WO2013142328A1

WO2013142328A1 - Small molecule antagonists of pf4 containing ultra large complexes

Info

Publication number: WO2013142328A1
Application number: PCT/US2013/032092
Authority: WO
Inventors: Bruce SACHAIS; John RUX
Original assignee: University of Pennsylvania Penn
Current assignee: University of Pennsylvania Penn
Priority date: 2012-03-23
Filing date: 2013-03-15
Publication date: 2013-09-26
Anticipated expiration: 2014-09-23

Description

SMALL MOLECULE ANTAGONISTS OF PF4 CONTAINING ULTRA LARGE COMPLEXES

This invention was made with government support under Grant Nos.

5R01HL078726-04 and 3R01HL078726-04-S1 awarded by the National Institutes of Health. The government has certain rights in the invention.

BACKGROUND OF THE INVENTION

Heparin-induced thrombocytopenia (HIT) and thrombosis (HITT) are serious complications of heparin therapy. HITT is a severe prothrombotic disease, with affected individuals having a 20-50% risk of developing new thromboembolic events, and has a mortality rate of about 20% with an additional about 10% of patients requiring amputations or suffering other major morbidity. Since a large number of hospitalized patients are exposed to heparin, HITT is a major iatrogenic cause of morbidity and mortality in this patient population. No specific therapies to treat HITT are reported. Management consists of general measures such as withdrawal of heparin, use of a non-heparin anticoagulant, and supportive care.

PF4 is a 70 amino acid, lysine-rich 7.8 kDa platelet-specific protein that belongs to the CXC (or beta) chemokine subfamily. PF4 is synthesized by megakaryocytes and comprises 2-3% of the total released protein in mature platelets. PF4 exists as a tetramer in the a-granules of platelets and is secreted in high concentrations when platelets are activated. PF4 tetramer binds avidly to

glycosaminoglycans (GAGs), but only a few high affinity protein receptors have been identified to date. The interaction of PF4 with GAGs is central to the pathogenesis of heparin induced thrombocytopenia as well as thrombosis.

Rauova, "Ultralarge Complexes of PF4 and heparin are central to the pathogenesis of heparin-induced thrombocytopenia", Blood, 105(1): 131 (January 1, 2005), which is hereby incorporated by reference, found that heparin:PF4 complexes exist in a dynamic equilibrium and that ULCs are subject to dissociation under certain conditions. Although PF4 crystallizes as a tetramer, in solution it exists in a dynamic equilibrium between monomeric, dimeric and tetrameric forms. The dimers associate to form the tetramer with energy contributed by salt bridges. See, Petersen, "A chondroitin sulfate proteoglycan on human neutrophils specifically binds platelet factor 4 and is involved in cell activation", J. Immunol, 161 :4347 (1998), which is hereby incorporated herein by reference.

Similarly, Zhang, "Crystal structure of recombinant human platelet factor 4",

Biochemistry, 33:8361-8366 (1994), which is hereby incorporated herein by reference, noted the charge-charge interactions (salt bridges) between the positively charged lysine residues (Lys50 in the monomer) and the negatively charged glutamic acid residues (Glu28 in the monomer) stabilize the tetrameric form of PF4.

Krauel, "Heparin-induced thrombocytopenia - therapeutic concentrations of danaparoid, unlike fondaparinux and direct thrombin inhibitors, inhibit formation of platelet factor 4-heparin complexes". J. Thrombosis and Haemostatis, 6:2160-2167 (2008), which is hereby incorporated herein by reference, recently reported that treatment of HITT patients with danaproid (a glycosaminoglycan mixture approved for anticoagulation in HITT) may decrease heparin:PF4 complex size, resulting in less antibody mediated platelet activation.

Reilly, "Prothrombotic factors enhance heparin-induced thrombocytopenia and thrombosis in vivo in a mouse model", J. Thrombosis and Haemostatis, 4:2687-2694 (2006) (Reilly I) and Reilly, "Heparin-induced thrombocytopenia/thrombosis in a transgenic mouse model requires human platelet factor 4 and platelet activation through FcyRIIA", Blood, 98(8):2442-2447 (October 15, 2001) (Reilly II), which are hereby incorporated herein by reference, discussed that the clinical manifestations of HITT are caused by antibodies that recognize a complex composed of heparin and PF4. The transgenic mouse model of HITT conclusively demonstrated that heparin, PF4, antiheparin/PF4 antibody, and platelet FcyRIIa are necessary and sufficient to recapitulate the salient features of HITT in mice.

There is a need in the art for compounds and methods for preventing or treating conditions related to the formation of PF4 tetramers, such as HITT. SUMMARY OF THE INVENTION

In one aspect, methods for (i) preventing formation of, or (ii) disrupting PF4 tetramers, are provided and include administering a compound to a subject. The compounds useful in such methods bind to PF4 dimers or PF4 monomers. The compounds also disrupt the salt bridges of PF4 tetramers.

In another aspect, methods for (i) preventing formation of or (ii) disrupting ultra-large complexes (ULCs) containing a PF4 tetramer and a glycosaminoglycan (GAG) and include administering a compound to a subject. The compounds useful in such methods bind to PF4 dimers or PF4 monomers or disrupt the salt bridges of PF4 tetramers.

In still a further aspect, methods for (i) preventing medical conditions related to the formation of PF4 tetramers, such as HITT and atherosclerosis, (ii) treating medical conditions related to the formation of PF4 tetramers, such as HITT, (iii) correcting a platelet imbalance, (iv) preventing a decrease in platelet production, (v) increasing high density lipoproteins in a subject, (vi) preventing or treating inflammation, or (vii) modulating clotting or hemostasis are provided. The compounds useful in such methods bind to PF4 dimers or PF4 monomers or disrupt the salt bridges of PF4 tetramers.

In yet another aspect, the compounds useful in these methods and

compositions noted above contain a moiety of the following structure, wherein R^x,

R^Y, R^x', R^Y', X, n, and n' are defined herein:

O

P— (CR^xR^Y)_n(CR^xCR^Y)_rf-X^v

HO . Pharmaceutically acceptable salts or prodrugs of such compounds are also useful in the methods and compositions described herein.

In still a further embodiment, compositions and kits are provided and contain (i) a pharmaceutically acceptable carrier and (ii) a compound as described above or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment, compositions and kits are provided and contain (i) a medication which causes the formation of PF4 tetramers, a medication which disrupts PF4 tetramers, or a combination thereof; and (ii) a compound as described above or a pharmaceutically acceptable salt or prodrug thereof.

Other aspects and advantages of the invention will be readily apparent from the following detailed description of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

Figures 1A and IB are molecular modeling diagrams, shown in two orientations, representing the binding of a small molecule to the dimer interface on PF4 (here shown as a dimer), i.e., antagonist, described herein. The antagonistic compound is light gray and the PF4 tetramer is black. Figure IB contains the molecular model of Figure 1A and rotated 90°.

Figure 2 is a distribution of DOCK scores over 1.1 million compounds and found to be potential ULC antagonists. Dock scores are empirical with lower values representing higher affinity for PF4. As noted, the docking scores approximate a Gaussian distribution with a mean value of -26.6 and standard deviation (sd) of 3.3. The 100 compounds identified scored more than 10 sd below the mean (-73.8 or less).

Figure 3 is a bar graph of data obtained using photon correlation spectroscopy on a DynaPro® DLS instrument and Dynamics® software (V6.7.6; Microsoft) to obtain correlation function. Samples analyzed included PF4 incubated in the absence or presence of unfractionated heparin (UFH) for 20 minutes at room temperature. The bar graph shows the percentage of ULCs and small PF4 particles. The solid bars include data for the small particles representing a population of particles with a mean hydrodynamic diameter of about 1 nm. The striped bars include data for the large particles representing a population of particles with a mean hydrodynamic diameter of about 300 nm. Data are expressed as the percent of total intensity from each measurement, the mean of 10 measurements, and representative of two such experiments.

Figures 4A and 4B are bar graphs of data obtained from SDS PAGE of PF4 after BS3 crosslinking and show the ability of compounds 34, 24, 1, 80, 88 and 96 to inhibit formation of PF4 tetramers. Compounds 34, 24, 1, and 96 were tested at 0.1 mM and 1 mM and compounds 80 and 88 were tested at 0.1 mM, 1 mM, and 5 mM.

The solid bars represent PF4 tetramer formed; dotted bars represent PF4 trimer formed; striped bars represent PF4 dimer formed; and the brick-like bars represent

PF4 monomer present in the samples.

Figure 5 is a quantitation of data obtained from a dynamic light scattering

(DLS) analysis as function of ULC diameter vs. the % inhibition using compound 96.

Specifically, Figure 5 provides a bar graph mapping the concentration (μΜ) of compound 96 as a function of small PF4 particles (solid bar) and large ULCs (striped bar) formed.

Figure 6 is a bar graph demonstrating the ability of compound 96 to inhibit serotonin release. The graph provides the percentage of serotonin released using compound 96, as compared to a sample, i.e., buffer, containing no antagonistic compound.

Figure 7 is a line graph illustrating the dose response inhibition of PF4 tetramer formation using compound 1 (filled circles (·) at 250 μΜ), 34 (filled triangles (T ) at 500 μΜ), 80 (open triangles (Δ) at 250 μΜ), 101 (open circles (o) at 250 μΜ, and 96 (open diamonds (0) at 500 μΜ). The antagonists were incubated at the noted concentrations with PF4 (10 μg/mL) for 60 minutes at room temperature, followed by the addition of cross-lining reagent BS (0.2 mM). The data are the mean ± SEM of at least three independent experiments. Curves represent fit of data to the indirect Hill equation.

Figure 8 A is a line graph which illustrates the ability of compounds of the invention to inhibit the formation and stability of PF4:heparin ULCs as measured by ELISA. Compounds 1 (filled circles; ·), 34 (filled triangles; T), 80 (open triangles; Δ), 101 (open circles; o), and 96 (open diamonds; 0) solutions in varying

concentrations were preincubated with PF4 (7.5 μg/mL) for 1 hour, followed by addition of heparin (0.2 U/mL). Data are the mean ± SEM of at least three independent experiments performed in triplicate. Curves represent fit of data to the indirect Hill equation.

Figure 8B is a bar graph of compiling data from experiments showing the ability of compounds of the invention at varying concentrations to inhibit ULC formation formed using varying concentrations of heparin. One mM of compounds 1, 34, 80, 101, and 96 were preincubated with PF4 (7.5 μg/mL) for 1 hour, followed by addition of heparin (0.2 U/mL). One control contained PF4 and heparin (0.2 U/mL) and the other control contained PF4^K50E (7.5 μg/mL) and heparin (0.2 U/mL). Data are representative of two or more experiments.

Figure 8C illustrates the interaction of ULCs, formed using varying concentrations of heparin, with the PF4 antagonists of the invention. Briefly, 1 mM of compounds 1, 34, 80, and 101 were preincubated with PF4 (7.5 μg/mL) for 1 hour, followed by addition of varying concentrations of heparin (0.05, 0.1, 0.2, 0.4, 0.8, and 1.6 U/mL). The controls contained PF4 (7.5 μg/mL) and varying concentrations of heparin (0.05, 0.1, 0.2, 0.4, 0.8, and 1.6 U/mL)

Figure 8D demonstrates antibody binding to ULCs in the absence and presence of PF4 antagonists of the invention. Briefly, ULCs, prepared by incubating PF4 (5 μg/mL) and heparin (0.2 U/mL) and diluting the mixture to a final PF4 concentration (0.1 μg/mL), were incubated with 1 mM of each of compounds 1, 34, 80, 101, and 96. These mixtures were then incubated in wells pre-coated with KKO. Data are the mean ± SEM of at least three independent experiments performed in triplicate.

Figure 8E shows the dose response of the PF4 antagonists of the invention in disrupting preformed ULCs. ULCS were formed by incubating PF4 (5 μg/mL) and heparin at a 1.5: 1 ratio for 30 minutes. Independent solutions were prepared containing PF4 antagonist 1 (2 runs: 125 μΜ and 63 μΜ), 80 (250 μΜ), 101 (500 μΜ), 96 (1 mM), and 34 (2 mM) and the ULC presence was measured. Data are mean ± SEM of at least three independent experiments performed in triplicate.

Figures 9A-9F demonstrate FcyRIIA-mediated activation of cells and inhibition by PF4 antagonists.

Figure 9A is a bar graph showing the activation of DT40 cells transfected with FcyRIIA and a Luc reporter. The basal condition is a buffer only control; Hep is heparin; IV.3 is the anti-FcyRIIA monoclonal antibody in the presence of anti-lgG antibody.

Figure 9B is a line graph providing the dose-response of DT40 activation by heparin in the presence of constant amounts of PF4.

Figure 9C provides the dose-response of compounds 1 (·), 34 (T), 80 (Δ),

101 (o), and 96 (0) in inhibition of DT40 activation. Data are the mean ± SEM of at least three independent experiments performed in triplicate. Curves C represent fit of data to the indirect Hill equation.

Figure 9D illustrates the inhibition of DT40 activation by plasma obtained from three HIT patients. The control (white bar) represents data obtained in the absence of any PF4 antagonist. The dotted bars are the compilation of data for compound 1 ( ; - the middle bar) and the striped bars (the right bars) are the compilation of data for compound 101. Compounds 1 and 101, both at concentration of 100 μΜ, inhibited activation by KKO in patient samples. Data represent the mean ± SEM of at least two independent experiments performed in triplicate.

Figure 9E provides a bar graph illustrating activation of platelets as measured by release of ¹⁴C-5HT. Data are representative of at least two experiments.

Compounds 1, 34, 80, 101, and 96 were present at a concentration of 2.5 mM.

Figure 9F was generated similar to Figure E except is a line graph of activation (% max) vs. concentration of the noted PF4 antagonist ([PF4A]).

Activation was by plasma from patients with HIT using compounds 1 (circles; ·) and 101 (squares;□).

Figures lOA-C are line graphs and illustrate inhibition of PF4 tetramerization,

ULC formation, and FcyRIIA using the non-tetramerizing mutant PF4^K50E. % WT represents the % of total PF4 containing WT PF4, with the remainder comprised of PP4^K50E_

Figure 1 OA is a line graph of the presence of PF4 tetramer vs. wt PF4. PF4 and PR4^K50E (total mass 10 μg/mL) were incubated for 60 minutes at room temperature, followed by the addition of cross-lining reagent BS (0.2 mM). The data are the mean ± SEM of at least three independent experiments.

Figure 10B is a line graph of the presence of ULC vs. wt PF4. PF4 and PF4^K50E (total mass 7.5 μg/mL) were for 1 hour, followed by addition of heparin (0.2 U/mL) and detected by ELISA as in figure 8A. Data are the mean ± SEM of at least three independent experiments performed in triplicate.

Figure IOC is a line graph of FcyRIIA activation vs. wt PF4. PF4

concentrations were maintained constant by diluting wt PF4 with PF4^K50E. Data are the mean ± SEM of at least three independent experiments performed in triplicate.

DETAILED DESCRIPTION OF THE INVENTION

The inventors determined that compounds which prevent formation of or disrupt the PF4 tetramer or ULC containing the same, i.e., antagonists, are useful in treating and/or preventing diseases related to the same. Such conditions include HITT since heparin:PF4 complexes are central to the pathophysiology of HITT as the targets of the pathogenic antibodies. Specifically, the most pathogenic complexes of heparin and PF4 are very large and are referred to as ultralarge complexes (ULC). Heparin:PF4 complexes smaller than 600 kDa are typically referred to as small complexes (SC). In one embodiment, ULCs are 600 kDa or larger. In another embodiment, ULCs are 670 kDa or larger.

The term "PF4" as used herein refers to platelet factor 4 which is a 70 amino acid, lysine-rich, 7.8 kDa platelet-specific protein that belongs to the CXC (or beta) chemokine subfamily, in which the first two of the four conserved cysteine residues are separated by one amino acid residue. In one embodiment, PF4 is naturally occurring, i.e., wild-type. In another embodiment, PF4 may be synthesized by recombinant or chemical methods. The term PF4 also refers to mutations thereof in which one or more of the amino acids is replaced with a different amino acid.

Examples of PF4 mutations are described in International Patent Publication No. WO 02/006300, which is incorporated herein by reference. In one example, the mutated PF4 contains Arg28 and Glu50 mutations.

PF4:heparin ULCs are more pathogenic than heparin:PF4 SCs. Heparin:PF4

ULCs are better recognized by HITT antibodies and lead to more platelet activation in the presence of these antibodies. Therefore, disruption of ULC represents a valid and novel therapeutic target in the treatment of HITT.

PF4 tetramers and complexes formed therewith contribute to the onset or development of individuals at risk for certain diseases or medical conditions.

Therefore, compounds which disrupt PF4 tetramers or prevent their formation, i.e., antagonists, are desirable. By doing so, the antagonists are useful in preventing of treating these diseases or medical conditions. The term "antagonist" as used herein refers to any chemical compounds which are capable of binding to a PF4 tetramer, dimer or monomer. By doing so, the compound is thereby capable of preventing formation of or disrupting ULCs formed between the PF4 tetramer. Specifically, ULCs formed between glycosaminoglycans (GAG) and PF4 tetramers are responsible for the onset or development of individuals at risk for certain diseases or medical conditions. Therefore, desirable compounds are those which disrupt or prevent the formation of the PF4 tetramer and ULCs formed therewith. By doing so, the antagonist compound prevents formation of, or disrupts, ULCs. I. Compounds Useful in the Invention

The inventors determined that compounds having acidic moieties bound directly or indirectly to a heteroatom bind to PF4 monomers, PF4 trimers, PF4 dimers, and PF4 tetramers. These compounds also disrupt the salt bridge of PF4 tetramers and thereby inhibit formation of the PF4 tetramer. The compounds useful herein prevent the formation of the PF4 tetramer by binding to specific sites at the PF4 trimer, dimer or monomer. Alternatively, the compounds are capable of competing with the electrostatic interactions between the PF4 monomers, dimmers, and trimers in the PF4 tetramer and successfully disrupt to the salt bridge of the tetramer. See, Figure 1. In effect, the functional groups of the compounds described herein form a stronger bond or interaction with the PF4 monomer, dimer, and trimer than they do with each other.

The salt bridge of the PF4 tetramer is formed via electrostatic interactions of a negatively charged amino acid, i.e., glutamic acid of a first PF4 monomer or PF4 dimer and a positively charged amino acid, i.e., lysine, of a second PF4 monomer or PF4 dimer. This salt bridge is typically formed by at least via the interaction of at least one Glu and one Lys on a first PF4 monomer or PF4 dimer and at least one Lys and one Glu on a second PF4 monomer or PF4 dimer. In one embodiment, the salt bridge is formed via at least electrostatic interactions between Lys50 in a first PF4 monomer Glu28 in a second PF4 monomer. In a further embodiment, the salt bridge is formed via at least electrostatic interactions between Glul28, Lys350 of a first PF4 monomer or dimer and Glu328, Lysl50 of a second PF4 monomer or dimer. In another embodiment, the salt bridge is formed via at least electrostatic interactions between Glu228, Lys450 of a first PF4 monomer or dimer and Glu428, Lys250 of a second PF4 monomer or dimer.

In one embodiment, the compound may contain one or more of an acidic moiety. The term "acidic moiety" as used herein refers to a chemical group on the backbone of a molecule which is capable of losing a hydrogen atom from the moiety. Such acidic moieties are readily identified by one of skill in the art. In one embodiment, the acidic moiety contains a ~C(=0)~, carboxylic acid (~C(=0)OH), or carboxylic ester group (~C(=0)0~). In another embodiment, the acidic moiety contains a ~C(=S)~, thiocarboxylic acid (~C(=S)OH, ~C(=0)SH, or ~C(=S)SH), or thiocarboxylic ester group (~C(=S)0~, ~C(=0)S~, or ~C(=S)S~). In a further embodiment, the acidic moiety contains a P(=0), phosphinic acid (~P(=0)OH), phosphonic acid (~P(=0)(OH)₂), or phosphoric acid (~P(=0)(OH)₃) group. In still another embodiment, the acidic moiety contains a P(=S), thiophosphinic acid (~P(=S)OH, ~P(=0)SH, or ~P(=S)SH), thiophosphonic acid (~P(=S)(OH)₂, ~P(=0)(OH)(SH), ~P(=0)(SH)₂, ~P(=S)(OH)(SH), or ~P(=S)(SH)₂), or

thiophosphoric acid (~P(=S)(OH)₃, ~P(=0)(SH)(OH)₂, ~P(=0)(OH)(SH)₂,

~P(=S)(SH)(OH)₂, ~P(=S)(OH)(SH)₂, or ~P(=S)(SH)₃) group. In yet a further embodiment, the acidic moiety contains a S(=0), sulfuric acid (~S(=0)₂(OH)0~), sulfonic acid (~S(=0)₂(OH)), or sulfinic acid (~S(=0)(OH)) group.

The acidic moiety is desirably bound directly or indirectly to a heteroatom- containing moiety. The heteroatom-containing moiety contains at least one heteroatom. In one embodiment, the acidic moiety is bound directly to the heteroatom. In another embodiment, the acidic moiety is bound indirectly to the heteroatom through a hydrocarbon chain which is optionally unsaturated and optionally contains one or more additional heteroatom. In a further embodiment, the acidic moiety is bound indirectly to the heteroatom through a cyclic hydrocarbon which is optionally unsaturated and optionally contains one or more additional heteroatom. The heteroatom present in the compounds useful herein may be selected by one skilled in the art and may include, O (~OH, (=0), or ~0~), S (~SH, (=S) or ~S~), or N atoms, among others. The N-atom may be a primary amine (~NH₂), secondary amine (~NH~), tertiary amine (~N~), or may be doubly bound to another moiety such as a carbon atom. One of skill in the art would readily understand that the use of - in the above-noted description indicates that the atom to which it is attached is bound to another chemical moiety. Compound (I)

In one embodiment, the compound may contain a phosphorus atom in the backbone such as in a moiety of structure (I):

X'

vwX" (CR^UCR^V)_G(CR^U'CR^V')_G. P (CR^XR^Y)_N(CR^X'CR^Y')_N. ΧΛΛΛ

(OH)_D

(I)

wherein,

g, g', n and n' are, independently, 0 to 10, i.e., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; d is 0, 1, or 2;

X and X" are, independently, (i) absent, (ii) O, S, N, or P; or (iii) a ring containing one or more of O, S, N, or P;

X' is O or S;

R^u, R^v, R^u', R^v', R^x, R^Y, R^x', and R^Y' are, independently, H, OH, halogen, C₃ to Cio cycloalkyl, Ci to Cio thioalkyl, aryl, heteroaryl, heterocycle, SO2H, OP(0)OH, P(0)OH, Ci to Cio alkyl substituted at one or more carbon-atom by R^A, C2 to Cio alkenyl substituted at one or more carbon-atom by R^A, or C2 to Cio alkynyl substituted at one or more carbon-atom by R^A; or

R^u and R^v, R^u' and R^v', R^x and R^Y or R^x' and R^Y' are joined to form a ring containing C3 to Cio cycloalkyl, aryl, heterocycle, or heteroaryl, wherein the ring is optionally substituted by one or more R^A; and

R^A is H, Ci to Cio alkyl, Ci to Cio alkoxy, (=0), (=S), halogen, C(0)(Ci to Cio alkyl), aryl, heteroaryl, heterocycle, OH, C(0)OH, S0₂H, OP(0)OH, P(0)OH, P(0)(OCi to Cio alkyl)₂, Ci to C₁₀ aminoalkyl, Ci to Cio thioalkyl, or SH.

In a further embodiment, the compound may contain a ring having at least one phosphorus and one oxygen-atom in the backbone of the ring. In one example, the compound may contain a ring having one phosphorus and two oxygen-atoms in the backbone of the ring. In another example, the compound may contain a ring having one phosphorus, one oxygen, and one nitrogen-atom in the backbone of the ring. In a further example, the phosphorus atom forms the backbone of two rings and is the point of attachment for the two rings. The phosphorus atoms may be substituted with one or more of OH, Ci to Cio alkoxy, or Ci to Cio alkyl. The nitrogen-atoms may be substituted with one or more of OH, Ci to C₁₀ alkoxy, or Ci to C₁₀ alkyl, may be part of a five to fourteen membered heterocyclic or heteroaryl ring, or may be bound to another nitrogen-atom of the compound. These rings may be optionally substituted with Ci to Cio alkyl, among other substituents.

In another embodiment, the compound may contain a sulfur atom in the backbone such as a moiety of structure (IA):

(IA)

wherein: M is O or N; k and k' are, independently, 0 to 10, i.e. , 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R^D, R^E, R^D', and R^E' are, independently, H, OH, halogen, C₃ to C₁₀ cycloalkyl, Ci to C₁₀ thioalkyl, aryl, heteroaryl, heterocycle, SO2H, OP(0)OH,

P(0)OH, Ci to Cio alkyl substituted at one or more carbon-atom by R^A, C2 to C₁₀ alkenyl substituted at one or more carbon-atom by R^A, or C2 to Cio alkynyl substituted at one or more carbon-atom by R^A; or R^D and R^E or R^D and R^E are joined to form a ring containing C3 to Cio cycloalkyl, aryl, heterocycle, or heteroaryl, wherein the ring is optionally substituted by one or more R^A; or one carbon atom of CR^D, CR^E, CR^D , or CR^E is bound to the SO2 to form a C₃ to Cio cycloalkyl or aryl optionally substituted by one or more R^A; and R^A is H, Ci to Cio alkyl, Ci to Cio alkoxy, (=0),

(=S), halogen, C(0)(Ci to Cio alkyl), aryl, heteroaryl, heterocycle, OH, C(0)OH, OS0₂, S0₂H, OP(0)OH, P(0)OH, P(0)(OCi to Cio alkyl)₂, d to Cio aminoalkyl, Ci to Cio thioalkyl, or SH; or a pharmaceutically acceptable salt or prodrug thereof.

In still a further embodiment, the compound may contain a carboxylic acid

(C(=0)OH) group in the backbone such as a moiety of structure (IA):

o

HO C (CR^KR^L)_S(CR^K'R^L")_S. >A w

(IB)

wherein, s and s' are, independently, 0 to 10, i.e., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R^K, R^L, R^K', and R^L' are, independently, H, OH, halogen, C₃ to Cio cycloalkyl, Ci to Cio thioalkyl, aryl, heteroaryl, heterocycle, S0₂H, OP(0)OH, P(0)OH, Ci to Cio alkyl substituted at one or more carbon-atom by R^A, C2 to Cio alkenyl substituted at one or more carbon-atom by R^A, or C2 to C₁₀ alkynyl substituted at one or more carbon-atom by R^A; or R^K and R^L or R^K and R^L are joined to form a ring containing C3 to C₁₀ cycloalkyl, aryl, heterocycle, or heteroaryl, wherein the ring is optionally substituted by one or more R^A; or R^A is H, Ci to C₁₀ alkyl, Ci to C₁₀ alkoxy, CN, (=0), (=S), halogen, C(0)(Ci to C₁₀ alkyl), aryl, heteroaryl, heterocycle, OH, C(0)OH, OS0₂, S0₂H, OP(0)OH, P(0)OH, P(0)(OCi to C₁₀ alkyl)₂, d to C₁₀ aminoalkyl, Ci to C₁₀ thioalkyl, or SH; or a pharmaceutically acceptable salt or prodrug thereof.

Alternatively, the compound contains an anhydride group to form a moiety of structure (IC):

(IC)

wherein, R^K, R^L, and R^P are, independently, H, C₃ to C₁₀ cycloalkyl, Ci to C₁₀ thioalkyl, aryl, heteroaryl, heterocycle, Ci to C₁₀ alkyl substituted at one or more carbon-atom by R^A, C2 to C₁₀ alkenyl substituted at one or more carbon-atom by R^A, or C2 to Cio alkynyl substituted at one or more carbon-atom by R^A; or R^K and R^L, R^K and R^p, or R^L and R^p are joined to form a ring containing C₃ to C₁₀ cycloalkyl, aryl, heterocycle, or heteroaryl, wherein the ring is optionally substituted by one or more R^A; wherein at one of R^K, R^L, or R^p contains a heteroatom as described above; and R^A is H, Ci to Cio alkyl, Ci to C₁₀ alkoxy, CN, (=0), (=S), halogen, C(0)(Ci to C₁₀ alkyl), aryl, heteroaryl, heterocycle, OH, C(0)OH, OS0₂, S0₂H, OP(0)OH, P(0)OH, P(0)(OCi to Cio alkyl)₂, Ci to Cio aminoalkyl, Ci to Cio thioalkyl, or SH; or a pharmaceutically acceptable salt or prodrug thereof.

Compound (II)

In another embodiment, the compound has structure (II):

(II)

wherein, n is 0 to 5, i.e., 0, 1, 2, 3, 4, or 5; R¹ and R² are, independently, H, Ci to Cio alkyl, C(0)(Ci to Cio alkyl), C(0)(d to Cio alkyl), benzyl, C₃ to Cio cycloalkyl, C₂ to Cio alkenyl, or C2 to C₁₀ alkynyl; or R¹ and R² together comprise a heterocycle or heteroaryl, optionally substituted by one or more R⁵; R³ and R⁴ are, independently, H, OH, Ci to Cio alkyl, C3 to Cio cycloalkyl, benzyl, aryl, heteroaryl, or heterocycle; or R¹ and R³ together comprise a heterocycle or heteroaryl, each optionally substituted by one or more R⁵; R⁵ is Ci to Cio alkyl, Ci to Cio alkoxy, halogen, OH, C2 to Cio alkenyl, C2 to Cio alkynyl, C₃ to Cio cycloalkyl, aryl, or (=0); or a pharmaceutically acceptable salt or prodrug thereof.

In a further embodiment, the compound has structure (Ila), wherein R² is H, Ci to Cio alkyl, C₃ to Cio cycloalkyl, C2 to Cio alkenyl, or C2 to Cio alkynyl:

HO N— R²

(Ila)

In still another embodiment, the compound is selected from among:

pharmaceutically acceptable salts or prodrugs thereof.

In yet a further embodiment, the compound is selected from among:

, or pharmaceutically acceptable salts or prodrugs thereof

Compound (III)

The compounds described herein may also have structure (III)

OR¹⁶

I

0^^P (CR¹⁷R¹⁸)_q-R¹⁰

(III) wherein, q is 0 to 5, i.e., 0, 1, 2, 3, 4, or 5; R is Ci to C₁₀ alkyl. heteroaryl or aryl, each optionally substituted by one or more R¹⁹; R¹⁶ is H or Ci to C₁₀ alkyl; R¹⁷ and R¹⁸ are, independently, absent, H, Ci to C₁₀ alkyl, (Ci to C₁₀ alkyl)-P-(C₁ to C₁₀ alkyl), Ci to C₁₀ alkoxy, halogen, OH, N0₂, CN, C₂ to C₁₀ alkenyl, P(0)OH, C₂ to C₁₀ alkynyl, aryl, heteroaryl, or heterocycle, each optionally substituted by one or more

R 19 ; wherein when R 17 or R18 is absent and q is at least 2, the CR 17 R18 groups are bound through a stable double bond; R¹⁹ is H, Ci to C₁₀ alkyl, Ci to C₁₀ alkoxy, halogen, N0₂, CN, C(0)OH, C(0)(Ci to C₁₀ alkyl), C₂ to C₁₀ alkenyl, or C₂ to C₁₀ alkynyl; or a pharmaceutically acceptable salt or prodrug thereof.

In a further embodiment, the R¹⁰ or R¹¹ heterocycle is a five or six membered heterocycle and contains one O or S heteroatom.

In a further embodiment, the compound has structure (Ilia):

(Ilia)

wherein, each R is, independently, H, Ci to C₁₀ alkyl, Ci to C₁₀ alkoxy, halogen,

N0₂, CN, C(0)OH, C(0)(Ci to C₁₀ alkyl), C₂ to C₁₀ alkenyl, or C₂ to C₁₀ alkynyl; R¹⁴ and R¹⁵ are, independently, H, Ci to C₁₀ alkyl, C3 to C₁₀ cycloalkyl, C₂ to C₁₀ alkenyl, C₂ to Cio alkynyl, benzyl, aryl, heteroaryl, or heterocycle; R¹⁶ is H or Ci to C₁₀ alkyl; R¹⁷ and R¹⁸ are, independently, absent, H, Ci to C₁₀ alkyl, Ci to C₁₀ alkoxy, halogen, OH, N0₂, CN, C₂ to Cio alkenyl, P(0)OH, C₂ to C₁₀ alkynyl, aryl, heteroaryl, or heterocycle; wherein when R¹⁷ or R¹⁸ is absent and q is at least 2, the CR¹⁷R¹⁸ groups are bound through a stable double bond; or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment, R¹⁰ is a pyrrolidine and contains a (=0) in the backbone of said pyrrolidine.

In yet another embodiment, the compound has structure (Illb), wherein s is 1 to 10:

(nib)

In still another embodiment, R¹⁰ is pyridine.

In another embodiment, the compound has structure (IIIc):

(IIIIc)

In a further embodiment t,, tthhee ccooimpound has structure (Hid), wherein R is aryl, heterocycle, or heteroaryl.

In another embodiment, the compound is of structure (Hid) and R¹⁰ and R¹¹ are furan.

In a further embodiment, the compound has structure (Hie):

(me)

In yet another embodiment, the compound is selected from among:

or pharmaceutically acceptable salts or prodrugs thereof.

The compound may further have structure (Illf):

(Illf) wherein, r is 1 to 3, i.e., 1, 2, or 3; X is O, S, or NR³⁰; R³⁰ is H or Ci to C₁₀ alkyl; R³¹ and R³² are, independently, H, Ci to Cio alkyl, C3 to C1₀ cycloalkyl, C2 to C1₀ alkenyl, or C2 to Cio alkynyl, benzyl, aryl, heteroaryl, or heterocycle; or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment, the comp has structure (Illg), wherein r is 1 to 3 :

or a pharmaceutically acceptable salt or prodrug thereof.

In still another embodiment the compound is selected from among:

, or pharmaceutically acceptable salts or prodrugs thereof. Compound (IV)

The compounds useful herein may further have structure (IV):

(IV)

wherein, m is 0 to 2, i.e., 0, 1, or 2; R²⁰ is H, Ci to C₁₀ alkyl C3 to C₁₀ cycloalkyl, C2 to Cio alkenyl, or C2 to C₁₀ alkynyl, each optionally substituted by one or more R²⁴:

0 00 o~x

R , R , and R" are independently, H, Ci to Cio alkyl, or C₃ to Cio cycloalkyl, each optionally substituted by one or more R²⁴; R²⁴ is H, halogen, OH, CN, N0₂, d to Cio alkyl C3 to Cio cycloalkyl, C2 to Cio alkenyl, or C2 to Cio alkynyl, each optionally substituted by one or more R²⁷; R²⁵ is H, Ci to Cio alkyl C₃ to Cio cycloalkyl, C2 to Cio alkenyl, or C₂ to Cio alkynyl; R²⁶ is O or S; R²⁷ is H, P(0)OH, or Ci to Cio alkyl optionally substituted by halogen or OP(0)OH; or a pharmaceutically acceptable salt or prodrug thereof.

0 00 o~x

In one embodiment, the compound is of structure (IV) and R , R , and R are Ci to Ce alkyl.

In another embodiment, the compound has structure (IVa):

(IVa)

In another embodiment, the compound is:

acceptable salts Compound (V)

Also provided are compounds of structure (V):

O II

_R41' ^P^_R40

(V)

wherein, R⁴⁰ and R⁴¹ are, independently, H, Ci to Cio alkyl optionally substituted by one or more R⁴², aryl optionally substituted by one or more R⁴², or benzyl optionally substituted by one or more R⁴²; R⁴² is H, Ci to Cio alkyl, C(0)OH, NH₂, C(0)(Ci to Cio alkyl), C(0)0(Ci to Cio alkyl), Ci to Cio aminoalkyl, halogen, aryl, or heteroaryl or a pharmaceutically acceptable salt or prodrug thereof.

/ or pharmaceutically acceptable salts or prodrugs thereof.

Compound (VI)

The compound may alternatively have structure (VI):

OR⁵¹

0=P— OR⁵⁰

I

_R52

(VI)

wherein, R is i aarryyll,, hheetteerrooaarryyll,, oorr hheetteerrcocycle, each optionally substituted by one or more R⁵³; R⁵¹ is H, Ci to Cio alkyl, Ci to Cio aminoalkyl, each optionally substituted by halogen or C(0)OH; R⁵² is absent, Ci to Cio alkyl optionally substituted by P(0)2, or aryl optionally substituted by 0(Ci to Cio alkyl)-phenyl-C(0)OH; R⁵³ is Ci to Cio alkyl, halogen, or C(0)OH; or a pharmaceutically acceptable salt or prodrug thereof. In one embodiment, R⁵⁰ is heteroaryl or heterocycle.

In one embodiment the aryl of R⁵⁰ contains 5 to 8 carbon atoms, each carbon atom of R⁵⁰ contains one R⁵¹ substituent, at least one carbon atom contains a

C(=0)OH substituent, and R⁵¹ is H or Ci to C₆ alkyl.

In a further embodiment, R⁵⁰ is a benzene ring.

ompound is selected from among:

or pharmaceutically acceptable salts or prodrugs thereof.

Compound (VII)

The compound may further have structure (VII):

P— (CR⁶⁵R⁶⁶)_tR⁶⁰R⁶¹

HO

(VII)

wherein, t is 1 to 10, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R⁶⁰ is aryl, heteroaryl, or heterocycle; R⁶¹ is Ci to C₁₀ aminoalkyl, Ci to C₁₀ alkyl, C2 to C₁₀ alkenyl, C2 to C₁₀ alkynyl, C3 to C₁₀ cycloalkyl, aryl, heteroaryl, or heterocycle; R⁶⁵ and R⁶⁶ are, independently, H, OH, Ci to C₁₀ alkyl, C3 to C₁₀ cycloalkyl, C2 to C₁₀ alkenyl, C2 to Cio alkynyl benzyl, aryl, heteroaryl, or heterocycle; or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment, R⁶¹ is optionally substituted at one or more carbon atom by 0-2 R⁶³, R⁶³ is Ci to C₁₀ alkyl or phenyl substituted by 0-5 R⁶⁴, and R⁶⁴ is Ci to C₁₀ alkyl.

In a further embodiment, R is phenyl.

In another embodiment, the phenyl of R is substituted by 0-5 R and R 1 to Cio alkyl, C3 to C₁₀ cycloalkyl, Ci to C₁₀ alkoxy, or Ci to C₁₀ thioalkyl.

In still a further embodiment, R⁶³ is phenyl. Compound (VIII)

contemplated as useful antagonists are compounds of structure (VIII):

(VIII)

wherein, R , R , R , and R are, independently, H, Ci to Cio alkyl, C₂ to Cio alkenyl, Ci to Cio aminoalkyl, C(0)(Ci to Cio aminoalkyl), or heteroaryl, each optionally substituted by one or more R⁷⁸;R⁷² is H, Ci to Cio alkyl, 0(Ci to Cio alkyl), 0(Ci to Cio alkoxy), 0(Ci to Cio aminoalkyl), Ci to Cio aminoalkyl, or heteroaryl, each optionally substituted by one or more R⁷⁶; R⁷³ is Ci to Cio alkyl, Ci to Cio alkoxy, Ci to Cio aminoalkyl, each optionally substituted by one or more R⁷⁶; R⁷⁶ is C(0)OH, C(0)(Ci to Cio alkyl), NHC(0)(Ci to Cio alkyl), C(0)NH(phenyl optionally substituted by one or more R⁷⁷), C(0)0(Ci to Cio alkyl), heteroaryl optionally substituted by one or more R⁷⁷, heterocycle optionally substituted by one or more R⁷⁷, or phenyl optionally substituted by one or more R⁷⁷; R⁷⁷ is halogen, Ci to Cio aminoalkyl, Ci to Cio alkoxy, Ci to Cio alkyl, or C₂ to Cio alkenyl, each optionally substituted by one or more R⁷⁸; R⁷⁸ is CN, C(0)OH, C(0)(Ci to Cio alkyl), C(0)0(Ci to Cio alkyl), C(S)S(Ci to Cio alkyl)C(0)OH, or phenyl optionally substituted by one or more R⁷⁹; R⁷⁹ is OH, Ci to Cio alkyl, C₃ to Cio cycloalkyl, C₂ to C₁₀ alkenyl, C₂ to Cio alkynyl, halogen, or Ci to e alkoxy; or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment, R⁷⁰ to R⁷⁴ is halogen.

In another embodiment, the compound is selected from among:

, or pharmaceutically acceptable salts or prodrugs thereof.

Compound (IX)

The compounds may also have structure (IX):

(IX)

wherein, w is 1 to 10, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

w' is 1 to 10, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R⁸⁰ is H or Ci to C₁₀ alkyl; R⁸¹ to R⁸⁵ are, independently, H, OH, Ci to Cio alkyl, halogen, or Ci to Cio alkoxy; and R⁸⁶ to R⁸⁹ are, independently, H, Ci to Cio alkyl, or C3 to Cio cycloalkyl; or a

pharmaceutically acceptable salt or prodrug thereof. In one embodiment, R⁸⁰ is H or C₂ to Cio alkyl.

In one embodiment, the compound has structure (IXa) wherein R⁸⁰ to R⁸¹ are defined above:

(IXa)

In a further embodiment, R⁸¹ to R⁸⁵ in either compound (IX) or (IXa) is Ci to Ce alkoxy.

In another embodiment, two of R⁸¹ to R⁸⁵ in either compound (IX) or (IXa) is

Ci to Ce alkoxy. In a further embodiment, Ci to Ce alkoxy in R to R is OCH₃.

In yet another embodiment, the compound has structure (IXb), wherein R⁸⁰ is defined above:

(IXb)

Compound (X)

The antagonists useful herein may further be a compound of structure (X)

(X)

wherein, x is 1 to 10, i.e. , 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or a pharmaceutically acceptable salt or prodrug thereof. In one embodiment, x is 2 to 10.

In one embodiment, the compound is 2-amino-3-sulfino-propanoic acid:

In one embodiment, the compound is (S)-2-amino-3-sulfino-propanoic acid, or a pharmaceutically acceptable salt or prodrug thereof:

O

HO s

= II

NH₂ O

Compound (XI)

The compound may fu

(XI)

wherein, y is 1 to 10, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R⁹⁰ to R⁹⁴ are, independently, H, halogen, Ci to Cio alkyl, C2 to Cio alkenyl, C2 to Cio alkynyl, OH, or Ci to Cio aminoalkyl; and R⁹⁵ is heterocycle, heteroaryl, aryl, or Ci to Cio aminoalkyl; or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment, R⁹⁵ is a five or six membered heterocycle containing one O, S, or NR⁹² heteroatom and the carbon atoms of said heteroaryl are substituted by H or Ci to Ce alkyl.

In another embodiment, the compound has structure (XIa), wherein R⁹⁰, R⁹⁵, and y are defined above:

(XIa)

In a further embodiment, y in either structure (XI) or (XIa) is 2.

In still another embodiment, R⁹⁵ in either structure (XI or (XIa) is pyrrolidine.

Compound (XII)

The compound may further have structure (XII):

(XII)

wherein, R¹⁰⁵ is aryl, heteroaryl, or heterocycle; z is 1 to 10, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R¹⁰⁶ to R¹¹⁰ are, independently, H, Ci to Cio alkyl, C₃ to Cio cycloalkyl, OH, C2 to Cio alkenyl, or C2 to Cio alkynyl; or a pharmaceutically acceptable salt or prodrug thereof. In one embodiment, z is 2 to 10.

In a further embodiment, the compound has structure (Xlla):

(Xlla)

wherein, R¹⁰⁵ is aryl, heteroaryl, or heterocycle; z is 1 to 10, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R¹⁰⁶ to R¹¹⁰ are, independently, H, Ci to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, OH, C2 to Cio alkenyl, or C2 to C₁₀ alkynyl; or a pharmaceutically acceptable salt or prodrug thereof.

In yet another embodiment, the compound has structure (Xllb):

wherein, R¹⁰⁰ to R¹⁰⁴ are, independently, H, Ci to Ce alkyl, halogen, or Ci to alkoxy and R¹⁰⁵, R¹⁰⁶, and z are defined above.

In still a further embodiment, the compound has structure (XIIc):

(Xllb)

wherein, R¹⁰⁰ to R¹⁰⁴ are, independently, H, Ci to Ce alkyl, halogen, or Ci to Ce alkoxy and R¹⁰⁵, R¹⁰⁶, and z are defined above. In a further embodiment, R in either structure (XII) or (Xlla) is H.

In another embodiment, z is 1 in either structure (XII) or (Xlla).

In still a further embodiment, at least one of R¹⁰⁰ to R¹⁰⁴ in either structure (XII) or (Xlla) is Ci to C₆ alkyl.

In yet another embodiment, R¹⁰⁰ or R¹⁰⁴ in either structure (XII) or (Xlla) is

CH₃.

In a further embodiment, the compound is the following, or a

pharmaceutically acceptable salt or prodrug thereof such as a propionate salt:

In still another embodiment, the compound is the following, or a pharmaceutically acceptable salt or prodrug thereof:

Compound (XIII)

Also provided are compounds of structure (XIII):

(XIII)

wherein, a is 0 or 1; R¹²⁰ is absent, aryl, C3 to C1₀ cycloalkyl, heteroaryl, or heterocycle, each optionally substituted by one or more R¹²⁵; R¹²¹ is aryl containing one or more R , Ci to C₁₀ aminoalkyl optionally containing one or two aryl groups optionally substituted by one or more R¹²⁴, heterocycle optionally substituted by one or more R¹²⁵; R¹²³ is H, halogen, Ci to C₁₀ alkyl, or Ci to C₁₀ alkoxy; R¹²⁴ is H, halogen, Ci to C₁₀ alkyl, Ci to C₁₀ alkoxy, or Ci to C₁₀ aminoalkyl; R¹²⁵ is H, halogen, Ci to Cio alkyl, Ci to C₁₀ alkoxy, (=0), or C(0)OH; or R¹²⁰ and R¹²¹ join to form C₅ to Cio cycloalkyl optionally substituted by one or more R¹²⁶; and R¹²⁶ is H, halo gen, Ci to Cio alkyl, Ci to Cio alkoxy, or Ci to Cio aminoalkyl; or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment, the compounds have structure (Xllla), wherein R is a heterocycle having one SO₂ in the heterocycle backbone:

O

₀ S-0R"¹

(Xllla)

In another embodiment, the compound is selected from

or pharmaceutically acceptable salts or prodrugs thereof.

Compound (XIV)

Also provided as useful antagonistic compounds are those of structure (XIV):

(XIV)

wherein, R²⁰¹ is Ci to C₁₀ alkyl, Ci to C₁₀ aminoalkyl, C₂ to C₁₀ alkenyl, or C₂ to C₁₀

202 202

alkynyl, each optionally substituted by one or more R^{^}; R^{^} is H, CI to C₁₀ alkyl, halogen, CN, or N0₂; R²⁰⁰ is Ci to C₁₀ alkyl, Ci to C₁₀ alkoxy, aryl, C₂ to C₁₀ alkenyl,

203 203

Ci to Cio aminoalkyl, each optionally substituted by one or more R ; R is halogen, CN, NO₂, Ci to Cio alkoxy, or aryl optionally substituted by one or more R²⁰⁴; R²⁰⁴ is Ci to Cio alkyl, Ci to Cio alkoxy, halogen, CN, NO₂, or aryl; or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment, R²⁰¹ is Ci to Cio aminoalkyl.

In another embodiment, R²⁰¹ is CH₂CH₂NH₂.

In a further embodiment, R²⁰⁰ is Ci to Cio alkyl optionally substituted by one

203 203

or more R and R is Ci to Cio alkyl, Ci to Cio alkoxy, or halogen.

In still another embodiment, R²⁰³ is 1, 2, or 3-tolyl, 1, 2, or 3-methoxyphenyl, or 1, 2, or 3-halogenated phenyl.

In a further embodiment, R²⁰⁰ is C₂ to Cio alkenyl optionally substituted by

203 203

one or more R and R is Ci to Cio alkyl, Ci to Cio alkoxy, or halogen.

In still another embodiment, the compound is selected from among:

; or pharmaceutically acceptable salts or prodrugs thereof.

Compound (XV)

The compounds having structure (XV) are also useful as described herein:

(XV)

wherein, R is Ci to C₁₀ alkyl, Ci to C₁₀ aminoalkyl, C₂ to C₁₀ alkenyl, or C₂ to C₁₀

302 302

alkynyl, each optionally substituted by one or more R^JUZ; R^Juz is H, CI to C₁₀ alkyl, halogen, CN, or N0₂; R³⁰⁰ is Ci to C₁₀ alkyl, Ci to C₁₀ alkoxy, aryl, C₂ to C₁₀ alkenyl, Ci to Cio aminoalkyl, each optionally substituted by one or more R ; R is halogen,

_R304. _R304 _{ig C i tQ C io dkylj} CN, NO₂, or aryl optionally substituted by one or more

Ci to Cio alkoxy, halogen, CN, NO2, or aryl; or a pharmaceutically acceptable salt or prodrug thereof.

In a further embodiment, R³⁰¹ is Ci to Cio aminoalkyl.

In another embodiment, R is CH₂CH₂NH₂.

In a further embodiment, R³⁰⁰ is phenyl.

In still another embodiment, R³⁰³ is Ci to Cio alkyl or halogen.

In yet a further embodiment, the compound is selected from among:

or pharmaceutically acceptable salts or prodrugs thereof Compound (XVI)

Further provided are the compounds having structure (XVI) for use as described herein:

(XVI)

wherein, R⁴⁰⁰ is OH or O; R⁴⁰¹, R⁴⁰², and R⁴⁰³, are independently, OR⁴⁰⁵ or

_N(R406_)(R407_);

R⁴⁰⁴ is H, Ci to Cio alkyl, halogen, (=0), or Ci to Cio alkoxy; R⁴⁰⁵ is absent, Ci to Cio alkyl, heterocycle, aryl, or heteroaryl, optionally substituted by one or more R⁴⁰⁶; R⁴⁰⁶ is H, Ci to Cio alkyl, halogen, Ci to Cio alkoxy, C(0)(Ci to Cio alkyl), aryl, heteroaryl, C(0)(aryl optionally substituted by one or more R⁴⁰⁴; R⁴⁰⁷ is absent, H, Ci to Cio alkyl, halogen, Ci to Cio alkoxy, aryl, or heteroaryl; with the proviso that when R⁴⁰⁰ is O and R⁴⁰⁵ or R⁴⁰⁷ is absent, then R⁴⁰⁰ and R⁴⁰² join to form a 5 to 8-membered ring, wherein the 5 to 8-membered ring contains carbon atoms and optionally one or more heteroatom and wherein the 5 to 8-membered ring is optionally substituted by one or more R⁴⁰⁴; and with the proviso that when R⁴⁰¹ is OR⁴⁰⁵ and R⁴⁰³ is

N(R⁴⁰⁶)(R⁴⁰⁷) and R⁴⁰⁵ and R⁴⁰⁷ are absent, R⁴⁰¹ and R⁴⁰², and/or R⁴⁰¹ and R⁴⁰³, and/or R⁴⁰² and R⁴⁰³ join to form a 5 to 8-membered ring, wherein the 5 to 8- membered ring contains carbon atoms and optionally one or more heteroatom and wherein the 5 to 8- membered ring is optionally substituted by one or more R⁴⁰⁴; or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment, the compound is selected from among:

NH

or pharmaceutically acceptable salts or prodrugs thereof.

Compounds (XVII)

Also provided for use as described herein are compounds having structure (XVII):

(XVII)

wherein, R is Ci to C₁₀ aminoalkyl, R is benzyl optionally substituted by one or more R⁵⁰³; R⁵⁰¹ is H, Ci to C₁₀ alkyl, C3 to C₁₀ cycloalkyl, Ci to C₁₀ alkoxy, or aryl; f is 0 to 4, i.e., 0, 1, 2, 3, or 4; and R⁵⁰³ is H, Ci to C₁₀ alkyl, Ci to C₁₀ alkoxy, halogen, or aryl; or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment, the compound is the following or a pharmaceutically acceptable salt or prodrug thereof:

Compounds (XVIII)

Also provided as antagonistic compounds are those having structure (XVIII):

(XVIII) wherein, R is H, OH, Ci to C₁₀ alkyl, Ci to C₁₀ alkoxy, or C3 to C₁₀ cycloalkyl; R to R⁵¹⁰ are, independently, H, Ci to C₁₀ alkyl, Ci to C₁₀ alkoxy, C3 to C₁₀ cycloalkyl, or halogen; or a pharmaceutically acceptable salt or prodrug thereof.

Compounds (XIX)

Additional compounds useful as antagonistic compounds include those of structure (XIX):

(XIX)

wherein, R^bUU is Ci to C₁₀ alkyl, NH₂ or Ci to C₁₀ aminoalkyl; R^bVZ to R are, independently, Ci to C₁₀ alkyl, C3 to C₁₀ cycloalkyl, Ci to C₁₀ alkoxy, or halogen; or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment, the compound is the following or a pharmaceutically acceptable salt or prodrug the

Compounds (XX)

Further provided are compounds of structure (XX):

(XX)

wherein, R⁶⁰⁶ is H or Ci to C₁₀ alkyl; R⁶⁰⁷ to R⁶¹⁰ are, independently, H, Ci to C₁₀ alkyl, Ci to C₁₀ alkoxy, or halogen; or a pharmaceutically acceptable salt or prodrug thereof.

Compounds (XXI)

Additional compounds useful as antagonistic compounds include those of structure (XXI):

(XXI)

wherein, R ^uu to R are, independently, H, Ci to C₁₀ alkyl, C3 to CIO cycloalkyl, C₃ to Cio spirocycloalkyl, Ci to C₁₀ alkoxy, halogen, Ci to C₁₀ aminoalkyl, or CN and R⁷⁰⁵ is H or Ci to C₁₀ alkyl; or a pharmaceutically acceptable salt or prodrug thereof.

Compounds (XXII)

Also provided are comp II):

(XXII)

wherein, R⁸⁰⁰ to R⁸⁰⁴ and R⁸⁰⁶ and R⁸⁰⁹ are, independently, H, Ci to C₁₀ alkyl, halogen, NH₂, or Ci to C₁₀ alkoxy and R⁸⁰⁵ is H or Ci to C₁₀ alkyl; or a pharmaceutically acceptable salt or prodrug thereof.

Compounds (XXIII)

Further provided are compounds of structure (XVI) for use as described herein:

(XXIII) wherein, R ^UU is H or Ci to C₁₀ alkyl and R ^U1 to R is H, Ci to C₁₀ alkyl, C₂ to C₁₀ alkenyl, C2 to C₁₀ alkynyl, halogen, Ci to C₁₀ alkoxy, Ci to C₁₀ aminoalkyl, or NH₂; or a pharmaceutically acceptable salt or prodrug thereof.

Compounds XXIV

Also provided are compounds of structure (XXIV):

(XXIV)

wherein, R⁹⁰⁶ and R⁹⁰⁷ are, independently, Ci to C₁₀ alkyl or Ci to C₁₀ alkoxy; e is 0 to 5, i.e., 0, 1, 2, 3, 4, or 5; and R⁹⁰⁸ is H, halogen, Ci to C₁₀ alkyl, Ci to C₁₀ alkoxy, OH, CN, or NH₂; R⁹⁰⁹ is H or Ci to C₁₀ alkyl; or a pharmaceutically acceptable salt or prodrug thereof. In one embodiment, R⁹⁰⁷ is C2 to C₁₀ alkyl. In another embodiment, R⁹⁰⁹ is H. In a further embodiment, R⁹⁰⁹ is Ci to C₁₀ alkoxy. In yet another embodiment, R⁹⁰⁹ is ethoxy.

Compendium of Compounds

The following compounds may be utilized as PF4 antagonistic compounds 2-acetyl-3 -hydroxy-5-nitro-inden- 1 -one;

N-(hydroxy-dimethoxy-phosphoranyl)pyrrolidine- 1 -carboxamide;

N-(hydroxy-diisobutoxy-phosphoranyl)-5-methyl-pyridin-2-amine;

3 -(hydroxyphosphonoylmethyl)butanedioic acid;

[4-(hydroxyphosphonoyloxymethyl)cyclohexyl]methoxyphosphinic acid; 2-(2-hydroxyphosphonoylethyl-phenyl-phosphanyl)ethylphosphinic acid;

1- chloro-2-(2-chloroethyoxyphosphonoyloxy)ethane;

4-(4-dimethylaminophenyl)phosphonoyl-N,N-dimethyl-aniline;

2,3 -bis(methoxycarbonyl)propylphosphinic acid;

(2-hydroxyphosphonoyl-2-phenyl-ethyl)phosphinic acid;

1 -ethoxyphosphonoylbutane;

2- diethoxyphosphorylethylphosphinic acid;

2- hydroxyphosphonoylindane- 1 -carboxylic acid;

(l S,2S)-2-hydroxyphosphonoylindane-l-carboxylic acid;

(lR,2R)-2-hydroxyphosphonoylindane-l -carboxylic acid;

(l S,2R)-2-hydroxyphosphonoylindane-l-carboxylic acid;

(lR,2S)-2-hydroxyphosphonoylindane-l-carboxylic acid;

p-tolylphosphinic acid;

3- phenyl-4-sulfinooxy-thiolane- 1 , 1 -dioxide;

(3 S,4R)-3 -phenyl-4-sulfinooxy-thiolane- 1 , 1 -dioxide;

(3 R,4S)-3 -phenyl-4-sulfinooxy-thiolane- 1 , 1 -dioxide;

(3 S,4S)-3 -phenyl-4-sulfinooxy-thiolane- 1 , 1 -dioxide;

(3 S,4R)-3 -phenyl-4-sulfinooxy-thiolane- 1 , 1 -dioxide;

[hydroxy-(3-pyridyl)methyl]phosphinic acid;

styrylphosphinic acid;

2-(2-furyl)ethylphosphinic acid;

l-benzylphosphonoyl-4-phenyl-benzene;

l-hydroxy-3-phenyl-prop-2-enyl]phosphinic acid;

[(E, lR)-l-hydroxy-3-phenyl-prop-2-enyl]phosphinic acid;

[(Z, 1 R)- 1 -hydroxy-3 -phenyl-prop-2-enyl]phosphinic acid; [(E, 1S)-1 -hydroxy-3 -phenyl-prop-2-enyl]phosphinic acid;

[(Z, 1 S)- 1 -hydroxy-3 -phenyl-prop-2-enyl]phosphinic acid

benzylphosphonic acid;

2-chloroethylphosphonoylbenzene;

(2,4-dimethoxyphenyl)phosphinic acid;

2-chloroethoxyphosphonoyloxybenzene;

2-butoxyphosphonoyl-2-methyl-propane;

1 -(2-phenylacetyl)aminoethylphosphinic acid;

a compound having the following structure:

1 -butylphosphonoylbutane;

( 1 -benzhydrylamino-3 -methyl-butyl)phosphinic

phenoxyphosphinic acid;

1 ,4-dichloro-2-sulfino-benzene;

styrylphosphinic acid;

diethoxy-thioxo-phosphorane;

(3 -chloro-4-methyl-phenyl)phosphinic acid;

2-carbazol-9-ylethylphosphinic acid;

a compound having the following structure:

[4-[2-(2-chlorophenoxy)ethoxy]-3-methoxy-phenyl]methanamine; 2-[4-(2-diethylaminoethoxy)phenyl]thiazole-4-carboxylic acid;

N-(bis(dimethylamino)-hydroxy-phosphoranyl)-4-chloro-benzamide; 1 -ethoxyphosphonoylbutane;

2-cyano-3-[4-(2-diethylaminoethoxy)-3-methoxy-phenyl]prop-2-enoic (E)-2-cyano-3-[4-(2-diethylaminoethoxy)-3-methoxy-phenyl]prop-2-enoic acid;

(Z)-2-cyano-3-[4-(2-diethylaminoethoxy)-3-methoxy-phenyl]prop-2-enoic acid;

2- [2-(3-methoxyphenyl)thiazolo[2,3-e][l,2,4]triazol-6-yl]ethanamine;

4-(ethoxycarbonylmethylsulfanyl)naphthalene-l,8-dicarboxylic acid;

3- [2-[2-[(2-methoxy-5-methyl-phenyl)amino]-2-oxo-ethoxylphenyl]propanoic acid;

2-[2-[2-(4-fluorophenyl)ethyl]thiazolo[2,3-e][l,2,4]triazol-6-yl]ethanamine; 3 - [2- [2 - [(2-methoxy-5 -methyl-phenyl)amino] -2-oxo-ethoxy]phenyl]propionic acid;

2- [2-[2-(4-fluorophenyl)ethyl]thiazolo[2,3-e][l,2,4]triazol-6-yl]ethanamine;

3- [3-(2-diethylaminoethoxy)-4-methoxy-phenyl]propanoic acid;

2-[2-[2-(o-tolyl)vinyl]thiazolo[2,3-e][l,2,4]triazol-6-yl]ethanamine;

2-[2-[(E}-2-(o-tolyl)vinyl]thiazolo[2,3-e][l,2,4]triazol-6-yl]ethanamine; 2-[2-[(Z}-2-(o-tolyl)vinyl]thiazolo[2,3-e][l,2,4]triazol-6-yl]ethanamine;

4- (aminomethyl)-8-(3-fluorophenyl)-7-thia-l,5,9-triazabicyclo[4.3.0]nona- 3,5,8-trien-2-one;

4-(aminomethyl)-8-(4-chlorophenyl)-7-thia-l,5,9-triazabicyclo[4.3.0]nona- 3,5,8-trien-2-one;

[5-(4-benzyl-l-piperidyl)-l,3,4-oxadiazol-2-yl]methanamine;

2-cyano-N-[2-[4-(2-diethylaminoethoxy)-3-ethoxy-phenyl]ethyl]acetamide;

2-(4-ethylpiperazin- 1 -yl)- 1 -( 1 H-indol-3 -yl)-2-phenyl-ethanone;

2-( 1 -cyclopropylethylcarbamoylmethyl-methyl-amino)-N-(2,4,6- trimethylphenyl)-acetamide;

2-cyano-3-[3-(2-diethylaminoethoxy)-4-methoxy-phenyl]prop-2-enoic acid;

(E)-2-cyano-3-[3-(2-diethylaminoethoxy)-4-methoxy-phenyl]prop-2-enoic acid;

(Z)-2-cyano-3-[3-(2-diethylaminoethoxy)-4-methoxy-phenyl]prop-2-enoic acid;

2- chloroethylphosphonoylbenzene;

3- indolin-7-yl-2-(phosphonomethyl)prop-2-enoic acid; (Z)-3-indolin-7-yl-2-(phosphonomethyl)prop-2-enoic acid;

(E)-3-indolin-7-yl-2-(phosphonomethyl)prop-2-enoic acid;

methyl 2-[4-(aminomethyl)phenyl]-4-methyl-thiazole-5-carboxylate;

2-cyano-3-[4-(3-dimethylaminopropoxy)-3-ethoxy-phenyl]prop-2-enoic acid;

(Z)-2-cyano-3-[4-(3-dimethylaminopropoxy)-3-ethoxy-phenyl]prop-2-enoic acid;

(E)-2-cyano-3-[4-(3-dimethylaminopropoxy)-3-ethoxy-phenyl]prop-2-enoic acid;

5-[l-aminoethyl]-N-[l, l-dioxothiolan-3-yl]-N-methyl-furan-2-carboxamide; 5-[(lR)-l-aminoethyl]-N-[(3R)-l, l-dioxothiolan-3-yl]-N-methyl-furan-2- carboxamide;

5-[(l S)- l-aminoethyl]-N-[(3R)- 1 , 1 -dioxothiolan-3-yl]-N-methyl-furan-2- carboxamide;

5-[(lR)-l-aminoethyl]-N-[(3S)-l, l-dioxothiolan-3-yl]-N-methyl-furan-2- carboxamide;

5- [( 1 S)- 1 -aminoethyl]-N- [(3 S)- 1 , 1 -dioxothiolan-3 -yl] -N-methyl-furan-2- carboxamide;

2-[2-[2-(p-tolyl)vinyl]thiazolo[2,3-e][l,2,4]triazol-6-yl]ethanamine;

2-[2-[(E)-2-(p-tolyl)vinyl]thiazolo[2,3-e][l,2,4]triazol-6-yl]ethanamine; 2-[2-[(Z)-2-(p-tolyl)vinyl]thiazolo[2,3-e][l,2,4]triazol-6-yl]ethanamine; 4-(aminomethyl)-8-(3-methoxyphenyl)-7-thia-l,5,9-triazabicyclo[4.3.0]nona- 3,5,8-trien-2-one;

4-[2-[2-(3-dimethylaminopropoxy)phenyl]ethylamino]-4-oxo-butanoic acid;

2-[2-[2-(m-tolyl)ethyl]thiazolo[2,3-e][l,2,4]triazol-6-yl]ethanamine;

2- [ [3 -methyl-2-[(2-methylbenzoyl)amino]butanoyl] amino] -3 -sulfidopropionic acid;

(2S)-2-[[(2S)-3-methyl-2-[(2-methylbenzoyl)amino]butanoyl]amino]-3- sulfidopropionic acid;

(2R)-2-[[(2R)-3-methyl-2-[(2-methylbenzoyl)amino]butanoyl]amino]-3- sulfidopropionic acid;

(2R)-2-[[(2S)-3-methyl-2-[(2-methylbenzoyl)amino]butanoyl]amino]-3- sulfidopropionic acid; (2S)-2-[[(2R)-3-methyl-2-[(2-methylbenzoyl)amino]butanoyl]amino]-3- sulfidopropionic acid;

2- cyano-3-[3-[2-(2-methoxyphenoxy)ethoxy]phenyl]prop-2-enoic acid; (Z)-2-cyano-3-[3-[2-(2-methoxyphenoxy)ethoxy]phenyl]prop-2-enoic acid; (E)-2-cyano-3-[3-[2-(2-methoxyphenoxy)ethoxy]phenyl]prop-2-enoic acid;

[4-[(2-methoxyphenoxy)methyl]phenyl]methanamine;

4-[(2-phosphonophenoxy}methyl]benzoic acid;

[5-(aminomethyl)-2-furyl]-[2-ethyl-l-piperidyl]methanone;

[5-(aminomethyl)-2-furyl]-[(2R)-2-ethyl-l-piperidyl]methanone;

[5-(aminomethyl)-2-furyl]-[(2S)-2-ethyl-l-piperidyl]methanone;

[4-[2-(3,5-dimethylphenoxy)ethoxy]-3-methoxy-phenyl]methanamine;

1 - [2-(4-tert-butylphenoxy)ethy 1 ]piperazine;

[3-methoxy-4-(o-tolylmethoxy)phenyl]methanamine;

4-[[4-(dimethylaminomethyl)phenyl]methylsulfamoyl]benzoic acid; and 3-[(3,5-dimethoxybenzoyl)amino]-3-(p-tolyl)propanoic acid;

(3R)-3-[(3,5-dimethoxybenzoyl)amino]-3-(p-tolyl)propanoic acid;

(3S)-3-[(3,5-dimethoxybenzoyl)amino]-3-(p-tolyl)propanoic acid; and

3- [l-(ethoxycarbonylmethyl}-5-(4-chlorophenyl)-pyrrol-2-yl]propanoic acid. The term "alkyl" is used herein to refer to both straight- and branched-chain saturated aliphatic hydrocarbon groups. In one embodiment, an alkyl group has 1 to about 10 carbon atoms (i.e., Ci, C₂, C3, C₄, C5 Ce, C₇, C₈, C9, or C₁₀). In another embodiment, an alkyl group has 1 to about 6 carbon atoms (i.e., Ci, C₂, C3, C₄, C5 or Ce). In a further embodiment, an alkyl group has 1 to about 4 carbon atoms (i.e., Ci, C₂, C₃, or C₄).

The term "alkenyl" is used herein to refer to both straight- and branched-chain alkyl groups having one or more carbon-carbon double bonds. In one embodiment, an alkenyl group contains 2 to about 10 carbon atoms (i.e., C₂, C3, C₄, C5, Ce, C₇, C₈, C9, or Cio). In another embodiment, an alkenyl group has 1 or 2 carbon-carbon double bonds and 2 to about 6 carbon atoms (i.e., C₂, C3, C₄, C5 or Ce).

The term "alkynyl" is used herein to refer to both straight- and branched-chain alkyl groups having one or more carbon-carbon triple bonds. In one embodiment, an alkynyl group has 2 to about 10 carbon atoms (i.e., C₂, C3, C₄, C5, Ce, C₇, C₈, C9, or Cio). In another embodiment, an alkynyl group contains 1 or 2 carbon-carbon triple bonds and 2 to about 6 carbon atoms (i.e., C₂, C3, C₄, C5, or Ce).

The term "cycloalkyl" is used herein to refer to cyclic, saturated aliphatic hydrocarbon groups. The term cycloalkyl may include a single ring or two or more rings fused together to form a multicyclic ring structure. A cycloalkyl group may thereby include a ring system having 1 to about 5 rings. In one embodiment, a cycloalkyl group has 3 to about 14 carbon atoms (i.e., C3, C₄, C5, Ce, C₇, C₈, C9, C₁₀, C₁₁, C₁₂, Ci₃, or C14). In another embodiment, a cycloalkyl group has 3 to about 10 carbon atoms (i.e., C3, C₄, C5 or Ce). In a further embodiment, a cycloalkyl group has 3 to about 6 carbon atoms (i.e., C3, C₄, C5 or Ce).

The term "alkoxy" as used herein refers to the O-(alkyl) group, where the point of attachment is through the oxygen-atom and the alkyl group is defined above.

The term "thioalkyl" as used herein refers to the S-(alkyl) group, where the point of attachment is through the sulfur-atom and the alkyl group is defined above.

The term "aminoalkyl" as used herein refers to both secondary and tertiary amines where the point of attachment is through the nitrogen-atom and the alkyl groups are defined above. The alkyl groups can be the same or different.

The term "halogen" as used herein refers to CI, Br, F, or I groups.

The term "aryl" as used herein refers to an aromatic, carbocyclic system, e.g., of about 5 to 20 carbon atoms, which can include a single ring or multiple unsaturated rings fused or linked together where at least one part of the fused or linked rings forms the conjugated aromatic system. An aryl group may thereby include a ring system having 1 to about 5 rings. The aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl, indene, benzonaphthyl, and fluorenyl.

The term "benzyl" as used herein refers to a ~CH₂-phenyl group.

The term "heteroaryl" as used herein refers to a stable, aromatic 5- to 20- membered monocyclic or multicyclic heteroatom-containing ring. The heteroaryl ring has in its backbone carbon atoms and one or more heteroatoms including nitrogen, oxygen, and sulfur atoms. In one embodiment, the heteroaryl ring contains 1 to about 4 heteroatoms in the backbone of the ring. When the heteroaryl ring contains nitrogen or sulfur atoms in the backbone of the ring, the nitrogen or sulfur atoms can be oxidized. Further, when the heteroaryl ring contains nitrogen atoms, the nitrogen atoms may optionally substituted by H, Ci to C₁₀ alkoxy, C(0)(Ci to Ce alkyl), or C(0)0(Ci to Ce alkyl). The heteroaryl ring can be attached through a heteroatom or carbon atom provided the resultant heterocyclic ring structure is chemically stable. When the heteroaryl ring is a multicyclic heteroatom-containing ring, it may contain 2, 3, 4, or 5 rings.

A variety of heteroaryl groups are known in the art and include, without limitation, oxygen-containing rings, nitrogen-containing rings, sulfur-containing rings, mixed heteroatom-containing rings, fused heteroatom containing rings, and combinations thereof. Examples of heteroaryl groups include, without limitation, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, azepinyl, thienyl, dithiolyl, oxathiolyl, oxazolyl, thiazolyl, oxadiazolyl, oxatriazolyl, oxepinyl, thiepinyl, diazepinyl, benzofuranyl, thionapthene, indolyl, benzazolyl, purindinyl, pyranopyrrolyl, isoindazolyl, indoxazinyl, benzoxazolyl, quinolinyl, isoquinolinyl, benzodiazonyl, napthylridinyl, benzothienyl, pyridopyridinyl, acridinyl, carbazolyl, and purinyl rings.

The term "heterocycle" or "heterocyclic" as used herein can be used interchangeably to refer to a stable, saturated or partially unsaturated 3- to 20- membered monocyclic or multicyclic heterocyclic ring. The heterocyclic ring has carbon atoms and one or more heteroatoms including nitrogen, oxygen, and sulfur atoms in its backbone. In one embodiment, the heterocyclic ring has 1 to about 4 heteroatoms in the backbone of the ring. When the heterocyclic ring contains nitrogen or sulfur atoms in the backbone of the ring, the nitrogen or sulfur atoms can be oxidized. Further, when the heterocyclic ring contains nitrogen atoms, the nitrogen atoms may optionally be substituted with H, Ci to Ce alkyl, substituted Ci to Ce alkyl, C0₂ (Ci to C₆ alkyl), S0₂(Ci to C₆ alkyl), S0₂(substituted Ci to C₆ alkyl), S0₂aryl, S0₂substituted aryl, CO(Ci to C₆ alkyl), CO(substituted Ci to C₆ alkyl), COaryl or COsubstituted aryl. The heterocyclic ring can be attached through a heteroatom or carbon atom provided the resultant heterocyclic ring structure is chemically stable. When the heterocyclic ring is a multicyclic ring, it may contain 2, 3, 4, or 5 rings.

A variety of heterocyclic groups are known in the art and include, without limitation, oxygen-containing rings, nitrogen-containing rings, sulfur-containing rings, mixed heteroatom-containing rings, fused heteroatom containing rings, and combinations thereof. Examples of heterocyclic groups include, without limitation, tetrahydrofuranyl, piperidinyl, 2-oxopiperidinyl, pyrrolidinyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, pyranyl, pyronyl, dioxinyl, piperazinyl, dithiolyl, oxathiolyl, dioxazolyl, oxathiazolyl, oxazinyl, oxathiazinyl, benzopyranyl, benzoxazinyl and xanthenyl.

The term "substituted" as used herein refers to the substituted of an atom or moiety for another atom of moiety, provided that the substitution results in stable chemical compound. The substitution may occur at a carbon atom and/or heteroatom. One of skill in the art would readily be able to determine if a chemical compound is "stable".

II. Methods of Production

The compounds described above may be prepared by known chemical synthesis techniques. These compounds may also be purchased from commercial vendors, e.g., the Sigma-Aldrich Co. Among such preferred techniques known to one of skill in the art are included the synthetic methods described in conventional textbooks relating to the construction of synthetic compounds. III. Compositions Containing the Antagonistic Compounds

Pharmaceutical compositions useful herein, in one embodiment, contain a compound discussed above in a pharmaceutically acceptable carrier with other optional suitable pharmaceutically inert or inactive ingredients. In another embodiment, a compound described above is present in a single composition. In a further embodiment, a compound described above is combined with one or more excipients and/or other therapeutic agents as described below.

1. Salts

The antagonistic compounds discussed above may encompass tautomeric forms of the structures provided herein characterized by the bioactivity of the drawn structures. Further, the compounds may also be used in the form of salts derived from pharmaceutically or physiologically acceptable acids, bases, alkali metals and alkaline earth metals. In one embodiment, pharmaceutically acceptable salts can be formed from organic and inorganic acids including, e.g., acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids.

In another embodiment, pharmaceutically acceptable salts may also be formed from inorganic bases, desirably alkali metal salts including, e.g., sodium, lithium, or potassium, such as alkali metal hydroxides. Examples of inorganic bases include, without limitation, sodium hydroxide, potassium hydroxide, calcium hydroxide, and magnesium hydroxide. Pharmaceutically acceptable salts may also be formed from organic bases, such as ammonium salts, mono-, di-, and trimethylammonium, mono-, di- and triethylammonium, mono-, di- and tripropylammonium (iso and normal), ethyldimethylammonium, benzyldimethylammonium, cyclohexylammonium, benzyl- ammonium, dibenzylammonium, piperidinium, morpholinium, pyrrolidinium, piperazinium, 1 -methylpiperidinium, 4-ethylmorpholinium, 1 -isopropylpyrrolidinium, 1,4-dimethylpiperazinium, 1 -n-butyl piperidinium, 2-methylpiperidinium, l-ethyl-2- methylpiperidinium, mono-, di- and triethanolammonium, ethyl diethanolammonium, n-butylmonoethanolammonium, tris(hydroxymethyl)methylammonium, phenylmono- ethanolammonium, diethanolamine, ethylenediamine, and the like. In one example, the base is selected from among sodium hydroxide, lithium hydroxide, potassium hydroxide, and mixtures thereof.

These salts, as well as other compounds, can be in the form of esters, carbamates and other conventional "pro-drug" forms, which, when administered in such form, convert to the active moiety in vivo. In one embodiment, the prodrugs are esters. In another embodiment, the prodrugs are carbamates. See, e.g., B. Testa and J. Caldwell, "Prodrugs Revisited: The "Ad Hoc" Approach as a Complement to Ligand Design", Medicinal Research Reviews, 16(3):233-241, ed., John Wiley & Sons (1996), which is incorporated by reference.

The compounds discussed herein also encompass "metabolites" which are unique products formed by processing the compounds in vivo, i.e., by the cell or subject. Desirably, metabolites are formed in vivo. As described herein, a therapeutically or prophylactically effective amount of an antagonistic compound is that amount of a compound which prevents PF4 tetramer formation or disrupts PF4 tetramers, optionally present in an ULC. The effective amount of a compound may vary depending upon the formulation and route of delivery. In one embodiment, effective amount (i.e., per unit) of a compound is less than about 10 g/kg. In another embodiment, the dosage is less than about 5 g/kg, 500 mg/kg, 400 mg/kg, 300 mg/kg, 200 mg/kg, 100 mg/kg, 50 mg/kg, 25 mg/kg, 10 mg/kg, 1 mg/kg, 0.5 mg/kg, 0.25 mg/kg, 0.1 mg/kg, 100 μg/kg, 75 μg/kg, 50 μg/kg, 25 μg/kg, 10 μg/kg, or 1 μg/kg. However, the effective amount to be used is subjectively determined by the attending physician. The variables involved include the specific cognitive deficit and the size, age and response pattern of the patient. These effective amounts may be provided on regular schedule, i.e., daily, weekly, monthly, or yearly basis or on an irregular schedule with varying administration days, weeks, months, etc. Alternatively, the effective amount to be administered may vary. In one embodiment, the effective amount for the first dose is higher than the effective amount for one or more of the subsequent doses. In another embodiment, the effective amount for the first dose is lower than the effective amount for one or more of the subsequent doses.

2. Carriers

The pharmaceutical compositions of this invention include compounds described herein formulated neat or with one or more pharmaceutical carriers for administration, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmacological practice. The pharmaceutical carrier(s) may be solid or liquid. Formulations may incorporate both solid and liquid carriers.

The compounds described herein may be administered to a subject by any desirable route, taking into consideration the specific condition for which it has been selected. The compounds may, therefore, be delivered orally, by injection, inhalation (including orally, intranasally and intratracheally), ocularly, trans dermally, intravenously, subcutaneous ly, intramuscularly, sublingually, intracranially, epiduraly, rectally, and vaginally, among others. In one embodiment, the compound is delivered orally, intravenously, subcutaneously, or intramuscularly. Although the compound may be administered alone, it may also be administered in the presence of one or more pharmaceutical carriers that are physiologically compatible. The carriers may be in dry or liquid form and must be pharmaceutically acceptable. Liquid pharmaceutical compositions are typically sterile solutions or suspensions.

When liquid carriers are utilized, they are desirably sterile liquids. Liquid carriers are typically utilized in preparing solutions, suspensions, emulsions, syrups and elixirs. In one embodiment, the antagonistic compound is dissolved a liquid carrier. In another embodiment, the antagonistic compound is suspended in a liquid carrier. One of skill in the art of formulations would be able to select a suitable liquid carrier, depending on the route of administration. In one embodiment, the liquid carrier includes, without limitation, water, organic solvents, oils, fats, or mixtures thereof. In another embodiment, the liquid carrier is water containing cellulose derivatives such as sodium carboxymethyl cellulose. In a further embodiment, the liquid carrier is water and dimethylsulfoxide (DMSO). In yet another embodiment, the liquid carrier contains water and up to 5% of DMSO. Examples of organic solvents include, without limitation, alcohols such as monohydric alcohols and polyhydric alcohols, e.g., glycols and their derivatives, among others. Examples of oils include, without limitation, fractionated coconut oil, arachis oil, corn oil, peanut oil, and sesame oil and oily esters such as ethyl oleate and isopropyl myristate. The liquid carrier can contain other suitable excipients, including those described below.

Alternatively, the antagonistic compounds may be formulated in a solid carrier. In one embodiment, the composition may be compacted into a unit dose form, i.e., tablet or caplet. In another embodiment, the composition may be added to unit dose form, i.e., a capsule. In a further embodiment, the composition may be formulated for administration as a powder. The solid carrier may perform a variety of functions, i.e., may perform the functions of two or more of the excipients described below. For example, solid carrier may also act as a flavoring agent, lubricant, solubilizer, suspending agent, filler, glidant, compression aid, binder, disintegrant, or encapsulating material. Suitable solid carriers include, without limitation, calcium phosphate, dicalcium phosphate, magnesium stearate, talc, starch, sugars (including, e.g., lactose and sucrose), cellulose (including, e.g., microcrystalline cellulose, methyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidine, low melting waxes, ion exchange resins, and kaolin. The solid carrier can contain other suitable excipients, including those described below.

The composition may also be sub-divided to contain appropriate quantities of the antagonistic compound. For example, the unit dosage can be packaged compositions, e.g., packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.

Examples of excipients which may be combined with one or more of the antagonistic compounds include, without limitation, adjuvants, antioxidants, binders, buffers, coatings, coloring agents, compression aids, diluents, disintegrants, emulsifiers, emollients, encapsulating materials, fillers, flavoring agents, glidants, granulating agents, lubricants, metal chelators, osmo-regulators, pH adjustors, preservatives, solubilizers, sorbents, stabilizers, sweeteners, surfactants, suspending agents, syrups, thickening agents, or viscosity regulators. See, the excipients described in the "Handbook of Pharmaceutical Excipients", 5^th Edition, Eds.: Rowe,

Sheskey, and Owen, APhA Publications (Washington, DC), December 14, 2005, which is incorporated herein by reference.

In one embodiment, the compositions may be utilized as inhalants. For this route of administration, compositions may be prepared as fluid unit doses using an antagonistic compound and a vehicle for delivery by an atomizing spray pump or by dry powder for insufflation.

In another embodiment, the compositions may be utilized as aerosols, i.e., oral or intranasal. For this route of administration, the compositions are formulated for use in a pressurized aerosol container together with a gaseous or liquefied propellant, e.g., dichlorodifluoromethane, carbon dioxide, nitrogen, propane, and the like. Also provided is the delivery of a metered dose in one or more actuations.

In another embodiment, the compositions may be administered by a sustained delivery device. "Sustained delivery" as used herein refers to delivery of an antagonistic compound which is delayed. Those of skill in the art know suitable sustained delivery devices. For use in such sustained delivery devices, the compounds are formulated as described herein. 3. Pharmaceutical Compositions Containing Multiple Compounds

In addition to the components described above for use in the composition and the antagonistic compound, the compositions may contain one or more medication or therapeutic agent.

In one aspect, the additional medication causes as an undesired side effect of the formation of PF4 tetramers or ULCs. In one embodiment, the medication modulates clotting, i.e., is an anti-coagulant or induces hemostasis. In one example, the clotting modulator is a blood thinner such as heparin. In a further example, the clotting modulator is aspirin or a non-steroidal anti-inflammatory drug. In another example, the clotting modulator is dipyridamole. In yet a further example, the clotting modulator is ticlopidine or clopidogrel. In still another example, the clotting modulator is a GPIIB/IIIA inhibitor. In still another embodiment, the medication causes hemostasis and includes, without limitation, a vasoconstrictor or an agent which induces platelet aggregation. In another embodiment, the medication is a chemotherapeutic. In a further embodiment, the medication is a cardiotonic. In another embodiment, the medication is a blood pressure lowering agent. In yet a further embodiment, the medication is a cholesterol lowering agent. Examples of chemotherapeutics, cardiotonics, blood pressure lowering agents, and cholesterol lowering agents include those recited in the "Physician's Desk Reference", 64^th Edition, Thomson Reuters, 2010, which is hereby incorporated by reference.

In another aspect, the medication has the desirable effect of disrupting PF4 tetramers and/or ULCs. In one embodiment, the additional medication works synergistically with the PF4 antagonists discussed herein. Such medications which disrupt PF4 tetramers may be selected by one of skill in the art and may include, without limitation, cyclic peptides which inhibit the interaction of PF4 with CCL5 (CKEY2), carbohydrates such as desulfated heparin (ODSH), or a combination thereof. The PF4 tetramer disruption agents may be combined with the PF4 antagonist compounds discussed herein either in the compositions set forth above and/or kits and methods for using the same and discussed below.

In one embodiment, the compounds described herein and/or other therapeutic agents may be administered in a single composition. However, the present invention is not so limited. In other embodiments, the compounds described herein invention may be administered in one or more separate formulations from other compounds described herein, chemotherapeutic agents, or other agents as is desired.

IV. Kits Containing the Antagonistic Compound

Also provided herein are kits or packages of pharmaceutical formulations containing the compounds or compositions described herein. The kits may be organized to indicate a single formulation or combination of formulations to be taken at each desired time.

Suitably, the kit contains packaging or a container with the compound formulated for the desired delivery route. Suitably, the kit contains instructions on dosing and an insert regarding the active agent. Optionally, the kit may further contain instructions for monitoring circulating levels of product and materials for performing such assays including, e.g., reagents, well plates, containers, markers or labels, and the like. Such kits are readily packaged in a manner suitable for treatment of a desired indication. For example, the kit may also contain instructions for use of the spray pump or other delivery device. Other suitable components to include in such kits will be readily apparent to one of skill in the art, taking into consideration the desired indication and the delivery route. The doses are repeated daily, weekly, or monthly, for a predetermined length of time or as prescribed.

The compounds or compositions described herein can be a single dose or for continuous or periodic discontinuous administration. For continuous administration, a package or kit can include the antagonistic compound in each dosage unit (e.g., solution, lotion, tablet, pill, or other unit described above or utilized in drug delivery). When the compound is to be delivered with periodic discontinuation, a package or kit can include placebos during periods when the compound is not delivered. When varying concentrations of a composition, of the components of the composition, or of relative ratios of the antagonist compounds or agents within a composition over time is desired, a package or kit may contain a sequence of dosage units, so varying.

A number of packages or kits are known in the art for the use in dispensing pharmaceutical agents for oral use. In one embodiment, the package has indicators for each period. In another embodiment, the package is a labeled blister package, dial dispenser package, or bottle. The packaging means of a kit may itself be geared for administration, such as an inhalant, syringe, pipette, eye dropper, or other such like apparatus, from which the formulation may be applied to an infected area of the body, such as the lungs, injected into a subject, or even applied to and mixed with the other components of the kit.

The compositions of these kits also may be provided in dried or lyophilized forms. When reagents or components are provided as a dried form, reconstitution generally is by the addition of a suitable solvent. It is envisioned that the solvent also may be provided in another packaging means.

The kits of the present invention also will typically include a means for containing the vials in close confinement for commercial sale such as, e.g., injection or blow-molded plastic containers into which the desired vials are retained.

Irrespective of the number or type of packages, the kits of the invention also may include, or be packaged with a separate instrument for assisting with the

injection/administration or placement of the ultimate complex composition within the body of an animal. Such an instrument may be an inhalant, syringe, pipette, forceps, measuring spoon, eye dropper or any such medically approved delivery means. Other instrumentation includes devices that permit the reading or monitoring of reactions in vitro.

In one embodiment, a pharmaceutical kit is provided and contains a medication which causes the formation of PF4 tetramers, medication which disrupts PF4 tetramers, or a combination thereof and one or more of an antagonistic compound selected from those described above. The antagonistic compound may be in the presence or absence of one or more of the carriers or excipients described above. The kit may optionally contain instructions for administering the medication(s) and the compound to a subject having cancer.

In another embodiment, a pharmaceutical kit is provided and contains a medication which causes the formation of PF4 tetramers in a first dosage unit and one or more of an antagonistic compound selected from those described above in a second dosage unit. The antagonistic compound may be in the presence or absence of one or more of the carriers or excipients described above. The kit may optionally contain instructions for administering the medication(s) and the compound to a subject having cancer. In a further embodiment, a pharmaceutical kit is provided and contains a medication which disrupts PF4 tetramers in a first dosage unit and one or more of an antagonistic compound selected from those described above in a second dosage unit. The antagonistic compound may be in the presence or absence of one or more of the carriers or excipients described above. The kit may optionally contain instructions for administering the medication(s) and the compound to a subject having cancer.

In still a further embodiment, a pharmaceutical kit is provided and contains a medication which causes the formation of PF4 tetramers in a first dosage unit, a medication which disrupts PF4 tetramers in a second dosage unit, and one or more of an antagonistic compound selected from those described above in a third dosage unit. The antagonistic compound may be in the presence or absence of one or more of the carriers or excipients described above. The kit may optionally contain instructions for administering the medication(s) and the compound to a subject having cancer.

In a further embodiment, a pharmaceutical kit is provided and contains a medication which causes the formation of PF4 tetramers in a first dosage unit, one or more of an antagonistic compound selected from those described above in a second dosage unit, and one or more of the carriers or excipients described above in a third dosage unit. The kit may optionally contain instructions for administering the medication(s) and the compound to a subject having cancer.

In yet another embodiment, a pharmaceutical kit is provided and contains a medication which disrupts PF4 tetramers in a first dosage unit, one or more of an antagonistic compound selected from those described above in a second dosage unit, and one or more of the carriers or excipients described above in a third dosage unit. The kit may optionally contain instructions for administering the medication(s) and the compound to a subject having cancer.

In yet a further embodiment, a pharmaceutical kit is provided and contains a medication which causes the formation of PF4 tetramers in a first dosage unit, a medication which disrupts PF4 tetramers in a second dosage unit, and one or more of an antagonistic compound selected from those described above in a third dosage unit, and one or more of the carriers or excipients described above in a third dosage unit. The kit may optionally contain instructions for administering the medication(s) and the compound to a subject having cancer. V. Methods of Treatment Using the Antagonistic Compounds

As noted above, the formation of PF4 tetramers is linked to a subject acquiring specific diseases or conditions. The terms "patient" or "subject" as used herein refer to a mammalian animal. In one embodiment, the patient or subject is a human. In another embodiment, the patient or subject is a veterinary or farm animal, a domestic animal or pet, or animal normally used for clinical research. In a further embodiment, the subject or patient has elevated levels of PF4 tetramer. In yet a further

embodiment, the subject or patient has elevated levels of PF4 tetramenGAG ULCs. In still another embodiment, the subject or patient has elevated levels of PF4 tetramer :heparin ULCs. In a further embodiment, the subject or patient is asymptomatic for medical conditions related to elevated levels of PF4 tetramer, PF4 tetramenGAG ULCs, or PF4 tetramenheparin ULCs. In another embodiment, the subject shows clinical signs of medical conditions related to elevated levels of PF4 tetramer, PF4 tetramenGAG ULCs, or PF4 tetramenheparin ULCs. In another embodiment, the subject shows clinical signs of developing or has HIT or HITT. In still a further embodiment, the subject or patient has cancer. The subject or patient has either been recognized as having or at risk of having one or more of the diseases or conditions discussed above, i.e., a primary disease or medical condition.

Alternatively, the one or more diseases or medical conditions in a subject may be the result of another disease or medical condition, i.e., a secondary disease or condition.

The term "disease" or "condition" as used herein refers to any disease or medical condition related directly or indirectly to the formation of PF4 tetramers. The disease or medical condition may also be caused by the formation of PF4 tetramers. The methods described herein thereby are useful in treating or preventing these diseases or conditions.

In one embodiment, the disease or medical condition is heparin-induced thrombocytopenia (HIT). As known in the art, HIT results from the development of thrombocytopenia, i.e., low platelet counts, due to the administration of one of the forms of the anticoagulant. In another embodiment, the disease or medical condition is heparin-induced thrombocytopenia and/with thrombosis (HITT). As known in the art, HITT results when HIT precedes thrombosis, i.e., abnormal blood clots form inside a blood vessel and abnormal antibodies form.

Although there are treatment options for atherosclerotic vascular disease and thrombocytopenia and increasing HDL, none of the therapies are directed toward PF4 tetramer formation/interactions. Specifically, treatment of atherosclerotic vascular disease involves anti-platelet therapy, i.e., aspirin, the Plavix® drug, among others, and is not tolerated in all patients. For the treatment of thrombocytopenia, TPO analogs and mimetics (MPL agonists which activate MPL-the TPO receptor) may be used, but these drugs do not work in all patients, and have significant side effects/compliance issues. Finally, some lipid lowering therapies are able to increase HDL, but the ability of available drugs to do so is limited.

In a further embodiment, the disease or medical condition is atherosclerosis. Typically, atherosclerosis resulting from the formation of a PF4 tetramer may be treated according to the invention described herein. In still another embodiment, the disease or medical condition is a platelet imbalance. The treatment method thereby includes correcting this platelet imbalance or preventing a platelet imbalance. In one example, platelet levels are increased by stimulating platelet production. In another example, a decrease in platelet production is prevented. In a further example, the platelet imbalance, i.e., low levels of platelets, results from the formation of PF4 tetramer. In yet another example, the platelet imbalance, i.e., low levels of platelets, results from heparin administration to a subject.

The compounds discussed herein may also be an alternative therapy utilized to treat diseases related to thrombopoietin (TPO).

The compounds discussed herein may further be useful in inhibiting the activation of nuclear factor κ-light-chain-enhancer of activated B ( F-κΒ) cells and thereby treating conditions related to an imbalance NF-κΒ. Such conditions may include, without limitation, cancer, inflammatory disease, autoimmune diseases, septic shock, viral infection, among others.

The compounds discussed herein may also be contemplated for use in preventing or treating inflammation which results from the formation of PF4 tetramers. The inflammation may be the caused by any number of factors. In one embodiment, the inflammation is acute or chronic and localized or systemic. The inflammation may be the result of a variety of factors and/or conditions. In another embodiment, the inflammation is caused by NF-κΒ activation.

Given that Lys50Glu, or non-tetrameric PF4 variant, does not activate NFKB, the inventors hypothesized that compounds which inhibit tetramer formation will inhibit the activation of NFKB. TO test this hypothesis, mutation of Lys50 to Glu disrupted these interactions and created a mutant PF4 that readily forms dimers but not tetramers. Further, formation of ULC requires tetrameric PF4, as Lys50Glu does not form ULC with heparin. The importance of PF4 tetramers in complex formation is supported by subsequent biophysical studies as reported in Rauova.

The compounds described herein may also be useful in therapies for subjects having atherosclerotic vascular disease in which the patient is intolerant to the conventional treatments, i.e., statins.

The compounds discussed herein may further be useful for modulating clotting or hemostasis. In one embodiment, protein C is upregulated. In another embodiment, protein C is downregulated. The term "upregulated" as used herein refers to an increase of protein or nucleic acid in level or function. Similarly, the term

"downregulated" as used herein refers to a decrease of protein or nucleic acid in level or function. The term "level" references the amount of protein or nucleic acid present and the term "function" references the action of the protein or nucleic acid.

The compounds discussed above may be useful in patients that are intolerant to these conventional therapies. Alternatively, the compounds discussed above may be synergistic with the conventional therapies.

As used herein, "treatment" encompasses treatment of a subject clinically diagnosed as having a disease or medical condition. In one embodiment, the subject is treated and the disease or medical condition is eradicated, i.e., the subject is cured.

In another embodiment, the subject is treated for chronic diseases and the symptoms resulting from the disease or medical conditions are relieved.

As used herein, "prevention" encompasses prevention of symptoms in a subject who has been identified as at risk for the condition, but has not yet been diagnosed with the same and/or who has not yet presented any symptoms thereof.

Not only can the antagonists described herein be used to prevent or treat diseases and medical conditions, but the same are also useful in increasing high density lipoproteins (HDL) in a subject. Alternatively, the antagonists are useful in preventing a decrease of HDLs.

As known to those skilled in the art, GAGs are long unbranched

polysaccharides having a repeating disaccharide unit (a hexose (six-carbon sugar) or a hexuronic acid, linked to a hexosamine (six-carbon sugar containing nitrogen)). One of skill in the art would readily be able to determine the GAGs which are capable of binding to PF4 tetramers. In one embodiment, the GAG is selected from among wild- type GAGs or synthetically produced GAGs. In one embodiment, the GAG is heparin, hyaluronan, hyaluronic acid, dermatan sulfates, keratan sulfates, and chondroitins, among others or derivatives, salts, or prodrugs thereof. In another embodiment, the GAG is heparin. In a further embodiment, the GAG is heparan sulfate. GAGs as described herein may also be variations of the those described above, i.e., they may vary in the type of hexosamine, hexose or hexuronic acid unit they contain (e.g., glucuronic acid, iduronic acid, galactose, galactos amine, glucosamine).

The methods described above, either for treating or preventing the stated medical conditions or disease, may be performed in vivo or ex vivo as determined by the attending physician or clinician.

The methods described herein may be performed by administering one or more of the compounds described above via a combination therapy in prior to, concurrently with, or subsequent to another medication. Such combination treatment may occur by administering compositions containing multiple active ingredients, as described above. However, this invention also encompasses a method of

administration of anti-cancer agents or therapies in conjunction with a composition containing an antagonistic compound. In one embodiment of such a method, the antagonistic compound and additional medications are administered to the patient by one or more selected routes of administration sequentially. In one embodiment, a chemotherapeutic agent is administered before treatment with a composition of the invention. In another embodiment, a chemotherapeutic agent is administered after treatment with a composition of the invention. In still another embodiment, a chemotherapeutic agent is administered during treatment with a composition of the invention. In one embodiment, a chemotherapeutic agent is administered before treatment with a composition of the invention. In another embodiment, a

chemotherapeutic agent is administered after treatment with a composition of the invention. In still another embodiment, a chemotherapeutic agent is administered before, during or after treatment with a composition of the invention. In a further embodiment, the composition of the invention is administered prior to another medication which disrupts PF4 tetramers. In another embodiment, the composition of the invention is administered concurrently with another medication which disrupts PF4 tetramers. In yet further embodiment, the composition of the invention is administered subsequent to another medication which disrupts PF4 tetramers.

In one embodiment, methods for disrupting PF4 tetramers are provided and include measuring a first level of PF4 tetramer in a first biological sample obtained from a subject and administering a first effective amount of the compound required to decrease the first PF4 tetramer level.

In another embodiment, methods for disrupting PF4 tetramers are provided and include measuring a first level of PF4 tetramer in a first biological sample obtained from a subject, administering a first effective amount of the compound discussed herein required to decrease the first PF4 tetramer level, and optionally administering a medication which disrupts PF4 tetramers. The medication which disrupts PF4 tetramers may be administered prior to, concurrent with, or subsequent to the PF4 antagonists discussed herein.

As used herein, the term "biological sample" refers to a body fluid or tissue. The body fluid can include, without limitation, whole blood, serum, plasma, peripheral blood, synovial fluid, cerebrospinal fluid, saliva, urine, semen, or other fluid secretion. The term "tissue" can include, without limitation, bone marrow and lymph node, as well as samples of other tissues.

In another embodiment, methods for disrupting PF4 tetramers are provided and include measuring a first level of PF4 tetramer in a first biological sample obtained from a subject, administering a first effective amount of the compound required to decrease the first PF4 tetramer level, measuring a second level of PF4 tetramer in a second biological sample obtained from the subject, and administering a second effective amount of the compound required to decrease the second PF4 tetramer level. Multiple samples can be obtained from the subject at any interval required to prevent or treat the medical condition.

In yet another embodiment, methods for disrupting PF4 tetramers are provided and include measuring a first level of PF4 tetramer in a first biological sample obtained from a subject, administering a first effective amount of the compound required to decrease the first PF4 tetramer level, optionally administering a first effective amount of a medication which disrupts PF4 tetramers, measuring a second level of PF4 tetramer in a second biological sample obtained from the subject, administering a second effective amount of the compound required to decrease the second PF4 tetramer level, and optionally administering a second effective amount of a medication which disrupts PF4 tetramers. Multiple samples can be obtained from the subject at any interval required to prevent or treat the medical condition. The medication which disrupts PF4 tetramers may be administered prior to, concurrent with, or subsequent to the PF4 antagonists discussed herein.

In a further embodiment, methods for disrupting ULCs containing PF4 tetramers and heparin are provided. These methods include measuring a first level of ULCs in a first biological sample obtained from a subject and administering a first effective amount of the compound required to decrease the first ULC tetramer level.

In still a further embodiment, methods for disrupting ULCs containing PF4 tetramers and heparin are provided. These methods include measuring a first level of ULCs in a first biological sample obtained from a subject, administering a first effective amount of the compound required to decrease the first ULC tetramer level, and administering a first effective amount of a medication which disrupts PF4 tetramers. The medication which disrupts PF4 tetramers may be administered prior to, concurrent with, or subsequent to the PF4 antagonists discussed herein.

In yet another embodiment, methods for disrupting ULCs containing PF4 tetramers and heparin are provided. These methods include measuring a first level of ULCs in a first biological sample obtained from a subject, administering a first effective amount of the compound required to decrease the first ULC level, measuring a second level of ULCs in a second biological sample obtained from the subject, administering a second effective amount of the compound required to decrease the second ULC level. In a further embodiment, methods for disrupting ULCs containing PF4 tetramers and heparin are provided. These methods include measuring a first level of ULCs in a first biological sample obtained from a subject, administering a first effective amount of the compound required to decrease the first ULC level, optionally administering a first effective amount of a medication which disrupts PF4 tetramers, measuring a second level of ULCs in a second biological sample obtained from the subject, administering a second effective amount of the compound required to decrease the second ULC level, and optionally administering a second effective amount of a medication which disrupts PF4 tetramers. The medication which disrupts PF4 tetramers may be administered prior to, concurrent with, or subsequent to the PF4 antagonists discussed herein.

In still a further embodiment, methods for preventing the formation of PF4 tetramers are provided and include measuring a first level of PF4 tetramer in a first biological sample obtained from a subject and administering a first effective amount of the compound required to prevent formation of the PF4 tetramer.

In another embodiment, methods for preventing the formation of PF4 tetramers are provided and include measuring a first level of PF4 tetramer in a first biological sample obtained from a subject, administering a first effective amount of the compound required to prevent formation of the PF4 tetramer, and administering a first effective amount of a medication which disrupts PF4 tetramers. The medication which disrupts PF4 tetramers may be administered prior to, concurrent with, or subsequent to the PF4 antagonists discussed herein.

In still a further embodiment, methods for preventing the formation of PF4 tetramers are provided. These methods include measuring a first level of PF4 tetramer in a first biological sample obtained from a subject, administering a first effective amount of the compound required to prevent formation of the PF4 tetramer, measuring a second level of PF4 tetramer in a second biological sample obtained from the subject, and administering a second effective amount of the compound required to prevent formation of PF4 tetramer.

In yet a further embodiment, methods for preventing the formation of PF4 tetramers are provided. These methods include measuring a first level of PF4 tetramer in a first biological sample obtained from a subject, administering a first effective amount of the compound required to prevent formation of the PF4 tetramer, optionally administering a first effective amount of a medication which disrupts PF4 tetramers, measuring a second level of PF4 tetramer in a second biological sample obtained from the subject, administering a second effective amount of the compound required to prevent formation of PF4 tetramer, and optionally administering a second effective amount of a medication which disrupts PF4 tetramers. The medication which disrupts PF4 tetramers may be administered prior to, concurrent with, or subsequent to the PF4 antagonists discussed herein.

In a further embodiment, methods for preventing the formation of ULCs containing PF4 tetramers and heparin are provided. These methods include measuring a first level of ULCs in a first biological sample obtained from a subject and administering a first effective amount of the compound required to prevent formation of the ULCs.

In another embodiment, methods for preventing the formation of ULCs containing PF4 tetramers and heparin are provided. These methods include measuring a first level of ULCs in a first biological sample obtained from a subject, administering a first effective amount of the compound required to prevent formation of the ULCs, and administering a first effective amount of a medication which disrupts PF4 tetramers. The medication which disrupts PF4 tetramers may be administered prior to, concurrent with, or subsequent to the PF4 antagonists discussed herein.

In yet another embodiment, methods for preventing the formation of ULCs containing PF4 tetramers and heparin are provided. These methods include measuring a first level of ULCs in a first biological sample obtained from a subject and administering a first effective amount of the compound required to prevent formation of the ULCs, measuring a second level of ULCs in a second biological sample obtained from the subject, and administering a second effective amount of the compound required to prevent formation of ULCs.

In yet a further embodiment, methods for preventing the formation of ULCs containing PF4 tetramers and heparin are provided. These methods include measuring a first level of ULCs in a first biological sample obtained from a subject and administering a first effective amount of the compound required to prevent formation of the ULCs, optionally administering a first effective amount of a medication which disrupts PF4 tetramers, measuring a second level of ULCs in a second biological sample obtained from the subject, administering a second effective amount of the compound required to prevent formation of ULCs and/or administering a second effective amount of a medication which disrupts PF4 tetramers. The medication which disrupts PF4 tetramers may be administered prior to, concurrent with, or subsequent to the PF4 antagonists discussed herein.

VI. Screening Methods Using the Antagonistic Compounds

Also provided are methods for using the antagonistic compounds described herein for determining a subject's sensitivity to side effects or secondary medical conditions related to heparin administration. Further provided are methods for determining the likelihood of a subject to acquire a medical condition related to the formation of PF4 tetramers or ULCs containing PF4 tetramers and heparin. In one embodiment, these screening methods are useful in monitoring cancer patients. In another embodiment, these screening methods are useful in determining the likelihood of cancer patients being administered heparin in developing HIT or HITT.

According to this method, biological samples are obtained from subjects and the level of PF4 tetramer and/or PF4 tetramer:GAG (heparin) ULC measured. The screening may be conducted using techniques commonly known and used in the art. Comparison of the levels of PF4 tetramer and/or PF4 tetramenheparin ULC to a control level and/or negative control provides evidence that the patient may be treated using one or more of the antagonistic compounds described herein. In one embodiment, if the subject's PF4 tetramer and/or PF4 tetramer :heparin ULC level is higher than the PF4 tetramer and/or PF4 tetramer :heparin ULC level of a healthy subject, then antagonistic compound administration may be contemplated.

The following examples are illustrative of methods using the antagonistic compounds described herein. It will be readily understood by one of skill in the art that the specific conditions described herein for producing these compounds can be varied without departing from the scope of the present invention. It will be further understood that other compounds encompassed by the structures described herein, as well as other salts, hydrates, and/or prodrugs thereof, are within the scope of the invention.

EXAMPLES

Unfractionated heparin was an injectable sodium salt from porcine intestinal mucosa (Sagent Pharmaceuticals, Schaumberg, IL). HiTrap® heparin affinity columns for protein purification were purchased from GE Healthcare (Uppsala, Sweden). Immunochemicals included horseradish peroxidase-conjugated sheep polyclonal anti-human PF4 from Enzyme Research Laboratory (South Bend, ΓΝ), mouse immunoglobulin G 2bK (IgG2bK; MOPC 141) was purchased from Sigma (St. Louis, MO), and sheep anti-mouse IgG and alkaline phosphatase-conjugated goat anti-mouse IgG were from Jackson ImmunoResearch Labs (West Grove, PA). Murine monoclonal antibodies KKO (anti-human PF4-heparin complex), RTO (anti-human PF4), and IV.3 (FcyRIIA-blocking antibody) may be prepared according to Arepally, "Characterization of a murine monoclonal antibody that mimics heparin-induced thrombocytopenia antibodies", Blood, 95(5): 1533-1540 (2000), which is hereby incorporated by reference. Human plasma samples were obtained from patients with a high clinical suspicion for HIT (see, Cuker, "The HIT expert probability (HEP) score: a novel pre-test probability model for heparin-induced thrombocytopenia based on broad expert opinion", J. Thromb. Haemost, 8(12):2642-2650 (2010), which is hereby incorporated by reference) and who had positive heparin/PF4 ELISA (GTI X- HAT45; Waukesha, WI) and serotonin release assay results. The Bicinchoninic acid (BCA) Protein Assay Reagent Kit and bis(sulfosuccinimidyl)suberate (BS3) crosslinker were obtained from Pierce (Rockford, IL). Immulon® 4 HBX microtiter plates for ELISA were purchased from Fisher Scientific (Pittsburgh, PA). Bovine serum albumin (BSA), ionomycin, phorbol myristate acetate (PMA) and p- nitrophenyl phosphate (pNPP) tablets were obtained from Sigma and the 3,3,5,5- tetramethylbenzidine (TMB) liquid substrate system for ELISA was purchased from KPL (Gaithersburg, MD). Dose response data were analyzed using the indirect Hill relationship using GraphPad® Prism® software (version 5.03, sigmoidal dose- response, variable slope model). Example 1: Identification of ULC antagonists

To identify potential ULC antagonists, the Dock® program, as described in Moustakas et al, "Development and validation of a modular extensible docking program: DOCK 5", J. Comput. Aided Mol. Des., 20:601-619 (2006), which is hereby incorporated by reference, was utilized to screen a library of about 1.1 million leadlike compounds from the Zinc® database. See, Irwin and Shoichet, "ZINC— a free data base of commercially available compounds for virtual screening", J. Chem. Inf. Model, 45: 177-182 (2005), which is hereby incorporated by reference. Specifically, these compounds were screened in an effort to identify those having the potential to bind in the cavity containing the salt bridge described above, thereby impeding the formation of PF4 tetramers.

A set of overlapping spheres which fill the binding site were generated, known as sphere centers, using the Sphgen™ program. See, Kuntz, "A geometric approach of macromolecule-ligand interactions", J. Mol. Biol, 161(2):269-288 (1982), which is incorporated by reference. The sphere centers were permitted to touch the surface of the molecule, were not permitted to intersect the surface, and were used to represent the negative image of the binding site on PF4. The coordinates of the sphere centers were used to orient ligands within the target site. Sphere-sphere distances were then compared to ligand atom-atom distances and the compatible orientations of the ligand were found. A scoring grid to evaluate ligand orientations was then produced using the program GRID as described in Shoichet, "Molecular docking using shaper descriptions", J. Comp. Chem., 13(3):380-397 (1992) which is hereby incorporated by reference.

The docking calculations were run in parallel, using 56 simultaneous processes, on a 14-node compute cluster as described in Papadopoulos, "NPACI Rocks: tools and techniques of easily deploying manageable Linux clusters", Concurrency Computat: Pract. Exper., 15:707-725 (2003), which is hereby incorporated by reference. Rigid docking with automated matching, a maximum of 1000 orientations per ligand, grid scoring and ligand conformation optimization required about 10 days (at about 1 compound/sec) to perform. Dock scores were empirical with lower values representing higher affinity. The docking scores approximated a Gaussian distribution (Figure 2) with a mean value of -26.6 and a standard deviation of 3.3. Of the over 1.1 million compounds modeled, the 101 compounds of Table 1 bound PF4 near Lys50. These 100 compounds scored greater than 5 standard deviations below the mean (-73.8 or less).

Table 1

Name # Name

4-(aminomethyl)-8-(3-fluorophenyl)-7-

[hydro xy-(3 -pyridyl)methyl]phosphinic acid 71 thia-l,5,9-triazabicyclo[4.3.0]nona-3,5,8- trien-2-one

4-(aminomethyl)-8-(4-chlorophenyl)-7-

72 thia-l,5,9-triazabicyclo[4.3.0]nona-3,5,8- trien-2-one

[5-(4-benzyl- 1 -piperidyl)- 1 ,3 ,4-oxadiazol- styrylphosphinic acid 73

2-yl]methanamine

2-cyano-N-[2-[4-(2-diethylaminoethoxy)-

(acetyl-allyl-amino)methylphosphinic acid 74

3-ethoxy-phenyl]ethyl]acetamide

2-(4-ethylpiperazin- 1 -yl)- 1 -( 1 H-indol-3 -

2-(2-furyl)ethylphosphinic acid 75

yl)-2-phenyl-ethanone

2-( 1 -cyclopropylethylcarbamoylmethyl- l-benzylphosphonoyl-4-phenyl-benzene 76 methyl-amino)-N-(2,4,6- trimethylphenyl)-acetamide

(E)-2-cyano-3-[3-(2-diethylaminoethoxy)-

77

4 -methoxy-phenyl]prop -2 -enoic acid

[(E, 1 R)- 1 -hydro xy-3 -phenyl-prop-2-

78 2-chloroethylphosphonoylbenzene enyllphosphinic acid

(Z)-3-indolin-7-yl-2-

79

(pho sphonomethyl)prop -2 -enoic acid

3 -[ 1 -(carboxymethyl} -5-(4-

80

chlorophenyl)-pyrrol-2-yl]propanoic acid methyl 2 - [4-(aminomethyl)pheny 1] -4 - benzylphosphonic acid 81

methyl -thiazole-5 -carboxylate

(Z)-2-cyano-3-[4-(3-

(2-hydroxyphosphonoyl-2-phenyl-

82 dimethylaminopropoxy)-3-ethoxy- ethyl)phosphinic acid

phenyl]prop-2-enoic acid

5 - [( 1 R)- 1 -aminoethyl] -N-[(3 R)- 1 , 1 -

2-chloroethylphosphonoylbenzene 83 dioxothiolan-3 -yl] -N-methyl-furan-2- carboxamide

2-[2-[(E)-2-(p-tolyl)vinyl]thiazolo[2,3-

(5-oxotetrahydrofuran-3 -yl)phosphinic acid 84

e] [ 1 ,2,4]triazol-6-yl]ethanamine

N-methyl- 1 -[4-(2-pyrrolidin- 1 -

(2,4-dimethoxyphenyl)phosphinic acid 85

ylethoxy)phenyl]-propan-2 -amine

4-(aminomethyl)-8-(3-methoxyphenyl)-7-

86 thia-l,5,9-triazabicyclo[4.3.0]nona-3,5,8- trien-2-one

4-[2-[2-(3-

2-chloroethoxyphosphonoyloxybenzene 87 dimethylaminopropoxy)phenyl] ethylaminol-4-oxo-butanoic acid

2-[2-(3,4-dimethoxyphenyl)ethyl-methyl-

2 -butoxypho sphonoyl-2 -methyl-prop ane 88

thiocarbamoyl] sulfanylacetic acid

2-[2-[2-(m-tolyl)ethyl]thiazolo[2,3-

1 -(2-phenylacetyl)aminoethylphosphinic acid 89

e] [ 1 ,2,4]triazol-6-yl]ethanamine a compound having the following

(2S)-2-[[(2S)-3-methyl-2-[(2-

90 methylbenzoyl)amino]butanoyl] amino] -3 - sulfidopropionic acid structure ⁰— '

(Z)-2-cyano-3-[3-[2-(2-

1 -butylphosphonoylbutane 91 methoxyphenoxy)ethoxy]phenyl]prop-2- enoic acid

[4-[(2-methoxyphenoxy)methyl]phenyl]

92

methanamine # Name # Name

4 - [(2 -pho sphonophenoxy } methyljbenzoic

43 93

acid

( 1 -benzhydrylamino-3 -methyl - [5-(aminomethyl)-2-furyl]-[(2R)-2-ethyl-

44 94

butyl)phosphinic acid 1 -piperidyllmethanone

[4-[2-(3,5-dimethylphenoxy)ethoxy]-3-

45 phenoxyphosphinic acid 95

methoxy-phenyllmethanamine

(benzylamino-phenyl-methyl)phosphinic

46 96 2-phosphonooxybenzoic acid acid

l-[2-(4-tert-

47 97

butylphenoxy)ethy 1 Jpiperazine

[3-methoxy-4-(o-

48 98

tolylmethoxy)phenyl]methanamine

4 - [ [4 -(dimethyl aminome thy l)pheny 1]

49 2-amino-3-sulfino-propanoic acid 99

methylsulfamoyl]benzoic acid

(3R)-3-[(3,5-dimethoxybenzoyl)amino]-

50 100

3-(p-tolyl)propanoic acid

3-[5-(4-chlorophenyl)-l-(2-ethoxy-2-

101

oxyethyl)-lH-pyrrol-2-yl] propanoic acid

Figure 1 provides molecular models of a representative compound from these 101 compounds. As noted, the representative compound fits in the pocket formed by the PF4 tetramer and is adjacent to the salt bridge of the PF4 tetramer. Figure IB is 5 the same molecule model as Figure 1A, but rotated 90°.

The 15 compounds of Table 2 were selected from the compounds of Table 1 and were selected to determine their ability to disrupt of inhibit PF4 formation.

Table 2

Example 2: Prevention of PF4 tetramer Formation using Antagonistic Compounds

The 15 compounds from Example 1 in Table 2 were then tested using SDS 5 PAGE analysis of BS3 crosslinked PF4 for their ability to prevent PF4 tetramer

formation.

As is known in the art, DLS is useful in distinguishing PF4 ULCs from PF4 alone. See, Suvarna and Greinacher et al, "Heparin-induced thrombocytopenia: a stoichiometry-based model to explain the differing immunogenicities of

10 unfractionated heparin, low-molecular-weight heparin, and fondaparinux in difference clinical settings", Throm. Res, 122:21 1-220 (2008), which are hereby incorporated by reference, for a detailed description of this technique. cDNA encoding human PF4 was cloned into the plasmid pMT/BiPN5-His A (Invitrogen Corp., Carlsbad CA) for expression in the Drosophila Expression System (Invitrogen, Carlsbad, CA). Cloning was performed using Bgl II and Age I cloning sites. A hexanucleotide encoding Bgl II site was then eliminated by site-directed mutagenesis so that the expressed protein contained full-length wild type (wt) PF4 or PF4^K50E with an identical sequence as their counterparts expressed in E. coli. See, Park described above. PF4 expression was induced by adding copper sulfate (0.5 mM). The induced S2 cells were incubated in serumfree Insect-Xpress™ media (Lonza, Walkersville, MD) for 3-5 days; supernatants were collected, sodium azide (0.02% final concentration) and EDTA (2.5 mM final concentration) were added, and the media were filtered through an Express® PLUS 0.22 μιη filter (Millipore Corp., Billerica, MA).

Wild-type (WT) human PF4 in the pT7-7 vector (Novagen (Madison, WI)) was expressed in the Escherichia coli strain BL21DE30 pLysS (Stratagene (La Jolla, CA)), and purified and characterized as described Rauova cited above and Park et al, "Biologic and biochemic properties of recombinant platelet factor 4 demonstrate identity with the native protein", Blood, 75: 1290-1295 (1990), which is hereby incorporated by reference. Briefly, recombinant protein was isolated from the supernatant of the bacterial lysate by affinity chromatography using a HiTrap high- performance (HP) affinity column.

WT PF4 was purified from the media on a heparin HiTrap® column on an ATKAPrime™ system (GE Healthcare) at 4°C in Tris (10 mM), EDTA (1 mM), and pH 8 buffer. Media was loaded in buffer containing NaCl (0.5 M) and PF4 was eluted at 1.8 M NaCl using a linear gradient. Fractions containing purified PF4 as detected by silver staining of 12% NuPAGE Bis-Tris gels (Invitrogen) were pooled, concentrated and buffer exchanged into 50 mM HEPES, 0.5 M NaCl, pH - 7.2 using an Amicon® Ultra centrifugal filter (3K NMWL, Millipore Corp). Protein was quantified using a BCA assay. A. Experiment 1

Compounds 34, 24, 1, 80, 88, and 96 were then tested for their ability to inhibit PF4 tetramer formation using a cross-linking assay as described in Rauova cited above. Specifically, hPF4 (10 μg/mL) in phosphate-buffered saline (PBS) was incubated at 37°C for 15 minutes in the absence of the antagonistic compounds (control sample) and presence of compounds 34, 24, 1, 80, 88 and 96. See, the following Table 3, which provides the reagents and amounts. Samples 1 and 18 were the molecular weight markers.

Table 3

Cross linking and SDS-PAGE analysis were then performed as described in "Analysis of PF4 multimerization" of Rauova. The relative amounts of PF4 in each of the monomer, dimer, trimer and tetramer form were calculated by analyzing the samples on a 12% SDS-polyacrylamide gel under reducing conditions. Bands were quantified using the Kodak ID Image Analysis system (Kodak, Rochester, NY). The SigmaMarker™ reagent served as the molecular weight standard. Data was compiled and bar graphed as % PF4 for the tetramer, trimer, dimer, and monomer as a function of concentration for the test and control samples. See, Figures 4A and 4B.

These data show that all of the compounds were effective in inhibiting PF4 tetramer formation at tested concentrations. However, compound 96 had the best ability to inhibit tetramer formation at 1 mM. B. Experiment 2

This experiment was performed in a manner similar to experiment 1, but PF4 (10 μg/mL) in PBS was independently incubated with compound 1 (250 μΜ), 34 (500 μΜ), 80 (250 μΜ), 101 (250 μΜ), and 96 (500 μΜ) for 60 minutes at room temperature, followed by the addition of cross-linking reagent

bis(sulfosuccinimidyl)suberate (0.2 mM) for 30 minutes at room temperature. The reaction was stopped by adding NuPAGE® lithium dodecyl sulfate (LDS) sample buffer, and denatured by heating to 70°C for 10 minutes according to the

manufacturer's instructions. The analysis and compilation of the data also was performed as described above in Experiment 1.

These data show that all of compounds 1, 80, 101, and 96 demonstrated a dose-dependent and ultimately complete inhibition of PF4 tetramer formation. See, Figure 7 and the following Table 4.

Table 4

Example 3: Disruption of ULC and/or PF4 tetramer Formation using

Antagonistic Compounds

Since ULCs are formed as part of a dynamic equilibrium between heparin and PF4, dynamic light scattering (DLS) was performed to measure the ability of compound 34, 1, 80, 96, and 100 to disrupt preformed ULCs.

In an effort to validate the following findings, samples were analyzed and included PF4 incubated in the absence or presence of unfractionated heparin (UFH) for 20 minutes at room temperature at PF4:heparin ratios (PHR) of 1 :0 (no heparin), 2: 1, and 0.64: 1. The samples were then analyzed using photon correlation spectroscopy on a DynaPro® DLS instrument and Dynamics® software (V6.7.6; Microsoft) to obtain correlation function. Figure 3 shows the results of the DLS analysis and is a bar graph showing the percentage of ULCs and small PF4 particles. The solid bar represent the data for the small particles (a population of particles with a mean hydrodynamic diameter of about 1 nm) and the striped bars represent the data for the large particles (a population of particles with a mean hydrodynamic diameter of about 300 nm). Data are expressed as the percent of total intensity from each measurement, the mean of 10 measurements, and representative of two such experiments. As noted from this figure, larger amounts of heparin result in the disruption of larger particles, i.e., ULCs, demonstrated by the presence of virtually all of the PF4 as small particles (Figure 3). A. Analysis of Compound 96

ULCs were formed as described in Rauova cited above. Specifically, hPF4 (10 μg/mL) in phosphate-buffered saline (PBS) was incubated at 37°C for 15 minutes in the presence of heparin (0.34 U/mL) - molar ratio of PF4:heparin is 2.5: 1). After removal of three aliquots of this PF4 and heparin solution containing ULCs, the aliquots were incubated with 0.1 μΜ, 1 μΜ, or 10 μΜ of compound 96 at 37°C. The total percentage of ULC (%) was measured and graphed. See, Figure 5 which is a bar graph of DLS data demonstrating ULC antagonistic activity for compound 96 as % inhibition vs. ULC diameter.

These data show that the sample lacking compound 96 results in exclusively ULCs. However, regardless of concentration, compound 96 is effective in disruption the preformed ULCs. Specifically, even at 0.1 μΜ, compound 96 reduces the amount of ULC and increases the formation of small particles. In fact, the use of 10 μΜ of compound 96 results in almost complete disruption of all ULCs. PF4 is present as small particles (similar to PF4 alone) when ULC are disrupted.

B. Analysis of Compounds 34, 1, 80, 96, and 101

This experiment was performed to evaluate the ability of compounds 1, 34, 80, 101, and 96 to facilitate the disruption of preformed ULC. ULC were formed as described above and then independently incubated with compounds 1 (125 μΜ and 63 μΜ), 34 (2 mM), 80 (250 μΜ), 101 (500 μΜ), and 96 (1 mM) or buffer for 24 hours at 37°C. Figure 8E shows that compounds 1, 80 and 101 facilitated dissociation of preformed ULC in a dose dependent manner. Under the conditions examined, breakdown was incomplete (some ULC were still present). However, for compounds 1 and 101, less than 50% of ULC remained as compared to the baseline. Of interest, compound 96 did not promote breakdown of preformed ULC despite successfully preventing de novo ULC formation, as discussed in Example 4. Compound 34 did not inhibit the stability of preformed ULC.

Example 4: Inhibition of ULC Formation

Since the data of Example 3 demonstrated that the PF4 antagonists discussed herein are capable of disrupting preformed ULCs, this example was performed to determine if the PF4 antagonists of the invention were capable of preventing formation of ULCs.

A. ELISA Measurement of ULC Inhibition

In this experiment, solutions containing varying concentrations of compound 1 (1, 2, 4, 8, 16, 31, 62, 125, 250, 500, and 100 μΜ), 34 (125, 250, 500, and 1000 μΜ),

80 (31, 62, 125, 250, 500, and 1000 μΜ), 101 (8, 16, 31, 62, 125, 250, and 500 μΜ), and 96 (16, 31, 62, 125, 250, 500, 1000, 2500, and 5000 μΜ) were preincubated with

PF4 (7.5 μg/mL) for 1 hour at 37°C. Heparin (0.2 U/mL) was then added to each sample and the mixtures (final PF4 concentration of 5 μg/mL) were incubated for an additional 15 minutes at 37 °C. The total percentage of ULC (%) was measured by

ELISA and the data plotted. See, Figure 8A which is line graph demonstrating ULC antagonistic activity for the tested compounds.

The data of Figure 8 A show that compounds 1, 80, 101, and 96 inhibited ULC formation in a dose-dependent matter. Inhibition was complete at the highest concentrations tested. Further, the relative potency of the tested PF4 antagonists, as measured by IC5₀ and provided in the following Table 5 is similar to that in Example

2.

Table 5

PF4 Antagonist ICso (μΜ)

101 190

96 1300

B. Gel Filtration Measurement of ULC Inhibition

In this experiment, independent 1 mM solutions of compound 1, 34, 80, 101, and 96 were preincubated with PF4 (7.5 μg/mL) for 1 hour at 37°C. Heparin (0.2 U/mL) was then added to each sample and the mixtures (final PF4 concentration of 5 μg/mL) were incubated for an additional 15 minutes at 37 °C. One control contained PF4^K50E and the other control contained PF4 (5 μg/mL) and heparin (0.2 U/mL). The total percentage of ULC (%) was measured using gel filtration as described in Ranuova, Blood, 10591): 131-138 (2005) cited above and the percentage of ULC provided for the tested compounds. See, Figure 8B which is a bar graph

demonstrating ULC antagonistic activity for the tested compounds.

The data of Figure 8B shows that compounds 1, 80, 101, and 96 substantially inhibited ULC formation. C. Varying Heparin Concentrations on ULC Inhibition

In this experiment, the ability of PF4 antagonists to inhibit ULC formation over a range of heparin concentrations was determined. Specifically, 1 mM of each of compounds 1, 34, 80, and 101 were independently preincubated with PF4 (7.5 μg/mL) for 1 hour, followed by the addition of varying concentrations of heparin (0.05, 0.1, 0.2, 0.4, 0.8, and 1.6 U/mL). The controls contained PF4 (7.5 μg/mL) and varying concentrations of heparin (0.05, 0.1, 0.2, 0.4, 0.8, and 1.6 U/mL). Absorbance of each solution was measure at 450 nm in a Packard SpectraCount™ plate reader. See, Figure 8C which provides the absorbance for each of the varying heparin containing solutions.

The data of Figure 8C illustrates that 1, 80, and 101 inhibited ULC formation over a range of heparin concentrations that span the parabolic dose response curve. These data show that inhibition of ULC by PF4 antagonists is not dependent on the amount of heparin present. Example 5: Effect of PF4 Antagonists on Antibody Binding to ULCs

The effect of the PF4 antagonists of the invention on antibody binding to intact ULCs was evaluated. ULC were formed as described in Part B of Example 2, with the exception that the PF4 was incubated with heparin for 30 minutes.

Compounds 1, 34, 80, 101, and 96 (1 mM) were then added to wells pre-coated with KKO. These solutions were then incubated in the KKO wells overnight at 37°C. Antibody binding was detected by adding HRP -conjugated sheep polyclonal anti- human PF4 antibody and developed with TMB substrate. After stopping the enzymatic reaction with 1 M H₃PO₄, absorbance was measured at 450 nm in a Packard SpectraCount™ plate reader. A direct ELISA was then performed as described in Arepally.

Figure 8D demonstrates antibody binding to ULCs in the absence and presence of PF4 antagonists of the invention. Specifically, these data show that compounds 1, 34, 101, and 96 do not directly inhibit antibody binding to preformed ULCs.

Example 6: Inhibition of Platelet Activation

Since one of the therapeutic goals of using ULC antagonists in patients with HITT is to prevent activation, compound 96 was evaluated for its ability to inhibit platelet activation. These data were generated using a serotonin release assay as described in Hirschman, "The use of platelet serotonin release as a sensitive method for detecting anti-platelet antibodies and a plasma anti-platelet factor in patients with idiopathic thrombocytopenic purpura", Br. J. Haematol, 24(6):793-802 (1973), which is hereby incorporated by reference.

In this assay, platelet rich plasma (PRP) from healthy donors was incubated with 0.5 μϊ_^ carbon- 14 labeled 5-hydroxytryptamine creatinine sulfate (GE Life Sciences, Piscataway, NJ) per milliliter of PRP for 20 minutes at 37°C. Serotonin uptake was inhibited by adding 1 mmol/mL imipramine (Sigma-Aldrich, St. Louis, MO) to the PRP.

Negative and positive controls contained sera from patients previously known to have negative or positive serotonin release, respectively. Heparin (1 U/mL) was added to the positive control serum in the absence or presence of compound 96 (3 niM). The percent release of serotonin was calculated for all conditions as previously described and plotted. Figure 6 is a bar graph of % of serotonin release for samples lacking (buffer only) and containing compound 96.These data illustrate that compound 96 is effective in inhibiting serotonin release, thereby inhibiting platelet activation.

Example 7: Serotonin Release Assay

This example assesses the activity of certain PF4 antagonists described herein as described in Hirschman, "The use of platelet serotonin release as a sensitive method for detecting anti-platelet antibodies and a plasma anti-platelet factor in patients with idiopathic thrombocytopenic purpura", Br. J. Haematol, 24(6):793-802 (1973), and Rauova and Cines, "Heparin-associated thrombocytopenia", N. Engl. J. Med., 303 :788-795 (1980), which are hereby incorporated by reference.

Briefly, platelet rich plasma (PRP) from healthy donors was incubated with 0.5 μΐ_^ ¹⁴C-5-hydroxytryptamine creatinine sulfate (GE Life Sciences, Piscataway, NJ) per milliliter of PRP for 20 minutes at 37°C to produce ¹⁴C-labeled platelets. Serotonin uptake was inhibited by adding 1 mmol/mL imipramine (Sigma-Aldrich, St. Louis, MO) to the PRP.

The radiolabeled platelets were mixed with KKO (170 μg/mL) or with known platelet-activating HIT plasma in the absence (buffer control) or presence of PF4 antagonist compounds 1, 34, 80, 101, and 96 (2.5 mM). The assay was performed in the presence of heparin (1.0 U/mL) and in the absence of heparin (background).

Negative controls without antibody were studied in parallel. ¹⁴C-5-hydroxytryptamine released from platelets is measured by scintillation counter. Data are expressed as % maximal release of radioactivity with release by the positive control plasma and 1.0 U/mL heparin defined as 100%.

Compounds 1, 80, 101 and 96 inhibited platelet activation by KKO as measured by the serotonin release assay (Figure 9E). The rank order of potency for inhibition of cellular activation by these compounds paralleled their ability to inhibit tetramer formation. Further, compounds 1 and 101 inhibited serotonin release from platelets activated by plasma from patients with HIT (Figure 9F). Example 8: HIT antibodies bound to ULC on platelets initiate activation by engaging FcyRIIA

This example was performed using the described below. Further, the assays described in the application entitled "Methods of Identifying HIT -Antibodies and PF4 Antagonists and Cells Lines for Use Therein", i.e., US Provisional Patent Application No. 61/614,829, filed March 23, 2012 and hereby incorporated by reference.

A. Preparation of B cells containing NFAT-Luc and FcyRIIA plasmids.

NFAT-Luc was prepared as described in Shapiro, "c-rel Regulation of IL-2 gene expression may be mediated through activation of AP-1 ", J. Exp. Med.,

184(5): 1663-1669 (1996), hereby incorporated by reference. The NFAT reporter contained three copies of a composite NFAT-activator protein- 1 (AP-1) element from the human interleukin-2 (IL-2) gene promoter, and is activated by binding of NFAT (nuclear factor of activated T-cells). pEF6-FcyRIIA, which contained the human FcyRIIA coding sequence under the control of the human EF- 1 a promoter, was constructed by cloning a human FcyRIIA IMAGE clone into the multiple cloning site of pEF6c (Invitrogen).

DT40 cells (chicken B cells) were cultured in RPMI supplemented with 10% fetal bovine serum, 1% chicken serum (Gibco), 50 μΜ 13-mercaptoethanol, 2 mM GlutaMAX (Gibco), 100 U/mL penicillin and 100 U/mL streptomycin at 37°C under 5% CO₂. Cells were co-transfected with pEF6-FcyRIIA (5 μg) and pEF6-NFAT-Luc (20 μg) by electroporation.

B. Validation of B Cells

This experiment validated that the transfected cells were useful in measuring inhibition of FcyRIIA mediated activation by HIT antibodies in the presence of PF4 and heparin.

On the day following transfection as described in Pary A, cells were pelleted by centrifugation and re-suspended at 2 x 10⁶ cells/mL in fresh medium without serum. Cell aliquots (50 μΚ) were placed into each well of a 96 well plate. To establish basal expression, 50 μΐ_^ media was added. The cells were also incubated, independently, with the following: PF4, heparin, RTO antibody, KKO antibody, ULCs alone, ULCs and RTO; ULCs and KKO and IV.3 antibody. Monoclonal antibody IV.3 (FcyRIIA-blocking antibody) was used as a positive control for FcyRIIA signaling. IV.3 (8 μg/mL) was added for 15 minutes at 37°C under 5% CO_2, followed by sheep anti-mouse-lgG secondary antibody (50 uL) at 15 μg/mL to crosslink and activate these receptors. As a positive control for an intact intracellular signaling pathway, phorbol myristate acetate (PMA; 25 ng/mL) with ionomycin (1 μΜ) was added.

Data show that the cells are activated by the antiFcyRIIA monoclonal antibody IV.3, as well as by the HIT-like monoclonal antibody KKO in the presence of ULC (Figure 9A). However, RTO, an isotype control that binds avidly to PF4 but does not mimic the pathological properties of HIT, failed to activate these cells. Importantly, KKO/ULC did not activate cells lacking FcyRIIA (transfected with pEF6-NFAT-Luc alone) which demonstrated that activation in this system is FcyRIIA dependent.

Furthermore, addition of PF4, heparin, KKO, or RTO alone did not activate the FcyRIIA-expressing cells, demonstrating the relevance of this assay in measuring the functional activity of HIT antibodies (Figure 9A).

It was next examined whether FcyRIIA activation was heparin-dependent. To do so, activation by KKO was measured using a constant amount of PF4 and increasing amounts of heparin. As seen in Figure 9B, the previously described bell- shaped dose-dependence of heparin concentration on platelet activation was observed. Taken together, the data support the use of the DT40 cell activation system as an assay of cellular activation via FcyRIIA dependent on PF4, heparin and HIT antibody and therefore as a means to assess the effect of PF4 antagonists discussed herein.

See, Kelton, "Heparin-induced thrombocytopenia: Laboratory studies", Blood, 72(3):925-930 (1988) and Reilly, "Heparin-induced thrombocytopenia/thrombosis in a transgenic mouse model requires human platelet factor 4 and platelet activation through FcyRIIA", 98(8):2442-2447 (2001), which are hereby incorporated by reference. Example 9: Measurement of FcyRIIA activation in DT40 cells

This example measured the inhibitory capacity of the PF4 antagonist compounds described herein. PF4 (10 μg/mL) and various concentrations of compounds 1, 34, 80, 96, and 101 were independently co-incubated for 60 minutes at 37°C under 5% CO₂ followed the addition of heparin (0.3 U/mL) for 15 minutes at 37°C in 5% CO₂. KKO (20 μg/mL) or plasma from patients with serotonin release assay confirmed HIT (1 :800 dilution) was then added. Fifty μϊ_^ of each mixture was added to the 96 well plate containing 50 μΐ_^ of cells at a concentration of 2 x 10⁶ cells/mL in fresh medium without serum. Plates were incubated for 6 hours at 37°C under 5% CO₂, and then frozen at -80°C. To measure activation, cells were thawed and lysed with 5X Passive Lysis Buffer (Promega) for 15 minutes. Luciferase activity was measured on a Berthold MultiLumat™ LB 9506 Luminometer (10 second readings) using Promega's Luciferase Assay Reagent following the manufacturer's instructions.

These data illustrate that compounds 1 and 101 were the most potent inhibitors of cellular activation (Table 6 and Figure 9C), causing complete inhibition at the highest doses tested. Compounds 80 and 96 were less potent and compound 34 was not inhibitory. Importantly, compounds 1 and 101 both inhibited activation by human HIT plasma with a similar potency as activation by KKO (Figure 9D).

Table 6

Example 10: Effect of PF4 Mutant, PF4 , on PF4 Solutions

This example provides the results using non-tetramerizing PF4 mutant, PF4^K50E as an antagonist of WT PF4 on solutions containing PF4.

PF4^K50E was prepared and purified as described for WT-PF4 in Example 2, but using MES (50 mM), EDTA (1 mM), pH 6.5 as the column buffer system. Media was loaded in buffer containing 0.3 M NaCl and PF4^K50E eluted at NaCl (1.3 M) using a linear gradient.

PF4 and PR4^K50E (total mass 10 μg/mL) were incubated for 60 minutes at room temperature, followed by the addition of cross-lining reagent BS (0.2 mM). Independent solutions of PF4 and PF4 (total mass 7.5 μg/mL) were incubated for 1 hour, followed by addition of heparin (0.2 U/mL). The samples were analyzed by ELISA, as described in Example 4 (Figure 8A), and data generated therefrom compiled.

Figures 1 OA- IOC show that while keeping the total PF4 concentration constant, as the percentage of WT PF4 mixed with PF4^K50E is decreased,

tetramerization (Figure 10A), ULC formation (Figure 10B) and FcyRIIA activation (Figure IOC) are all inhibited in a similar dose dependent manner. These data provide independent evidence that inhibition of PF4 tetramerization leads to inhibition of FcyRIIA activation by decreasing ULC formation.

Example 11 : Inhibition of Endothelial Activation using ULC antagonists

The 15 compounds from Example 1 are examined for their ability to inhibit HITT related cellular activation. Specifically, the ability of these compounds to inhibit platelet activation from HITT antibodies is measured. These compounds are also analyzed for their ability to inhibit PF4 activation of NFKB in endothelial cells in vitro.

A. Inhibition of cellular activation as related to HITT

The 15 compounds from Example 1 are evaluated for their ability to inhibit cellular activation related to HIT using the assays described in Warkentin, "Heparin- induced thrombocytopenia: diagnosis and management", Circulation, 110(18):e454-8 (2004) and Kelton, "Heparin-induced thrombocytopenia: a historical perspective", Blood, 1 12(7):2607-16 (2008).

It is anticipated that the data will show that the 15 compounds inhibit cellular activation as related to HITT.

B. Inhibition of PF4 activation of NFKB

The 15 compounds from Example 1 are analyzed for their impact on the ability of PF4 to activate NFKB in endothelial cells as described in Yu, "Endothelial expression of E-selectin is induced by the platelet-specific chemokine platelet factor 4 through LRP in an NF- {kappa} B-dependent manner", Blood, 105(9):3545 (May 1, 2005), which is hereby incorporated by reference using human umbilical vein endothelial cells (HUVECs).

The data are anticipated to provide support that the antagonists discussed herein inhibit PF4 tetramerization and interfere with PF4 activation of endothelial cells, which is directly relevant to HITT.

Example 12: Prevention of Thrombocytopenia and Thrombosis in a Murine Model using ULC Antagonists

The 15 compounds from Example 1 are evaluated for their ability to decrease thrombocytopenia and thrombosis in the HITT murine model system as described in Reilly I and Reilly II cited above and incorporated herein by reference.

The murine model system consists of mice homozygous for FcyRIIa and hPF4 and null for mPF4, hereafter designated IIa^+/+/hPF4^+/+/mPF4 ^~/_.

IIa^+/+/hPF4^+/+/mPF4 ^-/_ mice are weaned at 3 weeks of age and fed on SD (Lab Rodent Chow, Purina 5020; 4.5% fat). At 6 weeks of age, sex- and weight-matched littermates are either maintained on the SD (normocholesterolemic controls) or switched to a hypercholesterolemic diet (HD). The HD contains 15% cocoa butter, 1% cholesterol and 0.5% sodium cholate, in addition to essential nutrients, vitamins and minerals (TD.88051, Harlan-Teklad, Madison, WI, USA). HD-fed animals remain on the diet for only 4 weeks {i.e., until 10 weeks of age).

Mice are anesthetized by isofluorane inhalation for i.p. and s.c. injections and for blood collections. Blood is collected via the retro-orbital plexus using 50 μΐ, EDTA- or heparin-coated microcapillary tubes (Microcaps® tubes, Drummond Scientific, Broomall, PA, USA).

Plasma cholesterol is measured in all mice at 6 weeks of age (i.e., before initiation of the HD in the experimental group) and weekly thereafter. Mice in both diet groups are fasted for 4 hours before each blood collection. Total plasma cholesterol is determined by enzymatic assay (Thermo Electron, Louisville, CO, USA). Reactivity of platelets from HD-fed mice and SD-fed controls is evaluated at the age of 10 weeks by whole blood impedance aggregometry (the Chronolog® 540- VS instrument, Chronolog Corp., Havertown, PA, USA). Whole blood, collected in heparin, is mixed with 0.9% NaCl to adjust the final platelet count to 150,000 μ/L. Platelet aggregation is induced by collagen (1.5 μg/mL) and measured as the increase in impedance over time. Plasma levels of soluble vascular cell adhesion molecule (sVCAM) are measured by ELISA (Mouse sVCAM Immunoassay, R & D Systems, Minneapolis, M , USA).

After four weeks of HD feeding, each mouse receives i.p. injections of an antagonist compound of Example 1, followed by daily s.c. injections of unfractionated heparin (1200 or 1400 U/kg). Blood samples are collected from each mouse in EDTA, beginning 3 days before antagonist compound administration and are utilized as control samples 1-13, and then on days 1, 2, 3, 4 and 7 after antagonist compound injections. Complete blood counts on all 26 samples are measured using a Hemavet® analyzer (Model 850, CDC Technologies, Oxford, CT, USA). Platelet counts are monitored to assess thrombocytopenia. Red blood cell counts and hematocrit are monitored to ensure against unapparent hemorrhage. Thrombin-antithrombin complex III (TAT) levels are measured by an ELISA (Enzygnost® TATmicro reagents, Dade Behring, Newark, DE, US).

Experimental mice exhibiting signs of distress subsequent to heparin and antagonist compound injections are sacrificed by CO₂ inhalation. The major organs (lungs, heart, liver, kidneys, and spleen) are immediately harvested and fixed in neutral-buffered 10% formalin. Similarly treated, paired SD-fed mice are sacrificed at the same time. Formalin-fixed organs are embedded in paraffin and cut into 5-μιη sections. Hematoxylin and eosin-stained sections are evaluated by a comparative pathologist blinded to the experimental conditions. The area of each tissue examined is measured using the NIH ImageJ® software and the number of thrombi per 10 mm² are determined.

For immunohistochemistry, sections are sequentially blocked with ¾(¾ in methanol (to inhibit endogenous peroxidase activity) and 10% mouse serum before staining with directly biotinylated anti-hPF4 antibodies. Specificity for hPF4 is confirmed by staining mouse spleens, where antibodies react specifically with megakaryocytes.

The bound antagonist compounds are detected by incubating biotinylated horseradish peroxidase plus avidin followed by staining with diaminobenzidine. Immunohistochemistry sections are then lightly counterstained with hematoxylin and examined by light microscopy.

The data are anticipated to show that mice treated with the 15 compounds of Example 1 did not develop thrombocytopenia or that such treatment decreases the severity of thrombocytopenia. It is also expected that the data will show that mice treated with the 15 compounds of Example 1 did not develop thrombosis. Finally, it is expected that these data will demonstrate that the 15 compounds of Example 1 prevent formation of PF4 tetramers and PF4 tetramenheparin ULCs when administered concurrently with heparin administration.

All publications and priority application including US Provisional Patent Application No. 61/614,709, filed March 23, 2012, cited in this specification are incorporated herein by reference. While the invention has been described with reference to particular embodiments, it will be appreciated that modifications can be made without departing from the spirit of the invention. Such modifications are intended to fall within the scope of the appended claims.

Claims

WHAT IS CLAIMED IS:

1. A compound for use in preventing formation of platelet factor-4 (PF4) tetramers in a subject, wherein said compound is selected from the group consisting of:

(a) a compound of formula (II):

(II)

wherein:

n is 0 to 5;

R¹ and R² are, independently, H, Ci to C₁₀ alkyl, C(0)(C₁ to C₁₀ alkyl), C(0)(Ci to Cio alkyl), benzyl, C₃ to C₁₀ cycloalkyl, C2 to C₁₀ alkenyl, or C2 to Cio alkynyl; or

R¹ and R² together comprise a heterocycle or heteroaryl, optionally substituted by one or more R⁵;

R³ and R⁴ are, independently, H, OH, Ci to Cio alkyl, C₃ to Cio cycloalkyl, benzyl, aryl, heteroaryl, or heterocycle; or

R¹ and R³ together comprise a heterocycle or heteroaryl, each optionally substituted by one or more R⁵;

R⁵ is Ci to Cio alkyl, Ci to Cio alkoxy, halogen, OH, C2 to Cio alkenyl, C2 to Cio alkynyl, C₃ to Cio cycloalkyl, aryl, or (=0);

(b) a compound of formula (III):

OR¹⁶

I

0^^P^(CR¹⁷R¹⁸)_Q-R¹⁰

(HI)

wherein:

q is 0 to 5;

R¹⁰ is Ci to Cio alkyl. heteroaryl or aryl, each optionally substituted by one or more R¹⁹;

R¹⁶ is H or Ci to Cio alkyl; R¹⁷ and R¹⁸ are, independently, absent, H, Ci to C₁₀ alkyl, (Ci to C₁₀ alkyl)-P-(Ci to C₁₀ alkyl), Ci to C₁₀ alkoxy, halogen, OH, N0₂, CN, C₂ to C₁₀ alkenyl, P(0)OH, C₂ to C₁₀ alkynyl, aryl, heteroaryl, or heterocycle, each optionally substituted by one or more R¹⁹;

17 18 17 18 wherein when R or R is absent and q is at least 2, the CR R groups are bound through a stable double bond;

R¹⁹ is H, Ci to Cio alkyl, Ci to C₁₀ alkoxy, halogen, N0₂, CN, C(0)OH, C(0)(Ci to Cio alkyl), C₂ to Cio alkenyl, oxo, or C₂ to Cio alkynyl; (c) a compound of formula (IV):

(IV)

wherein:

m is 0 to 2;

R²⁰ is H, Ci to Cio alkyl C₃ to Cio cycloalkyl, C₂ to C₁₀ alkenyl, or C₂ to Cio alkynyl, each optionally substituted by one or more R²⁴;

R²¹, R²², and R²³ are independently, H, Ci to Cio alkyl, or C₃ to Cio cycloalkyl, each optionally substituted by one or more R²⁴;

R²⁴ is H, halogen, OH, CN, N0₂, Ci to Cio alkyl C₃ to Cio cycloalkyl, C₂ to Cio alkenyl, or C₂ to Cio alkynyl, each optionally substituted by one or more R²⁷;

R²⁵ is H, Ci to Cio alkyl C₃ to Cio cycloalkyl, C₂ to C₁₀ alkenyl, or C₂ to Cio alkynyl;

R²⁶ is O or S;

R²⁷ is H, P(0)OH, or Ci to Cio alkyl optionally substituted by halogen or OP(0)OH;

(d) a compound of formula (V):

O II

. P.

(V)

wherein: R and R are, independently, H, Ci to C₁₀ alkyl optionally substituted by one or more R⁴², aryl optionally substituted by one or more or benzyl optionally substituted by one or more R⁴²;

R⁴² is H, Ci to Cio alkyl, C(0)OH, NH₂, C(0)(d to C₁₀ alkyl), C(0)0(Ci to Cio alkyl), Ci to Cio aminoalkyl, halogen, aryl, or heteroaryl;

(e) a compound of formula (VI):

OR⁵¹

0=P— OR⁵⁰

I

_R52

(VI)

wherein:

R⁵⁰ is heteroaryl or heterocycle, each optionally substituted by one or more R⁵³;

R⁵¹ is H, Ci to Cio alkyl, Ci to Cio aminoalkyl, each optionally substituted by halogen or C(0)OH;

R⁵² is absent, Ci to Cio alkyl optionally substituted by P(0)2, or aryl optionally substituted by 0(Ci to Cio alkyl)-phenyl-C(0)OH;

R⁵³ is Ci to Cio alkyl, halogen, or C(0)OH;

(f) a compound of formula (VII):

O

\\

P— (CR⁶⁵R⁶⁶)_tR⁶⁰R⁶¹

HO

(VII)

wherein:

t is 1 to 10;

R⁶⁰ is aryl, heteroaryl, or heterocycle;

R⁶¹ is Ci to Cio aminoalkyl, Ci to Cio alkyl, C2 to Cio alkenyl, C2 to Cio alkynyl, C3 to Cio cycloalkyl, aryl, heteroaryl, or heterocycle;

R⁶⁵ and R⁶⁶ are, independently, H, OH, Ci to Cio alkyl, C₃ to Cio cycloalkyl, C2 to Cio alkenyl, C2 to Cio alkynyl benzyl, aryl, heteroaryl, or heterocycle;

(g) a compound of formula (VIII):

(VIII)

wherein:

R , R , R^/4, and R^/5 are, independently, H, Ci to C₁₀ alkyl, C₂ to C₁₀ alkenyl, Ci to Cio aminoalkyl, C(0)(Ci to Cio aminoalkyl), or heteroaryl, each optionally substituted by one or more R⁷⁸;

R⁷² is H, Ci to Cio alkyl, 0(d to Cio alkyl), 0(d to Cio alkoxy), 0(d to Cio aminoalkyl), Ci to Cio aminoalkyl, or heteroaryl, each optionally substituted by one or more R⁷⁶;

R⁷³ is Ci to Cio alkyl, Ci to Cio alkoxy, Ci to Cio aminoalkyl, each optionally substituted by one or more R⁷⁶;

R⁷⁶ is C(0)OH, C(0)(Ci to Cio alkyl), NHC(0)(Ci to Cio alkyl), C(0)NH(phenyl optionally substituted by one or more R⁷⁷), C(0)0(C₁ to Cio alkyl), heteroaryl optionally substituted by one or more R⁷⁷, heterocycle optionally substituted by one or more R⁷⁷, or phenyl optionally substituted by one or more R⁷⁷;

R⁷⁷ is halogen, Ci to Cio aminoalkyl, Ci to Cio alkoxy, Ci to Cio alkyl, or C2 to Cio alkenyl, each optionally substituted by one or more R⁷⁸;

R⁷⁸ is CN, C(0)OH, C(0)(Ci to Cio alkyl), C(0)0(Ci to Cio alkyl), or phenyl optionally substituted by one or more R⁷⁹;

R⁷⁹ is OH, Ci to Cio alkyl, C₃ to Cio cycloalkyl, C₂ to Cio alkenyl, C₂ to Cio alkynyl, halogen, or Ci to Ce alkoxy;

(h) a compound of formula (IX):

(IX)

wherein:

w is 1 to 10; w' is 1 to 10;

R⁸⁰ is H or C₂ to Cio alkyl;

R⁸¹ to R⁸⁵ are, independently, H, OH, Ci to Cio alkyl, halogen, or Ci to Cio alkoxy; and

R⁸⁶ to R⁸⁹ are, independently, H, Ci to Cio alkyl, or C3 to Cio cycloalkyl;

(i) a compound of formula (X):

(X)

wherein:

x is 2 to 10;

(j) a compound of formula (XI):

(XI)

wherein:

y is 1 to 10;

R⁹⁰ to R⁹⁴ are, independently, H, halogen, Ci to Cio alkyl, C2 to Cio alkenyl, C2 to Cio alkynyl, OH, or Ci to Cio aminoalkyl; and

R⁹⁵ is heterocycle, heteroaryl, aryl, or Ci to Cio aminoalkyl;

(k) a compound of formula (XII):

(XII)

wherein: R is aryl, heteroaryl, or heterocycle;

z is 2 to 10;

R¹⁰⁶ to R¹¹⁰ are, independently, H, Ci to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, OH, C2 to Cio alkenyl, or C2 to C₁₀ alkynyl;

(1) a compound of formula (XIII):

(XIII)

wherein:

a is 0 or 1;

R¹²⁰ is absent, aryl, C3 to C₁₀ cycloalkyl, heteroaryl, or heterocycle, each optionally substituted by one or more R¹²⁵;

R¹²¹ is aryl containing one or more R¹²³, Ci to C₁₀ aminoalkyl optionally containing one or two aryl groups optionally substituted by one or more R¹²⁴, heterocycle optionally substituted by one or more R¹²⁵;

R¹²³ is H, halogen, Ci to C₁₀ alkyl, or Ci to C₁₀ alkoxy;

R¹²⁴ is H, halogen, Ci to C₁₀ alkyl, Ci to C₁₀ alkoxy, or Ci to C₁₀ aminoalkyl;

R¹²⁵ is H, halogen, Ci to C₁₀ alkyl, Ci to C₁₀ alkoxy, (=0), or C(0)OH; or

R and R join to form C5 to Cio cycloalkyl optionally substituted by one or more R¹²⁶; and

R¹²⁶ is H, halogen, Ci to Cio alkyl, Ci to Cio alkoxy, or Ci to Cio aminoalkyl;

(m) a compound of fo

(XIV)

wherein: R is Ci to Cio alkyl, Ci to Cio aminoalkyl, C₂ to Cio alkenyl, or C₂ to Cio alkynyl, each optionally substituted by one or more R²⁰²;

R²⁰² is H, CI to Cio alkyl, halogen, CN, or 0₂; R²⁰⁰ is Ci to Cio alkyl, Ci to Cio alkoxy, aryl, C₂ to Cio alkenyl, Ci to Cio aminoalkyl, each optionally

203 203

substituted by one or more R ;R is halogen, CN, NO2, Ci to Cio alkoxy, or aryl optionally substituted by one or more R²⁰⁴;

R²⁰⁴ is Ci to Cio alkyl, Ci to Cio alkoxy, halogen, CN, N0₂, or aryl; (n) a compound of formula (XV):

wherein:

R³⁰¹ is Ci to Cio alkyl, Ci to Cio aminoalkyl, C₂ to Cio alkenyl, or C₂ to

_R302

Cio alkynyl, each optionally substituted by one or more

R³⁰² is H, Ci to Cio alkyl, halogen, CN, or N0₂; R³⁰⁰ is Ci to Cio alkyl, Ci to Cio alkoxy, aryl, C₂ to Cio alkenyl, Ci to Cio aminoalkyl, each optionally substituted by one or more R³⁰³;

R³⁰³ is halogen, CN, NO₂, or aryl optionally substituted by one or more

304.

R

R is Ci to Cio alkyl, Ci to Cio alkoxy, halogen, CN, N0₂, or aryl;

(0) a compound of formula (XVI):

(XVI)

wherein:

R⁴⁰⁰ is OH or O;

R⁴⁰¹, R⁴⁰², and R⁴⁰³, are independently, OR⁴⁰⁵ or N(R⁴⁰⁶)(R⁴⁰⁷);

R⁴⁰⁴ is H, Ci to Cio alkyl, halogen, (=0), or Ci to Cio alkoxy; R⁴⁰⁵ is absent, Ci to C₁₀ alkyl, heterocycle, aryl, or heteroaryl,

_R406

optionally substituted by one or more

R⁴⁰⁶ is H, Ci to Cio alkyl, halogen, Ci to C₁₀ alkoxy, C(0)(Ci to C₁₀ alkyl), aryl, heteroaryl, C(0)(aryl optionally substituted by one or more _R404

R⁴⁰⁷ is absent, H, Ci to C₁₀ alkyl, halogen, Ci to C₁₀ alkoxy, aryl, or heteroaryl;

with the proviso that when R⁴⁰⁰ is O and R⁴⁰⁵ or R⁴⁰⁷ is absent, then R⁴⁰⁰ and R⁴⁰² join to form a 5 to 8-membered ring, wherein the 5 to 8- membered ring contains carbon atoms and optionally one or more heteroatom and wherein the 5 to 8-membered ring is optionally substituted by one or more R⁴⁰⁴; and

with the proviso that when R⁴⁰¹ is OR⁴⁰⁵ and R⁴⁰³ is N(R⁴⁰⁶)(R⁴⁰⁷) and R⁴⁰⁵ and R⁴⁰⁷ are absent, R⁴⁰¹ and R⁴⁰², and/or R⁴⁰¹ and R⁴⁰³, and/or R⁴⁰² and R⁴⁰³ join to form a 5 to 8-membered ring, wherein the 5 to 8- membered ring contains carbon atoms and optionally one or more heteroatom and wherein the 5 to 8-membered ring is optionally substituted by one or more R⁴⁰⁴;

(p) a compound of formula (XVII):

(XVII)

wherein:

R is Ci to Cio aminoalkyl;

R⁵⁰² is benzyl optionally substituted by one or more R⁵⁰³; R⁵⁰¹ is H, Ci to Cio alkyl, C3 to Cio cycloalkyl, Ci to Cio alkoxy, or aryl;

f is 0 to 4; and

R⁵⁰³ is H, Ci to Cio alkyl, Ci to Cio alkoxy, halogen, or aryl;

(q) a compound of formula (XVIII):

(XVIII)

wherein:

R⁵⁰⁷ is H, OH, C i to Cio alkoxy, or C₃ to C₁₀ cycloalkyl;

_R508 _{tQ R}5io _are^ independently, H, C_i to C_io alkyl, d to Cio alkoxy, to Cio cycloalkyl, or halogen; and

(r) a compound of formula (XIX):

(XIX)

wherein:

R⁶⁰⁰ is Ci to Cio alkyl, NH₂ or Ci to Cio aminoalkyl;

R⁶⁰² to R⁶⁰⁵ are, independently, Ci to Cio alkyl, d to Cio cycloalkyl, Ci to Cio alkoxy, or halogen;

(s) a compound of formula (XX):

(XX)

wherein:

R⁶⁰⁶ is H or Ci to Cio alkyl;

R⁶⁰⁷ to R⁶¹⁰ are, independently, H, d to Cio alkyl, d to Cio alkoxy, or halogen;

(t) a compound of formula (XXI):

(XXI) wherein:

_R7oo _{tQ R}704 _ar6j independently, H, Ci to C₁₀ alkyl, C3 to CIO cycloalkyl, C3 to C₁₀ spirocycloalkyl, Q to C₁₀ alkoxy, halogen, Ci to C₁₀ aminoalkyl, or CN; and

R⁷⁰⁵ is H or Ci to C₁₀ alkyl;

(u) a compound of formula (XXII):

(XXII)

wherein:

_R8oo _{tQ R}804 _{and R}806 ^ _R809 ^ independently, H, C_i to C₁₀ alkyl, halogen, NH₂, or Ci to C₁₀ alkoxy and

8⁰⁵ is H or Ci to C₁₀ alkyl;

(XXIII)

wherein:

R^JUU is H or Ci to C₁₀ alkyl; and

R⁹⁰¹ to R⁹⁰⁵ is H, Ci to Cio alkyl, C₂ to C₁₀ alkenyl, C₂ to C10 alkynyl, halogen, Ci to C₁₀ alkoxy, Ci to C₁₀ aminoalkyl, or H₂; and

(w) a compound of formula (XXIV):

(XXIV)

wherein:

R⁹⁰⁶ is Ci to Cio alkyl or Ci to C₁₀ alkoxy;

R⁹⁰⁷ is C2 to Cio alkyl or Ci to Cio alkoxy;

e is 0 to 5;

R⁹⁰⁸ is H, halogen, Ci to Cio alkyl, Ci to Cio alkoxy, OH, CN, or NH₂; and

R⁹⁰⁹ is H or Ci to Cio alkyl;

or a pharmaceutically acceptable salt or prodrug thereof.

2. The compound according to claim 1, wherein said compound binds to a PF4 dimer or PF4 monomer.

3. A compound for use in disrupting platelet factor-4 (PF4) tetramers in a subject, wherein said compound is selected from the group consisting of:

(a) a compound of formula (II):

(II)

wherein:

n is 0 to 5;

R¹ and R² are, independently, H, Ci to Cio alkyl, C(0)(Ci to Cio alkyl), C(0)(Ci to Cio alkyl), benzyl, C3 to Cio cycloalkyl, C2 to Cio alkenyl, or C2 to Cio alkynyl; or

R¹ and R³ together comprise a heterocycle or heteroaryl, each optionally substituted by one or more R⁵; R⁵ is Ci to Cio alkyl, Ci to Cio alkoxy, halogen, OH, C₂ to Cio alkenyl, C₂ to Cio alkynyl, C3 to Cio cycloalkyl, aryl, or (=0);

(b) a compound of formula (III):

OR 16

O^' (CR¹⁷R¹⁸)_q-R 10

(III)

wherein:

q is 0 to 5;

R¹⁶ is H or Ci to Cio alkyl;

R¹⁷ and R¹⁸ are, independently, absent, H, Ci to Cio alkyl, (Ci to Cio alkyl)-P-(Ci to Cio alkyl), Ci to Cio alkoxy, halogen, OH, N0₂, CN, C₂ to Cio alkenyl, P(0)OH, C2 to Cio alkynyl, aryl, heteroaryl, or heterocycle, each optionally substituted by one or more R¹⁹;

wherein when R¹⁷ or R¹⁸ is absent and q is at least 2, the CR¹⁷R¹⁸ groups are bound through a stable double bond;

(IV)

wherein:

m is 0 to 2;

R²¹, R²², and R²³ are independently, H, Ci to Cio alkyl, or C₃ to Cio cycloalkyl, each optionally substituted by one or more R²⁴; R is H, halogen, OH, CN, N0₂, d to C₁₀ alkyl C₃ to C₁₀ cycloalkyl, C₂ to Cio alkenyl, or C₂ to C₁₀ alkynyl, each optionally substituted by one or more R²⁷;

R²⁶ is O or S;

(d) a compound of formula (V):

O II

_R41' ^P^_R40

(V)

wherein:

R⁴⁰ and R⁴¹ are, independently, H, Ci to Cio alkyl optionally substituted by one or more R⁴², aryl optionally substituted by one or more R⁴², or benzyl optionally substituted by one or more R⁴²;

R⁴² is H, Ci to Cio alkyl, C(0)OH, NH₂, C(0)(d to Cio alkyl), C(0)0(Ci to Cio alkyl), Ci to Cio aminoalkyl, halogen, aryl, or heteroaryl;

(e) a compound of formula (VI):

OR⁵¹

0=P— OR⁵⁰

I

_R52

(VI)

wherein:

R⁵² is absent, Ci to Cio alkyl optionally substituted by P(0)₂, or aryl optionally substituted by 0(Ci to Cio alkyl)-phenyl-C(0)OH;

R⁵³ is Ci to Cio alkyl, halogen, or C(0)OH;

(f) a compound of formula (VII):

(VII)

wherein:

t is 1 to 10;

R⁶⁰ is aryl, heteroaryl, or heterocycle;

R⁶¹ is Ci to Cio aminoalkyl, Ci to C₁₀ alkyl, C2 to C₁₀ alkenyl, C2 to Cio alkynyl, C3 to Cio cycloalkyl, aryl, heteroaryl, or heterocycle;

(g) a compound of formula (VIII):

(VIII)

wherein:

R , R , R , and R^/5 are, independently, H, Ci to Cio alkyl, C₂ to Cio alkenyl, Ci to Cio aminoalkyl, C(0)(Ci to Cio aminoalkyl), or heteroaryl, each optionally substituted by one or more R⁷⁸;

R⁷² is H, Ci to Cio alkyl, 0(Ci to Cio alkyl), 0(Ci to Cio alkoxy), 0(Ci to Cio aminoalkyl), Ci to Cio aminoalkyl, or heteroaryl, each optionally substituted by one or more R⁷⁶;

R⁷⁶ is C(0)OH, C(0)(Ci to Cio alkyl), NHC(0)(Ci to Cio alkyl), C(0)NH(phenyl optionally substituted by one or more R⁷⁷), C(0)0(Ci to Cio alkyl), heteroaryl optionally substituted by one or more R⁷⁷, heterocycle optionally substituted by one or more R⁷⁷, or phenyl optionally substituted by one or more R⁷⁷; R is halogen, Ci to C₁₀ aminoalkyl, Ci to C₁₀ alkoxy, Ci to C₁₀ alkyl, or C₂ to Cio alkenyl, each optionally substituted by one or more R⁷⁸;

(h) a compound of formula (IX):

(IX)

wherein:

w is 1 to 10;

w' is 1 to 10;

R⁸⁰ is H or C₂ to Cio alkyl;

R⁸⁶ to R⁸⁹ are, independently, H, Ci to Cio alkyl, or C₃ to Cio cycloalkyl;

(i) a compound of formula (X):

(X)

wherein:

x is 2 to 10;

G) a compound of formula (XI):

(XI)

wherein:

y is 1 to 10;

R⁹⁰ to R⁹⁴ are, independently, H, halogen, Ci to C₁₀ alkyl, C₂ to C₁₀ alkenyl, C₂ to C₁₀ alkynyl, OH, or Ci to C₁₀ aminoalkyl; and

R⁹⁵ is heterocycle, heteroaryl, aryl, or Ci to C₁₀ aminoalkyl;

(k) a compound of formula (XII):

(XII)

wherein:

R¹⁰⁵ is aryl, heteroaryl, or heterocycle;

z is 2 to 10;

R¹⁰⁶ to R¹¹⁰ are, independently, H, Ci to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, OH, C₂ to Cio alkenyl, or C₂ to C₁₀ alkynyl;

(1) a compound of formula (XIII):

(XIII)

wherein:

a is 0 or 1;

R¹²⁰ is absent, aryl, C3 to Cio cycloalkyl, heteroaryl, or heterocycle, each optionally substituted by one or more R¹²⁵; R is aryl containing one or more R , Ci to C₁₀ aminoalkyl optionally containing one or two aryl groups optionally substituted by one or more R¹²⁴, heterocycle optionally substituted by one or more R¹²⁵;

R¹²³ is H, halogen, Ci to C₁₀ alkyl, or Ci to C₁₀ alkoxy;

R¹²⁴ is H, halogen, Ci to Cio alkyl, Ci to Cio alkoxy, or Ci to Cio aminoalkyl;

R¹²⁵ is H, halogen, Ci to Cio alkyl, Ci to Cio alkoxy, (=0), or C(0)OH; or

(m) a compound of formula (XIV):

j2

(XIV)

wherein:

R is Ci to Cio alkyl, Ci to Cio aminoalkyl, C2 to Cio alkenyl, or C2 to Cio alkynyl, each optionally substituted by one or more R²⁰²;

203 203

substituted by one or more R ;R is halogen, CN, NO₂, Ci to Cio alkoxy, or aryl optionally substituted by one or more R²⁰⁴;

R²⁰⁴ is Ci to Cio alkyl, Ci to Cio alkoxy, halogen, CN, N0₂, or aryl; (n) a compound of fo

(XV)

wherein:

R³⁰¹ is Ci to Cio alkyl, Ci to Cio aminoalkyl, C₂ to C₁₀ alkenyl, or C₂ to

_R302

Cio alkynyl, each optionally substituted by one or more

R³⁰² is H, Ci to Cio alkyl, halogen, CN, or 0₂; R³⁰⁰ is Ci to Cio alkyl, Ci to Cio alkoxy, aryl, C₂ to Cio alkenyl, Ci to Cio aminoalkyl, each optionally

303.

substituted by one or more R

R is halogen, CN, NO₂, or aryl optionally substituted by one or more

R 304.

R³⁰⁴ is Ci to Cio alkyl, Ci to Cio alkoxy, halogen, CN, N0₂, or aryl; (0) a compound of formula (XVI):

(XVI)

wherein:

R⁴⁰⁰ is OH or O;

R⁴⁰⁴ is H, Ci to Cio alkyl, halogen, (=0), or Ci to Cio alkoxy;

R⁴⁰⁵ is absent, Ci to Cio alkyl, heterocycle, aryl, or heteroaryl,

_R406

optionally substituted by one or more

R⁴⁰⁶ is H, Ci to Cio alkyl, halogen, Ci to Cio alkoxy, C(0)(Ci to Cio alkyl), aryl, heteroaryl, C(0)(aryl optionally substituted by one or more _R404

_R407

R is absent, H, Ci to Cio alkyl, halogen, Ci to Cio alkoxy, aryl, or heteroaryl;

with the proviso that when R⁴⁰¹ is OR⁴⁰⁵ and R⁴⁰³ is N(R⁴⁰⁶)(R⁴⁰⁷) and R⁴⁰⁵ and R⁴⁰⁷ are absent, R⁴⁰¹ and R⁴⁰², and/or R⁴⁰¹ and R⁴⁰³, and/or R⁴⁰² and R join to form a 5 to 8-membered ring, wherein the 5 to 8- membered ring contains carbon atoms and optionally one or more heteroatom and wherein the 5 to 8-membered ring is optionally substituted by one or more R⁴⁰⁴;

(p) a compound of formula (XVII):

(XVII)

wherein:

R is Ci to Cio aminoalkyl;

f is 0 to 4; and

R⁵⁰³ is H, Ci to Cio alkyl, Ci to Cio alkoxy, halogen, or aryl;

(q) a compound of formula (XVIII):

(XVIII)

wherein:

R⁵⁰⁷ is H, OH, Ci to Cio alkoxy, or C₃ to Cio cycloalkyl;

R⁵⁰⁸ to R⁵¹⁰ are, independently, H, Ci to Cio alkyl, Ci to C₁₀ alkoxy, C₃ to Cio cycloalkyl, or halogen; and

(r) a compound of formula (XIX):

(XIX)

wherein:

R⁶⁰⁰ is Ci to Cio alkyl, NH₂ or Ci to Cio aminoalkyl; R to R are, independently, Ci to Cio alkyl, C₃ to Cio cycloalkyl, Ci to Cio alkoxy, or halogen;

(s) a compound of formula (XX):

(XX)

wherein:

R⁶⁰⁶ is H or Ci to Cio alkyl;

_R607 _{10 R}6io _are^ independently, H, C_i to C_io alkyl, d to C_io alkoxy, or halogen;

(t) a compound of formula (XXI):

(XXI)

wherein:

_R7oo _{tQ R}704 _are^ independently, _H, C_i to C_io alkyl, C3 to C I O cycloalkyl, C₃ to Cio spirocycloalkyl, d to Cio alkoxy, halogen, d to Cio aminoalkyl, or CN; and

R⁷⁰⁵ is H or Ci to Cio alkyl;

(u) a compound of

(XXII)

wherein:

_R8oo _{t0 R}804 _{and R}806 _{ω(1 R}809 ^ _{independently; H>} Q _{to Cl0} alkyl, halogen, NH₂, or Ci to C₁₀ alkoxy and

R⁸⁰⁵ is H or Ci to C₁₀ alkyl;

(v) a compound o

wherein:

R⁹⁰⁰ is H or Ci to Cio alkyl; and

_R9oi _{tQ R}905 _{is Hj C i to alkyli C2 10 alkenyl5 Cl t0 C l0} aikyny^ halogen, Ci to Cio alkoxy, Ci to Cio aminoalkyl, or H₂; and

(w) a compoun

(XXIV)

wherein:

R⁹⁰⁶ is Ci to Cio alkyl or d to C₁₀ alkoxy;

R⁹⁰⁷ is C₂ to Cio alkyl or Ci to C₁₀ alkoxy;

e is 0 to 5;

R^JUJ is H or Ci to Cio alkyl;

or a pharmaceutically acceptable salt or prodrug thereof

4. The compound according to claim 3, wherein said compound disrupts the salt bridge of said PF4 tetramer.

5. A compound for use in preventing formation of ultra-large complexes (ULCs) comprising a PF4 tetramer and a glycosaminoglycan (GAG) in a subject, wherein said compound is selected from the group consisting of:

(a) a compound of formula (II):

(II)

wherein:

n is 0 to 5;

R¹ and R² are, independently, H, Ci to C₁₀ alkyl, C(0)(C₁ to C₁₀ alkyl), C(0)(Ci to Cio alkyl), benzyl, C₃ to C₁₀ cycloalkyl, C₂ to C₁₀ alkenyl, or C₂ to Cio alkynyl; or

R³ and R⁴ are, independently, H, OH, Ci to Cio alkyl, C3 to Cio cycloalkyl, benzyl, aryl, heteroaryl, or heterocycle; or

R⁵ is Ci to Cio alkyl, Ci to Cio alkoxy, halogen, OH, C₂ to Cio alkenyl, C₂ to Cio alkynyl, C₃ to Cio cycloalkyl, aryl, or (=0);

(b) a compound of formula (III):

OR¹⁶

I

O ^(CR¹⁷R¹⁸)_q-R¹⁰

(HI)

wherein:

q is 0 to 5;

R¹⁶ is H or Ci to Cio alkyl;

R¹⁷ and R¹⁸ are, independently, absent, H, Ci to Cio alkyl, (Ci to Cio alkyl)-P-(Ci to Cio alkyl), Ci to Cio alkoxy, halogen, OH, N0₂, CN, C₂ to Cio alkenyl, P(0)OH, C₂ to C₁₀ alkynyl, aryl, heteroaryl, or heterocycle, each optionally substituted by one or more R¹⁹;

R¹⁹ is H, Ci to Cio alkyl, Ci to Cio alkoxy, halogen, N0₂, CN, C(0)OH, C(0)(Ci to Cio alkyl), C₂ to Cio alkenyl, oxo, or C₂ to Cio alkynyl; (c) a compound of formula (IV):

(IV)

wherein:

m is 0 to 2;

R²⁶ is O or S;

(d) a compound of formula (V):

O II

. P.

(V)

(e) a compound of formula (VI):

OR⁵¹

0=P— OR⁵⁰

I

_R52

(VI)

wherein:

R⁵³ is Ci to Cio alkyl, halogen, or C(0)OH;

(f) a compound of formula (VII):

O

\\

P— (CR⁶⁵R⁶⁶)_tR⁶⁰R⁶¹

HO

(VII)

wherein:

t is 1 to 10;

R⁶⁰ is aryl, heteroaryl, or heterocycle;

(g) a compound of formula (VIII):

(VIII)

wherein:

R⁷⁰, R⁷¹, R⁷⁴, and R⁷⁵ are, independently, H, Ci to C₁₀ alkyl, C₂ to C₁₀ alkenyl, Ci to C₁₀ aminoalkyl, C(0)(Ci to C₁₀ aminoalkyl), or heteroaryl, each optionally substituted by one or more R⁷⁸:

R⁷² is H, Ci to Cio alkyl, 0(d to C₁₀ alkyl), 0(d to C₁₀ alkoxy), 0(d to Cio aminoalkyl), Ci to C₁₀ aminoalkyl, or heteroaryl, each optionally substituted by one or more R⁷⁶;

R⁷³ is Ci to Cio alkyl, Ci to Cio alkoxy, Ci to Cio aminoalkyl, each optionally substituted by one or more R⁷⁶:

(h) a compound of formula (IX):

(IX)

wherein: w is 1 to 10;

w' is 1 to 10;

R⁸⁰ is H or C₂ to Cio alkyl;

R⁸⁶ to R⁸⁹ are, independently, H, Ci to Cio alkyl, or C3 to Cio

cycloalkyl;

(i) a compound of formula (X):

wherein:

x is 2 to 10;

(j) a compound of formula (XI)

(XI)

wherein:

y is 1 to 10;

R⁹⁵ is heterocycle, heteroaryl, aryl, or Ci to Cio aminoalkyl;

(k) a compound of formula (XII):

(XII)

wherein:

R¹⁰⁵ is aryl, heteroaryl, or heterocycle;

z is 2 to 10;

R¹⁰⁶ to R¹¹⁰ are, independently, H, Ci to Cio alkyl, C₃ to Cio cycloalkyl, OH, C2 to Cio alkenyl, or C2 to Cio alkynyl;

(1) a compound of formula (XIII):

(XIII)

wherein:

a is 0 or 1;

R¹²⁰ is absent, aryl, C3 to Cio cycloalkyl, heteroaryl, or heterocycle, each optionally substituted by one or more R¹²⁵;

R¹²¹ is aryl containing one or more R¹²³, Ci to Cio aminoalkyl optionally containing one or two aryl groups optionally substituted by one or more R¹²⁴, heterocycle optionally substituted by one or more R¹²⁵;

R¹²³ is H, halogen, Ci to Cio alkyl, or Ci to Cio alkoxy;

R¹²⁵ is H, halogen, Ci to Cio alkyl, Ci to Cio alkoxy, (=0), or C(0)OH; or

(m) a compound of formula (XIV):

j2

(XIV)

wherein:

R is Ci to Cio alkyl, Ci to Cio aminoalkyl, C₂ to Cio alkenyl, or C₂ to Cio alkynyl, each optionally substituted by one or more R²⁰²;

203 203

(XV)

wherein:

R is Ci to Cio alkyl, Ci to Cio aminoalkyl, C₂ to Cio alkenyl, or C₂ to

_R302

Cio alkynyl, each optionally substituted by one or more

R³⁰³ is halogen, CN, NO₂, or aryl optionally substituted by one or more

R³⁰⁴;

(XVI)

wherein:

4^UU is OH or O;

R is H, Ci to Cio alkyl, halogen, (=0), or Ci to Cio alkoxy;

R⁴⁰⁵ is absent, Ci to Cio alkyl, heterocycle, aryl, or heteroaryl,

_R406

optionally substituted by one or more

R⁴⁰⁶ is H, Ci to Cio alkyl, halogen, Ci to Cio alkoxy, C(0)(Ci t

404. alkyl), aryl, heteroaryl, C(0)(aryl optionally substituted by one or more R RR⁴⁰ is absent, H, Ci to Cio alkyl, halogen, Ci to Cio alkoxy, aryl, or heteroaryl;

(p) a compound of formula (XVII):

(XVII)

wherein:

R⁵⁰⁰ is Ci to Cio aminoalkyl;

R⁵⁰² is benzyl optionally substituted by one or more R⁵⁰³; R⁵ to Cio alkyl, C3 to Cio cycloalkyl, Ci to Cio alkoxy, or aryl;

f is 0 to 4; and

R⁵⁰³ is H, Ci to Cio alkyl, Ci to Cio alkoxy, halogen, or aryl;

(q) a compound of formula (XVIII):

(XVIII)

wherein:

R⁵⁰⁷ is H, OH, Ci to Cio alkoxy, or C₃ to Cio cycloalkyl;

R⁵⁰⁸ to R⁵¹⁰ are, independently, H, Ci to do alkyl, Ci to C₁₀ alkoxy, C₃ to Cio cycloalkyl, or halogen; and

(r) a compound of

(XIX)

wherein:

R⁶⁰⁰ is Ci to Cio alkyl, NH₂ or Ci to Cio aminoalkyl;

_R ⁶⁰² _{tQ R} ⁶os _{are^ mc}j_epen(jently, Ci to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, Ci to Cio alkoxy, or halogen;

(s) a compound of formula (XX):

(XX)

wherein:

R⁶⁰⁶ is H or Ci to Cio alkyl;

R⁶⁰⁷ to R⁶¹⁰ are, independently, H, Ci to do alkyl, Ci to do alkoxy, or halogen;

(t) a compound of formula (XXI):

(XXI) wherein:

R^70S is H or Ci to C₁₀ alkyl;

(u) a compound of formula (XXII):

(XXII)

wherein:

_R8oo _{tQ R}804 _{and R}806 ^ _R809 ^ independently, H, C_i to C₁₀ alkyl, halogen, NH2, or Ci to C₁₀ alkoxy and

8⁰⁵ is H or Ci to C₁₀ alkyl;

(XXIII)

wherein:

R^JUU is H or Ci to do alkyl; and

R⁹⁰¹ to R⁹⁰⁵ is H, Ci to Cio alkyl, C₂ to C₁₀ alkenyl, C₂ to C₁₀ alkynyl, halogen, Ci to C₁₀ alkoxy, Ci to C₁₀ aminoalkyl, or H₂; and

(w) a compound of formula (XXIV):

(XXIV)

wherein:

R⁹⁰⁶ is Ci to Cio alkyl or Ci to Cio alkoxy;

R⁹⁰⁷ is C2 to Cio alkyl or Ci to Cio alkoxy;

e is 0 to 5;

R⁹⁰⁹ is H or Ci to Cio alkyl;

or a pharmaceutically acceptable salt or prodrug thereof.

6. The compound according to claim 5, wherein said compound binds to a PF4 dimer or PF4 monomer.

7. A compound for use in disrupting ultra-large complexes (ULCs) comprising a PF4 tetramer and a glycosaminoglycan (GAG) in a subject, wherein said compound is selected from the group consisting of:

(a) a compound of formula (II):

(II)

wherein:

n is 0 to 5;

R¹ and R² are, independently, H, Ci to Cio alkyl, C(0)(Ci to Cio alkyl), C(0)(Ci to Cio alkyl), benzyl, C₃ to Cio cycloalkyl, C2 to Cio alkenyl, or C2 to Cio alkynyl; or

R³ and R⁴ are, independently, H, OH, Ci to Cio alkyl, C₃ to Cio cycloalkyl, benzyl, aryl, heteroaryl, or heterocycle; or R¹ and R³ together comprise a heterocycle or heteroaryl, each optionally substituted by one or more R⁵;

R⁵ is Ci to Cio alkyl, Ci to Cio alkoxy, halogen, OH, C₂ to Cio alkenyl, C₂ to Cio alkynyl, C3 to Cio cycloalkyl, aryl, or (=0);

(b) a compound of formula (III):

OR¹⁶

I

^(CR¹⁷R¹⁸)_q-R¹⁰

(III)

wherein:

q is 0 to 5;

R¹⁶ is H or Ci to Cio alkyl;

R¹⁹ is H, Ci to Cio alkyl, Ci to C₁₀ alkoxy, halogen, N0₂, CN, C(0)OH, C(0)(Ci to Cio alkyl), C₂ to Cio alkenyl, oxo, or C₂ to Cio alkynyl;

(c) a compound of formula (IV):

(IV)

wherein:

m is 0 to 2;

R²⁰ is H, Ci to Cio alkyl C₃ to Cio cycloalkyl, C₂ to C₁₀ alkenyl, or C₂ to Cio alkynyl, each optionally substituted by one or more R²⁴; R , R , and R are independently, H, Ci to C₁₀ alkyl, or C₃ to C₁₀ cycloalkyl, each optionally substituted by one or more R²⁴;

R²⁴ is H, halogen, OH, CN, N0₂, d to C₁₀ alkyl C₃ to C₁₀ cycloalkyl, C₂ to Cio alkenyl, or C₂ to C₁₀ alkynyl, each optionally substituted by one or more R²⁷;

R²⁶ is O or S;

(d) a compound of formula (V):

O II

_R41' ^P^_R40

(V)

wherein:

(e) a compound of formula (VI):

OR⁵¹

0=P— OR⁵⁰

I

_R52

(VI)

wherein:

R⁵² is absent, Ci to Cio alkyl optionally substituted by P(0)₂, or aryl optionally substituted by 0(Ci to Cio alkyl)-phenyl-C(0)OH; R is Ci to Cio alkyl, halogen, or C(0)OH;

(f) a compound of formula (VII):

(VII)

wherein:

t is 1 to 10;

R⁶⁰ is aryl, heteroaryl, or heterocycle;

(g) a compound of formula (VIII):

(VIII)

wherein:

R⁷⁶ is C(0)OH, C(0)(Ci to Cio alkyl), NHC(0)(Ci to Cio alkyl), C(0)NH(phenyl optionally substituted by one or more R⁷⁷), C(0)0(Ci to Cio alkyl), heteroaryl optionally substituted by one or more R⁷⁷, heterocycle optionally substituted by one or more R , or phenyl optionally substituted by one or more R⁷⁷;

R⁷⁷ is halogen, Ci to C₁₀ aminoalkyl, Ci to C₁₀ alkoxy, Ci to C₁₀ alkyl, or C₂ to Cio alkenyl, each optionally substituted by one or more R⁷⁸;

(h) a compound of formula (IX):

(IX)

wherein:

w is 1 to 10;

w' is 1 to 10;

R⁸⁰ is H or C₂ to Cio alkyl;

(i) a compound of formula (X):

(X)

wherein:

x is 2 to 10;

G) a compound of formula (XI):

(XI)

wherein:

y is 1 to 10;

R⁹⁵ is heterocycle, heteroaryl, aryl, or Ci to C₁₀ aminoalkyl;

(k) a compound of formula (XII):

(XII)

wherein:

R¹⁰⁵ is aryl, heteroaryl, or heterocycle;

z is 2 to 10;

(1) a compound of formula (XIII):

(XIII)

wherein:

a is 0 or 1;

R¹²⁰ is absent, aryl, C₃ to Cio cycloalkyl, heteroaryl, or heterocycle, each optionally substituted by one or more R¹²⁵; R is aryl containing one or more R , Ci to C₁₀ aminoalkyl optionally containing one or two aryl groups optionally substituted by one or more R¹²⁴, heterocycle optionally substituted by one or more R¹²⁵;

R¹²³ is H, halogen, Ci to C₁₀ alkyl, or Ci to C₁₀ alkoxy;

R¹²⁵ is H, halogen, Ci to Cio alkyl, Ci to Cio alkoxy, (=0), or C(0)OH; or

(m) a compound of formula (XIV):

j2

(XIV)

wherein:

R²⁰² is H, CI to Cio alkyl, halogen, CN, or 0₂; R²⁰⁰ is Ci to Cio alkyl, Ci to Cio alkoxy, aryl, C2 to Cio alkenyl, Ci to Cio aminoalkyl, each optionally

203 203

(XV)

wherein:

_R302

Cio alkynyl, each optionally substituted by one or more

303.

substituted by one or more R

R is halogen, CN, NO₂, or aryl optionally substituted by one or more

R 304.

(XVI)

wherein:

R⁴⁰⁰ is OH or O;

R⁴⁰⁴ is H, Ci to Cio alkyl, halogen, (=0), or Ci to Cio alkoxy;

R⁴⁰⁵ is absent, Ci to Cio alkyl, heterocycle, aryl, or heteroaryl,

_R406

optionally substituted by one or more

_R407

(p) a compound of formula (XVII):

(XVII)

wherein:

R⁵⁰⁰ is Ci to Cio aminoalkyl;

R⁵⁰² is benzyl optionally substituted by one or more R⁵⁰³; R⁵ to Cio alkyl, C3 to C₁₀ cycloalkyl, Ci to C₁₀ alkoxy, or aryl;

f is 0 to 4; and

R⁵⁰³ is H, Ci to Cio alkyl, Ci to Cio alkoxy, halogen, or aryl;

(q) a compound of formula (XVIII):

(XVIII)

wherein:

R⁵⁰⁷ is H, OH, Ci to Cio alkoxy, or C₃ to Cio cycloalkyl;

(r) a compound of formula (XIX):

(XIX)

wherein:

R⁶⁰⁰ is Ci to Cio alkyl, NH₂ or Ci to Cio aminoalkyl; R to R are, independently, Ci to Cio alkyl, C₃ to Cio cycloalkyl, Cio alkoxy, or halogen;

(XX)

wherein:

R⁶⁰⁶ is H or Ci to Cio alkyl;

R⁶⁰⁷ to R⁶¹⁰ are, independently, H, Ci to Cio alkyl, Ci to Cio alkoxy, or halogen;

(t) a compound of formula (XXI):

(XXI)

wherein:

_R7oo _{tQ R}704 _{are^ independentlyj Hj Cl t0 Cl0} aiky^ C3 to CIO cycloalkyl, C3 to Cio spirocycloalkyl, Ci to Cio alkoxy, halogen, d to C io aminoalkyl, or CN; and

R⁷⁰⁵ is H or Ci to Cio alkyl;

(u) a compound of formula (XXII):

(XXII)

wherein:

_R ⁸oo _{tQ R} ⁸⁰4 _{and R} ⁸⁰⁶ _{and R} ⁸⁰⁹ ^ _indep_endently5 H, C_[ to C₁₀ alkyl, halogen, NH₂, or Ci to Cio alkoxy and

R^80S is H or Ci to Cio alkyl;

(v) a compound of formula (XXIII):

wherein:

R⁹⁰⁰ is H or Ci to Cio alkyl; and

_R9oi _{tQ R}905 _{is Hj Ci tQ alkyli C2 10 alkenyl; Cl t0 C l0} aikynyi, halogen, Ci to Cio alkoxy, Ci to Cio aminoalkyl, or H₂; and

(w) a compound of formula (XXIV):

wherein:

R⁹⁰⁶ is Ci to Cio alkyl or Ci to Cio alkoxy;

R⁹⁰⁷ is C₂ to Cio alkyl or Ci to C₁₀ alkoxy;

e is 0 to 5;

R⁹⁰⁸ is H, halogen, d to C io alkyl, Ci to Cio alkoxy, OH, CN, or NH₂; and

R⁹⁰⁹ is H or Ci to Cio alkyl;

or a pharmaceutically acceptable salt or prodrug thereof.

8. The compound according to claim 7, wherein said compound disrupts the salt bridge of said PF4 tetramer.

9. The compound according to claim 5 or 7, wherein said GAG is heparin.

10. The compound according to claim 5 or 7, wherein said ULC is greater than about 600 kD.

11. A compound for use in preventing or treating heparin induced

thrombocytopenia and thrombosis (HITT) in a subject, wherein said compound is selected from the group consisting of:

(a) a compound of formula (II):

(II)

wherein:

n is 0 to 5;

(b) a compound of formula (III):

OR¹⁶

I

0^^P (CR¹⁷R¹⁸)_q-R¹⁰

(HI)

wherein:

q is 0 to 5;

R¹⁰ is Ci to Cio alkyl. heteroaryl or aryl, each optionally substituted by one or more R¹⁹; R^lb is H or Ci to C₁₀ alkyl;

R¹⁷ and R¹⁸ are, independently, absent, H, Ci to C₁₀ alkyl, (Ci to C₁₀ alkyl)-P-(Ci to C₁₀ alkyl), Ci to C₁₀ alkoxy, halogen, OH, N0₂, CN, C₂ to C₁₀ alkenyl, P(0)OH, C₂ to C₁₀ alkynyl, aryl, heteroaryl, or heterocycle, each optionally substituted by one or more R¹⁹;

(IV)

wherein:

m is 0 to 2;

R²⁰ is H, Ci to Cio alkyl C₃ to Cio cycloalkyl, C₂ to Cio alkenyl, or C₂ to Cio alkynyl, each optionally substituted by one or more R²⁴;

R²⁵ is H, Ci to Cio alkyl C₃ to Cio cycloalkyl, C₂ to Cio alkenyl, or C₂ to Cio alkynyl;

R²⁶ is O or S;

(d) a compound of formula (V):

O II

- P. (V)

wherein:

R⁴⁰ and R⁴¹ are, independently, H, Ci to C₁₀ alkyl optionally substituted by one or more R⁴², aryl optionally substituted by one or more R⁴², or benzyl optionally substituted by one or more R⁴²;

R⁴² is H, Ci to Cio alkyl, C(0)OH, NH₂, C(0)(Ci to C₁₀ alkyl), C(0)0(Ci to Cio alkyl), Ci to Cio aminoalkyl, halogen, aryl, or heteroaryl;

(e) a compound of formula (VI):

OR⁵¹

0=P— OR⁵⁰

I

_R52

(VI)

wherein:

R⁵³ is Ci to Cio alkyl, halogen, or C(0)OH;

(f) a compound of formula (VII):

P— (CR⁶⁵R⁶⁶)_tR⁶⁰R⁶¹

HO

(VII)

wherein:

t is 1 to 10;

R⁶⁰ is aryl, heteroaryl, or heterocycle;

R⁶⁵ and R⁶⁶ are, independently, H, OH, Ci to Cio alkyl, C₃ to Cio cycloalkyl, C2 to Cio alkenyl, C2 to Cio alkynyl benzyl, aryl, heteroaryl, or heterocycle; (g) a compound of fo

(VIII)

wherein:

R , R , R , and R ^s are, independently, H, Ci to C₁₀ alkyl, C₂ to C₁₀ alkenyl, Ci to C₁₀ aminoalkyl, C(0)(Ci to C₁₀ aminoalkyl), or heteroaryl, each optionally substituted by one or more R⁷⁸:

(h) a compound of formula (IX):

(IX)

wherein: w is 1 to 10;

w' is 1 to 10;

R⁸⁰ is H or C₂ to Cio alkyl;

R⁸¹ to R⁸⁵ are, independently, H, OH, Ci to Cio alkyl, halogen, Cio alkoxy; and

(i) a compound of formula (X):

(X)

wherein:

x is 2 to 10;

G) a compound of formula (XI):

(XI)

wherein:

y is 1 to 10;

R⁹⁵ is heterocycle, heteroaryl, aryl, or Ci to Cio aminoalkyl;

(k) a compound of formula (XII):

(XII) wherein:

R¹⁰⁵ is aryl, heteroaryl, or heterocycle;

z is 2 to 10;

R¹⁰⁶ to R¹¹⁰ are, independently, H, Ci to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, OH, C2 to Cio alkenyl, or C2 to C10 alkynyl;

(1) a compound of formula (XIII):

(XIII)

wherein:

a is 0 or 1;

R¹²³ is H, halogen, Ci to Cio alkyl, or Ci to Cio alkoxy;

R¹²⁵ is H, halogen, Ci to Cio alkyl, Ci to Cio alkoxy, (=0), or C(0)OH; or

R¹²⁰ and R¹²¹ join to form C5 to Cio cycloalkyl optionally substituted by one or more R¹²⁶; and

(m) a compound of formula (XIV):

(XIV) wherein:

R²⁰² is H, CI to Cio alkyl, halogen, CN, or 0₂; R²⁰⁰ is Ci to Cio alkyl, Ci to Cio alkoxy, aryl, C2 to Cio alkenyl, Ci to Cio aminoalkyl, each optionally substituted by one or more R 203 ;R 203 is halogen, CN, NO2, Ci to Cio alkoxy, or aryl optionally substituted by one or more R²⁰⁴;

(XV)

wherein:

R is Ci to Cio alkyl, Ci to Cio aminoalkyl, C2 to Cio alkenyl, or C2 to Cio alkynyl, each optionally substituted by one or more _R302

R³⁰² is H, Ci to Cio alkyl, halogen, CN, or N0₂; R³⁰⁰ is Ci to Cio alkyl, Ci to Cio alkoxy, aryl, C2 to Cio alkenyl, Ci to Cio aminoalkyl, each optionally substituted by one or more R³⁰³;

R³⁰³ is halogen, CN, NO2, or aryl optionally substituted by one or more

R³⁰⁴;

(XVI)

wherei

R⁴⁰⁵ is absent, Ci to C₁₀ alkyl, heterocycle, aryl, or heteroaryl,

_R406

optionally substituted by one or more

with the proviso that when R⁴⁰¹ is OR⁴⁰⁵ and R⁴⁰³ is N(R⁴⁰⁶)(R⁴⁰⁷) and R⁴⁰⁵ and R⁴⁰⁷ are absent, R⁴⁰¹ and R⁴⁰², and/or R⁴⁰¹ and R⁴⁰³, and/or R⁴⁰² and R⁴⁰³ join to form a 5 to 8-membered ring, wherein the 5 to 8- membered ring contains carbon atoms and optionally one or more heteroatom and wherein the 5 to 8-membered ring is optionally substituted by one or more R"

(p) a compound of formula (XVII):

(XVII)

wherein:

R⁵⁰⁰ is Ci to Cio aminoalkyl;

f is 0 to 4; and

R⁵⁰³ is H, Ci to Cio alkyl, Ci to Cio alkoxy, halogen, or aryl;

(q) a compound of formula (XVIII):

wherein:

R is H, OH, Ci to Cio alkoxy, or C₃ to C₁₀ cycloalkyl;

_R508 _{tQ R}5io _are^ independently, H, Ci to Cio alkyl, Ci to Cio alkoxy, C₃ to Cio cycloalkyl, or halogen; and

(r) a compound of formula (XIX):

(XIX)

wherein:

R is Ci to Cio alkyl, NH? or Ci to Cio aminoalkyl;

R⁶⁰² to R⁶⁰⁵ are, independently, Ci to Cio alkyl, C₃ to Cio cycloalkyl, Ci to Cio alkoxy, or halogen;

(s) a compound of formula (XX):

(XX)

wherein:

R^6Ub is H or Ci to Cio alkyl;

(t) a compound of formula (XXI):

(XXI)

wherein: _R ^/uu _{tQ R}/u4 _are^ _{independentlyj Hj Cl t0 Cl0 alkylj} C3 to CIO cycloalkyl, C₃ to C₁₀ spirocycloalkyl, Ci to C₁₀ alkoxy, halogen, Ci to C₁₀ aminoalkyl, or CN; and

R⁷⁰⁵ is H or Ci to do alkyl;

(u) a compound of

(XXII)

wherein:

_R8oo _{tQ R}804 _{and R}806 _{and R}809 ^ _{independently5} H, C_i to C₁₀ alkyl, halogen, NH₂, or Ci to C₁₀ alkoxy and

R^80S is H or Ci to C₁₀ alkyl;

(v) a compound of formula (XXIII):

(XXIII)

wherein:

R⁹⁰⁰ is H or Ci to do alkyl; and

_R9oi _{to R}905 _{is H}^ _{C i tQ alkyl) C2 10 alkenyl) Cl t0 Cl0} alkynyl_^ halogen, Ci to Cio alkoxy, Ci to Cio aminoalkyl, or H₂; and

(w) a compound of formula (XXIV):

(XXIV)

wherein:

R⁹⁰⁶ is Ci to Cio alkyl or Ci to C₁₀ alkoxy;

R⁹⁰⁷ is C₂ to Cio alkyl or Ci to C₁₀ alkoxy;

e is 0 to 5;

R⁹⁰⁸ is H, halogen, Ci to Cio alkyl, Ci to Cio alkoxy, OH, CN, or H₂; and

R⁹⁰⁹ is H or Ci to Cio alkyl;

or a pharmaceutically acceptable salt or prodrug thereof.

12. A compound for use in preventing atherosclerosis in a subject, wherein said compound binds to PF4 dimers or PF4 monomers or disrupts the salt bridge of PF4 tetramers.

13. The compound according to claim 12, wherein said atherosclerosis results from PF4 tetramer formation.

14. The compound according to claim 12, wherein the formation of GAG-PF4 complex results in said atherosclerosis.

15. A compound for use in correcting a platelet imbalance in a subject, wherein said compound binds to PF4 dimers or PF4 monomers or disrupts the salt bridge of PF4 tetramers.

16. The compound according to claim 15, wherein said platelet imbalance results from said PF4 tetramer formation.

17. The compound according to claim 15, wherein said platelet imbalance results from heparin administration to said subject.

18. The compound according to any one of claims 15 to 17, wherein platelet production is stimulated.

19. A compound for use in preventing a decrease in platelet production in a subject, wherein said compound binds to PF4 dimers or PF4 monomers or disrupts the salt bridge of PF4 tetramers.

20. The compound according to claim 19, wherein said decrease in platelets results from PF4 tetramer formation.

21. The compound according to claim 19, wherein said decrease in platelets results from heparin administration to said subject.

22. A compound for use in preventing a decrease of or increasing high density lipoproteins in a subject, wherein said compound binds to PF4 dimers or PF4 monomers or disrupts the salt bridge of PF4 tetramers.

23. A compound for use in preventing or treating inflammation in a subject, wherein said compound binds to PF4 dimers or PF4 monomers or disrupts the salt bridge of PF4 tetramers.

24. The compound according to claim 23, wherein said inflammation is caused by NF-KB activation.

25. A compound for use in modulating clotting or hemostasis in a subject, wherein said compound binds to PF4 dimers or PF4 monomers or disrupts the salt bridge of PF4 tetramers.

26. The compound according to claim 25, wherein protein C is upregulated.

27. The compound according to claim 25, wherein protein C is downregulated.

28. The compound according to any one of claims 1 to 27, wherein said PF4 is wild-type PF4.

29. The compound according to any one of claims 1 to 27, wherein said compound binds to Lys50 in said monomer or dimer, Glu28 in said monomer or dimer, or a combination thereof.

30. The compound according to claim 29, wherein said salt bridge comprises Glul28, Lys350 of a first PF4 monomer and Glu328, Lysl50 of a second PF4 monomer.

31. The compound according to claim 29, wherein said salt bridge comprises Glu228, Lys450 of a first PF4 monomer and Glu428, Lys250 of a second PF4 monomer.

32. The compound according to any one of claims 12 to 27, wherein said compound has structure (II):

(II)

wherein:

n is 0 to 5;

R¹ and R² are, independently, H, Ci to C₁₀ alkyl, C(0)(C₁ to C₁₀ alkyl),

C(0)(Ci to Cio alkyl), benzyl, C3 to C₁₀ cycloalkyl, C2 to C₁₀ alkenyl, or C2 to C₁₀ alkynyl; or

R³ and R⁴ are, independently, H, OH, Ci to C₁₀ alkyl, C3 to C₁₀ cycloalkyl, benzyl, aryl, heteroaryl, or heterocycle; or

R⁵ is Ci to Cio alkyl, Ci to Cio alkoxy, halogen, OH, C2 to Cio alkenyl, C2 to Cio alkynyl, C3 to Cio cycloalkyl, aryl, or (=0); or a pharmaceutically acceptable salt or prodrug thereof.

33. The compound according to any one of claims 1 to 27, wherein said compound is selected from the group consisting of:

₀r a pharmaceutically acceptable salt or prodrug thereof.

34. The compound according to any one of claims 1 to 27, wherein said compound is selected from the group consisting of:

, or a pharmaceutically acceptable salt or prodrug thereof.

35. The compound according to any one of claims 12 to 27, wherein said compound has structure (III):

OR¹⁶

I

^(CR¹⁷R¹⁸)_q-R¹⁰

(III)

wherein:

q is 0 to 5;

R¹⁶ is H or Ci to Cio alkyl;

R¹⁷ and R¹⁸ are, independently, absent, H, Ci to Cio alkyl, (Ci to Cio alkyl)-P- (Ci to Cio alkyl), Ci to C₁₀ alkoxy, halogen, OH, N0₂, CN, C₂ to C₁₀ alkenyl, P(0)OH, C₂ to Cio alkynyl, aryl, heteroaryl, or heterocycle, each optionally substituted by one or more R¹⁹;

R¹⁹ is H, Ci to Cio alkyl, Ci to Cio alkoxy, halogen, N0₂, CN, C(0)OH, C(0)(Ci to Cio alkyl), C₂ to Cio alkenyl, or C₂ to Cio alkynyl; or a pharmaceutically acceptable salt or prodrug thereof.

36. The compound according to any one of claims 1 to 27, wherein said compound is:

(Ilia)

wherein:

each R¹⁹ is, independently, H, Ci to Cio alkyl, Ci to Cio alkoxy, halogen, NO₂, CN, C(0)OH, C(0)(Ci to Cio alkyl), C₂ to Cio alkenyl, oxo, or C₂ to Cio alkynyl; R¹⁷ and R¹⁸ are, independently, absent, H, Ci to Cio alkyl, Ci to Cio alkoxy, halogen, OH, N0₂, CN, C₂ to Cio alkenyl, P(0)OH, C₂ to C₁₀ alkynyl, aryl, heteroaryl, or heterocycle;

or a pharmaceutically acceptable salt or prodrug thereof.

37. The compound according to claim any one of claims 1 to 27, wherein said compound is:

(Hid).

38. The compound according to any one of claims 1 to 27, wherein said compound is selected from the group consisting of:

or a pharmaceutically acceptable salt or prodrug thereof.

39. The compound according to any one of claims 1 to 27, wherein said compound is:

(Illf)

wherein:

r is 1 to 3;

X is O, S, or R³⁰;

R³⁰ is H or Ci to C₁₀ alkyl;

R³¹ and R³² are, independently, H, Ci to Cio alkyl, C3 to Cio cycloalkyl, C2 to Cio alkenyl, or C2 to Cio alkynyl, benzyl, aryl, heteroaryl, or heterocycle;

or a pharmaceutically acceptable salt or prodrug thereof. The compound according to any one of claims 12 to 27, wherein said

or a pharmaceutically acceptable salt or prodrug thereof.

41. The compound according to any one of claims 1 to 27, wherein said compound is selected from the group consisting of:

or pharmaceutically acceptable salt or prodrug thereof.

42. The compound according to any one of claims 12 to 27, wherein said compound has structure (IV):

(IV)

wherein:

m is 0 to 2; R is H, Ci to Cio alkyl C3 to Cio cycloalkyl, C2 to Cio alkenyl, or C2 to Cio alkynyl, each optionally substituted by one or more R²⁴:

R²¹, R²², and R²³ are independently, H, Ci to Cio alkyl, or C3 to Cio cycloalkyl, each optionally substituted by one or more R²⁴:

R²⁴ is H, halogen, OH, CN, N0₂, Ci to Cio alkyl C₃ to Cio cycloalkyl, C₂ to Cio alkenyl, or C2 to Cio alkynyl, each optionally substituted by one or more R²⁷;

R²⁵ is H, Ci to Cio alkyl C3 to Cio cycloalkyl, C2 to Cio alkenyl, or C2 to Cio alkynyl;

R²⁶ is O or S;

R²⁷ is H, P(0)OH, or Ci to Cio alkyl optionally substituted by halogen or OP(0)OH; or a pharmaceutically acceptable salt or prodrug thereof.

43. The compound according to any one of claims 1 to 27, wherein said compound is:

(IVa).

44. The compound according to any one of claims 1 to 27, wherein said compound is selected from the group consisting of:

, and or a pharmaceutically acceptable salt or prodrug thereof.

45. The compound according to any one of claims 12 to 27, wherein said compound has structure (V):

O II

_R41 - ^P^ _R40 (V)

wherein:

R⁴⁰ and R⁴¹ are, independently, H, Ci to C₁₀ alkyl optionally substituted by one or more R⁴², aryl optionally substituted by one or more R⁴², or benzyl optionally substituted by one or more R⁴²:

R⁴² is H, Ci to Cio alkyl, C(0)OH, NH₂, C(0)(Ci to C₁₀ alkyl), C(0)0(Ci to Cio alkyl), Ci to Cio aminoalkyl, halogen, aryl, or heteroaryl or a pharmaceutically acceptable salt or prodrug thereof.

46. The compound according to any one of claims 1 to 27, wherein said

47. The compound according to any one of claims 12 to 27, wherein said compound has structure (VI):

OR⁵¹

0=P— OR⁵⁰

I

_R52

(VI)

wherein:

R⁵⁰ is aryl, heteroaryl= or heterocycle, each optionally substituted by one or more R ;

R⁵¹ is H, Ci to Cio alkyl, Ci to Cio aminoalkyl, each optionally substituted by halogen or C(0)OH; R is absent, Ci to C₁₀ alkyl optionally substituted by P(0)2, or aryl optionally substituted by 0(Ci to C₁₀ alkyl)-phenyl-C(0)OH;

R⁵³ is Ci to Cio alkyl, halogen, or C(0)OH; or a pharmaceutically acceptable salt or prodrug thereof.

48. The compound according to any one of claims 12 to 27, wherein said compound is selected from the group consisting of:

or a pharmaceutically acceptable salt or prodrug thereof.

49. The compound according to claims 1 to 27, wherein said compound is

o— P— o

II

o or a pharmaceutically acceptable salt of prodrug thereof.

50. The compound according to any one of claims 12 to 27, wherein said compound has structure (VIII):

(VIII)

wherein: R , R , R , and R are, independently, H, Ci to C₁₀ alkyl, C₂ to C₁₀ alkenyl, Ci to Cio aminoalkyl, C(0)(Ci to Cio aminoalkyl), or heteroaryl, each optionally substituted by one or more R⁷⁸:

R⁷² is H, Ci to Cio alkyl, 0(d to Cio alkyl), 0(d to Cio alkoxy), 0(d to Cio aminoalkyl), Ci to Cio aminoalkyl, or heteroaryl, each optionally substituted by one or more R ;

R⁷³ is Ci to Cio alkyl, Ci to Cio alkoxy, Ci to Cio aminoalkyl, each optionally substituted by one or more R⁷⁶; R^/b is C(0)OH, C(0)(Ci to C₁₀ alkyl), NHC(0)(Ci to C₁₀ alkyl),

C(0)NH(phenyl optionally substituted by one or more R⁷⁷), C(0)0(C₁ to C₁₀ alkyl), heteroaryl optionally substituted by one or more R⁷⁷, heterocycle optionally substituted by one or more R⁷⁷, or phenyl optionally substituted by one or more R⁷⁷;

R⁷⁷ is halogen, Ci to Cio aminoalkyl, Ci to Cio alkoxy, Ci to Cio alkyl, or C2 to Cio alkenyl, each optionally substituted by one or more R⁷⁸:

R⁷⁸ is CN, C(0)OH, C(0)(Ci to Cio alkyl), C(0)0(Ci to Cio alkyl), C(S)S(d to Cio alkyl)C(0)OH, or phenyl optionally substituted by one or more

R⁷⁹ is OH, Ci to Cio alkyl, C₃ to C₁₀ cycloalkyl, C₂ to Cio alkenyl, C₂ to C₁₀ alkynyl, halogen, or Ci to Ce alkoxy; or a pharmaceutically acceptable salt or prodrug thereof.

51. The compound according to any one of claims 1 to 27, wherein said compound is selected from the group consisting of:

pharmaceutically acceptable salt or prodrug thereof.

52. The compound according to any one of claims 12 to 27, wherein said

compound is

or a pharmaceutically acceptable salt or prodrug thereof.

53. The compound according to any one of claims 12 to 27, wherein said compound has structure (IX):

(IX)

wherein:

w is 1 to 10;

w' is 1 to 10;

R⁸⁰ is H or Ci to C₁₀ alkyl;

R⁸⁶ to R⁸⁹ are, independently, H, Ci to Cio alkyl, or C₃ to Cio cycloalkyl; or a pharmaceutically acceptable salt or prodrug thereof.

54. The compound according to any one of claims 12 to 27, wherein said compound has structure (X):

(X)

wherein:

x is 1 to 10; or a pharmaceutically acceptable salt or prodrug thereof.

55. The compound according to any one of claims 12 to 27, wherein said compound is the following or a pharmaceutically acceptable salt or prodrug thereof:

O

„OH

HO^' >r ^{^}s'

= II

NH₂ O

56. The compound according to any one of claims 12 to 27, wherein said compound has structure (XI):

(XI)

wherein:

y is 1 to 10;

R⁹⁰ to R⁹⁴ are, independently, H, halogen, Ci to C₁₀ alkyl, C2 to C₁₀ alkenyl, C2 to Cio alkynyl, OH, or Ci to C₁₀ aminoalkyl; and

R⁹⁵ is heterocycle, heteroaryl, aryl, or Ci to C₁₀ aminoalkyl;

or a pharmaceutically acceptable salt or prodrug thereof.

57. The compound according to any one of claims 12 to 27, wherein said compound has structure (XII):

(XII)

wherein:

R¹⁰⁵ is aryl, heteroaryl, or heterocycle;

z is 1 to 10;

_R ⁱo⁶ _{tQ R} ⁱⁱo _ar6j independently, H, C_i to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, OH, C2 to Cio alkenyl, or C2 to C₁₀ alkynyl;

or a pharmaceutically acceptable salt or prodrug thereof.

58. The compound according to any one of claims 12 to 27, wherein said compound is the following, or a pharmaceutically acceptable salt or prodrug thereof:

59. The compound according to any one of claims 12 to 27, wherein said compound has structure (XIII):

(XIII)

wherein:

a is 0 or 1 ;

R¹²³ is H, halogen, Ci to C₁₀ alkyl, or Ci to C₁₀ alkoxy;

R¹²⁰ and R¹²¹ join to form C5 to C10 cycloalkyl optionally substituted by one or more R¹²⁶; and

R¹²⁶ is H, halogen, Ci to C₁₀ alkyl, Ci to C₁₀ alkoxy, or Ci to C₁₀ aminoalkyl; or a pharmaceutically acceptable salt or prodrug thereof.

60. The compound according to any one of claims 1 to 27, wherein said compound has structure (XHIa), wherein R¹²¹ is a heterocycle having one SO₂ in the heterocycle backbone:

O II

^S-OR 121

O^"

(XHIa).

61. The compound according to any one of claims 1 to 27, wherein said compound is selected from the group consisting of:

pharmaceutically acceptable salt or prodrug thereof.

62. The compound according to any one of claims 12 to 27, wherein said compound structure (XIV):

(XIV)

wherein:

R is Ci to Cio alkyl, Ci to Cio aminoalkyl, C2 to C1₀ alkenyl, or C2 to C1₀ alkynyl, each optionally substituted by one or more R²⁰²;

R²⁰² is H, CI to Cio alkyl, halogen, CN, or 0₂; R²⁰⁰ is Ci to Cio alkyl, Ci to Cio alkoxy, aryl, C2 to Cio alkenyl, Ci to Cio aminoalkyl, each optionally substituted by one or more R ;R is halogen, CN, NO2, Ci to Cio alkoxy, or aryl optionally substituted by one or more R²⁰⁴;

R²⁰⁴ is Ci to Cio alkyl, Ci to Cio alkoxy, halogen, CN, N0₂, or aryl;

or a pharmaceutically acceptable salt or prodrug thereof.

63. The compound according to any one of claims 1 to 27, wherein said compound is selected from the group consisting of:

thereof.

64. The compound according to any one of claims 12 to 27, wherein said compound is:

(XV)

wherein:

R³⁰¹ is Ci to Cio alkyl, Ci to Cio aminoalkyl, C2 to C1₀ alkenyl, or C2 to C1₀ alkynyl, each optionally substituted by one or more R³⁰²;

R³⁰² is H, CI to Cio alkyl, halogen, CN, or 0₂; R³⁰⁰ is Ci to Cio alkyl, Ci to Cio alkoxy, aryl, C2 to Cio alkenyl, Ci to Cio aminoalkyl, each optionally substituted by one or more R³⁰³;

R³⁰³ is halogen, CN, NO2, or aryl optionally substituted by one or more R³⁰⁴:

R³⁰⁴ is Ci to Cio alkyl, Ci to Cio alkoxy, halogen, CN, N0₂, or aryl;

or a pharmaceutically acceptable salt or prodrug thereof.

65. The compound according to any one of claims 1 to 27, wherein said compound is selected from the group consisting of:

pharmaceutically acceptable salt or prodrug thereof

66. The compound according to any one of claims 12 to 27, wherein said compound has structure (XVI):

(XVI)

wherein:

R⁴⁰⁰ is OH or O;

R⁴⁰⁴ is H, Ci to Cio alkyl, halogen, (=0), or Ci to C₁₀ alkoxy;

R⁴⁰⁵ is aabbsseenntt,, CCii ttoo C Cio alkyl, heterocycle, aryl, or heteroaryl, optionally

.406.

substituted by one or more R

RR^440U6b iiss HH,, CCii ttoo CCiioo aallkyl, halogen, Ci to Cio alkoxy, C(0)(Ci to Cio alkyl),

404.

aryl, heteroaryl, C(0)(aryl optionally substituted by one or more R

RR⁴⁰ is absent, H, Ci to Cio alkyl, halogen, Ci to Cio alkoxy, aryl, or heteroaryl;

with the proviso that when R^4lJlJ is O and R^4U5 or R^{4lJ /} is absent, then R^4lJlJ and R⁴⁰² join to form a 5 to 8-membered ring, wherein the 5 to 8-membered ring contains carbon atoms and optionally one or more heteroatom and wherein the 5 to 8- membered ring is optionally substituted by one or more R⁴⁰⁴; and

with the proviso that when R⁴⁰¹ is OR⁴⁰⁵ and R⁴⁰³ is N(R⁴⁰⁶)(R⁴⁰⁷) and R⁴⁰⁵ and R⁴⁰⁷ are absent, R⁴⁰¹ and R⁴⁰², and/or R⁴⁰¹ and R⁴⁰³, and/or R⁴⁰² and R⁴⁰³ join to form a 5 to 8-membered ring, wherein the 5 to 8- membered ring contains carbon atoms and optionally one or more heteroatom and wherein the 5 to 8-membered ring is optionally substituted by one or more R⁴⁰⁴; or a pharmaceutically acceptable salt or prodrug thereof.

67. The compound according to any one of claims 1 to 27, wherein said

68. The compound according to any one of claims 12 to 27, wherein said compound is:

(XVII)

wherein:

R is Ci to Cio aminoalkyl;

R⁵⁰² is benzyl optionally substituted by one or more R⁵⁰³; R⁵⁰¹ is H, Ci to C₁₀ alkyl, C3 to Cio cycloalkyl, Ci to Cio alkoxy, or aryl;

f is 0 to 4; and

R⁵⁰³ is H, Ci to Cio alkyl, Ci to Cio alkoxy, halogen, or aryl;

or a pharmaceutically acceptable salt or prodrug thereof.

69. The compound according to any one of claims 1 to 27, wherein said compound is the following or a pharmaceutically acceptable salt or prodrug thereof:

70. The compound according to any one of claims 12 to 27, wherein said compound has structure (XVIII)

(XVIII)

wherein:

R⁵⁰⁷ is H, OH, Ci to Cio alkyl, Ci to C₁₀ alkoxy, or C₃ to C₁₀ cycloalkyl;

R⁵⁰⁸ to R⁵¹⁰ are, independently, H, Ci to C₁₀ alkyl, Ci to C₁₀ alkoxy, C₃ to C₁₀ cycloalkyl, or halogen;

or a pharmaceutically acceptable salt or prodrug thereof.

71. The compound according to any one of claims 12 to 27, wherein said compound is the following or a pharmaceutically acceptable salt or prodrug thereof:

72. The compound according to any one of claims 12 to 27, wherein said compound has structure (XIX)

wherein:

R⁶⁰⁰ is Ci to Cio alkyl, NH₂ or Ci to C₁₀ aminoalkyl;

R⁶⁰² to R⁶⁰⁵ are, independently, Ci to Cio alkyl, C3 to Cio cycloalkyl, Ci to Cio alkoxy, or halogen;

or a pharmaceutically acceptable salt or prodrug thereof.

73. The compound according to any one of claims 1 to 27, wherein said compound is the following or a pharmaceutically acceptable salt or prodrug thereof:

74. The compound according to any one of claims 12 to 27, wherein said compound has structure (XX):

(XX)

wherein:

R⁶⁰⁶ is H or Ci to C₁₀ alkyl;

R⁶⁰⁷ to R⁶¹⁰ are, independently, H, Ci to C₁₀ alkyl, Ci to C₁₀ alkoxy, or halogen;

or a pharmaceutically acceptable salt or prodrug thereof.

75. The compound according to any one of claims 1 to 27, wherein said compound is the following or a pharmaceutically acceptable salt or prodrug thereof:

76. The compound according to any one of claims 12 to 27, wherein said compound has structure (XXI):

(XXI)

wherein: R ^uu to R are, independently, H, Ci to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, C₃ to Cio spirocycloalkyl, Ci to Cio alkoxy, halogen, Ci to Cio aminoalkyl, or CN; and R⁷⁰⁵ is H or Ci to Cio alkyl;

or a pharmaceutically acceptable salt or prodrug thereof.

77. The compound according to any one of claims 1 to 27, wherein said compound is the following or a pharmaceutically acceptable salt or prodrug thereof:

78. The compound according to any one of claims 12 to 27, wherein said compound has structure (XXII):

(XXII)

wherein:

_R8uu _{tQ R}8U4 _{and R}8u_{b and R8uy} ^ _{independentlyj Hj Cl to Cl0 alkylj} halogen,

NH₂, or Ci to Cio alkoxy and

R⁸⁰⁵ is H or Ci to Cio alkyl;

or a pharmaceutically acceptable salt or prodrug thereof.

79. The compound according to any one of claims 1 to 27, wherein said compound is the following or a ph eptable salt or prodrug thereof:

80. The compound according to any one of claims 12 to 27, wherein said compound has structure (XVI

wherein:

R⁹⁰⁰ is H or Ci to C₁₀ alkyl; and

R⁹⁰¹ to R⁹⁰⁵ is H, Ci to Cio alkyl, C₂ to C₁₀ alkenyl, C₂ to C₁₀ alkynyl, halogen, Ci to Cio alkoxy, Ci to Cio aminoalkyl, or NH₂;

or a pharmaceutically acceptable salt or prodrug thereof.

81. The compound according to any one of claims 1 to 27, wherein said compound is the following or a pharmaceutically acceptable salt or prodrug thereof:

82. The compound according to any one of claims 12 to 26, wherein said compound has structure (XXIV):

R and R are, independently, Ci to Cio alkyl or Ci to Cio alkoxy;

e is 0 to 5; and

R⁹⁰⁸ is H, halogen, Ci to Cio alkyl, Ci to Cio alkoxy, OH, CN, or NH₂ R⁹⁰⁹ is H or Ci to Cio alkyl; or a pharmaceutically acceptable salt or prodrug thereof.

83. The compound according to any one of claims 12 to 27, wherein said compound is the following or a pharmaceutically acceptable salt or prodrug thereof:

84. The compound according to any one of claims 1 to 27, wherein said compound is the following or a pharmaceutically acceptable salt or prodrug thereof:

85. The compound according to any one of claims 1 to 84, wherein the pharmaceutically acceptable salt is of a base.

86. The compound according to claim 85, wherein said base is selected from the group consisting of sodium hydroxide, lithium hydroxide, potassium hydroxide, and mixtures thereof.

87. The compound according to any one of claims 1 to 85, wherein the pharmaceutically acceptable salt is of an acid.

88. The compound according to claim 87, wherein said acid is selected from the group consisting of acetic acid, propionic acid, lactic acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid, malic acid, phthalic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, napthalenesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, and camphorsulfonic acid.

89. The compound according to any one of claims 1 to 84, wherein said compound is delivered to said subject orally, ocularly, by injection, by inhalation, transdermally or by suppository.

90. The compound according to any one of claims 3 or 7 to 89, further comprising: (a) measuring a first level of PF4 tetramer in a first biological sample obtained from said subject; and

(b) administering a first effective amount of said compound required to decrease said PF4 tetramer level.

91. The compound according to claim 90, further comprising:

(c) measuring a second level of PF4 tetramer in a second biological sample obtained from said subject; and

(d) administering a second effective amount of said compound required to decrease said PF4 tetramer level.

92. The compound according to any one of claims 1, 5, or 7 to 89, further comprising:

(a) measuring a first level of PF4 tetramer in a first biological sample obtained from said subject; and

(b) administering a first effective amount of said compound required to prevent formation of said PF4 tetramer.

93. The compound according to claim 92, further comprising:

(d) administering a second effective amount of said compound required to prevent formation of said PF4 tetramer.

94. The compound according to any one of claims 90 to 93, wherein said effective amount is about 500 mg/kg or lower.

95. The compound according to any one of claims 1 to 94, wherein said subject has cancer.

96. A composition comprising:

(i) a medication which causes the formation of PF4 tetramers, a medication which disrupts PF4 tetramers, or a combination thereof; and

(ii) a compound selected from the group consisting of:

(a) a compound of formula (II):

(II)

wherein:

n is 0 to 5;

R¹ and R² are, independently, H, Ci to C₁₀ alkyl, C(0)(C₁ to Cio alkyl), C(0)(C₁ to C₁₀ alkyl), benzyl, C₃ to C₁₀ cycloalkyl, C₂ to Cio alkenyl, or C₂ to Cio alkynyl; or

R⁵ is Ci to Cio alkyl, Ci to Cio alkoxy, halogen, OH, C2 to Cio alkenyl, C2 to Cio alkynyl, C3 to Cio cycloalkyl, aryl, or (=0);

(b) a compound of formula (III):

OR¹⁶

I

0^^P (CR¹⁷R¹⁸)_q-R¹⁰

(HI)

wherein:

q is 0 to 5;

R¹⁶ is H or Ci to Cio alkyl;

R¹⁷ and R¹⁸ are, independently, absent, H, Ci to Cio alkyl, (Ci to Cio alkyl)-P-(Ci to Cio alkyl), Ci to Cio alkoxy, halogen, OH, N0₂, CN, C₂ to Cio alkenyl, P(0)OH, C₂ to Cio alkynyl, aryl, heteroaryl, or heterocycle, each optionally substituted by one or more R¹⁹;

wherein when R¹⁷ or R¹⁸ is absent and q is at least 2, the CR¹⁷R¹⁸ groups are bound through a stable double bond; R is H, Ci to Cio alkyl, Ci to C₁₀ alkoxy, halogen, N0₂, CN, C(0)OH, C(0)(Ci to Cio alkyl), C₂ to C₁₀ alkenyl, oxo, or C₂ to C₁₀ alkynyl;

(c) a compound of formula (IV):

(IV)

wherein:

m is 0 to 2;

R²⁶ is O or S;

(d) a compound of formula (V):

(V)

wherein:

R and R are, independently, H, Ci to Cio alkyl optionally substituted by one or more R⁴², aryl optionally substituted by one or more R⁴², or benzyl optionally substituted by one or more R⁴²; R⁴² is H, Ci to Cio alkyl, C(0)OH, NH₂, C(0)(Ci to Cio alkyl), C(0)0(Ci to Cio alkyl), Ci to Cio aminoalkyl, halogen, aryl, or heteroaryl;

(e) a compound of formula (VI):

OR⁵¹

0=P— OR⁵⁰

I

_R52

(VI)

wherein:

R⁵³ is Ci to Cio alkyl, halogen, or C(0)OH;

(f) a compound of formula (VII):

P— (CR⁶⁵R⁶⁶)_tR⁶⁰R⁶¹

HO

(VII)

wherein:

t is 1 to 10;

R⁶⁰ is aryl, heteroaryl, or heterocycle;

(g) a compound of formula (VIII):

(VIII)

wherein:

R⁷⁰, R⁷¹, R⁷⁴, and R⁷⁵ are, independently, H, Ci to C₁₀ alkyl, C₂ to Cio alkenyl, Ci to C₁₀ aminoalkyl, C(0)(Ci to C₁₀ aminoalkyl), or heteroaryl, each optionally substituted by one or more R⁷⁸:

R⁷² is H, Ci to Cio alkyl, 0(d to Cio alkyl), 0(d to Cio alkoxy), 0(Ci to Cio aminoalkyl), Ci to Cio aminoalkyl, or heteroaryl, each optionally substituted by one or more R⁷⁶:

R⁷⁶ is C(0)OH, C(0)(Ci to Cio alkyl), NHC(0)(Ci to Cio alkyl), C(0)NH(phenyl optionally substituted by one or more R⁷⁷), C(0)0(Ci to Cio alkyl), heteroaryl optionally substituted by one or more R⁷⁷, heterocycle optionally substituted by one or more R⁷⁷, or phenyl optionally substituted by one or more R⁷⁷;

R⁷⁷ is halogen, Ci to Cio aminoalkyl, Ci to Cio alkoxy, Ci to Cio alkyl, or C2 to Cio alkenyl, each optionally substituted by one or

78

more R ;

R⁷⁹ is OH, Ci to Cio alkyl, C₃ to Cio cycloalkyl, C₂ to Cio alkenyl, C2 to Cio alkynyl, halogen, or Ci to Ce alkoxy;

(h) a compound of formula (IX):

(IX)

wherein:

w is 1 to 10;

w' is 1 to 10;

R⁸⁰ is H or C₂ to Cio alkyl;

(i) a compound of formula (X):

(X)

wherein:

x is 2 to 10;

(j) a compound of formula (XI):

(XI)

wherein:

y is 1 to 10;

R⁹⁵ is heterocycle, heteroaryl, aryl, or Ci to Cio aminoalkyl; (k) a compound of formula (XII):

(XII)

wherein:

R^10S is aryl, heteroaryl, or heterocycle;

z is 2 to 10;

_Rio6 _{10 R} ^{i i}o _ar6j independently, H, Ci to C₁₀ alkyl, C₃ to Cio cycloalkyl, OH, C₂ to C₁₀ alkenyl, or C₂ to C₁₀ alkynyl;

(1) a compound of formula (XIII):

(XIII)

wherein:

a is 0 or 1;

R^12~ is H, halogen, Ci to C₁₀ alkyl, or Ci to C₁₀ alkoxy;

R¹²⁴ is H, halogen, Ci to C₁₀ alkyl, Ci to C₁₀ alkoxy, or Ci to Cio aminoalkyl;

R^12S is H, halogen, Ci to Cio alkyl, Ci to Cio alkoxy, (=0), or C(0)OH; or

R and R join to form C5 to Cio cycloalkyl optionally substituted by one or more R¹²⁶; and R is H, halogen, Ci to C₁₀ alkyl, Ci to C₁₀ alkoxy, or Ci to Cio aminoalkyl;

(m) a compound of formula (XIV):

(XIV)

wherein:

R²⁰⁴ is Ci to Cio alkyl, Ci to Cio alkoxy, halogen, CN, N0₂, or aryl;

(n) a compound of formula (XV):

(XV)

wherein:

R is Ci to Cio alkyl, Ci to Cio aminoalkyl, C2 to Cio alkenyl, or C2 to Cio alkynyl, each optionally substituted by one or more R³⁰²;

R³⁰² is H, Ci to Cio alkyl, halogen, CN, or N0₂; R³⁰⁰ is Ci to Cio alkyl, Ci to Cio alkoxy, aryl, C2 to Cio alkenyl, Ci to Cio aminoalkyl, each optionally substituted by one or more R³⁰³; R³⁰³ is halogen, CN, O₂, or aryl optionally substituted by one or more R³⁰⁴;

R³⁰⁴ is Ci to Cio alkyl, Ci to C₁₀ alkoxy, halogen, CN, N0₂, or aryl;

(0) a compound of formula (XVI):

(XVI)

wherein:

R⁴⁰⁰ is OH or O;

R⁴⁰¹, R⁴⁰², and R⁴⁰³, are independently, OR⁴⁰⁵ or N(R⁴⁰⁶)(R⁴⁰⁷); R⁴⁰⁴ is H, Ci to Cio alkyl, halogen, (=0), or Ci to Cio alkoxy; R⁴⁰⁵ is absent, Ci to Cio alkyl, heterocycle, aryl, or heteroaryl,

_R406

optionally substituted by one or more

R⁴⁰⁶ is H, Ci to Cio alkyl, halogen, Ci to Cio alkoxy, C(0)(Ci to Cio alkyl), aryl, heteroaryl, C(0)(aryl optionally substituted by one or more R⁴⁰⁴;

R⁴⁰⁷ is absent, H, Ci to Cio alkyl, halogen, Ci to Cio alkoxy, aryl, or heteroaryl;

with the proviso that when R⁴⁰⁰ is O and R⁴⁰⁵ or R⁴⁰⁷ is absent, then R⁴⁰⁰ and R⁴⁰² join to form a 5 to 8-membered ring, wherein the 5 to 8-membered ring contains carbon atoms and optionally one or more heteroatom and wherein the 5 to 8-membered ring is optionally substituted by one or more R⁴⁰⁴; and

with the proviso that when R⁴⁰¹ is OR⁴⁰⁵ and R⁴⁰³ is

_N(R406_)(R407_{) R}405 ^ _R407 ^ _R401 ^ _R40_{2j R}401 and R⁴⁰³, and/or R⁴⁰² and R⁴⁰³ join to form a 5 to 8-membered ring, wherein the 5 to 8- membered ring contains carbon atoms and optionally one or more heteroatom and wherein the 5 to 8-membered ring is optionally substituted by one or more R⁴⁰⁴;

(p) a compound of formula (XVII):

(XVII)

wherein:

R⁵⁰⁰ is Ci to Cio aminoalkyl;

R⁵⁰² is benzyl optionally substituted by one or more R⁵⁰³; R⁵ is H, Ci to Cio alkyl, C_? to Cio cycloalkyl, Ci to Cio alkoxy, or aryl; f is 0 to 4; and

R⁵⁰³ is H, Ci to Cio alkyl, Ci to Cio alkoxy, halogen, or aryl; (q) a compo

(XVIII)

wherein:

R⁵⁰⁷ is H, OH, Ci to do alkoxy, or C₃ to C₁₀ cycloalkyl;

_Rso8 _{tQ R}5 io _are^ independently, H, C_i to C_io alkyl, C_i to C_io alkoxy, C3 to Cio cycloalkyl, or halogen; and

(r) a compound of formula (XIX):

(XIX)

wherein:

R⁶⁰⁰ is Ci to Cio alkyl, NH₂ or Ci to Cio aminoalkyl;

_R602 _{tQ R}605 _are^ independently, C_i to C_io alkyl, C₃ to C_io cycloalkyl, Ci to Cio alkoxy, or halogen;

(s) a compound of formula (XX):

(XX)

wherein:

R⁶⁰⁶ is H or Ci to Cio alkyl;

_R607 _{tQ R}6io _{ar6j indep}endently, H, Ci to Cio alkyl, Ci to Cio alkoxy, or halogen;

(t) a compou

(XXI)

wherein:

_R ^/oo _{to R}/o4 _are^ independently, H, Ci to Cio alkyl, C3 to CIO cycloalkyl, C3 to Cio spirocycloalkyl, Ci to Cio alkoxy, halogen, Ci to Cio aminoalkyl, or CN; and

R⁷⁰⁵ is H or Ci to Cio alkyl;

(u) a compo

(XXII)

wherein: _R800 _{tQ R}804 _RW_{b R}S0y _{ar6j independent}l_yj H, C_l tO C alkyl, halogen, NH₂, or Ci to Cio alkoxy and

8⁰⁵ is H or Ci to do alkyl;

(v) a compound of formula (XXIII):

(XXIII)

wherein:

R^9UU is H or Ci to Cio alkyl; and

R⁹⁰¹ to R⁹⁰⁵ is H, Ci to Cio alkyl, C₂ to Cio alkenyl, C₂ to Cio alkynyl, halogen, Ci to Cio alkoxy, Ci to Cio aminoalkyl, or H₂; and (w) a compound of formula (XXIV):

(XXIV)

wherein:

R^JU6 is Ci to Cio alkyl or Ci to Cio alkoxy;

R⁹⁰⁷ is C₂ to Cio alkyl or Ci to Cio alkoxy;

e is 0 to 5;

R⁹⁰⁹ is H or Ci to Cio alkyl;

or a pharmaceutically acceptable salt or prodrug thereof.

97. The composition according to claim 96, wherein said medication is a chemotherapeutic, cardiotonic, blood pressure lowering agent, or cholesterol lowering agent.

98. The composition according to claim 96, wherein said medication which disrupts PF4 tetramers is CKEY2, ODSH (o-desulfated heparin), or a combination thereof.

99. A composition comprising:

(i) a pharmaceutically acceptable carrier; and

(ii) a compound selected from the group consisting of:

(a) a compound of formula (II):

(II)

wherein:

n is 0 to 5;

R¹ and R² are, independently, H, Ci to C₁₀ alkyl, C(0)(C₁ to Cio alkyl), C(0)(C₁ to C₁₀ alkyl), benzyl, C₃ to C₁₀ cycloalkyl, C₂ to Cio alkenyl, or C2 to C₁₀ alkynyl; or

(b) a compound of formula (III):

OR¹⁶

I

0^^P (CR¹⁷R¹⁸)_q-R¹⁰

(HI)

wherein:

q is 0 to 5;

R¹⁷ and R¹⁸ are, independently, absent, H, Ci to C₁₀ alkyl, (Ci to Cio alkyl)-P-(Ci to C₁₀ alkyl), Ci to C₁₀ alkoxy, halogen, OH, N0₂, CN, C₂ to Cio alkenyl, P(0)OH, C₂ to Cio alkynyl, aryl, heteroaryl, or heterocycle, each optionally substituted by one or more R¹⁹;

R¹⁹ is H, Ci to Cio alkyl, Ci to Cio alkoxy, halogen, N0₂, CN, C(0)OH, C(0)(Ci to Cio alkyl), C₂ to Cio alkenyl, oxo, or C₂ to Cio alkynyl;

(c) a compound of formula (IV):

(IV)

wherein:

m is 0 to 2;

R²⁶ is O or S;

(d) a compound of formula (V): O

II

_R41- ^P^_R40

(V)

wherein:

(e) a compound of formula (VI):

OR⁵¹

0=P— OR⁵⁰

I

_R52

(VI)

wherein:

R⁵³ is Ci to Cio alkyl, halogen, or C(0)OH;

(f) a compound of formula (VII):

O

\\

P— (CR⁶⁵R⁶⁶)_tR⁶⁰R⁶¹

HO

(VII)

wherein:

t is 1 to 10;

R⁶⁰ is aryl, heteroaryl, or heterocycle;

R⁶¹ is Ci to Cio aminoalkyl, Ci to Cio alkyl, C2 to Cio alkenyl, C2 to Cio alkynyl, C3 to Cio cycloalkyl, aryl, heteroaryl, or heterocycle; R^M and Br are, independently, H, OH, Ci to C₁₀ alkyl, C₃ to Cio cycloalkyl, C2 to C₁₀ alkenyl, C2 to C₁₀ alkynyl benzyl, aryl, heteroaryl, or heterocycle;

(g) a compound of formula (VIII):

(VIII)

wherein:

R , R , R^/4, and R^/5 are, independently, H, Ci to Cio alkyl, C₂ to Cio alkenyl, Ci to Cio aminoalkyl, C(0)(Ci to Cio aminoalkyl), or heteroaryl, each optionally substituted by one or more R⁷⁸;

R⁷² is H, Ci to Cio alkyl, 0(d to Cio alkyl), 0(d to Cio alkoxy), 0(Ci to Cio aminoalkyl), Ci to Cio aminoalkyl, or heteroaryl, each optionally substituted by one or more R⁷⁶;

78

more R ;

(h) a compound of formula (IX):

(IX)

wherein:

w is 1 to 10;

w' is 1 to 10;

R⁸⁰ is H or C₂ to C io alkyl;

R⁸¹ to R⁸⁵ are, independently, H, OH, d to C₁₀ alkyl, halogen, or Ci to Cio alkoxy; and

R⁸⁶ to R⁸⁹ are, independently, H, d to Cio alkyl, or C₃ to Cio cycloalkyl;

(i) a compound of formula (X):

(X)

wherein:

x is 2 to 10;

G) a compound of formula (XI):

wherein:

y is 1 to 10;

R⁹⁰ to R⁹⁴ are, independently, H, halogen, d to Cio alkyl, C₂ to Cio alkenyl, to Cio alkynyl, OH, or d to Cio aminoalkyl; and

R⁹⁵ is heterocycle, heteroaryl, aryl, or d to Cio aminoalkyl; (k) a compound of formula (XII):

(XII)

wherein:

R¹⁰⁵ is aryl, heteroaryl, or heterocycle;

z is 2 to 10;

_Rio6 _{tQ R} ^{i i}o _ar6j independently, H, C_i to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, OH, C2 to C₁₀ alkenyl, or C2 to C₁₀ alkynyl;

(1) a compound of formula (XIII):

(XIII)

wherein:

a is 0 or 1;

R¹²³ is H, halogen, Ci to C₁₀ alkyl, or Ci to C₁₀ alkoxy;

R¹²⁰ and R¹²¹ join to form C5 to C₁₀ cycloalkyl optionally substituted by one or more R¹²⁶; and R is H, halogen, Ci to C₁₀ alkyl, Ci to C₁₀ alkoxy, or Ci to Cio aminoalkyl;

(m) a compound of formula (XIV):

(XIV)

wherein:

R²⁰⁴ is Ci to Cio alkyl, Ci to Cio alkoxy, halogen, CN, N0₂, or aryl;

(n) a compound of formula (XV):

(XV)

wherein:

(0) a compound of formula (XVI):

(XVI)

wherein:

R⁴⁰⁰ is OH or O;

_R406

optionally substituted by one or more

with the proviso that when R⁴⁰¹ is OR⁴⁰⁵ and R⁴⁰³ is

(p) a compound of formula (XVII):

(XVII)

wherein:

R^5UU is Ci to Cio aminoalkyl;

R⁵⁰² is benzyl optionally substituted by one or more R⁵⁰³; R⁵ is H, Ci to Cio alkyl, C₃ to Cio cycloalkyl, Ci to Cio alkoxy, or aryl; f is 0 to 4; and

R⁵⁰³ is H, Ci to Cio alkyl, Ci to Cio alkoxy, halogen, or aryl; (q) a compound of formula (XVIII):

(XVIII)

wherein:

R is H, OH, Ci to Cio alkoxy, or C₃ to Cio cycloalkyl;

_R508 _{10 R}5 io _are^ independently, H, C_i to C_io alkyl, Ci to C_io alkoxy, C_? to Cio cycloalkyl, or halogen; and

(r) a compound of formula (XIX):

(XIX)

wherein:

R⁶⁰⁰ is Ci to Cio alkyl, NH₂ or Ci to Cio aminoalkyl;

R602 _{tQ R}605 _are^ _{indeperideritlyi} C_i to C_io alkyl, C₃ to C_io cycloalkyl, Ci to Cio alkoxy, or halogen;

(s) a compound of formula (XX):

(XX)

wherein:

R^WJb is H or Ci to Cio alkyl;

_R607 _{10 R}6io _are^ independently, H, C_i to C_io alkyl, C_i to C_io alkoxy, or halogen;

(t) a compou

(XXI)

wherein:

R to R^/04 are, independently, H, Ci to Cio alkyl, C3 to C IO cycloalkyl, C3 to Cio spirocycloalkyl, Ci to Cio alkoxy, halogen, Ci to Cio aminoalkyl, or CN; and

R⁷⁰⁵ is H or Ci to Cio alkyl;

(u) a compou

(XXII)

wherein: _Raoo _{tQ R}8U4 _{and R}w_{b and ar6i independently5} H, C_i to C_lO alkyl, halogen, NH₂, or Ci to C₁₀ alkoxy and

R⁸⁰⁵ is H or Ci to C₁₀ alkyl;

(v) a compound of formula (XXIII):

(XXIII)

wherein:

R⁹⁰⁰ is H or Ci to C₁₀ alkyl; and

_R9oi _{t0 R}9os _{is Hj C i tQ alky]) C2 10 Ci o alkenyl > Cl t0 C l 0} alkynyl, halogen, Ci to Cio alkoxy, Ci to Cio aminoalkyl, or NH₂; and (w) a compound of formula (XXIV):

(XXIV)

wherein:

R⁹⁰⁶ is Ci to Cio alkyl or Ci to Cio alkoxy;

R⁹⁰⁷ is C₂ to Cio alkyl or d to C₁₀ alkoxy;

e is 0 to 5;

R⁹⁰⁹ is H or Ci to Cio alkyl;

or a pharmaceutically acceptable salt or prodmg thereof.

100. The composition according to any one of claims 94 to 99, wherein said compound is selected from the group consisting of:

101. The composition according to any of claims 96 to 100, further comprising an adjuvant, syrup, elixir, diluent, excipient, binder, lubricant, surfactant, granulating agent, emollient, metal chelator, pH adjustor, filler, and disintegrant.

102. The composition according to claim 101, wherein said diluent is water.

103. A kit comprising:

(i) a medication which causes the formation of PF4 tetramers, a medication which disrupts PF4 tetramers, or a combination thereof;

(ii) a compound selected from the group consisting of:

(a) a compound of formula (II):

(II) wherein:

n is 0 to 5;

(b) a compound of formula (III):

OR¹⁶

I

0^^P (CR¹⁷R¹⁸)_q-R¹⁰

(III)

wherein:

q is 0 to 5;

R¹⁶ is H or Ci to Cio alkyl;

R¹⁹ is H, Ci to Cio alkyl, Ci to Cio alkoxy, halogen, N0₂, CN, C(0)OH, C(0)(Ci to Cio alkyl), C₂ to Cio alkenyl, oxo, or C₂ to Cio alkynyl; a compound of formula (IV):

(IV)

wherein:

m is 0 to 2;

R^2U is H, Ci to Cio alkyl C₃ to C₁₀ cycloalkyl, C₂ to C₁₀ alkenyl, or C₂ to Cio alkynyl, each optionally substituted by one or more R²⁴:

R²¹, R²², and R²³ are independently, H, Ci to Cio alkyl, or C₃ to Cio cycloalkyl, each optionally substituted by one or more R²⁴:

R²⁴ is H, halogen, OH, CN, N0₂, d to Cio alkyl C₃ to Cio cycloalkyl, C₂ to Cio alkenyl, or C₂ to Cio alkynyl, each optionally substituted by one or more R²⁷;

R²⁶ is O or S;

(d) a compound of formula (V):

O

_R41 - ^ _R40

(V)

wherein:

R⁴⁰ and R⁴¹ are, independently, H, Ci to Cio alkyl optionally substituted by one or more R⁴², aryl optionally substituted by one or more R⁴², or benzyl optionally substituted by one or more R⁴²:

(e) a compound of formula (VI): OR⁵¹

0=P— OR⁵⁰

I

_R52

(VI)

wherein:

R⁵³ is Ci to Cio alkyl, halogen, or C(0)OH;

(f) a compound of formula (VII):

P— (CR⁶⁵R⁶⁶)_tR⁶⁰R⁶¹

HO

(VII)

wherein:

t is 1 to 10;

R⁶⁰ is aryl, heteroaryl, or heterocycle;

(g) a compound of formula (VIII):

(VIII)

wherein: R , R , R , and R are, independently, H, Ci to C₁₀ alkyl, C₂ to Cio alkenyl, Ci to Cio aminoalkyl, C(0)(Ci to Cio aminoalkyl), or heteroaryl, each optionally substituted by one or more R⁷⁸;

R⁷⁸ is CN, C(0)OH, C(0)(Ci to Cio alkyl), C(0)0(Ci to Cio alkyl), or phenyl optionally substituted by one or more

(h) a compound of formula (IX):

(IX)

wherein:

w is 1 to 10;

w' is 1 to 10;

R⁸⁰ is H or C₂ to Cio alkyl;

R⁸¹ to R⁸⁵ are, independently, H, OH, Ci to Cio alkyl, halogen, or Ci to Cio alkoxy; and R to R are, independently, H, Ci to Cio alkyl, or C3 to Cio cycloalkyl;

(i) a compound of formula (X):

(X)

wherein:

x is 2 to 10;

(j) a compound of formula (XI):

(XI)

wherein:

y is 1 to 10;

(XII)

wherein:

R¹⁰⁵ is aryl, heteroaryl, or heterocycle;

z is 2 to 10; _Rio6 _{tQ R} ^{i i}o _ar6j independently, H, C_i to C₁₀ alkyl, C₃ to C₁₀ cycloalkyl, OH, C2 to C₁₀ alkenyl, or C2 to C₁₀ alkynyl;

(1) a compound of formula (XIII):

(XIII)

wherein:

a is 0 or 1;

R¹²³ is H, halogen, Ci to C₁₀ alkyl, or Ci to C₁₀ alkoxy;

R¹²⁰ and R¹²¹ join to form C5 to C₁₀ cycloalkyl optionally substituted by one or more R¹²⁶; and

R¹²⁶ is H, halogen, Ci to C₁₀ alkyl, Ci to C₁₀ alkoxy, or Ci to Cio aminoalkyl;

(m) a compound of formula (XIV):

(XIV)

wherein: R is Ci to Cio alkyl, Ci to Cio aminoalkyl, C₂ to C₁₀ alkenyl, or C₂ to Cio alkynyl, each optionally substituted by one or more R²⁰²;

R²⁰² is H, CI to Cio alkyl, halogen, CN, or 0₂; R²⁰⁰ is Ci to Cio alkyl, Ci to Cio alkoxy, aryl, C₂ to Cio alkenyl, Ci to Cio

203 203 aminoalkyl, each optionally substituted by one or more R ;R is halogen, CN, NO₂, Ci to Cio alkoxy, or aryl optionally substituted by one or more R²⁰⁴;

R²⁰⁴ is Ci to Cio alkyl, Ci to Cio alkoxy, halogen, CN, N0₂, or aryl;

(n) a compound of formula (XV):

(XV)

wherein:

R is Ci to Cio alkyl, Ci to Cio aminoalkyl, C₂ to Cio alkenyl,

_R302 or C₂ to Cio alkynyl, each optionally substituted by one or more

R³⁰³ is halogen, CN, NO₂, or aryl optionally substituted by one or more R³⁰⁴;

R³⁰⁴ is Ci to Cio alkyl, Ci to Cio alkoxy, halogen, CN, N0₂, or aryl;

(0) a compound of formula (XVI):

(XVI)

wherein:

R^4UU is OH or O; R⁴⁰¹, R⁴⁰², and R⁴⁰³, are independently, OR⁴⁰⁵ or N(R⁴⁰⁶)(R⁴⁰⁷); R⁴⁰⁴ is H, Ci to Cio alkyl, halogen, (=0), or Ci to C₁₀ alkoxy; R⁴⁰⁵ is absent, Ci to Cio alkyl, heterocycle, aryl, or heteroaryl,

_R406

optionally substituted by one or more

with the proviso that when R⁴⁰¹ is OR⁴⁰⁵ and R⁴⁰³ is

_N(R406_)(R407_{) R}405 ^ _R407 ^ _R401 ^ _R40_{2j R}401 and R⁴⁰³, and/or R⁴⁰² and R⁴⁰³ join to form a 5 to 8-membered ring, wherein the 5 to 8- membered ring contains carbon atoms and optionally one or more heteroatom and wherein the 5 to 8-membered

_R404

ring is optionally substituted by one or more

(p) a compound of formula (XVII):

(XVII)

wherein:

R⁵⁰⁰ is Ci to Cio aminoalkyl;

R⁵⁰² is benzyl optionally substituted by one or more is H, Ci to Cio alkyl, C3 to Cio cycloalkyl, Ci to Cio alkoxy, or aryl; f is 0 to 4; and

(XVIII)

wherein:

R is H, OH, Ci to Cio alkoxy, or C₃ to do cycloalkyl;

_R5⁰⁸ _{tQ R}5 ⁱo _are> independently, H, C_i to C_io alkyl, C_i to C_io alkoxy, C₃ to Cio cycloalkyl, or halogen; and

(r) a comp

(XIX)

wherein:

R⁶⁰⁰ is Ci to Cio alkyl, NH₂ or Ci to Cio aminoalkyl;

_R ⁶⁰2 _{tQ R} ⁶⁰5 _are> independently, C_i to C_io alkyl, C₃ to C_io cycloalkyl, Ci to C io alkoxy, or halogen;

(s) a compound of formula (XX):

(XX)

wherein:

R^ is H or Ci to Cio alkyl;

(t) a compound of formula (XXI):

(XXI)

wherein:

_R7oo _{tQ R}704 _ar6j independently, _H, Ci to C₁₀ alkyl, C3 to CIO cycloalkyl, C3 to C₁₀ spirocycloalkyl, Ci to C₁₀ alkoxy, halogen, d to Cio aminoalkyl, or CN; and

R⁷⁰⁵ is H or Ci to C₁₀ alkyl;

(u) a compound of formula (XXII):

(XXII)

wherein:

R^8UU to R^8U and R^8UO and R^suv are, independently, H, Ci to C₁₀ alkyl, halogen, NH₂, or Ci to C₁₀ alkoxy and

R⁸⁰⁵ is H or Ci to Cio alkyl;

(v) a compound of formula (XXIII):

(XXIII)

wherein:

R⁹⁰⁰ is H or Ci to Cio alkyl; and R^yui to R^yu3 is H, Ci to Cio alkyl, C₂ to C₁₀ alkenyl, C₂ to C₁₀ alkynyl, halogen, Ci to C₁₀ alkoxy, Ci to C₁₀ aminoalkyl, or NH₂; and (w) a compound of formula (XXIV):

(XXIV)

wherein:

R is Ci to Cio alkyl or Ci to Cio alkoxy;

R⁹⁰⁷ is C₂ to Cio alkyl or Ci to Cio alkoxy;

e is 0 to 5;

R⁹⁰⁹ is H or Ci to Cio alkyl;

or a pharmaceutically acceptable salt or prodrug thereof; and

(iii) instructions for administering said medication and said compound to a subject having cancer.

104. The kit according to claim 103, wherein said medication which causes the formation of PF4 tetramers is a chemotherapeutic, cardiotonic, blood pressure lowering agent, or cholesterol lowering agent.

105. The kit according to claim 103, wherein said medication which disrupts PF4 tetramers is CKEY2, ODSH (o-desulfated heparin), or a combination thereof

106. A kit comprising:

(i) a pharmaceutically acceptable carrier;

(ii) a compound selected from the group consisting of:

(a) a compound of formula (II):

(II)

wherein:

n is 0 to 5; R¹ and R² are, independently, H, Ci to C₁₀ alkyl, C(0)(C₁ to Cio alkyl), C(0)(C₁ to C₁₀ alkyl), benzyl, C₃ to C₁₀ cycloalkyl, C₂ to Cio alkenyl, or C₂ to Cio alkynyl; or

(b) a compound of formula (III):

OR¹⁶

I

^(CR¹⁷R¹⁸)_q-R¹⁰

(III)

wherein:

q is 0 to 5;

R¹⁶ is H or Ci to Cio alkyl;

(c) a compound of formula (IV):

(IV)

wherein:

m is 0 to 2;

R²⁰ is H, Ci to Cio alkyl C₃ to C₁₀ cycloalkyl, C₂ to C₁₀ alkenyl, or C₂ to Cio alkynyl, each optionally substituted by one or more R²⁴:

R²⁶ is O or S;

(d) a compound of formula (V):

O II

_R41 ' ^P^ _R40

(V)

wherein:

(e) a compound of formula (VI): OR⁵¹

0=P— OR⁵⁰

I

_R52

(VI)

wherein:

R⁵³ is Ci to Cio alkyl, halogen, or C(0)OH;

(f) a compound of formula (VII):

P— (CR⁶⁵R⁶⁶)_tR⁶⁰R⁶¹

HO

(VII)

wherein:

t is 1 to 10;

R⁶⁰ is aryl, heteroaryl, or heterocycle;

(g) a compound of formula (VIII):

(VIII)

(h) a compound of formula (IX):

(IX)

wherein:

w is 1 to 10;

w' is 1 to 10;

R⁸⁰ is H or C₂ to Cio alkyl;

(i) a compound of formula (X):

(X)

wherein:

x is 2 to 10;

(j) a compound of formula (XI):

wherein:

y is 1 to 10;

R⁹⁵ is heterocycle, heteroaryl, aryl, or Ci to Cio aminoalkyl; a compound of formula (XII)

(XII)

wherein:

R¹⁰⁵ is aryl, heteroaryl, or heterocycle;

z is 2 to 10;

_R ⁱo⁶ _{tQ R} ^{i i}o _ar6j independently, H, C_i to C_io alkyl, C₃ to C_io cycloalkyl, OH, C2 to Cio alkenyl, or C2 to Cio alkynyl; (1) a compound of formula (XIII):

(XIII)

wherein:

a is 0 or 1;

R¹²⁰ is absent, aryl, C3 to C10 cycloalkyl, heteroaryl, or heterocycle, each optionally substituted by one or more R¹²⁵;

R¹²³ is H, halogen, Ci to C₁₀ alkyl, or Ci to C₁₀ alkoxy;

R¹²⁴ is H, halogen, Ci to C10 alkyl, Ci to C10 alkoxy, or Ci to Cio aminoalkyl;

(m) a compound of formula (XIV):

j2

(XIV)

wherein:

R is Ci to Cio alkyl, Ci to Cio aminoalkyl, C2 to Cio alkenyl, to Cio alkynyl, each optionally substituted by one or more R²⁰²; R^zvz is H, CI to Cio alkyl, halogen, CN, or 0₂; R is Ci to Cio alkyl, Ci to Cio alkoxy, aryl, C₂ to Cio alkenyl, Ci to Cio aminoalkyl, each optionally substituted by one or more R ;R is halogen, CN, NO₂, Ci to Cio alkoxy, or aryl optionally substituted by one or more R²⁰⁴;

R²⁰⁴ is Ci to Cio alkyl, Ci to Cio alkoxy, halogen, CN, N0₂, or aryl;

(n) a compound of formula (XV):

(XV)

wherein:

R is Ci to Cio alkyl, Ci to Cio aminoalkyl, C₂ to Cio alkenyl,

_R302 or C2 to Cio alkynyl, each optionally substituted by one or more

R³⁰⁴ is Ci to Cio alkyl, Ci to Cio alkoxy, halogen, CN, N0₂, or aryl;

(0) a compound of formula (XVI):

(XVI)

wherein:

4^UU is OH or O;

R is H, Ci to Cio alkyl, halogen, (=0), or Ci to Cio alkoxy; R⁴⁰⁵ is absent, Ci to Cio alkyl, heterocycle, aryl, or heteroaryl,

_R406

optionally substituted by one or more

with the proviso that when R⁴⁰¹ is OR⁴⁰⁵ and R⁴⁰³ is

_R404

ring is optionally substituted by one or more

(p) a compound of formula (XVII):

(XVII)

wherein:

R⁵⁰⁰ is Ci to Cio aminoalkyl;

R⁵⁰² is benzyl optionally substituted by one or more R⁵⁰³; R⁵ is H, Ci to Cio alkyl, C3 to Cio cycloalkyl, Ci to Cio alkoxy, or aryl; f is 0 to 4; and

(XVIII)

wherein:

R⁵⁰⁷ is H, OH, Ci to Cio alkoxy, or C₃ to Cio cycloalkyl;

_R508 _{10 R}5 io _are^ independently, H, Ci to Cio alkyl, Ci to Cio alkoxy, C₃ to Cio cycloalkyl, or halogen; and

(r) a compo

wherein:

R⁶⁰⁰ is Ci to Cio alkyl, NH₂ or Ci to Cio aminoalkyl;

_R602 _{tQ R}605 _are> independently, Ci to Cio alkyl, C₃ to Cio cycloalkyl, Ci to Cio alkoxy, or halogen;

(s) a compound of formula (XX):

(XX)

wherein:

R⁶⁰⁶ is H or Ci to Cio alkyl;

_R607 _{tQ R}6io _are> independently, H, Ci to Cio alkyl, Ci to Cio alkoxy, or halogen;

(t) a compound of formula (XXI):

(XXI)

wherein:

_R7oo _{tQ R}704 _{ar6j independentlyj Hj Cl t0 Cl0} aiky^ C3 _{t0 C 10} cycloalkyl, C₃ to C₁₀ spirocycloalkyl, Ci to C₁₀ alkoxy, halogen, Ci to Cio aminoalkyl, or CN; and

R⁷⁰⁵ is H or Ci to C₁₀ alkyl;

(u) a compo

(XXII)

wherein:

_R800 _{tQ R}804 _R806 ^ _R809 ^ _independentl_{yj H}, C_l tO C alkyl, halogen, NH₂, or Ci to C₁₀ alkoxy and

8⁰⁵ is H or Ci to C₁₀ alkyl;

(XXIII)

wherein: R^yuu is H or Ci to C₁₀ alkyl; and

R⁹⁰¹ to R⁹⁰⁵ is H, Ci to Cio alkyl, C₂ to C₁₀ alkenyl, C₂ to C₁₀ alkynyl, halogen, d to Cio alkoxy, Ci to C₁₀ aminoalkyl, or H₂; and (w) a compound of formula (XXIV):