Method for using cyclic peptides to capture interleukin-1 beta

Abstract

This specification provides a method for using compounds that bind to interleukin-1 beta (IL-1β) in the interleukin-1 beta (IL-1β) binding pocket identified herein, thereby capturing IL-1β and inhibiting its interaction with the interleukin-1 receptor type I (IL-1R1).

Description

[Technical Field]

[0001] 1. Cross-references to related applications This application claims the interests of U.S. Provisional Patent Application No. 63 / 507,984 filed on 13 June 2023 and U.S. Provisional Patent Application No. 63 / 612,878 filed on 20 December 2023, the disclosures of which are incorporated herein by reference.

[0002] 2. Sequence Listing This application includes a computer-readable sequence listing file submitted with this application in XML format, the entire contents of which are incorporated herein by reference. The sequence listing XML file submitted with this application is titled "14463-089-228_SEQ_LISTING.xml", was created on June 10, 2024, and has a size of 46,471 bytes.

[0003] 3. Field This disclosure relates to methods for using compounds such as cyclic peptides or compounds of formula (I), (II), (IIA), (III), (IIIA), or (IV) that bind to interleukin-1 beta (IL-1β), capture IL-1β, and prevent it from interacting with the interleukin-1 receptor type I (IL-1R1). [Background technology]

[0004] 4.Background Interleukin-1β (IL-1β) signals by binding to its cell surface receptor, interleukin-1 receptor type I (IL-1R1), via interactions between IL-1β and the three binding domains (D1, D2, D3) of IL-1R1. The binding interaction between IL-1β and IL-1R1 can be disrupted or inhibited by allosterically modifying the conformation of IL-1β or by orthosterically binding to IL-1β and competitively disrupting the binding interaction between IL-1β and the D3 domain of IL-1R1. The ongoing development of compounds that are allosteric and / or orthosteric inhibitors of IL-1β-induced IL-1R1 signaling is a pressing need. [Overview of the Initiative]

[0005] 5.Summary In one embodiment, the Specified provides a method for inhibiting the binding of human interleukin-1 beta (IL-1β) to the human interleukin-1 receptor type I (IL-1R1), comprising contacting IL-1β with a compound that binds to the lipophilic binding pocket of interleukin-1 beta (IL-1β) or a pharmaceutically acceptable salt thereof.

[0006] In another embodiment, the Specified provides a method for inhibiting the binding of human interleukin-1 beta (IL-1β) to the human interleukin-1 receptor type I (IL-1R1), comprising contacting IL-1β with a compound that binds to IL-1β in a binding pocket defined by the amino acid residues Gly177-Leu178-Lys179-Glu180-Lys181-Asn182-Leu183-Tyr184 (SEQ ID NO: 16) and Val201-Asp202-Pro203-Lys204-Asn205-Tyr206-Pro207 (SEQ ID NO: 17) of IL-1β.

[0007] In some embodiments, the compound allosterically or orthosterically inhibits the binding of IL-1β to IL-1R1. In some embodiments, the compound inhibits the binding of IL-1β to the D3 domain of IL-1R1 (SEQ ID NO: 7).

[0008] In some embodiments, the compound binds to one or both of the IL-1β residues Lys179 or Pro207. In some embodiments, the compound comprises at least one moiety selected from a) a pi-effect interaction moiety capable of receiving a cation-pi interaction from the side chain of the IL-1β residue Lys179, or b) a pi-effect interaction moiety capable of receiving a polar-pi interaction from the backbone of the IL-1β residue Pro207.

[0009] In some embodiments, the binding pocket further comprises Val119, Arg120, and / or Ser121 of IL-1β. In some embodiments, the compound binds to one or more of Val119, Arg120, Ser121, Pro203, or Lys204 of IL-1β.

[0010] In some embodiments, the compound includes at least one portion selected from a) a hydrogen bonding interaction moiety capable of donating a hydrogen bond to the carbonyl skeleton of residue Val119 of IL-1β, b) a pi effect interaction moiety capable of receiving a cation-pi interaction from the side chain of residue Arg120 of IL-1β, c) a hydrogen bonding interaction moiety capable of donating a hydrogen bond to the carbonyl skeleton of residue Ser121 of IL-1β, d) a hydrogen bonding interaction moiety capable of donating a hydrogen bond to the carbonyl skeleton of residue Pro203 of IL-1β, or e) a hydrogen bonding interaction moiety capable of donating a hydrogen bond to the carbonyl skeleton of residue Lys204 of IL-1β.

[0011] In some embodiments, the compound includes at least one portion selected from a) a hydrogen bonding interaction moiety capable of donating a hydrogen bond to the carbonyl skeleton of residue Val119 of IL-1β, b) a pi effect interaction moiety capable of receiving a cation-pi interaction from the side chain of residue Arg120 of IL-1β, c) a hydrogen bonding interaction moiety capable of donating a hydrogen bond to the carbonyl skeleton of residue Ser269 of IL-1β, d) a hydrogen bonding interaction moiety capable of receiving a hydrogen bond to the carbonyl skeleton of residue Ser269 of IL-1β, or e) a basic moiety capable of electrostatic interaction with the C-terminal carboxylic acid of IL-1β.

[0012] In some embodiments, the compound includes at least one portion selected from a) a hydrogen bonding interaction moiety capable of accepting a hydrogen bond from the NH backbone of the residue Arg120 of IL-1β, b) a hydrogen bonding interaction moiety capable of accepting a hydrogen bond from the side chain of the residue Arg120 of IL-1β, c) a hydrogen bonding interaction moiety capable of accepting a hydrogen bond from the NH backbone of the residue Ser121 of IL-1β, or d) a hydrogen bonding interaction moiety capable of accepting a hydrogen bond from the side chain of the residue Lys204 of IL-1β.

[0013] In some embodiments, the compound binds to Tyr206 of IL-1β. In some embodiments, the compound includes a hydrogen bonding interaction moiety that can donate a hydrogen bond to the carbonyl skeleton of the Tyr206 residue of IL-1β.

[0014] In some embodiments, the binding pocket further comprises Phe162 and / or Ser269 of IL-1β. In the method according to claim 20, the compound binds to one or both of the residues Phe162 or Ser269 of IL-1β.

[0015] In some embodiments, the compound comprises one or more moieties selected from: a) a pi-effect interaction moiety capable of donating a polar-pi interaction to residue Phe162 of IL-1β; b) a hydrogen bonding interaction moiety capable of accepting a hydrogen bond from the side chain of residue Ser269 of IL-1β; or c) a pi-effect interaction moiety capable of accepting a polar-pi interaction from residue Ser269 of IL-1β.

[0016] In some embodiments, the compound is a peptide. In some embodiments, the peptide is a cyclic peptide. In some embodiments, the peptide or cyclic peptide has a length of 12 to 16 amino acid residues.

[0017] In some embodiments, the compound has a molecular weight of about 1200 Da to about 3000 Da, about 1500 Da to 2500 Da, or about 1750 to about 2250 Da.

[0018] In another aspect, provided herein is a method of inhibiting the binding of human IL-1β to human IL-1R1, comprising contacting IL-1β with a compound that competes for binding to IL-1R1, wherein the compound has the structure of formula (I), (II), (IIA), (III), (IIIA), (IV) or a pharmaceutically acceptable salt thereof, wherein X 1 X 2 X 3 A 1 A 2 R 1 ~R 7 R 8a R 8b R 9a R 9b R 10 R 11 R 12 R 13a R 13b and R 14 are as described herein.

[0019] In another embodiment, this specification provides a method for inhibiting the binding of human IL-1β to human IL-1R1, comprising contacting IL-1β with a compound that competes for binding to IL-1R1, wherein the compound is a peptide having a sequence selected from SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, or SEQ ID NO: 15, or a pharmaceutically acceptable salt thereof.

[0020] In another embodiment, this specification provides a method for inhibiting the binding of human IL-1β to human IL-1R1, comprising contacting IL-1β with a compound that competes for binding to IL-1R1, wherein the compound is a peptide having a sequence selected from compound A, compound B, compound C, compound D, compound E, compound F, compound G, compound H or pharmaceutically acceptable salts thereof.

[0021] 6. Brief explanation of the drawing The above overview and the following detailed description relating to specific embodiments of this application will be better understood when read in conjunction with the accompanying drawings. However, it should be understood that this application is not limited to the exact embodiments shown in the drawings. [Brief explanation of the drawing]

[0022] [Figure 1] Figure 1 shows the identified binding site on IL-1β, where the compounds described herein can bind to inhibit or disrupt the binding of IL-1β to IL-1R1. The indicated binding site is a lipophilic binding pocket located between the N-terminal and C-terminal domains of the tertiary structure of IL-1β, adjacent to the third binding domain of IL-1R1. [Figure 2A] Figures 2A–2D show the amino acid residue numbering schemes for specific macrocyclic peptides of formulas (I), (II), (III), and (IV) as described herein, respectively. [Figure 2B]Figures 2A - 2D show the numbering schemes of the amino acid residues of specific macrocyclic peptides of formulas (I), (II), (III), and (IV) described herein, respectively. [Figure 2C] Figures 2A - 2D show the numbering schemes of the amino acid residues of specific macrocyclic peptides of formulas (I), (II), (III), and (IV) described herein, respectively. [Figure 2D] Figures 2A - 2D show the numbering schemes of the amino acid residues of specific macrocyclic peptides of formulas (I), (II), (III), and (IV) described herein, respectively. [Figure 3] Figure 3 shows a three - dimensional cartoon plot of compound A (SEQ ID NO: 8) of the present disclosure bound to the hydrophobic binding pocket of IL - 1β determined by X - ray crystallographic analysis. The side chains at amino acid positions 1, 2, 6, 7, and 10 of the macrocyclic peptide are shown using stick representation and are named. The amino acid residues Arg120, Ser121, Lys179, and Lys204 of IL - 1β are named. [Figure 4A] Figures 4A - 4B show two - dimensional diagrams of the binding interactions between compound A (SEQ ID NO: 8) and the residues of the hydrophobic binding pocket of IL - 1β determined by X - ray crystallographic analysis. Figure 4A shows the binding interactions between the lower part (amino acids 1 - 7) of compound A (SEQ ID NO: 8) and the residues of the binding pocket. Figure 4B shows the binding interactions between the upper part (amino acids 8 - 14) of compound A (SEQ ID NO: 8) and the residues of the binding pocket. Hydrogen - bond interactions between the compound and IL - 1β residues (acceptor / donor) are represented using dashed - line arrows, and the tip of the arrow indicates the hydrogen - bond acceptor. Pi - effect interactions (e.g., arene - H) are represented by dashed - line arrows with the H:benzene symbol. [Figure 4B]Figures 4A-4B show two-dimensional diagrams of the binding interactions between compound A (SEQ ID NO: 8) and residues in the lipophilic binding pocket of IL-1β, as determined by X-ray crystallography. Figure 4A shows the binding interactions between the lower part of compound A (SEQ ID NO: 8) (amino acids 1-7) and residues in the binding pocket. Figure 4B shows the binding interactions between the upper part of compound A (SEQ ID NO: 8) (amino acids 8-14) and residues in the binding pocket. Hydrogen bonding interactions between the compound and IL-1β residues (acceptor / donor) are represented by dashed arrows, with the arrowhead indicating a hydrogen bond acceptor. Pi-effect interactions (e.g., arene-H) are represented by dashed arrows with the symbol H: benzene. [Figure 5] Figure 5 shows a three-dimensional cartoon plot of compound B (SEQ ID NO: 9) of this disclosure bound to the lipophilic binding pocket of IL-1β, as determined by X-ray crystallography. The side chains at amino acid positions 1, 2, 6, 7, and 10 of the macrocyclic peptide are shown using bars and labeled with their names. The amino acid residues Arg120, Ser121, Lys179, and Lys204 of IL-1β are labeled with their names. [Figure 6A] Figures 6A and 6B show two-dimensional diagrams of the binding interactions between compound B (SEQ ID NO: 9) and residues in the lipophilic binding pocket of IL-1β, as determined by X-ray crystallography. Figure 6A shows the binding interactions between the lower part of compound B (SEQ ID NO: 9) (amino acids 1-7) and residues in the binding pocket. Figure 6B shows the binding interactions between the upper part of compound B (SEQ ID NO: 9) (amino acids 8-14) and residues in the binding pocket. Hydrogen bonding interactions between the compound and IL-1β residues (acceptor / donor) are represented by dashed arrows, with the arrowheads indicating hydrogen bond acceptors. Pi-effect interactions (e.g., arene-H) are represented by dashed arrows with the symbol H: benzene. [Figure 6B]Figures 6A and 6B show two-dimensional diagrams of the binding interactions between compound B (SEQ ID NO: 9) and residues in the lipophilic binding pocket of IL-1β, as determined by X-ray crystallography. Figure 6A shows the binding interactions between the lower part of compound B (SEQ ID NO: 9) (amino acids 1-7) and residues in the binding pocket. Figure 6B shows the binding interactions between the upper part of compound B (SEQ ID NO: 9) (amino acids 8-14) and residues in the binding pocket. Hydrogen bonding interactions between the compound and IL-1β residues (acceptor / donor) are represented by dashed arrows, with the arrowheads indicating hydrogen bond acceptors. Pi-effect interactions (e.g., arene-H) are represented by dashed arrows with the symbol H: benzene. [Figure 7] Figure 7 shows a three-dimensional cartoon plot of compound C (SEQ ID NO: 10) of this disclosure bound to the lipophilic binding pocket of IL-1β, as determined by X-ray crystallography. The side chains at amino acid positions 1, 2, 6, 7, and 10 of the macrocyclic peptide are shown using bars and labeled with their names. The amino acid residues Arg120, Ser121, Lys179, and Lys204 of IL-1β are labeled with their names. [Figure 8A] Figures 8A and 8B show two-dimensional diagrams of the binding interactions between compound C (SEQ ID NO: 10) and residues in the lipophilic binding pocket of IL-1β, as determined by X-ray crystallography. Figure 8A shows the binding interactions between the lower part of compound C (SEQ ID NO: 10) (amino acids 1-7) and residues in the binding pocket. Figure 8B shows the binding interactions between the upper part of compound C (SEQ ID NO: 10) (amino acids 8-14) and residues in the binding pocket. Hydrogen bonding interactions between the compound and IL-1β residues (acceptor / donor) are represented by dashed arrows, with the arrowheads indicating hydrogen bond acceptors. Pi-effect interactions (e.g., arene-H) are represented by dashed arrows with the symbol H: benzene. [Figure 8B]Figures 8A and 8B show two-dimensional diagrams of the binding interactions between compound C (SEQ ID NO: 10) and residues in the lipophilic binding pocket of IL-1β, as determined by X-ray crystallography. Figure 8A shows the binding interactions between the lower part of compound C (SEQ ID NO: 10) (amino acids 1-7) and residues in the binding pocket. Figure 8B shows the binding interactions between the upper part of compound C (SEQ ID NO: 10) (amino acids 8-14) and residues in the binding pocket. Hydrogen bonding interactions between the compound and IL-1β residues (acceptor / donor) are represented by dashed arrows, with the arrowheads indicating hydrogen bond acceptors. Pi-effect interactions (e.g., arene-H) are represented by dashed arrows with the symbol H: benzene. [Figure 9] Figure 9 shows a three-dimensional cartoon plot of compound D (SEQ ID NO: 11) of this disclosure bound to the lipophilic binding pocket of IL-1β, as determined by X-ray crystallography. The side chains at amino acid positions 1, 2, 6, 7, and 10 of the macrocyclic peptide are shown using bars and labeled with their names. The amino acid residues Arg120, Ser121, Lys179, and Lys204 of IL-1β are labeled with their names. [Figure 10A] Figures 10A and 10B show two-dimensional diagrams of the binding interactions between compound D (SEQ ID NO: 11) and residues in the lipophilic binding pocket of IL-1β, as determined by X-ray crystallography. Figure 10A shows the binding interactions between the lower part of compound D (SEQ ID NO: 11) (amino acids 1-7) and residues in the binding pocket. Figure 10B shows the binding interactions between the upper part of compound D (SEQ ID NO: 11) (amino acids 8-14) and residues in the binding pocket. Hydrogen bonding interactions between the compound and IL-1β residues (acceptor / donor) are represented by dashed arrows, with the arrowheads indicating hydrogen bond acceptors. Pi-effect interactions (e.g., arene-H) are represented by dashed arrows with the symbol H: benzene. [Figure 10B]Figures 10A and 10B show two-dimensional diagrams of the binding interactions between compound D (SEQ ID NO: 11) and residues in the lipophilic binding pocket of IL-1β, as determined by X-ray crystallography. Figure 10A shows the binding interactions between the lower part of compound D (SEQ ID NO: 11) (amino acids 1-7) and residues in the binding pocket. Figure 10B shows the binding interactions between the upper part of compound D (SEQ ID NO: 11) (amino acids 8-14) and residues in the binding pocket. Hydrogen bonding interactions between the compound and IL-1β residues (acceptor / donor) are represented by dashed arrows, with the arrowheads indicating hydrogen bond acceptors. Pi-effect interactions (e.g., arene-H) are represented by dashed arrows with the symbol H: benzene. [Figure 11] Figure 11 shows a three-dimensional cartoon plot of compound E (SEQ ID NO: 12) of this disclosure bound to the lipophilic binding pocket of IL-1β, as determined by X-ray crystallography. The side chains at amino acid positions 1, 2, 6, 7, and 10 of the macrocyclic peptide are shown using bars and labeled with their names. The amino acid residues Arg120, Ser121, Lys179, and Lys204 of IL-1β are labeled with their names. [Figure 12A] Figures 12A and 12B show two-dimensional diagrams of the binding interactions between compound E (SEQ ID NO: 12) and residues in the lipophilic binding pocket of IL-1β, as determined by X-ray crystallography. Figure 12A shows the binding interactions between the lower part of compound E (SEQ ID NO: 12) (amino acids 1-7) and residues in the binding pocket. Figure 12B shows the binding interactions between the upper part of compound E (SEQ ID NO: 12) (amino acids 8-14) and residues in the binding pocket. Hydrogen bonding interactions between the compound and IL-1β residues (acceptor / donor) are represented by dashed arrows, with the arrowheads indicating hydrogen bond acceptors. Pi-effect interactions (e.g., arene-H) are represented by dashed arrows with the symbol H: benzene. [Figure 12B]Figures 12A and 12B show two-dimensional diagrams of the binding interactions between compound E (SEQ ID NO: 12) and residues in the lipophilic binding pocket of IL-1β, as determined by X-ray crystallography. Figure 12A shows the binding interactions between the lower part of compound E (SEQ ID NO: 12) (amino acids 1-7) and residues in the binding pocket. Figure 12B shows the binding interactions between the upper part of compound E (SEQ ID NO: 12) (amino acids 8-14) and residues in the binding pocket. Hydrogen bonding interactions between the compound and IL-1β residues (acceptor / donor) are represented by dashed arrows, with the arrowheads indicating hydrogen bond acceptors. Pi-effect interactions (e.g., arene-H) are represented by dashed arrows with the symbol H: benzene. [Figure 13] Figure 13 shows a three-dimensional cartoon plot of the lipophilic binding pockets of IL-1β bound to compounds A (SEQ ID NO: 8), B (SEQ ID NO: 9), C (SEQ ID NO: 10), D (SEQ ID NO: 11), and E (SEQ ID NO: 12) of this disclosure, as determined by X-ray crystallography and shown as a superposition. The side chains at amino acid positions 1, 2, 6, 7, and 10 of the macrocyclic peptides are shown using bars and are labeled. The amino acid residues Arg120, Ser121, Lys179, and Lys204 of the IL-1β binding pocket are labeled. [Figure 14] Figure 14 shows a three-dimensional cartoon plot of compound F (SEQ ID NO: 13) of this disclosure bound to the lipophilic binding pocket of IL-1β, as determined by X-ray crystallography. The side chains at amino acid positions 1, 3, 6, 9, 10, and 15 of the macrocyclic peptide are shown using bars and labeled with their names. The amino acid residues Arg120, Ser121, Lys179, and Lys204 of the IL-1β binding pocket are also labeled with their names. [Figure 15A]Figures 15A and 15B show two-dimensional diagrams of the binding interactions between compound F (SEQ ID NO: 13) and residues in the lipophilic binding pocket of IL-1β, as determined by X-ray crystallography. Figure 15A shows the binding interactions between the lower part of compound F (SEQ ID NO: 13) (amino acids 1-8) and residues in the binding pocket. Figure 15B shows the binding interactions between the upper part of compound F (SEQ ID NO: 13) (amino acids 9-15) and residues in the binding pocket. Hydrogen bonding interactions between the compound and IL-1β residues (acceptor / donor) are represented by dashed arrows, with the arrowhead indicating a hydrogen bond acceptor. Pi-effect interactions (e.g., arene-H) are represented by dashed arrows with the symbol H: benzene. [Figure 15B] Figures 15A and 15B show two-dimensional diagrams of the binding interactions between compound F (SEQ ID NO: 13) and residues in the lipophilic binding pocket of IL-1β, as determined by X-ray crystallography. Figure 15A shows the binding interactions between the lower part of compound F (SEQ ID NO: 13) (amino acids 1-8) and residues in the binding pocket. Figure 15B shows the binding interactions between the upper part of compound F (SEQ ID NO: 13) (amino acids 9-15) and residues in the binding pocket. Hydrogen bonding interactions between the compound and IL-1β residues (acceptor / donor) are represented by dashed arrows, with the arrowhead indicating a hydrogen bond acceptor. Pi-effect interactions (e.g., arene-H) are represented by dashed arrows with the symbol H: benzene. [Figure 16] Figure 16 shows a three-dimensional cartoon plot of compound G (SEQ ID NO: 14) of this disclosure bound to the lipophilic binding pocket of IL-1β, as determined by X-ray crystallography. The side chains at amino acid positions 1, 2, 6, 7, and 10 of the macrocyclic peptide are shown using bars and are labeled. The amino acid residues Arg120, Ser121, Lys179, and Lys204 of the IL-1β binding pocket are labeled. [Figure 17A]Figures 17A and 17B show two-dimensional diagrams of the binding interactions between compound G (SEQ ID NO: 14) and residues in the lipophilic binding pocket of IL-1β, as determined by X-ray crystallography. Figure 17A shows the binding interactions between the lower part of compound G (SEQ ID NO: 14) (amino acids 1-7) and residues in the binding pocket. Figure 17B shows the binding interactions between the upper part of compound G (SEQ ID NO: 14) (amino acids 8-14) and residues in the binding pocket. Hydrogen bonding interactions between the compound and IL-1β residues (acceptor / donor) are represented by dashed arrows, with the arrowheads indicating hydrogen bond acceptors. Pi-effect interactions (e.g., arene-H) are represented by dashed arrows with the symbol H: benzene. [Figure 17B] Figures 17A and 17B show two-dimensional diagrams of the binding interactions between compound G (SEQ ID NO: 14) and residues in the lipophilic binding pocket of IL-1β, as determined by X-ray crystallography. Figure 17A shows the binding interactions between the lower part of compound G (SEQ ID NO: 14) (amino acids 1-7) and residues in the binding pocket. Figure 17B shows the binding interactions between the upper part of compound G (SEQ ID NO: 14) (amino acids 8-14) and residues in the binding pocket. Hydrogen bonding interactions between the compound and IL-1β residues (acceptor / donor) are represented by dashed arrows, with the arrowheads indicating hydrogen bond acceptors. Pi-effect interactions (e.g., arene-H) are represented by dashed arrows with the symbol H: benzene. [Figure 18] Figure 18 shows a three-dimensional cartoon plot of compound H (SEQ ID NO: 15) of this disclosure bound to the lipophilic binding pocket of IL-1β, as determined by X-ray crystallography. The side chains at amino acid positions 1, 2, 6, 7, and 10 of the macrocyclic peptide are shown using bars and are labeled. The amino acid residues Arg120, Ser121, Lys179, and Lys204 of the IL-1β binding pocket are labeled. [Figure 19A]Figures 19A and 19B show two-dimensional diagrams of the binding interactions between compound H (SEQ ID NO: 15) and residues in the lipophilic binding pocket of IL-1β, as determined by X-ray crystallography. Figure 19A shows the binding interactions between the lower part of compound H (SEQ ID NO: 15) (amino acids 1-7) and residues in the binding pocket. Figure 19B shows the binding interactions between the upper part of compound H (SEQ ID NO: 15) (amino acids 8-13) and residues in the binding pocket. Hydrogen bonding interactions between the compound and IL-1β residues (acceptor / donor) are represented by dashed arrows, with the arrowheads indicating hydrogen bond acceptors. Pi-effect interactions (e.g., arene-H) are represented by dashed arrows with the symbol H: benzene. [Figure 19B] Figures 19A and 19B show two-dimensional diagrams of the binding interactions between compound H (SEQ ID NO: 15) and residues in the lipophilic binding pocket of IL-1β, as determined by X-ray crystallography. Figure 19A shows the binding interactions between the lower part of compound H (SEQ ID NO: 15) (amino acids 1-7) and residues in the binding pocket. Figure 19B shows the binding interactions between the upper part of compound H (SEQ ID NO: 15) (amino acids 8-13) and residues in the binding pocket. Hydrogen bonding interactions between the compound and IL-1β residues (acceptor / donor) are represented by dashed arrows, with the arrowheads indicating hydrogen bond acceptors. Pi-effect interactions (e.g., arene-H) are represented by dashed arrows with the symbol H: benzene.

[0023] 7. Detailed explanation 7.1 definition Throughout the preceding "Background" and this specification, various publications, articles, and patents are cited or mentioned, and each of these references is incorporated herein by reference in its entirety. The consideration of documents, regulations, materials, apparatus, articles, etc. included herein is intended to present the background of the present invention. Such consideration does not constitute an admission that any or all of these matters constitute part of the prior art with respect to any invention disclosed or claimed.

[0024] Unless otherwise defined, all scientific and technical terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In other cases, specific terms used in this specification have the meaning set forth herein.

[0025] It should be noted that, unless the context clearly dictates otherwise, the singular forms used in this specification and the appended claims also include the plural forms.

[0026] Unless otherwise indicated, any numerical values, such as concentrations or concentration ranges, described in this specification should be understood to be modified in all cases by the term "about". Thus, the numerical values typically include ±10% of the recited value. For example, a concentration of 1 mg / mL includes from 0.9 mg / mL to 1.1 mg / mL. Similarly, a concentration range of 1% to 10% (w / v) includes from 0.9% (w / v) to 11% (w / v). The use of numerical ranges in this specification, unless the context clearly dictates otherwise, explicitly includes all possible subranges, all individual numerical values within that range (including integers and fractions of such values).

[0027] Unless otherwise indicated, the term "at least" before a series of elements should be understood to refer to each element in the series. One of ordinary skill in the art will recognize or be able to ascertain many equivalents to the specific embodiments of the methods described herein using only routine experimentation. Such equivalents are intended to be encompassed by this invention.

[0028] In this specification, the words “include,” “contain,” “include,” “incorporate,” “have,” “possess,” “contain,” or “contain,” or any other variation thereof, mean inclusion of the integer or set of integers described and not exclusion of any other integer or set of integers, and are intended to be non-exclusive or open-ended. For example, a composition, mixture, process, method, article, or apparatus containing the enumerated elements is not necessarily limited to those elements alone, but may include other elements not expressly enumerated, or other elements specific to such composition, mixture, process, method, article, or apparatus. Furthermore, unless expressly indicated otherwise, “or” means inclusive “or” and not exclusive “or.” For example, condition A or B is satisfied by one of the following: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists), and both A and B are true (or exist).

[0029] As used herein, the conjunction "and / or" between multiple enumerated elements is understood to encompass both individual options and combined options. For example, when two elements are connected by "and / or," the first option refers to the first element being applicable in the absence of the second element. The second option refers to the second element being applicable in the absence of the first element. The third option refers to the first and second elements being applicable together. Any one of these options is understood to fall under the meaning of the term "and / or" as used herein, and therefore satisfy the requirements of the term. If multiple of those options are applicable simultaneously, it is also understood to fall under the meaning of the term "and / or," and therefore satisfy the requirements of the term.

[0030] The word “consisting of,” as used herein, or variations such as “consisting of” or “consisting of,” as used throughout this specification and the claims, indicate the inclusion of any integer or set of integers listed, but that no additional integers or sets of integers can be added to the specified method, structure, or composition.

[0031] As used herein, the phrase “essentially from,” or variations such as “essentially from” or “essentially from,” as used throughout this specification and the claims, indicate the inclusion of any integer or set of integers listed, and the optional inclusion of any integer or set of integers listed, which does not substantially alter the fundamental or novel properties of the specified method, structure or composition. See MPEP §2111.03.

[0032] As used herein, “subject” means any animal, preferably a mammal, most preferably a human. As used herein, the term “mammal” includes all mammals. Examples of mammals, though not limited to, include cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans, most preferably humans.

[0033] Furthermore, the words “about,” “approximately,” “generally,” “substantially,” and similar terms used herein when referring to the dimensions or properties of the components of the methods provided herein indicate that the dimensions / properties described are not strict boundaries or parameters, but are functionally identical or similar to those understood by those skilled in the art, and do not exclude small variations from them. At the very least, such references, including numerical parameters, will include variations that do not change the minimum significant figures when using mathematical and industrial principles accepted in the art (e.g., rounding, measurement or other systematic errors, manufacturing tolerances, etc.).

[0034] The terms “decrease,” “reduction,” or “reduction” generally mean that the test molecule may produce a reduced response (i.e., a downstream effect) compared to the response produced by the control or vehicle. A reduction can be a statistically significant difference in the measured response between the test molecule and the control (or vehicle), or a decrease in the measured response, e.g., approximately 1.1, 1.2, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or 30 times or more, e.g., a decrease of 500, 600, 700, 800, 900, or 1000 times or more.

[0035] The terms “enhancement,” “promotion,” or “increase” generally mean that the test molecule can produce a larger response (i.e., a downstream effect) compared to the response produced by the control or vehicle. Enhancement can be a statistically significant difference in the measured response between the test molecule and the control (or vehicle), or an increase in the measured response, e.g., an increase of approximately 1.1, 1.2, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or 30 times or more, e.g., an increase of 500, 600, 700, 800, 900, or 1000 times or more.

[0036] The term "recombinant" refers to polynucleotides, polypeptides, vectors, viruses, and other macromolecules produced, expressed, prepared, or isolated by recombinant means.

[0037] The terms “specifically bind,” “specifically bind,” “specifically bind,” or “bound” mean that the compounds described herein bind to IL-1R1, for example, in the binding pocket of interleukin-1 receptor type I (IL-1R1), or to specific residues of IL-1R1.

[0038] The term "subject" includes all humans and non-human animals. "Non-human animals" includes all vertebrates, such as mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cattle, chickens, amphibians, and reptiles. In this specification, the terms "subject" and "patient" may be used interchangeably.

[0039] Throughout this disclosure, the terms “compounds of the disclosure,” “compounds of the disclosure,” and “compounds disclosed herein” are interchangeable and are understood to include the disclosed cyclic peptides and compounds of formulas (I), (II), (IIA), (III), (IIIA), and (IV). References to compounds of formula (I) include other compounds of the general formulas that fall within the scope of formula (I), including but not limited to compounds of formula (IA). References to compounds of formula (II) include other compounds of the general formulas that fall within the scope of formula (II), including but not limited to compounds of formula (IIA). References to compounds of formula (III) include other compounds of the general formulas that fall within the scope of formula (III), including but not limited to compounds of formula (IIA). References to compounds of formula (IV) include other compounds of the general formulas that fall within the scope of formula (IV). Compounds of formulas (I), (II), (IIA), (III), (IIIA), and (IV) can form salts, which are also included within the scope of this disclosure. References to the compounds of this disclosure (or compounds of formula (I), (II), (IIA), (III), (IIIA), or (IV)) in this specification are understood to include references to their salts unless otherwise specified. As used herein, “salt” means an acidic salt formed with an inorganic acid and / or an organic acid, and a basic salt formed with an inorganic base and / or an organic base. Furthermore, if a compound of formula (I), (II), (IIA), (III), (IIIA), or (IV) contains both a basic moiety (e.g., an amino group, pyrrolidine, or imidazole) and an acidic moiety (e.g., a carboxylic acid), an amphoteric ion (“intramolecular salt”) may be formed, and amphoteric ions are also included in the term “salt” as used herein. In one embodiment, the salt is a pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salt. In another embodiment, the salt is a salt other than a pharmaceutically acceptable salt.Salts of compounds of formula (I) can be formed, for example, by reacting compounds of formula (I), (II), (IIA), (III), (IIIA), or (IV) with a certain amount (e.g., equivalent) of acid or base in a medium (e.g., a medium on which the salt precipitates) or an aqueous medium, and then freeze-drying them.

[0040] "Acyl" refers to an alkyl-C(O)- group, where alkyl is defined as described below. The bond to the parent group is via the carbon atom of the carbonyl group.

[0041] The terms "alkyl" and other groups having the prefix "alk" (e.g., alkoxy) refer to a carbon chain that contains the indicated number of carbon atoms and can be linear, branched, or a combination thereof. For example, C1-C6 alkyl refers to an alkyl group having 1 (i.e., methyl) to 6 (i.e., hexyl) carbon atoms. In certain embodiments, linear alkyl groups have 1 to 6 carbon atoms, and branched alkyl groups have 3 to 7 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.

[0042] "Alkoxy" and "alkyl-O-" are used interchangeably and refer to an alkyl group bonded to oxygen.

[0043] "Amino" refers to the H2N- group. The bond to the parent group is via a nitrogen atom.

[0044] "Amino acids" means naturally occurring α-amino acids and their stereoisomers, as well as unnatural amino acids (e.g., β-amino acids and substituted amino acids) and their stereoisomers. In the sequences shown with respect to peptides (compounds) according to this disclosure, amino acid residues have their usual meanings. Thus, "G" is glycine, "W" is tryptophan, "A" is alanine, "S" is serine, and so on. "D" isomers should be understood to be indicated by a single-letter code or "d" before the amino acid name; for example, dA is the D isomer of L-alanine. Amino acid residues not included above have the definitions set out in the table in the Examples section below.

[0045] In this specification, "arene" means aryl or heteroaryl.

[0046] As used herein, "aryl" refers to a monocyclic six-membered ring or a bicyclic ten-membered ring system in which at least one ring is aromatic and all ring atoms are carbon.

[0047] A "bicyclic ring system" refers to two linked rings. These rings may be fused (i.e., sharing two adjacent atoms) or they may be "spirocyclic" (i.e., sharing only a single atom).

[0048] "Carboxylate" refers to the HO2C- group. The bond to the parent group is via the carbon atom of the carbonyl component.

[0049] "Cycloalkyl" refers to a saturated cyclic hydrocarbon group. In certain embodiments, a cycloalkyl group has 3 to 12 carbon atoms and forms a 1 to 3 condensed carbon ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl.

[0050] "Fluoroalkyl" includes monosubstituted alkyl groups, multiple fluorine-substituted alkyl groups, and perfluorosubstituted alkyl groups. Examples include fluoromethyl, 1,1-difluoroethyl, trifluoromethyl, or 1,1,1,2,2-pentafluorobutyl.

[0051] Unless otherwise specified, "halogen" or "halo" includes fluorine (fluoro), chlorine (chloro), bromine (bromo), and iodine (iod). In one embodiment, the halo is fluoro (-F) or chloro (-Cl).

[0052] "Heterocycloalkyl" means a non-aromatic monocyclic, bicyclic, or tricyclic ring system containing about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, where one or more atoms in the ring system are elements other than carbon, such as nitrogen, oxygen, or sulfur, either alone or in combination. There are no adjacent oxygen and / or sulfur atoms in the ring system. In some embodiments, heterocycloalkyls contain about 5 to about 6 ring atoms. The prefixes aza, oxa, or thia preceding the base name heterocyclyl mean that at least one nitrogen, oxygen, or sulfur atom is present as a ring atom, respectively. In some embodiments, the nitrogen or sulfur atom of the heterocycloalkyl may, optionally, be oxidized to the corresponding N-oxide, S-oxide, or S,S-dioxide. Non-exclusive examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydropyranyl, and tetrahydrothiophenyl.

[0053] "Heteroaryl" refers to an aromatic monocyclic, bicyclic, or tricyclic ring structure in which one or more atoms (heteroatoms) in the ring are elements other than carbon. Heteroatoms are typically O, S, or N atoms. Examples of heteroaromatic groups include pyridinyl, pyrimidinyl, pyrrolyl, pyridadinyl, isoxazolyl, thiazolyl, oxazolyl, indolyl, benzoxazolyl, benzothiazolyl, and imidazolyl.

[0054] In formulas (I), (II), (IIA), (III), (IIIA), or (IV) or other general formulas herein, or in any of the components, any variable (e.g., R C1 If multiple ) are present, their definition in each presence is independent of their definition in the other presences. Combinations of substituents and / or variable compounds are permitted only if such combinations result in a stable compound. When selecting compounds of this disclosure, various substituents (e.g., R) are permitted. C9 Those skilled in the art will recognize that the substituents should be selected in accordance with well-known principles of chemical structure bonding and stability. Unless otherwise specified, substitutions by the substituents listed are permissible at any atom within the ring (e.g., aryl, heteroaryl, or saturated heteroaryl ring). However, such ring substitutions must be chemically permissible and result in a stable compound. A “stable” compound is one that can be prepared and isolated and whose structure and properties remain essentially unchanged, or can be made essentially unchanged, for a period of time sufficient to enable the use of the compound for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject).

[0055] The term “substitution” (or “substituted”) shall be deemed to include multiple degrees of substitution by the substituents listed. If multiple substituent parts are disclosed or claimed, the substituted compound may be independently substituted by one or more of the disclosed or claimed substituent parts, one or more of them. Independent substitution means that the substituents (two or more) may be the same or different.

[0056] Unless explicitly illustrated or described otherwise, a variable represented by a “floating” bond in a structural formula can exist on any bondable carbon atom within the ring to which the variable is bonded. Where it is indicated in formulas (I), (II), (IIA), (III), (IIIA), or (IV) or any embodiment thereof that a part may be “optionally substituted”, it means that formulas (I), (II), (IIA), (III), (IIIA), or (IV) or embodiments thereof include compounds containing the indicated (one or more) substituents in the part, and also compounds that do not contain the indicated (one or more) substituents in the part.

[0057] The wavy lines used in this specification [ka]

[0058] The symbol indicates the binding site to the remainder of the compound.

[0059] Some of the compounds described herein may exist as tautomers. Tautomers have different hydrogen bonding sites, involving one or more double bond rearrangements. For example, ketones and their enol forms are keto-enol tautomers. Individual tautomers and mixtures thereof are encompassed by the compounds of this disclosure.

[0060] In the compounds of this disclosure, atoms may exhibit their natural isotopic abundance. Alternatively, in specific isotopes having the same atomic number but with atomic masses or mass numbers different from those predominantly found in nature, one or more atoms may be artificially enriched. This disclosure, as described and claimed herein, is intended to include all appropriate isotopic variants of the compounds of this disclosure and its embodiments. For example, various isotopes of hydrogen (H) include protium ( 1 H) and deuterium ( 2 This includes H (also referred to herein as D). Protium is the primary hydrogen isotope found in nature. Deuterium enrichment may result in certain therapeutic benefits, such as an extension of the in vivo half-life or a relaxation of administration requirements, or it may result in compounds useful as standards for characterizing biological samples. The isotopic enriched compounds of this disclosure may be prepared without excessive experimentation by methods similar to those described herein in the schemes and examples using appropriate isotopic enrichment reagents and / or intermediates, or by common art well known to those skilled in the art.

[0061] The term "pharmaceutically acceptable salt" means a salt prepared from a pharmaceutically acceptable, non-toxic base or acid. If a compound of this disclosure is acidic (or has a functional group that may be anionic), its corresponding salt can be readily prepared from pharmaceutically acceptable, non-toxic bases, including inorganic and organic bases. Suitable examples of inorganic cations include alkali metal ions, such as Li. + kaNa + and K + , alkaline earth metal cations, for example, Ca2 + and Mg2 + , as well as other cations, such as Al 3+ and Zn + This includes, but is not limited to, the following: A suitable example of an organic cation is the ammonium ion (i.e., NH4). +This includes, but is not limited to, substituted ammonium ions. Suitable examples of substituted ammonium ions include those derived from methylamine, ethylamine, diethylamine, triethylamine, and ethylenediamine. If the compounds of this disclosure are basic, their corresponding salts can be readily prepared from pharmaceutically acceptable, non-toxic acids, including inorganic and organic acids. Examples of such acid addition salts include salts formed from hydrohalic acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid), formic acid, acetic acid, capric acid, and citric acid. Salts containing acetates, formates, caprinates, chlorides, or sodium salts are typical for applications using the compounds of this disclosure. In some embodiments, salts of the compounds of this disclosure may be formed by exchanges well known to those skilled in the art, such as anion exchanges (e.g., substitution of trifluoroacetate ions with chloride ions).

[0062] Furthermore, the compounds of this disclosure may exist in amorphous and / or crystalline forms. Therefore, all amorphous and crystalline forms of the compounds of formula (I), (II), (IIA), (III), (IIIA), or (IV), as well as mixtures thereof (including those in the examples), are intended to be within the scope of this disclosure. Also, some of the compounds of this disclosure may form solvates with water (i.e., hydrates) or common organic solvents, such as (but not limited to) acetic acid or acetonitrile. Such solvates and hydrates of the compounds of this disclosure, in particular pharmaceutically acceptable solvates and hydrates, along with their non-solvated and anhydrous forms, are also within the scope of this disclosure.

[0063] Any pharmaceutically acceptable prodrug modifications of the compounds disclosed herein that result in in vivo conversion to compounds within the scope of this disclosure are also within the scope of this disclosure.

[0064] This disclosure also relates to methods for producing compounds of formula (I), (II), (IIA), (III), (IIIA), or (IV), as described in the following examples, and which make the compounds of this disclosure available.

[0065] 7.2 method In one embodiment, the Specified provides a method for inhibiting the binding of interleukin-1 beta (IL-1β) to the interleukin-1 receptor type I (IL-1R1), comprising contacting interleukin-1 beta (IL-1β) with a compound described herein or a pharmaceutically acceptable salt thereof.

[0066] In another embodiment, this specification provides a method for inhibiting the binding of IL-1β to IL-1R, comprising contacting IL-1β with a compound described herein that competes for binding to IL-1R1 (e.g., a compound that competes with IL-1β for binding to IL-1R1) or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments of the methods described herein, the compounds described herein bind to IL-1β in the binding pocket of IL-1β, thereby inhibiting the binding of IL-1β to IL-1R1. In some embodiments, the binding pocket of IL-1β is the lipophilic binding pocket and / or hydrophobic binding pocket of IL-1β.

[0068] In some embodiments of the methods described herein, the compounds described herein inhibit the binding of IL-1β to the A site of IL-1R1 (e.g., the A site of IL-1R1 as described in Section 5.4). In some embodiments, inhibition of IL-1β binding to the A site of IL-1R1 inhibits one or more of the biological functions of IL-1R1 (e.g., inhibition of inflammation propagation, e.g., inhibition of inflammation propagation in a subject). In some embodiments, the compounds described herein inhibit or reduce the binding of IL-1β to the D1 and / or D2 domains of IL-1R1. In some embodiments, inhibiting the binding of IL-1β to the D1 and / or D2 domains of IL-1R1 inhibits one or more of the biological functions of IL-1R1 (e.g., inhibition of inflammation propagation, e.g., inhibition of inflammation propagation in a subject).

[0069] In some embodiments of the methods described herein, the compounds described herein inhibit the binding of IL-1β to the B site of IL-1R1 (e.g., the B site of IL-1R1 as described in Section 5.4). In some embodiments, inhibition of IL-1β binding to the B site of IL-1R1 inhibits one or more of the biological functions of IL-1R1 (e.g., inhibition of inflammation propagation, e.g., inhibition of inflammation propagation in a subject). In some embodiments, the compounds described herein inhibit the binding of IL-1β to the D3 domain of IL-1R1. In some embodiments, inhibition of IL-1β binding to the D3 domain of IL-1R1 inhibits one or more of the biological functions of IL-1R1 (e.g., inhibition of inflammation propagation, e.g., inhibition of inflammation propagation in a subject).

[0070] In some embodiments of the methods described herein, the compounds described herein inhibit the binding of IL-1β to both the A-site and B-site binding sites of IL-1R1. In some embodiments, inhibition of IL-1β binding to both the A-site and B-site binding sites of IL-1R1 inhibits one or more of the biological functions of IL-1R1 (e.g., inhibition of inflammation propagation, e.g., inhibition of inflammation propagation in a subject). In some embodiments, the compounds described herein inhibit the binding of IL-1β to the D1, D2, and D3 domains of IL-1R1. In some embodiments, inhibition of IL-1β binding to the D1, D2, and D3 domains of IL-1R1 inhibits one or more of the biological functions of IL-1R1 (e.g., inhibition of inflammation propagation, e.g., inhibition of inflammation propagation in a subject).

[0071] In some embodiments, the compounds described herein orthosterically inhibit the binding of IL-1β to IL-1R1. In some embodiments, orthosteric inhibition of IL-1R1 involves the binding of the compounds described herein to an orthosteric site (e.g., primary binding site) of IL-1R1. In some embodiments, the orthosteric site (e.g., primary binding site) is the active site of IL-1R1. In some embodiments, the orthosteric site (e.g., primary binding site) is the binding site of IL-1R1 (e.g., the binding site to the compounds described herein), which is the binding site of IL-1R1 that is specific to IL-1β.

[0072] In some embodiments, the compounds described herein allosterically inhibit the binding of IL-1β to IL-1R1. In some embodiments, allosteric inhibition of IL-1R1 involves the binding of the compounds described herein to an allosteric site (e.g., a secondary binding site) of IL-1R1. In some embodiments, the allosteric site (e.g., a secondary binding site) is not the active site of IL-1R1. In some embodiments, the allosteric site (e.g., a secondary binding site) of IL-1R1 is the binding site of IL-1R1 (e.g., the binding site to the compounds described herein), and this is not the binding site of IL-1R1 that is specific to IL-1β.

[0073] In some embodiments of the methods described herein, the compound is a compound described herein (e.g., Examples). In some embodiments, the compound is a compound of structural formula (I), (II), (IIA), (III), (IIIA), (IV) or a pharmaceutically acceptable salt thereof, where X 1 , X 2 , X 3 , A 1 , A 2 , R 1 ~R 7 , R 8a , R 8b , R 9a, R 9b , R 10 , R 11 , R 12 , R 13a , R 13b and R 14 This is as described herein.

[0074] 7.3 Interleukin-1 beta (IL-1β) Interleukin-1β (IL-1β) is a cytokine protein involved in inflammation. In some embodiments, IL-1β is also known as a leukocyte pyrogen, a leukocyte endogenous mediator, a mononuclear cell factor, a lymphocyte activator, IL1B, IL-1, IL1-BETA, IL1F2, or IL1 beta. In some embodiments, IL-1β is encoded by the IL1B gene (e.g., the human IL1B gene). The precursor form of IL-1β is cleaved by cytoplasmic caspase 1 (e.g., interleukin-1β convertase) to produce the mature form of IL-1β and the cleaved propeptide.

[0075] In some embodiments, IL-1β is a precursor form of IL-1β. In some embodiments, IL-1β is a mature form of IL-1β. In some embodiments, the mature form of IL-1β does not contain one or more or all of the amino acids of the IL-1β propeptide. In some embodiments, IL-1β (e.g., precursor IL-1β, IL-1β propeptide, or mature IL-1β) is human IL-1β. In some embodiments, the precursor form of human IL-1β contains or consists of the amino acid sequence (e.g., amino acids 1-269) of the human IL-1β precursor form described in UniProt accession number P01584. In some embodiments, the precursor form of human IL-1β contains or consists of the amino acid sequence of SEQ ID NO: 1. In some embodiments, the propeptide of human IL-1β contains or consists of the amino acid sequence (e.g., amino acids 117-269) of the human IL-1β propeptide described in UniProt accession number P01584. In some embodiments, the propeptide of human IL-1β contains or consists of the amino acid sequence of SEQ ID NO: 2. In some embodiments, the mature form of human IL-1β contains or consists of the amino acid sequence of the mature form of human IL-1β described in UniProt accession number P01584 (e.g., amino acids 117-269). In some embodiments, the mature form of human IL-1β contains or consists of the amino acid sequence of SEQ ID NO: 3. Exemplary amino acid sequences of these forms of human IL-1β are shown in Table 1 below. [Table 1]

[0076] References herein to specific amino acid residue numbers in the precursor form of IL-1β (e.g., in the methods described herein) are assumed to also refer to the corresponding residues in the mature form of IL-1β (e.g., residue Val119 in the precursor form of IL-1β corresponds to residue Val3 in the mature form of IL-1β). The corresponding residue number in the mature form of IL-1β can be determined by subtracting the number of amino acids in the cleaved propeptide of IL-1β (e.g., 116 residues) from the specific residue number in the precursor form of IL-1β.

[0077] 7.3.1 IL-1β binding pocket and interaction residues The compounds of the methods described herein may bind to IL-1β in one or more of the binding pockets of IL-1β. In some embodiments, the binding pocket of IL-1β is a lipophilic binding pocket of IL-1β. In some embodiments, the binding pocket of IL-1β is a hydrophobic binding pocket of IL-1β. In some embodiments, the lipophilic or hydrophobic binding pocket of IL-1β is recognizable from the primary, secondary, or tertiary amino acid sequence of IL-1β. In some embodiments, the binding pocket of IL-1β is the binding pocket of IL-1β shown in Figure 1. In some embodiments, the binding pocket of IL-1β is a binding pocket for compounds of formulas (I), (II), (IIA), (III), (IIIA), (IV) described herein or pharmaceutically acceptable salts thereof, where X 1 , X 2 , X 3 , A 1 , A 2 , R 1 ~R 7 , R 8a , R 8b , R 9a , R 9b , R 10 , R 11 , R 12 , R 13a , R 13b and R 14 This is as described herein.

[0078] In some embodiments, the IL-1β binding pocket is defined by the IL-1β residues described herein (e.g., the IL-1β binding pocket located between the N-terminal and C-terminal domains of the tertiary structure of IL-1β, as shown in Figure 1). In some embodiments, the IL-1β binding pocket is located in or adjacent to the D3 domain of IL-1R1 in the IL-1β / IL-1R1 complex. In some embodiments, the IL-1β / IL-1R1 complex is a macromolecular complex of IL-1β bound to IL-1R1, formed in the absence of a compound that inhibits the formation of the IL-1β / IL-1R1 complex (e.g., a compound described herein).

[0079] In some embodiments, the IL-1β binding pocket contains or consists of the amino acid residues Gly177-Leu178-Lys179-Glu180-Lys181-Asn182-Leu183-Tyr184 (SEQ ID NO: 16) and / or Val201-Asp202-Pro203-Lys204-Asn205-Tyr206-Pro207 (SEQ ID NO: 17) of IL-1β. In some embodiments, the IL-1β binding pocket contains or consists of the amino acid residues 177-184 and 201-207 of IL-1β (SEQ ID NO: 1). In some embodiments, when the compounds described herein bind to the IL-1β binding pocket, all of the residues listed with respect to the IL-1β binding pocket are bound by the compound. In some embodiments, when the compounds described herein bind to the IL-1β binding pocket, one or more of the residues listed with respect to the IL-1β binding pocket are bound by the compound, but not all of them. In some embodiments, the IL-1β binding pocket further comprises additional IL-1β residues, for example, additional residues of the IL-1β binding pocket described herein.

[0080] In some embodiments, the binding between the residues of the IL-1β binding pocket and the compounds described herein is via non-covalent interactions. In some embodiments, the non-covalent interactions described herein may be donated by the residues of the IL-1β binding pocket and accepted by the compounds. In some embodiments, the non-covalent interactions described herein may be donated by the compounds and accepted by the residues of the IL-1β binding pocket. For example, a pi-effect interaction may involve a cation from the binding pocket (e.g., hydrogen from the backbone of the residues of the binding pocket) being donated to the pi orbital of the compound and accepted by the pi orbital to form a cation-pi interaction. A cation-pi interaction may occur between a cationic side chain of either lysine or arginine and an aromatic substance. In some embodiments, the residues of the IL-1β binding pocket bind to the compounds described herein via lipophilic interactions and / or hydrophobic interactions (e.g., minimizing the exposure of non-polar surface area to polar molecules). In some embodiments, the residues of the IL-1β binding pocket bind to the compounds described herein via electrostatic interactions (e.g., Coulomb attractive interactions). In some embodiments, the residues of the IL-1β binding pocket bind to the compounds described herein via ionic interactions (e.g., valence interactions). In some embodiments, the residues of the IL-1β binding pocket bind to the compounds described herein via hydrogen bonding (H bond) interactions (e.g., backbone or side-chain H bond interactions). In some embodiments, the residues of the IL-1β binding pocket bind to the compounds described herein via halogen bonding interactions (e.g., side-chain halogen bonding interactions). In some embodiments, the residues of the IL-1β binding pocket bind to the compounds described herein via van der Waals interactions (e.g., dipole-dipole interactions, dipole-induced dipole interactions, or London dispersion forces).In some embodiments, the residue of the IL-1β binding pocket binds to the compounds described herein via pi-effect interactions (e.g., pi-pi interactions, CH-pi interactions, cation-pi interactions, anion-pi interactions, or polar-pi interactions) with the IL-1β residue. In some embodiments, the pi-effect interaction is a stacking interaction (e.g., a pi-pi interaction). In some embodiments, the pi-effect interaction is a nonpolar pi-effect interaction. In some embodiments, the polar-pi interaction is a polar hydrogen-pi interaction. In some embodiments, the polar-pi interaction is a polar nitrogen-pi interaction. In some embodiments, the non-covalent interaction may be characterized as one of the multiple types of non-covalent interactions described herein.

[0081] In some embodiments, the IL-1β binding pocket residue described herein binds to the compound at a functional group of the compound. In some embodiments, the functional group of the compound is a functional group on a side chain or skeletal portion. In some embodiments, the functional group of the compound is an amino group (e.g., NH group, NH2 group, or NH3+ group), a carbonyl group, a carboxylate group, or a cyclic π system of the compound (e.g., arene, aryl, or biaryl). In some embodiments, the IL-1β binding pocket residue described herein binds to the compound at a non-functional group portion of the compound.

[0082] In some embodiments, the IL-1β binding pocket comprises one or more amino acids corresponding to residues 177-184 and 201-207 of IL-1β (SEQ ID NO: 1), and optionally one or more additional residues of IL-1β. In some embodiments, the IL-1β binding pocket is defined by one or more amino acid residues of IL-1β (SEQ ID NO: 1) Gly177-Leu178-Lys179-Glu180-Lys181-Asn182-Leu183-Tyr184 (SEQ ID NO: 16) and Val201-Asp202-Pro203-Lys204-Asn205-Tyr206-Pro207 (SEQ ID NO: 17) (e.g., Gly177-Tyr184 and Val201-Pro207), and optionally one or more additional residues of IL-1β. In some embodiments, the one or more additional residues are selected from the group consisting of Val119, Arg120, Ser121, Phe162, and Ser269 of SEQ ID NO: 1. In some embodiments, the one or more additional residues are selected from the group consisting of Val119, Arg120, Ser121, Phe162, Ser269, Ala117, Pro118, Leu122, Asn123, Ser159, and Phe266 of SEQ ID NO: 1.

[0083] In some embodiments, the IL-1β binding pocket further includes an amino acid corresponding to residue 119 of IL-1β (SEQ ID NO: 1). In some embodiments, the IL-1β binding pocket is further defined by the amino acid residue Val119 of IL-1β (SEQ ID NO: 1). In some embodiments, the IL-1β binding pocket further includes an amino acid corresponding to residue 120 of IL-1β (SEQ ID NO: 1). In some embodiments, the IL-1β binding pocket is further defined by the amino acid residue Arg120 of IL-1β (SEQ ID NO: 1). In some embodiments, the IL-1β binding pocket further includes an amino acid corresponding to residue 121 of IL-1β (SEQ ID NO: 1). In some embodiments, the IL-1β binding pocket is further defined by the amino acid residue Ser121 of IL-1β (SEQ ID NO: 1). In some embodiments, the IL-1β binding pocket further includes an amino acid corresponding to residue 162 of IL-1β (SEQ ID NO: 1). In some embodiments, the binding pocket of IL-1β is defined by the amino acid residue Phe162 of IL-1β (SEQ ID NO: 1). In some embodiments, the binding pocket of IL-1β further includes the amino acid corresponding to residue 269 of IL-1β (SEQ ID NO: 1). In some embodiments, the binding pocket of IL-1β is further defined by the amino acid residue Ser269 of IL-1β (SEQ ID NO: 1).

[0084] In some embodiments, the IL-1β binding pocket further includes an amino acid corresponding to residue 117 of IL-1β (SEQ ID NO: 1). In some embodiments, the IL-1β binding pocket is further defined by the amino acid residue Ala117 of IL-1β (SEQ ID NO: 1). In some embodiments, the IL-1β binding pocket further includes an amino acid corresponding to residue 118 of IL-1β (SEQ ID NO: 1). In some embodiments, the IL-1β binding pocket is further defined by the amino acid residue Pro118 of IL-1β (SEQ ID NO: 1). In some embodiments, the IL-1β binding pocket further includes an amino acid corresponding to residue 122 of IL-1β (SEQ ID NO: 1). In some embodiments, the IL-1β binding pocket is further defined by the amino acid residue Leu122 of IL-1β (SEQ ID NO: 1). In some embodiments, the IL-1β binding pocket further includes an amino acid corresponding to residue 123 of IL-1β (SEQ ID NO: 1). In some embodiments, the IL-1β binding pocket is further defined by the amino acid residue Asn123 of IL-1β (SEQ ID NO: 1). In some embodiments, the IL-1β binding pocket further includes the amino acid corresponding to residue 159 of IL-1β (SEQ ID NO: 1). In some embodiments, the IL-1β binding pocket is further defined by the amino acid residue Ser159 of IL-1β (SEQ ID NO: 1). In some embodiments, the IL-1β binding pocket further includes the amino acid corresponding to residue 266 of IL-1β (SEQ ID NO: 1). In some embodiments, the IL-1β binding pocket is further defined by the amino acid residue Phe266 (SEQ ID NO: 1) of IL-1β.

[0085] In some embodiments, the IL-1β binding pocket for the compounds described herein further comprises or consists of one or more amino acids corresponding to residues selected from IL-1β (SEQ ID NO: 1) residues 119, 120, 121, 162, 179, 203, 204, 206, 207, or 269. In some embodiments, the IL-1β binding pocket for the compounds described herein further comprises or consists of one or more amino acid residues selected from IL-1β (SEQ ID NO: 1) residues Val119, Arg120, Ser121, Phe162, Lys179, Pro203, Lys204, Tyr206, Pro207, or Ser269.

[0086] In certain embodiments, the IL-1β binding pocket for the compounds described herein contains or consists of amino acids corresponding to residues 119, 120, 121, 203, and 204 of IL-1β (SEQ ID NO: 1). In certain embodiments, the IL-1β binding pocket for the compounds described herein contains or consists of residues Val119, Arg120, Ser121, Pro203, and Lys204 of IL-1β (SEQ ID NO: 1). In certain embodiments, IL-1β (SEQ ID NO: 1) does not interact further with the compound. In certain embodiments, the IL-1β binding pocket for the compounds described herein contains or consists of 1, 2, 3, 4, or 5 amino acids corresponding to residues selected from residues 162, 179, 206, 207, or 269 of IL-1β (SEQ ID NO: 1). In certain embodiments, the IL-1β binding pocket of the compounds described herein contains or consists of one, two, three, four, or five residues selected from Phe162, Lys179, Tyr206, Pro207, or Ser269 of IL-1β (SEQ ID NO: 1). In certain embodiments, the IL-1β binding pocket of the compounds described herein contains or consists of at least amino acids corresponding to residue 179 and / or residue 207 of IL-1β (SEQ ID NO: 1). In certain embodiments, the IL-1β binding pocket contains at least amino acids corresponding to residue Lys179 and / or Pro207 of IL-1β (SEQ ID NO: 1).

[0087] In certain embodiments, the IL-1β binding pocket for the compounds described herein includes or consists of amino acids corresponding to residues 119, 120, 121, 179, 203, 204, 206, 207, and 269 of IL-1β (SEQ ID NO: 1). In certain embodiments, the IL-1β binding pocket for the compounds described herein includes or consists of Val119, Arg120, Ser121, Lys179, Pro203, Lys204, Tyr206, Pro207, and Ser269 of IL-1β (SEQ ID NO: 1).

[0088] In certain embodiments, the IL-1β binding pocket for the compounds described herein contains or consists of amino acids corresponding to residues 119, 120, 121, 179, 203, 204, and 206 of IL-1β (SEQ ID NO: 1). In certain embodiments, the IL-1β binding pocket for the compounds described herein contains or consists of IL-1β corresponding to Val119, Arg120, Ser121, Lys179, Pro203, and Lys204 of IL-1β (SEQ ID NO: 1).

[0089] In certain embodiments, the IL-1β binding pocket for the compounds described herein includes or consists of amino acids corresponding to residues 119, 120, 121, 162, 179, 203, 204, 206, 207, and 269 of IL-1β (SEQ ID NO: 1). In certain embodiments, the IL-1β binding pocket for the compounds described herein includes or consists of IL-1β corresponding to Val119, Arg120, Ser121, Phe162, Lys179, Pro203, Lys204, Tyr206, Pro207, and Ser269 of IL-1β (SEQ ID NO: 1).

[0090] In certain embodiments, the IL-1β binding pocket for the compounds described herein contains or consists of amino acids corresponding to residues 119, 120, 121, 179, 203, 204, 206, and 207 of IL-1β (SEQ ID NO: 1). In certain embodiments, the IL-1β binding pocket for the compounds described herein contains or consists of IL-1β corresponding to Val119, Arg120, Ser121, Lys179, Pro203, Lys204, Tyr206, and Pro207 of IL-1β (SEQ ID NO: 1).

[0091] In some embodiments, the binding of the compound to a specified residue in the IL-1β binding pocket is mediated by the backbone or side chain of the specified residue (for example, the NH, carbonyl, or side-chain functional group of the specified IL-1β residue interacts with the compound). In some embodiments, one or more residues of the IL-1β binding pocket mediate a non-covalent interaction with the compound described herein. In some embodiments, one or more residues of IL-1β that mediate the interaction between the binding pocket and the compound described herein are selected from Val119, Arg120, Ser121, Phe162, Lys179, Pro203, Lys204, Tyr206, Pro207, or Ser269.

[0092] In some embodiments, residues of the IL-1β binding pocket (e.g., Val119, Arg120, Ser121, Phe162, Lys179, Pro203, Lys204, Tyr206, Pro207, or Ser269) mediate non-covalent interactions with the compounds described herein. In some embodiments, residues of the IL-1β binding pocket (e.g., Val119, Arg120, Ser121, Phe162, Lys179, Pro203, Lys204, Tyr206, Pro207, or Ser269) mediate lipophilic and / or hydrophobic interactions with the compounds described herein. In some embodiments, residues of the IL-1β binding pocket (e.g., Val119, Arg120, Ser121, Phe162, Lys179, Pro203, Lys204, Tyr206, Pro207, or Ser269) mediate electrostatic interactions with the compounds described herein. In some embodiments, residues of the IL-1β binding pocket (e.g., Val119, Arg120, Ser121, Phe162, Lys179, Pro203, Lys204, Tyr206, Pro207, or Ser269) mediate ionic interactions with the compounds described herein. In some embodiments, residues of the IL-1β binding pocket (e.g., Val119, Arg120, Ser121, Phe162, Lys179, Pro203, Lys204, Tyr206, Pro207, or Ser269) mediate hydrogen bonding (H bond) interactions with the compounds described herein. In some embodiments, residues of the IL-1β binding pocket (e.g., Val119, Arg120, Ser121, Phe162, Lys179, Pro203, Lys204, Tyr206, Pro207, or Ser269) mediate halogen bonding interactions with the compounds described herein. In some embodiments, residues of the IL-1β binding pocket (e.g., Val119, Arg120, Ser121, Phe162, Lys179, Pro203, Lys204, Tyr206, Pro207, or Ser269) mediate van der Waals interactions with the compounds described herein.In some embodiments, residues in the IL-1β binding pocket (e.g., Val119, Arg120, Ser121, Phe162, Lys179, Pro203, Lys204, Tyr206, Pro207, or Ser269) mediate van der Waals interactions (e.g., dipole-dipole interactions, dipole-induced dipole interactions, or London dispersion forces) with the compounds described herein. In some embodiments, residues in the IL-1β binding pocket (e.g., Val119, Arg120, Ser121, Phe162, Lys179, Pro203, Lys204, Tyr206, Pro207, or Ser269) mediate pi-effect interactions (e.g., pi-pi interactions, CH-pi interactions, cation-pi interactions, anion-pi interactions, or polar-pi interactions) with the compounds described herein. In some embodiments, residues of the IL-1β binding pocket (e.g., Val119, Arg120, Ser121, Phe162, Lys179, Pro203, Lys204, Tyr206, Pro207, or Ser269) mediate several non-covalent interactions described herein, which may be of different types.

[0093] In certain embodiments, the residue Val119 of IL-1β mediates hydrogen bonding (H bond) interactions with the compounds described herein. In certain embodiments, the residue Arg120 of IL-1β mediates hydrogen bonding (H bond) interactions with the compounds described herein. In certain embodiments, the residue Ser121 of IL-1β mediates hydrogen bonding (H bond) interactions with the compounds described herein. In certain embodiments, the residue Pro203 of IL-1β mediates hydrogen bonding (H bond) interactions with the compounds described herein. In certain embodiments, the residue Lys204 of IL-1β mediates hydrogen bonding (H bond) interactions with the compounds described herein. In certain embodiments, the residue Tyr206 of IL-1β mediates hydrogen bonding (H bond) interactions with the compounds described herein. In certain embodiments, the residue Pro207 of IL-1β mediates hydrogen bonding (H bond) interactions with the compounds described herein. In certain embodiments, the IL-1β residue Ser269 mediates hydrogen bonding (H bond) interactions with the compounds described herein. Such hydrogen bonding (H bond) interactions may be mediated by the IL-1β residue's backbone (e.g., an NH group or a carbonyl group) or side chain (e.g., a functional group on the side chain, e.g., a carboxylate group or an OH group).

[0094] In certain embodiments, the residue Arg120 of IL-1β mediates pi-effect (e.g., CH-pi, cation-pi, or polar-pi) interactions with the compounds described herein. In certain embodiments, the residue Phe162 of IL-1β mediates pi-effect (e.g., CH-pi, cation-pi, or polar-pi) interactions with the compounds described herein. In certain embodiments, the residue Lys179 of IL-1β mediates pi-effect (e.g., CH-pi, cation-pi, or polar-pi) interactions with the compounds described herein. In certain embodiments, the residue Pro207 of IL-1β mediates pi-effect (e.g., CH-pi, cation-pi, or polar-pi) interactions with the compounds described herein. In certain embodiments, the residue Ser269 of IL-1β mediates pi-effect (e.g., CH-pi, cation-pi, or polar-pi) interactions with the compounds described herein. Such pi effects (e.g., CH-pi, cation-pi, or polar-pi) interactions can be mediated by the IL-1β residue's backbone (e.g., an NH group or a carbonyl group) or side chain (e.g., a functional group on the side chain, e.g., hydrogen, OH, or an amine).

[0095] In certain embodiments, the IL-1β residue Lys204 mediates ionic interactions with the compounds described herein. In certain embodiments, the IL-1β residue Ala117 mediates ionic interactions with the compounds described herein. In certain embodiments, the IL-1β residue Arg120 mediates ionic interactions with the compounds described herein. Such ionic interactions may be mediated by the IL-1β residue's backbone (e.g., an NH group or a carbonyl group) or side chain (e.g., a functional group on the side chain).

[0096] In some embodiments, when compound A is bound to IL-1β as determined by X-ray crystallography, the IL-1β binding pocket contains an IL-1β residue having a skeleton or side chain within 5 angstroms from the van der Waals plane of compound A. In some embodiments, when compound B is bound to IL-1β as determined by X-ray crystallography, the IL-1β binding pocket contains an IL-1β residue having a skeleton or side chain within 5 angstroms from the van der Waals plane of compound B. In some embodiments, when compound C is bound to IL-1β as determined by X-ray crystallography, the IL-1β binding pocket contains an IL-1β residue having a skeleton or side chain within 5 angstroms from the van der Waals plane of compound C. In some embodiments, when compound D is bound to IL-1β as determined by X-ray crystallography, the IL-1β binding pocket contains an IL-1β residue having a skeleton or side chain within 5 angstroms from the van der Waals plane of compound D. In some embodiments, when compound E is bound to IL-1β as determined by X-ray crystallography, the IL-1β binding pocket contains residues of IL-1β having a backbone or side chain within 5 angstroms from the van der Waals plane of compound E.

[0097] In certain embodiments, the binding interaction between the compounds described herein and IL-1β is as shown in any one of the drawings disclosed herein.

[0098] 7.4 Interleukin-1 receptor type I (IL-1R1) Interleukin-1 receptor type I (IL-1R1) is a cytokine receptor for at least interleukin-1 alpha (IL-1α), interleukin-1 beta (IL-1β), and the interleukin-1 receptor antagonist (IL-1RA). In some embodiments, IL-1R1 is also known as CD121A, D2S1473, IL-1R-alpha, IL1R1, P80, or interleukin-1 receptor type I. IL-1R1 is one of two forms of the interleukin-1 receptor (e.g., type I and type II). IL-1R1 functions, among other things, to propagate the inflammatory effects of interleukin-1 (IL-1). In some embodiments, IL-1R1 is encoded by the IL1R1 gene (e.g., the human IL1R1 gene).

[0099] In some embodiments, IL-1R1 is human IL-1R1. In some embodiments, IL-1R1 includes or consists of the amino acid sequence of full-length human IL-1R1 described in accession number P14778 (e.g., amino acids 1-569). In some embodiments, human IL-1R1 includes or consists of the amino acid sequence of SEQ ID NO: 4. Human IL-1R1 contains an ectodomain comprising three Ig-like domains, namely domain 1 (D1), domain 2 (D2), and domain 3 (D3). As shown in Figure 1, IL-1R1 forms a tertiary structure resembling a grasping hand when it binds to cytokines (e.g., IL-1α, IL-1β, or IL-1RA). The D1, D2, and D3 domains of IL-1R1 can form two distinct binding sites, namely the A site and the B site of IL-1R1, which drive the interaction between IL-1R1 and IL-1 cytokines (e.g., IL-1β). Two of the IL-1R1 domains, D1 and D2, can together form the A site binding site of IL-1R1. The D3 domain of IL-1R1 can form the B site binding site of IL-1R1.

[0100] In some embodiments, the D1 domain of IL-1R1 contains or consists of the amino acid sequence (e.g., amino acids 23-110) of the Ig-like C2-1 type domain of human IL-1R1 described in UnitProt accession number P14778. In some embodiments, the D1 domain of IL-1R1 contains or consists of amino acids 23-110 of SEQ ID NO: 4. In some embodiments, the D1 domain of IL-1R1 contains or consists of the amino acid sequence of SEQ ID NO: 5. In some embodiments, the D2 domain of IL-1R1 contains or consists of the amino acid sequence (e.g., amino acids 118-210) of the Ig-like C2-2 type domain of human IL-1R1 described in UniProt accession number P14778. In some embodiments, the D2 domain of IL-1R1 contains or consists of amino acids 118-210 of SEQ ID NO: 4. In some embodiments, the D2 domain of IL-1R1 contains or consists of the amino acid sequence of SEQ ID NO: 6. In some embodiments, the D3 domain of IL-1R1 contains or consists of the amino acid sequence of the Ig-like C2-3 type domain of human IL-1R1 (e.g., amino acids 226-I listed in UniProt accession number P14778). In some embodiments, the D3 domain of IL-1R1 contains or consists of amino acids 226-328 of SEQ ID NO: 4. In some embodiments, the D3 domain of IL-1R1 contains or consists of the amino acid sequence of SEQ ID NO: 6. Exemplary amino acid sequences of full-length human IL-1R1 and its D1, D2, and D3 domains are shown in Table 2 below. [Table 2]

[0101] 7.5 compound This specification provides compounds that inhibit the binding of interleukin-1 beta (IL-1β) to the interleukin-1 receptor type I (IL-1R1). In some embodiments, the compounds of this disclosure contact IL-1β to inhibit its binding to IL-1R1. In some embodiments, the compounds of this disclosure compete with the binding of IL-1β to IL-1R1.

[0102] In some embodiments, the compounds described herein inhibit the binding of IL-1β to the A site of IL-1R1, thereby inhibiting one or more of the biological functions of IL-1R1. In some embodiments, the compounds described herein inhibit the binding of IL-1β to the D1 and / or D2 domains of IL-1R1, thereby inhibiting one or more of the biological functions of IL-1R1. In some embodiments, the compounds described herein inhibit the binding of IL-1β to the B site of IL-1R1, thereby inhibiting one or more of the biological functions of IL-1R1. In some embodiments, the compounds described herein inhibit the binding of IL-1β to the D3 domain of IL-1R1, thereby inhibiting one or more of the biological functions of IL-1R1. In some embodiments, the compounds described herein inhibit the binding of IL-1β to the A and B sites of IL-1R1, thereby inhibiting one or more of the biological functions of IL-1R1. In some embodiments, the compounds described herein inhibit the binding of IL-1β to the D1, D2, and D3 domains of IL-1R1, thereby inhibiting one or more of the biological functions of IL-1R1. In some embodiments, the biological function of IL-1R1 is inflammation (e.g., in a subject). In some embodiments, the biological function of IL-1R1 is the expression of IL-6. In some embodiments, the biological function of IL-1R1 is the expression of C-reactive protein (CRP).

[0103] In some embodiments, the compounds described herein are orthosteric inhibitors of the binding of IL-1β to IL-1R1. In some embodiments, the compounds bind to the orthosteric site (e.g., the primary binding site) of IL-1β to IL-1R. In some embodiments, the compounds bind to the active site of IL-1β to IL-1R.

[0104] In some embodiments, the compounds described herein are allosteric inhibitors of the binding of IL-1β to IL-1R1. In some embodiments, the compounds bind to the allosteric site (e.g., secondary binding site) of IL-1β to IL-1R. In some embodiments, the compounds do not bind to the active site of IL-1β to IL-1R.

[0105] In some embodiments, the compounds described herein are peptides. In some embodiments, the peptide comprises or consists of an amino acid sequence having a length of 9 to 28 amino acids (e.g., 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 amino acids). In some embodiments, the peptide comprises or consists of an amino acid sequence having a length of 10 to 24 amino acid residues. In some embodiments, the peptide comprises or consists of an amino acid sequence having a length of 11 to 20 amino acid residues. In some embodiments, the peptide comprises or consists of an amino acid sequence having a length of 12 to 16 amino acid residues. In some embodiments, the peptide comprises or consists of an amino acid sequence having a length of 13 to 15 amino acid residues. In some embodiments, the peptide comprises or consists of an amino acid sequence having a length of 14 amino acid residues.

[0106] In some embodiments, the peptide is a cyclic peptide. In some embodiments, the cyclic peptide contains or consists of an amino acid sequence having a length of 9 to 28 amino acid residues (e.g., 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 amino acids). In some embodiments, the cyclic peptide contains or consists of an amino acid sequence having a length of 10 to 24 amino acid residues. In some embodiments, the cyclic peptide contains or consists of an amino acid sequence having a length of 11 to 20 amino acid residues. In some embodiments, the cyclic peptide contains or consists of an amino acid sequence having a length of 12 to 16 amino acid residues. In some embodiments, the cyclic peptide contains or consists of an amino acid sequence having a length of 13 to 15 amino acid residues. In some embodiments, the cyclic peptide contains or consists of an amino acid sequence having a length of 14 amino acid residues.

[0107] In some embodiments, the peptide is a macrocyclic peptide. In some embodiments, the cyclic peptide contains or consists of an amino acid sequence having a length of 9 to 28 amino acid residues (e.g., 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 amino acids). In some embodiments, the macrocyclic peptide contains or consists of an amino acid sequence having a length of 10 to 24 amino acid residues. In some embodiments, the macrocyclic peptide contains or consists of an amino acid sequence having a length of 11 to 20 amino acid residues. In some embodiments, the macrocyclic peptide contains or consists of an amino acid sequence having a length of 12 to 16 amino acid residues. In some embodiments, the macrocyclic peptide contains or consists of an amino acid sequence having a length of 13 to 15 amino acid residues. In some embodiments, the macrocyclic peptide contains or consists of an amino acid sequence having a length of 14 amino acid residues.

[0108] In some embodiments, the compounds described herein (e.g., peptides, cyclic peptides, or macrocyclic peptides) have a molecular weight of about 1000 Da to about 3200 Da. In some embodiments, the compounds described herein (e.g., peptides, cyclic peptides, or macrocyclic peptides) have a molecular weight of about 1200 Da to about 3000 Da. In some embodiments, the compounds described herein (e.g., peptides, cyclic peptides, or macrocyclic peptides) have a molecular weight of about 1500 Da to about 2500 Da. In some embodiments, the compounds described herein (e.g., peptides, cyclic peptides, or macrocyclic peptides) have a molecular weight of about 1750 Da to about 3000 Da. In some embodiments, the compounds described herein (e.g., peptides, cyclic peptides, or macrocyclic peptides) have a molecular weight approximately equal to the molecular weight of compound A, compound B, compound C, compound D, or compound E.

[0109] In some embodiments, the compound is one of the compounds described herein (e.g., in the Examples). In some embodiments, the compound described herein that binds to IL-1β in the binding pocket described herein is a lipophilic compound comprising one or more lipophilic moieties. In some embodiments, the compound described herein that binds to IL-1β in the binding pocket described herein is a hydrophobic compound comprising one or more hydrophobic moieties.

[0110] In some embodiments of the methods described herein, the compound has the structure of formula (I) or a pharmaceutically acceptable salt thereof, where X 1 , X 2 , X 3 , A 1 , A 2 , R 1 ~R 7 , R 8a , R 8b , R 9a , R 9b , R 10 , R 11 , R 12 , R13a , R 13b and R 14 This is as described herein.

[0111] In some embodiments of the methods described herein, the compound is of formula (I): [ka]

[0112] or having a pharmaceutically acceptable salt structure thereof, where, R 1 This is CH3C(O)NH-CH2CH2-O- or C 1 is; C 1 teeth, (i) a 5-6 member monocyclic aryl or heteroaryl, wherein the heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; or (ii) A 5-6 member monocyclic or bicyclic saturated cycloalkyl or heterocycloalkyl containing 1-2 heteroatoms selected from the group consisting of N, O, and S; or (iii) A monocyclic or bicyclic cycloalkyl group with 5-6 members; Here, C 1 The RC is either unsubstituted or consists of 1 to 3 RCs independently selected from the group comprising halo, C1-C3 alkyl, C1-C3 fluoroalkyl, carboxy, C1-C3 alkoxy, and C2-C3 acyl. 1 Substituting with a substituent; R 2 is H, C1-C3 alkyl, benzyl, or phenyl-CH2CH2-; R 3 is a 9-10 membered bicyclic aryl or heteroaryl, where the heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; Here, R 3is unsubstituted or is independently selected from one to three Rs selected from the group consisting of halo, C1-C3 alkyl, C1-C3 fluoroalkyl, hydroxy and C1-C3 alkoxy 3a substituted by a substituent; R 4 is C1-C3 alkyl, HO2C-(CH2) m -, H2NC(O)-(CH2) m -, (CH3)2NC(O)-(CH2) m - or tetrazolyl-(CH2) m -; R 5 is amino, H2N(CH2) n -, H2NC(O)-(CH2) n -, CH3C(O)NH-, CH3C(O)NH(CH2) n C 5 or C 5 -CH2-; C 5 is (i) a 5- to 6-membered monocyclic aryl or heteroaryl, where the heteroaryl contains one or two heteroatoms selected from the group consisting of N, O and S; (ii) a 9- to 10-membered bicyclic aryl or heteroaryl, where the bicyclic heteroaryl contains one to three heteroatoms selected from the group consisting of N, O and S; (iii) a 5- to 6-membered monocyclic or 9- to 10-membered heterocycloalkyl, where the heterocycloalkyl is saturated or partially unsaturated and contains one or two heteroatoms selected from the group consisting of N, O and S; (iv) a 5- to 6-membered monocyclic cycloalkyl; or (v) 2,3-dihydroindolyl; where C 5 is unsubstituted or is halo, amino, hydroxy, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, H2N-(CH2) k -, H2NC(O)-(CH2) k- 1 to 3 R independently selected from the group consisting of H2C=CH-CH2O- and phenyl C5 Substituting with a substituent; R 6 H, C1-C5 alkyl, H2N(CH2) p -, HOCH2-, (CH3)2NCH2-, H3CO-(CH2) q - or C 6 It is -CH2-; C 6 This is a 5-membered or 6-membered monocyclic saturated heterocycloalkyl containing 1 to 2 heteroatoms selected from the group consisting of N, O, and S, and C 6 R is either unsubstituted or independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 fluoroalkyl, hydroxy, and C1-C3 alkoxy. C6 Substituting with a substituent; R 7 is H or C1-C3 alkyl; R 8a H, C1-C5 alkyl, HOCH2-, H2N(CH2) r -, (CH3)3N + (CH2) r -or CH3C(O)NH(CH2) r -is; R 8b is H or C1-C3 alkyl; R 9a is H or C1-C3 alkyl; R 9b H, C1-C5 alkyl, C 9 -CH2- or C 9 It is -CH2CH2-; C 9 teeth, (i) a 5-6 member monocyclic aryl or heteroaryl, wherein the heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; or (ii) A 5-6 member monocyclic saturated cycloalkyl or heterocycloalkyl, wherein the heterocycloalkyl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; Here, C 9 is unsubstituted, or halo, amino, hydroxy, cyano, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, H2N-(CH2) k -, H2NC(O)-(CH2) k - One to three R independently selected from the group consisting of H2NCH2CH2O-, CH3C(O)NH-CH2CH2O-, and morpholinyl-CH2CH2O- C9 Substituting with a substituent; R 10 is H, halo, or C1-C3 alkyl; R 11 is H, halo, or C1-C3 alkyl; Each existence of the subscript k is independently either 1 or 2; The subscript 'm' is either 1 or 2; The subscript n is 1, 2, 3, or 4; The subscript p is 1, 2, 3, or 4; The subscript q is either 1 or 2; The subscript r is 1, 2, 3, or 4; X 1 , X 2 and X 3 is independently C(H) or N; and A 1 and A 2 The following are independently selected from the group consisting of HO2C-, H2NC(O)-, CH3C(O)N(H)-, H2NS(O)2-, CH3S(O)2N(H)-, tetrazolyl, and 5-oxoxadiazolyl.

[0113] In some embodiments of the methods described herein, the compound is a compound of formula (I), where, R 5 is amino, H2N(CH2) n-, H2NC(O)-(CH2) n -, C 5 or C 5 It is -CH2-; C 5 teeth, (i) A 5-6 member monocyclic aryl or heteroaryl, wherein the heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, and S: (ii) A 9-10 member bicyclic aryl or heteroaryl, wherein the bicyclic heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S; (iii) a 5-6 member monocyclic or 9-10 member heterocycloalkyl, wherein the heterocycloalkyl is saturated or partially unsaturated and contains 1-2 heteroatoms selected from the group consisting of N, O, and S; or (iv) It is 2,3-dihydroindolyl; Here, C 5 is unsubstituted, or halo, amino, hydroxy, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, H2N-(CH2) k -, H2NC(O)-(CH2) k - 1 to 3 R independently selected from the group consisting of H2C=CH-CH2O- and phenyl C5 Substituting with a substituent; R 6 H, C2-C5 alkyl, H2N(CH2) p -, HOCH2-, (CH3)2NCH2-, H3CO-(CH2) q - or C 6 It is -CH2-; R 8a is H, C1-C3 alkyl, HOCH2- or H2N(CH2) r -is; R 9a H is; R 9b H, C1-C3 alkyl, C 9 -CH2- or C 9 It is -CH2CH2-; R10 H is; R 11 H is; The subscript p is 1, 2, or 3; and The subscript r is 2, 3, or 4.

[0114] In some embodiments of the methods described herein, the compound of formula (I) has structural formula (IA): [ka]

[0115] It holds.

[0116] In some embodiments of the methods described herein, the compound is a compound of formula (I), where, C1 is phenyl, pyrimidyl, or piperazinyl, where C 1 is not substituted, or has 1-2 R C1 Substituting with a substituent; R 3 is naphthyl or indolyl, R 3 It is either unsubstituted or substituted with one or two R3a substituents; C 5 is phenyl, pyridyl, pyrimidyl, naphthyl, indolyl, 7-azaindyl, indazolyl, 2,3-dihydroindolyl, piperidinyl, tetrahydropyranyl, or cyclohexyl, where C 5 is not substituted, or has 1-2 R C5 Substituting with a substituent; C 6 C is tetrahydropyranyl or morpholinyl, where C 6 is not substituted, or has 1-2 R C6 Substituting by substituents; and C 9a is H or methyl; C 9bC is phenyl, pyridyl, cyclohexyl, morpholinyl, or piperidinyl, where C 9 is not substituted, or has 1-2 R C9 It is substituted by a substituent.

[0117] In some embodiments of the methods described herein, the compound is a compound of formula (I), where, R 1 is C 1 And here, C 1 C is phenyl, pyrimidyl, or piperazinyl, where C 1 is not substituted, or has 1-2 R C1 Substituting with a substituent; R 3 R is naphthyl or indolyl, where R 3 It is either unsubstituted or substituted with one or two R3a substituents; C 5 is phenyl, pyridyl, pyrimidyl, naphthyl, indolyl, 7-azaindyl, indazolyl, 2,3-dihydroindolyl, piperidinyl, tetrahydropyranyl, or cyclohexyl, where C 5 is not substituted, or has 1-2 R C5 Substituting with a substituent; C 6 is tetrahydropyranyl or morpholinyl, C 6 is not substituted, or has 1-2 R C6 Substituting with a substituent; C 9a is H or methyl; C 9b C is phenyl, pyridyl, cyclohexyl, morpholinyl, or piperidinyl, where C 9 is not substituted, or has 1-2 R C9 It is substituted by a substituent.

[0118] In some embodiments of the methods described herein, the compound is a compound of formula (I), where, X 1 and X 2 is C(H); and R 1 It is a phenyl compound substituted with a carboxyl group.

[0119] In some embodiments of the methods described herein, the compound is a compound of formula (I), where, X 1 and X 2 is C(H); and R 1 It is CH3C(O)NH-CH2CH2-O-

[0120] In some embodiments of the methods described herein, the compound is a compound of formula (I), where R 2 H is H.

[0121] In some embodiments of the methods described herein, the compound is a compound of formula (I), where R 3 This is an indolyl replaced by a single halo.

[0122] In some embodiments of the methods described herein, the compound is a compound of formula (I), where R 3 It is naphthyl.

[0123] In some embodiments of the methods described herein, the compound is a compound of formula (I), where R 4 is HO2C-(CH2) m - is

[0124] In some embodiments of the methods described herein, the compound is a compound of formula (I), where X 3 is C(H).

[0125] In some embodiments of the methods described herein, the compound is a compound of formula (I), where R 5 is H2N(CH2)n - These are indole, 7-azaindole, naphthyl, or pyridyl.

[0126] In some embodiments of the methods described herein, the compound is a compound of formula (I), where R 5 is H2N(CH2) n - These are indole, naphthyl, or pyridyl.

[0127] In some embodiments of the methods described herein, the compound is a compound of formula (I), where R 6 is H, HOCH2-, C2-C5 alkyl or H2N(CH2) p - is

[0128] In some embodiments of the methods described herein, the compound is a compound of formula (I), where R 6 is C2-C5 alkyl or H2N(CH2) p - is

[0129] In some embodiments of the methods described herein, the compound is a compound of formula (I), where R 7 H is H.

[0130] In some embodiments of the methods described herein, the compound is a compound of formula (I), where R 8a is methyl or H2NCH2CH2-; and R 8b H is H.

[0131] In some embodiments of the methods described herein, the compound is a compound of formula (I), where R 9b teeth, [ka]

[0132] That is the case.

[0133] In some embodiments of the methods described herein, the compound is a compound of formula (I), where R 9b teeth, [ka]

[0134] That is the case.

[0135] In some embodiments of the methods described herein, the compound is a compound of formula (I), where A 1 This is selected from the group consisting of HO2C-, H2NC(O)-, CH3C(O)N(H)-, H2NS(O)2-, CH3S(O)2N(H)-, tetrazolyl, and 5-oxoxadiazolyl. Those skilled in chemistry will recognize that such a part in an amino acid residue may be represented by the following substructures. [ka]

[0136] In some embodiments of the methods described herein, the compound is a compound of formula (I), where A 2 This is selected from the group consisting of HO2C-, H2NC(O)-, CH3C(O)N(H)-, H2NS(O)2-, CH3S(O)2N(H)-, tetrazolyl, and 5-oxoxadiazolyl. Those skilled in chemistry will recognize that such a part in an amino acid residue may be represented by the following substructures. [ka]

[0137] In some embodiments of the methods described herein, the compound is a compound of formula (I), where, R 10 is H; and R 11 is H, F, or Cl.

[0138] In some embodiments of the methods described herein, the compound is a compound of formula (I), where A 1 and A 2 Both are HO2C- (i.e., carboxyl).

[0139] In some embodiments of the methods described herein, the compound is a compound of formula (I), where, R 1 These are 4-CH3C(O)-piperazin-1-yl, CH3C(O)NH-CH2CH2-O-, 5-CO2H-pyrimidine-2-yl, or 4-CO2H-phenyl; R 2 is H, ethyl, benzyl, or phenyl-CH2CH2-; R 3 These are naphtho-1-yl, 4-fluoroindole-3-yl, or 4-chloroindole-3-yl; R 4 is methyl, HO2C-(CH2) m -or H2NC(O)-(CH2) m -is; R 5 is amino, H2N(CH2) n - is naphtho-1-yl, indole-3-yl, 7-aza-indole-3-yl, indazole-1-yl, 2,3-dihydroindole-1-yl, pyrido-3-yl, pyrido-4-yl, piperidine-4-yl, 3-aminomethylphenyl, 4-aminomethylphenyl, 3-aminophenyl, 4-aminophenyl, phenyl, pyrido-4-yl-CH2-, pyrimidine-5-yl, tetrahydropyran-4-yl, H2NC(O)-(CH2)2-, 3-biphenyl, 3-CH2=CH-CH2O-phenyl, CH3C(O)NH-, CH3C(O)NH(CH2)3- or cyclohexyl; R 6 is H, (CH3)2CHCH2-, (CH3)3CCH2-, H2N(CH2) p-, HOCH2-, H3CCH2CH2-, morpholin-4-yl-CH2-, tetrahydropyran-4-yl-CH2-, (CH3)2NCH2- or H3CO-(CH2) q -is; R 7 is H or methyl; R 8a H, methyl, HOCH2-, H2N(CH2) r -, (CH3)3NCH2CH2- or CH3C(O)NH(CH2)4-; R 8b is H or methyl; R 9a is H or methyl; R 9b These are H, methyl, H3CCH2CH2CH2-, 4-HO-phenyl-CH2CH2-, phenyl-CH2CH2-, cyclohexyl-CH2CH2-, 5-NC-pyrido-3-yl-CH2CH2-, 4-F3C-phenyl-CH2-, 3-F3C-phenyl-CH2-, 2-F3C-phenyl-CH2-, morpholin-4-yl-CH2CH2O-phenyl-CH2-, 4-aminophenyl-CH2-, 4,4-difluorocyclohexyl-CH2-, 4-H2NCH2CH2O-phenyl-CH2-, 4-H2NCH2CH2O-pyrido-3-yl-CH2-, piperidine-4-yl-CH2- or 4-CH3C(O)NH-CH2CH2O-phenyl-CH2-; R 10 is H, fluoro, or methyl; R 11 is H, fluoro, or chloro; A 1 and A 2 Both are HO2C-; and X 1 , X 2 and X 3 is C(H).

[0140] In some embodiments of the methods described herein, the compound is a compound of formula (I), where, R 1These are 4-CH3C(O)-piperazin-1-yl, CH3C(O)NH-CH2CH2-O-, 5-CO2H-pyrimidine-2-yl, or 4-CO2H-phenyl; R 2 is H, ethyl, benzyl, or phenyl-CH2CH2-; R 3 These are naphtho-1-yl, 4-fluoroindole-3-yl, or 4-chloroindole-3-yl; R 4 is methyl, HO2C-(CH2) m -or H2N(O)C-(CH2) m -is; R 5 is amino, H2N(CH2) n - is naphtho-1-yl, indole-3-yl, 7-aza-indole-3-yl, indazole-1-yl, 2,3-dihydroindole-1-yl, pyrido-3-yl, pyrido-4-yl, piperidine-4-yl, 3-aminomethylphenyl, 4-aminomethylphenyl, 3-aminophenyl, 4-aminophenyl, phenyl, pyrido-4-yl-CH2-, pyrimidine-5-yl, tetrahydropyran-4-yl-, H2N(O)C-(CH2)2-, 3-biphenyl or 3-CH2=CH-CH2O-phenyl; R 6 H, (CH3)2CHCH2-, H2N(CH2) p -, HOCH2-, H3CCH2CH2-, morpholin-4-yl-CH2-, tetrahydropyran-4-yl-CH2-, (CH3)2NCH2- or H3CO-(CH2) q -is; R 7 is H or methyl; R 8a H, methyl, HOCH2-, or H2N(CH2) r -is; R 8b is H or methyl; R 9a H is; R 9bThese are H, methyl, 4-HO-phenyl-CH2CH2-, phenyl-CH2CH2-, 5-NC-pyrido-3-yl-CH2CH2-, 4-F3C-phenyl-CH2-, 3-F3C-phenyl-CH2-, 2-F3C-phenyl-CH2-, morpholin-4-yl-CH2CH2O-phenyl-CH2-, 4-aminophenyl-CH2-, 4,4-difluorocyclohexyl-CH2-, 4-H2NCH2CH2O-phenyl-CH2-, 4-H2NCH2CH2O-pyrido-3-yl-CH2-, piperidine-4-yl-CH2- or 4-CH3C(O)NH-CH2CH2O-phenyl-CH2-; R 10 and R 11 Both are H; and A 1 and A 2 Both are HO2C-.

[0141] In some embodiments of the methods described herein, the compound is of formula (II): [ka]

[0142] or having a pharmaceutically acceptable salt structure thereof, where, R 1 This is CH3C(O)NH-CH2CH2-O- or C 1 is; C 1 teeth, (i) a 5-6 member monocyclic aryl or heteroaryl, wherein the heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; or (ii) A 5-6 member monocyclic or bicyclic saturated cycloalkyl or heterocycloalkyl containing 1-2 heteroatoms selected from the group consisting of N, O, and S, or (iii) A monocyclic or bicyclic cycloalkyl group with 5-6 members; Here, C 1R is either unsubstituted or independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 fluoroalkyl, HO2C-, C1-C3 alkoxy, and C2-C3 acyl. C1 Substituting with a substituent; R 3 is a 9-10 membered bicyclic aryl or heteroaryl, where the heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; Here, R 3 It is either unsubstituted or substituted with 1 to 3 R3a substituents independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 fluoroalkyl, hydroxy, and C1-C3 alkoxy; R4a and R4b are independently C1-C3 alkyl, HO2C-(CH2) m -, H2NC(O)-(CH2) m -, (CH3)2NC(O)-(CH2) m -or tetrazolyl-(CH2) m -is; R 5 is hydroxyl, amino, H2N(CH2) n -, H2NC(O)-(CH2) n -, CH3C(O)NH-, CH3C(O)NH(CH2) n -, C 5 or C 5 It is -CH2-; C 5 teeth, (i) a 5-6 member monocyclic aryl or heteroaryl, wherein the heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; (ii) A 9-10 member bicyclic aryl or heteroaryl, wherein the bicyclic heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S; (iii) A 5-6 member monocyclic or 9-10 member heterocycloalkyl, wherein the heterocycloalkyl is saturated or partially unsaturated and contains 1-2 heteroatoms selected from the group consisting of N, O, and S; (iv) A monocyclic cycloalkyl group with 5-6 members; or (v) It is 2,3-dihydroindolyl; Here, C 5 is unsubstituted, or halo, amino, hydroxy, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, H2N-(CH2) k -, H2NC(O)-(CH2) k - 1 to 3 R independently selected from the group consisting of H2C=CH-CH2O- and phenyl C5 Substituting with a substituent; R 6 H, C1-C5 alkyl, H2N(CH2) p -, H2NC(O)(CH2) p -, HOCH2-, (CH3)2NCH2-, H3CO-(CH2) q - or C 6 It is -CH2-; C 6 This is a 5-membered or 6-membered monocyclic saturated heterocycloalkyl containing 1 to 2 heteroatoms selected from the group consisting of N, O, and S, and C 6 R is either unsubstituted or independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 fluoroalkyl, hydroxy, and C1-C3 alkoxy. C6 Substituting with a substituent; R 7 is H or C1-C3 alkyl; R 8a H, C1-C5 alkyl, HOCH2-, H2N(CH2) r -, (CH3)3N + (CH2) r -or CH3C(O)NH(CH2) r -is; R 9a is H or C1-C3 alkyl; R 9b H, C1-C5 alkyl, C 9 -CH2- or C 9 It is -CH2CH2-; C 9 teeth, (i) a 5-6 member monocyclic aryl or heteroaryl, wherein the heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; or (ii) A 5-6 member monocyclic saturated cycloalkyl or heterocycloalkyl, wherein the heterocycloalkyl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; Here, C 9 is unsubstituted, or halo, amino, hydroxy, cyano, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, H2N-(CH2) k -, H2NC(O)-(CH2) k - One to three R independently selected from the group consisting of H2NCH2CH2O-, CH3C(O)NH-CH2CH2O-, and morpholinyl-CH2CH2O- C9 Substituting with a substituent; R 10 is H, halo, or C1-C3 alkyl; R 11 is H, halo, or C1-C3 alkyl; R 12 It is a halo; R 13a and R 13b These are independently H or C1-C3 alkyl groups; R 14 It is a C1-C5 alkyl group; C 14 teeth, (i) a 5-6 member monocyclic aryl or heteroaryl, wherein the heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; or (ii) A 5-6 member monocyclic saturated cycloalkyl or heterocycloalkyl, wherein the heterocycloalkyl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; Here, C 14 is unsubstituted, or halo, amino, hydroxy, cyano, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, H2N-(CH2) k -, H2NC(O)-(CH2) k - One to three R independently selected from the group consisting of H2NCH2CH2O-, CH3C(O)NH-CH2CH2O-, and morpholinyl-CH2CH2O- C14 Substituting with a substituent; Each existence of the subscript k is independently either 1 or 2; The subscript 'm' is either 1 or 2; The subscript n is 1, 2, 3, or 4; The subscript p is 1, 2, 3, or 4; The subscript q is either 1 or 2; The subscript r is 1, 2, 3, or 4; X 1 and X 2 is independently C(H) or N; and A 1 The group is selected from HO2C-, H2NC(O)-, CH3C(O)N(H)-, H2NS(O)2-, CH3S(O)2N(H)-, tetrazolyl, and 5-oxoxadiazolyl.

[0143] In some embodiments of the methods described herein, the compound is a compound of formula (II), where, R 1 is C 1 And here, C 1 teeth, (i) a 5-6 member monocyclic aryl or heteroaryl, wherein the heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; or (ii) A 5-6 member monocyclic or bicyclic saturated cycloalkyl or heterocycloalkyl containing 1-2 heteroatoms selected from the group consisting of N, O, and S; or (iii) A monocyclic or bicyclic cycloalkyl group with 5-6 members; Here, C 1 R is either unsubstituted or independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 fluoroalkyl, HO2C-, C1-C3 alkoxy, and C2-C3 acyl. C1 Substituting with a substituent; R 3 is a 9-10 member bicyclic aryl or heteroaryl, where the heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, and S, and R 3 It is either unsubstituted or substituted with 1 to 3 R3a substituents independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 fluoroalkyl, hydroxy, and C1-C3 alkoxy; R4a and R4b are independently C1-C3 alkyl, HO2C-(CH2) m -, H2NC(O)-(CH2) m -, (CH3)2NC(O)-(CH2) m -or tetrazolyl-(CH2) m -is; R 5 is hydroxyl, amino, H2N(CH2) n -, H2NC(O)-(CH2) n -, CH3C(O)NH- or CH3C(O)NH(CH2) n -is; R 6 H, C1-C5 alkyl, H2N(CH2) p -, H2NC(O)(CH2) p -, HOCH2-, (CH3)2NCH2-, or H3CO-(CH2) q -is; R 7 is H or C1-C3 alkyl; R 8ais H or C1-C5 alkyl; R 9a is H or C1-C3 alkyl; R 9b is H or C1-C5 alkyl; R 10 is H, halo, or C1-C3 alkyl; R 11 is H, halo, or C1-C3 alkyl; R 12 It is a halo; R 13a and R 13b These are independently H or C1-C3 alkyl groups; R 14 is C1-C5 alkyl-C 14 And here, C 14 teeth, (i) a 5-6 member monocyclic aryl or heteroaryl, wherein the heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; or (ii) A 5-6 member monocyclic saturated cycloalkyl or heterocycloalkyl, wherein the heterocycloalkyl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; Here, C 14 is unsubstituted, or halo, amino, hydroxy, cyano, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, H2N-(CH2) k -, H2NC(O)-(CH2) k - One to three R independently selected from the group consisting of H2NCH2CH2O-, CH3C(O)NH-CH2CH2O-, and morpholinyl-CH2CH2O- C14 Substituting with a substituent; Each existence of the subscript k is independently either 1 or 2; The subscript 'm' is either 1 or 2; The subscript n is 1, 2, 3, or 4; The subscript p is 1, 2, 3, or 4; The subscript q is either 1 or 2; The subscript r is 1, 2, 3, or 4; X 1 and X 2 is independently C(H) or N; and A 1 The group is selected from HO2C-, H2NC(O)-, CH3C(O)N(H)-, H2NS(O)2-, CH3S(O)2N(H)-, tetrazolyl, and 5-oxoxadiazolyl.

[0144] In some embodiments of the methods described herein, the compound is a compound of formula (II), where, X 1 and X 2 is C(H); and R 1 It is a phenyl compound substituted with a carboxyl group.

[0145] In some embodiments of the methods described herein, the compound is a compound of formula (II), where R 3 This is an indolyl replaced by a single halo.

[0146] In some embodiments of the methods described herein, the compound is a compound of formula (II), where R 6 is H, HOCH2-, C2-C5 alkyl or H2N(CH2) p - is

[0147] In some embodiments of the methods described herein, the compound is a compound of formula (II), where R 6 is C2-C5 alkyl or H2N(CH2) p - is

[0148] In some embodiments of the methods described herein, the compound is a compound of formula (II), where, R 8a is methyl or H2NCH2CH2-; and R 8bH is H.

[0149] In some embodiments of the methods described herein, the compound is a compound of formula (II), where R C14 It is a halo.

[0150] In some embodiments of the methods described herein, the compound is of formula (IIA): [ka]

[0151] It has the structure of [the object].

[0152] In some embodiments of the methods described herein, the compound is a compound of formula (II), where, R 1 is C 1 And here, C 1 is phenyl, and the phenyl is unsubstituted or has 1-2 R C1 Substituting with a substituent; R 3 R is naphthyl or indolyl, where R 3 It is either unsubstituted or substituted with one or two R3a substituents; R4a and R4b are independently C1-C3 alkyl groups; R 5 is hydroxyl, amino, H2N(CH2) n -, H2NC(O)-(CH2) n -, CH3C(O)NH- or CH3C(O)NH(CH2) n -is; R 6 H, C1-C5 alkyl, H2N(CH2) p -, H2NC(O)(CH2) p -, HOCH2-, (CH3)2NCH2-, or H3CO-(CH2) q -is; R 7 H is; R 8aH is; R 9a H is; R 9b H is; R 10 H is; R 11 H is; R 12 It is a halo; R 13a and R 13b These are independently H or C1-C3 alkyl groups; R 14 It is a C1-C5 alkylphenyl, which is unsubstituted or has 1-2 R C14 Substituting with a substituent; The subscript n is 1, 2, 3, or 4; The subscript 'p' is 1, 2, 3, or 4.

[0153] X 1 and X 2 is independently C(H) or N; and A 1 The group is selected from the group consisting of HO2C-, H2NC(O)-, and CH3C(O)N(H)-.

[0154] In some embodiments of the methods described herein, the compound is of formula (III): [ka]

[0155] or having a pharmaceutically acceptable salt structure thereof, where, R 1 It is CH3C(O)NH-CH2CH2-O- or C1; C1 is (i) a 5-6 member monocyclic aryl or heteroaryl, wherein the heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; or (ii) A 5-6 member monocyclic or bicyclic saturated cycloalkyl or heterocycloalkyl containing 1-2 heteroatoms selected from the group consisting of N, O, and S, or (iii) A monocyclic or bicyclic cycloalkyl group with 5-6 members; Here, C 1 R is either unsubstituted or independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 fluoroalkyl, HO2C-, C1-C3 alkoxy, and C2-C3 acyl. C1 Substituting with a substituent; R 2 is H, C1-C3 alkyl, benzyl, or phenyl-CH2CH2-; R 3 is a 9-10 membered bicyclic aryl or heteroaryl, where the heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; Here, R 3 R is either unsubstituted or independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 fluoroalkyl, hydroxy, and C1-C3 alkoxy. 3 It is substituted with a substituent; R 4 C1-C3 alkyl, HO2C-(CH2) m -, H2NC(O)-(CH2) m -, (CH3)2NC(O)-(CH2) m -or tetrazolyl-(CH2) m -is; R 5 is amino, H2N(CH2) n -, H2NC(O)-(CH2) n -, CH3C(O)NH-, CH3C(O)NH(CH2) n -, C 5 or C 5 It is -CH2-; C 5 teeth, (i) a 5-6 member monocyclic aryl or heteroaryl, wherein the heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; (ii) A 9-10 member bicyclic aryl or heteroaryl, wherein the bicyclic heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S; (iii) A 5-6 member monocyclic or 9-10 member heterocycloalkyl, wherein the heterocycloalkyl is saturated or partially unsaturated and contains 1-2 heteroatoms selected from the group consisting of N, O, and S; (iv) A 5-6 member monocyclic cycloalkyl; or (v) It is 2,3-dihydroindolyl; Here, C 5 is unsubstituted, or halo, amino, hydroxy, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, H2N-(CH2) k -, H2NC(O)-(CH2) k - 1 to 3 R independently selected from the group consisting of H2C=CH-CH2O- and phenyl C5 Substituting with a substituent; R 6 H, C1-C5 alkyl, H2N(CH2) p -, HOCH2-, (CH3)2NCH2-, H3CO-(CH2) q - or C 6 It is -CH2-; C 6 This is a 5-membered or 6-membered monocyclic saturated heterocycloalkyl containing 1 to 2 heteroatoms selected from the group consisting of N, O, and S, and C 6 R is either unsubstituted or independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 fluoroalkyl, hydroxy, and C1-C3 alkoxy. C6 Substituting with a substituent; R 7 is H or C1-C3 alkyl; R 8aH, C1-C5 alkyl, HOCH2-, H2N(CH2) r -, (CH3)3N+(CH2) r -or CH3C(O)NH(CH2) r -is; R 8b It is H or C1-C3 alkyl.

[0156] Alternatively, R 8b It does not exist, R 8a and R 7 It is bonded to form a 5-6 member monocyclic saturated cycloalkyl or heterocycloalkyl, where the heterocycloalkyl contains 1-2 heteroatoms selected from the group consisting of N, O, and S, where the 5-6 member monocyclic saturated cycloalkyl or heterocycloalkyl is unsubstituted, or halo, amino, hydroxy, cyano, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, H2N-(CH2) k -, H2NC(O)-(CH2) k - One to three R independently selected from the group consisting of H2NCH2CH2O-, CH3C(O)NH-CH2CH2O-, and morpholinyl-CH2CH2O- C8a Substituting with a substituent; R 9a is H or C1-C3 alkyl; R 9b H, C1-C5 alkyl, C 9 -CH2- or C 9 It is -CH2CH2-; C 9 teeth, (i) a 5-6 member monocyclic aryl or heteroaryl, wherein the heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; or (ii) A 5-6 member monocyclic saturated cycloalkyl or heterocycloalkyl, wherein the heterocycloalkyl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; Here, C 9is unsubstituted, or halo, amino, hydroxy, cyano, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, H2N-(CH2) k -, H2NC(O)-(CH2) k - One to three R independently selected from the group consisting of H2NCH2CH2O-, CH3C(O)NH-CH2CH2O-, and morpholinyl-CH2CH2O- C9 Substituting with a substituent; Alternatively, R 9a and R 9b It is bonded to form a 5-6 member monocyclic saturated cycloalkyl or heterocycloalkyl, where the heterocycloalkyl contains 1-2 heteroatoms selected from the group consisting of N, O, and S, where the 5-6 member monocyclic saturated cycloalkyl or heterocycloalkyl is unsubstituted, or halo, amino, hydroxy, cyano, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3-1,1'-biphenyl, C1-C3 alkoxy, H2N-(CH2) k -, H2NC(O)-(CH2) k - One to three R independently selected from the group consisting of H2NCH2CH2O-, CH3C(O)NH-CH2CH2O-, and morpholinyl-CH2CH2O- C9ab Substituting with a substituent; R 10 is H, halo, or C1-C3 alkyl; R 11 is H, halo, or C1-C3 alkyl; Each existence of the subscript k is independently either 1 or 2; The subscript 'm' is either 1 or 2; The subscript n is 1, 2, 3, or 4; The subscript p is 1, 2, 3, or 4; The subscript q is either 1 or 2; The subscript r is 1, 2, 3, or 4; X 1 , X 2 and X 3 is independently C(H) or N; and A 1 and A 2 The following are independently selected from the group consisting of HO2C-, H2NC(O)-, CH3C(O)N(H)-, H2NS(O)2-, CH3S(O)2N(H)-, tetrazolyl, and 5-oxoxadiazolyl.

[0157] In some embodiments of the methods described herein, the compound is a compound of formula (III), where, R 1 is C 1 And here, C 1 teeth, (i) a 5-6 member monocyclic aryl or heteroaryl, wherein the heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; or (ii) A 5-6 member monocyclic or bicyclic saturated cycloalkyl or heterocycloalkyl containing 1-2 heteroatoms selected from the group consisting of N, O, and S; or (iii) A monocyclic or bicyclic cycloalkyl group with 5-6 members; Here, C 1 It is either unsubstituted or substituted with 1 to 3 RC1 substituents independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 fluoroalkyl, HO2C-, C1-C3 alkoxy, and C2-C3 acyl; R 2 is H or C1-C3 alkyl; R 3 is a 9-10 membered bicyclic aryl or heteroaryl, where the heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; Here, R 3 R is either unsubstituted or independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 fluoroalkyl, hydroxy, and C1-C3 alkoxy. 3a Substituting with a substituent; R 4 C1-C3 alkyl, HO2C-(CH2)m -, H2NC(O)-(CH2) m -, (CH3)2NC(O)-(CH2) m -or tetrazolyl-(CH2) m -is; R 5 is C 5 or C 5 -CH2-, where C 5 teeth, (i) a 5-6 member monocyclic aryl or heteroaryl, wherein the heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; (ii) A 9-10 member bicyclic aryl or heteroaryl, wherein the bicyclic heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S; (iii) A 5-6 member monocyclic or 9-10 member heterocycloalkyl, wherein the heterocycloalkyl is saturated or partially unsaturated and contains 1-2 heteroatoms selected from the group consisting of N, O, and S; (iv) It is a 5-6 membered monocyclic cycloalkyl; (v) It is 2,3-dihydroindolyl; Here, C 5 is unsubstituted, or halo, amino, hydroxy, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, H2N-(CH2) k -, H2NC(O)-(CH2) k - 1 to 3 RCs independently selected from the group consisting of H2C=CH-CH2O- and phenyl 5 Substituting with a substituent; R 6 H, C1-C5 alkyl, H2N(CH2) p -, HOCH2-, (CH3)2NCH2-, or H3CO-(CH2) q -is; R 7 is H or C1-C3 alkyl; R 8a is H or C1-C5 alkyl; R8b It is H or C1-C3 alkyl.

[0158] Alternatively, R 8b It does not exist, R 8a and R 7 It is bonded to form a 5-6 member monocyclic saturated cycloalkyl or heterocycloalkyl, where the heterocycloalkyl contains 1-2 heteroatoms selected from the group consisting of N, O, and S, where the 5-6 member monocyclic saturated cycloalkyl or heterocycloalkyl is unsubstituted, or halo, amino, hydroxy, cyano, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, H2N-(CH2) k -, H2NC(O)-(CH2) k - One to three R independently selected from the group consisting of H2NCH2CH2O-, CH3C(O)NH-CH2CH2O-, and morpholinyl-CH2CH2O- C8a Substituting with a substituent; R 9a is H or C1-C3 alkyl; R 9b It is H or C1-C5 alkyl.

[0159] Alternatively, R 9a and R 9b It is bonded to form a 5-6 member monocyclic saturated cycloalkyl or heterocycloalkyl, where the heterocycloalkyl contains 1-2 heteroatoms selected from the group consisting of N, O, and S, where the 5-6 member monocyclic saturated cycloalkyl or heterocycloalkyl is unsubstituted, or halo, amino, hydroxy, cyano, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3-1,1'-biphenyl, C1-C3 alkoxy, H2N-(CH2) k -, H2NC(O)-(CH2) k - One to three R independently selected from the group consisting of H2NCH2CH2O-, CH3C(O)NH-CH2CH2O-, and morpholinyl-CH2CH2O- C9ab Substituting with a substituent; R 10 is H, halo, or C1-C3 alkyl; R 11 is H, halo, or C1-C3 alkyl; Each existence of the subscript k is independently either 1 or 2; The subscript 'm' is either 1 or 2; The subscript n is 1, 2, 3, or 4; The subscript p is 1, 2, 3, or 4; The subscript q is either 1 or 2; The subscript r is 1, 2, 3, or 4; X 1 , X 2 and X 3 is independently C(H) or N; and A 1 and A 2 The following are independently selected from the group consisting of HO2C-, H2NC(O)-, CH3C(O)N(H)-, H2NS(O)2-, CH3S(O)2N(H)-, tetrazolyl, and 5-oxoxadiazolyl.

[0160] In some embodiments of the methods described herein, the compound is of formula (IIIA): [ka]

[0161] It has the structure of [the object].

[0162] In some embodiments of the methods described herein, the compound is a compound of formula (III), where, R 1 is C 1 And here, C 1 It is phenyl, which is unsubstituted or has 1-2 R's. C1 Substituting with a substituent; R 2 is H or C1-C3 alkyl; R 3R is naphthyl or indolyl, where R 3 is not substituted, or has 1-2 R 3a Substituting with a substituent; R 4 C1-C3 alkyl, HO2C-(CH2) m -, H2NC(O)-(CH2) m -, (CH3)2NC(O)-(CH2) m -or tetrazolyl-(CH2) m -is; R 5 is C 5 or C 5 -CH2-, where C 5 is naphthyl or indolyl, which is unsubstituted or has 1-2 R C5 Substituting with a substituent; R 6 H, C1-C5 alkyl, H2N(CH2) p -, HOCH2-, (CH3)2NCH2-, or H3CO-(CH2) q -is; R 8b It does not exist, R 8a and R 7 It binds to form pyrrolidinyl, which is either unsubstituted or has 1-2 R's. C8a Substituting with a substituent; R 9a and R 9b It binds to form pyrrolidinyl, which is either unsubstituted or has 1-2 R's. C9ab Substituting with a substituent; R 10 is H or C1-C3 alkyl; R 11 is H or C1-C3 alkyl; The subscript 'm' is either 1 or 2; X 1 , X 2 and X 3 is independently C(H) or N; and A 1 and A 2The group consisting of HO2C-, H2NC(O)-, or CH3C(O)N(H)- is independently selected.

[0163] In some embodiments of the methods described herein, the compound is a compound of formula (III), where, X 1 and X 2 is C(H); and R 1 It is a phenyl compound substituted with a carboxyl group.

[0164] In some embodiments of the methods described herein, the compound is a compound of formula (III), where R 2 H is H.

[0165] In some embodiments of the methods described herein, the compound is a compound of formula (III), where R 3 This is an indolyl replaced by a single halo.

[0166] In some embodiments of the methods described herein, the compound is a compound of formula (III), where R 4 is HO2C-(CH2) m - is

[0167] In some embodiments of the methods described herein, the compound is a compound of formula (III), where X 3 is C(H).

[0168] In some embodiments of the methods described herein, the compound is a compound of formula (III), where R 5 is H2N(CH2) n - These are indole, 7-azaindole, naphthyl, or pyridyl.

[0169] In some embodiments of the methods described herein, the compound is a compound of formula (III), where R 5is H2N(CH2) n - These are indole, naphthyl, or pyridyl.

[0170] In some embodiments of the methods described herein, the compound is a compound of formula (III), where R 6 H is H.

[0171] In some embodiments of the methods described herein, the compound is a compound of formula (III), where R 8b It does not exist, R 8a and R 7 It combines with 1-2 R C8a It forms pyrrolidinyl molecules substituted with substituents.

[0172] In some embodiments of the methods described herein, the compound is a compound of formula (III), where R 9a and R 9b It combines with 1-2 R C9ab It forms pyrrolidinyl molecules substituted with substituents.

[0173] In some embodiments of the methods described herein, the compound is a compound of formula (III), where R C98a It is a hydroxyl group.

[0174] In some embodiments of the methods described herein, the compound is a compound of formula (III), where R C9ab It is C1-C3-1,1'-biphenyl.

[0175] In some embodiments of the methods described herein, the compound is a compound of formula (III), where A 1 It is -CO2H.

[0176] In some embodiments of the methods described herein, the compound is a compound of formula (III), where A 2 It is -CO2H.

[0177] In some embodiments of the methods described herein, the compound is of formula (IV): [ka]

[0178] or having a pharmaceutically acceptable salt structure thereof, where, R 1 It is CH3C(O)NH-CH2CH2-O- or C1; C1 is (i) a 5-6 member monocyclic aryl or heteroaryl, wherein the heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; or (ii) A 5-6 member monocyclic or bicyclic saturated cycloalkyl or heterocycloalkyl containing 1-2 heteroatoms selected from the group consisting of N, O, and S; or (iii) A monocyclic or bicyclic cycloalkyl group with 5-6 members; Here, C1 is either unsubstituted or substituted by 1 to 3 RC1 substituents independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 fluoroalkyl, HO2C-, C1-C3 alkoxy, and C2-C3 acyl; R 2 H, C1-C3 alkyl, benzyl, heteroaryl-(CH2) m C(O)- or phenyl-CH2CH2-, where the heteroaryl is a 5-6 member monocyclic heteroaryl containing 1-2 heteroatoms selected from the group consisting of N, O, and S, where R 2 R is either unsubstituted or independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 fluoroalkyl, HO2C-, C1-C3 alkoxy, and C2-C3 acyl. C2 Substituting with a substituent; R 3is a 9-10 membered bicyclic aryl or heteroaryl, where the heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; Here, R 3 R is either unsubstituted or independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 fluoroalkyl, hydroxy, and C1-C3 alkoxy. 3a Substituting with a substituent; R 4 C1-C3 alkyl, HO2C-(CH2) m -, H2NC(O)-(CH2) m -, (CH3)2NC(O)-(CH2) m -or tetrazolyl-(CH2) m -is; R 5 is amino, H2N(CH2) n -, H2NC(O)-(CH2) n -, CH3C(O)NH-, CH3C(O)NH(CH2) n -, C 5 or C 5 It is -CH2-; C 5 teeth, (i) a 5-6 member monocyclic aryl or heteroaryl, wherein the heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; (ii) A 9-10 member bicyclic aryl or heteroaryl, wherein the bicyclic heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S; (iii) A 5-6 member monocyclic or 9-10 member heterocycloalkyl, wherein the heterocycloalkyl is saturated or partially unsaturated and contains 1-2 heteroatoms selected from the group consisting of N, O, and S; (iv) It is a 5-6 membered monocyclic cycloalkyl; (v) It is 2,3-dihydroindolyl; Here, C 5is unsubstituted, or halo, amino, hydroxy, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, H2N-(CH2) k -, H2NC(O)-(CH2) k - 1 to 3 R independently selected from the group consisting of H2C=CH-CH2O- and phenyl C5 Substituting with a substituent; R 6 H, C1-C5 alkyl, H2N(CH2) p -, HOCH2-, (CH3)2NCH2-, H3CO-(CH2) q - or C 6 It is -CH2-; C 6 This is a 5-membered or 6-membered monocyclic saturated heterocycloalkyl containing 1 to 2 heteroatoms selected from the group consisting of N, O, and S, where C 6 The RC is either unsubstituted or independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 fluoroalkyl, hydroxy, and C1-C3 alkoxy. 6 Substituting with a substituent; R 7 is H or C1-C3 alkyl; R 8a H, C1-C5 alkyl, HOCH2-, H2N(CH2) r -, (CH3)3N + (CH2) r -or CH3C(O)NH(CH2) r -is; R 8b is H or C1-C3 alkyl; R 9a is H or C1-C3 alkyl; R 9b H, C1-C5 alkyl, C 9 -CH2- or C 9 It is -CH2CH2-; C 9 teeth, (i) a 5-6 member monocyclic aryl or heteroaryl, wherein the heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; or (ii) A 5-6 member monocyclic saturated cycloalkyl or heterocycloalkyl, wherein the heterocycloalkyl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; Here, C 9 is unsubstituted, or halo, amino, hydroxy, cyano, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, H2N-(CH2) k -, H2NC(O)-(CH2) k - One to three R independently selected from the group consisting of H2NCH2CH2O-, CH3C(O)NH-CH2CH2O-, and morpholinyl-CH2CH2O- C9 Substituting with a substituent; R 10 is H, halo, or C1-C3 alkyl; R 11 is H, halo, or C1-C3 alkyl; Each existence of the subscript k is independently either 1 or 2; The subscript 'm' is either 1 or 2; The subscript n is 1, 2, 3, or 4; The subscript p is 1, 2, 3, or 4; The subscript q is either 1 or 2; The subscript r is 1, 2, 3, or 4; X 1 , X 2 and X 3 is independently C(H) or N; and A 1 and A 2 The following are independently selected from the group consisting of HO2C-, H2NC(O)-, CH3C(O)N(H)-, H2NS(O)2-, CH3S(O)2N(H)-, tetrazolyl, and 5-oxoxadiazolyl.

[0179] In some embodiments of the methods described herein, the compound is a compound of formula (IV), where, R 1 It is CH3C(O)NH-CH2CH2-O-; R 2 is heteroaryl-(CH2) m C(O)-, where the heteroaryl is a 5-6 member monocyclic heteroaryl containing 1-2 heteroatoms selected from the group consisting of N, O, and S, where R 2 It is either unsubstituted or substituted with one or two RC2 substituents; R 3 is a 9-10 membered bicyclic aryl or heteroaryl, where the heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; Here, R 3 R is either unsubstituted or independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 fluoroalkyl, hydroxy, and C1-C3 alkoxy. 3a Substituting with a substituent; R 4 C1-C3 alkyl, HO2C-(CH2) m -, H2NC(O)-(CH2) m -, (CH3)2NC(O)-(CH2) m -or tetrazolyl-(CH2) m -is; R 5 is C 5 or C 5 -CH2-, where C 5 teeth, (i) A 5-6 member monocyclic aryl or heteroaryl, wherein the heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, and S.

[0180] (ii) A 9-10 member bicyclic aryl or heteroaryl, wherein the bicyclic heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S; (iii) A 5-6 member monocyclic or 9-10 member heterocycloalkyl, wherein the heterocycloalkyl is saturated or partially unsaturated and contains 1-2 heteroatoms selected from the group consisting of N, O, and S; (iv) It is a 5-6 membered monocyclic cycloalkyl; (v) It is 2,3-dihydroindolyl; Here, C 5 is unsubstituted, or halo, amino, hydroxy, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, H2N-(CH2) k -, H2NC(O)-(CH2) k - 1 to 3 R independently selected from the group consisting of H2C=CH-CH2O- and phenyl C5 Substituting with a substituent; R 6 is H or C1-C5 alkyl; R 7 is H or C1-C3 alkyl; R 8a is H or C1-C5 alkyl; R 8b is H or C1-C3 alkyl; R 9a is H or C1-C3 alkyl; R 9b is H or C1-C5 alkyl; R 10 is H, halo, or C1-C3 alkyl; R 11 is H, halo, or C1-C3 alkyl; Each existence of the subscript k is independently either 1 or 2; The subscript 'm' is either 1 or 2; X 1 , X 2 and X 3 is independently C(H) or N; and A 1 and A 2The following are independently selected from the group consisting of HO2C-, H2NC(O)-, CH3C(O)N(H)-, H2NS(O)2-, CH3S(O)2N(H)-, tetrazolyl, and 5-oxoxadiazolyl.

[0181] In some embodiments of the methods described herein, the compound is a compound of formula (IV), where, R 1 It is CH3C(O)NH-CH2CH2-O-; R 2 is benzyl, pyridinyl-(CH2) m C(O)- or phenyl-CH2CH2-, where the heteroaryl is a 5-6 member monocyclic heteroaryl containing 1-2 heteroatoms selected from the group consisting of N, O, and S, where R 2 R is either unsubstituted or independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 fluoroalkyl, HO2C-, C1-C3 alkoxy, and C2-C3 acyl. C2 Substituting with a substituent; R 3 is naphthyl or indolyl, R 3 is not substituted, or has 1-2 R 3a Substituting with a substituent; R 4 C1-C3 alkyl, HO2C-(CH2) m -, H2NC(O)-(CH2) m -, (CH3)2NC(O)-(CH2) m -or tetrazolyl-(CH2) m -is; R 5 is C 5 or C 5 -CH2-, where C 5 is naphthyl or indolyl, which is not substituted, or has 1-2 R C5 Substituting with a substituent; R 6 is H or C1-C5 alkyl; R 7is H or C1-C3 alkyl; R 8a is H or C1-C5 alkyl; R 8b is H or C1-C3 alkyl; R 9a is H or C1-C3 alkyl; R 9b is H or C1-C5 alkyl; R 10 is H or C1-C3 alkyl; R 11 is H or C1-C3 alkyl; The subscript 'm' is either 1 or 2; X 1 , X 2 and X 3 is independently C(H) or N; and A 1 and A 2 The following are independently selected from the group consisting of HO2C-, H2NC(O)-, CH3C(O)N(H)-, H2NS(O)2-, CH3S(O)2N(H)-, tetrazolyl, and 5-oxoxadiazolyl.

[0182] In some embodiments of the methods described herein, the compound is a compound of formula (IV), where, X 1 and X 2 is C(H); and R 1 It is CH3C(O)NH-CH2CH2-O-

[0183] In some embodiments of the methods described herein, the compound is a compound of formula (IV), where R 2 It is pyridinyl-(CH2)2-C(O)-.

[0184] In some embodiments of the methods described herein, the compound is a compound of formula (IV), where R 3 It is naphthyl.

[0185] In some embodiments of the methods described herein, the compound is a compound of formula (IV), where R 4 is HO2C-(CH2) m - is

[0186] In some embodiments of the methods described herein, the compound is a compound of formula (IV), where X 3 is C(H).

[0187] In some embodiments of the methods described herein, the compound is a compound of formula (IV), where R 5 is H2N(CH2) n - These are indole, 7-azaindole, naphthyl, or pyridyl.

[0188] In some embodiments of the methods described herein, the compound is a compound of formula (IV), where R 5 is H2N(CH2) n - These are indole, naphthyl, or pyridyl.

[0189] In some embodiments of the methods described herein, the compound is a compound of formula (IV), where R 6 H is H.

[0190] In some embodiments of the methods described herein, the compound is a compound of formula (IV), where R 7 H is H.

[0191] In some embodiments of the methods described herein, the compound is a compound of formula (IV), where R 9a It is methyl.

[0192] In some embodiments of the methods described herein, the compound is a compound of formula (IV), where R 9b It is butyl.

[0193] In some embodiments of the methods described herein, the compound is a compound of formula (IV), where A 1 It is -CO2H.

[0194] In some embodiments of the methods described herein, the compound is a compound of formula (IV), where A 2 It is -CO2H.

[0195] In some embodiments of the methods described herein, the compound is a compound of formula (I), where the compound is selected from the group consisting of SEQ ID NOs: 8, 9, 10, 11, 12, 13, 14, and 15.

[0196] In some embodiments, the compound is a peptide (e.g., a macrocyclic peptide) containing the amino acid sequence of SEQ ID NO: 8. In some embodiments, the compound is compound A. In some embodiments, the compound is a peptide (e.g., a macrocyclic peptide) containing the amino acid sequence of SEQ ID NO: 9. In some embodiments, the compound is compound B. In some embodiments, the compound is a peptide (e.g., a macrocyclic peptide) containing the amino acid sequence of SEQ ID NO: 10. In some embodiments, the compound is compound C. In some embodiments, the compound is a peptide (e.g., a macrocyclic peptide) containing the amino acid sequence of SEQ ID NO: 11. In some embodiments, the compound is compound D. In some embodiments, the compound is a peptide (e.g., a macrocyclic peptide) containing the amino acid sequence of SEQ ID NO: 12. In some embodiments, the compound is compound E. In some embodiments, the compound is a peptide (e.g., a macrocyclic peptide) containing the amino acid sequence of SEQ ID NO: 13. In some embodiments, the compound is compound F. In some embodiments, the compound is a peptide (e.g., a macrocyclic peptide) containing the amino acid sequence of SEQ ID NO: 14. In some embodiments, the compound is compound G. In some embodiments, the compound is a peptide (e.g., a macrocyclic peptide) containing the amino acid sequence of SEQ ID NO: 15. In some embodiments, the compound is compound H.

[0197] While not bound by any particular theory, the applicant believes that the compounds of this disclosure capture interleukin-1β, inhibit IL-1 receptor-mediated signaling, and therefore reduce the downstream markers IL-6 and CRP.

[0198] 7.5.1 Compound interactions with IL-1β In some embodiments, the compounds described herein bind to IL-1β in one or more of its binding pockets. In some embodiments, the compounds described herein bind to the lipophilic and / or hydrophobic binding pockets of IL-1β.

[0199] In some embodiments, the compounds described herein bind to IL-1β in the IL-1β residues described herein as the IL-1β binding pocket (e.g., the IL-1β binding pocket located between the N-terminal and C-terminal domains of IL-1β). In some embodiments, when IL-1β is complexed with IL-1R1, the compounds described herein bind to the IL-1β binding pocket located in or adjacent to the D3 domain of IL-1R1. In some embodiments, the compounds described herein bind to IL-1β in the IL-1β binding pocket containing or consisting of the amino acid residues Gly177-Leu178-Lys179-Glu180-Lys181-Asn182-Leu183-Tyr184 (SEQ ID NO: 16) and / or Val201-Asp202-Pro203-Lys204-Asn205-Tyr206-Pro207 (SEQ ID NO: 17). In some embodiments, the compounds described herein bind to all of the residues listed with respect to the IL-1β binding pocket in the IL-1β binding pocket. In some embodiments, the compounds described herein bind to one or more, but not all, of the residues listed with respect to the IL-1β binding pocket in the IL-1β binding pocket. In some embodiments, the compounds described herein bind to the IL-1β binding pocket including additional IL-1β residues (e.g., additional residues of the binding pocket described herein).

[0200] In some embodiments, the compounds described herein bind to the binding pocket of IL-1β via a non-covalent interaction between a portion of the compound and a residue in the binding pocket. In some embodiments, a portion of the compound may donate or accept the non-covalent interaction described herein. In some embodiments, the non-covalent interaction described herein may be donated by a residue in the binding pocket of IL-1β (e.g., the residue's backbone or side chain) and accepted by a compound (e.g., a portion of the compound). In some embodiments, the non-covalent interaction described herein may be donated by a compound (e.g., a portion of the compound) and accepted by a residue in the binding pocket of IL-1β (e.g., the residue's backbone or side chain). For example, a hydrogen bond (H bond) interaction may involve hydrogen being donated from a compound (e.g., a portion of the compound) to a residue in the binding pocket and accepted by a residue in the binding pocket to form an H bond interaction. In some embodiments, a portion of the compound is a functional group of the compound (e.g., one described herein). In some embodiments, a portion of the compound includes multiple functional groups of the compound (for example, those described herein).

[0201] In some embodiments, the compounds described herein bind to the residue of IL-1β in the binding pocket of IL-1β via lipophilic interactions and / or hydrophobic interactions (e.g., minimizing the exposure of nonpolar surface area to polar molecules). In some embodiments, the compounds described herein include a lipophilic interaction moiety and / or hydrophobic interaction moiety that can receive lipophilic interactions and / or hydrophobic interactions from the residue of the IL-1β binding site described herein (e.g., the residue's backbone or side chain). In some embodiments, the compounds described herein include a lipophilic interaction moiety and / or hydrophobic interaction moiety that can donate lipophilic interactions and / or hydrophobic interactions to the residue of the IL-1β binding site described herein (e.g., the residue's backbone or side chain). In some embodiments, the compounds described herein bind to the residue of IL-1β in the binding pocket of IL-1β via electrostatic interactions (e.g., Coulomb attraction interactions). In some embodiments, the compounds described herein include an electrostatic interaction moiety capable of receiving electrostatic interactions from the IL-1β binding site residue (e.g., the residue's backbone or side chain) as described herein. In some embodiments, the compounds described herein include an electrostatic interaction moiety capable of donating electrostatic interactions to the IL-1β binding site residue (e.g., the residue's backbone or side chain) as described herein. In some embodiments, the compounds described herein bind to the IL-1β residue in the IL-1β binding pocket via ionic interactions (e.g., valence interactions). In some embodiments, the compounds described herein include an ionic interaction moiety capable of receiving ionic interactions from the IL-1β binding site residue (e.g., the residue's backbone or side chain) as described herein. In some embodiments, the compounds described herein include an ionic interaction moiety capable of donating ionic interactions to the IL-1β binding site residue (e.g., the residue's backbone or side chain) as described herein.In some embodiments, the compounds described herein bind to the IL-1β binding pocket via hydrogen bonding (H bond) interactions (e.g., backbone or side-chain H bond interactions) with the IL-1β residue. In some embodiments, the compounds described herein include an H bond interaction moiety capable of receiving H bond interactions from the residue of the IL-1β binding site described herein (e.g., the residue's backbone or side chain). In some embodiments, the compounds described herein include a hydrogen bond interaction moiety capable of donating hydrogen bond interactions to the residue of the IL-1β binding site described herein (e.g., the residue's backbone or side chain). In some embodiments, the compounds described herein bind to the IL-1β residue in the IL-1β binding pocket via halogen bond interactions (e.g., side-chain halogen bond interactions). In some embodiments, the compounds described herein include a halogen bond interaction moiety capable of receiving halogen bond interactions from the residue of the IL-1β binding site described herein (e.g., the residue's backbone or side chain). In some embodiments, the compounds described herein include a halogen-binding interaction moiety capable of donating a halogen-binding interaction to the residues of the IL-1β binding site described herein (e.g., the residue's backbone or side chain). In some embodiments, the compounds described herein bind to the IL-1β residues in the IL-1β binding pocket via van der Waals interactions (e.g., dipole-dipole interactions, dipole-induced dipole interactions, or London dispersion forces). In some embodiments, the compounds described herein include a van der Waals interaction moiety capable of receiving van der Waals interactions from the residues of the IL-1β binding site described herein (e.g., the residue's backbone or side chain). In some embodiments, the compounds described herein include a van der Waals interaction moiety capable of donating a van der Waals interaction to the residues of the IL-1β binding site described herein (e.g., the residue's backbone or side chain).In some embodiments, the compounds described herein bind to the residue of IL-1β in the binding pocket of IL-1β via pi-effect interactions (e.g., pi-pi interactions, CH-pi interactions, cation-pi interactions, anion-pi interactions, or polar-pi interactions). In some embodiments, the compounds described herein include a pi-effect interaction moiety capable of receiving pi-effect interactions from the residues of the IL-1β binding site described herein (e.g., the residue's backbone or side chain). In some embodiments, the compounds described herein include a pi-effect interaction moiety capable of donating pi-effect interactions to the residues of the IL-1β binding site described herein (e.g., the residue's backbone or side chain). In some embodiments, the pi-effect interaction is a stacking interaction (e.g., a pi-pi interaction). In some embodiments, the pi-effect interaction is a nonpolar pi-effect interaction. In some embodiments, the pi-effect interaction is a CH-pi interaction. In some embodiments, the pi-effect interaction is a polar-pi interaction. In some embodiments, the polar-pi interaction is a polar hydrogen-pi interaction. In some embodiments, the polar-pi interaction is a polar nitrogen-pi interaction. In some embodiments, the pi-effect interaction may be characterized as one of several types of pi-effect interactions described herein. In some embodiments, the non-covalent interaction may be characterized as one of several types of non-covalent interactions described herein.

[0202] In some embodiments, the non-covalent interacting moieties of a compound (e.g., lipophilic interacting moieties, hydrophobic interacting moieties, electrostatic interacting moieties, ionic interacting moieties, hydrogen-bonding interacting moieties, halogen-bonding interacting moieties, van der Waals interacting moieties, or pi-effect interacting moieties) include functional groups or moieties, groups, or substituents of the compounds described herein. In some embodiments, the non-covalent interacting moieties are NH groups, NH2 groups, NH3 groups, lone pairs, OH groups, carbonyls, carboxylates, arenes (e.g., aryl or biaryls), atoms, such as H, N, O, F, Cl, or other groups or atoms defined herein or elsewhere as interacting non-covalently. For example, common donor and acceptor atoms in hydrogen-bonding non-covalent interactions include second-period elements, such as nitrogen (N), oxygen (O), and fluorine (F).

[0203] In some embodiments, the compounds described herein bind to the IL-1β binding pocket containing one or more amino acids corresponding to residues 177-184 and 201-207 of IL-1β (SEQ ID NO: 1). In some embodiments, the compounds described herein bind to the IL-1β binding pocket defined by the amino acid residues Gly177-Leu178-Lys179-Glu180-Lys181-Asn182-Leu183-Tyr184 (SEQ ID NO: 16) and Val201-Asp202-Pro203-Lys204-Asn205-Tyr206-Pro207 (SEQ ID NO: 17) (e.g., Gly177-Tyr184 and Val201-Pro207) of IL-1β (SEQ ID NO: 1).

[0204] In some embodiments, the compounds described herein bind to one or both amino acids corresponding to residues selected from 179 or 207 of IL-1β (SEQ ID NO: 1). In some embodiments, the compounds described herein bind to one or both amino acid residues Lys179 or Pro207 of IL-1β (SEQ ID NO: 1). In some embodiments, the compounds bind to one or both Lys179 or Pro207 via a moiety that can interact with residue Lys179 and / or residue Pro207 via a pi-effect interaction (e.g., accepting a pi-effect interaction). In some embodiments, the moiety that can interact via a pi-effect interaction from residue Pro207 includes an arene moiety. In some embodiments, the moiety that can interact via a pi-effect interaction from residue Pro207 includes a biaryl moiety. In some embodiments, the biaryl moiety is a 9-10 membered bicyclic aryl or heteroaryl. In some embodiments, the heteroaryl contains one or two heteroatoms selected from the group consisting of N, O, and S. In some embodiments, the 9-10 membered bicyclic aryl or heteroaryl is either unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 fluoroalkyl, hydroxy, and C1-C3 alkoxy. In some embodiments, the biaryl moiety is a substituted or unsubstituted indole or naphthyl.

[0205] In some embodiments, the compounds described herein bind to IL-1β in an IL-1β binding pocket further comprising an amino acid corresponding to residue 119 of IL-1β (SEQ ID NO: 1). In some embodiments, the compounds described herein bind to IL-1β in an IL-1β binding pocket further defined by the amino acid residue Val119 of IL-1β (SEQ ID NO: 1). In some embodiments, the compounds described herein bind to IL-1β in an IL-1β binding pocket further comprising an amino acid corresponding to residue 120 of IL-1β (SEQ ID NO: 1). In some embodiments, the compounds described herein bind to IL-1β in an IL-1β binding pocket further defined by the amino acid residue Arg120 of IL-1β (SEQ ID NO: 1). In some embodiments, the compounds described herein bind to IL-1β in an IL-1β binding pocket further comprising an amino acid corresponding to residue 121 (SEQ ID NO: 1). In some embodiments, the compounds described herein bind to IL-1β in a binding pocket of IL-1β further defined by the amino acid residue Ser121 (SEQ ID NO: 1) of IL-1β. In some embodiments, the compounds described herein bind to IL-1β in a binding pocket of IL-1β further comprising the amino acid corresponding to residue 203 (SEQ ID NO: 1) of IL-1β. In some embodiments, the compounds described herein bind to IL-1β in a binding pocket of IL-1β further defined by the amino acid residue Pro203 (SEQ ID NO: 1) of IL-1β. In some embodiments, the compounds described herein bind to IL-1β in a binding pocket of IL-1β further comprising the amino acid corresponding to residue 204 (SEQ ID NO: 1) of IL-1β. In some embodiments, the compounds described herein bind to IL-1β in a binding pocket of IL-1β further defined by the amino acid residue Lys204 (SEQ ID NO: 1) of IL-1β.

[0206] In some embodiments, the compounds described herein bind to IL-1β in a binding pocket further comprising an amino acid corresponding to residue 162 of IL-1β (SEQ ID NO: 1). In some embodiments, the compounds described herein bind to IL-1β in a binding pocket further defined by the amino acid residue Phe162 of IL-1β (SEQ ID NO: 1). In some embodiments, the compounds described herein bind to IL-1β in a binding pocket further comprising an amino acid corresponding to residue 206 of IL-1β (SEQ ID NO: 1). In some embodiments, the compounds described herein bind to IL-1β in a binding pocket further defined by the amino acid residue Tyr206 of IL-1β (SEQ ID NO: 1). In some embodiments, the compounds described herein bind to IL-1β in a binding pocket further comprising an amino acid corresponding to residue 269 of IL-1β (SEQ ID NO: 1). In some embodiments, the compounds described herein bind to IL-1β in a binding pocket further defined by the amino acid residue Ser269 of IL-1β (SEQ ID NO: 1).

[0207] In some embodiments, the compounds described herein bind to IL-1β in a binding pocket further comprising an amino acid corresponding to residue 117 of IL-1β (SEQ ID NO: 1). In some embodiments, the compounds described herein bind to IL-1β in a binding pocket further defined by the amino acid residue Ala117 of IL-1β (SEQ ID NO: 1). In some embodiments, the compounds described herein bind to IL-1β in a binding pocket further comprising an amino acid corresponding to residue 118 of IL-1β (SEQ ID NO: 1). In some embodiments, the compounds described herein bind to IL-1β in a binding pocket further defined by the amino acid residue Pro118 of IL-1β (SEQ ID NO: 1). In some embodiments, the compounds described herein bind to IL-1β in a binding pocket further comprising an amino acid corresponding to residue 122 of IL-1β (SEQ ID NO: 1). In some embodiments, the compounds described herein bind to IL-1β in a binding pocket further defined by the amino acid residue Leu122 of IL-1β (SEQ ID NO: 1). In some embodiments, the compounds described herein bind to IL-1β in a binding pocket further comprising an amino acid corresponding to residue 123 of IL-1β (SEQ ID NO: 1). In some embodiments, the compounds described herein bind to IL-1β in a binding pocket further defined by the amino acid residue Asn123 of IL-1β (SEQ ID NO: 1). In some embodiments, the compounds described herein bind to IL-1β in a binding pocket further comprising an amino acid corresponding to residue 159 of IL-1β (SEQ ID NO: 1). In some embodiments, the compounds described herein bind to IL-1β in a binding pocket further defined by the amino acid residue Ser159 of IL-1β (SEQ ID NO: 1). In some embodiments, the compounds described herein bind to IL-1β in a binding pocket further comprising an amino acid corresponding to residue 266 of IL-1β (SEQ ID NO: 1).In some embodiments, the compounds described herein bind to IL-1β in a binding pocket further defined by the amino acid residue Phe266 of IL-1β (SEQ ID NO: 1).

[0208] In some embodiments, the compounds described herein bind to one or more amino acids in the binding pocket of IL-1β, corresponding to residues selected from 119, 120, 121, 162, 179, 203, 204, 206, 207, or 269 of IL-1β (SEQ ID NO: 1). In some embodiments, the compounds described herein bind to one or more amino acid residues selected from Val119, Arg120, Ser121, Phe162, Lys179, Pro203, Lys204, Tyr206, Pro207, or Ser269 of IL-1β (SEQ ID NO: 1), in the binding pocket of IL-1β.

[0209] In certain embodiments, the compounds described herein bind to amino acids corresponding to residues 119, 120, 121, 203, and 204 of IL-1β (SEQ ID NO: 1) in the binding pocket of IL-1β. In certain embodiments, the compounds described herein bind to residues Val119, Arg120, Ser121, Pro203, and Lys204 of IL-1β (SEQ ID NO: 1) in the binding pocket of IL-1β. In certain embodiments, the compounds do not engage in any further binding interactions with IL-1β (SEQ ID NO: 1). In certain embodiments, the compounds further bind to 1, 2, 3, 4, or 5 amino acids corresponding to residues selected from residues 162, 179, 206, 207, or 269 of IL-1β (SEQ ID NO: 1) in the binding pocket of IL-1β. In certain embodiments, the compound further binds to 1, 2, 3, 4, or 5 residues selected from Phe162, Lys179, Tyr206, Pro207, or Ser269 of IL-1β (SEQ ID NO: 1) in the binding pocket of IL-1β. In certain embodiments, the compounds described herein bind to IL-1β in the binding pocket to at least the amino acids corresponding to residues 179 and / or 207 of IL-1β (SEQ ID NO: 1). In certain embodiments, the compounds described herein bind to IL-1β in the binding pocket to at least the amino acids corresponding to residues Lys179 and / or Pro207 of IL-1β (SEQ ID NO: 1).

[0210] In certain embodiments, the compounds described herein bind to the amino acids corresponding to residues 119, 120, 121, 179, 203, 204, 206, 207, and 269 of IL-1β (SEQ ID NO: 1) in the binding pocket of IL-1β. In certain embodiments, the compounds described herein bind to residues Val119, Arg120, Ser121, Lys179, Pro203, Lys204, Tyr206, Pro207, and Ser269 of IL-1β (SEQ ID NO: 1) in the binding pocket of IL-1β.

[0211] In certain embodiments, the compounds described herein bind to the amino acids corresponding to residues 119, 120, 121, 179, 203, 204, and 206 of IL-1β (SEQ ID NO: 1) in the binding pocket of IL-1β. In certain embodiments, the compounds described herein bind to residues Val119, Arg120, Ser121, Lys179, Pro203, and Lys204 of IL-1β (SEQ ID NO: 1) in the binding pocket of IL-1β.

[0212] In certain embodiments, the compounds described herein bind to the amino acids corresponding to residues 119, 120, 121, 162, 179, 203, 204, 206, 207, and 269 of IL-1β (SEQ ID NO: 1) in the binding pocket of IL-1β. In certain embodiments, the compounds described herein bind to residues Val119, Arg120, Ser121, Phe162, Lys179, Pro203, Lys204, Tyr206, Pro207, and Ser269 of IL-1β (SEQ ID NO: 1) in the binding pocket of IL-1β.

[0213] In certain embodiments, the compounds described herein bind to the amino acids corresponding to residues 119, 120, 121, 179, 203, 204, 206, and 207 of IL-1β (SEQ ID NO: 1) in the binding pocket of IL-1β. In certain embodiments, the compounds described herein bind to residues Val119, Arg120, Ser121, Lys179, Pro203, Lys204, Tyr206, and Pro207 of IL-1β (SEQ ID NO: 1) in the binding pocket of IL-1β.

[0214] In some embodiments, the binding of a compound to a specific residue in the IL-1β binding pocket is mediated by an interaction between a portion or functional group of the compound and the backbone or side chain of a specific residue of IL-1β. In some embodiments, the compounds described herein bind to one or more residues in the IL-1β binding pocket via non-covalent interactions. In some embodiments, the compounds described herein bind to one or more residues of IL-1β selected from Val119, Arg120, Ser121, Phe162, Lys179, Pro203, Lys204, Tyr206, Pro207, or Ser269.

[0215] In some embodiments, the compounds described herein bind to the residue of IL-1β in the binding pocket of IL-1β via lipophilic and / or hydrophobic interactions mediated by the lipophilic and / or hydrophobic interacting moieties of the compounds. In some embodiments, the compounds described herein bind to the residue of IL-1β in the binding pocket of IL-1β via electrostatic interactions mediated by the electrostatic interacting moieties of the compounds. In some embodiments, the compounds described herein bind to the residue of IL-1β in the binding pocket of IL-1β via ionic interactions mediated by the ionic interacting moieties of the compounds. In some embodiments, the compounds described herein bind to the residue of IL-1β in the binding pocket of IL-1β via hydrogen bonding interactions mediated by the hydrogen bonding (H bond) interacting moieties of the compounds. In some embodiments, the compounds described herein bind to the residue of IL-1β in the binding pocket of IL-1β via halogen bonding interactions mediated by the halogen bonding interacting moieties of the compounds. In some embodiments, the compounds described herein bind to the residue of IL-1β in the binding pocket of IL-1β via van der Waals interactions (e.g., dipole-dipole interactions, dipole-induced dipole interactions, or London dispersion forces) mediated by the van der Waals interaction moiety of the compound. In some embodiments, the compounds described herein bind to the residue of IL-1β in the binding pocket of IL-1β via pi-effect interactions (e.g., pi-pi interactions, CH-pi interactions, cation-pi interactions, anion-pi interactions, or polar-pi interactions) mediated by the pi-effect interaction moiety of the compound. In some embodiments, the aforementioned moiety of the compound comprises one or more functional groups of the compound (e.g., those described herein). In some embodiments, the compounds described herein bind to the residue of IL-1β in the binding pocket of IL-1β via a plurality of non-covalent interactions (which may be of different types) described herein.In some embodiments, a portion of the compound binds to a residue of IL-1β via a plurality of non-covalent interactions (which may be of different types) as described herein.

[0216] In some embodiments, the compounds described herein bind to the IL-1β binding pocket defined by the amino acid residues Gly177-Leu178-Lys179-Glu180-Lys181-Asn182-Leu183-Tyr184 (SEQ ID NO: 16) and Val201-Asp202-Pro203-Lys204-Asn205-Tyr206-Pro207 (SEQ ID NO: 17) (e.g., Gly177-Tyr184 and Val201-Pro207). In some embodiments, the compounds bind to at least one additional residue of the IL-1β binding pocket described herein. In some embodiments, the compounds described herein bind to one or more residues selected from Val119, Arg120, Ser121, Phe162, Lys179, Pro203, Lys204, Tyr206, Pro207, or Ser269 in the IL-1β binding pocket described herein.

[0217] In certain embodiments, the compounds described herein bind to the residue Val119 of IL-1β via hydrogen bonding (H bond) interactions. In certain embodiments, the compounds described herein bind to the residue Arg120 of IL-1β via hydrogen bonding (H bond) interactions. In certain embodiments, the compounds described herein bind to the residue Ser121 of IL-1β via hydrogen bonding (H bond) interactions. In certain embodiments, the compounds described herein bind to the residue Pro203 of IL-1β via hydrogen bonding (H bond) interactions. In certain embodiments, the compounds described herein bind to the residue Lys204 of IL-1β via hydrogen bonding (H bond) interactions. In certain embodiments, the compounds described herein bind to the residue Tyr206 of IL-1β via hydrogen bonding (H bond) interactions. In certain embodiments, the compounds described herein bind to the residue Pro207 of IL-1β via hydrogen bonding (H bond) interactions. In certain embodiments, the compounds described herein bind to residue Ser269 of IL-1β via hydrogen bonding (H bond) interactions. In embodiments, the hydrogen bonding (H bond) interactions are mediated by an NH group, carbonyl group, carbokillate group, oxygen or other functional group of the compounds (e.g., those described herein).

[0218] In certain embodiments, the compounds described herein bind to residue Arg120 of IL-1β via pi-effect (e.g., CH-pi, cation-pi, or polar-pi) interactions. In certain embodiments, the compounds described herein bind to residue Phe162 of IL-1β via pi-effect (e.g., CH-pi, cation-pi, or polar-pi) interactions. In certain embodiments, the compounds described herein bind to residue Arg179 of IL-1β via pi-effect (e.g., CH-pi, cation-pi, or polar-pi) interactions. In certain embodiments, the compounds described herein bind to residue Pro207 of IL-1β via pi-effect (e.g., CH-pi, cation-pi, or polar-pi) interactions. In certain embodiments, the compounds described herein bind to residue Ser269 of IL-1β via pi-effect (e.g., CH-pi, cation-pi, or polar-pi) interactions. In some embodiments, the pi effect (e.g., CH-pi, cation-pi, or polar-pi) interaction is mediated by the functional group of the compound (e.g., the functional groups described herein).

[0219] In certain embodiments, the compounds described herein bind to the Lys204 residue of IL-1β via ionic interactions. In certain embodiments, the compounds described herein bind to the Ala117 residue of IL-1β via ionic interactions. In certain embodiments, the compounds described herein bind to the Arg120 residue of IL-1β via ionic interactions. Such ionic interactions may be mediated by the functional groups of the compounds (e.g., the functional groups described herein).

[0220] In certain embodiments, the binding interaction between the compound and IL-1β is as shown in any one of the drawings disclosed herein.

[0221] 8. Examples 8.1 Example 1: Exemplary compounds that bind to IL-1B The specific macrocyclic peptides used in the examples described herein include the following compounds: [ka] TIFF2026520185000017.tif215157TIFF2026520185000018.tif214155TIFF2026520185000019.tif213154TIFF2026520185000020.tif117152

[0222] 8.2 Example 2: Exemplary synthesis of specific compounds that bind to IL1B The compounds described herein can be prepared using appropriate materials according to the procedures of the following schemes and examples, which are further illustrated by the following specific examples. The examples also include methods for testing such compounds in cell assays. However, the compounds illustrated in the examples should not be construed as forming the sole genus considered to be part of this disclosure.

[0223] The examples further illustrate details relating to the preparation of the compounds of this disclosure. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparation procedures may be used to prepare these compounds. For example, in some cases, the order in which the steps of the reaction scheme are performed may be altered to accelerate the reaction or to avoid undesirable reaction products. Starting materials and intermediates for the final compound may be purchased, prepared by known methods, or prepared by methods otherwise illustrated. The examples are provided for further illustration purposes only and do not limit the disclosure.

[0224] NMR data were acquired in CDCl3, DMSO-d6, or methanol-d4 using a 300 MHz or 400 MHz instrument, and chemical shifts are shown relative to tetramethylsilane standards. Resonance signals are indicated by the following abbreviations: s = singleline, d = doubleline, t = tripleline, q = quadrupleline, dd = doubleline of doubleline, m = multiline or non-equivalent resonance overlap. Coupling constants (J) are shown in Hertz (Hz).

[0225] Throughout the synthesis schemes and examples, unless otherwise specified, abbreviations and acronyms may be used in the following senses as defined in Table 3. [Table 3] TIFF2026520185000022.tif236170TIFF2026520185000023.tif233170

[0226] 8.2.1 Synthesis of intermediates: The amino acids used in the synthesis of the final compounds described in Section 8.2.2 can be produced by the following methods and are also commercially available.

[0227] 8.2.1.1 Synthesis Scheme 1 [ka]

[0228] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-(4-(tert-butoxycarbonyl)phenyl)pyridine-3-yl)propanoic acid Step 1: To a stirred solution of NiCl2-glyme (0.918 g, 4.18 mmol) in DMA (100 mL), 1,10-phenanthroline (0.905 g, 4.18 mmol) was added under a nitrogen atmosphere at room temperature. The resulting solution was stirred at 50°C for 1 hour. 2-chloro-5-iodopyridine (5 g, 20.88 mmol), tert-butyl (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodopropanoate (12.36 g, 25.06 mmol), TBAI (8.01 g, 20.88 mmol), and Zn (2.73 g, 41.8 mmol) were added to the mixture at room temperature, and the resulting mixture was stirred at 25°C for 2 hours. The reaction was quenched with H2O (200 mL) and extracted with siRNA (2 × 500 mL). The combined organic layer was washed with brine (3 × 200 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with 0-30% siRNA in PE to obtain tert-butyl(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-chloropyridine-3-yl)propanoate. MS ESI:C 27 H 28 ClN2O4[M+H] + Calculated value: 479.17; Measured value: 479.20.

[0229] Step 2: To a stirred solution of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-chloropyridine-3-yl)propanoate (5 g, 10.48 mmol) in DCM (5 mL), TFA (10 mL) was added at room temperature. The solution was stirred at 25 °C for 1 hour. The solvent was concentrated under reduced pressure, and the residue was purified by RP-flash under the following conditions: Column: Flash C18 (330 g); Mobile phase A: Water (0.1% TFA), Mobile phase B: MeCN; (Gradient: Hold 5% B for 5 minutes, up to 30% B within 15 minutes, hold 30% B for 5 minutes; up to 95% B within 20 minutes, hold 95% B for 10 minutes); Flow rate: 90 mL / min; Detector: UV 210 nm; RT = 40 min. The product-containing fraction was collected and evaporated under vacuum to obtain (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-chloropyridine-3-yl)propanoic acid. MS ESI:C 23 H 20 ClN2O4[M+H] + Calculated value: 423.10; Measured value: 423.10.

[0230] Step 3: To a stirred solution of (S)-2-(((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-chloropyridine-3-yl)propanoic acid (3 g, 7.09 mmol) in THF (25 mL) and water (5 mL), (4-(tert-butoxycarbonyl)phenyl)boronic acid (1.890 g, 8.51 mmol) and K3PO4 (7.53 g, 35.5 mmol) were added under nitrogen at 25°C. The resulting solution was stirred at 25°C for 10 minutes. Pd(dtbpf)Cl2 (0.694 g, 1.064 mmol) was added to the solution, and the mixture was then stirred at 60°C for 16 hours. The reaction mixture was cooled to room temperature, quenched with H2O (200 mL), and extracted with ELISA (500 mL x 2). The combined organic layers were washed with brine (200 mL x 3), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by RP-flash under the following conditions: Column: Flash C18 (330 g); Mobile phase A: Water (0.1% TFA), Mobile phase B: MeCN; (Gradient: Hold 5% B for 5 minutes, to 60% B within 15 minutes, reach 60% B within 15 minutes, hold 60% B for 15 minutes; to 95% B within 10 minutes, hold 95% B for 10 minutes); Flow rate: 90 mL / min; Detector: UV 210 nm; RT = 55 min. The product-containing fraction was collected and evaporated under vacuum to obtain (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(6-(4-(tert-butoxycarbonyl)phenyl)pyridine-3-yl)propanoic acid. MS ESI:C 34 H 33 N2O6[M+H] + Calculated value: 565.23; Measured value: 565.15; 1 H NMR(400MHz, methanol-d4)δ 8.66(d,J=1.9Hz,1H),8.12-8.07(m,3H),7.99-7.92(m,3H),7.77(d,J=7.5Hz,2H),7.59-7.56(m,2H),7.37-7.33(m,2H),7. 30-7.22(m,2H),4.60-4.56(m,1H),4.29-4.27(m,2H),4.14-4.10(m,1H),3.45-3.41(m,1H),3.14-3.10(m,1H),1.62(s,9H).

[0231] 8.2.1.2 Synthesis Scheme 2 [ka]

[0232] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4'-(tert-butoxycarbonyl)-[1,1'-biphenyl]-4-yl)propanoic acid Argon gas was blown into a mixture of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-bromophenyl)propanoic acid (6 g, 12.87 mmol), (4-(tert-butoxycarbonyl)phenyl)boronic acid (4.29 g, 19.30 mmol), and K3PO4 (8.19 g, 38.6 mmol) in THF (40 mL) for 10 minutes, and then [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (0.839 g, 1.287 mmol) was added. The resulting mixture was stirred at 50°C for 16 hours, then diluted with ELISA (300 mL), washed with saturated aqueous NaHCO3 (3 × 80 mL) and brine (2 × 40 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a gradient of 0% to 50% Â in PE. The product-containing fraction was collected and rotated under vacuum. The residue was re-purified by Combi-Flash under the following conditions: Column: C18 gel column (330 g), 20-35 μm; Mobile phase A: 0.5% TFA aqueous solution; Mobile phase B: MeCN; (Gradient: Hold 0% B for 10 minutes, to 62.3% B within 25 minutes, hold 62.3% B for 6.2 minutes; to 95% B within 2 minutes, hold 95% B for 10 minutes); Flow rate: 90 mL / min; Detector: UV254 and 210 nm; RT: 32.32 min. The product-containing fraction was collected and concentrated under reduced pressure to obtain (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4'-(tert-butoxycarbonyl)-[1,1'-biphenyl]-4-yl)propanoic acid. MS ESI:C 35 H 34 NO6[M+1] +Calculated value: 564.23; Measured value: 564.15. 1 H NMR(300MHz, methanol-d4)δ 7.97-7.95(m,2H),7.78-7.76(m,2H),7.61-7.53(m,6H),7.38-7.21(m,2 H),4.51-4.11(m,4H),3.32-3.25(m,1H),3.03-2.95(m,1H),1.61(s,9H).

[0233] 8.2.1.3 Synthesis Scheme 3 [ka]

[0234] (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(5-cyanopyridine-3-yl)butanoic acid Step 1: To a stirred solution of (((9H-fluoren-9-yl)methoxy)carbonyl)-L-homoserine (15 g, 43.9 mmol) in DCM (200 mL), tert-butyl (Z)-N,N'-diisopropylcarbamimidate (35.2 g, 176 mmol) was added at room temperature. The solution was stirred at 30°C for 4 hours. The solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with 0-32% ethyl acetate in PE to obtain tert-butyl (((9H-fluoren-9-yl)methoxy)carbonyl)-L-homoserine. MS ESI:C 23 H 28 NO5 [M+H] + Calculated value: 398.19; Measured value: 398.15. 1 H NMR(300MHz,CDCl3)δ 7.81-7.74(m,2H),7.64-7.56(m,2H),7.45-7.37(m,2H),7.37-7.28(m,2H),5.61(d,J=7.7Hz,1H),4.54- 4.32(m,3H),4.22(t,J=6.9Hz,1H),3.76-3.52(m,2H),2.25-2.07(m,1H),1.71-1.55(m,1H),1.48(s,9H).

[0235] Step 2: To a stirred solution of PPh3 (12.67 g, 48.3 mmol) and 1H-imidazole (4.38 g, 64.4 mmol) in DCM (200 mL), I2 (12.26 g, 48.3 mmol) was added under a nitrogen atmosphere at room temperature. The mixture was stirred at room temperature for 10 minutes. Tert-butyl (((9H-fluoren-9-yl)methoxy)carbonyl)-L-homoselinate (12.8 g, 32.2 mmol) was added to the mixture and stirred at 25°C for 2 hours. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluted with 0-18% siRNA in PE to obtain tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-iodobutanoate. MS ESI:C 23 H 26 INO4Na[M+Na] + Calculated value: 530.09; Measured value: 530.20. 1 H NMR(300MHz,CDCl3)δ 7.83-7.71(m,2H),7.65-7.56(m,2H),7.47-7.36(m,2H),7.36-7.28(m,2H),5.35(d,J=8.3Hz,1H),4.52 -4.35(m,2H),4.34-4.16(m,2H),3.21-3.04(m,2H),2.52-2.32(m,1H),2.28-2.07(m,1H),1.48(s,9H).

[0236] Step 3: NiCl2-glyme (1.321 g, 6.01 mmol) was added to a stirred solution of 1,10-phenanthroline (1.083 g, 6.01 mmol) in DMA (300 mL) under an argon atmosphere at room temperature. The mixture was stirred at 50 °C for 1 hour and then cooled to room temperature. Then tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-iodobutanoate (15.25 g, 30.1 mmol), 5-bromonicotinonitrile (5.5 g, 30.1 mmol), TBAI (15.25 g, 30.1 mmol), and zinc (3.93 g, 60.1 mmol) were added to the mixture at room temperature and stirred at 35 °C for 2.5 hours. The mixture was cooled to room temperature and diluted with water (500 mL) and toluene (800 mL). The solid was filtered off and the organic layer was separated. The organic layer was washed with brine (3 × 150 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with 0-40% ethyl acetate in PE to obtain tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(5-cyanopyridine-3-yl)butanoate. MS ESI:C 29 H 30 N3O4[M+H] + Calculated value: 484.22; Measured value: 484.20. 1 H NMR(300MHz,CDCl3)δ 8.75(s,1H),8.66(s,1H),7.87-7.71(m,3H),7.61(d,J=7.4Hz,2H),7.47-7.28(m,4H),5.40(d,J=7.8Hz,1H) ,4.55-4.37(m,2H),4.36-4.18(m,2H),2.85-2.59(m,2H),2.26-2.08(m,1H),2.02-1.82(m,1H),1.49(s,9H).

[0237] Step 4: To a stirred solution of tert-butyl (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(5-cyanopyridine-3-yl)butanoate (7.5 g, 15.51 mmol) in DCM (50 mL), TFA (100 mL) was added at room temperature. The solution was stirred at 25 °C for 3 hours and then concentrated under reduced pressure. The residue was purified by RP flush under the following conditions: C18 column, 330 g, 5%-5% for 10 min, 5%-55% for 40 min, 55%-55% for 10 min, MeCN in water (0.05% TFA). This yielded (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(5-cyanopyridine-3-yl)butanoic acid. MS ESI:C 25 H 22 N3O4[M+H] + Calculated value: 428.15; Measured value: 428.05. 1 H NMR(400MHz,DMSO-d6)δ 12.78(br,1H),8.87(s,1H),8.75(s,1H),8.18(s,1H),7.92-7.90(m,2H),7.76-7.73(m,3H),7 .44-7.33(m,4H),4.39-4.20(m,3H),3.94-3.89(m,1H),2.79-2.67(m,2H),2.09-1.89(m,2H).

[0238] 8.2.1.4 Synthesis Scheme 4 [ka] TIFF2026520185000028.tif34153

[0239] (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(benzylamino)pyrrolidine-2-carboxylic acid Step 1: A mixture of 1-(tert-butyl)2-methyl(2S,4R)-4-aminopyrrolidine-1,2-dicarboxylate (10 g, 40.9 mmol) in DCM (100 mL) was mixed with TEA (14.26 mL, 102 mmol) and NsCl (10.89 g, 49.1 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The resulting solution was quenched with water (150 mL) and extracted with ELISA (3 × 300 mL). The organic layers were combined, washed with brine (2 × 150 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography eluting under a gradient of 0% to 45% ethyl acetate in PE to obtain 1-(tert-butyl)2-methyl(2S,4R)-4-((4-nitrophenyl)sulfonamide)pyrrolidine-1,2-dicarboxylate. MS ESI:C 17 H 24 N3O8S[M+H-Boc] + Calculated value: 330.12; Measured value: 330.10. 1 H NMR(400MHz,CDCl3)δ 8.18-8.16(m,1H),7.91-7.87(m,1H),7.79-7.75(m,2H),4.40-4.29(m,1H),4.18-4.15(m ,1H),3.72(s,3H),3.66-3.62(m,1H),3.26-3.19(m,1H),2.29-2.15(m,2H),1.38(s,9H).

[0240] Step 2: To a mixture of 1-(tert-butyl)-2-methyl(2S,4R)-4-((4-nitrophenyl)sulfonamide)pyrrolidine-1,2-dicarboxylate (17 g, 39.6 mmol) in DCM (60 mL), TFA (30 mL, 389 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours, then concentrated under vacuum to obtain methyl (2S,4R)-4-((4-nitrophenyl)sulfonamide)pyrrolidine-2-carboxylate. MS ESI:C 12 H 16 N3O6S[M+H] + Calculated value: 330.07; Measured value: 330.10.

[0241] Step 3: To a solution of methyl (2S,4R)-4-((4-nitrophenyl)sulfonamide)pyrrolidine-2-carboxylate (18.5 g, 39.3 mmol) in THF (150 mL) and water (150 mL), NaHCO3 (16.52 g, 197 mmol) and Alloc-OSu (5.46 mL, 35.4 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 4 hours, then diluted with water (100 mL) and extracted with ethyl acetate (3 × 250 mL). The organic layers were combined, washed with brine (2 × 150 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 55% ethyl acetate in PE to obtain 1-allyl 2-methyl(2S,4R)-4-((4-nitrophenyl)sulfonamide)pyrrolidine-1,2-dicarboxylate. MS ESI:C 16 H 20 N3O8S[M+H] + Calculated value: 414.09; Measured value: 413.95. 1 H NMR(300MHz,CDCl3)δ 8.18-8.15(m,1H),7.91-7.88(m,1H),7.82-7.77(m,2H),5.84-5.70(m,1H),5.30-5.16(m,2H),4.58-4.5 2(m,2H),4.50-4.48(m,1H),4.47-4.15(m,1H),3.78-3.73(m,4H),3.32-3.28(m,1H),2.30-2.19(m,2H).

[0242] Step 4: To a solution of 1-allyl-2-methyl-(2S,4R)-4-((4-nitrophenyl)sulfonamide)pyrrolidine-1,2-dicarboxylate (8.1 g, 19.59 mmol) in DMF (100 mL), (bromomethyl)benzene (4.02 g, 23.51 mmol) and K2CO3 (8.12 g, 58.8 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 4 hours, then quenched with water (100 mL), and extracted with ELISA (250 mL x 3). The organic layers were combined, washed with brine (200 mL x 4), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography using a gradient of ethyl acetate in PE (0% to 55%) to obtain 1-allyl 2-methyl (2S,4R)-4-((N-benzyl-4-nitrophenyl)sulfonamide)pyrrolidine-1,2-dicarboxylate. MS ESI:C 23 H 26 N3O8S[M+H] + Calculated value: 504.14; Measured value: 504.20. 1 H NMR(300MHz,CDCl3)δ 7.88-7.84(m,1H),7.68-7.67(m,2H),7.66-7.55(m,1H),7.29-7.23(m,5H),5.85-5.7 5(m,1H),5.25-5.18(m,2H),4.19-4.15(m,6H),3.73-3.25(m,5H),2.23-2.15(m,2H).

[0243] Step 5: To a solution of 1-allyl 2-methyl (2S,4R)-4-((N-benzyl-4-nitrophenyl)sulfonamide)pyrrolidine-1,2-dicarboxylate (9.3 g, 18.47 mmol) in DMF (40 mL), 4-methoxybenzenethiol (3.11 g, 22.16 mmol) and K2CO3 (7.66 g, 55.4 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 1 hour, then diluted with water (100 mL) and extracted with siRNA (3 × 150 mL). The organic layers were combined, washed with brine (2 × 100 mL), dried over anhydrous sodium 2SO4, and filtered. The residue was purified by RP flush under the following conditions: Column: Flash C18 (330 g); Mobile phase A: Water (0.05% TFA), Mobile phase B: MeCN (Gradient: Hold 5% B for 5 minutes, up to 32% B within 15 minutes, hold 32% B for 6 minutes; up to 95% B within 5 minutes, hold 95% B for 5 minutes); Flow rate: 90 mL / min; Detector: UV 210 nm; RT = 36 min. The product-containing fraction was collected and concentrated under vacuum to obtain 1-allyl 2-methyl (2S,4R)-4-(benzylamino)pyrrolidine-1,2-dicarboxylate. MS ESI:C 17 H 23 N2O4[M+H] + Calculated value: 319.16; Measured value: 319.10. 1 H NMR (300MHz, CDCl3)δ 7.39-7.34(m,5H),5.90-5.85(m,1H),5.32-5.17(m,2H),4.60-4.36(m,3H),3.96-3.57(m,8H),2.07-1.99(m,2H).

[0244] Step 6: To a solution of 1-allyl 2-methyl (2S,4R)-4-(benzylamino)pyrrolidine-1,2-dicarboxylate (4.5 g, 12.72 mmol) in DCM (40 mL), Boc2O (4.16 g, 19.08 mmol) and TEA (5.32 mL, 38.2 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 4 hours, then quenched with water (30 mL), and extracted with ethyl acetate (3 × 200 mL). The organic layers were combined, washed with brine (2 × 100 mL), dried over anhydrous sodium 2SO4, and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography eluting with a gradient of 0% to 40% ethyl acetate in PE to obtain 1-allyl 2-methyl (2S,4R)-4-(benzyl(tert-butoxycarbonyl)amino)pyrrolidine-1,2-dicarboxylate. MS ESI:C 22 H 31 N2O6[M+H] + Calculated value: 419.21; Measured value: 419.15. 1 H NMR(300MHz,CDCl3)δ 7.34-7.15(m,5H),5.90-5.85(m,1H),5.25-5.18(m,2H),4.58-4.32(m,6 H),3.74-3.44(m,5H),2.49-2.38(m,1H),2.12-1.99(m,1H),1.42(s,9H).

[0245] Step 7: A mixture of 1-allyl 2-methyl (2S,4R)-4-(benzyl(tert-butoxycarbonyl)amino)pyrrolidine-1,2-dicarboxylate (3 g, 5.73 mmol) in THF (15 mL) was added to LiOH (11.47 mL, 11.47 mmol, 1 M in water) at 0°C. The reaction mixture was stirred at room temperature for 2 hours, then acidified to pH 3-4 with aqueous HCl, and extracted with ELISA (3 × 150 mL). The organic layers were combined, washed with brine (2 × 80 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under vacuum to obtain (2S,4R)-1-((allyloxy)carbonyl)-4-(benzyl(tert-butoxycarbonyl)amino)pyrrolidine-2-carboxylic acid. MS ESI:C 21 H 29N2O6[M+H] + Calculated value: 405.19; Measured value: 405.30. 1 H NMR(300MHz,CDCl3)δ 7.35-7.14(m,5H),5.89-5.75(m,1H),5.14-5.19(m,2H),4.61-4.30(m,6H),3.82-3.32(m,2H),2.47-2.18(m,2H),1.42(s,9H).

[0246] Step 8: AcOH (0.751 mL, 13.11 mmol) and Pd(Ph3P)4 (0.126 g, 0.109 mmol) were added at room temperature to a mixture of (2S,4R)-1-((allyloxy)carbonyl)-4-(benzyl(tert-butoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (2.6 g, 5.46 mmol) in DCM (150 mL). Then Bu3SnH (1.749 g, 6.01 mmol) was added to the reaction mixture. After stirring the reaction mixture at room temperature for 4 hours, it was concentrated under reduced pressure to obtain (2S,4R)-4-(benzyl(tert-butoxycarbonyl)amino)pyrrolidine-2-carboxylic acid. MS ESI:C 17 H 25 N2O4[M+H] + Calculated value: 321.17; Measured value: 321.15.

[0247] Step 9: NaHCO3 (2.098 g, 24.97 mmol) was added to a mixture of (2S,4R)-4-(benzyl(tert-butoxycarbonyl)amino)pyrrolidine-2-carboxylic acid (3.2 g, 4.99 mmol) in THF (50 mL) and water (50 mL) to adjust the pH to 8-9. Then Fmoc-OSu (1.516 g, 4.49 mmol) was added to the reaction mixture. The resulting mixture was stirred at room temperature for 4 hours, then acidified to pH 3-4 with aqueous HCl, and extracted with ELISA (3 × 200 mL). The organic phases were combined, washed with brine (2 × 100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under vacuum to obtain the crude product. The residue was purified by RP flash under the following conditions: Column: Flash C18 (330g); Mobile phase A: Water (0.05% TFA), Mobile phase B: MeCN; (Gradient: Hold 5% B for 5 minutes, up to 70% B within 25 minutes, hold 70% B for 8 minutes; up to 95% B within 2 minutes, hold 95% B for 5 minutes); Flow rate: 90 mL / min; Detector: UV 210 nm; RT = 45 min. The product-containing fraction was collected and concentrated under vacuum to obtain (2S,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(benzyl(tert-butoxycarbonyl)amino)pyrrolidine-2-carboxylic acid. MS ESI:C 32 H 35 N2O6[M+H] + Calculated value: 543.24; Measured value: 543.20. 1 H NMR(400MHz,DMSO-d6)δ 12.93(s,2H),7.88(d,J=7.6Hz,2H),7.61-7.57(m,2H),7.43-7.18(m,9H),4.43-4 .15(m,8H),3.53-3.25(m,2H),2.51-2.50(m,1H),2.03-1.92(m,1H),1.37(s,2H).

[0248] 8.2.1.5 Synthesis Scheme 5 [ka]

[0249] (2S,3S)-2-amino-3-(4-fluoro-1H-indole-3-yl)butanoic acid In a 1 L three-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere, 4-fluoro-1H-indole (10 g, 1.00 equivalent), L-threonine (10.6 g, 1.20 equivalent), DMSO (100 mL), and potassium phosphate buffer (0.2 M, 300 mL, pH=7.4) were added. The reaction mixture was heated to 65°C, and then PfTrpB-7E6 (2.5 g, 25 wt%) and 3-hydroxy-2-methyl-5-([phosphonooxy]methyl)-4-pyridinecarboxaldehyde (0.078 g, 0.004 equivalent) were added. The resulting solution was stirred overnight at 65°C. The mixture was then cooled to room temperature and used directly in the next step.

[0250] THF (100 mL), sodium carbonate (23.56 g, 3.0 equivalents), and 2,5-dioxopyrrolidine-1-yl 9H-fluoren-9-ylmethyl carbonate (29.96 g, 1.20 equivalents) were added to the reaction mixture at 0°C. The resulting solution was stirred overnight at room temperature. The pH was adjusted to 4 with 3 M HCl, and the solid precipitate was filtered off. The resulting solution was extracted with Depositphotos (3 × 500 mL). The organic fractions were combined, washed with brine (1 L), dried over anhydrous sodium sulfate, and concentrated under vacuum. The mixture was applied to a silica gel column using MeOH:DCM = 1:5. HPLC-MS: (ES, m / z): [M+1]: 459. 1 H NMR(300MHz,DMSO-d6)δ 12.60(s,1H),11.15(s,1H),7.87(d,J=7.6Hz,2H),7.76-7.49(m,3H),7.47-7.34(m,2H),7.34-7.16(m,4H),7.03(td,J=7.9,5.0Hz,1 H),6.73(dd,J=11.8,7.7Hz,1H),4.36(t,J=8.5Hz,1H),4.31-4.02(m,3H),3.51(q,J=7.4Hz,1H),1.31(d,J=7.0Hz,4H),0.78(s,1H).

[0251] 8.2.1.6 Synthesis Scheme 6 [ka]

[0252] ( 2S,3S)-2-amino-3-(4-chloro-1H-indole-3-yl)butanoic acid In a 1 L three-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere, 4-chloro-1H-indole (10 g, 1.00 equivalent), L-threonine (14.09 g, 1.8 equivalent), DMSO (100 mL), and potassium phosphate buffer (0.2 M, 300 mL, pH=7.4) were added. The reaction mixture was heated to 65°C, and then PfTrpB-7E6 (7.5 g, 25 wt%) and 3-hydroxy-2-methyl-5-([phosphonooxy]methyl)-4-pyridinecarboxaldehyde (174 mg, 0.01 equivalent) were added. The resulting solution was stirred at 65°C for 36 hours. The mixture was cooled to room temperature and used directly in the next step.

[0253] THF (100 mL), sodium carbonate (20.9 g, 3.0 equivalents), and 2,5-dioxopyrrolidine-1-yl 9H-fluoren-9-ylmethyl carbonate (31.0 g, 1.40 equivalents) were added to the reaction mixture at 0°C. The resulting solution was stirred overnight at room temperature. The pH was adjusted to 4 with 3 M HCl, and the solid precipitate was removed by filtration. The resulting solution was extracted with ELISA (3 × 500 mL). The organic fractions were combined, washed with brine (1 L), dried over anhydrous sodium sulfate, and concentrated under vacuum. HPLC-MS: (ES, m / z): [M+1]: 475.

[0254] 8.2.1.7 Synthesis Scheme 7 [ka] TIFF2026520185000032.tif39155

[0255] (2S,3S)-2-amino-3-(naphthalene-1-yl)butanoic acid Step 1: Benzyl bromide (250 g, 2.00 equivalents) was added dropwise at 20°C to a solution of (2S,3R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-hydroxybutanoic acid (250 g, 1.00 equivalent) in DMF (1.5 L). Cesium carbonate (477 g, 2.00 equivalents) was then added, and the solution was stirred at 20°C for 3 hours. The reaction mixture was poured into ice H2O (3 L) and extracted with ELISA (500 mL x 3). The organic phase was washed with 3% LiCl solution (500 mL x 2) and brine (500 mL), dried over sodium sulfate, and concentrated under vacuum at 40°C. The crude product was ground with methyl tert-butyl ether:PE = 6:1. 1 H NMR(400MHz,CDCl3):δ 7.77(d,J=7.6Hz,1H),7.40(d,J=8.0Hz,1H),7.31-7.36(m,10H),5.65-5.71 m,1H),5.13-5.31(m,3H),4.39-4.43(m,3H),4.22-4.25(m,1H),1.25(d,J=6.4Hz,3H).

[0256] Step 2: In a three-necked round-bottom flask, under a nitrogen-inert atmosphere, (2S,3R)-benzyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-hydroxybutanoate (125 g, 1.00 equivalent) and DCE (750 mL) were added. The reaction mixture was cooled to 0°C, and then NIS (195 g, 3.00 equivalent) and PPh3 (228 g, 3.00 equivalent) were added. The temperature was raised to 50°C, and the reaction mixture was stirred for 3 hours. The reaction mixture was poured into ice H2O (500 mL) and extracted with DCM (500 mL x 2). The organic phase was dried over sodium sulfate and concentrated under vacuum at 40°C. The residue was purified by silica gel column chromatography (PE / siRNA = 1 / 0 to 0 / 1). 1 H NMR(400MHz,CDCl3):δ 7.78(d,J=7.6Hz,2H),7.68(d,J=7.2Hz,2H),7.33-7.43(m,9H),5.27-5.68(m,1 H),5.21-5.23(m,2H),4.39-4.52(m,3H),4.25-4.38(m,1H),1.91-1.95(m,3H).

[0257] Step 3: In a three-necked round-bottom flask, 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-iodobutanoate, 1-iodonaphthalene (42.2 g, 1.20 equivalents), TBAI (76.7 g, 1.50 equivalents), Zn (19.0 g, 2.10 equivalents), and DMA (750 mL) were added. In a second three-necked round-bottom flask, picoline imidamide·2HCl (42.2 g, 1.20 equivalents), NiCl2.glyme (7.61 g, 0.25 equivalents), and DMA (750 mL) were added at 25°C. Under argon, the contents of the second flask were added to the first flask. The resulting mixture was then stirred at 25°C for 12 hours. The reaction mixture was poured into ice H2O (3 L) and extracted with ethyl acetate (1 L x 2). The organic phase was dried over sodium sulfate and concentrated under vacuum at 40°C. The crude product was purified by reverse-phase HPLC (MeCN:H2O). HPLC-MS:[M+23]:564. 1 H NMR(400MHz,CDCl3)δ: 8.17-8.24(m,1H),8.15-8.17(m,1H),7.77-7.87(m,2H),7.76-7.77(m,4H),7.30-7.41(m,10H),5.30-5. 38(m,1H),4.96-5.04(m,3H),4.85-4.87(m,1H),4.30-4.34(m,1H),4.18-4.26(m,4H),1.43-1.45(m,3H).

[0258] Step 4: 143 g of (2S)-benzyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(naphthalen-1-yl)butanoate was separated by SFC. The organic phase was concentrated under vacuum at 35°C.

[0259] Peak 1: (2S,3R)-benzyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(naphthalene-1-yl)butanoate. 1H NMR(400MHz,DMSO-d6):δ 8.11-8.12(m,2H),8.10-8.11(m,1H),7.88-7.90(m,2H),7.54-7.88(m,1H),7.44-7.53(m,2H),7. 42-7.44(m,4H),7.33-7.42(m,3H),7.27-7.33(m,6H),7.08-7.09(m,2H),4.91-4.94(m,1H),4.79- 4.82(m,1H),4.58(t,J=8.0Hz),4.17-4.25(m,4H),1.39(d,J=6.8Hz,3H). Peak 2: (2S,3S)-benzyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(naphthalene-1-yl)butanoate. 1 H NMR(400MHz,DMSO-d6):δ 7.92-8.15(m,1H),7.86-7.92(m,1H),7.84-7.86(m,1H),7.57-7.84(m,2H),7.56-7.57(m,1H),7.41-7.54(m,4H),7.30-7.38 (m,4H),7.27-7.30(m,7H),5.08-5.14(m,2H),4.65(t,J=8.0Hz),4.23-4.26(m,1H),4.05-4.18(m,3H),1.30(d,J=6.8Hz,3H).

[0260] Step 5: (2S,3S)-benzyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(naphthalen-1-yl)butanoate (40.0 g, 1.00 equivalent) and THF (200 mL) were added to a three-necked round-bottom flask. 10% wet Pd / C (7.00 g) was added, the reaction mixture was purged three times with H2, and stirred at 25°C for 12 hours under H2 (15 psi). The reaction mixture was filtered through a Celite pad and concentrated under vacuum at 35°C. The crude product was ground with PE at 25°C for 1 hour. After filtration, the filter cake was dissolved in MeCN (100 mL) and concentrated under vacuum at 35°C to remove residual solvent. HPLC-MS: [M+23]: 474. 1H NMR(400MHz,DMSO-d6)δ 12.78(s,1H),8.23(d,J=7.6Hz,1H),7.86-7.88(m,1H),7.80-7.86(m,2H),7.61-7.80(m,2H),7.55-7.59(m,4H),7.481-7.55(m,1H),7 .40-7.48(m,3H),7.27-7.29(m,2H),4.28-4.60(m,1H),4.24-4.28(m,1H),4.17-4.24(m,2H),4.04-4.15(m,1H),1.36(d,J=6.8Hz,3H).

[0261] 8.2.1.8 Synthesis Scheme 8 [ka]

[0262] L-tyrosine O-ethylacetamide or (S)-3-(4-(2-acetamidoethoxy)phenyl)-2-aminopropanoic acid Step 1: Potassium carbonate (14.04 g, 102 mmol) was added at room temperature to a stirred solution of methyl (tert-butoxycarbonyl)-L-tyrosinate (10.0 g, 33.9 mmol), benzyl (2-bromoethyl) carbamate (26.2 g, 102 mmol), and TBAB (5.46 g, 16.93 mmol) in DMF (150 mL). The mixture was then stirred at 50 °C for 24 hours. The mixture was cooled to room temperature, quenched with water (250 mL), and extracted with ethyl acetate (2 × 500 mL). The combined organic layer was washed with brine (3 × 150 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with 0-30% ethyl acetate in PE. MS ESI:C 25 H 32 N2O7[M+Na] + Calculated value: 495.22; Measured value: 495.10; 1H NMR(300MHz,CDCl3)δ 7.38-7.32(m,5H),7.04(d,J=8.4Hz,2H),6.81(d,J=8.4Hz,2H),5.31(br,1H),5.21(s,2H),4.97(br,1H), 4.56-4.53(m,1H),4.03(t,J=5.0Hz,2H),3.72(s,3H),3.64-3.58(m,2H),3.06-3.01(m,2H),1.43(s,9H).

[0263] Step 2: To a stirred solution of methyl(S)-3-(4-(2-((benzyloxy)carbonyl)amino)ethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (16.0 g, 33.9 mmol) and acetic anhydride (6.39 mL, 67.7 mmol) in THF (200 mL), Pd / C (3.60 g, 33.9 mmol, dry, 10% wt) was added at room temperature under a nitrogen atmosphere. The mixture was degassed three times with hydrogen and stirred at 20°C for 4 hours. DIPEA (17.74 mL, 102 mmol) was added to the mixture and stirred at 20°C for 1 hour. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0-3% MeOH in DCM. MS ESI:C 19 H 28 N2O6[M+Na] + Calculated value: 403.19; Measured value: 403.10; 1 H NMR(300MHz,CDCl3)δ 7.05(d,J=8.4Hz,2H),6.85-6.80(m,2H),5.99(br,1H),5.32(br,1H),4.99-4.97(m,1H),4.02 (t,J=5.0Hz,2H),3.72(s,3H),3.69-3.63(m,2H),3.10-2.89(m,2H),2.02(s,3H),1.42(s,9H).

[0264] Step 3: To a stirred solution of methyl (S)-3-(4-(2-acetamidoethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (12.5 g, 32.9 mmol) in THF (100 mL), lithium hydroxide (65.7 mL, 65.7 mmol, 1 N in water) was added at room temperature. The solution was stirred at 20 °C for 2 hours. The pH of the solution was adjusted to 3 with 1 N HCl. The aqueous layer was extracted with ELISA (2 × 250 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. MS ESI[M+H] + :367.10.

[0265] Step 4: To a stirred solution of (S)-3-(4-(2-acetamidoethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (12.5 g, 30.7 mmol) in THF (20 mL), 4N HCl in dioxane (200 mL) was added at room temperature. The solution was stirred at 20 °C for 1 hour. The solvent was concentrated under reduced pressure. MS ESI[M+H] + :267.05.

[0266] Step 5: Fmoc-OSu (7.62 g, 22.59 mmol) was added at room temperature to a stirred mixture of (S)-3-(4-(2-acetamidoethoxy)phenyl)-2-aminopropanoate (9.50 g, 25.1 mmol) and NaHCO3 (10.54 g, 126 mmol) in THF (100 mL) and water (100 mL). The mixture was stirred at 20 °C for 1 hour. The pH of the solution was adjusted to 3 with 1 N HCl. The aqueous phase was extracted with ELISA (2 × 500 mL). The combined organic phase was washed with brine (150 mL), dried over anhydrous sodium bicarbonate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from ELISA (200 mL). MS ESI[M+H] + :489.05; 1H NMR(300MHz, methanol-d4)δ 7.79(d,J=7.6Hz,2H),7.62-7.57(m,2H),7.42-7.26(m,4H),7.17-7.14(m,2H),6.83(d,J=8.4Hz,2H),4.41-4.31(m,2 H),4.29-4.10(m,2H),3.96(t,J=4.8Hz,2H),3.51(t,J=5.4Hz,2H),3.19-3.13(m,1H),2.92-2.84(m,1H),1.94(s,3H).

[0267] 8.2.1.9 Synthesis Scheme 9 [ka]

[0268] ( 2R,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(4-fluorobenzyl)pyrrolidine-2-carboxylic acid Step 1: Potassium 2-methylpropane-2-olate (4.92 g, 43.8 mmol) was added to a mixture of (4-fluorobenzyl)triphenylphosphonium chloride (17.82 g, 43.8 mmol) in THF (30 mL) under argon. The reaction mixture was stirred at room temperature for 1 hour. A solution of di-tert-butyl (R)-4-oxopyrrolidine-1,2-dicarboxylate (5 g, 17.52 mmol) in THF (20 mL) was added to the mixture. The reaction mixture was stirred at room temperature for 2 hours. The resulting solution was quenched with water (50 mL) and extracted with ethyl acetate (3 × 300 mL). The organic layers were combined, washed with brine (2 × 50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum, and the residue was purified by silica gel chromatography using an ethyl acetate:petroleum ether (0:1~1:5) gradient to obtain di-tert-butyl (R,E)-4-(4-fluorobenzylidene)pyrrolidine-1,2-dicarboxylate (4.8 g, 12.72 mmol, yield 73%) as a colorless oil. MS ESI:C 21 H 31 FNO4[M+H] + Calculated value: 380.22; Measured value: 380.20.

[0269] Step 2: To a mixture of di-tert-butyl (R,E)-4-(4-fluorobenzylidene)pyrrolidine-1,2-dicarboxylate (5 g, 13.25 mmol) in MeOH (50 mL), Raney Ni (1.2 g, 20.45 mmol) was added at room temperature under an argon atmosphere. The suspension was degassed under vacuum, purged several times with H2, and the reaction solution was stirred at room temperature under 2 atm H2 for 6 hours. LC-MS showed that the major component was the product. The resulting solution was filtered. The filtrate was concentrated under vacuum to obtain di-tert-butyl (2R)-4-(4-fluorobenzyl)pyrrolidine-1,2-dicarboxylate (4.5 g, 11.86 mmol, yield 90%) as a colorless oil. MS ESI:C 21 H 31 FNO4[M+H] + Calculated value: 380.22; Measured value: 380.20.

[0270] Step 3: Di-tert-butyl (2R)-4-(4-fluorobenzyl)pyrrolidine-1,2-dicarboxylate (4.5 g, 11.86 mmol) in TFA (10 mL) and DCM (25 mL) was added at room temperature. The solution was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure, and the residue was purified by RP flash under the following conditions: Column: Flash C18 (330 g); Mobile phase A: Water (0.1% TFA), Mobile phase B: ACN; (Gradient: Hold 5% B for 5 minutes, up to 42% B within 15 minutes, hold 42% B for 5 minutes; up to 95% B within 5 minutes, hold 95% B for 5 minutes); Flow rate: 90 mL / min; Detector: UV 210 nm; RT = 26 min. The product-containing fraction was collected and rotated under vacuum to obtain tert-butyl (2R)-4-(4-fluorobenzyl)pyrrolidine-2-carboxylate (2.8 g, 10.02 mmol, yield 85%) as a pale yellow oil. MS ESI:C 16 H 23 FNO2[M+H] + Calculated value: 280.17; Measured value: 280.25.

[0271] Step 4: Tert-butyl (2R)-4-(4-fluorobenzyl)pyrrolidine-2-carboxylate (2.8 g, 10.02 mmol) was separated by preparative SFC under the following conditions: Column: Lux Cellulose-4, 4.6 * Column: 50 mm, 3 μm; Mobile phase A: Hex (0.1% NH3·H2O); Mobile phase B: Preparative MeOH; Flow rate: 1.0 mL / min; Gradient: 30% B. Column temperature: 25°C; Back pressure: 100 bar; 190 nm; RT1: 3.42 min; RT2: 4.16 min. The fraction of the first peak (RT1: 3.42 min) was collected and rotated and evaporated in vacuum to obtain tert-butyl (2R,4S)-4-(4-fluorobenzyl)pyrrolidine-2-carboxylate (300 mg, 1.074 mmol, yield 11%) as a yellow oil. MS ESI: C 16 H 23 FNO2[M+H] + Calculated value: 280.17; measured value: 280.25. The fraction of the second peak (RT2: 4.16 mins) was collected and rotated in vacuum to obtain tert-butyl (2R,4R)-4-(4-fluorobenzyl)pyrrolidine-2-carboxylate (2.1 g, 7.52 mmol, yield 75%) as a yellow oil. MS ESI:C 16 H 23 FNO2[M+H] + Calculated value: 280.17; Measured value: 280.25. 1 ¹H NMR (400MHz, methanol-d4) δ 7.25-7.21 (m,2H), 7.05-7.01 (m,2H), 4.35-4.31 (m,1H), 3.43-3.39 (m,1H), 3.08-3.03 (m,1H), 2.78-2.77 (m,2H), 2.76-2.72 (m,1H), 2.48-2.47 (m,1H), 1.77-1.74 (m,1H), 1.52 (s,9H).

[0272] Step 5: A solution of tert-butyl (2R,4R)-4-(4-fluorobenzyl)pyrrolidine-2-carboxylate (2.1 g, 7.52 mmol) in CH2Cl2 (10 mL) and TFA (10.00 mL) was stirred at 25°C for 3 hours. The reaction was monitored by LC-MS. The reaction mixture was concentrated under vacuum to obtain crude (2R,4R)-4-(4-fluorobenzyl)pyrrolidine-2-carboxylic acid (1.678 g, approximately 7.52 mmol, 100% yield) as a yellow solid. MS ESI:C 12 H 15 FNO2[M+H] + Calculated value: 224.11; Measured value: 224.15.

[0273] Step 6: To a solution of (2R,4R)-4-(4-fluorobenzyl)pyrrolidine-2-carboxylic acid (1.678 g, 7.52 mmol) in THF (10 mL) and water (10.00 mL), sodium bicarbonate (3.95 g, 47.0 mmol) and N-(9-fluorenylmethoxycarbonyloxy)succinimide (2.86 g, 8.47 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 16 hours and then extracted with ethyl acetate (3 × 200 mL). The combined organic phase was washed with brine (3 × 100 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated and purified as follows: Column: Flash C18 (120 g); Mobile phase A: Water (0.1% TFA), Mobile phase B: ACN (Gradient: Hold 5% B for 5 minutes, up to 65% B within 25 minutes, hold 65% B for 2.6 minutes; up to 95% B within 2 minutes, hold 95% B for 5 minutes); Flow rate: 70 mL / min; Detector: UV 210 nm; RT = 26 min. The product-containing fraction was collected and rotated under vacuum to obtain (2R,4R)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(4-fluorobenzyl)pyrrolidine-2-carboxylic acid (2.6866 g, 6.03 mmol, yield 80%) as a white solid. MS ESI:C 27 H 25 FNO4[M+H] + Calculated value: 446.18; Measured value: 446.25. 1H NMR(300MHz, methanol-d4)δ 7.78-7.71(m,2H),7.63-7.53(m,2H),7.39-7.26(m,4H),7.21-7.14(m,2H),7.07-6.97(m,2H),4.39-4.37(m,1H), 4.32-4.14(m,3H),3.68-3.32(m,1H),3.22-2.96(m,1H),2.71-2.37(m,2H),2.43-2.36(m,2H),1.81-1.62(m,1H).

[0274] 8.2.2 Manufacturing of the final compound: A. General procedure for the synthesis of linear peptide precursors The peptides in Table 4 were synthesized using standard solid-phase synthesis methods employing the Fmoc / tBu chemical process, as exemplified in the following: Chan, WC; White, PD “Fmoc Solid-Phase Synthesis: a Practical Approach”, Oxford University Press, Oxford, 2000; Steward, J.; Young, J. “Solid Phase Peptide Synthesis”, Pierce Chemical Company, Rockford, 1984; Benoiton, NL “Chemistry of Peptide Synthesis”, CRC Press, New York, 2006; and Lloyd-Williams, P.; Albericio, F.; Giralt, E. “Chemical Approaches to the Synthesis of Peptides and Proteins”, CRC Press, New York, 1997.

[0275] During the peptide chain elongation reaction, the α-amino group of each amino acid was protected with a 9H-fluoren-9-ylmethoxycarbonyl group (Fmoc group). To avoid side reactions during the chain elongation process, the reactive amino acid side chains also contained acid-instability protecting groups, effectively shielding (masking) the reactive groups until removal during strong acid treatment. After the completion of each coupling step, the Fmoc group of the N-terminal amino acid was removed with piperidine or 4-methylpiperidine, and the resin was thoroughly washed to prepare for subsequent coupling of Fmoc-protected amino acid derivatives.

[0276] The side-chain protecting groups used were as follows: tert-butyl (tBu) for S, hY, Bip4CO2H, Phe4COOH, F4pcCCA, F4ptCCA, F4bcpA; tert-butoxycarbonyl (Boc) for Dap, dDab, dK, dOrn, K, Prot4NH2, dDap, daMeDab; and β-methylpentyl ester (OMpe) for D.

[0277] Fmoc-protected amino acids were typically obtained from vendors such as Sigma-Aldrich, Novabiochem, Chem-Impex, and Combi-Block.

[0278] B. Synthesis method used to produce cyclic peptides Synthesis scheme [ka]

[0279] Protocol A for solid-phase synthesis of peptides As summarized in Scheme 25 above, peptides were synthesized using a standard solid-phase synthesis method employing the Fmoc / tBu chemical process in a CEM Corporation Liberty Blue® synthesizer. N,N'-diisopropylcarbodiimide (DIC) and ethyl cyano(hydroxyimino)acetate (Oxyma) were used as coupling agents to form an amide bond between the free amino terminus of the resin-bound protected peptide and the carboxylic acid of the Fmoc-protected amino acid.

[0280] 2-chlorotrityl resin (200-400 mesh, 0.79 mmol / g loading, 1% cross-linked polystyrene, Novabiochem) loaded with H-Gly was used for synthesis. All amino acids were dissolved in DMF (N,N-dimethylformamide) at a concentration of 0.2 M. The amino acids were activated with equimolar Oxyma solution (0.5 M in DMF) and a 2x molar excess of DIC solution (1.0 M in DMF). Alternatively, the amino acids were dissolved in DMF (N,N-dimethylformamide) at a concentration of 0.125 M. The amino acids were activated with equimolar Oxyma Pure solution (0.125 M in DMF; containing 0.05 M DIEA) and a 2x molar excess of DIC solution (0.25 M in DMF). The reaction was typically carried out on a 25 μmol scale.

[0281] Each synthetic cycle included: Fmoc amino acid deprotection with 20% piperidine in DMF (90°C, microwave-assisted heating, 2 minutes), and coupling using Fmoc-protected amino acids / DIC / Oxyma (5, 5, and 10 equivalents, respectively; 90°C, microwave-assisted heating, 2 or 4 minutes) (two repeats were possible in case of difficult coupling). The cycle of Fmoc deprotection and Fmoc-protected amino acid coupling was repeated with the desired monomers until a complete linear peptide was formed.

[0282] Protocol B for solid-phase synthesis of peptides Alternatively, as summarized in Scheme 25 above, peptides were synthesized in a Biotage® SyroII peptide synthesizer using standard solid-phase synthesis with the Fmoc / tBu chemical method. HATU and DIPEA were used as coupling agents to create an amide bond between the free amino terminus of the resin-bound protected peptide and the carboxylic acid of the Fmoc-protected amino acid. 2-chlorotrityl resin (200-400 mesh, 0.79 mmol / g loading, 1% cross-linked polystyrene, Novabiochem) loaded with H-Gly was used for synthesis. All amino acids were dissolved in 1:1 DMF:NMP at a concentration of 0.2 M. The reaction was typically carried out on a 25 μmol scale.

[0283] Each synthetic cycle consisted of the following: (1) Coupling using Fmoc-protected amino acids / HATU / DIPEA (4, 4, and 8 equivalents, respectively; room temperature; 15 minutes) (repeated twice). The mixture was filtered and the peptidyl resin was washed with DMF (2 × 1 mL); (2) Fmoc deprotection (repeated three times): 20% 4-methylpiperidine in DMF (1 mL; room temperature; 3 minutes). The mixture was filtered and the peptidyl resin was washed with DMF (4 × 1 mL). The cycle of Fmoc deprotection and Fmoc-protected amino acid coupling was repeated with the desired monomers until a complete linear peptide was formed.

[0284] Selective cleavage and macrolactamization of protective peptides To cleave the protected linear peptide from the solid support, peptidyl resin (approximately 16 mg) was treated with 25% hexafluoroisopropanol (HFIP) in DCM at room temperature for 20 minutes, filtered, and the solvent was removed under reduced pressure. The resulting residue was dissolved in DMF (5 mL) and HATU (0.44 equivalents) and DIPEA (2.5 equivalents) were added. The mixture was stirred at room temperature for 5 minutes. An additional 0.66 equivalents of HATU were then added. Once macrolactamization was complete, as monitored by UPLC-MS, the solvent was removed under reduced pressure.

[0285] Final side chain deprotection A solution of TFA / H2O / TIS (90 / 8 / 2, v / v / v, 1 mL) was added to the crude protected cyclic peptide. The mixture was stirred at room temperature for 10 minutes. Cold diethyl ether (15 mL) was added to the solution. The peptide was precipitated by centrifugation (3200 rpm, -10°C). The precipitate was washed with diethyl ether (2 × 10 mL) and dried overnight under vacuum to obtain the crude deprotected cyclic peptide as a solid.

[0286] HPLC purification Using a Waters MS-Directed AutoPurification HPLC / MS system, a Waters X-Bridge Prep C18 OBD Prep column (130 angstroms, 5 pm, column size 19) was used. * Purification was performed by preparative reverse-phase high-performance liquid chromatography (RP-HPLC) at 100 mm. Mobile phase: (A) 0.16% TFA in HPLC water and (B) 0.16% TFA in HPLC acetonitrile; flow rate: 25 mL / min; UV wavelength λ=215 nm; gradient: 25-50% B over 5 minutes. Alternatively, purification was performed using an Agilent 1290 Infinity II preparative LC system and LC-MSD XT mass spectrometer on a Waters CSH-C18 column (19 × 250 mm, 5 μM). Mobile phase: (A) 0.1% formic acid in HPLC water and (B) 0.1% formic acid in HPLC acetonitrile; flow rate: 25 mL / min; UV wavelength λ=215 nm; gradient: 20% B over 2.5 minutes, 55% B over 2.5-20 minutes. The UV absorption fraction containing the target m / z ions was collected, and the product-containing fraction was identified by LC / MS.

[0287] The identity and purity of the final compound were confirmed and evaluated by UPLC-MS using a reversed-phase Waters Acquity UPLC-MS system. Column: Waters XSelect CSH C18 column (130 angstroms, 2.5 μm, column size 2.1 *(50 mm). Mobile phase: (A) 0.05% TFA in HPLC water and (B) 0.05% TFA in HPLC acetonitrile; injection volume: 1 μL; flow rate: 1 mL / min; UV wavelength λ = 215 nm; gradient: 5-100% B at 5 min. Lyophilization of the combined fraction containing pure peptides gave the final cyclization product as a powder.

[0288] 8.2.3 Biological assays: Procedure for IL-6 assay in MRC5 cells Inhibition of IL-1β-induced IL-6 secretion was evaluated in MRC5 cells. 2×EC 80Recombinant human IL-1β (BioLegend 579404) was prepared in seeding medium EMEM (ATCC 30-2003) containing 0.025% BSA (Sigma A9576), 1× penicillin / streptomycin (Gibco 15070-063), 1× NEAA (Gibco 11140-050), 1× GlutaMax (Gibco 35050-061), and 1× sodium pyruvate (Gibco 11360-070). 20 μL of IL-1β was added to a 384-well collagen-coated plate (Corning 354664) and pre-incubated at room temperature for 1 hour with 200 nL of compound dispensed using an ECHO 555 liquid handler. Human lung fibroblasts (MRC5 cells, ATCC CCL-171) were added at a density of 3000 cells / 20 μL per well. These cells were prepared by passage three times in collagen-coated T175 flasks (Greiner 661950) in EMEM growth medium (ATCC 30-2003) containing 10% fetal bovine serum (Gibco 16140-071), 1× penicillin / streptomycin (Gibco 15070-063), 1× NEAA (Gibco 11140-050), 1× GlutaMax (Gibco 35050-061), and 1× sodium pyruvate (Gibco 11360-070). After digestion with 0.25% trypsin-EDTA (Gibco 25200056) for 5 minutes, the cells were harvested in seeding medium. A 384-well collagen-coated plate containing a final volume of 40 μL was incubated overnight at 37°C and 5% CO2. 5 μL of prepared medium was transferred to a 384-well AlphaLISA plate (PerkinElmer 6005350), and IL-6 was detected using the human AlphaLISA IL6 kit (PerkinElmer AL223F) according to the manufacturer's protocol. 20 μL of the acceptor bead / biotinylated antibody mixture was added to the 384-well AlphaLISA plate and incubated at room temperature for 1 hour. The donor bead mixture was shielded from light, 25 μL was added to the plate, and incubated at room temperature for 30 minutes.AlphaLISA plates were read using an EnVision multimode plate reader (Perkin Elmer model 2104) with the AlphaScreen setting (laser excitation at 680 nm and emission at 570 nm). Dose-response curves and IC50 values ​​were analyzed using the four-parameter logistic regression equation with Spotfire software (Tibco, Palo Alto, CA).

[0289] Table 4 below shows the amino acid sequences, biological activity (MRC IC50), calculated monoisotopic mass, molecular formula, calculated molecular weight, and mass spectral data ([M+H]+ or [M+2H] / 2+) of compounds A-H (SEQ ID NOs: 8, 9, 10, 11, 12, 13, 14, and 15). [Table 4]

[0290] 8.3 Example 3: Crystallographic characterization of compound A / IL-1B complex Crystal structure analysis protocol IL-1β was recombinantly expressed and purified by chromatography. For co-crystallization, the ligand (e.g., compound A) was dissolved in 100% deuterated DMSO at a concentration of 100 mM and diluted 50-fold with a 20 mg / ml IL-1β protein sample to achieve a ligand:protein molar ratio of approximately 2:1. After 1 hour of incubation, the sample was divided into two aliquots, and 125 mM zinc chloride solution was added to one aliquot to a final concentration of 1 mM. Extensive screening of crystallization conditions was performed at 18°C ​​using commercially available screening methods. Screening preparations were made using Mosquito (TTP Labtech), dispensing 200 nL of sample solution into two separate subwells with 100–200 nL of precipitant solution added, either in the presence or absence of exogenous zinc. The mixtures were incubated in RockImager (Formulatrix) at 18°C. Crystals appeared at 2–45 days. For rapid freezing and data acquisition, a cryoprotection solution enhanced with 20% v / v glycerol, with pH and precipitant concentration suitable for crystallization conditions, was added to the crystallization droplets. The crystals were then collected using LithoLoop (Molecular Dimensions) and rapidly frozen in liquid nitrogen.

[0291] Data was acquired at the Industrial Macromolecular Consortium Association (IMCA) beamline at the Advanced Photon Source (APS) or the macromolecular crystal structure analysis beamline at the Canadian Light Source (CLS). Data was processed using autoPROC (Global Phasing) software, which makes calls to XDS, POINTLESS (CCP4), and STARANISO (Global Phasing) for integration, space group determination, and scaling, respectively. Structural analysis was performed by molecular substitution using the MOLREP program (CCP4). Structural refinement was performed using COOT (CCP4) and autoBUSTER (Global Phasing). The crystallographic parameters of the compound A / IL-1β complex are shown in Table 5 below. [Table 5]

[0292] Figure 3 shows a three-dimensional cartoon representation of compound A bound to the lipophilic binding pocket of IL-1β, which uses bars to indicate the side chains at amino acid positions 1, 2, 6, 7, and 10 of the macrocyclic peptide. The amino acid residues Arg120, Ser121, Lys179, and Lys204 of IL-1β are labeled. Figure 13 shows the compound A / IL-1β complex superimposed with other compounds that have complexed with IL-1β.

[0293] Figures 4A and 4B show two-dimensional contact maps of the interaction between compound A and IL-1β residues. Figure 4A shows the binding interaction between the lower part of compound A (amino acids 1-7) and the residues in the binding pocket. Figure 4B shows the binding interaction between the upper part of compound A (amino acids 8-14) and the residues in the binding pocket.

[0294] 8.4 Example 4: Crystallographic characterization of compound B / IL-1B complex Cocrystals of IL-1β and compound B were prepared and analyzed according to the protocol of Example 3 (for example, the crystal structure analysis method in Section 8.3). The crystallographic parameters of the compound B / IL-1β complex are shown in Table 6 below. [Table 6]

[0295] Figure 5 shows a three-dimensional cartoon representation of compound B bound to the lipophilic binding pocket of IL-1β, which uses bars to indicate the side chains at amino acid positions 1, 2, 6, 7, and 10 of the macrocyclic peptide. The amino acid residues Arg120, Ser121, Lys179, and Lys204 of IL-1β are labeled. Figure 13 shows the compound B / IL-1β complex superimposed with other compounds that have complexed with IL-1β.

[0296] Figures 6A and 6B show two-dimensional contact maps of the interaction between compound B and IL-1β residues. Figure 6A shows the binding interaction between the lower part of compound B (amino acids 1-7) and the residues in the binding pocket. Figure 6B shows the binding interaction between the upper part of compound B (amino acids 8-14) and the residues in the binding pocket.

[0297] 8.5 Example 5: Crystallographic characterization of the compound C / IL-1B complex Cocrystals of IL-1β and compound C were prepared and analyzed according to the protocol of Example 3 (for example, the crystal structure analysis method in Section 8.3). The crystallographic parameters of the compound C / IL-1β complex are shown in Table 7 below. [Table 7]

[0298] Figure 7 shows a three-dimensional cartoon representation of compound C bound to the lipophilic binding pocket of IL-1β, which uses bars to indicate the side chains at amino acid positions 1, 2, 6, 7, and 10 of the macrocyclic peptide. The amino acid residues Arg120, Ser121, Lys179, and Lys204 of IL-1β are labeled. Figure 13 shows the compound C / IL-1β complex superimposed with other compounds that have complexed with IL-1β.

[0299] Figures 8A and 8B show two-dimensional contact maps of the interaction between compound C and IL-1β residues. Figure 8A shows the binding interaction between the lower part of compound C (amino acids 1-7) and the residues in the binding pocket. Figure 8B shows the binding interaction between the upper part of compound C (amino acids 8-14) and the residues in the binding pocket.

[0300] 8.6 Example 6: Crystallographic characterization of the compound D / IL-1B complex Cocrystals of IL-1β and compound D were prepared and analyzed according to the protocol of Example 3 (for example, the crystal structure analysis method in Section 8.3). The crystallographic parameters of the compound D / IL-1β complex are shown in Table 8 below. [Table 8]

[0301] Figure 9 shows a three-dimensional cartoon representation of compound D bound to the lipophilic binding pocket of IL-1β, which uses bars to indicate the side chains at amino acid positions 1, 2, 6, 7, and 10 of the macrocyclic peptide. The amino acid residues Arg120, Ser121, Lys179, and Lys204 of IL-1β are labeled. Figure 13 shows the superposition of the compound D / IL-1β complex with other compounds that have complexed with IL-1β.

[0302] Figures 10A and 10B show two-dimensional contact maps of the interaction between compound D and IL-1β residues. Figure 10A shows the binding interaction between the lower part of compound D (amino acids 1-7) and the residues in the binding pocket. Figure 10B shows the binding interaction between the upper part of compound D (amino acids 8-14) and the residues in the binding pocket.

[0303] 8.7 Example 7: Crystallographic characterization of the compound E / IL-1B complex Cocrystals of IL-1β and compound E were prepared and analyzed according to the protocol of Example 3 (for example, the crystal structure analysis method in Section 8.3). The crystallographic parameters of the compound E / IL-1β complex are shown in Table 9 below. [Table 9]

[0304] Figure 11 shows a three-dimensional cartoon representation of compound E bound to the lipophilic binding pocket of IL-1β, which uses bars to indicate the side chains at amino acid positions 1, 2, 6, 7, and 10 of the macrocyclic peptide. The amino acid residues Arg120, Ser121, Lys179, and Lys204 of IL-1β are labeled. Figure 13 shows the superposition of the compound E / IL-1β complex with other compounds that have complexed with IL-1β.

[0305] Figures 12A and 12B show two-dimensional contact maps of the interaction between compound E and IL-1β residues. Figure 12A shows the binding interaction between the lower part of compound E (amino acids 1-7) and the residues in the binding pocket. Figure 12B shows the binding interaction between the upper part of compound D (amino acids 8-14) and the residues in the binding pocket.

[0306] 8.8 Example 8: Crystallographic characterization of the compound F / IL-1B complex Cocrystals of IL-1β and compound F were prepared and analyzed according to the protocol of Example 3 (for example, the crystal structure analysis method in Section 8.3). The crystallographic parameters of the compound F / IL-1β complex are shown in Table 10 below. [Table 10]

[0307] Figure 14 shows a three-dimensional cartoon representation of compound F bound to the lipophilic binding pocket of IL-1β, which uses bars to indicate the side chains at amino acid positions 1, 3, 6, 7, 10, and 15 of the macrocyclic peptide. The amino acid residues Arg120, Ser121, Lys179, and Lys204 of IL-1β are labeled.

[0308] Figures 15A and 15B show two-dimensional contact maps of the interaction between compound F and IL-1β residues. Figure 15A shows the binding interaction between the lower part of compound F (amino acids 1-7) and the residues in the binding pocket. Figure 15B shows the binding interaction between the upper part of compound F (amino acids 8-14) and the residues in the binding pocket.

[0309] 8.9 Example 9: Crystallographic characterization of the compound G / IL-1B complex Cocrystals of IL-1β and compound G were prepared and analyzed according to the protocol of Example 3 (for example, the crystal structure analysis method in Section 8.3). The crystallographic parameters of the compound G / IL-1β complex are shown in Table 11 below. [Table 11]

[0310] Figure 16 shows a three-dimensional cartoon representation of compound G bound to the lipophilic binding pocket of IL-1β, which uses bars to indicate the side chains at amino acid positions 1, 2, 6, 7, and 10 of the macrocyclic peptide. The amino acid residues Arg120, Ser121, Lys179, and Lys204 of IL-1β are labeled.

[0311] Figures 17A and 17B show two-dimensional contact maps of the interaction between compound G and IL-1β residues. Figure 17A shows the binding interaction between the lower part of compound F (amino acids 1-7) and the residues in the binding pocket. Figure 17B shows the binding interaction between the upper part of compound G (amino acids 8-14) and the residues in the binding pocket.

[0312] 8.10 Example 10: Crystallographic characterization of the compound H / IL-1B complex Cocrystals of IL-1β and compound H were prepared and analyzed according to the protocol of Example 3 (for example, the crystal structure analysis method in Section 8.3). The crystallographic parameters of the compound H / IL-1β complex are shown in Table 12 below. [Table 12]

[0313] Figure 18 shows a three-dimensional cartoon representation of compound H bound to the lipophilic binding pocket of IL-1β, which uses bars to indicate the side chains at amino acid positions 1, 2, 6, 7, and 10 of the macrocyclic peptide. The amino acid residues Arg120, Ser121, Lys179, and Lys204 of IL-1β are labeled.

[0314] Figures 19A and 19B show two-dimensional contact maps of the interaction between compound H and IL-1β residues. Figure 19A shows the binding interaction between the lower part of compound F (amino acids 1-7) and the residues in the binding pocket. Figure 19B shows the binding interaction between the upper part of compound G (amino acids 8-14) and the residues in the binding pocket.

Claims

1. A method for inhibiting the binding of human interleukin-1 beta (IL-1β) to human interleukin-1 receptor type I (IL-1R1), comprising contacting IL-1β with a compound that binds to IL-1β in a binding pocket defined by the amino acid residues Gly177-Leu178-Lys179-Glu180-Lys181-Asn182-Leu183-Tyr184 (SEQ ID NO: 16) and Val201-Asp202-Pro203-Lys204-Asn205-Tyr206-Pro207 (SEQ ID NO: 17) of human interleukin-1 beta (IL-1β) (SEQ ID NO: 1), or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, wherein the compound allosterically inhibits the binding of IL-1β to IL-1R1.

3. The method according to claim 1 or 2, wherein the compound orthosterically inhibits the binding of IL-1β to IL-1R1.

4. The method according to any one of claims 1 to 3, wherein the compound inhibits the binding of IL-1β to the D3 domain of IL-1R1 (SEQ ID NO: 7).

5. The method according to any one of claims 1 to 4, wherein the compound is bound to one or both of the IL-1β residues Lys179 or Pro207.

6. The compound, a) A pi-effect interaction moiety that can accept cation-pi interactions from the side chain of the residue Lys179 of IL-1β, b) A PI-effect interaction moiety from the Pro207 residue of IL-1β that can accept polar-PI interactions. The method according to claim 5, comprising at least one part selected from.

7. a) The pi-effect interaction moiety that can accept cation-pi interactions from residue Lys179 is an arene. b) The PI effect interaction moiety that can accept polar-PI interactions from residue Pro207 is an arene. The method according to claim 6.

8. The method according to claim 7, wherein the one or more of the arenes are biaryl portions.

9. The aforementioned one or more biaryl portions include a 9-10 membered bicyclic aryl or heteroaryl, where the heteroaryl contains one or two heteroatoms selected from the group consisting of N, O, and S, and the 9-10 membered bicyclic aryl or heteroaryl is unsubstituted or halo, C １ -C ３ Alkyl, C １ -C ３ Fluoroalkyl, hydroxy, and C １ -C ３ The method according to claim 8, wherein the molecule is substituted with one to three substituents independently selected from the group consisting of alkoxys.

10. The method according to claim 8 or 9, wherein the one or more biaryl portions are substituted or unsubstituted indole or naphthyl.

11. The method according to any one of claims 1 to 10, wherein the binding pocket further comprises Val119, Arg120, Ser121 and / or Ser269 of IL-1β.

12. The method according to any one of claims 1 to 10, wherein the binding pocket further comprises Val119, Arg120, and / or Ser121 of IL-1β.

13. The method according to any one of claims 1 to 11, wherein the compound is bonded to one or more of Val119, Arg120, Ser121, Pro203, Lys204, and Ser269 of IL-1β.

14. The compound, a) A hydrogen bonding interaction moiety that can donate a hydrogen bond to the carbonyl skeleton of residue Val119 of IL-1β, b) A pi-effect interaction moiety from the side chain of residue Arg120 of IL-1β that can accept cation-pi interactions, c) A hydrogen bonding interaction moiety that can donate a hydrogen bond to the carbonyl skeleton of residue Ser121 of IL-1β, d) A hydrogen bonding interaction moiety capable of donating a hydrogen bond to the carbonyl skeleton of residue Pro203 of IL-1β, or e) A hydrogen bonding interaction moiety that can donate a hydrogen bond to the carbonyl skeleton of the IL-1β residue Lys204. The method according to claim 13, comprising at least one portion selected from.

15. The compound, a) A hydrogen bonding interaction moiety that can donate a hydrogen bond to the carbonyl skeleton of residue Val119 of IL-1β, b) A pi-effect interaction moiety from the side chain of residue Arg120 of IL-1β that can accept cation-pi interactions, c) A hydrogen bonding interaction moiety that can donate a hydrogen bond to the carbonyl skeleton of residue Ser269 of IL-1β, d) A hydrogen bonding interaction moiety capable of accepting a hydrogen bond to the carbonyl skeleton of residue Ser269 of IL-1β, or e) Basic moiety of IL-1β capable of electrostatic interaction with the C-terminal carboxylic acid The method according to claim 13, comprising at least one portion selected from.

16. a) The hydrogen bond donating portion of the IL-1β residue Val119, which can donate a hydrogen bond to the carbonyl skeleton, contains a skeleton NH group. b) The side chain of the residue Arg120 of IL-1β contains an arene, which is a pi-effect interaction moiety capable of accepting cation-pi interactions. c) The hydrogen bond donating portion of residue Ser121 of IL-1β, which can donate a hydrogen bond to the carbonyl skeleton, contains a skeleton NH group. d) The hydrogen bond donating portion of the IL-1β residue Pro203 that can donate a hydrogen bond to the carbonyl skeleton contains a skeleton NH group. e) The hydrogen bond donating portion of the Lys204 residue of IL-1β that can donate a hydrogen bond to the carbonyl skeleton is the side chain NH3. ＋ or NH2 ＋ Includes the base, The method according to claim 14.

17. The compound, a) A hydrogen bond interaction moiety that can accept hydrogen bonds from the NH backbone of the Arg120 residue of IL-1β, b) A hydrogen bonding interaction moiety from the side chain of residue Arg120 of IL-1β that can accept hydrogen bonds, c) A hydrogen bonding interaction moiety that can accept a hydrogen bond from the NH backbone of residue Ser121 of IL-1β, or d) Hydrogen bonding interaction moiety from the side chain of the IL-1β residue Lys204 that can accept hydrogen bonds The method according to any one of claims 13 to 16, comprising at least one part selected from.

18. a) The hydrogen bonding interaction portion of the Arg120 residue of IL-1β, which can accept hydrogen bonds from the NH backbone, contains a carbonyl group. b) The hydrogen bonding interaction portion of the side chain of the residue Arg120 of IL-1β contains a carboxylate group, c) The hydrogen bonding interaction portion of the IL-1β residue Ser121, which can accept a hydrogen bond from the NH backbone, contains a carbonyl group, or d) The hydrogen bonding interaction portion of the side chain of the IL-1β residue Lys204 contains a carbonyl group or a carboxylate group, The method according to claim 17.

19. The method according to any one of claims 1 to 18, wherein the compound is bound to Tyr206 of IL-1β.

20. The method according to claim 19, wherein the compound includes a hydrogen bonding interaction moiety capable of donating a hydrogen bond to the carbonyl skeleton of the Tyr206 residue of IL-1β.

21. The method according to claim 20, wherein the hydrogen bonding interaction portion capable of donating a hydrogen bond to the carbonyl skeleton of the residue Tyr206 of IL-1β includes a skeleton NH group.

22. The method according to any one of claims 1 to 21, wherein the binding pocket further comprises Phe162 and / or Ser269 of IL-1β.

23. The method according to claim 22, wherein the compound is bound to one or both of the IL-1β residues Phe162 or Ser269.

24. The compound, a) A pi-effect interaction moiety capable of donating a polar-pi interaction to residue Phe162 of IL-1β, b) A hydrogen bonding interaction moiety from the side chain of residue Ser269 of IL-1β that can accept a hydrogen bond, or c) A PI-effect interaction moiety from residue Ser269 of IL-1β that can accept polar-PI interactions. The method according to claim 23, comprising one or more parts selected from.

25. a) The PI-effect interaction portion that can donate a polar-PI interaction to residue Phe162 of IL-1β includes a NH moiety in the skeleton. b) The hydrogen bonding interaction portion of the side chain OH of residue Ser269 of IL-1β contains oxygen, or c) The PI-effect interaction moiety of IL-1β that can accept polar-PI interactions from residue Ser269 contains an arene. The method according to claim 24.

26. The method according to any one of claims 1 to 25, wherein the compound is a peptide.

27. The method according to claim 26, wherein the peptide is a cyclic peptide.

28. The method according to claim 27, wherein the cyclic peptide has a length of 12 to 16 amino acid residues.

29. The method according to any one of claims 1 to 28, wherein the compound has a molecular weight of about 1200 Da to about 3000 Da, about 1500 Da to 2500 Da, or about 1750 to about 2250 Da.

30. A method for inhibiting the binding of human IL-1β to human IL-1R1, comprising contacting IL-1β with a compound that competes for binding to IL-1R1, wherein the compound is of formula (I): 【Chemistry 1】 [In the formula, R １ is CH ３ C(O)NH-CH ２ CH ２ -O- or C １ is; C １ teeth, (i) a 5-6 member monocyclic aryl or heteroaryl, wherein the heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; or (ii) A 5-6 member monocyclic or bicyclic saturated cycloalkyl or heterocycloalkyl containing one or two heteroatoms selected from the group consisting of N, O, and S; or (iii) A monocyclic or bicyclic cycloalkyl group with 5-6 members; Here, C １ is not substituted, or halo, C １ -C ３ Alkyl, C １ -C ３ Fluoroalkyl, carboxy, C １ -C ３ Alkoxy and C ２ -C ３ From the group consisting of acyls, 1 to 3 RCs are independently selected. １ Substituting with a substituent; R ２ H, C １ -C ３ Alkyl, benzyl, or phenyl-CH ２ CH ２ - is; R ３ is a 9-10 membered bicyclic aryl or heteroaryl, where the heteroaryl contains one or two heteroatoms selected from the group consisting of N, O, and S; Here, R ３ is not substituted, or halo, C １ -C ３ Alkyl, C １ -C ３ Fluoroalkyl, hydroxy, and C １ -C ３ One to three R components are independently selected from the group consisting of alkoxys. ３ａ Substituting with a substituent; R ４ is C １ -C ３ Alkyl, HO ２ C-(CH ２ ) ｍ -, H ２ NC(O)-(CH ２ ) ｍ -, (CH ３ ) ２ NC(O)-(CH ２ ) ｍ - or tetrazolyl - (CH ２ ) ｍ - is; R ５ is amino, H ２ N(CH ２ ) ｎ -, H ２ NC(O)-(CH ２ ) ｎ - , CH ３ C(O)NH-, CH ３ C(O)NH(CH ２ ) ｎ -, C ５ or C ５ -CH ２ - is; C ５ teeth, (i) a 5-6 member monocyclic aryl or heteroaryl, wherein the heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; (ii) A 9-10 membered bicyclic aryl or heteroaryl, wherein the bicyclic heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S; (iii) A 5-6 member monocyclic or 9-10 member heterocycloalkyl, wherein the heterocycloalkyl is saturated or partially unsaturated and contains 1-2 heteroatoms selected from the group consisting of N, O, and S; (iv) A 5-6 member monocyclic cycloalkyl group; or (v) 2,3-dihydroindolyl; Here, C ５ is unsubstituted, or halo, amino, hydroxy, C １ -C ３ Alkyl, C １ -C ３ Fluoroalkyl, C １ -C ３ Alkoxy, H ２ N-(CH ２ ) ｋ -, H ２ NC(O)-(CH ２ ) ｋ -, H ２ C = CH - CH ２ One to three R groups independently selected from the group consisting of O- and phenyl Ｃ５ Substituting with a substituent; R ６ is H, C １ -C ５ alkyl, H ２ N(CH ２ ) ｐ -, HOCH ２ (CH ３ ) ２ NCH ２ -, H ３ CO-(CH ２ ) ｑ - or C ６ -CH ２ -; C ６ This is a 5-membered or 6-membered monocyclic saturated heterocycloalkyl containing one or two heteroatoms selected from the group consisting of N, O, and S, where C ６ is not substituted, or halo, C １ -C ３ Alkyl, C １ -C ３ Fluoroalkyl, hydroxy, and C １ -C ３ One to three R components are independently selected from the group consisting of alkoxys. Ｃ６ Substituting with a substituent; R ７ is H or C １ -C ３ It is alkyl; R ８ａ H, C １ -C ５ Alkyl, HOCH ２ -, H ２ N(CH ２ ) ｒ -, (CH ３ ) ３ N ＋ (CH ２ ) ｒ - or CH ３ C(O)NH(CH ２ ) ｒ - is; R ８ｂ is H or C １ -C ３ It is alkyl; R ９ａ is H or C １ -C ３ It is alkyl; R ９ｂ H, C １ -C ５ Alkyl, C ９ -CH ２ - or C ９ -CH ２ CH ２ - is; C ９ teeth, (i) a 5-6 member monocyclic aryl or heteroaryl, wherein the heteroaryl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; or (ii) A 5-6 member monocyclic saturated cycloalkyl or heterocycloalkyl, wherein the heterocycloalkyl contains 1-2 heteroatoms selected from the group consisting of N, O, and S; Here, C ９ is not substituted, or halo, amino, hydroxy, cyano, C １ -C ３ Alkyl, C １ -C ３ Fluoroalkyl, C １ -C ３ Alkoxy, H ２ N-(CH ２ ) ｋ -, H ２ NC(O)-(CH ２ ) ｋ -, H ２ NCH ２ CH ２ O-, CH ３ C(O)NH-CH ２ CH ２ O- and morpholinyl-CH ２ CH ２ One to three R's are independently selected from the group consisting of O-. Ｃ９ Substituting with a substituent; R １０ is H, halo, or C １ -C ３ It is alkyl; R １１ is H, halo, or C １ -C ３ It is alkyl; Each existence of the subscript k is independently either 1 or 2; The subscript m is either 1 or 2; The subscript n is 1, 2, 3, or 4; The subscript p is 1, 2, 3, or 4; The subscript q is either 1 or 2; The subscript r is 1, 2, 3, or 4; X １ , X ２ and X ３ is independently C(H) or N; and A １ and A ２ , HO ２ C-, H ２ NC(O)-, CH ３ C(O)N(H)-, H ２ NS(O) ２ - , CH ３ S(O) ２ [Independently selected from the group consisting of N(H)-, tetrazolyl, and 5-oxoxadiazolyl] The method having a structure of a pharmaceutically acceptable salt thereof.

31. A method for inhibiting the binding of human IL-1β to human IL-1R1, comprising contacting IL-1β with a compound that competes for binding to IL-1R1, wherein the compound is a) Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMe1Nal-D-dNMeA-G-Bip4CO2H-AlaTHP4-Dap-dA-h3PaL5CN (Sequence ID 8), b) Bip4CO2H-W-Phe4COOH-G-Prot4NH2-SbMeW4F-D-dNMeA-G-Bip4CO2H-K-L-dA-hY (Sequence ID 9), c) TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-1Naal-L-dA-hY (Sequence ID 10), d) TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-W-L-dA-hY (Sequence ID 11), or e) Bip4CO2H-W-Phe4COOH-G-Prot4NHBn-SbMe1Nal-D-dNMeA-G-Bip4CO2H-W-Dap-dA-hY (Sequence ID 12), f) Bip4CO2H-4Pa-Phe4COOH-G-Proc4F-SbMeW4F-Aib-A-W-Aib-S-Q-Dab-G-dProc4Bn4F (Sequence ID 13), g) TyrEtNAc-W-Phe4COOH-G-Prot4NH2-SbMeW4Cl-D-dNMeA-G-Bip4CO2H-W-G-dProt4OH-Prot4CH2Bip (Sequence ID 14), h) TyrEtNAc-W-Phe4COOH-G-Prot4NHCO3Py-SbMe1Nal-D-dPip-G-Bip4CO2H-W-deNC2NH2Gly-aMeNle (Sequence ID 15) The method, wherein the peptide having a sequence selected from or a pharmaceutically acceptable salt thereof.

32. A method for inhibiting the binding of human IL-1β to human IL-1R1, comprising contacting IL-1β with a compound that competes for binding to IL-1R1, wherein the compound is 【Chemistry 2】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 The method having a structural formula of a pharmaceutically acceptable salt thereof.

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