WO2010011325A2

WO2010011325A2 - Synthesis and utilization of small molecules for the treatment of inflammation associated with interleukin-1 signaling

Info

Publication number: WO2010011325A2
Application number: PCT/US2009/004283
Authority: WO
Inventors: Julius Rebek; Enrique Mann; Lionel Moisan
Original assignee: The Scripps Research Institute
Priority date: 2008-07-23
Filing date: 2009-07-23
Publication date: 2010-01-28
Also published as: WO2010011325A3

Abstract

The invention describes synthetic compounds, methods of preparation and their uses thereof an anti-inflammatory compounds that reduce inflammation associated with interleukin-1signaling.

Description

SYNTHESIS AND UTILIZATION OF SMALL MOLECULES FOR THE TREATMENT OF INFLAMMATION ASSOCIATED WITH INTERLEUKIN-1

SIGNALING

Cross Reference to Related Application

This application claims priority from U.S. Provisional Application Serial No. 61/137,003,filed July 23, 2008, whose disclosures are incorporated herein by reference.

Field of the Invention

The invention relates generally to synthetic compounds, and method for preparation and uses thereof, and pharmaceutical compositions comprising the compounds and their utilization as anti-inflammatory agents. In particular, the invention relates to a family of compounds that reduces inflammation associated with interleukin-1 signaling.

Related Art

The information contained in this section relates to the background of the art of the present invention without any admission as to whether or not it legally constitutes prior art.

The interleukin-1 receptor (IL-IR) is a member of Toll-like receptor IL-IR (TLR/IL-IR super-family). Some members of the IL-I family, IL- lβ and IL-33, are highly inflammatory cytokines. They can lead to severe pathological effects when their expression is not regulated. The activity of IL-I β is highly regulated via the soluble receptor, IL-IRl, and a natural antagonist protein, IL-IRa.

The IL- lβ signaling begins with activation of IL-IRl, it then forms a heterodimer with IL-I receptor accessory protein (IL-IRAcP). Like other members of TLR/IL-1 super-family, IL- IRl and IL-IRAcP posses a cytoplasmic ToML-I Receptor (TIR) domain, their dimerization is thought to occur via corresponding TIR domains. This is followed by recruitment of a post receptor complex containing the adaptor MyD88. MyD88 is a modular protein with a TIR domain as well as a protein interaction domain termed the death domain. Its TIR domain is thought to bind to that of the receptor via a TIR/adaptor-TIR/receptor association. Its death domain activates the Interleukin Receptor- Associated Kinases 1-4 (IRAKI -4). Phosphorylated IRAK-I dissociates from MyD88, and then associates with the tumor necrosis factor (TNF) receptor associated factor-6 (TRAF6). TRAF-6 and IRAK-I dissociate from the receptor and interact at the membrane with a preformed complex of TGF-β associated kinase 1 (TAKl) and two TAKl binding proteins called TABl and TAB2. A sequence of protein-protein interactions culminates in the activation of signals such as the mitogen-activated protein kinases (MAPKinase) p38, Jun N-terminal Kinase (JNK), and nuclear factor-κB (NF-κB) (Helle Frobose et al, MoI. Endocrinology, 2006, 20, pi 596). These signals elicit the production of essential effector molecules for immune and inflammatory responses. Some inflammatory cytokines released upon IL-I signaling are IL- 6, INF-γ and TNF-α, IL-4, IL-I β, and IL-5. These cytokines play major roles in asthma and other respiratory diseases ((Lappalainen, U. et al, 2005, Am. J. Respir. Cell MoI. Biol. 32, p318. Frossard, N., et al, 2005, Eur. Respir. J. 26:5-20. Y. Zhang et al, 2007, Respir. Res., 8, p29.), inflammation-linked cancer (W. Naugler et al, 2007, Science, 317, pl27.), sepsis, septic shock, RA, autoimmunity and Type I diabetes (Zhou, L., et al, 2007, Nature Immunol., 8, p474).

The initial IL-l-receptor/MyD88 adaptor interaction evoked by IL- lβ is a critical step in signaling to the nucleus and, therefore, it is a potential target for anti-inflammatory agents. The interaction between IL-IR and MyD88 homolog occurs through their corresponding TIR domains. The secondary structure of TIR domain contains five β-strands (βA, βB, βC, βD and βE) surrounded by five α-helices (αA, αB, αC, αD and αE). The β strands and α helices create five loops-AA, BB, CC, DD, and EE (Li, C. et al, 2005, J. Biol. Chem. 280 p26159). The BB-loop emerges as key to the TIR domain-mediated protein-protein interaction required for IL-I signaling (Xu et al, 2000, Nature, 408, pplll-115). The TIR domain of TLR/IL-1R proteins and MyD88 adaptor contains a consensus sequences (F/V/D)-(L/Y/V/I)-(P/V) in the BB-loop region that is critical for signaling. Synthetic molecules mimicking this region — BB-loop mimetics— inhibit association of IL-IR and MyD88, interfere with IL-IR signaling, and have therapeutic applications in inflammation linked diseases.

Protein-protein interactions play key roles in several biological processes and, therefore, are attractive targets in research and medicine. Protein-protein interaction inhibitors, mimicking protein surface structure and function, are novel and alternative approach to traditional medicinal chemistry.

In view of the high prevalence of inflammation-linked complications, e.g., cancer, type I diabetes, sepsis, rheumatoid arthritis and asthma, and more importantly due to lack of effective treatment, pharmaceutical companies have great interest in the development of anti-inflammatory new drugs. Such drugs maybe designed to block signaling cascade of proteins involved in inflammation.

The background information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should be construed, that any of the preceding information constitutes prior art against the present invention. Moreover, publications referred to in the following discussion are hereby incorporated by reference in their entireties in this application.

SUMMARY OF THE INVENTION

The disclosed embodiments are directed to the treatment of inflammation associated with IL-I signaling, e.g., rheumatoid arthritis, asthma and upper airway inflammation, inflammation-linked cancer, autoimmune disease, type I diabetes, septic shock and sepsis by interfering with the IL- l β signaling pathway using structure-based synthetic organic molecules called BB-loop mimetics.

The molecules are designed to block interaction between certain proteins in IL- 1 β signaling pathway. More specifically, they interfere with interactions of IL-IR (receptor protein) and MyD88 (adaptor protein). The molecules are designed based on a large conserved surface in the TIR domain of IL-IR and MyD88, the BB-loop, with consensus sequences (OfV)- (Y/L)-(V/P). Such molecules are used to interfere with homotypic (TIRreceptor - TIR_re_cept_or interaction or TIRad_aptor - TIR_ad_aptor interaction) and/or heterotypic dimerization of TIR domains (TIRreceptor - TIRadapto_r interaction).

In one aspect, the present invention relates in part to: BB-loop mimetics of Formula I; to processes for preparing compounds of Formula I; to pharmaceutical compositions including compounds of Formula I:

B

Formula I

Wherein, in the compounds of Formula I the spacer is independently selected from the following structures:

Wherein, X is independently either C-H, N, N⁺-O^", N⁺-F, or lST^any biologically relevant counter ion), preferred species are represented by the following structures:

Wherein, Rj is selected from a group consisting of side chains of amino acids other than glycine; a substituted or un-substituted arylalkyl or heterocyclylalkyl group; a substituted Ci-io alkyl group, optionally comprising one or more unsaturated bonds within the alkyl chain, and optionally substituted with -OR⁴, C(O)-pyrrolidine (substituted and un- substituted ring), C(O)-piperazine (substituted and un-substituted ring), C(O)-morpholine (substituted and un-substituted ring), C(O)-piperidine (substituted and un-substituted ring), C(O)-thiomorpholine (substituted and un-substituted ring), C(O)-thiomorpholine 1,1- dioxide (substituted and un-substituted ring),-C(O)R⁴, -COOR⁴, -S(O)_qR⁴, -NR⁴R⁵, - C(Y)NR⁴R⁵, -N(R⁴)C(Y)OR⁵, -NR⁶C(Y)NR⁴R⁵, -NR⁶C(NR⁷)NR⁴R⁵, -C(NR⁶)NR⁴R⁵, - C(Y)NR⁴OR⁵, -SO₂NR⁴R⁵, -NR⁴-SO2-R⁵, and wherein Y is O or S and q is independently 0-2; -CH(NH₂)=NH; -NO₂.

R⁴, R⁵, R⁶, and R⁷, at each occurrence, are independently hydrogen or a substituted or un- substituted Ci_-8 alkyl, C_2-8 alkenyl, (C_0-6 alkylene)(C_6-io aryl), or (C_0-6 alkylene)(C_3-9 heterocylyl) group, or together with the N, to which they are attached, form a substituted heterocyclyl group.

R and R at each occurrence, are independently a side chain of an amino acid other than glycine, a substituted or un-substituted aralkyl, alkyl halide or hetercyclylalkyl groups; a Ci- io alkyl groups, optionally comprising one or more unsaturated bonds within the alkyl chain, and optionally substituted with -OR⁴, -C(O)R⁴, -COOR⁴, -S(O)_qR⁴, -NR⁴R⁵, -C(Y)NR⁴R⁵, - N(R⁴)C(Y)OR⁵, -NR⁶C(Y)NR⁴R⁵, -NR⁶C(NR⁷)NR⁴R⁵, -C(NR⁶)NR⁴R⁵, -C(Y)NR⁴OR⁵, - SO₂NR⁴R⁵, -NR⁴-SO2-R⁵ , and wherein Y is O or S; and

Examples are the following:

jγ^Nvy OH

O

More examples are: Z= OH, NMe₂, NH₂, NO₂, OMe

Z= O, NMe, S, SO₂

In the compounds of Formula I, A is selected from a group consisting of :

Where in Z is CH₂ or O and R₂ is selected from a group consisting of halogens, side chains of amino acids; a substituted or un-substituted arylalkyl, or heterocyclylalkyl groups; a substituted Ci_io alkyl groups, optionally comprising one or more unsaturated bonds within the alkyl chain, and optionally substituted with halogens, -OR⁴, -C(O)R⁴, -COOR⁴, - S(O)_qR⁴, -NR⁴R⁵, -C(Y)NR⁴R⁵, -N(R⁴)C(Y)OR⁵, -NR⁶C(Y)NR⁴R⁵, -NR⁶C(NR⁷)NR⁴R⁵, - C(NR⁶)NR⁴R⁵, -C(Y)NR⁴OR⁵, -SO₂NR⁴R⁵, -NR⁴-SO2-R⁵ , and wherein Y is O or S; - C(O)-NH- R⁸; and -NH-C(O)-R⁹.

R⁴, R⁵, R⁶,- and R⁷, at each occurrence, are independently hydrogen or a substituted or un- substituted Ci_-8 alkyl, C_2-8 alkenyl, (Co-6 alkylene)(C_6-io aryl), or (Co-₆ alkylene)(C_3-9 heterocylyl) group, or together with the N to which they are attached, form a substituted heterocyclyl group.

R⁸ and R⁹ at each occurrence, are independently a side chain of an amino acid other than glycine, a substituted or un-substituted aralkyl, alkyl halide or hetercyclylalkyl groups; a Q- io alkyl groups, optionally comprising one or more unsaturated bonds within the alkyl chain, and optionally substituted with -OR⁴, -C(O)R⁴, -COOR⁴, -S(O)_qR⁴, -NR⁴R⁵, -C(Y)NR⁴R⁵, - N(R⁴)C(Y)OR⁵, -NR⁶C(Y)NR⁴R⁵, -NR⁶C(NR⁷)NR⁴R⁵, -C(NR⁶)NR⁴R⁵, -C(Y)NR⁴OR⁵, - SO₂NR⁴R⁵, -NR⁴-SO2-R⁵ , and wherein Y is O or S; and

In the compounds of Formula I, B is selected from a group consisting of:

Where in Z is CH₂ or O and R₃ is selected from a group consisting of hydrogen, side chains of amino acids; a substituted or un-substituted arylalkyl, or heterocyclylalkyl groups; a substituted Ci_-I0 alkyl groups, optionally comprising one or more unsaturated bonds within the alkyl chain, and optionally substituted with fluorine, -OR⁴, -C(O)R⁴, -COOR⁴, -S(O)_qR⁴, -NR⁴R⁵, -C(Y)NR⁴R⁵, -N(R⁴)C(Y)OR⁵, -NR⁶C(Y)NR⁴R⁵, -NR⁶C(NR⁷)NR⁴R⁵, - C(NR⁶)NR⁴R⁵, -C(Y)NR⁴OR⁵, -SO₂NR⁴R⁵, -NR⁴-SO2-R⁵ , and wherein Y is O or S, q is independently 0-2; halides; -C(O)-NH- R⁸; and -NH-C(O)-R⁹.

R⁴, R⁵, R⁶, and R⁷, at each occurrence, are independently hydrogen or a substituted or un- substituted Cl-8 alkyl, C2-8 alkenyl, (CO-6 alkylene)(C6-10 aryl), or (CO-6 alkylene)(C3-9 heterocylyl) group, or together with the N to which they are attached, form a substituted heterocyclyl group.

R⁸ and R⁹ at each occurrence, are independently a side chain of an amino acid other than glycine, a substituted or un-substituted aralkyl, alkyl halide or hetercyclylalkyl groups; a Ci- io alkyl groups, optionally comprising one or more unsaturated bonds within the alkyl chain, and optionally substituted with -OR⁴, -C(O)R⁴, -COOR⁴, -S(O)_qR⁴, -NR⁴R⁵, -C(Y)NR⁴R⁵, - N(R⁴)C(Y)OR⁵, -NR⁶C(Y)NR⁴R⁵, -NR⁶C(NR⁷JNR⁴R⁵, -C(NR⁶)NR⁴R⁵, -C(Y)NR⁴OR⁵, - SO₂NR⁴R⁵, -NR⁴-SO2-R⁵ , and wherein Y is O or S; and Preferred species are presented by the following structures:

Formula Il Formula I Formula IV

Another aspect of the invention is directed to a method for binding a compound to a receptor or protein. The method comprises the step of contacting a receptor or protein with the compound of Formula I. In a preferred aspect of this invention, the receptor is a Toll receptor. In another preferred aspect, the receptor is IL-IRl . In another preferred mode, the protein is MyD88.

Another aspect of the invention is directed to a method for treating a biological condition involving protein-protein interactions. The method comprises the step of administering to a subject in need thereof an effective amount of the compound of Formula I. In a preferred mode of this aspect of the invention, the biological condition is rheumatoid arthritis. In another aspect of the invention, the biological condition is asthma and upper airway hypersensitivity. In another aspect of the invention, the biological condition is chronic obstructive pulmonary disease.

Another aspect of the invention is directed to a method of disrupting protein-protein interactions in IL-I signaling. The method comprises the step of contacting IL-IR with an effective amount of the compound of Formula I for preventing or lessening the binding of MyD88 to BB-loop region of IL-IR.

Another aspect of the invention is directed to a method of preparing the compounds of Formula II, III and IV.

Another aspect of the invention provides pharmaceutical compositions which may be prepared by mixing one or more compounds of the invention, pharmaceutically acceptable salts thereof, with pharmaceutically acceptable additives, and pharmaceutically acceptable carriers to treat or ameliorate inflammation associated with asthma and upper airway hypersensitivity. The composition of the invention may be used to create Formulations that would treat asthma. Such composition can be in the form of, for example, tablets, capsules, syrup, powder, granules, suspensions, or solutions. The instant composition can be formulated for various routes of administration, for example, by oral administration, by nasal administration, subcutaneous injection, intravenous injection, intramuscular injection, or intraperitoneal injection. The following dosage forms are given by way of example and should not be construed as limiting the instant invention.

For oral administration, powders, suspensions, granules, tablets, pills, capsules, and gelcaps are acceptable as solid dosage forms. This can be prepared by mixing one or more compounds of the instant invention, with pharmaceutical acceptable salts, and additives such as starch or other additives. Optionally, oral dosage forms can contain other ingredients to aid in administration, such as an active diluent, or lubricants such as magnesium stearate, or preservatives such as parben or sorbic acid, or antioxidants such as ascorbic acid, tocopherol, or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents or perfuming agents. Tablets and pills may be further treated with suitable coating materials known in the art.

Liquid dosage forms for oral administration maybe in the form of pharmaceutically acceptable emulsions, syrups, suspensions or solutions, which may contain an inactive diluent, such as water. Pharmaceutical Formulations and medicaments maybe prepared as liquid suspensions or solutions using a sterile liquid, such as, but not limited to, an oil, water, an alcohol, and combination of these.

For nasal administration, the pharmaceutical Formulations maybe a spray or aerosol containing an appropriate solvent(s) and optionally other compounds such as, but not limited to, stabilizer, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combination of these. A propeller for an aerosol Formulation may include compressed air, nitrogen, carbon dioxide, or a hydrocarbon-based low boiling solvent(s).

Injectable dosage forms generally include aqueous suspensions or oil suspensions which maybe prepared using a suitable dispersant or wetting agent. Injectable forms maybe in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution or isotonic aqueous saline solution. Alternatively, aqueous oil maybe employed as solvents or suspending agents. Typically, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di-, tri-glycerides.

For injection, the pharmaceutical Formulation may also be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but not limited to, freeze dried, or spray dried powders, amorphous powders, granules, precipitates or particulates. For injection, the Formulation amy contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combination of these.

Specific dosages maybe adjusted depending on conditions of the disease, the age, body weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and combination of drugs. Any of the above dosage forms containing effective amounts are well within the scope of the invention.

A therapeutically effective amount of a compound of the present invention may vary depending upon the route of administration and dosage form. The typical compound or compounds of the invention is a formulation that exhibits a high therapeutic index. The therapeutic index is the dose ration between toxic and therapeutic effects which can be expressed as the ratio between LD50 and ED50. The LD50 is the dose lethal to 50% of the population and the ED50 is the dose therapeutically effective in 50% of the population. The LD50 and ED50 are determined by standard pharmaceutical procedures in animal cell cultures or experimental animals.

BRIEF DESCRIPTION OF THE DRAWINGS SCHEME I illustrates stepwise synthesis of compound of Formula II. SCHEME II depicts stepwise synthesis of synthesis of compounds of Formula III and IV.

DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

The invention provided methods for preparing compound of Formula II. In this invention, the synthesis of the compound of Formula II was proceeded with deblocking of Boc- pyrrolidyl L-valine in the presence of trifluoroacetic acid in an organic solvent, e.g. dichloromethane followed by alkylation of the resulting amine with l-(3- bromopropyl)benzene. The resulting compound was added to a solution of 2,5-pyridine dicarboxylic acid, methylene chloride, dimethylformamide, and thionyl chloride (Davis et al, 2006, PNAS, 103, pp2953-2958). The resulting compound was methylated in the presence of methyl iodide to form compound of Formula II (SCHEME I).

Another aspect of the invention provided methods for preparing compounds of Formula III and IV. In this invention, the synthesis of the compounds of Formula III and IV proceeded from commercially available 3-(3-fluorophenyl)propionic acid and 3-(4- trifluoromethylphenyl)propionic acid, respectively. In a preferred mode of this aspect of the invention, the acids were reduced in the presence of sodium borohydride and isobutyl chloroformiate in tetrahydrofuran. This reduction generated 3-(3-fluorophenyl)propanol and 3 -(4-trifluoromethylphenyl)propanol .

The alcohols 3-(3-fluorophenyl)propanol and 3-(4-trifluoromethylphenyl)propanol were dissolved in an appropriate organic solvent, e.g. dichloromethane and were brominated in the presence of triphenyl phosphine and an appropriate brominating agents, e.g., carbontetrabromide to form the following bromides.

The above bromides were exposed to a solution of the trifluoroacetic salt of pyrrolidyl valine in a suitable organic solvent, e.g., dimethyl formamide in the presence of potassium carbonate to form the following secondary amines:

The above amines were added to a stirred solution of 2, 5-pyridinedicarboxylic in an organic solvent, e.g., methylene dichloride and PyBroP and stirred at room temperature for 36 hours. Purification of the crude mixtures followed by exposure to methylene iodide formed compounds of Formula III and IV (SCHEME II).

Claims

We Claim:

1. A compound having Formula I

Spacer

B Formula

Wherein: in the compound of Formula I the spacer is independently selected from a group consisting of

Wherein: X is independently C-H, N, N⁺-O^", N⁺-I^", or ^-(any biologically relevant counter ion),

Wherein: A is selected from a group consisting of:

Wherein: Z is CH₂ or O.

Wherein: B is selected from a group consisting of:

Wherein: Z is CH₂ or 0.

Wherein: Rj is selected from a group consisting of side chains of amino acids; a substituted or un-substituted arylalkyl or heterocyclylalkyl group; a substituted Ci_-I0 alkyl groups, optionally comprising one or more unsaturated bonds within the alkyl chain, and optionally substituted with -OR⁴, C(O)-pyrrolidine (substituted and un-substituted ring), C(O)- piperazine (substituted and un-substituted ring), C(O)-morpholine (substituted and un- substituted ring), C(O)-piperidine (substituted and un-substituted ring), C(O)- thiomorpholine (substituted and un-substituted ring), -CH(NR⁴R⁵)=NH, C(O)- thiomorpholine 1,1 -dioxide (substituted and un-substituted ring),-C(O)R⁴, -COOR⁴, - S(O)_qR⁴, -NR⁴R⁵, -C(Y)NR⁴R⁵, -N(R⁴)C(Y)OR⁵, -NR⁶C(Y)NR⁴R⁵, -NR⁶C(NR⁷)NR⁴R⁵, - C(NR⁶)NR⁴R⁵, -C(Y)NR⁴OR⁵, -SO₂NR⁴R⁵, -NR⁴-SO2-R⁵, and wherein Y is O or S; -NO₂; -C(O)-NH- R⁸; and -NH-C(O)-R⁹.

R₂ and R₃ are independently selected from a group consisting of a halogen, side chains of amino acids; a substituted or un-substituted arylalkyl or heterocyclylalkyl group; a substituted C_MO alkyl groups, optionally comprising one or more unsaturated bonds within the alkyl chain, and optionally substituted with -OR⁴, C(O)-pyrrolidine (substituted and un- substituted ring), C(O)-piperazine (substituted and un-substituted ring), C(O)-morpholine (substituted and un-substituted ring), C(O)-piperidine (substituted and un-substituted ring), C(O)-thiomorpholine (substituted and un-substituted ring), -CH(NR⁴R⁵)=NH, C(O)- thiomorpholine 1,1 -dioxide (substituted and un-substituted ring),-C(O)R⁴, -COOR⁴, - S(O)_qR⁴, -NR⁴R⁵, -C(Y)NR⁴R⁵, -N(R⁴)C(Y)OR⁵, -NR⁶C(Y)NR⁴R⁵, -NR⁶C(NR⁷)NR⁴R⁵, - C(NR⁶)NR⁴R⁵, -C(Y)NR⁴OR⁵, -SO₂NR⁴R⁵, -NR⁴-SO2-R⁵, and wherein Y is O or S; -NO₂; -C(O)-NR⁶;

R⁴, R⁵, R⁶, and R⁷, at each occurrence, are independently hydrogen or a substituted or un- substituted Ci_-8 alkyl, C_2-8 alkenyl, (Co_-6 alkylene)(C6-io aryl), or (C_0-6 alkylene)(C3-9 heterocylyl) group, or together with the N to which they are attached, form a substituted heterocyclyl group;

R⁸ and R⁹ at each occurrence, are independently a side chain of an amino acid other than glycine, a substituted or un-substituted aralkyl, alkyl halide or hetercyclylalkyl groups; a Ci- io alkyl groups, optionally comprising one or more unsaturated bonds within the alkyl chain, and optionally substituted with -OR⁴, -C(O)R⁴, -COOR⁴, -S(O)_qR⁴, -NR⁴R⁵, -C(Y)NR⁴R⁵, - N(R⁴)C(Y)OR⁵, -NR⁶C(Y)NR⁴R⁵, -NR⁶C(NR⁷)NR⁴R⁵, -C(NR⁶)NR⁴R⁵, -C(Y)NR⁴OR⁵, - SO₂NR⁴R⁵, -NR⁴-SO2-R⁵ , and wherein Y is O or S; and

Each q is independently 0-2; and

Stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof.

2. The compound of claim 1, wherein Ri, R₂ and R₃ are halogens, side chains of amino acids; a substituted or un-substituted arylalkyl or heterocyclylalkyl group; a substituted Ci- io alkyl groups, optionally comprising one or more unsaturated bonds within the alkyl chain, and optionally substituted with -OR⁴, C(0)-pyrrolidine (substituted and un-substituted ring), C(O)-piperazine (substituted and un-substituted ring), C(0)-morpholine (substituted and un-substituted ring), C(O)-piperidine (substituted and un-substituted ring), C(O)- thiomorpholine (substituted and un-substituted ring), -CH(NR⁴R⁵)=NH, C(O)- thiomorpholine 1,1 -dioxide (substituted and un-substituted ring),-C(O)R⁴, -COOR⁴, - S(O)_qR⁴, -NR⁴R⁵, -C(Y)NR⁴R⁵, -N(R⁴)C(Y)OR⁵, -NR⁶C(Y)NR⁴R⁵, -NR⁶C(NR⁷)NR⁴R⁵, - C(NR⁶)NR⁴R⁵, -C(Y)NR⁴OR⁵, -SO₂NR⁴R⁵, -NR⁴-SO2-R⁵, and wherein Y is O or S; -NO₂; -C(O)-NR⁶;

3. The compound according to claim 2, wherein Ri , R₂ and R₃ are C_MO alkyl groups, optionally substituted with halogens; -OR⁴, C(O)-pyrrolidine (substituted and un-substituted ring), C(O)-piperazine (substituted and un-substituted ring), C(O)-morpholine (substituted and un-substituted ring), C(O)-piperidine (substituted and un-substituted ring), C(O)- thiomoφholine (substituted and un-substituted ring), C(O)-thiomorpholine 1,1 -dioxide (substituted and un-substituted ring),-C(O)R⁴, -COOR⁴, -NR⁴R⁵, -C(O)NR⁴R⁵, -NO₂

4. The compound of claim 2, wherein Rj, R₂ and R₃ are independently -F, -C(O)- pyrrolidine, C(O)-piperazine , C(O)-morpholine, C(O)-piperidine, C(O)-thiomoφholine, C(0)-thiomoφholine 1,1 -dioxide, -NO₂, -CF₃, -CH₃, -OCH₃, -CH₂CH₃, -CH₂CH(CH₃)CH₃, -CH₂CH₂CH(CH₃)CH₃, -CH₂C(O)OH, -(CH₂)₂C(O)OH, -(CH₂)₅C(O)OH, -(CH₂) ₂OH, - CH(OH)CH₃, -CH₂NH₂ , -CH₂CH₂N(CH₃)₂ , -CH₂-imidazole, -CH₂-indole, -CH₂SH, - (CH₂)₃NH₂, -(CH₂)₃CO NH₂, -CH₂CO NH₂, -CH(NH₂)=NH; benzyl, -CH₂-cyclohexyl, - CH₂CH₃, -OCH₂CH₃.

5. The compound according to claim 1, represented by the following structure:

Formula Il

6. The compound according to claim 1, represented by the following structure:

Formula I

7. The compound according to claim 1, represented by the following structure:

Formula IV

8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

9. A method for binding a compound of claim 1 to a receptor or a protein.

10. The method of claim 9, wherein the receptor is IL-IR.

11. The method of claim 9, wherein the receptor is MyD88.

12. A method treating a biological condition mediated by a receptor or a protein, the method comprising administering to a subject in need thereof an effective amount of compound of claim 1.

13. The method of claim 12, wherein the biological condition involves IL-I signaling.

14. The method of claim 12, wherein the biological condition is rheumatoid arthritis.

15. The method of claim 12, wherein the biological condition is asthma.

16. The method of claim 12, wherein the biological condition is upper airway hypersensitivity.

17. The method of claim 12, wherein the receptor is IL-IR and the biological condition is inflammation-linked cancer.

18. The method of claim 12, wherein the protein is MyD88 and the biological condition is inflammation-linked cancer.

19. The method of claim 12, wherein the receptor is IL-IR and the biological condition is Type I diabetes.

20. The method of claim 12, wherein the protein is MyD88 and the biological condition is Type I diabetes.

21. The method of claim 12, wherein the receptor is IL-IR and the biological condition is sepsis.

22. The method of claim 12, wherein the protein is MyD88 and the biological condition is sepsis.

23. The method of claim 12, wherein the receptor is IL-IR and the biological condition is rheumatoid arthritis.

24. The method of claim 12, wherein the protein is MyD88 and the biological condition is rheumatoid arthritis.

25. A method of disrupting protein-protein interactions, the method comprising contacting a protein or a receptor with an effective amount of a compound of claim 1, thereby preventing or lessening a signaling cascade.

26. A method of claim 25, wherein the signaling cascade is IL-I signaling.

27. A method of claim 25, wherein the interacting proteins are IL-IR and MyD88.