PCT
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`A61K 38/00, 39/00, 39/44, 39/395, 51/00,
`
`C07K 2/00, 4/00, G01N 33/53, 33/543,
`33/566
`
`(11) International Publication Number:
`
`WO 99/64044
`
`16 December 1999 (16.12.99)
`
`(43) International Publication Date:
`
`
`
`(51) International Patent Classification 6 :
`
`(21) International Application Number:
`
`PCT/US99/ 12751
`
`(22) International Filing Date:
`
`7 June 1999 (O7.06.99)
`
`(30) Priority Data:
`60/088,466
`60/092,938
`60/096,606
`
`8 June 1998 (08.06.98)
`15 July 1998 (l5.07.98)
`14 August 1998 (14.08.98)
`
`US
`US
`US
`
`(63) Related by Continuation (CON) or Continuation-in-Part .
`(CIP) to Earlier Applications
`US
`Filed on
`US
`Filed on
`US
`Filed on
`
`60/088,466 (CON)
`8 June 1998 (08.06.98)
`60/092,938 (CON)
`15 July 1998 ( 15.07.98)
`60/096,606 (CON)
`14 August 1998 ( 14.08.98)
`
`(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): MARQUESS, Daniel
`[GB/US]; Unit #107, 820 Sea Spray Lane, Foster City, CA
`94404 (US). GRIFFIN, John, H. [US/US]; 56 Walnut Av-
`enue, Atherton, CA 94027 (US). CHOI, Seok—Ki [KR/US];
`839 University Avenue, Palo Alto, CA 94301 (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, 51,
`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 5-HT RECEPTORS
`
`(57) Abstract
`
`Novel multibinding compounds are disclosed. The compounds of the invention comprise from 2-10 ligands covalently connected,
`each of said ligands being capable of binding to a 5-HT receptor, thereby modulating the biological processes/functions thereof.
`
`
`
`   
`


`
`Lannett Holdings, Inc. LAN 1005
`
`

`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`BE
`BF
`BG
`BJ
`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
`Cote d'Ivoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`ES
`Fl
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`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
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`SI
`SK
`SN
`SZ
`TD
`TG
`TJ
`TM
`TR
`TT
`UA
`UG
`US
`UZ
`VN
`YU
`ZW
`
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Nam
`Yugoslavia
`Zimbabwe
`
`

`
`WO 99/64044 (cid:9)
`
`PCT/US99/12751
`
`Novel Therapeutic Agents that Modulate 5HT Receptors
`
`5 (cid:9)
`
`Cross Reference to Related Applications
`
`This application claims the benefit of United States Provisional Application Serial
`
`Numbers 60/088,466, filed June 8, 1998, 60/092,938, filed July 15, 1998, and
`
`60/096,606, filed August 14, 1998, all of which are incorporated by reference in their
`
`entirety.
`
`10
`
`Field of the Invention
`
`This invention relates to novel therapeutic agents that bind to 5-HT receptors and
`
`modulate their role in living systems. More particularly, the invention relates to novel
`
`therapeutic agents that bind to 5-HT receptors and modulate their activity by acting as a
`
`15 (cid:9) multibinding agent. 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 are capable of binding to a 5-HT receptor and
`
`modulating its activity. The manner in which the ligands are linked is such that the
`
`multibinding agents so constructed demonstrate an increased biological and/or
`
`20 (cid:9)
`
`therapeutic effect as compared to the same number of unlinked ligands available for
`
`binding to the 5-HT receptor.
`
`The compounds of the invention are particularly useful in treating conditions in a
`
`mammal that are mediated by 5-HT receptors. Accordingly, the invention also relates to
`
`pharmaceutical compositions comprising a pharmaceutically acceptable excipient and an
`
`25 (cid:9)
`
`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
`
`conditions.
`
`Still further, the invention relates to methods of preparing such compounds.
`
`1
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`

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`WO 99/64044
`
`Background
`
`PCT/US99/12751 -
`
`Serotonin (5-hydroxytryptamine) is a major neurotransmitter in mammals, and
`
`plays a role that is central to the function of the central and peripheral nervous system. It
`
`is responsible for controlling important physiological functions such as sleep, appetite,
`
`5
`
`pain, movement, and temperature regulation. Accordingly, much emphasis has been
`
`placed on modulating the action of serotonin for treating disease states such as migraine,
`
`headache, itch, motion sickness, depression, emesis, memory loss, anxiolytic disorders,
`
`obesity, gastrointestinal disorders, irritable bowel syndrome, and the like.
`
`Serotonin is the endogenous ligand for a variety of cell surface receptors. These
`
`10 (cid:9)
`
`include the seven transmembrane G-protein coupled receptors (GPCR), receptor ligand
`
`gated ion channels (e.g. 5HT3), and the twelve transmembrane serotonin reuptake
`
`protein.
`
`Within the GPCR class, there are believed to be at least 14 mammalian 5HT
`
`receptor subtypes. These receptors may be positively coupled to adenylate cyclase
`
`15 (cid:9)
`
`(5HT4, 5HT6, 5HT7) or negatively coupled to adenylate cyclase (5HT1A, 5HT1B,
`
`5HT1D, 5HT1F) or coupled to phospholipase C (5HT2A, 5HT2B, 5HT2C). The effector
`
`system for the remaining subtypes, 5HT5A and 5HT5B has not been determined.
`
`Significantly, the 5HT1 class is negatively coupled to adenlyate cyclase through Gi (see,
`
`for example, Saxena, Pramod R. Modern 5-HT receptor classification and 5-HT based
`
`20 (cid:9)
`
`drugs. Expert Opin. Invest. Drugs (1994), 3(5), 513-23).
`
`A number of clinically useful drugs have been developed for these serotonin
`
`receptors. One category of such drugs is the triptan class, which are small molecule
`
`agonists (or partial agonists) for seven transmembrane cell surface receptors. They are
`
`believed to act both through peripheral and central mechanisms. The triptan class of
`
`25 (cid:9)
`
`drugs shows mixed subtype activity across a minimum of four serotonin subtypes. For
`
`example, it is the agonism of the 5HT1 receptor, in particular the 5HT1B, 5HT1D, and
`
`5HT1F receptors, that is proposed to be responsible for the efficacy of triptans in the
`
`treatment of migraine. Nonetheless, drugs that act indiscriminately upon two or more of
`
`these subtypes (i.e. are not selective for the targeted subtype) are reported to have
`
`30 (cid:9)
`
`undesirable side effects e.g. cardiovascular contraindications, including chest tightness
`
`(cid:9)
`

`
`WO 99/64044 (cid:9)
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`PCT/US99/12751 -
`
`and pressure. Conversely, a drug that is selective for the 5HT1D receptor (for example)
`
`may reduce these side effects.
`
`Existing drugs have many disadvantages, including lack of selectivity for the
`
`targeted 5HT receptor subtype, low potency, slow onset of action, short duration of
`
`5 (cid:9)
`
`action, toxicity, and the like, which in man gives rise to undesirable side effects, slow
`
`onset of action, headache reoccurrence, and the like. Accordingly, it would be
`
`advantageous to provide compounds that demonstrate high activity and selectivity toward
`
`the targeted 5HT receptor subtype, and are of low toxicity. It would also be desirable to
`
`provide a method for designing such compounds.
`
`10 (cid:9)
`
`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,
`
`15 (cid:9)
`
`each of said ligands comprising a ligand domain capable of binding to a 5-HT receptor.
`
`The preferred multibinding agents are represented by Formula I:
`
`(L)p(X)q
`
`Formula
`
`in which L is a ligand that may be the same or different at each occurrence;
`
`20 (cid:9)
`
`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;
`
`or a salt thereof;
`
`wherein each of said ligands comprises a ligand domain state capable of binding to a 5-
`
`25 (cid:9)
`
`HT receptor.
`
`Preferably q is less than p.
`
`In a second aspect, the invention relates to a method of modulating 5-HT
`
`receptors 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
`
`30 (cid:9)
`
`a compound of Formula I, or a salt thereof
`
`3
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

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`WO 99/64044
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`PCT/US99/12751 -
`
`In a third aspect, the invention relates to a pharmaceutical composition
`
`comprising a therapeutically effective amount of one or more compounds of Formula I,
`
`or a pharmaceutically available salt thereof, admixed with at least one pharmaceutically
`
`acceptable excipient.
`
`5 (cid:9)
`
`In a fourth aspect, the invention relates to processes for preparing the compounds
`
`of Formula I.
`
`In a fifth aspect, the invention relates to a method for identifying a multibinding
`
`agent capable of binding to a 5-HT receptor, comprising preparing an array of multimeric
`
`agents, contacting the multimeric agent array with a 5-HT receptor, and selecting a
`
`10 (cid:9) multibinding agent based upon its ability to bind to the 5-HT receptor.
`
`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 (a ligand) or
`
`15 (cid:9)
`
`portion of a molecule (a ligand domain). One example of this process is the interaction
`
`between ligands (drugs) and 5-HT receptors. The result of this interaction can be either
`
`to initiate the desired biological effect of the 5-HT receptor, or alternatively to inhibit or
`
`alter (i.e. to modulate) the normal function of the 5-HT receptor. Accordingly, the
`
`modulation of such processes is regarded as an important target for drug development.
`
`20 (cid:9)
`
`The interaction of a 5-HT receptor with a ligand may be described in terms of
`
`"affinity" and "specificity". The affinity and specificity of any given ligand/receptor
`
`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
`
`25 (cid:9)
`
`different ligands binding to the same receptor subtype, or the same ligand binding to
`
`different receptor subtypes.
`
`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 part arises
`
`30 (cid:9)
`
`from their ability to bind in a multivalent manner with 5-HT receptors (i.e. the ligand
`
`binding site), and thus lower the energetic costs of binding. Multivalent binding
`
`4
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

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`WO 99/64044 (cid:9)
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`PCT/US99/12751 -
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`interactions are characterized by the concurrent interaction of at least two ligands of a
`
`multibinding agent with multiple ligand binding sites, which may be multiple distinct 5-
`
`HT receptors or multiple distinct binding sites on a single 5-HT receptor. Multivalent
`
`interactions differ from collections of individual monovalent interactions in that they give
`
`5 (cid:9)
`
`rise to an enhanced biological effect.
`
`Definitions
`
`As used herein:
`
`The term "alkyl" refers to a monoradical branched or unbranched saturated
`
`10 (cid:9)
`
`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, isopropyl, n-
`
`butyl, secondary butyl, tert-butyl, n-hexyl, n-octyl, n-decyl, n-dodecyl, 2-ethyldodecyl,
`
`tetradecyl, and the like, unless otherwise indicated. The term "lower alkyl" referes to an
`
`alkyl group as defined above having from 1-6 carbon atoms.
`
`15 (cid:9)
`
`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,
`
`20 (cid:9)
`
`thioheteroaryloxy, thioheterocyclooxy, thiol. thioalkoxy, substituted thioalkoxy, aryl,
`
`aryloxy, heteroaryl. heteroaryloxy, heterocyclic, heterocyclooxy. hydroxyamino,
`
`alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -S02-alkyl, -S02-aryl, -SO2-
`
`heteroaryl, and -NRaRb, wherein Ra and Rb may be the same or different and and are
`
`chosen from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl,
`
`25 (cid:9)
`
`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 (-CI-1,0, ethylene (-CH2CH2-), the propylene isomers (e.g., -CH7CI+CH2- and
`
`30 (cid:9)
`
`-CH(CH3)CH2-) and the like.
`
`The term "substituted alkylene" refers to:
`
`5
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

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`WO 99/64044 (cid:9)
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`PCT/US99/12751 -
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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,
`
`5 (cid:9)
`
`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 -NRale, wherein Ra and Rb may be the same or different
`
`and are chosen from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl,
`
`10 (cid:9)
`
`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
`
`15 (cid:9)
`
`substituents independently chosen from oxygen, sulfur and Nle-, wherein Ra is chosen
`
`from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,
`
`aryl, heteroaryl and 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.
`
`20 (cid:9)
`
`Examples of substituted alkylenes are chloromethylene (-CH(Cl)-), aminoethylene
`
`(-CH(NH2)CH2-), 1-(dodecanoylamino)propylene (-CH[NHC(0)-(CH2)11-CH3] CH2-),
`1-(4-phenylbenzoylamino)pentylene (-CHNHC(0)-Z} (CH2)4) ,2-carboxypropylene
`isomers (-CH2CH(CO2H)CH2-), ethoxyethyl (-CH2CH2 O-CH2CH2-), -),
`ethylmethylaminoethyl (-CH2CH2 N(CH3) CH2CH2-), 1-ethoxy-2-(2-ethoxy-
`
`25 (cid:9)
`
`ethoxy)ethane (-CH2CH2 O-CH2CH2-O-CH2CH2 0-CH2CH2-), and the like.
`
`The term "lower alkylene" refers to the group alkylene as defined above having
`
`from 1-6 carbon atoms.
`
`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
`
`30 (cid:9)
`
`exemplified by benzyl, phenethyl, and the like.
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`6
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`(cid:9)
`(cid:9)
`(cid:9)
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`WO 99/64044 (cid:9)
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`PCT/US99/12751 -
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`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, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy,
`
`5 (cid:9)
`
`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.
`
`10 (cid:9)
`
`The term "alkylalkoxy" refers to the groups -alkylene-0-alkyl,
`
`alkylene-O-substituted alkyl, substituted alkylene-O-alkyl and substituted alkylene-0-
`
`substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as
`
`defined herein. Examples of such groups are methylenemethoxy (-CH2OCH3),
`ethylenemethoxy (-CH2CH2OCH3), n-propylene-iso-propoxy
`
`15 (cid:9)
`
`(-CH2CH2CH2OCH(CH3)2), methylene-t-butoxy (-CH2-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
`
`20 (cid:9)
`
`way of example, methylenethiomethoxy (-CH2SCH3), ethylenethiomethoxy
`
`(-CH2CH2SCH3), n-propylene-iso-thiopropoxy (-C H2CH2CH2SCH(CH3)2), methylene-t-
`
`thiobutoxy (-CH2SC(CH3)3) and the like.
`
`"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,
`
`25 (cid:9) 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-5-enyl, 5-
`
`ethyldodec-3,6-dienyl, and the like.
`
`The term "substituted alkenyl" refers to an alkenyl group as defined above having
`
`from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy,
`
`30 (cid:9)
`
`acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano,
`
`halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted
`
`7
`
`(cid:9)
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`WO 99/64044 (cid:9)
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`PCT/US99/12751 -
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`thioalkoxy, aryl, heteroaryl, heterocyclic, aryloxy, thioaryloxy, heteroaryloxy,
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`thioheteroaryloxy, heterocyclooxy, thioheterocyclooxy, nitro, -SO-alkyl, -SO-substituted
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`alkyl, -SO-aryl, -SO-heteroaryl, -S02-alkyl, -502-substituted alkyl, -S02-aryl, -SO2-
`heteroaryl, and. -NRaRb, wherein Ra and Rb may be the same or different and are chosen
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`5 (cid:9)
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`from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,
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`aryl, heteroaryl and heterocyclic.
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`"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
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`10 (cid:9)
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`by such radicals as 1,2-ethenyl, l,3-prop-2-enyl, 1,5-pent-3-enyl. : .4-hex-5-enyl, 5-ethyl-
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`1,12-dodec-3,6-dienyl, and the like.
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`The term "substituted alkenylene" refers to an alkenylene group as defined above
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`having from 1 to 5 substituents, selected from the group consisting of alkoxy, substituted
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`alkoxy, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino,
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`15 (cid:9)
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`azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thiol,
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`thioalkoxy, substituted thioalkoxy, aryl, aryloxy, thioaryloxy. heteroaryl, heteroaryloxy,
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`thioheteroaryloxy, heterocyclic, heterocyclooxy, thioheterocyclooxy, nitro, and NRaRb,
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`wherein Ra and Rb may be the same or different and are chosen from hydrogen,
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`optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl
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`20 (cid:9)
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`and heterocyclic. Additionally, such substituted alkenylene groups include those where
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`2 substituents on the alkenylene group are fused to form one or more cycloalkyl,
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`substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic or
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`heteroaryl groups fused to the alkenylene group.
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`"Alkynyl" refers to a monoradical of an unsaturated hydrocarbon, preferably
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`25 (cid:9)
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`having from 2 to 40 carbon atoms, preferably 2-10 carbon atoms, more preferably 2-6
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`carbon atoms, and preferably having 1-6 triple bonds. This term is further exemplified by
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`such radicals as acetylenyl, prop-2-ynyl, pent-3-ynyl, hex-5-ynyl, 5-ethyldodec-3,6-
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`diynyl, and the like.
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`The term "substituted alkynyl" refers to an alkynyl group as defined above having
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`30 (cid:9)
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`from 1 to 5 substituents, selected from the group consisting of alkoxy. substituted alkoxy,
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`acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, azido, cyano,
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`WO 99/64044
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`PCT/US99/12751 -
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`halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted
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`thioalkoxy, aryl, aryloxy, thioaryloxy, heteroaryl, heteroaryloxy, thioheteroaryloxy,
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`heterocyclic, heterocyclooxy, thioheterocycloxy, nitro, -SO-alkyl, -SO-substituted alkyl,
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`-SO-aryl, -SO-heteroaryl, -S02-alkyl, -S02-substituted alkyl, -S02-aryl, -S02-heteroaryl,
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`5 (cid:9)
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`S02-heterocyclic, NRaRb, wherein Ra and Rb may be the same or different and are chosen
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`from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,
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`aryl, heteroaryl and heterocyclic.
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`"Alkynylene" refers to a diradical of an unsaturated hydrocarbon radical,
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`preferably having from 2 to 40 carbon atoms, preferably 2-10 carbon atoms, more
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`10 (cid:9)
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`preferably 2-6 carbon atoms, and preferably having 1-6 triple bonds. This term is further
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`exemplified by such radicals as 1,3-prop-2-ynyl, 1,5-pent-3-ynyl, 1,4-hex-5-ynyl, 5-
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`ethy1-1,12-dodec-3,6-diynyl, and the like.
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`The term "acyl" refers to the groups -CHO, alkyl-C(0)-, substituted alkyl-C(0)-,
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`cycloalkyl-C(0)-, substituted cycloalkyl-C(0)-, cycloalkenyl-C(0)-, substituted
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`15 (cid:9)
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`cycloalkenyl-C(0)-, aryl-C(0)-, heteroaryl-C(0)- and heterocyclic-C(0)- where alkyl,
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`substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted
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`cycloalkenyl, aryl, heteroaryl and heterocyclic are as defined herein.
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`The term "acylamino" refers to the group -C(0)NRR where each R is
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`independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic or where
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`20 (cid:9)
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`both R groups are joined to form a heterocyclic group (e.g., morpholino) wherein alkyl,
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`substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
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`The term "aminoacyl" refers to the group -NRC(0)R where each R is
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`independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein
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`alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
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`The term "aminoacyloxy" refers to the group -NRC(0)OR where each R is
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`independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein
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`alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
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`The term "acyloxy" refers to the groups alkyl-C(0)O-, substituted alkyl-C(0)O-,
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`cycloalkyl-C(0)O-, substituted cycloalkyl-C(0)O-, aryl-C(0)O-, heteroaryl-C(0)O-, and
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`heterocyclic-C(0)0- wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,
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`aryl, heteroaryl, and heterocyclic are as defined herein.
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`WO 99/64044
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`PCT/US99/12751 -
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`The term "aryl" refers to an unsaturated aromatic carbocyclic group of from 6 to
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`20 carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings
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`(e.g., naphthyl or anthryl).
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`Unless otherwise constrained by the definition for the aryl substituent, such aryl
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`groups can optionally be substituted with from 1 to 5 substituents selected from the group
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`consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl,
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`cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted
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`alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, aminoacyl, acylamino,
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`alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl,
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`heternaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy,
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`substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -
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`SO-aryl, -SO-heteroaryl, -S02-alkyl, -502-substituted alkyl, -S02-aryl, -S02-heteroaryl,
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`trihalomethyl, NRaRb, wherein Ra and Rb may be the same or different and are chosen
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`from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,
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`aryl, heteroaryl and heterocyclic. Preferred aryl substituents include alkyl, alkoxy, halo,
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`cyano, nitro, trihalomethyl, and thioalkoxy.
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`The term "aryloxy" refers to the group aryl-O- wherein the aryl group is as
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`defined above including optionally substituted aryl groups as also defined above.
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`The term "arylene" refers to a diradical derived from aryl or substituted aryl as
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`defined above, and is exemplified by 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-
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`naphthylene and the like.
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`The term "carboxyalkyl" refers to the group "-C(0)Oalkyl" where alkyl is as
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`defined above.
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`The term "cycloalkyl" refers to cyclic alkyl groups of from 3 to 20 carbon atoms
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`having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include,
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`by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl,
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`cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
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`The term "substituted cycloalkyl" refers to cycloalkyl groups having from
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`1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy,
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`cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino,
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`aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto,
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`WO 99/64044 (cid:9)
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`PCT/US99/12751 -
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`thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,
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`thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy,
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`heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-
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`substituted alkyl, -SO-aryl, -SO-heteroaryl, -S02-alkyl, -S02-substituted alkyl, -S02-aryl,
`-S02-heteroaryl, and NRaRb, wherein Ra and Rb may be the same or different and are
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`5 (cid:9)
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`chosen from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl,
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`alkynyl, aryl, heteroaryl and heterocyclic.
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`The term "cycloalkenyl" refers to cyclic alkenyl groups of from 4 to 20 carbon
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`atoms having a single cyclic ring or fused rings and at least one point of internal
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`unsaturation. Examples of suitable cycloalkenyl groups include, for instance, cyclobut-2-
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`enyl, cyclopent-3-enyl, cyclooct-3-enyl and the like.
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`The term "substituted cycloalkenyl" refers to cycloalkenyl groups having from 1
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`to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy,
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`cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,
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`acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano,
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`halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy,
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`thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,
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`aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino,
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`alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -S0,-
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`alkyl, -S02-substituted alkyl, -S02-aryl, -S02-heteroaryl, and NRaRb, wherein Ra and Rb
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`may be the same or different and are chosen from hydrogen, optionally substituted alkyl,
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`cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic.
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`The term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo.
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`"Haloalkyl" refers to alkyl as defined above substituted by 1-4 halo groups as
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`25 (cid:9)
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`defined above, which may be the same or different, such as 3-fluorododecyl, 12,12,12-
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`trifluorododecyl, 2-bromooctyl, -3-bromo-6-chloroheptyl, and the like.
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`The term "heteroaryl" refers to an aromatic group of from 1 to 15 carbon atoms
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`and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring
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`(if there is more than one ring).
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`Unless otherwise constrained by the definition for the heteroaryl substituent, such
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`heteroaryl groups can be optionally substituted with 1 to 5 substituents selected from the
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`WO 99/64044 (cid:9)
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`PCMS99/12751 -
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`group consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl,
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`cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl,
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`substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, aminoacyl,
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`acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro,
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`5 (cid:9)
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`heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino,
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`thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-
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`substituted alkyl, -SO-aryl, -SO-heteroaryl, -S02-alkyl, -S02-substituted alkyl, -S02-aryl,
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`-S02-heteroaryl, trihalomethyl, mono-and di-alkylamino, mono- and NRaRb, wherein Ra
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`and Rb may be the same or different and are chosen from hydrogen, optionally substituted
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`10 (cid:9)
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`alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic.
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`Preferred heteroaryls nclude pyridyl, pyrrolyl and furyl.
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`The term "heteroaryloxy" refers to the group heteroaryl-O-.
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`The term "heteroarylene" refers to the diradical group derived from heteroaryl or
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`substituted heteroaryl as defined above, and is exemplified by the groups 2,6-pyridylene,
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`15 (cid:9)
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`2,4-pyridiylene, 1,2-quinolinylene, 1,8-quinolinylene, 1,4-benzofuranylene, 2,5-
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`pyridinylene, 1,