Neutrophil exocytosis inhibitors

Abstract

The present invention relates to compounds and compositions comprising same. Additionally, methods of use are provided, such as for the treatment and prevention of neutrophil-related diseases or conditions in a subject in need thereof.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 289,771, filed December 15, 2021, the contents of which are incorporated herein by reference in their entirety.

[0002] Electronic Sequence Listing Reference The contents of the electronic sequence listing (IMUX-P-003-PCT SQL.xml, size: 12,970 bytes and creation date: December 11, 2022) are incorporated herein by reference in their entirety.

[0003] The present invention is in the field of neutrophil pathologies. [Background technology]

[0004] Neutrophils are potent effector cells in a wide range of infectious, inflammatory and autoimmune conditions, as well as cancer. In certain instances, the natural role of neutrophils as cells that drive cytotoxic inflammation can have deleterious consequences. Uncontrolled neutrophil secretion poses a major danger. Diseases characterized by excessive neutrophil-mediated tissue damage require therapeutic agents that can temporarily inhibit neutrophil effector function but do not cause neutrophil cell death and neutropenia. There is a great need for therapeutics that can balance the need to inhibit effector function without killing neutrophils. Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention provides a compound represented by any one of the formulas disclosed herein.A composition comprising the compound and a nanoparticle comprising the compound are also provided.A method for treating neutrophil-related diseases or conditions is also provided.

[0006] According to a first aspect, there is provided a compound represented by any one of the formulas provided herein.

[0007] According to another aspect, there is provided a compound, including any stereoisomer or salt thereof, comprising the compound of formula I: [ka] (I) Or, the expression: [ka] (In the formula: A is a methyl group, an isopropyl group, a tert-butyl group, a linear or branched C1-C 10 Alkyl groups, substituted or unsubstituted, linear or branched, C2-C 10 Alkyl groups, substituted C2-C 10 Alkyl groups, optionally substituted C3-C containing one or more carbocyclic rings 10 Cycloalkyl groups, optionally substituted C2-C containing one or more heteroatoms 10 Alkyl groups, C1-C 10 Haloalkyl groups, substituted C1-C 10 Haloalkyl groups, C1-C 10 Alkylhydroxy group, halo group, C1-C 10 Alkoxy groups, C3-C 10 Cycloalkyl groups, substituted C3-C 10 represents a cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, a bicyclic aromatic ring, an unsaturated aliphatic ring, a bicyclic aliphatic ring, or a combination thereof; Y is absent or is N, NH, NR 1 , C.H., H.C.R. 1 , CH2, S, SH, and O; n is an integer from 0 to 5; X is hydrogen or a halo group, a methyl group, an isopropyl group, a C2-C 10 Alkyl groups, substituted C2-C 10represents a substituent selected from the group consisting of an alkyl group, an alkoxy group, an amino group, and a hydroxy group; Each R independently represents zero or one or more substituents, each independently being a methyl group, an isopropyl group, a C2-C 10 Alkyl groups, substituted C2-C 10 Alkyl group, halo, oxo, -NO2, amino, hydroxy, -CN, -OH, -CONH2, -CONR'2, -CNNR'2, -CSNR'2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR', ​​-NC(=S)OR', -NC(=S)NR', ​​-SOR', -SR', -SO2OR', -SON(R')2, -NHNR'2, -NNR', C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NR'R', -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 halo and any one of the following: alkoxy, hydroxy(C1-C6 alkyl), hydroxy(C1-C6 alkoxy), alkoxy(C1-C6 alkyl), alkoxy(C1-C6 alkoxy), C1-C6 alkyl-NR'2, C1-C6 alkyl-SR', -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -CO2H, -CO2R', -OCOR, -OCOR', -OC(=O)OR', -OC(=O)NR', ​​-OC(=S)OR', -OC(=S)NR', ​​-OR', -NR'R', or combinations thereof; each R' independently represents hydrogen or, where permitted by valence, an optionally substituted C1-C 10 Alkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, amino, hydroxy, halo, oxo, cyano, optionally substituted C-C 10 alkyl, or any combination thereof; R 1 and R 2 are each independently hydrogen, oxygen, C1-C 20Alkyl groups, optionally substituted linear or branched C1-C 20 Aminoalkyl groups, optionally substituted linear, branched or cyclic C1-C optionally containing one or more heteroatoms 20 Alkyl groups, substituted C1-C 20 Alkyl groups, C1-C 20 Haloalkyl groups, substituted C1-C 20 Haloalkyl groups, aliphatic linear or branched C3-C, optionally containing one or more heterocycles 20 aminoalkyl groups or R 1 and Y are interconnected to form an optionally substituted 4- to 8-membered ring, or R 1 and R 2 are interconnected to form an optionally substituted 4-8 membered ring, optionally containing one or more heteroatoms, or any combination thereof; R 3 is hydrogen, absent, or a methyl group, an isopropyl group, a C2-C 10 Alkyl groups, substituted C2-C 10 Alkyl groups, C1-C 10 Haloalkyl groups, substituted C1-C 10 Haloalkyl groups, C1-C 10 Alkylhydroxy group, halo group, C1-C 10 Alkoxy group, amino group, thioalkoxy group, thioalkyl group, hydroxy group, mercapto group, allyl group, C1-C 10 Ether group, vinyl group, cyano group, nitro group, C1-C 10 Alkylamino groups, C1-C 10 Alkylamido group, C3-C 10 Cycloalkyl groups, substituted C3-C 10 cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, bicyclic aromatic ring, unsaturated ring, bicyclic aliphatic ring, any combination thereof, or R 3 and A are interconnected to form an optionally substituted 4- to 8-membered ring; or R 3 and Y are interconnected to form an optionally substituted 4- to 8-membered ring; R4 is absent, hydrogen, or a methyl group, an isopropyl group, a C2-C 10 Alkyl groups, substituted C2-C 10 Alkyl groups, C1-C 10 Haloalkyl groups, substituted C1-C 10 Haloalkyl groups, C1-C 10 Alkylhydroxy group, halo group, C1-C 10 Alkoxy groups, C3-C 10 Cycloalkyl groups, substituted C3-C 10 cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, bicyclic aromatic ring, unsaturated aliphatic ring, bicyclic aliphatic ring, or a combination thereof, or R 3 and R 4 are interconnected to form an optionally substituted 4- to 8-membered ring.

[0008] According to some embodiments, R 1 and R 2 is oxygen, then Y is N.

[0009] According to some embodiments, the compound has formula IIa: [ka] Or formula IIb: [ka] (In the formula, R 5 and R 6 are each independently selected from the group consisting of hydrogen, methyl, isopropyl, C2-C 10 Alkyl groups, substituted C2-C 10 Alkyl groups, C1-C 10 Haloalkyl groups, substituted C1-C 10 Haloalkyl groups, C1-C 10 Alkylhydroxy group, halo group, C1-C 10Alkoxy group, amino group, hydroxy group, allyl group, C1-C 10 Ether group, vinyl group, C1-C 10 Alkylamino groups, C1-C 10 Alkylamido group, C3-C 10 Cycloalkyl groups, substituted C3-C 10 represents a cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, a bicyclic aromatic ring, an unsaturated aliphatic ring, a bicyclic aliphatic ring, or any combination thereof; n is an integer ranging from 0 to 5; R 7 and R 8 are each independently selected from the group consisting of hydrogen, methyl, isopropyl, C2-C 10 Alkyl groups, substituted C2-C 10 Alkyl groups, C1-C 10 Haloalkyl groups, substituted C1-C 10 Haloalkyl groups, C1-C 10 Alkylhydroxy group, halo group, C1-C 10 Alkoxy group, amino group, hydroxy group, allyl group, C1-C 10 Ether group, vinyl group, C1-C 10 Alkylamino groups, C1-C 10 Alkylamido group, C3-C 10 Cycloalkyl groups, substituted C3-C 10 cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, bicyclic aromatic ring, unsaturated aliphatic ring, bicyclic aliphatic ring, any combination thereof, or R 7 and R 8 are interconnected to form an optionally substituted 4- to 8-membered ring.

[0010] According to some embodiments, the compound has formula IIIa: [ka] Or formula IIIb: [ka] It is represented by:

[0011] According to some embodiments, the compound has the formula: [ka] (Wherein, A is a methyl group, an isopropyl group, a tert-butyl group, a linear or branched C1-C 10 Alkyl groups, optionally substituted C3-C containing one or more carbocyclic rings 10 Cycloalkyl groups, linear or branched C2-C 10 Alkyl groups, linear or branched, substituted C2-C 10 is selected from the group consisting of alkyl groups, R 1 and R 2 each independently represents hydrogen, an optionally substituted linear, branched or cyclic C-C 20 Alkyl groups; optionally substituted C1-C 20 Alkyl groups; optionally substituted linear or branched C5-C 20 Alkyl-aminoalkyl groups; containing one or more nitrogen atoms, C1-C 10 Alkyl groups, cyclic or acyclic C1-C 10 Alkylamino groups, and cyclic or acyclic C1-C 10 A linear, branched or cyclic C5-C alkyl group optionally substituted with one or more substituents independently selected from aminoalkyl groups. 20 or R 1 and R 2 is C1-C 10 Alkyl groups, cyclic or acyclic C1-C 10 Alkylamino groups, and cyclic or acyclic C1-C 10 R are interconnected to form one or more 4-8 membered rings optionally substituted with one or more substituents independently selected from aminoalkyl groups, or any combination thereof; 1 and R 2At least one of the branched or cyclic C1-C 20 Alkyl groups; optionally substituted linear or branched C5-C 20 Alkyl-aminoalkyl groups; containing one or more nitrogen atoms, C1-C 10 Alkyl groups, cyclic or acyclic C1-C 10 Alkylamino groups, and cyclic or acyclic C1-C 10 A linear, branched or cyclic C5-C alkyl group optionally substituted with one or more substituents independently selected from aminoalkyl groups. 20 The aminoalkyl group is represented by the formula:

[0012] According to some embodiments, the compound has formula IVa: [ka] Or formula IVb: [ka] (In the formula, R 9 and R 10 are each independently selected from the group consisting of hydrogen, methyl, isopropyl, C2-C 10 Alkyl groups, substituted C2-C 10 Alkyl groups, C1-C 10 Haloalkyl groups, substituted C1-C 10 Haloalkyl groups, C1-C 10 Alkylhydroxy group, halo group, C1-C 10 Alkoxy group, amino group, hydroxy group, allyl group, C1-C 10 Ether group, vinyl group, C1-C 10 Alkylamino groups, C1-C 10 Alkylamido group, C3-C 10 Cycloalkyl groups, substituted C3-C 10cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, bicyclic aromatic ring, unsaturated aliphatic ring, bicyclic aliphatic ring, any combination thereof, or R 9 and R 10 are interconnected to form one or more optionally substituted 4- to 8-membered rings; m is an integer ranging from 0 to 7; R 11 and R 12 are each independently selected from the group consisting of hydrogen, methyl, isopropyl, C2-C 10 Alkyl groups, substituted C2-C 10 Alkyl groups, C1-C 10 Haloalkyl groups, substituted C1-C 10 Haloalkyl groups, C1-C 10 Alkylhydroxy group, halo group, C1-C 10 Alkoxy group, amino group, hydroxy group, allyl group, C1-C 10 Ether group, vinyl group, C1-C 10 Alkylamino groups, C1-C 10 Alkylamido group, C3-C 10 Cycloalkyl groups, substituted C3-C 10 cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, bicyclic aromatic ring, unsaturated aliphatic ring, bicyclic aliphatic ring, any combination thereof, or R 11 and R 12 are interconnected to form an optionally substituted 4- to 8-membered ring.

[0013] According to some embodiments, the compound has the formula: [ka] , or the expression: [ka] wherein n is 1 to 3; each Y is independently CHR' 1or NR' 1 and R' 1 is absent or is one or more substituents, each of which optionally contains one or more nitrogen atoms, 20 Alkyl groups; optionally substituted C1-C 20 Alkyl groups; optionally substituted linear or branched C5-C 20 Alkyl-aminoalkyl groups; containing one or more nitrogen atoms, C1-C 10 Alkyl groups, cyclic or acyclic C1-C 10 Alkylamino groups, and cyclic or acyclic C1-C 10 A linear, branched or cyclic C5-C alkyl group optionally substituted with one or more substituents independently selected from aminoalkyl groups. 20 Aminoalkyl groups; halo, oxo, -NO2, amino, hydroxy, -CN, -OH, -CONH2, -CONR'2, -CNNR'2, -CSNR'2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR', ​​-NC(=S)OR', -NC(=S)NR', ​​-SOR', -SR', -SO2OR', -SON(R')2, -NHNR'2, -NNR', C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NR'R', -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1- represents a substituent independently selected from the group including C6 haloalkoxy, hydroxy(C1-C6 alkyl), hydroxy(C1-C6 alkoxy), alkoxy(C1-C6 alkyl), alkoxy(C1-C6 alkoxy), C1-C6 alkyl-NR'2, C1-C6 alkyl-SR', -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -CO2H, -CO2R', -OCOR, -OCOR', -OC(=O)OR', -OC(=O)NR', ​​-OC(=S)OR', -OC(=S)NR', ​​-OR', -NR'R', or combinations thereof; each R' independently represents hydrogen or an optionally substituted C1-C 10 Alkyl, optionally substituted C3-C 10Cycloalkyl, optionally substituted C3-C 10 Heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, amino, hydroxy, halo, oxo, cyano, optionally substituted C-C 10 alkyl, or combinations thereof.

[0014] According to some embodiments, A is tert-butyl.

[0015] According to some embodiments, the compound has the formula: [ka] It is represented by:

[0016] According to some embodiments, R' 1 is absent or is one or more substituents, optionally substituted cyclic C5-C6 aliphatic rings each containing one or more nitrogen atoms; optionally substituted linear, branched or cyclic C1-C 20 Alkyl group; containing one or more nitrogen atoms, C1-C 10 Alkyl groups, cyclic or acyclic C1-C 10 Alkylamino groups and cyclic or acyclic C1-C 10 A linear, branched or cyclic C5-C alkyl group optionally substituted with one or more substituents independently selected from aminoalkyl groups. 20 Aminoalkyl groups; represent substituents independently selected from the group including halo, oxo, -NO2, amino, hydroxy, -CN, -OH, -CONH2.

[0017] According to some embodiments, R' 1 is an optionally substituted cyclic C5-C6 aliphatic ring containing one or more nitrogen atoms, and the optionally substituted cyclic C5-C6 aliphatic ring is bonded via a nitrogen atom.

[0018] According to some embodiments, the compound is [ka] and [ka] is selected from the group consisting of:

[0019] According to some embodiments, the compound is selected from the group consisting of T1, T3 and T4, including any cis or trans isomers thereof. According to some embodiments, the compound is selected from the group consisting of T1, T3 and T4.

[0020] According to some embodiments, the compound is T3.

[0021] According to some embodiments, the compound is the Z isomer.

[0022] According to another aspect, there is provided a nanoparticle comprising a core and a shell, the shell comprising a lipid layer and the core comprising a compound of the invention.

[0023] According to some embodiments, the lipid layer comprises a phospholipid and a sterol.

[0024] According to some embodiments, the nanoparticles are in the form of liposomes or micelles.

[0025] According to some embodiments, the nanoparticles are characterized by a size between 50 nanometers (nm) and 500 nm.

[0026] According to some embodiments, the nanoparticles further comprise a peptide comprising an amino acid sequence selected from SEQ ID NOs: 1-13.

[0027] According to some embodiments, the nanoparticles comprise SEQ ID NO:9.

[0028] According to some embodiments, the peptide is conjugated to an 8-amino-3,6-dioxaoctanoic acid (Doa) residue.

[0029] According to some embodiments, the nanoparticles comprise a peptide multimer comprising a branched scaffold comprising at least four peptides comprising an amino acid sequence selected from SEQ ID NOs: 1-13.

[0030] According to some embodiments, the peptide is attached to the outside of the shell.

[0031] According to some embodiments, the peptide is covalently conjugated to the outside of the shell.

[0032] According to some embodiments, the peptide further comprises a C-terminal cysteine ​​residue conjugated to a maleimide in the shell by a thiol-maleimide reaction.

[0033] According to another aspect, there is provided a pharmaceutical composition comprising a compound of the invention or a nanoparticle of the invention and a pharma- ceutically acceptable carrier.

[0034] According to some embodiments, the pharmaceutical composition is for use in treating a neutrophil-associated disease or condition.

[0035] According to some embodiments, the pharmaceutical composition is for use in treating a disease or condition associated with accumulation of neutrophils in a diseased or damaged tissue or site.

[0036] According to some embodiments, the disease or condition is selected from the group consisting of cancer, an inflammatory disease or condition, and an inflammatory autoimmune disease or condition.

[0037] According to some embodiments, the disease or condition is an inflammatory disease or condition.

[0038] According to some embodiments, the inflammatory disease or condition is selected from chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (IBD), peritonitis, and an inflammatory skin disorder or disease.

[0039] According to some embodiments, the inflammatory disease or condition is IBD.

[0040] According to some embodiments, the disease or condition is cancer.

[0041] According to some embodiments, the cancer is selected from the group consisting of renal cancer, hepatocellular carcinoma (HCC), and head and neck squamous cell carcinoma (HNSCC).

[0042] According to some embodiments, the cancer is renal cancer. According to some embodiments, the renal cancer comprises renal cell carcinoma (RCC).

[0043] According to some embodiments, the composition is formulated for at least one of systemic administration, intravenous administration, subcutaneous administration, topical administration, rectal administration, oral administration, intratumoral administration, and local administration to a site of inflammation.

[0044] According to another aspect, there is provided a method of treating a neutrophil-associated disease or condition in a subject in need thereof, comprising administering a pharmaceutical composition of the invention to the subject.

[0045] According to some embodiments, the disease or condition is selected from the group consisting of cancer, an inflammatory disease or condition, and an inflammatory autoimmune disease or condition.

[0046] According to some embodiments, the disease or condition is an inflammatory disease or condition.

[0047] According to some embodiments, the inflammatory disease or condition is selected from COPD, IBD, and peritonitis.

[0048] According to some embodiments, the inflammatory disease or condition is IBD.

[0049] According to some embodiments, the disease or condition is cancer. According to some embodiments, the cancer is renal cancer.

[0050] According to some embodiments, the disease or condition is an inflammatory skin condition.

[0051] According to some embodiments, the administering comprises any one of systemic administration, intravenous administration, subcutaneous administration, topical administration, rectal administration, oral administration, intratumoral administration, and local administration to the site of inflammation.

[0052] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs.Although methods and materials similar or equivalent to those described herein can be used to carry out or test embodiments of this invention, exemplary methods and / or materials are described below.In case of conflict, the patent specification, including definitions, shall prevail.In addition, the materials, methods and examples are illustrative only and are not necessarily intended to be limiting.

[0053] Further embodiments and the full scope of applicability of the present invention will become apparent from the detailed description given hereinafter. It should be understood, however, that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. [Brief description of the drawings]

[0054] [Figure 1] 1 is an image of the chemical structures of compounds T1 to T7. [Figure 2A] 1 is a bar graph showing the effect of compounds T1, T3 and T4, both E and Z isomers, on the degranulation process of stimulated human neutrophils. [Figure 2B] 1 is a bar graph showing the effect of compounds T1, T3 and T4 in both E and Z isomers on the degranulation process of stimulated mouse neutrophils. Mean fluorescence intensity (MFI) of CD11b, a marker of degranulation, is provided. MFI levels are normalized to the fluorescence after PMA stimulation of the control. [Figure 3A] 1 is a bar graph showing the effect of compounds T1, T3 and T4, in both the E and Z isomers, on reactive oxygen species (ROS) production by stimulated human neutrophils. [Figure 3B] 1 is a bar graph showing the effect of compounds T1, T3 and T4, in both the E and Z isomers, on reactive oxygen species (ROS) production by stimulated mouse neutrophils. [Figure 4] FIG. 1 is a line graph showing the effect of T1 and T3 compounds on neutrophil NETosis induced by PMA. Steradin (Ste) is a previously identified neutrophil ROS inhibitor and is used as a positive control. [Diagram 5] 1 is a bar graph showing the in vivo effect of T3 on LPS-induced inflammation. Free compound T3, T3 incorporated into liposomes, and T3 incorporated into targeted liposomes (TENN-T3) were tested for their effect on surface neutrophil CD11b levels after LPS stimulation. MFI of CD11b staining was normalized to neutrophil CD11b levels after LPS stimulation. ***p<0.001. [Figure 6A] : Bar graph of colon length in DSS colitis model mice treated with T3 and empty targeted nanoparticles (TENNs) in various formulations. [Figure 6B] (Top) Luminescence photomicrographs showing ROS levels in colons from healthy control mice and DSS-treated colitic mice with and without TENN-T3 administration. White arrows point to positive luminescence signals. (Bottom) Bar graph quantification of luminescence. Luminescence in DSS-treated mice is increased compared to controls (no DSS treatment), whereas TENN-T3 reduces ROS levels. [Figure 6C]Fig. 1 is a bar graph of colon length in DSS colitis model mice treated with various concentrations of TENN-T3. Cyclosporine A (Cyclo) was used as a positive control. [Figure 7] Figure 1 is a line graph of tumor growth in RENCA-injected Balb / C mice. Two weeks after injection (day 0), when tumors reached 100 mm3, mice were treated with TENN-T3 as a positive control or anti-PD-L1 antibody. Tumor size was measured every other day (N=6 per group). On day 0, tumor size of each mouse was normalized to its original tumor size. Tumor growth rate is given as a percentage of the size on day 0. Thus, on day 0, all mice are plotted with 100% tumor size. [Figure 8A] 1 is an outline of a synthetic scheme for the production of compound T1. [Figure 8B] 1 is an outline of a synthetic scheme for the production of compound T1. [Figure 8C] 1 is an outline of a synthetic scheme for the production of compounds of formula IV. [Figure 9A] 1 is an overview of the synthetic mechanism for the production of compound T3. [Figure 9B] 1 is an outline of a synthetic scheme for the production of compounds of Formula IIa-IIIc. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0055] According to a first aspect, there is provided a compound represented by any one of formulas I-IVb described herein.

[0056] In another aspect, there is provided a compound represented by formula I as described herein. In another aspect, there is provided a compound represented by formula II as described herein. In another aspect, there is provided a compound represented by formula IIa as described herein. In another aspect, there is provided a compound represented by formula IIb as described herein. In another aspect, there is provided a compound represented by formula III as described herein. In another aspect, there is provided a compound represented by formula IIIa as described herein. In another aspect, there is provided a compound represented by formula IIIb as described herein. In another aspect, there is provided a compound represented by formula IIIc as described herein. In another aspect, there is provided a compound represented by formula IV as described herein. In another aspect, there is provided a compound represented by formula IVa as described herein. In another aspect, there is provided a compound represented by formula IVb as described herein. In another aspect, there is provided a compound as provided in FIG. 1.

[0057] Another aspect provides nanoparticles comprising a compound of the invention.

[0058] According to another aspect, there is provided a composition comprising a compound of the invention. According to another aspect, there is provided a composition comprising a nanoparticle of the invention.

[0059] Another aspect provides a method of treating, preventing, or ameliorating a disease or condition comprising administering a compound of the invention, thereby treating the disease or condition.

[0060] According to another aspect, there is provided a method of treating, preventing or ameliorating a disease or condition comprising administering a pharmaceutical composition of the invention, thereby treating the disease or condition.

[0061] Another aspect provides a compound or composition of the invention for use in the treatment, prevention, or amelioration of a disease or condition.

[0062] compound According to some embodiments, the present invention provides a compound, including any stereoisomer and / or any salt thereof, comprising the compound of formula I: [ka] or the expression: [ka] (Wherein, A is a methyl group, an isopropyl group, a tert-butyl group, a C2-C 10 Alkyl groups, substituted C2-C 10 Alkyl groups, C1-C 10 Haloalkyl groups, linear or branched C1-C 10 Alkyl groups, substituted or unsubstituted, linear or branched, C2-C 10 Alkyl groups, optionally substituted C3-C containing one or more carbocyclic rings 10 Cycloalkyl groups, optionally substituted C2-C containing one or more heteroatoms 10 Alkyl groups, substituted C1-C 10 Haloalkyl groups, C1-C 10 Alkylhydroxy group, halo group, C1-C 10 Alkoxy groups, C3-C 10 Cycloalkyl groups, substituted C3-C 10 represents a cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, bicyclic aromatic ring, unsaturated ring, aliphatic ring, aliphatic ring, or a combination thereof; n is an integer from 0 to 5; Y is absent or is N, NH, NR 1 , H.C.R. 1 , CH2, C(R 1 )2, CH, S, SH and O; X is hydrogen or a halo group, a methyl group, an isopropyl group, a C-C 10 Alkyl groups, substituted C2-C 10 represents a substituent selected from the group consisting of an alkyl group, an alkoxy group, an amino group, and a hydroxy group; each R independently represents none or one or more substituents, each independently being selected from the group consisting of a methyl group, an isopropyl group, a C2-C 10Alkyl groups, substituted C2-C 10 Alkyl group, halo, oxo, -NO2, amino, hydroxy, -CN, -OH, -CONH2, -CONR'2, -CNNR'2, -CSNR'2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR', ​​-NC(=S)OR', -NC(=S)NR', ​​-SOR', -SR', -SO2OR', -SON(R')2, -NHNR'2, -NNR', C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NR'R', -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1-C6 halo and any one of the following: alkoxy, hydroxy(C1-C6 alkyl), hydroxy(C1-C6 alkoxy), alkoxy(C1-C6 alkyl), alkoxy(C1-C6 alkoxy), C1-C6 alkyl-NR'2, C1-C6 alkyl-SR', -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -CO2H, -CO2R', -OCOR, -OCOR', -OC(=O)OR', -OC(=O)NR', ​​-OC(=S)OR', -OC(=S)NR', ​​-OR', -NR'R', or combinations thereof; each R' independently represents hydrogen or, where permitted by valence, an optionally substituted C1-C 10 Alkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, amino, hydroxy, halo, oxo, cyano, optionally substituted C-C 10 Aminoalkyl, optionally substituted C1-C 10 hydroxyalkyl, or any combination thereof; R 1 and R 2 are each independently hydrogen, oxygen, C1-C 20 Alkyl groups, optionally substituted linear or branched C1-C 20 Aminoalkyl groups, optionally substituted linear, branched or cyclic C1-C optionally containing one or more heteroatoms20 Alkyl groups, substituted C1-C 20 Alkyl groups, C1-C 20 Haloalkyl groups, substituted C1-C 20 Haloalkyl groups, aliphatic linear or branched C3-C, optionally containing one or more heterocycles 20 aminoalkyl groups or R 1 and Y are interconnected to form an optionally substituted 4- to 8-membered ring, or R 1 and R 2 are interconnected to form an optionally substituted 4- to 8-membered ring, optionally containing one or more heteroatoms, or any combination thereof; R 3 does not exist, is hydrogen, and is a methyl group, an isopropyl group, C2-C 10 Alkyl groups, substituted C2-C 10 Alkyl groups, C1-C 10 Haloalkyl groups, substituted C1-C 10 Haloalkyl groups, C1-C 10 Alkylhydroxy group, halo group, C1-C 10 Alkoxy group, amino group, thioalkoxy group, thioalkyl group, hydroxy group, mercapto group, allyl group, C1-C 10 Ether group, vinyl group, cyano group, nitro group, C1-C 10 Alkylamino groups, C1-C 10 Alkylamido group, C3-C 10 Cycloalkyl groups, substituted C3-C 10 represents cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, bicyclic aromatic ring, aliphatic unsaturated ring, bicyclic aliphatic ring, any combination thereof, or R 3 and Y are interconnected to form an optionally substituted 4- to 8-membered ring; or R 3 and A are interconnected to form an optionally substituted 4- to 8-membered ring; R 4 is absent, hydrogen, or a methyl group, an isopropyl group, a C2-C 10 Alkyl groups, substituted C2-C 10 Alkyl groups, C1-C 10 Haloalkyl groups, substituted C1-C10 Haloalkyl groups, C1-C 10 Alkylhydroxy group, halo group, C1-C 10 Alkoxy groups, C3-C 10 Cycloalkyl groups, substituted C3-C 10 cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, bicyclic aromatic ring, unsaturated aliphatic ring, bicyclic aliphatic ring, or a combination thereof, or R 3 and R 4 are interconnected to form an optionally substituted 4- to 8-membered ring.

[0063] In some embodiments, R 3 is hydrogen or a methyl group, an isopropyl group, a C2-C 10 Alkyl groups, substituted C2-C 10 Alkyl groups, C1-C 10 Haloalkyl groups, substituted C1-C 10 Haloalkyl groups, C1-C 10 Alkylhydroxy group, halo group, C1-C 10 Alkoxy group, amino group, thioalkoxy group, thioalkyl group, hydroxy group, mercapto group, allyl group, C1-C 10 Ether group, vinyl group, cyano group, nitro group, C1-C 10 Alkylamino groups, C1-C 10 Alkylamido group, C3-C 10 Cycloalkyl groups, substituted C3-C 10 In some embodiments, R represents a cycloalkyl, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, a bicyclic aromatic ring, an aliphatic unsaturated ring, a bicyclic aliphatic ring, or any combination thereof. 3 and A are interconnected to form an optionally substituted 4- to 8-membered ring.

[0064] In some embodiments, when Y is absent, R 3 and R 4 does not exist.

[0065] In some embodiments, R1 and R 2 is oxygen, then Y is N.

[0066] According to some embodiments, the present invention provides a compound represented by formula IIa or IIb (including any stereoisomers thereof). In some embodiments, the compound has formula IIa: [ka] Or formula IIb: [ka] (In the formula, R 5 and R 6 are each independently selected from the group consisting of hydrogen, methyl, isopropyl, C2-C 10 Alkyl groups, substituted C2-C 10 Alkyl groups, C1-C 10 Haloalkyl groups, substituted C1-C 10 Haloalkyl groups, C1-C 10 Alkylhydroxy group, halo group, C1-C 10 Alkoxy group, amino group, hydroxy group, allyl group, C1-C 10 Ether group, vinyl group, C1-C 10 Alkylamino groups, C1-C 10 Alkylamido group, C3-C 10 Cycloalkyl groups, substituted C3-C 10 represents a cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, bicyclic aromatic ring, unsaturated aliphatic ring, bicyclic aliphatic ring, or any combination thereof; n is an integer ranging from 0 to 5; R 7 and R 8 are each independently selected from the group consisting of hydrogen, methyl, isopropyl, C2-C 10 Alkyl groups, substituted C2-C 10 Alkyl groups, C1-C 10 Haloalkyl groups, substituted C1-C 10 Haloalkyl groups, C1-C10 Alkylhydroxy group, halo group, C1-C 10 Alkoxy group, amino group, hydroxy group, allyl group, C1-C 10 Ether group, vinyl group, C1-C 10 Alkylamino groups, C1-C 10 Alkylamido group, C3-C 10 Cycloalkyl groups, substituted C3-C 10 cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, bicyclic aromatic ring, unsaturated aliphatic ring, bicyclic aliphatic ring, any combination thereof, or R 7 and R 8 are interconnected to form an optionally substituted 4-8 membered ring. In some embodiments, n is an integer ranging from 0 to 4, 0 to 3, or 0 to 2. Each possibility represents a separate embodiment of the present invention. In some embodiments, n is 0, 1, 2, 3, 4, or 5. Each possibility represents a separate embodiment of the present invention.

[0067] According to some embodiments, the present invention provides a compound represented by formula IIIa or IIIb (including any stereoisomers thereof). In some embodiments, the compound has formula IIIa: [ka] Or formula IIIb: [ka] (In the formula, n, R 5 , R 6 and R 7 is as described herein above).

[0068] According to some embodiments, the present invention provides a compound represented by formula IIIc. In some embodiments, the compound has formula IIIc: [ka] (In the formula, R 13 is hydrogen or a methyl group, an isopropyl group, a C2-C 10 Alkyl groups, substituted C2-C 10 Alkyl groups, C1-C 10 Haloalkyl groups, substituted C1-C 10 Haloalkyl groups, C1-C 10 Alkylhydroxy group, halo group, C1-C 10 Alkoxy group, amino group, hydroxy group, allyl group, C1-C 10 Ether group, vinyl group, C1-C 10 Alkylamino groups, C1-C 10 Alkylamido group, C3-C 10 Cycloalkyl groups, substituted C3-C 10 R represents a cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, bicyclic aromatic ring, unsaturated aliphatic ring, bicyclic aliphatic ring, or any combination thereof; 6 is as described herein above).

[0069] According to some embodiments, the present invention provides a compound represented by formula IV, IVa, or IVb (including any stereoisomers thereof). According to some embodiments, the compound is represented by formula IV: [ka] (Wherein, A is a methyl group, an isopropyl group, a tert-butyl group, a linear or branched C1-C 10 Alkyl groups, optionally substituted C3-C containing one or more carbocyclic rings 10 Cycloalkyl groups, linear or branched C2-C 10 Alkyl groups, linear or branched, substituted C2-C 10 alkyl group, R 1 and R 2 each independently represents hydrogen, an optionally substituted linear, branched or cyclic C-C 20 Alkyl groups; optionally substituted C1-C20 Alkyl groups; optionally substituted linear or branched C5-C 20 Alkyl-aminoalkyl groups; containing one or more nitrogen atoms, C1-C 10 Alkyl groups, cyclic or acyclic C1-C 10 Alkylamino groups, and cyclic or acyclic C1-C 10 A linear, branched or cyclic C5-C alkyl group optionally substituted with one or more substituents independently selected from aminoalkyl groups. 20 or R 1 and R 2 is C1-C 10 Alkyl groups, cyclic or acyclic C1-C 10 Alkylamino groups, and cyclic or acyclic C1-C 10 R are interconnected to form one or more 4-8 membered rings optionally substituted with one or more substituents independently selected from aminoalkyl groups, or any combination thereof; 1 and R 2 At least one of the branched or cyclic C1-C 20 Alkyl groups; optionally substituted linear or branched C5-C 20 Alkyl-aminoalkyl groups; containing one or more nitrogen atoms, C1-C 10 Alkyl groups, cyclic or acyclic C1-C 10 Alkylamino groups, and cyclic or acyclic C1-C 10 A linear, branched or cyclic C5-C alkyl group optionally substituted with one or more substituents independently selected from aminoalkyl groups. 20 The aminoalkyl group is represented by the formula:

[0070] In some embodiments, the compound is represented by formula IV, wherein A represents a C2-C10 branched or linear alkyl, R is optionally absent, and R 1 and R 2 At least one of the C1-C 10 Alkyl groups, cyclic or acyclic C1-C 10Alkylamino groups, and cyclic or acyclic C1-C 10 A linear, branched or cyclic C5-C optionally substituted with one or more substituents independently selected from aminoalkyl groups. 20 In some embodiments, the compound is represented by formula IV, wherein A represents a C2-C10 branched or linear alkyl, R is optionally absent, and R 1 and R 2 at least one of which contains 1, 2 or 3 nitrogen atoms, C1-C 10 Alkyl groups, cyclic or acyclic C1-C 10 Alkylamino groups and cyclic or acyclic C1-C 10 C5-C optionally substituted with one or more substituents independently selected from aminoalkyl groups 20 In some embodiments, the compound is represented by formula IV, wherein A represents a C2-C10 branched or linear alkyl, R is optionally absent, and R 1 and R 2 At least one of the C5-C 20 Aminoalkyl groups, each ring containing 1, 2 or 3 nitrogen atoms, C1-C 10 Alkyl groups, cyclic or acyclic C1-C 10 Alkylamino groups and cyclic or acyclic C1-C 10 Optionally substituted with one or more substituents independently selected from aminoalkyl groups.

[0071] In some embodiments, the term "stereoisomer" encompasses cis and / or trans isomers of a compound.

[0072] In some embodiments, the compound has formula IVa: [ka] Or formula IVb: [ka] (In the formula: R 9 and R 10 are each independently selected from the group consisting of hydrogen, methyl, isopropyl, C2-C 10 Alkyl groups, substituted C2-C 10 Alkyl groups, C1-C 10 Haloalkyl groups, substituted C1-C 10 Haloalkyl groups, C1-C 10 Alkylhydroxy group, halo group, C1-C 10 Alkoxy group, amino group, hydroxy group, allyl group, C1-C 10 Ether group, vinyl group, C1-C 10 Alkylamino groups, C1-C 10 Alkylamido group, C3-C 10 Cycloalkyl groups, substituted C3-C 10 cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, bicyclic aromatic ring, unsaturated aliphatic ring, bicyclic aliphatic ring, any combination thereof, or R 9 and R 10 are interconnected to form an optionally substituted 4- to 8-membered ring; m is an integer ranging from 0 to 7; R 11 and R 12 are each independently selected from the group consisting of hydrogen, methyl, isopropyl, C2-C 10 Alkyl groups, substituted C2-C 10 Alkyl groups, C1-C 10 Haloalkyl groups, substituted C1-C 10 Haloalkyl groups, C1-C 10 Alkylhydroxy group, halo group, C1-C 10 Alkoxy group, amino group, hydroxy group, allyl group, C1-C 10 Ether group, vinyl group, C1-C 10 Alkylamino groups, C1-C 10 Alkylamido group, C3-C 10 Cycloalkyl groups, substituted C3-C 10cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, bicyclic aromatic ring, unsaturated aliphatic ring, bicyclic aliphatic ring, any combination thereof, or R 11 and R 12 are interconnected to form an optionally substituted 4-8 membered ring. In some embodiments, m is an integer ranging from 0 to 6, 0 to 5, 0 to 4, 0 to 3, or 0 to 2. Each possibility represents a separate embodiment of the present invention. In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, or 7. Each possibility represents a separate embodiment of the present invention.

[0073] In some embodiments, the compound has the formula: [ka] wherein A and R are as described herein, and R' 1 is absent or is one or more substituents, each of which optionally contains one or more nitrogen atoms, 20 Alkyl groups; optionally substituted C1-C 20 Alkyl groups; optionally substituted linear or branched C5-C 20 Alkyl-aminoalkyl groups; containing one or more nitrogen atoms, C1-C 10 Alkyl groups, cyclic or acyclic C1-C 10 Alkylamino groups, and cyclic or acyclic C1-C 10 A linear, branched or cyclic C5-C alkyl group optionally substituted with one or more substituents independently selected from aminoalkyl groups. 20Aminoalkyl groups; halo, oxo, -NO2, amino, hydroxy, -CN, -OH, -CONH2, -CONR'2, -CNNR'2, -CSNR'2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR', ​​-NC(=S)OR', -NC(=S)NR', ​​-SOR', -SR', -SO2OR', -SON(R')2, -NHNR'2, -NNR', C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NR'R', -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, C1- represents a substituent independently selected from the group including C6 haloalkoxy, hydroxy(C1-C6 alkyl), hydroxy(C1-C6 alkoxy), alkoxy(C1-C6 alkyl), alkoxy(C1-C6 alkoxy), C1-C6 alkyl-NR'2, C1-C6 alkyl-SR', -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -CO2H, -CO2R', -OCOR, -OCOR', -OC(=O)OR', -OC(=O)NR', ​​-OC(=S)OR', -OC(=S)NR', ​​-OR', -NR'R', or combinations thereof; each R' independently represents hydrogen or an optionally substituted C1-C 10 Alkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, amino, hydroxy, halo, oxo, cyano, optionally substituted C-C 10 alkyl, or combinations thereof.

[0074] In some embodiments, the compound has the formula: [ka] (wherein n is 1 to 3, and each Y is independently CHR' 1 or NR' 1 and R' 1In some embodiments, up to two Y's are represented by NR' 1 In some embodiments, each Y is CHR' 1 In some embodiments, A is tert-butyl.

[0075] In some embodiments, the compound has the formula: [ka] (Wherein, R and R' 1 In some embodiments, the compound is as described herein above, and R' 1 is an optionally substituted cyclic C5-C6 aliphatic ring which is absent or contains one or more nitrogen atoms; an optionally substituted linear, branched or cyclic C1-C 20 Alkyl group; containing one or more nitrogen atoms, C1-C 10 Alkyl groups, cyclic or acyclic C1-C 10 Alkylamino groups, and cyclic or acyclic C1-C 10 A linear, branched or cyclic C5-C alkyl group optionally substituted with one or more substituents independently selected from aminoalkyl groups. 20 an aminoalkyl group; one or more substituents each independently selected from the group including halo, oxo, -NO2, amino, hydroxy, -CN, -OH, -CONH2. In some embodiments, the compound is as described herein above, and R' 1 is an optionally substituted cyclic C5-C6 aliphatic ring containing one or more nitrogen atoms, said optionally substituted cyclic C5-C6 aliphatic ring being bonded via a nitrogen atom.

[0076] In some embodiments, the compound is [ka] and [ka] (including any stereoisomers thereof).

[0077] In some embodiments, the compound is [ka] It is.

[0078] In some embodiments, the compound is [ka] It is.

[0079] In some embodiments, the compound is [ka] (T7) It is.

[0080] In some embodiments, the compound is [ka] It is.

[0081] In some embodiments, the compound is [ka] It is.

[0082] In some embodiments, the compound is [ka] (T3) It is.

[0083] In some embodiments, the compound is [ka] It is.

[0084] In some embodiments, the compound is selected from T1, T2 and T4. In some embodiments, the compound is the Z (or cis) isomer of the compound. In some embodiments, the compound is the E (or trans) isomer of the compound. In some embodiments, the compound is the T1 Z isomer. In some embodiments, the compound is the T1 E isomer. In some embodiments, the compound is the T3 Z isomer. In some embodiments, the compound is the T3 E isomer. In some embodiments, the compound is the T4 Z isomer. In some embodiments, the compound is the T4 E isomer. It will be understood by those skilled in the art that the Z and E isomers refer to the carbon-carbon double bonds found outside the carbocyclic ring. Each of T1-T7 contains only one carbon-carbon double bond that is outside the carbocyclic ring.

[0085] Reference is now made to Figures 8A and 8B, which provide two different synthetic schemes for the production of compound T1. Both of these schemes can be used to produce compound T1 as a mixture of Z and E isomers, both of which can be separated by liquid chromatography (e.g., by using chiral liquid chromatography columns as are known in the art) to yield substantially pure Z or E isomers.

[0086] 8C provides a general synthetic scheme for the production of compounds of formula IV. Exemplary reaction conditions for each synthetic step are provided herein below. Step 1: 1 (1 equiv), 2 (1.05 equiv), K2CO3 (1.05 equiv), acetone, reflux, 18 h. Step 2: 4 (1 equivalent), 16 (1.5 equivalent), K2CO3 (2 equivalent), CuI (0.1 equivalent), DMSO, 80°C, 20 hours. Step 3 is performed as shown in FIG. 8B. Step 4: 14 (1 eq), Me2NH.HCl (2 eq), MeOH, reflux, 18 h Step 5: 15 (1 eq.), H2 (1 atm), PtO2 (10% w / w), HCl (12M / H2O, 18 eq.), MeOH, room temperature, 6 hours.

[0087] See also Figure 9A, which provides a synthetic scheme for the production of compound T3. Both Z and E isomers can be produced (at the INT-1 stage) and then separated by liquid chromatography (e.g., by using a chiral liquid chromatography column as known in the art) to provide a substantially pure Z or E isomer of INT-1. Each of the Z / E INT-1 can be further reacted according to the synthetic steps shown in Figure 9A to provide a substantially pure Z or E isomer of T3.

[0088] 9B provides a non-limiting general synthetic scheme for the production of compounds of Formulae IIa-IIIc. Exemplary reaction conditions for each synthetic step are provided herein below.

[0089] Steps 1 and 2 are carried out as described herein above.

[0090] Step 3.14 (1 eq), 4-bromo-1-methylpiperidine (1.1 eq), K2CO3 (2.6 eq), dioxane, 100 °C, 20 h.

[0091] Step 4: NaBr (0.11 equivalent), DMF, 150°C, 24 hours.

[0092] In some embodiments, the compound is an inhibitor of neutrophil function or activity. In some embodiments, the compound is a neutrophil exocytosis inhibitor. In some embodiments, the compound inhibits neutrophils. In some embodiments, inhibiting neutrophils comprises inhibiting neutrophil activation. In some embodiments, inhibiting neutrophils comprises inhibiting neutrophil degranulation. In some embodiments, inhibiting neutrophils comprises inhibiting neutrophil exocytosis. In some embodiments, inhibiting neutrophils comprises inhibiting reactive oxygen species (ROS) production. In some embodiments, ROS production is ROS secretion. In some embodiments, inhibiting neutrophils comprises inhibiting neutrophil-mediated killing. In some embodiments, inhibiting neutrophils comprises inhibiting neutrophil-mediated cytotoxicity. In some embodiments, inhibiting neutrophils comprises inhibiting protease secretion. In some embodiments, inhibiting neutrophils comprises inhibiting NET production. In some embodiments, inhibiting neutrophils does not inhibit NET production. In some embodiments, inhibiting neutrophils comprises inhibiting inflammation. In some embodiments, the compound inhibits the binding of RAB27a to SYTL1. Ras-related protein Rab-27a (RAB27a) is a small GTPase essential for neutrophil exocytosis. Synaptotagmin-like protein 1 (SYTL1), also known as JFC1, is a Rab27a effector that regulates trafficking, docking and exocytosis. In some embodiments, the compound is at least as effective as Nexinhib20. In some embodiments, the compound is superior to Nexinhib20. In some embodiments, the compound is at least as effective as trifluoperazine (Stelazine). In some embodiments, the compound is superior to trifluoropiperazine (Stelazine).

[0093] Nanoparticles According to some embodiments, the invention provides nanoparticles comprising a compound of the invention. In some embodiments, the nanoparticle comprises a core. In some embodiments, the nanoparticle comprises a shell. In some embodiments, the core faces the shell. In some embodiments, the shell is a lipid layer. In some embodiments, the core is aqueous. In some embodiments, the core is hydrophilic. In some embodiments, the shell comprises a lipid layer and the core comprises a compound as described herein above. In some embodiments, the lipid layer comprises a phospholipid. In some embodiments, the compound is in the shell. In some embodiments, the compound is in the core. In some embodiments, the compound is dissolved in the aqueous core. In some embodiments, the compound is dissolved in an aqueous solution and loaded into the nanoparticle. In some embodiments, the compound is dissolved in an aqueous solution and loaded into the core. In some embodiments, a portion of the compound is in the shell and a portion of the compound is in the core. In some embodiments, the hydrophobic portion of the compound is in the shell. In some embodiments, the hydrophobic portion is a hydrophobic portion. In some embodiments, the hydrophilic portion of the compound is in the core. In some embodiments, the hydrophilic portion is a hydrophilic portion.

[0094] In some embodiments, the compounds described herein are loaded onto nanoparticles. In some embodiments, the compounds described herein are carried by the nanoparticles (e.g., by interaction with a shell).

[0095] In some embodiments, the nanoparticles are submicron sized particles. In some embodiments, the nanoparticles are 50 nm to 500 nm, 70 nm to 500 nm, 80 nm to 500 nm, 100 nm to 500 nm, 50 nm to 200 nm, 70 nm to 200 nm, 80 nm to 200 nm, 100 nm to 200 nm, 50 nm to 150 nm, 70 nm to 150 nm, 80 nm to 150 nm, 100 nm to 150 nm, 50 nm to 100 nm, 7 The nanoparticles may be characterized by particle sizes of 0 nm to 100 nm, 80 nm to 100 nm, 80 nm to 130 nm, 90 nm to 150 nm, 90 nm to 120 nm, 100 nm to 130 nm, 130 nm to 150 nm, 150 nm to 200 nm, 200 nm to 300 nm, 80 nm to 300 nm, 50 nm to 300 nm, 50 nm to 80 nm, 80 nm to 150 nm, including any range therebetween. Each possibility represents a separate embodiment of the present invention. In some embodiments, the nanoparticles comprise an average size of about 100 nm. In some embodiments, the nanoparticles comprise an average size of 70 to 150 nm. In some embodiments, the nanoparticles comprise an average size of 100 to 150 nm. In some embodiments, the nanoparticles comprise an average size of 80 to 100 nm. The size of the nanoparticles can be determined by any method known in the art, such as dynamic light scattering (DLS) to determine the hydrodynamic diameter of the particle and transmission electron microscopy (TEM) to determine the exact geometric nanoparticle size.

[0096] According to some embodiments, the size of the nanoparticles is 50-1000, 100-1000, 200-1000, 250-1000, 300-1000, 500-1000, 600-1000, 700-1000, 50-900, 100-900, 200-900, 250-900, 300-900, 500-900, 600-1000, 700-1000, The nanoparticles may be in the range of 00-900, 700-900, 50-800, 100-800, 200-800, 250-800, 300-800, 500-800, 600-800, 700-800, 50-600, 100-600, 200-600, 250-600, 300-600, 500-600, or 50-200 nm. Each possibility represents a separate embodiment of the present invention. According to some embodiments, the nanoparticles are selected from nanospheres and nanorods. As used herein, the term "nanosphere" refers to nanoparticles having a spherical shape. The term "nanorod" refers to nanoparticles having a rod-like shape. According to some embodiments, the nanoparticles are liposomes. According to other embodiments, the nanoparticles are polymeric nanoparticles. According to further embodiments, the polymeric nanoparticles include poly(lactic-co-glycolic acid) (PLGA). According to further embodiments, the nanoparticles are metal nanoparticles. According to some embodiments, the nanoparticles are DSPE-PEG nanoparticles. According to some embodiments, the nanoparticles are DSPE-PEG-maleimide nanoparticles. According to some embodiments, the PEG is 3400. According to some embodiments, the PEG is 2000. According to some embodiments, the PEG is 5000. According to certain embodiments, the nanoparticles are fluorescently labeled. According to some embodiments, the nanoparticles are modified with PEG. According to some embodiments, the nanoparticles include a PLGA core. In some embodiments, the nanoparticles are coated with a reactive agent. In some embodiments, the reactive agent is suitable for conjugating a peptide, peptide multimer, or peptide complex to the nanoparticle. Reactive groups for conjugation are well known in the art, and examples of such are provided herein below. According to some embodiments, the reactive group is a binding group or a capture group.In some embodiments, the binding or capture group is for binding or capturing a peptide or a linker or spacer. In some embodiments, the reactive group is streptavidin (SA). In some embodiments, the SA is for binding a peptide / multimer / complex that contains biotin. In some embodiments, the reactive group is a thiol. In some embodiments, the thiol is for binding a peptide / multimer / complex that contains cysteine. In some embodiments, the cysteine ​​is a free cystine. In some embodiments, the cysteine ​​is in a linker. In some embodiments, the linkage is a maleimide linkage.

[0097] In some embodiments, the nanoparticles are characterized by a diameter of at least 50 nm, at least 60 nm, at least 70 nm, at least 80 nm, at least 90 nm, or at least 100 nm, including any value therebetween. Each possibility represents a separate embodiment. In some embodiments, the nanoparticles are characterized by a diameter of at most 130 nm, at most 150 nm, at most 170 nm, at most 180 nm, at most 200 nm, at most 250 nm, at most 300 nm, including any value therebetween. Each possibility represents a separate embodiment of the present invention.

[0098] In some embodiments, the lipid layer comprises a phospholipid and a sterol. In some embodiments, the sterol comprises cholesterol. In some embodiments, the phospholipid comprises a zwitterionic lipid, an anionic lipid, or a PEGylated lipid, including any combination thereof. In some embodiments, the nanoparticle is in the form of a liposome or a micelle. In some embodiments, the nanoparticle is a liposome. In some embodiments, the nanoparticle is a micelle.

[0099] In some embodiments, the lipid is or comprises one or more phospholipids. In some embodiments, the phospholipid is a liposome-forming lipid. As used herein, the term "liposome-forming lipid" encompasses phospholipids that self-assemble to form stable liposomes when dispersed or dissolved in aqueous solution at a temperature above the transition temperature (Tm). As used herein, the term Tm refers to the temperature at which the phospholipid undergoes a phase transition from a solid (ordered phase, also called gel phase) to a fluid (disordered phase, also called fluid crystalline phase). Tm also refers to the temperature (or temperature range) at which the maximum change in heat capacity occurs during the phase transition.

[0100] In some embodiments, the lipid layer and / or nanoparticles comprise 45-70, 45-65, 45-60, 45-55, 45-50, 50-70, 50-65, 50-60, 50-55, 55-70, 55-65, 55-60, 60-70, 60-65, or 65-70 mole percent of phospholipids. Each possibility represents a separate embodiment of the present invention. In some embodiments, the lipid layer comprises 50-65 mole percent of phospholipids. In some embodiments, the lipid layer comprises 50-65 mole percent of phospholipids.

[0101] In some embodiments, the nanoparticles encapsulate the compound. In some embodiments, the nanoparticles comprise a hydrophilic core and the compound is in the core. In some embodiments, the nanoparticles comprise a hydrophobic core and the compound is in the core. In some embodiments, the compound is associated with the surface of the nanoparticle. In some embodiments, the compound is linked or conjugated to the surface of the nanoparticle by a side chain of the compound. In some embodiments, the compound is embedded in the shell of the nanoparticle by a side chain of the compound.

[0102] According to some embodiments, the present invention provides a composition comprising a plurality of nanoparticles as described herein above.

[0103] In some embodiments, the nanoparticles of the present invention are characterized by a polydispersity index of less than 0.6, less than 0.5, less than 0.3, less than 0.2, or less than 0.1, including any value therebetween. Each possibility represents a separate embodiment of the present invention. In some embodiments, the nanoparticles of the present invention are characterized by a polydispersity index of less than 0.1.

[0104] In some embodiments, the nanoparticles of the invention are characterized by a polydispersity index of 0.001-0.3, 0.001-0.2, 0.001-0.1, 0.005-0.3, 0.005-0.2, 0.005-0.1, 0.01-0.3, 0.01-0.2, 0.01-0.1, 0.05-0.3, 0.05-0.2, or 0.05-0.1, including any value and range therebetween, with each possibility representing a separate embodiment of the present invention. In some embodiments, the nanoparticles of the invention are characterized by a median size as described herein above and further characterized by a polydispersity index of 0.001-0.3, 0.001-0.2, 0.001-0.1, 0.005-0.3, 0.005-0.2, 0.005-0.1, 0.01-0.3, 0.01-0.2, 0.01-0.1, 0.05-0.3, 0.05-0.2, or 0.05-0.1, including any values ​​and ranges therebetween, with each possibility representing a separate embodiment of the present invention.

[0105] In some embodiments, at least 80%, at least 85%, at least 90%, at least 95%, at least 97% by weight of the nanoparticles of the invention are characterized by a particle size in the range of 50 nm to 500 nm, 50 nm to 300 nm, 50 nm to 200 nm, 80 nm to 200 nm, 80 nm to 100 nm, 80 nm to 150 nm, 80 nm to 130 nm, 100 nm to 150 nm, 150 nm to 200 nm, 200 nm to 250 nm, 250 nm to 300 nm, including any value and range therebetween, with each possibility representing a separate embodiment of the present invention.

[0106] The terms "particle size" and "particle size" are used interchangeably herein and refer to the average cross-sectional size of nanoparticles (e.g., the maximum linear distance between two points on the surface of a nanoparticle) within a liquid composition. In some embodiments, the term "average cross-sectional size" may refer to, for example, either the average of at least 70%, 80%, 90% or 95% of the particles, or, in some embodiments, the median size of a plurality of nanoparticles. In some embodiments, the term "average cross-sectional size" may refer to the number average of a plurality of nanoparticles. In some embodiments, the term "average cross-sectional size" may refer to the average diameter of substantially spherical nanoparticles.

[0107] In some embodiments, the nanoparticles of the present invention are or include lipid-based particles. In some embodiments, the nanoparticles of the present invention are or include liposomes. In some embodiments, liposomes refer to vesicles with an inner core surrounded by a lipid bilayer and are widely used as drug carriers. This is largely due to their unique characteristics, such as good biocompatibility, low toxicity, lack of immune system activation and the ability to incorporate both hydrophobic and hydrophilic compounds. As described herein, liposomes are known in the art as artificial vesicles typically, but not exclusively, composed of a substantially spherical lipid bilayer containing phospholipids, sterols, such as cholesterol, and other lipids.

[0108] In some embodiments, "vesicle" and "carrier" are synonymous and refer to a particle (e.g., a nanoparticle of the present invention) that includes a core and a shell that encapsulates or encloses the core. In some embodiments, the nanoparticle of the present invention includes a core and a shell that encapsulates or encloses the core. In some embodiments, the core is a hollow core or a core filled with a solid or liquid material. In some embodiments, the nanoparticle of the present invention can have a spherical shape or any other geometric shape. In some embodiments, the nanoparticle of the present invention includes a monolayer or multilayer membrane (or lipid layer). In some embodiments, the nanoparticle of the present invention includes one or more different types of nanoparticles. In some embodiments, "different types" is meant to refer to liposomes that encapsulate different active agents (e.g., compounds of the present invention). In some embodiments, "different types" is meant to refer to liposomes of different structures and configurations.

[0109] In some embodiments, the liposomes disclosed herein can be any one or combination of vesicles selected from the group consisting of small unilamellar vesicles (SUVs), large unilamellar vesicles (LUVs), multilamellar vesicles (MLVs), multivesicular vesicles (MVVs), large multivesicular vesicles (LMVs (giant multivesicular vesicles, sometimes referred to by the term "GMVs"), oligolamellar vesicles (OLVs), and the like. In some embodiments, the liposomes are large unilamellar vesicles (LUVs). Methods for preparing and characterizing pharmaceutical liposomal compositions are known in the art (see, for example, Lasic D. Liposomes: From physics to applications, Elsevier, Amsterdam 1993; G. Greoriadis (Ed.), Liposome Technology, 3rd ed., vol. 1-3, CRC Press, Boca Raton, 2006; Hong et al., J. Immunol. 1999, 144:1111-1115, 1999). (see, al., U.S. Patent No. 8,147,867, which is incorporated by reference in its entirety for all purposes).

[0110] In some embodiments, liposomes are characterized by the right packing parameters. As used herein and in the art, "packing parameters" are a relative measure of a given lipid composition, and depend on factors such as the size relationship between lipid head groups and lipid hydrocarbon chains, loading and the presence of stabilizers such as cholesterol. It should also be noted that packing parameters do not have to be constant. In some embodiments, the parameters depend on various conditions that affect the volume of the hydrophobic chains, the cross-sectional area of ​​the hydrophilic head groups and the length of the hydrophobic chains, respectively. Factors that may affect these include, but are not limited to, the properties of the solvent, the temperature of the solvent and the ionic strength of the solvent.

[0111] In some embodiments, suitable packing parameters are in the range of 0.3 to 1, for example, 0.3, 0.5, 0.7, 0.9, or 1, including any values ​​and ranges therebetween.

[0112] The term "core" as used herein refers to the central portion of a particle having a different composition than the shell. In some embodiments, the core is encapsulated by the shell. In some embodiments, the core is bound to the inner portion of the shell. In some embodiments, the core comprises a compound as described herein above encapsulated by the shell.

[0113] In some embodiments, the core is a liquid. In some embodiments, the core comprises an aqueous solution. In some embodiments, the core comprises an aqueous solution of a compound as described herein. In some embodiments, the core comprises a compound as described herein substantially located therein.

[0114] In some embodiments, there is a composition comprising a plurality of nanoparticles of the invention, the nanoparticles being the same or different. In some embodiments, "different nanoparticles" is meant to refer to particles that encapsulate different active agents (e.g., compounds of the invention).

[0115] In some embodiments, the shell is or comprises a lipid layer. In some embodiments, the shell is in the form of a membrane. In some embodiments, the shell comprises one or more lipid layers. In some embodiments, the shell comprises a lipid bilayer. As used herein, the term "shell" refers to the outer portion of a particle that has a different composition than the core.

[0116] In some embodiments, the lipid layer comprises a phospholipid. In some embodiments, the phospholipid comprises a single phospholipid species or multiple chemically distinct phospholipids. In some embodiments, the phospholipid is or comprises a liposome-forming lipid, the liposome-forming lipid being as described herein above.

[0117] In some embodiments, at least one of the liposome-forming lipids is a phospholipid having one or two C14-C24 hydrocarbon tails, typically acyl, alkyl or alkenyl chains, with varying degrees of unsaturation, ranging from lipids that are fully saturated to lipids that are fully, partially or non-hydrogenated (thus the level of saturation can affect the stiffness of the formed liposomes (typically liposomes formed from lipids with saturated chains are more rigid than liposomes formed from lipids of the same chain length, particularly where unsaturated chains with cis double bonds are present). In some embodiments, at least one of the liposome-forming lipids is a phospholipid having one or two C14-C20, C16-C20 or C16-C18 hydrocarbon tails, including any values ​​and ranges therebetween. Each possibility represents a separate embodiment of the present invention. In some embodiments, at least one of the liposome-forming lipids is fully saturated.

[0118] Additionally, the lipid membranes may be of natural origin (eg, naturally occurring phospholipids), semi-synthetic or fully synthetic lipids, and may be electrically neutral, negatively charged or positively charged.

[0119] In some embodiments, the primary liposome-forming phospholipids are characterized by a Tm of greater than about 40° C., greater than about 45° C., greater than about 50° C., greater than about 52° C., including any range therebetween.

[0120] In some embodiments, the liposome forming phospholipids comprise one or more saturated and / or unsaturated hydrocarbon tails. In some embodiments, each hydrocarbon tail independently comprises 14-24, 16-24, 17-24, 17-20, 14-17, 20-24, 18-20 carbon atoms, including any range therebetween. In some embodiments, the hydrocarbon tails of the lipids have the same or different chemical compositions.

[0121] In some embodiments, the phospholipid is hydrogenated soy phosphatidylcholine (HSPC), 1,2-distearoyl-sn-glycero-3-phosphorylethanolamine (DSPE), distearoylphosphatidylcholine (DSPC) or egg sphingomyelin (ESM). In some embodiments, the phospholipid is HSPC. In some embodiments, the phospholipid is DSPC. In some embodiments, the phospholipid is a combination of HSPC and DSPC. The term "phospholipid" as used herein refers to any one or combination of phospholipids capable of forming liposomes. Neutral phospholipids may include diacylphosphatidylcholine, dialkylphosphatidylcholine, sphingomyelin, and diacylphosphatidylethanolamine. Phosphatidylcholines (PC), including those obtained from egg, soybean, or other plant sources, or those partially or fully synthetic, or those of variable lipid chain length and unsaturation, are suitable for use in the compositions of the present invention. Synthetic, semi-synthetic and natural product phosphatidylcholines, including but not limited to distearoylphosphatidylcholine (DSPC), DSPE, hydrogenated soy phosphatidylcholine (HSPC), soy phosphatidylcholine (soy PC), egg phosphatidylcholine (egg PC), hydrogenated egg phosphatidylcholine (HEPC), and dipalmitoylphosphatidylcholine (DPPC), are suitable phosphatidylcholines for use in preparing liposomes. Charged phospholipids can include phosphatidylglycerol, cardiolipin, or head group modified lipids such as N-succinyl-phosphatidylethanolamine, N-glutaryl-phosphatidylethanolamine, and PEG-derivatized phosphatidylethanolamine.

[0122] In some embodiments, the lipid layer comprises one or more sterols.Non-limiting examples of sterols include, but are not limited to, β-sitosterol, β-sitostanol, stigmasterol, stigmatanol, campesterol, campestanol, ergosterol, avenasterol, brassicasterol, fucosterol, cholesterol (CHOL), cholesteryl hemisuccinate and cholesteryl sulfate, or any combination thereof.

[0123] In some embodiments, the sterol is a plant-derived sterol, i.e., a plant sterol. According to this embodiment, the sterol is selected from the group consisting of β-sitosterol, β-sitostanol, stigmasterol, stigmastanol, campesterol, campestanol, ergosterol, avenasterol, brassicasterol, and any combination thereof.

[0124] In some embodiments, the lipid layer and / or nanoparticles are 30-55, 33-55, 35-55, 37-55, 40-55, 43-55, 45-55, 47-55, 50-55, 53-55, 30-53, 33-53, 35-53, 37-53, 40-53, 43-53, 45-53, 47-53, 50-53, 30-50, 33-50, 35-50, 37-50, 40-50, 43-50, 45-50, 47-53, 50, 30-47, 33-47, 35-47, 37-47, 40-47, 43-47, 45-47, 30-45, 33-45, 35-45, 37-45, 40-45, 43-45, 30-43, 33-43, 35-43, 37-43, 40-43, 30-40, 33-40, 35-40, 37-40, 30-37, 33-37, 35-37, 30-35, 33-35, or 30-33 mole percent of sterol. Each possibility represents a separate embodiment of the present invention. In some embodiments, the lipid layer comprises 33-50 mole percent of sterol. In some embodiments, the nanoparticle comprises 33-50 mole percent of sterol.

[0125] In some embodiments, the liposomes comprise polymer-conjugated lipids that can be used in liposome formulations to increase circulation longevity by decreasing liposome clearance by the liver and spleen, or to improve liposome stability against aggregation during storage. The polymer-conjugated lipid may comprise a poly(ethylene glycol)-conjugated (PEGylated) phospholipid (PEG-lipid), such as PEG(mol wt 2,000) methoxy-poly(ethylene glycol)-1,2-distearoyl-sn-glycerol (PEG(2000)-distearoylglycerol, PEG-DSG), PEG(mol wt 2,000) 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (PEG(mol wt 2,000)-distearoylphosphatidylethanolamine, PEG-DSPE or DSPE-PEG), or PEG(mol wt 2,000) N-palmitoyl-sphingosine-1-{succinyl[methoxy(polyethylene glycol)-2000]} (PEG-ceramide). The molecular weight of the PEG moiety in the PEG-lipid component can also vary from 1,500 to 5,500 g / mol, but is preferably about 2,000 MW. In some embodiments, the PEG is PEG3400. In some embodiments, the PEG comprises a MW of about 5000. Other polymers used for conjugation to lipid anchors can include poly(2-methyl-2-oxazoline) (PMOZ), poly(2-ethyl-2-oxazoline) (PEOZ), polyamide oligomers, polysarcosine, poly-N-vinylpyrrolidone (PVP), polyglycerol, poly(hydroxyethyl L-asparagine) (PHEA), and poly(hydroxyethyl L-glutamine) (PHEG).

[0126] In some embodiments, the nanoparticles of the invention encapsulate an effective amount (e.g., a therapeutically effective amount) of a compound as described herein above. In some embodiments, the nanoparticles of the invention are characterized by a loading of a compound of the invention (also referred to herein as an active compound or active agent) sufficient to be utilized in the treatment or prevention of a disease.

[0127] In some embodiments, the process for producing liposomes containing compounds therein includes the steps of (a) preparing liposomes containing a trapping agent composed of an ammonium or substituted ammonium salt of a polyanion, (b) subsequently removing the trapping agent from the exterior of the liposome to form an electrochemical gradient across the lipid membrane, and (c) adding the active compound desired to be encapsulated under conditions effective for the compound to enter the liposome and be stabilized as the corresponding salt with the remaining intraliposomal polyanion. A liposome composition containing a trapping agent in the interior of the liposome can be made by forming the liposome in a solution of the trapping agent. A transmembrane concentration gradient of the trapping agent can be formed throughout the liposome by removal of the trapping agent outside the liposome or dilution of the liposome either after liposome formation or prior to drug loading (trapping).

[0128] In some embodiments, the salt form inside the liposome is a polyanion, such as citrate, sulfate, sucroceoctasulfate, dextran sulfate, suramin, polyphosphate, or inositol hexaphosphate. In some embodiments, the intraliposomal salt of the drug precipitates or gels to improve retention of the drug upon administration.

[0129] In some embodiments, the compositions of the invention comprise an effective amount (e.g., a therapeutically effective amount) of a compound described herein. In some embodiments, the compositions of the invention are pharmaceutical compositions that comprise a therapeutically effective amount of a compound described herein.

[0130] As used herein, "therapeutically effective amount" or "effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result. The therapeutically effective amount of a therapeutic agent depends on the nature of the disorder or condition and the specific agent, and can be determined by standard clinical techniques known to those skilled in the art. As used herein, the term "therapeutically active agent" refers to a chemical entity that exhibits therapeutic activity when administered to a subject.

[0131] In some embodiments, the nanoparticles (eg, liposomes) of the present invention are composed of pharma- ceutically acceptable components (such as phospholipids and / or sterols) or pharma- ceutically acceptable salts thereof.

[0132] The present invention is based, at least in part, on the surprising discovery that the compounds of the present invention can be easily loaded into nanoparticles, particularly lipid-based nanoparticles (i.e., liposomes).The unique structure of the compounds of the present invention allows for effective loading into nanoparticles, so that therapeutically effective doses of the compounds can be easily loaded.These compounds are more useful and superior to other similar compounds known in the art in that they can be efficiently and highly loaded into nanoparticles (i.e., liposomes).

[0133] In some embodiments, the nanoparticle further comprises a peptide that binds to neutrophils. In some embodiments, the peptide is a neutrophil targeting peptide. In some embodiments, the peptide is bound or linked to the surface of the nanoparticle. In some embodiments, the peptide is bound or linked to the shell of the nanoparticle. In some embodiments, the peptide is bound or linked to the exterior of the nanoparticle. In some embodiments, the link is covalent. In some embodiments, the exterior is the side that does not face the core. In some embodiments, the peptide is bound to the nanoparticle. In some embodiments, the peptide is bound to the nanoparticle and is free to interact with neutrophils outside the nanoparticle.

[0134] In some embodiments, the peptide is conjugated to an activated PEG lipid, such as maleimide-terminated PEG-distearoylphosphatidylethanolamine (DSPE). The PEG linker is 1,500-5,000 MW and 1,900-3,600. Preferably, the PEG linker is larger (e.g., 3,400 MW) than the PEG (e.g., 2,000 MW) used to prevent aggregation or to extend circulation lifetime. In some embodiments, the nanoparticle comprises DSPE-PEG. In some embodiments, the lipid layer comprises DSPE-PEG. In some embodiments, the activated PEG lipid is DSPE-PEG. In some embodiments, the DSPE-PEG comprises a maleimide moiety.

[0135] In some embodiments, the lipid layer and / or nanoparticles comprise 1-10, 2-10, 3-10, 4-10, 5-10, 6-10, 7-10, 8-10, 9-10, 1-9, 2-9, 3-9, 4-9, 5-9, 6-9, 7-9, 8-9, 1-8, 2-8, 3-8, 4-8, 5-8, 6-8, 7-8, 1-7, 2-7, 3-7, 4-7, 5-7, 6-7, 1-6, 2-6, 3-6, 4-6, 5-6, 1-5, 2-5, 3-5, 4-5, 1-4, 2-4, 3-4, 1-3, 2-3, or 1-2 mole percent of activated PEG lipids. Each possibility represents a separate embodiment of the invention. In some embodiments, the lipid layer comprises 2-5 mole percent of activated PEG lipids. In some embodiments, the nanoparticles comprise between 2 and 5 mole percentage of activated PEG lipids.

[0136] The term "neutrophil" as used herein refers to the most abundant type of white blood cell in mammals, which forms an important part of the innate immune system. Neutrophils form part of the family of polymorphonuclear cells (PMN), with basophils and eosinophils. Neutrophils are normally found in the bloodstream. During the initiation (acute) phase of inflammation, especially as a result of bacterial infection and certain forms of cancer, neutrophils are among the first immune cells to migrate toward the site of inflammation / tumor. They migrate through the blood vessels and then through the interstitial tissue, following chemical signals such as interleukin-8 (IL-8) and C5a. The term "neutrophil" as used herein encompasses all types of neutrophils, whether mature, immature, high density or low density, including but not limited to high density neutrophils-HDN and low density neutrophils (LDN).

[0137] The term "peptide" refers to a short chain of amino acid residues linked by peptide bonds, i.e., covalent bonds formed between the carboxyl group of one amino acid and the amino group of an adjacent amino acid. The term "peptide" refers to short sequences having up to 50 amino acids. A chain of amino acid monomers longer than 50 amino acids is called a "polypeptide". Such polypeptides can also be classified as proteins, more specifically low or medium molecular weight proteins, if they have more than 50 amino acid residues.

[0138] The term "peptide" also encompasses the term "peptide analog". The terms "peptide analog" and "analog" are used interchangeably herein and refer to an analog of a peptide having at least 80% identity with the original peptide, where the analog retains the activity of the original peptide. Thus, the terms "analog" and "active analog" may be used interchangeably. The term "analog" refers to a peptide that contains substitutions, rearrangements, deletions, additions and / or chemical modifications to the amino acid sequence of the parent peptide. According to some embodiments, a peptide analog has at least 80%, at least 90% or at least 95% sequence identity with the original peptide. In one embodiment, an analog has about 70% to about 95%, about 80% to about 90% or about 85% to about 95% sequence identity with the original peptide. According to some embodiments, an analog of the present invention comprises the sequence of the original peptide with one or two deletions, additions and / or substitutions.

[0139] The term "peptide" also encompasses the term "peptide fragment." The term "fragment" refers to a fragment of the original peptide or an analog thereof in which one or two amino acid residues have been deleted, and which fragment retains the activity of the original peptide or analog. Thus, the terms "fragment" and "active fragment" may be used interchangeably.

[0140] The amino acid substitutions may be conservative or non-conservative. Non-conservative substitutions include the replacement of one amino acid with any other amino acid. In a particular embodiment, the amino acid is replaced with a non-natural amino acid.

[0141] The term "analog" also encompasses the term "conservative analog". Conservative substitutions of amino acids known to those skilled in the art are within the scope of the present invention. Conservative amino acid substitutions include replacing an amino acid with another amino acid having the same type of functional group or side chain, e.g., aliphatic, aromatic, positively charged, negatively charged. Those skilled in the art will recognize that each substitution is a "conservatively modified analog", where the modification replaces an amino acid with a chemically similar amino acid. Conservative substitution tables providing functionally similar amino acids are well known in the art. One typical example of a conservative substitution is provided below.

[0142] Each of the following six groups contains amino acids that are conservative substitutions for one another: (1) alanine (A), serine (S), threonine (T), (2) aspartic acid (D), glutamic acid (E), (3) asparagine (N), glutamine (Q), (4) arginine (R), lysine (K), (5) isoleucine (I), leucine (L), methionine (M), valine (V), and (6) phenylalanine (F), tyrosine (Y), tryptophan (W). In other embodiments, conservative substitutions include substitutions with chemically similar unnatural amino acids.

[0143] Thus, in some embodiments, the analog is a conservative analog of peptide.According to some embodiments, the conservative analog of the present invention comprises the sequence of the original peptide with one or two conservative substitutions.According to another embodiment, the analog consists of the amino acid sequence of the original peptide with one or two conservative substitutions.Thus, the analog consists of the amino acid sequence of the original peptide with one or two conservative substitutions.

[0144] The term "amino acid" as used herein refers to an organic compound containing both amine and carboxylic acid functional groups, which may be either natural or unnatural amino acids. The 22 natural amino acids are aspartic acid (Asp), tyrosine (Tyr), leucine (Leu), tryptophan (Trp), arginine (Arg), valine (Val), glutamic acid (Glu), methionine (Met), phenylalanine (Phe), serine (Ser), alanine (Ala), glutamine (Gln), glycine (Gly), proline (Pro), threonine (Thr), asparagine (Asn), lysine (Lys), histidine (His), isoleucine (Ile), cysteine ​​(Cys), selenocysteine ​​(Sec), and pyrrolysine (Pyl). Non-limiting examples of unnatural amino acids include diaminopropionic acid (Dap), diaminobutyric acid (Dab), ornithine (Orn), aminoadipic acid, β-alanine, 1-naphthylalanine, 3-(1-naphthyl)alanine, 3-(2-naphthyl)alanine, γ-aminobutyric acid (GABA), 3-(aminomethyl)benzoic acid, p-ethynyl-phenylalanine, p-propargyl-oxy-phenylalanine, m-ethynyl-phenylalanine, p-bromophenylalanine, p-iodophenylalanine. , p-azidophenylalanine, p-acetylphenylalanine, azidonorleucine, 6-ethynyl-tryptophan, 5-ethynyl-tryptophan, 3-(6-chloroindolyl)alanine, 3-(6-bromoindolyl)alanine, 3-(5-bromoindolyl)alanine, azidohomoalanine, p-chlorophenylalanine, α-aminocaprylic acid, O-methyl-L-tyrosine, N-acetylgalactosamine-α-threonine, and N-acetylgalactosamine-α-serine. According to one embodiment, the substitution is with a non-natural amino acid.

[0145] In some embodiments, the peptide comprises an amino acid sequence selected from the group consisting of KFPDLDSRRLPHMSL (SEQ ID NO: 1), LATTHMVFSPDH (SEQ ID NO: 2), PSSNLESTPLSLL (SEQ ID NO: 3), SSLMTTQLIATSI (SEQ ID NO: 4), PELDSKPYFPPL (SEQ ID NO: 5), ELVTASMPRPNN (SEQ ID NO: 6), SLESSPMAQLPQ (SEQ ID NO: 7), SELRSTPLLVPS (SEQ ID NO: 8), LQIQSWSSSP (SEQ ID NO: 9), STMTILGTGS (SEQ ID NO: 10), TETSLRIVSTNP (SEQ ID NO: 11), LSIVSGSALNHL (SEQ ID NO: 12) and LTLVSERPMI (SEQ ID NO: 13), or a salt thereof. In some embodiments, the peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-13. In some embodiments, the peptide consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-13. In some embodiments, the peptide comprises or consists of SEQ ID NO: 1. In some embodiments, the peptide comprises or consists of SEQ ID NO: 2. In some embodiments, the peptide comprises or consists of SEQ ID NO:3. In some embodiments, the peptide comprises or consists of SEQ ID NO:4. In some embodiments, the peptide comprises or consists of SEQ ID NO:5. In some embodiments, the peptide comprises or consists of SEQ ID NO:6. In some embodiments, the peptide comprises or consists of SEQ ID NO:7. In some embodiments, the peptide comprises or consists of SEQ ID NO:8. In some embodiments, the peptide comprises or consists of SEQ ID NO:9. In some embodiments, the peptide comprises or consists of SEQ ID NO:10. In some embodiments, the peptide comprises or consists of SEQ ID NO:11. In some embodiments, the peptide comprises or consists of SEQ ID NO:12. In some embodiments, the peptide comprises or consists of SEQ ID NO:13. In some embodiments, the peptide comprises or consists of an amino acid sequence selected from SEQ ID NOs:1-8 and binds to human neutrophils.In some embodiments, the peptide comprises or consists of an amino acid sequence selected from SEQ ID NOs: 9-13 and binds to mouse neutrophils.

[0146] As used herein, the term "salt" refers to both salts of carboxyl groups and acid addition salts of amino or guanidino groups of peptide molecules. Salts of carboxyl groups can be formed by means known in the art, and include inorganic salts, such as sodium, calcium, ammonium, iron or zinc salts, and salts with organic bases, such as salts formed with amines, such as triethanolamine, piperidine, procaine, etc. For example, acid addition salts include salts with mineral acids, such as acetic acid or oxalic acid. Salts herein also describe ionic components added to peptide solutions to promote hydrogel formation and / or mineralization of calcium minerals.

[0147] The peptides, analogs and salts of the present invention can be produced by any method known in the art, including recombinant methods and synthetic methods.Synthetic methods include exclusive solid-phase synthesis, partial solid-phase synthesis, fragment condensation, or classical solution synthesis.Solid-phase peptide synthesis procedures are well known to those skilled in the art.Synthetic methods for producing peptides include, but are not limited to, FMOC solid-phase peptide synthesis, as described, for example, in Fields GB, Noble R., Int.J.Pept.Protein Res.,35:161-214,1990.

[0148] In some embodiments, the synthetic peptides are purified by preparative high performance liquid chromatography and the peptide sequence is confirmed by amino acid sequencing by methods known to those of skill in the art.

[0149] In some embodiments, the peptides and peptide multimers of the invention (composed of unbranched structures) are produced using recombinant protein techniques well known in the art.

[0150] According to some embodiments, the peptide comprises at most 500, 450, 400, 350, 300, 250, 200, 150, 100, 90, 80, 70, 60, 50, 45, 40, 35, 30, 25, 20, 15, or 10 amino acids. Each possibility represents a separate embodiment of the present invention. In some embodiments, the peptide comprises at most 100 amino acids. In some embodiments, the peptide comprises at most 50 amino acids. In some embodiments, the peptide comprises at most 30 amino acids. In some embodiments, the peptide comprises up to 30 amino acids. In some embodiments, the peptide comprises at most 20 amino acids. In some embodiments, the peptide comprises at most 15 amino acids.

[0151] According to some embodiments, the peptide comprises 6-100, 6-50, 6-40, 6-30, 6-25, 6-20, 6-15, 5-12, 6-10, 10-100, 10-50, 10-40, 10-30, 10-25, 10-20, 10-15, 10-12, 12-100, 12-50, 12-40, 12-30, 12-25, 12-20, 12-15, 15-100, 15-50, 15-40, 15-30, 15-25, or 15-20 amino acids. Each possibility represents a separate embodiment of the invention. According to some embodiments, the peptide comprises at least 6 amino acids. According to some embodiments, the peptide comprises at least 8 amino acids. According to some embodiments, the peptide comprises at least 10 amino acids. According to some embodiments, the peptide comprises at least 12 amino acids. According to some embodiments, the peptide comprises at least 15 amino acids.

[0152] According to some embodiments, the peptide is conjugated to at least one moiety that can increase solubility. According to some embodiments, the peptide is conjugated to at least one moiety that can increase permeability. According to some embodiments, the peptide is conjugated to at least one moiety that can increase solubility or permeability. According to some embodiments, at least one is a plurality of moieties. In some embodiments, the plurality is 2. In some embodiments, the plurality is at least 2, 3, 4, 5, 6, 7, 8, 9, or 10. Each possibility represents a separate embodiment of the present invention.

[0153] According to other embodiments, the peptide is conjugated to at least one linker or spacer. According to further embodiments, the peptide is conjugated to at least one moiety that can increase solubility or permeability and optionally at least one linker or spacer. According to still further embodiments, the peptide is conjugated to at least one moiety that can increase solubility or permeability and at least one linker or spacer. According to still further embodiments, the peptide is conjugated to at least one moiety that can increase solubility or permeability and at least one linker or spacer, and the at least one moiety that can increase solubility or permeability and at least one linker or spacer are covalently bonded to each other.

[0154] In some embodiments, the linker is an amino acid linker. In some embodiments, the linker is a chemical linker. In some embodiments, the linker is a bond. In some embodiments, the bond is a covalent bond. In some embodiments, the bond is a peptide bond. In some embodiments, the spacer is an amino acid spacer. In some embodiments, the linker or spacer comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids. Each possibility represents a separate embodiment of the invention. In some embodiments, the linker or spacer is a single amino acid. In some embodiments, the linker or spacer comprises at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 75, 80, 90, or 100 amino acids. Each possibility represents a separate embodiment of the invention. In some embodiments, the linker or spacer comprises at most one amino acid. In some embodiments, the linker or spacer comprises at most 10 amino acids.

[0155] In some embodiments, the linker is a cysteine ​​residue. In some embodiments, the linker is a lysine residue. In some embodiments, the linker is at least one repeat of the dipeptide lysine-alanine. In some embodiments, the linker is at least two repeats of the dipeptide KA. In some embodiments, the linker is two repeats of the dipeptide KA. In some embodiments, the linker comprises or consists of KAKA (SEQ ID NO: 16).

[0156] In some embodiments, the first peptide is separated from the second peptide by a spacer. In some embodiments, the first peptide is linked to the second peptide by a linker. In some embodiments, the peptide is separated from the moiety by a spacer. In some embodiments, the peptide is linked to the moiety by a linker. In some embodiments, the first moiety and the second moiety are separated by a spacer. In some embodiments, the first moiety and the second moiety are linked by a linker. In some embodiments, the linkage is a C-terminal linkage. In some embodiments, the linkage is an N-terminal linkage. In some embodiments, the linkage is not an N-terminal linkage. In some embodiments, there is no linkage to the N-terminus of the peptide. In some embodiments, the peptide comprises a free N-terminus.

[0157] According to some embodiments, the peptide is conjugated to at least one moiety via the C-terminus of the peptide. According to some embodiments, the peptide is conjugated to at least one linker or spacer via the C-terminus of the peptide. According to some embodiments, the N-terminus of the peptide is unmodified. According to other embodiments, the peptide has a free amine group at its N-terminus. Without being bound by any theory or mechanism, it is speculated that the amine group at the N-terminus of the peptide may be involved in binding to neutrophils.

[0158] Moieties capable of increasing solubility are well known in the art, and any such moiety may be used in the peptides of the present invention. Moieties capable of increasing solubility include, but are not limited to, 8-amino-3,6-dioxaoctanoic acid (Doa) residues, polyethylene glycol (PEG) of any length, and peptides comprising the amino acid sequence GGGS (SEQ ID NO: 17) or GGGGS (SEQ ID NO: 18). In some embodiments, the moiety is a DOA residue. In some embodiments, the moiety is a PEG. In some embodiments, the linker comprises at least one repeat of SEQ ID NO: 17. In some embodiments, the linker comprises at least one repeat of SEQ ID NO: 18. In some embodiments, the linker comprises or consists of at least 1, 2, 3, 4, or 5 repeats of SEQ ID NO: 17. Each possibility represents a separate embodiment of the present invention. In some embodiments, the linker comprises or consists of at least 1, 2, 3, 4, or 5 repeats of SEQ ID NO: 18. Each possibility represents a separate embodiment of the present invention.

[0159] According to specific embodiments, the moiety capable of increasing solubility comprises an 8-amino-3,6-dioxaoctanoic acid (Doa) residue. According to some embodiments, the peptide is conjugated to 1, 2, 3, 4 or 5 Doa residues. Each possibility represents a separate embodiment of the invention. According to some embodiments, the peptide is conjugated to two Doa residues. According to further embodiments, the Doa residues are covalently linked to each other, to the peptide sequence and / or to the linker. According to some embodiments, the peptide is conjugated to two units of Doa residues covalently linked to each other. In some embodiments, the covalent bond is a peptide bond. In some embodiments, the peptide and the residue are in a single amino acid chain.

[0160] The term "conjugated" or "peptide conjugate" as used herein refers to a molecule in which a peptide moiety is attached (i.e., bound or linked) by a covalent chemical bond to at least one peptidic or non-peptidic molecule, either directly or through a linker or spacer.

[0161] The terms "linker" and "spacer" are used interchangeably herein and refer to any molecule that covalently bonds and thus links two molecules. Non-limiting examples of linkers are amino acids, peptides or any other organics that can be used to allow distance between two linked molecules. According to specific embodiments, the linker is a flexible linker. According to specific embodiments, the linker is a flexible peptide. According to further specific embodiments, the linker is a flexible peptide that includes at least one glycine residue. According to certain embodiments, the linker includes multiple lysine residues. According to some specific embodiments, the linker includes 3-12 lysine residues. According to certain embodiments, the linker includes a 3-maleimidopropionic acid (Mpa) residue.

[0162] According to some embodiments, a peptide conjugate comprising at least one peptide selected from SEQ ID NOs: 1-13 and at least one moiety capable of increasing solubility is attached to the nanoparticles. According to other embodiments, a peptide conjugate comprising at least one peptide selected from SEQ ID NOs: 1-13 and at least one linker or spacer is attached to the nanoparticles. According to further embodiments, the peptide conjugate comprises at least one peptide selected from SEQ ID NOs: 1-13, at least one moiety capable of increasing solubility and optionally at least one linker or spacer. According to still further embodiments, the peptide conjugate comprises at least one peptide selected from SEQ ID NOs: 1-13, at least one moiety capable of increasing solubility and at least one linker or spacer. According to still further embodiments, the peptide conjugate comprises at least one moiety capable of increasing solubility and at least one linker or spacer, and the at least one moiety capable of increasing solubility and at least one linker or spacer are covalently bonded to each other.

[0163] According to some embodiments, the peptide conjugate comprises at least one peptide selected from SEQ ID NOs: 1-13 and 1, 2, 3, 4 or 5 units of Doa residues. Each possibility represents a separate embodiment of the invention. According to further embodiments, the peptide conjugate comprises at least one peptide selected from SEQ ID NOs: 1-13 and 2, 3, 4 or 5 units of Doa residues, the Doa residues being covalently linked to each other by the peptide sequence and / or the linker.

[0164] According to a further embodiment, the peptide conjugate comprises at least one peptide selected from SEQ ID NOs: 1-13, at least one Doa residue and at least one Mpa residue.

[0165] According to some embodiments, the peptide conjugate comprises at least one moiety capable of increasing solubility, and the at least one moiety is conjugated to the peptide via the C-terminus of the peptide. According to some embodiments, the peptide conjugate comprises at least one linker or spacer, and the at least one linker or spacer is conjugated to the peptide via the C-terminus of the peptide. According to some embodiments, the N-terminus of the peptide conjugate is unmodified. According to other embodiments, the peptide conjugate has a free amine group at its N-terminus.

[0166] According to some embodiments, the peptide conjugate has a structure according to Formula V: Peptide-Doa-Doa-C (Formula V) (wherein "C" is a cysteine ​​residue and "peptide" refers to a peptide of the invention or a salt thereof.) In some embodiments, "peptide" refers to a peptide of the invention or a salt thereof.

[0167] According to some embodiments, a peptide multimer comprising multiple peptides is attached to a nanoparticle.

[0168] According to some embodiments, the plurality of peptides is a plurality of the same peptides. According to some embodiments, the plurality of peptides is a plurality of different peptides. According to some embodiments, the peptides are the same or different peptides. According to some embodiments, the present invention provides a peptide multimer comprising a plurality of the same or different peptides selected from the peptides of the present invention or salts thereof. According to other embodiments, the present invention provides a peptide multimer for use in targeting human neutrophils, the peptide multimer comprising a plurality of the same or different peptides selected from the group consisting of SEQ ID NOs: 1-8 or salts thereof. According to other embodiments, the present invention provides a peptide multimer for use in targeting mouse neutrophils, the peptide multimer comprising a plurality of the same or different peptides selected from the group consisting of SEQ ID NOs: 9-13 or salts thereof.

[0169] The terms "peptide multimer" and "multimeric peptide" are used interchangeably herein to refer to a construct containing multiple (at least two, typically at least three or more) peptides that are not necessarily contiguous.

[0170] According to some embodiments, the peptide multimer is a branched molecule. According to other embodiments, the peptide multimer is a non-branched molecule. According to other embodiments, the peptide multimer is a linear molecule. According to other embodiments, the peptide multimer is a cyclic molecule.

[0171] According to some embodiments, the peptide multimer comprises at most 4, 6, 8, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, or 50 peptides, each possibility representing a separate embodiment of the present invention. According to some embodiments, the peptide multimer comprises at least 2, 4, 6, 8, 10, 12, 14, or 16 peptides. Each possibility representing a separate embodiment of the present invention. According to some embodiments, the peptide multimer comprises 2-20, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, or 2-4 identical or different peptides. Each possibility representing a separate embodiment of the present invention. According to some embodiments, the peptide multimer comprises 2-20, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, or 2-4 peptides. Each possibility representing a separate embodiment of the present invention. According to some embodiments, the peptide multimer comprises 2-20 peptides. According to some embodiments, the peptide multimer comprises 2 to 4 peptides. According to some embodiments, the peptide multimer comprises 2 peptides. According to some embodiments, the peptide multimer comprises 4 peptides. According to some embodiments, the peptide multimer comprises 16 peptides. According to specific embodiments, the peptide multimer comprises 4 identical or different peptides.

[0172] According to some embodiments, the peptides in the peptide multimer are covalently attached to one another, either directly or through a linker or spacer. According to other embodiments, the peptides in the peptide multimer are covalently attached to the scaffold, either directly or through a linker or spacer.

[0173] According to some embodiments, the peptide multimer comprises a plurality of identical or different peptide conjugates. According to some embodiments, the peptide multimer comprises a peptide conjugate comprising at least one peptide selected from SEQ ID NOs: 1-8. According to some embodiments, the peptide multimer comprises a peptide conjugate comprising at least one peptide selected from SEQ ID NOs: 9-13. According to some embodiments, the peptide multimer comprises 2-20, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, or 2-4 identical or different peptide conjugates comprising at least one peptide selected from SEQ ID NOs: 1-8. According to other embodiments, the peptide multimer comprises 2-20, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, or 2-4 identical or different peptide conjugates comprising at least one peptide selected from SEQ ID NOs: 9-13. According to a specific embodiment, the peptide multimer comprises four identical or different peptide conjugates.

[0174] According to some embodiments, the peptide conjugates in the peptide multimer are covalently linked to each other, either directly or through a linker or spacer. According to other embodiments, the peptide conjugates in the peptide multimer are covalently linked to the scaffold, either directly or through a linker or spacer. According to further embodiments, the peptide conjugates in the peptide multimer are non-covalently linked to the scaffold, either directly or through a linker or spacer. According to some embodiments, the scaffold is a branched scaffold. According to other embodiments, the scaffold is a non-branched scaffold.

[0175] According to some embodiments, each one of the peptides or peptide conjugates is bound to the nanoparticles directly or through a linker or spacer. In some embodiments, the peptide monomers are linked or bound to the nanoparticles directly or through a linker or spacer. In some embodiments, the linker is a cysteine ​​residue. In some embodiments, the thiol group of the cysteine ​​residue reacts with a maleimide on the nanoparticle. According to other embodiments, the peptides or peptide conjugates are covalently bound to each other and at least one peptide / peptide conjugate is bound to the nanoparticles directly or through a linker or spacer. According to some embodiments, each one of the peptides or peptide conjugates is bound to the scaffold directly or through a linker or spacer. According to other embodiments, the peptides or peptide conjugates are covalently bound to each other and at least one peptide / peptide conjugate is bound to the scaffold directly or through a linker or spacer.

[0176] According to some embodiments, the scaffold is a peptidic or polypeptidic scaffold. According to other embodiments, the peptidic or polypeptidic scaffold connects peptides to each other at a single position within the scaffold or at different positions on the scaffold. Each possibility represents a separate embodiment of the invention. According to some embodiments, the scaffold comprises at least one lysine (Lys) residue. According to other embodiments, the scaffold comprises at least three Lys residues. According to further embodiments, the at least three Lys residues are linked together by amide bonds to form a branched multimeric scaffold. According to some embodiments, at least one amide bond is formed between the epsilon amine of one Lys residue and the carboxy group of another Lys residue.

[0177] According to some embodiments, the peptide multimer comprises the molecular Mpa-cysteine ​​peptide.

[0178] According to some embodiments, the peptide multimer has the scheme: [ka] where X represents the C-terminus of a peptide selected from a carboxy acid, amide or alcohol group and optionally a linker or spacer, and each "peptide" independently represents a peptide of the invention or a salt thereof.

[0179] According to some specific embodiments, at least one of the peptides is present in multiple copies. According to some embodiments, the multiple copies are linked, thereby forming a multi-target peptide multimer. According to some embodiments, the peptide copies are linked through a linker. According to other embodiments, the peptide copies are directly linked. According to further embodiments, the multimer includes copies linked both directly and via a linker.

[0180] According to some embodiments, peptide multimers comprise multiple neutrophil-binding peptides arranged in an alternating polymeric structure B(X1X2X3...Xm)nB or a block copolymeric structure B(X1)nZ(X2)nZ(X3)nZ...(Xm)n, where B is any sequence of 1-10 amino acid residues, n is independently in each occurrence an integer from 2 to 50, m is an integer from 3 to 50, each of X1, X2...Xm is the same or different peptides of the invention, and Z in each occurrence is a bond or spacer of 1-4 amino acid residues. Each possibility represents a separate embodiment of the invention.

[0181] The term "block copolymer structure" means that all copies of a single peptide contained in the multimer are arranged contiguous.

[0182] According to some embodiments, the scaffold comprises or is formed from polyethylene glycol (PEG) molecules or modified PEG molecules. According to certain embodiments, the scaffold comprises branched PEG molecules. According to some embodiments, the branched molecules comprise at least two sites available for coupling to the peptides of the invention. According to other embodiments, the scaffold comprises 2-100, 3-90, 4-60, 5-50, 6-40, 7-35, 8-30, 9-25, or 10-20 or 2-50 sites available for coupling to the peptides.

[0183] According to some embodiments, the PEG molecule is a branched molecule that includes at least two separate connections to the peptide. According to other embodiments, the PEG is attached to an additional PEG molecule. According to certain embodiments, multiple PEG molecules are attached to provide a multi-arm PEG molecule. According to certain embodiments, the peptide is linked to the PEG scaffold through an amide bond formed between the amino groups of the NH2-PEG molecule. According to still other embodiments, at least one peptide is linked to the PEG scaffold through a Lys residue.

[0184] According to some embodiments, the peptide multimer comprises a branched scaffold comprising at least one Lys residue linked directly or through a spacer or linker to a peptide or peptide conjugate. According to a specific embodiment, the peptide multimer comprises a branched scaffold comprising two Lys residues linked directly or through a spacer or linker to a peptide or peptide conjugate. According to a further specific embodiment, the peptide multimer comprises a branched scaffold comprising the amino acid sequence Lys-Ala-Lys-Ala (KAKA, SEQ ID NO: 16) linked directly or through a spacer or linker to a peptide or peptide conjugate.

[0185] According to some embodiments, the peptide multimer further comprises a biotin moiety covalently attached to the peptide multimer directly or via a spacer or linker. According to some embodiments, the biotin is attached to the peptide multimer through the C-terminus. The biotin moiety renders the peptide multimer available for fluorescent detection and manipulation. According to other embodiments, the peptide multimer further comprises a biotin moiety, which is non-covalently attached to the peptide multimer. According to some embodiments, the peptide multimer further comprises an avidin moiety attached to the peptide multimer directly or via a spacer or linker. According to some embodiments, the peptide multimer further comprises a streptavidin moiety attached to the peptide multimer directly or via a spacer or linker. According to further embodiments, the peptide multimer comprises a biotin moiety and an avidin / streptavidin moiety attached to each other through a biotin-avidin interaction.

[0186] According to some embodiments, the multimeric peptide is a homomultimer. According to other embodiments, the multimeric peptide is a heteromultimer.

[0187] As used herein, the term "homomultimer" refers to a multimeric peptide that contains multiple copies of a single peptide. According to some embodiments, the multimeric peptide contains 2-20, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, or 2-4 identical peptides.

[0188] The term "heteromultimer" as used herein refers to a multimeric peptide that comprises one or more copies of at least two different peptides. The term "different peptides" refers to peptides that have different sequences and are not two copies of the same peptide. According to some embodiments, the multimeric peptide comprises one or more copies of at least two different peptides of the invention. According to specific embodiments, the multimeric peptide comprises one or more copies of at least two different peptides of the invention.

[0189] According to some embodiments, the heteromultimeric peptide comprises 2, 3, 4, 5, 6, 7 or 8 different peptide sequences of the invention or salts thereof.

[0190] Peptide multimers containing four copies of a single neutrophil-binding peptide have been shown to bind to circulating neutrophils more efficiently than monomeric peptides. Without being bound by any theory or mechanism, it is believed that heteromultimeric peptides containing at least two substantially different peptides target a much higher proportion of neutrophils than homomultimeric peptides.

[0191] According to some embodiments, the heteromultimeric peptide comprises 2-20, 2-10, or 2-5 copies of at least one of the different peptides. According to other embodiments, the heteromultimeric peptide comprises 2-20, 2-10, or 2-5 copies of at least two of the different peptides. According to further embodiments, the heteromultimeric peptide comprises 2-20, 2-10, or 2-5 copies of at least three of the different peptides. Each possibility represents a separate embodiment of the present invention.

[0192] According to a specific embodiment, the peptide multimer is a tetrameric peptide presenting a neutrophil-binding peptide on four branches. According to a further embodiment, at least one peptide in the tetramer has a free amine group at its N-terminus. According to yet a further embodiment, each one of the neutrophil-binding peptides in the tetramer has a free amine group at its N-terminus. According to a specific embodiment, the multimeric peptide is a tetrameric peptide with four copies of one neutrophil-binding peptide on four branches. According to a further specific embodiment, the multimeric peptide is a tetrameric peptide with four copies of one neutrophil-binding peptide on four branches, at least one copy of the neutrophil-binding peptide has a free amine group at its N-terminus. According to a further embodiment, the multimeric peptide is a tetrameric peptide with four copies of one neutrophil-binding peptide on four branches, each one of the copies of the neutrophil-binding peptide has a free amine group at its N-terminus.

[0193] According to some embodiments, the peptide multimer comprises a structure according to formula VI: [ka] Equation VI wherein each "peptide" independently represents a peptide of the present invention or a salt thereof.

[0194] In some embodiments, the peptide multimer comprises a structure according to formula VI, wherein each "peptide" independently represents a peptide of the invention or a salt thereof, and at least two peptides are different. In other embodiments, the peptide multimer comprises a structure according to formula VI, wherein each "peptide" independently represents a peptide of the invention or a salt thereof, and at least three peptides are different. In other embodiments, the peptide multimer comprises a structure according to formula VI, wherein each "peptide" independently represents a different peptide sequence, and each peptide sequence comprises a sequence selected from the group consisting of SEQ ID NOs: 1-13, or a salt thereof. In some embodiments, the peptide multimer comprises a structure according to formula VI, wherein each "peptide" independently represents a peptide of the invention or a salt thereof, and at least two peptides are identical. In other embodiments, the peptide multimer comprises a structure according to formula VI, wherein each "peptide" independently represents a peptide of the invention or a salt thereof, and at least three peptides are identical. According to yet another embodiment, the peptide multimer comprises a structure according to formula VI, where "peptide" represents a peptide of the invention or a salt thereof. In another embodiment, the peptide multimer comprises a structure according to formula VI, where each "peptide" independently represents a peptide of the invention or a salt thereof, and the four peptides are identical.

[0195] According to some embodiments, the peptide multimer comprises a structure according to Formula VII: [ka] Formula VII wherein each "peptide" independently represents a peptide of the present invention or a salt thereof.

[0196] In some embodiments, the peptide multimer comprises a structure according to formula VII, wherein each "peptide" independently represents a peptide of the invention or a salt thereof, and at least two peptides are different. In other embodiments, the peptide multimer comprises a structure according to formula VII, wherein each "peptide" independently represents a peptide of the invention or a salt thereof, and at least three peptides are different. In other embodiments, the peptide multimer comprises a structure according to formula VII, wherein each "peptide" independently represents a different peptide sequence, and each peptide sequence comprises a sequence selected from the group consisting of SEQ ID NOs: 1-13, or a salt thereof. In some embodiments, the peptide multimer comprises a structure according to formula VII, wherein each "peptide" independently represents a peptide of the invention or a salt thereof, and at least two peptides are identical. In other embodiments, the peptide multimer comprises a structure according to formula VII, wherein each "peptide" independently represents a peptide of the invention or a salt thereof, and at least three peptides are identical. According to yet another embodiment, the peptide multimer comprises a structure according to formula VII, where "peptide" represents a peptide of the invention or a salt thereof. In another embodiment, the peptide multimer comprises a structure according to formula VII, where each "peptide" independently represents a peptide of the invention or a salt thereof, and the four peptides are identical.

[0197] In some embodiments, the peptide complex comprising at least two peptide multimers is bound to the nanoparticle. As used herein, the term "peptide complex" refers to a construct containing multiple (at least two, typically at least three or more) identical or different peptide multimers that are not necessarily adjacent. According to some embodiments, the peptide complex comprises at least two peptide multimers, the peptide multimer comprising at least one peptide of the present invention or a salt thereof. According to certain embodiments, the present invention provides a peptide complex for use in targeting human neutrophils, the peptide complex comprising at least two peptide multimers, the peptide multimer comprising at least one peptide comprising a sequence selected from SEQ ID NOs: 1-13 or a salt thereof. According to some embodiments, the peptide multimers in the peptide complex are covalently linked to each other, either directly or via a linker or spacer. According to some embodiments, the linker or spacer is selected from the group consisting of, but not limited to, amino acids, peptides and any other organic matter that can be used to allow distance between two linked molecules. According to other embodiments, the peptide multimers in the peptide complex are non-covalently linked to each other. According to some embodiments, the peptide multimers in the peptide complex are non-covalently bound to each other through biotin-avidin interactions. According to some embodiments, the peptide complex comprises at least two biotin moieties and an avidin / streptavidin moiety, where the at least two biotin moieties are covalently bound to the peptide multimers, and the avidin / streptavidin moiety is non-covalently bound to the biotin moiety. According to a specific embodiment, the peptide complex comprises four peptide multimers and an avidin / streptavidin moiety, where each one of the peptide multimers is covalently bound to the biotin moiety, and the four peptide multimers are non-covalently bound to the avidin / streptavidin moiety.

[0198] According to some embodiments, the peptides and / or nanoparticles are those peptides and / or nanoparticles disclosed in International Patent Publication WO2022003674, the entirety of which is incorporated herein by reference.

[0199] composition In some embodiments, the compound of the present invention is in a composition. In some embodiments, the nanoparticle of the present invention is in a composition. In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition comprises a compound of the present invention, a pharma- ceutically acceptable salt thereof, or both. In some embodiments, the pharmaceutical composition of the present invention comprises a therapeutically effective amount of a compound of the present invention and / or any pharma- ceutically acceptable salt thereof and / or derivative thereof. In some embodiments, the composition comprises a nanoparticle of the present invention, a pharma- ceutically acceptable salt thereof, or both. In some embodiments, the pharmaceutical composition of the present invention comprises a therapeutically effective amount of a nanoparticle of the present invention and / or any pharma- ceutically acceptable salt thereof and / or derivative thereof. In some embodiments, the therapeutically effective amount is sufficient to alleviate at least one symptom, or to substantially alleviate the severity and / or inhibit the progression of a disease, disorder, or condition as described herein above. In some embodiments, the therapeutically effective amount is sufficient to inhibit neutrophils. In some embodiments, the therapeutically effective amount can be determined as described herein below.

[0200] In some embodiments, provided herein are compositions comprising one or more compounds of the invention, including any salts (e.g., pharma- ceutically acceptable salts), any tautomers, and / or any stereoisomers thereof. In some embodiments, a compound as described herein above is the only active ingredient in a composition (e.g., a pharmaceutical composition) of the invention.

[0201] Non-limiting examples of pharma- ceutically acceptable salts include, but are not limited to, acetate, aspartate, benzenesulfonate, benzoate, bicarbonate, carbonate, halide (bromide, chloride, iodide, fluoride, etc.), bitartrate, citrate, salicylate, stearate, succinate, sulfate, tartrate, decanoate, edetate, fumarate, gluconate, and lactate salts, or any combination thereof.

[0202] In some embodiments, the liposome composition comprises a salt of the compound, the salt being a sulfate salt, a citrate salt, a sucrosophate salt, a salt with a phosphorylated or sulfated polyol, or a salt with a phosphorylated or sulfated polyanionic polymer. In some embodiments, the liposome composition comprises a sulfate salt of the compound.

[0203] In some embodiments, the composition comprises a pharma- ceutically acceptable carrier, excipient or adjuvant.As used herein, the term "carrier", "excipient" or "adjuvant" refers to any component of a pharmaceutical composition that is not an active agent.As used herein, the term "pharma-ceutically acceptable carrier" refers to a non-toxic inert solid, semi-solid liquid filler, diluent, encapsulating material, any type of formulation auxiliary, or simply a sterile aqueous medium, such as physiological saline. Some examples of materials which may function as pharma- ceutically acceptable carriers are sugars such as lactose, glucose and sucrose, starches such as corn starch and potato starch, cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; tragacanth powder; 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 polyols; esters, e.g., ethyl oleate and ethyl laurate, agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline, Ringer's solution; ethyl alcohol and phosphate buffers, as well as other non-toxic compatible substances used in pharmaceutical formulations. Some non-limiting examples of the material that can function as carrier herein are sugar, starch, cellulose and its derivatives, enriched tragacanth, malt, gelatin, talc, stearic acid, magnesium stearate, calcium sulfate, vegetable oil, polyol, alginic acid, pyrogen-free water, isotonic saline, phosphate buffer, cocoa butter (suppository base), emulsifier, and other non-toxic pharmaceutically compatible material used in other pharmaceutical preparations.Wetting agents and lubricants such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, excipients, stabilizers, antioxidants and preservatives can also be present.Any non-toxic, inert and effective carrier can be used to formulate the composition contemplated herein.Suitable pharma- ceutically acceptable carriers, excipients and diluents in this regard are well known to those skilled in the art, and are described in, for example, The Merck Index, 13th edition, Budavari et al., Eds., Merck&Co., Inc., Rahway, NJ (2001); CTFA (Cosmetic and Toiletries Manufacturers Association) International Cosmetic Ingredient Dictionary and Handbook, 10th edition (2004); and "Inactive Ingredient Guide" U.S. Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) Administration, the contents of all of which are incorporated herein by reference in their entirety.Examples of pharma-ceutically acceptable carriers, excipients and diluents useful in the compositions of the present invention include distilled water, physiological saline, Ringer's solution, dextrose solution, Hank's solution and DMSO. These additional inactive components, as well as effective formulation and administration procedures, are well known in the art and are described in standard textbooks such as Goodman and Gillman's: The Pharmacological Bases of Therapeutics, 8th Edition, Gilman et al. Eds. Pergamon Press (1990); Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co., Easton, Pa. (1990); and Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, Philadelphia, Pa., (2005), each of which is incorporated herein by reference in its entirety. The compositions described herein may also be contained in engineered structures such as liposomes, ISCOMS, sustained release particles, and other vehicles that increase the half-life of peptides or polypeptides in serum. Liposomes for use with the peptides described herein are generally formed from standard vesicle-forming lipids, including neutral and negatively charged phospholipids and sterols, such as cholesterol.The selection of lipids is generally determined by consideration of liposome size and stability in blood, etc. Various methods for preparing liposomes are available, as reviewed in, for example, Coligan, JE et al, Current Protocols in Protein Science, 1999, John Wiley & Sons, Inc., New York, and see also U.S. Patent Nos. 4,235,871, 4,501,728, 4,837,028, and 5,019,369.

[0204] The carriers may in total constitute from about 0.1% to about 99.99999% by weight of the pharmaceutical compositions presented herein.

[0205] In some embodiments, the pharmaceutical composition is for use in treating a disease or disorder. In some embodiments, the pharmaceutical composition is for use in treating a medical condition in which neutrophils play a role in the pathogenesis. In some embodiments, the pharmaceutical composition is for use in treating a neutrophil-associated disease or condition.

[0206] In some embodiments, the medical condition is a disease. In some embodiments, the medical condition is a condition. In some embodiments, the medical condition is a disorder. In some embodiments, the medical condition is a neutrophil-associated disease or condition. In some embodiments, the medical condition is a disease or condition mediated by neutrophils. In some embodiments, the medical condition is a disease or condition exacerbated by neutrophils. In some embodiments, the medical condition is a disease or condition associated with accumulation of neutrophils. In some embodiments, the accumulation is in a diseased tissue or site. In some embodiments, the accumulation is in an injured tissue or site. In some embodiments, the medical condition is selected from the group consisting of cancer, an infectious disease, an inflammatory disease or disorder, and an autoimmune disease or disorder. In some embodiments, the medical condition is cancer. In some embodiments, the medical condition is inflammation. In some embodiments, the medical condition is an inflammatory disease or condition. In some embodiments, the inflammatory disease or condition is an autoimmune inflammatory disease or condition.

[0207] In some embodiments, the pharmaceutical composition is for use in treating a neutrophil-associated disease or condition. In some embodiments, the pharmaceutical composition is for use in treating a disease or condition associated with accumulation of neutrophils in a diseased or damaged tissue or site. In some embodiments, the disease or condition is selected from the group consisting of cancer, an inflammatory disease or condition, and an inflammatory autoimmune disease or condition. In some embodiments, the disease or condition is an inflammatory disease or condition. In some embodiments, the disease or condition is cancer. In some embodiments, the disease or condition is inflammation. In some embodiments, the inflammation is neutrophil-induced inflammation. In some embodiments, the disease or condition is a skin disease. In some embodiments, the inflammatory disease or condition is an inflammatory skin disease. In some embodiments, the skin disease is an inflammatory skin disease. In some embodiments, the skin disease comprises a neutrophilic skin disease (ND). In some embodiments, the ND comprises neutrophil accumulation within a skin layer. In some embodiments, the skin disease is selected from the group consisting of Sweet's syndrome (SS), pyoderma gangrenosum (PG), rheumatic neutrophilic dermatitis, gut-associated dermatosis arthritis syndrome, subcorneal pustulosis (Sneddon-Wilkinson), acute generalized exanthematous pustulosis (AGEP), acrodermatitis continua of Allopeau (ACH), palmoplantar pustulosis (PPP), pustular bacteriopathia (PB), neutrophilic eccrine hidradenitis, hidradenitis suppurativa (HS), and Behcet's disease. In some embodiments, the skin disease is selected from the group consisting of SS, PPP, PG, and HS.

[0208] In some embodiments, the medical condition is a disease in which the release of neutrophil extracellular NETosis is part of the pathophysiology. In some embodiments, the medical condition is a disease characterized by excessive neutrophil-mediated tissue damage. Non-limiting examples of diseases characterized by excessive neutrophil-mediated tissue damage are pulmonary diseases such as acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD). In some embodiments, the medical condition is ARDS. In some embodiments, the medical condition is COPD. In some embodiments, the disease is COPD. In some embodiments, the medical condition is selected from the group consisting of cancer, an inflammatory disease, condition or disorder, and an autoimmune disease, condition or disorder. According to some embodiments, the autoimmune disease, condition or disorder is an inflammatory autoimmune disease, condition or disorder. According to other embodiments, the medical disease is selected from the group consisting of thrombosis, Alzheimer's disease, and a neutrophil-mediated skin disease. According to some embodiments, the medical condition is a neutrophil-mediated skin disease. According to some embodiments, the medical condition is cancer. According to some embodiments, the medical condition is an inflammatory condition. According to some embodiments, the medical condition is an inflammatory disease. According to some embodiments, the inflammatory disease or condition is selected from chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (IBD) and peritonitis. According to some embodiments, the inflammatory disease or condition is COPD. According to some embodiments, the inflammatory disease or condition is IBD. According to some embodiments, the IBD includes Crohn's disease. According to some embodiments, the IBD includes colitis. In some embodiments, the inflammatory disease or condition is colitis. According to some embodiments, the inflammatory disease or condition is peritonitis. In some embodiments, the IBD includes colitis and Crohn's disease. In some embodiments, the IBD is colitis. In some embodiments, the colitis is ulcerative colitis.

[0209] According to some embodiments, the inflammatory disease is a disease in which neutrophils are involved in the pathogenesis. According to some embodiments, the inflammatory disease or disorder is selected from the group consisting of peritonitis, colitis, vasculitis, atherosclerosis, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), bronchiectasis, neutrophilic asthma, rheumatoid arthritis (RA), lupus, cystic fibrosis (CF), sepsis, multiple sclerosis, psoriasis, and traumatic injury. Each possibility represents a separate embodiment of the invention. According to some embodiments, the disease or disorder is systemic lupus erythematosus (SLE). According to some embodiments, the disease or disorder is rheumatoid arthritis (RA). According to some embodiments, the disease or disorder is gout. According to some embodiments, the disease or disorder is inflammatory arthritis.

[0210] According to some embodiments, the disease is cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a solid cancer. In some embodiments, the cancer is a blood cancer. According to some embodiments, the cancer is selected from solid tumor cancer and blood cancer. According to some embodiments, the solid cancer is selected from the group consisting of breast cancer, lung cancer, colon cancer, pancreatic cancer, liver cancer, head and neck cancer, and kidney cancer. Each possibility represents a separate embodiment of the present invention. According to some embodiments, the blood cancer is leukemia. According to some embodiments, the cancer is liver cancer. In some embodiments, the liver cancer comprises hepatocellular carcinoma (HCC). In some embodiments, the cancer comprises head and neck squamous cell carcinoma (HNSCC). According to some embodiments, the cancer is kidney cancer. In some embodiments, the kidney cancer is selected from renal cell carcinoma (RCC), transitional cell carcinoma (TCC), and Wilms' tumor.

[0211] In some embodiments, the pharmaceutical compositions of the present invention are for use as a medicament. In some embodiments, the compositions are formulated for systemic administration. In some embodiments, the compositions are formulated for administration to a subject. In some embodiments, the subject is a human. In some embodiments, the compositions are formulated for intravenous administration. In some embodiments, the compositions are formulated for subcutaneous administration. In some embodiments, the compositions are formulated for topical administration. In some embodiments, the compositions are formulated for oral administration. In some embodiments, the compositions are formulated for rectal administration. In some embodiments, the compositions are formulated for inhalation. In some embodiments, the compositions are formulated for intratumoral administration. In some embodiments, the compositions are formulated for local administration to a site of inflammation.

[0212] The pharmaceutical composition of the present invention may be administered by any known method. The term "administering" a substance, compound or agent to a subject or "administration of" a compound or agent may be performed using one of a variety of methods known to those skilled in the art. For example, the compound or agent may be administered intravenously, intraarterially, intradermally, intramuscularly, intraperitoneally, intravenously, subcutaneously, intraocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (e.g., by absorption through the skin tract). The compound or agent may also be suitably introduced by rechargeable or biodegradable polymeric or other devices, such as patches and pumps, or formulations that provide sustained, delayed or controlled release of the compound or agent. Administering may also be performed, for example, once, multiple times, and / or over one or more extended periods of time. In some embodiments, administration includes both direct administration, including self-administration, and indirect administration, including the act of prescribing a drug. For example, as used herein, a physician who instructs a patient to self-administer a drug or has another physician administer the drug, and / or provides a patient with a prescription for a drug, is administering a drug to a patient.

[0213] According to some embodiments, the pharmaceutical composition is administered by an invasive mode of administration, such as intramuscularly, intravenously, intraarterially, intraarticularly, or parenterally. According to specific embodiments, the pharmaceutical composition is administered intravenously. According to some embodiments, the composition is administered systemically. According to some embodiments, the composition is administered to a site of inflammation. In some embodiments, the composition is formulated for administration to a subject. According to some embodiments, the composition is formulated for systemic administration. According to some embodiments, the composition is formulated for administration to a site of inflammation. In some embodiments, the composition is formulated for administration to a site of disease. In some embodiments, the composition is formulated for intratumoral administration.

[0214] It will be apparent to those of skill in the art that a therapeutically effective amount of a molecule according to the invention will depend, among other things, on the administration schedule, the unit dose of the molecule administered, whether the molecule is administered in combination with other therapeutic agents, the immune and health status of the patient, the therapeutic activity of the administered molecule, and the judgment of the treating physician. As used herein, a "therapeutically effective amount" refers to the amount of a molecule required to alleviate one or more symptoms associated with the disorder being treated over a period of time.

[0215] The appropriate dosage of the molecule of the present invention varies depending on the route of administration, the type of molecule (polypeptide, polynucleotide, organic molecule, etc.), the age, weight, sex or condition of the patient, but is ultimately determined by the physician. Various considerations in arriving at an effective dosage are described, for example, in Goodman and Gilman's: The Pharmacological Bases of Therapeutics, 8th ed., Pergamon Press, 1990; and Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Co., Easton, Pa., 1990.

[0216] For example, the term "pharmaceutical acceptable" can mean approved by a regulatory agency of the Federal or state government, or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeias, for use in animals, or, more specifically, in humans. In some embodiments, the compounds of the invention are referred to herein as active ingredients of pharmaceutical compositions.

[0217] In some embodiments, the pharmaceutical composition comprising the compound of the present invention is in unit dosage form.In some embodiments, pharmaceutical composition is prepared by any method well known in the field of pharmacy.In some embodiments, unit dosage form is in the form of tablet, capsule, lozenge, wafer, patch, ampoule, vial or pre-filled syringe.

[0218] In addition, in vitro assays can be optionally used to help identify optimal dosage ranges. The exact dose to be used in the formulation also depends on the route of administration and the nature of the disease or disorder, and should be determined according to the judgment of the practitioner and each patient's circumstances. Effective doses can be extrapolated from dose-response curves derived from in vitro or in vivo animal model test bioassays or systems. In some embodiments, effective doses are determined as described herein above.

[0219] In another embodiment, the pharmaceutical compositions of the present invention are administered in any conventional oral, parenteral, or transdermal dosage form.

[0220] Pharmaceutically acceptable salts In some embodiments, the compounds of the present invention can be present in free form or as a pharma- ceutically acceptable salt for treatment.

[0221] As used herein, the term "pharmaceutical acceptable salt" refers to any non-toxic salt of the compound of the present invention that, upon administration to a subject, such as a human, can provide, either directly or indirectly, the compound of the present invention or an inhibitory active metabolite or residue thereof. For example, the term "pharmaceutical acceptable" can mean approved by a regulatory agency of the federal or state government or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, more specifically in humans.

[0222] Pharmaceutically acceptable salts are well known in the art.For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19.Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases.These salts can be prepared in situ during the final isolation and purification of the compound.Acid addition salts can be prepared by 1) reacting the purified compound in its free base form with a suitable organic or inorganic acid, and 2) isolating the salt thus formed.

[0223] Examples of pharma- ceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acids, or with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acids, or by using other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, gluconate, hemisulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanoate, tert-butyl ester ... Examples of the salts include phenylsulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0224] Further pharma- ceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations, formed where appropriate using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates and arylsulfonates, etc. Other acids and bases, while not themselves pharma- ceutically acceptable, may be used in the preparation of salts which are useful as intermediates in obtaining the compounds of the invention and their pharma- ceutically acceptable acid or base addition salts.

[0225] In some embodiments, the compounds described herein are chiral compounds (i.e., have asymmetric carbon atoms). In some embodiments, diastereomers, geometric isomers and individual isomers are included within the scope of the present invention. In some embodiments, the chiral compounds described herein are in the form of racemic mixtures. In some embodiments, the chiral compounds are in the form of a single enantiomer in which the asymmetric carbon atom has an R configuration. In some embodiments, the chiral compounds are in the form of a single enantiomer in which the asymmetric carbon atom has an S configuration, as described herein above.

[0226] In some embodiments, the chiral compound is in the form of a single enantiomer with an enantiomeric purity of greater than 70%. In some embodiments, the chiral compound is in the form of a single enantiomer with an enantiomeric purity of greater than 80%. In some embodiments, the chiral compound is in the form of a single enantiomer with an enantiomeric purity of greater than 90%. In some embodiments, the chiral compound is in the form of a single enantiomer with an enantiomeric purity of greater than 95%.

[0227] In some embodiments, the compounds of the invention that contain unsaturated bonds are in the form of trans or cis isomers. In some embodiments, the compounds of the invention are in the form of a single isomer having an isomeric purity of greater than 70%, greater than 80%, greater than 90%, 90-99%, 95-99%, 97-99%, 95-97%, including any range therebetween. In some embodiments, the chiral compound is in the form of a Z isomer having an isomeric purity of greater than 95%. In some embodiments, the compositions of the invention include a mixture of cis and trans isomers as described herein above.

[0228] In some embodiments, the compounds described herein can exist in solvated forms, including nonsolvated forms and hydrated forms.In general, solvated forms are equivalent to nonsolvated forms and are included within the scope of the present invention.Certain compounds of the present invention can exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the use contemplated by the present invention and are intended to be within the scope of the present invention.

[0229] The term "solvate" refers to a complex of variable stoichiometry (e.g., di-, tri-, tetra-, penta-, hexa-, etc.) formed by a solute (a conjugate as described herein) and a solvent, whereby the solvent does not interfere with the biological activity of the solute. Suitable solvents include, for example, ethanol, acetic acid, etc.

[0230] The term "hydrate" refers to a solvate, as defined hereinabove, wherein the solvent is water.

[0231] Unless otherwise indicated, the structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, geometric, conformational and rotational) forms of the structures. For example, the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers are included in the present invention. As will be understood by those skilled in the art, substituents can freely rotate around any rotatable bond. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, geometric, conformational and rotational mixtures of the compounds of the present invention are within the scope of the present invention.

[0232] Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0233] Furthermore, unless otherwise indicated, the structures shown herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms.For example, compounds having this structure except for the replacement of hydrogen with deuterium or tritium, or the replacement of carbon with 13C or 14C enriched carbon are within the scope of this invention.Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0234] In another embodiment, the compositions of the present invention take the form of a solution, suspension, emulsion, tablet, pill, capsule, powder, gel, cream, ointment, foam, paste, sustained release formulation, etc. In another embodiment, the compositions of the present invention can be formulated as a suppository with traditional binders and carriers such as triglycerides, microcrystalline cellulose, tragacanth gum, or gelatin. Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by EW Martin, the contents of which are incorporated herein by reference. Such compositions contain a therapeutically effective amount of the polypeptide of the present invention, preferably in substantially purified form, together with a suitable amount of carrier to provide the form for proper administration to the subject.

[0235] How to use According to some embodiments, the present invention provides a method of treating, preventing or ameliorating a neutrophil-related disease or condition in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition described herein above. In some embodiments, the disease or condition is in a subject in need thereof. In some embodiments, the method comprises administering a compound. In some embodiments, the method comprises administering a nanoparticle. In some embodiments, the method comprises administering a composition.

[0236] In some embodiments, the disease or condition is selected from the group consisting of cancer, inflammatory disease or condition, and inflammatory autoimmune disease or condition. In some embodiments, the disease or condition is a neutrophil-associated disease or condition. In some embodiments, the disease or condition is a disease or condition characterized by neutrophil pathology. In some embodiments, the disease or condition is a disease or condition characterized by neutrophil activity. In some embodiments, the disease or condition is a disease or condition characterized by neutrophils and treatable by inhibiting neutrophils. In some embodiments, inhibiting neutrophils comprises inhibiting neutrophil activation. In some embodiments, inhibiting neutrophils comprises inhibiting neutrophil degranulation. In some embodiments, inhibiting neutrophils comprises inhibiting neutrophil NETosis. In some embodiments, inhibiting neutrophils comprises inhibiting neutrophil exocytosis. In some embodiments, inhibiting neutrophils comprises inhibiting reactive oxygen species (ROS) production. In some embodiments, the ROS production is ROS secretion. In some embodiments, inhibiting neutrophils comprises inhibiting neutrophil-mediated killing. In some embodiments, inhibiting neutrophils comprises inhibiting neutrophil-mediated cytotoxicity. In some embodiments, inhibiting neutrophils comprises inhibiting protease secretion. In some embodiments, inhibiting neutrophils comprises inhibiting NET production. In some embodiments, inhibiting neutrophils does not inhibit NET production. In some embodiments, inhibiting neutrophils comprises inhibiting inflammation. In some embodiments, inflammation is in the subject.

[0237] In some embodiments, the cancer comprises high neutrophil load. In some embodiments, high neutrophil load comprises an increased neutrophil count, an increased activity of neutrophils, or both. In some embodiments, neutrophil load comprises a ratio of neutrophil count to lymphocyte count. In some embodiments, neutrophil load is compared to a predetermined threshold. In some embodiments, high neutrophil load is above a predetermined threshold. In some embodiments, neutrophil load is examined in a biopsy obtained from a subject in need thereof. In some embodiments, neutrophil load is examined in tumor tissue. In some embodiments, neutrophil load is examined in the tumor microenvironment (TME).

[0238] According to some embodiments, the cancer is selected from solid tumor cancer and hematological cancer. Each possibility represents a separate embodiment of the present invention. According to some embodiments, the solid cancer is selected from the group consisting of breast cancer, lung cancer, colon cancer, pancreatic cancer, liver cancer, head and neck cancer, and kidney cancer. According to some embodiments, the hematological cancer is leukemia. According to some embodiments, the cancer is kidney cancer. In some embodiments, the kidney cancer comprises renal cell carcinoma (RCC). In some embodiments, the cancer comprises hepatocellular carcinoma (HCC). In some embodiments, the cancer comprises head and neck squamous cell carcinoma (HNSCC). Each possibility represents a separate embodiment of the present invention.

[0239] In some embodiments, treating cancer comprises administering a composition disclosed herein and an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor comprises immune checkpoint blockade. In some embodiments, the immune checkpoint is programmed cell death protein 1 (PD-1), programmed cell death protein ligand 1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), or any combination thereof.

[0240] According to some embodiments, the inflammatory disease is a disease in which neutrophils are involved in the pathogenesis. According to some embodiments, the inflammatory disease or disorder is selected from the group consisting of peritonitis, colitis, vasculitis, atherosclerosis, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), bronchiectasis, neutrophilic asthma, rheumatoid arthritis (RA), lupus, cystic fibrosis (CF), sepsis, multiple sclerosis, psoriasis, and traumatic injury. Each possibility represents a separate embodiment of the invention. According to some embodiments, the disease or disorder is systemic lupus erythematosus (SLE). According to some embodiments, the disease or disorder is rheumatoid arthritis (RA).

[0241] In some embodiments, the inflammatory disease or condition is selected from chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (IBD), and peritonitis. In some embodiments, the inflammatory disease or condition is COPD. In some embodiments, the inflammatory disease or condition is IBD. In some embodiments, the inflammatory disease or condition is peritonitis. According to some embodiments, the IBD comprises Crohn's disease. According to some embodiments, the IBD comprises colitis. In some embodiments, the inflammatory disease or condition is colitis. In some embodiments, the colitis is ulcerative colitis (UC).

[0242] In some embodiments, the method includes administering an effective amount of at least one of a compound, nanoparticle, composition, or any combination thereof. In some embodiments, the effective amount is the human equivalent of a mouse dose of 5 mg / kg body weight. In some embodiments, the human equivalent of the mouse dose depends on the route of administration. In some embodiments, the effective amount is the human equivalent of a mouse dose of 1.25-5 mg / kg body weight. In some embodiments, the effective amount is the human equivalent of a mouse dose of 2.5-5 mg / kg body weight. In some embodiments, the effective amount is about 0.4 mg / kg body weight. In some embodiments, the effective amount is about 0.2 mg / kg body weight. In some embodiments, the effective amount is about 0.1 mg / kg body weight.

[0243] chemical definition Compounds are described using standard nomenclature. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0244] The compounds described herein include enantiomers, mixtures of enantiomers, diastereomers, tautomers, racemates and other isomers, such as rotamers, as if each was specifically described, unless otherwise indicated or excluded by context. It should be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be either (R-) or (S-) configuration. The compounds provided herein may be enantiomerically pure or may be diastereomeric or enantiomeric mixtures. It should be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. Thus, those skilled in the art will recognize that administration of a compound in its (R-) form is equivalent to administration of a compound in its (S-) form for compounds that undergo epimerization in vivo. Unless otherwise stated, formulas in which chemical bonds are shown only as solid lines and not as wedges or dashed lines contemplate each possible isomer, e.g., each enantiomer, diastereomer, and meso compound, as well as mixtures of isomers, e.g., racemic or scalenic mixtures.

[0245] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -(C=O)NH2 is attached through the carbon of the keto (C=O) group.

[0246] The term "substituted" as used herein means that any one or more hydrogens on the specified atom or group are replaced with a moiety selected from the indicated group, provided that the normal valence of the specified atom is not exceeded and the resulting compound is stable. For example, if the substituent is oxo (i.e., =O), then two hydrogens on the atom are replaced. For example, a pyridyl group substituted with oxo is a pyridine. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable active compound refers to a compound that can be isolated and formulated into a dosage form with a shelf life of at least one month. A stable manufacturing intermediate or precursor to an active compound is stable if it does not decompose within the time period required for reaction or other use. A stable moiety or substituent is one that does not decompose, react or decay within the time period required for use. Non-limiting examples of unstable moieties are those that combine heteroatoms in unstable configurations, as typically known and identifiable by those skilled in the art.

[0247] Any suitable group may be present at the "substituted" or "optionally substituted" positions that will form a stable molecule and fulfill the desired objectives of the present invention, including, but not limited to, alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halo, hydroxy, keto, nitro, cyano, azido, oxo, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, sulfonylamino, or thiol. As used herein, the term "substituted" or "substituent" refers to one or more (e.g., 2, 3, 4, 5, or 6) substituents, where the substituents are as described herein.

[0248] As used herein, the term substituents includes halo, oxo, amino, hydroxy, -NO2, -CN, -OH, -CONH2, -CONR'2, -CNNR'2, -CSNR'2, -CONH-OH, -CONH-NH2, -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR', ​​-NC(=S)OR', -NC(=S)NR', ​​-SOR', -SOR', -SR', -SO2OR', -SON(R')2, -NHNR'2, -NNR', C1-C6 haloalkyl, optionally substituted C1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkoxy, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl), ... and R' is an optionally substituted alkoxy, C1-C6 haloalkoxy, hydroxy(C1-C6 alkyl), hydroxy(C1-C6 alkoxy), alkoxy(C1-C6 alkyl), alkoxy(C1-C6 alkoxy), C1-C6 alkyl-NR'2, C1-C6 alkyl-SR', -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -CO2H, -CO2R', -OCOR, -OCOR', -OC(=O)OR', -OC(=O)NR', ​​-OC(=S)OR', -OC(=S)NR', ​​OR', -NR'R', or combinations thereof; each R' independently represents hydrogen or, where permitted by valence, optionally substituted C1-C 10 Alkyl, optionally substituted C1-C 10 Aminoalkyl, optionally substituted C1-C 10 Hydroxyalkyl, optionally substituted C3-C 10 Cycloalkyl, optionally substituted C3-C 10 Heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, amino, hydroxy, halo, oxo, cyano, optionally substituted C-C 10 alkyl, or any combination thereof.

[0249] As used herein, the term "alkyl" refers to an aliphatic hydrocarbon, including straight-chain and branched-chain groups. The term "alkyl" as used herein also encompasses saturated or unsaturated hydrocarbons, and thus the term further encompasses alkenyl and alkynyl.

[0250] The term "alkenyl" refers to an unsaturated alkyl, as defined herein, having at least two carbon atoms and at least one carbon-carbon double bond. The alkenyl may be unsubstituted or substituted by one or more substituents, as described herein above.

[0251] The term "alkynyl," as defined herein, is an unsaturated alkyl having at least two carbon atoms and at least one carbon-carbon triple bond. The alkynyl may be substituted or unsubstituted by one or more substituents as described herein above.

[0252] The term "cycloalkyl" refers to an all-carbon monocyclic or fused ring (i.e., rings which share adjacent pairs of carbon atoms) group in which one or more of the rings does not have a fully conjugated pi-electron system. Cycloalkyl groups may be substituted or unsubstituted as indicated herein.

[0253] The term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a fully conjugated pi-electron system. Aryl groups may be substituted or unsubstituted as indicated herein.

[0254] The term "alkoxy" refers to both -O-alkyl and -O-cycloalkyl groups as defined herein. The term "aryloxy" refers to -O-aryl groups as defined herein.

[0255] Each of the alkyl, cycloalkyl and aryl groups in the general formulas herein may be substituted with one or more substituents, each of which may be, independently, for example, halide, alkyl, alkoxy, cycloalkyl, nitro, amino, hydroxyl, thiol, thioalkoxy, carboxy, amido, aryl and aryloxy, depending on the substituent and its position in the molecule. Additional substituents are also contemplated.

[0256] The terms "halide", "halogen" or "halo" refer to fluorine, chlorine, bromine or iodine. The term "haloalkyl" refers to an alkyl group, as defined herein, further substituted with one or more halides. The term "haloalkoxy" refers to an alkoxy group, as defined herein, further substituted with one or more halides. The terms "hydroxyl" or "hydroxy" refer to an -OH group. The terms "mercapto" or "thiol" refer to an -SH group. The term "thioalkoxy" refers to both an -S-alkyl group and an -S-cycloalkyl group, as defined herein. The term "thioaryloxy" refers to both an -S-aryl and an -S-heteroaryl group, as defined herein. The term "amino" refers to an -NR'R'' group or a salt thereof, where R' and R'' are as defined herein.

[0257] The term "heterocyclyl" refers to a monocyclic or fused ring group having one or more atoms in the ring, such as nitrogen, oxygen, and sulfur. The ring may also have one or more double bonds. However, the ring does not have a fully conjugated pi-electron system. Representative examples are piperidine, piperazine, tetrahydrofuran, tetrahydropyran, morpholino, etc.

[0258] The term "carboxy" refers to the group -C(O)OR' or a carboxylate salt thereof, where R' is hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl (bonded through a ring carbon) or heterocyclyl (bonded through a ring carbon), or "carboxylate", as defined herein.

[0259] The term "carbonyl" refers to the group -C(O)R', where R' is as defined herein above. The term also includes its thio derivatives, thiocarboxy and thiocarbonyl.

[0260] The term "thiocarbonyl" refers to a -C(S)R' group, where R' is as defined herein above. A "thiocarboxy" group refers to a -C(S)OR' group, where R' is as defined herein. A "sulfinyl" group refers to a -S(O)R' group, where R' is as defined herein. A "sulfonyl" or "sulfonate" group refers to a -S(O)R' group, where R' is as defined herein.

[0261] A "carbamyl" or "carbamate" group refers to an -OC(O)NR'R" group, where R' is as defined herein and R" is as defined for R'. A "nitro" group refers to an -NO2 group. The term "amide" as used herein includes C-amide and N-amide. The term "C-amide" refers to a -C(O)NR'R" terminal group or a -C(O)NR'- linking group, where R' and R" are as defined herein, as these terms are defined herein above. The term "N-amide" refers to a -NR"C(O)R' terminal group or a -NR'C(O)- linking group, where R' and R" are as defined herein, as these terms are defined herein above.

[0262] The term "cyano" or "nitrile" refers to the -CN group. The terms "azo" or "diazo" refer to the -N=NR' terminal group or the -N=N- linking group, as these terms are defined hereinabove. The term "guanidine" refers to the -R'NC(N)NR''R''' terminal group or the -R'NC(N)NR''- linking group, as these terms are defined hereinabove, where R', R'' and R''' are as defined herein. As used herein, the term "azide" refers to the -N3 group. The term "sulfonamide" refers to the -S(O)2NR'R'' group, as these terms are defined hereinabove, where R' and R'' are as defined herein.

[0263] The term "phosphonyl" or "phosphonate" refers to the group -OP(O)-(OR')2, where R' is as defined herein above. The term "phosphinyl" refers to the group -PR'R'' where R' and R'' are as defined herein above. The term "alkylaryl" refers to an alkyl, as defined herein, substituted with an aryl, as described herein. An exemplary alkylaryl is benzyl.

[0264] The term "heteroaryl" refers to a monocyclic or fused ring (i.e., rings sharing adjacent pairs of atoms) group having one or more atoms in the ring, such as nitrogen, oxygen, and sulfur, and also having a fully conjugated pi-electron system. As used herein, the term "heteroaryl" refers to an aromatic ring in which at least one atom forming the aromatic ring is a heteroatom. Heteroaryl rings can be formed by three, four, five, six, seven, eight, nine, and more than nine atoms. Heteroaryl groups can be optionally substituted. Examples of heteroaryl groups include, but are not limited to, aromatic C3-8 heterocyclic groups and their substituted derivatives containing one oxygen or sulfur atom, or two oxygen atoms, or two sulfur atoms, or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom and up to two nitrogen atoms, and benzo-fused and pyrido-fused derivatives, for example, bonded through one of the ring-forming carbon atoms. In certain embodiments, heteroaryl is selected from among oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinal, pyrazinyl, indolyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl.

[0265] In some embodiments, the heteroaryl group is selected from the group consisting of pyrrolyl, furanyl (furyl), thiophenyl (thienyl), imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3-oxazolyl (oxazolyl), 1,2-oxazolyl (isoxazolyl), oxadiazolyl, 1,3-thiazolyl (thiazolyl), 1,2-thiazolyl (isothiazolyl), tetrazolyl, pyridinyl (pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, 1, Heteroaryl is selected from among 2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetraazinyl, indazolyl, indolyl, benzothiphenyl, benzofuranyl, benzothiazolyl, benzimidazolyl, benzodioxolyl, acridinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, thienothiophenyl, 1,8-naphthyridinyl, other naphthyridinyl, pteridinyl, or phenothiazinyl. When a heteroaryl group contains more than one ring, each additional ring is in saturated (perhydro) or partially unsaturated (e.g., dihydro or tetrahydro) form, or in maximally unsaturated (non-aromatic) form. Thus, the term heteroaryl includes bicyclic groups in which two rings are aromatic and bicyclic groups in which only one ring is aromatic. Examples of such heteroaryls include 3H-indolinyl, 2(1H)-quinolinonyl, 4-oxo-1,4-dihydroquinolinyl, 2H-1-oxoisoquinolyl, 1,2-dihydroquinolinyl, (2H)quinolinyl N-oxide, 3,4-dihydroquinolinyl, 1,2-dihydroisoquinolinyl, 3,4-dihydro-isoquinolinyl, chromonyl, 3,4-dihydroisoquinolinyl, 4-(3H)quinazolinonyl, 4H-chromenyl, 4-chromonyl, Manonyl, oxindolyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-quinolinyl, 1H-2,3-dihydroisoindolyl, 2,3-dihydrobenzo[f]isoindolyl, 1,2,3,4-tetrahydrobenzo-[g]isoquinolinyl, 1,2,3,4-tetrahydrobenzo[g]isoquinolinyl, chromanyl, isochromanonyl, 2,3-dihydrochromonyl, 1,4-benzo-dioxanyl, 1,2,3,4-Tetrahydro-quinoxalinyl, 5,6-dihydro-quinolyl, 5,6-dihydroisoquinolyl, 5,6-dihydroquinoxalinyl, 5,6-dihydroquinazolinyl, 4,5-dihydro-1H-benzimidazolyl, 4,5-dihydro-benzoxazolyl, 1,4-naphthoquinolyl, 5,6,7,8-tetrahydro-quinolinyl, 5,6,7,8-tetrahydro-isoquinolyl, 5,6,7,8-tetrahydroquinoxalinyl, 5,6,7,8-tetrahydroquinazolyl, 4,5,6,7-tetrahydro-1H-benzimidazolyl, 4,5 ,6,7-Tetrahydro-benzoxazolyl, 1H-4-oxa-1,5-diaza-naphthalen-2-onyl, 1,3-dihydroimidizolo-[4,5]-pyridin-2-onyl, 2,3-dihydro-1,4-dinaphthoquinonyl, 2,3-dihydro-1H-pyrrole[3,4-b]quinolinyl, 1,2,3,4-tetrahydrobenzo[b]-[1,7]naphthyridinyl, 1,2,3,4-tetrahydro-benzo[b][1,6]-naphthyridinyl, 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolyl, 1,2,3,4-tetrahydro-benzo[b]-[1,7]naphthyridinyl, 1,2,3,4-tetrahydro-benzo[b][1,6]naphthyridinyl, 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indolyl, 1,2,3,4-tetrahydro-benzo[b]-[1,7]naphthyridinyl, 9H-pyrido[4,3-b]indolyl, 2,3-dihydro-1H-pyrrolo-[3,4-b]indolyl, 1H-2,3,4,5-tetrahydroazepino[3,4-b]indolyl, 1H-2,3,4,5-tetrahydroazepino[4,3-b]indolyl, 1H-2,3,4,5-tetrahydroazepino[4,5-b]indolyl, 5,6,7,8-tetrahydro[1,7]naphthyridinyl, 1,2,3,4-tetrahydro-[2,7]naphthyridyl, 2,3-dihydro[1,4]dioxino[2,3-b]pyridyl, 2,3- Dihydro[1,4]-dioxino[2,3-b]pyridyl, 3,4-dihydro-2H-1-oxa[4,6]diazanaphthalenyl, 4,5,6,7-tetrahydro-3H-imidazo-[4,5-c]pyridyl, 6,7-dihydro[5,8]diazanaphthalenyl, 1,2,3,4-tetrahydro[1,5]-naphthyridinyl, 1,2,3,4-tetrahydro[1,6]naphthyridinyl, 1,2,3,4-tetrahydro[1,7]naphthyridinyl, 1,2,3,4-tetrahydro-[1,8]naphthyridinyl or 1,2,3,4-tetrahydro[2,6] naphthyridinyl. In some embodiments, the heteroaryl group is optionally substituted. In one embodiment, the one or more substituents are each independently selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, C1-6-alkyl, C1-6-haloalkyl, C1-6-hydroxyalkyl, C1-6-aminoalkyl, C1-6-alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl.

[0266] Examples of heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine, furazan, 1,2,3 oxadiazole, 1,2,3 thiadiazole, 1,2,4 thiadiazole, triazole, benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine, cinnoline, phthalazine, quinazoline and quinoxaline. In some embodiments, the substituents are halo, hydroxy, cyano, O-C1-6-alkyl, C1-6-alkyl, hydroxy-C1-6-alkyl and amino-C1-6-alkyl.

[0267] As used herein, the terms "halo" and "halide," referred to interchangeably herein, refer to an atom of the halogens, i.e., fluorine, chlorine, bromine, or iodine, and are also referred to herein as fluoride, chloride, bromide, and iodide.

[0268] "Pharmaceutically acceptable salts" are derivatives of the disclosed compounds in which the parent compound is modified by making its inorganic and organic pharma- ceutically acceptable acid or base addition salts. Salts of the compounds of the present invention can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (e.g., Na, Ca, Mg, or K hydroxides, carbonates, bicarbonates, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where feasible. Salts of the compounds of the present invention further include solvates of the compounds and compound salts. Examples of pharma-ceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include salts that are acceptable for human consumption, and quaternary ammonium salts of parent compounds formed from inorganic or organic salts.Examples of such salts include, but are not limited to, those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and those prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, mesylic acid, esylic acid, besylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH2)1-4-COOH, and the like, or those prepared using different acids that produce the same counter ion.Further lists of suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

[0269] As used herein, substantially pure means sufficiently homogeneous so as not to contain readily detectable impurities as determined by standard analytical methods used by those skilled in the art to assess such purity, such as, for example, thin layer chromatography (TLC), nuclear magnetic resonance (NMR), gel electrophoresis, high performance liquid chromatography (HPLC) and mass spectrometry (MS), gas chromatography-mass spectrometry (GC-MS), or sufficiently pure so that further purification does not detectably alter the physical and chemical properties, such as the enzymatic and biological activity, of the substance. Both traditional and modern methods for purification of compounds to produce substantially chemically pure compounds are known to those skilled in the art. However, a substantially chemically pure compound may be a mixture of stereoisomers.

[0270] general As used herein, the term "about" refers to ±10%.

[0271] The terms "comprises," "comprising," "includes," "including," "having" and their conjugations mean "including, but not limited to."

[0272] The term "consisting of" means "including and limited to."

[0273] The term "consisting essentially of" means that a composition, method, or structure may include additional components, steps, and / or moieties, but only if the additional components, steps, and / or moieties do not materially alter the basic and novel characteristics of the claimed composition, method, or structure.

[0274] The word "exemplary" is used herein to mean "serving as an example, instance, or illustration." Any embodiment described as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments and / or to exclude the incorporation of features from other embodiments.

[0275] The word "optionally" is used herein to mean "provided in some embodiments and not provided in other embodiments." Any particular embodiment of the invention may include multiple "optional" features unless such features are inconsistent.

[0276] As used herein, the singular forms "a," "a," and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" can include a plurality of compounds, including mixtures thereof.

[0277] Throughout this application, various embodiments of the invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Thus, the description of a range should be considered to have specifically disclosed all possible subranges and individual numerical values ​​within that range. For example, a description of a range such as 1-6 should be considered to have specifically disclosed subranges such as 1-3, 1-4, 1-5, 2-4, 2-6, 3-6, and the individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0278] Whenever a numerical range is given herein, it is meant to include any recited numbers (fractional or integer) within the given range. The phrases "ranging / ranges between" a first indicated number and a second indicated number and "ranging / ranges from" a first indicated number "to" a second indicated number are used interchangeably herein and are meant to include the first and second indicated numbers and all fractional and integer numbers therebetween.

[0279] As used herein, the term "method" refers to manners, means, techniques and procedures for accomplishing a given task, including but not limited to those manners, means, techniques and procedures that are either known to those of skill in the art of chemistry, pharmacology, biology, biochemistry and medicine or that can be readily developed from known manners, means, techniques and procedures by those of skill in the art.

[0280] As used herein, the term "treating" includes arresting, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating the clinical or cosmetic symptoms of a condition, or substantially preventing the appearance of clinical or cosmetic symptoms of a condition.

[0281] It is understood that certain features of the invention that are described for clarity in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, various features of the invention that are described for brevity in the context of a single embodiment may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments should not be considered essential features of those embodiments, unless the embodiment is inoperable without those elements.

[0282] While the present invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications, and variations that fall within the spirit and broad scope of the appended claims.

[0283] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference.In addition, citation or identification of any reference in this application should not be construed as an admission that such reference is available as prior art to the present invention.To the extent section headings are used, they should not be construed as necessarily limiting. EXAMPLES

[0284] In general, the nomenclature used herein and the laboratory procedures utilized in the present invention include molecular, biochemical, microbiological and recombinant DNA techniques. Such techniques are fully explained in the literature. See, for example, "Molecular Cloning: A laboratory Manual" Sambrook et al., (1989); "Current Protocols in Molecular Biology" Volumes I-III Ausubel, RM, ed. (1994); Ausubel et al., "Current Protocols in Molecular Biology", John Wiley and Sons, Baltimore, Maryland (1989); Perbal, "A Practical Guide to Molecular Cloning", John Wiley&Sons, New York (1988); Watson et al., "Recombinant DNA", Scientific American Books, New York; Birren et al. (eds.) "Genome Analysis: A Laboratory Manual Series", Vols. 1-4, Cold Spring Harbor Laboratory Press, New York. New York (1998); methodologies described in U.S. Patent Nos. 4,666,828; 4,683,202; 4,801,531; 5,192,659 and 5,272,057; Cell Biology: A Laboratory Handbook, Volumes I-III, edited by Cellis, JE (1994); Culture of Animal Cells-A Manual of Basic Technique, 3rd ed., by Freshney, Wiley-Liss, NY (1994); Current Protocols in Immunology, Volumes I-III, edited by Coligan JE (1994); Stites et al.(eds), Basic and Clinical Immunology (8th ed.), Appleton & Lange, Norwalk, CT (1994); Mishell and Shiigi (eds.), Strategies for Protein Purification and Characterization--A Laboratory Course Manual, CSHL Press (1996), all of which are incorporated by reference. Other general references are provided throughout this document.

[0285] method Degranulation assay (human neutrophils): 5 mL of human blood was collected in EDTA-containing tubes. Neutrophils were purified on a FICCOL gradient and 100,000 neutrophils were used per sample. Phorbol myristate acetate (PMA, 50 nM) was added for neutrophil stimulation. Samples were incubated with either PMA alone or with compounds (50 μM) for 30 min at 37°C and then stained with anti-CD66b Ab to detect neutrophil populations and with anti-CD11b Ab to detect degranulation, which were then assessed by FACS. Nexinhib20 (50 μM) was used as a positive control. DMSO was used as a negative control. Mean fluorescence intensity (MFI) of CD11b was normalized to the levels after PMA stimulation.

[0286] Degranulation assay (mouse neutrophils): 1 mL of mouse blood was collected from mouse heart into EDTA-containing tubes. Neutrophils were purified on a FICCOL gradient and 100,000 neutrophils were used per sample. Samples were incubated with either PMA alone (50 nM) or with compounds (50 μM) for 30 min at 37°C and then stained with anti-Ly6GAb to detect neutrophil populations and anti-CD11b Ab to detect degranulation, which were then assessed by FACS. Nexinhib20 (50 μM) was used as a positive control. DMSO was used as a negative control. MFI of CD11b was normalized to the levels after PMA stimulation.

[0287] ROS Assay (Human Neutrophils): 5 mL of human blood was collected in EDTA-containing tubes. Red blood cells (RBCs) were lysed and white blood cells (WBCs) were isolated by spinning down and washing. An average of 5,000 WBCs / well were stimulated with 100 nM PMA and incubated in the presence of compounds at a concentration of 5 μM for 30 min at 37°C. Luminol was added to the wells and activity was read on a luminescence plate reader (cycle #16, 22.5 min). Nexinhib20 (5 μM) and DPI (1 μM) were used as positive controls. HBSS buffer or buffer with DMSO was used as negative controls. Luminescence signals were normalized to control (DMSO alone).

[0288] ROS Assay (Mouse Neutrophils): 0.5 mL of mouse blood was collected in EDTA-containing tubes. RBCs were lysed and WBCs were isolated by spinning down and washing. An average of 2,000 WBCs / well were stimulated with 100 nM PMA and incubated in the presence of compounds at a concentration of 5 μM for 30 min at 37°C. Luminol was added to the wells and activity was read on a luminescence plate reader (cycle #16, 22.5 min). Nexinhib20 (5 μM) and DPI (1 μM) were used as positive controls. HBSS buffer or buffer with DMSO was used as negative controls. Luminescence signals were normalized to control (DMSO alone).

[0289] NETosis Assay: The assay was performed as previously described (Gupta et al., "A High-Throughput Real-Time Imaging Technique To Quantify NETosis and Distinguish Mechanisms of Cell Death in Human Neutrophils." J Immunol. 2018;200:869-879, incorporated herein by reference in its entirety). Briefly, human neutrophils (2×10 6Cells (100,000 cells / mL) were incubated for 5 min in the dark at RT with NUCLEAR-ID Red DNA dye to stain the nuclei (Enzo Life Sciences, Inc.). Cells were washed twice and resuspended in 1 mL of RPMI medium. NUCLEAR-ID Red stained neutrophils were seeded in 96-well flat microplates (20,000 neutrophils per 100 μL). Stimulation of neutrophil NETosis was performed with PMA alone (50 nM) or with PMA in the presence of T1 compounds (10 μM) or T3 compounds (10 μM). Unstimulated neutrophils served as negative controls. Neutrophils stimulated with PMA in the presence of trifluoperazine (Stelazine, 100 ng / ml) were used as positive controls. A final concentration of 0.1 μM of membrane-impermeable dsDNA fluorescent Sytox Green nucleic acid stain (Life Technologies, Inc.) was added to the seeded cells simultaneously with stimulation. Neutrophils were imaged within 10 min of plating using phase contrast, red (800 ms exposure) and green (400 ms exposure) channels on an IncuCyte ZOOM™ platform (Essen BioScience, Inc.) located in a 5% CO2, 37°C cell incubator. Four sets of images from separate areas per well were taken every 20-30 min for 8 h using a 20x dry objective. For the red channel, a radius of 10 μm, a fluorescence threshold of 0.5 red correction units and an area of ​​15 μm were used. 2 A filter was applied to exclude objects smaller than 10 μm in radius, 1.00 fluorescence threshold green correction units, and 100 μm in area for the green channel. 2Objects smaller than 10 were excluded. The number of green objects divided by the number of red objects represents the percentage of cells passing through NETosis of total neutrophils. Liposome preparation: 2.5% DSPE-PEG3400-maleimide liposomes were prepared in 250 mM ammonium sulfate. Liposomes were prepared with a molar ratio of HSPC:cholesterol:DSPE-PEG-Mal:DilC18(5)-DS of 56.5:41:2.5:0.09. Lipids were prepared by a standard ethanol injection protocol and, after extrusion, were found to have an average size of 118.9 nm and an average polydispersity index (DPI) of 0.085.

[0290] LQI monomer conjugation: Liposomes were buffer exchanged into PBS and empty unconjugated liposomes were kept as a control. The LQI peptide, LQIQSWSSSP (SEQ ID NO: 9), was extended to include a C-terminal cysteine ​​(LQIQSWSSSPC, SEQ ID NO: 14) and reacted with the maleimide on the surface of the liposome to covalently attach the peptide to the liposome surface. After conjugation, the free maleimide was quenched with L-cysteine ​​and the coupled liposomes were then washed and filtered.

[0291] Active drug loading into liposomes: 50 mg of drug was dissolved in 7.5% dextrose and the pH was adjusted to approximately 6 with MES buffer. Control "empty" liposomes were still loaded with 7.5% dextrose supplemented with 10 μl of MES buffer. For loading, liposomes were mixed with dissolved drug at 60°C for 30 min and then cooled on ice for 15 min. Loaded liposomes had a size range of approximately 135-145 nm. Unloaded free drug was separated from the liposomes using size exclusion with a PD-10 column. Drug and cholesterol content in the final liposomes was measured using HPLC.

[0292] To monitor drug retention within the liposomes, the liposomes were analyzed over a 4-month storage period. Although a small amount of leakage was observed, the relative amount of drug to lipid did not change significantly over 4 months. Data regarding the liposome composition are provided in Table 1.

[0293] [Table 1] EXAMPLES

[0294] In vitro effects of T1, T3 and T4 compounds on neutrophil activation Initially, the in vitro effects of compounds T1, T3 and T4 on neutrophil activation were examined. The chemical structures of the compounds are presented in Figure 1.

[0295] First, neutrophils were purified from human blood and either left unstimulated or stimulated with phorbol myristate acetate (PMA). The three compounds were added (50 μM) to both unstimulated and PMA-stimulated cells, with DMSO used as a negative control. Two isomers of each compound were examined: the Z and E isomers. After PMA stimulation, neutrophils are known to degranulate, and increased surface expression of CD11b is a well-known marker of this phenomenon. Treatment of neutrophils with T1 (E and Z isomers), T3 (E and Z isomers) and T4 (Z isomers) significantly reduced PMA-induced degranulation (Figure 2A). Indeed, the T1 Z isomer and the T3 Z isomer were able to restore CD11b levels to those of unstimulated neutrophils. Notably, the Z isomers of all three molecules performed better than the E isomers. Nexinhib-20 is known to inhibit degranulation, and the Z isomer of T3 was as good as Nexinhib-20. Similar results were obtained when mouse neutrophils were tested (Figure 2B).

[0296] Neutrophil stimulation is also known to increase reactive oxygen species (ROS) production. Next, the in vitro effects of the compounds on PMA-induced ROS production by neutrophils were examined. As expected, the addition of PMA increased ROS production in human neutrophils to 2-3 times the basal level (Figure 3A). All tested molecules, including both E and Z isomers, significantly reduced ROS production in untreated neutrophils. This demonstrates that the molecules inhibit even basal ROS production. T1 (E and Z isomers), T3 (E and Z isomers) and T4 (Z isomers) also significantly reduced the PMA-induced increase in ROS, with ROS levels reduced at least to levels observed in unstimulated neutrophils (Figure 3A). The T3 Z isomer showed the best ROS inhibition, with levels after PMA stimulation being significantly lower than control levels without PMA. This inhibition was comparable to that produced by Nexinhib20, and T3Z was almost as potent as diphenyliodonium (DPI), an inhibitor known to almost completely abolish ROS production by inhibiting NAD(P)H (Figure 3A). Similar results were observed in mouse PMA-stimulated neutrophils (Figure 3B).

[0297] In addition to degranulation, neutrophils can kill pathogens extracellularly by releasing neutrophil extracellular traps (NETs), a process known as NETosis. Examination of PMA-induced NETosis was monitored by an Incucyte live cell analysis system (Figure 4). PMA treatment resulted in a steady increase in NETosis-positive events, starting 2 hours after treatment. Trifluoperazine (sold as Stelazine), a known inhibitor of NETosis, resulted in a steady decrease after PMA treatment. In contrast, both T1 and T3 completely inhibited the increase in NETosis early on. An increase was observed only after 4 hours with T1 and 5 hours with T3. T3 was very similar to the control showing only a slight increase in NETosis events only at very late time points (Figure 4). EXAMPLES

[0298] In vivo effects of T3 on inflammation The next objective was to test the in vivo effects of T3 compounds in inflammatory diseases and cancer. T3 compounds (Z isomers) were prepared in three compositions: (i) T3 as a free molecule (free drug), (ii) T3 in liposomes, and (iii) T3 in liposomes targeted to neutrophils by a surface peptide (TENN). Specifically, liposomes were conjugated to a peptide consisting of the sequence LQIQSWSSSP (SEQ ID NO: 9), called the LQI-peptide. This peptide is known in the art to specifically bind to neutrophils, as described in Vols et al., "Targeted nanoparticles modify neutrophil function in vivo," Front Immunol. 2022 Oct. 5; 13: 1003871, which is incorporated herein by reference in its entirety.

[0299] The in vivo effects of three compositions of T3 were examined in a mouse model of inflammation. Balb / C mice were injected intraperitoneally with 1 mg / kg LPS to induce inflammation and neutrophil toxicity. One hour later, T3-free molecules, T3 in liposomes and T3 in targeted liposomes (TENN-T3) were administered IV at a final concentration of 3 mg / kg body weight. Three hours later, 0.5 mL of blood was collected from each mouse and degranulation of peripheral blood neutrophils was assessed by flow cytometric analysis of surface CD11b levels (neutrophils were identified by Ly6G staining). Neutrophils activated by LPS become toxic and degranulate, and T3 in its free form induced a moderate but not statistically significant decrease in degranulation (Figure 5). T3 in liposomes only produced a slightly larger decrease, which was also not statistically significant. However, targeted liposomes containing T3 (TENN-T3) resulted in a greater than 50% reduction in granulation, more than three-fold the reduction caused by free molecular T3. Overall, it is clear that T3 inhibits neutrophil activation in vivo and that targeting greatly enhances the effect.

[0300] Next, the ability of T3 administration to treat colitis, a disease caused at least in part by neutrophil cytotoxicity, was tested in a mouse model. Colitis was induced in C57BL / 6 mice by administering 3% dextran sulfate sodium (DSS) in drinking water for 5 consecutive days. 2.5 mg / kg of T3 in its three formulations was administered on days 5, 7, and 9. Colitis induction by DSS caused a significant shortening of the mouse colon. Free T3 or T3 loaded into non-targeted liposomes was comparable to the negative control administration of empty targeted liposomes (Figure 6A). However, T3 loaded into targeted liposomes (TENN-T3) led to a significant elongation of the colon, with an average improvement of about 62% compared to the no treatment (DSS only) group. Furthermore, measurement of ROS levels in the colon (from mice sacrificed on day 11) by luminol-based bioluminescence imaging showed a significant reduction in ROS levels in the colon of TENN-T3-treated mice compared to the DSS alone group (Figure 6B).

[0301] Lower doses of TENN-T3 were also tested. Targeted liposomes were administered on days 5 and 7, mice were sacrificed on day 10, and colon length was measured. A dose of 1.25 mg / kg body weight was able to improve colon length better than cyclosporine (7.5 mg / kg body weight), a known colitis treatment and considered a positive control for the DSS model (Figure 6C). A dose of 2.5 mg / kg TENN-T3 had an even larger, statistically significant effect. EXAMPLES

[0302] In vivo treatment of cancer with T3 Neutrophils are known to have a variety of cancer-promoting properties. Therefore, the therapeutic potential of TENN-T3 as a means of inhibiting solid tumor growth was examined. Renca cells are epithelial cells isolated from the kidneys of male mice bearing renal cortical adenocarcinoma. The Renca syngeneic mouse model is therefore a renal cancer model utilized to study the efficacy of antitumor drugs. BALB / c mice were administered a subcutaneous injection of 1 million Renca cells, which allowed tumors to grow to 100 mm 3The tumor cells were allowed to grow to a size of 100x the size of 1 ...

[0303] While the present invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications, and variations that fall within the spirit and broad scope of the appended claims.

Claims

1. A compound, including any stereoisomer or salt thereof, comprising the compound of Formula I: 【Chemistry 1】 (In the formula: A is a methyl group, an isopropyl group, a tert-butyl group, a linear or branched C １ -C １０ alkyl group, substituted or unsubstituted linear or branched C ２ -C １０ Alkyl group, substituted C ２ -C １０ alkyl groups, optionally substituted C containing one or more carbocyclic rings ３ -C １０ cycloalkyl groups, optionally substituted C containing one or more heteroatoms; ２ -C １０ Alkyl group, C １ -C １０ Haloalkyl groups, substituted C １ -C １０ Haloalkyl group, C １ -C １０ Alkylhydroxy group, halo group, C １ -C １０ Alkoxy group, C ３ -C １０ Cycloalkyl group, substituted C ３ -C １０ represents a cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, bicyclic aromatic ring, unsaturated aliphatic ring, or bicyclic aliphatic ring; Y is absent or is N, NH, NR １ , C.H., H.C.R. １ , C.H. ２ , S, SH, and O; n is an integer from 0 to 5; X is hydrogen or a halo group, a methyl group, an isopropyl group, C ２ -C １０ Alkyl group, substituted C ２ -C １０ represents a substituent selected from the group consisting of an alkyl group, an alkoxy group, an amino group, and a hydroxy group; Each R independently represents zero or one or more substituents, each independently a methyl group, an isopropyl group, C ２ -C １０ Alkyl group, substituted C ２ -C １０ Alkyl group, halo group, oxo group, -NO group ２ , amino, hydroxy, -CN, -OH, -CONH ２ , -CONR' ２ , -CNNR' ２ , -CSNR' ２ , -CONH-OH, -CONH-NH ２ , -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR', ​​-NC(=S)OR', -NC(=S)NR', ​​-SO ２ R', -SOR', -SR', -SO ２ OR', -SO ２ N(R') ２ , —NHNR′ ２ , -NNR', C １ -C ６ Haloalkyl, optionally substituted C １ -C ６ Alkyl, —NH ２ , -NR'R', -NH(C １ -C ６ alkyl), -N(C １ -C ６ alkyl) ２ , C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, hydroxy (C １ -C ６ alkyl), hydroxy (C １ -C ６ alkoxy), alkoxy(C １ -C ６ alkyl), alkoxy (C １ -C ６ Alkoxy), C １ -C ６ Alkyl-NR' ２ , C １ -C ６ Alkyl-SR', -CONH(C １ -C ６ alkyl), -CON(C １ -C ６ alkyl) ２ , -CO ２ H, -CO ２ R', -OCOR, -OCOR', -OC(=O)OR', -OC(=O)NR', ​​-OC(=S)OR', -OC(=S)NR', ​​-OR', and -NR'R'; each R' independently represents hydrogen or, where allowed by valence, optionally substituted C １ -C １０ Alkyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, amino, hydroxy, halo, oxo, cyano, and optionally substituted C １ -C １０ selected from the group including alkyl; R １ and R ２ are each independently hydrogen, oxygen, or C １ -C ２０ alkyl group, optionally substituted linear or branched C １ -C ２０ Aminoalkyl groups, optionally substituted linear, branched or cyclic C groups optionally containing one or more heteroatoms １ -C ２０ Alkyl group, substituted C １ -C ２０ Alkyl group, C １ -C ２０ Haloalkyl groups, substituted C １ -C ２０ aliphatic linear or branched C containing haloalkyl groups and, optionally, one or more heterocycles; ３ -C ２０ aminoalkyl groups or R １ and Y are interconnected to form an optionally substituted 4- to 8-membered ring, or R １ and R ２ are interconnected to form an optionally substituted 4-8 membered ring, optionally containing one or more heteroatoms; when R 1 and R 2 are oxygen, then Y is N; R ３ is hydrogen, is absent, or is a methyl group, an isopropyl group, C ２ -C １０ Alkyl group, substituted C ２ -C １０ Alkyl group, C １ -C １０ Haloalkyl groups, substituted C １ -C １０ Haloalkyl group, C １ -C １０ Alkylhydroxy group, halo group, C １ -C １０ Alkoxy group, amino group, thioalkoxy group, thioalkyl group, hydroxy group, mercapto group, allyl group, C １ -C １０ Ether group, vinyl group, cyano group, nitro group, C １ -C １０ Alkylamino group, C １ -C １０ Alkylamide group, C ３ -C １０ Cycloalkyl group, substituted C ３ -C １０ represents a cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, bicyclic aromatic ring, unsaturated ring, or bicyclic aliphatic ring, or R ３ and A are interconnected to form an optionally substituted 4- to 8-membered ring; or R ３ and Y are interconnected to form an optionally substituted 4- to 8-membered ring; R ４ is absent, hydrogen, a methyl group, an isopropyl group, C ２ -C １０ Alkyl group, substituted C ２ -C １０ Alkyl group, C １ -C １０ Haloalkyl groups, substituted C １ -C １０ Haloalkyl group, C １ -C １０ Alkylhydroxy group, halo group, C １ -C １０ Alkoxy group, C ３ -C １０ Cycloalkyl group, substituted C ３ -C １０ represents a cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, bicyclic aromatic ring, unsaturated aliphatic ring, or bicyclic aliphatic ring, or R ３ and R ４ are interconnected to form an optionally substituted 4- to 8-membered ring; or The compound has the formula I': 【Chemistry 2】 (In the formula: A represents a methyl group, an isopropyl group, a tert-butyl group, a linear or branched C 1 -C 10 alkyl group, a substituted or unsubstituted linear or branched C 2 -C 10 alkyl group, a substituted C 2 -C 10 alkyl group, an optionally substituted C 3 -C 10 cycloalkyl group containing one or more carbocyclic rings, an optionally substituted C 2 -C 10 alkyl group containing one or more heteroatoms, a C 1 -C 10 haloalkyl group, a substituted C 1 -C 10 haloalkyl group, a C 1 -C 10 alkylhydroxy group, a halo group, a C 1 -C 10 alkoxy group, a C 3 -C 10 cycloalkyl group, a substituted C 3 -C 10 cycloalkyl, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, a bicyclic aromatic ring, an unsaturated aliphatic ring, or a bicyclic aliphatic ring; Y is selected from the group consisting of N, NH, NR 1 , CH, HCR 1 , CH 2 , S, SH, and O; n is an integer from 1 to 5; X is hydrogen or a substituent selected from the group consisting of halo, methyl, isopropyl, C 2 -C 10 alkyl, substituted C 2 -C 10 alkyl, alkoxy, amino, and hydroxy; Each R independently represents none, one or more substituents, each independently being a methyl group, an isopropyl group, a C 2 -C 10 alkyl group, a substituted C 2 -C 10 alkyl group, halo, oxo, -NO 2 , amino, hydroxy, -CN, -OH, -CONH 2 , -CONR' 2 , -CNNR' 2 , -CSNR' 2 , -CONH-OH, -CONH-NH 2 , -NHCOR, -NHCSR, -NHCNR, -NC(═O)OR, -NC(═O)NR', ​​-NC(═S)OR', -NC(═S)NR', ​​-SO 2 R', -SOR', -SR', -SO 2 OR', -SO 2 N(R') 2 , or -NHNR' 2 . , —NNR′, C 1 -C 6 haloalkyl, optionally substituted C 1 -C 6 alkyl, —NH 2 , —NR′R′, —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, hydroxy(C 1 -C 6 alkyl), hydroxy(C 1 -C 6 alkoxy), alkoxy(C 1 -C 6 alkyl), alkoxy(C 1 -C 6 alkoxy), C 1 -C 6 alkyl-NR′ 2 , C 1 -C 6 alkyl-SR′, —CONH(C 1 -C 6 alkyl), —CON(C 1 -C 6 alkyl) 2 , —CO 2 H, —CO 2 R' is selected from the group consisting of -R', -OCOR, -OCOR', -OC(=O)OR', -OC(=O)NR', ​​-OC(=S)OR', -OC(=S)NR', ​​-OR', and -NR'R'; each R' independently represents hydrogen or, when allowed by valence, is selected from optionally substituted C 1 -C 10 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 3 -C 10 heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, amino, hydroxy, halo, oxo, cyano, optionally substituted C 1 -C 10 alkyl; R 1 and R 2 are each independently selected from the group consisting of hydrogen, oxygen, a C 1 -C 20 alkyl group, an optionally substituted linear or branched C 1 -C 20 aminoalkyl group, an optionally substituted linear, branched or cyclic C 1 -C 20 alkyl group optionally containing one or more heteroatoms, a substituted C 1 -C 20 alkyl group, a C 1 -C 20 haloalkyl group, a substituted C 1 -C 20 haloalkyl group, and an aliphatic linear or branched C 3 -C 20 aminoalkyl group optionally containing one or more heterocycles, or R 1 and Y are interconnected to form an optionally substituted 4-8 membered ring, or R 1 and R 2 are interconnected to form an optionally substituted 4-8 membered ring optionally containing one or more heteroatoms; R 3 is hydrogen, absent, or represents a methyl group, an isopropyl group, a C 2 -C 10 alkyl group, a substituted C 2 -C 10 alkyl group, a C 1 -C 10 haloalkyl group, a substituted C 1 -C 10 haloalkyl group, a C 1 -C 10 alkylhydroxy group, a halo group, a C 1 -C 10 alkoxy group, an amino group, a thioalkoxy group, a thioalkyl group, a hydroxy group, a mercapto group, an allyl group, a C 1 -C 10 ether group, a vinyl group, a cyano group, a nitro group, a C 1 -C 10 alkylamino group, a C 1 -C 10 alkylamido group, a C 3 -C 10 cycloalkyl group, a substituted C 3 -C 10 cycloalkyl group, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, a bicyclic aromatic ring, an unsaturated ring, or a bicyclic aliphatic ring; or R 3 and A are interconnected to form an optionally substituted 4- to 8-membered ring; or R 3 and Y are interconnected to form an optionally substituted 4- to 8-membered ring; R 4 is absent, hydrogen, or represents a methyl group, an isopropyl group, a C 2 -C 10 alkyl group, a substituted C 2 -C 10 alkyl group, a C 1 -C 10 haloalkyl group, a substituted C 1 -C 10 haloalkyl group, a C 1 -C 10 alkylhydroxy group, a halo group, a C 1 -C 10 alkoxy group, a C 3 -C 10 cycloalkyl group, a substituted C 3 -C 10 cycloalkyl group, a heteroaryl, a substituted heteroaryl, a heterocyclyl, a substituted heterocyclyl, a bicyclic aromatic ring, an unsaturated aliphatic ring, or a bicyclic aliphatic ring, or R 3 and R 4 are interconnected to form an optionally substituted 4-8 membered ring.

2. The compound has the formula IIa: 【Transformation 3】 or Formula IIb: 【Chemistry 4】 (In the formula: R ５ and R ６ are each independently selected from the group consisting of hydrogen, a methyl group, an isopropyl group, C ２ -C １０ Alkyl group, substituted C ２ -C １０ Alkyl group, C １ -C １０ Haloalkyl groups, substituted C １ -C １０ Haloalkyl group, C １ -C １０ Alkylhydroxy group, halo group, C １ -C １０ Alkoxy group, amino group, hydroxy group, allyl group, C １ -C １０ Ether group, vinyl group, C １ -C １０ Alkylamino group, C １ -C １０ Alkylamide group, C ３ -C １０ Cycloalkyl group, substituted C ３ -C １０ represents cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, bicyclic aromatic ring, unsaturated aliphatic ring, and bicyclic aliphatic ring; n is an integer ranging from 0 to 5; R ７ and R ８ are each independently selected from hydrogen, a methyl group, an isopropyl group, C ２ -C １０ Alkyl group, substituted C ２ -C １０ Alkyl group, C １ -C １０ Haloalkyl groups, substituted C １ -C １０ Haloalkyl group, C １ -C １０ Alkylhydroxy group, halo group, C １ -C １０ Alkoxy group, amino group, hydroxy group, allyl group, C １ -C １０ Ether group, vinyl group, C １ -C １０ Alkylamino group, C １ -C １０ Alkylamide group, C ３ -C １０ Cycloalkyl group, substituted C ３ -C １０ represents a cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, bicyclic aromatic ring, unsaturated aliphatic ring, or bicyclic aliphatic ring, or R ７ and R ８ are interconnected to form an optionally substituted 4- to 8-membered ring.

3. The compound has the formula IIIa: 【Transformation 5】 or Formula IIIb: 【Transformation 6】 3. The compound of claim 1 or 2, represented by:

4. The compound has the formula (IV): 【Transformation 7】 (Wherein A represents a methyl group, an isopropyl group, a tert-butyl group, a linear or branched C １ -C １０ alkyl groups, optionally substituted C containing one or more carbocyclic rings ３ -C １０ Cycloalkyl groups, linear or branched C ２ -C １０ Alkyl group, linear or branched chain substitution C ２ -C １０ selected from the group comprising alkyl groups, R １ and R ２ are each independently hydrogen, an optionally substituted linear, branched or cyclic C １ -C ２０ alkyl groups; optionally substituted C １ -C ２０ alkyl groups; optionally substituted linear or branched C ５ -C ２０ alkyl-aminoalkyl groups containing one or more nitrogen atoms and C １ -C １０ alkyl group, cyclic or acyclic C １ -C １０ alkylamino groups, and cyclic or acyclic C １ -C １０ a linear, branched or cyclic C optionally substituted with one or more substituents independently selected from aminoalkyl groups; ５ -C ２０ aminoalkyl groups, or R １ and R ２ is C １ -C １０ alkyl group, cyclic or acyclic C １ -C １０ alkylamino groups, and cyclic or acyclic C １ -C １０ are interconnected to form one or more 4- to 8-membered rings optionally substituted with one or more substituents independently selected from aminoalkyl groups; R １ and R ２ At least one of the branched or cyclic C １ -C ２０ alkyl groups; optionally substituted linear or branched C ５ -C ２０ alkyl-aminoalkyl groups containing one or more nitrogen atoms and C １ -C １０ alkyl group, cyclic or acyclic C １ -C １０ alkylamino groups, and cyclic or acyclic C １ -C １０ a linear, branched or cyclic C optionally substituted with one or more substituents independently selected from aminoalkyl groups; ５ -C ２０ 3. The compound of claim 1, wherein the aryl group is an aminoalkyl group.

5. The compound has the formula IVa: 【Transformation 8】 Or formula IVb: 【Chemistry 9】 (In the formula: R ９ and R １０ are each independently selected hydrogen or a methyl group, an isopropyl group, C ２ -C １０ Alkyl group, substituted C ２ -C １０ Alkyl group, C １ -C １０ Haloalkyl groups, substituted C １ -C １０ Haloalkyl group, C １ -C １０ Alkylhydroxy group, halo group, C １ -C １０ Alkoxy group, amino group, hydroxy group, allyl group, C １ -C １０ Ether group, vinyl group, C １ -C １０ Alkylamino group, C １ -C １０ Alkylamide group, C ３ -C １０ Cycloalkyl group, substituted C ３ -C １０ cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, bicyclic aromatic ring, unsaturated aliphatic ring, bicyclic aliphatic ring, any combination thereof, or R ９ and R １０ are interconnected to form one or more optionally substituted 4- to 8-membered rings; m is an integer ranging from 0 to 7; R １１ and R １２ are each independently selected from the group including hydrogen, or a methyl group, an isopropyl group, C ２ -C １０ Alkyl group, substituted C ２ -C １０ Alkyl group, C １ -C １０ Haloalkyl groups, substituted C １ -C １０ Haloalkyl group, C １ -C １０ Alkylhydroxy group, halo group, C １ -C １０ Alkoxy group, amino group, hydroxy group, allyl group, C １ -C １０ Ether group, vinyl group, C １ -C １０ Alkylamino group, C １ -C １０ Alkylamide group, C ３ -C １０ Cycloalkyl group, substituted C ３ -C １０ cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, bicyclic aromatic ring, unsaturated aliphatic ring, bicyclic aliphatic ring, or any combination thereof, or R １１ and R １２ are interconnected to form an optionally substituted 4- to 8-membered ring.

6. The compound has the formula V': 【Chemistry 10】 or formula V′a: 【Chemistry 11】 wherein n is 1 to 3; each Y is independently CHR' １ or NR' １ and R' １ is absent or is one or more substituents, each optionally containing one or more nitrogen atoms, and is an optionally substituted linear, branched or cyclic C １ -C ２０ alkyl groups; optionally substituted C １ -C ２０ alkyl groups; optionally substituted linear or branched C ５ -C ２０ alkyl-aminoalkyl groups containing one or more nitrogen atoms and C １ -C １０ alkyl group, cyclic or acyclic C １ -C １０ alkylamino groups, and cyclic or acyclic C １ -C １０ a linear, branched or cyclic C optionally substituted with one or more substituents independently selected from aminoalkyl groups; ５ -C ２０ Aminoalkyl groups; halo, oxo, -NO ２ , amino, hydroxy, -CN, -OH, -CONH ２ , -CONR' ２ , -CNNR' ２ , -CSNR' ２ , -CONH-OH, -CONH-NH ２ , -NHCOR, -NHCSR, -NHCNR, -NC(=O)OR, -NC(=O)NR', ​​-NC(=S)OR', -NC(=S)NR', ​​-SO ２ R', -SOR', -SR', -SO ２ OR', -SO ２ N(R') ２ , —NHNR′ ２ , -NNR', C １ -C ６ Haloalkyl, optionally substituted C １ -C ６ Alkyl, —NH ２ , -NR'R', -NH(C １ -C ６ alkyl), -N(C １ -C ６ alkyl) ２ , C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, hydroxy (C １ -C ６ alkyl), hydroxy (C １ -C ６ alkoxy), alkoxy(C １ -C ６ alkyl), alkoxy (C １ -C ６ Alkoxy), C １ -C ６ Alkyl-NR' ２ , C １ -C ６ Alkyl-SR', -CONH(C １ -C ６ alkyl), -CON(C １ -C ６ alkyl) ２ , -CO ２ H, -CO ２ R', -OCOR, -OCOR', -OC(=O)OR', -OC(=O)NR', ​​-OC(=S)OR', -OC(=S)NR', ​​-OR', -NR'R', or combinations thereof; each R' independently represents hydrogen or an optionally substituted C １ -C １０ Alkyl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ３ -C １０ Heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, amino, hydroxy, halo, oxo, cyano, optionally substituted C １ -C １０ 3. The compound of claim 1, wherein the aryl group is selected from the group consisting of aryl, aryl, aryl, alkyl, or combinations thereof.

7. 3. The compound of claim 1 or 2, wherein A is tert-butyl and the compound is the Z isomer.

8. The compound has the formula VI': 【Chemistry 12】 8. The compound of claim 7, represented by the formula: wherein R' 1 is absent or one or more substituents independently selected from the group consisting of: an optionally substituted cyclic C 5 -C 6 aliphatic ring, each containing one or more nitrogen atoms; an optionally substituted linear, branched or cyclic C 1 -C 20 alkyl group; a linear, branched or cyclic C 5 -C 20 aminoalkyl group containing one or more nitrogen atoms and optionally substituted with one or more substituents independently selected from a C 1 -C 10 alkyl group, a cyclic or acyclic C 1 -C 10 alkylamino group, and a cyclic or acyclic C 1 -C 10 aminoalkyl group; halo, oxo, -NO 2 , amino, hydroxy, -CN, -OH, -CONH 2 .

9. The compound is 【Chemistry 13】 and 【Chemistry 14】 3. The compound of claim 1 or 2, selected from the group consisting of:

10. 10. The compound of claim 9, wherein the compound is T3.

11. 11. The compound of claim 10, wherein the compound is a Z isomer.

12. A nanoparticle comprising a core and a shell, wherein the shell comprises a lipid layer and the core comprises a compound according to claim 1 or 2.

13. The nanoparticle of claim 12 , wherein the lipid layer comprises a phospholipid and a sterol.

14. The nanoparticle of claim 12 , wherein the nanoparticle is in the form of a liposome or a micelle.

15. The nanoparticles of claim 12, wherein the nanoparticles are characterized by a size between 50 nanometers (nm) and 500 nm.

16. The nanoparticle of claim 12, further comprising a peptide comprising an amino acid sequence selected from SEQ ID NOs: 1-13.

17. A pharmaceutical composition comprising the nanoparticles of claim 12 and a pharmaceutically acceptable carrier.

18. The pharmaceutical composition of claim 17 for use in treating a neutrophil-related disease or condition.

19. The pharmaceutical composition for use according to claim 18, wherein the disease or condition is selected from the group consisting of cancer, an inflammatory disease or condition, and an inflammatory autoimmune disease or condition.

20. The pharmaceutical composition for use according to claim 19, wherein the inflammatory disease or condition is selected from chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (IBD), peritonitis, and inflammatory skin disorders or diseases.

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