PCT
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`
`
`lNTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`WO 99/64037
`(11) International Publication Number:
`(51) International Patent Classification 6 :
`
`A61K 38/00, 39/00, 39/44, 39/395, 51/00,
`C07K 2/00, 4/00, G01N 33/53, 33/543,
`33/566
`
`Al
`
`(43) International Publication Date:
`
`16 December 1999 (16.12.99)
`
`(21) International Application Number:
`
`PCT/US99/ 12620
`
`(22) International Filing Date:
`
`8 June 1999 (08.06.99)
`
`(30) Priority Data:
`60/088,448
`60/093,072
`
`8 June 1998 (08.06.98)
`16 July 1998 (16.07.98)
`
`US
`US
`
`
`
`(63) Related by Continuation (CON) or Continuation—in-Part
`(CIP) to Earlier Applications
`US
`Filed on
`US
`Filed on
`
`60/088,448 (CON)
`8 June 1998 (08.06.98)
`60/093,072 (CON)
`16 July 1998 (16.07.98)
`
`(71) Applicant (for all designated States except US): ADVANCED
`MEDICINE, INC. [US/US]; 280 Utah Avenue, South San
`Francisco, CA 94080 (US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): GRIFFIN, John, H.
`[US/US]; 56 Walnut Avenue, Atherton, CA 94027 (US).
`JUDICE, J., Kevin [US/US]; 146 1st Street, Montara, CA
`94037 (US).
`
`('74) Agents: SWISS, Gerald, F. et al.; Burns, Doane, Swecker &
`Mathis, L.L.P., PO. Box 1404, Alexandria, VA 22313—1404
`(US).
`
`(81) Designated States: AE, AL, AM, AT, AU, AZ, BA, BB, BG,
`BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB,
`GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG,
`KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK,
`MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI,
`SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA,
`ZW, ARIPO patent (GH, GM, KE, LS, MW, SD, SL, SZ,
`UG, ZW), Eurasian patent (AM, AZ, BY, KG, KZ, MD,
`RU, TJ, TM), European patent (AT, BE, CH, CY, DE, DK,
`ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OAPI
`patent (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR,
`NE, SN, TD, TG).
`
`Published
`With international search report.
`Before the expiration of the time limit for amending the
`claims and to be republished in the event of the receipt of
`amendments.
`
`(54) Title: NOVEL THERAPEUTIC AGENTS THAT MODULATE ENZYMATIC PROCESSES
`
`(57) Abstract
`
`Novel multi—binding compounds are disclosed that modulate enzymatic processes. The compounds of the invention comprise from
`2—10 ligands covalently connected, each of said ligands being capable of binding to an enzyme, enzyme substrate or enzyme cofactor
`thereby modulating the biological processes/functions thereof,
`
`
`
`

`

`FOR THE PURPOSES OF INFORMATION ONLY
`
`
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`SI
`Slovenia
`LS
`Lesotho
`ES
`Slovakia
`LT
`SK
`FI
`Lithuania
`LU
`SN
`FR
`Senegal
`Luxembourg
`SZ
`Swaziland
`LV
`Latvia
`GA
`TD
`Chad
`Monaco
`MC
`GB
`TG
`MD
`GE
`Togo
`Republic of Moldova
`GH
`MG
`TJ
`Tajikistan
`Madagascar
`TM
`MK
`Turkmenistan
`GN
`The former Yugoslav
`TR
`GR
`Turkey
`Republic of Macedonia
`TT
`Mali
`HU
`Trinidad and Tobago
`UA
`Ukraine
`IE
`Mongolia
`UG
`Mauritania
`IL
`Uganda
`US
`United States of America
`Malawi
`IS
`UZ
`Uzbekistan
`Mexico
`IT
`VN
`Viet Nam
`JP
`Niger
`YU
`KE
`Netherlands
`Yugoslavia
`Zimbabwe
`ZW
`KG
`Norway
`New Zealand
`KP
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`
`
`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`BE
`BF
`BG
`13.]
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`CU
`CZ
`DE
`DK
`EE
`
`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Céte d’Ivoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People‘s
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`
`
`

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`WO 99/64037
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`PCT/US99/12620
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`Novel Therapeutic Agents that Modulate Eggymatic Processes
`
`5
`
`Cross Reference to Related Applications
`
`This application claims the benefit of United States Provisional Application Serial
`
`Numbers 60/088,448, filed June 8, 1998, and 60/093,072, filed July 16, 1998, both of which are
`
`incorporated by reference in their entirety.
`
`10
`
`Field of the Invention
`
`This invention relates to modulators of enzymatic processes. More particularly, the
`
`invention relates to compounds that modulate enzymatic processes by acting as multibinding
`
`agents. The multibinding agents of the invention comprise from 2-10 ligands covalently
`
`connected by a linker or linkers, wherein said ligands in their monovalent (i.e. unlinked) state
`
`have the ability to bind to an enzyme, enzyme substrate, or enzyme cofactor, and are accordingly
`
`capable of modulating an enzymatic process. The manner in which the ligands are linked is such
`
`that the multibinding agents so constructed demonstrate an increased biological and/or
`
`therapeutic effect related to enzymatic processes as compared to the same number of unlinked
`
`ligands available for binding to the enzyme, enzyme substrate, or enzyme cofactor.
`
`The compounds of the invention are useful for modulating enzymatic processes. They
`
`are in particular useful for treating pathologic conditions mediated in one form or another by
`
`enzymatic processes. Accordingly, the invention also relates to pharmaceutical compositions
`
`comprising a pharmaceutically acceptable excipient and an effective amount of a compound of
`
`the invention, and to methods of using such compounds and pharmaceutical compositions
`
`containing them for the treatment of such pathologic conditions.
`
`Still further, the invention also relates to methods of preparing such compounds.
`
`Background
`
`Enzymes are the catalysts that mediate the chemical reactions of biological systems (for
`
`example, see: Walsh, CT. 1979. Enzymatic Reaction Mechanisms. W.H. Freeman: New York;
`
`Fersht, A. 1985. Enzyme Structure and Mechanism. W.H. Freeman: New York; Boyer, P., ed.
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`1970—1976. The Enzymes, 3rd ed. 13 vols. New York: Academic Press). Through the processes
`of mutation and natural selection, enzymes have evolved into very efficient catalysts, and
`
`typically effect reaction rate accelerations of many orders of magnitude relative to uncatalyzed
`
`processes, and display high selectivity for catalysis of desired reactions relative to other
`processes.
`‘
`
`It is clear that enzymes are critical to the survival of living organisms. However, because
`
`enzymes control the rate of biochemical reactions in metabolic pathways, they also have the
`
`potential for involvement in the development and persistence of pathological conditions. For
`
`example, autoimmune disorders (such as psoriasis, multiple sclerosis, rheumatoid arthritis,
`
`insulin-dependent diabetes, and the like) are characterized by excessive enzymatic production of
`
`inflammatory cytokines. Breast cancer and prostate cancer hormones at early stages of their
`
`development are dependent upon the enzymatic production of steroids. Blood Clotting is
`
`regulated by the action of enzymes such as thrombin or Factor Xa, and thus undesired blood
`
`clotting activity can be modified by inhibiting the action of such enzymes. Hypertension can be
`
`treated by inhibiting angiotensin converting enzyme, and inflammation may be regulated by
`
`inhibition of cyclooxygenase production of inflammatory lipids. The treatment of
`
`neurodegenerative disorders, such as Parkinson’s Disease, may be aided by treating patients with
`
`inhibitors of catechol 0-methyl transferase (COMT). Inhibition of the activity of this enzyme
`
`improves the efficacy of treatment with the drug L-dopa and decreases the formation of 3-OMD,
`
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`
`20
`
`a metabolite of L-dopa with toxic effects.
`
`Other examples of diseases in which enzymes are involved include infectious diseases
`
`caused by bacteria, protozoa or fungi, viral diseases such as AIDS (e. g.. reverse transcriptase or
`
`protease enzymes), arthritis, metastatic cancer and tumor growth related to metalloprotease
`
`enzymes, stress and hypertension related to l lB-hydroxysteroid dehydrogenase and/0r
`
`25
`
`angiotensin.
`
`Given the role played by enzymes in biological systems, it can be seen that enzymatic
`
`processes are probably involved at some level in all disease states or pathological conditions.
`
`Accordingly, the inhibition of enzymatic processes is regarded as an important target for drug
`
`development.
`
`30
`
`Any substance that reduces the rate of an enzymatic conversion of substrate to product is
`
`defined as an enzyme inhibitor. There are several fundamental mechanisms by which enzymatic
`
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`WO 99/64037
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`PCT/US99/12620
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`processes may be inhibited, for example reversible competitive inhibition, noncompetitive and
`uncompetitive inhibition, irreversible inhibition, substrate adulteration, and substrate
`
`sequestration. In reversible competitive inhibition, the inhibitor combines reversibly with free
`
`enzyme in a manner that excludes or reduces binding by the normal substrate for the enzyme.
`
`When a competitive inhibitor only reduces but does not totally exclude substrate binding, the
`
`inhibition is called partial competitive inhibition. In reversible noncompetitive inhibition, the
`
`inhibitor and substrate bind reversibly, randomly and independently at different sites. The
`
`enzyme:substrate:inhibitor complex is totally inactive or the rate of conversion of substrate to
`
`product is reduced in partial noncompetitive inhibition. In reversible uncompetitive inhibition,
`
`the inhibitor can only bind to the enzyme-substrate complex. Enzymes may also be inhibited
`
`irreversibly; e.g., they may undergo inactivating covalent modification by inhibitors. Irreversible
`
`inhibitors fall into two broad categories, depending upon whether they require pre—activation by
`
`the enzyme. Irreversible inhibitors such as reactive affinity labels, often used to probe enzyme
`
`active site structure, are intrinsically reactive with their target active site and require no pre-
`
`activation. In contrast, mechanism—based inactivators ("suicide substrates") are not intrinsically
`
`reactive with chemical functional groups on the enzyme, but these molecules are converted to
`
`reactive species in a process catalyzed at enzyme active sites. Finally, enzymes may be inhibited
`
`through mechanisms that do not involve direct interaction of the inhibitor with the enzyme. For
`
`example, inhibitors may bind to and sequester the substrate(s) for a given enzymatic process. In
`
`another possibility, inhibitors are activated by one enzyme and the activated species might
`
`inactivate or reversibly inhibit another enzyme, e. g. is isoniazid. Additionally, viral reverse
`
`transcriptase incorporates nucleotide analogs into growing DNA strands, which terminates the
`
`possibility for chain extension, thus inhibiting the subsequent enzymatic process (“substrate
`
`adulteration”).
`
`I
`
`It has been estimated that approximately one-third of the targets of current commercial
`
`drugs are enzymes or enzymatic processes (Drews, J.; Ryser, S. Nature Biotechnology 1997).
`
`Nonetheless, existing drugs have many disadvantages, including lack of selectivity for the
`
`targeted enzyme, low potency, short duration of action, toxicity, and the like.
`
`Accordingly, it would be advantageous to discover enzyme-inhibiting compounds that
`
`demonstrate high activity and selectivity toward target enzymes, and are of low toxicity. It
`
`would also be desirable to find a method for designing such compounds.
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`'
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`PCT/US99/12620
`
`Summary of the Invention
`This invention addresses the above needs by providing novel multibinding agents.
`
`Accordingly, in one aspect, the present invention relates to novel multibinding agents
`
`wherein a multibinding agent comprises 2-10 ligands, which may be the same or
`different, covalently connected by a linker or linkers, which may be the same or different, each
`
`of said ligands compromising a ligand domain capable of binding to an enzyme, enzyme
`
`substrate, or enzyme cofactor.,
`
`The preferred multibinding agents are represented by Formula I:
`
`10
`
`(L)p(X)q
`
`Formula I
`
`in which L is a ligand that may be the same or different at each occurrence;
`
`X is a linker that may be the same or different at each occurrence;
`
`p is an integer of 2-10; and
`
`q is an integer of 1-20;
`
`15
`
`or a salt thereof;
`
`wherein each of said ligands comprises a ligand domain capable of binding to an enzyme,
`
`enzyme substrate, or enzyme cofactor, thereby modulating the activity of the enzyme, enzyme
`
`substrate, or enzyme cofactor. Preferably q is less than p.
`
`In a second aspect, the invention relates to a method of inhibiting enzymatic processes in
`
`20
`
`a biologic tissue, preferably in a mammalian or avian subject, comprising administering to a
`
`subject in need of such treatment a therapeutically effective amount of a multibinding agent;
`
`wherein a multibinding agent comprises 2-10 ligands, which may be the same or different,
`
`covalently connected by a linker or linkers, which may be the same or different, each of said
`
`ligands compromising a ligand domain capable of binding to an enzyme, enzyme substrate, or
`
`25
`
`enzyme cofactor.
`
`In a third aspect, the invention relates to a method of inhibiting enzymatic processes in a
`
`biologic tissue, preferably in a mammalian or avian subject, comprising administering to a
`
`subject in need of such treatment a therapeutically effective amount of a compound of Formula I,
`
`or a salt thereof.
`
`30
`
`In a fourth aspect, the invention relates to a pharmaceutical composition comprising a
`
`therapeutically effective amount of one or more multibinding agents, or a pharmaceutically
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`WO 99/64037
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`PCT/U599/12620
`
`acceptable salt thereof, said multibinding agent comprising 2-10 ligands, which may be the same
`or different, covalently connected by a linker or linkers, which may be the same or different,
`
`each of said ligands compromising a ligand domain capable of binding to an enzyme, enzyme
`
`substrate, or enzyme cofactor, admixed with at least one pharmaceutically acceptable excipient.
`
`In a fifth aspect, the invention relates to a pharmaceutical composition comprising a
`
`therapeutically effective amount of one or more compounds of Formula I, or a pharmaceutically
`
`acceptable salt thereof, admixed with at least one pharmaceutically acceptable excipient.
`
`In a sixth aspect, the invention relates to a method for identifying a multibinding agent capable of
`
`binding to an enzyme, comprising preparing an array of multimeric agents, contacting the
`
`multimeric agent array with an enzyme, enzyme substrate, or enzyme cofactor, and slecting a
`
`multibinding agent based upon its ability to bind to the enzyme.
`
`In a sixth aspect, the invention relates to a method for identifying a multimeric ligand
`
`compound that possesses multibinding properties with respect to enzymes, comprising preparing
`
`an array of multimeric agents, contacting the multimeric agent array with an enzyme, and
`
`selecting a multibinding agent based upon its ability to bind to that enzyme.
`
`In a seventh aspect, the invention relates to processes for preparing the compounds of
`
`Formula I.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`Reaction Schemes 1-16 and the Figures and Tables of the Appendix illustrate various
`
`aspects of the invention.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`Biological systems in general involve molecular interactions between bioactive ligands and
`
`their receptors, in which the receptor “recognizes” a molecule (which may be a ligand or a substrate)
`
`or portion of a molecule (or ligand domain). Thus, enzymatic processes involve interaction of an
`
`enzyme with a ligand or substrate that is “recognized” by the enzyme. The result of this interaction
`
`can be either to initiate the desired biological effect of the enzyme, or alternatively to inhibit or alter
`
`(i.e. to modulate) the normal function of the enzyme. As noted above, whereas enzymes are critical
`
`to the survival of living organisms, they also play a role in disease states, and the inhibition of
`
`enzymatic processes is regarded as an important target for drug development.
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`The interaction of an enzyme with a ligand may be described in terms of “affinity” and
`“specificity”. The affinity and specificity of any given ligand/enzyme interaction are dependent upon
`
`the complementarity of molecular binding surfaces and the energetic costs of complexation. Affinity
`
`may be quantified by the equilibrium constant of complex formation. Specificity relates to the
`difference in affinity between different ligands binding to the same receptor (here an enzyme,
`
`enzyme substrate, or enzyme cofactor), or the same ligand binding to different receptors.
`
`The compounds of the invention are multibinding agents, and although not wishing to be bound
`
`or restricted by any particular theory or proposed mechanism of action, it is believed that the
`
`surprising activity of these compounds at least in pan arises from their ability to bind in a
`
`multivalent manner with the enzyme receptor, enzyme substrate or enzyme cofactor, and thus
`
`lower the energetic costs of binding to the enzyme, enzyme substrate, or enzyme cofactor.
`
`Multivalent binding interactions are characterized by the concurrent interaction of at least two
`
`ligands of a multibinding agent with multiple ligand binding sites (enzymes, enzyme substrate,
`
`or enzyme cogactors), which may be multiple distinct enzymes or multiple distinct binding sites
`
`on a single enzyme. Multivalent interactions differ from collections of individual monovalent
`
`interactions in that they give rise to an enhanced biological effect.
`
`Definitions
`
`As used herein:
`
`The term "alkyl" refers to a monoradical branched or unbranched saturated hydrocarbon
`
`chain, preferably having from 1 to 40 carbon atoms, preferably 1-10 carbon atoms, more
`
`preferably 1-6 carbon atoms, such as methyl, ethyl, n-propyl, is opropyl, n-butyl, secondary
`
`butyl, text—butyl, n-hexyl, n-octyl, n-decyl, n-dodecyl, 2-ethyldodecyl, tetradecyl, and the like,
`
`unless otherwise indicated.
`
`The term "substituted alkyl" refers to an alkyl group as defined above having from 1 to 5
`
`substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl,
`
`substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino,
`
`aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo,
`
`carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy,
`
`substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,
`
`hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO—aIyl, -SO-heteroaryl, -SOz-alkyl, -SOz-aryl, -
`
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`SOz-heteroaryl, and -NRaRb, wherein R3 and Rb may be the same or different and and are chosen
`
`from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl,
`
`heteroaryl and heterocyclic.
`
`The term "alkylene" refers to a diradical of a branched or unbranched saturated
`hydrocarbon chain, preferably having from 1 to 40 carbon atoms, preferably 1~10 carbon atoms,
`
`more preferably 1-6 carbon atoms. This term is exemplified by groups such as methylene
`
`(-CH2-), ethylene (~CH2CH2-), the propylene isomers (e.g., -CH2CH2CH2- and -CH(CH3)CH2-)
`
`and the like.
`
`The term "substituted alkylene" refers to:
`
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`
`(a)
`
`an alkylene group as defined above having from 1 to 5 substituents selected from the
`
`group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl,
`
`substituted cycloalkenyl, acyl, acylamino (including, for example, N-glucosaminecarbonyl,
`
`benzoylamino, biphenylcarbonylamino, and the like), acyloxy, amino, aminoacyl, aminoacyloxy,
`
`oxyacylamino, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thiol,
`
`thioalkoxy, substituted thioalkoxy, aryl, aryloxy, thioaryloxy, heteroaryl, heteroaryloxy,
`
`thioheteroaryloxy, heterocyclic, heterocyclooxy, thioheterocyclooxy, nitro, and -NRaRb, wherein
`
`Ra and Rb may be the same or different and are chosen from hydrogen, optionally substituted
`
`alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic. Additionally,
`
`such substituted alkylene groups include those where 2 substituents on the alkylene group are
`
`fused to form one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted
`
`cycloalkenyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group.
`
`(b)
`
`an alkylene group as defined above that is interrupted by 1-20 atoms or substituents
`
`independently chosen from oxygen, sulfur and NRa-, wherein R8 is chosen from hydrogen,
`
`optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and
`
`25
`
`heterocyclic; or
`
`(c)
`
`an alkylene group as defined above that has both from 1 to 5 substituents as defined
`
`above and is also interrupted by 1-20 atoms as defined above.
`
`Examples of substituted alkylenes are chloromethylene (—CH(Cl)-), aminoethylene
`
`(~CH(NH2)CH2-), 1-(dodecanoylamino)propylene (—CH[NHC(O)—(CH2)”-CH3] CH2-),
`
`30
`
`l-(4-phenylbenzoylamino)penty1ene (-CH[NHC(O)-Z] (CH2)4) ,2-carboxypropylene isomers (-
`
`CH2CH(C02H)CH2—), ethoxyethyl (-CH2CH2 O-CHZCH2—), -), ethylmethylaminoethyl (-CH2CH2
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`N(CH3) CH2CH2-), l—ethoxy-2-(2-ethoxy-ethoxy)ethane (-CHZCHZ O—CHzCHz-O-CHZCHz O-
`CH2CH2-), and the like.
`
`The term "alkaryl" or “aralkyl”refers to the groups -alkylene-aryl and -substituted
`
`alkylene-aryl in which alkylene and aryl are as defined herein. Such alkaryl groups are
`
`exemplified by benzyl, phenethyl and the like.
`
`The term "alkoxy" refers to the groups alkyl-O-, alkenyl-O-, cycloalkyl-O-,
`
`cycloalkenyl—O-, and alkynyl-O-, where alkyl, alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are
`
`as defined herein. Preferred alkoxy groups are alkyl-O- and include, by way of example,
`
`methoxy, ethoxy, n-propoxy, is o-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-
`
`hexoxy, 1,2-dimethylbutoxy, and the like
`
`The term "substituted alkoxy" refers to the groups substituted alkyl-O-, substituted
`
`alkenyl-O-, substituted cycloalkyl-O-, substituted cycloalkenyl-O-, and substituted alkynyl-O-
`
`where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl and
`
`substituted alkynyl are as defined herein.
`
`The term "alkylalkoxy" refers to the groups -alky1ene-O—alkyl,
`
`alkylene~O-substituted alkyl, substituted alkylene-O-alkyl and substituted alkylene-O-substituted
`
`alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein.
`
`Examples of such groups are methylenemethoxy (-CH20CH3), ethylenemethoxy
`
`(-CHZCHZOCH3), n-propylene-iso-propoxy (—CHZCHZCHZOCH(CH3)2), methylene-t-butoxy
`
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`
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`
`(-CHz-O—C(CH3)3) and the like.
`
`The term "alkylthioalkoxy" refers to the group —alkylene-S-alkyl,
`
`alkylene—S-substituted alkyl, substituted alkylene-S—alkyl and substituted alkylene-S-substituted
`
`alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein.
`
`Preferred alkylthioalkoxy groups are alkylene-S-alkyl and include, by way of example,
`
`methylenethiomethoxy (-CstCH3), ethylenethiomethoxy (-CHzCHZSCH3), n-propylene-iso-
`
`thiopropoxy (-CHzCHZCH28CH(CH3)2), methylene-t-thiobutoxy (-CH28C(CH3)3) and the like.
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`“Alkenyl” refers to a monoradical of a branched or unbranched unsaturated hydrocarbon
`
`preferably having from 2 to 40 carbon atoms, preferably 2-10 carbon atoms, more preferably 2—6
`
`carbon atoms, and preferably having 1-6 double bonds. This term is further exemplified by such
`
`radicals as vinyl, prop-2-enyl, pent-3-enyl, hex-S-enyl, 5-ethy1dodec—3,6-dienyl, and the like.
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`to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl,
`acylamino, acyloiry, amino, aminoacyl, aminoaeyloxy, oxyaminoacyl, azido, cyano, halogen,
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`hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl,
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`heteroaryl, heterocyclic, aryloxy, thioaryloxy, heteroaryloxy, thioheteroaryloxy, heterocyclooxy,
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`thioheterocyclooxy, nitro, -SO-alkyl, -SO-substituted alkyl, -SO—aryl, —SO-heteroaryl, -SOz—
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`alkyl, -SOz-substituted alkyl, -SOz—aryl, -SOz-heteroaryl, and. oNRaRb, wherein R3 and Rb may
`
`be the same or different and are,chosen from hydrogen, optionally substituted alkyl, cycloalkyl,
`
`alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic.
`
`“Alkenylene” refers to a diradical of an unsaturated hydrocarbon, preferably having from
`
`2 to 40 carbon atoms, preferably 2-10 carbon atoms, more preferably 2-6 carbon atoms, and
`
`preferably having 1—6 double bonds. This term is further exemplified by such radicals as 1,2-
`
`ethenyl, 1,3-prop-2-enyl, 1,5-pent-3-enyl, 1,4-hex-5-enyl, 5-ethyl-1,12-dodec-3,6-dienyl, and the
`
`like.
`
`The term "substituted alkenylene" refers to an alkenylene group as defined above having
`
`from 1 to 5 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl,
`
`acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, azido, cyano, halogen,
`
`hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl,
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`aryloxy, thioaryloxy, heteroaryl, heteroaryloxy, thioheteroaryloxy, heterocyclic, heterocyclooxy,
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`thioheterocyclooxy, nitro, and NRaRb, wherein Ra and Rb may be the same or different and are
`
`chosen from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,
`
`aryl, heteroaryl and heterocyclic. Additionally, such substituted alkenylene groups include
`
`those where 2 substituents on the alkenylene group are fused to form one or more cycloalkyl,
`
`substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic or heteroaryl
`
`groups fused to the alkenylene group.
`
`“Alkynyl” refers to a monoradical of an unsaturated hydrocarbon, preferably having from
`
`2 to 40 carbon atoms, preferably 2-10 carbon atoms, more preferably 2-6 carbon atoms, and
`
`preferably having 1—6 triple bonds. This term is further exemplified by such radicals as
`
`acetyleny1,prop—2-ynyl, pent-3-ynyl, hex-S-ynyl, 5—ethyldodec-3,6-diynyl, and the like.
`
`The term "substituted alkynyl" refers to an alkynyl group as defined above having from 1
`
`to 5 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl,
`
`acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, azido, cyano, halogen,
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`hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl,
`aryloxy, thioaryloxy, heteroaryl, heteroaryloxy, thioheteroaryloxy, heterocyclic, heterocyclooxy,
`
`thioheterocycloxy, nitro, -SO-a1kyl, -SO-substituted alkyl, -SO—aryl, -SO-heteroaryl, -SOz-alkyl,
`
`-SOz-substituted alkyl, -SOz-aryl, -SOz-heteroaryl, SOz-heterocyclic, NRaRb, wherein R8 and Rb
`
`may be the same-or different and are chosen from hydrogen, optionally substituted alkyl,
`
`cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic.
`
`“Alkynylene” refers to a diradical of an unsaturated hydrocarbon radical, preferably
`
`having from 2 to 40 carbon atoms, preferably 2-10 carbon atoms, more preferably 2-6 carbon
`
`atoms, and preferably having 1—6 triple bonds. This term is fiirther exemplified by such radicals
`
`as 1,3-prop-2-ynyl, 1,5-pent-3-ynyl, 1,4-hex-5-ynyl, 5-ethyl—l,l2—dodec-3,6-diynyl, and the like.
`
`The term "acyl" refers to the groups -CHO, alkyl-C(O)-, substituted alkyl-C(O)-,
`
`cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-
`
`C(O)-, aryl-C(O)—, heteroaryl-C(O)- and heterocyclic—C(O)- where alkyl, substituted alkyl,
`
`cycloalkyl, substituted cycloalkyl, cycloalkeny], substituted cycloalkenyl, aryl, heteroaryl and
`
`heterocyclic are as defined herein.
`
`The term "acylamino" refers to the group -C(O)NRR where each R is independently
`
`hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic or where both R groups are
`
`joined to form a heterocyclic group (e.g., morpholino) wherein alkyl, substituted alkyl, aryl,
`
`heteroaryl and heterocyclic are as defined herein.
`
`The term "aminoacyl" refers to the group -NRC(O)R where each R is independently
`
`hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted
`
`alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
`
`The term "aminoacyloxy" refers to the group -NRC(O)OR where each R is independently
`
`hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted
`
`alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
`
`The term "acyloxy" refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-,
`
`cycloalkyl—C(O)O-, substituted cycloalkyl-C(O)O-, aryl-C(O)O-, heteroaryl-C(O)O-, and
`
`heterocyclic-C(O)O- wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl,
`
`heteroaryl, and heterocyclic are as defined herein.
`
`The term "aryl" refers to an unsaturated aromatic carbocyclic group of from 6 to 20
`
`carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g.,
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`naphthyl or anthryl).
`
`Unless otherwise constrained by the definition for the aryl substituent, such aryl groups
`
`can optionally be substituted with from 1 to 5 substituents selected from the group consisting of
`
`acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
`
`substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted
`
`cycloalkyl, substituted cycloalkenyl, amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido,
`
`carboxyl, carboxylalkyl, cyano,} halo, nitro, heteroaryl, heteroaryloxy, heterocyclic,
`
`heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy,
`
`thjoheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO—aryl, -SO-heteroaryl, -SOz-alkyl, ~302-
`
`substituted alkyl, -SOz-aryl, -SOz-heteroaryl, trihalomethyl, NRaRb, wherein R8 and Rb may be
`
`the same or different and are chosen from hydrogen, optionally substituted alkyl, cycloalkyl,
`
`alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic. Preferred aryl substituents
`
`include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy.
`
`The term "aryloxy" refers to the group aryl-O- wherein the aryl group is as defined above
`
`including optionally substituted aryl groups as also defined above.
`
`The term “arylene” refers to a diradical derived from aryl or substituted aryl as defined
`
`above, and is exemplified by 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene and
`
`the like.
`
`The term "carboxyalkyl" refers to the group "—C(O)Oalkyl" where alkyl is as defined
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`above.
`
`The term "cycloalkyl" refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a
`
`single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of
`
`example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the
`
`like, or multiple ring structures such as adamantanyl, and the like.
`
`The term "substituted cycloalkyl" refers to cycloalkyl groups having from
`
`1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl,
`
`cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl,
`
`aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl,
`
`carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted
`
`thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,
`
`hydroxyamino, alkoxyamino, nitro, -SO-alky1, —SO-substituted alkyl, -SO-aryl, —SO-heteroaryl, -
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`SOz-alkyl, -SOz-substituted alkyl, —SOz-aryl, -SOz-heteroaryl, and NRaR", wherein R3 and Rh
`
`may be the same or different and are chosen from hydrogen, optionally substituted alkyl,
`
`cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic.
`
`The term "cycloalkenyl" refers to cyclic alkenyl groups of from 4 to 20 carbon atoms
`
`having a single cyclic ring or fused rings and at least one point of internal unsaturation.
`
`Examples of suitable cycloalkenyl groups include, for instance, cyclobut-Z-enyl, cyclopent-3—
`
`enyl, cyclooct-3-enyl and the like.
`
`The term "substituted cycloalkenyl" refers to cycloalkenyl groups having from 1 to 5
`
`s