IIIIUUIUIUUUIUIIIIIIIUIIIIIIIIUIIIUIIIUIIIUUIUIIIIIUUUUUIUUUIIIIIIII
`
`US 20100098633A1
`
`(i9) United States
`(12) Patent Application Publication
`XIMM K R M /II.N et al.
`
`(i o) Pub. No.: US 2010/0098633 A1
`(43) P ub. Date: A
`pr . 22, 2 0 1 0
`
`(54) SELECTIVE SEPRASE INHIBITORS
`
`(75) Inventors:
`
`Craig XIMiiF RMAN, Topsfield,
`MA (US): John W. Babich,
`Cambridge, MA (US); John Joyal,
`Melrose, MA (IJS); John Marquis,
`Nashua, Nl I (US); Jianwheng
`Wang, 1<evere, MA (US)
`
`Correspondence Address:
`FOLEY AND LARDNER LLP
`SUITE 500
`3000 K STREFT NW
`WVASIIINGTON, DC 20007 (US)
`
`(73) Assignee:
`
`Molec u lar Insight
`Pharmaceuticals, Inc.
`
`(21) Appl. No.:
`
`12/5 6 6,324
`
`(22) F i led:
`
`Sep. 24, 2009
`
`Related U.S. Application Data
`
`(60) Provisional application No. 61/100.178, filed on Sep.
`25, 2008.
`
`Publication Classification
`
`(51)
`
`Int. Cl.
`A61E 51/04
`861E 31/69
`
`(2006.01)
`(2006.01)
`
`36M 31/555
`(2006.01)
`A6M 31/4//
`(2006.01)
`Cr/7F 13/W
`(2006.01)
`361P 35/W
`(2006.01)
`(52) U.S. Cl.......... 424/1.85; 424/1.65; 514/64; 514/184;
`514/423; 544/225; 546/12; 548/402
`
`(57)
`Novel radiopharmaceuticals that are useful in diagnostic
`imaging and therapeutic treatment of disease characterized
`by ovcnmpwwsion of scprase include complex<a that contains
`a prol inc moiety and a radionuclide adapted for radioimagiug
`and/or radiotherapy:
`
`M etal-Chelate~
`
`w V
`
`R3
`
`0
`
`C'
`
`100
`
`80
`
`Percent 60
`of Control
`
`40
`
`20
`
`~
`
`No Inhibitor
`
`Co mpound 1023
`~
`~ C o mpound 1024
`~ Compound 1025
`~
`Co mpound 1051
`~
`Co mpound 101 0
`
`0.001
`
`0 . 0 1
`
`0.1
`
`10
`
`100
`
`1000
`
`Inhibitor Concentration (uMj
`
`Petitioner GE Healthcare – Ex. 1004, p. 1
`
`

`

`Patent Application Publication Ap r . 22, 2010 Sheet 1 of 5
`
`US 2010/0098633 A1
`
`80
`
`Percent 60
`of Control
`
`40
`
`20
`
`No Inhibitor
`~
`Co mpound 'l023
`~
`~ C o mpound 1024
`~ C o mpound 1025
`~ C o mpound 1051
`~ C o mpound 101 0
`
`0.001
`
`0. 0 1
`
`0.1
`
`10
`
`100
`
`1000
`
`Inhibitor Concentration (uM)
`
`Fig. 2
`
`I
`
`0 N+ N
`
`0
`
`iB OH
`HO
`
`l-131 labeled Compound 1024
`
`Nal
`
`Petitioner GE Healthcare – Ex. 1004, p. 2
`
`

`

`Patent Application Publication Ap r . 22, 2010 Sheet 2 of 5
`
`US 2010/0098633 A1
`
`Fig. 3
`
`1-131 Labelled Compound 1024
`RCP 97%
`TOM+1hour 37C
`
`200
`150
`100
`50
`0
`
`l-1 31 Labelled Compound 1024
`RCP 87%
`TOM+ 24 hours 37 C
`
`10
`
`15
`
`20
`
`25
`
`99m l
`
`N
`
`Scale 25 mCi; 10 M; 71% RCY
`>98% RCP (atter Rp-HPLC)
`97% RCP atsh
`
`at Shrs
`
`N yN
`
`HO
`
`Petitioner GE Healthcare – Ex. 1004, p. 3
`
`

`

`Patent Application Publication Ap r . 22, 2010 Sheet 3 of 5
`
`US 2010/0098633 A1
`
`Fig. 5
`
`Seprase Cell Based Enzyme Assay
`~ w/ o Compound 1024
`EKE with Compound 1024
`
`Hek293
`
`H22
`Cell Line
`
`Fig. 6
`
`4000000
`3500000
`3000000
`2500000
`RFU Q 15 min 2000000
`1500000
`1000000
`500000
`0
`
`70
`60
`50
`
`h r
`~ 1
`IK94 h
`
`%ID/g
`
`30
`20
`10
`0
`
`d
`
`gazoo q8 ' go0 ~ <
`
`Q
`
`e
`
`• 8
`cQ • 8
`9
`. ec
`0
`>8
`ice.@ge~ ~s qi4' ~i4' ~ac
`gO g4 +<a »~e»e
`iO Scn
`
`Petitioner GE Healthcare – Ex. 1004, p. 4
`
`

`

`Patent Application Publication
`
`A pr . 22, 2010 Sheet 4 of 5
`
`US 2010/0098633 A1
`
`Fig. 7
`
`(OC4 Re ~
`
`~
`
`,B-OH
`HO
`
`70
`60
`50
`o/,(p/g 40
`30
`20
`10
`0
`e
`. e
`o
`s
`o
`. e (
`s
`ie
`qioo qe> ~o0 ~i< Wee . g~e'l ~s< pi c+ ex4' ~so yea
`~go
`iO
`
`h r
`~ 1
`EK34 h
`
`Fig. 8
`
`h r
`~ 1
`5K94 h
`SK924 h
`
`20
`18
`16
`14
`12
`
`8 6 2 0
`
`/.ip/g
`
`e . e (
`gyo @e oc ~ i~ ye
`
`e xe e
`e > . e , e
`('
`'~
`i(
`~e8~$ e% e% ee% oop yo y(e ~(o .~o
`
`e o(
`
`0
`
`B- OH
`
`0
`
`HO
`
`Petitioner GE Healthcare – Ex. 1004, p. 5
`
`

`

`Patent Application Publication Ap r . 22, 2010 Sheet 5 of 5
`
`US 2010/0098633 A1
`
`Fig. 9
`
`h r
`~ 1
`IKS1 h block
`
`12
`10
`
`%ID/g
`
`4 0
`
`( e e< eo qe g , y e .ge ee xe ge g 4 qe o<
`~go @e gc' jx+ ~ye g@ ye oo gb ee< p+ qo gee' g5 .go
`P> >b'
`8 gi +~o +~+ +a+ 4 +
`'9
`~O gg
`~e
`eG
`
`0
`
`N~
`
`N
`
`0
`
`B OH
`
`HO
`
`Petitioner GE Healthcare – Ex. 1004, p. 6
`
`

`

`US 2010/0098633 A1
`
`Apr. 22, 2010
`
`SKI.KCTIVK SKPRASK fNHIBITORS
`
`CROSS-REI'ERENCE TO RELATED
`APPLI(.:Al'lONS
`
`[0001] 'I'his application claims the benefit of U.S. Provi(cid:173)
`sional Patent Application No. 61/100,178, filed Sep. 25,
`2008, thc disclosure of which is incorpomted herein by ref(cid:173)
`erence in it's entirety.
`
`FIELD
`
`[0002] This invention rclatcs in gcncral to small molcculc
`inhibitors of seprasc that can be used ds therapeutic agents
`through inhibition of seprase's enzymatic activity, or as
`radiopharmaceuticals that bind to seprase and therefore
`ellabl» imaging of tissues tllat express scprase or for dclivn(cid:173)
`ing radiotherapy to tumor tissues that express seprase.
`
`BACKGROUND
`
`[0003] Seprase, also known as hbroblast activation protein
`alplla (FAP-u), is a trdnsmcmbranc scrine peptidase that
`belongs to the prolyl peptidase family. The plolyl peptidase
`family includes serine proteases that cleave peptide substrates
`aller B prolin» rcwidue. Seprase is expressed in epithelial
`cancers and has been implicated in extracellular matrix
`remodeling, tumor gttlwth, and metastasis.
`[0004] Th» prolyl peptidase family include enzymes such
`Bs, but not limited to. dipeptidyl pcptidase-IV (DPP-IV),
`DPP-VII, DPP-VIII, DPP-IX, prolyl oligopeptidase (POP),
`acylpcptide hydrolasc and prolyl carboxypcptidase. These
`enzymes differ in structure at the N terminus, but are related
`in that each has a (".-terminal a[I-hydrolase domain that con(cid:173)
`tains the catalytic Ser, Asp, and II is residues. Similar to
`scprase, human DPP-IV is expressed constitutively on brush
`border membranes of intestine and kidney epithelial cells and
`is transiently expressed in activated T-cells and migratory
`endothclial cells.
`[0005] The expression of distinct proteins on the surface of
`tumor cells offers the opportunity to diagnose and character(cid:173)
`ize discds» by probing thc phenotypic id»ntity and biochnni(cid:173)
`cal composition and activip of the tumor. Radioactive mol(cid:173)
`ecules that selectively bind to specific tumor cell surface
`proteins allow for the use of noninvasive imaging techniques,
`such as molecular imaging or nuclear medicine, for detecting
`the presence and quantity of tumor associated proteins. Such
`methods may provide vital information reiattxI to thc diagno(cid:173)
`sis Bnd extent of disease, prognosis and therapeutic manage(cid:173)
`ment options. For example, therapy may be realized through
`the use of radiopharmaccuticals that are not only capable of
`imaging disease, but also are capable of delivering B thcm(cid:173)
`peutic radionuclide to the diseased tissue.'I'he expression of
`seprase on tumors makes it an attmctive target to exploit for
`nonlnvaslvc lnldglng ds well ds targeted fadlothcldpy.
`[0006] Furthermore, since seprase has both dipeptidyl pep(cid:173)
`tidase and endopeptidase activity, and DPP-IV exhibits only
`dip»ptidyl peptidase activity, selective scpmsc inhibitors
`would be useful to reduce unwanted side effects.
`
`[0007] Small molecule inhibitors of seprase are plovided
`for use Bs therapeutic medicines or as rddiopharmaceuticals
`useful in diagnostic imaging and in the therapeutic treatment
`of diseases characterized by overexpression of seprase. The
`radiophannaceuticals include complexes or compounds that
`
`contain a functionalized proline moiety which is capable of
`selectively inhibiting seprasc, and a radionuclide adapted for
`Idlhollnaglng Bn(Uof ldlllothcrapy.
`[0008] In one aspect, a complex of Formula I, its enanti(cid:173)
`omer, stereoisomcr, racematc or pharmaccutically acceptable
`salt is provided:
`
`0
`
`1J
`
`[0009] where:
`[11010] U is B(OII)2, C N, C O2II, or P (O)(OPh)
`
`[0011] G is H, alkyl, substimted alkyl, carboxyalkyl, het(cid:173)
`eroalkyl, aryl, heteroatyl, heterocycle, or alylalkyl;
`[11012] V is a bond, 0, S, NII, (CI12~ 1 12 — X)„, or a
`Youp of formula
`
`0
`
`[0013] X is 0, S, CH2, or NR;
`[11014] R is I I, Me or CI 12CO21 I;
`[11015] W is H or NHR',
`[11016] R' is hydrogen, acetyl, t-butyloxycarbonyl (Boc),
`9I I-fluorcn-9-ylmethoxycarbonyl (Fmoc), trifluoro(cid:173)
`acetyl, benzoyl, benzyloxycarbonyl (Cbz) or substituted
`benzoyl;
`[0017] n is an integer ranging from 0 to 6;
`[11018] m is an integer ranging from 0 to 6;
`[11019] Metal represents a metalhc moiety including a
`mdionuclide; Bnd
`[0020] Chelate represents a chelating moiety that coor(cid:173)
`dinates with said radionuclide.
`[0021]
`In another Bspcwt, a compound of general I'ormula
`ll, its enantiomer, stereoisomer, racemate or pharmaceuti(cid:173)
`cally acceptable salt is provided:
`
`[0022] where:
`[0023] U is — B(OH)„— CN, — CO,H, or — P(O)(OPh)
`2>
`[0024] G is I I, alkyl, substituted alkyl, carboxyalkyl, hct(cid:173)
`eroalkyl, aryl, heteromyl, heterocycle, or arylalkyl;
`[11025] Y isa bond, 0
`, ~ H2
`, OCH2 , NR,
`— NR — CI12, or CI I2 — NR —;
`
`Petitioner GE Healthcare – Ex. 1004, p. 7
`
`

`

`US 2010/0098633 A1
`
`Apr. 22, 2010
`
`[0026] R is H, Me or C'H~C'.O~H;
`[0027] q is an integer ranging from 0 to 24; and
`[0028] R,. Rz. R,. R4 and R, are independently hydro(cid:173)
`gen, halogen, cyano, carboxyl, alkyl, alkylamino,
`atkoxy, or substituttxI or unsubstitutcd amino; with the
`proviso that at least one of R,, R,. R» R and R, is a
`halogen (including radiohalogen).
`[0029] In another aspect, a method of imaging tissue of a
`mammal which expresses seprase is provided which includes
`administering to the mammal an effective amount of a radio(cid:173)
`labclcd compound or complex that selectively inhibits
`seprase or binds to the enzymatic domain of seprase. In one
`embodiment, the radiolabeled complex includes a metal
`radionuclidc-containing chelate derivative of a s eprasc
`inhibitor. In another embodiment, the radiolabeled com(cid:173)
`pound includes a radioactive halogenated derivative of a
`scprase inhibitor. In another embodiment, an effective
`ainount of a complex or compound of I ormula I and II, its
`enantiomer, stereoisomer, racemate or pharmaceutically
`acceptable salt is administered to the mammal.
`[0030] In a further aspect, a method of treating a mammal
`suffering a disease which is characterized by overexpression
`of sepras, is provided. The method includes admimstering to
`the manunal a therapeutically effective amount of a radiola(cid:173)
`beled seprase inhibitor, such as a radionuclide-containing
`chelate derivative. or a radioactive halogen derivative. In
`some entbodintcnts, thc method includes administering to a
`mammal a complex or compound of Formula I or Il, its
`enantiomer, stereoisomer, racemate or pharmaceutically
`acceptable salt.
`[0031] ln still another aspect, a kit is provided including the
`subject complexes or compounds and a pharmaceutically
`acceptable carrier, and optionally instructions for their use.
`Uses for such kits include therapeutic management and medi(cid:173)
`cal imaging applications.
`
`BRIEF DESCRIPTION Ol' THE DRAWINGS
`
`[0032] Flti. I is a graphical representation of the data pre(cid:173)
`sented in Table I: Percent of C'.ontrol versus C'.oncentration of
`Inhibitor, for several compounds presented in the exampk».
`[0033] Fl(1. 2 presents radiochromatogram of the HPL(."
`purified 1-131 labelled Compound 1024 in comparison to
`non-mdiolabelled Compound 1024 as an identity standaid,
`according to one embodiment.
`[0034] FIG. 3 shows stability of radiolabelcxI Compound
`1024 after 24 hours (bottom radiochromatogram) in compari(cid:173)
`son to after one hour (top), according to one embodiment.
`[0035] FIG. 4 shows stability of C'.ompound 1109, at 5
`hours, according to onc embodiment.
`[0036] F l(h 5 is a graphical representation of seprase cell
`based enzyme assay with Compound 1024. Cells were incu(cid:173)
`bated for 15 min. +/-25 IiM, according to one embodiment.
`[0037] FICr. 6 is a graph of the tissue biodistribution of
`Compound 1014/1109 in normal mice, expressed as % ID/gx
`(SEM), according to one embodiment.
`[0038] FICr. 7 is a graph of the tissue biodistribution of
`Compound 1018/I I IO in normal mice, expressed as% ID/gx
`(SEM), according to one embodiment.
`[0039] FIG. II is a graph of the tissue biodistribution of
`1-131 labeled Compound 1024 in FaDu XenogrnII mice,
`expressed as % ID/g*(SEM), according to one embodiment.
`[0040] FIG. 9 is a graph of the tissue biodistribution of
`1-123 labeled Compound 1024 in 1122(+) Xenogrvft mice
`
`aAer I hour, with or without blocking, expressed as % ID/g
`(SEM), according to one embodiment.
`
`DE,'IAILED DESCRIPI'ION OF PREFERRED
`
`[0041] Various embodiments are described hcreinalter. It
`should be noted that the specific embodiments are not
`intended as an exhaustive description or as a limitation to the
`broader aspects discussed herein. One aspect described in
`conjunction with a particular embodiment is not necessarily
`limited to that embodiment and can be practiced with any
`other embodiment(s).
`[0042] As used herein, the following definitions of terms
`shall apply unless otherwise indicated.
`[0043] As used herein, "about" will be understood by per(cid:173)
`sons of ordinary skill in the art and will vary to some extent
`depending upon the context in which it is used. If there are
`uses of the term which are not clear to persons of ordinary
`skill in the art, given the context in which it is used, "about"
`will mean up to plus or minus 10% of the particular term.
`[0044] The use of the terms "a" and "an" and "the" and
`similar referents in the context of describing the elements
`(espwially in the context of the following claims) are to bc
`construed to cover both the singular and the plural, unless
`otherwise indicated herein or clearly contradicted by context.
`Recitation of ranges of values herein are merely intended to
`serve as a shorthand method of referring individually to each
`separate value falling within the range, unless otherwise indi(cid:173)
`cated herein, and each separate value is incorporated into thc
`specification as if it were individually recited herein. All
`methods described herein can be performed in any suitable
`order unless otherwisc indicated herein or otherwisc clearly
`contradicted by context. The use of any and all examples, or
`exemplary language (e.g., "such as") provided herein, is
`intended merely to better illuminate the embodiments and
`does not pose a limitation on the scope of the claims unless
`otherwise stated. No language in the specification should be
`construed as indicating any non-claimed element as essential.
`[0045] The embodiments, illustratively described herein
`may suitably be practiced in the absence of any element or
`elements, limitation or limitations, not specifically disclosed
`herein. 'Thus, for example, the terms "comprising," "includ(cid:173)
`ing," "containing," etc. shall be read expansively and without
`limitation. Additionally, the terms and expressions employed
`herein have been used as terms of description and not of
`limitation, and there is no intention in the use of such terms
`and expressions of excluding any equivalents of the features
`shown and described or portions thereof, but it is recognized
`that various modiTications are possible within the scope of the
`claimed technology. Additionally, the phrase '"consisting
`essentially of' will bc understood to include those elements
`specifically recited and those additional elements that do not
`materially affect the basic and novel characteristics of the
`claimed technology. Thc phrase "consisting of' excludes any
`element not specified.
`[0046] "(:omplex" refers to a compound formed by the
`union of one or more electron-rich and electron-poor mol(cid:173)
`ecsiles or atoms capable of independent existence with one or
`more electronically poor molecules or atoms, each of which is
`also capable of independent existence.
`[0047] "L i gand" refers to a slxx:ies that interacts in some
`fashion with another species. In one example, a ligand may be
`a lewis base that is capable of forming a coordinate bond
`with a Lewis Acid. In other examples, a ligand is aspecie,
`
`Petitioner GE Healthcare – Ex. 1004, p. 8
`
`

`

`US 2010/0098633 A1
`
`Apr. 22, 2010
`
`often organic, that forms a coordinate bond with a metal ion.
`Ligands, vvhen coordinated to a metal ion, may have a variety
`of binding modes know to those of skill in the art, which
`include. for example, terminal (i.e., bound to a single metal
`ion) and bridging (i.c., one atom of the Lewis base bound to
`more than one metal ion).
`[0048] "Chclate" or "chelating agent" refers to a molecule,
`often an organic one, and often a Lewis base, having two or
`morc unshared clcctfon pairs dvdtldblc for tlonatlon to d Inctdl
`ion. The metal ion is usually coordinated by two or more
`electron pairs to the chelating agent. The terms, "bidentatc
`chelating agent", "tridentate chelating agent", and "tetradcn(cid:173)
`tate chelating agent" refer to chelating agents having, respec(cid:173)
`tively, two, three, and four electron pairs readily available for
`simultaneous donation to a metal ion coorditrdted by the
`chelating agent. Usually, the electron pairs of a chelating
`agent forms coordinate bonds with a single metal ion; how(cid:173)
`ever, in certain examples, a chelating agent may form coor(cid:173)
`dinate bonds with more than one metal ion, with a variety of
`binding modes being possible.
`[0049] "Radionuclidc" refers to molecule that is capable of
`generating a detectable image that can be detected either by
`the naked eye or using an appropriate instrument, e.g.
`positron emission tomogmphy PET) and single photon emis(cid:173)
`sion computed tomography (SPECT). Radionuclides useful
`within the present disclosure include penetrating photon
`mnit ters including gannna emit ters and X-my emit ters. Thc~
`rays accompany nuclear transformation such as electron cap(cid:173)
`ture ) beta cm1ss1on Bnd Isomcrtc trans1tlon. Radlonuchdcs
`useful include those with photons between 80 and 400 kcV
`and positron producers, 511 kH annihilation photons and
`acceptable radiation doses due to absorbed photons, particles
`and half life. Radionuclides include radioactive isotopes of an
`element.Examplcsofrddionuclidesinclude' 'I, ' 'I,
`TC,
`1SE 62("
`166H
`2 1 1At 898
`9Ely 212 q
`1311 186R
`111 1
`9+
`100pd 212pb 109pd 67g 6sg
`163S
`67C
`64C
`'"'Rh,
`'Ru." Lu, ' "Lu, ''C,and "Br."Radiohalogen,"a
`used herein, refers to those radionuclides that are also halo(cid:173)
`gens (i.e. F, Rr, I, or At).
`[0050] "Coordination" refers to an interaction in which one
`multi-electron pair donor coordinatively bonds (is "coordi(cid:173)
`nated") to one metal ion.
`[0051] "Tether" refers to a c hemical linking moiety
`between a metal ion center and another chemical moiety.
`[0052] " Lcm is base" and "Lewis basic" are att-rccogniztxf
`and generally refer to a chemical moiety capable of donating
`a pair of electrons under certain reaction conditions. It may be
`possible to characterize a Lewis base as donating a single
`electron in certain complexes, depending on the identity of
`the I,ewis base and the metal ion, but for most purpose,
`however, a Lewis base is best understood as a hvo electron
`donor. Examples of Lewis basic moieties include unchatged
`compounds such as alcohols, thiols, and amines, and charged
`moieties such as alkoxidcs, thiolates, carbanions, and a vari(cid:173)
`ety of other orgtuuc anions. In certain examples, a Lewis base
`may consist of a single atom, such as oxide (02 ). In certain,
`less common circumstances, a I~is base or ligand may be
`positively cltargcd. A Lewis base, when coordinated to a
`metal ion, is often referred to as a ligand.
`[0053] In general, "substituted" refers to a group, as defined
`below (c.g., an alkyl or aryl group) in which one or more
`bonds to a hydrogen atom contained therein are replaced by a
`bond to non-hydrogen or non-carbon atoms. Substituted
`gruups also include groups in which onc or morc bonds to a
`
`'I
`
`'I
`
`'I
`
`carbon(s) or hydrogen(s) atom are replaced by one or more
`bonds, including double or triple bonds, to a hcteroatom.
`Thus, a substituted group will be substituted with one or more
`substituents, unless otherwise specified. In some embodi(cid:173)
`ments, a substituted group is substituted with I, 2, 3, 4, 5, or
`6 substituents. Examples of substituent groups include: halo(cid:173)
`gens (i.e., I', Cl, Hr, and I); hydroxyls; alkoxy, alkenoxy,
`alkynoxy, aryloxy, aralkyloxy, heterocyclyloxy, and hctcro(cid:173)
`cyclylalkoxy groups; carbonyls(oxo); carboxyls; esters; ure(cid:173)
`thanes;
`o x i mes; hyd r oxylamines; al k o xyamines;
`aralkoxyamines; thiols; sulhdes; suffoxidm; sulfones; sulfo(cid:173)
`nyls; s ulfonamides; amincw", N-oxides; h ydmzincw",
`hydrazides; hydrazones; azides; amides; ureas; amidines;
`guanidines; enamines; imides; isocyanates; isothiocyanates;
`cyanates; thiocyanates; imincw", nitro groups; nitriles (i.e.,
`CN); and the like.
`[0054] Alkyl groups include straight chain and bmnched
`alkyl groups having from I to 20 carbon atoms or, in some
`embodiments, from I to 12, 1 to 8, I to 6, or I to 4 carbon
`atoms. Alkyl groups further include cycloalkyl groups.
`Examples of straight chain alkyl groups include those with
`from I to 8 carbon atoms sucll Bs Incthyl, ethyl, Q-propyl,
`n-butyl, n-pentyl, n-hexyl, n-hep+I, and nwctyl groups.
`Examples of branchtxf alkyl groups include, but are not lim(cid:173)
`ited to, isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl,
`isopentyl, and 2,2-dimethylpropyl groups. Representative
`substituttxf alkyl groups may be substituted one or more times
`with substituents such as those listed above. Where the term
`haloalkyl is used, the alkyl group is substituted with one or
`more halogen atoms.
`[0055] Cycloalkyl groups are cycltc alkyl groups such as,
`but not limited to, cyclopropyl, cyclobutyl, cyclopcntyl,
`cyclohexyl, cycloheptyl, and cyclooctyl groups. In some
`embodiments, the cycloalkyl group has 3 to 8 ring members,
`whereas in other embodiments the number of ring carbon
`atoms range from 3 to 5, 3 to 6, or 3 to 7. Cycloalkyl groups
`further include mono-, bicyclic and polycyclic ring systems,
`such as, for example bridged cycloalkyl gmups as described
`below, and fustxf rings, such as, but not limited to, decalinyl,
`and the like. In some embodiments, polycyclic cycloalkyl
`groups have three rings. Substituted cycloalkyl groups may
`be substituted one or more times with, non-hydrogen and
`non-carbon groups as dcf~
`a b o ve. However, substituted
`cycloalkyl groups also include rings that are substituted with
`stmight or branched chain alkyl groups as defmed above.
`Representative substituted cycloalkyl groups may be mono(cid:173)
`substituted or substituted more than once, such as, but not
`limited to, 2,2-, 2,3-, 2,4-2,5- or 2,64isubstituted cyclohexyl
`groups, which may be substituttxf with substituents such as
`those listed above.
`[0056] Alkenyl groups include straight and branchtxf chain
`and cycloalkyl groups as defined above, except that at least
`one double bond exists between two carbon atoms. Thus,
`alkenyl groups have from 2 to about 20 carbon atoms, and
`typically from 2 to 12 carbons or, in some embodiments, from
`2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments,
`alkenyl groups include cycloalkenyl groups having from 4 io
`20aubon atoms, 5 to 20 carbon atoms, 5 to 10 carbon atoms,
`or even 5, 6, 7, or 8 carbon atoms. I',xamples include, but are
`n ot limited to vinyl, allyl, CH~ H ( C H3), CH — C(CH3)2,
`~( C I Is) CI 1 2, — C(CI 12) CI I(CI IS), — C(CI 12CI 12)
`~".H„cycfohexenyl, cyclopentenyl, cyclohexadienyl, buta(cid:173)
`dienyl, pentadienyl, and hexadienyl, among others. Repre(cid:173)
`sentative substitutcxf alkenyl groups may be mono-substituted
`
`Petitioner GE Healthcare – Ex. 1004, p. 9
`
`

`

`US 2010/0098633 A1
`
`Apr. 22, 2010
`
`or substituted more than once, such as, but not limited to,
`mono-, di- or tri-substituted with substituents such as those
`listed above.
`[0057] Al kynyl groups include straight and branched chain
`alkyl groups, except that at least onc triple bond exists
`between two carbon atoms. Thus, alkynyl groups have from 2
`to about 20 carbon atoms, and typically from 2 to 12 carbons
`or, in some embodiments, from 2 to g, 2 to 6, or2 to 4 carbon
`atoms. Examples include, but are not limited to ~
`C H,
`— (' =— C(CH,), — ("= — C(CH,CH,),
`— (:H~('=— CH,
`C II2C~ ( C H3), and CH2C — C(CH2CHs), among oth(cid:173)
`ers. Representative substituted alkynyl groups may be mono(cid:173)
`substituted or substituted more than once, such as, but not
`limited to, mono-, di- or tri-substituted with substituents such
`as those Iistcxl above.
`[0050] A f v l . of Bfelle, gloups Bfe cycltc Bfolnattc hydttocaf(cid:173)
`bons that do not contain heteroatoms. Aryl groups include
`monocyclic, bicyclic and polycyclic ring systems. Thus, aryl
`groups include, but are not limited to, phenyl, azulenyl, hep(cid:173)
`talenyl, biphenylenyl, indacenyl, Iluorenyl, phenanthfenyl,
`triphcnylcnyl, pyrcnyl, naphthaccnyl, chrysenyl, biphcnyl,
`anthracenyl. indenyl, indanyl. pentalenyl, and naphthyl
`groups. In some embodiments, aryl groups contain 6-14 car(cid:173)
`bons, and in others from 6 to 12 or even 6-10 carbon atoms in
`the ring portions of the groups. Although the phrase "aryl
`groups" includes groups containing fused rings, such as fused
`aromatic-aliphatic ring systems (e.g., indanyl, tetrahy(cid:173)
`dtunaphthyI, and the like), it does not include aryl groups that
`have other groups, such as alkyl or halo groups, bonded to one
`of thc ring members. Rather, groups such as tolyl are referred
`to as substituted aryl groups. Representative substituted aryl
`groups may be mono-substituted or substituted more than
`once. For example, monosubstituted aryl groups include, but
`are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or
`naphthyl groups. which may be substituted with substituents
`such as those listed above.
`[0059] "I leterualkyl" refers to alkyl groups containing one
`or more heteroatoms (e.g., N, 0, S, or the like) as part of the
`hydrocarbyl groups, and having in the range of I up to about
`10 carbon atoms. Exemplary hcteroalkyl groups include
`hydroxyalkyl, aminoalkyl, mercaptoalkyl, e.g., hydroxym(cid:173)
`ethyl, aminobutyl, 4-guanidinylbutyl, 3-indolylmethyl, mer(cid:173)
`captomcthyl, and the like.
`[0060] "Carboxyalkyl" refers to alkyl groups containing
`one or more carboxylic acids, e.g. carboxymethyl, carboxy(cid:173)
`cthyl and the like.
`[0061] "Alkoxy" refers to the group — 0-alkyl wherein
`alkyl is defined herein. Alkoxy includes, by way of example,
`methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy,
`sec-butoxy, and n-pentoxy.
`[0062] "Amino acid" refers to all compounds, whether
`natuml, unnatural or synthetic, which include both an amino
`Iunctlonallty Bnd Bn Beld Iuncttonallty, mciudlng Blntno Bctd
`analogs and derivatives.
`[0063] "Carboxy" or "carboxyl" refers to ~OOI I or salts
`thereof.
`[0064] "Anuno" refers to the group NI I 2. "Cyano" refers
`to the group — CN. "Carbonyl" refers to the divalent group
`~: (O) — which is equivalent tn — (:(=()) —. "Nitro" refers
`t o the group N O 2. "Oxo" refers to the atom (~ ) . "Sulfo(cid:173)
`nyl" refers to the divalent group — S(O)2 —. "Thiol" refers to
`the group — SH. "'Iluocarbonyl" refers to the divalent group
`C(S) — which is equivalent to C( — S) . "Hydroxy" or
`"hydroxyl"' refers to th» group — OI I.
`
`[0065] "H e teroatom" refers to an atom of any element other
`than carbon or hydrogen. Exemplary hcteroatoms are boron,
`nitrogen, oxygen, phosphorus, sulfur and selenium.
`[0066] "I Ialogen" or "halo group" refers to — I', — Cl, — Dr
`o r — I, including its radioactive isotopes such as '"I. '" I ,
`"'I, "F or "Br.
`[0067] "Haloalkyl" refers to alkyl groups substituted with I
`to 5, I to 3, or I to 2 halo groups, wherein alkyl and halo arc
`as defined herein.
`[0068] "Acyl" refers to the groups H C(O ), a l k yl-C
`(0) —, substituted alkyl-C(O) —, alkenyl-C(O) —, substi(cid:173)
`tuted alkenyl-C(O) —, alkynyl&(O) —, substituted alkynyl(cid:173)
`C(O), cycloalkyl-C(O) , substituted cycloalkyl-C(O)
`cycloalkenyl-C(O) —, substituted cycloalkenyl-C(O) —,
`Btyl-C (O) —, substituted aryl-C(O) —, heteroaryl-C(O) —,
`substituted heteroatyl-C (O) —, heterocyclic-C(O) —, and
`substituted heterocyclic-('(0) —, wherein alkyl, substituted
`alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alky(cid:173)
`nyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substi(cid:173)
`tuted cycloalkenyl, aryl, substituted aryl, hetefoaryl, substi(cid:173)
`tuttxI hetcroaryl, heterocyclic, and substituted heterocyclic
`are as delined herein. Acyl includes the "acetyl" group CH,C
`(0) —.
`[0069] "Acyloxy" refers to the groups alkyl-C(O)O —, sub(cid:173)
`stituted alkyl-C(O)O , alkenyl&(O)O , s ubstituted alk(cid:173)
`cnyl-C(O)O —, alkynyl-C(O~ ,
`s ubstitutnI alkynyl-C(O)
`() —, aryl<:(())() —, substituted aryl-(".(0)() —, cycloaIkyl-(:
`(O)O ,
`s ubstituted cycloalkyl-C(O)O , c y cloalkenyl-C
`(O)O —, sUbstttutetl cycloalkenyl-C(O)O —, hetefoafyW
`(O)O —, substituted heteroaryl-C(O)O —, heterocyclic-C(O)
`0,
`a n d substituted heterocyclic-C(O)O w h erein alkyl,
`substituted alkyl, alkenyl, substituted alkenyl, alkynyl, sub(cid:173)
`stituted Blkynyl, cycloalkyl, substlnnetl cycloalkyl, cyGloalk(cid:173)
`enyl, substituted cycloalkenyl, aryl, substituted aryl, hct(cid:173)
`efoaryl, substituted heteroaryl, heterocyclic, and substituted
`heterocyclic are as defined herein.
`[ 0070] "Aminocarbonyl" refers to the group C( O )
`NR' R" independently selected from the group consisting of
`hydrogen, alkyl, substituted alkyl, alkenyl, substituted alk(cid:173)
`enyl, alkynyl, substituted alkynyl, aryl, substituted aryl,
`cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted
`cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic,
`a nd substituted heterocyclic and where R' an d R " a r c
`optionally joinml together with the nitrogen bound thereto to
`form a heterocyclic or substituted heterocyclic group, and
`wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl,
`alkynyl, substituted alkynyl, c y cloalkyl, s ubstituted
`cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, sub(cid:173)
`stituted aryl, hetemaryl, substituted heteroaryl, heterocyclic,
`and substituted heterocyclic arc as defined herein.
`[0071] "A minothiocarbonyl" refers to the group — C(S)
`NR'"R" where R' and R" arc independently selected from
`the group consisting of hydrogen, alkyl, substituted alkyl,
`alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
`aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,
`cycloalkenyl, substituted cycloalkenyl, heteroaryl, substi(cid:173)
`tuted hetefoaryl, heterocyclic, and substituted heterocyclic
`and where R' and R" are optionally joined together with the
`nitrogen bound thereto to form a heterocyclic or substituted
`heterocyclic group, and wherein alkyl, substituted alkyl, alk(cid:173)
`enyl, substituted alkenyl, alkynyl, substituted alkynyl,
`cycloalkyl, substituttxI cycloalkyl, cycloalkenyl, substituted
`
`Petitioner GE Healthcare – Ex. 1004, p. 10
`
`

`

`US 2010/0098633 A1
`
`Apr. 22, 2010
`
`cycloalkenyl, aryl. substituted aryl, hetemaryl, substituted
`hetcroaryl, heterocyclic, aad substituted heterocyclic are as
`defined herein.
`[ 0072] "Aminosulfonyl" refers to the group S O2NR'
`R' ' where R'" and R' ' are independently selccttxf from the
`group consisting of hydmgen, alkyl, substituted alkyl, alk(cid:173)
`enyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,
`substituted aryl, cvcloalkyl, substituted cycloalkyl, cycloalk(cid:173)
`enyl, substituted cycloalkenyl, heteroaryl, substituted het(cid:173)
`elvaryl, hetelvcydic, and substituted heterocyclic and where
`R'" and R' ' arc optionally joined together with the nitrogen
`bound thereto to form a heterocyclic or substituted heterocy(cid:173)
`clic group, and wherein alkyl, substituted alkyl, alkenyl, sub(cid:173)
`stituted alkenyl,alkyl, substituted alkynyl, cycloalkyl, sub(cid:173)
`stituted cyclodlkyl, cycloalkenyl, substituted cycloalkeayl,
`aryl, substituted alyl, heteroaryl, substituted hetemaryl, het(cid:173)
`elvcyclic, and substituted hctcrocyclic are as dehncd herein.
`[0073] "Arylafkyl" refers to alkyl groups containing one or
`more aryl groups, e.g. arylmethyl, arylethyl and the like.
`[0074] "I letervaryl" refers to an aromatic group of fivm I
`to 10 carbon atoms and 1 to 4 hetematoms selected from the
`glvup consisting of oxygen, nitmgen and sulfur within the
`ring. Such hetcroaryl groups can llavc a single ring (c.g.,
`pyridinyl, thiadiazolyl or furyl) or multiple condensed rings
`(e.g., indoli7dnyl or benzothienyl) wherein the condensed
`rings may or maV aot bc alvmatic and/or contaia a heteroatom
`provided that the point of attachment is through an atom of the
`alvmatic heteroaryl group. In one embodiment, the mtrogen
`and/or thc sulfur ring atom(s) of thc hctcroaryl group are
`optionally oxidized to provide for the N-oxide (N~O), sulfi(cid:173)
`nyl, or sulfonyl moieties. Preferred hetemaryls include
`pyridinyl, pyrrolyl, indolyl, thiophcnyl, thiadiazolyl and fura(cid:173)
`ayl.
`"hetemcy(cid:173)
`"heterocyclic" or
`[0075] "Hetemcycle" or
`cloalkyl"' or "hctemcyclyl" rcfcrs include aromatic (also
`referred to as heteroaryl) and non-aromatic ring compounds
`containing 3 or more ring members, of which one or more is
`a hctcrvatom such as, but