CA2319174A1 - Novel therapeutic agents that modulate 5-ht receptors - Google Patents

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.

Description

Novel Therapeutic Agents that Modulate SHT Receptors 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.
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 multibinding agent. The multibinding agents of the invention comprise from 2-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 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 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.

Background 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, 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 to 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 I4 mammalian SHT
receptor subtypes. These receptors may be positively coupled to adenylate cyclase (SHT4, SHT6, SHT7) or negatively coupled to adenylate cyclase (SHT1A, SHT1B, SHT1D, SHT1F) or coupled to phospholipase C (SHT2A, SHT2B, SHT2C). The effector system for the remaining subtypes, SHTSA and SHTSB has not been determined.
Significantly, the SHTI class is negatively coupled to adenlyate cyclase through Gi (see, for example, Saxena, Pramod R. Modern 5-HT receptor classification and ~-HT
based 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 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 SHTIB, SHT1D, and SHT1F 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 undesirable side effects e.g. cardiovascular contraindications, including chest tightness and pressure. Conversely, a drug that is selective for the 5HT1 D receptor (for example) may reduce these side effects.
Existing drugs have many disadvantages, including lack of selectivity for the targeted SHT receptor subtype, low potency, slow onset of action, short duration of 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.
t0 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, ~5 each of said ligands comprising a ligand domain capable of binding to a ~-HT receptor.
The preferred multibinding agents are represented by Formula I:
(L)P(X)a Formula I
in which L is a ligand that may be the same or different at each occurrence;
2o 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 I-20;
or a salt thereof;
wherein each of said ligands comprises a ligand domain state capable of binding to a ~-25 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 3o a compound of Formula I, or a salt thereof.

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.
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 muItibinding 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 to 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 I5 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.
2o 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 complementarily 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 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 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 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 rise to an enhanced biological effect.
Definitions As used herein:
The term "alkyl" refers to a monoradical branched or unbranched saturated to 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, tent-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.
The term "substituted alkyl" refers to an alkyl group as defined above having from I to ~ 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-aryl, -SO-heteroaryl, -S02-alkyl. -S02-aryl, -SO~
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, 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 (-CH2CH~-), the propylene isomers (e.g., -CH~CH~CH~- and -CH(CH3)CH2-) and the like.
The term "substituted alkylene" refers to:

(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 Iike), 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, cycloaIkyl, alkenyl, to 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 cycIoalkenyl, 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 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 ~ substituents as defined above and is also interrupted by 1-20 atoms as defined above.
Examples of substituted alkylenes are chloromethylene (-CH(C1)-), aminoethylene (-CH(NH2)CH2-), 1-(dodecanoylamino)propylene (-CH[NHC(O)-(CHI)"-CH3] CH2-), 1-(4-phenylbenzoylamino)pentylene (-CH[NHC(O)-Z) (CH2).~) ,2-carboxypropylene isomers (-CHZCH(C02H)CH2-), ethoxyethyl (-CH2CHz O-CHaCHZ-), -), ethylmethylaminoethyl (-CHzCH2 N(CH3) CH~CH2-), 1-ethoxy-2-(2-ethoxy-ethoxy)ethane (-CH2CH2 O-CHZCH2-O-CH~CHZ O-CH~CH~-), 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 3o exemplified by benzyl, phenethyl, and the like.

The term "alkoxy" refers to the groups alkyl-O-, aikenyl-O-, cycloalkyl-O-, cycloalkenyl-O-, and alkynyl-O-, where alkyl, alkenyI, 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, 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 -alkylene-O-alkyl, alkylene-O-substituted alkyl, substituted aIkylene-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 (-CH2CH20CH3), n-propylene-iso-propoxy (-CH2CH2CH20CH(CH3)2), methylene-t-butoxy (-CHI-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 (-CH~SCH3), ethylenethiomethoxy (-CH2CH2SCH3), n-propylene-iso-thiopropoxy (-CH~CH2CH~SCH(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, 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, ~-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, 3o acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, aryloxy, thioaryloxy, heteroaryloxy, thioheteroaryloxy, heterocyclooxy, thioheterocyclooxy, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -S02-alkyl, -S02-substituted alkyl, -S02-aryl, -S02-heteroaryl, and. -NRaRb, wherein Ra and Rh 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 to by such radicals as 1,2-ethenyl, 1,3-prop-2-enyl, 1,5-pent-3-enyl, : .4-hex-~-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, 15 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 2o 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 25 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 acetylenyl, prop-2-ynyl, pent-3-ynyl, hex-5-ynyl, S-ethyldodec-3,6-diynyl, and the like.
The term "substituted alkynyl" refers to an alkynyl group as defined above having 3o from 1 to ~ 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, aryloxy, thioaryloxy, heteroaryl, heteroaryloxy, thioheteroaryloxy, heterocyclic, heterocyclooxy, thioheterocycloxy, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -S02-alkyl, -S02-substituted alkyl, -S02-aryl, -S02-heteroaryl, S02-heterocyclic, 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.
"Alkynylene" refers to a diradical of an unsaturated hydrocarbon radical, preferably having from 2 to 40 carbon atoms, preferably 2-10 carbon atoms, more t0 preferably 2-6 carbon atoms, and preferably having 1-6 triple bonds. This term is further exemplified by such radicals as 1,3-prop-2-ynyl, 1,5-pent-3-ynyl, 1,4-hex-~-ynyl, ~
ethyl-1,12-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 15 cycloalkenyl-C(O)-, aryl-C(O)-, heteroaryl-C(O)- and heterocyclic-C(O)-where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, 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 2o both R groups are joined to form a heterocycIic 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.
25 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 3o 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., 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, cycIoalkyl, 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, 1o heter~aryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -S02-alkyl, -S02-substituted alkyl, -S02-aryl, -SOz-heteroaryl, trihalomethyl, 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. 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 2o defined above, and is exemplified by I,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 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 S substituents selected from the group consisting of alkoxy, substituted alkoxy, 3o 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-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SOZ-alkyl, -S02-substituted alkyl, -S02-aryl, -S02-heteroaryl, 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.
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 to unsaturation. Examples of suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and the like.
The term "substituted cycloalkenyl" refers to cycloalkenyl groups having from to 5 substituents selected from the group consisting of alkoxy. substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acy l, IS 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, vitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl. -SO-heteroaryi, -SO~-2o alkyl, -SO~-substituted alkyl, -SO~-aryl, -S02-heteroaryl, 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.
The term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo.
"HaloalkyI" refers to alkyl as defined above substituted by 1-4 halo groups as 25 defined above, which may be the same or different, such as 3-fluorododecyl, 12,12,12-trifluorododecyl, 2-bromooctyl, -3-bromo-6-chloroheptyl, and the like.
The term "heteroaryl" refers to an aromatic group of from 1 to 1 ~ carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring (if there is more than one ring).
30 Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to ~ 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, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -S02-alkyl, -S02-substituted alkyl, -S02-aryl, -S02-heteroaryl, trihalomethyl, mono-and di-alkylamino, mono- and NRaRb, wherein Ra and Rb may be the same or different and are chosen from hydrogen, optionally substituted 1o alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic.
Preferred heteroaryls nclude pyridyl, pyrrolyl and furyl.
The term "heteroaryloxy" refers to the group heteroaryl-O-.
The term "heteroarylene" refers to the diradical group derived from heteroaryl or substituted heteroaryl as defined above, and is exemplified by the groups 2,6-pyridylene, 15 2,4-pyridiylene, 1,2-quinolinylene, 1,8-quinolinylene, 1,4-benzofuranylene, 2,~-pyridinylene, 1,3-morpholinylene, 2,~-indolenyl, and the like.
The term "heterocycle" or "heterocyclic" refers to a monoradical saturated or unsaturated group having a single ring or multiple condensed rings, from I to 40 carbon atoms and from 1 to 10 hetero atoms, preferably 1 to 4 heteroatoms, selected from 20 nitrogen, sulfur, phosphorus, and/or oxygen within the ring.
Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 5, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, 25 amino, aminoacyl, aminoacyloxy, oxyaminoacyl, 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-substituted alkyl, -SO-aryl, -SO-heteroaryl, -S02-alkyl, -S02-substituted alkyl, -SOz-aryl, 30 -S02-heteroaryl, 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. Such heterocyclic groups can have a single ring or multiple condensed rings.
Examples of nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like as well as N-alkoxy-nitrogen containing to heterocycles.
A preferred class of heterocyclics include "crown compounds" which refers to a specific class of heterocyclic compounds having one or more repeating units of the formula [-(CH2-)mY-] where m is equal to or greater than ?, and Y at each separate occurrence can be O, N, S or P. Examples of crown compounds include, by way of 15 example only, [-(CH2)3-NH-]3, [-((CH~)~-O).~-((CHs)-NH)~] and the like.
Typically such crown compounds can have from 4 to 10 heteroatoms and 8 to 40 carbon atoms.
The term "heterocycloalkyl" refers to heterocycle as defined above linked to alkyl as defined above, for example piperidin-4-ylmethyl, oxazolidin-2-one-3-ylethyl, and the like.
20 The term "heterocyclooxy" refers to the group heterocyclic-O-.
The term "thioheterocyclooxy" refers to the group heterocyclic-S-.
The term "heterocyclene" refers to the diradical group derived from a heterocycle as defined herein, and is exemplified by the groups 2,6-morpholino, 2,~-morpholino and the like.
25 The term "oxyacylamino" refers to the group -OC(O)NRR 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 "thiol" refers to the group -SH.
The term "thioalkoxy" refers to the group -S-alkyl.
3o The term "substituted thioalkoxy" refers to the group -S-substituted alkyl.

The term "thioaryloxy" refers to the group aryl-S- wherein the aryl group is as defined above including optionally substituted aryl groups also defined above.
The term "thioheteroaryloxy" refers to the group heteroaryl-S- wherein the heteroaryl group is as defined above including optionally substituted aryl groups as also defined above.
As to any of the above groups which contain one or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible.
In addition, the compounds of this invention include all stereochemical isomers arising from the substitution of these compounds.
"Alkyl optionally interrupted by 1-5 atoms chosen from O, S, or N" refers to alkyl as defined above in which the carbon chain is interrupted by O, S, or N.
Within the scope are ethers, sulfides, and amines, for example 1-methoxydecyl, 1-pentyloxynonane, 1-(2 isopropoxyethoxy)-4-methylnonane, 1-(2-ethoxyethoxy)dodecyl, 2-(t-butoxy)heptyl, 1-pentylsulfanylnonane, nonylpentylamine, and the like.
"Heteroarylalkyl" refers to heteroaryl as defined above linked to alkyl as defined above, for example pyrid-2-ylmethyl, 8-quinolinylpropyl, and the like.
"Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where 2o said event or circumstance occurs and instances in which it does not. For example.
optionally substituted alkyl means that alkyl may or may not be substituted by those groups enumerated in the definition of substituted alkyl.
"Ligand" as used herein denotes a compound that is a binding partner for a 5-HT
receptor, preferably a 5-HT1 receptor, and is bound thereto by complementarity. The specific region or regions of the ligand that is (are) recognized by the ~-HT
receptor is designated as the "ligand domain". By virtue of the ligand domain, a ligand may be either capable of binding to a 5-HT receptor by itself, or may require the presence of one or more non-ligand components for binding (e.g. Ca2T~ Mg'Y, or a water molecule is required for the binding of a ligand domain to various receptors).
3o Examples of ligands useful in this invention, including the triptan class, are given below. Those skilled in the art will appreciate that portions of the ligand structure that are not essential for molecular recognition and binding activity (i.e. that are not part of the ligand domain) may be varied substantially, replaced or substituted with unrelated structures (for example, with ancillary groups as defined below), and, in some cases, omitted entirely without affecting the binding interaction. Accordingly, it should be understood that the term ligands is not intended to be limited to compounds known to be useful as 5-HT agonists, antagonists, modulators, or the like. (for example, known drugs).
Those skilled in the art will understand that the term ligand can equally apply to a molecule that is not normally recognized as having useful properties related to binding to a S-HT receptor, in that Iigands that exhibit minimally useful properties as monomers can be highly active as multibinding agents, due to the biological benefit (increased biological effect) conferred by multivalency. The primary requirement for a ligand as defined herein is that it has a ligand domain as defined above.
Preferred ligands include AH-25086, Almotriptan (LAS-31416), Alniditan, ALX-0646, Avitriptan (BMS-180048), CP 122,288, 5-CT, Eletriptan (UK-116044), IS-159, LY-334370, L-694,247, a-Methyl-5-HT, 2-Methyl-5-HT, Naratriptan, Oxymetazoline, PNU-109291, PNU-142633, Rizatriptan (MK-462), (L-741, 19), S-9977, S-20749 SB209509 (VML251), Sumatriptan, VML-2~1, Zolmitriptan, Alnespirone (S-20499), B-20991, BAY x 3702, Buspirone, Cisapride, CGS-12066B. CP93129. Gepirone, GR
127935, Ipsaperone, MDL 74.721, S-Methoxytryptamine. Methysergide, Metoclopramide, MKC-242. Mosapride citrate, 8-OH-DPAT, Quipazine, Renzapride, RS67506, Tandospirone, VB20B7, Zelmac, (R) Zacopride.Zacopride, Zalospirone, Umespirone, Enilospirone, WY-48723, SUN-8399, Flesinoxan. Lesopitron, Ebalzotan.
Adatanserin, Frovatriptan, Ondansetron, Granisetron, F-11356, LY-344864, LY-228729, F-8910-RS, U-93385, SL-87.0765, FG-5893, S-14506, EMD-56551. HT-90B, F-92502-CN, E-4414, F-12439, BIMT-17, LY-39, SL-88.0338, SR-57746A, LY-175644. A-74283, BAY-r-1531, CGP-50281, WAY-100012, 3a,4,4a,6a,7,-7a-hexahydro-2-[4-[4-(2-pyrimidinyl)-1-[piperazinyl]butyl]-4,7-ethenocyclobuta[f]-1,2-benzisothiazol-3 (2H) -one 1,1-dioxide, cis-7-chlor-IO-methoxy-Sa lOb-dihydro-3N-n-propyl-6H-indeno[1,2-d]azepine, 1-cyclohexyl-3-[4-[4-(2,3-dihydro-2,2-dimethylbenzofuran-7-yl)-1-piperazinyl]-1-butyl]-2-imidazolidone, 1-[3-amino-2H-1-benzopyran-2-one-8-yl]piperazine, Oxafloxane, RU-5031, L-0076, ALX-062, VS-39~, and L-747201.
1~

It should be understood that Formula I is intended to include racemic ligands L
and racemic linker X, as well as the individual stereoisomers of the ligands and linkers, including enantiomers and non-racemic mixtures thereof. The scope of the invention as described and claimed encompasses the racemic forms of the ligands and linkers as well as the individual enantiomers and non-racemic mixtures thereof.
"Multibinding agent" or "multibinding compound" as used herein refers to a compound that is capable of multivalency as defined herein, and which has 2-10 ligands as defined herein, which may be the same or different, connected by one or more covalent linker or linkers, which may be the same or different, preferably from 1-20 in 1o number. A multibinding agent provides an improved biological ~.;d/or therapeutic effect as measured against that achieved by the same number of unlinked ligands available for binding to the ligand binding site of the 5-HT receptor. Examples of increased biological and/or therapeutic effect with respect to the target include, for example, increased specificity, increased affinity, increased selectivity, increased potency, increased efficacy, 15 increased therapeutic index, a change in the duration of action, decreased toxicity, decreased side effects, improved bioavailability, improved pharmacokinetics.
improved activity spectrum; and the like. The multibinding compounds of the invention exhibit one or more of the foregoing effects.
"Potency" as used herein refers to the minimum concentration at which a ligand is 2o able to achieve a desirable biological or therapeutic effect. The potency of a ligand is typically proportional to its affinity for its ligand binding site. In some cases, the potency may be non-linearly correlated with its affinity. In comparing the potency of two drugs, e.g., a multibinding agent and the aggregate of its unlinked ligand, the dose-response curve of each is determined under identical test conditions (e.g., in an in vitro or in vivo 25 assay or in an appropriate animal model. The finding that the multibinding agent produces an equivalent biological or therapeutic effect at a lower concentration than the aggregate unlinked ligand (e.g., on a per weight, per mole, or per ligand basis) is indicative of enhanced potency.
"Univalency" as used herein refers to a single binding interaction between the 30 ligand domain of one ligand as defined herein with the ligand recognition site of a 5-HT

receptor. It should be noted that a compound having multiple copies of a ligand (or ligands) exhibits univalency when only one ligand of that compound is interacting with a ligand binding site. Examples of univalent interactions are depicted below.
C~
where the arrow represents a ligand domain and the indent represents the ligand binding site of a receptor, "Multivalency" as used herein refers to the concurrent binding of 2 to 10 linked ligands (which may be the same or different) and two or more corresponding ligand binding sites of one or more 5-HT receptors.
to Accordingly, two ligands connected by a linker that bind concurrently to two ligand binding sites of one or more 5-HT receptors would be considered to be a bivalent compound; similarly, three ligands thus connected provide a trivalent compound. An example of trivalent binding, illustrating a multibinding agent bearing three ligands is shown below.
It should be understood that all compounds that contain multiple copies of a ligand attached to a linker (or linkers) do not necessarily exhibit the phenomena of multivalency, i.e. that improved biological and/or therapeutic effect of the multibinding agent is obtained as measured against that produced by the same number of unlinked ligands available for binding to a, ligand binding site. For multivalency to occur, the ligand domains of the ligands that are connected by a linker have to be presented to their appropriate receptors) (i.e. the ligand binding sites) by the linker in a specific manner in order to bring about the desired ligand-orienting result, and thus produce a multibinding event. Thus, the term ''multimeric ligand compound" refers to multiple copies of a ligand attached to a linker (or linkers) that may or may not exhibit the phenomena of multivalency. "Multimeric ligand compound library" refers to the collection of multimeric ligand compounds that are provided by the synthetic methods disclosed herein.

WO 99!64044 PCT/US99/12751 "Selectivity" or "specificity" is a measure of the binding preferences of a ligand for different receptors and/or different ligands for the same receptor. The selectivity of a ligand with respect to its target receptor relative to another receptor is given by the ratio of the respective values of Kd (i.e., the dissociation constants for each ligand-receptor complex), or in cases where a biological effect is observed below the ICd, selectivity is given by the ratio of the respective ECsos (i.e. the concentrations that produce 50% of the maximum response for the ligand interacting with the two distinct receptors).
The term "ligand recognition site" or "ligand binding site" as used herein denotes the site on a 5-HT receptor that recognizes a ligand domain and provides a binding t0 partner for a ligand. The ligand binding site may be defined by monomeric or multimeric structures. This interaction may be capable of producing a unique biological effect, for example, agonism, antagonism, modulatory effect, and the like, or may maintain an ongoing biological effect.
It should be recognized that the ligand binding sites of receptors that participate in biological multivalent binding interactions are constrained to varying degrees by their intra- and intermolecular associations (e.g_, they may be covalently joined in a single or multiple structure, noncovalently associated in a multimeric structure, embedded in a membrane or polymeric matrix, and so on) and therefore have less relative translational and rotational freedom than if the same receptors were present as monomers in solution.
The terms "agonism'' and ''antagonism" are well known in the art. By the term "modulatory effect" we mean the ability of a ligand to change the biological effect of an agonist or antagonist through binding to a receptor.
As used herein, the terms "inert organic solvent" or "inert solvent" mean a solvent inert under the conditions of the reaction being described in conjunction therewith [including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform {"CHCI;"), methylene chloride (or dichloromethane or "CH2C12), diethyl ether, ethyl acetate, acetone, methylethyl ketone, methanol, ethanol, propanol, isopropanol, tent-butanol, dioxane, pyridine, and the like].
Unless specified to the contrary, the solvents used in the reactions of the present invention are inert solvents.

WO 99/64044 PCTlUS99/12751 -"Pharmaceutically acceptable salt" means those salts which retain the biological effectiveness and properties of the multivalent compounds of the invention, and which are not biologically or otherwise undesirable. The multivalent compounds of the invention are capable of forming both acid and base salts by virtue of the presence of amino and carboxyl groups respectively.
1. Pharmaceutically acceptable base addition salts may be prepared from inorganic and organic bases. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and ter~iary to amines, substituted amines including naturally-occurring substituted amines, and cyclic amines, including isopropylamine, trimethyl amine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, and N-15 ethylpiperidine. It should also be understood that other carboxylic acid derivatives would be useful in the practice of this invention, for example carboxylic acid amides, including carboxamides, lower alkyl carboxamides, di(lower alkyl) carboxamides, and the like.
2. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, 2o hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, maIonic acid, succinic acid, malefic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
25 The term "treatment" as used herein covers any treatment of a condition or disease in an animal, particularly a mammal, more particularly a human, and includes:
(i) preventing the disease or condition from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it;
(ii) inhibiting the disease or condition, i.e. arresting its development;
30 (iii) relieving the disease or condition, i.e. causing regression of the condition; or.
(iv) relieving the conditions caused by the disease, i.e. symptoms of the disease.

The term "disease or condition which is alleviated by treatment with a multibinding agent" as used herein covers all conditions and disease states which are generally acknowledged in the art to be usefully treated with the ligands as defined in general, and those disease states which have been found to be usefully treated by the specific multibinding agents of our invention, including the compounds of Formula I.
The term covers prophylactic treatment as well as relief or regression of the disease. It also covers the treatment of conditions that are not necessarily considered as disease states, for example the use of multibinding agents as contraceptives, as pregnancy limiting agents, for the treatment of insomnia, treatment of obesity, and the like.
l0 Such disease states include, but are not limited to, treatment of a mammal for modifying physiological functions related to sleep, appetite, pain, movement, and temperature regulation, and includes disease states such as migraine, headache. itch, motion sickness, depression, emesis, memory loss, anxiolytic disorders, obesity, gastrointestinal disorders, irritable bowel syndrome, and the Iike.
The term "therapeutically effective amount" refers to that amount of a multibinding agent, for example a compound of Formula I, that is sufficient to effect treatment, as defined above, when administered to a mammal or avian in need of such treatment. The therapeutically effective amount will vary depending on the subject and disease state being treated, the severity of the affliction and the manner of administration, 2o and the like, and may be determined routinely by one of ordinary skill in the art.
The term "protecting group" or "blocking group" refers to any group which when bound to one or more hydroxyl, thiol, amino or carboxyl groups of the compounds prevents reactions from occurnng at these groups and which protecting group can be removed by conventional chemical or enzymatic steps to reestablish the hydroxyl, thio, amino or carboxyl group. The particular removable blocking group employed is not critical and preferred removable hydroxyl blocking groups include conventional substituents such as allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidine, phenacyl, t-butyl-diphenylsilyl and any other group that can be introduced chemically onto a hydroxyl functionality and later selectively removed either by chemical or enzymatic methods in mild conditions compatible with the nature of the product.
Protecting groups are disclosed in more detail in T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis" 2"d Ed., 1991, John Wiley and Sons, N.Y.
Preferred removable amino blocking groups include conventional substituents such as t-butyoxycarbonyl (t-BOC), benzyloxycarbonyl (CBZ), fluorenylmethoxycarbonyl (FMOC), allyloxycarbonyl (ALOC) and the like, which can be removed by conventional conditions compatible with the nature of the product.
Preferred carboxyl protecting groups include esters such as methyl, ethyl, propyl, t-butyl etc. which can be removed by mild conditions compatible with the nature of the product.
to "Linker" or "linkers" as used herein, identified where appropriate by the symbol X, refers to a group or groups that covalently links) from 2-10 iigands (as defined herein) in a manner that provides a compound capable of multivalency. The linker is a ligand domain orienting entity that permits attachment of multiple copies of ligands (which may be the same or different) thereto. The extent to which multivalent binding is realized depends upon the efficiency with which the linker that joins the ligands permits the ligand domains to be presented to the ligand recognition sites substrates). Beyond presenting ligand domains for multivalent interactions with receptors, the linker spatially constrains these interactions to occur within dimensions defined by the linker. Thus, the structural features of the linker (valency, geometry, orienting capabilities, size, flexibility, chemical composition) are features of multibinding agents that play an important role in determining their activities. The term linker, however, does not include solid inert supports such as beads, resins, glass particles, rods, fibers, and the like, but it should be understood that the multibinding compounds of the invention can be attached to a solid support if desired to provide, for example, a material useful for separation and purification processes (e.g. affinity chromatography).
The ligands are covalently attached to the linker or linkers using conventional chemical techniques, for example reaction between a carboxylic acid and an amine to form an amide, an amine and a sulfonyl halide to form a sulfonamide, an alcohol or phenol with an alkyl or aryl halide to form an ether, and the like.
The linker (or linkers) is attached to the ligand at a position such that the ligand domain is permitted to orient itself appropriately in order to bind to the ligand binding site. In some instances, the linker is attached to an existing sidechain of a Iigand. In order to avoid confusion in such cases, the linker X is normally defined as including the sidechain, and the ligand is defined as excluding the sidechain. For example, the compound of Formula I having a structure:
~(CH2~
N/ N
F i ~ F
I N ~ ~. \ / ~ ~ N
O w N N~ O
H H
could be viewed as two ligands (LY-334370) joined by a (CH2}S group. However, for the purposes of this application, it will be designated and claimed as a compound of Formula I linked 3,3 in which the ligand is:
F
i H R3 N i o wI
N
H
where R3 is the linking position;
Io and the linker is:
-(CH,), ~ -(CH,)_-.
-CH N-(CH=)~-N CH
i----(CHI),-' :--(CH=),-, IS The relative orientation in which the ligand domains are displayed derives from the particular point or points of attachment of the ligands to the linker, and on the framework geometry. The determination of where acceptable substitutions can be made on a ligand is typically based on prior knowledge of structure-activity relationships of the ligand and/or congeners and/or structural information about ligand-receptor complexes 20 (e.g., from X-ray crystallography, NMR). Such positions and the synthetic methods for covalent attachment are well known in the art.
Suitable linkers are discussed below.

At present, it is preferred that the multibinding agent is a bivalent compound, in which two ligands are covalently linked.
"Biological effect" as used herein includes, but is not limited to, increased affinity, increased selectivity, increased potency, increased efficacy, increased duration of action, decreased toxicity, and the like.
Combinatorial Libraries The methods described above Iend themselves to combinatorial approaches for selecting compounds that have multibinding properties related to the 5-HT
receptor, in to particular the SHT1 receptor, from a library of multimeric compounds.
Specifcally, factors such as the proper juxtaposition of the individual SHT
ligands of a multibinding compound with respect to the relevant array of binding sites on a target or targets is important in optimizing the interaction of the multibinding compound with its targets) and to maximize the biological advantage through 15 multivalency. One approach is to identify a library of candidate multibinding compounds with properties spanning the multibinding parameters that are relevant for a particular target. These parameters include: (I) the identity of Iigand(s), (2) the orientation of ligands, (3) the valency of the construct, (4) linker length, (~) linker geometry, (6) linker physical properties, and (7) linker chemical functional groups.
20 Libraries of multimeric compounds potentially possessing multibinding properties (i.e., candidate multibinding compounds) and comprising a multiplicity of such variables are prepared and these libraries are then evaluated via conventional assays corresponding to the Iigand selected and the multibinding parameters desired. Considerations relevant to each of these variables are set forth below:
Selection of ligand(s) A single 5-HT ligand or set of ~-HT ligands is (are) selected for incorporation into the libraries of candidate multibinding compounds. The only requirement for the ligands chosen is that they are capable of interacting with a ~-HT receptor(s), preferably a 5-HTl receptor. Thus, 5-HT1 ligands may be known drugs, modified forms of known drugs, substructures of known drugs or substrates of modified forms of known drugs (which are competent to interact with the target), or other compounds. 5-HTl ligands are preferably chosen based on known favorable properties that may be projected to be carried over to or amplified in multibinding forms. Favorable properties include demonstrated safety and efficacy in human patients, appropriate PK/ADME profiles, synthetic accessibility, and desirable physical properties, such as solubility, loge, etc. However, it is crucial to note that 5-HT ligands which display an unfavorable property from among the previous list may obtain a more favorable property through the process of multibinding compound formation; i.e., 5-HT ligands should not necessarily be excluded on such a basis. For example, a S-HT ligand that is not sufficiently potent at a particular target so as to be to efficacious in a human patient may become highly potent and effic.~:,ious when presented in multibinding form. A 5-HT ligand that is potent and efficacious but not of utility because of a non-mechanism-related toxic side effect may have increased therapeutic index (increased potency relative to toxicity) as a multibinding compound.
Compounds that exhibit short in vivo half lives may have extended half Lives as multibinding 15 compounds. Physical properties of 5-HT ligands that limit their usefulness (e.g. poor bioavailability due to low solubility, hydrophobicity, hydrophilicity) may be rationally modulated in multibinding forms, providing compounds with physical properties consistent with the desired utility.
2o Orientation: selection of ~-HT ligand attachment points and linkin chemistry Several points are chosen on each 5-HT ligand at which to attach the 5-HT
ligand to the linker. The selected points on the 5-HT ligand/linker for attachment are functionalized to contain complementary reactive functional groups. This permits probing the effects of presenting the 5-HT ligands to their receptors) in multiple relative 25 orientations, an important multibinding design parameter. The only requirement for choosing attachment points is that attaching to at least one of these points does not abrogate activity of the 5-HT ligand. Such points for attachment can be identified by structural information when available. For example, inspection of a co-crystal structure of a protease inhibitor bound to its target allows one to identify one or more sites where 30 linker attachment will not preclude the enzyme:inhibitor interaction.
Alternatively, evaluation of ligand/target binding by nuclear magnetic resonance will permit the identification of sites non-essential for ligand/target binding. See, for example, Fesik, et al., U.S. Patent No. 5,891,643. When such structural information is not available, utilization of structure-activity relationships (SAR) for ligands will suggest positions where substantial structural variations are and are not allowed. In the absence of both structural and SAR information, a library is merely selected with multiple points of attachment to allow presentation of the 5-HT ligand in multiple distinct orientations.
Subsequent evaluation of this library will indicate what positions are suitable for attachment.
It is important to emphasize that positions of attachment that do abrogate the 1o activit_~ of the monameric S-HT ligand may also be advantageously included in candidate multibinding compounds in the library provided that such compounds bear at least one 5-HT ligand attached in a manner which does not abrogate intrinsic activity.
This selection derives from, for example, heterobivalent interactions within the context of a single target molecule. For example, consider a receptor agonist 5-HT1 ligand bound to its target IS receptor, and then consider modifying this 5-HT1 ligand by attaching to it a second copy of the same 5-HT1 ligand with a linker which allows the second ~-HTI ligand to interact with the same receptor molecule at sites proximal to the antagonist binding site, which include elements of the receptor that are not part of the formal antagonist binding site and/or elements of the matrix surrounding the receptor such as the membrane.
Here, the 2o most favorable orientation for interaction of the second 5-HTl ligand molecule with the receptor/matrix may be achieved by attaching it to the linker at a position which abrogates activity of the 5-HT1 ligand at the formal agonist binding site.
Another way to consider this is that the SAR of individual 5-HT1 ligands within the context of a multibinding structure is often different from the SAR of those same S-HT1 ligands in 25 momomeric form.
The foregoing discussion focused on bivalent interactions of dimeric compounds bearing two copies of the same 5-HT ligand joined to a single linker through different attachment points, one of which may abrogate the binding/activity of the monomeric 5-HT ligand. It should also be understood that bivalent advantage may also be attained 30 with heterodimeric constructs bearing two different ~-HT ligands. wich may be agonists or antagonists, that bind to common or different targets.

Once the 5-HT ligand attachment points have been chosen, one identifies the types of chemical linkages that are possible at those points. The most preferred types of chemical linkages are those that are compatible with the overall structure of the S-HT
ligand (or protected forms of the 5-HT ligand) readily and generally formed, stable and intrinsically inocuous under typical chemical and physiological conditions, and compatible with a large number of available linkers. Amide bonds, ethers, amines, carbamates, ureas, and sulfonamides are but a few examples of preferred linkages.
Linkers: spanning relevant multibinding parameters through selection of valency, linker length. linker geometry, rigidity, physical properties, and chemical functional groups In the library of linkers employed to generate the library of candidate multibinding compounds, the selection of linkers employed in this library of linkers takes into consideration the following factors:
Valency. In most instances the library of linkers is initiated with divalent linkers.
The choice of 5-HT ligands and proper juxtaposition of two 5-HT ligands relative to their binding sites permits such molecules to exhibit target binding affinities and specificities more than sufficient to confer biological advantage. Furthermore, divalent linkers or constructs are also typically of modest size such that they retain the desirable biodistribution properties of small molecules.
Linker length. Linkers are chosen in a range of lengths to allow the spanning of a range of inter-Iigand distances that encompass the distance preferable for a given divalent interaction. In some instances the preferred distance can be estimated rather precisely from high-resolution structural information of targets, typically enzymes and soluble receptor targets. In other instances where high-resolution structural information is not available (such as 7TM G-protein coupled receptors), one can make use of simple models to estimate the maximum distance between binding sites either on adjacent receptors or at different locations on the same receptor. In situations where two binding sites are present on the same target (or target subunit for multisubunit targets), preferred linker distances are 2-20 angstroms, with more preferred linker distances of 3-12 angstroms. In situations 3o where two binding sites reside on separate (e.g., protein) target sites, preferred linker distances are 20-100 angstroms, with more preferred distances of 30-70 angstroms.

Linker geometry and rigidity. The combination of 5-HT ligand attachment site, linker length, linker geometry, and linker rigidity determine the possible ways in which the 5-HT ligands of candidate multibinding compounds may be displayed in three dimensions and thereby presented to their binding sites. Linker geometry and rigidity are nominally determined by chemical composition and bonding pattern, which may be controlled and are systematically varied as another spanning function in a multibinding array. For example, linker geometry is varied by attaching two 5-HT ligands to the ortho, meta, and para positions of a benzene ring, or in cis- or trans-arrangements at the I,I- vs.
1,2- vs. 1,3- vs. 1,4- positions around a cyclohexane core or in cis- or trans-arrangements 1o at a point of ethylene unsaturation. Linker rigidity is varied by controlling the number and relative energies of different conformational states possible for the linker. For example, a divalent compound bearing two 5-HT ligands joined by 1,8-octyl linker has many more degrees of freedom, and is therefore less rigid than a compound in which the two 5-HT ligands are attached to the 4,4' positions of a biphenyl linker.
Linker physical properties. The physical properties of linkers are nominally determined by the chemical constitution and bonding patterns of the linker, and linker physical properties impact the overall physical properties of the candidate multibinding compounds in which they are included. A range of linker compositions is typically selected to provide a range of physical properties (hydrophobicity, hydrophilicity, amphiphilicity, polarization, acidity, and basicity) in the candidate multibinding compounds. The particular choice of linker physical properties is made within the context of the physical properties of the S-HT ligands they join and preferably the goal is to generate molecules with favorable PK/ADME properties. For example, linkers can be selected to avoid those that are too hydrophilic or too hydrophobic to be readily absorbed and/or distributed in vivo.
Linker chemical functional groups. Linker chemical functional groups are selected to be compatible with the chemistry chosen to connect linkers to the ligands and to impart the range of physical properties sufficient to span initial examination of this parameter.
Combinatorial synthesis WO 99!64044 PCT/US99/12751 Having chosen a set of n 5-HT ligands (n being determined by the sum of the number of different attachment points for each 5-HT ligand chosen) and m linkers by the process outlined above, a library of (n!)m candidate divalent multibinding compounds is prepared which spans the relevant multibinding design parameters for a particular target.
For example, an array generated from two S-HT ligands, one which has two attachment points (A1, A2) and one which has three attachment points (B l, B2, B3) joined in all possible combinations provide for at least I 5 possible combinations of multibinding compounds:
to Al-AI A1-A2 A1-B1 AI-B2 A1-B3 A2-A2 A2-B1 A2-B2 When each of these combinations is joined by 10 different linkers, a library of 150 candidate multibinding compounds results.
Given the combinatorial nature of the library, common chemistries are preferably used to join the reactive functionalies on the S-HT ligands with complementary reactive functionalities on the Linkers. The library therefore lends itself to efficient parallel synthetic methods. The combinatorial library can employ solid phase chemistries well known in the art wherein the 5-HT ligand and/or linker is attached to a solid support.
Alternatively and preferably, the combinatorial libary is prepared in the solution phase.
After synthesis, candidate multibinding compounds are optionally purified before assaying for activity by, for example, chromatographic methods (e.g., HPLC).
Analysis of array by biochemical, analytical, pharmacological and com utational methods Various methods are used to characterize the properties and activities of the candidate multibinding compounds in the library to determine which compounds possess multibinding properties. Physical constants such as solubility under various solvent conditions and logD/clogD values can be determined. A combination of NMR
spectroscopy and computational methods is used to determine low-energy conformations of the candidate multibinding compounds in fluid media. The ability of the members of the library to bind to the desired target and other targets is determined by various standard methods, which include radioligand displacement assays for receptor and ion channel targets, and kinetic inhibition analysis for many enzyme targets. In vitro efficacy, such as for receptor agonists and antagonists, ion channel blockers, and antimicrobial activity, can also be determined. Pharmacological data, including oral absorption, everted gut penetration, other pharmacokinetic parameters and efficacy data can be determined in appropriate models. In this way, key structure-activity relationships are obtained for multibinding design parameters which are then used to direct future 1 o work.
The members of the library which exhibit multibinding properties, as defined herein, can be readily determined by conventional methods. First those members which exhibit multibinding properties are identified by conventional methods as described above including conventional assays (both in vitro and in vivo).
15 Second, ascertaining the structure of those compounds which exhibit muItibinding properties can be accomplished via art recognized procedures. For example, each member of the iibrary can be encrypted or tagged with appropriate information allowing determination of the structure of relevant members at a later time. See, for example, Dower, et al., International Patent Application Publication No. WO 93/06121;
Brenner, et 2o al., Proc. Natl. Acad. Sci., USA, 89:5181 (1992); Gallop, et al., U.S.
Patent No.
5,846,839; each of which are incorporated herein by reference in its entirety.
Alternatively, the structure of relevant multivalent compounds can also be determined from soluble and untagged libaries of candidate multivalent compounds by methods known in the art such as those described by Hindsgaul, et aL, Canadian Patent 25 Application No. 2,240,325 which was published on July I I, 1998. Such methods couple frontal affinity chromatography with mass spectroscopy to determine both the structure and relative binding affinities of candidate multibinding compounds to receptors.
The process set forth above for dimeric candidate multibinding compounds can, of course, be extended to trimeric candidate compounds and higher analogs thereof.

Follow-up synthesis and analysis of additional arrays) Based on the information obtained through analysis of the initial library, an optional component of the process is to ascertain one or more promising multibinding "lead" compounds as defined by particular relative 5-HT ligand orientations, linker lengths, linker geometries, etc. Additional libraries can then be generated around these leads to provide for further information regarding structure to activity relationships.
These arrays typically bear more focused variations in linker structure in an effort to further optimize target affinity and/or activity at the target (antagonism, partial agonism, etc.), and/or alter physical properties. By iterative redesign/analysis using the novel principles of multibinding design along with classical medicinal chemistry, biochemistry, and pharmacology approaches, one is able to prepare and identify optimal multibinding compounds that exhibit biological advantage towards their targets and as therapeutic agents.
To further elaborate upon this procedure, suitable divalent linkers include, by way of example only, those derived from dicarboxylic acids, disulfonylhalides, dialdehydes, diketones, dihalides, diisocyanates,diamines, diols, mixtures of carboxylic acids, sulfonylhalides, aldehydes, ketones, halides, isocyanates, amines and diols.
In each case, the carboxylic acid, sulfonylhalide, aldehyde, ketone, halide, isocyanate, amine and diol functional group is reacted with a complementary functionality on the S-HT
ligand to 2o form a covalent linkage. Such complementary functionality is well known in the art as illustrated in the following table:
COMPLEMENTARY BINDING CHEMISTRIES
First Reactive Group Second Reactive Group Linkage hydroxyl isocyanate urethane amore epoxide ~i-hydroxyamine sulfonyl halide amine sulfonamide carboxyl acid amine amide hydroxyl alkyl/aryl halide ether aldehyde amine/NaCNBH~ amine ketone amine/NaCNBH2 amine amine isocyanate urea Exemplary linkers include those described in the Appendix.
Pharmaceutical Formulations When employed as pharmaceuticals, the compounds of the invention are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
This invention also includes pharmaceutical compositions that contain, as the active ingredient, one or more of the compounds of formula I above associated with one or more pharmaceutically acceptable earners. In making the compositions of this invention, the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a earner which can be in the form of a capsule. sachet.
paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active 2o ingredient. Thus, the compositions can be in the form of tablets. pills, powders, lozenges.
sachets, cachets, elixirs, suspensions, emulsions, solutions. syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates;
sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
The compositions are preferably formulated in a unit dosa~~~ form, each dosage containing from about 0.1 mg to about I g, more usually about 1 to about 100 mg, of the active ingredient. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Preferably, the compound of formula I above is employed at no more than about 20 weight percent of the pharmaceutical composition, more preferably no more than about 15 weight percent, with the balance being pharmaceutically inert carrier(s).
The active compound is effective over a wide dosage range and is generally 2o administered in a pharmaceutically effective amount. It. will be understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preforrnulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0. I to about 500 mg of the active ingredient of the present invention.
The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
A vanety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably t5 flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as corn oiI, cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases.
Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 19th Edition, 1995, the complete disclosure of which is hereby incorporated by reference. The composition or formulation to be administered will, in any event, contain a quantity of the active compounds) in an amount effective to alleviate the symptoms of the subject being treated.
UTILITY
s The multibinding agents of the invention are useful in medical treatments related to the modulation of 5-HT receptors, and accordingly exhibit biological effects well known to those skilled in the art. Examples of such activity include the modification of physiological functions related to sleep, appetite, pain, movement, and temperature regulation, and includes disease states such as migraine, headache, itch, motion sickness, depression, emesis, memory loss. anxiolytic disorders, obesity, gastrointestinal disorders, irritable bowel syndrome, and the like.
TESTING
is The multibinding agents of the invention are useful in medical treatments and exhibit biological effects that can be demonstrated in routine tests well known to those skilled in the art. For example, measurement of in vitro binding assay/affinity using radioligand binding assays, evaluation of agonist/partial agonist character in in vitro functional assays. measurement of functional activity in in vitro reporter gene assay.
2o measurement of efficacy ex vivo functional assays, and utilization of in vivo models. See Example 28.
METHODS OF PREP ARATION
25 Linker The linker (or linkers), when covalently attached to multiple copies of the 5-HT
ligands, provides a biocompatible, substantially non-immunogenic multibinding agent.
The biological effects of the multibinding agent is highly sensitive to the valency, geometry, composition, size, flexibility or rigidity, the presence or absence of anionic or 3o cationic charge, and similar considerations (including hydrophilicity and hydrophobicity as discussed below) with respect to the linker. Accordingly, the linker is preferably chosen to maximize the desired biological effect. The linker may be biologically "neutral", i.e. not itself contribute any biological activity to the compound of Formula I, or it may be chosen to enhance the biological effect of the molecule. In general, the linker may be chosen from any organic molecule that orients two or more ligands to the 5-HT receptors,aand permits multivalency. In this regard, the linker can be considered as a "framework" on which the ligands are arranged in order to bring about the desired ligand-orienting result, and thus produce a multibinding agent.
For example, different orientations can be achieved by including in the framework groups containing monocyclic or polycyclic groups, including aryl and heteroaryl groups, to or structures incorporating one or more carbon-carbon multiple bonds (i.e., alkenes and alkynes). Other groups can also include oligomers and polymers which are branched- or straight-chain species. In preferred embodiments, rigidity is imparted by the presence of cyclic groups (e.g., aryl, heteroaryl, cycloalkyl, heterocycles, etc.). In other preferred embodiments, the ring is a six-or ten membered ring. In still further preferred embodiments, the ring is an aromatic group such as, for example, phenyl or naphthyl.
Different frameworks can be designed to provide preferred orientations of the ligands. Such frameworks may be represented by using an array of dots (as shown below) wherein each dot may potentially be an atom. such as C, O, N, S, P, H, F, Cl, Br, and F, or the dot may alternatively indicate the absence of an atom at that position. To 2o facilitate the understanding of the framework structure, the framework is illustrated as a two dimensional array in the following diagram, although clearly the framework is a three dimensional array in practice:

m I I ~ I I I I I I .....
~ I I I I I I I I I .....
cp I I I I I I I ~ I .....
in I I I I I I I I I .....
I I I I I I I ~ I .....
r, I I I I I I I I I .....
N I I I I I I I ~ I .....
I I I I I I I I I .....
o I I I I I I I I I .....
4 1 2 3 4 5 6 7 g Each dot is either an atom, chosen from carbon, hydrogen, oxygen, nitrogen, sulfur, phosphorus, or halogen, or the dot represents a point in space (i.e. an absence of an atom). Only certain atoms on the grid have the ability to act as an attachment point for the ligands, namely C, O, N, S, and P.
Atoms can be connected to each other via bonds (single, double, or triple with acceptable resonance and tautomeric forms), with regard to the usual constraints of chemical bonding. Ligands may be attached to the framework via single, double.
or triple bonds (with chemically acceptable tautomeric and resonance forms).
Multiple ligand groups (2 to 10) can be attached to the framework such that the minimal, shortest t0 path distance between adjacent ligand groups does not exceed 100 atoms or angstroms.
An example of a linker as represented by the grid is shown below for a biphenyl construct.

o. . . . . ~ . r ..~ . . . . . . . . , .
m ~ ~ . r ~ . ~ . I
,.. . . . . .
r ~ . . . . . . . . ~
N . . ~ ~ ~ ~ ~ n n .- . . . . ~ . .
. ~ ~ ~
0 ~ 2 g 4 5 8 7 8 9 t0 Nodes ( 1,2), (2,0), (4,4), (5,2), (4,0), (6,2), (7,4), (9,4), ( 10,2), (9,0), (7,0) all represent carbon atoms. Node (10,0) is a chlorine atom. All other nodes (or dots) are points in space (i.e. represent an absence of atoms).
Nodes (1,2) and (9,4) are attachment points.
Hydrogen atoms are affixed to nodes (2,4), (4,4), (4,0), (2,0), (7,4), (10,2), and (7,0).
Nodes (5,2) and (6,2) are connected by a single bond.
The carbon atoms present are connected by either single or double bonds.
taking to into consideration the principle of resonance and/or tautomerism.
The intersection of the framework (linker) and the ligand group, and indeed, the framework (linker} itself can have many different bonding patterns. Examples of acceptable patterns of three contiguous atom arrangements within the linker and at the linker-ligand interface are shown in the following diagram.
., CCN

OCN SCN PCN
CCO NCO

OCO CO PC
O

CCP NCP P

OCP SCP CP

CNC N
CNN

NN
ONN SNN PNN

NNO S~ O

CNP ~ SNP PNS
ONP pNp COC S OOC SOC POC
ON

C O _ ~ ~ D-U~O S~ P O
O

COP

CSC NSC OSC OSC PSC

CSO OSN SSN PSN

NSO OSO SSO p-~-O

CSP NSS _ NSP

OSP ~ P

CPC NPC OPC SPC PPC

CPN NPN
~

~ NPO ppp SPO

CP NPS OPS _ gpP
CPP NPP OPP P-P-P

One skilled in the art would be able to identify bonding patterns that would produce multivalent compounds. Methods for producing these bonding arrangements are described in "Advanced Organic Chemistry, 4t" Edition' by March (Wiley-Interscience (New York), 199?). These anangements are described in the grid of dots shown in the Scheme above. All of the possible arrangements for the five most preferred atoms are shown. Each atom has a variety of acceptable oxidation states. The bonding arrangements underlined are less acceptable and are not preferred.
Examples of molecular structures in which the above bonding patterns could be to employed as components of the linker are shown below.

O ~ w wO.C,C~ wN.C,C~
~O~O~ ~ ' J w I J ~
N N O N O' \
wC.C.C~ wC.O,C~ C. C
~C.N,Ci ~C,C~C~ ~C.N~Ci O O O O
I! w ,C, wN~Ni wO~N~ ~C~N~ C ~C'' O
n ~ ~ O
wC.S.Ni ~C,S.N~ wC.S~C~ wC.S~C~ ~C.S.Si O O
O O O
wC.S.C~ wC.O.N~ ~O~N~ ~C,S,C~ wC.S~C~
O
O-~
wN.S.Ni ~O~C~O~ ~N~N~ ~ % wC.N:C~
p ~N N
wS~C.O.~ wS.C~S~. wN.C.O~ ~N~ ~ ~N~N
N
O
wN.N.N~ wC.P~Ci w .P~ i n N o_ C w0. P~C
O-The identification of an appropriate framework geometry for ligand domain presentation is an important first step in the construction of a multivalent binding agent with enhanced activity. Systematic spatial searching strategies can be used to aid in the identification of preferred frameworks through an iterative process. Various strategies are known to those skilled in the art of molecular design and can be used for preparing the compounds of this invention.
Display vectors around similar central core stmctures such as phenyldiacetylene and cyclohexane dicarboxylic acid can be varied, as can the spacing of the ligand domain WO 99!64044 PCT/US99/12751 -from the core structure (i.e., the length of the attaching moiety). It is to be noted that core structures other than those shown here can be used for determining the optimal framework display orientation of the ligands. The process may require the use of multiple copies of the same central core structure or combinations of different types of display cores.
The above-described technique can be extended to trimers and compounds of higher-order valency as exemplified by structures shown in the Appendix.
Assay of each of the individual compounds of a collection generated as described above will lead to a subset of compounds with the desired enhanced activities (e.g., to potency, selectivity). The analysis of this subset using a technique such as Ensemble Molecular Dynamics will provide a framework orientation that favors the properties desired. A wide diversity of linkers is commercially available (see, e.g., the Available Chemicals Directory, (ACD), Chem. Sources USA, Chem. Sources International, Chemical Abstracts). Many of the linkers that are suitable for use in this invention fall into this category. Others can be readily synthesized, e.g., by methods known in the art and described below.
Having selected a preferred framework geometry. the physical properties of the linker can be optimized by varying the chemical composition. The composition of a linker can be varied in numerous ways to achieve the desired physical properties.
It can therefore be seen that there is a plethora of possibilities for the composition of a linker. Examples of linkers include aliphatic moieties, aromatic moieties, steroidal moieties, peptides, and the Like. Specific examples are peptides or polyamides.
hydrocarbons, aromatic groups, ethers, lipids, cationic or anionic groups, or a combination thereof, and many specific examples of linkers are shown in the Appendix.
Examples are given below, but it should be understood that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. For example, properties of the linker can be modified by the addition or insertion of ancillary groups into the linker, for example, to change solubility of the multibinding agent (in water, fats, lipids, biological fluids, etc.), hydrophobicity, 3o hydrophilicity, linker flexibility, antigenicity, molecular size, molecular weight, in vivo half life, in vivo distribution, biocompatability, immunogenicity, stability, and the like.

For example, the introduction of one or more poly or preferably oligo(ethylene glycol) (PEG) groups onto the linker enhances hydrophilicity and water solubility of the multibinding agent, increases both molecular weight and molecular size and, depending on the nature of the unPEGylated linker, may increase the in vivo retention time. Further, PEG may decrease antigenicity and potentially enhances the overall rigidity of the linker.
Ancillary groups that enhance the water solubility/hydrophilicity of the linker are useful in practicing the present invention. Thus, it is within the scope of the present invention to use ancillary groups such as, for example, polyethylene glycol), alcohols, polyols (e.g., glycerin, glycerol propoxylate, saccharides, including mono-, oligo- and polysdxharides, etc.), carboxylates, polycarboxylates (e.g., polyglutamic acid, polyacrylic acid, etc.), amines, polyamines (e.g., polylysine, poly(ethyleneimine), etc) to enhance the water solubility and/or hydrophilicity of the compounds of Formula I. In preferred embodiments, the ancillary group used to improve water solubility/hydrophilicity will be a polyether. In particularly preferred embodiments, the ancillary group will be a polyethylene glycol).
The incorporation of lipophilic ancillary groups within the structure of the linker to enhance the lipophilicity and/or hydrophobicity of the compounds of Formula I is within the scope of the present invention. Lipophilic groups of use in practicing the instant invention include, but are not limited to, aryl and heteroaryl groups.
The aromatic groups may be either unsubstituted or substituted with other groups, but are at Least substituted with a group which allows their covalent attachment to the linker.
Other lipophilic groups of use in practicing the instant invention include fatty acid derivatives which do not form bilayers in aqueous medium until higher concentrations are reached.
Also within the scope of the present invention is the use of ancillary groups which result in the compound of Formula I being incorporated into a vesicle such as a liposome or a micelle. The term "lipid" refers to any fatty acid derivative that is capable of forming a bilayer or micelle such that a hydrophobic portion of the lipid material orients toward the bilayer while a hydrophilic portion orients toward the aqueous phase.
Hydrophilic characteristics derive from the presence of phosphato, carboxylic, sulfato, amino, sulfhydryl, nitro, and other like groups. Hydrophobicity could be conferred by the inclusion of groups that include, but are not limited to, long chain saturated and unsaturated aliphatic hydrocarbon groups of up to 20 carbon atoms and such groups substituted by one or more aryl, heteroaryl, cycloalkyl and/or heterocyclic group(s).
Preferred lipids are phosphoglycerides and sphingolipids, representative examples of which include phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, palmitoyloIeoyl phosphatidylcholine, Iysophosphatidylcholine, lysophosphatidyl-ethanoIamine, dipalmitoylphosphatidylcholine, dioleoylphosphatidylcholine, distearoyl-phosphatidylcholine or dilinoleoylphosphatidylcholine could be used. Other compounds lacking phosphorus, such as sphingolipid and glycosphingolipid families are also within 1o the group designated as lipid. Additionally, the amphipathic lipids described above may be mixed with other lipids including triglycerides and sterols.
The flexibility of the linker can be reduced by the inclusion of ancillary groups which are bulky and/or rigid. The presence of bulky or rigid groups can hinder free rotation about bonds in the linker or bonds between the linker and the ancillary groups) is or bonds between the linker and the functional groups. Rigid groups can include, for example, those groups whose conformational lability is restrained by the presence of rings and/or multiple bonds, for example, aryl, heteroaryl, cycloalkyl, and/or heterocyclic. Other groups which can impart rigidity include polymeric groups such as oligo- or polyproline chains.
2o Rigidity can also be imparted electrostatically. Thus, if the ancillary groups are either negatively or positively charged, the similarly charged ancillary groups will force the presenter linker into a configuration affording the maximum distance between each of the like charges. The energetic cost of bringing the like-charged groups closer to each other will tend to hold the linker in a configuration that maintains the separation between 25 the like-charged ancillary groups. Further, ancillary groups bearing opposite charges will tend to be attracted to their oppositely charged counterparts and potentially may enter into both inter- and intramolecular ionic bonds. This non-covalent bonding mechanism will tend to hold the linker into a conformation which allows bonding between the oppositely charged groups. The addition of ancillary groups which are charged, or 3o alternatively, bear a latent charge which is unmasked, following addition to the linker, by deprotection, a change in pH, oxidation, reduction or other mechanisms known to those of skill in the art, is within the scope of the present invention.
Rigidity may also be imparted by internal hydrogen bonding, or by hydrophobic collapse.
Bulky groups can include, for example, large atoms and/or ions (e.g., iodine, sulfur, metal ions, etc.) groups containing large atoms, polycyclic groups, including aromatic groups, non-aromatic groups and structures incorporating one or more carbon-carbon multiple bonds (i.e., alkenes and alkynes). Bulky groups can also include oligomers and polymers which are branched- or straight-chain species. Species that are branched are expected to increase the rigidity of the structure more per unit molecular weight gain than are straight-chain species.
In preferred embodiments, rigidity is imparted by the presence of cyclic groups (e.g., aryl, heteroaryl, cycloalkyl, heterocycles, ete.). In other preferred embodiments, the ring comprises one or more six-membered rings. In still further preferred embodiments, the ring is an aryl group such as, for example, phenyl or naphthyl.
Eliminating or reducing antigenicity of the compounds of Formula I by judicious choice of ancillary groups) is within the scope of the present invention. In certain applications, the antigenicity of a compound of Formula I may be reduced or eliminated by the use of groups such as, for example, polyethylene glycol).
As explained above, the multibinding agents of the invention comprise 2-10 ligands attached to a linker that connects the ligands in such a manner that they are presented to the 5-HT receptors for multivalent interactions with the appropriate receptors (ligand binding site). The linker spatially constrains these interactions to occur within dimensions defined by the linker, thus increasing the biological effect of the multibinding agent as compared to the same number of individual units of the ligand.
The multivalent compounds of the invention, the compounds of Formula I, are represented by the empirical formula (L)P(X)q. This is intended to include the several ways in which the ligands can be linked together in order to achieve the objective of multivalency, and a more detailed explanation is given below. However, as previously noted, the linker can be considered as a framework, and it should be understood that the ligands can be attached to this framework at any intermediate point on the framework, 4~

and/or on the termini of the framework. For example, if the linker is a linear chain, a bivalent compound can be constructed by attaching two ligands at the two ends of the linear chain, or alternatively attaching two ligands at some intermediate atom along the chain. The same considerations apply to the compounds of the present invention containing more than 2 ligands. _ The simplest (and preferred) muItibinding agent is a bivalent compound, which can be represented as L-X-L, where L is a ligand and is the same or different, and X is the linker. It should be noted that the linker X can be linear or cyclic, or a combination of both linear and cyclic constructs, and that the two ligands may be located at the termini of 1 o the linker or may be attached at some intermediate attachment point. This concept is diagrammed in the Appendix. The same is true for a trivalent compound, which can also be represented in a linear fashion, i.e. as a sequence of repeated units L-X-L-X-L, in which L is a ligand and is the same or different at each occurrence, as can X.
or a compound comprising three Iigands attached to a central core, and thus represented as (L)3X, where the linker X could include, for example. an aryl or cycloalkyl group. See the Appendix for a pictorial representation of this concept, in which the shaded objects represent a ligand and the remaining structure represents the linker.
The same considerations of geometry apply to the compounds of the present invention containing 4-10 ligands. For example, a tetravalent compound could be represented as L-X-L-X-L-X-L,orL-X-L-X-L
L
i.e. a branched construct analogous to the isomers of butane (n-butyl. sec-butyl, tert-butyl). Alternatively, it could be represented as an aryl or cycloalkyl derivative as above with four ligands attached to the core linker. The same principles apply to the higher multibinding agents, e.g. pentavalent to decavalent compounds. However, for multibinding agents attached to a central linker such as benzene, there is the self evident constraint that there must be sufficient attachment sites on the linking moiety to 3o accommodate the number of ligands present; for example, a benzene ring could not accommodate more than six ligands, whereas a saturated anmd/or mufti-ring linker (cyclohexyl, cyclooctyl, biphenyl, etc.) could accommodate a larger number of ligands.

The formula (L)p(X)q is also intended to represent a cyclic compound of formula (-L-X-)", where n is 2-10. For example, where n is 3:
X
X~L/X
All of the above variations are intended to be within the scope of the invention as defined by the Formula I (L)P(X)q.
The preferred linker length will vary depending upon the distance between adjacent ligand recognition sites , and the geometry, flexibility and composition of the linker. The length of the linker will preferably be in the range of about 2-100 Angstroms, more preferably about 2-50 Angstroms, and even more preferably about 5-20 Angstroms.
l0 With the foregoing in mind, preferred linkers may be represented by the following formula:
in which:
m is an integer of 0-20;
-X,-Z,-(Y,-Z")m-Y"-Z,-X,-IS X' at each separate occurrence is -O-, -S-, -S(O)-, -S(O)2-, -NR- (where R
is as defined below), -C(O)-, or a covalent bond;
Z' and Z" at each separate occurrence are alkylene, cycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, heterocycloalkylene, or a covalent bond;
2o Y' and Y" at each separate occurrence are ~N ~N~N~
~ , ' ' ' , .
-N N
N~ ~N~ -P(C)1(~R~~-~ , >
\N~N/ -S(O~,-CR'R"-. -S(O~,-NR'-.
R~ , -O-Z'-O-, -N(R)-Z'-N(R}, -S-S-, or a covalent bond;
in which:
n is 0, 1 or 2; and R, R' and R" at each separate occurrence are chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, and heterocyclo.
Additionally, the linker moiety can be optionally substituted at any atom in the chain by alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, halo, nitro, aryl, heteroaryl, or heterocyclo.
Preparation of Compounds of Formula I
Examples of the chemistry for connecting ligands by a linker are shown in the table below, where R' and R'' represent a ligand and/or the linking group.

O
R~ O I ~Rz Rz R~
O
O HATU, HOAX' I' + ,Rz iPrzNEt, NMP R~~N'Rz R~~OH HzN H
NaBH3CN, ~ - Rz R H + HzN. Rz 1 % AcOH, DMF R' H
HO~ N. Rz R1 + HzN. Rz TR H
O
~CI ~ SH
CI O R' O
~N.Rz iPrzNEt CI II N,R iPrzNEi R' S~N.R

H H
(OMe, NHAc, Ph,Me...) O ~ (OMe, NHAc, Ph,Me...) R~~ H + ~N ~ Rz + I ~ ~ . Rz R' H
R; OH TsCI, Pyr R,~OTs+ HS.Rz iPrzNQ R ~S\R
z O O
C II
R ~~N + HzN.Rz ~ R~~H~H'Rz O O
R ~S02CI + H N'Rz iPrzNEt R1~S.Rz O
R~ H N' Rz iPrzNEt 0~ H. Rz ~O~CI + z R~
O

As indicated above, the simplest (and preferred) construct is a bivalent compound, which can be represented as L-X-L, where L is a ligand that is the same or different at each occurrence, and X is the linker.
Accordingly, an example of the preparation of a bivalent multibinding agent is given below as an illustration of the manner in which multibinding agents of Formula I
are obtained.
Preferred ligands are triptans. Examples of such compounds are disclosed in the following patents and patent applications, the complete disclosure of which is hereby incorporated by reference. DE 3131728, US 5565447, WO 9317017, WO 9506638, WO
l0 9744602, WO 9842344, US 4252803, WO 9206973, W09629075, US 5317103, WO
9606601, EP 0303507, EP 0497512, US 347437, US X173491, US 5332759, US
5618948, US 5037845, and US 5863935.
Preferred ligands may be represented by the following structure:
R
Rz R
Formula II
wherein:
Rl, R2, R6 and R' are all hydrogen; and R3 is hydrogen, heterocyclic, heterocycloalkyl, alkylaminoalkyl, dialkylaminoalkyl, or a linking position;
R4 is hydrogen or heterocyclic; and RS is hydrogen, fluorine, alkyl, heterocyclic, heteroaryl, heteroarylalkyl, amidoalkyl, alkylaminosulfonylalkyl, dialkylaminosulfonylalkyl, arylsulfonylalkyl, heterocyclosulfonylalkyl, arylcarbonylamino, alkylsulfonamido, or alkylsulfonylalkyl, or a linking position; or Ra R2 and R3 when taken together with the carbons to which they are attached represents optionally substituted cycloalkenyl.
all of which may be optionally substituted as defined in the Detailed Description of the Invention.
Particularly preferred are those l~gands in which:
R3 is dimethylaminoethyl, I-methylpiperidin-4-yl, I-methylpyrrolidin-2-yl, methylamino;
or a linking position;
RS is methylaminosulfonylmethyl, methylaminosulfonylethyl, 1,3,-oxazolidin-2-one-3-methyl, I-triazolemethyl, 4-fluorobenzoylamino, phenylsulfonylethyl, and I-to pyrro:idinsulfonylmethyl; and R2 and R3 when taken together with the carbons to which they are attached represent 4-methylaminocyclohexene.
For example, sumatriptan is a compound of Formula II in which R', R', R~, R6 and R' are all hydrogen, R3 is (CH3)2NCHZCH2-, and RS is CH3NHSOZCH~-, that is:

~N CHs H
N
CH3~ ~S, O
H
Similarly, naratriptan is a compound of Formula II in which RI . R2, R4, R6 and R~ are all hydrogen, R3 is N-methylpiperidin-4-yl-, and RS is CH3NHS02CH,-, that is:

i -N
H
H
Zolmitriptan is a compound of Formula II in which R l , R2, R4, R6 and R7 are all hydrogen, R3 is (CH3)2NCHZCH2-, and RS is oxazolidin-2-one-4-methyl, that is:
Rizatriptan is a compound of Formula II in which Rl, R2, R4, R6 and R7 are all hydrogen, R3 is (CH3)ZNCHZCHz-, and RS is 1H-1,2,4-triazole-1-methyl, that is:
N'N
N H
LY-334370 is a compound of Formula II in which Rl, R2, R4, R6 and R7 are all hydrogen, R' is N-methylpiperidin-4-yl-, and R~ is 4-fluorophenylcarboxamido, that is:
SO

N
F
N
O w ~ N
H
Eletriptan is a compound of Formula II in which R1, R~, R4, R6 and R~ are all hydrogen, R3 is N-methylpyrrolidine-2-methyl and RS is 2-(phenylsulfonyl)ethyl, that is:
O, ,O J
i ~ S I w \ N
a N
H
Almotriptan is a compound of Formula II in which R1, R~, R~, R6 and R~ are all hydrogen, R3 is (CH3)2NCHzCH2-, and R5 is pyrrolidin-1-ylsulfonylmethyl, that is:
N' ~N.
OSO I i \
N
H
VML-251 is a compound of Formula II in which Rl, R4, R6 and R~ are all hydrogen, R
and R3 when taken together with the carbons to which they are attached represents 4-to methylaminocyclohexene, and R' is carboxamido, that is~
H
~N
O
HzN I ~ \
N
H

The triptans may be linked via any position on the ring, including the indole nitrogen. Preferred are linkers that utilize the existing substituents at the 3-position and/or the 5-position side chain, e.g., for sumatriptan, linking via the (CH3)2NCH2CH2-and/or CH3NHS02CH2 - groups can be utilized.
Ligands can be linked at a variety of positions using known synthetic methodology.
An example of positions on a ligand that may be utilized for linking is shown below (Figure 1 ), using sumatriptan as an example; the positions available for linking are indicated by arrows.
H3C~
N ~.,-CH3 *
H
* ~~ ~C
* N
~CH3~ ~S,~
H
Figure 1 The positions indicated by a star are the preferred positions for linking.
Additionally, the 3 and 5 positions are preferred for linking in those instances where there is no existing sidechain at the 3 or 5 position.
In some cases, it is preferred to link ligands directly, using the functionality already present in the known drug. For example, a ring nitrogen (e.g., an indole N) may be used for direct linking. In other cases, it is preferred to accomplish linking indirectly by first preparing an intermediate that upon reaction yields the multibinding agents of~the invention. Such intermediates may be commercially available, or are prepared by means well known in the art. The intermediates can be linked to each other before the intermediate is modified to the target ligand structure, or linking can occur after such modification. In some cases, it may be necessary to protect portions of the ligand that are not involved in linking reactions; protecting groups are well known to those skilled in the art. Examples of the preparation and use of such intermediates are shown below in figures 5-15.
In general, the ligand or the ligand intermediate is reacted with a 'core' molecule having two or more functional groups with reactivity that is complementary to that of the functional groups on the ligand, thus linking ligands by a linker. Selecting different core molecules allows control of linker size, shape, orientation, rigidity, acidity/basicity, hydrophobicity/hydrophilicity, hydrogen bonding characteristics, and number of ligands connected. Examples of "cores" are shown below in Figure 2. The solid circle is used in l0 the following figures and reaction schemes to represent any of the possible core molecules. That is, the solid circle is equivalent to a linker as defined above after reaction.

Alkyl Cores Aromatic Cores ...
H
;",,. \ l \ l w i , w i H-bond donor/acceptor cores O f O O
f S ~'~O x N ~~
_ _ - ~~N~/~,~ ' f N~tt~' I f ~./~0~.~
AcidicBasic cores CO=H I N
_~_ _ ~ \ i ~ , ~~N~~
V>2 cores .
- ~ - N J'~ ~ \ / ~ ~ ~4 y ~fNNN~'~
I
- O
_ - - N
/ \ \ / ~N~ ~N w N
I ~ ~ O

The preferred compounds of the invention are bivalent. Accordingly, for the sake of simplicity, the following figures and reaction schemes illustrate the synthesis of bivalent triptans. It should be noted, however, that the same techniques can be used to ~U~~TUTE SHEET (RULE 26) prepare multibinding agents that are derived from ligands other than triptans, and also generate higher order multibinding compounds, i.e. the compounds of the invention where n is 3-10.
SYNTHESES OF BIVALENT COMPOUNDS
Linking at the 1-Position In the triptan class, linking at the R' position can be accomplished by starting with a monovalent ligand, since the indole N can function as a nucleophile. Using this strategy, the triptan is reacted with a core molecule presenting two or more appropriate to electrophilic groups. Figure 3 demonstrates this strategy, as applied to sumatriptan, where the electrophilic groups chosen are alkyl bromides. One skilled in the art would recognize that many electrophiles equivalent to bromides (for example, other halides, mesylates, tosylates, etc.) may be used.

Br~ R, I ~ \
gr ~ N
R (2) R
N
NaH
N
C1) R5 I i /

In general, about two molecular equivalents of the ligand ( 1 ) are reacted with about 1 molecular equivalent of the dihalide of formula (2) under conventional reaction conditions, for example in an inert solvent in the presence of a base.
Linking at the 2-Position Linking at the R2 position can also be accomplished by using the monovalent ligand as the starting material, since this position can be functionalized by known techniques.
After an electrophilic functional group has been introduced as a sidechain at R', a core molecule presenting two or more appropriate nucleophilic groups, such as amines, is SS

added. A variety of such coupling reactions are well known in the art;
examples are shown in Figure 4.

Rs I ~ \ o N H
H
s ~S R3 Rs i Rs i Pd(Ph3)~, CO
I \ AcOH ~ \ Br TFH, reflux ChiCIZ N
(I) (3) R3 Rs ~ \ O
I ~ N OH
H

(5) Ra Ra ~N~N
H H
Rs NaBH4 PBrs R3 (~ R; Rs Rs I ~ \ O Rs \ Rs I ~ \ ~ i ( R3 etc. I ~ N Br CHCI3 H N N\ H
H H H
pyridine Ra Ra (6) (1) Ra Ra ~N--~N
H H
R R~ O (7) _ Rs R3 R R~
s i % \ I ~ \ ~ \ I
H H NaBH(OAc)s H a ~N, 8 H
AcOH R R

(4) ( I ) Ra Ra ~N~N

R5 H (7) H Rs ~ R 0 O R R~
s R I \ \ 0 DlC I ~ N N~N N w I
H OH DMFA H Ra ~Re H
(5) (I) Where Rg is hydrogen , alkyl, alkaryl, alkenyl, alkynyl, cycloalkyl, all of which are optionally substituted as defined in the Detailed Description of the Invention.

SUSSTf TUTE SHEET (RULE 26) WO 99/64044 PC'T/US99/12751 -Linking at the 3-Position A preferred method of linking ligands utilizes the sidechains already present on the ligand to form a linker. The preferred method for linking these sidechains in many cases requires the preparation of a suitable intermediate. For example, linking two triptans through their (CH3)2NCH2CH2- groups (see, for example, sumatriptan) at the R3 position can be accomplished indirectly through an electrophilic intermediate at the second carbon of the sidechain. The preparation of such a compound is shown in Figure 5 (the preparation of the alcohol intermediate (10} is discussed in more detail in WO
9617842).
OMs MsCI Rs I \
O CI OH / H
o Ct ~~ ( ) R ~ CI O s ~ s 11 \ -~. R ~ \ O R ~ \
~ i N ~ i N SwertJPCC O
H H H Rs H
(9) (10) N
H
(12) O
Rs OOH
--r I w \
N
H
(13) This intermediate is then reacted with a core molecule that has two or more appropriate nucleophilic functional groups. A variety of such coupling reactions are well known in the art; Figure 6 illustrates several examples.

RS RS RS RS
OMs H ~ H N;--N
R5 (7) Rs Rs CHC13 / H H \
pyridine (11) (I) RS RS
RS RS
O N~N . i H H N-~-N
RS .H (7) .
R5 \ ~ Rs N CH Cl I N N
H NaBH(OAc)3 / H H
p12) AcOH
(1) O RS RS
N-.-N, ~ , H 7 H N-~-N
Rs OH ( ) Rs ~O O~ R5 ~ \
DIC
DIPEA / H H
(13) DMF
(I) Where Rg is hydrogen , alkyl, alkaryl, alkenyl, alkynyl, cycloalkyh all of which are optionally substituted as defined in the Detailed Description of the Invention.
Linking two ligands through (CH3)aNCH2CH2- groups at the R3 position can also be accomplished indirectly by introducing a secondary amine, of the form (CH3)HNCH2CH2-, into the 3-position of the triptan as an intermediate,. The preparation of such a compound is shown in Figure 7.
IO

H
H~. Pd/C N
~OMe CN
RS Me0 -RS H,NMe R5 ~ N.NHz H3oC4, ~ N ~ N
H z H H
(14) (15) (16) The reactions are described in more detail in German Patents Nos. DE 3527648 and DE
3320521, and in Drugs of the Future 1997, 22(3):260-269.
This intermediate is then reacted with a core molecule having two or more appropriate electrophilic functional groups. A variety of such coupling reactions are well known in the art, as shown in Figure 8.

\N.H Br~Br \1'1~N~
~- (2) Rs Rs R ~ ~ i I , \ CHZCIZ I ~ N N ~ I
N
H pyridine H H
(1) (16) O~H
~N~H H~O ~N~Ni ( 17) R I \ \ R~ ~ \ / ~ R5 N CHZCh I
H NaBH(OAc)3 H N
AcOH H
(I) (16) O, - .OH
O O
~N,H HO O ~''~'~
(18) N - N

~ \ R5 ~ i R5 I / H DMFA I / N N \ I
H H
( 16) Similar linking reactions may be carned out on ligands having a piperazine substituent at the 3-position, e.g., a ligand derived from naratriptan, for example, having a structure:
H
N
O"O
( 16a) H ~ i \
N
H
or derived from the compound identified as LY-334370, structure WO 99/64044 PC'T/US99/12751 H
IV
F
( 16b) 4 ~ i N
H
Such a compound is prepared starting from N-(4-fluoro)benzoylation according to a literature procedure (Johnson, Kirk; Phebus, Lee, PCT WO 98/11895, 1997).
Linkin at the 5-Position Known ligands exhibit greater variety at the R' position, but all can be linked to cores using known chemistry. For example, linking two ligands through CH3NHSO~CH~
groups (e.g. sumatriptan or naratriptan) can be accomplished by first preparing an electrophilic intermediate of the form (Ph0)S02CH~-R. The preparation of such an intermediate is shown in Figure 9, and the preparation is described in more detail in DE
3527648 and EP 145459.
(a) PdIC CN
HtOAc ~OMe C,~ H,. Pd/C N _ HNMe=
PhO.s ~ Ph0.5' ~ Me0 PhO.S I ~ \ ~ PhO.s I w \
NO, O O ~ i N.NH, H PO . O n~ O O ~ N
J
H H,0 H H
(b) NaN03 _ (19) SnCl2 (2p) (21) (22) ~5 FIGURE 9 This intermediate is then reacted with a core molecule with two or more appropriate nucleophilic groups, such as amines, as shown in Figure 10.

N~N R8 R8 R3 OPh H H R3 ~N-~-N R3 N w I O S:O ( ) N w ( O S:O OSO I i N
DMF, DIPEA, RT H H
(23) ( I ) Where Rg is hydrogen , alkyl, alkaryl, alkenyl, alkynyl, cycloalkyl, all of which are optionally substituted as defined in the Detailed Description of the Invention.
Linking ligands through an oxazolidinone sidechain (for example, as in zolmitriptan), can be accomplished directly from the ligand by f rst protecting the indole nitrogen, as shown in Figure 11. After coupling to a core molecule with two or more appropriate electrophilic functional groups, the indole nitrogen is deprotected Br O~~' I
~N
R3 BoczO Ra Br p H
I ~ \ ~ ~\. ~ \ (2} TFA
DMAP, h.,.NH I i N -O H CHzCl2 O Boc NaH CH,CI, TEA
(24) (25} o N I w N
a R

Linking ligands through an oxazolidine sidechain groups can also be accomplished indirectly by first preparing a nucleophilic intermediate of the form (NH2)(CHZOH)CHCH2-R. The preparation of such a compound for zolmitriptan is known (ref: Drugs of the Future 1997, 22(3):260-269). This intermediate is reacted with a core molecule with two or more appropriate electrophilic functional groups, as shown in Figure 12. After linking, the oxazolidine ring is formed by known cyclization reactions.

O~H HO H ', ~ ~ O~~' H ~-N

R (tg) CI SCI
HO~~~ ~ w HEN i N LfegH(OAc~ TEA, CH,CI, H AcOH N O H
(26) Ho ~ ~ ~ o N ~ ~ N
Rs R3 (27) (t) Another strategy for linking at the ~-position starts from 5-nitroindole, which is commercially available. As shown below in Figure 13. the first step involves substitution at the 3-position by a desired substituent, for example N-methylpiperidine, and then reduction by conventional means to the 5-amino derivative.
Me Me N N
02N / I ~ ---~.02N / I ~ --:. HzN
N ~ N ~ H
N H
(40) (41 ) Alternatively, a 5-aminoindole substituted at the 3-position by a 2-(dimethylamino)ethyl group can be prepared as shown in Figure 14 WO 99/64044 PCTlUS99/12751 -Me O ~N-R~ Me,N-R1 OzN \ I N OzN \ I \ \O -'-~ OzN / \
H
H
(42) (43) where R' is hydrogen or methyl Me Me N-H ~N-Boc OzN / I \ HzN / I \
N ~ N
H f-'.
(43) (44) where R' is hydrogen The compounds of formula (41 ) and (44), or any similar 5-amino derivative, can be converted to a compound of Formula I by reaction of the 5-amino group with a linker via any of the routes shown above, e.g., by reacting with .a dicarboxylic acid, a dihalide, a dialdehyde (reductive alkylation), a disulfonyl halide, a diacid halide, a diisocyanate (to give a diureido derivative), and the like.
Alternatively, the compounds of formula (41 ) and (44), or any similar ~-amino to derivative, can be converted to a compound of Formula I that are linked at the 3-position by first reacting the ~-amino group with a desired reagent, for example reaction with 4-fluorobenzoyl chloride to form the desired 5-(4-fluorobenzoylamino) derivative, and then linking the 3-popsition by first removing the Boc protecting group under standard conditions and then reacting the free amino group as described above, e.g., with .a IS dicarboxylic acid, a dihalide, a dialdehyde (reductive alkylation), a disulfonyl halide, a diacid halide, a diisocyanate (to give a diureido derivative), and the like, to form a bivalent compound.
Linking at the 5-positon can also be accomplished by first preparing a ~-carboxy indole derivative, as shown in Figure 15.

Me Me N
H02C , I ~ ~ H02C , ( \ ~EtO
N
H H
Me (45) (46) N

wl y N
H
(47) The compounds of formula (45) and (47), or any similar 5-carboxy derivative, can be converted to a compound of Formula I by reaction of the 5-carboxy group with a linker via any of the routes shown above, e.g., by reacting with a diamine, a dihalide, a disulfonyl halide, a diisocyanate (to give a dicarbamate derivative), and the like.
5-HT ligands that are not triptans may be prepared and used for linking with triptans.
For example, a naphthalene derivative can be prepared as shown in Figure 16.
i H3 NHZ CH3 CN_ HO I / / f N ~ HO I w w i i CI CI
(48) The compound of formula (4$), or any similar hydroxy bearing ligand, can be converted to a compound of Formula I in which both ligands are the same by reaction of about 2 molar equivalents of the 5-hydroxy group with about 1 molar equivalent of a linking moiety via any of the routes shown above, e.g., by reacting with .a dihalide, a disulfonyl halide, a dicarboxylic acid, and the like. Alternatively, to prepare a compound of Formula I where the ligands are different, a compound of formula (48), or a similar S-hydroxy derivative, is reacted with a large excess of a dihalo compound, for example a dihaloalkane derivative, to give ~ compound of the formula:

CND
i i ~-(CHy)n-X
where X is halogen.
The compound of formula (49) can then be further reacted with a different ligand to provide a compound of Formula I where the ligands are different.
l0 Thus, by following the above procedures, compounds of Formula I where p is 2 and q is 1 can be prepared in which the SHT ligands are the same, both being SHT
agonists or both being SHT antagonists, or are different, in which case both ligands may still both be SHT agonists or SHT antagonists, or alternatively a compound of Formula I
where one SHT ligand is a SHT agonist and the other ligand is a 5HT antagonist may be prepared.
15 For example, reaction of the~compound of formula (49) with a triptan SHT
ligand gives a compound of Formula I with Similarly, reaction of a ligand bearing a 5-amino group with an excess of a dicarboxylic acid, a dihalide, a dialdehyde (reductive alkylation), a disulfonyl halide, a diacid halide, a diisocyanate (to give a diureido derivative), and the like, provides a 20 suitably substituted ligand that can be further reacted with a different ligand to provide a compound of Formula I where the ligands are different.
Similarly. reaction of a ligand bearing a 5-carboxy derivative with an excess of a diamine, a dihalide, a disulfonyl halide, a diisocyanate (to give a dicarbamate derivative), and the like, provides a suitably substituted ligand that can be further reacted with a 25 different ligand to provide a compound of Formula I where the ligands are different.

Another strategy, which can be applied to all ligands, is to introduce a 'spacer' at any desired position on the molecule before coupling to the central core. Such a spacer can itself be chosen from the possible core compounds, and comprises an electrophile or nucleophile on one end and an electrophile or nucleophile on the other. That is, the ligand is coupled to the spacer, aid the product of that reaction is then coupled, after deprotection if necessary, with an appropriate central core. Examples of this type of linking as applied to the 3-position are shown below in Figure 17.

WO 99/64044 PCT/US99/12?51 O
O Ra Rs NH '~ OH
OEt ' N~N
Rs w (28) -OH N H (7) H
I ~ \ ~. Rs (29) H NaH I ~ N DIC
H DMF
(16) Rs 'N R R N/ Rs N N
I ~ \ O O / i I
/ H (I) H \

R ' - 'NH OOH
Bf 'NH NN
Boc N HO O
Rs (30) TFA (18) I \ Rs (31) N I
H ~ H DIPEA
DMF
(16) ' , N O O ~N
Rs N ~ N Rs I w \ R9 R9 / i I
/ H ([) H
'N O O Rs Ra H OEt ~N-~-N
O (32) -OH ~OH H ' H
R H 'N ( ) I \ CH,CI, s DIC
NaBH(OAc); R I ~ \ (33) DMFA
AcOH i N
H
(12) R5 'N ~IV~Na~ N/ Rc O O /
N N w H (1) H
Rio OOH
N-~-N R i ~o H Boc v i HO O
O (34) TFA N N (18) H
s H
R I ~ ~ CH,CI, Rs I ~ \ DiC
NaBH(OAc); i N (35) DMFA
AcOH H
(12) 'N~ O O ~N~
w Rs I \ Rto Rio / ~ I Rs N N
H ([) H

Where R9 and R'° are independently chosen from hydrogen, alkyl, alkaryl, alkenyl, alkynyl, cycloalkyl, all of which are optionally substituted as defined in the Detailed Description of the Invention.
The same reactions may be employed starting from any amine, for example the s compounds of formula ( 16a) and ( 16b) can be reacted with a haloeater of formula (28).
To give the corresponding derivatives of formula (29a) and (29b), etc. Also, the same strategy can be used for introducing a spacer at any position of the ligand, in particular the 5-position.
All of the synthetic strategies described above employ a step in which the ligand, l0 attached to spacers or not, is symmetrically linked to a central core in a single reaction to give a bivalent compound. Higher order compounds (i.e. multibinding agents in which n is 3-10) can also be synthesized using an asymmetric. linear approach. This strategy is preferred when the target compound is not symmetric.
Linear synthesis is preferred when linking two or more monomers at different points i5 of connectivity. For example, the R3 of one sumatriptan monomer can be linked to the R' or R' of another sumatriptan monomer, as shown in Figure I 8.

N' i PhO, NH R9 S. ~ ~ \ R9 N r B~'-~-N O O i N ~ r--~-N~
~ i \ 30 Boc TFA (22) H H pSp ~ \ \
N ( ) N' / H
H ~ S. ~
NaH O O ~ N
(36) H (~) NH
_N O B~ O , H
-N\ ,O ~ N.S w S.O OEt S'O O O ~ i N
( g) OH (36) H
\ / \ /
w NH NaH
,OH
DIPEA
p Dl~ff (36) (37) -N DSO
\ /
~ N O
~N ~N~
H
S.N
N w ~ 00 H

Where R9 is hydrogen , alkyl, alkaryl, alkenyl, alkynyl, cycloalkyl, all of which are optionally substituted as defined in the Detailed Description of the Invention.
The above reaction schemes concentrate upon triptan derivatives. However, it should be understood that also within the scope of the invention are non-triptan ligands.
They can be linked in the same manner as shown above where appropriate. The example l0 below (FIGURE 19) shows the preparation of compounds of Formula I where p is 2 and q is 1, and the ligands are the same (a homodimer) or different (a heterodimer), using PNU-109291 as an example.

O ~OMe H I ' O N~.JN
Type 4 Type I ~ ~ ypc 3 Type 2 Type ! Homodimers Type 3 Type ! Hete~odimers Me0 ~ i ON~N~ i OMe O

H H I ~ _O w I 'N ~ O OMe N1 ~N H I ~ O ~N ~ ~ I
',N y ~ ~.N.J r-H ~li Or,N
"t.NJ
Type 2 Homodimers o 0 ~~ N
, H 't. i i O~ H
N.~, N .i Type 3 Homodimers O ~N~
,H I ' 0 JV NJ 0 H I H
N
JN
s Type 4 Homodimers 0.Ø.o N.
~H I ~ ON JN~ I i I H

',N.i ~UgST~IffE SHEET ~R~I.E 26) Synthesis of Type 1 Homodimers ~.O,i NH 0 0 , ' I OOH ~~ Me0 ~ ~ N, O- ' ~ N w,OrN t ~ ~ N ~ ~ OMe 'N ~ HOAT/HATU/DMF 'N.i s s- N ~
Synthesis of Type 2 Homodimers O
~N Br Br .H ' 0, ~, N
H y O -~ N~N~ 0 . ~ H
N
NH DMF~DII'EA _ .
O
Synthesis of Type 3 Homodimers O
O ,--( ~ ~'-. .H ~' OrN , ~ rN
~N Br- " Br H N J ' N / 0 'i H
H~ r'NH ' N.
H O
s N J DMF/D<PEA
. O
Synthesis of Type 4 Homodimers O
0 ~~-wNfCi .N ' i p.~Nw.O i .N ~ ~i OH ~_ H . p~.N~ ~N10~H.
N/ 'Ni H ' ' 0 ~ N ~ DMF~CsiCO~
Ni Synthesis of Type 3-Typel Heterodimers HO i OMe O ~~ p~N~ 'N . O
i~ 0~ ~N/ H ~~ O~ ~. 0 'iOMe ~NiH ~N/ H ~N
~Ni HOAThtATU/DMF
A method of preparing multibinding agents where n is 3-10 is illustrated in Figure 20, 5 in which sumatriptan is linked from RS to R3.

NBoc PhO, NH Br R OSO ~ % \ R9 NBoc H N N ~ i-~-N
\ Boc TFA 38) H H N ~g w \
N (30) -.. ---~ N. O O I ~ N
H NaH / OSO ~ ~ \ H
N
H
TFA (30) TFA (38) TFp (30) TFA (38) TFA
.-~ -~ -.~ ~ -.~
NaH NaH
R9 N' I
w-~-N
R9 N \S. ~ ~ \
R9 N-~-N. O O ~ N
I S.. ~ w \ H
vN~-N~ ~ O O ~ N
S H
H O .O ~ i 'N'S ~ \ H
O O ~ i H (j) Where R9 is hydrogen , alkyl, alkaryl, alkenyl, alkynyl, cycloalkyl, all of which are optionally substituted as defined in the Detailed Description of the Invention.
A linear strategy can also be extended to the synthesis of compounds of Formula I in which L is different. Examples of such reactions are shown in Figure 21, which is a simple extension of the strategies described above.
H N~O~N N ~N~NH ~ .N
v ~ ~ /
\ / ~ ~ O / w ~ OSO O O
H N~ HN~ H
H O
(!) (1) Sumatriptan Zolmitriptan Sumatriptan Naratriptaa It should be noted that while all figures are drawn with aliphatic couplings for the sake of simplicity, an alternate linking strategy involves direct substitution on an aryl ring. An example of this is shown in Figure 22.
Br-~-Br HN-~-NH
Br Br R R
Br \ / Br Br \ ~ Br \ / R R
NH
IrNHz ' ~ \ / NH ' ~ \ / ' ~ \ /
_ R It R It Pd~ O

This strategy can be applied to any of the linking steps described above.
t0 Isolation and Purification of the Compounds Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick-layer chromatography, preparative low or high-pressure liquid chromatography or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the Examples hereinbelow. However, other equivalent separation or isolation procedures could, of course, also be used.
The following abbreviations have the following meanings. If an abbreviation is 2o not defined, it has its generally accepted meaning.
BOC - tert-butyloxycarbonyl Cbz - carbobenzyloxy DCC - N,N-dicyclohexylcarbodiimide DIPEA - diisopropylethylamine, Hunig's base DMA - N,N-dimethylacetamide - 4-(N,N-dimethylamino)pyridine DMAP

DMF - N,N-dimethylformamide DMSO - dimethylsulfoxide DPPA - diphenylphosphoryl azide ~Bll~fE SHEET (RULE 26) HATU - 6-(7-azabenzotriazol-I-yl)-N,N,NN'-tetramethyluronium hexafluorophosphate HBTU - 1-hydroxybenzotriazole HOAT - 1-hydroxy-7-azabenzotriazole PyBOP - pyridine benzotriazol-1-yloxy-tris(dimethyl-amino)phosphonium hexafluorophosphate TEA - triethylamine TFA - trifluoroacetic acid THF - tetrahydrofuran General: Unless noted otherwise, starting material (including di-amines, di-acids, di-halid~s, di-isocyanates, di-sulfonyl chlorides, and etc.) and solvents were purchased from commercial suppliers (Aldrich, Fluka, Sigma, and etc.), and used without further purification.
Reactions were run under nitrogen atmosphere, unless noted otherwise such as in hydrogenation reaction. Progress of reaction mixtures was monitored by thin layer chromatography (TLC).
analytical high performance liquid chromatography (anal. HPLC), and mass spectrometry, the details of which are given below and separately in specific examples of reactions. Reaction mixtures were worked up as described specifically in each reaction; normally it was purified by flash column chromatography with silica gel. Other purification methods include preparative TLC, temperature-, and solvent-dependent crystallization, precipitation, and distillation. In addition, reaction mixtures were routinely purified by preparative HPLC: a general protocol is described below. Characterization of reaction products was routinely performed by I H-NMR
spectrometry; samples were dissolved in deuterated solvent (CD;OD, CDC13, or DMSO-d6), and followed by acquisition of its 1H-NMR spectra with a Varian Gemini 2000 instrument (300 MHzj under standard observe parameters. Mass spectrometric identification of compounds was performed by an electrospray ionization method (ESMS) with a Perkin Elmer instrument (PE
SCIEX API 1 SO EX).
3o A general protocol for analytical HPLC: Each of crude compounds was dissolved in 50%
MeCN/H20 (with 0.1% TFA) at 0.5-1.0 mg/mL concentration, and was analyzed by using anal.
HPLC: 1) reverse-phased anal. column, Bonus-RP (2.1 x SO mm; ID = ~ Vim); 2) flow rate: 0.~
mL/min; 3) 10% MeCN/H20 (0.1% TFA) (0 - 0.~ min), 10 to 70% (linear gradient;
0.5 - 5 min);
4) detection: 214, 254, and 280 nm.
7~

A general protocol for preparative HPLC purification: Crude compounds were dissolved in 50% MeCN/H20 (with 0.1% TFA) at 30-45 mg/mL concentration, filtered, and injected into a reversed column. It was purified under following conditions: 1 ) column; YMC
Pack-Pro C I 8 (SOa x 20 mm; ID = 5 ~,m); 2) linear gradient: 2 to 40 % MeCN (O.I% TFA)/H20 (0.1% TFA) over 15 min; 3) flow rate: 40 mL/min; 4) detection: 214, 254, or 280 nm.

to Preparation of Compounds of Formula I
Preparation of a Compound of Formula I in which L is LY-334370 linked via the Sidechain at the 3-Position, p is 2 and q is 1 Preparation of a Compound of Formula ( 16b) A. The compound of formula (16b) was synthesized according to a literature protocol (Johnson, Kirk: Phebus, Lee, PCT WO 98/11895, 1997). 5-(4-fluorobenzoyl)amino-3-(piperidin 4-yl)-1H-indole: H'-NMR (CD30D, 299.96 MHz): 8 (ppm) 8.02-7.99 (dd, 2H), 7.92 (s, 1 H), 7.38-7.28 (m, 2H), 3.15-3.07 (br d, 2H), 2.98-2.86 (ddd, 1H), 2.8-2.7 (ddd, 2H), 2.06-1.98 (d, 2H), 1.78-1.62 (ddd, 2H); ESMS (C2°H2°F,N30,): calcd. 337.4, obsd. 338.1 [M+H]+, 675.2 [2M+H]+.
Preparation of a Compound of Formula I
B. A solution of DMF (1 mL) containing 5-(4-fluorobenzoyl)amino-3-(piperidin-4-yI)-1H-indole (67.4 mg, 0:2 mmole), and 1,2-dibromoethane (18.79 mg, 0.1 mmole) in a sealed vial was heated at 72°C for 48h while shaking. The reaction mixture was mixed into ether (45 mL) in a plastic bottle, and the mixture was shaken to homogeneity, precipitating a pale brown oily residue. Precipitate in the bottle was collected by spinning it down at 300 rpm for 20 min, rinsed with ether (50 mL), and dried in air. The crude reaction mixture was dissolved in 2 mL of 50%
MeCN/H20 (O.I % TFA), and purified by reversed phase semi-preparative HPLC.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) = 3.74 min. ESMS
(C42H.~~FZN602): calcd.
700.83, obsd. 701.3 [M+H]+.

C. Similarly, by optionally replacing 5-(4-fluorobenzoyl)amino-3-(piperidin-4-yl)-1H-indole with other compounds of formula (16) and optionally replacing dibromoethane with other dihalides in 1 B above, the following compounds of Formula I were prepared.
Table 1, compound 14 was prepared in an analogous manner from 1,3-diiodopropane.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over S min) = 3.74 min. ESMS
(C43H44F2N6~2)~ calcd. 714.86, obsd. 715.4 (M+H]+.
Table 1, compound 8 was prepared in an analogous manner from 1,6-dibromohexane.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) = 3.82 min. ESMS
(C4sHsoF2N602): calcd. 756.94, obsd. 757.5 [M+H]+.
l0 Table 1, compound 1 was prepared in an analogous manner from 1,7-dibromoheptane.
Retention time (anal. HPLC: 10 to 70% MeCN/Hz0 over 5 min) = 3.90 min. ESMS
(C4~H;2F2N~Ch): calcd. 770.97, obsd. 771.6 [M+H]+.
Table l, compound 2 was prepared in an analogous manner from 1,9-dibromononane.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) = 4.10 min. ESMS
(C49H56F2N6~2)~ calcd. 799.02, obsd. 799.5 [M]+.
Table 1, compound 3 was prepared in an analogous manner from 1,10-dibromodecane.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over S min) = 4.19 min. ESMS
(C;oH;8F2N602): calcd. 813.05, obsd. 813.6 [M]+.
Table 1, compound 4 was prepared in an analogous manner from 1,11-dibromoundecane.
2o Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) = 4.31 min. ESMS
(C;,H6oF2N60z): calcd. 827.08, obsd. 827.4 [M]+.
Table 1, compound 5 was prepared in an analogous manner from 1,12-dibromododecane.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) = 4.41 min. ESMS
(Cs2H62F2N64z): calcd. 841.10, obsd. 841.5 [M]+.
Table 1, compound 12 was prepared in an analogous manner from 1,2-dibromo-3,3,3-trifluoropropane. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over ~ min) =
4.74 min.
ESMS (C43H:~,F;N602): calcd. 768.83, obsd. 769.2 [M+H]~.
Table 1, compound 15 was prepared in an analogous manner from 1,3-dibromo-2-propanol. Retention time (anal. HPLC: 10 to 70% MeCN/HZO over 5 min) = 3.71 min. ESMS
(C43H~.~F2N603): calcd. 730.86, obsd. 731.4 [M+H]+.

Table 1, compound 16 was prepared in an analogous manner from 2,3-dibromopropionamide. Retention time (anal. HPLC: I O to 70% MeCN/H20 over 5 min) = 4.03 min. ESMS (C43H43F2N7~3)~ calcd. 743.86, obsd. 744.6 [M+H]+.
Table 1, compound 13 was prepared in an analogous manner from t-butyl 2,4-dibromobutyrate. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over S min) =
4.13 min.
ESMS (C4gH52F2N604): calcd. 814.98, obsd. 815.4 jM+H]+.
Table 1, compound 7 was prepared in an analogous manner from 1,2-bis(2-iodoethoxy)ethane. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) = 3.68 min.
ESMS (C46HSOF2N6~4)~ calcd. 788.94, obsd. 789.6 [M+H]+.
Table 1, compound 6 was prepared in an analogous manner from bis(2-chloroethoxy)ethylether. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) = 3.69 min. ESMS (C4gH5.~FzN605): calcd. 832.99, obsd. 833.4 [M+H]+.
Table 1, compound 11 was prepared in an analogous manner from a.a'-dichloro-m-xylene. Retention time (anal. HPLC: 10 to 70% MeCN/HZO over S min) = 3.86 min.
ESMS
(C4gH46F2N602): calcd. 776.93, obsd. 777.3 [M+H]+.
Table 1, compound 32 was prepared in an analogous manner from 1,4-dibromo-2-butene.
Retention time (anal. HPLC: 10 to 70% MeCN/Ha0 over ~ min) = 3.28 min. ESMS
(CaaHaaF2N64~): calcd. 727.87, obsd. 727.4 [M]T.
Table l, compound 33 was prepared in an analogous manner from a,a'-dibromo-p-xylene.
2o Retention time (anal. HPLC: 10 to 70% MeCN/H~O over 5 min) _ 3.37 min. ESMS
(C4gH46FZN60~}: calcd. 776.93, obsd. 777.3 [M+H]a.
Table 1, compound 9 was prepared in an analogous manner from 2,6-bis(bromomethyl)pyridine. Retention time (anal. HPLC: 10 to 70% MeCN/H~0 over 5 min) _ 3.71 min. ESMS (Ca7Ha5F2N~0~): calcd. 777.92, obsd. 778.5 [M+H]+.
Table 1, compound 17 was prepared in an analogous manner from 3-(2'-bromoethyl)-1 H-indole. Retention time (anal. HPLC: i0 to 70% MeCN/H~O over ~ min) = 4.02min.
ESMS
(C3oH29F~N40,): calcd. 480.59, obsd. 481.3 [M+H]+.
D. Similarly, by optionally replacing 5-(4-fluorobenzoyl)amino-3-(piperidin-4-yl}-1 H-indole with other compounds of formula ( 16) and optionally replacing dibromoethane with other dihalides in I B above, other compounds of Formula I are prepared.

E. The foregoing is an example of reaction of 2 molar equivalents of a ligand bearing an amino group with 1 molar equivalent of a linker having two chemically complementary groups (bromo) to form a compound of Formula I having two identical ligands (a homodimer). Reaction of I molar equivalent each of two dissimilar ligands bearing an amino group with 1 molar equivalent of a linker having two chemically complementary groups forms a compound of Formula I having two different ligands (a heterodimer). Alternatively, reaction of 1 molar equivalent of a ligand bearing an amino group with 1 molar equivalent of a linker having two chemically complementary groups followed by reaction of the intermediate thus formed with a second (and diferent) ligand t0 provides a compound of Formula I that is a heterodimer.
FXAMPT.P 7 Preparation of Compounds of Formula I
Preparation of a Compound of Formula I in which L is a Compound of Formula II
in which R', R2, R4, R6, and R' are Hydrogen, and RS is 4-Fluorobenzoylamino, linked via the Sidechain at the 3-Position, p is 2 and q is 1 A. Preparation of a Compound of Formula (42) 5-Nitroindole-3-N-methylglyoxamide was synthesized following similar procedures from a literature protocol (Macor, John E.; Post, Ronald; Ryan, Kevin, Syn. Commun.
1993, 23, 65-72). To a suspension of 5-nitroindole (10 g, 61.67 mmole) and phthalimide (4g, 27.17 mmole) in 2o ether (220 mL) at 0°c was added oxalyl chloride (13 mL, 149.1 mmole) in ether (30 mL) over 30 min. The reaction mixture was stirred for 3 days at room temperature under Na atmosphere. The reaction mixture was cooled to 0°C, followed by dropwise addition of 2M
MeNHz in THF (400 mL). After addition, the mixture was warmed gradually to room temperature, and stirred for 2 h.
The reaction mixture was concentrated in vacuo, yielding a pale yellow solid residue. It was partitioned between water (300 mL) and CH2C12 (500 mL), and the organic phase was removed.
Solid mass in the aqueous phase was collected on Buchner funnel, and washed with water (300 mL), 1.0 M NaOH (200 mL), water (300 mL), and MeOH (500 mL). The product, 5-nitroindole-3-N-methylglyoxamide, was obtained as a pale yellow solid (14g, 92%). H~ NMR
(CD30D, 299.96 MHz): 8 (ppm) 9.05 (d, 1 H), 8.98 (d, 1 H), 8.78 (d, 1 H), 8.16-8. I 2 (dd, 1 H), 7.33-7.30 (d, 1 H), 2.76-2.74 (d, 3H); ESMS (C "H9N30,~): calcd. 247.21, obsd. 248.7 [M+H]+, B. Preparation of a Compound of Formula (43) To a suspension of 5-nitroindole-3-N-methylglyoxamide: (6.0 g, 24.27 mmole) in anhydrous THF in ice bath was added l OM BH3-THF complex (85 mL) dropwise over 30 min.
After completion of the addition, the mixture was stirred for 2 h at 0°C, and for 22 h at rt, at which mass spectrometric analysis of the mixture indicated complete consumption of the reactant, and formation of the desired product. The reaction mixture was cooled in ice bath, and was quenched by adding MeOH (50 mL) slowly under stream of nitrogen gas. The mixture was stirred for 30 min, and concentrated, yielding a pale yellow solid. It was dissolved in MeOH(50 mL)-TFA (5 mL), and concentrated, yielding a pale red oil. The residue was redissolved in MeOH (50 mL), and followed by addition of 6M HCl until the pH of the solution became --4.
The acidic solution was concentrated, and diluted with EtOH, which led to formation of pale red precipitates. The precipitate was collected, washed with EtOH, and dried. The product (3-(2-methylaminoethyl)-5-nitro-1H-indole was obtained as an HCl salt (3.72 g, 60%).
Rf= 0.38 (5% i-PrNH2/10% MeOH/CH2C12). H~-NMR (CD30D, 299.96 MHz): 8 (ppm) 8.63 (d, 1H), 8.1-8.05 (dd, 1H), 7.51-7.48 (d, 1H), 7.43 (s, 1H), 3.35-3.33 (t, 2H), 3.25-3.22 (t, 2H), 2.73 (s, 3H); ESMS
t5 (C"HI3N302): calcd. 219.24, obsd. 220.6 [M+H]+, C. Preparation of a Compound of Formula (44) To a suspension of MeOH (80 mL) and (3-(2-methylaminoethyl)-5-nitro-1H-indole salt (4.2 g, 16.44 mmole) was added NaOH (0.696 g, 17.4 mmole). The mixture was stirred at 70°c for 20 min. After cooling of the mixture, (Boc)ZO (3.76 g, 17.22 mmole) in MeOH (20 mL) was added, and the final mixture was stirred for 24 h at room temperature. The reaction mixture (a yellow suspension) was concentrated, and dispersed in cold 20% aq. EtOH. A
yellow precipitate was collected, washed with cold aq. 20% EtOH, and dried to afford 3.09 g (59%). of 3-(N-Boc-2-methylarninoethyl)-5-nitro-1H-indole): H'-NMR (CD30D, 299.96 MHz):
b (ppm) 8.56 (d, 1 H), 8.04-8.01 (dd, 1 H), 7.46-7.42 (d, 1 H), 7.26 (s, 1 H), 3.55-3.52 (br m, 2H), 3.04-3.01 (t, 2H), 2.84 (br s, 3H), 1.16 (s, 9H); ESMS (Ci6H~lN30~): calcd. 319.36, obsd. 342.0 [M+Na]+, 639.5 [2M]+, A solution of EtOH (60 mL) containing 3-(N-Boc-2-methylaminoethyl)-5-nitro-1H-indole): (2.37 g, 7.43 mmole) was saturated with nitrogen gas, and followed-by addition of Pd/C
( 10%; 0.5 g) in EtOH ( 10 mL). The mixture was degassed, and hydrogenated under H2 ( 1 atm) 3o for 48 h at room temperature. The reaction mixture was filtered, and the catalyst was washed with EtOH (100 mL). The filtrates were combined, and concentrated, yielding a pale pink oil that slowly crystallized. (5-amino-3-(N-Boc-2-methylaminoethyl}-1H-indole): The product was pure enough according to analysis with H-NMR, MS, and anal. HPLC, and used in next step without further treatment. H'-NMR (CD30D, 299.96 MHz): 8 (ppm) 7.16-7.12 (d, 1 H), 6.97 (br s, 1 H), 6.92 (br s, IH), 6.70-6.67 (dd, IH), 3.~-3.42 (t, 2H), 2.90-2.85 (t, 2H), 2.81 (s, 3H), 1.21 (s, 9H);
ESMS (C,6H23N302): calcd. 289.38, obsd. 290.8 [M+H]+, D. Preparation of a Compound of Formula I
To a solution of THF (60 mL) containing 5-amino-3-(N-Boc-2-methylaminoethyl)-indole (2.15 g, 7.44 mmole} and i-Pr2NEt (4.93 mL, 28.30 mmole) was added 4-fluorobenzoylchloride (0.97 mL, 8.21 mmole). The mixture was stirred at rt for 24 h, and to concentrated to half volume. The solution was partitioned between CHZC12 (150 mL) and water (150 mL). The organic phase was collected, washed with sat. citric acid, sat.
NaHC03, and brine.
After drying under MgS04, the organic solution was evaporated yielding pale yellow oil. It was slowly solidified to a pale brown solid (5-(4-fluorobenzoyl)amino-3-(N-Boc-2-methylaminoethyl)-1H-indole): (3.0 g, 95%). H'-NMR (CD30D, 299.96 MHz): ~
(ppm) 8.24-8.20 (dd, 1 H), 8.04-7.99 (dd, 2H). 7.35-7.32 (m, 1 H), 7.27-7.2 I (dd, 2H), 7.88-7.82 (br d, 1 H).
7.1-7.05 (br d, 1H), 3.56-3.48 (br t, 2H), 2.98-2.93 (t, 2H), 2.83 (s, 3H}, 1.20 (s, 9H).
A suspension of CH2C12 (IS mL) containing ~-(4-fluorobenzoyl)amino-3-(N-Boc-2-methylaminoethyl)-1H-indole (3.16 g, 7.69 mmole) and i-Pr3SiH (0.~ mL) was stirred under nitrogen atmosphere in ice bath, followed by addition of TFA ( 1 ~ mL). The mixture was stirred for 90 min at 0°c, and concentrated in vacuo, yielding a pale brown-pink residue, which was dissolved in 5% MeOH/CH2C12, and purified by flash silica column chromatography: 3°~0 MeOH/CH2Cl2 to 5% i-PrNH2/10% MeOH/CHzCl2. The product (5-(4-fluorobenzoyl)amino-3-(2-methylaminoethyl}-1 H-indole): was obtained as a pale brown solid ( 1.8 g, 75%). Rf = 0.43 (5% i-PrNH2/10% MeOH/CH2C12). H'-NMR (CD30D, 299.96 MHz): 8 (ppm) 8.05-7.99 (dd, 2H), 7.95-7.94 (d, 1 H), 7.39-7.36 (dd, 1 H), 7.28-7.22 (m, 3H), 7.21 (s, I
H), 3.28-3.22 (t, 2H), 3.14-3.08 (t, 2H), 2.65 (s, 3H); ESMS (C,gH,gN30,F,): calcd. 31 I.4, obsd.
313.0 [M+HJ', 623.3 [2M+H]+.
A solution of DMF (1 mL) containing 5-(4-lluorobenzoyl)amino-3-(2-methylaminoethyl)-IH-indole (65 mg, 0.21 mmole), 1,12-dibromododecane (32.8 mg, 0.1 mmole), and i-Pr~NEt (0.1 mL, 0.57 mmole) in a sealed vial was heated at 72°C for 72h while shaking. The reaction mixture was mixed into ether (45 mL) in a plastic bottle, and the mixture was shaken to homogeneity, precipitating a pale brown oily residue. The precipitate in the bottle was collected by spinning it down at 3500 rpm for 20 min, rinsed with ether (50 mL), and dried in air. The crude reaction mixture was dissolved in 2 mL of 50% MeCN/H20 (0.1 % TFA), and purified by reversed phase semi-preparative HPLC. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) = 3.70 min. ESMS (C48HSgF2N6O2): calcd. 789.03, obsd. 789.6 [M]+.
C. Similarly, by optionally replacing 5-amino-3-(N-Boc-2-methylaminoethyl)-1H-indole with other compounds of structure similar to the compound of formula (44) and optionally replacing 1,12-dibromododecane with other dihalides in 2B above, the following compounds of Formula I were prepared.
Table 1, compound 20 was prepared in an analogous manner from I,2-dibromoethane.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over ~ min) = 3.41 min. ESMS
(C38H38F2N602): calcd. 648.76, obsd. 649.4 [M+H]+.
is Table 1, compound 2I was prepared in an analogous manner from 1,3-diiodopropane.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) = 3.32 min. ESMS
(C39H,~oFZN602): calcd. 662.79, obsd. 663.5 [M+H]+.
Compound 13c was prepared in an analogous manner from 1,7-dibromoheptane.
2o Retention time (anal. HPLC: 10 to 70% MeCN/H~O over 5 min) = 3.22 min. ESMS
(C43H4gF2N602): calcd. 718.89, obsd. 719.3 [M+H]T.
Table 1, compound 22 was prepared in an analogous manner from 1,8-diiodooctane.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over ~ min) = 3.29 min. ESMS
25 (C38H38F2N60z): calcd. 732.92, obsd. 733.5 [M+H]+.
Table 1, compound 23 was prepared in an analogous manner from 1,11-dibromoundecane.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over ~ min) = 3.~6 min: ESMS
(C47Hs6F2N602): calcd. 775.00, obsd. 775.5 [M]+.

Table 1, compound 24 was prepared in an analogous manner from 1,4-dibromo-2-butene.
Retention time (anal. HPLC: 10 to 70% MeCN/Hz0 over S min) = 3.09 min. ESMS
(C4oH4oF2N6dz): calcd. 674.80, obsd. 675.2 [M+H]+.
Compound 13h was prepared in an analogous manner from 1,2-dibromo-3,3,3-trifluoropropane. ESMS (C39H~7FSN6O2): calcd. 716.76, obsd. 717.5 [M+H]+.
Compound 13i was prepared in an analogous manner from 2,3-dibromo-2-propanol.
ESMS (C39H40F2N6~3)~ calcd. 678.78, obsd. 679.4 [M+H]+.
to Table i, compound 27 was prepared in an analogous manner from 2,3-dibromo-I-propanol. Retention time (anal. HPLC: 10 to 70% MeCN/Hz0 over ~ min) = 3.22 min. ESMS
(C39H4oF2N603): calcd. 678.78, obsd. 679.4 [M+H]+.
Table 1, compound 26 was prepared in an analogous manner from 2,3-dibromopropionamide. Retention time (anal. HPLC: I 0 to 70% MeCN/Hz0 over 5 min) = 3.63 min. ESMS (C39H39F~N7O3): calcd. 691.79, obsd. 692.3 [M+H]y.
Compound 13l was prepared in an analogous manner from t-butyl 2,4-dibromobutyrate.
Retention time (anal. HPLC: 10 to 70% MeCN/Hz0 over ~ min) = 3.43 min. ESMS
(C~H48FzN604): calcd. 762.90, obsd. 763.5 [M+H]T.
Table 1, compound 28 was prepared in an analogous manner from bis(4-chlorobutyl)ether.
Retention time (anal. HPLC: 10 to 70% MeCN/Hz0 over 5 min) = 3.20 min. ESMS
(C44HSOF2N603): calcd. 748.92, obsd. 749.4 [M+H]+.
Table 1, compound 29 was prepared in an analogous manner from 1,2-bis(2-iodoethoxy)ethane. Retention time (anal. HPLC: 10 to 70% MeCN/Hz0 over ~ min) = 3.08 min.
ESMS (C4zH46FZN604): calcd. 736.87, obsd. 737.7 [M+H]+.

Compound 13o was prepared in an analogous manner from bis(2-chloroethoxy)ether.
ESMS (C~aH5oF2N605): calcd. 780.92, obsd. 781.5 [M+H]+.
Table 1, compound 18 was prepared in an analogous manner from a,a'-dichloro-m-xylene. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) = 3.20 min.
ESMS
(C~aH42F2N60Z): calcd. 724.86, obsd. 725.3 (M+H]+.
Table 1, compound 31 was prepared in an analogous manner from 2,6-bis(bromomethyl)pyridine. Retention time -(anal. HPLC: 10 to 70% MeCN/H20 over 5 min} _ l0 3.14 min. ESMS (Ca3H4,F2N~02): calcd. 725.84, obsd. 726.5 [M+H]+.
Table 1, compound 30 was prepared in an analogous manner from 4,4'-bis(chloromethyl)-1,I'-biphenyl. Retention time (anal. HPLC: 10 to 70% MeCN/H~O over S min) =
3.29 min.
ESMS (C50H46F2N6O2): calcd. 800.95, obsd. 801.3 [M+H]+.
Table l, compound 25 was prepared in an analogous manner from 3-(2'-bromoethyl)-1H-indole. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) = 3.08 min.
ESMS
(C2gH27F,N40,): calcd. 454.55, obsd. 455.2 [M+H]+.
2o D. Similarly, by optionally 5-amino-3-(N-Boc-2-methylaminoethyl)-1H-indole with other compounds of structure similar to the compound of formula (44) and optionally replacing 1,12-dibromododecane with other dihalides in 2B above, other compounds of Formula I are prepared.
E. The foregoing is an example of reaction of 2 molar equivalents of a ligand bearing a 5-amino group with 1 molar equivalent of a linker having two chemically complementary groups (bromo) to form a compound of Formula I having two identical ligands (a homodimer). Reaction of 1 molar equivalent each of two dissimilar ligands bearing an amino group with 1 molar equivalent of a linker having two chemically complementary groups forms a compound of Formula I having two different ligands (a heterodimer). Alternatively, reaction of 1 molar equivalent of a ligand bearing an amino group with 1 molar equivalent of a linker having two chemically complementary groups followed by reaction of the intermediate thus formed with a second (and diferent) ligand provides a compound of Formula I that is a heterodimer.
8~

w w w a a~ a~ a~
a a L~, 7 3 ~ 7 3 C~ ~,'s ,r-I ~ ~ rr d' , , , , , n n ~ ~ n U U U U U

..a oo x z x z x ...
z z z z z ' c c ~ c o n ~
w a o .
4.. , o N o c o o c v ~ c' c ~ c o .~ , , , , Q
, , , ~' , a, 0 0 0 0 0 U U U U U

V .. ~ x Z

z z z z z w o ~, w Q

w > , N f' ....7 "L1 N 'CS

~ :
i ... ._~. ._:. _.
p p -U - U U U
a~ a~ .~ _ ~ -, --U

~ i I
~

E ~ o ~ N ~ N r1 rl 1.1 T N N N
U

W "C! ~ U U U v U U ~ U U

O ~ ~ ! I
o ~ j ~ ! I z o ! z ~ z . _ _ _ _ z z _ _ o _ =

o ~. . ~., ~ ~. ... ..
z z z z x G. U U U U U
U . . ...
.

0 3 ~ ~ ~ ' ' _ ~. z z z z -.' -c ~ _ _ _ j ! ~ j i j j .: ;: :; ~ ~: ~ .: : .:: .
.;

tsp _. ,-, , x~ 2 Z x Z Z x x x x C x C w. U U U U U U U U U U

V V ~ ~ ~ ! s ~

~ c ~ x I x x x ~ x ~ ~

_ a _U -U _ _U _ __U _U _ p _ N

O
.a _.. _ _ M M M M M

_ U ~%, W %, r%, r:, ' v, ...

O

~y c Z -~ N M C' ~1 c a c c c c N N N N N N

C C C C C C C
N N ~ a .

O O O O O O O

7 3 ~ 7 > > >

C
I ' ' V V ~ V

O O O O O O O

U U U U U U U

x Z ~ ~ T Z

z z z z z z z N N N N N N N

C C C C C C C

O O O O O O O

O ~ 7 7 7 7 C ~ ~ C

VI ~ C C d' O O O O O O O

V U U V V U U
, 1 1 1 1 , z z ~

z z z z z 1 .

v x U - >', s 1 N G. G

N N x ~o M

x V U _ i U ; I ~ Ii - Z - .: N N N _-:-' N ~ ~ _ U
Z _ v v ~
x U U .c t I I

..., 3 1 ~
U j ~ ~ = ~ .~ ~:, - z U _ 1 - U - . ..=
x, _ %r - ~U ~ i i ; _ - U U
i I U

~ N N N N N ~ N I
N - Z
-I

O U_ U U U U U U U

O _ _ v _ ~
~ ~

z I z _ U
z -z- N - z -z I

1 x ~ ..~. v v p z U = U :, ' O x U N U N

.J 1 ~. ~ U
N N

z ~ z a z - - ~ -- z ~ ~ ; i ~ - z -~r~ :1 ~ z i;
rl N

i i ~ i ~ ~ T n ~ n N N
N rv r x x z =

N N U U x x U U ~ " T'U U
x x " ' U
' Z " 'r U U ; U
U U .. .. ...-x U j' x " x ~ i x ~ i .:.i ~ x x - U - - U -U -U - -U - U - U
, 1 1 - - -M M M M M M M
, 1 1 1 1 1 , M M M M M M
M

O -- N

n oo Q~ ~ --C C C C C C

C c C C

N N N N N N N N N

a ~ ~ ~ ~

. .
D

O O O O O O O O O O

3 7 ~ 7 7 3 3 C ~ ~ ~ C
-V~ ~' VI V~ V~ 'V ~ V VI

O O O O Q Q o Q o Q

U V U U U U U U U U

x x x x x x T x Z Z

z z z z x z z z z z z a> a~ a~ a~ v a~ n> ~ a~ a~ a~

c c c c c c c c c c c a a d a~ a~ a~ ~ a~ a> a c~
N N N N N N N N N N

N

~ v v L L L. L L L

. V L L L L
0 0 0 0 0 0 0 o O o 0 O O O O o O O O O o Q

U U U U U U U U U U U

Z Z Z Z Z x z ~ '- y. T

z z z z z z z z z z z c x 1 U _ 1 r, Z

_ V U a _ .-. N ~ _ N
I

x I i U V ~N % ~: a~
N

I i x ... -==
U _, -z - 1 U ~
1 ~ ~/ ~I

_ , I , _U I

I I ~! 1 N 1 _z ~/ N ~ /1 /~ N
l V x x =' U
1 x x (~ x Z ....U U U

1 ~ ~ ~ ~ ~
o v v z U

0 x ~ ~ z ~ ~ z s o z v _ o v =' ~ ~ v v _ z ~. z :. v v ~ z z z N N 1 ~ 1 z =. ~: . , r U x x U N Z Z
V V

Z " ~ ~ ~ U U U U U U

U _z _z _~ _z _ z -, .. ...

~ I I I h 4 i z s x z = z ~

I ' , N I N U V U V U U
N ,=: ~ ,-. ~: N ~/
~ ~; .-. C~1 hl NI N N

~ ~ x x = _ i x z z z z z z N 1 x Jr x x U V U U U V U V
l ~r ~ v ~r v ~ v ~r n i~ i~ n ~ n l l x x I x I x T T = ... x x ~

-U -~

M M M M M M M M M M M

M M M M M M M M M M M

M ~ ~1 ~G ~ 00 O~ 0 N f'!N

a c c c c a c c c c N N N N N N N N N N

C C C C C C C C C C
~ d N N N N

O O O O O O O O O O

O O O~ O O O O O O O

7 3 O 7 O 7 > > 7 7 G G C G G G C G G C
, , , , , , , , , , i i i n ~ i i i iw iv . ~ 1 v v ~
0 ~ 0 U U U U U U U V U U

x z z x z z s T s =
' z z z z z z z z z z , , , , , , , , , , G

N N N N N N N N N

N N ~ N 4~l~ N N

O O O O O O O O O

3 O 3 '7 7 7 O O O
G G G G G G C C G
, , , , , , , ~ d' ~ ~ C' ~' V
V' ~ i ~ ~ ~ ~ ~
0 ~ ~ ~ C) 0~ ~ 0 ~ . . a . ~ .r . . . .

..i r .. . V U .. , U
U V U U V U
, , , , , , ~ Z Z .Tr Z Z
Z

z y z z z z z z z z T 7, C C
N

.,.~ _ p. 'C
Y.

C
, a , 'v.~c c ~i ~i v U II II , ~; ' N -r il N ~ a> a~ _ (~j N
_ N ~ = N N j N
Z T .:'U

V U Z 3 >
r, z r n -~ -s ~ ... , ~ >
... ~. U t. ~ = 2 r "

N r~ .:.
~ ~ w ~ V

, V U T = U U I ; U
S v V

"
z ~. ~ ~ "_ z ::
_ z o ~, , z w ~ z V U N ~ V U Z v U

Z Z U V

~ ' T ~ ~ , O O U U U T

U ~ .=: N N ~ U

V Z N

T = Z x = ~ T Z U ;.
U U U

U U
U .. V U ~ ~ z _ U
~ ~ -, Z z S T 2 Z ~ x U U U U U U U U .:' i iN
.':

z z z z z z z z ~ z ~
' -_ , , ~ , ~ , , , V U , _ ~ .: ~ ~ .~ N ~ .... U U
w r, ra ..

U U T U U U U U ~ I
V V ~ U J

.. ~. ~. ~. ~. ...._ _ , , , , , , ~ , , , M M M M M M M M M M
, , , , , , , , , , M M M M M M
M M M M

N N N N N ~l ~ M M M

Preparation of Compounds of Formula I
Preparation of a Compound of Formula I in which the Ligand is a SHT ligand, linked via the Sidechain at the 5-Position, p is 2 and q is 1 A. Preparation of S-amino-3-(I-methylpiperidin-4-yl)-IH-indole To a solution of 5-nitroindole (10 g, 62 mmole) and KOH (10.4 g, 185 mmole) in 200mL of methanol was added I-methyl-4-piperidone (14 g, 123 mmole). The mixture was refluxed for 22 hours, and cooled. The precipitate was collected on a Buchner funnel, and washed with methanol and ether. The desired product, 5-nitro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)indole, was obtained as a yellow solid. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) = 2.~
min. ESMS (C,4H,SN302); calcd. 257.29; obsvd. 258.3[M+H]'.
B. A suspension of 5-nitro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)indole (7.3g, 28.4mmol) and 10% Pd/C (3.Og) in anhydrous methanol was shaken under a hydrogen atmosphere for 36 h. The mixture was filtered through Celite, washed with methanol, and concentrated under reduced pressure. The residue was taken up in dichloromethane and concentrated to give an off white solid. It was washed with ether, and dried in air to afford the product, 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole, as an off white solid (5.2g, 80%).
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 3 min) = 0.8 min. ESMS
(C,:~H,9N3):
calcd. 229.3; obsd. 230.1 [M+H]t.
C. Preparation of a Compound of Formula I
To a cooled (0°C) solution of anhydrous DMF (1 mL) containing ~-amino-3-(I-methylpiperidin-4-yl)-indole (46 mg, 0.2 mmole) and di-isopropylethylamine (54 pl, 0.3 mmole) was added 4,4'-biphenyldisulfvnylchloride (35.1 mg, 0.1 mmole) in ImL of anhydrous DMF.
The mixture was stirred at rt overnight, and then concentrated in vacuo, yielding the crude product as a tarry residue. It was dissolved in SmL of SO% aqueous acetonitrile (with 0.1 trifluoroacetic acid), and purified by preparative HPLC: 10 to 70% MeCN/H20 over ~ min; 254 nm. Fractions with correct mass data were combined, and lyophilized to afford the product as an off white solid (a compound of Formula where L is 3-(1-methylpiperidin-4-yl)-indole, p is 2, q is 1, linked at the 3-position by -NHS02QS02NH-, in which Q is 4,4'-biphenyl).
Retention time (anal. HPLC: 10-70% over 5 min) = 2.80 min. ESMS (C4oH~N60aSz); calcd. 736.96;
obsd. 737.9 [M+H]+.
D. Similarly, by optionally replacing 5-amino-3-(1-methylpiperidin-4-yl)-indole with other 5-aminoindoles, and optionally replacing 4,4'-biphenyldisulfonylchloride with other chlorosulfonyl dihalides or acid dihalides in 4C above, the compounds of Formula I
as shown in Table 2 were prepared.
Table 2, compound 28: Retention time (anal. HPLC: 10-70% MeCN/H20 over ~ min) _ 2.9 min. ESMS (C4EH46N6O4S2): calcd. 750.99; obsd. 751.5 [M+H]+.
Table 2, compound 48: Retention time (anal. HPLC: 10-70 over 5 min) = 2.00 min.
ESMS (C3qH40N6~4s2)~ calcd. 660.86; obsd. 661.4 [M+H]+.
Table 2, compound 49: Retention time (anal. HPLC: 10-70% MeCN/H20 over ~ min) _ 3.00 min. ESMS (C4oH~4N605Sz); calcd. 752.96; obsd. 753.3 [M+H]+.
Table 2, compound 50: Retention time (anal. HPLC: 10-70% MeCN/H20 over ~ min) _ 2.70 min. ESMS (C3gH,~gN6O4S2): calcd. 716.97; obsd. 717.5 [M+H]+.
Table 2, compound 51: Retention time (anal. HPLC: 10-70% MeCN/H20 over S min) _ 2.90 min. ESMS (C3$H4pN6O3S,); calcd. 624.81; obsd. 625.4 [M+H]+.
Synthesis of Table 2, compound 52, (Scheme 8) Table 2, compound 52: (anal. HPLC: 10-70% MeCN/H20 over 5 min) = 2.70 min.
ESMS (C36H4gN6O6); calcd. 660.81; obsd. 661.4 [M+H]+.
F. Similarly, by optionally replacing S-amino-3-(1-methyipiperidin-4-yl)-indole with other 5-aminoindoles, and optionally replacing 4,4'-biphenyldisulfonylchloride with other chlorosulfonyl dihalides or acid dihalides in 4C above, or diisocyantes in 3E above, other compounds of Formula I are prepared.
Preparation of Compounds of Formula I linked 5-5 with a Urea Linker To a solution of S-amino-3-(1-methylpiperidin-4-yl)-IH-indole (46.0 mg, 0.1 mmole) in 2 mL of anhydrous DMF was added 1,6-diisocyanatohexane (0.1 mmole). The mixture was stirred at rt overnight, and concentrated in vacuo, yielding tarry residue. Methylene chloride was added to the resulting residue, which led to crystallization of the product. The solid was collected, and was dissolved in 2 mL of SO% aqueous acetonitrile (with 0.1 % trifluoroacetic acid). The solution l0 was purified by preparative HPLC. The product was obtained as gummy residue. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) = 2.8 min. ESMS (C36H;oNg02);
calcd. 626.8;
obsd. 627.5 [M+H]+.
Similarly, the following compounds of Table 2 were prepared.
Table 2, compound 29 was prepared in an analogous manner from 1,12-diisocyanatododecane. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) = 3.7 min. ESMS (C42H62N802); calcd..711.01; obsd. 7I 1.2 [M]+.
Table 2, compound 31 was prepared in an analogous manner from I,5-diisocyanato-methylpentane. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) =
2.8 min.
ESMS (C36H;oN802); calcd. 626.85; obsd. 627.5 [M+H]+.
Table 2, compound 32 was prepared in an analogous manner from I ,8-diisocyanatooctane.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) = 3. I min. ESMS
(C38H;4Ng02);
calcd. 654.90; obsd. 655.7 [M+H]+.
Table 2, compound 33 was prepared in an analogous manner from 3,3'-dimethoxy-4,4'-biphenylenediisocyanate. Retention time (anal. HPLC: 10 to 70% MeCN/H~O over 5 min) = 3.6 min. ESMS (C,~.~HSONgO,~); calcd. 754.93; obsd. 755.4 [M+H]+.

Table 2, compound 34 was prepared in an analogous manner from isophorone diisocyanate. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) = 3.3 min. ESMS
(C~aH5oNg04); calcd. 680.94; obsd. 681.5 [M+H]+.
Table 2,~compound 35 was prepared in an analogous manner from 4,4'-methylenebis(cyclohexyl isocyanate). Retention time (anal. HPLC: 10 to 70%
MeCN/Hz0 over 5 min) = 3.5 min. ESMS (C43H60N8~2)~ calcd. 722.00; obsd. 721.4 [M]+.
Table 2, compound 36 was prepared in an analogous manner from4,4'-methylenebis(2,6-l0 Biphenyl isocyanate). Retention time (anal: HPLC: 10 to 70% MeCN/H20 over 5 min) = 3.8 min.
ESMS (C;,H~N802); calcd. 822.12; obsd. 821.7 [M]+.
Table 2, compound 37 was prepared in an analogous manner from 4,4'-methylenebis(phenyl isocyanate). Retention time (anal. HPLC: 10 to 70%
MeCN/H~O over ~
~ 5 min) = 3.6 min. ESMS (C43H3gNg02); calcd. 708.91; obsd. 709.4 [M+H]+.
Table 2, compound 38 was prepared in an analogous manner from 4,4'-oxybis(phenyl isocyanate). Retention time (anal. HPLC: 10 to 70% MeCN/H,O over ~ min) = 3.5 min. ESMS
(C42H46N8~3)s calcd. 710.88; obsd. 711.5 [M+H]+.
Table 2, compound 41 was prepared in an analogous manner from tolylene-2.6-diisocyanate. Retention time (anal. HPLC: 10 to 70% MeCN/H~O over 5 min) =
2.85 min.
ESMS (C3~H:~aN802); calcd. 632.81; obsd. 633.5 [M+H]'.
Table 2, compound 42 was prepared in an analogous manner from 2,4,4-trimethyl-1,6-diisocyanatohexane. Retention time (anal. HPLC: 10 to 70% MeCN/H~O over ~ min) = 3.2 min.
ESMS (C39H;6NgO2); calcd. 668.93; obsd. 669.5 [M+H]'.
Table 2, compound 43 was prepared in an analogous manner from 1,3-3o bis(isocyanatomethyl)benzene. Retention time (anal. HPLC: 10 to 70%
MeCN/H20 over ~ min) = 2.8 min. ESMS (C3gH46N802); calcd. 64fn84; obsd. 647.6 [M+H]+.

WO 99/64044 PC'TNS99/12751 -Table 2, compound 44 was prepared in an analogous manner from 1,3-bis(isocyanatomethyl)cyclohexane. Retention time (anal. HPLC: 10 to 70%
MeCN/H20 over 5 min) = 2.9 min. ESMS (C3gH52Ng02); calcd. 652.88; obsd. 653.6 [M+H)+.
Table 2,'compound 45 was prepared in an analogous manner from 1,3-bis(2-isocyanatopropyl)benzene. Retention time (anal. HPLC: I O to 70% MeCN/H20 over 5 min) = 3.3 min. ESMS (C42H54N8O2); calcd. 702.94; obsd. 703.4 [M+H]+.
Table 2, compound 46 was prepared in an analogous manner from trans-1,4-to cyclohexylenediisocyanate. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over ~ min) _ 2.7 min. ESMS (C36H4gNg02); calcd. 624.83; obsd. 625.7 [M+H)+.
Table 2, compound 47 was prepared in an analogous manner from 1,4-diisocyanatobutane.
Retention time (anal. HPLC: 10 to 70% MeCN/H~O over S min) = 2.4 min. ESMS
(C3.~H:~6N80~);
1s calcd. 598.79; obsd. 599.3 [M+H]+.
E. Similarly, by optionally replacing 5-amino-3-(1-methylpiperidin-4-yl)-indole with other 5-aminoindoles, and replacing 4,4'-biphenyldisulfonylchloride with diisocyanates in 3C above, employing the following procedure, other compounds of Formula I
are 20 prepared.
F. The foregoing is an example of reaction of 2 molar equivalents of a ligand bearing a 5-amino group with 1 molar equivalent of a linker having two chemically complementary groups to form a compound of Formula I having two identical ligands (a 25 homodimer). Reaction of 1 molar equivalent each of two dissimilar ligands bearing an amino group with 1 molar equivalent of a linker having two chemically complementary groups forms a compound of Formula I having two different ligands (a heterodimer).
Alternatively, reaction of 1 molar equivalent of a Iigand bearing an amino group with 1 molar equivalent of a linker having two chemically complementary groups followed by 3o reaction of the intermediate thus formed with a second (and diferent) ligand provides a compound of Formula I that is a heterodimer.

Preparation of Compounds of Formula I
Preparation of a Compound of Formula I in which L is a Compound of Formula II
in which R~, R2, R4, R6, and R' are Hydrogen, and R3 is 2-(Dimethylamino)ethyl, linked via an Amine Sidechain at the 5-Position, p is 2 and q is 1 A. Preparation of a Compound of Formula (42) where Rt is Methyl To a suspension of 5-nitroindole (10 g, 62 mmole) and phthalimide (4 g, 10% by weight) to in 250mL of anhydrous ether was added oxalyl chloride (25 g, 3. I equiv. to indole) dropwisely with stirnng. The mixture was stirred vigorously for 72 h, and cooled to 0°C. A solution of dimethylamine (2M, 1.0 L) in THF was added slowly to the previous mixture, followed by stirring for 2 h. The heterogeneous mixture was filtered to afford solid mass and a filtrate: both of which were then processed separately. First, the solid was suspended in ethyl acetate, and filtered. Concentration of the filtrate gave first crop of the product as a light tan solid. Second, the original filtrate was partitioned between methylene chloride and water, and the pH of the water was adjusted to 3. The organic layer was drained, and the aqueous layer was further extracted with CHzCl2 (3X 200 mL). The organic layers were combined, and dried with MgS04).
Concentration of the organic solution in vacuo afforded 5-nitroindole-3-N,N-dimethylglyoxamide 2o as a crude solid. It was purified by recrystaiization from methanol.
Retention time (anal. HPLC:
10 to 70% MeCN/H20 over ~ min) = 3.3 min. ESMS (Ci~H"N30:~); calcd. 261.24;
obsd. 262 [M+H~+.
B. Preparation of a Compound of Formula (43) where R1 is Methvl To a stirred solution of ~-nitroindole-3-N,N-dimethylglyoxamide (5.3 g, 20.5 mmole) in 150mL of anhydrous THF was added 79 mL of 1.OM BH3-THF dropwisely. The mixture was stirred vigorously under nitrogen for 16 hours,and the reaction quenched by treating with saturated sodium bicarbonate solution. The mixture was then extracted with ether, dried with MgS04, and concentrated in vacuo to give the product (as borane complex) as an amorphous orange solid. To dissociate the product-horane complex, the crude product was taken up in 150mL of absolute ethanol, followed by addition of cesium fluoride (6.9 g) and potassium carbonate (6.9g). The mixture was refluxed under nitrogen for 16 h, cooled, and filtered through celite. Concentration of the filtrate under reduced pressure gave oily residue, which was subsequently purified by silica gel chromatography: CH2C12/MeOH to CH2C12/MeOH/Isopropylamine. The desired product was obtained as a yellow solid. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) = 2.3 min. ESMS (C,2H15N302);
calcd.
233.27; obsd. 234 [M+H]+.
C. Preparation of a Compound of Formula (44) where Rl is Methyl A suspension of 3-(2-dimethylaminoethyl)-5-nitroindole ( 1.6 g, 7.5 mmole) and 10% Pd/C
(0.4 g) in ethanol was shaken under a hydrogen atmosphere for 20 hours. The mixture was filtered through Celite, and the catalyst was rinsed with ethanol. The filtrates were combined, and concentrated under reduced pressure to give the product, 5-amino-3-(N,N-dimethylaminoethyl)-indole, as a colorless oil. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) = 0.8 min: ESMS (C12H,~N3); calcd. 203.29; obsd. 204 [M+H]+.
D. Preparation of a Compound of Formula I
To a solution of 5-amino-3-(N,N-dimethylaminoethyl)-1 H-indole (81 mg, 0.4 mmole) and di-isopropylethylamine (54 pl, 0.3 mmole) in 1mL of anhydrous DMF was added a solution of (al,a2,~i3,X34)-2,4-bis(4-hydroxyphenyl)-1,3-cyclobutanedicarboxylic acid (33 mg, 0.1 mmole}, HOAT (34 mg, 0.2 mmole), and HATU (95 mg, 0.2 mmole) in I mL of anhydrous DMF.
The mixture was stirred at room temperature overnight, and then concentrated. in vacuo, yielding tar residue. It was dissolved in 5mL of 50% aqueous acetonitrile (with 0.1 %
trifluoroacetic acid), and purified by preparative HPLC. Fractions with correct mass were pooled, and lyophilized to give the product of Formula I as a white solid. Retention time (anal. HPLC: 10 to 70%
MeCN/H20 over 5 min) = 3.2min. ESMS (C,~2H:~6N60.~); calcd. 698.87; obsd.
699.5 [M+H]+.
E. Preparation of Compounds of Formula I
Similarly, by optionally replacing 5-amino-3-{N,N-dimethylaminoethyl)-1 H-indole with other 5-aminoindoles, and optionally replacing (a 1,a2,~33,[i4)-2,4-bis(4-hydroxyphenyl)-1,3-cyclobutanedicarboxylic acid with other dicarboxylic acids or acid dihalides in SD above, the following compounds of Formula I as shown in Table 2 were prepared.
Table 2, compound 92 was prepared in an analogous manner from 3,4-dimethylthieno(2,3-b)thiophene-2,5-dicarboxylic acid. Retention time (anal.
HPLC: 10-70 over 5 min) = 2.63 min. ESMS (C3qH3gN60O2s2): calcd. 626.9, obsd. 627.4 [M+H]+.
Table 2, compound 93 was prepared in an analogous manner from 1,10-decanedioic acid.
Retention time (anal. HPLC: 10-70 over ~ min) = 2.85 min. ESMS (C36H52N6O2):
calcd. 600.9, obsd. 601.4 [M+H]+.
Table 2, compound 94 was prepared in an analogous manner from diphenic acid.
Retention time (anal. HPLC: 10-70 over ~ min) = 2.45 min. ESMS (C3gH4oN60~):
calcd. 612.8, obsd: 613.2 [M+H]+.
Table 2, compound 9~ was prepared in an analogous manner from 1,12-dodecanedioic acid. Retention time (anal. HPLC: 10-70 over 5 min) = 3.10 min. ESMS
(C;gH;6N6O~): calcd.
628.9, obsd. 629.4 (M+H]+.
Table 2, compound 96 was prepared in an analogous manner from 1,14-tetradecanedioic acid. Retention time (anal. HPLC: 10-70 over 5 min) = 3.42 min. ESMS
(C:~oH6oN60~): calcd.
657.0, obsd. 657.6 [M+H]+.
Table 2, compound 97 was prepared in an analogous manner from 2,2-bis(4-carboxyphenyl)hexafluoropropane. Retention time (anal. HPLC: 10-70 over ~ min) = 3.22 min.
ESMS (C4iH4oF6NbO2): calcd. 762.8, obsd. 763.4 [M+H]+.
Synthesis of Table 2, compounds 5 to 68 General procedure: To a solution of 5-amino-3-( 1-methylpiperidin-4-yl)-1 H-indole (46mg, 0.2 mmole) with di-isopropylethylamine (54 pl, 0.3 mmole) in anhydrous DMF (200 pL), was added a solution of di-acid (0.1 mmole), HOAt (34 rng, 0.25 mmole), and HATU (9~ mg, 0.25 mmole) in anhydrous DMF (400 pL). The mixture was shaken overnight, then concentrated in vacuo. This reaction was dissolved in of a 1:1 mixture of acetonitriIe and water, with 0.1 trifluoroacetic acid (2 mls). This mixture was then purified by preparative HPLC.
Table 2, compound S was synthesized from 3,S-pyrazoledicarboxylic acid in a similar manner. Retention time (anal. HPLC: 10 to 70% MeCN/H~O over S min) = 2.7 min.
ESMS
(C33H3gNg~); calcd. 578.72; obsd. 579.4 [M+H]+.
Table 2, compound 6 was synthesized from terephthalic acid in a similar manner.
1o Retention time (anal. HPLC: 10 to 70% MeCN/H20 over S min) = 2.82 min. ESMS
(C36H40N602)s calcd. 588.75; obsd. 589.4 [M+H]+.
Table 2, compound 69 was synthesized from 2,S-pyridinedicarboxylic acid in a similar manner. Retention time (anal. HPLC: 10 to 70% MeCN/H~O over S min) = 2.9 min.
ESMS
(C3gH3gN7~); calcd. 589.74; obsd. 590.3 [M+H]+.
Table 2, compound 8 was synthesized from 2,6-pyridinedicarboxylic acid in a similar manner. Retention time (anal. HPLC: 10 to 70% MeCN/H~O over S min) = 2.9~ min.
ESMS
(C3sH39N~02); calcd. 589.74; obsd. 590.3 [M+HJ+.
Table 2, compound 70 was synthesized from 3,~-pyridinedicarboxylic acid in a similar manner. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over S min) = 2.6 min.
ESMS
(C3SH39N~02); calcd. 589:74; obsd. 590.3 [M+H)+.
2S Table 2, compound 71 was synthesized from sebacic acid in a similar manner.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over S min) = 3.1 min. ESMS (C3gH;2N60~);
calcd.
624.87; obsd. 625.7 [M+H]+.
Table 2, compound 72 was synthesized from suberic acid in a similar manner.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over S min) = 2.8 min. ESMS
(C36H.~gN6Oo): calcd.
596.82; obsd. S97.S [M+H]+.

Table 2, compound 73 was synthesized from succinic acid in a similar manner.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) = 2.0 min. ESMS (C32H4oN602);
calcd.
540.71; obsd. 541.3 [M+HJ+.
Table 2, compound 74 was synthesized from tetrafluoroisophthalic acid in a similar manner. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) = 3.1 min.
ESMS
(C36H36F4N6~2); calcd. 660.71; obsd. 661.4 [M+H]+.
to Table 2, compound 75 was synthesized from 3,3-tetramethyleneglutaric acid in a similar manner. Retention time (anal. HPLC: 10 to 70% MeCN/H,O over 5 min) = 3.01 min.
ESMS
(C37HqgN6~); calcd. 608.83; obsd. 609.5 [M+H)+.
Table 2, compound 76 was synthesized from thiodiglycolic acid in a similar manner.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) = 1.74 min. ESMS
(C32H,,oN602S,); calcd. 661.9; obsd. 662.3 [M+HJ~'.
Table 2, compound 77 was synthesized from 3,3'-thiodipropionic acid in a similar manner. Retention time (anal. HPLC: 10 to 70% MeCN/H~O over ~ min) = 2.48 min.
ESMS
zo (C34H44N6~2S1); calcd. 600.83; obsd. 601.4 [M+H)'.
Table 2, compound 78 was synthesized from 2,5-thiophenedicarboxylic acid in a similar manner. Retention time {anal. HPLC: 10 to 70% MeCN/H20 over S min) = 2.94 min.
ESMS
(C34H3gN602Si); calcd. 594.78; obsd. 595.4 [M+H)'.
Table 2, compound 79 was synthesized from 1,13-tridecanedioic acid in a similar manner.
Retention time (anal. HPLC: 10 to 70% MeCN/I-hO over 5 min) = 3.58 min. ESMS
(C4IHSgN602); calcd. 666.95; obsd. 667.4 [M+H)+.

Table 2, compound 80 was synthesized from 1,11-undecanedioic acid in a similar manner.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) = 3.28 min. ESMS
(C39H54N602)~ calcd. 638.90; obsd. 639.5 [M+H]+.
Table 2, compound 81 was synthesized from 1,4-phenylenedipropionic acid in a similar manner. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) = 2.96 min.
ESMS
(C4oH4sN60z); calcd. 644.86; obsd. 645.5 [M+H]+.
Table 2, compound 58 was synthesized from hexadecanedioic acid in a similar manner.
io Retention time (anal. HPLC: 10 to 70% MeCN/H~O over S min) = 3.4 min. ESMS
(C44H64N6~2)~
calcd. 709.03; obsd. 709.7 [M+H]+.
Table 2, compound 59 was synthesized from homophthalic acid in a similar manner.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) = 2.17 min. ESMS
(C3JH42N6~2)~ calcd. 602.78; obsd. 603.5 [M+H]+.
Table 2. compound 60 was synthesized from trans-'~-hydromuconic acid in a similar manner. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) = 1.98 min.
ESMS
(C34H42N602). calcd. 566.75; obsd. 567.4 [M+H]+.
Table 2, compound 61 was synthesized from 2,2'-iminodibenzoic acid in a similar manner. Retention time (anal. HPLC: 10 to 70% MeCN/H~O over ~ min) = 2.8 min.
ESMS
(C42Ha5N7~2); calcd. 679.87; obsd. 680.6 [M+H]f.
Table 2, compound 62 was synthesized from isophthalic acid in a similar manner.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) = 2.3 min. ESMS
(C36H,~pN6O~);
calcd. 588.75; obsd. 589.4 [M+H]+.
Table 2, compound 63 was synthesized from malonic acid in a similar manner.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) = 1.8 min. ESMS (C31H3gN6O2);
calcd.
526.68; obsd. 527.2 [M+H]y.

Table 2, compound 64 was synthesized from traps, traps-muconic acid in a similar manner. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over S min) = 2.28 min.
ESMS
(C34H40N6~2); calcd. 564.73; obsd. S6S.3 [M+H]+.
Table 2, compound 4 was synthesized from 2,6-napthalenedicarboxylic acid in a similar manner. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over S min) = 2.65 min.
ESMS
(C4oHa2Nb~z)~ calcd. 638.81; obsd. 639.5 [M+H)+.
Table 2, compound 65 was synthesized from cis-5-norbornene-endo-2,3-dicarboxylic acid in a similar manner. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over S
min) = 2.47 min.
ESMS (C3~H44IV602); calcd. 604.80; obsd. 605.6 [M+H]T.
Table 2, compound 11 was synthesized from 4,4'-oxybis(benzoic acid) acid in a similar manner. Retention time (anal. HPLC: 10 to 70% MeCN/Hz0 over S min) = 3.36 min.
ESMS
(C42H44N6~3)~ calcd. 680.85; obsd. 681.5 [M+H]+.
Table 2, compound 66 was synthesized froml,3-phenylenediacetic acid in a similar manner. Retention time (anal. HPLC: I O to 70% MeCN/H~0 over ~ min) = 2.8 min.
ESMS
(C3gH44N6Os); calcd. 6I6.8I ; obsd. 617.3 [M+H]'.
Table 2, compound 67 was synthesized froml,3-phenylenediacrylic acid in a similar manner. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over ~ min) = 3.30 min.
ESMS
(CaoHa4Nb~z)~ calcd. 640.83; obsd. 641.6 [M+H]+.
Table 2, compound 68 was synthesized from 1,2-phenylenedioxyacetic acid in a similar manner. Retention time (anal. HPLC: 10 to 70% MeCN/H~O over S min) = 2.9 min.
ESMS
(C3gH44N6O.~); calcd. 648.81; obsd. 649.4 [M+H]+.
Synthesis of Table 2, compounds 98 to 117 l0l General Procedure: To a solution of 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole (46 mg, 0.2 mmole) with di-isopropylethylamine (54 p,l, 0.3 mmole) in 1 mL of anhydrous DMF, was added a solution of di-carboxylic acid (0. I mmole), HOAt (34 mg, 0.2 mmole), and HATU (95 mg, 0.2 mmole} in ImL of anhydrous DMF. The mixture was shaken overnight, then stripped of solvent under vacuum. The resulting tarry mixture was dissolved in 2 mL of a 1:1 mixture of acetonitrile and water (with 0.1 % trifluoroacetic acid). The crude product was purified by preparative HPLC.
Table 2, compound 98 was synthesized in a similar manner from I,3-adamantanediacetic Io acid. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over ~ min) = 3.28 min. ESMS
(CazHs4N60?); calcd. 674.9; obsd. 675.4 [M+H]+.
Table 2, compound 99 was synthesized in a similar manner from 2-allylmalonic acid.
Retention time (anal. HPLC: 10 to 70% MeCN/Ha0 over ~ min) = 2.87 min. ESMS
t5 (C3.~H42N60z); calcd. 566.8; obsd. 567.2 [M+H]+.
Table 2, compound 100 was synthesized in a similar manner from 2-benzylmalonic acid.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over ~ min} = 3.27 min. ESMS
{C3gH.~4NbOz); calcd. 616.8; obsd. 617.4 [M+H]+.
Table 2, compound 101 was synthesized in a similar manner from 2-butvlmalonic acid.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over ~ min) = 3.2~ min. ESMS
(C35H46N6~2); calcd. 582.8; obsd. 583.4 [M+H]+.
Table 2, compound 102 was synthesized in a similar manner from N-Cbz-(DL)-aspartic acid. Retention time {anal. HPLC: 10 to 70% MeCN/H~0 over 5 min) = 3.10 min.
ESMS
(C4oH.~zNzO.~): calcd. 689.9; obsd. 690.2 (M+1-1]*.
Table 2, compound 103 was synthesized in a similar manner from 2-3o carboxybenzenepropionic acid. Retention time (anal. HPLC: 10 to 70%
MeCN/H20 over 5 min) = 2.9I min. ESMS (C3gH~4N6O2); calcd. 616.8; obsd. 617.4 (M+H]+.

Table 2, compound 104 was synthesized in a similar manner from 1,1-cyclobutanedicarboxylic acid. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over S min) _ 2.68 min. ESMS (C34H42N6O2); calcd. 566.7; obsd. 567.2 [M+HJ+.
Table 2, compound 105 was synthesized in a similar manner from traps-1,2-cyclohexanedicarboxylic acid. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) _ 2.52 min. ESMS (C36Hq61~16~2); calcd. 594.8; obsd. 595.4 M+H]+.
Table 2, compound 106 was synthesized in a similar manner from N-Cbz-(L)-aspartic Io acid. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) = 3.1 I
min. ESMS
(CaoH47N~0.~); calcd. 689.9; obsd. 690.2 [M+H]+.
Table 2, compound 107 was synthesized in a similar manner from (ethylenedithio)diacetic acid: Retention time (anal. HPLC: 10 to 70% MeCN/H20 over S min) = 2.70 min.
ESMS
(C34H44N602S2); calcd. 632.9; obsd. 633.2 [M+HJ+.
Table 2, compound I 08 was synthesized in a similar manner from 2-ethylmalonic acid.
Retention time (anal. HPLC: 10 to 70% MeCN/Hz0 over ~ min) = 2.71 min. ESMS
(C33Hq~N60z); calcd. 554.7; obsd. 55.2 [M+HJ+.
2o Table 2, compound 109 was synthesized in a similar manner from 2,2-bis(4-carboxyphenyl)hexafluoropropane. Retention time (anal. HPLC: 10 to 70%
MeCN/Ha0 over ~
min) = 2.71 min. ESMS (Ca;H.~4F6N602); calcd. 814.9; obsd. 81 ~.4 [M+HJ+.
Table 2, compound 110 was synthesized in a similar manner from 2-methylmalonic acid.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over ~ min) = 2.22 min. ESMS
(C32H40N6~)s calcd. 540.7; obsd. 541.2 [M+H)+.
Table 2, compound 111 was synthesized in a similar manner from 3-3o methylenecyclopropane-traps-1,2-dicarboxylic acid. Retention time (anal.
HPLC: 10 to 70%
MeCN/H,O over 5 min) = 2.5~ min. ESMS (C3.~H~oN60~); calcd. 564.7; obsd. 565.2 [M+H]+.

Table 2, compound 112 was synthesized in a similar manner from 5-oxoazelaic acid.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) = 2.52 min. ESMS
(C37H4gN6O3); calcd. 624.8; obsd. 625.4 [M+H]+.
Table 2, compound I 13 was synthesized in a similar manner from pentadecanedioic acid.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over S min) = 4.13 min. ESMS
U43H62N6~2)s calcd. 695.0; obsd. 695.6 [M+Hj+.
1o Table 2, compound 114 was synthesized in a similar manner from 1,2-phenylenediacetic acid. Retention time (anal. HPLC: 10 to 70% MeCN/H~O over S min) = 2.85 min.
ESMS
(C38H44N602); calcd. 616.8; obsd. 617.4 [M+HJ+.
Table 2, compound 115 was synthesized in a similar manner from (R)-(-)-phenylsuccinic acid. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) = 3.04 min.
ESMS
(C3gH44N602); calcd. 616.8; obsd. 617.4 [M+H]+.
Table 2, compound 116 was synthesized in a similar manner from a,a,a',a'-tetramethylheptanedioic acid. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) _ 3.12 min. ESMS (C39H;4N6O2); calcd. 638.9; obsd. 639.4 [M+H]+.
Table 2, compound 117 was synthesized in a similar manner from N-p-toluenesulfonyIimino-3,3.'-dipropionic acid. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 5 min) = 3.23 min. ESMS (C4,H;,N~04Si); calcd. 738.0; obsd. 738.4 [M+H~+.
F. Preparation of Compounds of Formula I
Similarly, by optionally replacing 5-amino-3-(N,N-dimethylaminoethyl)-1H-indole with other ~-aminoindoles, and optionally replacing (al,a2,[33,[34)-2,4-bis(4-hydroxyphenyl)-1,3-cyclobutanedicarboxylic acid with other dicarboxylic acids or acid dihalides in 4D above, other compounds of Formula I are prepared.

G. The foregoing is an example of reaction of 2 molar equivalents of a ligand bearing a 5-amino group with 1 molar equivalent of a linker having two chemically complementary groups (a diacid) to form a compound of Formula I having two identical ligands (a homodimer). Reaction of 1 molar equivalent each of two dissimilar ligands bearing an amino group with 1 molar equivalent of a linker having two chemically complementary groups forms a compound of Formula I having two different ligands (a heterodimer). Alternatively, reaction of 1 molar equivalent of a ligand bearing an amino group with 1 molar equivalent of a linker having two chemically complementary groups followed by reaction of the intermediate thus formed with a second (and diferent) ligand provides a compound of Formula I that is a heterodimer.

Following the procedures of Examples 3 and 4 above, the following compounds of Formula I (L~-X-L2) linked at the 5-position of each ligand were prepared.
In the Table, "3a" refers to the substituent at the 5-position on first ligand L,, and "3b" refers to the substituent at the 3-position on second ligand. L~.

7, 7, T T ~ T ?. ?, ?. >, >, T >, >, >, r , , , r r , ~ , , , , r V ~t d' ~ ~' V et ~ ~f , , , , , ~ r r , , , r , , C C C C C C c C C C C C C C C

'p 'C 'O 'Q b 'C '~ 'fl;fl ~ 'O ~ ~ :O b ' ' ' 'L ~~L 'L 'L L L L L L L. L L V V
a a1 N C7 ~ 41 ~ N G7 N N ~ ~ N
a a a a a a a a n. a a a a a ~ ' ' ' ' ' ' - ' ' ' ' ~a. 'a ~o, a o. c. o. a a a a a a a a , , - " " r _ s s _ s , >, >, 7s T 7a i~ ~, T >, >, ?, T 7, T T
S ~ ~ ~ at..~ ~ .L..L S -C gi s t N ~ N N N CJ ~ N N dj ~ N ~ N dj E E E E E E E E E E E E E E E
, , , r , , , , , , , , M i i i ~ i i i i ~ i i i i i i T T T T T ~ ~ T >, ~, T T. >. T T
, , , , , , , , n , , n , n d' ~h ~ 'O'~' '~ Q ~t ~' ~f V' ~ ~' ~ V

, , , r , , , r , , , C C C C C C C C C C C C c C C

'O 'C b b_ 'fl'fl 'D ~ ;D '~ 'b :C 'C 'O 'C
' ' ' ' ' ' ' ' ' ' L. 'L L 1..L L L L L L L L L L L

Q7 N N N ~ CJ 41 N N N ~ ~ ~ ~ N
a a n. a a a a a a c n. o. a n n . . . . . . . .

a a a a a a a a _, _r _, _, _, , _, _, _, _, 7, T >, T T >. T T T T T T 7, T T
s L s .G t .C S L .C L t t t N N ~ N N N N dj ~ N N N N N N

E E E E E E E E E E E E E E
;

, , ~ , , , , ~ _ r , , M ~ n n , i ~ s ~ n n ~ , n i , T

c a~

t a.

II

N

L

v II
>, ~ N
o c c ~ ~1 _, 3 c, ~ L~ , L
z o. m ~ '-' z z 3 L 'C s ~
~ ~ il -; :, , a 'L v p O x , _ N U
V flll,n ~I y o ~ ~ II v ~ ~ U CJ
ri fV V N N II U U' x N N N N N 3 ~ N , , .r Z N x , 0 _' ' ' ' ' _' ~ ' O = U
a~ a~ a~ z a~ a~ v ._:.a~ z ~. N
3 3 3 3 3 3 z 3 ' V z N
n O
~

rv , , , , , , ~ , x ~ i.n z x x x O x x x o x U
v z z z ~ z z z ~ z z , :, :. .I., ... ~. .; , ~. , v ~ z 0 0 0 0 -~ 0 0 o N o o - ' Z U U U ~ U U U O U ~ ~ " ~''x U N N N ~ N N N N N x~ x U x U
U U U

, , , _, , , r _, , , ... .~.... O O O O O
O O O O O O O O O O
v ~.r~r ~r ~r .r .,r~r ~r U ~r ~ ~r .r V U U U U U U U U V U U U U
, , , , , , ~ ~ T , ~ , r >~ x x x x x z x x T x z ~- x x z z z z z z z z z z z z z z z H

H

V1 V1 V1 V1 ,!1V1 ~1 V1 V1 v1 V1 N V1 v1 V1 U , , r , , , , , , , , , , , , ~n v, ,n ~n ~n v, ~n v, ,n ,n v, ,n ,.,,r,v, o t o - gy m.,c ,n ~o c~

z M ~ ~, .~ ~ ~ ~. _ _ _ _ >, T T T T ~, ?, T >. >, >, >, >, >, ~ ~, , , , , , , , , , , , , , et e~ et ~ ~' V d' ~ V ~ V ~ ~ ~ V' ~' V' , , , , , , i , , , , , C_ C C C_ C _C C_ C C_ _C C_ C_ C C C C C

'a 'D 'Q :C 'O 'O ;C 'fl_-O~ 'C ;G 'G 'D _ 'D ' ~ ~ ~ ~ ~ ~ ~ ~ C O

L L L Y L L L. L L L L L. L ~L.' _ a a ~ a~ a~ a~ a~ v a~ w a~ a~ a~ ' L
~' a a a a ~ a~

. a a . a a a a a a . . . . . . . . . . .

a a a Q 0. ~ a a a Q a , ~ .n..a .n.
, ~ ~ _ ' ~ ~ , , , _ , , _ _ , _ _ _ _ _ _ _, >, >, i, 7, ?, ~, >, ~ T 7, ~ >, >, >, >, ?, >, r r r r r r r r r r r r r r r .C r N ~ N N N ~ ~ N N W N N W a) E E E E E E E E E E c E E E E E E
, , ~ , y , ~ , , ~ , , , ~ ~ , T T T ~ T T T T >. ~, ~, >, ?, T ~, ?a T
, , , , , , , , i , ~ ~ e? V',V
V~ V Q' ~ ~. .~ V ~ ~ ~' ~ V d' C G C C_ C C C_ C C_ C_ C_ C C C C C C

:C ~ 'C 'fl'9 '9 'D 'd ~ 'D 'n '~ ~ _ _ :C
L L ~L - L L L ~L ~ ~ ~L ~ ~ 'a ~~ ~

. . L L L L L L L 4., aJ a~ a~ a~ a> a~ a> a~ sJ a~ a~ a~ a> v v a~ c~
o a a a a n n a a a . g . , a a a c. c. a . . . ' ' ' ' ' ' ' ' a a a a a a a a a a n. 'a 'a .s~.-a..fi.
, , , ~ , ~ _ , , _ T _ _ _ _ T _ _ T T >, >, ~ >, >, T ~ T

t r s r .~ r ~ t r L ,t r .c .c s .c .

N N ~ N N N ~ d 4J N

E E E E E E C E E E E E E E E E E

, , , , n n n n , , n n n , n n i i ~ ~ ~ ~ ~ , ~ ~ , ~ ~ , , , T

C T
C

r v a t II a N ;a a~ , L
ai T M

T
T , X M
C

T
T z r _ ~ v ~

z , r _ a n x O ~ ~ c ti >, .a . s a J c a O r N
c v v ' ~ o v "' a U !
J

N. N ~ II v N = G. li = s ~

z ~ ~ v ' N z N

~ ~ ~ , V ~ ~ L ~ /1 a ~ _, ~ 1 . 1 i i r r" t i O N 3 Z Z Z 3 z N N 3 tV N = N ... U ..., ~

z ~ U

3 3 V 3 3 z ~ 3 " z z U

O z z ~ ~ ~ z = U ...o x z, z Z z U , ~ , z Z (~ U z , ~ .r. U r. ' Z N
i U ' :. N = _ ~, .

U U U ' x O O ~ O O O ~ ~

z J ,.. U N U

V ' L

, , , , '. ~ ~ O
N N U U N N U U U N N Z Z z z z z cJw ' ' , , ' ' , ~ , ' _ _ _ _ _ _ _ _ _ ~
O O O O O O O O O ~ ~ O ~ n n n V
~ r O O O
O

U U U U U U U U U , , , , , , , ~ , T ~ , ~ , T T T T Z T Z z Z .T.T _T. T .T,Z Z

z z z z z z z z z z z z z z z z z~~
, , , , , , , , , , , , , , , , , , , , , ~. o _ N M ~. ~ ~ ~ ~ ~ ~ -~ ~ C'Jf~l N CJ N N N N f~1N M M M M M
J

T >, T ~ T ~ ~ T 7s T ~ T ~
, 1 1 1 1 r 1 1 1 1 1 r 1 ~
d' ~ ~ VI Vr ~ V C ~ tt C' 'd'V G C C
c C C_ C C C C_ C
C c c c c c _ _ ~C C ~ :O ~ 'G :C :C :O :C '_~ :C Z7 _ _ 'O :C
~ 'D ~

1.~L. L L L L L L 6, L L V L ~L L ~L.L
a~ a~ a~ a~ a~ a~ v a~ ar ~ ~',a ~. a a b. a a a a. a a a a a a a ' ' ' ' ' ' ' ' ' ' ' ' ' c. a a n. a a n. a o. n. n n. n. 'a 1 1 'o.'n.'a , 1 1 , 1 1 1 1 1 1 ~ , , >, ~, >, >, >, >, >, >, >, >, >, >, >. ~, i, >, s s s s s s s s s s s s s s s s a> a~ a~ a~ a~ a> a v o; a~ a~ d d a~

1 ~ 1 1 = 1 ~ ~ , 1 1 1 1 ~ 1 ; ~ 1 ~ , , ~ ~ , , ~ ~ ~

>, >, >, >, >, >, ~, >, >, >, >, >, >, ~, >, >, >, 1 1 1 1 1 1 , 1 , 1 1 1 VI V' V Vr V' ~ ~ VI VI Vr ~ VI er , 1 1 , c c c c c c c c c c c a c a c c c ;o ;n ;n :v ;v :v y y v ;o vo y ;W v :v ;a L. L L L L. L L ~L L L L L. L i~. ~L L L
N N N N N N N ~ N N 4J Q! ~ N ~ ~ G~
g a a a a. g o. a n, a a a a a a a a . . . . . .
.

a a Q a a ~ ~ .Q .a .a .a .a 7, T T >, >, >. T ~ ~ T ~ T >, j, ~, ?, s s s s s s - s s s >, s s s s s s w a~ d a~ v a~ a~ a~ m v a~ a~ n~ y y~ y y E E E E E E E E E E E E E E E E E
1 1 ~ r 1 = 1 1 1 1 ~ 1 1 ~

1 ~ ~ 1 1 ~ ~ ~ ~ ~ ~ ~ ~ 1 1 c c a> rT. X v a a o 'v c ~ ~ .- - a.
>, s >, N
v , a~ >, T a U X
~,., N n. a v =
U - a j~ x M M T v v~ ~ ~. ~ ~ ~ ZI II II 3 t~ >, II ~II~II ~ E T N N y a~
N N N -c s 1 U ~ ~ Z >. 1 il G. n. c~ ~ v a~ z ~ c ~ --a~ v L N M ~ M n -c '-.1 ~ ~O c a~ v ~, ~ -~ 3 3 p ~ ~- v-, 3 3 3 a~ n _ n U 1 1 v n ~ ~ a s N a N = x x U ~ z ~ a 1 x x z 3 ~ N ~ ~ z z L M s r a~ ~ a~ N :. .'-.z a~ II N
z z z 3 . 3 y ~ ? ~ y II -z ~ a~ NL' II
O O D T 3 Z ~I z z U 1 ~ 3 'L' Z T = ~ U z Z v z ' _ ~ L
Z Z T Z U .i.
z z z = p z O U N O 3 z 3 3 N N N Z (~ U U U U ~ ~V z '~
r ~ O 1 1 1 T 1 O z z x x x N .-x U x H N N Z' ~ .~ Z
U U U o z z x z z v z = o N N N N N x N V U U U N V ~ 1 V
1 1 z r 1 1 1 1 1 1 x x x x x N x S x x x Z x z z z z z 1 z z z z z z z N v. N N
x 1 z /1 N h1 N N
~ ~ ~1 ~ ~ /~ n n n I~ n ~I a ~I a ~I ~I ~/ ~/ VI ~/ _ _ _ _ U U U U U U U U U U U U U c%~ c'~nv~ c%
, 1 1 1 1 1 r 1 1 1 1 ~ 1 r 1 1 1 x x x x x x x x x x x x x x ..~.x x z z z z z z z z z z z z z z z z z 1 1 1 1 1 1 1 1 , 1 1 1 1 1 , , 1 1 1 1 1 1 1 1 1 t1 ~M M ~ M ~ ~ V ~f V ~ C' 'Y ~ V ~ v'1 ~

T T >, >, ~ 70 >, ~ >, >, >, T 7, 7, ~, >, ' ' ' et ~ ~ ~ V ~ V '~ '~'et V V ~t .~,' , , ~ i , , , , , , , , i ' ~ C C C
C_ C G _C C C C_ C_ C C C C C

;fl t7 ~ ;C ~ -C b . ;C ~ 'O '9 '~ 'fl'G 'D b V L -V L :D L ~ ~ ' ~
~

L L L L L . L L L L 4" L L
N ~ N' N N N G7 N ~ N ~ ~ v N 'U N
a a a n. a a a a a a a a a a a a ' ' ' ' ' ' ' ' ' ' ' ' ' a a a a a a - a a a a a n. 'a 'n.'a 'c.
, , , , , a _ ~ , ~ , , , , ~ , , >, ~, >, T 7, T T >, >, ?, >, >, >, >, _ >. >, y s .c s .c .C s s s .~ .c s .c s >, s t .c a a~ a o> a~ a~ a~ a~ a~ a~ v a~ n~ a~ v a~
E E E E E E E E ~E E E E E E E E E
, , , , _ ~ , , , , ?a >, ~ T T T >, >, T T ~, ~, T T T T T
, i i , , , , i , , i i i i V~ ~ V ~ V~ ~ ~ ~' V V~ Vw t C ~ ~f ' C G _C C_ C C C _C C C_ C C C C C

'_D 'C 'fl -p '~ -p '~ "O "' ;~ ~ 'O _ TJ '~ ~9 ~ ~ ~ ~ ~ ~ ~ ~ .0 ' L L L L L L L L L L L L- ~L L ~ ~L L
w a~ a~ v a~ a~ c~ a~ v as a~ a~ a~ ~L c~ v . n. a. o. n. a o. a. a n. n. a, a n. v c. c.
. . . . . . . . a .

a a a a a a a a a a ' - ' ~ ~ , , , ~ , 7~ T ~, >, T _ 7, _ _ T _ _ T ~, ~, _T j, t t .= t T t T T L 7, T S t "C
.~ .G L t t a~ v a~ a~ a~ v v u~ a~ a~ y a~ v a~ a~ c~ c~
E E E E E E E c E E E E c E E

i I
I a c v a N

>, ~.

c --s ~i T c a tv _ c Z v t N O 7, t G

II ?. T :' N _ ~ v _ ~ I
T a i I

y t a _ v0 M N G

' t d N ~ v1 II y y 3 ~ i ~ ' N ~

_ ' N iI II a. ~ v N

U z N Z a~ r., a: .C

~ L' z ~ - - 3 ~ ' 0 ' -~ ~ " 3 N N .T..z O
; ~ z 3 ' z O ...
~

. , , _ .~ , ~ V .;. L Z ' ~, '~ U
z = z c ' V U z z Z ~ z z U ,=. . Z z 3 ~ ' , U
O ;r O_ .. O ~ O_ ' , O ' '~ .i r' O " O V O

N U ~ U = V U Z U
N U U N : V U ~ V N

.Z ~ N , ri a N U ~ .. N
O n ~ n n , yr ~ N ~ ' i i N n r ~

U . ~ ~ =_ ~ z v T_ "'- v =
.; N ~ ~ V U U _ ' ~ , _ O ~ U T' U

U U N N U N V U
: ~ ~ = ' ' ' - = : ' ' ' ' ' O . . O . O ,. . . , , O O O O J O
O O . . . . , .
O O O O O O

U U U U U U U U U U U U U U U U U
~, x T Z Z x 2 Z .i. Z
~

z z z z z z z z z z z z z z z z z s , , , , , , , , , , o_ N r~ ~ ,w 0 t~ 00 O~ O - cn r~ ~t vW O r~
v7 'n h W W W v1 vD ~O ~O ~D ~ ~O ~O ~O ~O

~, 7, 7, ~ ~, T 7, T 7, T T T >, ~, ?~, , n i , n n n n , n n , , , n C' ~ ~t ~t ~t et ~' a ~ V' et ~ ~ V' ~' C
, , , , , , i , , , i , ~ , , , C C C C C C C C C C C C C C C C C

_ _ _ :C ~ ~ :J b :p :O :J ;C :C O ~D :C ~ ~ ;G 'O
~

L L L V L L. L. L L L. L. L V _ ~L 4., U v ~ v U v v v N v v v L v y y ' a a v a a a a a a a a a v a a a ' ' n. ' ' ' ' ' ' ' . a ' a a a a a a a a a a c 'n. 'a 'a 'a 'a s - ~ _ _ a _, _~ _, , _, _, _, , , , , ~

>, ?~ >. T >, ?v ~ T >, T >, >, _ _ _ _ .~,cs s s s s s s s s s s s ~, ~ 7, >, s s s s v a> e~ a~ a~ v a a~ a> a~ c~ a; v a~ a~ a~ a E E E E E E E E E E E E E E E E E

7, 7, 7, T T T T 7, T >, T :, T 7s ?, 7, T
, , ~ , , ~ , ~ i , i i V~ ~ ~' V' ~ V V ~ ~ 'V Vi '~ V' V V~ V~' C C_ C_ C _C C C_ C C C C_ C C G C

~D D ~ ~D b '0 'Q :J 'C ~9 '~ '~ _ "G ~ 'fl~
~ ~

L L L L L L W L L L L L L. ~L ~L ~L
v v v v v v v v v v v v v v v v a a a a a a a a a a a a a a a a . . . . . . . . . . . .

a ~ G a ~ a a Q Q a ~ ~ .~ .Q .a .a 7, T T T T 7, ~ T >, >, >. >, T >, ~, ~, T
s s s s s t t s t .C s L s .C

a~ v a~ a~ a~ a~ a~ w a> i a~ c~ c~ y a~ a~ a~
E E E E E E E E E E E E E E E E
, ~ , ~ , , , , I
>, c ' ~, >, s a a s v o o c. .I
v U Q
U
I

_ T I v >, >, v ~ N ~ r.

c c ,o ~ ~ s y o ~; ~ a 3 O
.'= .~ ~ v , o 3 >, .:
n~'.a m ~ -~ z O 2 ,n p ,.:~s ~ "., Z ~

_ ~ z z z ~ ~ N z V V ' O N ,~ O a :.,' i. .T..T L z z '- ' '~ .- 'a .~.
s " U U
z z z t O O ~ ~ z .1 'r U
% V U ~~ 3 z ~ I~ z .r z ~ _ _ p ". ;. ~ U ' O p U .~'O
O O N N
z z ~ ~ ~ z ~ ~ ~, z v -- N U
U v O O N - _ N v~ .~ p .r .~ ~; s O N

U U t Z 2 (~ ..: ..:'~ U x 2 Z~ 3 N :
' .
N N V U ~ N U U U N U U U ~ T .
O U_ U_ =. .'... ~. ~. ~. ~. .~... .-, ...O O
O O O O O O O O O O O N Z z .. .r .~ .. ~.

U V U U U U U V U V U U U U
w z x s z - x z z = _ ~ o O
.~

z z z z z z z z z z z z z z U v U

, , , , , , ~ , o~ o - tv r~ ~r vw p r o0 0 o - cu r, vw o ~o r r r r r r r r r r o0 00 00 00 00 00 11~

>, >, '>, >, >, >, >, v ~t v v _C C_ C_ C C C C

N ~ N N ! N N _ ' y N n y n n n n n n L L v a a Z a x Z T 2 T Z a n 1..n a , .
'a 'a v 'a U U U U U 'n 'a 'a ' . U , a z z z z z z z - -' ' ~ ,, , , ,, N _ s , , s s s E E = ~ y = x z T _ ~ E
x E E
,_, _ U Z ,_,U U U U U U _, ..r.. , , , 1 , , , , ~; ~ ~. , , , >, T ~ >, >, , , V' ? 'S et' C G_ C_ C C C C

N '~ 1 N 1 r L L ~ ~

"~ . n n n n y N 6a n. c. x n. x x ~ Z '- "

a a a a 'a 'a V 'c U U U U U U '~ '~ -n 'a z . z z z z z , , . -z ~ - - - ' ' ' ' , , , , , ~ ' ' ' , , , , .. ~ .r c s s s .

_ _ _ _ _ N ........N N N N
I

,_, ,_, U ~ U U U U U U

v _ , , n n = " a ~ a , , n n , C
N

s Q.

O_ L_ , M

N W

_ N
O

O

N
's v ~' n. ~ c V M
a N

T
a O
w s v a a~ a ' :_' v ~ J

M , y ~ . N 1 z s 1:, ~.~ ~ ~ z 3 x ~ N N 3 ~ .~ z N N N 0 =

N

N , a a z , 1 , -, H x N N z z ~ x .
x = x o U U U z ~ ~ ' , z ~ z U

O ~ O ~ Z s x ~ ~ .~ _, ~
s O O
z ,r rv N 0 3 z a z a v ~

. v v v N rv V O ~ O O N ~ x N

x x x ~ v ~~ U N

U U V N z U Z U U ., ' NU

0 0 o x z ~ ~ 1 '- T x "' U U _ O O N ' '' , ~. U
N N U ' '. ... .. , U U ..
U ~

~, N ~-Z U Z U x .Tr.U = -:-= T'-' i~ _ ' ..
U = Z x V N U ' V U N U U U .
. N .~ ~ U

U V , ,-., , ~ .~ ,~ :. .=.:. ,=,r. ,.=.
U .-. ~ .-. .-.

j_Z i o o z o 0 0 0 o c o 0 0 0 U U ,~ U U U U U U U U U U

0 o x - o x z x x x ~ z z ' v v z z v z z z z z z . z z z z 1 , , , , 1 , , ~

, , , , , , r o0 0~ o - N M v ~w o r o0 0 o 0 00 00 0o c o. c o. o~ c o ~ o v _..

>. T ~ >, >, ~ ?. T 7, T ~, ?> >, >, T

, , r , , , r , r r ~ ~ , , r et V ~' ~t C V eh ~' ~' ~f ~' ~t V C
, v , r r , r , , r , r , r C C_ C_ C C_ G C_ C C_ _C C_ C C C_ C C

_ _ ~ ' ~ - ~ ~ H

L L L L L L L L L V L L L L ~L L
N N ~ ~ ~ N N N N N N ~ N ~ C7 W

a, a a a a a a a a ti.a a a a a a Z

'a 'c. 'a 'a 'n. 'a 'n.'a.'n. 'a 'a 'a 'a 'a 'n. 'a V
, , , , , , , r , _ , _ , _ , _, ~, >, >, T >, T T >, >, ~, >, >, >, >, ?, >, s s s_ s_ s_ ~ s s_ s_ s_ s_ s s_ s s s _ _ _ _ _ N N N N ~ N N N N N ~ C! CJ N ~ N N

E E c E E 8 E E E E E E E E E E V

, , r , r r , , , , , , , , _ _ ~ ~ , , , r r , , , , , r ~ ~

T T 7, T >-. T ?, ?, >, >, ~ >, >, T T T
, r , ~ , , , r r r , , eY ~ ~t ~' V ~ '~ ~ et ~t ~ V ~ rt ~f V
, , r r r , r , , , r r , C C C_ C C C C C C C G_ C C G C C

_ 'D '~ 'fl'O 'O ~ ~ 'O 'fl ~ ~D ~ '~ 'C ~ ~ m ~ ~ ~ ~ ~
- _ L L Y. L L L L L L L L L L - L L
o o a n a a c n n ~ L

. . . . . . . n. n. n, n. n. Z

'a 'o. ~a.-a.'c ~n.~n.~a 'c 'a -a 'a 'n.-n.'n. 'n V
, , , , , , r , , r _ _ _ _ _ _ _ _ _ _ _ _ _ _, _r _, 7, T T T T 7, ~ ?~ ?, ?-,T >, >, >, T T

.C .C ..GL L t s s t S L .C t S S iv N d N N N W ~ N v ~ ~ 6J ~ N N

E E E E E E E E E E E E E E E E V

r , ~ , r r , , , r r r , , T

C

s T

a N ~ a . ~ ' n II -~

V

>

> v a~ s , ~ v 3 >, Z v Z C N i. a. T s T 3 i _ r ~ G_ C
z T O O ~ y l\I~ = Z :.

E ~ z , O

o ~ ~' ~ N .:, a I z ~. U

N N .:. O

N >, v~ ~ z ~ cn Z S ~ O U '., v N N :. s c~~Z a~ a~ V , 3 _ Z 3 v O 3 . ~ U

~ 3 N N U ~ Z ~ N V T V

' Z z = O
U

V Z :' ~ ~ U O %~ _ ~ '; r z z N

( O z c ~ O cjy~ . V z O ~ U :

0 3 3 U ~ ~ U ~ 3 .-.~,:.,U U ~' . U
' p p ~ ~ ~ N r ~ , , U O .. V

(j 2 Z Z 2 ~ Z O . T, N z z Z V V ~ ~ Z U V U U ~ z I1 ~ y ~7.n ~ ~ ~ ' /''~h r, ~

r O O U U U U O ~. .~. N N ~ ~ U
"

T U U ' Z = U = U Z Z ~ = V Z_ ' N N ~ U U N U N U U U _ U ~ U
U T

U , , , r r , " ~ r , - r ~ : : , c .. . .-... ~. ..,, .. .~ ~. , ~ .. ... ..
0 . 0 0 0 0 0 . 0 0 0 . 0 0 0 e~ o ~

.. .....,.. ~ .r ... .r '. ~. ... ...
U U U U U U U U U U U U U U U a U
r , r r , r r , ~ U
j, r r r Z 2 Z ~ T 2 Z ~T. ~ Z ' ._T.Z 2 Z'y T
' z z z z z z z z z z z z z z z z z r r r , r r r , r ~
, , r , , , , , , r r , , , ~, 0 0 0 _ T >, >. 7, ~ ~ ~, T ~ 7, ~

V~ ~ ~ ~ ~ V

G C C c C _C c c c_ C _ ~ C

N N N N ~ ~C 'C ~ 'C 'C ~ 'D 'C ;G ~ :C 'C
~ L ~ ~

~ ~ , L L L L L L L L L 'L L L
U V n ' n. a n. a ~ a c n n c~'a V

U _ . . . . .
'a 'n. '~'' ~ ~a''- 'n.
' ' a' 'a 'a 'a 'a 'a z z z z T ?, _ _ >, .7, ~ T 7, T ~ >, ~s >, i~ ~ n n S L s S .J= .C s s s .c t s s 2 T Z = ' o~ a~ a~ v w a~ a~ a~ a~ a~ o~ as E E E E E E E E

~ E E E
1 ~ 1 _ ~ - , 1 1 1 1 , 1 1 1 1 1 _ ~ _ - ;

T 7, ~ ~, >, ?1 >, >, T 7, ~ ~, ' ' ' V ~ V V ~ V V er ~ ~' ~ V' V' , 1 c C_ C c_ C c_ c_ c G c N n N TJ 'D '0 ~J 'D ~ 'O 'D 'L7 ~C TJ 'O
n M W n -, y ~ ~ y y N v y 41 4.7L N Gl U U o a ~' a a n U U ' _ _' _ _. n_.a a a I 1 1 . a n. a ~a 'n. 'c .a .a z z z z _ _ _ _ _ _ 1 _, T T >, ~, T >, ~ ?, ~, T ~, T
>, t s S t .r=L s S t .C L

z z z z v v v U U U U , , ~r ~r ~r v .-..-. 1 ~. ._ ~ 1 ~ 1 ~ 1 _ _ N
L

t O

>, U ~
O

v N U
'_ U .c .

c ~ .-.
o J

a = s U .
o O

c:~ ~, ,:.. U ~ z U p c O n ";

~ =
~I zy " N z N .~ -,'..
U a N .' ~, N ... U U
~ N z _ ' a> >, y ~ . , L CL t N 1 ~ ' . T' , c%~' U 3 ~ n'' O ~ = = U
s O ' U

p 3 U U

Z 1 N U U ..r~, .'. x ~ ~. 1 T

o z s ' ~ ...U O = z ~ ~ ~
z "' r, ~. z v ,Tr, = U
O ~, U V ,-~,~ O = z U
O V , -~ U 1 ~

, U O 3 _ ~ z " = z ~ p U V ,-. ", N x z U ~ z V ~ O_ z ~ U ~ _ 'T
.~ . O
.

V U N z _ U -~=~_ O .y Z ~ ..
' Z ~ T U , U ' U

--y=O U ~ V U U N -r ~ .r Z Z Z
~, N V =' U V V U N V '-'~ .,-'N .,-'~: U V
a a 1 e~ I~ ~.,~ ~ ~Ln i i' r r U U U U N 'T' T '~ - _ ~ C> -~ U = T' _I _I _I _ _I U V ~ V U U
O O O O U U U U U .
O

U U U U U Z z z z z ,;"'z z z z z z ~

' ' ' ' ~ _ _ _ _ _ _ _ .T. .T..~ _ .T..O O O O O O U
" yr w r wr O

Z z Z z Z U U U U U z U V U U U U
1 ~ 1 1 1 ~ 1 1 1 1 ~~ 1 1 1 N

~m n In Im n In v~ vo v~ ~n v~ v~ In v v~ v~
1 1 1 1 1 1 ~

m Im n Im n In v~ In W o v~ In In In v In c o - N M v ~n ~o c~ oo c o = N M
N N (V N N f'Jl'!N N ('I M

~ M M M M M

>, >. ~, T ~ T ~ ~ T ?v ~ >. >, ~ >, V ~ ~ ~I'Q ~t C' d' ~' V C_ , Y , , , i , i i , ' ~_ C_ C C C
C _C C_ _C C_ C C C_ C C_ C_ ;G
_'C 'G 'fl ;'G'fl:C 'D 'O b 'C ~ 'fl 'fl'p ;C ;~
L. L V ~L L W L. ~L ~L L ~L ~L L V a '$. c. a ~ a a c. b'.n. a a n. a n. a', a 'a 'a a 'n.'a 'a 'a 'a 'a 'a 'a 'a 'a 'a 'a 'a _, _, _~ 'a _ _, _ _, _, _ ~ _ _ , , i~ T ~ _, ~ ~ i~ ~ >, ~ >, >, T 7, s t .c s ~ .c .c s s s .c s s ~ .~ s s a a~ a~ s a~ a~ a~ a~ a~ a~ a; v a~ a a a~ a E E E a~ E E E E E E E E E E E E E
, , E , , , , , ~ , ~ , , , , T ~, ~, ~ >, T ?, ~ ~ T >, i. >, >, T T
d' ~ ~ V~ ~t C V~ 'V W V~
, , , , , , t' , V, ~, V,'V V,' C C
C C C_ C C C_ C_ C_ , _C _C C C_ c_ C
'C ~ 'O 'C 'fl:G :O 'flC_ _b b 'fl ~ ''?.'O ~ 'D
L. L ~L ~L ~L L L ~L '9 L ~~ ~ ~ ~L L ~4 ~1., a ~. a a 'a a a n. ~L d. ci.a a n, a, ~ a, .a 'a 'n. 'a 'a 'n.'a 'o.n. 'a .~.'a 'a 'a.'n. 'c 'ri , _, _, _, _~ _, ~ _ 'a. r T 7, ~ T T >, _ ~ T . ~ s '~' .r.
t Z t .C .C t >, S ~ ~ .L T ~ L .G S
N 57 N N N N .C N ~ s s N
N N E N QJ N N N
E E E E E E E E E E E E E E E E
, , , , , i , , , i i , "

, , , , i ~ ~ ~ i i ~ , ~ i ~ ~ ~ , i T

_C

, L
j, '' X O T y ' ' o V ' p ~ = c a.
.. ~, >, O
v o a Q z s U o . , cv , C1 i N X U
~ N " N V ~_ ~
il ~ , , , II ~ o ~ Z
U " ' U ' , ~' ~ y N o ' z s z , .~ z ~ ~ ~ ~
~ z 3 z 3 z 3 ~ ~ _~
z ....~.o ~ o ~ ~ N o o z o o o U
< ~. .., z .. o o ~, ~. , V ' o o ~ o U U U ~ U U C) ~ U z O
S z = U U x .=.z N z s ~
~ z U Z Z Z x = z ' 3 'N Z
U z , U ~, U .., ~. z ~ U_ T , z z U .r z ~' z z = ~ U O
'-' p Z z z z U O m N
N , N U ' ... N N ~ N ~ z ~ - N z N N j x z z j T z z z z z z Z z U U U z U V U U U U V N U T z U , ~ ~ ~ , U U
v ~ z z x z z z z z z z ~ z z z z z z z z z z z , , , , , z , , , , z z z z z z z .. ,~ ~. .. .. ~ ~ :.
0 0 0 0 0 :. 0 0 0 0 0 0 0 0 0 0 0 ~r ~r a 'r ~ 0 v ~r ~r ~ ~r ~r ~r ~
U U U U U ~ U U U U U U U U U J U
U , v1 v~ ,n ,n v1 v, 'n v; ,n ,n v~,,n v, ,n v~ v~
, ~ , , , n v~ vi h v~ ,n ,n vm n v~ ,n ,n 'W n v W

~O I~ 00 O~ O ~ f'! M ~' V1 ~O t~ 00 O~ O -M M ~ c1 ~ ~T V '~t~ V C 'd' ~' ~ v1 V1 h ~'r , 1 , c c c v b w . .

L ' .' a a a . .

a a .Q

, , , >. ~, >, s s s .. .

a~ a~ .
a~

E E E

p, i, , , , v , 1 , c c c _W W n ~ ~

L~ L L

N N N

n. a a ' ' ' n. a. a 1 , , T >, >, s s s .

a~ a>
.

E E E

, , O

~
O U

U ~

z z z v , , ..:
~ N

~ U
O

z U O

, o :.

~ N

z ~, x ' x U
:

.
U '-' .r U O x ' U
U ~

, N

x U

U

.~. U

x x z z z , ., .:. ~

.. .. .r U U U

1 , , h M !f V1 h h ~

Preparation of Compounds of Formula I
Preparation of a Compound of Formula I in which L is a Compound of Formula II
in which R', R2, R4, R6, and R' are Hydrogen, and R3 is N-Methylpiperidin-4 yl, linked via a Carboxy Sidechain at the 3-Position, p is 2 and q is 1 A. Preparation of a Compound of Formula (45) To a solution of 5-carboxyindole (10 g, 62 mmole) and KOH (10.4 g, 185 mmole) in 200mL of methanol was added 1-methyl-4-piperidone ( 14 g, 123 mmole). The mixture was refluxed for 27 h, cooled, and concentrated in vacuo. The residue was taken up in 150mL of to water, and brought to pH 7 with 1N HCI, which led to precipitation of solid. It was collected on a Buchner funnel, and washed with water and then ether. The product, 5-carboxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-indole, was obtained as an off white solid.
Retention time (anal.
HPLC: 10 to 70% MeCN/H20 over 5 min) = 2.5 min. ESMS (C,SH,6N202); calcd.
256.30; obsd.
257.3 [M+H~+.
B. Preparation of a Compound of Formula (47) A suspension of 5-carboxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-indole (7.6 g, 30.0 mmole) in 40 mL of 1 M HC1, followed by 200 mL of HzO, and 10% Pd/C (~3.Og), was shaken under a hydrogen atmosphere for 12 h. The mixture was filtered through Celite, washed with 2o water, and lyophilized to give 5-carboxy-3-(1-methyl-piperidin-4-yl)-indole an off white solid.
Preparation of a Compound of Formula I
To a solution of 3-(2-(N-methylamino)ethyl)-1 H-indole ( 17.4 mg, 0.1 mlnole) and di-isopropylethylamine (22 pl, 0.13 mmole) in 0.5 mL of anhydrous DMF was added a solution 5-carboxylic acid-3-(piperidin-4-yl)-1H-idole hydrogen chloride (29.5 mg, 0.1 mmole), HOAt (17 mg, 0.13 mmole), and HATU (47.5 mg, 0.13 mmole) in 0.5 mL of anhydrous DMF.
The mixture was stirred at rt overnight, and concentrated in vacuo, yielding oily residue.
It was dissolved in 5mL of 50% aqueous acetonitrile (with 0.1% trifluoroacetic acid), and purified by preparative HPLC. Fractions with con ect mass data were combined, and lyophilized to afford the product as 3o an off white solid. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) = 2.577 min.
ESMS (C26H3oNaO); calcd. 414.54; obsd. 415.3 [M+H]+.

Table 3, compound 20 was synthesized in an analogous way from tryptamine.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) = 2.657 min. ESMS
(C25H28N40); calcd.
400.52; obsd. 401.1 [M+H]+.
Table 3, compound 21 was synthesized in an analogous way from 5-methoxytryptamine.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) = 2.524 min. ESMS
(Cz6H3oN40Z); calcd. 430.54; obsd. 431.2 [M+H]+.
1 o Table 3, compound 22 was synthesized in an analogous way from 6-methoxytryptamine.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) = 2.627 min. ESMS
(C26H30N4O2O calcd. 430.54; obsd. 431.2 [M+H]+.
Table 3, compound 23 was synthesized in an analogous way from DL-a-i5 methyltryptamine. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) _ 2.788 min.
ESMS (C26H3oNa0); calcd. 414.54; obsd. 415.3 [M+H]+.
FXAMPT.F ~
2o Preparation of Compounds of Formula I
Preparation of a Compound of Formula I in which the Ligands are different To a solution of 3-(2-(N-methylamino)ethyl)-1H-indole (17.4 mg, O.I mmole) and di-isopropylethylamine (22 pl, 0.13 mmole) in 0.5 mL of anhydrous DMF was added a solution 5-carboxylic acid-3-(piperidin-4-yl)-1 H-idole hydrogen chloride (29.5 mg, 0. I
mmole), HOAt ( 17 25 mg, 0.13 mmole), and HATU (47.S,mg, 0.13 mmole) in 0.5 mL of anhydrous DMF.
The mixture was stirred at room temperature overnight, and concentrated in vacuo, yielding oily residue. It was dissolved in SmL of 50% aqueous acetonitrile (with 0.1% trifluoroacetic acid), and purified by preparative HPLC. Fractions with correct mass data were combined, and lyophilized to afford the product of Formula I as an off white solid. Retention time (anal. HPLC: 10 to 70%
30 MeCN/H20 over 6 min) = 2.577 min. ESMS (C26H3oN4O); calcd. 414.54; obsd. 41 ~.3 [M+H]+.

Table 3, compound 20 was synthesized in an analogous way from tryptamine.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) = 2.657 min. ESMS
(C25H2gN40); calcd.
400.52; obsd. 401.1 [M+H]+.
Table 3, compound 21 was synthesized in an analogous way from 5-methoxytryptamine.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) = 2.524 min. ESMS
(C26H3oNaO2); calcd. 430.54; obsd. 431.2 [M+H]+.
Table 3, compound 22 was synthesized in an analogous way from 6-methoxytryptamine.
to Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) = 2.627 min.
ESMS
(C26H3oN402); calcd. 430.54; obsd. 431.2 [M+H]+.
Table 3, compound 23 was synthesized in an analogous way from DL-a-methyltryptamine. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) =
2.788 min.
ESMS (C26H3oNa0); calcd. 414.54; obsd. 415.3 [M+H]+.6 min) = 2.788 min. ESMS
(C26H3oN40); calcd. 414.54; obsd. 415.3 [M+H]+.

2o Preparation of Compounds of Formula I
Preparation of a Compound of Fonwula I in which the Ligands are different A. To a solution of 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole (22.9 mg, 0.1 mmole) and di-isopropylethylamine (22 ~1, 0.13 mmole) in 0.5 mL of anhydrous DMF was added a solution of indole-3-acetic acid (17.5 mg, 0.1 mmole), HOAt (17 mg, O.I3 mmole), and HATU (47.~ mg, 0.13 mmole} in 0.5 mL of anhydrous DMF. The mixture was stirred at rt overnight, and concentrated in vacuo, yielding oily residue. It was dissolved in SmL of 50%
aqueous acetonitrile (with 0.1% trifluoroacetic acid), and purified by preparative HPLC. Fractions with correct mass data were combined, and lyophilized to afford the product as a white solid.
Retention time (anal.
HPLC: 10 to 70% MeCN/H20 over 6 min) = 2.82 min. ESMS (C24H26N40); calcd.
386.50; obsd.
387.0 [M+H]+.

B. Similarly, replacing indole-3-acetic acid by other carboxylic acids, the following compounds were prepared:
To a solution of 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole (230 mg, 1.0 mmole) and di-isopropylethylamine (170 pl, l.Ommole) in I2 mL of anhydrous DMF was added a solution of 4-fluorobenzoic acid (140 mg, 1!0 mmole), HOAt (136 mg, I.0 mmole), and HATU
(380 mg, 1.0 mmole) in 6 mL of anhydrous DMF. The mixture was stirred at rt overnight, and concentrated in vacuo, yielding tang residue. It was dissolved in SmL of SO% aqueous acetonitrile (with 0.1%
trifluoroacetic acid), and purified by preparative HPLC. Fractions with correct mass data were combined, and lyophilized to afford the product as a white solid. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over S min) = 2.00 min. ESMS (CZ,HZZF~N30,); calcd. 351.42;
obsd. 352 [M+H]+.
The compound of Table 3, compound 7 to Table ~, compound 2 were synthesized following the general procedure by using 0.1 mmole of 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 0.1 mmole of an appropriate acid (given below).
Table 3, compound 7 was synthesized from 1-methyl-3-indoleacetic acid.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) = 2.99 min. ESMS (C~;H~8N.~0,);
calcd.
400.52; obsd. 401.1 [M+H]+.
Table 3, compound 8 was synthesized from I-methylindole-3-carboxylic acid.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) = 2.88 min. ESMS (C24H26NaO);
calcd.
386.50; obsd. 387.0 [M+H]+.
Table 3, compound 9 was synthesized from 5-methoxyindole-3-acetic acid.
Retention time (anal. HPLC: 10 to 70% MeCN/HZO over 6 min) = 2.60 min. ESMS
(C2;H28N402); calcd.
416.52; obsd. 417.4 [M+H]+.
Table 5, compound 1 was synthesized from S-methoxyindole-. 2-carboxylic acid.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) = 3.I2 min. ESMS
(C24H26N:~Oz); calcd. 402.50; obsd. 403.2 [M+H]+.
Table 3, compound 10 was synthesized from indole-3-butyric acid. Retention time (anal.
HPLC: 10 to 70% MeCN/H20 over 6 min) = 3.17 min. ESMS (C~6H3oN.~0); calcd.
4I4.~5; obsd.
415.30 [M+H]+.

Table 3, compound 11 was synthesized from indoIe-3-propionic acid. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) = 2.89 min. ESMS (C25HzgN,~O);
calcd. 400.52;
obsd. 401.1 [M+H]+.
Table 3, compound 12 was synthesized from N-acetyl-DL-tryptophan. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) = 2.44 min. ESMS (C2~H31N502);
calcd.
457.58; obsd. 458.2 [M+H]+.
Table 3, compound 13 was synthesized from 1-benzylindole-3-carboxylic acid.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) = 3.65 min. ESMS (C3oH3oNa0);
calcd.
462.59; obsd. 463.3 [M+H]+.
Table 3, compound 90 was synthesized from indole-6-cai~oxylic acid. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) = 2.75 min. ESMS (C23H2aN4C);
calcd. 372.~i7;
obsd. 372.9 [M+H]+.
Table 3, compound I4 was synthesized from 2-phenylindole-3-acetic acid.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) = 3.52 min. ESMS (C3oH3oNa0);
calcd. 462.59;
obsd. 463.3 [M+H]+.
Table 3, compound I 5 was synthesized from 5-methoxy-2-methylindole-3-acetic acid.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) = 2.77 min. ESMS
(C26H3oN40z); calcd. 430.55; obsd. 431.2 [M+H]+.
Table 3, compound 91 was synthesized from indole-4-carboxylic acid. Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) = 2.50 min. ESMS (C~;H~4N:~0);
calcd. 372.-17;
obsd. 372.9 [M+H]~'.
Table 5, compound 2 was synthesized from I-methylindole-2-carboxylic acid.
Retention time (anal. HPLC: ~ 10 to 70% MeCN/H20 over 6 min) = 3.24 min. ESMS
(C24H26N40); calcd.
386.50; obsd. 387.0 [M+H]+.
Table 3, compound 7 was synthesized in a similar way from I-methyl-3-indoleacetic acid (18.9 mg, O.lmmol). Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) = 2.99 min. ESMS (C25H28N40); calcd. 400.52; obsd. 401.1 [M+H]+.
Table 3, compound 8 was synthesized in a similar way from 1-methylindole-3-carboxylic acid (17.5 mg, 0.1 mmol). Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) _ 2.88 min. ESMS (C24H26Na0); calcd. 386.50; obsd. 387.0 [M+H]+.

Table 3, compound 9 was synthesized in a similar way from 5-methoxyindole-3-acetic acid (20.5 mg, 0.1 mmol). Retention time (anal. HPLC: 10 to 70% MeCN/Hz0 over 6 min) _ 2.60 min. ESMS (CZSHZ8N40z); calcd. 416.52; obsd. 417.4 [M+H]+.
Table 5, compound 1 was synthesized in a similar way from 5-methoxyindole-2-carboxylic acid (19.1 mg, 0.1 mrriol). Retention time (anal. HPLC: 10 to 70%
MeCN/H20 over 6 min) = 3.12 min. ESMS (C24Hz6Na0z): calcd. 402.50; obsd. 403.2 [M+H]+.
Table 3, compound 10 was synthesized in a similar way from indole-3-butyric acid (20.3 mg, 0.1 mmol). Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) =
3.17 min.
ESMS (C26H3oNa4); calcd. 414.55; obsd. 415.30 [M+H]*.
l0 Table 3, compound 11 was synthesized in a similar way from indole-3-propionic acid (18.9 mg, 0.1 mmol). Retention time (anal. HPLC: 10 to 70% MeCN/Hz0 over 6 min) = 2.89 min. ESMS (CZSHZ8N40); calcd. 400.52; obsd. 401.1 [M+H]*.
Table 3, compound 12 was synthesized in a similar way from N-Acetyl-DL-tryptophan (24.6 mg, 0.1 mmol). Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) = 2.44 min. ESMS (CZ~H31N502); calcd. 457.58; obsd. 458.2 [M+H]'.
Table 3, compound 13 was synthesized in a similar way from 1-benzylindole-3-carboxylic acid (25.1 mg, 0.1 mmol). Retention time (anal. HPLC: 10 to 70% MeCN/Hz0 over 6 min) _ 3.65 min. ESMS (C3oH3oNa0); calcd. 462.59; obsd. 463.3 [M+H]'.
Table 2, compound 90 was synthesized in a similar way from indole-6-carboxylic acid 2o (16.1 mg, 0.1 mmol). Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) = 2.7~
min. ESMS (C23HZ.,N.~O); calcd. 372.47; obsd. 372.9 [M+H]'.
Table 2, compound 91 was synthesized in a similar way from indole-~-carboxylic acid (16.1 mg, 0.1 mmol). Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) = 2.60 min. ESMS (Cz3Hz4N40); calcd. 372.47; obsd. 372.9 [M+H]+.
Table 3, compound 14 was synthesized in a similar way from 2-phenylindole-3-acetic acid (25.1 mg, 0.1 mmol). Retention time (anal. HPLC: 10 to 70% MeCN/HZO over 6 min) = 3.~2 min. ESMS (C3oH3oNa0); calcd. 462.59; obsd. 463.3 [M+H]*.
Table 3, compound 1 ~ was synthesized in a similar way from ~-methoxy-2-methyl-indoleacetic acid (21.9 mg, 0.1 mmol}. Retention time (anal. HPLC: 10 to 70%
MeCN/H~O over 6 min) = 2.77 min. ESMS (C26H3oNaOz); calcd. 430.»; obsd. 431.2 [M+H]+.

Table 2, compound 91 was synthesized in a similar way from indole-4-carboxylic acid (16.1 mg, 0.1 mmol). Retention time {anal. HPLC: 10 to 70% MeCN/HZO over 6 min) = 2.50 min. ESMS {C23H24N4O); calcd. 372.47; obsd. 372.9 [M+H]+.
Table 5, compound 2 was synthesized in a similar way from 1-methylindole-2-carboxylic acid (17:5 mg, 0.1 mmol). Retention time (anal. HPLC: 10 to 70% MeCN/Hz0 over 6 min) _ 3.24 min. ESMS (C24H26N40); calcd. 386.50; obsd. 387.0 [M+H]+.
Table 3, compound 24 was synthesized in a similar way from 5-bromoindole-3-acetic acid (25.4 mg, 0. I mmol). Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) = 2.981 min. ESMS (C2.~H25BrN40); calcd. 465.39; obsd. 465.1, 467.4 [M+H]+.
l0 Tabh, 3, compound 25 was synthesized in a similar way from 3-indoleglyoxylic acid (18.9 mg, 0.1 mmol). Retention time (anal. HPLC: 10 to 70% MeCN/Hz0 over 6 min) = 2.953 min. ESMS
(CzaHzaNa4z); calcd. 400.47; obsd. 401.1 [M+H]+.

Preparation of Compounds of Formula 1 Preparation of a Compound of Formula I in which the Li ands are different Preparation of a Compound of Formula (29a~
To a solution of 5-(4-fluorobenzoyl)amino-3-(piperidin-4-yl)-1H-indole (337.4 mg, 1.00 mmole) and di-isopropylethylamine (0.218 mL, 1.25 mmole) in 10.0 mL of anhydrous DMF was added a solution of ethyl 5-bromovalerate (0.158 mL, 1.00 mmole). The mixture was heated at 80°C overnight under NZ, and concentrated in vacuo, yielding oily residue. It was diluted with 10 mL of ethyl acetate and quenched by adding 5 mL of saturated sodium bicarbonate. The desired product was extracted with ethyl acetate, and organic layers were collected.
After drying with sodium sulfate, the organic solution was concentrated in vacuo. The crude product was purified by flash silica column chromatography: dichloromethane, dichloromethane/ethyl ether, ethyl ether, and finally ethyl acetate. The desired product was obtained as an off white solid (414 mg, 89%). Retention time (anal. HPLC: 10 to 70% MeCN/Hz0 over 6 min) = 3.40 min.
ESMS
(CZ~H32FN303); calcd. 465.57; obsd. 466.3 [M+H]+.
A solution of the ester thus obtained (200.0 mg, 0.46 mmole) in 10.0 mL of 1/1 mixture of methanol and THF was added lithium hydroxide monohydrate (33.6 mg, 0.80 mmole). The mixture was refluxed overnight under N2, and then concentrated in vacuo, yielding oily residue.
It was then dissolved in 20.0 mL of water, and the pH of the mixture was adjusted to ~7.0 with 1.0 M HCI. The neutralization of the mixture led to precipitation of the product. The precipitates were collected, and rinsed with anhydrous ethyl ether. The product, of 5-(4-fluorobenzoyl)amino-3-(1-(3-carboxypropyl)piperidin-4-yl)-1H-indole was obtained as off white solid (107.4 mg, 85%). Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) = 2.85 min.
ESMS
(C24H26FN303); calcd. 423.49; obsd. 424.0 [M+H]+.
Similarly prepared were the following compounds 1o Preparation of a Compound of Formula I
To a solution of S-amino-3-(I-methylpiperidin-4-yl)-IH-indole (22.9 mg, 0.1 mmole) and di-isopropylethylamine (22 ~l, 0. I 3 mmole) in 0.5 mL of anhydrous DMF was added a solution ofof5-(4-fluorobenzoyl)amino-3-(I-(3-carboxypropyl)piperidin-4-yl)-1H-indole (42.3 mg, 0.1 mmole), HOAt (17 mg, 0.13 mmole), and HATU (47.5 mg, 0.13 mmole) in 0.5 mL of anhydrous DMF. The mixture was stirred at room temperature overnight, and concentrated in vacuo, yielding oily residue. It was dissolved in SmL of 50% aqueous acetonitrile (with 0. I
trifluoroacetic acid), and purified by preparative HPLC. Fractions with correct mass data were combined, and lyophilized to afford the product (TFA salt) as an off white solid (36.0 mg, 42%).
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min} = 2.78 min. ESMS
(C38H43FN6O2); calcd. 634.80; obsd. 635.3 [M+H]+.
Table 3, compound 5 was synthesized in an analogous manner yield 41.3%.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) = 3.12 min. ESMS
(C,~ZH43FN6O2); calcd.
682.84; obsd. 683.3 [M+H]+.
Table 3, compound 16 was synthesized in an analogous manner: yield 25.1 %.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) = 3.47 min. ESMS
(Cy.~H;;FN602); calcd.
718.96; obsd. 719.3 [M+H]+.
Table 3, compound 17 was synthesized in an analogous manner: yield 11.7%.
Retention time (anal. HPLC: 10 to 70% MeCN/Hz0 over 6 min) = 3.04 min. ESMS
(C4,H,,9FN60z); calcd.
676.88; obsd. 677.3 [M+H]+.

Table 3, compound 18 was synthesized in an analogous manner, yield 30.2%.
Retention time (anal. HPLC: 10 to 70% MeCN/H20 over 6 min) = 2.82 min. ESMS
(C39H45FN602); calcd.
648.82; obsd. 649.4 [M+H)+.

Following the procedures of Examples 7 and 8 above, the following compounds of Formula I (L,-X-L2) linked from the 3-position of the first ligand L, to the 5-position of the second ligand L2 were prepared. In the Table, "I a, 2a, Sa, and 6a "
refers to the 1o substituents at the 1,2, 5-and 6 positions on first ligand L,, and "3b"
refers to the substituent at the 3-position on the second ligand. L2.

o z x x x z x x x z N z z x x z z x x x T

z x x s z x z v v ?~ T ?, T T T T

'C ~' ~ ~ ~ tt 1 , , 1 1 C C C C C C C

.0 ;~ "~ Z7 'n ' it L L. 1. L. ~L ~1r ~a "a a a b' " ' . . . . , n. a .

~ a a s s ,r s s s s s a~ a~ v a~ a~ a~ a~
E E E E c ' ' M ~ Z , , , , , 1 a~ a~ a e~
C C C C C

N N N N h G C C C C
O

.D ~ ~ .
O O O O D
O

O O O O O
3 O a C O

Cr C
, , , , eY' ~ ~ ~ V
, 1 , , i n ~. n .
O O O O O
r v ~r v ~ ~r U U U U U
1 , , , 1 Z ~ x z z z z z = _ z s , , z x x z z z N

0 0 0 ' O O U U U '_ , U U ~: .: N
1 , ~, , z x' z ~' s V U

U U U
, , , , , _z-, z_ _z _ z _ _z i -, ' _ _ i I ~ ~ ~ I f I I ; x N N N N N ~ z z .. :: ,.. ... ~. ~ .~: :, N N N N N N N f" N %~ ~.11 x z x z z z z z x. x o o z a. U U U U U U U U U U '-'" z .. .r ... '. ~ ... v ..r V U , i i 2 ~ I T .T.. ~ T ~ = i ~ - O
- U I I - U -- - U - U - -- U U V
U

CV M ~f ~1 ~D I~ 00 z z z z z z z z z z z z z x z z Z z z 'a V z z z z z z N

z s z z ~ z z x z z z z z a T ~ >, ~ ?, ~, T 7, T

C C C G C C C_ C C_ G C C C

'fl _ . ;C .

n. n. a n. a a n. n. n. n. a n. a . . . . . . . . .

a a a. a n. o. a a a. .o. .a .n..n.

s .~ .c s .~ s s s s ~ s ~ s a~ a~ a~ a~ a~ a~ a~ ~ y v E E E E ; ~ E E E E E E E

N N N

.D .~ .a O O O

C C

, Q

O O O

U U U Z

-T. Z = U

z z ~i,z z _ z z z O
_ _ , , z z z z z z z z U U V U
, , , , z ~ z _. , U

U U V Q

_ z ~ Z z z z U

- O O
z Z Z V = = f _ _i i = ~",..
~ ~
~

~ ~ z z z ' I ~ z U U
N J N N , , /~1I1 _ ~ / ~
N N ;

T z z z O U U " z O O T z z z -~
' ' ' ' ' Z " U V U U U U
U N ' U
N N V ~ U ~.- ..

U ~ ~ ~ O ~, '' y'- ~ z i ' ! U U U
U U U U - U - j - U - U --o _ N ~ ~ ~, ~ ~ ~ ~ ~
_ .~ fV N
l Z Z T

z z x z x x x z 7, T ~ ~' >, >, v ~ ~
' , ~ C C
C C C C
~

;O _ _ ~ ' N N
'D b W
. .

a n. n. a a n. a.
. . .

.n. .a .a .n. n. a a s s s s s s a~ d E

E ~ E E

~ i ~ N ~ i C
C

N N N

O

> > 7 C

~t V
' , U

T Z
' x x m _ ~, z z z o , v ~ ~ z ' U 2 U
W ' ~

v n - z U , o , , v , z - _ ~ ~

x z z x Z U .:.~ ~: ~. U ::
0 " N , 0 = _ U U U ~ - V ~ U

N N N N Z ._ Preparation of Compounds of Formula I
Preparation of a Compound of Formula I in which L is Sumatriptan linked via the Sidechain at the 3-Position, p is 2 and q is 1 A. The compound of formula (I 1) where RS is CH3NHS02CH2- (693 mg, 2 mmols) is dissolved in CHC13 (10 ml), diisopropylethylamine (DIPEA) (2 mmols) added, and the reaction then heated to 40° C. A solution of 1,5-bis(methylamino)-3-oxapentane, a diamine of formula (7) (132 mg, I mmol), in CH2C12 (5 ml) is added to the warmed l0 solution over 30 minutes. The reaction mixture is heated at reflux for two hours and then allowed to cool. The solvent is removed under vacuum. The crude reaction mixture is then treated with aqueous saturated NH.~CI solution and then extracted with EtOAc. The organic layer is then filtered off, and the solvent removed under vacuum to provide the crude product. The desired material is then purified from this mixture using reverse phase HPLC, to yield a compound of Formula I.
B. Similarly, by replacing the compounds of formula (7) and (I 1) in IA above with other compounds of formula ( 11 ) and other diamines of formula (7), other compounds of Formula I are prepared.

Preparation of Compounds of Formula I
Preparation of a Compound of Formula I in which L is Sumatriptan linked via the Sidechain at the 3-Position, p is 2 and q is 1 A. The compound of formula (16) where RS is CH3NHSOZCH2- (563 mg, 2 mmol) is dissolved in CHC13 (10 ml). Acetic acid (0.5 ml) is then added and the reaction is heated to reflux. 1,4-benzenedicarboxaldehyde, a di-aldehyde of formula ( I 7) ( 134 mg, 1 mmol) dissolved in CH2C12 (10 ml) is then added dropwise to the refluxing solution over 60 3o minutes and the reaction is refluxed for a further 60 minutes. At this point, NaBH(OAc)3 is added in portions and the reaction is stirred at reflux for a further 2 hours. The reaction is allowed to cool, and is then quenched with aqueous NH4C1 solution until the pH of the solution is adjusted to pH 7.0 using either 1 M HC1 or 1 M NaOH. The product is extracted from this aqueous phase with EtOAc. The organic layer is dried using Na2S04, the drying agent is then filtered off and the solvent removed in vacuo to provide the crude product. The desired material is purified.from this mixture using reverse phase HPLC.
B. Similarly, by replacing the compounds of formula ( 16) and ( 17) in 2A
above with other compounds of formula (16) and other dialdehydes of formula (17), other compounds of Formula I are prepared.

Preparation of Compounds of Formula I
Preparation of a Compound of Formula I in which L is Sumatriptan (inked via the Sidechain at the 5-Position, p is 2 and q is 1 A. The compound of formula (23) where R3 is CH3NHSOZCH~- (717 mg. 2 mmol) is dissolved in CH2C12 (10 ml) and DIPEA (2 mmol) is then added. A solution of 1,5-bis(methylamino)-3-oxapentane, a diamine of formula (7) (72 mg. I mmol) in CHZC1~
( 10 ml) is then added dropwise over 1 hour via syringe pump. The reaction is then allowed to stir at room temperature for a further hour. The solvent is removed in vacuo and the crude reaction mixture is diluted with CHC13. The organic layer is treated with 1 M NaOH and dried using NaS04. After the drying agent is filtered off, the solvent is removed under vacuum to provide the crude product. The desired materal is then purified from this mixture using reverse phase HPLC, giving a compound of Formula I.
B. Similarly, by replacing the compounds of formula (23) and (7) in 3A above with other compounds of formula (23) and other diamines of formula (7), other compounds of Formula I are prepared.

Preparation of Compounds of Formula I
Preparation of a Compound of Formula I in which L is Zolmitriptan linked via the Sidechain at the 3-Position, p is 2 and q is 1 s A. The compound of formula ( 11 ) in which RS is oxazolidin-2-one-4-methyl (677 mg, 2mols) is dissolved in CHC13 ( 10 mL), DIPEA (2 mmols) is then added and the reaction is heated to 40° C. A solution of 1,4-benzenedimethanamine, a diamine of formula (7) (164 mg, 1 mmol) in CH2C12 (10 ml) is added to the warmed solution over 30 minutes. The reaction is then heated at reflux for two hours and then allowed to cool.
to The solvent is removed under vacuum. The crude reaction mixture is then treated with aqueous saturated NH.~CI solution and then extracted with EtOAc. The organic layer is then dried using Na2S04, the drying agent is filtered off. and the solvent removed in vacuo to provide the crude product. The desired material is then purified from this mixture using reverse phase HPLC, giving a compound of Formula I.
IS
B. Similarly, by replacing the compounds of formula { 11 ) and (7) in 4A above with other compounds of formula (11) and other diamines of formula (7), other compounds of Formula I are prepared.

Preparation of Compounds of Formula I
Preparation of a Compound of Formula I in which L is Zolmitriptan linked via the Sidechain at the 3-Position, p is 2 and q is 1 A. To a solution of pentanedioc acid, a compound of formula (I8) (132 mg, 1 mmol) in DMF (10 ml) is added DIPEA (2 mmol) and DIC (2 mmol). The reaction is then stirred at room temperature for 20 minutes. A solution of the compound of formula ( 16) where RS is oxazolidin-2-one-4-methyl (574 mg, 2 mmol) in DMF ( 10 ml) is then added dropwise over 1 hour. The reaction is then allowed to stir at room temperature for a further hour. The reaction is quenched with saturated aqueous NH4C1 solution and extracted with EtOAc. The organic layer is dried over Na2S0.~, the drying agent is then filtered off, and the solvent removed in vacuo to provide the crude product.
The desired material is then purified from this mixture using reverse phase HPLC.
B. Similarly, by replacing the compounds of formula ( I 6) and ( 18) in SA
above with other dicarboxylic acids of formula ( I 6) and other compounds of formula ( 18), other compounds of Formula I are prepared.

to Preparation of Compounds of Formula I
Preparation of a Compound of Formula I in which L is Zolmitriptan linked via the Sidechain at the 5-Position, p is 2 and q is I
A. Zolmitriptan (287 mg, lmmol) is dissolved in CHZCIz (10 ml). A solution of Boc20 ( 1.5 mmol) and DMAP (.OS mmol) is added dropwise and the reaction is stirred at room temperature overnight. The reaction is then diluted with saturated NH.~CI
solution, and extracted into EtOAc. The organic layer is then dried using Na~SO.~, the drying agent is then filtered off, and the solvent removed under vacuum to provide the crude product.
The desired material is then purified from this mixture using reverse phase HPLC.
This product (protected zolmitriptan) (387 mg, 1 mmol), is then dissolved in DMF
(10 ml) and cooled to 0°C. NaH (27 mg, 1.1 mmol) is then added to the cold solution, then the reaction vessel is allowed to warm to room temperature and stirred for 30 minutes. A solution of 1,4-bis(bromomethyl)benzene, a compound of formula (2) (132 mg, 0.5 mmols) in~DMF (10 ml) is added dropwise to the reaction vessel. After 2 hours, the reaction is quenched with saturated aqueous NaHC03, and extracted into EtOAc. The organic layer is then dried using NaZSO,~, the drying agent is then filtered off, and the solvent removed in vacuo to provide the crude product. The desired material is then purified from this mixture using reverse phase HPLC.
This product (protected zolmitriptan dimer) 19 (677 mg, I mmol), is-dissolved in CH2C1~ (4 ml). A solution of 10% trifluoroacetic acid in CHZCh ( 10 ml) is added, and the reaction is stirred for 1 hour at room temperature. The solvent is then remove under WO 99/64044 PC'T/US99/12751 -vacuum to provide the desired material as the TFA salt. The desired material is then purified from this mixture using reverse phase HPLC.
B. Similarly, by replacing 1,4-bis(bromomethyl)benzene with other compounds of formula (2) in 6A above, other compounds of Formula I are prepared.

In vitro 5-HT,F receptor binding assay to Sumatriptan has nanomolar affinity for the 5-HT,B, 5-HT~p and S-HT,F
binding sites, while 5-carboxamidotryptamine has nanomolar affinity for the 5-HT,B and 5-HT~p, but little affinity for 5-HT~F, receptors (Plosker and McTavish, 1994). The regional distribution of 5-HTiF receptors in guinea-pig brain has been studied using [3H]sumatriptan in the presence of suitable concentrations of ~-carboxamidotryptamine to mask the 5-HT~B and 5-HT,p receptors (Waeber and Moskowitz, 1995). In membranes of human frontal cortex, binding of [3H]sumatriptan to 5-HT, F receptors has also been demonstrated in the presence of ~-carboxamidotryptamine, 8-hydroxy-2-di-N-propylaminotetralin and mesulergine (to block 5-HT~B"o, S-HT~A and 5-HT2~
receptors respectively) (Castro et al., 1997). Accordingly, this approach can be used in the frontal 2o cortex from other species to determine the affinity of novel compounds at ~-HT~F
receptors. The selective 5-HT~F receptor agonist, LY-334370 (Wainscott et al., 1998), can be used as a standard in these assays as it displaces [3H]sumatriptan binding to 5-HTiF receptors with nanomolar affinity.
A similar assay using a radiolabelled version of a SHTiF selective ligand such as LY
334370 can also be used.
Castro, M.E., Pascual, J., Romon, T., Del Arco, C., Del Olmo, E. and Pazos, A.
(1997).
Differential distribution of [3H]sumatriptan binding sites (5-HTiB, 5-HT~D and S-HTiF
receptors) in human brain: focus on brainstem and spinal cord. NeuropharmacoL, 36, 535-542.

Plosker, G.L. and McTavish, D. (1994). Sumatriptan. A reappraisal of its pharmacology and therapeutic efficacy in the acute treatment of migraine and cluster headache. Drugs, 47, 622-651.
Waeber, C. ancf Mowkowitz, M.A. (1995). [3H]sumatriptan labels both 5-HT~D and HT,F receptor binding sites in the guinea-pig brain: an autoradiographic study. Naunyn-Schmiedeberg's Arch. Phalmacol., 352, 263-275.
Wainscott, D.B., Johnson, K.W., Phebus, L.A., Schaus, J.M. and Nelson, D.L.
(1998).
Human 5-HT,F receptor-stimulated [35S]GTPgammaS binding: correlation with inhibition of guinea pig dural plasma protein extravasation. Eur. J. Pharmacol., 352, 117-24.

5-HT1B Receptor Agonists: In vitro saphenous venoconstrictor assay The ability of compounds to contract the isolated saphenous vein of the rabbit or dog is used to determine the potency and efficacy of novel S-HT, B receptor agonists (Connor et al., 1997; Martin, 1997). As both the saphenous vein and cranial vasculature contain contractile 5-HTIB receptors, the former tissue is used as a marker for cranial vasoconstrictor activity of 5-HT1B receptor agonists.
Rings of the rabbit saphenous vein are mounted in organ baths containing a physiological Krebs solution and drug-induced changes in tension are recorded.
The potency and efficacy of compounds is measured.
Connor H.E., Feniuk, W., Beattie, D.T., North, P.C., Oxford, A.W., Saynor, D.A. and Humphrey, P.P. (1997). Naratriptan: biological profile in animal models relevant to migraine. Cephalalgia, 17, 145-152.
Martin, G.R. (1997). Pre-clinical pharmacology of zolmitriptan (Zomig;
formerly 311 C90), a centrally and peripherally acting 5HT1 B/1 D agonist for migraine.
Cephalalgia, 17 (Suppl. 18), 4-14.

5-HT,B Receptor Agonist; In vivo cranial vasoconstriction assay To determine in vivo 5-HTIB receptor agonist activity (i.e. potency, efficacy, speed of onset and duration of action), the ability of novel compounds to constrict the carotid vascular bed is investigated according to the method disclosed in Choppin et al., 1996;
Connor et al., 1997; Martin, 1997; Parsons et al., 1997) Adult rabbits are anesthetized with sodium pentobarbital (45mg/kg) injected via a marginal ear vein. The trachea is cannulated and the animals artificially respired. A
femoral artery and vein are cannulated for the continuous measurement of blood pressure 1o and heart rate, and i.v. drug administration respectively. A transonic flow probe is placed around the common carotid artery to allow measurement of carotid arterial blood flow and resistance. Cumulative dose-response curves to novel 5-HT,g receptor agonists (administered i.v. or via alternative routes) are constructed. Peripheral in vivo potency (expressed as a CD;o value, i.e. the cumulative dose producing SO% of the maximum increase in carotid vascular resistance), duration of action and speed of onset of compounds can be measured in this assay.
Choppin, A. and O'Connor, S.E. ( 1996). Influence of vascular tone on vasoconstrictor responses to the 5-HT,-like receptor agonist sumatriptan in anaesthetised rabbits. Eur. J.
Zo Pharmacol., 304, 87-92.
Connor H.E., Feniuk, W., Beattie, D.T., North, P.C., Oxford, A.W., Saynor, D.A. and Humphrey, P.P. (1997). Naratriptan: biological profile in animal models relevant to migraine. Cephalalgia, 17, 145-152.
Martin, G.R. (1997). Pre-clinical pharmacology of zolmitriptan (Zomig;
formerly 311C90), a centrally and peripherally acting SHT,g"o agonist for migraine.
Cephalalgia, 17 (Suppl. 18), 4-14.
Parsons, A.A., Parker, S.G., Raval, P., Campbell, C.A., Lewis, V.A., Griffiths, R., Hunter, A.J., Hamilton, T.C. and King F.D. (1997). Comparison of the cardiovascular effects of the novel 5-HTIHi,p receptor agonist, SB 209509 (VML251), and sumatriptan in dogs. J. Cardiovasc. Pharmacol., 30, 136-141.

FXAMP1 F t R
5-HT2A Agonists; In vitro rabbit thoracic aorta assay Activation of 5-HT2A receptors results in contraction of a variety of blood vessels (Krisch et al., 1992; MacLean et al., 1996). The selective 5-HT, receptor agonists that are clinically effective anti-migraine agents have little affinity for 5-HT2A
receptors (e.g.
sumatriptan; Humphrey et al., 1988). The rabbit isolated thoracic aorta is used to determine the 5-HT2A activity of novel compounds.
Thoracic aorta rings are mounted in organ baths containing a physiological Krebs solution, and drug-induced changes in tension are recorded. The potency and efficacy of 1 o compounds is measured Humphrey, P_P., Feniuk, W., Perren, M.J., Connor, H.E., Oxford, A.W., Coates, L.H. and Butina, D. ( 1988). GR43175, a selective agonist for the 5-HT,-like receptor in dog isolated saphenous vein. Br. J. Pharmacol., 94, 1123-1 I32.
IS Krisch, L, Budihna, M.V. and Rucman, R. (1992). Structure-activity study of some newly synthesized ergoline derivatives on 5-HT2 receptors and alpha-adrenoceptors in rabbit isolated aorta. Pharmacol., 45, 195-208 MacLean, M.R., Sweeney, G., Baird, M., McCulloch, K.M., Houslay, M. and Morecroft, I. (1996). 5-Hydroxytryptamine receptors mediating vasoconstriction in pulmonary 2o arteries from control and pulmonary hypertensive rats. Br. J. Pharmacol., 1 I9, 917-930.

S-HTjsiip Receptors: In vivo guinea-pig hypothermia assay 25 Activation of 5-HTiB~ip receptors in the CNS results in a hypothermic response in conscious guinea-pigs (Ennis et al., 1998; Hagan et al., 1997; Kalkman and Neumann, 1995; Skingle et al., 1996). Therefore, the ability of novel compounds to produce hypothermia in guinea-pigs, following peripheral administration, is used to demonstrate 5-HT,g"p receptor agonist activity in the CNS.
3o Compounds are administered to guinea-pigs subcutaneously, orally or intraperitoneally and body temperature is measured rectally at different time-points. The potency, efficacy, speed of onset and duration of action of novel compounds is determined.
Ennis, M.D., Ghazal, N.B., Hoffman, R.L., Smith, M.W., Schlachter, S.K., Lawson, C.F., Im, W.B., Pregenzer, J.F., Svensson, K.A., Lewis, R.A., Hall, E.D., Suner, D.M., Hams, L.T. and McCall, R.B. (1998). Isochroman-6-carboxamides as highly selective 5-HTiD
agonists: potential new treatment for migraine without cardiovascular side effects. J.
Med. Chem., 41, 2180-2183.
Hagan, J.J., Slade, P.D., Gaster, L., Jeffrey, P., Hatcher, J.P, and Middlemiss, D.N.
to (1997). Stimulation of 5-HT;B receptors causes hypothermia in the guinea pig. Eur. J.
Pharmacol., 331, 169-174.
Kalkman, H.O. and Neumann, V. (1995). Evidence for a S-HT,D receptor-mediated hypothermic effect of the alpha 1-adrenoceptor agonist, SDZ NVI-085, in guinea-pigs.
Eur. J. Pharmacol., 285, 313-315.
Skingle, M., Beanie, D.T., Scopes. D.L, Starkey, S.J., Connor, H.E., Feniuk, W. and Tyers, M.B. (1996). GR127935: a potent and selective 5-HT,o receptor antagonist.
Behav. Brain Res., 73, 157-161.
2o EXAMPLE 20 5-HT~B,ipoF Receptors; In vivo plasma protein extravasation assay Trigeminal nerve stimulation produces inflammation (consisting of plasma protein extravasation) in cranial tissues, an event implicated in migraine pathogenesis.
Activation of 5-HT~BaDiIF receptors inhibits plasma protein extravasation in the dura of anesthetized rats and guinea-pigs following either electrical or chemical trigeminal nerve stimulation (Buzzi and Moskowitz, 1992; Phebus et al., 1997; Shepheard et aL, 1997). It has been suggested that the inhibitory activity of 5-HT, receptor agonists (e.g.
sumatriptan) on neurogenic inflammation contributes to their anti-migraine efficacy.
Adult guinea-pigs or rats are anesthetized and placed in a stereotaxic frame.
The 3o skull is exposed by a midline incision and a hole is drilled on either side for electrode placement into each trigeminal ganglion. Novel compounds are administered, followed by '25I-bovine serum albumin. One trigeminal ganglion is electrically stimulated, and animals are then perfused with saline via the left cardiac ventricle. The right atrium is incised to allow outflow of perfusate. The eyelid, eyeball and dura are dissected out.
Tissues from the stimulated and unstimulated sides are weighed and counted for radioactivity in a gamma counter. The potency of compounds in inhibiting neurogenic cranial inflammation is determined. As an alternative to '25I-bovine serum albumin, Evan's Blue (SOmg/kg i.v.), detected by fluorescence microscopy or HPLC, can be used to measure the plasma protein extravasation evoked by trigeminal ganglion stimulation.
to Buzzi, M.G. and Moskowitz, M.A. (1992). The trigemino-vascular system and migraine. Pathologie Biologie, 40, 313-317.
Phebus, L.A., Johnson, K.W., Zgombick, J.M., Gilbert, P.J., Van Belle, K., Mancuso, V., Nelson, D.L., Calligaro, D.O., Kiefer, A.D. Jr., Branchek, T.A. and Flaugh, M.E. (1997).
Characterization of LY344864 as a pharmacological tool to study 5-HT1F
receptors:
binding affinities, brain penetration and activity in the neurogenic dural inflammation model of migraine. Life Sci., 61, 2117-2126.
Shepherd, S.L., Williamson, D.J., Beer, M.S., Hill. R.G. and Hargreaves, R.J.
(1997).
Differential effects of 5-HT~B,~p receptor agonists on neurogenic dural plasma extravasation and vasodilation in anaesthetized rats. Neuropharmacol., 36, 525-533.

In vitro 5-HT,B~tp receptor binding assay The 5-HT1B,~D binding affinity and selectivity of compounds is measured in radioligand displacement assays using commercially available membrane preparations (Euroscreen s.a., BrusselsBelgium) from a CHO-K1 cell Iine expressing the cloned human 5-HT,p and 5-HT~B receptors. Radioligand displacement assays are carried out at a constant concentration of the radioligand [''H]5-hydroxytryptamine with increasing concentrations ( 10'12 M - 10-6 M) of drug. Binding reactions are incubated for 1 hour at 3o room temperature in a buffer of 50mM Tris-HCl pH 7.4, 1mM EDTA, 12.~mM
MgCl2, 0.1% ascorbic acid and are stopped by rapid filtration over GFB glassfiber filters using a cell harvester. Filter-bound radioactivity is counted in a liquid scintillation counter. The selective 5-HTip agonists sumatriptan and rizatriptan may be used as standards in these assays.

This example illustrates the preparation of a representative pharmaceutical formulation for oral administration containing a multibinding compound of the invention.
Ingredients Quantity per tablet, mgs.
____________________________________________________________________________ Active Compound 200 Lactose, spray-dried 148 Magnesium stearate 2 The above ingredients are mixed and introduced into a hard-shell gelatin capsule.
Other multibinding compounds of the invention can be used as the active compound in the preparation of the orally administrable formulations of this example.
2o EXAMPLE 23 This example illustrates the preparation of another representative pharmaceutical formulation for oral administration containing a multibinding compound of the invention.
Ingredients Quantity per tablet, mgs.
___________________________________________________________ Active Compound 400 Cornstarch 50 Lactose 14~

Magnesium stearate 5 ____________________________________________________________________ The above ingredients are mixed intimately and pressed into single scored tablets.

Other multibinding compounds of the invention can be used as the active compound in the preparation of the orally administrable formulations of this example.

s This example illustrates the preparation of pharmaceutical a representative formulation containing a multibinding compound of the invention An oral suspension is prepared having the following composition.

Ingredients Active Compound I .0 g Fumaric acid 0.5 g Sodium chloride 2.0 g Methyl paraben 0.1 g Granulated sugar 25.5 g is Sorbitol (70% solution) 12_g~ g Veegum K (Vanderbilt Co.) 1.0 g Flavoring 0.035 ml Colorings 0.~ mg Distilled water q.s. to 100 ml ____________________________________________________________________ Other multibinding compounds of the invention can be used as the active compound in the preparation of the orally administrable formulations of this example.
2s EXAMPLE 25 This example illustrates the preparation of a representative pharmaceutical formulation containing a multibinding compound of the invention.
An injectable preparation buffered to a pH of 4 is prepared having the-following composition:

Ingredients Active Compound 0.2 g Sodium Acetate Buffer Solution (0.4 M) 2.0 ml HCL (1N~ q.s. to pH 4 Water (distilled, sterile) q.s. to 20 ml Other multibinding compounds of the invention can be used as the active compound in the preparation of the injectable formulations of this example.
l0 This example illustrates the preparation of a representative pharmaceutical formulation for injection containing a multibinding compound of the invention.
A reconstituted solution is prepared by adding 20 ml of sterile water to 1 g of the compound of Formula I. Before use, the solution is then diluted with 200 ml of an intravenous fluid that is compatible with the compound of Formula I. Such fluids are chosen from 5% dextrose solution, 0.9% sodium chloride, or a mixture of S%
dextrose and 0.9% sodium chloride. Other examples are lactated Ringer's injection, lactated Ringer's plus 5% dextrose injection. Normosol-M and 5% dextrose, Isolyte E, and acylated Ringer's injection Other multibinding compounds of the invention can be used as the active compound in the preparation of the injectable formulations of this example.

This example illustrates the preparation of a representative pharmaceutical formulation for topical application containing a multibinding compound of the invention.

Ingredients grams Active compound 0.2-10 Span 60 2 Tween 60 2 Mineral oil 5 Petrolatum 10 Methyl paraben 0.15 Propyl paraben 0.05 BHA (butylated hydroxy anisole) 0.01 Water q.s. to 100 All of the above ingredients, except water, are combined and heated to 60°C with stirring. A sufficient quantity of water at 60°C is then added with vigorous stirnng to emulsify the ingredients, and water then added q.s. 100 g.
Other multibinding compounds of the invention can be used as the active compound in the preparation of topical formulations of this example.

This example illustrates the preparation of a representative pharmaceutical formulation containing a multibinding compound of the invention.
A suppository totalling 2.5 grams is prepared having the following composition:
Ingredients Active Compound 500 mg Witepsol H-15; balance _______________________________________________________________________________ __ (~triglycerides of saturated vegetable fatty acid; a product of Riches-Nelson, Inc., New York, N.Y.) Other multibinding compounds of the invention can be used as the active compound in the preparation of the suppository formulations of this example.
While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to 1o the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

1. Meng, CQ., 1997. Migraine: Current Drug Discovery Trend. Current Med.
Chem., 4:385.
2. Chauveau, J., et al., 1997. Is 159: a high affinity specific 5 HTId full receptor agonist, effective in the acute treatment of migraine. Fr. Front. Headache Res.
6:287.
l0 3. Ennis, MD., et al., 1998. Isochroman-6-carboxamides as highly selective 5 HTId agonists:
potential new treatment for migraine without cardiovascular side effects. J.
Med. Chem., 41 (3):2180.
4. ~ Grain, A., 1997. SB-209509/VML-251. Antimigraine 5 HT1B/1D receptor Future 22(7):725.
5. Dugast, C., 1998. Is the potent 5-HTIa receptor agonist, alnespirane (SS-20499) dopaminergic systems in the rat brain. Eur. J. Pharmacol., 30(2/3):171.
6. Parsons, AA., 1997. Comparison of the cardiovascular effects of the novel ~-H-HTIb/ld agonist SB 209509 (VML251, and sumatatriptan in dogs. J. Cardiovasc.
Pharmacol., 30( 1 ); 136 7. Somboonthum, P., et al., 1998. MKC-242, a novel 5-HT 1 a receptor agonsit, facilitates corticol acetycholine release by a mechanism different from that of 8-OH-DPAT inawake rats. Neuropharmacology, 36(11/12):1733.
8. Beneytez, ME., 1998. Preclinical pharmacology of B-20991, a S-HT 1 a receptor agonist with anxiolytic activity. Eur. J. Pharmacol., 344(2/3):127.

9. DeVry, J., et al., 1998. Characterization of the aminomethylchroman derivative BAY x 3702 as a highly potent 5-hydroxytryptamine 1 A receptor agonist. J.
Pharmacol. Exp. Ther., 284(3): 1082 10. Petty, MA., 1997. The selectivity of MDL 74,721 in models of neurogenic versus vascular components of migraine. Eur. J. Pharmacol., 336(2/3):127.

11. Jagannathan, V., et aL, 1997. Pharmacokinetics and CNS pharmacodynamics of the S-HTIA agonist buspirone in humans following acute L-tryptophan deletion to challenge. MethodsFind. Exp. Clin. Pharmacol., 19(5):351.

12. Mansari, M., et al., 1996. Functional characterization of 5-HTI D
autoreceptors on the modulation of S-HT release in guinea pig mesencephalic raphe, hippocampus and frontal cortex. Br. J. Pharmacol. 118(3):681.

13. Yocca, FD., et al., 1991. Unique modulation of ~-HT2 receptor binding sitesand 5-HT2 receptor-mediated behaviour by continuous gepirone treatment. Life Sci., 49(24): I 777.
2o 14. Casanovas, JM., et al., 1996. Differential effects of ipsapirone on ~-and medianraphe neuronal pathways. J. Neurochem., 67(5):194.
15. Petty, MA.;et al., 1997. The selectivity of MDL 74,721 in models of neurogenic versus vascular components of migraine. Eur. J. Pharmacol. 336(2/3):127.
16. Yamada, J., 1997. Hyperglycemia induced by the 5-HT receptor agonist, S.methoxytryptamine, in rats: involvement of the peripheral ~-HT2A receptor.
Eur. J. Pharmacol., 323(2/3):23.

WO 99!64044 PCT/US99/12751 17. Licata, F., et al., 1993. Excitatory and inhibitory effects of 5-hydroxytrypatamine on the firing rate of medial vestibular nucleus neurons in the rat.. Neurosci.
Lett., 154(1-2).
18. Rizzi, CA., I 997. Regulation of plasma aldosterone levels by metoclopramide: a reappraisal of its mechanism from dopaminergic antagonism to serotonergic agonism. Neuropharmacology 36(6):763.
19. Mine, Y., et al., 1997. Comparisomof effect of mosapride citrate and existing 5-HT4 receptor agonists on gastrointestinal motility in vivo and in vitro. J.
Pharmacol. Exp. Ther. , 283(3):1000.
20. Kant, G.J., 1998. Effects of the serotonin agonists 8-OI-i-DPAT, buspirone, and DOI on water maze performance. Pharm. Biochem. Behav., 59(3):729.
21. Wolf A., 1998. Facilitation of female rat lordosis behaviour by hypothalamic infusion of ~-HT2A/2C receptor agonists. Brain Res., 779( 1.2):84.
22. Uchiyama-Tsuyuki, Y., 1996. Identification of the ~-I-IT4 receptor in the 2o intestinal tract and striatum of the guinea pig. Life Sci., X9(25/26):2129.
23. Nagakura, Y., et al., 1997. The selective 5-hydroxytryptamine-recptor agonist RS67506 enchances lower intestinal propulsion in mice. Jpn. J. Pharmacol., 74(2):209.
24. Takada, Y., et al., 1996. Changes in serotonergic measures in whole blood and various brain regions of rats administered with the 5-HTIA agonist tandospirone and/or exposed to electric foot-shock., Brain Res. Bull., 40( 1 ):~ 1.
14s 25. Ramirez, MJ., et al., 1997. VB20B7, a novel 5-HT-ergic agent with gastrokinetic activity. I. Interaction with 5-HT3 and 5-HT4 receptors. J. Pharm. Pharmacol., 49( 1 ):58.
26. Kenakin, T., Pharmacologic Analysis of Dru -Receptor Interaction, Lippincott-Raven, 1997, Maplepress, Philadlephia; Petrouka, S., Handbook of Receptors and Channels; G-Protein Coupled Receptors, CRC Press, 1994, Florida.
27. Saxena, Pramod R.; Ferrari, MicheI D,. Pharmacology of antimigraine 5-HT1D
receptor agonists. Expert Opin. Invest. Drugs (1996), 5(~), .~81-596.
28. Martin, G. R.; Robertson, A. D.; MacLennan, S. J.; Prentice, D. J.;
Barren, V. J.;
Buckingham, J.; Honey, A. C.; Giles, H.; Moncada, S;. Receptor specificity and trigemino-vascular inhibitory actions of a novel S-HT I B/ 1 D receptor partial a onist, Br. J. Phalmacol. (1997), 121(2), I~7-164.
29. Antimigraine ~-HT1D agonists, Ngo, J.; Mealy, N.; Castaner, J. Barcelona.
Spain.
Drugs of the Future (1997), 22(3}, 260-269.
30. Pauwels, Petrus J.; Van Gompel, Paul; Leysen, Josee E., Activity of serotonin (5-HT) receptor agonists, partial a onists and anta onists at cloned human 5-HT1A
receptors that are ne atively coupled to adenylate cvclase in permanently transfected~HeLa cells. Biochem. Pharmacol. (1993), 45(2), 375-83.
31. Schoeffter, Philippe; Hoyer, Daniel; Interactions with functional 5-HT1A, HTIB, 5-HT1C and 5-HT1D receptors. Naunyn-Schmiedeberg's Arch.
Pharmacol. ( 1989), 340( 1 ), 135-8.
32. Beer, M. S.; Stanton, J. A.; Bevan, Y.; Heald, A.; Reeve, A. J.; Street, L. J.;
3o Matassa, V. G.; Hargreaves, R. J.; Middlemiss, D. N. L-694.247: A potent ~
HTID receptor agonist,. Br. J. Pharmacol. (1993), 110(3), 1196-200.

33. Recombinant saphenous vein 5-HT1B receptors of the rabbit: comparative pharmacology with human 5-HT1B receptors; Wurch, Thierry; Palmier, Christiane; Colpaert, Francis C.; Pauwels, Petrus J. Laboratory of Cellular &
Molecular Neurobiology Centre de Recherche Pierre Fabre, Castres, 81106, Fr.
Br. J. Pharmacol. ( 1997), 120( 1 ), 153-159.
34. Veldman, Sarah A.; Bienkowski, Michael J. Cloning and pharmacological characterization of a novel human 5-hydroxytryptamine 1 D receptor subtype.
Mol.
to Pharmacol. (1992), 42(3), 439-44. (Expression of the receptor in Chinese hamster ovary cells creates high affinity binding sites for SHT that is coupled to the inhibition of adenyl cyclase).
35. ~ Adham, Nika; Borden, Laurence A.; Schechter, Lee E.; Gustafson, Eric L.;
Cochran, Tamara L.; Vaysse, Pierre J. J.; Weinshank, Richard L.; Branchek, Theresa A. Cell-specific coupling of the cloned human 5-HT1F receptor to multiple signal transduction pathways. Naunyn-Schmiedeberg's Arch. Pharmacol.
( 1993), 348(6), 566-75.
36. Cloning and characterization of the guinea pig 5-HT1 F receptor subtype: a comparison of the pharmacological profile to the human species homolog.
Adham, N.; Bard, J. A.; Zgombick, J. M.; Durkin, M. M.; Kucharewicz, S.;
Weinshank, R: L:; Branchek, T. A. Synaptic Pharmaceutical Corporation, Paramus, NJ, 07652, USA. Neuropharmacology (1997), 36(4h), 569-576.
37. Pauwels, Petrus J.; Van Gompel, Paul; Leysen, Josee E;. Activity of serotonin (S-HT) receptor agonists, partial agonists and antagonists at cloned human 5-HT1A
receptors that are negatively coupled to adenylate cyclase in permanently transfected HeLa cells. Biochem. Pharmacol. (1993), 4~(2), 375-83.

38. Pauwels, Petrus J.; Palmier, Christiane; Wurch, Thierry; Colpaert, Francis C
Pharmacology of cloned human 5-HT1 D receptor-mediated functional responses in stably transfected rat C6-glial cell lines: further evidence differentiating human 5-HT1D and 5-HT1B receptors. Naunyn-Schmiedeberg's Arch. Pharmacol.
(1996), 353(2}, 144-56.
39. Zgombick, John M.; Schechter, Lee E.; Adham, Nika; Kucharewicz, Stefan A.;
Weinshank, Richard L.; Branchek, Theresa A. Pharmacological characterizations of recombinant human 5-HT 1 D C. and 5-HT 1 D ~ receptor subtypes coupled to 1o adenylate cyclase inhibition in clonal cell lines: apparent differences in drug intrinsic efficacies between human 5-HT 1 D subtypes. Naunyn-Schmiedeberg's Arch. Pharmacol. (1996), 354(3), 226-236.
40. ' Adham, Nika; Borden, Laurence A.; Schechter, Lee E.; Gustafson, Eric L.;
Cochran, Tamara L.; Vaysse, Pierre J. J.; Weinshank, Richard L.; Branchek, Theresa A. Cell-specific coupling of the cloned human 5-HT1F receptor to multiple signal transduction pathways. Naunyn-Schmiedeberg's Arch. Pharmacol.
(1993), 348(6), 566-75.
41. George, S. E.; Bungay, P. J.; Naylor, L. H. Functional coupling of endogenous serotonin (5-HT1B) and calcitonin (Cla) receptors in CHO cells to a cyclic AMP-responsive luciferase reporter gene. J. Neurochem. (1997), 69(3), 1278-1285 42. Valentin, Jean-Pierre; Bonnafous, Regine; John, Gareth W. Influence of the endothelium and nitric oxide on the contractile responses evoked by 5-HT1D
receptor agonists in the rabbit isolated saphenous vein. Br. J. Pharmacol.
(1996), 119( 1 ), 35-42.
43. Van de Water, Andre; D'Aubioul, Jan; Van Gerven, Willy; Van Ammel, Karel;
De Clerck, Fred. Selective vasoconstriction by alniditan in the carotid vascular bed of anesthetized dogs. Eur. J. Pharmacol. (1996), 299(1-3), 127-37.

44. Yocca, F. D. The Preclincal Pharmacology of the Putative Antimigraine Agent BMS-180048, a Structurally Novel SHT-ld monist, Cephalagia, 1995, 1S, (Suppl 14) 174.
4S. Hamel, Edith; Fan, Enmei; Linville, Donald; Ting, Vincent; Villemure, Jean Guy;
Chia, Loo Sar. Expression of mRNA for the serotonin S-hydroxytryptamine 1 D
receptor subtype in human and bovine cerebral arteries. Mol. Pharmacol.
(1993), 44(2), 242-6.
to 46. .Longmore, J.; Boulanger, C. M.; Desta, B.; Hill, R. G.; Schofield, W. N.;
Taylor, A. A. S-HT1D receptor agonists and human coronary artery reactivity in vitro:
Crossover comparisons of S-HT and sumatriptan with rizatriptan and L-741,519.
w Br: J. Clin. Pharmacol. (1996), 42(4), 431-441.

47. Ferro, A.; Longmore, J.; Hill, R. G.; Brown, M. J. A comparison of the contractile effects of S-hydroxytryptamine, sumatriptan and MK-462 on human coronary artery in vitro. Br. J. Clin. Pharmacol. (I99S), 40(3), 24S-S1.

Diacids HD 0 ~ ~ " ~ CH3 HO~S~S~~O 0 0 X-3 OH H2C ~ HO ~ ~0 0 OH CH3 x 4 3 X-5 H0~~0 0 OH

x- 6 Ho X- 7 Ho °
° x-8 OH N ~ 0 0 0' ~0 x-g X-lp X-11 HD~ HO 0 HO HO

x-~5 x-is ° x-1~
OH OH

H3C '0 0 HO
OH
H3~ x-18 x- lg SUR~~~ S~~ET (RULE 26) HO ~0 ~ OH HO OH ,~~H
HO w ~ ~ 0 0 0~ ~'' S S
o X-20 X-21 HO --t0 H

HO ~ OH o 0 OH
i I OH
x-24 a HO
X-25 off OH

Hod' S'~S ~~ ~-o X-26 off ~ S o \ l / \ oS

Chiral N
X-27 0 off 0 off HO OH , 0 0 0 ~CH2 X-29 off 0 i HO ~ S'S ~~
v X-31 off 0 0 0 HO N
O~N OH

Chiral SUSS'~'TnJ~E SHFE1' ~IJL~ 26) i o 0 0 0H
0 0 " HO

HO N ~ HO Cl 0H H,3 C 0 O~N OH X-34 X-35 CH3 0 Chiral Ch iral HO
\ X-33 o D -L

HO ~ 0 HO F F X-37 off X-38 Ho X-36 0\ off 0 0 ~OH

OH CH OH 0 o~-CH3 0 'S-N
HO ~ i 0 i i N\S \ 0 0 CH \ \ I Ch irol X-39 0 0 X 40 H C'N~CH X 41 off X- 44 HO 0 Ho ~'~., 0 0 HO ~ / HO S 0 0 ~ o S o ~H

Chirol H3C OH

~u~S~IEET (RULE 26) OH OH

F N ~ -S N HO \ ~ 0 N
0 '--~ 0 HO -~ 0 F X- 51 Ch irol HO 0 0 Chirol F F X-52 HN~~%, 0 ~ ~%, 0 ~ S~ ~.0 0 , 0 ~ HO S I
~OH ~~ H OH
HO Ch irol HO X- 55 Ch irol H C ~0 0 HO- 0 ~ \
OH
X-57 Chirol ~N~ OH HO
HO ' \0 HO

Ch irol X- 60 NON 0 OH N~0 I i Ch irol ~[~I~ST~TUTE SHEET (RULE 26) 0 / ~ OH 0~ 0% D--~ ~'N OH
HO S~S~O HO ~ p H3 H3C OH
X-63 Chiral 0 ~ X-65 0 HO

OH

0 0 0 S~0 N
HO OH 0 \ l S - ~ 0 X-68 LO ~ 0 ~ ~ ~ Ho N
HO Ch irol HO / \ HO OH 0 FFFFFFFF 0 0 / \ HO - . OH
Chirol S FFFFFFFF

HO
HO~~ 0 ~ p OH HO 0 0 J 0 HO~S ~0 ~0~ ~OH 0 \

'OH I 'OH

HO ~- ~ ~ ., .~ ~ ~ ~ ~CH
OH

SURS11TUTE SHEET (RULE 26) 0 ~ 0 H CC 0 N~N I ~ 0 N~., 3 '~' ~ ~ ~N
CH3 0 OH 0 CH3 = 0 Ch iral 0 0 ~ Ch irol X-80 p p OH

i O~N p ~OH
HO N~ HO ~ ~ 0 OH HO OH h,0 0 0 0 Chirol X-83 su~s~sH~r ~u~.~ zs~

X-85 off 0 ~ N~... N OH 0 0 ~ 0 0 0 HO~,,.. ~
'w,~OH H OOH
Choral H 7 X-88 HO ~o X- 86 o X- 8 H0~ 0 OH 0 I0I ~N 0 ~OH
~N~ 0 w H~''. "~~~ 0 N
N 0 OH , HO \ J 0 ~(H
~oH X-90 ~ I o X-91 0 p OH OH
N,,.. I, H C
OH f..iO~S S ~0 2 ' OH

Ch iral 0 0 pH OH
HO
HO OH ~ FF FF FF FF FF 0 o X- 97 SUBST~ SN~~ET (RULE 26) HO
0 0 0 0 H3C CH3 H3C CN3 ~ f 0 N OH HO OH N \
I ~N 0 0 0 HO-FF FF FF FF
OH NO OH

X-1o2 FF FF FF

D
OH \ / ° 0 OH 0 OH ' I x- ~ 04 X- ~ 05 °

N
N OH ~ ~OH

N OH N

~0 ° ° ~ I x-108 X-109 °

SUF351TtldTE SF~E~f' {RULE 26) 0 N OH N .. OH
,, OH
HO 0 N 0~0 0 CI OH / 0 0 CH3 ~ CH3 X h~110 Br \ X-111 Chirol II 0;
N~OH / ~~~~ OH HO , 0 0 OH
p ~~ o Chirol N
/ 0 ~N N'' OH 0~ 0 \ I
Chirol 0 OH ~ 0 X-117 0 ,,,,~0 ~ OH HO!~~0 S,~OH OH
X-118 0/l X-120 HO~S~S'~0 HO Nf N OH

pX-122 0 i ~ 0 HD~ 0 ~ 0~~,~0 0 OH HO
~ 0 0 N~ S-S N - \0 OH OH HO 0 D
0 ~ pH X- l24 ~ o0H

/ Chiral 2 X-125 SUBSTITtnE SHEET (RULE 26) WO 99/64044 PCT/(TS99/12751 -o~N
OH
0 H0~0~OV \0 Chi~al 0 X-129 X-127 nv ~ H _. .

0 H.,,. OH
OH
~OH

Disul fon yl Halides 0 0 0 0-S ~ l ~ / S-CI

F-S~N I ~ N 0 X-134 p 0 0 i ~-S_F O~S ~S.CI
0 0 0 C% I , ~ I \0 0 S''0 i F_S 0 D 0~ \ I ~0 0 , I 0 0 0''SCI 0 S'CI ~~S w Sr '' ~ rr F
p C 33 X-137 p CI p F' S N N S''0 O~S ~S. CI
or I ~ ~ ~ I ~o C~ I ~ ~ I ~0 i 0 ~ i ~ CI
S,0 X-139 X-140 ~ ~ ~ w 0~ , ~ 0 SUBST~n.I"f~ StlE~1' (RULE 26) WO 99/64044 PC'T/US99/12751 -F
o=s=o H3C , CH3 D~ CI
0 ~N OS w I ~0 CI So0 Sv 0 ~ ' ~i ~CI ,S ~ \ CI
0 CI~ 0 0 w S

H2C \ p S\F X-143 0 X-144 0 0 F, ~0 CI
oS.F F.S,O ,,S
/~~00 N N 0 ~~NI
w NJ~ N'~' 1~ / I I ~ ~0 0 ~ ~S.

0 CI CH3~ ~ 0 i0 ~ 0 0 0 0 ~S S ~ CI~S I ~~ Os o w ~ F ~~ SCI
I \ CI ~~ ~ I iS~CI S ~ S 0 0 S ~~ ~0 H3C ~ CH3 ~ 0 F I ~ 0 ~ I S CI

X-147 X'-149 X-150 CLS I i I i SCI C ~S~ ~ i S~
0' '0 ~ 0 0 X-152 Dialdehydes 0 I i l Oi I ~ 0 0 p X-154 X-153 O~CH3 i 0~ ~ Ow W I i0 p X-155 ~0 ~ CH3 , 0 o , I i W I N
,0 0~

SU~tSHEET (RULE 26) 0' \ 0 ~ ~ o~~o \
o \ ~ \
o o\ p X-160 ~o IV~ ~ o i° ° ° o, o'~o \ /
X-161 ~0 X-162 i X-164 X-163 cH3 \ o ~ ~ ~ ~o w ~o o --' o ~ x-166 0 -o H3C~0 0 / \ p- _ p 0 X-168 S ~ ~ \ / ~ ~ w ~ , 0 x-169 X-170 o, ~N ~o ~ o H3c~o X-171 \ l o~ l \ ,0 S
X-172 Ho '' X-174 i X-173 CI CI .N ~ CI
Dihalides ~ CH3 X-177 CI--\_N\S
cyo~o~o~c~ o, oo X-176 Br ~Br Br Br I OH OH

SUB..STITU~ SH~k"~ (RULE 26) w CI~O~O~CI ~ % CI
Br Br 0 I I Bra CI ~ CI CI
Br CH2 CI
X-184 X-185 X_ 186 off Br Br 0 ~ ~ N~
CI
X-187 Br Br X-188 Br ~. I~I
Br Br I Br~''' 0 X- l91 X-189 X-190 0 Br Br 0 Br Br ~--0 0 CIH
Br /
CI~N~ CI ~0 OH Br v~
CH
3 Br Br X-196 X-197 ~( B 98 X'-195 Br I I f-13C 0 Br Br X-200 H3C~ ~~f ~ Br 0~ Br X-201 Br ~OH ~ Br Br 0 Br Br CI X-205 Br~O~,Br H3C r0 Br Br CI ~ ~ CI Br w Br H N~
H,3C--0 B~ 2 Br X-209 I X-210 CI

X-207 ~ o Br Br 0~0 CI ~N~N
Br Br cH3 ~ X-213 °
X-211 X-212 I l ~. ~~ ~ X-214 ~,~gST~TUTE SHEE'1!' (RULE 26) Diisocyonotes 0 N N ~ 0~ ~ I , 0 ~N w N
X-215 p X-216 / I t l N ~0 0 N N
N \ / \ / N II
H3C-0 0-CH3 X-218 p FF

H3C ~ ~ N ~ / I I \ ~0 N~0 ~N ~ ~N~

/N \ N\ 0 0 0\N '~ I N /0 i \p ~~ //
0 Br ~ CH3 N \ l \ l N CH3 p X-223 / o N~
N
N ~ I ~0 N
i ~N

p X-226 0 ( , , CH3 CH3 N I /0 ~N , ~ N
N~0 0/ ~ I N 0 ~ I I , 0 X-225 ~ X-229 X-228 ~ CI

N N / N~ /
~ ~o I ~ p /~ cl 0 w 0 CI ~ CH3 N
l SUBSTeTUTE SHEEP (RULE 26) 0 0 \ O~N N~0 N w w N/ ~N N w I H3C CH3 ~ X-235 r3 0 , ~ CH3 ~ 3 CH3 N N

CH I~ X-237 NI ~ 3 N X-238 v ~CH3 N ~
X-239 ~ H3 'v \ l \ ~ N

Cl Cl ~0 i ~~ N
N N ,N \0 0 ~ X-24 l 0 '/ X-242 N N-~CH
O~N ~ ~ ~ i N 3 D
~0 X-243 H3C H3C ~ I N N

SUBS ~I~UTE Sf~EET (RULE 26) 0 ~ ~ N~ 0 0 U
N / H3C \ l 0 \
/~ N H3C N N" " N
p X-246 II X-247 Diamin es N~O~O~N I

\ H2N ~\/~ N i\/~NH2 N'"~. N ~ ~ X-251 CH3 X-250 N H2N ~ N X-252 H2N ~NH2 H2N ~ w X-253 CH3 CH3 CH NH2 I ~ I
H2N~..%~~ \N

H2 ~0 0~ NH 2 ~N /

H N \ / Nl-~ 2 ~ NH2 H3C~ N N ~\/\ CH H2N~/\i 0 ~/\i NH2 H2N ~ ~ NH2 ~ NH2 I I / ~ I H2N~ ~ NH2 S

~UgSI~~E1C (F61.~!_F 2S) ~ \N N

i HO OH 0/-1 ~ I I , HO NON H2N~N~CH3 X-270 N N
H C N ~ CH3 C
CH NH2 H2N ~ NH2 3 X-273 H3C ~N~-N~ H2N NH2 w H C ~ NH2 H3C CH3 H2N I , NH2 H N l ~ l \ NH2 H N

H3C l \

NH2 NH2 HO~N~N~OH
x-278 x-28o H2N NH2 / \ 0 ~ \ NH2 U
~N N-' U w~
l ~ 0 ~ ~ NH2 H2N ~ N ~ I NH2 x-283 SUBS11TUTE SHEET (RULE 26) H2N~O~O~O~ NH2 H3C~N N~ CH3 H2N NH2 x-28s x-287 H2N \\Sl H2N ~ N ~ CH3 H2N '~ ~~ NH2 x-288 NH2 N~'N
H2N~ 0 O~NH X-292 \\//
S

X-29,~ H2N X-294 NH2 H2N NH2 ~

X-295 NH2 NH2 , I D'~0 I

H3C~ N ~ N ~ CH3 H2N NH2 w I I i H2N NH2 H2N NH2 / ~ I w ~ I I ~ i ~UgS'I~'~1JU; SHEI~If ~~il)t_~ 26) l \ 0 / \ S l \ 0 / \ H2N NH2 H2 ~O~O~NH N H2N NH

X-305 ~~.,N ~ CH3 X-307 Ch irol / w H2N l \ l \ l \ NH2 C -~0 0 CH3 H2N CH3 / w N ~ CH3 CH3 Chiral X-313 NH2 S~9~BS1~'~IJT1E SHEET' (RULE 26) X-315 H3C ~N'~N
X-316 H3 C ~CH3 CI CI
N N ~H H3 C \
_ N
off ~ ~ I ~
X-317 ~ I
N
Chirol \CH3 x-318 w I wNH2 X- 319 H C i~~H H2 x-32o H3C~'N N~CH3 H2N NH

H3CwN~N~CH3 H3C~N~N~CH3 H2N~O~NH2 Diols CH HO

Br j 3C ~ Br 0 I I
HO ~ 0 w ~ C ~ off X-,327 C
Br Br OH

N ~ OH

HO ~ N~N ~ OH

N
154 ~ OH
SURS~T~'ITfE SHEET (RULE 26) I~OH HO

i CH3 H3C 0 0 CH,3 H0~0 w I C OH
OH~OH

OH ~ OOH ~OH
OH ~ I 0 ~ N~ OH
H C

HO ~ 0~0 ~ 0~0 ~ 0~ OH
HO ~S~ OH

F F
F F F F H3C ~ OH
F F F HO
F F f T _ CH3 l r F F CH3 HO' ' X-341 OH
H3 C \0 ~ CH3 ~ OH
CH3 CH3 ~ I

HO OH

~~a~SMEET RULE 26) WO 99/64044 PCT/US99/12~5i -HO ~S~S~ OH
X-345 H~ ~'~.~~H

0~ ~0 OH
HO ~S~ OH H C CH3 HO ~ OH

X-347 X-348 off X-349 HO ~0~0~0~0~ OH HO ~ ~ OOH
~0 OH
HO' HO ~~ ~ OH

OH
F F
F F HO ~ ~ ~ OH
F ~ ~F i F F ~ X-355 Ho X-354 ~~ OH
HO ~~ OH HO

HO ~ OH

OH ~ OH
H3~ X-359 off X-360 off SURD SHEET (RULE 26) OH OH
HO HO

HO ~ CH 0\ l0 HO OH
2 HO ~~S
OH HO ~ I ~ X-365 X-363 ~H,3 OH OH
OH ~ '0 HO ~ I ~ H C/

HO ~O~O ~O~OH ~~,,, 0 HO

HO OH OH OH
X-370 ~ H3C - CH3 ~~H ~ I
OH

OH
OH

OH
HO HO

OH
suss rr~ur~ s~s~~T ~RU~E zs~

OH
OH ~ NCH
HO H3 C ~ ~ 3 HO OH
X- 376 H~ ~H X- 377 X- 378 H0 ~'N~OH HO~p~ - ~p~OH

HO ~ S~S ~ OH HO ~ p~ p ~ OH HO ~ 0 OH

F F
HO F
HD ~ OH F F OH

Dithiols HS
HS HS ~ \ SH
SH SH C

SH
HS
CH3 ~ ~ HS ~
HS SH

~U~ST~TIITE SHEET (RULE 26) HS~ ~0 HS SH HS
D 1~ SH I

HS ~OH
SH
X-395 H C I ~ CH

HS~0~0~ SH HSH 0 ~
S OH HS SH

CH3 HS-~ ~ HS~SH
HS w I S ~-- SH

~SH X-402 , HS SH HS ~N ~ SH \ l HS~S ~ SH HS SH HS SH

OH SH OH OH
SH
HS SH 0 _ 0 HS ~~ HS SH
OH ~0' OH OH SH

HS SH SH OH OH
0 0 HS~SH
\ l OH SH Chiral OH

HS ~ ~ SH i I I HS ~ I SH
S

X-417 t55 ~~~SHEET (RULE 26)

Claims (48)

IT IS CLAIMED:

1. A multibinding compound of the formula:
(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, each of said ligands comprising a ligand domain capable of binding to a 5-HT
receptor, or a salt thereof;
with the proviso that when the ligand is a compound of the formula:
wherein:
R1, R2, R6 and R7 are all hydrogen; and R3 is R a R b NR c-, in which R a and R b are lower alkyl and R c is lower alkylene; and R5 is the linking position; then X cannot be a linker connecting through a terminal oxygen atom; or when R3 is R a R b NR c- or 1-methylpiperidine; and R5 is the linking position; then X cannot be -(CH2)m-SO2N(CH3)-Q1-N(CH3)- SO2-(CH m)-, in which m is an integer of 1-3 and Q1 is any linker; or when R5 is -C(O)NH2 and R3 is the linking position, the linker X cannot be in which Q2 and Q4 are cyclohexyl or cyclohexenyl and Q3 is any linker

2. The compound of claim 1, in which the ligand is chosen from AH-25086, Almotriptan (LAS-31416), Alniditan, ALX-0646, Avitriptan (BMS-180048), CP
122,288, 5-CT, Eletriptan (UK-116044), IS-159, LY-334370, LY 344864, L-694,247, F11356, .alpha.-Methyl-5-HT, 2-Methyl-5-HT, Naratriptan, Oxymetazoline, PNU-109291, PNU 142633, Rizatriptan (MK-462), (L-741,519), S-9977, S-20749, SB209509 (VML251), Sumatriptan, VML-251, Frovatriptan, and Zolmitriptan.

3. The compound of claim 2, wherein p is 2, q is 1, and both ligands are the same,.

4. The compound of claim 3, wherein the linker is of the formula:
-X'-Z'-(Y'-Z")m-Y"-Z'-X'-in which:
m is an integer of 0-20;
X' of each separate occurrence is -O-, -S-, -S(O)-, -S(O)2-, -NR- (where R is as defined below), -C(O)-, or a covalent bond;
Z' and Z" at each separate occurrence are alkylene, cycloalkylene, alkenylene, alkynylene, arylene, heteroarylene, heterocycloalkylene, or a covalent bond;
Y' and Y" at each separate occurrence are:

-O-Z'-O-. -N(R)-Z'-N(R), -S-S-, or a covalent bond; in which:
n is 0, 1 or 2; and R, R' and R" at each separate occurrence are chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl. heteroaryl, and heterocyclo.

5. The compound of claim 4, wherein the ligand to which the linker is attached is represented by the structure:
wherein:R3 is heterocyclic, heterocyclic alkyl, alkylaminoalkyl, or dialkylaminoalkyl;
and R5 is the point of attachment of the linker.

6. The compound of claim 5, wherein R3 is 1-methylpiperidin-4-yl.

7. The compound of claim 6, wherein:
m is 1;
X' and Z' are covalent bonds at each occurrence;
Y' is -NH-C(O)- and Y" is -(O)C-NH-; and Z" is alkylene, alkenylene, arylene, or heteroarylene.

8. The compound of claim 7, wherein Z" is alkylene of 4-12 carbon atoms.

9. The compound of claim 8, wherein Z" is -(CH2)8.

10. The compound of claim 8, wherein Z" is -CH=CH-CH2-.

11. The compound of claim 8, wherein Z" is heteroarylene.

12. The compound of claim 11, wherein Z" is 1,3-thiophenylene.

13. The compound of claim 11, wherein Z" is 2,5-pyridinylene.

14. The compound of claim 6, wherein:
m is 1;
X' and Z' are covalent bonds at each occurrence;
Y' is -NH-SO2- and Y" is -SO2-NH-, and Z" is alkylene, alkenylene, arylene, or heteroarylene.

15. The compound of claim 14, wherein Z" is arylene.

16. The compound of claim 15, wherein Z" is 1,3-phenylene.

17. The compound of claim 15, wherein Z" is 2,4,5,6-tetrametthyl-1,3-phenylene.

18. The compound of claim 6, wherein:
m is 1;
X' and Z' are covalent bonds at each occurrence;
Y' and Y" are -NH-C(O)-NH-, and Z" is alkylene, alkenylene, arylene, or heteroarylene.
19. The compound of claim 18, wherein Z" is 4,4'-diphenylether.

19. The compound of claim 3, wherein the ligand to which the linker is attached is represented by the structure:

wherein:R3 is the point of attachment of the linker; and R5 is halogen, alkyl,, heterocyclic, heteroaryl, heteroarylalkyl, amidoalkyl, alkylaminosulfonylalkyl, dialkylaminosulfonylalkyl, arylsulfonylalkyl, heterocyclosulfonylalkyl, arylcarbonylamino, alkylsulfonamido, or alkylsulfonylalkyl

20. The compound of claim 19, wherein R5 is arylcarbonylamino.

21. The compound of claim 20, wherein R5 is 4-fluorobenzoylamino.

22. The compound of claim 5, wherein:
m is 0;
X' is a covalent bond;
Y" is alkylene- or -N(R)-alkylene-N(R)-; and Z' is heterocycloalkylene.

23. The compound of claim 22, wherein Z' is 1-piperidin-4-yl, and Y" is -(CH2)2-O (CH2)2-O-(CH2)2-.

24. The compound of claim 22, wherein Z' is 1-piperidin-4-yl, and Y" is -(CH2)7-.

25. The compound of claim 23, wherein Z' is -(CH2)2-, and Y" is -N(CH3)-(CH2)12-N(CH3)-.

26. The compound of claim 2, wherein p is 2, q is 1, and the ligands are different.

27. The compound of claim 25, wherein the first ligand to which the linker is attached is represented by the structure:
wherein:R3 is the point of attachment of the linker; and R5 is heterocyclic, heteroaryl, heteroarylalkyl, amidoalkyl, alkylaminosulfonylalkyl, dialkylaminosulfonylalkyl, arylsulfonylalkyl, heterocyclosulfonylalkyl, arylcarbonylamino, alkylsulfonamido, or alkylsulfonylalkyl and;
the second ligand to which the linker is attached is represented by the structure:
wherein:R3 is heterocyclic, heterocyclic alkyl, alkylaminoalkyl, or dialkylaminoalkyl;
and R5 is the point of attachment of the linker.

27. The compound of claim 26, wherein in said first ligand R5 is arylcarbonylamino and in said second ligand R3 is heterocyclic.

28. The compound of claim 27, wherein in said first ligand R5 is 4-fluorobenzoylamino and in said second ligand R3 is 1-methylpiperidin-4-yl.

29. The compound of claim 28, wherein:
m is 1;

X' is a covalent bond;
the first Z' is 1-piperidin-4-yl.
the second Z' is a covalent bond;
Y' and Y" are both covalent bonds;
Z" is -(CH2)6; and Y" -C(O)NH-.

30. A method for treating a disease or condition in a mammal resulting from an activity of a 5-HT receptor, comprising administering to a subject in need of such treatment a therapeutically effective amount of a multibinding agent of claim 1.

31. The method of claim 30, wherein the receptor is a 5-HT1 receptor.

32. The method of claim 30, wherein the disease or condition is chosen from migraine, headache, itch, motion sickness, depression, emesis, memory loss, anxiolytic disorders, obesity, gastrointestinal disorders, and irritable bowel syndrome.

33. The method of claim 32, wherein the condition is migraine.

34. A pharmaceutical composition comprising a therapeutically effective amount of one or more multibinding agents of claim 1, or a pharmaceutically acceptable salt thereof, admixed with at least one pharmaceutically acceptable excipient.

35. A method for identifying multimeric ligand compounds that possess multibinding properties with respect to a 5-HT receptor, which method comprises:
(a) identifying a ligand or mixture of ligands capable of binding to a 5-HT
receptor and having at least one chemically reactive functional group;
(b) identifying a library of linkers wherein each linker in said library comprises at least two functional groups having complementary chemical activity to at least one of the ligand functional groups;

(c) preparing a multimeric ligand compound by combining the ligand or ligands identified in step (a) with the library of linkers identified in step (b) under conditions sufficient to form covalent linkages between the complementary functional groups of the ligand or ligands and the linker;and (d) assaying the multimeric ligand compound library produced in step (c) and selecting multibinding agents based upon the ability of said library to bind to a 5-HT
receptor.

36. The method of claim 35, wherein said linker chain length ranges from about 2 to 100.ANG..

37. The method of claim 36, wherein said multimeric ligand compound comprises ligands that are the same.

38. The method of claim 36, wherein said multimeric ligand compound comprises ligands that are different.

39. The method of claim 36, wherein the ligand binds to a 5-HT 1 receptor.

40. A library of multimeric ligand compounds that may possess multibinding properties related to a 5-HT receptor, which method comprises;
(a) identifying a ligand or mixture of ligands capable of binding to a 5-HT
receptor and having at least one chemically reactive functional group;
(b) identifying a library of linkers wherein each linker in said library comprises at least two functional groups having complementary chemical activity to at least one of the ligand functional groups; and (c) preparing a multimeric ligand compound by combining the ligand or ligands identified in step (a) with the library of linkers identified in step (b) under conditions sufficient to form covalent linkages between the complementary functional groups of the ligand or ligands and the linker.

41. The library according to claim 40, wherein said library of linkers is selected from the group comprising flexible linkers, rigid linkers, hydrophobic linkers, hydrophilic linkers, linkers of different geometry, acidic linkers, basic linkers, and amphiphilic linkers.

42. The library according to claim 41, wherein each of said linkers in said linker library comprise linkers of different chain length and/or having different complementary reactive groups.

43. The library according to claim 42, wherein said linker chain length ranges from about 2 to 100.

44. The library according to claim 40, wherein said multimeric ligand compound is homomeric.

45. The library according to claim 40, wherein said multimeric ligand compound is heteromeric.

46. An iterative method for identifying multimeric ligand compounds possessing multibinding properties which method comprises:
(a) preparing a first collection or iteration of multimeric compounds, which is prepared by contacting at least two stoichiometric equivalents of a ligand or mixture of ligands that target a 5-HT-receptor with a linker or mixture of linkers wherein said ligand or mixture of ligands comprises at least one reactive functionality and said linker or mixture of linkers comprises at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand wherein said contacting is conducted under conditions wherein the complementary functional groups react to form a covalent linkage between said linker and at least two of said ligands;
(b) assaying said first collection or iteration of multimeric compounds to assess which if any of said multimeric compounds possess multibinding properties;
(c} repeating the process of (a) and (b) above until at least one multimeric compound is found to possess multibinding properties;

(d) evaluating what molecular constraints imparted or are consistent with imparting multibinding properties to the multimeric compound or compounds found in the first iteration recited in (a)- (c) above;
(e) creating a second collection or iteration of multimeric compounds which elaborates upon the particular molecular constraints imparting multibinding properties to the multimeric compound or compounds found in said first iteration;
(f) evaluating what molecular constraints imparted or are consistent with imparting enhanced multibinding properties to the multimeric compound or compounds found in the second collection or iteration recited in (e) above;
(g) optionally repeating steps (e) and (f) to further elaborate upon said molecular constraints.

47. The method of claim 46, wherein steps (e) and (f) are repeated from 2-50 times.

48. The method of claim 46, wherein steps (e) and (f) are repeated from 5-50 times.