghi . hsc- or branched alkeny 1 group has six or leaver carbon aknos in hs backbone tens, k Cy. for straight hain, Ch--kb for branched chai s The terns ;'0Η..Υ' includes alkeny I groups containing two in six carbon atones 'bbe renn "Cb-kb" ine lobes alkenyl groups eoniainbga threw to six varbon .a -es- jOsbSj The terns•iopnonab>- substituted alkeny Γ raters to unsubsbtukd aiksnyi or alkeny I having designated substiinents renlaeing one or more hydrogen atoms on ouv or more
hydrocarbon backbone carbon at ms, bach srehsthuents can ineinde, tbr example, alkyi, alkenyk slkyrgh, halogen, hydroxyl. alkyloarbonyloxyy arviearbony-oxy. alkoxycarhoinboxy.
aryhoxY arbony1oxy. carbosyhUe: aikyiearbonyl. sckcarbonyh nikoxyearbwuyl, anhusoarbonyl. alky sua; kioearbouyk diaikykuninocarbonyk alk bhuxauimnyl, alkoxyi., pho.phaie, pbosphonaio. ■dssspbinaro. asrnno (iackiding alkyianiiuo, dialkyiarnifxy arsianuno, dt ylamaiO and alkyPsrylannsto). aeyianiino foss!udlng alk kxntsyns-ianouo. arjicarboiS lunhus-, cas harnoyl and uneido), ansidsno, bnino, sulthydryb aikyhhio, aryktuo. dsrxxuboxyiaic. snltbkss aikyisuliinyL. SiUtonato, sudiarnoyk suhonarnklo.. rbtro. trii'iuo;omethyi:; eyaa;s. hereroeych I, ahiy!aryb or an aromatic or hckroaronsaoe nuaicfys
b'tkas 'tAJkynvk includes unxahusacd ahphaoc gontps a alogoie: in ieagth and osissibic subsbtuti si to the aikyis described above, but which, contain at least one triple h-ansh For c- anigls, 'adbyswf includes s;ta;ght chain kdkyn l groups ic y... e>hynyb propynyk buiynyb pcatcneb e oars yk lxang; k -ssi nyk n-agnyk rlecvnyp. ;s;.| is.ar-beu aiksn l gnsups. In oenain embodh'nenbe a simigiu chain r branched alkyreyi group has six or trover carbon atoms In da backbone P- .a ., Cy-hx, i r soalgra elnnn. bf-bo. id-' branched chain). The iein; ""C.rCV" incl de- a albyeyl groans connaning swo to six: carbon at ms. I Ik ?errn 'Xyiy Inelndex aikynyi groups containing three b> six carbon aronno
7 ] The term Aspbonaby simsib ed atk ny refers to unsabsdubed alkynyl or sikym I avng deslginued sobxbtne;Us replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms, boon substi utes an bans tor example, alk k alkenyb slbynyh halogen, hydroxy k alkyicarbonyloxv, arylcarbonyloxy. aikoxyearbonyloxy, nryio vcarbonyioxy earboxyiate. die. icarbonyk arylcarbonyk alkoxycatbenyh anbnoearbonyb alkyknnavocnrbonyk diaikyiaiidnocarb-snys. aikykhmeaibom i, aikoxyh phosphate, nlnsephonaio.. phocphsnato, amino (including aibylantino, bkbk; anna;-.-, arylammo, diaryiam o and aikykng lammob acylamino iinciuding eikylcarbonyiaobno, any!earbonykunino, earbamoxi and arelelok aobebuu. Imam, subhydryb alkylrhnp arylbao, thiocafboxylake. sulfates, alk> bn.btanvh etbiooanc xubamoyk subbnanakbm nbrce trblmnxarmbtyh cyamy acado. heierocye!yk aikylaryl. or an an onatie or hebooaromatie moleey.
[0271] hnhcr opbouaby --.or-ss eb moieties (such as optionally snbstitatcd cycioa!k , heterooycloalkvk aryh or hc'feroxryb include both the am ab-.boecb moieties and the mombes having one re mxsre of the designated sabsfitueoix. -■■■■ example, substituted hctcjocycioa!kyi Includes basse subabmted ih <.- or moe alkyl groups, snch as d.ds.d-i ranethyk i er ireyi and 2.2aonoctrarnedpd-d,2 -b--miraio:d
! bx) 72] i,;AryP include' cr u s with aroniaboby, including "eo ngatedo or nnbtlcysiic systems xvbh at least one amenabe ring and do not contain any hsicroaiom in die ring sbnebme.
bxampies include phenyl, bemcyk 1,2.3,-k-ien-abydronapiabaicayi., ekv
1 273] 'bieieroaryh~ gronpx are ana groups, as defined abo:m, except havin nx-ro one to iour heieroat'oms In the ring structure, and may also be referred to as Amyl ΙνηίοΓοοχοίοχ,'' or
"ncteroaroniatk s '" As u ed herein, the term 'laAeroaryr Is upended to seclude a stable , 6-. or fooembered monocyclic or 7-, 8-, b-5 o. ;· 1 I - r ib-mcsnbered hmycik: mornaoe hemromelb ring vvhieh eoncnS- ohoarbon aosms -em one or more hmerosaoms, e.g.. I or I -2 or I · ' or 1-4 or I -A or i-6 heseroaionos. or a y. J, 2, 3, 4, a, or o imteroatorns, nKlependendy selected trom the group conamhng ot nbrogom oxygen and sutbas T e nitrogen anon m y be substituted or uaubxab ed A.e.. bl o ffR wherein R Is H or other sebsbtaenta, as defined n The nitrogen and subbr heteroatoms may
Figure imgf000073_0001
be oxabeed (fx.. --0 are! bb>}.-,, where ρ :;; 1 or 2p It e lo be noted diet toml ri nber of S ami r) ;-.n;osns In ng aromatic iscieroeycle is not more tbart I . |0 7·Π hxcaripies onxxe oaryl gro s inAade pyrrole. Aran, kbopheae, bnaxxbe, lsAh;a;aole, koidaaoA. tria-o.-kg renaxole pyraaoA, Λ coax- kg c<oxaxoky pyndAe pyraelne, pyA.inxbex pyrimkiine, and die kke.
bA A; Portheonore, b<e Arms "and" and AseAroaryA in l de ranhicyckc aryi and heAroaryl groups, eye Sricyeke, bicyebe e.g. naphthalene, benxoxax.olc. hem:odioxaxoA benaoihaassbe, banx brhdaxoly bcnxobouphene. quinoline isoqinnohne, naphAry rkne. Indole banaoknae purine, benxsbnran. deaxaposine, boilxme.
[027 Aj in the as or ;onkloycho aromabc nm:>, only one oi the rings needs to be aromabe keys. !gaAihydrenuAley aithoagh ad k the- rings may b aromatic A.g., pemoline). The second ring can aAe be taxed or bridge'.;,
AAA; The oyckxbkyl, he iocycAaikyk aryk or heAroaryl rmg era) be subabmied a; one or more sang posihose (e.g., the m -i ndng carbon or heAroaiom snch as Ai with sack xeAainienrs aa dexonhed above, for example, aikyk alkenyk alkynyk halogem hydroxy!, alkoxyy alkylcnrbonyAxy. ary loarbrembxy. alkoxy >: asbonyloxy, ar Axycarhran.noxyy carboxylase., a!kykxnbony alkyknrinKxaa-bonyh a A; ·. krmexnoxe. ;. alAxo lamhaxxiib n
alkylcarbonyh arylc AonyL araikyiea boriyh alkeny lcarhonyk alkoxyearbony aminocarboayb aHsyhhkxxxbonyk pA'SpAke phospkonaKa phosphinato, amino gineiuding alkykunino, dkdkyknoino arylanbno, diary lamAo and aikysaip iamino). ac lamime fhxe!edkny
alkyloabxapvlanbno. agyk.arbonAa;rhno, carbamoyl and arekio). anhdbKy hnioo, sj i fh lr .L alkykhie, a;ykhkx ihAcarhoxykke, sukafes, alky hailt yi, aaiAnaPx snbnmoyk sdkmarnido. nioxa Oat!aofOioebyyk cyano, axkkx heteroeyeiyh Akykuyk or an arornauo or heteroaromatio moiety. .A y! and hcreronryi groups ears a bo be heed or bridged o nk alkyebc or heterooye uc ringa. which ase not aroma so aa io form a nubbcvchc cystem (op.. Atrabm
neohyknmde.eoqshcie I xach as
Figure imgf000074_0001
O'2'78] As used herein, AarbocyAe'' or 'carbocyeiie ring" is Inrerxkd n.> malade any stable monocyclka Acyclic or ρΑχχ ,- sis¾ having dse specified number of carbons, any otAhkh ma be xnurnAd. maxngnaued. or aromabe, earboeycle incAdes exoloAkyl and aryk For example, a CA<A; earboeycle i¾ intended fo m: kak a nionoeyclia. bicyeke o fnevd e ring Ae keg 3.4, 3, 6, A A 9, kg § k A, Id or A oarbssss anana, E;xanpAs ot'earboeveiea iiadnde. bn? are nor bn'oAd ax eycks r'-yp k eyeiobuiyi, e elobuiei b eyxJopenAf, eyesopentenyk eyckiiiexyl,
eyc-osaaptespyi, eyekak ptyf cyAohepteind, adaniantyl, cycJoocreL cyeiooetenys,
eyeiooaiadieio i. fiuorenyk phenyl napbb-yA indanyi. adaixanoi and teinavydronaphihyk ridged rings are also aednded as rhe i eii Paofi olAnrboeyAe, Αοηκηηρ, k.a- exanipko iAA.oliaeyciooCiane, [akkOjbk yclonoisane. and | .d.O s bieyelodecane and [xA.2] bicyAooagoe, Λ brdged ring ooorao w en one o; noax carbon aioma da? I · : o^n-ad aecn; carbon ahaxis. In o e enkbodimeny bridge nngs are one -or -vo car , atoms, it is naked thai a bridge ahvay:j eoave o. a nxnxxxxik r ng kao a naoyebe one. iisn a. baa k bndg d, da cnbehhoxxx racked for tbc ring nrxy alao be res nt on th bridge, based org., napnbyk teirabydroaaphtbyi) and apiro nngs are ako iodnded,
[0279] As osed besxna '1u4 rocvckk' or "baieroc obe gs p"' inehKica any rin strneonx pxnorenxt nncannated, <.;r arornauci kkh eonbbns at leasi one sang hekiOaan'n (e.y... N. ? S). rieienecyck inchKks heenxxxckxbky; aad iexer-anyd Exann'doa of hofcrneyde incknk. bus. are -a - !kxited to., morpbobne. pyrrolidine, (ctrabydrobbopbene, plperidine. pipera:ak;e< oaetane. pyraa, len'ahyd ropy ran. axeikiine, and ianoibyd oba'an,
[92x0] Examples oi bea-xOcyebc groups kxxiode, ink are nos. brnited bx aeridinyk axodnyk benxnrodazoiyb benaovutanyk benerabnabnany benzodn-pbeayb benaovixoiyh
benzoxaaobayl benadbaxokk he eon iaxoiyk benxktra.x.4y k bendsoxaxoiyk benzieotbkaaoiyk ben.anrddaaobnyb carbaxoiyk 4a/b-carbaxobyk earbcuinyk chrotxanyb cnn.anenyk cirn .4nryk daenkydroqnaa.dk! νϊ.2 k ·2ο·ο . a..: -.knn bo a dshydr it-n' J^ mih dr fyra .. iaranyk inraxanyb knidaaxbidnyvk mbdaxolinyb inndaao!yk i/kbndazdyi, ktdoknyk indonnyl nuionainyk kxxbyk .2 a laO a- ;. nauinoyk iyobeutxblaan k >aoabrojr;an b isoinda olyl.
roaudobnyh isoindoiyk isoquinoknyk mahiaxoiyb i xazoiy nnxOpkancdioxyphenyl pxg,, benxoki ijb dfjdioxokx-eyrb. nxxpbobrgyk naphUiyrnknyk txkbydroisoquinobnyk oxadiaaoiy k b2:.3''Oxadlaadyk ? 2k x->aadkxdyL kka^oxsdiaxoiyk krekosndiaxoiyk 1224- oxadkesok(4Hpone, oxaeobdinyk oxaxolyk oxbxioiyb pvrimkbnyb phenanbnidkyyk pnasnnnbrokny k phcaaxnq k pkoaoddaainyk p enoxathinyb pbenoxaanryk pbdndaa-ayk piperaoinyk piperkunyk dperkknsk 4qxipe;4donyk pspen>nyt pterkbnyk purkvyb pyranyk pyraaa;yk pyraxohdinyk pyraxohnyk pyraxoiyb pyridaaiuyh pynbocrxaxok, pxndonokkaok, pyrkkbhbaok:, nvrkbnyk pyndyk ; ·. aoidnr- k pynobdkyk yrrebnyl. arkpyrnxyk pyrro!yk qrbnaxolinyk qauKbinyk ak ganobainyk qrnnoaaingyk qnknseiKbnyk ktrakydrobnanyl teanbydroisoqainobeyk axo'ibydroq inoUnyL. nbraaolyk b//k.2d;klnadna:bnyi. b .:..·· tbuKbaaobd, i ,2,4 obiadkaoiyk ikkokknliaaolyk ! 2.4-dbadasadyb rbsanduony , ibaxxdyL dneayp ddoix absaarayk ddanaoxaaxkyb dbenoaaldaao!yk ddopboayL. naaday 2.3-f.r;a¾>h k k.2ybn43xoka, k2.xornaook k ;,a,inrsax'.4>1 and xaidkenyk
[0281] Tie; sarm ''Xabi.a;tna-dy': aa -¾d boredx n aa'sa dad: any -ana or aaare byerogen a^sa - n d;0 deaignaved atooi ;r re laced o nk a aaiooixo's rrons dr. indicated ητοηρχ nroraded ν;.ύ the designated ahao'k a-aarad vaienry ia not eaeoadsd, and that the rnbatsn i n nxasdea > a siabie ctarnxnani, ^ c;; a rabadiiava!' is ^o or koio {j.r.. -ij' , dxn> 2 bN<j;r- oa atoinr on on. aton; a?o replased. Rem snhsPments re not esen on arom tk moieties. Ring doubie bonds, a axed I meek, are doable bo ds that ;: e kneed beoseeo Pro aslkcsm nag ensrns uxg,, Cxkk Rks or kk-;N). ''Stabl •.••nmmmd' and "stable strucnnk" are meant m Indicate a compound dear a ran kdcmly sobasi a) survive mnakon to a useird de re or nnruy Rom a reaedon mixPce. and fkaoKdauoo into an efficacious therapeuuc a en
[028 1 When a bond as a subsotuerg ia shovm as cross a bond connecting two ae.aas In a ring, vhen suck aubsutuerrt may be bonded ΐο any atom in ike krgg, When a snbstlme Is ksnoi vvif ui Indicating ike aa -a-■ -a ssrack aesk xabsbtnem Is bonded to the rest okhe eo pouad or a g en formula, then suck suOxbraent any be bonded saa any aasra in suck tonrnda.
Romhuaskons oksrRagnrcnk and/oi variables are penniwabk, n i onlv it sack comblmnkns result k stahk compounds.
ksPk I When any variable R y.. R) cau s more than one time as any mmkkuem or foruuda lor a compound, its deOkkon at each occurrence as independesn of its definition at every other ooounonce, thus, tor es seeks if a gump is ^liowo to be so .emma a kk 0-2 R rnokdes, dsen ike group ma v s-ptlomnly be substituted with up as rsvo R mokbex suk R at eack occurrence s sekemd IndependenPv Rom tbe dekanmn or is. .Al o, oombkatmns ot erkstksents snd a carkkks are permissible, kg only If such somhirraPons result a* stable compounds, lOxakl The terra ''hydr " or "hydroayR in-, lades groups vvkh an -OR or a k
hkhsSk As used herein, 'kale" or "hahsgeik refers to fluo.ro, chioro, bromo aral kxk. The term "perlxdogemuod''' generally reters is; a inokis wherein all hydrogen new a are replaced by halogen atoms. The neon 'kaloalkyR or "ha!oslkoxyk refers to an alkyl or sdkoxyl sa.ks†.k.rted with one or more halogen atmns.
[028k] i ke tesm 'karbon Includes- csanpounds ark moieties which contain a carbon
eoas-casd with a donbk boar] a.) an osveen atom. Examples ok mokiles eoniuhung a carboayi InckKk, bra: are ran kmired as, akkhydes. ketones, carboxybc acids, amides, esters, anhydrides, ere.
[0287] The term kcuboxyk reikis io m.R)Ok or Its ChAR aikyi ester.
[Okkkj "AcyR includes moieues tkn contain use ae I radical · A a t g. : ;-.s- ¾ oarbon l groap, 'kaba uu cs! aoyT Iradudes aeyi grorigs oa'cere one or more of the hydrogen atoms are replaced by. toresana.de, alky! croupe, alkynk groups, halogen, yd.ro Rvp
Figure imgf000076_0001
aty karbonyloa , alkoxyearbonyioxys aryloxyearbonrloxys eas boxykie, alky karbsavyk aryleaksonyk alkoxycaibonyl. an;ua:sa::bonyk alkykradrtncartsaod, dial ylaadrao;atbonyi, alkykkioearboip k algtsxyk phosphate, phsoptKaiaio, pbosphinato, amino tlaelrkliig alkylannno, dbdlg lauoao, arylanono, olarylaa'nno and alky !ary!arn!ao ), acykanlnr> ilradudlng aikyicab aryiannno, arykxabenyhnuno. eaH. akeyi and ureidog anudhjo. brano, eukbydryk aikykhky arybhna, bb<oa¾rboxykoe, aaikbkxa dkyba!imyb aakoaana, sobbanoyk sabbaaiuido, nbao, tnOuaao ehgb. eyano, aaido, hek oeychyh abviaryk or an aronnuie or heieroarouxao 'k'k ,
idkbb "ΑκηΓ nnhodeo nKaedee ish an arvi heteroaru aiio nadery braaxl to a carbony! group- hxangbea of aroy! groups .Includ phenykan'boxy, napbthy! oabxrxy, arc,
iObyrb -y !ko.ayalkysb'; oi<;jky!«minooskyk''! and 'ahmalkraxyaikyk' einde ink ! goeups, -, descnbed above, raheroin oxygen, nitrogen, os sulfur
Figure imgf000077_0001
replace one or an-:-. hydrocarbon backbone carbon aroma.
1.0291 } The term · ok., o " or "aikoxyk* snolndea snbshokeh and rnraabadnacd akkyk nlkenyi and aikvnyi groups covakardv baked io aa oxygen atom, Examples oibbkoxy groups or alkoxyi radicals include, but ;.;re nor lurbted to, mcthoxy ethoxy, h¾propy!oxy, poopoxy, bao.axy arai penroxy group;-., kxaniplea oi -nXabo .a ibaoxy gr u s, mekale hakxyeraated alkoxy a: ay. 1 be alkoxy graaipa can bo aubadirked oo(h groapa anch .as alkeeyb alkyayl. halogen, dr xy!, lkykrarbony sya eryl ntxmyioxy, alkoxycarbonykvay, asa loaycarbonyloxy, carb-^xykue. akkykearbonyk ayxoarbon k ibkoxyoarboixh arrnaooarbonyk alk knrbnoearbonyb
cba!kykrn-naocarbon k akkykhbocarbonyk alkoaaa. phosphate, phoaphonato, phoaphinato, armao ginohKhng slkylaraino.. dkdkmamino ary!anhuo, dasrykaosao, and alk iaryknudnog aeylaudno (jnebidbga aikylcarbonylam o, aryioarboaa1a.m;no. carbamoyl and ureidog amkkuo, imlno, sraltyxbyk alkykh!o, arylthka fhiocarbnxghate, sakanss. aim I -obbo ! sulionaky aubaraoyb sobonaaubo, nitro, briiuorornotbyl, oys;v.;. axld^, heecrocycha, aikyknyh or an aromatic or heteromsxoabe aaobr a bxamples of Sralogea aabatbiaod akkoxy groapa include, fag am nor Ibrdied to. rkKxonaahoxy. duluorornebn-xs , irbhs;aomesboxya ihuoronmd xy, oadbosaaaedsoxy and trlchkn os uetbox y ,
|Όχν2| I be mrm la.nheb" or "ydkox " cludes; cmnpounds or raoiehes which eoniaut an oxygen bonded to ovo easbon aronxa or heteroatouw. For exana.de, ihe tenn includes bhkoxyalkyle'' which relora ro an alkyl. idkenyk aa- alkyrryl group eovabtnly bonded to an oxygen aaarn vouch la eovafeoly bonded to aa alk i r p.
pbgbb] The
Figure imgf000077_0002
eoniain a earbon or a hei ra-aton's boarid to :at oxygen aiont a.1beh is i-and^d ?o -bo c rb n adds canx-avyS group, Iba terra "-ster" a a, hak-. aikoxyaarboxy groapa aueis aa e;thoxycnrbonyh era.ixyaarb5.;rg; k
psa>poxyeaba<.aiya kaax>x year bony k pearoxycarboayi, ere,
[0 41 Ths icon ;rhioa;ky!" inohidea compounds or rooiebes which coataia aa alkyb group iroaaocted oath a aubar aiosra T'he ddoaiky! groapa caa be a batitraeri groups anch aa a!kyb
70 atkenyk abyn k bdogew nsdroxyh aikybxnbouyioxyy nrykarbonyloxy, aikoxyxarhoip k>xyx arykxycarhonyioxv. carbsceykuc. oud ocyaekk aikybsoTxxvyb aig Axwhonyb akx>\ysxaAonyh airnnocanxsyyi, aikybubnooarPonyh diakyxkusnaocasixuryk a!kykhxicarbonyb aikoxyk annuo Anoiuding atks bnnwx dkdkykunbw arybrnuKc dbr knn o nd aikykax bsrdnok ac> da hxa iinehsding abvkarbonvianhno. arykxwbonybndnss carbamoyl and uresrkd.. anurnno. umno. subhyxkyh aikyadno, aryhbuo, thiocnrboxykne, suii rea^ aikyhudkpyh sultbnaky auHasaoyb ubkaiamkky nkro, diiki ixsnerh h oyano, axkkc hwAwocyciyk aikybryh r an awxna.be r hetoroaron nab c rnoiehex
|'0 i] The wor- """U "J; ii I"" or Ahioca;boxy" nab ax sxxnpounds and axs-xa. ·· whueh contain a carbon connected with a double b nd t a sukur ;iiom.
I Is 2 6] The lorrn skbxba" inckxiex nanedec which csauain a. wdb; aAan bonded a.- rwo c ib a agana or bcarr ai ao. bxsixpks fdh ii sers bebde, bid a: a not kmned a;
akjhbaikvb, abthkxdkenykx and atkshkndkynyb. The ram? Ankdnoalkyb" hxcbde moieoea wnh an abkyk abenyh or abyuyi gro p, bonded k> a ·· agar atom which w bonded a > a a aikyi group, kbhbrhs the a/oa ''aibhioa!kenyb1'' wfcrs so unsbrbs herein an aikyk alkeryi or aikynyi grou w bonded to a sabkof atom which is eovaientiy hooded to an albeuyl groap; cad ¾ k s. ! i 5 a k s · I ; " ' sebrs So n-oieties a b ana an aikyk bkenyi or alkynyl group b bonded ΐο a sudo aioro which A eowakndy bonded o> an aSkyrwi s/oop,
[0297] As Used hereby "'andreb or Αχ-ηηκ refers to cii, s Ab Anew-' includes groups of cssnpounsb ohe eb die aUroaen obsdhA is boond to as 'cas one abyi ya a;- kxeragks oh eikybmmo g?oaps ineiode browx½nb;wx medrybndw.a eihytarnisKc pheraidoyknniao. ate.
) eg sexa:A inebdes groups whereas t e nitrogen oi'- M.; is bound as wvo cpx. I groups, hxampkx of dbbybndwe groups inckede. bai are not ikoiAd as. dmiethyhmbno and chethybnnno, XxrykuvdnrP" and "diaryiaudno" axsude g ups x heroin the nbxsyen is bonnci to as bast ono or tw apyi groups, respond veky xAminoaryA1 and "Amboarybxy" :>"bv b i5A^ arybxy subsudued with annuo. "'AtkybrybwnnoA Adkyknrdnoaryb or " xaryhnninoakiyb reters to an annuo groni.* winch is bound ^o as iisas one aikyi gro p and as leas* one aryi yuoap ''• lkai hasaikyb reiers is> n aikyi. albenyl o¾- aiky nyi gisaip brxaci to a nitrogen iorn whkh is abo boiani ίίχ a» aikyi gosuix "Aey nxiuo- nwinsJcs groisps whereii; nkrosyen is kiXind ;o an aeyi yaxwp, i::s ;andes ot acy iaixino sncinrb. but ase ;xx hsroied to, eiixdcabwsy/knrsuiO.
arviearbonyiamnxs, carharooyi and urealo g s.
'Odadj The ierui "anode"' or Auniuocas'bosy"- iiKdudos c-sn;ponnds or nsaebos risat ixsniau? a nitrogen saoni d;at is ho nd k:> six; carbon of a carisonyi or a thic'ca boiw i group, lw venn ineiudes ,a¾lk;sa' ssKxr-isrbs) y''> gi'oupc ri-at ίηοηκΐο sfkyL aiksn;A r.-r alkynyl gwxspa koarid io an amino gnoip ohich boons! >o dr.- carb n of a carbanyl or b b a:.-;' bon ? g mip. b bas ia-dabc Wa y!annnoearhoxy" r s that include aryi or heteR&n roomtiea houad s aa amino grou th i is. bound to the carbo of a carbonyi or hsmcarbonyi group. The terms
kdhylambxw<mboxs k gkkenylammocarbosyk knkynykusunoaarboxy" and
''srykurnnoearboxy" incbalo moretie;> svherein alfyh aii.aa-. b aikyny! and aryi moiehes.
respectively, ana boand to & ueo-cca atom a in- h a: in anas bound m das c rb n of a carbonyi group- Amides can be sabsthuted w s ssibsotacnta such as auaigin chain nikyk bran hed aikyk eycloalkyk aryk hateom yl or bensnscyds:. ¾bstbaenes on a nb oau-s may no Rasher aababiuicd.
[0299; Compoun s o( the present hw odion th i ocanain nitrogens can be converted to bkoxkles by treaimaib kh an oxideaing agem sa., , k-ehks^enetyf enx s acid oaCPBA> and a hydnagen per- oodem to- akord opser compounds ofihe pmsent inve bon. Thus, ad shown and claimed mhxgxas-eonnunhig ermrpounda arc considered, when allowed by valency and sbactung to Include bobs the conspound as shown and its -oxkk- derivative twhieh can be desigrnued as --..-0 or '-Ο"). Fnrdmrmore, in other imuancex the nhrogaas in t e compounds of she present mvenlion can be convcrtad to N -h droxy or hkaikresy e m u^d . i a -sanaks hkhyxkoxy compounda can be repared by oxidation of das parent mi e by an xidi in agom such as i-t ki t. a All shown and claimed nikogemomntaming compounds are alao consklercd.. when allmvad by valency and strueUne, to cover bath the compound as shown ,wg bs kkhydixwy (taw m-OH) d hhsbkoxy b.e.kho-OR wherem R is subssbuted or onsnbslkuted ks bk. alkyb R kk alksnyk by -C; alkynyk kkf membcred carbocyek or 3-14-rnembered heterocycle) derivat xw
[baud] in tbo preseru spceiiiaabon. ids su natural Rumrda of dm -a a;p>aass iepseaems a cermm isomer for ο· soar-nience in sonsa case-:., but the presetd invention inciudes nil isomers, such as geoasetneai is mers, opiieai is mers based on an asymmetrical carbon, siereorsomersc aHuomem, and the dbs. n being undevwoob b t not ad isomers may ha>e die a e level of ao ivm . in addition, a crystal poiymmphwa; may be prese tor dm conspoands represented by the iormuka it is nomd ben anv erys;ai harm, crystal terra mixture, or aahydtida or hydrate the eof k; included n the smme of dm present mvsntkm,
pfdHj kisomerisnR means compounds that have idenbeai moies ar taor lae bus difier in the seuaemx or bonding of iheir atoms or b; the arrangement of Ren aesns in apacv. isonsera thai d ffer in die ao-angenscra of their atoms m space are termed "stemisasosoers."' Stereoi omers that arc not rnirosr anages oi one another ara termed k^iaskreoisomerak and s^resbso-ners th i arc
Figure imgf000079_0001
rnuTor inuigea ol'cach oihcr are mrased ct somei seG raaaap ;;ίθί: , A mixture eomnahng egoai amounA f i dividual enxmlomeric Asms of opposik- cbiraheg is termed a naccirec mixinre,"
|A0gj o ca b mo bonded to four rr -radenneai aubsdmenir is iermed a ' chirnl ceruerd' | 3 3 "Chiral i om r' means a compound wuh at iensi. ne chirsl ccriteis Compounds with more than one ohoai center may exist enher no an individual barstervomer or as a nux ure of dlastemomers, termed Ahasiereennsric mixhnxA" When one eibra! corner is present a stereoisomer mav be charactermed by the absolute oonbguradon (R or Ss of thai ohiral oemer Absnhuv configuration raters to the ammgemcnt in space of the subs ituenta attached to the ohiral omer. The xubsPtuenta attached to the chiraS center nudes consideration arc ranked in aoeordsuce old; Pa-: Aopoaoc oba ot'o'elsu, hnsTI and Pre oe, (Cairn or no. rOgymo f¾em. Ager..Edti, L 6; 5, 385; errata 5 I k Cuhn rg oA Amgor. C&ws b:oo.7A; 4] ·; Cahn and !ngohi J Cdeos ,S . Ida I t London a 612: Cahn e; oA Av'pssoosna i 06., 12, 81 ; Caere .0 C/asn Afne. Agog 4 b ] she
[ΟΑΑΠ 'AAo etric isomer" means hse diasvercomerx thai owe their existence to hindered roistkm about double A enb or a cyckalbyi baker (e.g.. iA-wykoAuA i). These eouAgurationx are d fferentiated in their names by the prefixes cis and trans, or Z and lb which indic t hsa the groups are s ¾ the va e or sit side or the double bond in lire molecule according to the C a h n A j 5 go id - f 0 c i o g rid e ..
( 51 b is to he andersemd dtat the eo goo k -si u;e pro en; invention may be depicted as different ohiral Aornem or geomeose isomers, it should also be undersiood that when compounds have ehira! isomeric or gcome!ric isomeric terms, ad iaomeaio terms are mnioded to he ncl ded in the scope of the oreseoi mvenbon, rani Urn naming of use compounds does not exclude any isomeric forms, it being undersmwl thai not aii isomers may have the same level of activity.
(0306] Furthermore, the snaetunes and caber compounds discussed m this invention include ah an-..g:ae isomers thereof.3 being nuderstr-od dan not ad atrople isomers may have the same level of acihooo "Abopk A ners" are a type of sbnvxnsomer in which the atoms of two isomers arc arranged rubere ly in space. Αο-ορη: isomers >ewe their existence m a resoicied rmanon caosed be hindrance of rotati n of large groups abom a central bond. Such atropic isomers Apkaby eaasr as a mixture, however as a resub of recent advaacsa l¾ ¾ ebroma gmph; iecbrunues. it bus bcea possible r^ separaie ndxtures oiAo o ar^yde iso er ;n select eases- [03031 ;AauionscA is one of tw or more strrennral isomers that exn:t in cprabbriuin and is readily es'uvci'ied irons one isomeric form to siaahci. This conversion resnlts in she formal nugrarion r.sf a hydrogen atom accompanied by a s lieh oi'aoie-cern conjugated double bonds.
?o ;;!·ΐ· eaers exi t as a raixnue of a tanuunsnc set irs solution, la solutions whore auioaeisaaooa a; possible, a chemical espalibrlua; of the taraonters odd he reached. The exact ratio of the caatomera depends re; several cso ors. Including temperature., solvent are! pH. The conce at fautomers hai are mtercrsivertabje by tauwsnensaboas is ealied tataomerisaa
j sOf'] Of the various types of haetonnarism that are possible, two are oounrsonly observed, la k.ee enoi mtnomensm a slmulauteons sh ft: ofekeetrons aad a i- eeca anon oosars. ; : eao chain t::n.noeierism arises as a restdt of the aldehyde group e-C! 10} in a sugar chant moiecele reaoi s erith · -ac of the hydroxy groups pa a o ;¾·.. p¾c ,aaa- osa-wak to give it a cvehe (ring- shaped? torns as x i ited by glucose.
tpypo] Conurnsn tauaafaeric pairs are: ketoae-enoh amideuncrhe, iaciasrrdactlae aakle-hnkhe acid tautra'aeris at heterocyclic nags Onto in nuoieohuses c as guanine, thynnne aad eyoeiae;. hnine-ertaobne aad cruaOsra-eaai aae. fdxatnpks of laotanrdaethy; uunomemru are as shown helosv.
Figure imgf000081_0001
OilOi if is to be understood that das compounds of dee present iavcnta?a may lor departed as dPierent tack soars. It should alao be nderst od ilea when com o nds have ta omerte tonus, ad tautomeric forms are irnksodsd to be srtekided if? the seope of the present usvenPoig mi the naanng of the compounds does not exeiude any mutomer torm. It svih be understood that eerada taaa.an>vrs nag have a higher level of actevPy than others.
[0 1 Π The terut 'kryskb polynoa'ph 's
Figure imgf000081_0002
o; "crystal Psoas" means crystal sP'taaares a? srhleh a eoaaxnuss tor a salt or solvate h reof} can erystahiee in different crystal packing aimagentenev ali of which have the carne elemental eoatposition. Duierent crystal harms usually have different. X-ray didVactsoa patterns, irrfrared spe rah nnrabng pouns, density hardiness, crystal shape, optica! and electrical psopestles, stabllny and sohibbtty.
Reotgotabmanoa sofvent. rate of crvsadiisabon. storage ieaspcratta'c, and other the to s may caus oac as vsial form to oraniaate. Crystal polymorphs of the eteopoonds sari be r ared by ervrtauhzatkei aader dlftereni conditions a ! H>3 !>' j The · sup.-am.- m any f onorda described herele inviade t e corapoaeds deornevea. as a. eb as haslr vales aeb hso; sobatea, bSspplicable. .a salt to; esamgle, can be banned betweoe an anion and a pvsibsely chatgcb groap hag., amend on a subsbhued la sene cotupoend. Suitable amons nnalnde ohlonde, bromide, tedide, saifaas, hisnhaay subamate. aaaaa.
phosphate, eitrale, nmUemesuibemre, trihuoroacetase, gunatnate, gkaaronaie. gkaarvue, malaie, nndeapvs stalemate, turnsrale, ianraie, totglate, salicylate, iacaav. uaplbhalenestUhantaa and acetate ne,g„ h-hn-oroaceonea The term ''pharmaoeabeaiiy acceptable anion" refers to an anion statable lor lorming a pharmaceutically acceptable sail, f Ih-a.-■ '■· . a salt can aba; be formed between a cation and a ncgasively charged group (e,e,, carboxylase' oa a xubsptuted beus:eno compound, Sohabie cab a; . include sodium ion, potasAnm iota nutgneslant loa. calcium ioa. aad aa amuiomuna cation such as tehsu-nedpTaswnoniam ion The eabsbuaed benaene
aapcaa.a also include those sails coabaaing quaternary nitro n aamvs.
[0 1 ] Additionally, the oonvpoueds of the present invention, tor example, t e salts of da cmnpouutls. can easst m either hydraped or tnshydrared (the anhydnsteA form or as solvates oath otiar solvent molecules. sAubimitlng esannbes of hydra tes include nionohydraPcs, dihydraies, eh;. Nonllroalna osmples of solvates Inclede ethano! solvates, aeetoae solvates, etc iO j a] bv;|v,ne" means s be s u addition forma thai comaia either stolchiomeusc or non so,nohaoatea'ie car -aa: - of smvenh Some compounds have a tendency to trap a nxed moist rado mAolvem nKbeeeles in the crystalline solid sbaa. thus harming a s l ate, if the solvent is water the solvate f rmed is a hydrate: and if the sidvenr Is alcohol, die sol at f stated is aa ak-shohae. t deaaec am burned by the etaraslaaboa of one or n ae molecules of states* oath one molecule • a dv subsemee its vbueh the rsauer telams its molecular state as llvO.
[0315] As ased herein, the tent; "analog" rvibra to a chemical compound that ss neaaee!b sutaiar as another bat diners shghdy in composition : a : in the replacement of orre atom by an aene of a duhervnt xiesnem or In the presence ofa particnlar irercdonal groap, or the replacement of one renedonai group by another iancuonal groups Thus, aa analog Is a compound th t at saniiar or comparable in rnncoon sad appearanee, but not in structure or origm t the reference compound.
[031 d] Ac debaed herein, uve terns 'blers tl ve" relers to compounds that have a eoaars ,.:■· etae sttacrure, and are s bsubsted with ani- us groups as described aerem, fan oauaaie, ail or the eottiporasds renresenaed by Fc;;saraa bl) are stavtpaacd bes-.aeae -nr bieyelle bsieroasyi eoaspoartfss, and have PornnOa Π} ?.ss a eoutmon core.
[03 b?l The icon v aoisosίere', reters as a compound resuklag rom tie; exelaasg?.: of an aton or ofa groan <*f atoms dlt aaodter, broadly slntllar, tsm or grotip of taorns. Das obieeioe or a blokveaeric rcplaomncnt to a aeo compoond with similar biological pro-pea ties to he parent compeamd. The kwsostenc
Figure imgf000083_0001
may ho- physkmsaemioahy or topokwioaliy based. Examples c oubox hc aesd b isoepems soekbc; bus are not !bnlmd to, acy
:wdienlinkka: teOomoks, smketaie aod phosphonates,
Figure imgf000083_0002
a. p., Fatam . d baVok, <.¾-·.¾ wer 6, :m?ki7k
f 031 ] The pss-sent sovcnPon ss intemted to include all isoiopw: of atoms ccu r ng in t he- pr se-U compounds. Is t es Include those nPoms having the same atomic onoksr bat different news snnnbers. By way of general eaxnnpie and withma kronaisew isotopes of hydrogen nxJode bitit ; and detbera g and isotopes of carbon ho ba - C-io and Cad 4.
i03 tbl Tbe present invention provides methods oa m.- synthesis f the compounds of any i too hossmdae described herons. lie pressor Invention also provides deiabed methods t rihe symhesis of various dkcknvvd conipoonds f she present iuveaoon aeeordmg to she hsbkovnvg schemes aa shown in the Examples.
103201 Yhroughotn she descrnvdosg o-bere omnpowbons are described as having, including, or comprising apecdk com nent' , is cookmpkried thai oomposltions also consist essentially of or consist ok the roosted components, '--iookro where methods or processes are described as having, inciudkg. or eoogasising speckle process say. ·. the processes si · · consist essentially oi.. or consist of. the recked processing steps. Further, it shook! be nrnlerstood bee da; order oi steps or order 'Par periorrning oeriain ctions is immaterial so long as tbe invention remains operable. Moseswer, two or more steps or actions can be emK-incted sinHiUaneotisly.
[0321 I The synthetic processes of tbe Intention can okram in wide variety o bkrrcbonal groups, therefore various ub tituted starbog materials can be nscd. The pjocesses generaliy psovide the decked final com nd at or near the end of the overab process, aUhssmh it may be desirable in certain snstanoes to further cosovcrt tbe compound to a phanaaeeubcahy acceptable salt thereof.
[0322] konpvaonds of the present in vendors can bo prepared in a variety of ways using commercially avaliabk slaPing nuitetiahs compounds kanssvn in tbe keramrm or from readily prepared brie; mediates, by employing standard swnhetic method- and procedures either known to tboae sblbed in the arc or which wb! be apparent to the sbtbed artisan In ilghi of the teachings herein, btandasd symhcbe methods assd procedures for the pre paratloa of' o a c molecules and ίηηαΐοηηί group kasssksmabons and manipulaOous can be obtained from the relevant scientific boesvause or ;res'i> sPaasard tod e^k in 'he beld, k thon h iot Ibrnkd to any one r severs! sources, classic texts sush as Ssmih, M. C, blarcl'!, J,. Me rk a E2ar»:a-ak 'Tysnnk ki f*ko'; /vorayg.oss. Sbakooaoro reek baaoo/ieo.5"' ed!ilois. bdai Wbey aa Sosts: bieo' 2 orb.200 k
Greene. E.vV s kkts, Pki kb: /a ooaaso;- ,k f eosynbc o; obasvrv.3'1' edibon.. John Wbey o2 ά Sons: Ne York, oe:.: ay l.,fir< -;; , idvi /i he ive Orgatifc fhxgfoii oion VCH
Ptnbbeners ; P, I,, Fieser aad ; 1. Feasor, bests- non /becee s /seoyreno- for (A-gxaiv bYnrPesB. John WiBy and Seas ΠΥηΡρ aid I... Paquebe, ;-xL EnceeBwoYo qFiboey /P Pbo- Orgomr Pbea/ssvro John Wdey an boar γΡΟΥ. aw orp^nPed by reference ko-reiu, .><·. aseiuf and ;eeog;eaed reier¾-ra/:e iexdsoofe: or ryaaa: eyiPhens known i basse as the art. The totksosng desoriphoiw of syiHhebc methods ae designed to bk;stracef bur not ΐ hmiy cc;ar:0 procedures tor dw preparaOou or compounds of the e o-.cei invention.
:032a] PBoepounds of hse present invendon can be eonveniendy prepared by a sasieiy of awyhods Bumbar to those sbiiieu n¾ the an ca basse described in \VG 2ΟΒΡΒΥ50Τ BP).
20030425 Fi aad WO 2012/1 IS I2. whch are iiKorporated herein by rerewnee. The compounds of ink uwsenoon havuyr. aay oi: the Fonra.dao desenbed herein may be prepared accor ing to dte procedures iHusrrated a; iweonv. P-4 bebsw.. Bom eomsnerobdy available sPu-ring ewueriaB or sundry mateOais h ch can be prepared usi literature proeedums. 'The H groups (such at; Re: K?. R¾ era; r>) in Seasons ! -3 are as defined at any Porreuia described herein, urdess otherwise spec? nod.
[032-1] One of-sslbauy skill as the an will aore drat, daring the reaches-; sepneaeca and synthetic schemes described herein, the order or cenain steps may be changed, cosh as the imroducdon ami rernowB of proPscung gnsopw
[0225] One of ordinary skid m Use art verb recognise tbar certain groups may re uire rote ti n bean die reacuon conditions c th - ose of prsaecthsg groups. Po.aeetn?g groups may also he used to dOfbremd-ae similar B;nctlo;wb groups in moB-cuRs. A list of protecting groups and how to Introduce aad remo e these o s can be lorasd in ai:-:--.ss T.W.„ uts. *"'.·: a oi, /soieeYre
YeisYewo 3" edIBom Pam Wbley & Pom: Yew York, I99R RBYol Preferred protecting; rou s meiude. but are not bruited to:
[0327] bora huhoayi aioRiy: IBS, benzyl TOP.. Pa
[032a] For carhotwhe acids; berwyi esPet, rtuMiwi csrer. edsyl csicr.. ally! ester
[0320] Pur amines <3ba, i:P.X2,D B
[033 i Fra- dads: As (aPa TBS fs'2„ or when taken iogether aceroiddea
[033 si PotrhK)isaAe
[0332] For beardmnkrtobes: ST M. beuayi, P.M. , Fide B
[0333] But aideiyedes: di-aikyi aeetais such as dsaaerhoay acedd or diehyl acctci ,
[03 a] In tite reacta5; sciicascs d s r bed herein, renidpie srererasoiaer^ may be produced. When ao patticuiar saa ooisaaier is indicated., it is understood as nseaa ad possible siereoisoatecs dan eoaid be protiuced insn? bw aciara. A stetson t-f ordinary skid in U ¾s art wid recogidze
33 that ibe rea ions ran be o tbmxed is- ive on Isomer preicreinaby, or new schemes may be de ed K; produce a smgle Israner. If mAiarca ase produced, icehsbqncs stab; as p e xn bYC thin layer chromatography^ pieparauce BOLC. preparative bbed HBB03 or preparabve SFC may be m separate rhe isomers.
[0335] i he rbiiovvleg abb evations are used throughout the specification and are detmed Above;
A A am ion hmi aeetaie
[035?] AC A aeeto trbc
[0338] Ac acetyl
[0539] AcOH acetic acid
[0340] aim atmoaphc e
0ΑΠ] r p Apueona
10343] BID ta ba.d. bis in die OvAee a day)
10343] Oa uOK p Assium t-biursxlde
[0344] Ba be nay i
[0343] Box; teri-.b;a.ux>' carboayl
[0346] BOP {beneOna e hb .- l \y5†isidinieb lamii'io 0347] Chat bermyl xv carbonyi
[0343] CDCh demxmted ohlorolorm
[03 Vj AhDCh di..hk>iosvi th¾v¾
A350j roMU i I -f A a i-A., ah x> A-mxoeth;, bd maemo sy Kboaethy i- aniliHj-e r - hoiia -cta'beoiri i he atltiorophespbate
[03511 d days
[0352Ϊ DBA I --di eabic elo[5eb{bu?aice-?.e
Ϊ 553] i ay; i ,2 di h xpnaisa
[0554] DC 31 dicbloroaicthaac
103551 rpyen Diethyl aeod lea rbe-a late
[0350j Dl AD DIAopfopti <raoi.bearboxylaie
[o:>y?j DIB Ah - B dbs baiy! Aamlme hydride
[0358] DiPBA 'N/N«dhsopropyictbyaa;eiac tbhabab base)
[0353] DMA DboebiS biCeP-nvsdc
[ 360] DivlAP N. di eihyhAmmhvopyrhiloe
[0301] DMB 2..a da' eiloxv benxv [0362] D F NAA5 uo UiylA>riisani A
[ 5o8] DMF-DMA N AF-Danrihybbnrsanbde dimcih i aeAai
[0864] DM Dimethyl r4k?xlA¾
[0365] DPP A D h nyi hoNpFoiOc asade
[0366] Λ or fAOAc Ethyl cKiiie
[03(3] EDA: ED(A -<5M¾mevh iamkso ^
PAAA BiAA diethyl ether
[03 ] EES Evaporative P gin ScaberAg
[0370] I A- EAArospray aegaPve s oOo
bB7!j ESI-!- EAeAoNpray podFive snode
[0372] EAAAa-TbA P sO'ol snF/
[03AH] BSD A Ahassoi
[0374] FA torn sic aesd
[0375] PC r FCC Flash chromatogrpahy
[03 ?o] h hours
[03/7] FAO water
[0373] V!ATU iJ-PAAiah-i!Z irazoi- -νΑΕ ,.Ν,Ν'ΡΝ'- t A;:a ethylu!'onh.an Pexa hiorophosphaic
[03/9] !AA Aiydros > oj-azaberrsotAazole
[0380] HOBi ] Alydr xyb ns afia A
[058!] AC a N -4 Fy d o sxy su e c a F aa kA
[0882] ACS hydrogen chloride or hydrochloric acid [0385] HPFC Pbgh pedormaace Fquid chromatography [0384] KAAA pmasskao carbooaA
[0383] HM s PotasAum heoeameahykbshaAde
[0389] EC/MS r I C- F squid chromatography m ¾s ape-oman [038?] ADA hithkan doropropyk mde
[0388] AAlMDs Flthmrri hexamebiykAaprzirk
[0389] Li j sea Ase ro p
[03)0] M Akbar
[039 Π m¾ roasAoharge rado
[0392] sroCPBA so e ! a ~c h I o ro per be rs £ o i e a cs2
[0895] AAA A AcAoAAbe
[0504] N-k >D 04·· ;θΑ!βί 4 [0395 j Mro edgd Bdide
0 A 4. aaBeeeiar ska as
10367} Magnesium ardiate
[0'9}9j Ms Mcsyl
[0900] O P vk.yV'l chloride
=0401] Msg) Mesylate
(9402] 308 a a c Speecraa
ί 04031 MWI mic iXHva e j rr d an k a ¾
[0404] O gCgp aai aa aarboaate
[0405] bggdPp aodaaa su Paste
10406] NaBCX .. 'd: a: ba.a bonate
[046?1 N.'iH.MDs 9 d ! ai j hex m e h y Id i i Padd a
0)4041 &OH sedaa hgdreeode
[0409] NaRCCg s d um Oaaalxaaae
[0410] P9 4g.g codaae suiae
[93 Π] PBS e iodosecciaardde
[ 4131 BMP, Naekar 3/P¾aade K ¾<.?.n ;sc&
j ] rda os N overnight
[0400] o 6 0:4r- 3aa; aa v rboa
POiOp f}i:4-4:. ( P oa;H\idpheoy;pho^phirs i rrocene^
dschbj i riih;;daa5pll)5coo"!plaa a Oh Okhloa aedaase
[03 P>] PPAA BOpTp ae hosiphoak avid cyclic aahyddds pHl j Padadkao OiOjdroxkk
[0 ! 8} PE Pc! OiCiaa Paha;
[0 IV] p ; protecting groap
[0430] P B para raedioxybvnayi
ppa eaos par aOiOoa
a. per a¾- (oral adaadoaalons
p;cp i 07 : iaa rad a H h Perfoaaeaae Okadd P4a-oaaeeeraphy
[0333] prop 4 PC yicparauve Ooa layer ahrooiatograpOy
p-I's I-' gar - rosvcafiradP 'idc acid
jo43a] PpBOP iPeaa-O'KiCobd -gdoxg a i xa oiidiaigOajS boak o rieaadlaoropia¾phaB: [0427] QD r .il -.piaepie die οίκ a day)
[043R ROT -'ΛίηΟ boUea:a f sk
[0420] RP-MFi.-C Rcv s' e phase High Pes k>mancs O uOi eh arcuogrephy
Figure imgf000088_0001
[0430] M !443n5eO>yt¾4 R ih 5>iiieOyi
0O32] SO o4 dfrii dydsHyOediOx med d Od-OJc
[0433] SIR: Oup f critical ciiiom to r:;phy
0 1 SOC silica pel chr rmiiography
10 ] SORB ■Sodiun-i ekKSioxy boroh jmk
04434] IR3R Rra-c<v:i4ybiii¾! onk il oi'KR
= 043?) ΊΒΜΕ icrOBypyl methyl dier
TEA Tm-thyiommc
[0434] IF A kdliso aacOic cd
1.0440} 40
[044 !j TIW Riah dioRira;!
[4442] 1ΉΡ Rirahydropyiaa
[0443] OO =·: · = 4 tcr in die Rh>"ee omcs a day j
[0444] T! O thin layer ehroaxuography
cO 04 IRJSiO Trisn<a1y> 1O04 chloride
[0440] 10 tosy i
[5)447] 4344R toOe acd
[0448] \ ultraviolet
Figure imgf000088_0002
Figure imgf000089_0001
jo..p.pb Ά b. nv I vhooo the tonPboo of auhednned beneene com un s following a general roueo T a ijuno-i ropgion of oornpoamf AL ·Α· vaoe and
Figure imgf000089_0002
are ended and i rofubon b purged veiih an inert gay sub; ne argon. AigPldpg b dten added, Ore reaxddog resodon rrnxu¾re heated at aa elevated en^erature; e.g., 100 "b for a fe hours pe.g,> 6 .s to dtbrd Ad whieh is treated t hh aeki A,g... orA Mi p and then babfied ith, age., a NabCip aohpion to afford A3. lA«n NaBPL b .Ak-i P.; a eolation of A g ;plbrd s- np-end Λ i hen compound A4 is treated
Figure imgf000089_0003
phenol to afford eoropoaud A3, e. Poh ean then be hydrtay:oad to afford cornponnd At?. Ojntpormd Ad risen reaeta wnh 3damkun-oeUoab2pV dhoedp1pyrK?i;v-4{ ! Hp-one to afford c m ound Λ7. iaeisenie 2a >T ..... nΎ " "'
Figure imgf000089_0004
Figure imgf000090_0001
((M50 chema: 2 aaa 2b aa.-.e,,.- shoo the aynthe;as -.-A -■ ^ :?;··.· i≤ · ··: - : benzeas compounds.
Figure imgf000090_0002
!■>. a■). ;;, a. ί or : 0251] Schema 2 shows bar syntheso f modinsd hniaeoie analogs kh anng a genera! tooa; that utilizes cih-ecaabiichiai ohonmoy. iairodaohoii of a naro group s a T-ol l coanpoond «ο ha achieved using standard rbPsnoo condaions scab as nhrlc seal In suiiorlc acsd Pacp IP 'Th acid can be esieniaed by taeabticnr ith an a!kyladng aacas scab as nanhyhodide in rha presence ot a base each as onlkan oarhornsne n an appropriate poke solvcin each as DMF ibiep 22 Redaction o die nine' groan asnig an approprhac redaelng ageoi snob as sron with an acai such as smrnonhuy; chloride ;n a probe solvent such as cthanoi can o id an anihne sStcp ay Diaaobaahon oath an; appropriate reagent such as sodium ibis do in a polar soH rr s as acetic rid can lead cscll:mion to provide aa iadar.olc (Sbcp 4 a h veal be ap arent ;:o ns skilled as die an thai ihere are multiple v. ays so syndresize avdatcbes (J. caps tyeras sbbn "b. S i ed--8 ! ?. }. iinred'ie iOii or the by to do:- indaobe can be done e - g appropriaie R LG where I-O is a leaving grou sash as Old or Br. Subjec ng the unennedlatc a- R d -J a; d;e pre ¾ ace of a nR base snob as oeaioo; earbenate ;n an appropriate p:dar solvem -nich s Db b can give t e acsu- J -y i is. ed nKiaeole esler iSiep i s The cater moiety can be converted so an soobo losing a ■aanoard tw st r t c l. The ester can be hydn based io dee corresponding, acid o.-aa.- a suitable base such as sodum hydroxide s? a polar solvent such as etbanoi tSieap 6.1. The acid eae ihen ^e.-cr.d svph a vtsralard andde · ;s:.aaa- rcaedon thereupon die approprlaP? annne can be added long with a suitable amide coupling r agent such as PyBOP ts a suitable solvent such as D SO o give the desired antide deep sbiibdbs.J
Figure imgf000091_0001
i' 452] When R,. is n appropriate group sach as bromide or ttlOate. a variety tnbulwbtnenis conkl d;en be hiOs.staeed asiag standard iunvslbori megd-hased protoesds. For t-seun-bs the brofaide can be csenbaied with an appropriate boronic esier deri ati , in the pre en of a nidd base aad a pslladiuui catalyst in a polar solvent such as k o-neo water. ;e ekvaeoa eetnpeoittnvv so give sac desired indaaole (bchenve 4).
[0 a'.bj Λ person of ordi ry skid in (he art son! re- ognkc that as the above sebeases the order or usany oibhe steps arc h'derehangeahk.
ΙΰΤν-Π Compounds oPthe present bceeathsri inhibit the hlstone inethyUraesterase activity of kZHd or a tomans tbereor a p secordlngh. in one aspect ehbbe homnboir ccrhon compounds disclosed herein are candidates lor treating., or preventing certain conditions and diseases, in sohkh bbhie ia s a ode. I be present Invention provides me-hods Re treating•.••min; sv snsd diseases the coarse oi' which can be biluenced by neakhaiing dve nsethyiation status ot bistonea oi other proteins, wherein sain methytahon status is mediated at least in par? by bre activity or b H2. Modulation of die methykedon states of hisesws van in turn hrbaets:e the kuel of eapresseen oitarget genes activated by nsethy laden, and/or target genes suppressed by methybdsst. The method dado adauni-Pei ic ?.v a snidest in need oi'saeb p-easraent a therapeutically effective amount of a cosopouiKl of the presem invention, or a pbarnsaceuncally acceptable sah, oKnmr h. hxue. or atetssbsonvercv thereof
|oa■·;· ; fapess otherwise stated, asp- descriptive of method of heaimetst includes are of the compounds ;o prsunde such treatment or prophylaxis s Is described herein, a seell as use ol the compounds to prepare a medicament to tmar or pscvcra such condition. The o-.aaaao; includes beahoem of human or n. n-hu an amrmds im ladling rodents nd other disea e models.
[0-56] In stih another aspect, ibis invention relates to a method of rnodakiing the activity- of die EZFIZ the caialytle sabanii of die PRCs complex w ic catalyzes the mono- through t;a- nmthylation oi lysine 2? n hisioae 1-13 -13-K.2?) in a subject ia need htereof For example, the method oon rises do; step of administering io a su ject havmg a earner expressing a a taiU i v 115 a darrapeataraby efieeine ;nnouni of a ·.■·;:■/ ■ asai dmcribed herckc vZtereln the comprmtuioy inhibits hisioae meihyhosnsferase activity of PZH2, thereby h-eathya the cancer, ids 57] For exam le, the- ; ·;Ί ; .ο:;..:..|.. ί ·ρ oencer Is selected ti-o - she ryemp conslstnva oi lolhoular i .mphorm? and diffuse large B-oeii h phon · id or i : of germinal center B celhliise i C ) subtype. For esample, the cancer is hsnphoma, leukemia or melanoma, f referabiy. ihc Ksephoma Is nmvliodgblifs iyiv h mn (Nifio. iollleulas hm hooia diffuse large B-ccll iyusphoasa. s ltcrnauvely, the leukemia is chronic myek enous leukemia (('ML), acute myeloid leaFcmla, acute lymphocyto leukemia or mixed lineage ieebeafia.
[0438] For am le, the- bZRd edlaied piceanoerous emsdibon la rsiyelodysplasoc syndromes I I3S. formciiy known as preleukemia}.
0459] For example, the fZHvunedioted eat-ser is a henmtokysical cancer.
[0460] "The compoandtsl of die present inccnflcai inhibit the hlstone netliyltrnosss:rase activity of FZFI2 s- a snatai thereof and. accordingly, die present invention also provides methods tor ireating ussdulom; ami diseases the course ol which can be influenced by modrdat g the methvlatioo siatua of h?stoiK-¾ or other protests, wherein said rnei y Union status ss medlalvd at least in par; by the a tviy of EZIic. In one aspect of the Invention, -serpen compminrls dlseioaed herein arc candidates f r tre ting, or r venting ·. eneiu eondaions and diseases. Modulation of the meihy ulon stattss oi hisnanes can in turn Iriflaenoe the level of expression of target genes activated by meihylaiiou. ambo; target eyeries suppressed by meih labon. Use method includes adrmibsi.erltvg to a aahlect in need oi auei^ ti-earinesas a therapenhcapy i¾et.ivv ainor-nt of a eoiu esund of the presem ismcntan-i
|u4df| Aa used herein, a Xm!yleef ' ss asicsc ha iuaeable vvslh a mubiooi in need thvo-e-ra", boih of chiah refer io ;s sabieetdravlag a disorder in vhicb KZfko-nrediated psotein nscthylatloii plays a pari, or a sabprei having ass uvcrcased risk oi" developing such disorder relative o the popuhp!on
«1 el aegv. A AahAecA' meludes a eaen ak 11;-:· nmaeea? can b e g., a burner; or epproprkee u is- air f!O manenak such prlmeA. mouse, rat. b g, oat. coos hom , goal, maoer. sheep or ps - The sealed mas also be a bird or lowl. In one embodiment., the mammal is a human. A sebieei in need thereof can bo am oho has been reviously diagnosed or kleaohed as haveag saucer or a piecancerous condition, A suble so need hereo sen also be one who has (e.g., a; suffering from) cancer or a precancerous ondition. ieernabveiy, a subject in need ibereoi can be oa^ s has an increased isk or de elo ing such disorder rekaAe s the population ,a large (i.e., a suisjec; ¾ o ss predisposed to de elo in such disorder rekelve as dr. popeiadon at isege). A sablem la need thereof esn sieve a precancerous condition. A subject in need thereof have refractory or resAunU eaaeer fi e., cancer thai doesn't respo d or hasrf t yei responded to ueaauenA The subject may bo resisiant ra stmt οί treatment or may become res aea du ing Aeannenk \n soaae ciohodinienrs, the suhpoot in need thereor has cancer recurrence oi!o ing remission on most recent ihensp . in some enb-almmms, be: sc-aa, : in need das rent race iveb and Puled all knoere e teebve therapies kn earner treatment, in eorae emlxedlmente, tee subject in need thereof received at basi one prior therapy. In a pselerred eirdsodimenk dm saa-e-o has career or a osm.en.a-s ccaehtlom For xam le, the esaveer A lymphvnae leukemia, rnelaeonua or rhabdomyosarcomas, Pretereblyy the lym h ma A aoa-Hselgkia' s lymphoma, Addo-Par lymphoma r diliuse large kAceii lymphoma, sslternahvely. the ieukeioin Is chronic
myelogenous leukemia ICAab). s a-,- precancerous condition Is myelodysplasia' sysrdroines (MAN formerly known as pmk'Ukesnsak hs one emf id e p a ubject In eecd da-reol has an INi I -deficient Sumor.
p) 62 INI 1 is a regulatory complex baa opposes the eroyymatA fanction οίΈΖΗ.',ο Doc As a vaAep of genelle aherads-ns, INI I loses hs regulatory ianetion. As a result, EZkls actively A a-lsresadaied. causing E2B.2 to play a driving, oncogenic rele la a sel of geeebCidiy deiVncd saucers Peg iaclnde synovial sarcomas and makgnnre rhabdoid tumors. S novial sarcoma is e maligeam tumor of rue soA I issues' and ss one of die UK¾> coeuaoa soti tissue tuaasrs la adolescents and yoaag patients, hiean s « ot pauents at dasgnovis is approxl;aaa;ly 3n years, k bd go;. en rl-;abdold lunasrs. or MK'i , are a rare and deadly S OTS of chkhih d cancer thai is caused by a vpeolfc genede
Figure imgf000093_0001
that leads to ahsreaolaled EAfld taacooa. ΡΙΙΕΓ tsysleally preseals either In the kidney or Nam end Irs child en less dues two y>oes ofage.
04 ; .as used herein, s'ea;sdida.fe csanpomak' raters a conspoand of the present invention, or a piaasaaeemlcady aveepiable rah, p-dymorph as colssae dsereob that Isas i\-a ill be tossed in one or oaec ;o ; Aeo or /a Avo .deao kal assays, la order a? deoxr lnc if diet compound is bke!y to Alea a desired reoloeleai or medical response In a ceik ussac, system, aaanal or hunvan thar j being ssa.gght by a e se ar her o- elhhcinn- A ennsudntc cmoootavd is compound s4 bar pr nt :nvenhon. or a pharmaceutically acceptable ab, polymorph or solvate doe^-a ·' a,, biological or medssai response can bo the tre ment of c nc r. The iological r mesbca;
response can be irca mnr or prevention of a cell pmkferadve dis rder. The b logieai response or efksd can also include a ch nge Irs cob proliferation or growth that occurs o; vara or la n anlmn model, as well as■ ag.-r biological changes that are obsersabk m envo, A; wmo or a? rno bioiognvd assays ean include, bid are no honied to, emryinaoo activity ass ys, elecgephowik: ohbgy s4bh assays, reporter gene assays., a; wwo ceb \ edbng assays, and the assays desenbed herein.
P4e4| ; ex o pe, an a? rone bnaogleal assay that can be user] includes the steps of U } ising a hiateroe substrate gay;, an Isolated hlsmnc sample, an is lated histone peptide represe uia ties of human hisione I B residues 2 b-44 contanung either an uaumdiiled lysnve / eHa or dnsiethyiated lysine 2.7 Ala ddmedg or an Isolated ohgonucleosome aabstrate? evltb woombba r PRb'2 area mes boa. melube a wild type or nmtant bZI42 sabanb; id) adding a compound ofrhe invention to tbh; no store; (.>) adding nmoaxwhoactlve and AIAabe d S» Adencewa awthmnine sSAM) as start the reaction; (4) adding excessive amount■·;'·.■■■■■.■■■ radioactive SAlVl to stop the rcacgon; ;4) svastnng ff the free nonunesuporated lid- \ d g and (hps doteerlng the qnanhty of b-g.gsbeled hisione substrate by any methods known in the so dry , by a herk!nl:hmer lopCount p! eroader),
0 6b' I i ·■ example, an i tdvo study that can bo used Includes the steps oi { i } administering a oompoond -A'dPe Invention ink; a mouse model much as WSUuDLCI.2 veoograft tumor bearing mouse model or KA P.AS-422 Inanan dlflosetl large -Adoi! lymphoma mouse xenograft model) at curiam lesol or dosage tor certain periods oi time, e.g.,, A .g: da s; (2? sacrificing the mouw ano isohamg th tianor tissue; (a) measunng the tumor volume and Ively weight ao I t g eotraeilng hisione irons the tumor bssue for measuring the hlsmnc medwbPon by ELIdA.
p ion) As used herein, "trearlng" or Aream describes the management and earn of a patient tor tin; pur o e of eon usai ing a disease, condition, or disorder and an hobo h arhr n!strahon oi a compound \ ddhe present nsYenhmg or a pliarnuteeutleaby acceptable salt, polymorph or solvate thereof, to abeviate dr. symptoms or comnhcahons of a disease, Cisndnlon or disord r, or 4s oiimanate the dlseaoe, eondbson or disorder. The toon A.reuP" ean also include iroatnient ofdi ceh At ιοό(> or an ani al model.
104671 A c m o of the present mvention. or a pbaortneenticahy a ce t l salt, polyumrpb or solvate thereof ean csr ntay als he used to prevetn a ;vdev;og disease, vr;ndition or disorder, or to identity sodatde eaniddates for aneh purposes. As need hereits. <prev n ingA
A:> gnev sus'' r ;,; tsu;;: sr. on a' desonbes o.bu-. -or or olinbn dnti uv onset oidbe aympkana or oomphcabona of such disease, condition or disorde .
-5f>S Point mutatlom: <"dAhe E2H2 geee ;d 3 elegie amino aeni esidue (e.g.. Yds F A677, and AOS ?) of 02412 haw been eported to be baled to lymphoma.. Mos 'e ample of ! d d mutants and methods of treatment are described n IbS. Pafem A plication Publi ation . US 20 i t-004090e., t e eab -.-.ao-oa of which is incorpomted losson by mierence in u ennreos [0469] gme a klled in -be an may refer io general reference texts for dehbled descriptions of known eechnlques oiacnased hewin or egmvaleru tec niq es. These rexia sncinde Ausabei of add Current FowocoA■;.*<· .T/ofeerboo f>7o/ogm John Wiley and Sons, Inc. (2005 κ Sambrook of. Λΐοό v^edo' fVo^ggp gobo/wany . oeau/ is"1 ebltdas), Cokf Spring i bsrbor press, P- id Spong Harbors Nee: York idooo); Cobgan or of . Carre Prou>coP h> AnnmuoYggvf John Whey & Sons, .Y.: Puna or ;;/.. Om-onf iYotor dy : /¾nsoucceY:gg, John A g.e & Sons, KYo king! ei of. , /do Pharmacol ogiceit Pesos fl'herapciuic (1975), msnuogtooS /Vmivnoonaoon/ Si ooioe, Mark Publishing Co., Pastor:, PA. Iff' ehlbon (1990s, These te ts can:. of oousse. aiso be referred to in making or using an aspect viAhe cenOow
[0 70] As used herein. Assrobinaadon therapy'5 or ''codherapy'" includes s e adrniolsteaboe of a compound oidhe present iuvennoa. or a pharmaceutically acce ta le sail, polymorph or solvate Onareog and at ieasl a second agent as pan of specific dearrnent regimen intended to provide daa beucfkuai effect. ΟΌΟΪ d-e c- "-action olAhes!;: dterapeink ag nrs hhe beneficial OPSHU of the combination includes, hut is not l mited to, pharmacokinetic or gharnsaeodytuanie oo-aciion resnUing fossa the eonb)ksa-boe of therapeutic agents.
[04 / i] 4 Ac present mvenflon also provides pharauieeubeal compositions con;prssing a compound of any of use Formulae deseobed herein in combination odd at least one
phaunaceuhoahy acceptable escipient or carrier.
[0472] A 'gdusnnaceobeal oonnsosibcif is a tbrnnuation containing the compounds of das present Osveof i> us in a toon suitable tor nd ubstrabon to a subject, fa one embodiment, bv phar aceutical composition is la bulk or In unit dosage lonro i is. unit dosage form is any of v.niety of kn m, Y-dudme. tor -mamgle. a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a slab i be quantity of active ingredient pegs, a linsr; a latita t of the disclosed compound or salt, hydrate-, solvate or isomer mo; op? In a una dose of cooiposidoa is ass effective amount and 0; varied -.mcordlng to the pauleularneaboent Involved, fine skilled in the to o ld appsevhvge that It is sotneflmes nec ssa y to make routine variations to the dosage depending on the age and co bOon of the patient. Fhe dosage will also end on the route of aduinuatrabruv A variety of ounce are contemplated, etertlng oral. pulmonary, reclab parenteral, transderesab raibeureaeous. baraverasns, karaaurscuiar, iaaaperkaaeah inhalabenag buccal, euhhngaah ugsaplearuh luinahecab hasana-ad, sad ihv like. Dosage forms las the topical or baasdeoaai aondacbaooa of a eoaspoead of this unenooa ksAade powders, sprays., oanaa ate passes, ererane, lotions, gels, aolauons, patches sod mhake s. la one embodiment, the aeihss cornpoaad is mixed aader sterde eoadhlens with a pharmaceutically accefHabk cameo and svhh ;¾ay prcservabvec butlers, or prnpebaais beat are regubed.
[04731 As used herein, the phrase "pbarmaaeudcall acceptable" raters to those eorapouads, anions, aakoas, raaPsruds, eoupHwitknrs, earners, ami/or dosage hams which are, wnhia da- scope obsoaad mediae! judgment, suitable th-r se at eosnaoi wnh the ussnes at raanan beings aad ankaa!s sekhout excessi e toakbys irriratiorp ailergk ; espouse, or oshcr problem or compheatkna eannnensoraPe wkh a reasonable Paswtie'rish ratio,
b.!4?4j 'bbanmaeeuooally accepiarbe oscgeena' means an excmienmhal Is useful as preparing a phmnaceabcai conpsoskk jhai is generally sate, aoaaoxia and neither b:om i.-,uP nor ohserwise ondesaable, aad inc des exci plant th i ss aceeptabk ka; veiennary raw as web as human harmaceutic l ri e. A wdmrasaceutweky acceptable escg cnr as a a i In the speeuication aad claiuw ncl des booh one and naee bsaa oac ¾ueh excipiena
ί04?5Ι A pharaaieeaaeal corepesitkai of e ae -aaa-a Is bsnnulsned Us be compatible wkh Its ■'mended wane or adnbnic.rad- ax bksmpkw sa" roaiex of admlnb akai exdude pareereraf ear, rn'm-en us, kuradermal. soheataneous. oral■■■ .a . inhakalong transderm l (arpicau, aad Psnsrnucosnl adnkmsmatlon S-shaioas or suspensions used tar parenteral, mwadeimab or subcutaneous spphesbon can include the Ibhoclng components; a sterile daucni sued as carer Par upeebea, sallae s-.4ors.ap fixed oik, poiyedgylene alyeeka glycerine, [wopybne glycol or obwr synbwue seleenrs, aabbacierlal agenrs such as beaay l alcohol or mebpl parsibeas:
anooxnknts su h as ascorbic acid or seokan bisaliae; clwkPbgg agems saeb as
ethyknedaa-mncteiraaoetk aeld; batters saeb as acetatea ekralex or phosphates, aad ageats kn the adgoxnaso at bonk hy each as xodaea chloride or dextrose. The pH caa be adjusted oitb aeals or bases, sack as hydrochloric acid or sodium hvdroxak. 4 he parenteral prcparanoa caa bo eeeiosed k; auipomes. disposable syringes or umkiple dose vaals aaak or glass or plastic b04?al A compound -.a pbaoaaccrrbeal soroprasitss;s oibaa laveadoa saas be admlaisrered re a sabjact a; vaaa <rf ihc welb-knrova raedaak eerraath road lor ahensoiheo;peatk aeaarasah For sxaaapk, tor P aaaeal of eaacers, a coaspoaad shc ne-sdoi! roay be aaae eo da'cetly aar- traaerc irgcated labs the blood .-ae■■·.■■. r-r body ea aties ra sksa oraby >sr appbad through the skin oath psrcbov 4'be dose ehosaa should be satocieai to coraaiaaa et'tective baatmaat bat not GO bap- as o caasa raaseceptabte sge etieets. 'The slate of Uu- disease corabtaai us. us- caaccr. 5
precancer, and the kke) nd ih henna en the a em should preterabiy be closely monitored dn g nd he a seasonable period after treatment.
[pa Π| Ike 'Xn-.mpeuticaiiy ciTeedve amw.nuy as need herein, refers n> an :unonrn -at a plm aeeuhcel ngero a;, -.-.a aniok ate, or prevent an identit ed disease or condioon.. or to exhibit a detecnable tberapemie or inhimmry effect The cP '·.·/: can be d e ted by any assay method known i the art. "Fhe oreckxe ebleetive amount fair a snbaeot wbl depend upon the sobbeobs body sveighg ska. enki health; ;m nature and esicntof ifw oondnion and the dmrepeukc or eombmakon or dKsvtpeuPcs achated tor adnh etivioors, 'kkerapenraadiy vfkeehve na'i uska For a gi en sikebion can be ueXerm ed by routine experimeniahon tbrst is within ike skbi and judgment of die clinician, in preferred a ect the disease or eorxkbon to be treated is cancer, in another aspect, the disease or eoadiuon to be treated is a ceil prokferaiive disorder. 04?k] For any compound, the thernpeuOeaiiy effceiive amount can be esbnnned uhtiaby either in ceb culture assays, e.g.. okneopiaabc eeiis. or in animal nnnieb usually · a- abac, rabbiis. dogs, or pigs. The animal model are air;- bo need > deteonme ike sppnywkne eoneeniraiioo range and mute of administration Such inibrn-atasn can th n be used determine useful doses and routes for administrabon in humans. Therapeabe/prophyiaeiic eiticaox and to icity may be determined by standard pharmaceutical procedures in ceil coheres or experimental annuals, f.y, EDm (the dose thcrapentieaHy efbeeove a? 5 % of fhe gem ation) and Li -? (the o, ·.·,.· lethal in 5b¾ of tine population y The dose aai- - between toxic an-; dwuejpeahc effects is ike therapeutic index., ami it r an fa- expressed as the ratio.. Lhxyfb ;. Pnarmaeeai seal compositions that exhihk iarge therapeutic indices are preferred. 'The dosage may vary within this range depending upon tin; dosage torn; em l ed, sensnivky of the patiwn, and the ronte of administration.
04 Pi Dosage and ad inislnnion are adjusted to provide sofpeient levels s-f Pus active agentfs) or a.! mai ain the desired effeap kbwiors which may be taken into account include the seventy of the disease
Figure imgf000097_0001
gonerai heakh of dm subject age, wenghk and gender eabhe subjerk dieg t-me and frequence r-f adnhmsuarion, doe. eombimnwnfs). reaction senskh iiies. and kberance.ee spmsse m therapy, bongonsmg phanrwceuboal compositions may be administered every a to -t days, every week, or once every two weeks depending on hali-kbe and clearance rate of th pati scalar Ibrnubahon.
bkeOi i he phs maceaboal ossT!prwkiona containing aeiwe compournab of the present invmsbon may be rnamdncimed in a armer thai is generaik p.» . ;.gg.„ b means of conventional ■nixing, dissolving, granuiadng, rkagceonaking, levigating, en bafying, er&apsnlatmg, ernrapping, or ivophi!ieiny processes, fbja iriaeeuiieai co-V!poshioiv: may be tormn!aied in a conventional ioanner swing one or more pkarnmceuiscaky aeceptabic carriers eoniprisi-vg exclpienrs autbor a is s i h rs s that ae mtate oc s ing cl the active vontpounds mio preparations iba see be used pharmaceutically Of eeurae. the appropriate t rmuiahon la dependent n she route of admmistratlssr; clmsem
j 0 8 U hharmaeauboai cong>oshione suitable lor injectable use include ster ile aqavoes s . .!s U.=n. ifohere water soluble) or dispersions and sieoie powdes s fa the extemporaneous preparation of sterile anewsbx solutions or Pi uvrd. -n. ; - a mrravenons adufobsst iion.. -aaa-e;-; carriers include phyxmfogkrd saline, baeterioatabc ma e , Crernophos- gh T:v! (BASF, Parsippany, J ! phosphate btdTered saline (P y). In ad cases, die composition must be sterile artd should Pa rb.dd it.; a-: extent thai easy sgnngeabi lgy exists, ix must be stable under the condi ions of uianulacua'e and storage aad must be preserved a ybe ■· the eoo tromariug action of microorganisms such as bacteria ami fungi. T he earrier ears be a solvent or dispersion rueditiru containing, lor example, wenw. efoasrog p- d'-wi itor example, glycerol, propylene glycol, una liquid ah ethy lone glycol, and the like p and suitable ; ma c-, rhoreoh The proper fluidity can h¾ nubutameo, for examplv, by the use of a: coating such as lecithin, by die maintenance ofi.be required particle size in she ease of dispersion artel by the use of surfactants. Prevention of d e act ion oi euerooreamsma can bo achieved by various antibacterial end antifungal agents, ids' example, parabene. vhlorobetanoL ssltett g aseorbie acid, tbamerosal. and She Like, in many cases. It will be prcterrnrie to ineiude Isotorilc agents, hsr example, · cyan -, polyxleohols such as manitol trad sorbitol and sodium chloride lo the composition. Prolonged a o ti n, ot the Iruecaibie coatposibons ·. a a be bronchi about by meiatbng In the composition an agear which delay absorption, tor example., aluminum monostearate and gelatin, bbasfo] hterbe injectable solutions can be prepared by irteorposaling the active corn pound it the required amount la an apprs;priaie sob/ent with one or a combination of ingredients ennsrserated above, as required, fol lowed by fuiewd steriiissatfon. Generally, dlspemions are prepared by Ineos psaselng the esth e compound tne a sterile vehicle that contain? a basse dispersion medium and the required other ingredients from those enumerated above. In the case of sterile owders tor the preparation of sterile injectable solutions, methods of preparation are vacuum drying and tfecxeforying thai v xhds a powder of the aedve mgiecbem plus any additional desired ingredient rom a preciously stes ue-alitererl solution diereoh
Ibdeej Oral compositions generally include an inert diluent or an edible pharmaeeadeally acvepironle carries-, "i hcy can be cnek-seb in. gelatin capwiles■ s eomps essed into tablets, f or the pmgwse or oral ihvrepeuhc atnnlnismnion, dm acow compound can be incwanrratoti erirh exclplents and used In the. form of tablets, troches, or capsules. Oral e- xm>oslbon:; can also be prepared using a fjukl earrier tor use as a msaitfovash. wheroiir the compound tn the ilutd carrier gg a; applied orally and swished ¾ν ! expectosated or svvatloo-ecl. fliarmaeeotlealhg compatible binding gents, and/or adjovant materials can be mcloded s part of the composition. The tablets, pbb. capsules, troches and the kkc can contain any of the following ingrede ts, or eo poonds of a sknbar nature; a binder such as nberoerys a hne celloiore. oee: tmgacanfh r gelatin; an exoiplcnt sued a. starch or lacioee, a dnantegraiina agent such as alginlc ackl Prnnogeh or c m starch; a lubricant, such as rmsgnead ni staaraie or sberotes; eiklant saeh as coile<dai sdieon dioxide, a .0· -a-.-aoa's agent such as saerosc or aaceharm; or a ihvonng agent a-uch as peppermint, methyl sahaeinkx cu orange ilavoring,
¾ I ·· a administration by inhalation, the com u arc delivered in the for;n of an aerosol spray bom pressured corualrter o dispenser vebicb contains a ratable piopeliang e.gy a gaa snob aa carbon dioxide, or a nebtdixe?.
[0d Systemic administration ran also be by ira smoeosai or trasmdenntal means, for transmacosal or transdermal administration, penetrants appropriate to do- barrier to be petincaicd are used in the a sa-ei-aa-a Sncb penetrants are generally known in the ail, and toe!nde. for eaample, tor transmucosal adailniatrabon, detergents, bi salts, aval fusible ae!d derivatlvca Ί ratsmoeosal tklmmisttcnion aan be accomplished through the use of nasal sprays or suppositories, Fas1 Panadarniai adimnistmtion, the act ve compomids are formulated into oininteors, salves, gab, or oeams as generally known :a s e an.
[bdgbj The active eom oonds can be prepared with pharmaceutically aeceptable carriers that will protect the■ oa;p.aa;d against rapid elimination bran the body, suck as a controlled release iooruilabon, a-- mb-m: nnpiams and n'oeroeneapstdated delivery systems. Biodegradable, ;-h■-. -eeg-sihb polymer-, can be used, such as e h l ne vinyl acetate, polyanlnxh idee, pniyglyratbe ae;d, collagen, poivorilwesress. and polykicbc acid. Method? for preparation of sncb foun uanons veil! be apparent to those skilled tn iitc art. The materials can also be obaatned commercially born Alxa Corporation and Nova Pharmaceuticals, Ine, Liposomal suspensions i inchniing liposomes targetctl to infected cells b b motmc tonal antibodies to viral anogenst can also be aseri .a. plxnwiaeentnxbly acceptable earners, 1 hese can be prepared according to metho s ktmvvn to those skilled tn the ait, far example, as described in kbS. Pat. No, 4,522btl b [048?] b is especially advantageous to tbnrnnate oral or parenteral compoastious tn dosage una form tor ease of administration and unilbrmby of dosage. Dosage unit toon as ased herein a bar to pbysieaby discrete nabs anlted as unitary doaages tor the sub-ect to be treated; each runt containing a predetermined uantity of active compound calculated to produce the desired therapeutic effect in association wlrh the mgalred pharmaceutical carrier, lite specification tor Use d ;¾¾e unit forms sbOhe Invention are disrated by and direc l nee-, nose; on the unique characteristics of he acm e compound and she particular thera peutic effect so be achieved . 1 4¾; In therapeutic a plications the dosages of dye pharmaceutica l com sitions need in accordance wi h the in vention var depending on the agent, the age, weigbo and chnieal condition of the recipient patient, and the experience and j udgment of the clinician or practitioner adm in istering the therapy, among other factors affecting the selected dosage.
Generally, rise dose should be sufficient io result slow ing, and referabl regressing, the growth of tho motors and also preferably causing eornplote regression i d btc cancer. Dosages can range irorn about 0.01 mg/kg per day io ab ut 5000 mg/kg per day . In preferred aspects., dosages can range boot about I nsg Vg per day to bout .1000 no- kg per days in an aspect, d o dose svd i be the range of about 0, i mg/day to about SO gfeay; about 0. ! mgbJay to about 25 gklay; about 0. 1 oe.v d..o to about 10 g slay; about 0.1 mg to about g/day; or about 0.1 rng to about I gfeay, in single, divided, or continuous doses (which dose sway be adj usted tot the patientA weight, in kg, bock' surface area in ink and age in years). An effecti ve a ccen of a pharmaceutical agent is that w ich provides res objecti vely alcao i lsbk Improvemem as noted by the clinician or other qualified observer, for example., regression of a tumor in a patient atay be measured with reference to the diameter oi a tumor. Decrease in the diameter ok a tumor indicates regression. Regression rs also indicated by iadure of tumors to reoeotu after treatment has stopped . As used herein, the ter Alosage effective manner" refers to amount of an active compound to poadaee the desired biological effect. In a . ubfeci or cell ,
[0 80] The pharmaceutical cortvposit lons can be included in a container, pack , or dispenser together with instructions or administration.
[04001 'The compounds oidhe present invention n e capable of father forming sake. Al l of these lArrns are a lso contem plated within the scope of the claimed i nvention,
[0401 1 As sed herein, Abuu'roaeeausaife acceptable salttA refer to derivatives oiAhe compounds erf the present invention wherein the parent compound is modified by making acid os kase salts thereof examples of phanrmceutleally acceptable salts include, but are not limited to, m i neral or organic acid s-n! erf basic residues stick as annnes,, alkab or organic salts of acidic residues such as earbewybo acids, and the like. "The pharmaceutical ly acceptable salts Include the convent ional non-ooxle salts or the quaternary ammonium sa lts of the parent compound formed, ror example, ifom no; etoxlo morganfe or organic acids, for example, such
conventional nomtoxlc salts include, but are not lim ited to, those derived front inorganic and organic ac ids selected feom Astoetoxybeeeole, AAydi oxyethartc sulfonic, acetic, ascorbic, keneene sulfonic, henaolc, bicarbonim carbonic, citric, edetic, ethane dlstdtomc . fefeeihane
OP νηΐίοηκ-, fbinane; gkicehepnedc, gk muc, ginianuc, glyctbio.. gbcoilyarsanibe, hexyhvsoroinic, imteabn k. hydrohromks hydrochiobc, hydrolobk, hydrcssnnbeio., hybK>xynaphbsolo, Isethaonlc, bic m hiotobknbe. laurel sulfonic, mnkae, make, aiarx lk. an dma-. stnionio.
napsylie, nitrc, oxalic, pennon, panmthenic, phenylaeebs, phosphoric, posygnlnctaroibc.
propionic, aalkycllc, ste rc, subaeelie, succinic, sulfamic, solbubhc. sulfuric, tannic, hirtrakx toluene sulbbrbo, and die ,·· -mn occurring amine acids, e.g , glycine, alanine, pheoykbavune, a rg I nine, etc.
[0492] bkher ex mple of pharuaa-eoboalky accephsble salts n lude bexanoie acid,
eyolopentane propionic acid, p ruvc acid, Io ic acte, bkbbedroxybenxoybbenxoic acid, cionana;e acid,
Figure imgf000101_0001
ae>d, boupbrdndenesulihinc acid, aunluenesnltorac acid., eampho s-dioai-; acid.4- vaadr k^ic ek-'k2b.2]-ocyb-'eoC'b aarboxylle acid, e- pheirylpropionle acid, trmtedndacedo ackk tertiary bubbacebe nekh moronic acid, and Px like. The p!cseni iuvemmn dsn ence passes sake fornx-d when an acidic proven present in the rent eompnnnd either is re lac d
Figure imgf000101_0002
a metal ion, a y,, an alkali mend inn. an alkalme card; Ion, or an aiuntmuui ion, or coordinates obtb an organic base such a sdvmoiamlne. died'arebanbae, idethanolamine, nxanedasmlne. bbmebiy!yiooanbne, and the- like, In the aak toon, k is understood ban rhc rato of she compound a.; bx t son or anion ofbhc sab car; be I: b or any ration other bum I :b e.g.. e:b 2:b be, or 1 :3.
[0493] It should be understood thai ad references to pharmaceutically acceptable salts Include solvent addition bums issavatesi or crystal forms ( oly r hs) as defin d hereby or the same sab.
[04941 I he compounds of the p esent invention can also be prepared as esters, lot example, pharrnaeenbeaky acceptable cs;c;x, kor example, a ca boxy.be acid function group at a compound can be converted to ks corresponding ester, eye, a methyl, ethyl os other ester. Also, no alcohol gnoop in a compound can be convened a:; in; eocsespoodmg osier, e.g., avenue.
propk.-na.ie or otbc; aster.
[0495] "kite compounds, or ttkarioaccubcaby acceptable salts thereof, are admlmskaed oraky, nasally, mutsdermalby pulmonary, mhalabonaily. buccaily, subungual!}, mtraperltueneally. subcuenneousiy, kaxamusoularly.; Intra venooslys, recubiy, ntuapleurallv, inhsuhecally and parenteraky, ht one embodiment, die com oun Is administered oralis, Okie siailea in due art nail ec ni e the advantages or cerenn routes eb'admnbsuxition.
[049b] The dosage egime utlbxmg Ore compounds Is selected in accordance ebbs a variety o factors" including type, species, age, aeanx sex and medical condition ofbhe patient: ibe ■severity of the condition to be oea-etk tins route otbxkmmsoxnion; bo; renal arid hepatic function obhe pabeoc. and b½ paobcabr ί o;npoond or nh thereof engdoyed. An rd n ril shaded physician or eesarinanaa can reatab dsietin e sod presenbe a; efbebve amount of bee drug required to preveag eomaeo r arre t the progress f da- corbhiou.
[0 97] Techniques ios brauhadon and sdrnbisiraoon of do- uiscbs-d compounds of too invention can bo foaod in /fennnyhsre she ienc nd /AueOce ok/Assaeasee, ¾d'!; edition. Mack Publishing Esstois FA Ο¾05ρ In an onobodiroeno the compounds described herein, and the phauoaceutkaiiy acceptable ad:- thereof are u ed n pharmac utical preparations in combination v-lib a pbuavaceaucaby acceptable carrier or diluent ouaabb pharmaceutically acceptable cankers include ert solid libers or diluents and sarnie aqueous or organic sobboris, ihe etanpounds will ire present so sack pharniaoeapea! souiposubm; in sun sun-, snlTbiem to r vide b>e desired dosage amoura: in Use range described herein.
ptaiogj ag; ^.-com gaa and naba used buob. nabss rubera, oe Ukkcaied, are by weight. Obrer ieatnres and edvano¾ges of d« present intention are assmuu from dot αΟΑη'οηί xampba. The provided esnmp s idusaate dbbreni components nd uaobodology taeold practicing d;,- present hweoboa. The esarupies do noi Limi the churned bvemnre. Based oo Ore pressan disclosure me skilled artisan can identify and em loy other eomponema and methodology o ebb tor practicing the presont invvnOom
[04001 in die synthetic schemes described herein, eonnpounds may be drawn with one particular eonimuraaon tor simplicity. Snob panicuku eonfigurabons are noi a.; bo const ued as lioutlng ihe invendots to one or another isomeis afomer. rogioborner or siereoisonaeg nor does n ·,·. hob mlsierea of isomers, nan- sue. ·· regioisomers or stereoisomers; horeeves. it will he andorsa^od drat a given isomer, jaabmer. regbbomer or stereoisomer *nav have a higher vei af svbviey dsut another isomer. iaoteuum regloisomer or saneobomsr.
ObOO] bonmosaba designed, aebeted ami/or optimized by roeihods described above, once rod ced, >.an be ehaosoierberl using a sakeiy o†basays known so those skilled in the ao aa determine a Aether the compounds have blulogka aotbba.. Lot exurrnde, the nod-cubs -.an be charac-eriood b eortventsonai aasays, iacinding but noi ba;a,-c to those assays described el , to deaarnine vvhe&he-r dsey have a predi-oen aedvip-, bnabog acdvity andatr binding speedkab, i 0501 ] birthernsore. ioglrahroughpra sereerang ean be used to speed up anabsb using such assays- As a resub it aan be posbbk to rapidiy screen the rnoieeobs described iteren) Pa- acdv iy, usiog a;eisniiiuea knovva in die art. Generb iueUsodoiogses tor pertorndag high- davnigbpai sereealng -:a-e dessrbed, be- csanspie, in beb 1998) /¾/? /avipoguo doi eaoorc, Marcei i.)cid,er; and bpk ibtora bo. ay7o3,2iik Hadadessighpru assays ears a-e ane or m re obTerent assay•cchaiuues naabdbg. bai no^ iisnded to; basse described bekae. logof] Ail pubheabons earner docimeow caicd bewa- arc incorporated e ein by wfeieriee as if eawh such pubheabon r d ument y specifically and indlvednaby hwheareo io be hrc sporared herein b reiewnee Cga-am r prihlicahena and paaow cioeuownts ia noi aueaded as aa adnnasion dan any la perbnom proa are nor doe.> si oonsdone am unarsi a as to bee coiiteina dsste of s e wme. The in ent n haviny now been described by vow- of wribea desebptkag those of wjp in the art yvs!f reeogniase thai i invenbon can be praebeed in a ·· a; be of embodimenta and that the foregoing deaarips.ioo and e am les bdow e lor purposes of llkwtrauon and not imhiaooe of ihe claims bad bblow.
Preparatory Exam le 1: General I vB F eroding protocol:
j05iO] The carboxvhc aeld i I eprnvg was then dissolved n DM SO and an approprate areihanamine i f ego waa added i U. The reeeboa mlxtam was sbrred at r m temperaiure h>r ;5 nbn bef r PpB F ; i .a ecguvg and tneihe; ,o;o;' f Ϊ egtbv.s way added to b and sbrnng wew eonlmoed ior overnight. A tier eompleboe of ihe machom reaehon mess■■■■·. ·. poarad ;ae- ice. extracted wnh 10 % bT;()HdJC . e;ombh-ced orpanie layers ere dried, ooncennetted to obuan crude; winch then purified by column chromatography: prep. HPLC to aieab ihe Sergei compound. bveup 1 : etvn fmsfa of t uoom-
Figure imgf000103_0001
iOeO fbs I; byabeessc or mednd V-dbteomgbwhKwyviuyi) heneoaw:
p-we- ; go a. soared acdmioo of meihyi ddaooco-ewabor iwnaoaie (3 a, 12-04 m oh >a d aane lab ad c hib ybi -ehwwy vuv aianaaae bb78 gy is.25 mop ems added and the yoknfm was parged rth a?eon f r-20 !¾"ihi, PdbPPh¾p i .7 g, (b 02 n ricsi) was added and argon waa purged agais; tor ad min, The reyruhng eacboss ¾ as waa beeied at i(Hi "b: i'or b h. dim prngreas ol ihe reaelhai was nuuiUorsd by 41X2 PToo cornpiebon, the rescuon mixture as corwenneued io dryness under reduced pressure to afbsrd the tide coovpoend -2.5 g.127%) which was a .od in the su.H.seuu?.-ni wep dhoai: Uabwr purb'icabor>.
lOSOn] Step 2; Synthesis oldn ihyi dowetylwwhkwTwrwoste:
[0507] A nOxture of nwlhyl 3w:h;oro-4o wdhoxy vluyi; ben^oat (2.5 g.10.42 mojoi) and 35%
HQ (400 mi.,} was si died at w lor 2 h. I he progress - a 0;,,· reaohoo was monitored by 11X2
U on completion, the reacdon na sure was basified whh say N3HCO3 sokni n and filtered, The fdtraw w as expected with DCh'h Use combned organic layers evere dried over anh drous iw Co. and ihcn coneemrawd under rodwxd pressure. The erode compound u;ss purbsed by column eh onsWogmphy io alios d hw ode oompc-and (2 g, 9132).
10502] Step 3; Synthesis of meihyi 3--c on>4-4 l4wdroxye4sys)bens:oate:
(05091 b- :-s tirr d olution of nwbgd 4--acvtyb-3whIoro§wneoate it).5 g, 2-55 mmoi) m -vleOH
(10 mba as 0 Oy. was added NaBRs phbg] g.2.12 ownoh. reauldng reac i n mixture was stnsed at o io;' 1 re 3Te progress oi the reacdon w;w nsooiiored by 'PLC logon completion, the reaedon mrsnwc was quenched oath aer, evaporated node? reduced pressare and cxuncied wuh h>Chl the combined organic layers were dried over anhydrous Na::>SO: and idea eraseeoirated under redoeed pressure. The crude compound was purified by column
chrssnaaegraphy to afford the title compound {0.4 g, 7922!.
[05"h ] Sw 4: Xysnhesis of methyl IwOloro-To i-pheorw>etlw itbenxoare:
[051 I 1 To a sbrre solution or meim I ii-eh!oro-sp 1 dwdmyyelhvi}bcoeosw iO,40, bad mrnol)
In 4141' <5 mba at 0 Tt 4P0 (0.75 g, 2. SO -mw-p and phenol s 0.19 g.205 mmoi} were added and the soiation was !kred at ri tor 20 mho Then DbAD i0.39 g, 2,24 mmoi) was added at Owe and stirring was continued at ti fo 12 h, The progress of the reaction ems monitored by Tlx 2
Upon coinpleboo, dy reaction mixture was diluted a ah ;ge and extracted wuh ethyl aeeiate,
14'!·; -.oushmed orgaase layers -A ere dried o- wr n vosous a.c%}.. ^d eonoeniwued under reduced pressure. The crude sompourel was purified by column ohromstographv ¼ afford the bbc compound 10.4 e.74%). ■
[05121 Ste 5; ynlhesis of 3--eh!oro--4o og'asenoxyethyijbenxole acid:
[051.51 Tqaersw N&OH i'0.083 g; 2.06 nirnolt was added so the soisitiras or inerhvi swrdoro-o-' (; -ρΐκθ!· wyebp |)ben aie Ofd g. 1 ,37 snnsob in Ϊ.0. .Ι Ϊ ;5 mba and sbrred at 60 '22 Aw t h. I he progwss ijf slse waebon was nwasitoreh by 7.22. bgson eonipiebon, the et.ha.noi o as renw>ved under redo -red pressure and Use seaetio:- ioas was ael¾.l0ied rsslrw I I4CI assi extra-sod with ;0% baeoda/ DC PI The eonddned organic layers were chsed ld; pia wiO; awl Own concentrated under reduced ressure to afford bso tide compound (0.35 9232}.
105 bo i ·· [ Step 4; Synthesis rg 2g>fomeb f3..eofo3~^^
[ 515] Λ rnfotaw of
Figure imgf000105_0001
Π o g;: ] 2 iramol) and .22 rimebiyb4H" '3 du hwwow (373 i g, 1 2 nnnoh as h aved a; 203.' ros i h. The prepress of the rea-oson was eKubtored by 21.12 Upon wwpdOwa ihe reawbw nta>s wa eookd n> n. The erode m i rksi aTtamed was ddaed with ethyl acetate and iidxa d. The re idu w s washed with 50% ebgj aeetaaehexune aod dned under reduc d pressure s. afford Use btle eon-poarid ;4 g, 2230.
[OS 10; Step 7: Swnbesie el
Figure imgf000105_0002
[05 ! ?) 12> a soiaooa f 2g)foimebvy 1-4-ox -0.4-Tjihydropyridine-3-'earboidi;5k id p.27 romog as awO aed 020 o.b., a catalytic arnoaai of Raney ickel and a wmuba sohfow; ( 03..? wer added The reacdon mas a sbrrcd ai. ,n unde hydrogeo ressur (I atnb for 12 b. The progress cdOhe reaction was morbtored by 113.7 Upon cougdebon. the reachon. masa was dhered thr gh a bed or eelhe. washed -a ah meUsanoi and she fbrraar was conceno-aled anew reduced pressure to afiord die idle compound s .5 g, 6030 wldeh svaa used m the subsequent step wuhoru umbe purbkabon.
[051 S Slop fo Synthesis of 7'-ehk)ro-No"r74fapr!¾ehyb4..oso3 , Uiy¾r' r ki s n-2> ~y ! ">n-ierh ! s- 4 g 1 ghera.wyeihyf;beswara ide:
pw gg iv, a e hafoi of eobdoro-lg
Figure imgf000105_0003
aesd fo377 g. O.Oa aunob in DM SO (2 ad ·.3ganbra.aiwfoyfg2g (0.192 g.: 2.2? nuvsog and hicdpTardne (0526 ad ■ ' "3 aud; were added. The ros-.ew: rnwuae w.e> sbned at a for 15 mm before PyBOP 0)364 g,: 0.96 sr-rooh waa added p. ii at 037 and Owtber odrwd ai ri for \ 2 h. i be progress f the .ea ti n was momtored by 11.02 Upon compieborg the reastioy; m s was diluted wag water and oxtr&ei-d with 373 MeOdlwX. . l ar eorebaied r anic hsyew wew dried over NaTwb and concentrated under reduced pressure, The crude compound a;¾ P¾wbk3 by acetonirrde waslnngs is; afford Ore otic compound (0,07 g.27¾g
I sa>opg- 2: SytUbesis of Componawls 2 and 3
.. .
, ,oa .ggwgggrgy. '7 ·-; MOW
Figure imgf000106_0001
[052 j To a sOrred solution ofebol 3wwe4a.aanoate (50 a, 31000; mtvsoi) ebrano? ("200 rnfd, nwhyl Iwdowsne ( 1 .46 g, 423.07 ooye.ai was added a* 0 "0 - The resaUber areao mixture a a-. :aea at d '-'<20 r 8 . The progwss -.yf bar reaction was naauiored b TIC. Upon completion, the r acti ndxbue was coneeruraasd to dryness under reduced ressure and dw crude materal obtained was purfied by column ehronauooraphy to afford the rule compound { 32 g, 74%),
[0522] Step 2; nthesis sTawbkao- 13-dmtih !"iH-^ ra oie~ -e rbaideh <l :
[0523] To a a sture of 2 bimedoyb i ikpyr oh-T 21 Tboae (32 g.285.71 n:mol) sad POCK 123 ml.) a 0 o"213Mb f 26.35.nil.,.34235 mrnoO was added slowly. The: resulting reaction mixture was stared at 10027 a .:· 7 h. The progress of she reaction was monbored by TLC. U on cooiptelioa, the reaction mixture was eoncemrated ro dryness under r d c d pressure. The residue obtained was Ixs.sifisd with aq, sad Nbn4(X> sokidon nd extraesed wuh ethyl acetate,
'The coinbmed organic layers wore rb ;cd oce anhydmos a.40f) and conceabeted under
; educed pressure to afford the erode material winch was pnrdied by coOana chromatography to
:0 Ybrd Use tide compound a':T g, 62¾h
[0524] Step 2; Synthesis of
Figure imgf000106_0002
0)525] To a shored solution of 5-chloro-d . wdirnerbyi- i bbpyraaoie-4warbaidebvde a28 g, ■ 77.2] rooaa) s nouhanoi■' '40 robe, bydioxylamhar iodroeidorsde {'2a 03 g.554.43 mmoO ·;■■:: added Tsar resutbra; reaction mixture rww stirred ta 70 Of lor 5 h. The prognssa of the reaction was monitored by 11,02 flpors eouiplehon. the reaction uoaurc was concentrated to dryness. The residue obrasaed was dihaed wuh vwuar and extraeteri ith ethyl acetate, The combined organic layers a cre dried er fxoSO. nd erawentrated rsraiea reduced preasare to afford erode oxirne ira g} wloeb was used ;a bw snbsegneoi stop o ada.aa tasaher pasiiearsoa
[0526] !"o rbe abw e crude ox h ere Π 4 a, 30.92 msvia4), Pf .<;h (70 sob] o as adderl ar 0 'w d tl¾e reaction noxrare was iieaied at <5 ad p ;r 12 fa The progress of ihe wacaan w¾s oaand'osed b) TL.C. Upon completion, aw wandon rrnanae was coueeniraeen ro dryness.4 he residue obealned was b ss tied wuh aw bnddCby; solnraes end evaso;eri whh ebwl ucehee The coesbined o¾;ade hover;; were dried over bee-bho end eoee rdrated under reduced presxare to afford the crude aaueriai vbncd was purifiad by co uen chrraeanxgraphy 0s aOxnxi rise tide contpound il l g,
[0527] uep 4: Syntkewx r 5woebKew-b - m :iiy;--H - zeie- e; beab! iie:
To a srirred solution ·Τ
Figure imgf000107_0001
(8 g, 1.28 nneob n meth nol (30 ed ; at 0 "6255a<db1c (3ο>9 a, da, Ob numb- was added, i be resalbng reac i mass waw heated at rid ' ; ids- 12 is. The progress of d resctk>n was na.sdrored b 7'LCs I a—a completion, the reaction nbxbae wee ocascemrated to dryness. The residue obtained was diluted xvitb w e.a and esOxscted wadi 10% . eOH/DCrVi The e- wb'ancd organic layers xxere dried over banSTW end ooncernaaed under reduced presxuie ro afford the crude nueerhd which was purified b c lumn einomaoguiphy to efroed the brie ·. ·οοο·οο2 (3,5 a.45¾>,
[0528] Step a; Symhesis olbboiexOwsy- b. di nedx btH^^^
io a sibebnn of 5-eeedwwyw.3whnwxbyhi bbpyrnooiew warbonanle is.5 x.25.02 nnnok in nwlhancd y 40 rahg a catalytic ranouru of Raney :· · i e; and anxrooiea κθηθοη (10 rnha were- added, The reacbxn; nnws was xdrred sa rt under hyxfegen pressure bi atm¾ tor i 2 h. · ho proauxwy of the reaction was roonnored by 1 PA e Upon oornpionon, dr. reacdoa nxaxs xsns biteted through a bed ofwbiie, washed with methanol and the fihuae was eonoenaxaed under reduced pressure to afford (he bile compound (2.9 e.81%),
{0529] Ste to byethebs erf 3whlowfoyui Tum hoxy- t^ubmed bd i^pyr; tol-4--yj)irie-ihy-.S'b--b- ( bathe noxwwlwdYbenaanude:
[0550] Ida a sd red soluhon of 5-a:hloro--4-e by>haaos.yedtyl}benar>ic aeki 10.5 g; 1.81 uunol) iu Dh!SO id nbw at 0 bp,
Figure imgf000107_0002
(0.36 g, 565 aunob and ;raehyhaeuse to.75 ob...5.43 neaob vere added. The reaedoa austere xvaa stirred e r tor i 5 aun benae by'BOb (b4 i g, 2.71 aunob w ax added to it 0 '"Ty and stirring xvas coataa-ed ia rr for 15 a. 'bhe aroaroes of the feacdoa was rresnirored by That Upon eomaiebon. d?e reaction eawr o.as dilared aids wet- aad eairaetod w th lOge s an* a i · a >d The eoexbsaad orgaaic la ers w^cre dried coneandxaed to obtain crude aaueslai whioh xvas paribed by colnon; ehroaariraaaadxy to atrord dae i'Je οοοηχηηκΐ (0.4 g: 555at
[0531] area? 7; ¾ nda.-ee; of 'r-ehlooxb's-ei2:,5otiawaber.';-o.xot2 J-Oiip Jro-d fb. y aeoϊ-4-' y iiraedsvl}--4-(bg)beaoa;yxdiyi)beaaanade:
[0532] To a sorred sokaioa of eonspoand 3- hl o- -432^-me x<,'Xy«s ,3-0 teah>rkb; * yiai; i-- '- xsanedybeda i odHaa.w>edo4yben/;nnide (0.00 g. o.a:w aunob su rucdauada: Med b? mby Corse. HO (2 drops) vww added, The rcsrdbag reacuoa a'oxbwo was relksssad lor 12 h, Tbe progress of bav waefoat ose ae.abtoreb by TLO Upoa sompkhoa, the reaoiaat roasx; asw coaeemraied as dryn ss aad the cr de aaaerhb obrcfoed r pur de by cofomn
ohrsaaaewraphv re afford the ride eenwoaad prbba yi¾).
1 saapbv 3: % ο·
Figure imgf000108_0001
οί i Xaa iosab■! '" f&oav:
C¼00
Figure imgf000108_0002
[05 s.fj Ste I:- Syrdh sis of sw chw bd hbpvra.wdfofoHptaw:
[0534] To a surrO solution of ethyl 3 wwob a tarasaic (50■;. 3o4.o! mino!) as ebaaaoi (200 ad .y Iwdraobae hydeae (23.07 g.461.53 rnw b wes add d ar 0 "(5. The ooabbng reacboa aaaaa--- seas re-fluxed for 12 h, The progwss of (he reaedoa was sooobored by TLC, Upon corrspklesu, the reaeUvC; rrnxewa was cooled s a and the precipi0.Pcd solid was eoboeted b;. iihrabon and washed with b. waa as afford die btk c m nd (2? a, 72%b
[0535] Stop ; bysbhesis of b 5-dsmOn bi ! bpyr;wob3(2Huone:
[0536] To a sbrred aoludoa or 5-asaedyvh Howra o wdbboaw { 10 g 102 mmoi) in DCkl (1 0 ηύ..-} ar 1? 'T2 oh ads bwosfsujo ictraihaawhoonc (30. IS a, 204 owsoh wa added. The reaotion mi tur was wared at o for 16 . The progress of bw reaction as suoubce d by TLC. Upon coaspbalosa the reaeboa was gaenched wii owtlcaaoi aral solvent war- removed tawler radaesd preasnw as obohn the crude masons!, which w s puritkd by column cl wnaaography fo afford the tide comp eod (S g, 44%).
[053 y So p 3: bysbawas ei 3o:hkew i fofoao hyb [ (Lpyrwobefo -e,a ba!dehvdw
[0538] To a nwsiarc of i Twhaawhyh Hw- ywowdby 2Hf-oas ;5 ay 44.64 mrnok and bbjCb (12,2/ sob, I 33.92) at 0 by, OMF (4.12 ad 525? awoob oaa added slowbx Th rosabapj re;:aa;bsrs mwuao oas sbrred ,a Mo :-'C for 7 b.1 be posgreas oibhc rcaeiioo oaa oa.;aib>red by TLC Upon eoaybebwo tiso reaoboa aosbae caw er>!a-eatrarcd to dwaaas riodcr rsduei-d pressure. The residue obtained as broiiko seuh aq. NatiOXT. co bon and exoaoied with ethyl aeetato. The combined mcsaac layers wer dried er atdyvdroa; : " bhpkhn and cssueninued under sods seed pressore. The wade eonspouno bta ed was pw-likd by eolurna ehtcanawe/apby a; afford (he tide com nd (5 g, 71%).
[0539] Sla 4; Synthesis of 3whioro ,5wmwthyk §
Figure imgf000109_0001
pp bp ; , a sjfTod sekmw H ''wei · .da--s a; d p.pUq ::. :b.;..a.--;,ae::k;a::; da (5 a. bba aamoij so methanol (50 mhp hydaw kuione hydrochloride Of 3d g, 63.29 mruoh was added, i a : resold ag reaction akxmoe was sib d si SO '~'C for 12 h, 'The n¾reoc of iba reactkm was raoakored by i · Upoa com letion, the reaction nocture was eoacera.oo.ed to dryness under "reduced preware to a fiord Use crude oxeae (a gs which was used as the subcieqoem siep wlthotn fuofeer ptaiikation.
kk I ] bo d:e above c< ude sexkne ;' a g, 2b'T0 oared), P< a Ί s 5 ad · ·;. ;> added ? 0 T and ;hc Wi!cdoa roeonro was bear d ..a 65 " te ha h. The progress of the reaction w s monitored by IhC. Upon completion, 6·.· reaction mixture was concentrated to dryness, The residue obrainad was baaifkd wnh aq. od lCO: sokuaw and extracted warh eihyl aseuke. The csaabined organic layers score dried over a Skk and coiwenksked under reduced pressure to afford erode material which was purified by column chromatography to aff rd the (irk oonapound ·: ..'.''· a 5l k
•o542j Step 5: Synthesis. w'.2w"mihoxyd:ykkuediskb Hpsvraaydekwsrbomkibx
To a stirred aokaion oi 3oddorow koknwih lk H- y^^ (2,2 a kh!9 mrool) in roethaaol s2b mi .a at 0 '. aO e id .53 yy 2maH moiob was added. 'The reacikci naaw was heased ar an " < " for P -a 3 las progress of Use reaction ay morntcaed by PLC. Upon otaopkaioro the reaction mixture was eoocerorated to dryness. 'The residue obtained was dil te with water aad extracted oath 10% aokOffTkSkl The combined organic laycm were dried over ΟΤΡΧΛ and -omeennsaed under reduced tneasuee to afford cradeeuuenah ke, a was e illed by column ch omatog a hy ;o afford -he Otic compound i 1,2 p.56%).
[0543] Step Ox Synthesis of i Toywiboxy- kSoiioieihs b 1 f"fqsyrazeh-4-o.'i}orKahanausioe
"(-- a a i? r d soluuon of nei s-xy-kiwdin^ (ki g, 5.28 aanols as methan l (id ak..), a cataiyke amowu: of Raney klehcl and areaioma solution (2 rrd.q were added. The reaction mass t ro stirred at rt rasder hydrogen prescraw (1 arm) lor 12 h. The progress ml the reruH r? wyy OiOaitored bv "bl.C. ij br?
Figure imgf000109_0002
rbc reaciioa nsasa oxw fa kited hooud: a b d ofoehte and washed sxidi methanol The da seas concetkrated ta-der reduecd pressure to afford the "hbe eoatpoustd t f g; ss inch seas used In the sobseqaent sic without 1 urdnw pnrlbkxaioa. [054 j >wp 7: nthesi oi aOaodaouseOws lyifo r Hh t-] i'- i¾z l ](2hl) > e;
[05451 To a sowed solution of fdoeebwwyw.a-ajdYWth} h! H^y ¾zo!---i- i^s>:Oih niuoi?ig (0.55 JO dd . d oaaop so aietOaoodo ka (Id mLk coo i o ; (2w drops) svas added auo the i'es doo mwUae was surre as.80 'd: for 52 h, The rogres of the reacboa was mordi red by lid Uooa csaapiebors das raasvioa oaixaure was ooiiceraraied t dwsress undo; educed pressew > .gsos; Uw tnie compound (0.6 g; which was a --d In the subsequerd step whhoui iuwher piaatfeadoo.
[0546] Sto 8: yvruhesaa of 3-whkao 4-dn
Figure imgf000110_0001
y!goebsy HHd adw wwyed5yl;beazandde:
[0547] To a sowed sol tion ot7 -chioro.-4-(h-pheooAyed))1) i\:or -w acid (0,097 g, 0.35 ! mrmA ) In DMF (0.3 nwo al 0 of. Dipifa, ;(s;35 g, i 5S53 oaaw- and H ', l w pU4o c 0.336 amoH were added. The soiudon was stirred a rt for 50 mm. T h rs d- say-pa awthyiM-dwifowthyM H- pyraoof-3(2ttVoae hydroehfonde UfObg a 0,35 I rnawi) was added and the reacboa misdore was stirred at O for id h. The progress oidhe wacoon was monitored by Ί1.Λ7 Upon completion, dw reaction mixture oars qeenched with sat. NaFlC soknioa and extracted with 10%
MeOlldd M, Ida; c bined orgeok layers were dries? ove? ehweO.: nd conoe.nOwted under redaced pressure.3 be erode compound was purified by column c romat graphy to afford the idle .· aa-wsd (0.015 ;.·. to¾y h woopic 4;
Figure imgf000110_0002
of aa|wnmd 5
[0
Figure imgf000110_0003
bewsoaw:
0)540] To a adrred solution of rnei.hyl d^wmo-doiwdwdbe^woate (5 g, 2!. S3 ;aa -P n dioxane (50 ad.), tellway!(]-wthoay vioyJ paaooaoe (36? g:. a fad mamO was added and the wauoan a^ porged with argon hsr 20 rrna, .iV.UP.Ww}.; Π.20 g, I.Od amass's ¾as added and argoa was gorged gain for 20 tniw ' Ϊ he resulting reactawi mass s heated at 190 A/ for o h. The progress of the reaction was swatborcd by 4T55 I ; n completion, the reaction mixture was oonceritnaed to drvness under redu d pressure to afford the u compound ts 5a, fofo which eras used in da; subs uent step with t bather puriifosadon.
pegm; Map 2 Synthesis of mebtyl awetybgoredhyitwaaoate:
[055 hi A mixture -of m thyl eOd-etba vatyli-d-snebylbenxoaic (4.4 g„ 1 .90 mmrai i and 55% i fo4 (job mi..} as sarred at it for 1 h.4 he r ess of the reachou was monitored fo fhC, Upon co pietion.. the reaction mixture was basii!eb with sat. NaF!C h solution and iiitered. The tihraie eras exmwted oath 10'fo blewd bDtdbf The combined ssgnmc layers s¾t dried over anhydrous NafoO; and concentrated under renueed pressore. The crude material obtained was porOted by coins rm ehronwhography to arford the title compound {a a.783m
0)552] foe|> 3; Synthesis ofonefhyl ^ d w ir ycih; .^-2^¾ftth bere?. si«;
0)553] To stirred s luti n oi ractbs I 4-acew h-2-ntethyibcnxoate (3 g, 15.62 neew in McOH efo nb.4 at 0 X, NaBR. (0,53a a, 14. On mmel) was added. ]"■·.·· resuhiug reaction mixture was stirred at rt tor § b. lite progress of the reaction was monitored by 1145, Upon completion, the reaction mixture was otssxheb with water, eva rat d undet reduced pressure rid extracted with D M. The combined organic layers were dried over anhydrous afoO.; and concentrated under reduced pleasure, The crude ntateoas ata a -co was purb'hxi by oolumr; ohKanatoeraphy io afford tire title compound p2,S g.92¾y
10554] Step 4; Synthesis or methyl donetnyhdu l--phenr>xyethyi) hv-woate:
10555] To a stirred solution of methyl 4-g bigydroxyethylVaormdwdbenxoate (3 g.15,40 rnmol) in T.HF fob rnl. t at 0 "C, I id' gg,o? a 25.19 naaolt and phenol ( Lao g. i "7,0 i mrnoit were added and site solution acts stu'red at o for 20 nxin.4'hca DfAO (322 g, 18.55 rnrnoO was added at 0 '55 and stirt g was continued at o for 12 it, The progress of the reacOon wsta monitored by it, C. •spot* co;npictio;s, the reaction mixture was dilated with w^aw and expected with ebwl acelaee. I he combined organic layers were dried over srihydrmta sodium sulphate and concentrated under seduced pressure, ; he crud malarial obtai d was pu? abed by sabsma eiaxnrxgogrephy to aiioed the title compound (2 g,; 48¾),
hfoSh] Step 5: Synthesis ol' 2mserhrg.ya p. i^ aeid:
[0557] Aqueous NaOH (0,444 g, 11,11 tomoU was added to the solution uf methyl 2-anetnyb4- ; tidwaoxyetliyl;b ii/ a;e (2 g, 7.40 nanob in htObl (29 mL) and stlowd at 09 "C tor i ix the progress or the rcaetian was monitored by TT(2 U completion, erbanoi was oone -a ader reduced pressuic and the eact n max÷ was asntiPed raang i 11(51 and extracted wash 19% feOR/PC:VL T e c m n d organic !syers were iirscd e es anhydrous aodiup! sulphate and eoneennwted under reduced pressure so fford the du¾ compound 11,3 , 60w.y
[055S1 Smp 6; Symhesls
Figure imgf000112_0001
·( I•phenrwx^d'od ibewainsda;
[05591 Vo a solution of 2o:WPhyb y b-pheaoxvethyls benzoic acid (0.0 g, 0.7a mmok in D SO kdnLg :Ogaminornctbyi)-a.Pwianedori hydrochloride (0,20 g, 1.50 pwoois and Okbgylamlne op.22 np .1,50 mmnh wore added, i in reachon w!onro w s sdmed ai o for 15 nun before P B P fP.O; J J? mmok was added to It .0025 and fuoTer stirred at rt for 12 h. The progress sdOhe reaciion was nKaaio ed by TLC2 Upon completion, the reaction mass was di!aced with water and exiracted with 10% kktst kDCM 1 "he combkwd rganic layera were dried over aTiOg and coneemralerl under reducer! pressure, The crnde compound was pari bed by column chromansgraphy to afford the title om und ; 0.014 g.5% y
Exa le 5; yenth -*- ol fOmiponob o
Figure imgf000112_0002
[0560] Ste i: SyiUhesis of HgtdT-dl ethykd-wso^gkdb
4g I --phenosyedekjbcnzanbde:
[056 ] To a solution or2~nKid"ob .d1-- heoo>;.y hyl}b n oie acid ί .2 w 0.78 mmok in DMSO (3 rnbg 3sarninonwthyk'2ebwiinwdod s 0-23 g.1.50 mmok and oaedgTankw
(0,5 mk. 1.56 mmok were added. The reacPon mixure was surred at 0 for !5 m before PyBOP Uhd] g: 12 ? mmok was added to 0 at 0 % and further stored at >:t for 12 h. The progress of die reaction was rnonltored by TLC Upon completion, the reactnso mass seas diluted with waPcr and extracted wkh 1055 ekbo2 T5. The combined organic layers were dked over Na TOO. and csss/wdgsned under reduced pressure, The crud compound ee; purified by eohann cinoraawgraphy to afford the title compound (0,08 g, 26%). f. sample 6; Symtkesss of ComporooO
Figure imgf000113_0001
62] Ste 1: ym w a i i P aooa†hoay- (
Figure imgf000113_0002
idea
[Otaab To a tirr d soiuiiors f 2- -KiTb b --(b- h¾^' eihyi)bs;».i l acki (O.i g, 0.78 mm !) in UMBO
Figure imgf000113_0003
(0.22 g, an mmoS) arsd irie¾h l msn? (0,2.1 nfL, 56 mmoi) o. ·. ; e added. The reacti n nnsnure ·· a.- s irr d at st or j " nb« bebwe PyBOP {0 ό ! a. Id? nwaob woo; added io U at 0 X" and sbrring was condoned a tor id h. 'the pro ress of the reacdon was n* rbt fed by Tbba koor; c s^pk- k'ry d>o reaction arnas was ddured o bh oxU and extracted
Figure imgf000113_0004
lp% 5;··' d I so "d. The condoned organic layere vvere dried over R¾SO.> nod conaesuraied eager reduced pressure. The crude compound was ponded by c iunwi ehonnakwrapby ϊο aiford do uric cosryo.aani (0, 14 ic 5% . bsasopb: 7; S mhesb of CTns ornad
Figure imgf000113_0005
04 do; ; t; dyenhesk of hdi 1 J nraodi b3 x -23'C.dbydo- tbpyraoeb4w1}n;ethyip2- srsedod- -ri•■piiono;yodxyj)boozoro!do:
iOsdx To a stir ed ook;0on of 2o-ne ndRb.b-ebenoo etR^ «osd (0.1 g, 0.50 ns nob m
DCM:DMF (5 ml.■■■· I mb). TBIU {Odds g: o. o;y mm ¾ng Ld EA poial g; id? rnmoi) w re added and h aibo on as adored s n tor 20 mm, thee doaeiinornedodb bdoimrebiyb itbas aoob:T2 ib<n>e in dnwiboride CO. Odd , 0.30 nnnob was added and the reseiTn nd>dure stared at d lor ; ·· h.11* progress ordhe reacnon ay moneoeed by TLC, Upon eom ! oi , ••■e r acti n abxgwe was diluted with sad Odd IhOT .pUiion sad eskaokd with
Kbd> eC> kDCM. The
Figure imgf000114_0001
and oorwemnded under reduced pressure. The rude compound was pnrdkd by e- Teaa chresaadyyapby to afford the ide compound plod a, 15 ). b Nasay a 8;
Figure imgf000114_0002
ot Compound 9
Figure imgf000114_0003
Osddj \p p ! Syidhasis of atorh l s-chioro- ad -ethoxy vinyl rdonethyibenxoatro
[Oekfyj To a srkred solution ;ddnedyyl d-'b oas -Swhois^daKerli id-nzoate (5 g. IkOT mmo!) in dawiae- {50 mi.d. triouwl; 1 mthresysTt'. Itatamsane ί 7.5? g.20.99 mmok as added and the solution was urg d wah argon tea' 20 ma i baa PdiPPhw; (LI a.0.954 rnmoi) was added and argon was purged agabs ka 2s* mm. 'bhe testdbng reae ewi mass was heated a; 100 T.' km 6 h.
The progress of she r action as monbored by ITT. i Ιρο,ο ecsnplebom the reaction nwsture svas eoneenirated u dryness under radriced pressure t aiiwrd the tale compound (2,5 g, 51%,; hi was used Irs the subsequent wep wdhout bather purdieation.
P?:o.S| Ste 2: Synthwda of methyl 4owe;ylT-ehlorr>wowctb>abera'rarie;
( 6 ] A mixture of nwehyl Tehloro-Tl d mthoxysurniyTwrwthylbenwsate (25 g. O.ba rernol) aad tsw KCI Odd ad a was stared nr rf. ka 2 a The pnwress of the reavbon was momiowd by
I .2S. Up- -a completion, the reaedoa ¾ xture was basbVed oath sat. N MCO... sobsdon and dke! d.1 ha trltrate was exbaTed ¾nh DCb!, The oornblucd organn. iayew sveta dried over anhydrous Syy.ya>.; and coocenPated nodes reduced pressure ihe t rade compound w e pnrbkd by whama ehsomaiograohy be aitord the btie eompouad (2 g, vp%). b05?0j Swp 3: Syntheses ohroethyl 54ehk>r - ~i' hyx
[0571] To a sowed soiuoon of methyl 4-:(ooi o-- h o~2o' edi d o^ ;o g.4,84 nnwoi) f; fleOH (20 ml 0 ;si 0 ;;C. Nabthf; (0502 yr 5.06 rnmol? was added. The stakin reaction ruktere as stirred at ri l j h. The rog s of the reaction w¾s omniioreh by 414;, kpon completion, the reaobon rnixaare was quenched oath water, evaporated under reduced pressure and extracted with DCM. 'The eon-bined organk layers were dried over anhydrous ¾S(. and concentrated coder reduced syvire, The erode coetpound was paritaed by column ckr-noatography to adioul the tide compound (i ,5 g„ 74%).
[0572] O. 4:- ynthesis ofreobwl 5---ddor->2-rnethyk-hs 1 - henoayebwk benzoypw
[0573] 'To a stirred sokrnon ofnwdryi 5-whlorowA ! ~hydrex-ith 4}--2-;n thyi cnz aie (LS .·.
6.54 airn-4; ia 4440 (15 mk ) ;o o A5, ·: op < yep ^ v.y;. ;;;;r..p .:;w pheard {0 oa g.; y ;a w-a 4? were added and the srdeboa wws stirred at 0 '45 for 20 m. Idea DEAD (1.56 p.7.86 mm f) as added at 0 "0' ¾nd surrevg ova; ootuiaaed ai rt ror 12 .1 he pngress w 0·. reauion was aajoitored by 44.4" 4 Upon c m letion, the reaction uxture was diluted with water and extracted with ethyl aeetaiw The oombmed organic l yers wer driod over aahydnww ka^Sky and eencentrared cede: red ced pw saw The crude compound was pari bled by eoiurno
ciuxarnreyaophy a - afiord the tide coespeund Π .3 a, 65%y
[0574] Step 5; Synthesis o( 5-chkasw2uncthvk4--( p.phenoxyetiw i ibenoose acid:
[0575] Aqueous NaOH o). as ^ 4.90 mead) was added to the -so.hjv.iots of meth l >. aww-e- raed'wl--4a y-s.4wnoayed:yi)bea i.wve H a.3.27 rnuad} in i.O.OH $'1 ml.i aad stirred at 60 V; kn- j a. The progress or the eaction was motoawed by I1..C. Upon oompletiow the eOaae.4 was remo e coder reduced ressu e and the --wc-we avass was aciditkoi using IN I b ; nd extracted wuk HkeMeOhb44Ckk The combined organic kyers v>ere dned and cwowmrawd nder wdaeed pressure to afkwd the tale compound (0,0 a.6254; which was used In the subsequent step without furt er ptmfkation.
I A^'wj Step 6: ayrPheew ni 5--chkao-AAk knwdwwyk Aolnn
rnethyb4- T-piwra.wyetiw l)beaeaaMdo;
16557? 4o s s ?-T^(.i sokrikn oh5--shkm 2.-nwdgb-4d i-p^ nasi (0, (5 g,
0.517 maud) in C rDMF (> rut,■■!■ i rabw TB'hk (0.215 g, 0,072 ramaO and DIPBA (0745 g:. i 44 naaoy were added and the oAmion was stirred at rl or 50 e-ee I baa w-nwbxwy- 1.5- da¾edp4--i -l--pyrrreo|.-4-w57i;etlaoan5lne (O.04 g, 0,517 rrnooi- was added and the reaction ausiare was srewsd at rt asr 16 h. The proyrccs otdbe reaetaa; row nwauk-ooi by Ti..C. (spra¾ compeooa. the reaetioa rskxn.aw w as dilated with water aad eatracted with 10% MeOtil/DCoT ils-r w.-rnblneri epowac a^sas v- ere waslt d oatb oaaer, dried over bwAiht; and coneenOsaed ande; reduced ressure. The crude c-.>rupou«d was p rs i -d by ks - i chroma kseaeuhy to added dee d k c-.,- poiu><j (0.03 g, ! ''■"· ·
xa pl eg Sysstlseele of sm sss
Figure imgf000116_0001
[OcrS j Su I dyrnhes e cwh rekk i t,5~daYWth> d e^^
y d edgd kondiwT^
I'dd /d Id; a cdoed wduoon of 5wTkn'0--2orardyye-4-a dgTeoooeedgdabeeaok acid ;0.15 g, 0.51? mnv.fi) it) DC r M O snL I ad, a TBTU .d a idd/2 mroob and D!PFA i AHS gs kdd uiavak eee, added and rhe sokdka was raae-e ,a d a-r '.'■> ;ed:;. Then -dyaaiuo araUndr-h 5-d5Uivihyt- ! il-pyrazokedaHpoae hydrochloride i'0.0 i g„ 0.517 mraoh wsi added and the reacdon rndeere nai sirred at n ke la h. The proyeew ..a o.-c reaerioa wa-r soaa^.a'ed hy Had. Upon ooaopkdou., the reacdua rvdxkae was sheard whh. wader aad -.xha kd with Hkd kkOH/DCdi. The combi ed organec lay era were ashed wkb waaer. d wd ever codiatn saiphaie and coneendeaed under redrawn pressure. The crude compound a; es ded by ealuma ehronwadgrraohy ks aiford the d†k compound da04 a. leeky t- wooph^ IP; Svoheak ed kTmpotOid Π
Figure imgf000116_0002
(0>8 j Ste I; Syaybesis of
Figure imgf000117_0001
( 58 i j To a xek rxi of Swhioro'Toaethybd ; " he«o cU'Al}bo;¾:- i acid (0. i a.0517 ramon sis DM SO {2 ml..),
Figure imgf000117_0002
(0.157 g.005 mmop and treethyhoohw (0.2 i ml.. · roaaT were added., i ;■· :.x o- w xdxrare was shared a; o. tor 13 ra n before py OP {0.403 g.0.775 maxd) was added 0:> d at 0 and dadier sbrred at it bar 12 Is.. "Oho progresa ot ihe reachon was moodored by 11.37. Up n c o-s l O i). OR* yeacdoa. m ss wxa dih.ited dh aier and extracted wOh 10¾MeC)! 0CM. * : combined organic layers were dried o er Naw>C) :; and ooneewnued under tednecd pressure. The crude eompomul was purilkd by oeana s chrwnawgrapOy to a fiord the Ode covnpoand {0.026 g. I l¾t, f oa h: 11: SyathesH < f - mpftisssd .02
Figure imgf000117_0003
(0582] Soyj S : Synrhesis of s..chkxx>7wy(a,d.. hne†byl-0^^^
dwaethybddfyawnoxyebo ;}bes aadde:
(0553] T o a a-woden of 5 wbioo>2x cede b a 1 y>hewixyeihy|}benxok: awh (0. I 5 g, 0.5 Π rarnob in DiviSO (2 oil a 3-yaadao ;aethy0-a, d-dbrnxhyipyridawdid DHane hydrochloride (0.157jx 1.03 ooioO and methyl aaoae {0.2 \ an... b.55 romed) were xddsdyThe reaction snaxunx was sbrred n n for ;5 ηΌη be f re 0ybX)r (0.403 yy 0,775 oimok vesa added to it ¾t 0 "C and tcather abrred a; o. tor 12 h. The proyresa of hie reactKw; was aaxaKaxd by TLC2 Up n cr.an pieties a the reacbovi oxers wax dihaed wdh wener and extraesed wnh Κ7χ< ^-fcOH/DC. . The eraobined otyanic kwe:x -.w: dried over xodiora sedpbrae and wex.eanes.-d aseier tedrseed pressure. The wade compound wax pwltied iw ccsuro ehrooxatograpby a■ ailoro Ore tide eixsi oaad 0x0x5 g, ;5%7 kwoonb- 12: yyrokeafe of C s m 13 [0
Figure imgf000118_0001
584] Ste I: Symhesis oiboeggd
pobej To a stirred sob-hion of thyl 3^db:ir "4-di d ;;;ybcfii. «!.c (5 g.26.88 mmoi) in D F {50 m ), 34:ao ou tkmroberwonbrde ( .38 g.26.83 nnnok asm KyCChgOO'" g567/20 mrnok w e added. The resrdnag reaction nocture was stirred at 120 T: Or i.2 h. The ps gress of the re<icb i! swe rm;ohored by TbC. U on cornpkiiorg the vcacOon meawe d kaed with water as id exwaowd with 10'' - kieOifODCroL The ewnhbred organic krycrs were dred oves ide.ySO., and cemw rate under reduced prewure o afford the title oo poimd (3.5 g.35¾) which wsss used b- he .ebN sgi g step with tender puofioebon
i05bol Step .:: Svmhesis ef methyl 3 i e- -- ~c ^ --i¾'^yiki zsn~4--- i} phenoxy } hen.eoate: iOsxO] 'f a s rr d sokason of mehwi -g.0;m,eno- wweag:dterte y}^ (i g.
2. Oj nnaois end 4o4.4^5oeocnreethyiW Jjm ίθοοο g.2.74 annoi) in k!b Π 0 aO. y pcaaesium c-r one p.i.538 y, 54K mmon as added ami the sohuion was purged with ergon for 30 mho iw(dppt)i/b (0.3 g, 0,274 mrooh was added d apron gs ger.-ed again tor 20 iu.3 'he e ction mass as beared at 8:e'C for 12 b.4 he progwss oi dm .reacti n was reo uaed be 3 la' s Upon oorrspkabom the reaction mixture ee dik ed whh water and x cted with POT, eOB/DC , The combined organic layers ere dOed ve hkoSbk and eoncemreied under reduced pressure. The crude compound wax panned by · ware;
ehnnmoograpfw over bask asuodrc? w fkad the titie compound (0.7 b¼y
105381 Step a: Swmhexis of 5<hiorO' o2wyano- jupy K aeid; ;0522ρ le a surr d 5'j;=;; j; =;» of rncihy; .?-- l0i^--;l--; -oyiir s-^--i 'rld zi - '\1^ pheaox dheaxasae (0.7 g, lab aanoo so eihaaaj 7 ad ·, IN Ή ¾(.¾■! (5 atbt axw addad.4 he resulting. reacUoa axtx heated -a 60 ;'b for 50, The progresa f the reaalioa was iaoaaored by
44.2.7. bby i corapleiion. the waatioo ratxwae was aeklmeb wish !07¾ IdLl and esaaeted adth
K>¾. eOR-l --t. fhe cexobinesi orgsak: layer- ware dried aver asaO.- and e-oicemr ied under redu ed raswstae as afford die bile eorananad (0,6 ay winch seas uaed at Ohe. sabaeqaeat step idaaji huthar purlficaikn.
[0570] S e 4: Synthesis of
Figure imgf000119_0001
o- >sawiabdkxd!X.¾ lp
0)59! I I a a stirred solution of aPika aoykc mTw^ acid (0.2 a.. O.aOa naooP so MS i2 rnkg :27am a-a -oebpayaya^^^ 0x 04 v. O.Obs mrnoP aad diethyl euaae ί'0.24 nsL. I /0 mmol) ware added. The reaciioo io xusre was stirred at ri for 5 sua berone PyBOi" (0,44 ·.: 0446 mrnoh was added to a at 0 "C and srkrhyg w as aoeOnued at i for 16 h. The p g ss of das reaction was nnahtaaed by PLC iJpoo c-srapktioig th reaction mixture was d khed with water and extracted with K>% kleb.>R/DCkk The ewabbied orpank layers were dried over nhgSO.; and eoneeatraPed ooder reduced pressure. 4 e arurk osey ·: ad was pa- i kd by eohtma ohjonmanirxphy Ox uifosd ;he title compound (0,022 e: 9X¾a i -aoa 13; SyntPhesk of C m oasKs 14 aad J 5
Figure imgf000119_0002
[0292 i Step 1 :. S rahesia erf 7o4ikas- o2wyaao~2Hpyrh¾^ - p 5 "d triarhy f 2 f !pyer;:ao i -4 w4 a aarh a ! jbaaar rade:
[05w?j 47 > a stirred ¾s >iis i s¾ of 3w;biOoa.4a2 : a;K>k-.{p id xit!-4 I) acta :0,a g; a sx.4 atatoi"; Irs D21S t s ral.a, (2~rrie.iho.xy-l a-ajiYteOsyPHk ys ao™! w(a5' 5ethaa aii e OX; sS a. 202 aaao!? aad tfiethyi aataas (ar 36 ed.. a.aP rasnoi) a.ere addaa.4 ra reaeUvas fi re w s syaacd si 0 ior I 5 in betore OyBOP (0.66 ey I 2? nnrn'b) was added to ¾ at 0 'C and enrnng was cwuinued at 0 ke 16 h. The roprea'; ot b;c reeedon v. ' s mmdiored by TbC Upon completion., the wocbon m xture was dda;ed abb wausrand extracted vvuh 10%
K-k-OH/X3i.\ . i ·■·.·. combined organ-c layers owe dried ovekkasSkb arsd concentrated under reduced pressure. The cuke compound ^as pun tied by column einomatography to afford (he be c m u d (0.020 e.5 ¾).
[ 5 1 Ste a: Synthesis of
Figure imgf000120_0001
3wwo"2kwdhydrok H-pymxob -kys nrmthylibetvaarnide:
p.- v'.H "lo a atirrcd sokmon of 3~chkawkd.2owano-30pyrklarbro4-od
mebwwa -d ;-....a-e.. d; b i i bpy-i-ie-d-d kmouw ; uxsmnwbe i'0. a, 0. \M mmok n meik obe HO (2 e.d ■. konc. IK.' (2-3 rb ps) was added and rise reaction mixture was stnoed at 80 ki k>r ?2 k t he progress of sh r a ti n was monitowd by Tb . Upon eompledon. die reaction mrwme was eoncenOaied lo dryaess coder reduced presawx. Tim residue obtained was hardled oath arp sa . -wd 0 ! - so kit ion and extowted wbh id %adetabkDCM. The combined organic la ers o..■ a dried over Na>S<A: and soncsnirateu under reduced pressure to rknd de crude naoerad. which wore pardied by ookaym chronxnography over basc ahardoa So airord da ode compound ¾ .010 a. U%). kxarta k He Sysnhesk a; C hun nnad Id
Figure imgf000120_0002
[0506] bbep k Syathwxs of methyl a-oldoro-aonethoxyyro mdpyheuao ie: [OsO?] To ;t stirred solution of 1 ?r n >-e hloro-^ (55:.2k2'7 aunoU in !VfcOH (10 osL). Pd OAcs-; 0T476 g.242 ηοηοϊρ Xantphos s .22 g..2d2 nunon and u I ad; : amine (5,89 ml .-, 4254.mmof; were added and tin soktbor; wus pur ed with argon gfo 2d edm Then ca b mnniexade was purged her 20 nne. The waoboe mass was heated at 120 Xf at 20 Kb pressure for 6 h in atne-skwe. The prog ess oiXhe wacdon w s monitored by 21 - 2 Upon eempkaj p; ike wacooo mixture was Owowl through a bed of oebks and the tllkafe war eer esp-ated aader reduced pressute. The crude compound was punned by column
chKmrnmerspby to aflord die ride compound (1.5 g; 23:;;.y
[0598] Step 2; Synthesis akw:hknw-4d? d oayw Pedp2benerae acid:
10599] IT a udxaure of methyl 5-wh o- n ed" Wy'dTaiwthylben oaec (2.3 g, 15.42 rnmol) aad fhy In a-.etsc acsd (40 rni,) sees heated rk loo Xf tor 2 h. t la progress olXke nxa o .-a war monitored by TLC, upon oompledow the reaenoa nbxrtae was quenched wh.h aqueous sat. fiRCX.T solution and extraewd svirh ethyl acetale. Fhe c mbined organic layers were dried over Na;rSO> sad voeeentrated mrsXr redaeed pressure. The arade compound was puritkd by · cXuw ebromarograpky ka ai ord the on-., compound (2 g, 70Τ·}.
[OoOOj Step 3; Synthesis ot ethyl hk. --4- ndr x -2--;r!iik fbcri:i ;n<;;
[OoOlj To a shored ;:okklon of 5-whh:aw»4dyd oayPoKkbyk3eneei aerd 11.7 g, 9,12 mvrsoh In ebnarol (20 od,), eonc. KyyO dpi ; :ρ ρ w:w added and the reaobon mixture was reiluxed tor 12 h. The progress of the reacnon was monitored by TLC. Ijpon completion, the ethanol was removed node: reduced pressure ; k · residue obuilncd was braided wnh argwona sat. NaRiXX selotiou tud extracted with ethyl ¾cetaa-. fhe co bmed organic layers were dried over ekeSO.; and eonceekated under reduced pressure, Fhe erode compound was pnntkd by eohi n cl'nonxkswrapby i.o lypr rri us- hbe !o>rnpound i d.5 g, 76 ),
[0602] Ste 4: Symkwaes of ethyl aTadwoamX-eyanopkenoay vw..cidrro-T...uK¾h 1be xoa e:
[0607] To a stirred solution of et l 5"ehsoro--4- iys]rox;r-2oT:cthy!bcuaoaie i 1.5
Figure imgf000121_0001
7,01 mmo!) in DM k ¾ 15 k). ddwwnew hksrobenxwulrllc Id .82 g, 9.1 I mmoS and fiwYo (1.45 ¾ p) yp) iornofi were added. The resuOiug reaction mixtnre was arirred at iOO hsr ? h, Ike progress of the. reaction w:.w otoniioree fx f kC. fdson c'supiv e , the reawhsn nuauav was dikned svh:h wawr rue! exirarled■ ith ethyl acekue, The eomkiued organic layers were dried over a.;-S .;. and conceutraied auder reduced pwssnre. The crude compound was gurihed by coUeua ehtrunaksgraphy i aOrad dw ofw c-mpouud (1.5 g, 54(Τ}.
[0604] Ste 5; Sjadhesw of eth l 5 hloroXo wyaeowopyTklaramw^
usetiiylbenxoatx: F0605 j " a stored ;miee;on of ethyl so :nbroaww%;yanophern>sc V wido id .5 g53-8 t ηηηοθ nd 4oSg4p5T4en-aa;ei%^^^ 10.786 :.: ,81 tranol; a; DMF (15 tnL'P pwassium acetate (0.75 g, 7,64 tam !) was added and the sohniue a purged with argon tor 3d nun. Th n FdOippi 'iU (0.278 a, 0.381 tmoll was added nd argon w s gorged again ib? 20 min. Th reaction mass
Figure imgf000122_0001
heated at 85 ; for V2 h. The progress of the reaoOon was m uilosed by 41..C, Upon completion, the reacoon nnsoure oa (hinted w4h water and e meted with 8% bicOH/idOhl. The combined or anc layers were dried over
.;dOi and omwentrated nnder rensiced pressure.1 On crude compound was purified by column cnroaiatography to aifcrd the title compound (i.t g, 73%),
[9600 j
Figure imgf000122_0002
awd;
[0607] To a stirred soiution of ethyl >···!:;· ······ r-O-saO' - ;p; o n cw- bwtphwuo , atedwdbcrwoaie t 1.1 g, 2.79 nsmol) in eihanoi (10 nd t eg, NawH tO.lb? g, % mmob was added and the reaction was stirred at 60 w.' tor 2 in The progress of the reaction w n'mtfaored by 1138 Upon coetpiotiom the ethaeoi waa removed under reduced pressure and the residue ohmmed was mdiHed with dii, Fifd arid ecu acted o ah (0% MeOH ' IXuVL Use eontbined organic layers were dried own- hfwSO.; and eoacenieged under reduced pressure to afford hie dtie compound (d.7 g) which was used in the imbseguent step without further purittoation. (pope j SOe 7·; Synthesis of
d-w^-d w-dlhyd ogy ndin-%^
[0009] To a stirred solution
Figure imgf000122_0003
rnedsyiboneose aeni to. in g, 0.41 mrooi} in D31848 (2 an,), doatmno emyaKT to
da!ethv1pyriduo (i id).<>ae Or pW g% 0.822 mmoO and trieOneiarnine tft.f? mb, U28 mmof were added. The. waetion mixture was aOrred at rt tor 15 mm before PyBOP (0.32 g, 0.13 ourtol) was added to it ,e o ";(7 and sbrring was contented at w t sr in in the progress of the reaction mo moeuored by 1 LC. U on com let n, the reaction naetmc w rbiut-wl with water and extracted with 10% 38cf >HDCM, The combined organic layers were drier; over R¾SO# and concentrated under reduced pressure.4 he crude compound was pmaded by column chromatography to aiiord the this eompoue-d ire 1 g.4833). fssarnple 15: Synthi-aU oi' Cumprmnds Π and 18
Figure imgf000123_0001
[OolO] Se 1: Swuhesk o 5"eidoro- y2-s:wass>oo pv^^
(<%! ! ] To stared sohdon oi'5w;hksro-4-{2 ncw^
awahyibenaok swd (dw y, 0.822 mm !) DCM: D F (10 ;nL s 2 mkp IdsTk (0%% g. kb? ϊ'ίΐίϊϊ ΐ) and DIPkA (0, 18 g.2,4 ? sotocd? er added aod Use soiotion was stirred at rt for 20ein Then - daaw---- . i (-kncd a · ; ο;-: -.-ws- k- isa-w:,awwa;c (0.255 g, i .04 amud was added and bw reaeboa msauaw was sdrred s ύ ior so h, 2 he progress of the reaction was ••a- ana .>..·.¾ hy 11.< . f j si ctsnpkn a. the wsKtson odstare was dikaed whh wawr arid csPac d wsdt 10% eOHlJCM- The mbined organic layers we-e washed with wa r, dried over odiam sulphate .:ad eoneerarated raider reduced pressure. ) rw crude cowpound was arided by column chosnnuosa'aphy e> afford die tide compound (0.2 ¾ 48%;,
[Udi2] Se 2: Swauhesk
Figure imgf000123_0003
k¾--dSrnetbyk 2-'OX -2w-'dih d .--Udy)sraawi-4 l)niei!. d}*2'n5eih U¾ :i.a>'¾ ide;
[0613] id) a sdrred solution of
Figure imgf000123_0004
medwwy d
Figure imgf000123_0005
iO.k? g.0.13; nnmd) in rn«thaaeke HCi 02 ntky eonw HCi (2-3 drops) was added and the reaction irnaiure was stared at SO % for i d k The progress cdbbe rest don was nveasoxsl hy 41( 2 Upon eontyietsen. the roaekon ustere was crnwetursied i dryness otakr redisecd ressure. The residue obtaned was basrded wkh ap. sat, aHO , wai kst -and ewes-ess wkh 10% MeOiia)Cal hbe eonddned organis layers were dried over booSO.; and concentrated under reduced pressure ¾o afhasl the erode eases kb.. widviaeso. yaritwd by soknrm chn anaupwaphy ^klbrd :w: tide compound (k ik g, 4%). iwaapd-' Id: Systtkesis id Cssmpwnnd 13? 0>■.¾!>■! ο:--;·:·';·ϊ oswo WApiO WO
HO
Figure imgf000124_0001
Figure imgf000124_0002
sdobkj Step I ; Synthesis of U n¾h lro~. rl-- sras>- - lj!rscih::r i:
[0615] T a atuTod a-badon oi LAH Π in 3707 dike mk, 20.33 ηηηοΙ) at dry 'WW iaO ad s 0 Λ.Τ noahyi
Figure imgf000124_0003
(a g, 34,7 a aH w s added eede; rbsrogen atnwophere. T e resulting reaction mixture w s stirred at rt lor 3 h. The progress onhe reaotmrs was monkered ay TLC:. Upon eonybebon. the reeedoa was pnaaehad with water and with i ¾ ap. aOri 7 be prveipiPoed aokd wa fdterad threnmk a bed rb ceine aad the a - nan was washed with 7707 The bams- was eoiKwnnsPed eede: redaeed pnwaure i afsbrd ;be bbe eoiapoaad (3.9 g, '?%) whiok was ased as dse siabaeqtnwa: step without ba her pnriiioation. [OP ! 0] u 2; bymheaw of taaaasyd o-ebs w ramdwa.rbsddehybe:
[00 i 71 "Γο a stirred soknion of oxabi ekkaade ·: a ·' mL a 1.29 iwnak in day DCai < 3r> mlks at - o0 'T under nitrogen nionopheny a. solution f aahpdfoas DMSO of.44 g. 1.29 nano;; in dry DC 'M pro an.,) was added dropwise. The audition was stirred at ~b0 n€ for 10 abn. Then a soiaboa ofdaauaro drokfTyswaawT-Akimebtanoi (3.7 a, 28.44 nuuoO in dry DCM (30 ad.) wa added owpwiae within rain ami the reaedaa was atirsed at -6097 ;'···· IS awn. Then
Owikpgan e s" 19.7 ad., off.3 ownol ? w s dded within 5 nsia a -o0 '43 and stinky: was aonoeeeu at Use same temperature for 10 aun hebue the >eaebon nhxtare was skoswd to warm up as ambient temperature. The progress otbhe reaction as : siiK5i b TIC Upon coutpietkse the toacboo mwcare wets di te
Figure imgf000125_0001
watee The rgani lay r a-; separated ami the aquewis layer was estraateb with h>UM. The cornbmed organic Users vesre dried over bbi-SOs and er.a;oentrawd under reduced pressure to afford the title (2T5 g. C%} which was used a; the subsequent p ··· a:- - ; further p:-uihuh: aa
[06 IS] Step 3: Synthesis of 1 d alrah dr Cti^ r n-Ty p thafioi;
Coins To a arared - -lew -a of ar b d O"2tbc n---r> r kiahyda C.3 p.2 LOS uunca) ia dry ΤΉΡ CO mfp a; b a" under asr -eea atmosphere, methyl magnesiuso bromide (3.M in die thy! adso. 10.5 ml., 31.57 awi was added, i w resulting aa r ^ mixture wets stirred at rt lor 3 b. The progresc at she resatfou vvas momtwed by TIC Upon eem kbior5s the reaction was quenched with saturated ammonium chloride sohpion nd esamcted with ethyl acetate. The vombiaed organic layers wew dried over sodium sulphate and comentrared under seduced pressure. The etude compound w purified by column chromatography to afford the idle compound (La g, 5 Ufo.
10620] Step 4; Synthesis of 1 ate^ ahapmCbb-pvraa-b^ iedwl rrwiruatesultonate:
he 2 i I To a sore a soluion of bb ensaydfoCbbp a-4- Ipuhanoi Pi.5 :.·.3.84 fnmoi) I dry DCbi (S ml.} ar 0 wb trietgylamlne (1,1 ml.2.60 mrnoi) was added and the solution was stirred at same temperature for 15 ruin. The nioihanesaifbnyi chloride iP.35 mL.4,0] rn oi) was sioway added at 0 bis The .resulting reaction mUture ^ s stirred at n or 4 h. The progress of the r cton was monitored by TLU, Upon eornpLliora the reaction mixture was quenched with wsPeranci ..o.s a-b wnh DCS! The combined eayga c layers oew washed wbh CI HCl, sat. NaHUh.h ami brine then dried ewer how Sib: and concentrated unc.br reduced pres ure to afford the rule ecu-npouad cbUl g, bSUb wiesh was used in bw subsequent step without turiher purification,
106221 Step b Synthesis of 4-(b-aUdoerhyb tetisthv.:b.Cffa.wram
106231 3s a stirred la? i n of 1 Tiei^ahydro-Tfi-asyrcawb-pbuniwi metbarwsuHonaie (0.7 g, 3.76 asnoi s in dry Dhib (7 rubs sodium aaide (0,4-1 ys 6.73 mmou was aridad, 4iw reerhbrtg reacuoo obsbare was stirred at 70 C tor 12 la The progress rb the react ion seas monitored by LLC Upon compleuora the reaction miabne was diluted with water and extracted with ethyl acetate. The combined organic iayeo. wara dried over bSgSO.: and araawntrated under ieriueed p essing to rnibrd the title comp und (0.52 g, bb-sp which was w¾d in dm sub e u nt step withot-t btt her praitieaia -n.
524J Step 6: Sysnhesis of 1 ~{tvHr h d oS2H-^ jO&eaj 4o a stared sokaion i4-( /k; ^ yl}temi d i.^2i1- 5- f- pas g.3.22 annoi; in methanol ;5 mg). catalybc am nni of !0%Pd/ as added- The reacdon mass was sowed at o under hydrogen pressore ( i atop 6w id h. The gnwress o(4he reaedon wa nwnaowd by 11.6 'Upon eoegdsdon. the reastkni ear-. vras bhered through a bed of echo; and washed wdh rnePsanoi.4 he nitrate was sooeentraisd ismk'r redossd ressur So afford the tide c m o nd dad a, 72% which w s used in the sobsetawnt step without iurther urificati n
s 626) Step A; Symwsis of mebpyi 2a2^o.!n'a:^3h^ayi)-d"reaobiPsaa.au:e.
H)627j 4o a aOrred sointion of nwihyi d-Ocdwonanphenynacerare ( 2 g. a, 72 mxnol} m dry T.H (' 20 obw .a -7a wd LiHMDS ( i 6-1 in ss;; o.e.. i 7, a mL. j 74 sanad) was added eeOo; aiaogaa aora.wpla.aa and sdndng y eorvtmoed tor I h. Then sointion of UU I 6½dda.i.ol-d--yi yrthaeone li.15 g. 10,47 mawl; a? dry if-ihO.idviF (10 rai.:2red.g a a w r,; was added. Ida reacboa n-nxOne as fdaaasad to wane np to asbians wmperaoae. The progress otdhe reacOon wss rnonrnwed by 41,62 Upon completion, the reaction was igsenohed wdh aaUaated aaonorbeoj chloride, soiurion and eairacaed with edsyi aeeayhe. The combmed rganic layers were dred ove.r' bS .s and conscotrated under moused prsssuna fhe c ude eonipeund ;¾s gorbkd by eokeno
elwoneOwgeaphy k> afford the tills cwnpoaad (27 g, SX g
{0628] Step 'T Syauheso of ;Zy-nwdiyb2o2-aaonw*hcnyi ^7w( --(k4 a sdr --21d- > ¾n-- - yi)edw4'taadra>)but--.--ciw:>a a:
[0627] To a surred soiudon of ldieiridiydr --2H- ra?o- - i ttiiartt ¾ji5!C {02:6.: 226 mmoi) a? edewed r> mi..}, rnebryi 2-42-bromophenyi r .¾-oaobaianoate {'0.352 g. kiO mmol) and aeebc acid o.a077 g, 630 nauob re raided aad dsa waedoo miaoue was sbrred at 75 '27 for 12 h. The orogress oRbe nawuon was monitored by Tray. Upon compiebon. the reacdsai mass was voaeamrened 6 dryness. The erode eosaooaad seas ;;aa itad by a -bane ehromaiogrsphy to afford the tide eraopoaad pad g, .5 72 's,
(0636] S op 6; Synihesi:.- of methyl 2-omrrg bfgbnawrafo
7waP)oayiatc'
{06a? j To a sdrrsd soia oa of (X)--methU4Ta2-b.^
yi7nhyl}arnmo)6atw--sooate (0.3 g, 0,72 moud) in dawaae (4 ad. t sodium methoxkle (0,664 g. MS eeaok was added aad the solution seas ur ed o h argon for 15 ann. l iwn trieyc!ohexys pbosphiae {0.024 g, O.OKa asnwds and td-'ho. prewaaiyst 6ien d {OaO O g, 0,023 mnwij s e adder; and arena o-as paysed again ids' 15 mm, 4¾e reacdon sraew seas heaaoi ai iOO o; t^- 1 is The progress of dse rencuon seas na.adKa¾d by "id 73. Upon oompietion. iha seaedoa nnaaae was ddraed aads ado! acet te aad Π he-red through a ed of ecdte, diss idOate war- eonecmrated under reduced pwsxare s okaa; the crude material which wa pyriikd Oy column
chromatography aj affiosi lire tide compound (0.18.·.75%).
[0632] Sro|> 9; Synthesis of d-aoeihyi -ylyretrahydroodFh yfara-4-pd)eh>1ad H-dndide-d-- carboxyllc m. Id;
10033] To a stored xolotson of methyl dwnetlndkk Cteirarp^
iodsdekmarboxylare (0.1? g.0.36 mmok in ethanoi {3 mkk pk; NaOH (0.93 mk) was added aad Use reaodors rekexcd lord h, 3 he progress ofthe reaeUoa oaw omnltored by TLC. Upon completion, abe solvent■·. a-, w oved unskr seduced pressure and residue obtained w s aciditled wish lOsx 1 k I'd-, poeeipkated solid was oolleeied by kkration, washed -vaa esiter and dried under redoced pressure a aik.rsl ihe mJo compound (0J g; 61%).
[0634] Skp Ilk Symhesk of rwkaakdhnethylkdweo
mevhyk ik I p a,:n¾hydro--2H--pyran-d w }ed:ryi)-ddPandok''k'-carkxamsde:
[0635 To a xbrred solut of 2o 3hykk( kstetrahydrsrklkpyranm-yl^^^
earboxyhc acid (0.1 g.0,55 mood) in DMS (1 ruby 3-daadra:>uieihyk--4y3-din5adiy ipykdbx 2(1H one (0.098 g, 0.32 rmnok and ueedwaankoe (0.19 rob. Lad mmol) were added. The reaction mixture wax skrred at rt tor 13 mm betore PyBOP {0.273 p.0.52 mmok was added to ii al 0 kt and atioang w s comlnued al al for 16 h. Idee progress oikhe renedon w s monitored by fkC. Upon eompkkoiy die reackon mixture ws¾x ddaied wkh water and extracted with 1023 kleOH/DCM.4 he combined organic layers were dried over NapoOs and concentrated under reduced pressure. Use crude compound was puriOed by column chronndograpby s ailord the title eovnporsad (0.04 w 27%),
Separation eomktkms bo 19a and I9h:
OUkyj kacernie compound IV was resoked into the pure enanoomers on a (Jlkralpak 1A column 250x20 mux Mobile phase: 80:23. 0.1% DkA In mliexane: iCkkkleOU 180/20), Idem one: is.g mikmin. Loading; 2? rng. Ί he tastes moving enaodooaso 19a, k drawn as the S- enantiorner and the slower moving cramuomeo 19b. is drawn as the Rmrranbomer.
Sdereochcnkslry seas arbitrarily assigned, ndi slereoehermcal assignmesu has yet to be performed, a wunpk 17: Synthesis of komponok 20
Figure imgf000128_0001
0>03?1 Ste 1: Synthesis ob (2 ¾i;ihox -- -;n i y0 -OAO- ; , "dih d^ pyykiL '- ">'f}OK i)"
Figure imgf000128_0002
Oaxjaj TO aiirr soknkn; -4¾2oxedr4-,x-iF3^
wuboxyhc acid {0.05 g.0.174 mm l) rs WMF ("j mix. HAIl; (0.099 o.0.2 1 mmoh and OP x (0.067 ; 0.522 rnmoi) w re added. The aok ion x ,·- stirred at n be 0) mm. i h„: ; 3- ianononsetix, rTxooihosyxy-aa^^^ (0.044 g, 0.2oi nxmob wax added nd stirring was coutmucd at rt tor 6 h. 'The progwss of the f acucn was monitored by TLC3 Upon exxnpletion. the re c I OR m xur diluted wi h water and extracted with ethy acetate. The cornbmed organic iayera ore dried over bgySCo and s- a: wooox-J ondw txduaed pressure. The come compound was pus Oxo by c lumn c r matogra y to attord the tide eompouad (0.00? g, V¾).
Exmrspdo lit; Xv!>s esis ? 6 gsm osiud 21
! 05391 Ste : Synth
Figure imgf000128_0003
uwxhy 0-xy i -!ief ahydr> - H- ia: S" " (seth (!- hlxoaobxxwarbovxnide:
[0640] 'To a stirred solution of dxynxiryb ioi
carboxylk- acid iO.i? g.0.5^2 onmoF m i.T S 02 mix.3yarninmnetrn5T2whkxx>dr-- oxnhylpyridaxdi IHTotm iO.i 53 g„ 0.33 onnox end triethyiaabne (0,24 ^d 1.77 moiOi) ·· -.:r-- added. The reacti n rvd store was stirred ,η π in- 15 min bei'oix Py OP (0.46 y, ogx; aamob was added t it at 0 x and stirring waa couponed at rt tor 16 to "(bo progress oi the reaction was r snuorcd by TLC. U on complebcuy she Kwcboa mbanre was ddured "wit wales ami esbBeard wUh 10':' ¾ ble H/DCM, The combined organic layers- were dri d v fwwSbh d conccsPsted under r ced pressuw. The erode compound w:w pnrbied by coiumr; ahronnwogn hy as aiPsrd !he tub coaipooud ps032 g. oab boon ph.- lib b> ubsews of€onw>mmds 22 euwt 23
Figure imgf000129_0001
[0640 ] Step :; eynthesw of oOoi?etboxy-d wwiimebysh bHy>> a,¾>b4-y!anedwa)c2onethyb b-
Figure imgf000129_0002
H-dndokwOcarbos:a kks
Obdo] 'To a anrred wdubms of 2ooethyhd y;•4iebahydro-kiiy:w^-arn- wdicrhyipl Hbndoieco. earbowyhe acid b),2 a.0.096 mmoi) m DC'. : D F (3 ml. w 1 no T8TU (0.20 g, OdHH nuraol) and DiPcA (0.33 mi.,. i.94 nnno!) were added and dm sohbion was snob at rr ior 2(1 mho then Owneduwy--] .>durmb ybhbb (0.129 ¾\ 0.835 mmoo was added and th reaenoo mhaare was svsrred ru rs. ior bo ;.- ; no pmerc"- o he reaction mas moakmed by TIC, Upon completion., das ieaeben row! ore osas dilated with water and eairacied with Hbsy 'MeOi-i/ CM. t he combined organic layers were washed a lib wales, dried swer ;4a:;h0.i rid coucemnned under reduced pressure. The crude compound s purhied by column hroms grapiw to attbrd t e idle cornpouud p3.h?5 g, 59¾j.
10645) prep 2; byndmsis o' oU^ounwbwb bwoowadhe^
a to h v hi -ad ··( s a owi ?y d ro-211 -py rr nw4 wd ¾ hyl)-l bs--uKlolewm;.aToxamide:
[« >44] To a stored sohnion ot N-((J--meihoA
i-3 bs;etraiw^dro'w]: y ran-4-~yi;^ db I 3 g, P.353 nuooh in nnobaaobv Hha ;a nb..y eonw HO P t odd seas added and the reammn nmtuw: s. a-, iuirred ai 30 "C hw 12 h. Fhe progress or the reaeimn w v^ monitored by TLC, Upon om iebom he reaction ndsture vo > ooneentramd to dryness under rsdosed pressure. Tie; residue obtained was baamed wnb agucous sat. NaHb b s-dnbon and e.sO"aemd with I OwApy ytl.DCkh hhe combined rename layers were dried me hia-SOy and coaceraraasd nnoer W'jused pressure aPbrd she crude rnaaaaah whi h was pnrifkd by eoianio chromatography k; aiiord dr. idk ssaapouad 0.00° g. o¾). h caospk 2d; Syadkesk of C.Vaapar.iod 24
Figure imgf000130_0001
1.00··: 5] ΡΡ·ρ 15 Saaahesis ra77ea'nkK<k..yi5edw Pd<>;s.o-di -p} ' n--P"Ca b<'ird† U;;:
6 6'| To a stared sokitioa of ail (60% 19.0 gt 476 anaed) .in dry 4 Tr (400 ako at -10 O aiabnoodrde g31,37 gr 4/0 aanol) v.-as added arid die reaction was siinwd at sasne tempenPure id-r 20 min. Then ion-.ee. Two wrw- .7- -a-; (40 g, 476 awak ; was added ai -10 'Τ,' over period of 1 a ana. aad be.- reacdon war stirred at sarae Panpeosture for I h. Upon eoropletion, ho reaouoa was aeotra eod oath dikde HQ and eoaeeaPaled to dr ness k aikad the btk c mpound TO g, 707 k w nk; was need in the subsepaenr step wehout thrrPer pnrO cafk
[0047] Slo 2: Pyabicsis of 4dwsiroxy-a"roedp4T.-oao-T :2--dapv;d v!pyrid ?e-Now r0o itrib: [ppaa Λ ¾Τ:ρ1θί: f 3aarnneP 5¾b;yh4.-o>s jkripwrankwsrP^ratrbe P'O g.333 nmiob ia 1077 HCi P'OO ml.p was retlosed for-! h, Upr;a completion, die precipaae was coOcckd by tkrabon aad ashed whi eabi wak-.r aad Urea w:wresa:dnsed troas TTPPH P.- arrocd das Ode compound (45 ·.. kkk \vhi.ch was oswb la da- subsequent sasp wahoar tarther purification pk4p| St .k P iiTp -as or" ..o-ar0asay-aoae0 es--2-w-i"i ,2-dOp dropyrkiirw-'Toaraoaai e: iddypi To a stirred sokdion of
Figure imgf000130_0002
;30 w 200 ooool t ia Tap OsOO nkp ai 0 T7 POOp (27.6 y.300 ηποοθ and raetbyl iodkk pad.4 g, 300 rraooi f ware added. The resnking reaction aaws was stirred ai 60 for 30 nnn, The progress o; the reacksn a-as nwaikeed by 14.3.7 Upoa coaiggnkn. die w cOou rni i n was aOiw-eriP'aa'Ti to dryness, ike residaa was dikited wOh 303;> kleOfgkekt and filtered, washed ·· eh with ddk MkT-kDCiVa 3 he faps.de ass coneeorra-ed under .reduce pressure to afloal crude nuaerhd a ich wa purwled sdaxs gel olumn chwauan.gps::phy to aflord Uw tide compound (H g, 2s24s
[005 I ] 44ep ; xvoPwala of -gaa raa ad;;1y-a-!oe as - >-aoo io) rknn-TUH}ware:
[0652] To a stared solution f 4uoebwxs wt.nnedryb.2w>xo- 1 . ! h_y1r yridin * - a niti'i.ii; > I g„ a,09 wsmol} a; orethaum Π0 mLT a caaf ybc amoanv of Rnnsy ickel and ammonia sokalon (2 mL$ were added. The reaedon mass was sdrred i it under hydrogen ore- -o - Π atm > i 120. The ¾res3 of the reaction was oohored by iLC. Upon completion, the reaction mass ΊΌ;3 fikered Usroygh a bod of eehox washed ··. id; nwihanoi nd the fbtrak was
eoncem aeed under redrwed pressure to afford dse tide compound (04s g, 90%) which was ased In the snbaoyaaai step w th t rthe? pm srisauoo.
[0055] Ste 5: Symhcxia of y(4 oneds --0-aaedw4--.2- AO- 1.TolOwdropyrldinw-yimmtbylo 2οηη0ρ4·06 l-U u"ah xl o-\- bl'^ ¾ifa- " j)rih\ if i H-nrak4ewwsrbewamlde;
[0654] To a wowed solution f dwnHhyl^yRuet ah d
carboxyhc acid Org g, 49 mmob m D SO (2 mLf 5ya i;on;eth l)--a-a"nothosyw5-- medwlpsrlduwaOlhnwaae pj.254 g. i w9 mmol ? and tnedgymmine pl.24 ad .2444 mmo!) were added. The reaedon mlsiure was siirred s rt tor 1 a mm heiore PyBCJP (0.542 g, 1 ,04 mol) was added k- k a; 0 Pt d aursaag wae oonOneed -o w for id in The prepress of the. reaction e monitored by '11,(2, Upon completion, the reaedon m x u was diluted sv!tn water and exiraeted with 16*4 MeOlwDUM The combined swam-, layers w re dried over a ,666 and eoneeraraied under reduced pwssareyThe cwede compound was purltled by cohav chron apographs to afford die bfle eornpoand (0.12 y.2s %).
:>.b!2;l< t^
[0622] Rneermc csa-nporard 24 was resolved nwo he a ensrukeoers on a a'hushxnx ΪΑ column 256x20 mm. Mobile phase; 40;2(60,pyw)EA in mHexsuxx DCMmieOH 0n0/20e Flow wae: 14.0 mL/mim Loarhng: 20 mg. 'The hrwawwnovuu: emnaiomor.22 , ia drawn ax the $· enandorner and d-e slower moving ensotioiner 24b, is drawn aa Ihe Rmnamlo er.
Siereoohwni sow was arbnmnly assigned,, and full swreoohemleal aaslgnmcnl has pel so? be performed. f wnnelo 21: PvathewN ol Cr;no>onnd 25 wo-
Figure imgf000132_0001
Figure imgf000132_0002
iP656j Step 1: Oymhwds 5-bro;no-2 ηί&¾ή Ο -·π τ ό«ίΖθ5θ acid;
[06521 F sbrred solution ^' T'05 h b5w>droheir dc acid ( ¾ 1381 nenob in -nc B;202O Π00 -rdw ;n 0 'TO KX^dhromo-->T bmeO^ g, 82.87 η·ηκΜ} was ndded porPon w;se and the reacdon are. was sdrrod at r? lo? 6 h Th pnygress of she reaedon was monitored by TOO:, ί' -ροη compleuon. the reaeiisas. mass was poured on ice cold wwier, solid precieiiaied wa¾ uUewwl ashed with water and dried under red ced pen. -aw in ainwd the dde compound ?'2'- g, 8000,
ΟόΤΚο Step ; evnthesis -a wege j 5-4.s <'nody-nk-Owi-2odnve:naw:oate:
[0650] T a sPrred solution of 5~b ms^d--mL hy0^i«ni5?ob n'?O5C aeid (20 e.111.9 nuno!) n Dfvl (300 now, sodium earrK;nale utS w 447.4 mmo!) and reedryl iodide (0359 y.447,8 rnnsoO wew- added. The reselling wacPoo mass was heated ai 60 n2 for I 2 h. The progress of the re ction s;wrs ηκ? η·-ΓόΟ by ITC. i.'pon e;-rnp!edon( dsn wiaetion noxpne was (iiterral and washed with diethyl erhcr. The totraie was diluted with ware? and o raeted n!i di th l eiher.4ne c mbi d organic layers, ere dried over aTCo and voncentrnied en e- i'ednced prcesui'e. i no credo cono enwi w:w pesiOed by eoiomr; ehrornatoyraph>; to aitorri the btie con oaiid (30 g, Pn%'i
) 6601 ei p 0; Synthesis of ineited O-OyvSiWi- ; f3niviob>.4. a0 se0i e:
OoPO! 27s a siirrcii roluiion of medsyi 5· ron5 ■■2·ohsίsί ■·iki■oie5■;^:ί.> i" 025 g, Oi.24 rnnwd) in F (250 n-i.. ;. OMF-DMA =65.1-1 y. 7,44 mieot? vow added iowl the reacrion was stirred at IOP " . has' 12 h. 'The progress of ihe re ction was noninncd by T'L-C. LT>en c m leti n, ihe cear iiisn niixiure o s co-wooiralcd i'S diyswss under reduced pressure.2 he residue obiaineii was dissolved in aeebo acid i25p snL). iron oo'dsi (50 , 092, gs as added and the ieaedon nsixtnic
121 was stared ai SO % for 4 h. Th pr ogress of bw reaedoa wa nwntlnsred by TOO, Upoa eoeuplction, the reactron mixture w eonceaOcned to dryness under r daaed pressure. The residue obtained was dlUued vrhb ethanol and filleted. The idtrace was onuceturaied ender red ee pressure to aid ard the wu-k maierhb, which was purkkd by column chronmaxpwphy give hde con-pound bid g. §6%).
1/0662] Sbep 4: Synthesis oldtrerhyl ddxwmok-gsecdwaylH^
iOfow] IV· a srirr d sfommn ol Mali 160%, 0.755 g.. ] Skfo rnmol) m dry whig (40 adds at did methyl 6drc i andok-4warboxylaw (4 g, 15.74 warou) was added and the solution was stn seel at 0 w for 30 min. I hen ddwomobmaae 05.39 a, 39.34 tnmes) was added s 0 w' sad bw reaetasn was sdnxd at a for 14 h. The progs ess oidhe reaeuon o s onuored by i k. Upon completion, the reaction was quenched wsth water aad exulte wah ehryi aceggo. I be combined organic kvers were washed with wawis dried over socbam sulphate aad ecaweaaawd under reduced pressure, 's he etude compound was purified by eokatm ehtoouvktgraphv t-> ai!ord the tide compound Γ3 g, 41 %g
pfood] xlc 5; Svrehesls of m-. o bdwornok
Figure imgf000133_0001
[0662] To a mixture of nwihyi 6-bromu-l sec-hia h- 1 llondofok wttrboxyiate (3 g, 0.6? awwb and POeh (3.70 tab, 29.03} at 0 [ F (1.43 nk. 10.35 mnwd) was added ehwvly. d he reaulbng renstlon a;waa■ as..Wood ai SO ;iC (or 3 .4 he grogrwn ssdhe wacdoa was rnonhored by !LC, upon compleuon, the teasu- n n'dxhae was corwengvued its do. no... wax; reduced pressure The residue obtained was basrbed with aq, HaaKXh solnbou ant; extracted with ethyl aewate. The corobawd organic layers were dned over anhydrous bhg gw and coucevgrawd under reduced pressure. The crude compound seas purified by c lumn
chrooKiiography to afford Use due compound (1.3 geXtkyd.
[0Ck(b xo g 0: Synthesis >f methyl 6-bromo-T•(seedsnty! rkoneihykl H-dndolekwarhoxylate: i0o67] i'o a stfoed odabon or rneben udvonwknseefoaOdVd-aorrnylklu
id .5 g. -pay nrnwd) in DMP (15 an . PTSA f 0.11 g, 0.576 mmoib goolucne auUoav; hydraeide { 1 ,07 p.5wd nuno!) and cub'i lane (i 2 ad.) were added and the ;χ4;η!·>η w,/ns sdrred at 1 0 'w for 1 h, .y ter i it rhc reaeinx: tatciure was oofoed p. rt aad sodi m aj¾ob roh i 1dc (ΪΛ g. I7T naard; was added ar 0 "Pi. Fhe resuhlag waeiioa n'nwu eras sdrred at iOd wy g;>r 2 h. I'lw propresa oidhe reaction was rnonia-red by i I ; fipon eoiupleboa. dw reaedr>a stnaiaw oas dnuted with crater and extracted kh ethyl aee-are. ihe coatbascd org;ailc !ayera were dr-ed over aahydroua ag Ai and ccrwesgraied under reduced pressure. The crude compound was purided by solemn chromatography a · afford the Ode compound 11 .·.69%). jOPebj Ste 7b Svmhesis of metbyi eobwTinsodmtexycarhonrbp^
Figure imgf000134_0001
fbm
Oopoj 'To a sorred s l ti n of nseihyl odxusawU o ee- sbyyUovcd
earboxytate (i g.3.09 mrooh and nbdwg I 4o5^b4yye eir meb^
l 5a d i" ' ljpi ef¾zn -^--car i iii†e ii.32 g.3,3d mmo!) in dioxaneAvsuw rmxPne (a" ml., e 2 ml. h jPi ·. I '?!· g.2.25 mraob was added and di solution was ur ed oath argon tor 20 una. i.'0:Op;d b i (0.232 :.·.0.309 mmol) w added and argon as purged again for I ' ado. ; Is. ; auction mass was honied at 80 "f far a a. the progress of the maeuon was aorabacd by TL(g Upon completion, dee re ction mlvaure svaa diluted o ab wate and exhweted with eihyi acetate. The combined organic layer were dried ove; hhnSOy and wnweruraeed under reduced pressure. The ude compound was purified b) aobann ·. In snsn.-ranh-. to afford the hbe compound (0.8 g, eUw.
106/0 j Stop 5: by mhesis f 6o ( g a lerpbutox ccarbonyl ipiperaah } wdjpybbboa-y in Ί ~(s e- b iyl)--wmed\hv - fi-dndolc- Kaarb i.yljc acid:
|06 jj To a stirred sohuiou su nwbwi a-a b--Pb-; ierf Oww wyeabwnyi ipiperazbo i•x-"i) -i-Si1in-2- g .S g.1.58 namobi in bfOH (10 ral), urr
NaOB (0,252 a. b.32 nmwbj svas added and the reaction as stirred at 60 'X' for 1 h. The progress of the raacdon was monitored by TbC. Upon cssnpletion. ethanol was removed under reduced pressure and die reaction mass was acidified using dib Hoi to M 6 aad exiraobxd with i bebiwb l/DCbh The combined organic layers were dried, concernrated gisaag ibe respecdve acid (065 g) which was used in the subse uent step wit out bather ptninoabom
106721 Step 0: aymhesw of tertdauyi 4-foo
Figure imgf000134_0003
ddryd? pyridirabbo4)asethri}earbanK i
csrhcxyfote:
10623] ίο a xbned solutfon of 6..fo.g g en4;sOox !ri-s-v :· bui ]v-a"r: t vJ-d2^^ >d ks- -.c rbo y1se acid (0.3 . Oyfoo mmol) m DMS O ad.), 5-
Figure imgf000134_0004
I HHms iO.I 11 g.0/73 mawl) and nscbwharaae id, 25 rnh, 1.82 nuwl; were adder?, "bias reaction mixture was shared at r for' 15 wnn before Pyi30P oO.Oi-b g. O.Oi meed's was adrbb w> b rani stirring was wnbmued a; ft for 16 h. The progress of the amotion was rmmhored by Tbhx U on completion, the reaction mass was dduuoi with water a i extracted wuh 10% htebbi/hKbeh The combined organic heyew seere dried over s di m su!phiite and csutcentrab-d under reduced presses e. The crude compsausd was purified by column chrom t ga hy as afford the tide compound (0.1 g.26%). 2015/037715
[06?4j Stsp 10: byodwsis of I bsecdwuy!nwab—^ awth
yl';rneby b7uneibyiww g ipe a^
Okwej To sdnx-d aoludon eTlerebopb 4-g2w hyse^-br;t w^w^
ll dr rldis^d"yl}i)i?d- d)oiir ; i-5 > OTkanebgT I bbTKkdw>wl^
caroosylate i . ; g, 0.1 SO nwn lt in mebwwhc HO (2 srdA■ HO s2w drops.; was a d d and die reaedon ntOure a stirred at si lor 2 h. The progress oibhe reaeoon was monitored by ΊΠ..Ο U -n eongdebon, k?e reaction ioastute was concentrated oj dryness under redneeb pressure. 'The re idue obialned was basiffod wkh aqueous sat. NsHCX.K s luti n arid extrated with lo% bleOhi/DCM. Ike eowsbbred organic layers were dr-eo ove anhydrous NaySiT and eooeentrated under reduces! pressure. The crude eong>ound wa pordied by aceromirPe and pentane washing lo a word the ikie compound (0,018 g, 2r¾ s.
Example 22; as ado o id knrs oinfJ b
Figure imgf000135_0001
[0670] Skep 1; ywrnhesis
Figure imgf000135_0002
acid:
[06 7] Γο a sre ed sokau>o en owibe I -b os50- 1 o sec-4:nnyf w'wmebgT s H-dndrde-4- csrbswybPs (I g.3.03 nnno!) as biOM (10 orbs eg. NaOH (0. ISa g, 4.02 ramol} new added and the reacuon was sorred ar 0 C tor I b. doe progress obtbe reaebon ar monikned by 1T. . Upon eom-beerax ebwno! wws removed under reduced pwasare and the recedon snass was ackbOed acuta rbb HO up lo p; I o and extracted with 10% MebiH/DC . Ike combined organic iayers wwre dried over sodkao saiphaPs and concentrated under reduced pressure t afford i he- tide eompsnmd u),8 g) which was used i« the subsequent step oolhout bather pnrdkaboo. i0o78j Nop 2: O obaeaO of o.½ nk (s c" u-y^ sO
Figure imgf000136_0001
|'067d] To a -Orow aoOoon of 0-Ρποοο-7 g.^e-T iyTOO^^^ acO (0,5 g, 1,61 nonob in DM SO 0 wd a 3--Oa'daometbyO w«cb ^
i 0-406 g, 2.42 naoob and ob.bn eoOno (0.0? n-O 4.84 oineab were added, the w κ o- -o mOtuse was at n: tor i 5 rmn before byBOP ,26 g, 2.42 annol) a added to n and spring was eonbmwd a? b for 160, The proyresa of the reacrOn was moohored by ΠΟ. Upon cwrspOboo, (he reaeboa roaw; was dbakb whb waoar aoi eabaeted wgh OOs adoOfPDCbf I' s.- combined organic layers were dried er sodium sulphate and eonoenwated raider reduced press re. The crude compound wns panned by oohnno chronnnoyaaphY a.- abbrd de Ode compound (0,45 ys 602 .
[O gOj No p ; SynbiesO of D ee--bo -0--u2-ooedw^^
Figure imgf000136_0002
· b:S : W-O-yb- : :-CO.wO- CW meen
Obai] To a stafsd sokOon of 6^orca0 aec~b^^^
dshydropyndao'Oyf a ned p pO-meihyb ObhaOO-OwarboxyrnkO (0 a g, 0,652 mrnob aad OgO (4, laOweaanwthyb 03, -d a:wabosoOiv-2--vi}pyrOsa-a--- bpiperaabK: p0O26 y. ^ 0-3 mm-. so so dmsancovauw mwuae (S ad., a 2 rob;. t PO.; (0.^-14 g. 130 naoob was .-0-0 and rba aOodon was pweoo with argon for 20 mm, PdOppiaOb 0.053 g, 00o52 avb was added and rgon seas par.- 0 agaas for 15 mm. The ieacboa mass osw Ow-O at 80 O' tor 5 h. The prswrasa -.a do: reactio was monitored by TOO, Opoa cornphxOn, the iaa-.o -a .mixture was dilated v ay waver aa-j extraered whh 10% MeOH/OOOh The combined organic layers were dried over bbpSOs and ooncergraw-d under reduced pressure. The crude co p und was pwifOd by eoOrnn
otoronsatograpby to atford the title compound b.s.Oda g, 7%),
Exa pO 23: Synthesis
Figure imgf000136_0003
27
Figure imgf000136_0004
[0682] step ymheaO of imobuga -i-(50 -Oee ne ^
pvn.acohd--yl mua.hyTOarban h}0$d i · · sorred s l io
Figure imgf000137_0001
^H j ^.π^5h i-! ^ ukί ^ ^^ s;^yji acid k) .w yy o 'k I rnmok k; IXIvllk b s 10 mi. ÷ 2 ad.h TBTU i0.2!;n g, pbkM im;Cr? ¾m] DJkhA (uk7e a. . ? 3 mnwT wew added and the wdrkion was sowed ai it k>r 20 mie.1 hers h wwihos -d.S nnwbw H
yitme - o n-uae p).B2 ¾. Owae mmo?) was added and Use reacboa mrssure was stared at k tor tb h, The prepress oibhc reaches.; w s swwihoeed by TLC Uposi eornpkaeon., the reacti rness was oikuwb with wa er and esaraoted with bis, b!eOH/DCTi ; he e-sebsned orgaak iayers were dried oeee N;.oSO; arid conce arreted under seduced pressur The-- crude componed wsss poofied be oohuoa ehroesatryp-aphy ΐο alrord the tide eoespound irks g, 5 kkp,
pkkib Seep .k kyrkbe-as
Figure imgf000137_0002
y n) -i |}--3"-!i)e,d-!y;--6 6- S -;r .i ¾-'l wispy ridi»-a-yi)- rikadoks-4warbosssnmie;
Pegs] T a stirred solution of sn- xu i
Figure imgf000137_0003
>ρ;:Γ:·ηη ; · Π i - iO.Ub -.· 0. 7 asa-e · hi mctbenobe i b.1 as mkh corse. LK'\ -0 drops) was added aad the reacbori mswture s. .arreo at rt bw a h. The proaeess of the reaction as !nonitered by Tl C. Upon eonykchon, the reackoe sekause a- s conusetisaed to dryness tauter reduced pressure.4'he residue obtained wa hasiiled with aq. NaHf w seTkiou and eakasted with i % MeORIXuvL i be eomb ed osptaue layers were dried over anhydrous eakkk and coacemrated under reduced pressure. The crude eosnpouad seas purl bed by pentaae washiaa k; aikad the ik : weapoaed u). 24 g.5 %). bkaswbe ¾4 Syskhesks o!' Corn|>-»«nd 2S
Figure imgf000137_0004
ibbabi Step Ik Syarhesis ob ? -(seeksutyioNot
Figure imgf000137_0005
ii-pyraaob-4- y1)aKahy1)-3 -rnethyi--bkbopn>erariak--yiipyridn-rk-w (bbC a :,:?i cd Sob-boO o( W CorW S .; 4··: p.: ;·<. · p.-tgO.. ; 0 ;b- - \ . ; <···· lio PC-b Π
Figure imgf000138_0001
(O.Li g, 0.19 mroob BBd; irs isCM ; ml.) w s dded and dse reacdor; adxrure was sbrred as ·ΐ Lw 12 a. I s- grogrew r ds. reacrba; sww awwbtored by I'LC Upon eompiedos. das reaciion nuxiere was quenched wdth apueeus sab 'NaH(.4J:; soinbon and extracted with 10x4 ebdHbdCsab The combined organic iaycis were dried over anhydrsms bbpSbb and coricemwded codes reduced pressure. The crude compound was purbied by okan i ohronnUography ro sbbrd bw oik: compound (04=2 g, 204-w, bwmupie 25: S sifbwbs of Compound 2b
Figure imgf000138_0002
pmgg] Step I: !Cnbewas ofberbbuiyj 4·= : b-=gs , .::;; g .4 ··.! -.by a .·· w. bt- : g. oww. o '··· i I ;··
Figure imgf000138_0003
ibbibb '{'V; a sbrred ;w4uhsas op
Figure imgf000138_0004
brii>drb<o-oed'p'bbB4cdo --4w:arbox>isa acid (0.3 w 0,609 mmob in IXCLD F (10 roL a- 2 mby TB'FU Br 254 e.0.792 mmob aad DILEA (0,23a Lob mroob ware added and the sob-boa was adrred ai ri f r 20 mire 4 ben i i -ediyl-b-aserhosy. -a owwhy b ' bayoaoa-a.
yhroedsanamme f0.206 g, 1.21 mmoi? was added and the reaedon nnxhae was sbrred at b tor lb in The gress olbhe reaction was monitored by TL Upon coragiebon. tbe reaebsai mass was dihjred wdh waier and extracted svitb i0% MeUii/DCLh 1 he eonnbined organic layers wese dried sww bbgbhp . -.nvi Cisnseobsscd aadei redocxd pressure The erode csanpmnul oas w.s dbo bv sobann oheaT;abgwa.phy a> nffoni dw tide compound id, 2 g, 5 bob.
[Oo O] \wp 2; bymbesis oi Βί¾ο4ϊυΐν1)- -·ίί b-^
nctb)1^' ίacdόao ■ρ^■ooρeraein'-by } pyodnnb-yi i hhindoieCwarboxamKke
oOvs To a ^br eb eolation or wrbbaeyl 4-(yo s c^snt B-^
lHp>yowo!W- l')roed"w4)carbaaHyi}«3
carboxyiate (04x5 a, Oabw mrurbj m methauohc HCi (2 mby cone. ( b (2-3 drops) was added and (he reaeboa mixbue oas sbned a; rf Par J is t he progress ohtbe reaches! was moahoreb by TLC wpon aompieooo, d-e oeaodwi nnxmw was eoaacrnrawri ts> dryness nm!w reduced ressure, The residue ^oiaiaed was basided wit aqeeoos sat. Nat X.o sokaioa aad eatraoted vvith 10" a eOITIX'PT The combined orgy; si la rs were dried over araiydrr-as Ma-. ¾ arai e->aeea;rared ooder reduced pressor-;. I he erode om nd was purified by peetsae washing to Tlbrd the b 'e eorapouod Of 025 g;: 59%), eh' 2b: S ado-a> of Com aar 3
Figure imgf000139_0001
|0692 Sop 1' SyrPbosss of
Figure imgf000139_0002
a. -yi}nei.hyh^Tmed^^
[0693] To a >arr.o sol ion ob arrPbuiyi 4-g5o Pbsee--baayl)-'4apd .athy;-3-aocthoxy--5--ioetbyi-- i Hp aeb-ly^^^
earboaykae (0.. ¾a 0.233 ηηηοίΤ Π0 in Db'M Π u q was added and the reaction mixture eras stirred at rt tor 12 a. The progress of the eaed o wa n¾om†oreb by 1.1,C. U on eompkaiom die reaction a;ixosre w¾a quenched ward aq. sa; ^sHC o wOodo;; a ad esnaeerd -aab 0% MeOIJ/DCi'vl. 'The consb ed organ so layers wore dried over anhydrous N¾Si¼ aad
coneenoated nder re aeed reva se. The erode eosnpoaed was purified by eohann
chromak;yraphy to afhsd Use Ode compound PaOa g„ To.: b. woop!e 27: a thesis of€3omponnd a
Figure imgf000139_0003
[069-fj Step I Synthesis oi oddon.wMu au6n4odm^^
r tbykKhf
10695] To a stirred solution of lor T -aUTa!ssr^4^
kllmedrdaffiimdkoxdo acid (0.1 g, 0,295 mmoU in DM SO
Π ad ; 2.22s6ue0moedw4piperkihv m me (02569 p..0,442 mmol) and naedySannne (0,12 an,.9,885 mnwd) were added. The reaction mixdtre was sOrred at it lor I 5 mm bed-re PyBOP (0,22 g, 0,942 miiiol wa added to u at 0 '45 and sbrring was continued at rt for 16 h.4 he progress of Use reaction was ntondored by 91,62 Upon conviction, the reaehon mixua-e was diluted wnh waicr and ra t d with 10% MeOH/DCK Combi ed orgasne layers were dried over agSfn and ceeicemraied under reduced pressure. The crude compound was purified by prep 106 y so afford the tide comp und (0,04 g, 2s6¾f
1 wmn U id: Synthesis of Cos isnd 22
Figure imgf000140_0001
[0696] Step I; Synthesis of Smhbowued^
cyclohexylasuunon2oyndhy
[0697] To a sbrred solution of 5widoroyT{ethyi i{ nsrJs)*4-((2"rnsii-HSs>;yeh !}--(n- 4is> ÷ w aw-.-;. cyc.l hex !^aolsno)"2-«'iet y¾be.»,^o,ϊ cid (0,2 g, 0,523 auwd · in DMSO (2 mt).2::245,6- ten¾meihyipiperiilnv4-.arnlne (0,122 g, 0,785 mmol) and tnefaylarnine (0.22 ad .1.57 nunoO were added. The reaction onstene was sbrred ,a n tor 15 ours before PyBOF (0.408 g.0.725 uwnoi) was added to 2 a; 0 'to and stlrr g was■ -as aa-cd at rt (or io h. The progress of rhe reaction seas monnored by TOO. Upon eompkdkuy the rcacdon ndtture seas dikned with w¾ter and extracted with £0% MeOH/D€ , The combined organic iayers were dried oyer NayS6)q. and concentrated under reduced pressure The crude compound was purified by column
chromatography Ps s fiord the title compound (0.06 g.226a).
Exam le 29:
Figure imgf000140_0002
of C-osnponnd 22
Figure imgf000141_0001
[Oo bo To surred solution o outrausH-^ ^
meda:rxyeihoxy x4.aaedx4-
Figure imgf000141_0002
DxixO (2 ex · <···κ ο,χχ-χί· d e: ';· :·· baew - ίθ. H)3 e. O.dd ox; x t sad irierby! a>yui>e Ox S3 ml, L33 mrnou were adde The reswtivu. obxtexe as winxd at ri for I :> mix be r PyBOP 04343 a.0.66 aae-sO s added u it at 0 !C aad urm¾ was eonbrured at yi for i ... h. The progres of i fc reacdoo as uK>mtored by T'LC. lipoe eorapfoboix the reaction mixture rsaa diluted whh waxar arsd extracted w ih iP% b1eC>H/?.>C34. 'I' he eoixek i orxarho layers s a? ·. dried■· -- v Na. SC3: nd oooeer raied xxder redaeed ewwre-. [hi- erode comp nd, was oriibed by ρηψ b!PLC so afhxd dx btk ooffipooad (0.0S · 3! ¾).
E¾¾5ii k 3th Sy¾ths.-sss of Com rnmd 34
Figure imgf000141_0003
d'XO j bxep I; bymhxxas ohrneihyi
Figure imgf000141_0004
arohxo bwwoaxe- [070 lj To a stirred wdniian of raedryl -aii¾ino--5- r yi i-2-iT!Oihylben <i¾te 050 gs 204.0 mrnoh and ddwdro-sl ig ran-dbniywns (20,73 g¾ 307,3 aanol) io dlchkaoeibane ;500 ::o > aeeoe acid {73.7 a, 1229 aaaod sws added and she reaction wee stared at n (or 30 abro Then aodhno.
irbweiox bosxawabsde {'130.5 a, o i 5 mmo!) was added ·; o "C and the reaction uaa wined at O fo 16 h, 'The progsxow of die wacnon as monitored by 11,(7 Upon eompietkae da; reaction sva eeaabed wi h aqoeoos sat. wo it 7 a die organic leve was separaied and the aqaeoes higer was exgatted wuh I2C . The combbsed organle layers were dried over anhydrous twygdO,; asd srsisenoak'sS aedor reduced pressure. The crude eomposmd was nded by slbea gel e-\aaasn chromatography as aiiord th title compound 025 g.3?5er
[0702] St >2c Syndxwb ofmehiyi huxn wKsd'hyi i tege;b d O'e3tb- y i 'a-yli a¾los>)-2» srsodrxiben^ isx
[0703 i To a stirwd solution of methyl sronrnw-moth -yl) a am beiwoaie (25 g.70.21 rmnol) a ad aeeUddehyde (8,5? g; 191 nnools in dabboroeSharw (300 snbT aceOa acid {"27.43 g, a"? nnnol) w s added and the reaetioa w;?v srirrsd at rt roe 20 mm. Vhers sodium Oiaaea wyboroig) drsde {4a, 40 g, 228.0 mnob wee; added end the reaction aiirrsd at rt lea
ΪΟ ,h. 'Th progseas of she reachon was naaaiored bg 40X5 bason compienoa. the reaeikm was quenched with aqueoua xan Nal 4CO,. Siie organic layer was separated and the aqaeoos layer was extracted wi h dichh ixanedoixe- I c mbined organic layers seere dried over anhydrons a-Sf),; rid* eoaoesrtrawd under red wed pressure, The crude compound WHS pmaikd by salka gel colnu chronwaography to afford die utk eoropoaad (24 a.. SB 's.
(0504] gqe 2: Syrarawb of meshy! egedgl (teuxshydnxd5fhp.wiuv4.-yb a inowggg..
aiethrwye{iiox)p4'arwdiyl'41
Figure imgf000142_0001
[b7 bj g a sbrmd sohrtaxa of rneihgl
Figure imgf000142_0002
oseShyibeaaoeia ( i gs 2.41 mmoD nd 2o4a2oristboxye{hoxy}rsbeay; s«4A:b5wemsinebwh hw-d- dloxabcroiane 10.930 p, 3. eg m oi) in dloxane^ water raixoax (7 ml. ; 3 bo Na;i5l7; (S..07 g.
Kid 4 ronaoi) was added aad die sduhon was gorged sh argon lor 29 mas. PdiPPm.),- 10.325 e.
0.2SI rnawd} a-as added and argon was purged again tbr 20 mac "The reaction miaous; was heawd ay 100 '35 bn 5 h, "the progress oi rhe reaction new monitored by 4 he . (porn esanpjeuom dm reaeoon mbaura axis diluted wgh wana and exOaoieo with bra.3,3οΟΙ4/ί3(ΤΟ. The co; rdaeed isrganie layeis owre dried oeer ixa-ssbO and ciO'sse;s;;ated aader sxdisced peessnrw ilia csssde eouipsxaal w as paslbad by eolvarns ohnnwgography m, ;ril ?> the title con igound i i g. a 3 go a
10706] gi p 4; Ogsnhesla ra'abebrsi ist aliydTogyi-b-pyisni-Tavi) «m iso}-4!-i2"i^ th ^ e .i y)" 4-aa.aiiy i-g I . I '-bipherry ρ5?χχϊ; gewebe acid' [0707] go a siloed ¾ luii n or methyl S--{e†lm(^ sh^
n'ii*;h ^ ! x 5" "o;?L!ivj"[ ! .1 Ddghenvij A wfsrhovvkne (1 .134 nnnoi) In lAOD (5 m.l\ eg. INaOD (0.14 g, 3.51 nunok was added ¾ ai he reaeOrsi inDune as erined at 00 f e i 4 '.the progress of the reaouon w s roonhonoi by TLC. Upon sraOpklion, csh nei vsae teroewed under reduced pressure and dee rcacnon nuns was acidified o:oua I I h. ; ;>nd e P' cied - no 023 r set' 4 I i'a ':- i 'the combined organic laye s were dried., eoneennated giving respecOve acid (0.6 g) which eas used in One sabaegueni sag) vvnhout i' ibe?" purification.
[0708] Ste 5; Synthesis or er vKleimhy^
ue. ih- b wu 2. wesu:wwP. hope: 24·... DeD. i : AiAnsg 0 Α··ο;η D; . owCc
04091 42? a sorted solution of 5^thyi(tet aieG oA^
tne!h xyeihssxy ;-4oaedy4..[] J ^hlphenyfhA-oavboayile acid (02 ¾ 0.444 ηηηοΠ in DM SO (2 niDg 2.24r6-eetraaiorhyipiper;dla'-4.-ra'ni?'K- i(b09o g.0,54! ηη οΠ and Paedrykanhse (0.2 ml., 1.35 noon!) were added 70*· owebon nuvkae as stirred fn p. for 15 mm bcDre PyBOP (0.373 a. (3726 en n'ds w s .nklc-: a 4 a; 0 At and .staring w s continued ai ri lor 12 h.2t e progress of d'ie reaction as moauored by "OLD, Doon completion, die wacdon nvi>daw svas dlkiked with water and exuacwd ·. uh i.0¾ eOtl/ C'M combined sogamc layer;; o;ere dried over "Na7>Ck and csauseniraDd nnder reduced pressure, 4 he crude eornpouad wa purified by olum dn asateggraphy to atlbrd Ore Otic compound (042; g..7 >ls3).
|0? SO] The spectral d&va r die compounds D are listed as 'fable I A sigaw.
Example 31: iDusew probnmt and Gemerai erhnrh
l2D3A2 .fcgWai
(0 Π ) Or o,;!! nJatedasc n-adenosy haeddeainc DsA ). tOaders.nyliajmocAoinc fSAHh niseng K(4.43veen20. dluunlrylsuObxIde (DMSOs and bovine skin gelatin (BSG) can be paechased iron; Signus-Aidrleh at the highest DeD f parity possible, DnhtAhreko! kOTT) was purchased trom (AID. ADSAD can he purchased frorn Amenwm Radiolabeled Dhemscak with a activity of 40 (.s/mmei. aDA ed sueoknad Flashplates can be purchased Dom lAAlnkbuer.
(07; 2) SsAwrsuDsn Peptides representative of human bisione Ha reskkies 2i■- 43 esaSain g cither an unmodified lysine 27 Ui3K2?nve0j or oinsedyyhnsd lysine 2? tfials27nie2) are s nthe ! ed with a ( '-terniiaal Gflk-bsala) iDkcwafinnty ?ag rnotn and a (Atera inai andde cap by 2D" Geainry I^ocDovd ak. I3;e rnpddcs arc higlrgorD'rraanec !kaao chrornatograplgg (l-:nd.3'D purified to greater than 05'A pra ky and sontDneol by Ikgnd esaoirsaiography ntasv speotronsetry Ι ('Ά|χ). 4 he segaences are beted below. H.5 2?meO: A'rKAA SAPA rHj K 'rmYi P CJ bio-.l ^jijfk iSEQ ID NO; !) R5E27me2- ΑΤΚΑΛΗΚΑϊκΑ P (SKO A)
NO; 2)
PARI] AhicAss) eryshiocyso eAasa-uabeosonses ar parilkd .iron? Anod s) blood neoosAIng to esnAakhed r cedures.
[0? ; j -; oi;ddss;< o kl-R 2
Figure imgf000144_0001
Human REA2 esszysnes are purided as Aeona-a-sens esvxysne compRxes co-expressed in S dopieni iigipcrd MAR cells i a baonkobras ex resAoo sy.sk- rn. khe subarAs expsessed are obkkppe ; M A (NM 004450; or E2f A N i A N, Ik S orb; noitussts generated irosrs ike wdddype EAR c nsumed ELD {NMJ)03707f. SusA2 {A Oi 5 A3; aad ROA dk Rdai OOdioO;. fhe EkP> sabssna coalams a a N-serrnaai FLAG tag •'has A used as purify the entire 4-oorrax>nenl oosrsptex fr m stb ceil lysatea. The purify A · a .- c asplcAes sheets or exeeeds 95 A as deterrmncrl by SAs-e o a- aad Aabeat Bl Dan y.se analysts. Concesursjions of enzynn? stock co eenkadoaN ipeoeraiM if.3 - 1.0 sag ado is iieRnrdacd using a Bradfo assay agaansi a bovssne sennrs sH-ss A AAAM staadard,
[0715] A>auasd !A ieeAhtr IV>r FRC2 Err/passe Assays oss Pe Rd SnbsmAes. The assays are ait periorrned so a baiOr eosiskting of 20 rn.M Mesne (p.H ::: 7.0s, OA rn AM.0.003% BSsi aad O.OO A T e n20> prepared op, she day MMse C m unds so 100% DMSO (1 pip are spoped inSo polypropylene .· ·: a-A SMxatom pAtes (kkeAerl using a EAtensate 2 A 3 onAsised with a SMbchannel pipet bead hfhesYnof DMSO Π pi.) is added a> columns l b 12, 23, 24, roses A - A to; Use m in irn signal eonsnM and SAfk a known produet and .inhibitor of PAA2 A itk) se added so eoksnsns s I J 2, 23.24. ro s 1 - p Ar rise minknsaia .s a.2 control. A cocktail p40 pk3 -.oniabbny the wskMypc 0RC2 easyase nd HAfMA ed pepskle o aay oi the 33)4 i nusiam nz mes ,a;g H3K27s¾¾2 peptide is added by Mulrkkop f XnrsM (34no o}. 2 he
CsasnwsnAa are ado ed o enwk -a; with 0RR2 p=r f? m o as 25 A3, shea a cocktail OR) gk) conta-lnkse a ix ure of ssore-rad Massive sseS i A- -·\1 is added So kddate the reaction f.Onal v l me ::' 51 pkb as ail caws, rise Rnal ooocesrkaoons ar-v ;a; thbov, s: wiid-iype or nmkssst krw... enzyme a-a 4 :;Xb SAD ks the mnnmu-rs sMrsal control seeds wess I mM and the DMSO e-saceniraslors
Figure imgf000144_0002
are indicated in 3abA 4, bebs :a. The assays as¾ ssopped by Use addOko or of'n--radioaeoee SAM (10 ;d ; to a lose! osasoenu- boii foffs p24, o4aoh dnutee rke daAAM s.o a ievsd w r iss isasvs pis tbsi Inio the e sldo srsbssrate is ar= longes- deteAablc yo ¾., f the r act n in the sMksvMs
psbypropyleae pbsse is slsea tiasvs;er:¾d to a Scd-aeeii idasbplate and the biosnmated peptides art adovved so bind o the sireptavidin sssrlao lor as least lb before being washed three sa?ses wish A ]% 32s ¾ea20 in a Bioek s:d.,x4o5 plase Vvaslser. the pisses are slssa read In a fArkisRslaser fo Gn-iU obteseader as stseaswre t e ossnuky of 4 oiabeled i --^.- h u d so -he Fhsshplase swtaoe, measured us dk;kn grashe">s es' minute ;dpo; · or akesaunlvely, ssAeoed o> as counA per as bun (spats
To.ble 4; FboA * <>nw:sA> ,ubo;s of eotnposserssA for each assay · a; A >-;s ba .s-.d np Ε7ΛΪ2 sdrobw iwakbtypo or ¥ 1 oososol EXII2)
Figure imgf000145_0001
[07 J j (.beaersb hwsrwbs -.- fo 33 lab f v PR hts rne Asssy HO 1 Agoousebssswoe
ike assays were pessbmwd as a bosses consssbng ol 2o mkd bscne PpW ··· 7.0}, 0,5 mb 04150.005% A- y:. |00 ns KCi a-td 0.002% Tween2iX prepared on the dsy of ose, Compounds so 100% DM50 (1 uks were p ked hue poiypwpylene sisT-weii Yfooborn plates Airelrwr) aAng a PbUeDkste 2 A 5 isU'kk-d rtah a >7 bck eowl piper head · I loaes.^ DMSO i 1 uk.3 o/io ;*dded to eoUsmsss 11, 12, 23.24, rows A■··■ M for the se sjsrsorss Agnai eosnroi, and SAbb baovyn ph t and is ssbstor ot PRC:! (i plA ¾ added to eo!unnrs 1,12, 23, 24, ows 1 P ha e n-ooousso sig l coosroh A eockU'-sTi ;40 aba csa"aain;og the wild-type PRC2 oe/ye;e and chicken eryd'OGcyte oligemic ieosonse was added by sVbsitkbop Comb! (Thermo). The eompoamb ^re allowed as hwssbak; a bit PRAT ios 30 voso at 25 AA ihvrs a coekiail (10 uks comasnhsg a snktore of swnoradsoaosive susd A bSAM ees added s Initiate the reaetioo (lloal voksnw ::: 51 pin, The Anal eosnwntraboiw w re as follo s: svildAypc 20*55 esseysne is 4 nM, sawMSkboseove SAM is 530 nbk TbSAM wsw 12s.' .psd, chicken erythrocyte ebea^H-ck-.-.:. ;ο·.· wee- 120 abb SAki ir? she mlni urn signal conn-os wwils was i srbvi and the DMSO coneenharson was 1%. 4 he asaay was swpped by the addition ofbsonosM Inactive SAbi s 10 gh) to a rkra! eosakassrabo;) oi 600 nbk which dlbwag the 24ASA54 r-„- kwe! where sis ii!eiaposstiios! esio the ebsekea eryihrocyse <ihgootn;cieosonie sstbad'asc was no icirs r dereciab , 50 pk of the re etioa a; llw SAAweb p yps-epysesse plate was thet? tssoasteoed s^- a sbAvseb Fia.shpiak as¾.l 0¾ chicken ery ih-Ocyk-' tw beosorskw ·:■ ·, i;oosobb| >'d to the sas ibee of t akste. which was thsrs wa-shed three b-Oes w ibs 0.1% I'weetwiO so a Blotek s:Tw.405 plate washer. Oho plates ware then read as a P- is.e-s kow I<.;;'sc3"a.as;. i)k:aess;ados' ϊ<· srseacsaw the paaobi f Ί b-labeied ebsekea eryUasacvte okgonucleosome bound io the Fiaskpkue sua faee, measured as dismiegraEons per minute Εΐρηη or akemanveEs referred to as counts per nauwue (epre y
07 s 7] % la SiUioii F ah uePma
Figure imgf000146_0001
[07 I S] Where dpm di:dnicgratioris per rninuie, cmpd ::: nal in assay weik and mm and max are ike es ecu e minimum sard maximum signed contr l?.
s
Figure imgf000146_0002
f 72 Where toe and bottom are ihe normally aiiovved to Deal, bar may be tixed at 1 0 or 0 respeedveiy in a 3~parameter In. I ke idik Coefficient normaOy allowed to Hoar bay may also be fixed at i in a 3~parameter nt, Y ia ike % inkibOion and X is ike compound oorKentrabon .
[072 I j IC¾ alues for th PRC2 enoyme assays on peptide substrates (e.g., b y! id .· kd type aed Y64 ! mutant E2.H2 suck *. Yba ! F) are presented in "Fable 5 below. The symbols ia Table S below denote the following: deno ea an i€<a value betw een 10 μ.'Μ and 50 u : '^ '^ denotes an !C7, value between I μΜ and 10 gEl: ¾iSs '^' denotes an Ε¾-> value between 0. 1 μ.Μ and i μΚΊ; and deeohw an KhG value leas than 0.1 μΜ; denotes that a compound haa noi been measured for an lty,: value; and O C deno!es that a compound has been teased as not active lis a spec Ok assay.
I able 5
Figure imgf000146_0003
Figure imgf000147_0001
Figure imgf000148_0001
WSU AXCCL2 MrU^.tsikm Assay
[0722] VVSU-DI-CL2 ss^ensioa csaG so- purchased from DSMA o η:;.;· CoUecnon of MGrccaspamsms and Cd Cuhures, Br&uos h i:i : Ger asiy). RjXilY}bi†amas. Mediuuc PettBbhrvSPepi rnycG, bkcn biactivaied Petal Bovine A-oan. ai¾d D-PBS wcie purchased from Life rechnokpAes. Grand GGnd. NX USA. BXraeUvn BciGr and Nerdrahsadkri Butfer(SX) were purchased ii'om Acdve Modi. Carlsbad. CA, USA. Rabbh antBPhsiorre IB antibody is purchased bom Abeam, P ambridge, .MA. USA. Rabbit anndXK27n<e3 and HRPwaapngaXd ami -chPXa.g ; .:: parehssed bom Cob ignalin Technology, Darners. ΜΛ, USA. TM.B • nger Semsltwe" substrain is soorceo from BkbX Baboragniea, Gwmg¾ Mba.. MIX L'SA- SgGXsee Bovine S um whamm m purchaoX from GoLses? InmuUioReeearch. VVost Grose, AC USA. PBS wih Gvcen > j OA BBS'Id was pimbrased fm KPL:: Gahbersbaisg MD. USA, Suliurlc Acid is purchased Prom Rkea C:G,snkah ArhngAay TX. USA. hrsmG n ELi A l ks were purchased trcm Themxg RochesAg Y, USA. VAodons cob euhure piaies are purchased iron's Corning inc., Pkemng, NY, USA .Xboirom prhypropykne plates coe purchased a -m idresaer BioXAe. Monrrxy AC, USA,
[0X21 S XD .CL2 sarapeuaion cGis arc maGralned m grosvdi ajediran (HPMI BAib snppkmemed cad 10% Av boa; imrcbvated Baai b v e- serum and Bid uibtsdvd, peniolhiso sueptoinyom) and eahnreb a; 3/ A; coder sX CPA Under assay cmwntions, udk are iacabased In Assay Medium GPPSB AGO suppieracibed cab'! 30X v/v hocA avaXvaPed iePb bevsne sennn and 100 nnkwnP penkblimArepies-uycin) at 3 / A/ uude? 33¾ G Y; on a plate shade;; [ ?24j WXUddiX 1.2 wdh; art seeded n assas rnedaao χ s. concsatrauon of 5(1.000 sells per uB., K> a 96-wwh V-bo«or?i ceil eahore plate wah 200 pk. per wed. Booipoand s IpL) Ossa Oe w d scarce pFaes Is added diwedy lo VdwXcso cell place Piaiec arc Incadeecl on a oBp-phae shaker at .V? Xd 5% C(>- (or 90 hoars. Alter Baa days otdrre b tioa.. plates are spun at 2 1 x g ha nve oooeu ·■ and nooaaa was pirated gently d -a; each aeli raced plate wkhoni disturbin ceil pellet, PelXi is resnspended In 200 uL I3PBS and plates are spars again at 24? a g tor f v ndrndes. The sopeoaXarO Is aspiraXd and ecdd a-l r · Oxa edos; honor id OP pl.n is added e sveh. rkdes aw Ineabaied ai 4 AC on orbital shaker lor two hoars. Plates are spaa at 342? s a x 10 adnr es. Supernatant (80 pi, ;.<s r well) w oeuwierred P.? ias respective ocb lo 90 sveh Vd>otioiP pwypropylene pre- . Fkadrabeadoy; Butter 5X■ '."·> ah par odd ;y added so V· bottom polypropylene plate comairdng supemansrrB Xdxntom polypropylene places eonpriXng trade hasrooe preparation (€HP) arc Inoabaied on orbital shaker a use inauueo Cnsde iBsOane Preparauons are added (2 k per wed) to each respective ell To- duplicate 90 wed EBiXA plaXs eontanung u)y ak Coating Baiter (IX
Figure imgf000149_0001
o Ppa 0 new, w a. Pedes are se led and la- ada-X overnight at 4 X.3 'The BdlowkoAdaw plates o :w ashed rhwe lanes with 300 at., per well I X PBS I. Bwlls arc blocked Fa pro bows wirh 300 pi per ed I ply t Diluent {(PBS (I ) BOA (230 o and Tv^endO OrOyX vA p. Plates are was ed three daws wah i A BBST. For die klistone 313 dewcoon platw 100 at. per well are added o! wOa P.a w a \ : (J body (Abcsm., abBXB ; diluted BBBOOO in BidSA. D!hwm I · a I43F22? naawthykaion deteetion oiale. ? 00 ah per wed are added oi antBH3K27nw3 iluted 1 :Ρ00ό la BIAS A diluent. Flares are iacobawd tor 00 wdnuaw at oom a-arsperaiuy-o Phases are wasted inree daws whh 300 μΒ IX PBSl" per well. For HBtone 133 deawhow 100 p old IO.Pw:otnXgated amaeabbit lg<3 antibody diluted to 1:6000 in I I Pw diluent Is added per well, tot H3K2vmo3 ikaeeoom 100 akoldiRP eopiuaawd arakwbbu Igw eatlbody diluted to 1.3000 a¾ FkldA ddaenr is added par welk Piaaw are hc.ubaesd at rooa) ten's perature for 00 minutes. Plates are washed an- Oases wdii IX PBST 300 ak per well. TMB sabsrrale 100 ak Is added per wXF kksasae FX piatw are iaeabared tor fi e ndaraes at rooas torp eratra'e, H3X27nres piaies were hwubaied Asr 10 adnotes at r a ;erape:atare. The reacdoa ss stopped with salhase ae;d IN iiOO pi. per aeda Absodsaaee for each plate was wad at 45P any
10X2 1 I'drX. dw ratio lor eoch r XI o. deieooawd bv: I :o:.cs.:.:cdc osAswoes::.
• ' '■ .TP.;?:'. SS S C? · .·: ..O ;
[0726] Baels plate !nehw!es eighi eonnoa waeils of D Sia only irsaaoens. {XilrdrnaiO laldbilior!) as vreb as elahl >w>adol w-dls for araAlrnuai sphibhlss XXoligroand svells) P T/US2015/037715
[ 72'?1 51ae avera e of bee ratio values for each control type is eakuiaeed and used io tMerndue se persenl nbAnlbou lot each seat wdl us the pkaw Teal compound I serially dbrued three-bald la DM SO fbr a n%d ol ten lest coraremradons, beg n ing at 2a μ.Μ. Perceol ubbbiilon Is deArnbned and K'kis -a:■ ea were generated using duplicate '- eils per conoenrranoo of compear; el
072K] Percent Inhlbdlon - 1 0-
Figure imgf000150_0001
CeR pmkAeroRos !W;R ·>«.·
F072 ] Wgk-DkCIM snspesuuosi aella re noreheseb Rom RSMZ lAermnn Collection of Mlenowgaoisrns and Red b ubarea- Brnunsshwe-g, fwrmany a kbaipa ροη.η-η··. Rledhno, kenk blun-SrrepRa'iiycba fkal Inactivated f etal Bovine Vnae ax-,: purchased Iron; hife .
deehnokngles. Oo-;;d Rland, NY. USA. V-hs-ttom polypr- apylane 3S4- ell pialea are purchased Ron; Cnemer Biowtne. Monroe, Neb USA. Cell culture a!RAwe!l while opaepw plains are purchased Rons Pernio Elmer. AgOduam MA. USA Celkiker bdssfe is parchawd from Poanoga Rorporabon. Madison. Wl, USA. Speeuwblax Ma plan; reader is purchased from Molecular Devices LRC. SumsvvaM CA. USA.
[0 Mb] WSU-DiA 7.2 suspens-on cells are mannamed in groeth medlon? (REM! 1640 supplenwnted with 10% y heat inactivated felal bovine senon and eulhwed at 3? A3 under eR- Rb Usvier assay eondkloco. ceils are Incubated in Assay Medium (REM'i 1640 aupplemenled vwtn 3071, \ v heai insalivated fetal bo im; scram and 1(H) urblsAM. penica!lu-atrepu.mwcku at 37 ;!C; unde 3 . ; ·: p.
[OAs I 'I r-'or dm assessnnera: of dee eliees oAuwnpo-nuls on the poolkeraooo cbAhe AbslADf CIA ceil brse. eaponenkaiie growmg cells arc pkraed h> 84 -we: .11 white opaque otares al a deusdy of 1250 setibM in a dual olu e of 50 ni ol assay medium A c m ound source plaR is prepared bv perR-rnRna trlplicale nine-point 3-oRld serial dilutions In DM SO, beg uuvg nl 10 a est (iuud top eoneeruradon ol eouopouiKi in the assay was 30 pAi and the DviSO- oars 0,2%). A lo oR aliquot Pom rhe comnounsl stock piste is added o> ks respective well in the end pkue. The 100% inbibiuon w-raaol consists or cells o-eaied wkh 300 nM final corecemrallon ol staurosporine and he 0% abdbition cornroi consisted of DMSO neaus.1 cells. After addition of eoo;ponobs, assay pia-es arc Incubated for b days at 3775. aba C ¾ relative humidpy > 90% for o daw, R5eU vsabbky A meawned by quamwahon of All* present in she cell culknes. adding 35 g! of Cell T bet * bAly oeagaou k= s e el; gboes, Lammeseence is r ad in sh ygse^ Aaadss, M5. The c ncentration inhhvnmg cell vlabbky by 5P% o÷ deaermbyed asiag a 4-psra &irie fit of the nonnypyed dose iesponse curves, K'.'.p:. values for this avsas are calculated.
Kcumnle 32: lb ro :ooa- of she Loveers Cyk.no.dc Co^eemratloss (LCC)
[07 It is well established thai cellular proUbkrauon proceeds through ceil division th i results la a beebbey of b;e number of eci!s after di isi n, rebuo e to the number of ceils prior to division. Under a taxed set oi enCronnventai conditions ··■ a., p L km so ativvggih, temperature, cell density, sicdiam eontem of proteins and grovvth factors, a d the like) cells will probteone by consecutive doubling u.e,, division) acemdlng to the hblovrmg equation, provided sn sirifklem nuuuems and other regou'ed factors ate available.
Figure imgf000151_0001
whe;e by ss tic cell number at a rnoe pokn (u abet inlhabon rObhe observation penod, kg Is the cell number at the hbtiatlon of She observation period, t is bra hoae after Initiation o the ohser-ratkm period and t the bme Interval repaired tor cell doublmg. also re.terted to as the d- adding tone. I on o-a- A. I een be eomertea -as · ihe nvm; eooseiVie harm of an eyponenila eqoaboe la base e. takhgg advaniage of the equality, Oafbs kkdr
x ..').a
[0734] A'* ^bp' >υ (A.2)
[0 y'kxd 'The rate coastum lor cell prC'llieraAoa (kg, > is m-. e.o-.ci- related to the doubling time as kdkav;y
? 0,693 bp
( ?37'j Combining e uation Λ.3 and A, a yieldy.
[0778] ^ i ™" - ' fc- * iAA}- pf'koti Thus, ;. cording to eqoaiks! A, a eeli number is expected to iaerease exponeodaliv ohh lane - as a a: dva eatly period olOeii growth noeoed to as logedrise groo rb. byponetnlai eor;adoas like e uenon Λ,4 can be hneatieed by takiag live aa tarsi logsrnkm of each stdo. icAAp
Figure imgf000151_0002
iA.yt j' '74 II Th-s::: a plot of iosAp as a i;scsk>:; of time a: e e ed to vieid ;.e; s end n eboight line whit elope equal to k... and yonteroept equal t InfiAf
rO / d'j Chang in environmental conditions can saoadi as a change n the rave of cellulcr proliferation Pta a; quantifiable as changes in the proktenwion rate constant fe. Among conditions that eao result in a change pr liferati n taie is · h- · Itnroduellon as the system ot an aswlprohferatn e compound at (he iniiianon of the o e v ti n neood (i.e.. at t :': On When an aniipronferaHve c u d has an muTtediate impact on ceil no As. oaf -w one expects dun pi- ·· : or ha No as a sbneboo f time odd condone to be linear an Al eong?ooad cor eotratfens. with dirmnAhhig values οΠ;Ρ at increasing concentrations of compound,
[074 } J Dcpemhng on t e roeehenisoe bawls f amiprohteraf o e -·οη·η. so:w. compounds may not Imuwdlatele eifcA a change in psoi iteration rate. Ine'teaa. there may be a period of latency be sore the impact oi the compound A realized. In such eases a plot of ha'Np as a tnnehon of dose wal appear blphaeie, and a iinae point at which the impact of tbe compouud begiae can be identified as ihe breakpoint between phases. Regardless of whether a compound's impact on ee abA.-ooc Is tromeclhne r begins ader a kneney oeAod. the one constant tor proliferation at each com ound concentration is host defined by ihe slope of the hpK) vs. dux curve b m the nrne point at whch compound Impact begins to Pse end of die observation period of the evperins-ent,
O/aaj .a com nd applied to growbtg ee!ls may arieet the observed proliferation In one of two general aags: by mhlheaua nodas eeli dlvAion icytocmsls} or be eeb killing vpaoxieity r. If a compound Is cytostatic. Increasing concentration of compound will reduce the vah.se of A until dvere w no further ceil division. At tins point, the rate oi cell growth, rid deswaec the value off.-., w ah be aero. If. on the other band, the compound Is cytotoxic, then the va!oe oik;, wdi ha composed of two rate co-wtants: a rote constant tor coniinued cell growth In ihe presence ot the eonspctawi (kg) and a ode creossug lor cell killing by ;hc compound (kA. Ihe overall rate constant, lor prollieratlon at a fixed eoaeeraonion of compound will thus be the d fferen e betwe n the absolute values of these oppwong sate corn-gone
Figure imgf000152_0001
Γ07 f?l At compound concentrate ·;¾ lor which tlte rate of cell growth estseeds that oi eeli killing, the value of k„ veil! have a positive value Ac, p.. · bp At compound ct centruilons lo which she o:ac ofeeb growth Is ices than that for eeb kildng, the value of k;wsnl have a negative value (I.e., k, 0) and the cell number will decrease with time, indicative oi robucs cytotoxicity. When A exactly matches fe then rbe overall prnhterataso rate conspire.1.;;, e ld have a · car. oi S!'<;, We can buss defin the lo xo! cyt toxic eoooeatostlos; (L.C ) as that se>ncessiratlon of coropouini Ihai results so a value ok k,, equal to oeovo because aoy conceniraison greater than this wlli result in clearly olwervabie oviosoxlvdey. Afao noma at coacerstrabooa belo the LCC there a; likely to e cell biding · oxao -a.: bat s a rata thus, is s—: sha.;? h i of waklual cell prolncaatlom The beatmens here not hne led to efine the biological details of comp sed action. Rather, Use goal hex is to merely define a practical panvmeier with which to objectively qua ily the concentration of vonywtmd at winch the rate of cell killing exeeeda new cell growth. Indeed, the I CC κρν .wa-- a breakpoint or .critical eoocenlratnxi bove wh h thank oytotoxieky Is observed, rcbsw than a cytotoxic concentration per w In due regard, the LCC can be mewed snnbar to other physical breakpoint me ics, snob as the critical micelle eoocentratkai (C Ca need to define the concentration of lipid, detergent or othe suiiaeiani apeciea above winch all snokreuies nwwp- oac Into nboellar sbecteaxw,
[if/47] Irarhuoaally. the impact of aswipsoliierauve ceoipounds on cell growth has been moat commonly tgumllfaed by the b. .. value, which is defined as that coneemration of com ound that redncea the rate of cell prollferadon to one half that observed m the absence of eonvpvuud p.e., bar die hicle or sol ent control aasvsplef The IC¾K however, does not alkwv e investigator so dlfleaenoate berwecsr cytostatic and eytoaeela compounds. The LCC in contrast readily allows ne to nsake such a dbterciPi tleai and to Lather wi&otiiy the coueeniratson at whseh the tsara-ltson to robust cytotoxic behavior occurs,
[07-iS It one limns the observation brae windo to between the scan of Impact aad the end of the experiment, hwe the data wbt generally fit well to a linear equation when plotted as ins kip as a Iwsctiors or time paow .ogwog from tits of this type, the value obki; er 's be determined at each concentration of c m und tested, A rep lot. of the value of k;; as a .function of compound eonceo raiion s||i) will have the barm of a descending isotherny with a maximum value at [l ::: 0 of k;;::;:.- s defined by ihe vehicle or solvent control sample} and a rolnlmuos value at mfinite compound concentration of k;;;;:5.
Figure imgf000153_0001
whew Ι.,,,.ί Is the concentration - -f compound yielding a value os to- that Is midwa hevwoce the v bars of k.,,;.,. and C;;, (note thai the value
Figure imgf000153_0002
except, in the case of a complete a d punch cyiosnnk: compowKlg thus,, tuvlng she replot data to equation A.? provlie; imates? of k,-,-..,., C;„ ;awl hta.-.a lift coswsound is trwtade (as dobneri here), the value or k-^easm †. be less bans aero. Por cyioi sic compounds, %..:-. o id be icsa than z o and dc absolnpc caiue of k-- eih reiaC Obeedy > sho %ksAivene:ss of ihe eompr-aud n holing cells.
[0750] Th fused sahies derived [ sy- equation A...7 nan also be uoed to dens-noine Use value or her C.'A OeOnuion, %; .n j;j ----- rC('\ k,, ::: 0, I )■;·■■·, u d dn.-se e rjdiu rss e uati n A, becomes..
Figure imgf000154_0001
10752) Aig brasc rearrsngeroead A•• n A.n, A5; yields an equation lor die I 5X5
Figure imgf000154_0002
b- C j AHA aouiv^ae is snaple ;o uopiemeni wOh nonlinear curve lining -^Α··ο. nnd may he applied during celkdur assays of com nd sarivhy rheougin.au die drug discovery and deveioprneui process, thi rnannen the LCC nop ρο-'- id-, a duabie m -o lc foerhe assessment of compound SAR (sn-netufe--aenvii.y reiaboushipp
0 onnnie 33; /n vi Assays
M es
p;d\A female !%x Chase SCfC ddce (CB ί 7/!crAO 7¾fc.. kr!coCd, Charles River
Laboratoriess or arhynbe node mice 055 ;eAj(Ne )-- 7>yi; ;:.,. Charles River Laborafcnes! are 5- necks oiO and had a 0= A;. ·--· ed-i (BWj range of ld.0--2j .! g n Di of he study. The animals are ted obdOOiee narter (rveeise osmosis I ppm e.5) and NiH 1 CCdined and irradiated l.ab Dmemroraastiny f IS.0% made protein, 5.0% erode tat and 5,0% crude ilher. The moe are Cursed res Irradaacd fAn'ieh--od:ob-d:%>cduing in snrdc mleroosolators on a l2doar light eyaie at 20-22 7 i6if-72 %d and 40-60% humidify. AH procedures comply with die recommendations o dhe sAbrfc for dare 000 (Are of Laboratory Aedtsud seOh respec io easusung hnrOandiy, rmgknd procedures, A-cd and fhnd regulation, .eC vsferinafy care.
Temm Ceki dtnsre
lo?5nl ] luni n lymphoma eeil hues One are obmiued from dd%reni soeoxo (AfCC, DOMAy e. ., WsTMdCCIA obtained dean DS. Z. The ceil One- urn maintained as Piedmont as s s en n catenas in ROyi dOa o-edium eooCudng 100 oanson peololdln Pi sodium saip 100 g/mk sk - mrmyom, and 2a gOug gvntamaun. Th n;-/deea is sep lenvesao urh 1 % lePb b vim- -.-- -: and 2 mhd ghiOanine he cells' are euhmed in bssue culture flasks ia a hunddiiied ineehaev at a? °C2 aa ;eoK-s heiy of 5% eTgwnd 0g% air.
Ta r'h!oTmm>r I b tatUm
pT% "j Human ίνηψΡοην, ceh dri e, e.g., \VTTe-DL<'L2 edits are harvested daring smdoog nhare gn.avdy and o---suspendcd in PBS veirh y TThtangek^ i.BD Bkeasencesk Eaeh tnonee receives ] a kk cede (Oh mL eil suspensioni sub<: ataneoesk in the right dank. T mors' are aaiipered in two dinmnskavs to monitor go.rods as the mean volume approached d-e dashed 80- 120 mod range. Tumor size, in rrurk, is eaicuianad from: i'umor voiiime -— a
where sr ::: width and / ;:: length, in nan, of the τηηκη . Tumor weight ear; be .·■ d smg with ibe asrurnptiras ihar ! nog is -univalent aa 1 mrns ok tumor vodonne. After 1 - days mice oath k*8- Γ26 mm'' tumors are sorted nko treatment groups wish mean tumor v lum s oh 11?-! 19 rrmvh
I e Artmkss
[075a j last cmnpouuds are
Figure imgf000155_0001
?a room tempera w and promosed fas iigha Ors eaeh weat ent dag, fresh compound tbrmelaienrs are prepared by cospeadmg the gowakrs in 0.5% sod m oafboxynmihyicehniose i a CO and 0.1 % Tweeny 80 in deiomeed water. Compound i i ghee base) ss dissolved is? smnie saline ami h el 1 is adjusted as 4,5 svuh HO fresh everv day. Va: veh¾cies; 0.5%- RsCMC avid 0, 1% Iween!: HP in vieiooized water or sieriiv sai o pi! 4.5. are used lo or- a t e condol groups -a the same schedules. Foi-rntdarutrrs are stored away iron": light ar a 'C prior■ '■ · admbksn-arion. Unless otherwise speckled, compounds refimered to and tmaeO u this experiment are in dwir xpeerrk salt f rms menlkaied g-: igT paragraph.
Treatment Flats
10 %0] Mi e arc treated ar compound doses ranging irom la s - OOP mg/gg and at klD (three l me a. dag everv 8ha BID (2 dmes a day every or. h) or yd · ionce a dayt schedules for various amoums of da ,? by own gavage or inieerions via the mtrsperilouesi route. Eaeh dose is debvereO in a volume of 0.'; mL/20 g nwassu (10 mLd-ggk and sdjusied for the last seaorded weight - a' individual animals. The maximal treatment ieagpb is 2a days,
Medkrrs Tumor Vomrne ( TA s and Tusnnr < i <■:·.··. o< lubibiknti k!XiF) Anatysis
i 5
jPlbP] Treaaneni. efficac Is desernbned ess bw iast treatasera day- TVfng the utedasn tans a volume has the ruunTet ol annuals, ns evalaable on the km day. is deiemnnecl for each gsoup. Percent tureos grsassh inhibbknt (%Twi? can be defined several way a. f asay das Anwvn; ·· between ike off Vim of the dos>gnaied control group and be; a l 'V'(n) of t t draaPeeaPsj gsoep is expressed as a a-uccauno of the klT os) or the aoniosl group;
mG[ = ..:...s.ss..s...s:. j x I DO
{0761} nodeer a of caktsisbog %TGI is fakatg the change of t e Pastor slsse w-;n day 1 to day a info account with a being the last treatnwnt day.
Figure imgf000156_0001
Αη:Γΐ ;, - munA,>;^; - ΠρΙ A^,,; ΑΑΠρ;._.;,, ■ TVin)^^ ~MTV(i) ^r,,
Tosbedy
pf/621 Animals are assigned daily oa Days 1-5, and then iwass weekly oeab Use ooinpleuon or the study. The udoe are esamueed iVepaeadt' tor overl signs of am adverse, treatment•sj!aksJ side cinecm which arc documenied. Acceptable Pas led v t r he snaairaaas tolerated u- -a. f 'l ) is detmed as a group mean a 'a loss of iess tbar; 20% during die test, a: i a.- more Ch r; |P% nsortalby d e io TR deabev \ de th w to be classified as Til .if H is aitribumbie m acumcni vade efffcors as evidenced by cladcal signs and/or necropsy, ra' due to unknown causes during the dosarg pcilod. A death is a> be. clawatled as ATR inh r Is evidence thai the death a: umckued as aeauneui side eileels. 'AIR deaths during bar dosing Interval w ld A'pieally be eaaeeorAed as M l Ra piue as an accident or huntan coon or NTRm (du m necropsy^monfirmed tumor dAserninsbon by dns-Wion amfor metastasis). Orally iresred aaimaA that die bom unknown causes during the dosmg period may be clasalbed as ATRu when group pcrionnanec does not supporl. a TR classll eatasa aud necropsy, to rule oni dosing error. Is not feasible,
Asnpbsna
p.wba f .a : das s ? or A din an: the studies son e are santpie;:! la a pre wpecilkd rasibon as assess targei inbihalon In tumors. Tumors are b;avesied one specified nuee under KNAse bee P T/US2015/037715
conditions and bisected. Froaen tanww dssav bom e ch animal is s tPoaen in liquid N and ulverised wsth a uwwtar aoa pesds.
Statistical aeO <Aaspkaen3 AnaPyses
Or/Ogl Alt saisGOCid end goashlcnl analyses; era pertdamed with lobns Ao3 RA'aphPad) tor Wi d s, d icst statistical signiiieanse be;weo;t the control and Oeakd groups over the hole teeatn/cat time course a repealed measures AAOVA >est toliowed by Damson; multiple eomparken post test m a 2 wa ΑΝΟΥΛ ken a, a aa'ployed. iaa a:- repeats re ults as ;am- aigrnfkam nw; ar > 0.05, signdkam kymbodaed by at 0.0 a A < 0.0k very sigmikaaa a-- "·■ k ai 0.00! A 0.01 and exawmeiy signlAennt R- " *k a; P < 0.005.
FB one Fso ckm;
|0?05] -ar isolation ohhisionc:., 00-90 sg tamor u/sue is !n.anogenked n; F5 ml nuclear extraction butter uo mM TtisA RA 10 rnM MgCk 25 rnk! kkg Ok Frkon X- 100:.8.0*9 Sucrose, pins a Roche prokasc inhibitor uklet ; 236045; and iacabaied oa ice ior 5 mlnuka ualvs arc collected by eerariiugatiou at 600 for 5 minutes a; a As and washed once la F o, Srspc aasaUi Is removed and hi/tones cairacted tat esse hour, a lib vokcs iag every ;g aOnaks, wnh 0,9 A csdd sultarlc as Id. kvnnsi arc eiarrdad by centrdugaBon at 10,000 g a a 10 minutes at 4 A', and transferred to a heap! mles'ocentri0.;ge Ouw containing iOs, volume of lee cold acetone. Fksioneo aw preelpieued at -20 k." for 2 hoarswo ernlght. pelleted by ceatrliugaika! at 10,000 g tor P.; adautew and rcsuspended in water,
0.aPSA
[0700] IBkones arc prepared ia eguivslem cow.ena&tknis a; ecaadtg baAcr pPBS-; OA/klsSA; s Aiding OA eg/at <A /arnpk, aad s00 al ofAample or seawlard is added in duplicate to 2 eg.- web PFJSA plaice t TAenwo L.abeseaastw: Innnulon 4I4BX 93225.·. i is. phaee aw scaled aad Ineubareu encoded;: at 4 kg Ida Rdbwing day, plates are washed as wnh 3oO ukwed dog P ;P15gs -0.0m dbveen Ag ;og pugg g KPL ay g- gkog on a Bio Tab piato aashea Plaks arc Idoekcd a kit A)0 ekweO oi dltaeat (PBR-kkBdA a0 (g¾ Tween 20;, laenbaed eo. R ί lor a boura. and aasded 3a a ub PBST, All antibodies are dinged ia ddaere. 500 oJ/ d ohanb- PBK27 e3 tkSA dO/gg, gyge tgccrol atok 5 A.000; or iaaiarkd 213 (A beau; ah 1791. aO¾ glgcewd 1 Α ,ΟΟΟ'ί Is added k eac plate. Pbuas arc Ineabated lor 00 min as I; i and -vashed 3a aadi !dsold ilk; obavell ohaiUe4Akg<kHPP (C ll alanaPaa dcehaoiogs, 70?4) Is added I A, op i p¾ H3k27gio3 ob.ae and i gyOOO to the 513 plate and awabateri for 90 nkn at RT. Plate/ arc waslicd 3k wkh rg:\ 5 FOJ daiecOow Ida rd/oeO okl MA substraar ( l Fx r aboraa/ocs, a phtBd; a added and gkaes Inarkated la >he >Aa2 at is I k.a 3 rain, ideaedort is stopped w-ih 1 0 ul/well IN fBSek Absos-gance at 450 wo read on Slpeogtrrkee M5 adlcroplate reader,
da FB study
1 In order to o- a hdher a com ound can modulate the 123K27me3 hAteae mark in iumors /? tow, W3d.i--PI.g3B2 xen nib. Panor bea ing mice are treated vriih the compound at c er 200 ivpake id; > or -top no bc OD or vehicle t B3 schedule) for 7 days. There are 4 animals per group. Animals are e t ani d 3 !a after na at dose and tumor re preserved in a trozen state as tk-.se. jibed above, 'fallo i g !nstoae exirecdon the samples are applied to BLkSA assays e-aae aooo--b-e: directed against die tnmcth ku-ed stag- of hlswum i lake ; B3K.27rae3 > r total histoae H3. Based on these data Bee rado ot yb-h m: methylated to una; H3B27 is calculated. The mean global methyiatton ratios tor all groups as measured by BLISA indicates large! inlbbibon range -.eanpared to · -da, a'
3d day efficacy stntiy in WSI.BOI..-CL2 sce:g;r l) wbd
ρΑ,-sj pi order to teas whether a compound coatd induce a tumor growth inhibition m vAo WSlBDBedA xenograft gmtta bearing nuce are beater! with hie compound at 12.5, 23 or 30 mg/kg BM7 tor 23 daya
Figure imgf000158_0001
intraperitoneal injection, 7 amor wsiume and body- weights are deesrcnlned wice a week Λ parallel oohor ff ce tn:::4 per group; Is treated at the same; sawe;- tor 7 days, awl oboe are ettthanmed oa d y 7, 3 b aUer the last doee tot uuoor sampling and assessment of target inhi iti n. The result of she OBIS A measuring global meiirylation of ii3K27 e3 a -na..dwtd to a -as b ia determined,
E!kaey at tuiy o Og iucn:asmg dnaes ia w!>L€L2 aetrngtssfst modd
iOdgoj In ordsr to test whether a compound eoald induce an aniraurnor etieoi a; f, WSU- DI.33L2 senogodwannor bearing rrnee we treated with a oompwmd at, e,g., 37.5, 75 or 150 asg/kg l ib) lot 22 days, i here are 12 mice per group tor the efficacy arm of the experiment .2 parallel cohort ss dosed a.-;' 7 days at the same doses and schedules for assessment of target mhiblri-wt ager 7 days trow per groups tumor growth over the treatment -.oarse of 28 dato lor vehicle and eotnpouno treated r ? Is measured,
1022td Hbaones are extra-, ted iiosvs nnoors collected alter 7 days of dosing (parallel BD eoitort) and t the etui · a go study on day 2a lor tie; efnoaey c ort t2h ader the last dose for both cohorts). The H2R2?me3 medwi mark Is assessed tor modulation with treatment lit a dose dependent sua tier. Eiitcaey sssu!y at btfibrern dose chedule
[07? ; I I'Vj assess -heih ; a compound wooib lead s > panor grrwah inhlbioeo at other dosing schedules Pot blD a vVbbnDhCIA xenograft efhkaoy siody is perronned where ΠΊΧ BB and OD schedules ere cengxwed side by ssJe. There are 12 anneals er gongs, and rake arc incaaxl for 2b days. The bnnor gnawd; over the neapoern coarse of 28 days fur ehcle and con-pound treated groups is measured.
|0??2] Or; day 2a mice are oodia deeii and Paoora oaoe cdieeied 3b after < -. las; dose iur assessment el target mhibitlon.
Example 34: Antheasseee otlce* n she !bA!lPAS- 22 nomas; dimmed hops leg eU ivmplmn m<msc xenograft model
ί 077o ] A ;osi congs-und Is aaaiyoed tor Irs ani-cancer aedvpy b; igAPtPAS-422 m>-n..c xenograft mod l, ^iueh A a human diffused large B-Ce!i b aabr --as xen graft model. 45 female of Csgabl bygVoxai nrehrl(ftlj mice (Chancs River Laboratories Agsan) ab liA FAS- 422 nnnors sAaase nmao fuoior vok;me {"TV's reached appioxlmaiely 120 map' asc selected based on their TVs. and are r nd ml divided Into Ave groups. The oral adobnasTaOon of compound (e.g.. APT lot ..322, and 644 mevkg? or veh-ole is stared o s day I . Cornpoe-nd -s given orsee daily on day I rid day 29 and bvlee dais ev ry day from day 2 to d y 28, The admnbsrrabon vobane (0.1 mbfto g body weight) is oalcniamd irons the body weigh? before abnbnishatiun. Ί tie 2 V and 0,.sgy vveighf v-er¾ measured twic asveeb. The design fur due experimeni Is shown In T ble 6.
Table 9 Dosing she eme
Cbeonp No. ed 1 re.nnmas (tniee a day) oate nod
An Ins a Is brhmfuk
I 9 Vehicle {b.5% al fhyl AeHeAse, 0. bA fween- PC; Bi!b x 2b days
20}
'S b e A mg/kg Compound Pi); BID x 2b days
2 !) ! a ! agese e oropouoo As); BID v 32 days
4 9 322 mg/kg Csaopound Pig; BID s b days
5 0 6-14 mg/kg Compound Pb.g bid X 2g day s
(0774'| 'TV Is oalcedaien Irons caliper measurenmers by die rornada for the vobane id' a prolate ellipsoid U.'X A where b and A" arc the respective ordvsgsasal lergyth and vArah me,-snuemeoe, fa an). [0775] D;ua r eapresaed a;- sh mean .a i anJ deeiabon PSD a Thv differences in Ί V between t e vehkie-ercaied and emponnb••b'eared geonps ase anab aed by a "nvag-b measures analysm so variance iA. OVA.s fb!oveed by ?bs Dunnenoyps' rrmUspfe comparison nasi A salne old- 0.05 man ssdeb} >■ considered srausikabv signbieam. Si i ucai nnaiyses are neribnucd osing pea fb'km 5 sotivcare pacbaga version 5,04 (GraphPad Sobseare. nc Cb\, UbA).
[077o] s ha invention c r; be mb died in oiber specific tonne vvirhoat deparbreg from bio sprt or eaaaabai eharaceerisrks i ereoi. The foregoing ehbsobmerua ase diorefora t be co sidered n ail reapeera iUraarabve rather Usea hrnking on the irsvemion described? herein. Scsrpe of the buenbon is dsns indieaied by she appended cbaims rasher than by die rbreaohsg description, and ab changes that eerne
Figure imgf000160_0001
the mesnhm and range of ergovsbencs oibhe eiaims are ionsnbed ;o be embraced dnmis

Claims

Figure imgf000161_0001
compound of fonuoX si) O! a ph<omfiooid-cY Y accopiabie saH ihereor:
Figure imgf000161_0002
Figure imgf000161_0003
X{ is N -; ? ΠΧ;
X;, s . N X, K O, or X
XR¾ O, ΟΓ S O,!;00 V
Figure imgf000161_0004
·! X, iS N Of : WXOi V o
Figure imgf000161_0005
Y; isN rCH;
\ : ·■ M o (XX
YX >s N',. o.r (ΊΧ·:
X ο:Οί ·- XK?R;XX;; s s H or Rxx a? ich S!1 h Ci-C, aikyb C'.-C- askenyk CcRk a!kynyk C €2 c.wboalk h kx aryy 4 t ; -anon'b:aavd benorxaxkadkyl or 5-· (kaacrabewd baka oasa k and Rw is opponalk snbsbkncd Ά da one or more sobshtaeats selected awe he gr u ooaskkng of halo. hydroxyl, oxo. G:0.?OB\ C(0)Okb"Cv aikyb eyaao. G-Cs aikyb GAR alkoxyk amlao: m n> GAk aikyiarnnky dkG Ag, alkykarbno. (AAA cyokxdkyk GAA acyh 4 io k2-raomberob heWrocycRsikyb and or Aeneeiberad hekroaryk
each obRx G„ and by. kakaendenthr s --AgeA A us which Q; a a bond or CVCb alkyi baker opboaaby rehwnen d erbb ha x ro ncs hydroxyl or A o aikoxss aad "id is■ b bakr hydbo yl knOH.: eyanm a,-bdo. or k-o. in whkb R,;: is G AA aikyb f bAA alkenyh kbkA. alkynyk GAA alkoxyk CkkA bboalkyk CAkO-kg AA aikyb CORbk. SgyGHx AROaNHiG Ak alkylg AkkgrGakHw aikyb.;, GOr^Ab Ag, aikyb, - Sbk-NRgAk akybx. Cy-Ck oycloafkyh (k,-- 5.4 s aryh b G, aryioxy, awneo. aenaxkGkk aikylan'ono, dkbbAA AG 1 aa;aw 4 to ; .k meaibered hererooycioatkyk or 5- or•••a-'abaovb hemroaryh aad Ikw is oplioaahy subGAned with one or more auAakuens sekcoed horn aw gro eonskdag rd 'halo, hydroxy I ro C(0)OH,€(0)0--G--G ad.;. ·. f yaao, GAA a!kyb CGG, aikoxyh aakno, answx :··;..
a!kybaouax dk(g Ak alkylaakno, GAk cyoloalkyh G.~€b;> aryL 4 io 12-aiorabead
iwwroeyG:.adkyh aad 5- or oorwmbered hekroaryk
each of IG Rx IG::. aad R^yndepoademly. is H or hgAAalkyl opk ia.dk soGGmed wnh one or mo subskkxems rxbeckd Rom the group eonskkng of halo., hydroxy!, COO.IL k4kAOAkA.x aikyb eyaao. Cr(i. slkosvL amino, moaoog:Ag; alkyGGnos dikk-bk aikykmnoo. OGG cgcGaikyk Cxk.bi; a 'b 4 a.; GwaeuGesed hojerooycloal k aad >» or kaimmbered hemroaryk
c ds b xkpoidcody Is lb ham Oik, Gik A. -€(G) .S- - 00. ?k .
GgORbARa Gnk Obk. -S(Oy.R„. mRA}G;RJG, or R,;., in Gneh each of R:. and ;k.
iadepoiKkatly ;s H or R -; aad each of R¾ aad R^.x iadepemkaky, a; bb-kk; aikyb fbi-ik. rbkenyb r .a. y alkyny;, b: ,kk. cycioakkyh fk- bo aryk 4 a.. kanen;bcrcd hciorocyoloa;kyk or f so 6- raoaibraod bca:roaf> !■ or lbL; aad R;;; a'.>gc ho vvn b;c N akaa a.) which ihoy arc sc d, ϊΐ-ra· a 4 to ?-aierabofod iajicrocyoioaiial ring bavhu; o or ί addiUoaal beacroatoas to the k airaa; aad each of Rs¾ R..:;;. and die ;i a.; ?-ir:sabrcrod hcacrrHryoioalks ring oonrairaag R;. wnd lb. s opdraadly saaskaksd Hata oao -r aaao -Or-dk, alvrrcia Q;- is a boad ra Rg.Ry a.lk l b ke; eaci) oprioradiy sabadaraxb wkb haio, cyaao, hydroxyi or Cb-i.k alkoxy, aad k fi, icdo.; oyano, •i nk, --NRkkx okikdkkk ;bkk .kdfkR,, ~C(C?jO fj d;k))NRkkr -HRxfabpif,, ks ¾(:(() b)R,.. •SiO^ ., -SR»- ; I r or R¾. m which oach obR,, Rfi and R.r, iadependeaby is fi or A" k a pi si'aaa caiic isy accco-abio ardosr oaoh of R¾ aad
Figure imgf000162_0001
i da erKSc tly, ic kr(a, aikyb Co-k¾ ·, a ado : bR-g ;.} and A to o-oeiobore hewrocycloalkyh or 5 io b-mernbered heicnjaryk or Ik., and ik-s, together with bwRN a'nn to which drey are aPached, toro a 4 lo /--mennwred heteroc cloaikyl ring ha ng 0 or 1 additional heawoatonw i lire N atom, and oach obRs,;, i½, and a- 4 to dwoesnbereo heieroeycloalkyl ring containing Ik ia-d R(.,, k optionally rrReidoied with oao or more - -kk-'i R. wherena kg n a bond or cVCk alky; linker cacti opRonahy cabaRobed wild halo, oyano, ipg:,. 1 or R;--Ck alkoxy. and Ik k coieciod a- ;o the group conskbng okhh halo, eyamy Odd;., alkyh bg-Rk eyekadk-b. C -CR,-; aryk 4 to dwneodxaed heierocveloa!kyh a to bonernbered beRroa-yk RHR. (XX)ik- -$CO)-?R,:, --NRkk, and .-CR.RRRRR;. oach oflGand ¾■ independemiy bcnsg H or Cb-RR aikyl optionally saRwRnbed with Old, <MkwR aikyh or NHRky Rk, aihyk or -QG!R k oxo: c-r - R>r R : ·'· = ·'· o any t o neighboring hs-w ;. together wRh the alonrs to which the are aiiaobed f nrs a a- or 6-meaibered ring optionally eonkomsgy 1-4 heieroaionw selected iron's bk to and a and oodonaliy cobatnoied oath one or more wnwlbuems aelecred Ron; the gr u corobanng of halo, hedroxvk Ri.ngfi.€(0)0-C;-Cu aikyk oano. CR-Ck alkoayl anusKg nanse-adoRd alkykaoino, oj V'Ck alkybanis t d-d' eycloalkyb Go kg a ao b 4 to k-ncadaoicd lna'en.-cyaio¾lky1. rani ¾ io d-roombered bewroaryg provided s.hi>t w rod in
each Rv oxkpesKiendy a; ---RR-R o. in hch go R a bond, Ro-bk; aikyl linker, or ko-kk aikeoyl linker, each tinker opRonahy wgvgknted with baby cyano.. hydroxy! or k;w aikoxy, and Id is bk hake eyano; ?R¾ - ?κ ; ayg op ~C(0)O?¾¾; --CkbRbR;R!!s -€(C>)bRk }Ro ■ IGCtOjR;,. xn o p .. or R¾;. in which each of R,. and Ri;, ira.iependerdhy is H or ί½; each of 1G; and R . nKiependendy ia iR-lR alkyl Cykk oycloalkyh oG aryg 4 to bor nR>ered heierooycloaikyh or a aa o-iiieabe ed heowoaryk and each oibG. and IR-; is opRonaliy aubsiUtHed wnh one or more kk- G. wherein Gs k a bond. <dOr RRRiNiR , NRkdR.G Nik, SR Rj, NlRoRda. or kb-Ck ^Πρ i bnkea IR. being H o kVkR aikyl, and dg R R halo, RvRk alkyl.. R-R.k. aikcavk R;R.d aikynyk hvdroxyk eyano, k' r.pR ikoayk aonw ·, oonoo^t : RR aRgdunnno di-dd-Rg, alRyla-nino. id .-RR cyeioaikyk (d-Rd;. a!kyRneR. ,Rki: cycioaiiwi, (i^-Rd^ ar)R Cb-Ck aikyienc4.d,od!fi aryL 4 to tdoneoibered hcrerc yeioaikri, Rd-R-: » alkyieno-4 to ia« oierobered heier-wycloaikyl, 5·· or b-njonnxared boteroaryk or (R-RR. alkyiene-5- or boviornbesed bereroaryi, ar¾d 4R is optionally sobroinned walk o«e or snore aabxlitaonra yeieesei.1 Rorvt Pre group crnwRlina oghaio. R';Ri.d, aikyl hydroayh eyaiaj, C;~ .-, aikrwyh OR' sR.'-i aikyiene-'R.r-R:..
alkoark andno, n5ono-R R' ;, aligviaannv, di-Rg-RR aikylasnisKc i. Rt eychxRkyk RR- m aryk 4 ■: : 12-rncmbered baterr^y eloalkyl and 5· or Ronenkwred ηοίθ-ϊχηχΊ accept when Ik is R, iado, hydroayk or eya.no; or■■■(}■ ..-'is w cccg r vided dak -k.g:.-']\; n not 1 i and each f ¾. R::, a;X IX.·. IndepeiXenby , Is H, halo, hyon/awR XRXXL cwmo, ,^. Rdy^ or R KX H, in wh-ch ■ ·■ s XiXf- aikyk C.ysX sXenyk C; X' f: alkv nyk aoboso i'nonn RXf, aXyRoXno, or dfXxXY aXybonn s d RX« is; optionally aubsdtttoX wbh or mors
aoXtuem seXeXd irorn da oroop eoasisihnr of halo., hydroxy!, CXdOI I, CXXRYRy X alky, oyaoo. Cs-'C alkoxyk annno, nwnsoXyXX ahe Ranlno, and dRXYXi. nXylamksO;
n oaf h 2, R4, o>-5;and
a? m x one ot - d X:i is or ?\ a; lensi orx- or X,, X;, X;;; X;. yd. YR, ;:·Χ Yd X X or
XR:„ and X:. X;>, X/>:. Xd, VS;
Figure imgf000164_0001
in Form la X) is a bicvdlc heteroarX syaieno
The compound edXImm R wherein iho con/pomX ia of X orrrnda Π
Figure imgf000164_0002
dw an X is ORy or C.H' vR-;. a. The conspoinsd <X claim 1 or 2. hosom X X OR/, ;n which R; ia fd-Xoa aryi 5 to 6- roernbered beteroasyl opuooaiX aubsuixhed with one or sno e wd TX,
4. baa compo;md ot claim X wherein !¾.·.· is phenyl ops l yally aobsRRRed ax one os awne -XRXR.
X The compound or claim t o; 2, wTorem R is XI ΠΧΙΧ, In which R? is XdX., nd IR> is ;* . · Cif! aryl o.t 5 to bwneo bercd hcteroarvl optionally subsRaaed with one or more --QVTX and R;i is Xr-Ry lk/k 6 The com nd oiekam 3, wherein R..; i phony! ;:y>ho ab subsbuued odd n« or mos -CV'R.
7 The compound of oknm I, wiwwin the oompound is hormrha (do:
Figure imgf000165_0001
wh jem ;s -<R-4d. whore m b,p ·:· a bond f VCb aihyi imbo\ and I R < . ·*' alky! ophomdly seoonor d with one or m r - -CR-ld, fdRR cyeloaikyi optRnaliy snbrhinieb with one ''.'!"■ omre -odj-od, os: 4- to IdoYrernbemi heieroeyeioaikyt ophonahy ^ob-didded whh orm or more 0· · b d 5 ooosp und of ohbm wherein b . Is H.
Tbo compound of cbbm R whemm the eompoond is of Fonneba (Bp
Figure imgf000165_0002
wherein R-; is Q,;-'"VdS: wheen Q s a bond r meh l linker, and lb R by -d aikyi oprionahy subshuued whh one or more -bd-dd, CY-Cd cyckobky? ophonahy snbsOUneb whh one or more · byvld, or 4- k? hhsoembered hemrooydoaikyi opdonsby subsumRd vv h one or more R¾--R.
Kb 4 be okom 9, esmwbs R,-. is Cbvbd!: aryi or S~ or doiaembered heieroaryb each o which n ophomb . independently subsbmwd whh one or more --Rw-4d.
Figure imgf000165_0003
O.; is a bond or CYCd alky! bobey wwhR is H, halm cyano, 4>R0..NhRRc dKOVebfJw, - R;C(0).K,f odRyRR, · RORRRRR-:, r R , in winch each of R , and ¾, aa eiRkni R is H or b, each of κ:νΙ and R-w nwRpendvatiy, R RydR; uiksk or R. and R .. gsgebicr with ihc aioso to hi h ihey ore Uic«-hod: iom> o 4 to RownRoacd heterocydoa!k vs ring having 0 or 1 addiiionai heRroaParr, and each of" Rw, >;;-, and Use :1 to f-wcodvwd heteroc) cioaikyi Rng formed by hR and
Figure imgf000166_0001
r> ophonahy, independently sobaPpged wath one or mos -Q T'o wherein t/R is hood or CpiR .oh- i baker and 1 ί w seRcted trom rhe gou conswPng of R, haiw C;RY, aikyb 4 to '"?-ar>emRoed iwterocycRaikyh * nt .■ePROyRR, and -P RR, each ofR,. aid ?R indopendvady hoop; H o C R alky! optionally siRsOpge oath OK oRfRRR, aikyk or NfRC:--C¾ alky}, nr O R . is o¾ ; or any tw wnRRv«-R --RgYRR-., iogeb;er r. hh pw aooo-; to which they are anaehed (con ;· 5· or a- ioernbewd Pag optionally eonpuning 1-4 heRroaPnns setecPed fVoro N. P) aoP R i R T'ht; conpo -oad ot ciano "R wherein ¾ is pho ί or pyridyg OR a; a o -a j or methyl Hnker. aod 1, is R hako RPIR, ~NRcR.i? or RROpRARR ,
12, The compound of any oieianna ' R wherein X; la RRs, X,; s d Yd and Yd are each
13- 1 ho cooopoaod of any os khma RI2, wherein 1R R ieo'ahydropyrarryk pipw e.Pe-:
aobaoRUed by R a, or Ridd? aikyl group or cyckmexyl snbedmted hp RRRRd; ad \-:
wherein raw or both rRRhe RRRa aikyi R optionally snbstituied wdh C;RR: aikoxyP id. the compound of any ot chama i and PR R wherein R is aecdupT eveioperayg or iw> propel ihc compound of arw of claims !■-? ami 9-14. wherein .. s selected from Pw gmap
Figure imgf000166_0002
Figure imgf000167_0001
Figure imgf000167_0002
Figure imgf000167_0003
Figure imgf000168_0001
in which eaoh of |R uni o i R, and each of IX aad IX indepcirdeniiy is daw. (hX',; sik l. kd kd n!koxyh
Figure imgf000168_0002
e compound oj any o a an XIX w eren X
T e oaip an of any of Raaaa; XI 8, wherein X
Figure imgf000168_0003
The compooad of am of claiaw 1 X ?, wherein X is
Figure imgf000168_0004
aid The compound of claim 2i . herein ach of I , IX, a d K.u indepeademky, is XyXR, in which Qi is a bond or kdXd aikyl baker optionally sobshuned wit hake ami Id X R halo, hydroxyk kdkXOkk oyano, a;ddo, or I j.. n which 1½ is C 'd sikyk CdXy adwxyk kb y cycioais.) R C V: aryk XoT ; nr Bxy, amino, na noXXXf, aikylandao. dohd ad.; aikyRndno, 4 to kXmernbered hXeroeycioaikyk or 5 - or d-aacrabered heXroaryh and !½ a> opiweraily sabsbiuCed w ith one or ne.ee sabsiajcas «!ecced fr m dec group eonewbne: of halo, h dcoxyk kdOKXR d XXOXdXd, aRyk cyamy Cdwy aikyl CdwX aikoayw aruney asoaoXRXd;
aRyiamkay dkCbXy, aXykannKc X;;XR eyokedkyk Q-CX-? aryk d so kXoscnnwred
hcierocyeioalkyk and 5- or b--menibered bcteroaryX
23. The compound of claim 32 wherein each of R::;, b and d . independently, Is H r i. C\ alkyl.
2.4, ihe compound of any oi claims E-23, wherem n is 0. k J 3, 25, lire compound of claim 24, wherein n is k
2b. Use cornpoand of claim 1, wherein d;e compraaid B aeiecwd from tboce n "fable I A and Tables; 1-3 and pharmaceutically acceptable salf> thereof
22. The compound of claim 1, wherein xhe compound is aelecwd from th s in Table I A and phaoriacenuoady acceptable si lic duereof
23, A pharmaoeuUcal oomoosuion comprising a compound of any oi claims 1 - 7 or a phar aceuhcaHy accepegbie «η; th re and a harmaceutic lly aeoeprab!e carrier,
29, A method of ireabng cancer com risn admirnsrermg to a subject in need thereof a therapeuBcaiiy erteciive amoum of a con¾poraid of any of claim k-27 or a pharmaoeudcahy acceptable salt dwreok
30. The method of claim 29, wherein the caacer is lymphoma, leukemia or wwkmoma,
31.. The method of claim 30, \v herein da; lymphoma w a germmal center-derived lymphoma,
32. The method of claim 3 k o. herein ihe germinal ceraemderired lymphoma w an EZII2 wild ype germinal center B--cel? lymphoma.
33. ihe mediod of claim 31, wherein the germinal oentecoierwed lymphotna Is an EZH2 atam rmin l comer B-cell lymphoma,
.34, Tim method ol'any oae of claims 3B-33, 3w eln Ore gw'tnlnal center-derived lymphoma is fhtfacc large B-well lymphoma, rolhcnlar lymphoma, BurknPs lymphoma or ouAiodgkbrs bp mpboma of germinal owner B cell subtype.
35. The oeih d ofoiaaa 29. whcrea; i ancer is chroaac iydogeaaua kuksmia ;CML). i ' Ye m loid kokomay aeuse i ai hov ue leukemia, or mixed line kukerrda, or iii ek s iasii syodromas s v! Ss,
36. The nsedi d ofcfaia; 29. whereivs ?.he cancer a. maag am rhabdoai rumor ur ;Nf I- detacieni uaooa
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