1111111111111111 IIIIII IIIII 1111111111 11111 11111 111111111111111 lllll 111111111111111 11111111
`US 20100098633Al
`
`c19) United States
`c12) Patent Application Publication
`ZIMMERMAN et al.
`
`c10) Pub. No.: US 2010/0098633 Al
`Apr. 22, 2010
`(43) Pub. Date:
`
`A61K 311555
`(2006.01)
`A61K 31140
`(2006.01)
`C07F 13/00
`(2006.01)
`A61P35/00
`(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)
`
`ABSTRACT
`
`Novel radiopharmaceuticals that are useful in diagnostic
`imaging and therapeutic treatment of disease characterized
`by overexpression of seprase include complexes that contains
`a praline moiety and a radionuclide adapted for radioimaging
`and/or radiotherapy:
`
`II
`
`(54) SELECTIVE SEPRASE INHIBITORS
`
`(75)
`
`Inventors:
`
`Craig ZIMMERMAN, Topsfield,
`MA (US); John W. Babich,
`Cambridge, MA (US); John Joyal,
`Melrose, MA (US); John Marquis,
`Nashua, NH (US); Jian-cheng
`Wang, Revere, MA (US)
`
`Correspondence Address:
`FOLEY AND LARDNER LLP
`SUITE 500
`3000 K STREET NW
`WASHINGTON, DC 20007 (US)
`
`(73) Assignee:
`
`Molecular Insight
`Pharmaceuticals, Inc.
`
`(21) Appl. No.:
`
`12/566,324
`
`(22) Filed:
`
`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.
`A61K 51104
`A61K 31/69
`
`(2006.01)
`(2006.01)
`
`Percent
`of Control
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`0.001
`
`--- No Inhibitor
`___._ Compound 1023
`---r- Compound 1024
`~ Compound 1025
`-e-- Compound 1051
`~ Compound 1010
`
`0.01
`
`0.1
`
`10
`
`100
`
`1000
`
`Inhibitor Concentration (uM)
`
`

`

`Patent Application Publication Apr. 22, 2010 Sheet 1 of 5
`
`US 2010/0098633 Al
`
`Percent
`of Control
`
`100
`
`80
`
`60
`
`40
`
`20
`
`Fig. 1
`
`-a- No Inhibitor
`
`---A- Compound 1023
`-'v- Compound 1024
`_._ Compound 1025
`-e- Compound 1051
`-a-compound 1010
`
`04---A-..--.......aii--,--...... ______ __,ji;..._-...,.;i....,
`1000
`100
`10
`0.1
`0.01
`0.001
`
`Inhibitor Concentration (uM)
`
`Fig. 2
`
`1-131 labeled Compound 1024
`
`Nal
`
`I. ll'UI"' I' I
`
`a • • I
`
`r
`
`l l l i i
`
`I q
`
`

`

`Patent Application Publication Apr. 22, 2010 Sheet 2 of 5
`
`US 2010/0098633 Al
`
`Fig. 3
`
`200 1-131 Labelled Compound 1024
`150
`RCP97%
`100
`TOM + 1 hour 37 C
`50
`0
`
`888 1-131 Labelled Compound 1024
`RCP87%
`. . . .
`TOM + 24 hours 37 C
`. .
`
`~
`
`5
`
`10
`
`\ k X
`
`15
`
`20
`
`25
`
`30
`
`Fig. 4
`oc
`i~~i~
`o
`~N~~yQ
`
`O
`
`/B--oH
`HO
`
`Scale 25 mCi; 104 M; 71% RCY
`>98% RCP (after Rp-HPLC)
`97% RCP at5 h
`
`at 5hrs
`
`.
`. .
`
`. . .
`
`v
`
`I
`
`

`

`Patent Application Publication Apr. 22, 2010 Sheet 3 of 5
`
`US 2010/0098633 Al
`
`RFU @ 15 min
`
`Fig. 5
`
`Seprase Cell Based Enzyme Assay
`4000000-----------------------,
`c:::J w/o Compound 1024
`3500000
`~ with Compound 1024
`3000000
`2500000
`2000000
`1500000
`1000000
`500000
`0-1--....1....--==--......-....1....--"""=--......-....1....-■==-----1
`H24
`Hek293
`H22
`Cell Line
`
`Fig. 6
`
`%1D/g
`
`c:::J 1 hr
`~4h
`
`70
`60
`50
`40
`30
`20
`10
`O +--.----.-.....,. .....
`<o\ooo y,.e'<>-~, -v~~'2, 0--30~("\\ee~ o~e~'2, ~'3-c'('. e'2,~~e.e'2,~~~ t...-v'2,°'e <c'<-iP
`\f\" ~ \"I'
`-;;;,~ ~ '=:,\O
`\~~
`"'
`'=>.
`\..~ s~
`
`

`

`Patent Application Publication Apr. 22, 2010 Sheet 4 of 5
`
`US 2010/0098633 Al
`
`Fig. 7
`
`%1D/g
`
`70
`c::=J1 hr
`60
`50 ~4h
`40
`30
`20
`10
`o--------
`~\OoO Y'e'a-~, ,§ .. Q;'i;, 0--40~,n\00~ rf'e--4.'i;, ~,a.C~ e'i:1~~0 e,$~~~ t.,\)e:,c\0 ~'(~~
`"" 'f.'1
`,~~
`,~~ ~ ~'
`v
`C:,\0
`'3 •
`\.Q; $~
`
`Fig. 8
`
`c::=J1 hr
`~4h
`~24h
`
`%1D/g
`
`

`

`Patent Application Publication Apr. 22, 2010 Sheet 5 of 5
`
`US 2010/0098633 Al
`
`Fig. 9
`
`C:J1hr
`~1 h block
`
`12
`10
`8
`
`%1D/g
`
`d O
`
`I
`
`O
`
`6
`4
`2
`0 +,LJ""-.-Lt:a...,....L--<""--,--J'---""-,...J--1' ........... --"'"--,..,.J-.k: ......... -=-,....L..l<:l....,...C""'--,-...i....---r-1-""-r--.....-U~.L.=.. .......... ::a.....--
`;A'o 0:- . ~e . ~e ~e,'?> 00 ~e ~~ 0,c ~e ~o<..
`o°'
`rb-~ ~<o . Ne<.. 0~
`<8'-o x-,0 v..:,(;1- v ~i~o.~0 ~o<S'~~,0<o'~0'?~ "\ e,e:i ~..:,ta ~o ~\«...~~<:. &-~o ~ -s
`<;,; ~ {.' ~
`0~ • ~
`'2>
`~'+·
`( ) v ~
`~<..'l>-o'
`~YN'<
`/ 8-oH
`HO
`
`'
`
`

`

`US 2010/0098633 Al
`
`Apr. 22, 2010
`
`1
`
`SELECTIVE SEPRASE INHIBITORS
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`[0001] This application claims the benefit of U.S. Provi(cid:173)
`sional Patent Application No. 61/100,178, filed Sep. 25,
`2008, the disclosure of which is incorporated herein by ref(cid:173)
`erence in it's entirety.
`
`FIELD
`
`[0002] This invention relates in general to small molecule
`inhibitors of seprase that can be used as therapeutic agents
`through inhibition of seprase's enzymatic activity, or as
`radiopharmaceuticals that bind to seprase and therefore
`enable imaging of tissues that express seprase or for deliver(cid:173)
`ing radiotherapy to tumor tissues that express seprase.
`
`BACKGROUND
`
`[0003] Seprase, also known as fibroblast activation protein
`alpha (FAP-a), is a transmembrane serine peptidase that
`belongs to the prolyl peptidase family. The prolyl peptidase
`family includes serine proteases that cleave peptide substrates
`after a praline residue. Seprase is expressed in epithelial
`cancers and has been implicated in extracellular matrix
`remodeling, tumor growth, and metastasis.
`[0004] The prolyl peptidase family includes enzymes such
`as, but not limited to, dipeptidyl peptidase-IV (DPP-IV),
`DPP-VII, DPP-VIII, DPP-IX, prolyl oligopeptidase (POP),
`acylpeptide hydrolase and prolyl carboxypeptidase. These
`enzymes differ in structure at the N terminus, but are related
`in that each has a C-terminal a~-hydrolase domain that con(cid:173)
`tains the catalytic Ser, Asp, and H is residues. Similar to
`seprase, 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
`endothelial cells.
`[0005] The expression of distinct proteins on the surface of
`tumor cells offers the opportunity to diagnose and character(cid:173)
`ize disease by probing the phenotypic identity and biochemi(cid:173)
`cal composition and activity 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 related to the diagno(cid:173)
`sis and extent of disease, prognosis and therapeutic manage(cid:173)
`ment options. For example, therapy may be realized through
`the use of radiopharmaceuticals that are not only capable of
`imaging disease, but also are capable of delivering a thera(cid:173)
`peutic radionuclide to the diseased tissue. The expression of
`seprase on tumors makes it an attractive target to exploit for
`noninvasive imaging as well as targeted radiotherapy.
`[0006] Furthermore, since seprase has both dipeptidyl pep(cid:173)
`tidase and endopeptidase activity, and DPP-IV exhibits only
`dipeptidyl peptidase activity, selective seprase inhibitors
`would be useful to reduce unwanted side effects.
`
`SUMMARY
`[0007] Small molecule inhibitors of seprase are provided
`for use as therapeutic medicines or as radiopharmaceuticals
`useful in diagnostic imaging and in the therapeutic treatment
`of diseases characterized by overexpression of seprase. The
`radiopharmaceuticals include complexes or compounds that
`
`contain a functionalized praline moiety which is capable of
`selectively inhibiting seprase, and a radionuclide adapted for
`radioimaging and/or radiotherapy.
`[0008]
`In one aspect, a complex of Formula I, its enanti(cid:173)
`omer, stereoisomer, racemate or pharmaceutically acceptable
`salt is provided:
`
`[0009] where:
`[0010] U is-B(OH)2 , ----CN, -CO2H, or-P(O)(OPh)
`2,
`[0011] G is H, alkyl, substituted alkyl, carboxyalkyl, het(cid:173)
`eroalkyl, aryl, heteroaryl, heterocycle, or arylalkyl;
`[0012] V is a bond, 0, S, NH, (CH2-CH2-X)n, or a
`group of formula
`
`[0013] Xis 0, S, CH2 , or NR;
`[0014] R is H, Me or CH2CO2 H;
`[0015] Wis Hor NHR';
`[0016] R' is hydrogen, acetyl, t-butyloxycarbonyl (Boe),
`9H-fluoren-9-ylmethoxycarbonyl
`(Fmoc ),
`trifluoro(cid:173)
`acetyl, benzoyl, benzyloxycarbonyl (Cbz) or substituted
`benzoyl;
`[0017] n is an integer ranging from Oto 6;
`[0018] mis an integer ranging from Oto 6;
`[0019] Metal represents a metallic moiety including a
`radionuclide; and
`[0020] Chelate represents a chelating moiety that coor-
`dinates with said radionuclide.
`[0021]
`In another aspect, a compound of general Formula
`II, its enantiomer, stereoisomer, racemate or pharmaceuti(cid:173)
`cally acceptable salt is provided:
`
`II
`
`[0022] where:
`[0023] U is-B(OH)2 , ----CN, -CO2H, or-P(O)(OPh)
`2,
`[0024] G is H, alkyl, substituted alkyl, carboxyalkyl, het(cid:173)
`eroalkyl, aryl, heteroaryl, heterocycle, or arylalkyl;
`[0025] Y is a bond, -0-, -CH2- , ---OCH2 - , NR,
`-NR-CH2 , or CH2-NR-;
`
`

`

`US 2010/0098633 Al
`
`Apr. 22, 2010
`
`2
`
`[0026] R is H, Me or CH2CO2 H;
`[0027] q is an integer ranging from Oto 24; and
`[0028] Ri, R2 , R3 , R4 and Rs are independently hydro(cid:173)
`gen, halogen, cyano, carboxyl, alkyl, alkylamino,
`alkoxy, or substituted or unsubstituted amino; with the
`proviso that at least one of R 1 , R2 , R3 , R4 and Rs 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)
`labeled compound or complex that selectively inhibits
`seprase or binds to the enzymatic domain of seprase. In one
`embodiment, the radiolabeled complex includes a metal
`radionuclide-containing chelate derivative of a seprase
`inhibitor. In another embodiment, the radiolabeled com(cid:173)
`pound includes a radioactive halogenated derivative of a
`seprase inhibitor. In another embodiment, an effective
`amount of a complex or compound of Formula 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 seprase, is provided. The method includes administering to
`the mammal 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 embodiments, the method includes administering to a
`mammal a complex or compound of Formula I or II, its
`enantiomer, stereoisomer, racemate or pharmaceutically
`acceptable salt.
`[0031]
`In 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 OF THE DRAWINGS
`
`[0032] FIG. 1 is a graphical representation of the data pre(cid:173)
`sented in Table 1: Percent of Control versus Concentration of
`Inhibitor, for several compounds presented in the examples.
`[0033] FIG. 2 presents radiochromatogram of the HPLC
`purified 1-131 labelled Compound 1024 in comparison to
`non-radiolabelled Compound 1024 as an identity standard,
`according to one embodiment.
`[0034] FIG. 3 shows stability of radiolabeled 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 Compound 1109, at 5
`hours, according to one embodiment.
`[0036] FIG. 5 is a graphical representation of seprase cell
`based enzyme assay with Compound 1024. Cells were incu(cid:173)
`bated for 15 min. +/-25 µM, according to one embodiment.
`[0037] FIG. 6 is a graph of the tissue biodistribution of
`Compound 1014/1109 in normal mice, expressed as% ID/g±
`(SEM), according to one embodiment.
`[0038] FIG. 7 is a graph of the tissue biodistribution of
`Compound 1018/1110 in normal mice, expressed as% ID/g±
`(SEM), according to one embodiment.
`[0039] FIG. 8 is a graph of the tissue biodistribution of
`1-131 labeled Compound 1024 in FaDu Xenograft 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 H22( +) Xenograft mice
`
`after 1 hour, with or without blocking, expressed as % ID/g
`(SEM), according to one embodiment.
`
`DETAILED DESCRIPTION OF PREFERRED
`EMBODIMENTS
`
`[0041] Various embodiments are described hereinafter. 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
`( especially in the context of the following claims) are to be
`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 the
`specification as if it were individually recited herein. All
`methods described herein can be performed in any suitable
`order unless otherwise indicated herein or otherwise 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 modifications are possible within the scope of the
`claimed technology. Additionally, the phrase "consisting
`essentially of' will be 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. The phrase "consisting of' excludes any
`element not specified.
`[0046]
`"Complex" refers to a compound formed by the
`union of one or more electron-rich and electron-poor mol(cid:173)
`ecules 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]
`"Ligand" refers to a species 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 a species,
`
`

`

`US 2010/0098633 Al
`
`Apr. 22, 2010
`
`3
`
`often organic, that forms a coordinate bond with a metal ion.
`Ligands, when 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.e., one atom of the Lewis base bound to
`more than one metal ion).
`[0048]
`"Chelate" or "chelating agent" refers to a molecule,
`often an organic one, and often a Lewis base, having two or
`more unshared electron pairs available for donation to a metal
`ion. The metal ion is usually coordinated by two or more
`electron pairs to the chelating agent. The terms, "bidentate
`chelating agent", "tridentate chelating agent", and "tetraden(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 coordinated 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]
`"Radionuclide" 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 tomography (PET) and single photon emis(cid:173)
`sion computed tomography (SPECT). Radionuclides useful
`within the present disclosure include penetrating photon
`emitters including gamma emitters and X-ray emitters. These
`rays accompany nuclear transformation such as electron cap(cid:173)
`ture, beta emission and isomeric transition. Radionuclides
`useful include those with photons between 80 and 400 keV
`and positron producers, 511 keV annihilation photons and
`acceptable radiation doses due to absorbed photons, particles
`and halflife. Radionuclides include radioactive isotopes of an
`element. Examples of radionuclides include 1231, 1251, 99mTC,
`1sp 62Cu 111In 1311 1s6Re 9oy 212Bi 211At s9Sr 166Ho
`153Sm 67'cu 64Cu
`lOOPd 212pb 109Pd 67G; 68G~ 94Tc'
`105Rh,' 95Ru, '1 77Lu,' 170Lu, '11C, add 76Br. '"Radi~halo~en," a~
`used herein, refers to those radionuclides that are also halo(cid:173)
`gens (i.e. F, Br, 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 chemical linking moiety
`between a metal ion center and another chemical moiety.
`[0052]
`"Lewis base" and "Lewis basic" are art-recognized
`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 Lewis base and the metal ion, but for most purposes,
`however, a Lewis base is best understood as a two electron
`donor. Examples of Lewis basic moieties include uncharged
`compounds such as alcohols, thiols, and amines, and charged
`moieties such as alkoxides, thiolates, carbanions, and a vari(cid:173)
`ety of other organic anions. In certain examples, a Lewis base
`may consist of a single atom, such as oxide (02 -). In certain,
`less common circumstances, a Lewis base or ligand may be
`positively charged. 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 (e.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
`groups also include groups in which one or more bonds to a
`
`carbon(s) or hydrogen(s) atom are replaced by one or more
`bonds, including double or triple bonds, to a heteroatom.
`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 1, 2, 3, 4, 5, or
`6 substituents. Examples of substituent groups include: halo(cid:173)
`gens (i.e., F, Cl, Br, and I); hydroxyls; alkoxy, alkenoxy,
`alkynoxy, aryloxy, aralkyloxy, heterocyclyloxy, and hetero(cid:173)
`cyclylalkoxy groups; carbonyls(oxo); carboxyls; esters; ure(cid:173)
`thanes;
`oximes;
`hydroxylamines;
`alkoxyamines;
`aralkoxyamines; thiols; sulfides; sulfoxides; sulfones; sulfo(cid:173)
`nyls;
`sulfonamides;
`amines; N-oxides;
`hydrazines;
`hydrazides; hydrazones; azides; amides; ureas; amidines;
`guanidines; enamines; imides; isocyanates; isothiocyanates;
`cyanates; thiocyanates; imines; nitro groups; nitriles (i.e.,
`CN); and the like.
`[0054] Alkyl groups include straight chain and branched
`alkyl groups having from 1 to 20 carbon atoms or, in some
`embodiments, from 1 to 12, 1 to 8, 1 to 6, or 1 to 4 carbon
`atoms. Alkyl groups further include cycloalkyl groups.
`Examples of straight chain alkyl groups include those with
`from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl,
`n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups.
`Examples of branched 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
`substituted 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 cyclic alkyl groups such as,
`but not limited to, cyclopropyl, cyclobutyl, cyclopentyl,
`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 groups as described
`below, and fused 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 defined above. However, substituted
`cycloalkyl groups also include rings that are substituted with
`straight or branched chain alkyl groups as defined 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 2,6-disubstituted cyclohexyl
`groups, which may be substituted with substituents such as
`those listed above.
`[0056] Alkenyl groups include straight and branched 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 to
`20 carbon atoms, 5 to 20 carbon atoms, 5 to 10 carbon atoms,
`or even 5, 6, 7, or 8 carbon atoms. Examples include, but are
`not limited to vinyl, ally!, CH=CH(CH3), CH=C(CH3)2,
`----C(CH2CH3)
`----C(CH3)=CH2, -C(CH3)=CH(CH3),
`=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, buta(cid:173)
`dienyl, pentadienyl, and hexadienyl, among others. Repre(cid:173)
`sentative substituted alkenyl groups may be mono-substituted
`
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`or substituted more than once, such as, but not limited to,
`mono-, di- or tri-substituted with substituents such as those
`listed above.
`[0057] Alkynyl groups include straight and branched chain
`alkyl groups, except that at least one 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 8, 2 to 6, or 2 to 4 carbon
`atoms. Examples include, but are not limited to -C CH,
`-C==C(CH3 ),
`----C C(CH2 CH3 ),
`----CH2C CH,
`-CH2 C C(CH3 ), and----CH2 C C(CH2CH3 ), among oth-
`ers. Representative substituted alkynyl groups may be mono(cid:173)
`substituted or substituted more than once, such as, but not
`limited to, mono-, di- ortri-substituted with substituents such
`as those listed above.
`[0058] Ary!, or arene, groups are cyclic aromatic hydrocar(cid:173)
`bons that do not contain heteroatoms. Ary! 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, fluorenyl, phenanthrenyl,
`triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenyl,
`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)
`dronaphthyl, and the like), it does not include aryl groups that
`have other groups, such as alkyl or halo groups, bonded to one
`of the 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.
`"Heteroalkyl" refers to alkyl groups containing one
`[0059]
`or more heteroatoms ( e.g., N, 0, S, or the like) as part of the
`hydrocarbyl groups, and having in the range of 1 up to about
`10 carbon atoms. Exemplary heteroalkyl groups include
`hydroxyalkyl, aminoalkyl, mercaptoalkyl, e.g., hydroxym(cid:173)
`ethyl, aminobutyl, 4-guanidinylbutyl, 3-indolylmethyl, mer(cid:173)
`captomethyl, and the like.
`"Carboxyalkyl" refers to alkyl groups containing
`[0060]
`one or more carboxylic acids, e.g. carboxymethyl, carboxy(cid:173)
`ethyl and the like.
`"Alkoxy" refers to the group ---0-alkyl wherein
`[0061]
`alkyl is defined herein. Alkoxy includes, by way of example,
`methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy,
`sec-butoxy, and n-pentoxy.
`"Amino acid" refers to all compounds, whether
`[0062]
`natural, unnatural or synthetic, which include both an amino
`functionality and an acid functionality, including amino acid
`analogs and derivatives.
`"Carboxy" or "carboxyl" refers to -COOH or salts
`[0063]
`thereof.
`"Amino" refers to the group-NH2 . "Cyano" refers
`[0064]
`to the group -CN. "Carbonyl" refers to the divalent group
`-C(O)- which is equivalent to ----C(=O)-. "Nitro" refers
`to the group-NO2 . "Oxo" refers to the atom (=0). "Sulfo(cid:173)
`nyl" refers to the divalent group -S(O) 2- . "Thiol" refers to
`the group -SH. "Thiocarbonyl" refers to the divalent group
`-C(S)- which is equivalent to -C(=S)-. "Hydroxy" or
`"hydroxyl" refers to the group -OH.
`
`"Heteroatom" refers to an atom of any element other
`[0065]
`than carbon or hydrogen. Exemplary heteroatoms are boron,
`nitrogen, oxygen, phosphorus, sulfur and selenium.
`"Halogen" or "halo group" refers to -F, -Cl, -Br
`[0066]
`or -I, including its radioactive isotopes such as 1231, 1251,
`131 I, 1sp or 76Br.
`"Haloalkyl" refers to alkyl groups substituted with 1
`[0067]
`to 5, 1 to 3, or 1 to 2 halo groups, wherein alkyl and halo are
`as defined herein.
`"Acy!" refers to the groups H-C(O)-, alkyl-C
`[0068]
`(0)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substi(cid:173)
`tuted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl(cid:173)
`C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-,
`cycloalkenyl-C( 0 )-,
`substituted
`cycloalkeny 1-C( 0 )-,
`aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-,
`substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and
`substituted heterocyclic-C(O)-, 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, heteroaryl, substi(cid:173)
`tuted heteroaryl, heterocyclic, and substituted heterocyclic
`are as defined herein. Acy! includes the "acetyl" group CH3C
`(0)-.
`"Acyloxy" refers to the groups alkyl-C(O)O-, sub(cid:173)
`[0069]
`stituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alk(cid:173)
`enyl-C(O)O-, alkynyl-C(O)O-, substituted alkynyl-C(O)
`0-, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C
`(0)0-, substituted cycloalkyl-C(O)O-, cycloalkenyl-C
`(0)0-, substituted cycloalkenyl-C(O)O-, heteroaryl-C
`(0)0-, substituted heteroaryl-C(O)O-, heterocyclic-C(O)
`0-, and substituted heterocyclic-C(O)O- wherein alkyl,
`substituted alkyl, alkenyl, substituted alkenyl, alkynyl, sub(cid:173)
`stituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalk(cid:173)
`enyl, substituted cycloalkenyl, aryl, substituted aryl, het(cid:173)
`eroaryl, substituted heteroaryl, heterocyclic, and substituted
`heterocyclic are as defined herein.
`the group ----C(O)
`"Aminocarbonyl" refers to
`[0070]
`NR 10R 11 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, substitutedheteroaryl, heterocyclic,
`and substituted heterocyclic and where R 10 and R 11 are
`optionally joined 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,
`cycloalkyl,
`substituted
`cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, sub(cid:173)
`stituted aryl, heteroaryl, substituted heteroaryl, heterocyclic,
`and substituted heterocyclic are as defined herein.
`"Aminothiocarbonyl" refers to the group ----C(S)
`[0071]
`NR 10R 11 where R 10 and R 11 are 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 heteroaryl, heterocyclic, and substituted heterocyclic
`and where R 10 andR11 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, substituted cycloalkyl, cycloalkenyl, substituted
`
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`cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted
`heteroaryl, heterocyclic, and substituted heterocyclic are as
`defined herein.
`"Aminosulfonyl" refers to the group -SO2NR10
`[0072]
`R 11 where R 10 and R 11 are independently selected from the
`group consisting of hydrogen, alkyl, substituted alkyl, alk(cid:173)
`enyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,
`substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalk(cid:173)
`enyl, substituted cycloalkenyl, heteroaryl, substituted het(cid:173)
`eroaryl, heterocyclic, and substituted heterocyclic and where
`R 10 and R 11 are 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, alkynyl, substituted alkynyl, cycloalkyl, sub(cid:173)
`stituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,
`aryl, substituted aryl, heteroaryl, substituted heteroaryl, het(cid:173)
`erocyclic, and substituted heterocyclic are as defined herein.
`[0073]
`"Arylalkyl" refers to alkyl groups containing one or
`more aryl groups, e.g. arylmethyl, arylethyl and the like.
`[0074]
`"Heteroaryl" refers to an aromatic group of from 1
`to 10 carbon atoms and 1 to 4 heteroatoms selected from the
`group consisting of oxygen, nitrogen and sulfur within the
`ring. Such heteroaryl groups can have a single ring ( e.g.,
`pyridinyl, thiadiazolyl or fury!) or multiple condensed rings
`(e.g., indolizinyl or benzothienyl) wherein the condensed
`rings may or may not be aromatic and/or contain a heteroatom
`provided that the point of att