Inhibitors of cib1 interactions and methods of use

Abstract

Provided herein are CIB1 (calcium and integrin binding 1) inhibitors and methods of use. The compounds are useful in treating, ameliorating, and / or preventing thrombotic conditions, disease, and disorders. The compounds are also useful in treating, ameliorating, and / or preventing cancer, neurodegenerative diseases, immune system diseases, and inflammation.

Description

[0001] TITLE OF THE INVENTION Inhibitors of CIB1 Interactions and Methods of Use CROSS-REFERENCE TO RELATED APPLICATION 5 This application claims priority to U.S. Provisional Patent Application No. 63 / 529,184 entitled "INHIBITORS OF CIB1 INTERACTIONS AND METHODS OF USE," filed July 27, 2023, the disclosure of which is incorporated herein by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH 10 This invention was made with government support under 1ZIATR000289, HL113188, and HL142959, awarded by the National Institutes of Health. The government has certain rights in the invention. INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED VIA THE 15 OFFICE ELECTRONIC FILING SYSTEM This invention contains one or more sequences in a computer readable format in an accompanying text file titled "205961-7090WO1_Sequence_ST26.xml," the contents of which are incorporated herein by reference in their entirety. The size of the text file is 5,646 bytes and it was created on July 22, 2024. 20 BACKGROUND The primary function of platelets is to maintain hemostasis. At the site of vascular injury, platelets adhere to subendothelial proteins such as collagen and von Willebrand factor. Adherent platelets are rapidly activated resulting in platelet shape change, granule secretion, 25 and activation of integrin ^IIb^3. Adherent platelets also generate soluble platelet agonists such as thrombin and thromboxane A2(TxA2). Exposure of circulating platelets to these agonists results in their recruitment to the site of injury. Fibrinogen binding to activated integrin ^IIb ^3 triggers outside-in signaling leading to platelet aggregation, stabilization of platelet plug, and clot retraction. Upon atherosclerotic plaque rupture also causes platelet 30 plug formation, which underlies a number of cardiovascular diseases such as myocardial infarction and stroke. A number of anti-platelet drugs such as aspirin, clopidogrel, prasugrel, vorapaxar, and eptifibatide are currently available to prevent thrombotic complications. However, these anti- platelet agents have several limitations, including inherent variability in individual responses, resistance development, and serious bleeding side effects. Based on the analysis of the current anti-platelet drugs, it appears that the most useful therapeutic approach is to intersect the secondary responses such as integrin outside-in signaling or recruitment of platelets by 5 TxA2 and secreted ADP. Thus, there is an unmet clinical need for compounds that can largely preserve the primary hemostatic function of platelets but inhibit secondary response. The present disclosure solves this need. 10 BRIEF SUMMARY OF THE INVENTION In various aspects a method of preventing, treating, and / or ameliorating thrombosis is provided. The method includes administering to a subject in need thereof a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient or carrier and a therapeutically effective amount of at least one compound of Formula (I), or a 15 pharmaceutically acceptable salt, tautomer, enantiomer, or N-oxide thereof: , Formula (I), wherein: is a single or double bond; 20 A, Q, X, Y, and Z are each independently CH, N, NH, O, or S, provided that at least one of A, Q, X, Y, and Z is CH; LL is independently at each occurrence -O-, -OR, -S-, -S(=O)-, -S(=O)2-, -SR, -N(R)-, -NR2, -CR=, -C ^ ^ ^-CH2-, -CHR-, -CR2-, -CH3, -C(=O)-, or -C(=NR)-; zz is an integer from 1 to 20; 25 each occurrence of R1is independently selected from the group consisting of C1-12alkyl, C2-12alkenyl, C2-12alkynyl, OC1-12alkyl, C6-10aryl, C3-12cycloalkyl, C3-12heterocycloalkyl, C4-10 heteroaryl, and combinations thereof, wherein each R1is independently optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2; each occurrence of R is independently selected from the group consisting of C1-12alkyl, C2-12alkenyl, C2-12alkynyl, OC1-12alkyl, C6-10aryl, C3-12cycloalkyl, C3-125 heterocycloalkyl, and C4-10 heteroaryl; and n is an integer from 1 to 4. Also provided, in various aspects, are compounds and pharmaceutical compositions of compounds that include at least one compound of Formula (I). 10 BRIEF DESCRIPTION OF THE FIGURES The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments of the present application. FIGs.1A-1D show development and characterization of FP assay to identify inhibitors of CIB1. FIG.1A: Various concentrations of GST-CIB1 or GST alone titrated 15 with 100nM F-⍺IIbpeptide. Binding of protein and peptide was measured by increase in milli polarization. FIG.1B: Various concentrations of GST-CIB1 titrated with 100nM of F-⍺IIbpeptide in the presence and absence of 5mM EGTA. FIG.1C: Inhibition of GST-CIB1 (1µM) and F-⍺IIbpeptide (100nM) by unlabeled ⍺IIb peptide preincubated with for 1 hour. Percentage of inhibition was calculated using F-⍺IIb peptide milli polarization as 100% 20 inhibition and F-⍺IIbpeptide +GST-CIB1 milli polarization as 0% inhibition. FIG.1D: Milli polarization of F-⍺IIb peptide (100nM) alone and F-⍺IIb peptide +GST-CIB1 (1µM) across 100 different wells. Data represents ± SEM of three independent experiments. FIGs.2A-2C show screening and validation of potential hits. FIG.2A: Schematic representation of HTS assay triage summary. FIGs.2B-2C: Representative images of in-gel 25 assay showing a potentially non-inhibitory compound (FIG.2B) and a potentially inhibitory compound (FIG.2C). FIGs.3A-3E show binding characteristic and structures of most selective inhibitors in FP assay. FIGs.3A-3D: Dose response of four selected compounds (from 0.23 to 120µM) with 100nM F-⍺IIbpeptide and 1µM GST-CIB1. Data represents ±SEM of N=3 independent 30 experiments. FIG.3E: Chemical structures of four selected compounds used in FIGs.3A-3D. FIGs.4A-4D show tertiary validation and characterization of selected compounds by ITF assay. FIGs.4A-4D show dose response of four selected compounds with 10 µM F-⍺IIb peptide and 10 µM GST-CIB1. IC50 values are as follows NCGC00351170=15.6 µM (FIG. 4A), NCGC00186047=16.6 µM (FIG.4B), and NCGC00071855=53.1 µM (FIG.4C). Data represents ±SEM of N=3 independent experiments. FIGs.5A-5C show the effect of compounds on human platelet activation. Representative platelet aggregation tracings of washed human platelet suspensions treated 5 with vehicle (DMSO) or indicated compounds at 10μM for 30 minutes at 37OC followed by activation with thrombin (0.03U / mL). Data represents N=3 individual experiments. FIGs.6A-6E show assay optimization in 384-well plate. FIG.6A: A concentration of 50 nM F-⍺IIb[Probe] was chosen due to it exhibited a strong S:B7. FIG.6B: CIB1 Kddetermination with 25 nM αIIb. FIG.6C: Percent DMSO tolerance determination. FIG.6D: 10 Using the 1.56 μM concentration, 1 hour incubation time (RT) was selected to maximize Z’ factor. FIG.6E: GST-CIB1 titration with 25 nM F-αIIb in 384-well format (20 μL assay volume). FIGs.7A-7C show the specificity of F-αIIb peptide binding determination. FIG.7A: CIB1 Kd determination with 25 nM scrambled peptide. FIG.7B: Unlabeled αIIbpeptide in 1 15 or 2 μM CIB1 with 50 nM F-αIIb in 384-well format incubation (RT) = 1 hour. FIG.7C: Unlabeled αIIbpeptide in 1.25 μM CIB1 with 100 nM F-αIIb384 format Incubation (RT) = 15 min, 60 min. FIGs.8A-8D show assay optimization in 1536-well plates. FIG.8A: Optimum concentration of F-αIIb (probe) determination. FIG.8B: Specific binding of F-αIIb peptide 20 (IC50) determination using unlabled peptide. FIG.8C: LOPAC Screen: Unlabeled αIIb peptide titration in 0.85 μM GST-CIB1 with 100 nM F-αIIb in 1536-well format incubation (RT) = 15 mins. FIG.8D: TBB (NCGC00092352) was used as technical control. FIGs.9A-9D show example curves highlighting qHTS curve classification criteria. Lines connecting titration data corresponding to inhibitory compounds are shown. FIG.9A: 25 Classes 1.1 (blue; >80% efficacy) and 1.2 (orange; ≤80% efficacy) inhibitors display full and partial activity, respectively, with r2≥0.9. FIG.9B: Incomplete curves for inhibitors having AC50 values within and beyond the tested titration range are classes 2.1 (blue; >80% efficacy, r2>0.9) and 2.2 (orange; ≤80% efficacy, r2<0.9), respectively. FIG.9C: Incomplete inhibitory (blue) curves that show weak activity and poor fits are class 3. FIG.9D: Inactive 30 compounds are Class 4. FIG.10 shows the effect of GSH on F-⍺IIb peptide binding to GST-CIB1. Various concentrations of reduced GSH incubated with 1μ M of GST-CIB1 for 30 minutes. After incubation, 100nM of F-⍺IIbadded to each condition and further incubated for 15 minutes. Amount of peptide binding to protein was measured by fluorescence polarization. FIGs.11A-11J show the effect of GSH on selected compounds. Various doses (from 0.23 to 120 µM) of selected compounds were incubated with 1 µM GST-CIB1 for 1 hour in 5 the presence and absence of 10 μM reduced GSH followed by incubation with 100 nM F-⍺IIbpeptide for 15 minutes. Amount of binding was measured by fluorescence polarization. LoGIC50 values were shown the text box. FIGs.12A-12B show activity data for compounds described herein, according to various embodiments. Data is shown for a FP (fluorescence polarization) assay with GST- 10 CIB1 and FITC alpha IIB peptide in the presence of the indicated compounds. FIGs.13A-13D show activity data for compounds described herein, according to various embodiments. Data is shown for a FP (fluorescence polarization) assay with GST- CIB1 and FITC alpha IIB peptide in the presence of the indicated compounds. FIGs.14A-14D show activity data for compounds described herein, according to15 various embodiments. Data is shown for a FP (fluorescence polarization) assay with GST- CIB1 and FITC alpha IIB peptide in the presence of the indicated compounds. FIG.15 shows activity data for a compound described herein, according to various embodiments. Data is shown for a FP (fluorescence polarization) assay with GST-CIB1 and FITC alpha IIB peptide in the presence of the indicated compound. 20 FIG.16 shows aggregation to thrombin (0.03U) in the presence of compounds at various concentrations. FIG.17 shows an SDS-PAGE (sodium dodecyl sulfate–polyacrylamide gel electrophoresis) gel run. The numbered lanes are: 1, no induction; 2, two hours after induction (also lanes 3, 4, and 5); 6, lysate; 7, supernatant of lysate; 8, elute; 9, 1:20 dilution 25 of protein (2.05 µg). FIGs.18A-18B shows that CI306 inhibits the aggregation in Plk3- / -mice. (FIG.18A) Representative aggregation tracings of washed platelets isolated from Plk3- / -mouse induced by thrombin in the presence and absence of CI306. (FIG.18B) Quantification of corresponding values of FIG.18A. All the experiments were repeated more than 3 times. ns, 30 not significant; Thr, thrombin; **P<0.01. FIGs.19A-19H show that agonist-induced integrin αIIbβ3-activation is inhibited in the presence of CI306. (FIG.19A) Representative flowcytometric histogram of PAC-1 binding to thrombin-stimulated platelets in the presence and absence of CI306. (FIG.19B) The quantification of the corresponding MFI values of FIG.19A. (FIG.19C) Representative flowcytometric histogram of PAC-1 binding to thrombin-stimulated platelets in the presence of CI306 with increasing time (30s, 1 min and 2 min). (FIG.19D) The quantification of corresponding MFI values from FIG.19C. (FIG.19E) Representative flowcytometric histogram of PAC-1 binding to ADP-stimulated platelets, with and without CI306. (FIG. 5 19F) The quantification of the corresponding MFI values from FIG.19E. (FIG.19G) Representative flowcytometric histogram of PAC-1 binding to U46619-induced platelets in the presence and absence of CI306. (FIG.19H) The quantification of the corresponding MFI values from FIG.19G. Each dot represents an independent experiment from different donors. ns, not significant; Thr, thrombin; **P<0.01; ***P<0.001. 10 FIGs.20A-20H show agonist-induced platelet aggregation is attenuated upon preincubation with CI306. (FIG.20A) Representative aggregation tracings of platelet stimulated with thrombin, in the presence and absence of CI306, as specified. (FIG.20B) Quantification of values of maximal aggregation from FIG.20. (FIG.20C) Representative aggregation tracings of platelet stimulated with collagen, with and without CI306, as 15 indicated. (FIG.20D) Quantification of values of maximal aggregation from FIG.20C. (FIG. 20E) Representative aggregation tracings of platelet stimulated with ADP, in the presence and absence of CI306, as denoted. (FIG.20F) Quantification of values of maximal aggregation from FIG.20E. (FIG.20G) Representative aggregation tracings of platelet stimulated with U46619, with and without CI306, as indicated. (FIG.20H) Quantification of 20 values of maximal aggregation from FIG.20G. Utilizing platelets from various individual donors, all studies were performed more than three times. Thr, thrombin; *P<0.05; **P<0.01; ***P<0.001; ****P<0.0001. FIGs.21A-21D show that thromboxane generation is not affected but granule secretion is inhibited in thrombin-stimulated platelets treated with CI306. (FIG.21A) 25 Quantification of thromboxane B2(TXB2) in washed human platelets pre-treated with RGDS, following stimulation with thrombin in the presence and absence of CI306. (FIG.21B) Quantification of ATP secretion from thrombin-stimulated platelets with and without CI306. (FIG.21C) Representative flowcytometric histogram of P-selectin surface expression binding in thrombin-stimulated platelets with and without CI306. (FIG.21D) The quantification of 30 the corresponding MFI values from FIG.21C. Platelets were obtained from numerous individual donors and were utilized in over three experiments. ns, not significant; thr, thrombin; **P<0.001; ***P<0.001. FIGs.22A-22D shows that CI306 prevents thrombus development and platelet adherence to the collagen. (FIGs.22A-22B) Images demonstrating microfluidic chambers in which human blood with and without CI306 was flowed over a surface coated with immobilized collagen, repectively. Representative images were taken under 20X magnification with an EVOS microscope; DiOC6 (green stained; upper panel) and phase contrast (lower panel). (FIGs.22C-22D) Percentage of surface area coverage and 5 fluorescence intensity were analyzed with Image J (NIH), respectively. Experiments were conducted more than three times, utilizing platelets from different individual donors. Scale bar, 200 μm. **P<0.01; ****P<0.0001. FIGs.23A-23G show thrombin-stimulated Ca2+flux, RAP1-activation, and the interaction between β3 and talin are not interrupted in platelets treated with CI306. (FIG. 10 23A) Representative tracings of Ca2+rise in Fluo-4-loaded human platelets measured by flow cytometry upon stimulation with thrombin in the presence and absence of CI306, as indicated. Baseline calcium was measured for first 60 s before agonist addition and maximum fold change was assessed till 300 s after addition of thrombin. Vertical dotted line denotes position of thrombin addition. (FIG.23B) Quantification of corresponding values of FIG. 15 23A. (FIG.23C) Immunoblot showing the expression of Rap1-GTP in human platelets stimulated for 3 min with thrombin with and without CI306. (FIG.23D) Densitometric analysis of Rap1-GTP normalized against total Rap1 expression. (FIG.23E) Immunoblot showing β3 immunoprecipitation and co-precipitation of talin in thrombin-stimulated platelets in the presence of RGDS and CI306. The upper part of the membrane was blotted with anti- 20 talin and to ensure the equal loading, the lower part of the blot was probed with anti- β3. (FIG.23F) Densitometric analysis of talin from (FIG.23E), normalized to corresponding β3band. (FIG.23G) Platelet was stimulated with thrombin with and without CI306 treatment and proteins were subjected to 2D BN / SDS-PAGE. The membrane was immunoblotted for talin, followed by stripping and re-probing with anti-β3. Each dot represents an independent 25 experiment. Experiments were performed more than thrice, utilizing platelets from different donors. ns, not significant; Thr, thrombin; *P<0.05; **P<0.01. FIGs.24A-24H shows that CI306 impairs platelet spreading on immobilized fibrinogen. FIGs.24A-24D are representative confocal images of FITC-phalloidin-stained platelets with and without CI306 on an immobilized fibrinogen and a zoomed image of 30 platelets within the representative squares are shown. Images are representative of 5 different fields, each from more than 3 independent experiments. FIGs.24E-24H show corresponding quantification of platelet adhesion and spreading on fibrinogen matrix. *P<0.05; ***P<0.001. FIGs.25A-25B illustrate that thrombin-induced fibrinogen-binding is inhibited in the presence of CI306. (FIG.25A) Representative flowcytometric histogram of fibrinogen- binding to thrombin stimulated platelets in the presence and absence of CI306. (FIG.25B) The quantification of the corresponding MFI values from FIG.25A. Thr, thrombin; 5 ***P<0.001. DETAILED DESCRIPTION OF THE INVENTION CIB1 is a ubiquitously expressed, intracellular protein, which lacks enzymatic activity and displays a broad functionality in various cellular processes. CIB1 can regulate the 10 function of various proteins in platelets such as apoptosis signal regulating kinase (ASK1), p21-activated protein kinase 1 (PAK1), focal adhesion kinase (FAK), and platelet integrin ^IIb ^3. Interaction of CIB1 with ^IIb is required for the recruitment of FAK to propagate outside-in signaling. CIB1 null platelets show defect in functionality such as spreading and clot retraction. CIB1 null mice were shown to increased tail bleeding time and delayed 15 arterial occlusion in FeCl3 injury model. CIB1 binds to the cytoplasmic domain of αIIb chain in ^IIb^3heterodimers following platelet activation. CIB1 can be required for activation of integrin ^IIb ^3. Therefore, identification of inhibitors that disrupts the interaction of αIIb chain with CIB1 could be potential drug candidates to target the platelet function. Previous work identified a short sequence from the cytoplasmic region of αIIbtail that 20 binds to CIB1. To identify small-molecule inhibitors that block αIIb tail interaction with CIB1, here development of a high-throughput assay that measures interaction between αIIband CIB1 using fluorescence polarization (FP) is reported. A fluorescent probe is attached to the previously identified αIIbpeptide and the interaction of this labeled αIIbpeptide and GST- CIB1 measured using FP. A screen of 14,782 small molecules yielded 6 structurally distinct 25 inhibitors which were further validated as anti-platelet agents by platelet aggregation assay. Reference will now be made in detail to certain embodiments of the disclosed subject matter. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter. 30 Throughout this document, values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a range of "about 0.1% to about 5%" or "about 0.1% to 5%" should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement "about X to Y" has the same meaning as "about X to about Y," unless 5 indicated otherwise. Likewise, the statement "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z," unless indicated otherwise. In this document, the terms "a," "an," or "the" are used to include one or more than one unless the context clearly dictates otherwise. The term "or" is used to refer to a nonexclusive "or" unless otherwise indicated. The statement "at least one of A and B" or "at 10 least one of A or B" has the same meaning as "A, B, or A and B." In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting; information that is relevant to a section heading may occur within or outside of that particular section. All 15 publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference. In the methods described herein, the acts can be carried out in any order, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out 20 separately. For example, a claimed act of doing X and a claimed act of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process. Definitions 25 The term "about" as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range, and includes the exact stated value or range. The term "substantially" as used herein refers to a majority of, or mostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at 30 least about 99.999% or more, or 100%. The term "substantially free of" as used herein can mean having none or having a trivial amount of, such that the amount of material present does not affect the material properties of the composition including the material, such that the composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less. The term "substantially free of" can mean having a trivial amount of, such that a composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 5 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less, or about 0 wt%. The term "organic group" as used herein refers to any carbon-containing functional group. Examples can include an oxygen-containing group such as an alkoxy group, aryloxy group, aralkyloxy group, oxo(carbonyl) group; a carboxyl group including a carboxylic acid, carboxylate, and a carboxylate ester; a sulfur-containing group such as an alkyl and aryl 10 sulfide group; and other heteroatom-containing groups. Non-limiting examples of organic groups include OR, OOR, OC(O)N(R)2, CN, CF3, OCF3, R, C(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2)0- 2N(R)C(O)R, (CH2)0-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, 15 N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, C(=NOR)R, and substituted or unsubstituted (C1-C100)hydrocarbyl, wherein R can be hydrogen (in examples that include other carbon atoms) or a carbon-based moiety, and wherein the carbon-based moiety can be substituted or unsubstituted. 20 The term "substituted" as used herein in conjunction with a molecule or an organic group as defined herein refers to the state in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. The substitution can be direct substitution, whereby the hydrogen atom is replaced by a functional group or substituent, or an indirect substitution, whereby an intervening linker group replaces the hydrogen atom, and 25 the substituent or functional group is bonded to the intervening linker group. A non-limiting example of direct substitution is: RR-H ^ RR-Cl, wherein RR is an organic moiety / fragment / molecule. A ng example of indirect substitution is: RR-H ^ RR- (LL)zz-Cl, wherein RR is an organic moiety / fragment / molecule, LL is an int linker group, and 'zz' is an integer from 0 to 100 inclusive. When zz is 0, LL is absent, and direct 30 substitution results. The intervening linker group LL is at each occurrence independently selected from the group consisting of -H, -O-, -OR, -S-, -S(=O)-, -S(=O)2-, -SR, -N(R)-, - NR2, -CR=, -C ^ ^ ^-CH2-, -CHR-, -CR2-, -CH3, -C(=O)-, -C(=NR)-, and combinations thereof. (LL)zzcan be linear, branched, cyclic, acyclic, and combinations thereof. The term "functional group" or "substituent" as used herein refers to a group that can be or is substituted onto a molecule or onto an organic group. Examples of substituents or functional groups include, but are not limited to, a halogen (e.g., F, Cl, Br, and I); an oxygen atom in groups such as hydroxy groups, alkoxy groups, aryloxy groups, aralkyloxy groups, 5 oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxyamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of 10 substituents that can be bonded to a substituted carbon (or other) atom include F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO, NO2, ONO2, azido, CF3, OCF3, R, O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2)0-2N(R)C(O)R, (CH2)0-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, 15 N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, and C(=NOR)R, wherein R can be hydrogen or a carbon-based moiety; for example, R can be hydrogen, (C1-C100)hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl; or wherein two R groups bonded to a nitrogen atom or to 20 adjacent nitrogen atoms can together with the nitrogen atom or atoms form a heterocyclyl. The term "alkyl" as used herein refers to straight chain and branched alkyl groups and cycloalkyl groups having from 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n- 25 butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. As used herein, the term "alkyl" encompasses n-alkyl, isoalkyl, and anteisoalkyl groups as well as other branched chain forms of alkyl. Representative substituted alkyl groups can be substituted one or more times with any of the 30 groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term "alkenyl" as used herein refers to straight and branched chain and cyclic alkyl groups as defined herein, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to 40 carbon atoms, or 2 to about 20 carbon atoms, or 2 to 12 carbon atoms or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to vinyl, -CH=C=CCH2, -CH=CH(CH3), - CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others. 5 The term "alkynyl" as used herein refers to straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to 40 carbon atoms, 2 to about 20 carbon atoms, or from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to – C ^CH, -C ^C(CH3), -C ^C(CH2CH3), -CH2C ^CH, -CH2C ^C(CH3), and -CH2C ^C(CH2CH3) 10 among others. The term "acyl" as used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is bonded to a hydrogen forming a "formyl" group or is bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, 15 heteroaryl, heteroarylalkyl group or the like. An acyl group can include 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bonded to the carbonyl group. An acyl group can include double or triple bonds within the meaning herein. An acryloyl group is an example of an acyl group. An acyl group can also include heteroatoms within the meaning herein. A nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group within the 20 meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like. When the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen, the group is termed a "haloacyl" group. An example is a trifluoroacetyl group. The term "cycloalkyl" as used herein refers to cyclic alkyl groups such as, but not 25 limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings 30 such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined herein. Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term "cycloalkenyl" alone or in combination denotes a cyclic alkenyl group. The term "heterocycloalkyl" as used herein refers to a cycloalkyl group as defined 5 herein in which one or more carbon atoms in the ring are replaced by a heteroatom such as O, N, S, P, and the like, each of which may be substituted as described herein if an open valence is present, and each may be in any suitable stable oxidation state. The term "aryl" as used herein refers to cyclic aromatic hydrocarbon groups that do not contain heteroatoms in the ring. Thus aryl groups include, but are not limited to, phenyl, 10 azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain about 6 to about 14 carbons in the ring portions of the groups. Aryl groups can be unsubstituted or substituted, as defined herein. Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but 15 not limited to, a phenyl group substituted at any one or more of 2-, 3-, 4-, 5-, or 6-positions of the phenyl ring, or a naphthyl group substituted at any one or more of 2- to 8-positions thereof. The term "aralkyl" as used herein refers to alkyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as 20 defined herein. Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Aralkenyl groups are alkenyl groups as defined herein in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined herein. The term "heterocyclyl" as used herein refers to aromatic and non-aromatic ring 25 compounds containing three or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S. Thus, a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof. In some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members. The term heterocyclyl includes rings where a CH2group in the ring is 30 replaced by one or more C=O groups, such as found in cyclic ketones, lactones, and lactams. Examples of heterocyclyl groups containing a C=O group include, but are not limited to, β- propiolactam, γ-butyrolactam, δ-valerolactam, and ε-caprolactam, as well as the corresponding lactones. A heterocyclyl group designated as a C2-heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The 5 phrase "heterocyclyl group" includes fused ring species including those that include fused aromatic and non-aromatic groups. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein. The phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Heterocyclyl groups can be unsubstituted, or can be 10 substituted as discussed herein. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, 15 isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6- substituted, or disubstituted with groups such as those listed herein. 20 The term "heteroaryl" as used herein refers to aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members. A heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure. A heteroaryl group designated as a C5-heteroaryl is a chemically stable five-membered ring 25 with one, two, three, or four heteroatoms. Likewise, a C6-heteroaryl is a chemically stable six-membered ring with one, two, three, four, or five heteroatoms, and so forth. In this context, chemically stable means the ring does not spontaneously decompose or otherwise undergo a spontaneous reaction that alters the ring's chemical composition and / or structure at ambient conditions. The number of carbon atoms plus the number of heteroatoms sums up to 30 equal the total number of ring atoms. A heterocyclyl ring designated Cx-y can be any ring containing 'x' members up to 'y' members, including all intermediate integers between 'x' and 'y' and that contains one or more heteroatoms, as defined herein. In a ring designated Cx-y, all non-heteroatom members are carbon. Heterocyclyl rings designated Cx-ycan also be polycyclic ring systems, such as bicyclic or tricyclic ring systems. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, 5 adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed herein. Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed herein. Additional examples of aryl and heteroaryl groups include but are not limited to10 phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N- hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3- anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 15 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4- thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3- pyridazinyl, 4- pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-20 quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5- isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7- benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3- dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl),25 6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2- benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6- benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3- dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro- benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro- 30 benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1- benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl, 5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl), 5 10,11-dihydro-5H-dibenz[b,f]azepine (10,11-dihydro-5H-dibenz[b,f]azepine-1-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-3-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-4-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like. The term "heterocyclylalkyl" as used herein refers to alkyl groups as defined herein in 10 which a hydrogen or carbon bond of an alkyl group as defined herein is replaced with a bond to a heterocyclyl group as defined herein. Representative heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl. The term "heteroarylalkyl" as used herein refers to alkyl groups as defined herein in 15 which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined herein. The term "alkoxy" as used herein refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined herein. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and 20 the like. Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can include about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to the oxygen atom, and can further include double or triple 25 bonds, and can also include heteroatoms. For example, an allyloxy group or a methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structure are substituted therewith. The term "amine" as used herein refers to primary, secondary, and tertiary amines 30 having, e.g., the formula N(group)3 wherein each group can independently be H or non-H, such as alkyl, aryl, and the like. Amines include but are not limited to R-NH2, for example, alkylamines, arylamines, alkylarylamines; R2NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R3N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term "amine" also includes ammonium ions as used herein. The term "amino group" as used herein refers to a substituent of the form -NH2, - NHR, -NR2, -NR3+, wherein each R is independently selected, and protonated forms of each, 5 except for -NR3+, which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine. An "amino group" within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group. An "alkylamino" group includes a monoalkylamino, dialkylamino, and trialkylamino group. The terms "halo," "halogen," or "halide" group, as used herein, by themselves or as 10 part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. The term "haloalkyl" group, as used herein, includes mono-halo alkyl groups, poly- halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples15 of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3- difluoropropyl, perfluorobutyl, and the like. The terms "epoxy-functional" or "epoxy-substituted" as used herein refers to a functional group in which an oxygen atom, the epoxy substituent, is directly attached to two adjacent carbon atoms of a carbon chain or ring system. Examples of epoxy-substituted20 functional groups include, but are not limited to, 2,3-epoxypropyl, 3,4-epoxybutyl, 4,5- epoxypentyl, 2,3-epoxypropoxy, epoxypropoxypropyl, 2-glycidoxyethyl, 3-glycidoxypropyl, 4-glycidoxybutyl, 2-(glycidoxycarbonyl)propyl, 3-(3,4-epoxycylohexyl)propyl, 2-(3,4- epoxycyclohexyl)ethyl, 2-(2,3-epoxycylopentyl)ethyl, 2-(4-methyl-3,4- epoxycyclohexyl)propyl, 2-(3,4-epoxy-3-methylcylohexyl)-2-methylethyl, and 5,6- 25 epoxyhexyl. The term "monovalent" as used herein refers to a substituent connecting via a single bond to a substituted molecule. When a substituent is monovalent, such as, for example, F or Cl, it is bonded to the atom it is substituting by a single bond. The term "hydrocarbon" or "hydrocarbyl" as used herein refers to a molecule or 30 functional group that includes carbon and hydrogen atoms. The term can also refer to a molecule or functional group that normally includes both carbon and hydrogen atoms but wherein all the hydrogen atoms are substituted with other functional groups. As used herein, the term "hydrocarbyl" refers to a functional group derived from a straight chain, branched, or cyclic hydrocarbon, and can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, acyl, or any combination thereof. Hydrocarbyl groups can be shown as (Ca- Cb)hydrocarbyl, wherein a and b are integers and mean having any of a to b number of carbon atoms. For example, (C1-C4)hydrocarbyl means the hydrocarbyl group can be methyl (C1), ethyl (C2), propyl (C3), or butyl (C4), and (C0-Cb)hydrocarbyl means in certain embodiments 5 there is no hydrocarbyl group. As used herein, the term "C6-10-5-6 membered heterobiaryl" means a C6-10aryl moiety covalently bonded through a single bond to a 5- or 6-membered heteroaryl moiety. The C6-10 aryl moiety and the 5-6-membered heteroaryl moiety can be any of the suitable aryl and heteroaryl groups described herein. Non-limiting examples of a C6-10-5-6 membered 10 heterobiaryl include N . When the C6-10-5-6 mem nt (e.g., as an "R" group), the C6-10-5-6 membered heterobiaryl is bonded to the rest of the molecule through the C6-10moiety. 15 As used herein, the term "5-6 membered- C6-10heterobiaryl " is the same as a C6-10-5- 6 membered heterobiaryl, except that when the 5-6 membered- C6-10 heterobiaryl is listed as a substituent (e.g., as an "R" group), the 5-6 membered- C6-10heterobiaryl is bonded to the rest of the molecule through the 5-6-membered heteroaryl moiety. As used herein, the term "C6-10- C6-10biaryl" means a C6-10aryl moiety covalently 20 bonded through a single bond to another C6-10 aryl moiety. The C6-10 aryl moiety can be any of the suitable aryl groups described herein. Non-limiting example of a C6-10- C6-10biaryl include biphenyl and binaphthyl. The term "solvent" as used herein refers to a liquid that can dissolve a solid, liquid, or gas. Non-limiting examples of solvents are silicones, organic compounds, water, alcohols, 25 ionic liquids, and supercritical fluids. The term "independently selected from" as used herein refers to referenced groups being the same, different, or a mixture thereof, unless the context clearly indicates otherwise. Thus, under this definition, the phrase "X1, X2, and X3are independently selected from noble gases" would include the scenario where, for example, X1, X2, and X3are all the same, where X1, X2, and X3are all different, where X1and X2are the same but X3is different, and other analogous permutations. The term "room temperature" as used herein refers to a temperature of about 15 °C to 28 °C. 5 The term "standard temperature and pressure" as used herein refers to 20 °C and 101 kPa. As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound described herein with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a 10 patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration. A "disease" is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal's health continues 15 to deteriorate. In contrast, a "disorder" in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal's state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal's state of health. 20 As used herein, the terms "effective amount," "pharmaceutically effective amount" and "therapeutically effective amount" refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of 25 ordinary skill in the art using routine experimentation. As used herein, the term "efficacy" refers to the maximal effect (Emax) achieved within an assay. As used herein, the term "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the 30 compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained. As used herein, the language "pharmaceutically acceptable salt" refers to a salt of the administered compounds prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids or bases, organic acids or bases, solvates, hydrates, or clathrates thereof. Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, 5 hydrobromic, hydriodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate), and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate). Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, 10 ascorbic, glucuronic, maleic, malonic, saccharin, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2- hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic, galactaric and galacturonic acid. 15 Suitable pharmaceutically acceptable base addition salts of compounds described herein include, for example, ammonium salts, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N'-dibenzylethylene-diamine, 20 chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound. As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition or carrier, 25 such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound described herein within or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be 30 "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compound(s) described herein, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, 5 such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that 10 are compatible with the activity of the compound(s) described herein, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The "pharmaceutically acceptable carrier" may further include a pharmaceutically acceptable salt of the compound(s) described herein. Other additional ingredients that may be included in the pharmaceutical compositions used with the methods 15 or compounds described herein are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference. The terms "patient," "subject," or "individual" are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods 20 described herein. In a non-limiting embodiment, the patient, subject or individual is a human. As used herein, the term "potency" refers to the dose needed to produce half the maximal response (ED50). A "therapeutic" treatment is a treatment administered to a subject who exhibits signs of pathology, for the purpose of diminishing or eliminating those signs. 25 As used herein, the term "treatment" or "treating" is defined as the application or administration of a therapeutic agent, i.e., a compound or compounds as described herein (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has a condition contemplated herein or a symptom of 30 a condition contemplated herein, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect a condition contemplated herein, or the symptoms of a condition contemplated herein. Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics. Preparation of Compounds Compounds of Formula (I) or otherwise described herein can be prepared by the general schemes described herein, using the synthetic method known by those skilled in the art. The following examples illustrate non-limiting embodiments of the compound(s) 5 described herein and their preparation. In various embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof, tautomer, enantiomer, or N-oxide thereof is provided: , Formula (I), wherein: 10 is a single or double bond; A, Q, X, Y, and Z are each independently CH, N, NH, O, or S, provided that at least one of A, Q, X, Y, and Z is CH; LL is independently at each occurrence -O-, -OR, -S-, -S(=O)-, -S(=O)2-, -SR, -N(R)-, -NR2, -CR=, -C ^ ^ ^-CH2-, -CHR-, -CR2-, -CH3, -C(=O)-, or -C(=NR)-; 15 zz is an integer from 1 to 20; each occurrence of R1is independently selected from the group consisting of C1-12alkyl, C2-12alkenyl, C2-12alkynyl, OC1-12alkyl, C6-10aryl, C3-12cycloalkyl, C3-12heterocycloalkyl, C4-10 heteroaryl, and combinations thereof, wherein each R1is independently optionally substituted by at least one substituent selected from the 20 group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2; each occurrence of R is independently selected from the group consisting of C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, OC1-12 alkyl, C6-10 aryl, C3-12 cycloalkyl, C3-12 25 heterocycloalkyl, and C4-10 heteroaryl; and n is an integer from 1 to 4, provided the compound of Formula (I) is not a compound listed in Table 1 and / or Table 2. In various embodiments, the compound of Formula (I) is not any of the following 30 compounds: wherein the compound of Formula (I) is not any of the following compounds: , , 5 y C6-10aryl. In various embodiments, each R1is independently optionally substituted phenyl. In various embodiments, zz is 1. In various embodiments, at least one LL is -C(=O)-. 10 Each R1 in the compound of Formula (I) can be the same or different. In various embodiments, each R1in the compound of Formula (I) has the same structure. In various embodiments, each R1in the compound of Formula (I) have different structures. In various embodiments, the compound of Formula (I) has the structure: , wherein: Z is CH, N, or N-oxide; each R1is independently selected from the group consisting of C6-10aryl, C3-125 cycloalkyl, C3-12 heterocycloalkyl, C4-10 heteroaryl, and combinations thereof, each independently optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2; and 10 each occurrence of R is independently selected from the group consisting of C1-12alkyl, C2-12alkenyl, C2-12alkynyl, OC1-12alkyl, C6-10aryl, C3-12cycloalkyl, C3-12heterocycloalkyl, C4-10 heteroaryl, and combinations thereof. If the R1groups are different from each other, the N-oxide functionality, if present, can be present on any N atom in the compound of Formula (I). 15 In various embodiments, Z is N-oxide. In various embodiments, R1is phenyl ( ), optionally substituted by at least one substituent selected from the group consi Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2. In various 20 embodiments, when R1is phenyl, it is substituted by 1, 2, 3, or 4 substituents. In various embodiments, the compound of Formula (I) has the structure: , wherein n is indepe , , , , or 4 and R2is independently selected from the group consisting of F, Cl, Br, I, OR, 25 OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2. In various embodiments, R1is C5 heteroaryl optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2. In various 5 embodiments, when R1is C5 heteroaryl, it is substituted by 1, 2, 3, or 4 substituents. In various embodiments, the C5heteroaryl is furyl ( ) or thiophenyl ( ). When R1is C5 heteroaryl, it can be connected to the re f the molecule thro pen valence, for example, when the C heteroaryl is thiophenyl, it can 5 be connected as follows (wavy line indicates point of attachment to the rest of the molecule): 10 . ents, the compound of Formula (I) has the structure: , wherein n is indep , or 4 and R2is independently selected from the group consisting of F, Cl, Br, I, OR, 15 OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2. Table 1: CIB1 inhibitors KG# FP % Inhib of Conc Agonists Structure 1 1.1 - 10 Thrombin 0.03U

[0002] 4 6.7 - 10 Thrombin 0.03U 7 14 - 10 Thrombin 0.03U 10 7.7 >90 10 Thrombin 0.03U 14 0.6 >90 10 Thrombin 0.03U 18 8.4 >90 1 Thrombin 0.03U, Table 2: CIB1 Inhibitors of Formula (I) No FP IC50 % Agonists Structure (µM) Aggreg D10- 7.5 58 0.03U 5 Thr D10-13 D10-14 D10-19 Table 3: Correspondence Table For Compounds 1-23 and their NCGC Identifiers KG# Compound identity 1 NCGC0001600013C02 Table 4: Correspondence Table For Compounds D10-0 to D10-12 and their NCGC / PubChem Identifiers No Compound ID D100 NCGC0035117001 (D10) In certain emb compound 1. In certain embodiments, the com poun o ormu a ( ) s not compoun . n certain embodiments, the 5 compound of Formula (I) is not compound 3. In certain embodiments, the compound of Formula (I) is not compound 4. In certain embodiments, the compound of Formula (I) is not compound 5. In certain embodiments, the compound of Formula (I) is not compound 6. In certain embodiments, the compound of Formula (I) is not compound 7. In certain embodiments, the compound of Formula (I) is not compound 8. In certain embodiments, the 10 compound of Formula (I) is not compound 9. In certain embodiments, the compound of Formula (I) is not compound 10. In certain embodiments, the compound of Formula (I) is not compound 11. In certain embodiments, the compound of Formula (I) is not compound 12. In certain embodiments, the compound of Formula (I) is not compound 13. In certain embodiments, the compound of Formula (I) is not compound 14. In certain embodiments, 15 the compound of Formula (I) is not compound 15. In certain embodiments, the compound of Formula (I) is not compound 16. In certain embodiments, the compound of Formula (I) is not compound 17. In certain embodiments, the compound of Formula (I) is not compound 18. In certain embodiments, the compound of Formula (I) is not compound 19. In certain embodiments, the compound of Formula (I) is not compound 20. In certain embodiments, 20 the compound of Formula (I) is not compound 21. In certain embodiments, the compound of Formula (I) is not compound 22. In certain embodiments, the compound of Formula (I) is not compound 23. In certain embodiments, the compound of Formula (I) is not compound D10-0. In certain embodiments, the compound of Formula (I) is not compound D10-1. In certain 5 embodiments, the compound of Formula (I) is not compound D10-2. In certain embodiments, the compound of Formula (I) is not compound D10-3. In certain embodiments, the compound of Formula (I) is not compound D10-4. In certain embodiments, the compound of Formula (I) is not compound D10-5. In certain embodiments, the compound of Formula (I) is not compound D10-6. In certain 10 embodiments, the compound of Formula (I) is not compound D10-7. In certain embodiments, the compound of Formula (I) is not compound D10-8. In certain embodiments, the compound of Formula (I) is not compound D10-9. In certain embodiments, the compound of Formula (I) is not compound D10-10. In certain embodiments, the compound of Formula (I) is not compound D10-11. In certain 15 embodiments, the compound of Formula (I) is not compound D10-12. In certain embodiments, the compound of Formula (I) is not compound D10-13. In certain embodiments, the compound of Formula (I) is not compound D10-14. In certain embodiments, the compound of Formula (I) is not compound D10-15. In certain embodiments, the compound of Formula (I) is not compound D10-16. In certain 20 embodiments, the compound of Formula (I) is not compound D10-17. In certain embodiments, the compound of Formula (I) is not compound D10-18. In certain embodiments, the compound of Formula (I) is not compound D10-19. In certain embodiments, the compound of Formula (I) is not compound D10-20. In certain embodiments, the compound of Formula (I) is not compound D10-21. In certain 25 embodiments, the compound of Formula (I) is not compound D10-22. When platelets are activated, they undergo a series of intracellular signaling events, which result in a conformational change of a protein called integrin comprising of two distinct non-covalently associated subunits α and β. Each subunit consists of an extracellular region, a transmembrane spanning region and a short cytoplasmic tail. In resting platelets, 30 αIIbβ3 exhibits a closed conformation with low-binding affinity to the soluble ligand. Stimulation of platelets initiates inside-out signaling cascade that instigates a conformational change in the integrin αIIbβ3 to open conformation that reveals a high affinity ligand binding site. Integrin αIIbβ3in an open conformation binds to fibrinogen, which, in turn provokes outside-in-signaling that stimulates different signaling pathways that mediate cytoskeletal organization, adhesion, spreading, clot-retraction and irreversible aggregation. The cytoplasmic tails of subunits α and β are in proximity in basal conditions, which forces the integrin into a low-affinity conformation. Inside-out-signaling instigates 5 conformational changes in the ligand binding region that alter the interaction of αIIbβ3 in the transmembrane region. It is well known that the two tails of the integrin subunits separate because of cytoplasmic proteins especially talin / kindlin, binding to the β3-subunit, eliminating the constraint, and activating the integrin. Previous studies have shown that the integrin αIIb-subunit regulates extracellular binding affinity, but it is still unknown how the 10 αIIb-subunit and possible binding partners affect αIIbβ3activation. A Ca2+-binding protein known as Calcium- and integrin-binding protein (CIB1), a 22 kDa ubiquitously expressed protein, was previously discovered to interact exclusively with the cytoplasmic region of the αIIb subunit. In addition to interaction with integrin αIIbβ3, CIB1 has been known to interact with a wide range of proteins including kinases, phosphatases, 15 ion-channels, or cytoskeletal proteins that regulate different cellular processes like calcium signaling, migration, adhesion, proliferation, and survival. Earlier study has reported that CIB1 upon interaction with the cytoplasmic tail of αIIb-subunit, activates the integrin αIIbβ3, increasing its affinity for fibrinogen, in-vitro, in a Ca2+-dependent manner. Additionally, it has been shown that endogenous CIB1 and αIIbsimultaneously translocate to the Triton X- 20 100-insoluble cytoskeleton in aggregated platelets. It has been shown that CIB1 plays an important physiological role in integrin αIIbβ3activation and its downstream signaling in platelets. Studies from past have revealed that talin interaction with β3-subunit activate integrin but the role of αIIband its binding partners in integrin activation has not been studied up to now. 25 It was hypothesized that CIB1 binding to the integrin αIIbtail is necessary for the activation of integrin αIIbβ3 in addition to the interaction between talin and β3-subunit. It was postulated that in activated platelets the cytoplasmic tail of αIIband β3-subunit interacts with Ca2+-CIB1 and talin, respectively, that together dissociates the αIIbβ3 heterodimer resulting in its activation. Following a series of screening and validation procedures, four top hits were 30 identified that in vitro blocked the interaction between CIB1 and αIIb-peptide. From the four most successful hits, the most effective inhibitor, CI306, was used to investigate the role of CIB1 interaction with the cytoplasmic tail of αIIb in αIIbβ3 activation. Without being bound by theory, it is believed that binding of CIB1 to the αIIbsubunit is necessary for the conversion of inactive integrin into the active form along with the talin and β3-interaction. The compounds described herein can possess one or more stereocenters, and each stereocenter can exist independently in either the (R) or (S) configuration. In certain embodiments, compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically- 5 active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein. Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In 10 certain embodiments, a mixture of one or more isomer is utilized as the therapeutic compound described herein. In other embodiments, compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis and / or separation of a mixture of enantiomers and / or diastereomers. Resolution of compounds and isomers thereof is 15 achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography. The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of compounds having the structure of any 20 compound(s) described herein, as well as metabolites and active metabolites of these compounds having the same type of activity. Solvates include water, ether (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates and the like. In certain embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, and ethanol. In other embodiments, the 25 compounds described herein exist in unsolvated form. In certain embodiments, the compound(s) described herein can exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In certain embodiments, compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted into the parent drug in vivo. In certain 30 embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In other embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, sites on, for example, the aromatic ring portion of compound(s) described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the aromatic ring structures may reduce, minimize or eliminate this metabolic pathway. In certain embodiments, the appropriate substituent to decrease or 5 eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a deuterium, a halogen, or an alkyl group. Compounds described herein also include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. 10 Examples of isotopes suitable for inclusion in the compounds described herein include and are not limited to2H,3H,11C,13C,14C,36Cl,18F,123I,125I,13N,15N,15O,17O,18O,32P, and35S. In certain embodiments, isotopically-labeled compounds are useful in drug and / or substrate tissue distribution studies. In other embodiments, substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or 15 reduced dosage requirements). In yet other embodiments, substitution with positron emitting isotopes, such as11C,18F,15O and13N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. 20 In certain embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. The compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein and as described, 25 for example, in Fieser & Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4thEd., (Wiley 1992); Carey & Sundberg, Advanced 30 Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000,2001), and Green & Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compound as described herein are modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formula as provided herein. Compounds described herein are synthesized using any suitable procedures starting from compounds that are available from commercial sources, or are prepared using procedures described herein. In certain embodiments, reactive functional groups, such as hydroxyl, amino, imino, 5 thio or carboxy groups, are protected in order to avoid their unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. In other embodiments, each protective group is removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the 10 requirement of differential removal. In certain embodiments, protective groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and are used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected 15 with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties are blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl, in the presence of amines that are blocked with acid labile groups, such as t-butyl carbamate, or with carbamates that are both acid and base stable but hydrolytically removable. 20 In certain embodiments, carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties are protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or are blocked25 with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co- existing amino groups are blocked with fluoride labile silyl carbamates. Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and are subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid is deprotected with a palladium-catalyzed reaction 30 in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, that functional group is blocked and does not react. Once released from the resin, the functional group is available to react. Typically blocking / protecting groups may be selected from:

[0003] . to the creation of protecting groups and their removal are described in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and 5 Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure. Compositions The compositions containing the compound(s) described herein include a 10 pharmaceutical composition comprising at least one compound as described herein and at least one pharmaceutically acceptable carrier. In certain embodiments, the composition is formulated for an administration route such as oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal, intravesical, intrapulmonary, intraduodenal, 15 intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration. Methods of Treating Thrombosis The disclosure includes a method of treating, ameliorating, and / or preventing 20 thrombosis using the compounds of Formula (I). Non-limiting examples of thrombosis include deep vein thrombosis, pulmonary embolism, femoral vein thrombosis, Paget- Schroetter syndrome, myocardial infarction, superior vena cava thrombosis, jugular vein thrombosis, thrombotic stroke, cerebral venous sinus thrombosis, cavernous sinus thrombosis, retinal vein occlusion, May-Thurner syndrome, portal vein thrombosis, Budd- Chiari syndrome, renal vein thrombosis, and the like. The methods described herein include administering to the subject a therapeutically effective amount of at least one compound described herein, which is optionally formulated 5 in a pharmaceutical composition. In various embodiments, a therapeutically effective amount of at least one compound described herein present in a pharmaceutical composition is the only therapeutically active compound in a pharmaceutical composition. In certain embodiments, the method further comprises administering to the subject an additional therapeutic agent that treats thrombosis. 10 In certain embodiments, administering the compound(s) described herein to the subject allows for administering a lower dose of the additional therapeutic agent as compared to the dose of the additional therapeutic agent alone that is required to achieve similar results in treating thrombosis in the subject. For example, in certain embodiments, the compound(s) described herein enhance(s) the activity of the additional therapeutic compound, thereby 15 allowing for a lower dose of the additional therapeutic compound to provide the same effect. In certain embodiments, the compound(s) described herein and the therapeutic agent are co-administered to the subject. In other embodiments, the compound(s) described herein and the therapeutic agent are coformulated and co-administered to the subject. In certain embodiments, the subject is a mammal. In other embodiments, the mammal 20 is a human. Methods of Treating Other Diseases and Disorders The disclosure also includes a method of treating, ameliorating, and / or preventing cancer (such as breast cancer), neurodegenerative diseases (such as Alzheimer’s, and 25 Parkinson’s), and inflammation, using the compounds of Formula (I). For example, in addition to treating, ameliorating, and / or preventing thrombosis, provided herein are methods of preventing, treating, and / or ameliorating a disease or disorder associated with CIB1 that include administering to a subject in need thereof a therapeutically effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, tautomer, enantiomer, or N-oxide thereof, wherein the disease or disorder is selected from the group consisting of cancer, Parkinson’s disease, Alzheimer’s disease, immune system diseases, sepsis, and acute respiratory distress syndrome (ARDS). In this context, preventing, treating, and / or ameliorating a disease or disorder associated with CIB1 means administering an amount of the compound of Formula (I) sufficient to inhibit CIB1 and elicit a therapeutic effect in the subject for the disease or disorder being treated. The potency of the compound of Formula (I) to inhibit CIB1 and thereby prevent, treat, and / or ameliorate a disease or disorder selected from the group consisting of cancer, Parkinson’s disease, Alzheimer’s disease, immune system diseases, 5 sepsis, and acute respiratory distress syndrome can be, in various embodiments, an in vitro or in vivo potency (as measured by IC50or EC50) against CIB1 of less than, at least, or equal to about 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2 or about 1 µM. The potency of the compound of Formula (I) to inhibit CIB1 and thereby prevent, treat, and / or ameliorate a disease or disorder selected from the group consisting of cancer, Parkinson’s disease, Alzheimer’s disease, 10 immune system diseases, sepsis, and acute respiratory distress syndrome can be, in various embodiments, an in vitro or in vivo potency (as measured by IC50 or EC50) against CIB1 of less than, at least, or equal to about 900, 800, 700, 600, 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, 3020, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.1, 0.05, or about 0.01 nM. In various embodiments, the cancer that is prevented, treated, and / or ameliorated is 15 selected from the group consisting of liver cancer, breast cancer, pancreatic cancer, lung cancer, leukemia, lymphoma, colon cancer, stomach cancer, melanoma, testicular cancer, prostate cancer, and rectal cancer. Approaches to combination therapies, therapeutically effective dosages, dosage forms, and any other consideration described herein in relation to thrombosis is similarly 20 applicable to developing pharmaceutical compositions and administration regimens for preventing, treating, and / or ameliorating cancer, Parkinson’s disease, Alzheimer’s disease, immune system diseases, sepsis, and / or acute respiratory distress syndrome (ARDS). Combination Therapies 25 The compounds useful within the methods described herein can be used in combination with one or more additional therapeutic agents useful for treating, ameliorate, and / or prevent thrombosis. These additional therapeutic agents may comprise compounds that are commercially available or synthetically accessible to those skilled in the art. These additional therapeutic agents are known to treat and / or reduce the symptoms of thrombosis. 30 In various embodiments, a synergistic effect is observed when a compound as described herein is administered with one or more additional therapeutic agents or compounds. A synergistic effect may be calculated, for example, using suitable methods such as, for example, the Sigmoid-Emaxequation (Holford & Scheiner, 1981, Clin. Pharmacokinet.6:429-453), the equation of Loewe additivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol.114:313-326) and the median-effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul.22:27-55). Each equation referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination. The corresponding graphs associated with the equations referred to above are 5 the concentration-effect curve, isobologram curve and combination index curve, respectively. Administration / Dosage / Formulations The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the subject either prior to or after the onset 10 thrombosis. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation. 15 Administration of the compositions described herein to a patient, preferably a mammal, more preferably a human, may be carried out using known procedures, at dosages and for periods of time effective to treat a thrombosis in the patient. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of 20 the patient; and the ability of the therapeutic compound to treat thrombosis in the patient. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non-limiting example of an effective dose range for a therapeutic compound described herein is from about 1 and 25 5,000 mg / kg of body weight / per day. One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation. Actual dosage levels of the active ingredients in the pharmaceutical compositions described herein may be varied so as to obtain an amount of the active ingredient that is 30 effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. In particular, the selected dosage level depends upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts. A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may 5 readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds described herein employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. 10 In particular embodiments, it is especially advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. 15 The dosage unit forms of the compound(s) described herein are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding / formulating such a therapeutic compound. In certain embodiments, the compositions described herein are formulated using one 20 or more pharmaceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of a compound described herein and a pharmaceutically acceptable carrier. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and 25 the like), suitable mixtures thereof, and vegetable oils. The proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many 30 cases, it is preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin. In certain embodiments, the compositions described herein are administered to the patient in dosages that range from one to five times per day or more. In other embodiments, the compositions described herein are administered to the patient in range of dosages that include, but are not limited to, once every day, every two, days, every three days to once a 5 week, and once every two weeks. It is readily apparent to one skilled in the art that the frequency of administration of the various combination compositions described herein varies from individual to individual depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, administration of the compounds and compositions described herein should not be construed 10 to be limited to any particular dosage regime and the precise dosage and composition to be administered to any patient is determined by the attending physician taking all other factors about the patient into account. The compound(s) described herein for administration may be in the range of from about 1 µg to about 10,000 mg, about 20 µg to about 9,500 mg, about 40 µg to about 9,000 15 mg, about 75 µg to about 8,500 mg, about 150 µg to about 7,500 mg, about 200 µg to about 7,000 mg, about 350 µg to about 6,000 mg, about 500 µg to about 5,000 mg, about 750 µg to about 4,000 mg, about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg to about 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 20 mg to about 600 mg, about 80 mg to about 500 mg, and any and all whole or partial increments therebetween. In some embodiments, the dose of a compound described herein is from about 1 mg and about 2,500 mg. In some embodiments, a dose of a compound described herein used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or 25 less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, a dose of a second compound as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 30 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof. In certain embodiments, a composition as described herein is a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound described herein, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, prevent, or reduce 5 one or more symptoms of a disease or disorder in a patient. Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if 10 desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and / or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents. Routes of administration of any of the compositions described herein include oral, 15 nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical. The compounds for use in the compositions described herein can be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, 20 subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration. Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, 25 lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions described herein are not limited to the particular formulations and compositions that are described herein. 30 Oral Administration For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps. The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by known techniques for elegance or to 5 delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent. For oral administration, the compound(s) described herein can be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., polyvinylpyrrolidone, hydroxypropylcellulose or 10 hydroxypropyl methylcellulose); fillers (e.g., cornstarch, lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrates (e.g., sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulphate). If desired, the tablets may be coated using suitable methods and coating materials such as OPADRY™ film coating systems available from Colorcon, West Point, Pa. (e.g., OPADRY™ OY Type, OYC 15 Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type and OPADRY™ White, 32K18400). Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions. The liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., 20 lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxy benzoates or sorbic acid). Compositions as described herein can be prepared, packaged, or sold in a formulation suitable for oral or buccal administration. A tablet that includes a compound as described herein can, for example, be made by compressing or molding the active ingredient, optionally 25 with one or more additional ingredients. Compressed tablets may be prepared by compressing, in a suitable device, the active ingredient in a free-flowing form such as a powder or granular preparation, optionally mixed with one or more of a binder, a lubricant, an excipient, a surface active agent, and a dispersing agent. Molded tablets may be made by molding, in a suitable device, a mixture of the active ingredient, a pharmaceutically 30 acceptable carrier, and at least sufficient liquid to moisten the mixture. Pharmaceutically acceptable excipients used in the manufacture of tablets include, but are not limited to, inert diluents, granulating and disintegrating agents, dispersing agents, surface-active agents, disintegrating agents, binding agents, and lubricating agents. Suitable dispersing agents include, but are not limited to, potato starch, sodium starch glycollate, poloxamer 407, or poloxamer 188. One or more dispersing agents can each be individually present in the composition in an amount of about 0.01% w / w to about 90% w / w relative to weight of the dosage form. One or more dispersing agents can each be 5 individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w relative to weight of the dosage form. Surface-active agents (surfactants) include cationic, anionic, or non-ionic surfactants, 10 or combinations thereof. Suitable surfactants include, but are not limited to, behentrimonium chloride, benzalkonium chloride, benzethonium chloride, benzododecinium bromide, carbethopendecinium bromide, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cetylpyridine chloride, didecyldimethylammonium chloride, dimethyldioctadecylammonium bromide, dimethyldioctadecylammonium chloride, domiphen 15 bromide, lauryl methyl gluceth-10 hydroxypropyl dimonium chloride, tetramethylammonium hydroxide, thonzonium bromide, stearalkonium chloride, octenidine dihydrochloride, olaflur, N-oleyl-1,3-propanediamine, 2-acrylamido-2-methylpropane sulfonic acid, alkylbenzene sulfonates, ammonium lauryl sulfate, ammonium perfluorononanoate, docusate, disodium cocoamphodiacetate, magnesium laureth sulfate, perfluorobutanesulfonic acid, 20 perfluorononanoic acid, perfluorooctanesulfonic acid, perfluorooctanoic acid, potassium lauryl sulfate, sodium alkyl sulfate, sodium dodecyl sulfate, sodium laurate, sodium laureth sulfate, sodium lauroyl sarcosinate, sodium myreth sulfate, sodium nonanoyloxybenzenesulfonate, sodium pareth sulfate, sodium stearate, sodium sulfosuccinate esters, cetomacrogol 1000, cetostearyl alcohol, cetyl alcohol, cocamide diethanolamine, 25 cocamide monoethanolamine, decyl glucoside, decyl polyglucose, glycerol monostearate, octylphenoxypolyethoxyethanol CA-630, isoceteth-20, lauryl glucoside, octylphenoxypolyethoxyethanol P-40, Nonoxynol-9, Nonoxynols, nonyl phenoxypolyethoxylethanol (NP-40), octaethylene glycol monododecyl ether, N-octyl beta- D-thioglucopyranoside, octyl glucoside, oleyl alcohol, PEG-10 sunflower glycerides, 30 pentaethylene glycol monododecyl ether, polidocanol, poloxamer, poloxamer 407, polyethoxylated tallow amine, polyglycerol polyricinoleate, polysorbate, polysorbate 20, polysorbate 80, sorbitan, sorbitan monolaurate, sorbitan monostearate, sorbitan tristearate, stearyl alcohol, surfactin, Triton X-100, and Tween 80. One or more surfactants can each be individually present in the composition in an amount of about 0.01% w / w to about 90% w / w relative to weight of the dosage form. One or more surfactants can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w relative to weight of the dosage 5 form. Suitable diluents include, but are not limited to, calcium carbonate, magnesium carbonate, magnesium oxide, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, and sodium phosphate, Cellactose ® 80 (75 % ^- lactose monohydrate and 25 % cellulose powder), mannitol, pre-gelatinized starch, starch, 10 sucrose, sodium chloride, talc, anhydrous lactose, and granulated lactose. One or more diluents can each be individually present in the composition in an amount of about 0.01% w / w to about 90% w / w relative to weight of the dosage form. One or more diluents can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 15 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w relative to weight of the dosage form. Suitable granulating and disintegrating agents include, but are not limited to, sucrose, copovidone, corn starch, microcrystalline cellulose, methyl cellulose, sodium starch glycollate, pregelatinized starch, povidone, sodium carboxy methyl cellulose, sodium 20 alginate, citric acid, croscarmellose sodium, cellulose, carboxymethylcellulose calcium, colloidal silicone dioxide, crosspovidone and alginic acid. One or more granulating or disintegrating agents can each be individually present in the composition in an amount of about 0.01% w / w to about 90% w / w relative to weight of the dosage form. One or more granulating or disintegrating agents can each be individually present in the composition in an 25 amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w relative to weight of the dosage form. Suitable binding agents include, but are not limited to, gelatin, acacia, pre-gelatinized maize starch, polyvinylpyrrolidone, anhydrous lactose, lactose monohydrate, hydroxypropyl 30 methylcellulose, methylcellulose, povidone, polyacrylamides, sucrose, dextrose, maltose, gelatin, polyethylene glycol. One or more binding agents can each be individually present in the composition in an amount of about 0.01% w / w to about 90% w / w relative to weight of the dosage form. One or more binding agents can each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w relative to weight of the dosage form. Suitable lubricating agents include, but are not limited to, magnesium stearate, 5 calcium stearate, hydrogenated castor oil, glyceryl monostearate, glyceryl behenate, mineral oil, polyethylene glycol, poloxamer 407, poloxamer 188, sodium laureth sulfate, sodium benzoate, stearic acid, sodium stearyl fumarate, silica, and talc. One or more lubricating agents can each be individually present in the composition in an amount of about 0.01% w / w to about 90% w / w relative to weight of the dosage form. One or more lubricating agents can 10 each be individually present in the composition in an amount of at least, greater than, or less than about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w relative to weight of the dosage form. Tablets can be non-coated or they may be coated using known methods to achieve 15 delayed disintegration in the gastrointestinal tract of a subject, thereby providing sustained release and absorption of the active ingredient. By way of example, a material such as glyceryl monostearate or glyceryl distearate may be used to coat tablets. Further by way of example, tablets may be coated using methods described in U.S. Patent Nos.4,256,108; 4,160,452; and 4,265,874 to form osmotically controlled release tablets. Tablets may further 20 comprise a sweetening agent, a flavoring agent, a coloring agent, a preservative, or some combination of these in order to provide for pharmaceutically elegant and palatable preparation. Tablets can also be enterically coated such that the coating begins to dissolve at a certain pH, such as at about pH 5.0 to about pH 7.5, thereby releasing a compound as 25 described herein. The coating can contain, for example, EUDRAGIT ® L, S, FS, and / or E polymers with acidic or alkaline groups to allow release of a compound as described herein in a particular location, including in any desired section(s) of the intestine. The coating can also contain, for example, EUDRAGIT ® RL and / or RS polymers with cationic or neutral groups to allow for time controlled release of a compound as described herein by pH-independent 30 swelling. Parenteral Administration For parenteral administration, the compounds as described herein may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose and / or continuous infusion. Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and / or dispersing agents may be used. Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques 5 known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non- toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. Sterile, fixed oils are conventionally 10 employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain 15 alcohol diluent or dispersant, such as such as lauryl, stearyl, or oleyl alcohols, or similar alcohol. Additional Administration Forms Additional dosage forms suitable for use with the compound(s) and compositions described herein include dosage forms as described in U.S. Patents Nos.6,340,475; 20 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Additional dosage forms suitable for use with the compound(s) and compositions described herein also include dosage forms as described in U.S. Patent Applications Nos.20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional dosage forms suitable for use with the compound(s) and compositions described herein also include dosage 25 forms as described in PCT Applications Nos. WO 03 / 35041; WO 03 / 35040; WO 03 / 35029; WO 03 / 35177; WO 03 / 35039; WO 02 / 96404; WO 02 / 32416; WO 01 / 97783; WO 01 / 56544; WO 01 / 32217; WO 98 / 55107; WO 98 / 11879; WO 97 / 47285; WO 93 / 18755; and WO 90 / 11757. 30 Controlled Release Formulations and Drug Delivery Systems In certain embodiments, the formulations described herein can be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations. The term sustained release is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period. The period of time may be as long as a month or more and should 5 be a release which is longer that the same amount of agent administered in bolus form. For sustained release, the compounds may be formulated with a suitable polymer or hydrophobic material which provides sustained release properties to the compounds. As such, the compounds for use with the method(s) described herein may be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by 10 implantation. In some cases, the dosage forms to be used can be provided as slow or controlled- release of one or more active ingredients therein using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the 15 desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the pharmaceutical compositions described herein. Thus, single unit dosage forms suitable for oral administration, such as tablets, capsules, gelcaps, and caplets, that are adapted for controlled-release are encompassed by the compositions and dosage 20 forms described herein. Most controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum 25 amount of time. Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood level of the drug, and thus can affect the occurrence of side effects. 30 Most controlled-release formulations are designed to initially release an amount of drug that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various inducers, for example pH, temperature, enzymes, water, or other physiological conditions or compounds. 5 The term "controlled-release component" is defined herein as a compound or compounds, including, but not limited to, polymers, polymer matrices, gels, permeable membranes, liposomes, or microspheres or a combination thereof that facilitates the controlled-release of the active ingredient. In certain embodiments, the compound(s) described herein are administered to a patient, alone or in combination with another pharmaceutical agent, using a 10 sustained release formulation. In certain embodiments, the compound(s) described herein are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation. The term delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug 15 administration and that mat, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours. The term pulsatile release is used herein in its conventional sense to refer to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration. 20 The term immediate release is used in its conventional sense to refer to a drug formulation that provides for release of the drug immediately after drug administration. As used herein, short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all 25 whole or partial increments thereof after drug administration after drug administration. As used herein, rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration. 30 Dosing The therapeutically effective amount or dose of a compound described herein depends on the age, sex and weight of the patient, the current medical condition of the patient and the progression of thrombosis in the patient being treated. The skilled artisan is able to determine appropriate dosages depending on these and other factors. A suitable dose of a compound described herein can be in the range of from about 0.01 mg to about 5,000 mg per day, such as from about 0.1 mg to about 1,000 mg, for 5 example, from about 1 mg to about 500 mg, such as about 5 mg to about 250 mg per day. The dose may be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses. 10 It is understood that the amount of compound dosed per day may be administered, in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on. 15 In the case wherein the patient's status does improve, upon the doctor's discretion the administration of the compound(s) described herein is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday"). The length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 20 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday includes from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. 25 Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is reduced to a level at which the improved disease is retained. In certain embodiments, patients require intermittent treatment on a long-term basis upon any recurrence of symptoms and / or infection. 30 The compounds described herein can be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose. Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the 5 determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50 and ED50. The data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human. The dosage of such compounds lies 10 preferably within a range of circulating concentrations that include the ED50with minimal toxicity. The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized. Examples 15 Various embodiments of the present application can be better understood by reference to the following Examples which are offered by way of illustration. The scope of the present application is not limited to the Examples given herein. Materials and Methods 20 Reagents All general chemicals were purchased from Millipore Sigma, USA unless otherwise stated. Glutathione Sepharose beads were obtained from GE Healthcare. Black 384-well plates were purchased from Thermo Fisher Scientific, USA. Unlabeled and fluorescein isothiocyanate conjugated αIIb peptides, as well as scrambled control peptide, were custom 25 synthesized from Peptide 2.0, USA at >95% purity. All peptides were dissolved in DMSO, aliquoted and stored at -80oC. Sequence of unlabeled αIIb peptide: Acetyl- LVLAMWKVGFFKRNRK (purity is >95.00%), SEQ ID NO: 1. Sequence of F-αIIbpeptide: Acetyl-LVLAMWKVGFFKRNRK-FITC (purity is 95.83%), SEQ ID NO: 2. Sequence of F- scrambled αIIb-peptide: Acetyl-RKLFVKVMFWRLNGAK-FITC (purity is 95.37%), SEQ ID 30 NO: 3. Small molecule inhibitor of CIB1 and αIIbinteraction NCGC00071855 (CI306). Human α-thrombin and fibrinogen were acquired from Enzyme Research (South Bend, IN), while collagen (#P / N 385) and ADP (#P / N 384) were purchased from Chronolog (Havertown, PA). Mouse monoclonal anti-CIB1 antibody UN7.79 was generated as described. Mouse monoclonal IgG integrin (B-9 #sc-365938) and integrin β3 (D-11 #sc- 365679) were obtained by Santa Cruz Biotechnology (Santa Cruz, CA). Anti-talin antibody (#T3287), Dimethyl sulfoxide (DMSO #D8418), Arg-Gly-Asp-Ser (SEQ ID NO: 4) (RGDS #A9041), Prostaglandin E1 (#P5515), and U46619 (#D8174) were from Sigma–Aldrich (St. 5 Louis, MO). Fluo-4-AM (#F14201) and Alexa Fluor 488-conjugated fibrinogen from human plasma (#F13191) were purchased from Thermo Fisher Scientific. Fluorescein isothiocyanate (FITC)-anti-PAC-1 (#340507) and phycoerythrin (PE)-conjugated anti-P-selectin (#550561) were acquired from BD Pharmingen (San Jose, CA), while PE-conjugated JON / A (#M023-2) was obtained Emfret (Eibelstadt, Germany). The TxB2 ELISA kit (#AD1-900-002) was 10 purchased from Enzo Life Sciences, and the Rap1 Activation Assay kit (#17-321) was obtained from Millipore. All other chemicals were of analytical grade and bought from Sigma–Aldrich. Expression and purification of CIB1. Cloning and expression of CIB1 as 15 glutathione S-transferase fusion protein (GST-CIB1) has been previously reported. Single colony of BL-21 plus RIL cells transformed with GST-CIB1 expression construct or empty vector (pGEX-4T) was grown into log phase in the presence of 100 ^g / mL ampicillin and protein expression was induced by incubation with 100 ^M isopropyl- ^-D-thiogalactoside (IPTG) for three hours at 37°C. After incubation cells were harvested, resuspended in 20 mM 20 Tris pH 8.0, 500 mM NaCl, 1 mM phenylmethylsulfonyl fluoride, 10 ^g / mL aprotinin, 10 ^g / mL leupeptin and 5 mM DTT and lysed using French Press. The CIB1-GST fusion protein or free GST was purified using glutathione-affinity chromatography (GE HealthCare, Inc., USA) followed by elution with 10 mM reduced glutathione. CIB1-GST fusion protein as well as GST was extensively dialyzed for 18 h in 5 mM HEPES pH 7.5, 125 mM NaCl, 5 25 mM CaCl2and 0.25 mM DTT. The proteins were concentrated to 10 mg / mL, aliquoted, flash-frozen and stored at -80oC until further use. The purity of the protein preparation was analyzed by SDS-PAGE and Coomassie staining (Fig.17). The molecular weight of GST- CIB1 was 48 kDa whereas the molecular weight of GST alone was 26 kDa. CIB1-(His)6 protein, used in some experiments was purified using Ni-NTA resin column following 30 manufacturer instructions (Fisher Scientific, USA). Compound Screening. The LOPAC1280collection was purchased from Sigma- Aldrich. Four NCATS internal libraries screened in this study are the NPACT (5,099 compounds), MIPE v4 (1,912 compounds), the NCATS Pharmaceutical collection (2,816 compounds), and the NCATS Chemistry collection (7,448 compounds). The NCATS Chemistry collection is a library consisting of internally synthesized compounds. For a full list of compound structures, see PubChem Assay Identifier (AID) 1508620. 5 All compounds were initially sourced from the National Center for Advancing Translational Sciences (NCATS) / National Institutes of Health (NIH). All compounds were subjected to quality control by LC / UV, LC / MS, or High-resolution MS, with all compounds exhibiting >95% purity by peak area or m / z. 10 Fluorescence polarization (FP) assay in 96- and 384-well format. Initial experiments for FP assay development were set up in 96-well-plate in a total volume of 200 ^L. FITC labeled ^IIbpeptide (F-αIIb) and GST-CIB1 were incubated at indicated concentrations for 15 min at room temperature (RT) and the FP signal measured with Perkin Elmer Victor 3 plate reader. FP assay optimizations were carried out in 384-well solid-bottom black plates (Greiner 15 Bio-One, Monroe, NC). F- ^IIb in assay buffer (5 mM HEPES pH 7.4, 125 mM NaCl, 5 mM CaCl2, 0.01% Tween 20, and 0.25 mM DTT prepared fresh) was prepared at a starting concentration of 1 ^M and performed a 1:2 dilution (20 μL assay volume), in addition to a buffer only control sample. Samples were read for FP (Ex = 480(20) / Em = 540(25) S and P; FITC Dichroic mirror) on a ViewLux CCD imager and used the S-channel RFU’s to determine 20 S:B, choosing 50 nM (S:B ~20; Figure 6A). For determination of ^IIb binding to GST-CIB1, 10 μL F-αIIb(100 nM, final concentration) was incubated with various concentrations of GST- CIB1 protein (final concentration of 0 – 20 μM) in 10 μL assay buffer at RT in dark for indicated time points before measuring FP. To test the activity of the unlabeled peptide, 15 µL of CIB1-GST (final concentrations 25 of 1 μM) in assay buffer, was dispensed into a 384-well plate, followed by the transfer of 1 μL of unlabeled ^IIb peptide (2 mM, 1:2 dilution, 16-point, n = 3, in DMSO; final assay concentration range of 3.05 nM to 100 μM). Samples were incubated at RT for 15 min followed by a 5 µL addition of F- ^IIb (final concentration of 50 nM). Plates were centrifuged at 1000 RPM (164 x g) for 15 seconds, incubated at RT for 1 h, and read for FP using the above 30 detection settings. Data were normalized against protein-probe mixture, no-protein controls, and the resulting percent inhibition data were fitted to a 4-parameter Hill equation using Graphpad Prism software (version 9.1). FP assay in 1536-well format. Protein (3 μL of CIB1-GST, final assay concentration 1 μM) or assay buffer (5 mM HEPES pH 7.4, 125 mM NaCl, 5 mM CaCl2, 0.01% Tween 20) were dispensed into a 1,536-well solid-bottom black plate (Greiner Bio-One, Monroe, NC). Forty-six nL of compound (final assay concentration of 457 nM to 114 μM) were transferred 5 via Wako Pin-tool (Wako Automation, Richmond, VA). Samples were incubated at RT for 15 min followed by a 1 µL addition of F-αIIb(final concentration of 100 nM). Samples were centrifuged for 15 seconds at 1000 RPM (164 x g), followed by a RT incubation for 15 min, then read for FP. 10 qHTS data analysis and statistics. Data from each assay were normalized plate-wise to corresponding intra-plate controls (DMSO neutral control and assay buffer positive control as noted). The same controls were used for the calculation of the Z’ factor, a measure of assay quality control. Concentration-response curves (CRCs) were fitted and classified as previously described, categorized into four classes as shown in Figure 27A-27B: complete 15 response curves (class 1), partial curves (class 2), single point actives (class 3), and inactives (class 4). All CRCs were fitted as previously described and IC50 values were calculated using in-house software or GraphPad Prism (sigmoidal dose-response variable slope). Minimum significant ratio (MSR), a statistical parameter that characterizes the reproducibility of potency estimates from in vitro concentration-response (CRC) assays, was used to assess the 20 performance of the intraplate controls. The chemical structures were standardized using the LyChI (Layered Chemical Identifier) program (version 20141028). Hit selection criteria were aggregated for duplicate structures using LyChi-3 provided by the NCATS Resolver. This was all done within the Palantir Technologies Foundry Platform (Washington, DC), which is configured to ingest all HTS results generated at NCATS and harmonized this data 25 with other sources such as ChEMBL and OrthoMCL. All qHTS screening results are publicly available at PubChem (AIDs 1508617, 1508618, 1508619, 1508620). Gel-based binding assay. The Gel-based binding assay was performed by incubating 1 ^M GST-CIB1 with the compound in dose-response (60 μM, 1:2, 4-points, n = 1) for 1 h at 30 RT. After incubation, 400 nM of F-αIIb was added to each tube and incubated for further 15 min. To each reaction, 5X loading buffer (50mM Tris-HCl, pH6.8, 10% glycerol, 0.005% bromophenol blue) was added and samples were resolved using 10% SDS-PAGE. The level of F-αIIb peptide in complex with GST-CIB1 was measured by taking fluorescence image of gels using ChemiDoc MP Imaging System (Bio-Rad). Intrinsic tryptophan fluorescence (ITF) assay. ITF was performed using Tecan 5 Infinite 200 Pro Fluorescence spectrophotometer as described previously. Ten ^M GST- CIB1 in assay buffer (10 mM HEPES, pH 7.4, 125 mM NaCl, 5 mM CaCl2, and 0.25 mM DTT) was incubated with 10 ^M unlabeled ^IIb peptide for 15 min, and the fluorescence was measured with excitation wavelength 295 nm and emission at 345 nm. To assess the effect of compounds identified in the screen, 10 ^M of GST-CIB1 incubated with various 10 concentrations of compounds at RT for 1 h before incubating with the unlabeled peptide. MST Competitive binding study. The binding affinity of the compounds to CIB1- (His)6protein in the presence of αIIbpeptide was evaluated using FITC-labeled αIIbas well. Following manufacturer’s recommendation, a minimum concentration of F-αIIb was 15 determined by performing a titration of the fluorophore (1 μM, 1:2, 8-points; final concentration range of 7.8 nM to 1 μM) in a 10 μL assay volume. Solutions were placed in standard capillaries and evaluated for fluorescent signal using the Monolith NT.115 instrument. With a desired RFU of > 200 at LED power of 50%, 200 nM was selected to determine the Kdof the protein. CIB1-(His)6protein was titrated in a two-fold dilution series 20 (16-points, final concentration range of 15 nM to 500 μM), at a final volume of 12.5 μL. Equal volume of [2X] 200 nM FITC-labeled peptide was then added to each well and mixed, for a total volume of 25 μL. Solutions were placed in standard capillaries, incubated for approximately 1 h, and evaluated for fluorescent signal with 50% LED excitation power, 20%, 40%, or 60% MST power (low, medium, high, respectively), MST on-time of 30 s and 25 off-time of 5 s . Based on best fit parameters in the MO Affinity Analysis software, medium MST-power was used, and calculated a Kd of 2.6 μM. Again, following the manufacturers recommendation, a factor of (1.5 x Kd) was used and moved forward with a protein concentration of 4 μM protein. Compounds were titrated in a two-fold dilution series (16-points, final concentration 30 range of 6.1 nM to 200 μM) and mixed with an equal volume CIB1-(His)6protein and F-αIIbpeptide (final concentrations of 4 μM and 200 nM, respectively). Solutions were incubated for 1 h at RT then placed in standard capillaries and evaluated for fluorescent signal (in triplicate) at the following parameters: 50% LED excitation power, 40% MST power, MST on-time of 30 s and off-time of 5 s using Monolith NT.115 instrument. Dissociation constant (Kd) values were calculated by fitting the thermophoresis signal at 20 s of the thermograph using the MO Affinity Analysis software (Nanotemper Technologies, Munich, Germany) and confirmed using Graphpad Prism 7. 5 In-silico analysis. To gain deeper insights into the relationship between the activity of the compounds (NCGC00071855, NCGC00351170, and NCGC00351154) and their molecular structures, molecular docking studies were conducted. The crystal structure of CIB1 (PDB ID: 1XO5) was retrieved from Protein Data Bank database and was prepared for 10 docking procedure using Protein Preparation Wizard of the Schrödinger Suite (Schrödinger Release 2019-2, Schrödinger, LLC, New York, NY, 2019). During the protein preparation, hydrogen atoms were added, water molecules were removed, and optimal protonation states and ASN / GLN / HIS flips were determined. Residues Leu131, Ile153 and Phe173 were found to be reported to play a key role in ligand binding. Thus, the active site was defined 15 encompassing a 20 Å around these residues (X: 33.56, Y: -4.96, Z: 6.89). LigPrep module of Schrödinger Suite was used to generate the correct protonation states for the ligands, which were then used for the docking studies. The OPLS3e force field was applied for the minimization of the structures and different ionization states were generated by adding or removing protons from the ligand at a target pH of 7.0 ± 2.0 using Epik version 3.1. 20 Tautomers were also generated for each ligand. To generate stereoisomers, the information on chirality from the input file for each ligand was retained as is for the entire calculation. Docking was performed using the GlideXP scoring function implemented in Maestro. Platelet preparation and aggregation. Whole blood was drawn by venipuncture 25 from healthy adult volunteers (of both gender and race) with informed consent. Approval was obtained from the institutional review boards of the Thomas Jefferson University, according to the Declaration of Helsinki. Blood was collected in acidified citrate dextrose as an anticoagulant. Platelet-rich plasma (PRP) and washed platelets were prepared, as has been previously described. Platelet aggregation was performed using washed platelet suspensions 30 containing 2 × 108 / mL platelets using a Chrono-Log Lumi-Aggregometer (Chrono-Log), as described previously. Aggregation traces were recorded using Aggrolink software (Chrono- Log). Thrombin induced P-selectin (CD62P) exposure was performed using Accuri C6 flowcytometer (BD Bioscience) as described previously. Assay optimization of a 384-well FP-based assay for high-throughput screening To identify inhibitors of CIB1 and αIIbinteraction, a previously developed 96-well FP assay was adapted for use in a high-throughput format. In this FP assay, various concentrations (0-20 μM,) of GST-CIB1 were incubated with 100 nM (96-well) F-αIIb5 peptide. After equilibration, F-αIIb is excited by polarized light. Free F-αIIb tumbles rapidly in solution, and the emitted light is less polarized relative to emissions from GST-CIB1 bound F-αIIb complex. The results demonstrate that GST-CIB1 binds to F-αIIb in a concentration dependent manner at an EC50of 0.9 μM (Fig.1A). In contrast, GST-alone failed to bind to F-αIIb suggesting the interaction of F-αIIb is specific to CIB1 (Fig.1A). The 10 αIIbpeptide binds to CIB1 in a calcium dependent manner. Therefore, to further confirm the specificity of F-αIIb binding to GST-CIB1 in the FP assay, EGTA was used to chelate Ca2+. The binding assay was performed in the presence or absence of EGTA in the buffer (Fig.1B). In the presence of EGTA (absence of calcium), F-αIIb peptide binds weakly to GST-CIB1. This suggests that F-αIIbbinds specifically to CIB1 and their interaction is Ca2+dependent. 15 To further confirm the specificity of the interaction between CIB1 and F-αIIb, a competitive binding assay was performed using increasing doses of unlabeled αIIb peptide to a fixed concentration of GST-CIB1 (1 μM) and F-αIIb peptide (100 nM). In agreement with previous studies, unlabeled αIIb peptide was able to block the F-αIIb binding to GST-CIB1 with an IC50 of 11.2 μM (Fig.1C). To further assess assay reproducibility and uniformity to be suitable 20 for a high-throughput format, a complex of F-αIIb (100nM) and GST-CIB1 (1 μM) or F-αIIb alone were measured for FP. A Z’ score of 0.62 was observed, demonstrating the suitability of the FP assay for HTS (Fig.1D). Next, one sought to determine the Kd / EC50of GST-CIB1 and F-αIIb, which would lead to calculating an EC80 or EC90, or a concentration that would be desirable to screen at, as this 25 would balance strong signal with the ability for a small molecule to disrupt the interaction. A [2X] 50 μM solution of protein was prepared, and a 1:2 dilution, 15-points was performed, followed by the addition of [2X] 25 nM labeled peptide. Samples were then incubated (RT) for 15, 30, 60, and 90 minutes and read for FP at those respective times (detector g-factor was set to 100 mP using labeled peptide solution; Fig.6B). To determine an incubation (RT) 30 time, the 1.56 μM dilution point was used then Z’-factor at each respective time-point was calculated (Fig.6C). The 60-minute time-point was chosen with a signal window ( ^mP) of 58, Z’-factor of 0.78, and an EC50 value of 0.2 μM (Hill Slope = 1.03), leading to an EC90 value of 1.7 μM (Fig.6D). Using this value as a guide, a percent DMSO test was performed from 10% down to 0.312% with 1 μM protein and 50 nM probe, where tolerance was observed up to 5% (v / v) DMSO (Fig.6E). Next, the ability of GST-CIB1 to bind to the labeled scrambled-peptide was examined, using similar conditions to the above Kd determination. A [2X] 20 μM solution of 5 protein was prepared, a 15-point 1:2 dilution performed, then [2X] 25 nM F-scrambled- peptide added, incubated (RT) for 60 minutes, and read for FP using the detection settings describe previously. An EC50 value of 1.6 μM was observed (Fig.7A), indicating the preference of the GST-CIB1 to the native peptide by ~8-fold (1.6 vs.0.2 μM). To confirm that the F-αIIb and GST-CIB1 bound in a reversible manner, the unlabeled 10 peptide was used as "cold competitors". A titration of unlabeled ^IIb peptide (2 mM, 1:2 dilution, 16-point, n = 3) in DMSO was performed with F- ^IIb (final concentration of 50 nM), where an IC50 value of ~2.7 μM was observed (Fig.7B). Of note, at concentrations >25 μM of unlabeled peptide, a "hook-effect" was noticed and those points were excluded, possibly due to aggregation or quenching of signal. 15 Finally, to make the assay HTS-amenable, the incubation time was sought to be shortened and incubation times at 15 and 60 minutes were compared using the unlabeled peptide potency as the determining factor (Fig.7C). The signal window ( ^mP) and Z’-factor for 15 and 60 minutes were 66 and 65, 0.73 and 0.68, respectively, with identical IC50 values of 2.7 μM, indicating one can shorten the incubation time to 15 minutes. 20 1536-well quantitative high-throughput screening and compound triage Having identified starting points and conditions in the 384-well format, the 1536-well format was used, beginning by testing F- ^IIb concentrations at 25, 50 and 100 nM in a 4 μL assay volume, where signal: background (S:B) of 6.8, 9.5, and 18, respectively, was observed25 vs buffer only solution (Fig.8A). 100 nM was chosen due to the strong S:B, and the 384- well assay was used statistics as a guide, 1 μM CIB1-GST chosen as the initial 1536-well format assay concentration. The unlabeled F- ^IIbwas tested in 1,536-well format, resulting in an unlabeled peptide IC50value of ~12 μM, ~4-fold higher than the ~3 μM IC50observed in 384-well format (Fig.8B). Similar to the 384-well format, a "hook effect" was observed at 30 higher concentrations >35 μM unlabeled peptide. Strong assay statistics was observed, with a Z’-factor of 0.56 ( ^mP = 63), indicating the above conditions were acceptable for HTS. With the above conditions in place, a pilot screen was performed against the LOPAC1280compound library, consisting of 5-plates in quantitative high-throughput screening (qHTS) format (10 mM, 1:5 dilution) resulting in a final assay concentration of 457 nM to 114 μM, yielding a mean Z’-factor of ~0.8, signal window ~96 ^mP, and unlabeled- ^IIb peptide IC50 of 8.6 μM (MSR = 2.7; Fig.8C). Before proceeding to screening additional compound libraries, the assay buffer was modified by removing DTT due to its potential 5 effects on assay activity, where no difference was observed in assay performance (data not shown). Due to availability of reagent, the intraplate control was switched from the unlabeled- ^IIbpeptide to 4,5,6,7-Tetrabromobenzotriazole (TBB), which was identified in the LOPAC1280screen as double-digit micromolar inhibitor and could be used initially as a technical control (Fig.8D). 10 The NPACT, NPC, NCATS Chemistry collection (qHTS format dose-response of 5 or 6-points, the final concentration range of 91.5 nM to 114 μM) and MIPEv4 (11-point intraplate dilution, final concentration range of 0.97 nM to 57.2 μM) compound libraries were then screened, as they are made up of approved, investigational, and annotated compounds. As shown in Fig.2A, a total of 14,782 compounds (18,555 samples) were screened in dose- 15 response, with a cumulative Z’ of 0.8 and intraplate control TBB IC50of ~10.7 ± 3.5 µM (MSR = 2.5). Because of the low hit rate (typical of PPI), an initial low bar for selection was used, with any compound exhibiting a negative curve class (Figs.9A-9D). Using these criteria, 831 compounds (5.6% hit rate) were identified as potential inhibitors. Structural filters were then applied to eliminate electrophiles and other problematic compounds, 20 resulting in 415 requested for confirmatory testing, of which 378 were sourced for testing (final concentration range of 1.78 μM to 114 μM or 0.112 μM to 114 μM, respectively) using the primary screen and selectivity (counter screen) formats with the scrambled peptide (Fig. 2A). 25 Hit confirmation using in-gel assay and ITF Of the 378 compounds, 275 were confirmed (73%) using the primary screening assay format, but 131 exhibited activity vs the scrambled peptide, leaving 144 showing selectivity towards ^IIb. 108 of the 144 compounds were selected for testing in the 384-well plate assay using F- ^IIband F-scrambled peptide (see Methods Section). Of the 108, 93 exhibited 30 inhibition vs the ^IIb peptide, but 25 exhibited binding activity towards the scrambled F- ^IIb peptide (plus an additional 6 that were inconclusive), leaving 62 showing selectivity towards ^IIb (Table S4; defined as exhibiting a negative curve class and / or IC50 ratio of > 3-fold and / or > 2-fold efficacy). Next, a low throughput in-gel binding experiment was developed as a secondary assay to assess the compound’s activity. Because of the labor intensity involved, 18 compounds were selected for further characterization. In this assay, 1 μM of GST-CIB1 was incubated with 400 nM F- ^IIbpeptide in the presence or absence of test compounds (Table S4). An 5 example gel of active (exhibiting inhibition) and inactive (no inhibition) compounds are shown (Fig.2B). Of these 18, 10 compounds (56%) inhibited the interaction of F- ^IIbwith GST-CIB1 in the in-gel assay. Inspecting the 10 candidate inhibitors, two disulfide containing compounds, NCGC00091563 (Thiram) and NCGC00016000 (Disulfiram) were flagged as potential false 10 positives due to reducing agents can have different effects on compounds. To confirm the selectivity, the compounds were tested with the physiological reducing agent glutathione (GSH). Both disulfide containing compounds exhibited IC50 shifts of 8.3- and 8.5-fold for NCGC00091563 (Thiram) and NCGC00016000 (Disulfiram), respectively, indicating they were affected by the presence of GSH (Figs.11A-11J). Of the 10 candidates, 4 compounds 15 effectively blocked the GST-CIB1 interaction with F- ^IIb (Fig.3). To further exclude non-specific compounds, four of the compounds were sourced and tested in an intrinsic tryptophan fluorescence (ITF) assay with unlabeled ^IIbpeptide and GST-CIB1 (Fig.4). Tryptophan can be selectively excited at 295 nm and give rise to emission at 355 nm, with the ^IIbpeptide having the amino acid tryptophan in its sequence. 20 Upon binding to CIB1, the intensity of tryptophan fluorescence will shift. Of the four compounds tested, three (NCGC00186047, NCGC00351170, and NCGC00071855) exhibited inhibition in the ITF assay, with IC50values of [μM] 16.6, 15.6, and 53.1 respectively, and were selected for further studies. Human platelet preparation 25 Platelets were isolated from fresh human blood by differential centrifugation as described previously. Briefly, blood was collected in citrate-phosphate-dextrose adenine (ACD) and centrifuged at 200 g for 10 min at room temperature (RT) to obtain platelet-rich plasma (PRP). After adding prostaglandin E1 (PGE1) at the concentration of 1 µM to PRP, platelets were sedimented by centrifugation at 800g for 10 min. Platelets were then washed in 30 Tyrode’s buffer [135 mM NaCl, 2.68 mm KCl, 0.36 mM NaH2PO4, 10 mM HEPES, 5.5 mM glucose, 11.9 mm NaHCO3, 2 mM CaCl2, 1.05 mM MgCl2.6H2O, pH 7.2] containing 1 µM PGE1, 0.035% bovine serum albumin (BSA). Platelets were pelleted and finally resuspended in Tyrode’s buffer. The platelet count in the suspension was adjusted to 2-4 X 108for experiments using Tyrode’s buffer and was used within 3 hours of isolation. Murine platelet preparation 5 Platelet from both male and female mice of 8-14-weeks old WT, Cib1- / -and Plk3- / -was prepared as previously described. Briefly, blood from these mice was drawn into tubes with 3.8% sodium citrate at a 9:1 ratio. The blood was drawn from the posterior vena cava and was subsequently diluted in a ratio of 1:1 with calcium free Tyrode's buffer. After dilution, the blood was centrifuged at 200 g for 10 min at RT to collect PRP. PGE1 (1 µM) 10 was added to PRP and centrifuged at 400 g for 10 min. Pelleted platelet was resuspended in Tyrode’s buffer at a concentration of 2 x 108 / mL, and utilized within 3 hours post-isolation. Platelet aggregation Platelet aggregation was measured using light transmission Chrono-Log lumi- aggregometer (Chrono-Log, Havertown, PA, USA), as described earlier. Briefly, the 15 aggregation was performed by incubating platelets (2.5 x 108 / mL) at 37°C in aggregometer under continuous stirring at 1200 rpm. Human platelets were activated with thrombin (0.1 U / ml), collagen (1 µg / mL), ADP (10 μM) and U46619 (0.5 µM), whereas murine platelets were stimulated with thrombin (0.025 U / mL) for 5 min, in the presence and absence of CI306 (0.1, 0.2 and 0.5 μM). Platelets were preincubated with CI306 for 2 min. Percent change in 20 light transmission was recorded where 100% refers to transmittance through blank solution. Aggrolink software (Chrono-log) was used to record the aggregation traces. Flow cytometry Flow cytometry studies were carried out as previously described. Washed platelets 25 from human and mice (WT and Cib1- / -) was adjusted to the count of 0.6 X 108cells / mL and was pre-treated with CI306 at the concentration of 0.1, 0.2 and 0.5 μM for 2 min. Human platelets were incubated with either FITC-PAC1 (1 μg / mL), PE-labeled P-selectin (1 μg / mL) or Alexa fluor 488 fibrinogen (1 μg / mL) for 10 min and were stimulated with thrombin at a concentration of 0.1 U / mL, collagen at 1 µg / mL, ADP at 10 μM, and U46619 at 0.5 µM. 30 Mice platelets upon pre-incubation with PE- labeled JON / A (1 μg / mL) for 10 min at 37˚C, were activated with 0.025 U / mL of thrombin for 5 minutes at RT. The reaction was stopped by addition of 1% final volume of paraformaldehyde (PFA) containing 0.2% BSA in 1XPBS. The primary platelet population was gated and analysis was performed with BD AccuriTM C6 Plus Flow Cytometer using the BD AccuriC6 software. Each experiment was repeated independently more than three times. CIB1 inhibitor compounds inhibit thrombin-induced platelet aggregation 5 Integrin ^IIb ^3 is specific to megakaryocyte / platelet lineage and is a key regulator of platelet aggregation. CIB1 is a cytosolic protein binds integrin ^IIbtail and regulates platelet function. The effect of the three compounds that effectively block the interaction of ^IIbwith GST-CIB1 was evaluated on platelet function using a human platelet aggregation assay. Interestingly, all three compounds (used at a concentration of 10 μM) were able to completely 10 inhibit platelet aggregation induced by thrombin (0.03 U / mL), a physiological agonist of platelet activation (Fig.5). These results indicate that using this FP-based qHTS assay three potent inhibitors of platelet function were identified, which will be further evaluated for their use as anti-platelet agents. 15 Platelet adhesion and spreading on immobilized fibrinogen Platelet adhesion and spreading were performed as previously described. Briefly, glass coverslips were coated with 250 µl of fibrinogen (100 µg / mL in 1XPBS) for 1 h in humid chamber, followed by blocking with 0.5% BSA in 1XPBS for 1 h at 37°C. Washed platelets (1 × 106) were allowed to spread on fibrinogen immobilized on glass coverslips and 20 were left to adhere for 45 minutes. Adhered platelets were fixed with freshly prepared 4% PFA in 1XPBS for 20 minutes and were permeabilized with 0.2% Triton X-100 for 5 minutes. Permeabilized platelets were washed and stained with Alexa-488 phalloidin at 1:700 dilution (obtained from Invitrogen, Carlsbad, CA, USA) for 1 h at RT. Antifade mounting media was put on the coverslip to preserve fluorescence and adhered platelets were observed 25 with a Zeiss LSM 700 laser scanning confocal microscope using a 63× oil immersion objective and a pinhole size of 1 AU. Image capture and analysis were conducted using ZEN imaging software. The platelets in each image were counted and characterized as having filopodia, lamellipodia, or fully spread cells. Percentage of each population was calculated. Platelets having narrow cellular protrusions comprising bundles of actin filaments were 30 classified as platelets with filopodia, whereas platelets with lamellipodia had laterally more extended protrusions comprised of a network of cross-linked actin filaments. The platelets that were fully spread were identified based on a well-spread hyaloplasm and the absence of distinct pseudopodia, according to Goodman's criteria. Around 100 platelets were examined across five randomly selected fields in each experiment, which was replicated a minimum of three times. Thromboxane A2 generation 5 Thromboxane generation assay was performed by measuring the level of thromboxane B2(TxB2), the stable metabolites of Thromboxane A2(TxA2) using an enzyme immunoassay kit (Enzo Life Sciences), as described earlier. Briefly, 100 µL of washed human platelets (2.5 X 108 / mL) pretreated with DMSO or CI306 (0.1, 0.2 and 0.5 µM) for 2 minutes and were stimulated with 0.1 U / mL thrombin for 5 minutes. The reaction was 10 stopped by snap-freezing the platelets in liquid nitrogen. Snap-frozen platelets were brought at RT and was centrifuged at 10,000 rpm and platelet supernatant was diluted 10 times with assay diluent and TxB2was determined, according to the manufacturer’s instructions. Calcium mobilization measurement 15 The method for assessing intracellular calcium release in human platelets was carried out as previously described. Briefly, human platelets were washed and resuspended in Tyrode's buffer, containing no calcium, at a concentration of 1.0 × 106platelets / mL. Platelets were preincubated with CI306 (0.1, 0.2 and 0.5 µM) for 2 minutes and were then treated with 2.5 µM of Fluo-4-AM (Life Technologies), for 1 minute in a calcium-free Tyrode's buffer at 20 37°C. After establishing a 60-second baseline, the platelets were then stimulated with thrombin (0.1 U / mL) in the presence of 1 mM extracellular Ca2+. Real-time fluorescence intensity was monitored using an Accuri C6 flow cytometer. Results are presented as the fold change in fluorescence intensity, comparing the peak intensity to the baseline levels before stimulation. 25 RAP1-GTP pulldown assay This experiment was conducted using a Millipore Rap1 activation assay kit, in compliance with the manufacturer's guidelines. Using 500 μL of washed human platelets at a count of 4 x 108 / mL, the samples were pre-incubated with CI306 at concentrations of 0.1, 0.2, 30 and 0.5 µM for 2 minutes and subsequently stimulated with 0.1 U / mL of thrombin for 5 minutes. These platelets were then centrifuged for 5 minutes at 800 g and 22°C. The resulting pellet was lysed by pipetting it repeatedly with an equal volume of a specially prepared Rap1 Activation lysis buffer, which was diluted to 1X using 10% glycerol in deionized water and supplemented with 10 μg / mL each of aprotinin and leupeptin. The lysate was further centrifuged at 14,000 g for 5 minutes at 4°C, and the supernatant (300 μL) was incubated with 20 µl of Ral GDS-RBD agarose slurry. This mixture underwent a one-hour incubation at 4°C with gentle agitation. Post-incubation, the agarose beads were pelleted by a brief centrifugation at 14,000 g for 10 seconds at 4°C, washed three times with the lysis buffer, and 5 resuspended in 2X Laemmli reducing sample buffer. An additional 2 µL of 1M dithiothreitol was added before boiling to facilitate the release of Rap1 from the beads. Samples were subjected to SDS-PAGE, western blotted and probed with mouse anti-Rap1 antibody followed by goat anti-rabbit anti-IgG. Blots were incubated with SuperSignal West Atto Ultimate sensitivity chemiluminescent Substrate (ThermoFisher) and bands were detected 10 using ChemiDoc Imaging system (Bio-Rad Laboratories). Band intensities were quantified using NIH ImageJ software. Immunoprecipitation Immunoprecipitation studies were performed as described previously. Briefly, human 15 platelets (1 X 109 / mL) were pre-treated with CI306 (0.1, 0.2, and 0.5 µM) for 2 minutes, and then activated with thrombin (0.1 U / mL) for 5 minutes. Platelets were lysed using ice-cold lysis buffer (2X CHAPS, 150 mM NaCl, and 50 mM Tris-HCl pH 7.5 containing 10 μg / mL each of leupeptin, and aprotinin; 1 mM each of PMSF, NaF, and sodium orthovanadate) and centrifuged at 13,000 rpm for 15 minutes at 4°C. Collected supernatant was precleared as 20 processed, as described. Immunoblotting Under reducing conditions, proteins from the lysates or immunoprecipitates were electrophoresed by 5%-15% gradient sodium dodecyl sulfate-polyacrylamide gel (SDS- 25 PAGE) before being transferred to polyvinylidene difluoride (PVDF) membrane as described. After transfer, the blots were blocked with either 3% BSA or 3% non-fat dry milk as prescribed, incubated with the primary antibody i.e., anti-αIIb(1:1000), anti-CIB1 (1:500), anti-Rap1 (1: 500), anti-β3 (1:1000), and anti-talin (1:500) for overnight. The membrane was then exposed to the corresponding secondary antibody at the dilution of 1:5000 at RT for an 30 hour. ThermoFisher's SuperSignalTMWest Pico PLUS Chemiluminescent Substrate was used to identify the bands. To determine the protein in the immunocomplex, the blot was stripped and reprobed with the appropriate primary antibody, followed by secondary antibody. NIH Image J software was used to quantify the bands intensity. Blue native PAGE (BN-PAGE) BN-PAGE was performed as described. Non-gradient, 6.5% BN-PAGE technique was used to isolate a protein complex. Pre-treated platelets at a concentration of 4 x 108 / mL were lysed using a CHAPS-detergent mix in a sample buffer containing 75 mM Bis-Tris, 750 5 mM 6-aminocaproic acid, 10% of 87% glycerol, and 10 µg / mL each of leupeptin and aprotinin, along with 1 mM each of PMSF, NAF, and sodium orthovanadate. This lysate was kept on ice for 30 minutes before undergoing centrifugation at 72,000 g for another 30 minutes at 4°C. The collected supernatant was then combined with a sample buffer containing 5% coomassie blue G-250 in a 25:1 ratio and loaded onto a 6.5% BN gel prepared 10 with 150 mM Bis-Tris and 200 mM 6-aminocaproic acid, at pH 7.0. Electrophoresis was initiated at 4°C after adding a blue cathode buffer composed of 15 mM Bis-Tris, 50 mM tricine, and 0.02% coomassie blue G-250, and an anode buffer containing 50 mM Bis-Tris, both at pH 7.0 and processed as described. 15 Second dimensional SDS-PAGE Second dimensional SDS-PAGE was performed as mentioned previously. To further separate the complex, lanes from blue native gel were either cut out or if necessary were stored at 4˚C. Before placing the strips on SDS-PAGE, it was equilibrated in 2x SDS Laemmli buffer without β-mercaptoethanol for 30 minutes. Lanes from BN-PAGE was 20 placed upon second dimension for immunoblotting as described above. Microfluidics flow assay in an arterial shearing environment Microfluidics assay was performed as has been described. Briefly, Flow experiments in a microfluidic channel was coated with collagen at a concentration of 200 µg / mL. The 25 obtained human whole blood was diluted in a 1:2 ratio with Tyrode's buffer and then treated with DiOC6 from Sigma at a concentration of 1 mg / mL for 10 minutes at 37°C. The blood was run through the flow channel at a shear rate of 800 s-1for 3 minutes and following procedure was followed, as described. 30 Statistical analysis For statistical analysis of the data GraphPad Prism9 software was used. Significance of the data was determined using Student’s t-test, a one-way analysis of variance (ANOVA) or a two-way ANOVA. Values of < 0.05 were considered significant. Each experiment was repeated independently at least 3 times. Data was plotted as mean ± standard error of the mean using GraphPad Prism9. Comments 5 Disrupting protein-protein interactions (PPIs) are one of the more difficult strategies for drug development. Having identified the CIB1 protein and accompanying ^IIbpeptide as a PPI with potential therapeutic consequences, an FP assay was miniaturized and optimized to identify inhibitors of this interaction. A diverse set of ~14,782 compounds was screened, taking candidate hits through a series of secondary and orthogonal assays, to arrive at the top 10 three compounds with cellular activity: NCGC00186047, NCGC00351170, and NCGC00071855. The secondary and tertiary assays provided 10 distinct compounds as potential inhibitors of GST-CIB1 and F- ^IIb. However, it is possible that GST being a bulky molecule may influence inhibition kinetics. These 10 compounds are further tested using purified CIB1 without the bulky GST. 15 NCGC00186047 is also known as IPA-3, a well-studied compound from the LOPAC1280compound library. IPA-3 was initially identified as a PAK1 inhibitor in a PIP screening assay. Later, it has been shown to inhibit several platelet functions including aggregation and spreading. These effects were contributed to inhibition of PAK1 and PAK2 as primary mechanism of action. IPA-3 inhibits CIB1- ^IIb interaction in an independent 20 screening assay, indicating that mechanism through which IPA-3 inhibits platelet function may not be solely through PAK1 inhibition. Furthermore, CIB1 has been reported to bind PAK1 and induce its activation. Thus, it is possible that CIB1 and Cdc42 interact with PAK1 at the single binding site and IPA-3 may interfere with this interaction. It will be important to evaluate the relative potency (IC50) of inhibition of CIB1- ^IIband PAK1 / 2-Cdc42 25 interactions. NCGC00071855 (CID 573747) was included in the MSLMR and is also a well characterized molecule, with >930 biological test results in PubChem, including as an inhibitor for peptidyl-prolyl isomerase NIMA-interacting 1 (PIN1, US9730941). PIN1 isomerizes the cis-trans conformation between pSer / pThr and proline to regulate the function 30 and stability of the target proteins. PIN1 deficiency or inactivation is a potential cause of Alzheimer's disease. On the other hand overexpression of PIN1 is associated with various cancers. Since PIN1 is expressed in megakaryocytes, the precursor cells of platelets and it is known to regulate platelet production, it is possible that PIN1 plays a role in platelet activation. Thus, in the context of regulating platelet function, the PIN1 / CIB1 axis appears to be an interesting avenue for future studies. Recently, juglone (5-hydroxy-1,4- naphthoquinone), an inhibitor of PIN1 has been reported to inhibit platelet activation. The effect of NCGC00071855 on platelet function is tested in the presence of juglone. 5 The third compound NCGC00351170 is a structural analog of NCGC00071855 also showed a comparable potency profile in the assays providing additional validation of this chemotype in modulating the CIB1 function. CIB1 has been shown to interact with almost two dozen of proteins which play significant roles in cell adhesion and migration, cell cycle, and cytoskeletal rearrangements. It 10 is therefore considered as a target for a number of diseases such as cancer and neurodegenerative diseases. In an attempt to identify CIB1 inhibitors to inhibit cancer cell survival Puhl, et al., used a random peptide display library screening and identified a linear peptide that specifically binds CIB1 and inhibits its function in cancer cells. To overcome issues with stability and potency, a cyclic peptide was identified and characterized for its 15 effect on triple-negative breast cancer cell proliferation and survival. The small molecules reported here can be used for further characterization and validation in downstream assays including animal models and offer a separate avenue for identifying inhibitors of CIB1 that could be used as pharmacological interventions for various human diseases. 20 CI306 is a CIB1 specific inhibitor and it inhibits the interaction between αIIband CIB1 in platelets 25 To evaluate the specificity of CI306, ex vivo thrombin (0.025 U / mL)-induced platelet aggregation assays were carried out in WT, Cib1- / -, Plk3- / -and Ask1- / -mice. In WT mice, CI306 dose-dependently inhibited thrombin-induced aggregation at concentrations of 0.1, 0.2, and 0.5 µM. Quantitative analysis of experiments in WT mice showed the significant inhibition of thrombin-induced aggregation in the presence of CI306 in a dose dependent 30 manner. Platelets from Cib1- / -mice exhibited lower aggregation compared to WT mice and this reduced aggregation was not further decreased in the presence of CI306 (0.1, 0.2, and 0.5 µM). Additionally, to assess the specificity of CI306, αIIbβ3 activation was studied using JON / A-binding assays in both WT and Cib1- / -mice. Data quantification from several separate experiments demonstrated that thrombin-stimulated JON / A binding in WT mice was significantly inhibited in a dose-dependent manner by CI306 (0.1, 0.2, and 0.5 µM). In 5 contrast, Cib1- / -mice showed approximately 50% reduction in JON / A-binding compared to WT mice, which did not exhibit further reduction upon pre-incubation with CI306. CIB1 is known to interact with the wide variety of proteins, and it regulates several cellular processes like adhesion, migration, Ca2+signaling to cell survival and progression. Other CIB1 binding partners in the platelet like ASK1, FAK, PLK3 other than αIIb-subunit 10 were previously identified. To confirm whether CI306 inhibits the aggregation by attenuating the interaction between CIB1 and its other binding partners, an aggregation assay was conducted in Ask1- / -and Plk3- / -mice. With reference to FIGs.18A-18B, the results demonstrated that CI306 (0.5 µM) effectively inhibited thrombin (0.025 U / mL)-induced aggregation in both mouse models. These findings suggest that the observed reduction in 15 thrombin-induced platelet aggregation in the presence of CI306 is not solely attributed to the inhibition of the interaction between CIB1 and its binding partners, such as Ask1 or Plk3. Based on these findings CI306 can be considered as a CIB1-specific inhibitor. To assess the specificity of CI306, ex vivo thrombin-induced platelet aggregation assays were conducted in mice with different genetic backgrounds, including WT, Cib1- / -, 20 Plk3- / -, and Ask1- / -mice. In WT mice, CI306 exhibited a dose-dependent inhibition of thrombin-induced platelet aggregation at concentrations of 0.1, 0.2, and 0.5 µM (FIG.35A). Quantitative analysis of these experiments in WT mice revealed a significant dose-dependent reduction in thrombin-induced aggregation in the presence of CI306 (FIG.35B). Cib1- / -mice showed lower platelet aggregation compared to WT mice, and the presence of CI306 (0.1, 25 0.2, and 0.5 µM) did not further decrease this reduced aggregation, as demonstrated by aggregative tracings (FIG.35C) and quantification (FIG.35D). Additionally αIIbβ3activation was examined using JON / A-binding assays in both WT and Cib1- / -mice. Quantitative data from multiple independent experiments indicated that CI306 (0.1, 0.2, and 0.5 µM) significantly inhibited thrombin-stimulated JON / A binding in 30 WT mice platelets in a dose-dependent manner (FIG.35E). In contrast, Cib1- / -mice platelets reduced JON / A-binding compared to WT mice, with no further reduction observed upon pre- incubation with CI306 (FIG.35E). CIB1 is known to interact with a wide variety of proteins, regulating various cellular processes such as adhesion, migration, Ca2+signaling, cell survival, and progression. To confirm whether CI306 inhibits platelet aggregation by disrupting the interaction between CIB1 and these other binding partners, aggregation assays in Ask1- / -and Plk3- / -mice were performed. The results demonstrated that CI306 (0.5 µM) effectively inhibited thrombin (0.025 U / mL)-induced aggregation in both mouse models (Supplementary FIG.35A and B). 5 These findings suggest that the observed reduction in thrombin-induced platelet aggregation in the presence of CI306 cannot be solely attributed to the inhibition of the interaction between CIB1 and its binding partners, such as Ask1 or Plk3. Based on these findings, CI306 can be considered a specific inhibitor of CIB1. Previous work from several laboratories has established that CIB1 interacts with the 10 αIIb-subunit, using a variety of in vitro and in vivo techniques and this protein-protein interaction is crucial for facilitating focal adhesion kinase (FAK) recruitment, thus initiating the process of outside-in-signaling, a key event in platelet activation and aggregation. CIB1 immunoprecipitation assays were conducted using human platelets stimulated with thrombin (0.1 U / mL), both with and without the presence of varying concentrations of CI306 (0.1, 0.2, 15 and 0.5 μM). It was observed that when platelets were preincubated with CI306, the interaction between αIIb and CIB1 was significantly inhibited in a dose-dependent manner, highlighting the potent inhibitory effect of CI306 on this crucial interaction. Interaction between CIB1 and cytoplasmic tail of αIIbis required for integrin 20 αIIbβ3activation and fibrinogen binding The research findings have demonstrated a significant role of CIB1 interaction with the cytoplasmic tail of αIIb-subunit in the αIIbβ3 activation thus, increasing its affinity of αIIbβ3 for its ligands in platelets. The next question was what happens to the αIIbβ3activation and its affinity for its ligand in the presence of CI306, which disrupts the interaction between CIB1 25 and αIIb-subunit. When platelets were stimulated with thrombin (0.1 U / mL), αIIbβ3was activated as determined by high affinity binding of PAC-1, a monoclonal antibody specific for an active conformation of αIIbβ3.However no significant PAC-1 binding was detected even in the presence of thrombin when platelets were preincubated with CI306 at different concentration of 0.05, 0.1, 0.2 and 0.5 μM, to block the interaction between CIB1 and the30 cytoplasmic tail of αIIb (FIG.19A-19B. To investigate the time-dependent patterns of CI306- mediated inhibition of αIIbβ3activation, an experiment was conducted wherein platelets were preincubated with CI306 (0.5 μM) for various durations, including 30 seconds, 1 minute, and 2 minutes, followed by platelet stimulation with thrombin (0.1 U / mL). Surprisingly and unexpectedly, it was discovered that a remarkable and rapid inhibition of PAC1 binding within a mere 30-second preincubation period (FIG.19C and FIG.19D). This observation underscores the potent impact of CI306 on thrombin-induced platelet activation. Moreover, preincubation of human platelets with CI306 showed this inhibitory effect to other agonists such as collagen (1 μg / mL), ADP (10 μM), and U46619 (1 μM)-induced integrin activation. 5 Additionally, the impact of CIB1 and αIIb-subunit interaction on the affinity of αIIbβ3 for fibrinogen was investigated. Using Alexa Fluor 488-fibrinogen, it was observed that the binding of fibrinogen to αIIbβ3 in human platelets, was significantly reduced as a function of dose in the presence of CI306 (0.1, 0.2 and 0.5 μM), FIGs.25A-25B. These findings collectively suggest that the activation of αIIbβ3 and its subsequent binding to fibrinogen are 10 direct consequences of the interaction between CIB1 and the αIIb-cytoplasmic tail, shedding light on the intricate mechanisms involved in platelet function and aggregation. CIB1 interaction with αIIb-cytoplasmic tail is necessary for the platelet aggregation To evaluate the significance of CIB1 interaction with the cytoplasmic tail of αIIbin the 15 context of human platelet aggregation, a series of experiments were conducted. Platelets were preincubated with varying concentrations of CI306 (0.1, 0.2, and 0.5 µM) and subsequently subjected to stimulation with physiological agonists, including thrombin (FIGs.20A-20B), collagen (FIGs.20C-20D), ADP (FIGs.20E-20F), and U46619 (FIGs.20G-20H). The results demonstrate that preincubation with CI306 showed a significant and dose-dependent 20 inhibitory effect on platelet aggregation induced by these physiological agonists and it advances the understanding of the intricate molecular mechanisms underlying platelet aggregation. CIB1 and αIIb-cytoplasmic tail interaction is not needed for thromboxane 25 generation but for platelet granule secretion It is known that thromboxane generation is one of the important parts of inside-out- signaling. In the present study, the impact of CI306 at concentrations of 0.1, 0.2, and 0.5 µM on thrombin-stimulated thromboxane generation in human platelets was investigated and it was found that thromboxane generation was unaffected in the presence of CI306 (FIG.21A). 30 On the other hand, thrombin-induced dense (FIG.21B) and α-granule secretion (FIG.21C- 21D) was significantly attenuated in the presence of CI306. This reduction in ATP-secretion and P-selectin expression can be the result of reduced aggregation in the presence of CI306. Inhibiting the interaction between CIB1 and αIIb-cytoplasmic tail impairs the thrombus formation To evaluate the thrombus growth, in vitro thrombus formation was assayed by perfusing the whole blood with and without CI306, at arterial shear rate, through a 5 microfluidic device coated with fibrillar collagen. It was found that platelets pre-treated with CI306 adhered less as compared to control-treated platelets (FIGs.22A-22B). Interestingly, the number of platelets in a thrombus (a measure of thrombus size) as indicated by fluorescence intensity labeled platelets was significantly reduced in CI306 preincubated human blood than vehicle-treated human blood. 10 CIB1 and αIIbinteraction is essential for platelet adhesion and spreading on immobilized fibrinogen We have previously shown that association of CIB1 with integrin αIIbβ3 is required for platelet spreading on immobilized fibrinogen (Fg). To evaluate the importance of CIB1 and 15 αIIb interaction on the ability of platelets to spread on immobilized Fg, platelets with and without CI306 were allowed to spread on immobilized fibrinogen. As shown in FIGs.24A- 24D and FIG.24E, the number of adhered platelets decreased with the increasing concentration of CI306. Platelets preincubated with CI306 showed more filopodia formation (FIG.24F), as compared to vehicle-treated platelets which exhibited either more lamellipodia 20 extension (FIG.24H) or fully spread morphology (FIG.24E) platelets. These results suggest that CIB1 interaction with αIIbsubunit is required for platelets to achieve a fully spread morphology. CI306 did not affect inside-out signaling despite inhibiting the integrin αIIbβ325 activation In platelets, thrombin-mediated stimulation facilitates a rise in intracellular calcium (Ca2+), setting off a cascade of intracellular events leading to the activation of Rap1 in its GTP-bound state and subsequent binding of talin to the β3-subunit, collectively contributing to integrin activation. This pathway, referred to as inside-out signaling, is integral to platelet 30 function. In the context of this study, CI306, a compound that inhibits the interaction between CIB1 and the αIIbsubunit, was introduced to explore its potential influence on the inside-out signaling pathway. The preincubation of platelets with CI306 did not perturb several key elements of the inside-out signaling mechanism, like the thrombin-induced calcium flux (FIGs.23A-23B), the activation of the small GTPase Rap1 in its GTP-bound state (FIGs. 23C-23D), or the talin binding to the β3 subunit of the integrin receptor (FIGs.23E-23G), despite its inhibitory effect on the CIB1-αIIbinteraction. This indicates that the compound's effect is specifically cantered on integrin activation without perturbing the broader inside-out signaling pathway. The specific impact of CI306 on the CIB1-αIIbinteraction without 5 affecting the general inside-out signaling pathway demonstrates the essential role this interaction plays in integrin activation. Integrins, a family of transmembrane glycoprotein signaling receptors can convey bioinformation in both directions across the plasma membrane commonly referred to as inside-out or outside-in signaling. Both the α and β subunits are made up of large 10 extracellular domain, a single transmembrane helix, and a small cytoplasmic domain. It has been reported that the dissociation of the cytoplasmic domains of α and β subunits is critical for bidirectional transmembrane signaling events. Integrin αIIbβ3is highly expressed in platelets and their progenitors, where it is essential for platelet activities, haemostasis, and arterial thrombosis. During platelet activation by agonists integrin αIIbβ3on the platelet 15 surface is converted to an active conformation that binds soluble fibrinogen. An improved understanding of integrin αIIbβ3 signal transduction and regulation will result in greater progress in understanding thrombosis and developing therapeutic agents. According to several articles, the activation of integrin αIIbβ3 and subsequent platelet activation and aggregation depend on the several proteins that interact with the cytoplasmic tail of α and β 20 subunits. It has been reported in before that in the inside-out signaling pathway, the cytoskeletal protein talin / Kindlin bind to the cytoplasmic domain of β3-subunit that in turn activates integrin αIIbβ3. Apart from talin and kindlin, there are several other proteins that regulate αIIbβ3activation either positively or negatively. Positively regulating proteins are integrin-linked kinase, β3-endonexin, chloride channel regulatory protein, catalytic subunit of 25 protein phosphatase 1 ƴ, and vinculin. Negatively regulating proteins are docking protein 1, filamin, and tensin 1. CIB1, that binds specifically with integrin αIIb cytoplasmic domain has been shown to regulate integrin αIIbβ3activation both, positively or negatively. CIB1 might also play the role in inside-out-signaling by controlling integrin ^IIb^3activation, in addition to talin binding to ^3-subunit. Earlier studies demonstrate that agonist-induced inside-out 30 signaling in platelets enhances the association of CIB1 with the ^IIb-cytoplasmic tail which results in the activation of ^IIb ^3-integrin. The ^IIb ^3-subunits are supposed to be held together by a salt bridge, which keeps it in an inactive conformation. Inside-out signaling is triggered by agonist activation in platelets, which may disrupt the connection between the αIIbβ3-subunits and cause the subunits to switch from a latent to the active conformation. Most of the research till date has shown that cytosolic proteins regulate αIIbβ3activation by regulating directly or indirectly via β3-subunit, thus breaking the salt bridge between α and β subunits. The question is whether β3and talin / kindlin interaction is sufficient to break the salt 5 bridge between αIIbβ3 or the αIIb-subunit and its potential binding partners modulate integrin- αIIbβ3activation. Without being bound by theory, it was hypothesized that CIB1 interaction is required for the activation of αIIbβ3, and this interaction occurs in addition to the interaction between talin and β3-subunit. Together, these interactions facilitate the dissociation of the salt bridge between the αIIbβ3 heterodimer by pulling it apart in opposite directions, leading to 10 integrin αIIbβ3activation. CI306 inhibited the interaction between CIB1 and ^IIbsubunit in human platelets and this inhibition was CIB1 specific as CI306 reduced the level of platelet aggregation and JON / A binding in WT mouse platelets. Platelet aggregation in CIB1- / -mouse platelets were inhibited approximately half of the WT mouse platelets, which was not further decreased in 15 the presence of CI306. Considering that CIB1 interacts with various cytosolic proteins, it was pertinent to ask if the decrease in platelet aggregation is a result of CI306 blocking the interaction between CIB1 and the αIIb subunit's cytoplasmic tail, or if it is due to CI306 hindering CIB1's interactions with other cytoplasmic proteins. Aggregation assays were performed on platelets from Ask1- / -and Plk3- / -mice, both of which lack the proteins that 20 interact with CIB1. It was observed that platelet aggregation was inhibited in both knockout models. The reduced platelet aggregation seen in Ask1- / -and Plk3- / -mice, indicates that this reduction is likely a result of impaired interaction between CIB1 and the αIIbsubunit, rather than a consequence of disrupted interactions between CIB1 and other cytoplasmic binding partners. 25 When the interaction between CIB1 and the cytoplasmic tail of αIIb was inhibited, there was a significant decrease in the functional responses of platelets stimulated by agonists. This included the activation of surface integrins αIIbβ3, fibrinogen binding, platelet aggregation, and the release of contents from alpha-granules and dense granules. Inhibiting the interaction between CIB1 and αIIbusing CI306, significantly reduced platelet spreading 30 across immobilized fibrinogen in terms of both quantity and quality. Without being bound by theory, the interaction between CIB1 and the cytoplasmic tail of the αIIb-subunit in human platelets is essential for their accumulation on a collagen surface. Collectively, these findings imply that the interaction of CIB1 with the cytoplasmic tail of αIIbis necessary for the activation of αIIbβ3 and the proper functioning of platelets. CI306 did not interfere with the thrombin-induced rise in intracellular Ca2+, Rap1- activation, or the binding of talin to the β3- subunit. This suggests that the reduced platelet functions seen with CI306 are probably a result of its interference with the interaction between CIB1 and the αIIbcytoplasmic tail. The 5 influence of CI306 seems to be selective, without a widespread effect on inside-out signaling pathways. Taken all data together, a comprehensive mechanism for the activation of αIIbβ3 integrin can be suggested. In platelets activated by agonists, Ca2+-bound CIB1, attaches to the cytoplasmic domain of the αIIb subunit, with its N-terminal myristoyl group integrating into 10 the plasma membrane. The subsequent attachment of talin to the β3-subunit generates a pulling force, leading to the detachment of β3 from αIIb, which remains fixed due to its interaction with CIB1. This separation facilitates the activation of the αIIbβ3integrin. The terms and expressions employed herein are used as terms of description and not 15 of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the embodiments of the present application. Thus, it should be understood that although the present application describes specific embodiments and optional features, modification and variation of the compositions, 20 methods, and concepts herein disclosed may be resorted to by those of ordinary skill in the art, and that such modifications and variations are considered to be within the scope of embodiments of the present application. Enumerated Embodiments 25 The following enumerated embodiments are provided, the numbering of which is not to be construed as designating levels of importance: Embodiment 1 provides a method of preventing, treating, and / or ameliorating thrombosis, the method comprising: administering to a subject in need thereof a pharmaceutical composition comprising at 30 least one pharmaceutically acceptable excipient or carrier and a therapeutically effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, tautomer, enantiomer, or N-oxide thereof: , Formula (I), wherein: is a single o d; A, Q, X, Y, and Z are each independently CH, N, NH, O, or S, provided that at least one of A, Q, X, Y, and Z is CH; 5 LL is independently at each occurrence -O-, -OR, -S-, -S(=O)-, -S(=O)2-, -SR, -N(R)-, -NR2, -CR=, -C ^ ^ ^-CH2-, -CHR-, -CR2-, -CH3, -C(=O)-, or -C(=NR)-; zz is an integer from 1 to 20; each occurrence of R1is independently selected from the group consisting of C1-12alkyl, C2-12alkenyl, C2-12alkynyl, OC1-12alkyl, C6-10aryl, C3-12cycloalkyl, C3-1210 heterocycloalkyl, C4-10 heteroaryl, and combinations thereof, wherein each R1is independently optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2; 15 each occurrence of R is independently selected from the group consisting of C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, OC1-12 alkyl, C6-10 aryl, C3-12 cycloalkyl, C3-12 heterocycloalkyl, and C4-10heteroaryl; and n is an integer from 1 to 4. Embodiment 2 provides the method of embodiment 1, wherein n is 2. 20 Embodiment 3 provides the method of any one of embodiments 1-2, wherein each R1is independently C6-10aryl. Embodiment 4 provides the method of any one of embodiments 1-3, wherein zz is 1. Embodiment 5 provides the method of any one of embodiments 1-4, wherein at least one LL is -C(=O)-. 25 Embodiment 6 provides the method of any one of embodiments 1-5, wherein the compound has the structure: , wherein: Z is CH, N, or N-o x e; each R1is independently selected from the group consisting of C6-10 aryl, C3-12 cycloalkyl, C3-12heterocycloalkyl, C4-10heteroaryl, and combinations thereof, each independently optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, 5 SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2; and each occurrence of R is independently selected from the group consisting of C1-12alkyl, C2-12alkenyl, C2-12alkynyl, OC1-12alkyl, C6-10aryl, C3-12cycloalkyl, C3-12heterocycloalkyl, C4-10 heteroaryl, and combinations thereof. 10 Embodiment 7 provides the method of any one of embodiments 1-6, wherein Z is N- oxide. Embodiment 8 provides the method of any one of embodiments 1-7, wherein R1is phenyl optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, 15 SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2. Embodiment 9 provides the method of any one of embodiments 1-8, wherein R1is C5 heteroaryl optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, 20 SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2. Embodiment 10 provides the method of any one of embodiments 1-9, wherein the C5 heteroaryl is furyl or thiophenyl. Embodiment 11 provides the method of any one of embodiments 1-10, wherein the 25 compound has the structure: ein n is ind and R2is independently selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, 30 C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2. Embodiment 12 provides the method of any one of embodiments 1-11, wherein the compound has the structure: , wherein n is ind , 3, or 4; and 2 5 R is independently selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2. Embodiment 13 provides the method of any one of embodiments 1-12, wherein the 10 compound is selected from the group consisting of: , , , 3, wherein the thrombosis comprises at least one of deep vein thrombosis, pulmonary embolism, femoral 5 vein thrombosis, Paget-Schroetter syndrome, myocardial infarction, superior vena cava thrombosis, jugular vein thrombosis, thrombotic stroke, cerebral venous sinus thrombosis, cavernous sinus thrombosis, retinal vein occlusion, May-Thurner syndrome, portal vein thrombosis, Budd-Chiari syndrome, and renal vein thrombosis. Embodiment 15 provides the method of any one of embodiments 1-14, wherein the 10 compound is administered to the subject with an additional therapeutic agent. Embodiment 16 provides the method of any one of embodiments 1-15, wherein the administration is by a route selected from the group consisting of oral, transdermal, transmucosal, intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, 15 inhalation, and topical administration. Embodiment 17 provides the method of any one of embodiments 1-16, wherein the subject is human. Embodiment 18 provides the method of any one of embodiments 1-17, wherein the pharmaceutical composition is formulated in unit dose form. 20 Embodiment 19 provides a compound of Formula (I) or a pharmaceutically acceptable salt, tautomer, enantiomer, or N-oxide thereof: , Formula (I), wherein: is a single or ou e ond; A, Q, X, Y, and Z are each independently CH, N, NH, O, or S, provided that at 25 least one of A, Q, X, Y, and Z is CH; LL is independently at each occurrence -O-, -OR, -S-, -S(=O)-, -S(=O)2-, -SR, -N(R)-, -NR2, -CR=, -C ^ ^ ^-CH2-, -CHR-, -CR2-, -CH3, -C(=O)-, or -C(=NR)-; zz is an integer from 1 to 20; each occurrence of R1is independently selected from the group consisting of 5 C1-12alkyl, C2-12alkenyl, C2-12alkynyl, OC1-12alkyl, C6-10aryl, C3-12cycloalkyl, C3-12heterocycloalkyl, C4-10 heteroaryl, and combinations thereof, wherein each R1is independently optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, 10 C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2; each occurrence of R is independently selected from the group consisting of C1-12alkyl, C2-12alkenyl, C2-12alkynyl, OC1-12alkyl, C6-10aryl, C3-12cycloalkyl, C3-12heterocycloalkyl, and C4-10 heteroaryl; and n is an integer from 1 to 4, 15 wherein the compound of Formula (I) is not any of the following compounds: , , , n is 2. Embodiment 21 provides the compound of any one of embodiments 19-20, wherein 5 each R1is independently C6-10aryl. Embodiment 22 provides the compound of any one of embodiments 19-21, wherein zz is 1. Embodiment 23 provides the compound of any one of embodiments 19-22, wherein at least one LL is -C(=O)-. 10 Embodiment 24 provides the compound of any one of embodiments 19-23, wherein the compound has the structure: in: Z is CH, N, or N- each R1is independently selected from the group consisting of C6-10aryl, C3-1215 cycloalkyl, C3-12 heterocycloalkyl, C4-10 heteroaryl, and combinations thereof, each independently optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2; and 20 each occurrence of R is independently selected from the group consisting of C1-12alkyl, C2-12alkenyl, C2-12alkynyl, OC1-12alkyl, C6-10aryl, C3-12cycloalkyl, C3-12heterocycloalkyl, C4-10 heteroaryl, and combinations thereof. Embodiment 25 provides the compound of any one of embodiments 19-24, wherein Z is N-oxide. 25 Embodiment 26 provides the compound of any one of embodiments 19-25, wherein R1is phenyl optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2. Embodiment 27 provides the compound of any one of embodiments 19-26, wherein 5 R1is C5 heteroaryl optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2. Embodiment 28 provides the compound of any one of embodiments 19-27, wherein 10 the C5heteroaryl is furyl or thiophenyl. Embodiment 29 provides the compound of any one of embodiments 19-28, wherein the compound has the structure: , wherein n is indep , or 4; and 15 R2is independently selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2. Embodiment 30 provides the compound of any one of embodiments 19-29, wherein the compound has the structure: 20 , wherein n is indepe , or 4; and R2is independently selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2. 25 Embodiment 31 provides a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier or excipient and at least one compound of any one of embodiments 19-30. Embodiment 32 provides a method of preventing, treating, and / or ameliorating a disease or disorder associated with CIB1, the method comprising: administering to a subject in need thereof a therapeutically effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, tautomer, enantiomer, or N-oxide thereof: , Formula (I), wherein: is a single or double bond; A, Q, X, Y, and Z are each independently CH, N, NH, O, or S, provided that at least one of A, Q, X, Y, and Z is CH; LL is independently at each occurrence -O-, -OR, -S-, -S(=O)-, -S(=O)2-, -SR, -N(R)-, -NR2, -CR=, -C ^, -CH2-, -CHR-, -CR2-, -CH3, -C(=O)-, or -C(=NR)-; zz is an integer from 1 to 20; each occurrence of R1is independently selected from the group consisting of C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, OC1-12 alkyl, C6-10 aryl, C3-12 cycloalkyl, C3-12 heterocycloalkyl, C4-10heteroaryl, and combinations thereof, wherein each R1is independently optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2; each occurrence of R is independently selected from the group consisting of C1-12alkyl, C2-12alkenyl, C2-12alkynyl, OC1-12alkyl, C6-10aryl, C3-12cycloalkyl, C3-12heterocycloalkyl, and C4-10 heteroaryl; and n is an integer from 1 to 4; optionally wherein the at least one compound is formulated as a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient or carrier; and wherein the disease or disorder is selected from the group consisting of cancer, neurodegenerative diseases, immune system diseases, and inflammation. Embodiment 33 provides the method of embodiment 32, wherein n is 2. Embodiment 34 provides the method of any one of embodiments 32-33, wherein each R1is independently C6-10aryl. Embodiment 35 provides the method of any one of embodiments 32-34, wherein zz is 1. Embodiment 36 provides the method of any one of embodiments 32-35, wherein at least one LL is -C(=O)-. Embodiment 37 provides the method of any one of embodiments 32-36, wherein the compound has the structure: , wherein: Z is CH, N, or N-oxide; each R1is independently selected from the group consisting of C6-10 aryl, C3-12 cycloalkyl, C3-12heterocycloalkyl, C4-10heteroaryl, and combinations thereof, each independently optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2; and each occurrence of R is independently selected from the group consisting of C1-12alkyl, C2-12alkenyl, C2-12alkynyl, OC1-12alkyl, C6-10aryl, C3-12cycloalkyl, C3-12heterocycloalkyl, C4-10 heteroaryl, and combinations thereof. Embodiment 38 provides the method of any one of embodiments 32-37, wherein Z is N-oxide. Embodiment 39 provides the method of any one of embodiments 32-38, wherein R1is phenyl optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2. Embodiment 40 provides the method of any one of embodiments 32-39, wherein R1is C5 heteroaryl optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2. Embodiment 41 provides the method of any one of embodiments 32-40, wherein the C5heteroaryl is furyl or thiophenyl. Embodiment 42 provides the method of any one of embodiments 32-41, wherein the compound has the structure: , n is independently at each occurrence 0, 1, 2, 3, or 4; and R2is independently selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2. Embodiment 43 provides the method of any one of embodiments 32-42, wherein the compound has the structure: , n is independently at each occurrence 0, 1, 2, 3, or 4; and R2is independently selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2. Embodiment 44 provides the method of any one of embodiments 32-43, wherein the compound is selected from the group consisting of: , , he compound is administered to the subject with an additional therapeutic agent. Embodiment 46 provides the method of any one of embodiments 32-45, wherein the administration is by a route selected from the group consisting of oral, transdermal, transmucosal, intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration. Embodiment 47 provides the method of any one of embodiments 32-46, wherein the subject is human. Embodiment 48 provides the method of any one of embodiments 32-47, wherein the pharmaceutical composition is formulated in unit dose form. Embodiment 49 provides the method of any one of embodiments 32-48, wherein the cancer is selected from the group consisting of liver cancer, breast cancer, pancreatic cancer, lung cancer, leukemia, lymphoma, colon cancer, stomach cancer, melanoma, testicular cancer, prostate cancer, and rectal cancer.

Claims

CLAIMS What is claimed is:

1. A method of preventing, treating, and / or ameliorating thrombosis, the method comprising: administering to a subject in need thereof a therapeutically effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, tautomer, enantiomer, or N-oxide thereof: , Formula (I), wherein:is a single or double bond; A, Q, X, Y, and Z are each independently CH, N, NH, O, or S, provided that at least one of A, Q, X, Y, and Z is CH; LL is independently at each occurrence -O-, -OR, -S-, -S(=O)-, -S(=O)2-, -SR, -N(R)-, -NR2, -CR=, -C ^ ^ ^-CH2-, -CHR-, -CR2-, -CH3, -C(=O)-, or -C(=NR)-; zz is an integer from 1 to 20; each occurrence of R1is independently selected from the group consisting of C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, OC1-12 alkyl, C6-10 aryl, C3-12 cycloalkyl, C3-12 heterocycloalkyl, C4-10heteroaryl, and combinations thereof, wherein each R1is independently optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2; each occurrence of R is independently selected from the group consisting of C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, OC1-12 alkyl, C6-10 aryl, C3-12 cycloalkyl, C3-12 heterocycloalkyl, and C4-10heteroaryl; and n is an integer from 1 to 4; optionally wherein the at least one compound is formulated as a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient or carrier.

2. The method of claim 1, wherein n is 2.

3. The method of claim 2, wherein each R1is independently C6-10 aryl.

4. The method of claim 2, wherein zz is 1.

5. The method of claim 2, wherein at least one LL is -C(=O)-.

6. The method of claim 1, wherein the compound has the structure: , wherein:Z is CH, N, or N-oxide; each R1is independently selected from the group consisting of C6-10aryl, C3-12cycloalkyl, C3-12 heterocycloalkyl, C4-10 heteroaryl, and combinations thereof, each independently optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2; and each occurrence of R is independently selected from the group consisting of C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, OC1-12 alkyl, C6-10 aryl, C3-12 cycloalkyl, C3-12 heterocycloalkyl, C4-10heteroaryl, and combinations thereof.

7. The method of claim 6, wherein Z is N-oxide.

8. The method of claim 6, wherein R1is phenyl optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2.

9. The method of claim 6, wherein R1is C5heteroaryl optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN,NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2.

10. The method of claim 9, wherein the C5heteroaryl is furyl or thiophenyl.

11. The method of claim 6, wherein the compound has the structure: , whereinn is independently at each occurrence 0, 1, 2, 3, or 4; and R2is independently selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2.

12. The method of claim 6, wherein the compound has the structure: , whereinn is independently at each occurrence 0, 1, 2, 3, or 4; and R2is independently selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2.

13. The method of claim 1, wherein the compound is selected from the group consisting of:, ,14. The method of claim 1, wherein the thrombosis comprises at least one of deep vein thrombosis, pulmonary embolism, femoral vein thrombosis, Paget-Schroetter syndrome, myocardial infarction, superior vena cava thrombosis, jugular vein thrombosis, thrombotic stroke, cerebral venous sinus thrombosis, cavernous sinus thrombosis, retinal vein occlusion, May-Thurner syndrome, portal vein thrombosis, Budd-Chiari syndrome, and renal vein thrombosis.

15. The method of claim 1, wherein the compound is administered to the subject with an additional therapeutic agent.

16. The method of claim 1, wherein the administration is by a route selected from the group consisting of oral, transdermal, transmucosal, intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra- arterial, intravenous, intrabronchial, inhalation, and topical administration.

17. The method of claim 1, wherein the subject is human.

18. The method of claim 1, wherein the pharmaceutical composition is formulated in unit dose form.

19. A compound of Formula (I) or a pharmaceutically acceptable salt, tautomer, enantiomer, or N-oxide thereof: , Formula (I), wherein:is a single or double bond; A, Q, X, Y, and Z are each independently CH, N, NH, O, or S, provided that at least one of A, Q, X, Y, and Z is CH; LL is independently at each occurrence -O-, -OR, -S-, -S(=O)-, -S(=O)2-, -SR, -N(R)-, -NR2, -CR=, -C ^ ^ ^-CH2-, -CHR-, -CR2-, -CH3, -C(=O)-, or -C(=NR)-; zz is an integer from 1 to 20; each occurrence of R1is independently selected from the group consisting of C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, OC1-12 alkyl, C6-10 aryl, C3-12 cycloalkyl, C3-12 heterocycloalkyl, C4-10heteroaryl, and combinations thereof, wherein each R1is independently optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2;each occurrence of R is independently selected from the group consisting of C1-12alkyl, C2-12alkenyl, C2-12alkynyl, OC1-12alkyl, C6-10aryl, C3-12cycloalkyl, C3-12heterocycloalkyl, and C4-10 heteroaryl; and n is an integer from 1 to 4, wherein the compound of Formula (I) is not any of the following compounds: , ,20. The compound of claim 19, wherein n is 2.

21. The compound of claim 20, wherein each R1is independently C6-10 aryl.

22. The compound of claim 20, wherein zz is 1.

23. The compound of claim 20, wherein at least one LL is -C(=O)-.

24. The compound of claim 19, wherein the compound has the structure: , wherein:Z is CH, N, or N-oxide; each R1is independently selected from the group consisting of C6-10aryl, C3-12cycloalkyl, C3-12 heterocycloalkyl, C4-10 heteroaryl, and combinations thereof, each independently optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2; and each occurrence of R is independently selected from the group consisting of C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, OC1-12 alkyl, C6-10 aryl, C3-12 cycloalkyl, C3-12 heterocycloalkyl, C4-10heteroaryl, and combinations thereof.

25. The compound of claim 24, wherein Z is N-oxide.

26. The compound of claim 24, wherein R1is phenyl optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2.

27. The compound of claim 24, wherein R1is C5 heteroaryl optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2.

28. The compound of claim 27, wherein the C5heteroaryl is furyl or thiophenyl.

29. The compound of claim 19, wherein the compound has the structure: , whereinn is independently at each occurrence 0, 1, 2, 3, or 4; and R2is independently selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2.

30. The compound of claim 19, wherein the compound has the structure: , whereinn is independently at each occurrence 0, 1, 2, 3, or 4; and R2is independently selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2.

31. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier or excipient and at least one compound of claim 19.

32. A method of preventing, treating, and / or ameliorating a disease or disorder associated with CIB1, the method comprising: administering to a subject in need thereof a therapeutically effective amount of at least one compound of Formula (I), or a pharmaceutically acceptable salt, tautomer, enantiomer, or N-oxide thereof:, Formula (I), wherein:is a single or double bond; A, Q, X, Y, and Z are each independently CH, N, NH, O, or S, provided that at least one of A, Q, X, Y, and Z is CH; LL is independently at each occurrence -O-, -OR, -S-, -S(=O)-, -S(=O)2-, -SR, -N(R)-, -NR2, -CR=, -C ^ ^ ^-CH2-, -CHR-, -CR2-, -CH3, -C(=O)-, or -C(=NR)-; zz is an integer from 1 to 20; each occurrence of R1is independently selected from the group consisting of C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, OC1-12 alkyl, C6-10 aryl, C3-12 cycloalkyl, C3-12 heterocycloalkyl, C4-10heteroaryl, and combinations thereof, wherein each R1is independently optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2; each occurrence of R is independently selected from the group consisting of C1-12alkyl, C2-12alkenyl, C2-12alkynyl, OC1-12alkyl, C6-10aryl, C3-12cycloalkyl, C3-12heterocycloalkyl, and C4-10 heteroaryl; and n is an integer from 1 to 4; optionally wherein the at least one compound is formulated as a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient or carrier; and wherein the disease or disorder is selected from the group consisting of cancer, neurodegenerative diseases, immune system diseases, and inflammation.

33. The method of claim 32, wherein n is 2.

34. The method of claim 33, wherein each R1is independently C6-10 aryl.

35. The method of claim 33, wherein zz is 1.

36. The method of claim 33, wherein at least one LL is -C(=O)-.

37. The method of claim 32, wherein the compound has the structure: , wherein:Z is CH, N, or N-oxide; each R1is independently selected from the group consisting of C6-10 aryl, C3-12 cycloalkyl, C3-12 heterocycloalkyl, C4-10 heteroaryl, and combinations thereof, each independently optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2; and each occurrence of R is independently selected from the group consisting of C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, OC1-12 alkyl, C6-10 aryl, C3-12 cycloalkyl, C3-12 heterocycloalkyl, C4-10heteroaryl, and combinations thereof.

38. The method of claim 37, wherein Z is N-oxide.

39. The method of claim 37, wherein R1is phenyl optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2.

40. The method of claim 37, wherein R1is C5 heteroaryl optionally substituted by at least one substituent selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2.

41. The method of claim 40, wherein the C5 heteroaryl is furyl or thiophenyl.

42. The method of claim 37, wherein the compound has the structure:, whereinn is independently at each occurrence 0, 1, 2, 3, or 4; and R2is independently selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2.

43. The method of claim 37, wherein the compound has the structure: , whereinn is independently at each occurrence 0, 1, 2, 3, or 4; and R2is independently selected from the group consisting of F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO2, CF3, OCF3, R, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, and OC(O)N(R)2.

44. The method of claim 32, wherein the compound is selected from the group consisting of:, ,45. The method of claim 32, wherein the compound is administered to the subject with an additional therapeutic agent.

46. The method of claim 32, wherein the administration is by a route selected from the group consisting of oral, transdermal, transmucosal, intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra- arterial, intravenous, intrabronchial, inhalation, and topical administration.

47. The method of claim 32, wherein the subject is human.

48. The method of claim 32, wherein the pharmaceutical composition is formulated in unit dose form.

49. The method of claim 32, wherein the cancer is selected from the group consisting of liver cancer, breast cancer, pancreatic cancer, lung cancer, leukemia, lymphoma, colon cancer, stomach cancer, melanoma, testicular cancer, prostate cancer, and rectal cancer.

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