Methods of using cyclic peptides that bind to TNFR1

Abstract

Provided herein, in certain aspects, are methods for inhibiting a TNFR1 -mediated activity using a compound that binds to a binding pocket of TNFR1 between CRD3 and CRD4 of TNFR1.

Description

Attorney Ref. No.14463-061-228 METHODS OF USING CYCLIC PEPTIDES THAT BIND TO TNFR1 1. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] No. 63 / 548,748 filed February 1, 2024, the disclosure of which is incorporated by reference herein in its entirety. 2. SEQUENCE LISTING

[0002] This application contains a computer readable Sequence Listing which has been submitted in XML file format with this application, the entire content of which is incorporated by reference herein in its entirety. The Sequence Listing XML file submitted with this application is entitled “14463-061-228_SEQLISTING.xml”, was created on January 30, 2025, and is 26,200 bytes in size. 3. FIELD

[0003] The present disclosure relates, in certain aspects, to methods of binding to and inhibiting downstream activity of tumor necrosis factor (TNF) receptor 1 (TNFR1). 4. BACKGROUND

[0004] Tumor necrosis factor-alpha (TNF ) self-assembles into homo-trimeric moleculesand both the transmembrane and soluble form of TNF can interact with the TNFR1 membranereceptor. TNFR1 is expressed by almost all cell types at the transcript (mRNA) level. Once bound by a TNFR ligand (TNFL), TNFL–TNFR complexes cluster or oligomerize required for TNFR1 activation of downstream activity, such as modulation of inflammation, cell survival, and gene expression.

[0005] Development of methods to selectively bind to and inhibit TNFR1 mediatedsignaling in a non-competitive manner with TNF , provides one strategy for addressing anongoing need for anti-TNF medications, for example, to more effectively treat prevalentautoimmune and inflammatory diseases. 5. SUMMARY

[0006] In one aspect, the present disclosure provides a method of inhibiting a TNFR1- mediated activity, comprising contacting the TNFR1 with a compound that binds a pocket between cysteine-rich domain 3 (CRD3) and cysteine-rich domain 4 (CRD4) of the TNFR1. In another aspect, provided is a method for inhibiting the oligomerization of two or more TNFR1- TNFL complexes, comprising contacting one or more TNFR1 with a compound that binds a pocket of the TNFR1 between CRD3 and CRD4. In some embodiments, the method results in the inhibition of a TNFR1-mediated activity. In other embodiments, the method results in the NAI-1542604160v1Attorney Ref. No.14463-061-228 inhibition of a TNFL-mediated activity. In one embodiment, the pocket is a region that isdistinct from where a TNFL (e.g., TNF ) binds. In one embodiment, the compound selectivelybinds to the TNFR1. In one embodiment, the compound does not compete with the binding of aTNFL (e.g., TNF ) to the TNFR1. In one embodiment, the compound does not compete with thebinding of a TNFL (e.g., TNF ) to the TNFR1. In some embodiments, binding of the compoundto the pocket of the TNFR1 inhibits the interaction with or at a first TNFL-bound TNFR1 trimer interface with a second TNFL-bound TNFR1 trimer. In some embodiments, the binding of the compound to the pocket of the TNFR1 inhibits clustering of two or more TNFL-bound TNFR1 receptor species. In certain embodiments, the binding of the compound to the binding pocket in a first TNFR1 inhibits a second TNFL-bound TNFR1 from binding to the first TNFR1 that is further bound to a TNFL. In some embodiments, the binding of the compound to the TNFR1 binding pocket inhibits oligomerization of TNFR1. In specific embodiments, the TNFL isTNF .

[0007] In certain embodiments, the TNFR1 is membrane-bound TNFR1. In certain embodiments, the TNFR1 comprises an amino acid sequence according to SEQ ID NO:1. In certain embodiments, the binding pocket of TNFR1 comprises or consists of amino acid residues Asn134, Thr135, Cys137, and Asn148 of SEQ ID NO:1. In certain embodiments, the binding pocket of TNFR1 comprises or further comprises one or more of amino acid residues Ser118, Leu119, Cys120, Leu121, and Asn122 of SEQ ID NO:1. In certain embodiments, the binding pocket of TNFR1 comprises or further comprises one or more of amino acid residues Thr 138, Cys 139, Leu145, Asn148, Glu149, and Cys150 of SEQ ID NO:1. In certain embodiments, the binding pocket of TNFR1 comprises or consists of amino acid residues Ser118, Leu119, Cys120, Leu121, Asn122, Cys137, Thr138, Cys139, Leu145, Asn148, Glu149, and Cys150 of SEQ ID NO:1. In certain embodiments, the compound binds to the TNFR1 at one or more of residues Asn134, Thr135, Cys137, and Asn148 of SEQ ID NO:1.

[0008] In certain embodiments of the various methods provided herein, the compound that binds to the TNFR1 pocket comprises one or more moieties selected from: (a) an H-bond interaction moiety capable of donating an H-bond to residue Asn148 of the TNFR1; (b) an H-bond interaction moiety capable of accepting an H-bond from residue Cys137 of the TNFR1; and (c) an H-bond interaction moiety capable of donating an H-bond to residue Cys137 of the TNFR1. NAI-1542604160v1Attorney Ref. No.14463-061-228

[0009] In some embodiments, the compound further comprises one or more moieties selected from: (a) an H-bond interaction moiety capable of donating an H-bond to residue Thr135 of the TNFR1; and (b) an H-bond interaction moiety capable of accepting an H-bond from residue Asn134 of the TNFR1.

[0010] In certain embodiments of the various methods provided herein, the compound is a peptide. In specific embodiments, the compound is a cyclic peptide. In certain embodiments, the compound comprises 12 to 18 amino acid residues. In certain embodiments, the compound comprises 12 to 16 amino acid residues. In certain embodiments, the compound has a molecular weight of from about 1200 Da to about 3000 Da, from about 1500 Da to 2500 Da, or from about 1750 Da to about 2250 Da.

[0011] In certain embodiments of the various methods provided herein, the compound comprises a sequence of amino acids, wherein the compound binds to the binding pocket of the TNFR1 via an aliphatic or aliphatic-aryl (e.g., alkyl or aryl-alkyl) side chain side chain on a first amino acid in the sequence. In certain embodiments, the compound binds, or further binds to the binding pocket of TNFR1 via a bicyclic aryl or heteroaryl on the eighth amino acid in the sequence. In certain embodiments, the bicyclic aryl or heteroaryl is naphthyl or indolyl. In certain embodiments, the compound binds, or further binds to the binding pocket of TNFR1 the backbone of the eighth amino acid in the sequence. In certain embodiments, the compound binds, or further binds to the binding pocket of TNFR1 via a monocyclic aryl or heteroaryl moiety on the tenth amino acid of the sequence. In certain embodiments, the monocyclic aryl or heteroaryl moiety is phenyl. In certain embodiments, the compound binds or further binds to the binding pocket of TNFR1 via a hydroxyl moiety or an amine moiety on the third amino acid in the sequence. In some embodiments, the hydroxyl moiety or an amine moiety is comprised within an hydroxymethyl moiety, a piperidinyl moiety, or a piperazinyl moiety. In certain embodiments, the compound binds to the binding pocket of TNFR1 via a hydroxyl moiety on the ninth amino acid in the sequence. In some embodiments, the hydroxyl moiety is comprised within an hydroxymethyl moiety. In some embodiments, the eighth amino acid binds to Cys137 of the TNFR1 of SEQ ID NO:1. In some embodiments, the tenth amino acid binds to Asn134 of the TNFR1 of SEQ ID NO:1. In some embodiments, the third amino acid binds to Asn148 of the TNFR1 of SEQ ID NO:1. In some embodiments, the ninth amino acid binds to Thr135 of the TNFR1 of SEQ ID NO:1. In some embodiments, the first amino acid is (S)-2-aminoheptanoic acid (Ahp), L-norleucine (Nle), or L-phenylalanine (F). In some embodiments, the third amino NAI-1542604160v1Attorney Ref. No.14463-061-228 acid is (S)-piperazine-2-carboxylic acid (Pip2c), (S)-piperidine-2-carboxylic acid (Pip), or L- serine (S). In some embodiments, the eighth amino acid is 3-(2-naphthyl)-L-alanine (2Nal), (S)- 2-amino-3-(7-chloro-1H-indol-3-yl)propanoic acid (Trp7Cl), or L-tryptophan (W). In some embodiments, the ninth amino acid is -methyl-L-serine (aMeS) or L-serine (S). In some embodiments, the tenth amino acid is L-tyrosine (Y) or L-phenylalanine-4-carboxylic acid (Phe4COOH).

[0012] In another aspect, the present disclosure provides a method of inhibiting a TNFR1- mediated activity, comprising contacting the TNFR1 with a first compound that competes with a second compound for binding to TNFR1 at a binding pocket between CRD3 and CRD4 of TNFR1, wherein the second compound comprises a sequence selected from: (a) ClAc*-Ahp-4Pal-S-SbMeW-dP-N-Phe4COOH-2Nal-aMeS-Phe4COOH-H-Sar-aMeW-; (c) Nle*-4Pal-Pip-W-NMeE-N-4Pal-Trp7Cl-aMeS-Phe4COOH-Phe3CONH2-Sar- SbMeW7OMe-bhcLeu* (SEQ ID NO:8); or (d) ClAc*-F-Y-S-W-Sar-N-Y-W-S-Y-Y-Sar-W-C*-G-E-E-NH2(SEQ ID NO:9); or a pharmaceutically acceptable salt thereof, wherein * indicates attachment to form a cyclic peptide.

[0013] In another aspect, the present disclosure provides a method of inhibiting a TNFR1- mediated activity, comprising contacting the TNFR1 with a first compound that competes with a second compound for binding to TNFR1 at a binding pocket between CRD3 and CRD4 of TNFR1, wherein the second compound is Compound A, B, C, or D: NAI-1542604160v1Attorney Ref. No.14463-061-228 O OH ,NAI-1542604160v1Attorney Ref. No.14463-061-228 ,or a pharmaceutically acceptable salt thereof. NAI-1542604160v1Attorney Ref. No.14463-061-228

[0014] In another aspect, provided is a method for inhibiting oligomerization of two or more TNFR1-TNFL complexes, comprising contacting one or more TNFR1 with a first compound that competes with a second compound for binding to a pocket of the TNFR1 between CRD3 and CRD4. In another aspect, provided is a method for inhibiting oligomerization of two TNFL trimer-bound TNFR1 monomers, comprising contacting one or more TNFR1 with a first compound that competes with a second compound for binding to a pocket of the TNFR1 between CRD3 and CRD4. In another aspect, provided is a method for sterically inhibiting aninterface, for example, a clustering interface, in a TNF –TNFR1 trimer:trimer complex,comprising contacting one or more TNFR1 with a first compound that competes with a second compound for binding to a pocket of the TNFR1 between CRD3 and CRD4. In another aspect, provided is a method for inhibiting a TNFR1-mediated activity, comprising contacting the TNFR1 with a first compound that competes with a second compound for binding to a pocket of the TNFR1 between CRD3 and CRD4. In another aspect, provided is a method for inhibiting a TNFL-mediated activity, comprising contacting a TNFR1 with a first compound that competes with a second compound for binding to a pocket of the TNFR1 between CRD3 and CRD4. Inanother aspect, provided is a method for inhibiting a TNF -mediated activity, comprisingcontacting a TNFR1 with a first compound that competes with a second compound for binding to a pocket of the TNFR1 between CRD3 and CRD4. In another aspect, provided is a method for inhibiting a TNFR1-mediated signaling, comprising contacting the TNFR1 with a first compound that competes with a second compound for binding to a pocket of the TNFR1 between CRD3 and CRD4. In another aspect, provided is a method for inhibiting TNFL- mediated signaling, comprising contacting a TNFR1 with a first compound that competes with a second compound for binding to a pocket of the TNFR1 between CRD3 and CRD4. In anotheraspect, provided is a method for inhibiting a TNF -mediated signaling, comprising contacting aTNFR1 with a first compound that competes with a second compound for binding to a pocket of the TNFR1 between CRD3 and CRD4. In another aspect, provided is a first compound that competes with a second compound for binding to a pocket of the TNFR1 between CRD3 and CRD4, In one embodiment, the second compound comprises SEQ ID NO:6. In one embodiment, the second compound comprises SEQ ID NO:7. In one embodiment, the second compound comprises SEQ ID NO:8. In one embodiment, the second compound comprises SEQ ID NO:9. In one embodiment, the second compound comprises SEQ ID NO:6. In one embodiment, the second compound consists of SEQ ID NO:7. In one embodiment, the second compound consists of SEQ ID NO:8. In one embodiment, the second compound consists of SEQ ID NO:9. In another embodiment, the second compound is Compound A. In another embodiment, the second NAI-1542604160v1Attorney Ref. No.14463-061-228 compound is Compound B. In another embodiment, the second compound is Compound C. In another embodiment, the second compound is Compound D.

[0015] In one embodiment of the various methods provided herein, the TNFR1-mediated activity is inflammation. In one embodiment, the TNFR1-mediated activity is cytokine signaling. In one embodiment, the TNFR1-mediated activity is apoptosis. In one embodiment, the TNFR1-mediated activity is necroptosis. In one embodiment, the TNFR1-mediated activity is cell proliferation. In one embodiment, the TNFR1-mediated activity is cell survival. In one embodiment, the TNFR1-mediated activity is cell differentiation. In one embodiment, the TNFR1-mediated activity is MAPK signaling. In one embodiment, the TNFR1-mediatedactivity is NF- B signaling. In another embodiment of the various methods provided herein, theTNFL-mediated activity is inflammation. In one embodiment, the TNFL-mediated activity is cytokine signaling. In one embodiment, the TNFL-mediated activity is apoptosis. In one embodiment, the TNFL-mediated activity is necroptosis. In one embodiment, the TNFL- mediated activity is cell proliferation. In one embodiment, the TNFL-mediated activity is cell survival. In one embodiment, the TNFL-mediated activity is cell differentiation. In one embodiment, the TNFL-mediated activity is MAPK signaling. In one embodiment, the TNFL-mediated activity is NF- B signaling.6. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] The foregoing summary, as well as the following detailed description of specific embodiments of the present application, will be better understood when read in conjunction with the appended drawings. It should be understood, however, that the application is not limited to the precise embodiments shown in the drawings.

[0017] FIG. 1 depicts steric blocking of a clustering interface in a TNF –TNFR1trimer:trimer complex caused by the binding of Compound C (SEQ ID NO:8) as disclosed herein. The compounds are bound to the TNFR1 between the CRD3 and CRD4 and disruptoligomerization of the two depicted TNF trimer-bound TNFR1 monomers.

[0018] FIG.2 depicts the numbering scheme for the amino acid residues of compounds of Formula (II) as described herein.

[0019] FIGs.3A-3B depict two-dimensional representations of a fragment of Compound B bound in the binding pocket of the TNFR1 showing interactions between the compound and the pocket.

[0020] FIGs.4A-4B depict (A) a three-dimensional top view and (B) a three-dimensional bottom view of the TNFR1 binding pocket when bound to Compound A, Compound B, Compound C, and Compound D of the disclosure, as determined by X-ray crystallography and NAI-1542604160v1Attorney Ref. No.14463-061-228 presented as an overlay. The side chains of amino acids at positions / pep 1, 3, 8, 9, and 10 of the compounds are shown using stick representations and labeled. Amino acid residues Asn134, Thr135, Cys137, and Asn148 of the TNFR1 binding pocket are labeled.

[0021] FIGs.5A-5B depicts a three-dimensional cartoon representation of Compound B bound in the binding pocket of the TNFR1. FIG.5A depicts the compound in the pocket of TNFR1, but without showing the pocket or receptor itself. FIG.5B shows the pocket and water molecules. In the figure, the dashed lines without end bars (---) depict a H-bond, whereas the dashed lines with end bars (|---|) depicts a pi-pi interaction.

[0022] FIG.6 is a superimposed imaged depicting the displacement of the CDR4 of the TNFR1 upon binding of Compound B. The green / vertical line shading portion represent the unbound (apo form of) TNFR1 and red / dotted shading represents the TNFR1 bound to Compound B. 7. DETAILED DESCRIPTION 7.1. Definitions

[0023] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.

[0024] It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise.

[0025] Unless otherwise stated, any numerical values, such as a concentration or a concentration range described herein, are to be understood as being modified in all instances by the term “about.” Thus, a numerical value typically includes ± 10% of the recited value. For example, a concentration of 1 mg / mL includes 0.9 mg / mL to 1.1 mg / mL. Likewise, a concentration range of 1% to 10% (w / v) includes 0.9% (w / v) to 11% (w / v). As used herein, the use of a numerical range expressly includes all possible subranges, all individual numerical values within that range, including integers within such ranges and fractions of the values unless the context clearly indicates otherwise.

[0026] Unless otherwise indicated, the term “at least” preceding a series of elements is to be understood to refer to every element in the series. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the methods provided herein. Such equivalents are intended to be encompassed by the invention.

[0027] As used herein, the terms “comprises,” “comprising,” “includes,” “including,” “has,” “having,” “contains” or “containing,” or any other variation thereof, will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or NAI-1542604160v1Attorney Ref. No.14463-061-228 group of integers and are intended to be non-exclusive or open-ended. For example, a composition, a mixture, a process, a method, an article, or an apparatus that comprises a list of elements is not necessarily limited to only those elements but can include other elements not expressly listed or inherent to such composition, mixture, process, method, article, or apparatus. Further, unless expressly stated to the contrary, “or” refers to an inclusive or and not to an exclusive or. For example, a condition A or B is satisfied by any one of the following: A is true (or present), and B is false (or not present), A is false (or not present), and B is true (or present), and both A and B are true (or present).

[0028] As used herein, the conjunctive term “and / or” between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by “and / or,” a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the first. A third option refers to the applicability of the first and second elements together. Any one of these options is understood to fall within the meaning, and therefore satisfy the requirement of the term “and / or” as used herein. Concurrent applicability of more than one of the options is also understood to fall within the meaning, and therefore satisfy the requirement of the term “and / or.”

[0029] As used herein, the term “consists of,” or variations such as “consist of” or “consisting of,” as used throughout the specification and claims, indicate the inclusion of any recited integer or group of integers, but that no additional integer or group of integers can be added to the specified method, structure, or composition.

[0030] As used herein, the term “consists essentially of,” or variations such as “consist essentially of” or “consisting essentially of,” as used throughout the specification and claims, indicate the inclusion of any recited integer or group of integers, and the optional inclusion of any recited integer or group of integers that do not materially change the basic or novel properties of the specified method, structure, or composition.

[0031] It should also be understood that the terms “about,” “approximately,” “generally,” “substantially,” and like terms, used herein when referring to a dimension or characteristic of a component of the methods provided herein, indicate that the described dimension / characteristic is not a strict boundary or parameter and does not exclude minor variations therefrom that are functionally the same or similar, as would be understood by one having ordinary skill in the art. At a minimum, such references that include a numerical parameter would include variations that, using mathematical and industrial principles accepted in the art (e.g., rounding, measurement or NAI-1542604160v1Attorney Ref. No.14463-061-228 other systematic errors, manufacturing tolerances, etc.), would not vary the least significant digit.

[0032] The terms “decrease,” “lower” or “reduce,” refer generally to the ability of a test molecule to mediate a reduced response (e.g., downstream effect) when compared to the response mediated by a control or a vehicle. Decrease may be a statistically significant difference in the measured response between the test molecule and the control (or the vehicle), or a decrease in the measured response, such as a decrease of about 1.1, 1.2, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 or 30-fold or more, such as 500, 600, 700, 800, 900 or 1000 fold or more.

[0033] The terms “enhance,” “promote” or “increase,” refer generally to the ability of the test molecule to mediate a greater response (e.g., downstream effect) when compared to the response mediated by a control or a vehicle. Enhance may be a statistically significant difference in the measured response between the test molecule and control (or vehicle), or an increase in the measured response, such as an increase of about 1.1, 1.2, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 or 30-fold or more, such as 500, 600, 700, 800, 900 or 1000-fold or more.

[0034] As used throughout this disclosure, “a compound of the disclosure,” “a compound of the present disclosure” and “a compound disclosed herein” are used interchangeably and to be understood to include the disclosed cyclic peptides and compounds of Formula (I) or (II). The compounds of Formula (I) or (II) can form salts which are also within the scope of the present disclosure. Reference to a compound of the disclosure (or compound of Formula (I) or (II)) herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and / or organic acids, as well as basic salts formed with inorganic and / or organic bases. In addition, when a compound of Formula (I) or (II) contains both a basic moiety, such as, but not limited to an amino group, pyrrolidine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. In certain embodiments, the salt is a pharmaceutically acceptable (e.g., non-toxic, physiologically acceptable) salt. In another embodiment, the salt is other than a pharmaceutically acceptable salt. Salts of the compounds of Formula (I) or (II) may be formed, for example, by reacting a compound of Formula (I) or (II) with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0035] The term “alkyl,” as well as other groups having the prefix “alk,” such as alkoxy, dialkylamino, and trialkylammonium, and the like, refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced with a bond. An alkyl group may be straight or NAI-1542604160v1Attorney Ref. No.14463-061-228 branched and contain from about 1 to about 10 carbon atoms. In certain embodiments, an alkyl group contains from about 1 to about 10 carbon atoms. In different embodiments, an alkyl group contains from 1 to 6 carbon atoms (C1-6 alkyl) or from about 1 to about 3 carbon atoms (C1-3 alkyl). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n- butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl, and neohexyl. In certain embodiments, an alkyl group is linear. In another embodiment, an alkyl group is branched. Unless otherwise indicated, an alkyl group is unsubstituted.

[0036] “Aliphatic” refers to saturated hydrocarbon compounds that may be linear, branched, or cyclic.

[0037] “Alkoxy” refers to an alkyl (carbon and hydrogen chain) group linked to oxygen (R– O). Non-limiting examples of alkoxy are methoxy (CH3O–), ethoxy (CH3CH2O–), and propoxy (CH3CH2CH2O–).

[0038] “Amino” means a –NR2group where R is independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, benzyl, or heteroalkyl.

[0039] “Amino acid” refers to naturally-occurring -amino acids and their stereoisomers, aswell as unnatural amino acids (such as , -disubstituted amino acids, -substituted amino acids,-amino acids and substituted amino acids) and their stereoisomers. In the sequences given for the peptides (compounds) according to the present disclosure, the amino acid residues have their conventional meaning. Thus, “G” or “Gly” is glycine, “W” or “Trp” is tryptophan, “A” or “Ala” is alanine, “S” or “Ser” is serine, and so on. It is to be understood that “d” or “D” or “D” isomers are designated by a “D” or “D” before the three-letter code or amino acid abbreviation or amino acid name, such that for example D-Ala or D-Ala or dA is the D isomer of L-alanine. Amino acid residues not encompassed by the foregoing have the definitions provided in the Abbreviation Table (Table 1) below: Table 1: Abbreviations Abbreviation Definition 2CTC 2-Chl r trit l hl ridAttorney Ref. No.14463-061-228 Abbreviation Definition ATP Adenosine triphosphate bhL (1R3S)-3-Amin l ntn-1- rbxli idAttorney Ref. No.14463-061-228 Abbreviation Definition KDappApparent substrate dissociation constant k Di itin rt ntntAttorney Ref. No.14463-061-228 Abbreviation Definition rpm Revolutions per minute RPMI R w ll P rk M m ri l In tit t 1640 m di m idhydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, benzyl, or heteroalkyl.

[0041] “Aryl” means a monocyclic, bicyclic, or tricyclic carbocyclic aromatic ring or ring system containing 5-14 carbon atoms, wherein at least one of the rings is aromatic. Examples of aryl include phenyl, biphenyl, and naphthyl. In some embodiments of the present invention, aryl is phenyl.

[0042] “Bicyclic” or “bicyclic ring system” refers to two joined rings. The rings may be fused, e.g., share two adjacent atoms, or “spirocyclic,” e.g., share only a single atom.

[0043] “Carbonyl” means a functional group composed of a carbon atom double bonded to an oxygen atom (C=O).

[0044] “Carboxy” means a –CO2H group. The bond to the parent group is through the carbon atom of the carbonyl component. NAI-1542604160v1Attorney Ref. No.14463-061-228

[0045] “Cycloalkyl” means any univalent non-aromatic radical derived from a monocyclic, bicyclic, tricyclic, or tetracyclic ring system. The ring system may have 3 to 12 ring carbons atoms. These non-aromatic radicals, which have 3, 4, 5, 6, 7, 8, or up to 12 carbon ring atoms may be fully saturated, or partially unsaturated. Unless stated specifically in the specification, the cycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. Here, the point of attachment for a “cycloalkyl” to the rest of the molecule is on the saturated ring. Bicyclic cycloalkyl ring systems include fused ring systems, where two rings share two atoms (e.g., decalin), spiro ring systems where two rings share one atom (e.g., spiro[4.5]decanyl) and bridged groups (e.g., norbornyl). Additional examples within the above meaning include, but are not limited to univalent radicals of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.2]octanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, [1.1.1]-bicyclo pentane, bicyclo[3.1.0]hexanyl, cyclohexenyl, cyclopentenyl, 1-decalinyl, spiro[2.4]heptyl, spiro[2.2]pentyl, and norbornyl.

[0046] “Halo”, unless otherwise indicated, includes fluorine (fluoro), chlorine (chloro), bromine (bromo) and iodine (iodo). In certain embodiments, halo is fluoro (–F) or chloro (–Cl).

[0047] The term “heteroalkyl” refers to an alkyl group where 1, 2, 3, or 4 of the carbon atoms is substituted by a heteroatom independently chosen from nitrogen (N), oxygen (O), or sulfur (S).

[0048] The term “heteroaryl,” as used herein, represents a stable monocyclic, bicyclic, or tricyclic ring system containing 5 to 14 carbon atoms and containing at least one ring heteroatom selected from nitrogen (N), sulfur (S) (including S=O and SO2) and oxygen (O), wherein at least one of the heteroatoms containing rings is aromatic. In the case of a heteroaryl ring system where one or more of the rings are saturated and contain one or more nitrogen (N) atoms, the nitrogen (N) can be in the form of quaternary amine or quaternary ammonium cation. Bicyclic heteroaryl ring systems include fused ring systems, where two rings share two atoms, and spiro ring systems, where two rings share one atom. Heteroaryl groups within the scope of this definition include but are not limited to: azaindolyl, benzoimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzothiazolyl, benzo[d]isothiazolyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazolinyl, isoxazolinyl, pyranyl, pyrazinyl, pyrazolyl, pyrrolyl, pyrazolopyrimidinyl, pyridazinyl, pyridyl, pyrimidyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, 5H-pyrrolo[3,4- b]pyridine, thiazolyl, thienyl, triazolyl, triazinyl, benzothiazolyl, benzothienyl, quinolinyl, NAI-1542604160v1Attorney Ref. No.14463-061-228 quinazolinyl, and isoquinolinyl, and oxazolyl. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.

[0049] The term “heterocycloalkyl” as used herein refers to a stable and non-aromatic(including not fully aromatic, e.g., one double bond) 3- to 12-membered ring (e.g., C3-12heterocycloalkyl) radical that comprises two to twelve ring carbon atoms and from one to six ring heteroatoms selected from nitrogen, oxygen, and sulfur. Whenever it appears herein, a numerical range such as “3 to 12” or “3-12” refers to each integer in the given range. For example, “3 to 12 ring atoms” means that the heterocycloalkyl group may consist of 3 ring atoms, 4 ring atoms, 5 ring atoms, etc., up to and including 12 ring atoms. In some embodiments, it is a 5 to 10 ring heterocycloalkyl. In some embodiments, it is a 4 to 10 ring heterocycloalkyl. In some embodiments, it is a 3 to 10 ring heterocycloalkyl. In some embodiments, it is a 4 to 7 ring heterocycloalkyl. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen, or sulfur atom, respectively, is present as a ring atom. In some embodiments, the nitrogen or sulfur atom of the heterocycloalkyl can be optionally oxidized to the corresponding N-oxide, S-oxide (S=O) or S-dioxide (SO2). One or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. The heterocycloalkyl may be attached to the rest of a molecule through any atom of the ring(s).

[0050] In certain embodiments, a heterocycloalkyl group is monocyclic and has from about 3 to about 7 ring atoms. In another embodiment, a heterocycloalkyl group is monocyclic has from about 5 to about 8 ring atoms. In another embodiment, a heterocycloalkyl group is bicyclic and has from about 8 to about 11 ring atoms. In still another embodiment, a heterocycloalkyl group is monocyclic and has 5 or 6 ring atoms. In certain embodiments, a heterocycloalkyl group is monocyclic. In another embodiment, a heterocycloalkyl group is bicyclic. In another embodiment, a heterocycloalkyl group is tricyclic. There are no adjacent oxygen and / or sulfur atoms present in the ring system.

[0051] Non-limiting examples of heterocycloalkyl rings include decahydroisoquinoline, dioxaspiro[4.5]decane, 2,5-diazabicyclo[2.2.1]heptyl, quinuclidinyl, oxetanyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, beta-lactam, gamma-lactam, delta-lactam, beta-lactone, gamma-lactone, delta-lactone, piperidinyl, 3-azabixyclo[3.1.0]hexyl, 2-azabicyclo[2.1.1]hexyl, 6-azaspiro[2.5]octanyl, azetidinyl, 2,3-dihydro-1H-indenyl, dihydro-1H-indenyl, 3H- NAI-1542604160v1Attorney Ref. No.14463-061-228 spiro[benzofuran-2’,4’-piperidinyl, 2,3-dihydro-1H-pyrrolo[3,2,1-ij][1,6]naphthyridinyl, 3,4,6,7- tetrahydro-5H-imidazo[4,5-c]pyridyl, 3a,5,6,6a-tetrahydro-4H-pyrrolo[3,4-d]isoxazole, diazabicyclo[3.3.2]decanyl, 2,3,4,5,6,7-hexahydroisothiazolo[5,4-c]pyridyl, hexahydro-2H- pyrrolo[3,4-d]isothiazolyl, 3,9-diazabicyclo[3.3.2]decanyl, bicyclo[2,2,1]heptenyl, 2',3'-dihydro- 1'H-spiro[piperidine-4,4'-quinazolin], octahydropyrrolo[3,4-b][1,4]oxazinyl, (diazabicyclo[2.2.1]heptanyl), 2,5-diazabicyclo[2.2.1]heptanyl, tetrahydrobenzo[d]thiazolyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, 2,3-dihydrobenzofuranyl, oxabicyclo[2.1.1]hexyl, dihydro- 5H-pyrrolo[3,4-d]thiazolyl, 4,6-dihydro-5H-pyrrolo[3,4-d]thiazolyl, dihydro-5H-pyrrolo[3,4- d]oxazolyl, 4,6-dihydro-5H-pyrrolo[3,4-d]oxazolyl, dihydrothiazolo[5,4-c]pyridin-5(4H)-yl, 6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl, benzo[d]imidazolyl, 1H-enzo[d]imidazolyl, diazaspiro[4.4]nonanyl, and 2,7-diazaspiro[4.4]nonanyl, and pyrrolidinone, and oxides thereof and all isomers thereof. In some embodiments of the invention, heterocycloalkyl rings include: piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azeridinyl, azetidinyl.

[0052] “Hydroxyalkyl” refers to alkyl substituted with a hydroxy (–OH) group.

[0053] By “pharmaceutically acceptable” is meant that the ingredients of the pharmaceutical composition must be compatible with each other and not deleterious to the recipient thereof.

[0054] Where any amine is present in the compound, the nitrogen (N) atom may be optionally in the form of a quaternary amine having one or more appropriate additional substitutions, as further described herein.

[0055] When any variable (e.g., n, Ra, Rb, etc.) occurs more than one time in any constituent or in Formula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0056] When any ring atom is specified as being optionally substituted with, or in a specified form, for example, sulfur (S) substituted with oxo groups, or nitrogen (N) in the form of a N-oxide, this does not preclude the substitution of any ring atom with the other listed optional substituents when not substituted with oxo groups or in the form of a N-oxide.

[0057] The term “compound” refers to the compound and, in certain embodiments, to the extent they are stable, any hydrate or solvate thereof. A hydrate is the compound complexed with water, and a solvate is the compound complexed with an organic solvent.

[0058] It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples, and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences. NAI-1542604160v1Attorney Ref. No.14463-061-228

[0059] When a functional group in a compound is termed “protected,” this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al., Protective Groups in Organic Synthesis (1991), Wiley, New York.

[0060] Structural representations of compounds having substituents terminating with a methyl group may display the terminal methyl group either using the characters “Me”, “–Me”,“CH3”, “–CH3” or using a straight line representing the presence of the methyl group, e.g.," " , e.g., and have equivalent meanings.

[0061] the contrary, all ranges cited herein are inclusive. Forexample, a as containing from “1 to 4 heteroatoms” means the ring can contain, 1, 2, 3 or 4 heteroatoms. It is also to be understood that any range cited herein includes within its scope all of the sub-ranges within that range. Thus, for example, a heterocyclic ring described as containing from “1 to 4 heteroatoms” is intended to include as aspects thereof, heterocyclic rings containing 2 to 4 heteroatoms, 3 or 4 heteroatoms, 1 to 3 heteroatoms, 2 or 3 heteroatoms, 1 or 2 heteroatoms, 1 heteroatom, 2 heteroatoms, 3 heteroatoms, and 4 heteroatoms. Similarly, C1-C6 when used with a chain, for example an alkyl chains means that the chain can contain 1, 2, 3, 4, 5, or 6 carbon atoms. It also includes all ranges contained therein including C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C3-C6, C4-C6, C5-C6, and all other possible combinations.

[0062] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results from combination of the specified ingredients in the specified amounts.

[0063] When any variable occurs more than one time in any constituent or in Formula (I) or (II) or other generic formulas herein, its definition on each occurrence is independent of its definition at every other occurrence. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. In choosing compounds of the present disclosure, one of ordinary skill in the art will recognize that the various substituents are to be chosen in conformity with well-known principles of chemical structure connectivity and stability. Unless expressly stated to the contrary, substitution by a named substituent is permitted on any atom in a ring (e.g., aryl, heteroaryl ring, or saturated heteroaryl ring) provided such ring substitution is chemically allowed and results in a stable compound. A “stable” compound is a compound which can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the NAI-1542604160v1Attorney Ref. No.14463-061-228 compound for the purposes described herein (e.g., therapeutic, or prophylactic administration to a subject).

[0064] The term “substituted” means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom’s normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. “Substituted” shall be deemed to include multiple degrees of substitution by a named substituent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.

[0065] A wavy line ( ) and / or asterisk (*), as used herein, indicates a point ofattachment to the rest of the compound.

[0066] Some of the compounds described herein may exist as tautomers which have different points of attachment of hydrogen accompanied by one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed with compounds of the present disclosure.

[0067] In the compounds of the disclosure, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present disclosure as described and claimed herein is meant to include all suitable isotopic variations of the compounds of the disclosure and embodiments thereof. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H, also denoted herein as D). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements or may provide a compound useful as a standard for characterization of biological samples. Isotopically- enriched compounds of the disclosure can be prepared without undue experimentation by conventional techniques well-known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and / or intermediates.

[0068] The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present disclosure is acidic (or has a functional group which may be anionic), its corresponding salt can NAI-1542604160v1Attorney Ref. No.14463-061-228 be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Li+, Na+, and K+, alkaline earth metal cations such as Ca2+, and Mg2+, and other cations such as Al3+and Zn2+. Examples of suitable organic cations include, but are not limited to, ammonium ion (e.g., NH4+) and substituted ammonium ions. Examples of suitable substituted ammonium ions are those derived from methylamine, ethylamine, diethylamine, triethylamine and ethylenediamine. When a compound of the present disclosure is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Example of such acid addition salts include salts formed from hydrohalic acids (e.g., hydrochloric, hydrobromic, hydroiodic), formic acid, acetic acid, capric acid, and citric acid. Salts containing acetate, formate, caprate, chloride, or sodium salts are typical for use with the compounds of the present disclosure. In some embodiments, salts of compounds of the present disclosure can be formed by exchange well- known to those of ordinary skill in the art, such as by anion exchange, e.g., replacement of trifluoroacetate ions with chloride ions. 7.2. TNFR1

[0069] TNFR1 is a receptor protein involved in such activities as inflammation, cell proliferation, differentiation, apoptosis, necroptosis, and activation of transcription factor NF- B. In some embodiments, TNFR1 is also known as tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) or CD120a. In some embodiments, TNFR1 is encoded by the TNFR1 gene (e.g., human TNFR1 gene), which is also known as FPF, p55, p60, TBP1, TNF-R, TNFAR, TNFR1, p55-R, CD120a, TNFR55, TNFR60, TNF-R-I, or TNF-R55.

[0070] In some embodiments, the TNFR1 is a human TNFR1. TNFR1 is found inmembrane-bound and soluble forms that interact TNFLs, which include TNF , and LT 3.Binding of a TNFL (e.g., a trimer of TNF ) to the extracellular domain of membrane-boundTNFR1 induces TNFR1 trimerization and activation, which plays a role in cell survival, apoptosis, and inflammation. Proteolytic processing of TNFR1 results in release of the solubleform of the receptor, which can interact with free TNFLs (e.g., TNF ) to inhibit inflammation.sTNFR1 (SEQ ID NO:1) is the extracellular domain of membrane-bound TNFR1. SEQ ID NO:1 is shown below: LVPHLGDREK RDSVCPQGKY IHPQNNSICC TKCHKGTYLY NDCPGPGQDT DCRECESGSF TASENHLRHC LSCSKCRKEM GQVEISSCTV DRDTVCGCRK NQYRHYWSEN LFQCFNCSLC LNGTVHLSCQ EKQNTVCTCH AGFFLRENEC VSCSNCKKSL ECTKLCLPQI ENVKGTEDSG TT (SEQ ID NO:1). As used herein, SEQ ID NO:1 refers to both the extracellular domain of NAI-1542604160v1Attorney Ref. No.14463-061-228 membrane-bound TNFR1 and sTNFR and unless otherwise indicated, is used to encompass binding of the compound to both or either TNFR1 forms.

[0071] In addition to its extracellular domain, membrane-bound TNFR1 also has a transmembrane and a cytoplasmic domain. The full sequence of membrane-bound TNFR1 is represented by SEQ ID NO:2 below, wherein the extracellular domain is underlined, the transmembrane domain is bolded, and the cytoplasmic domain is double underlined: MGLSTVPDLL LPLVLLELLV GIYPSGVIGL VPHLGDREKR DSVCPQGKYI HPQNNSICCT KCHKGTYLYN DCPGPGQDTD CRECESGSFT ASENHLRHCL SCSKCRKEMG QVEISSCTVD RDTVCGCRKN QYRHYWSENL FQCFNCSLCL NGTVHLSCQE KQNTVCTCHA GFFLRENECV SCSNCKKSLE CTKLCLPQIE NVKGTEDSGT TVLLPLVIFF GLCLLSLLFI GLMYRYQRWK SKLYSIVCGK STPEKEGELE GTTTKPLAPN PSFSPTPGFT PTLGFSPVPS STFTSSSTYT PGDCPNFAAP RREVAPPYQG ADPILATALA SDPIPNPLQK WEDSAHKPQS LDTDDPATLY AVVENVPPLR WKEFVRRLGL SDHEIDRLEL QNGRCLREAQ YSMLATWRRR TPRREATLEL LGRVLRDMDL LGCLEDIEEA LCGPAALPPA PSLLR (SEQ ID NO:2).

[0072] In SEQ ID NO:2, the initial 29 amino acids are a signal sequence and may or may not be present in the TNFR1 to which the compounds disclosed herein are bound to inhibit TNFR1-mediated activity. TNFR1, without a signal sequence is represented below as SEQ ID NO:3: LVPHLGDREK RDSVCPQGKY IHPQNNSICC TKCHKGTYLY NDCPGPGQDT DCRECESGSF TASENHLRHC LSCSKCRKEM GQVEISSCTV DRDTVCGCRK NQYRHYWSEN LFQCFNCSLC LNGTVHLSCQ EKQNTVCTCH AGFFLRENEC VSCSNCKKSL ECTKLCLPQI ENVKGTEDSG TTVLLPLVIF FGLCLLSLLF IGLMYRYQRW KSKLYSIVCG KSTPEKEGEL EGTTTKPLAP NPSFSPTPGF TPTLGFSPVP SSTFTSSSTY TPGDCPNFAA PRREVAPPYQ GADPILATAL ASDPIPNPLQ KWEDSAHKPQ SLDTDDPATL YAVVENVPPL RWKEFVRRLG LSDHEIDRLE LQNGRCLREA QYSMLATWRR RTPRREATLE LLGRVLRDMD LLGCLEDIEE ALCGPAALPP APSLLR (SEQ ID NO:3).

[0073] Binding of the compounds disclosed herein to one or more residues of SEQ ID NO:1 of TNFR1 inhibit the downstream activity of the TNFR1. As used herein, binding of the compound to the binding pocket that inhibits TNFR1 activity will be made with reference to SEQ ID NO:1. However, it will be understood by one of skill in the art that the same binding pocket is also present in SEQ ID NO:2 and SEQ ID NO:3. Thus, binding of the compounds disclosed herein will also inhibit downstream activity of a TNFR1 that comprises an amino acid sequence of SEQ ID NO:2 and SEQ ID NO:3. One of skill in the art will further understand that a particular numbered residue of SEQ ID NO:1, e.g., Ser118, also includes and refers to the same residue in SEQ ID NO:2 after accounting for the leading 29 amino acids of the signaling NAI-1542604160v1Attorney Ref. No.14463-061-228 sequence present in SEQ ID NO:2. That is, the amino acid in SEQ ID NO:2 that corresponds to Ser118 in SEQ ID NO:1 is Ser147. 7.2.1. TNFR1 Binding Pocket and Interaction Residues

[0074] In some aspects, provided herein are methods of inhibiting TNFR1-mediated activity by binding of a compound to a binding site of TNFR1. Other methods are contemplated and described elsewhere herein.

[0075] In some embodiments of the methods disclosed herein, TNFR1 is membrane-bound TNFR1. In some embodiments, the membrane-bound TNFR1 comprises an amino acid sequence according to SEQ ID NO:1. In some embodiments, the membrane-bound TNFR1 comprises an amino acid sequence according to SEQ ID NO:2. In some embodiments, the membrane-bound TNFR1 comprises an amino acid sequence according to SEQ ID NO:3. In some embodiments, the membrane-bound TNFR1 is present as a monomer one TNFR1 species. In some embodiments, the membrane-bound TNFR1 is present as a pre-assembled (e.g., not yet bound to a TNFL) dimer comprising two TNFR1 species. In some embodiments, the membrane-bound TNFR1 is present as a pre-assembled (e.g., not yet bound to a TNFL) trimer comprising three TNFR1 species.

[0076] In some embodiments, TNFR1 is sTNFR1. In some embodiments, the sTNFR1 comprises an amino acid sequence according to SEQ ID NO:1. As used herein, and unless otherwise indicated, reference to “TNFR1” includes either or both of membrane-bound TNFR1 and sTNFR1.

[0077] In some embodiments of the methods disclosed herein, the binding pocket of TNFR1 comprises one or more residues of SEQ ID NO:1. In some embodiments, the TNFR1 binding pocket is recognizable from the primary sequence, secondary structure, or tertiary structure of the amino acid sequence of the TNFR1. In some embodiments, the TNFR1 binding pocket is between two cysteine-rich domains (CRD) of SEQ ID NO:1. In some embodiments, the TNFR1 binding pocket is between CRD3 and CRD4 of SEQ ID NO:1. In some embodiments, the TNFR1 binding pocket is between CRD3 and CRD4 of SEQ ID NO:2. In some embodiments, the TNFR1 binding pocket is between CRD3 and CRD4 of SEQ ID NO:3. In some embodiments, the TNFR1 binding pocket is the TNFR1 binding pocket as shown in FIG.1. In some embodiments, the TNFR1 binding pocket is a binding pocket for a compound according to Formula (II), SEQ ID NO:6, 7, 8, 9, Compound A, B, C, D, or a pharmaceutically acceptable salt thereof, as described herein.

[0078] In some embodiments of the methods disclosed herein, the TNFR1 binding pocket comprises or consists of the amino acid residues of Asn134, Thr135, Cys137, and Asn148 of NAI-1542604160v1Attorney Ref. No.14463-061-228 SEQ ID NO:1. In some embodiments, the TNFR1 binding pocket comprises or further comprises the amino acid residues of Ser118 through Asn122 (e.g., Ser118-Leu119-Cys120- Leu121-Asn122) of SEQ ID NO:1. In some embodiments, the TNFR1 binding pocket comprises or further comprises the amino acid residues of Cys137 through Cys139 (e.g., Cys137-Thr138- Cys139) of SEQ ID NO:1. In some embodiments, the TNFR1 binding pocket comprises or further comprises the amino acid residues of Leu145 and Asn148 through Cys150 (e.g., Asn148- Glu149-Cys150) of SEQ ID NO:1. In some embodiments, the TNFR1 binding pocket comprises or consists of the amino acid residues of Ser118-Leu119-Cys120-Leu121-Asn122, Cys137- Thr138-Cys139, Leu145, and Asn148-Glu149-Cys150 of SEQ ID NO:1. In some embodiments, when a compound as described herein binds at a TNFR1 binding pocket, all of the residues recited for the TNFR1 binding pocket are bound by the compound. In some embodiments, when a compound as described herein binds at a TNFR1 binding pocket, one or more but not all of the residues recited for the TNFR1 binding pocket are bound by the compound. In some embodiments, the TNFR1 binding pocket further comprises additional TNFR1 residues, such as those additional residues of the TNFR1 binding pocket as described herein.

[0079] In some embodiments of the methods disclosed herein, the binding between a residue of the TNFR1 binding pocket and a compound as described herein is via a non-covalent interaction. In some embodiments, a non-covalent interaction as described herein may be donated by a residue of the binding pocket of the TNFR1 and accepted by the compound. In some embodiments, a non-covalent interaction as described herein may be donated by the compound and accepted by a residue of the binding pocket of the TNFR1. For example, a pi- effect interaction may involve a cation from the binding pocket (e.g., a hydrogen from the backbone of a residue of the binding pocket) being donated to and accepted by a pi orbital of the compound, to form a cation-pi interaction. Cation-pi interactions can occur between cationic side chains of either a lysine or arginine and an aromatic. In some embodiments, a residue of the TNFR1 binding pocket binds to a compound as described herein via a lipophilic interaction and / or hydrophobic interaction (e.g., minimization of non-polar surface area exposure to polar molecules). In some embodiments, a residue of the TNFR1 binding pocket binds to a compound as described herein via an electrostatic interaction (e.g., Coulombic attraction interaction). In some embodiments, a residue of the TNFR1 binding pocket binds to a compound as described herein via an ionic interaction (e.g., electrovalent interaction). In some embodiments, a residue of the TNFR1 binding pocket binds to a compound as described herein via an H-bond interaction (e.g., backbone or side chain H-bond interaction). In some embodiments, a residue of the TNFR1 binding pocket binds to a compound as described herein via a Van der Waals NAI-1542604160v1Attorney Ref. No.14463-061-228 interaction (e.g., a dipole-dipole interaction; dipole-induced dipole interaction; or London dispersion forces). In some embodiments, a residue of the TNFR1 binding pocket binds to a compound as described herein via a pi-effect interaction (e.g., a pi-pi interaction; CH-pi interaction; cation-pi interaction; anion-pi interaction; or polar-pi interaction) to a residue of the TNFR1. In some embodiments, a pi-effect interaction is a stacking interaction (e.g., a pi-pi interaction). In some embodiments, the pi-effect interaction is a non-polar pi-effect interaction. In some embodiments, a polar-pi interaction is a polar hydrogen-pi interaction. In some embodiments, a polar-pi interaction is a polar nitrogen-pi interaction. In some embodiments, a non-covalent interaction may be characterized as more than one type of non-covalent interaction as described herein.

[0080] In some embodiments of the methods disclosed herein, a residue of a TNFR1 binding pocket as described herein binds to a compound at a functional group of a compound. In some embodiments, the functional group of the compound is a functional group on the side chain or backbone moiety. In some embodiments, a functional group of the compound is an amino group (e.g., NH group, NH2group, or NH3+group), carbonyl group, carboxylate group, or a cyclic pi- system of the compound (e.g., an arene, aryl, biaryl, heteroaryl, or heterobiaryl). In some embodiments, the functional group of the compound is a carbonyl oxygen of the backbone. In some embodiments, the functional group of the compound is a hydrogen of a backbone amino group.

[0081] In some embodiments of the methods disclosed herein, the TNFR1 binding pocket comprises one or more of the amino acids corresponding to residues 134, 135, 137, and 148 of SEQ ID NO:1 and optionally one or more additional residue of SEQ ID NO:1. In some embodiments of the methods disclosed herein, the TNFR1 binding pocket comprises one or more of the amino acids corresponding to residues 118-122, 137-139, 145, and 148-150 of SEQ ID NO:1 and optionally one or more additional residue of SEQ ID NO:1. In some embodiments, the TNFR1 binding pocket is defined by one or more of amino acid residues Ser118, Leu119, Cys120, Leu121, Asn122, Cys137, Thr138, Cys139, Leu145, Asn148, Glu149, and Cys150 of TNFR1 (SEQ ID NO:1) and optionally one or more additional residue SEQ ID NO:1. In some embodiments, the one or more additional residue is selected from the group consisting of Asn134 and Thr135 of SEQ ID NO:1.

[0082] In some embodiments of the methods disclosed herein, the TNFR1 binding pocket comprises or consists of one or more amino acids corresponding to residues selected from 118, 119, 120, 122, 134, 135, 137, 138, 139, 145, 148, 149, and 150 of the TNFR1 (SEQ ID NO:1). In some embodiments, the TNFR1 binding pocket comprises or consists of one or more amino NAI-1542604160v1Attorney Ref. No.14463-061-228 acid residues selected from residues Ser118, Leu119, Cys120, Leu121, Asn122, Asn134, Thr235, Cys137, Thr138, Cys139, Leu145, Asn148, Glu149, and Cys150 of the TNFR1 (SEQ ID NO:1).

[0083] In some embodiments of the methods disclosed herein, the binding of the compound at the TNFR1 binding pocket to a specified residue is mediated by the backbone or side chain of the specified residue (e.g., a backbone NH, backbone carbonyl, or side chain functional group of the specified TNFR1 residue interacts with the compound). In some embodiments, one or more residues of the TNFR1 binding pocket mediates a non-covalent interaction with a compound as described herein. In some embodiments, one or more residues of the TNFR1 binding pocket mediates an interaction with a compound as described herein via a bridging water. In some embodiments, the one or more residues of TNFR1 mediating the interaction between the binding pocket and a compound as described herein is selected from Ser118, Leu119, Cys120, Leu121, Asn122, Cys137, Thr138, Cys139, Leu145, Asn148, Glu149, and Cys150 of the TNFR1 (SEQ ID NO:1).

[0084] In some embodiments of the methods disclosed herein, a residue of the TNFR1 binding pocket (e.g., Ser118, Leu119, Cys120, Leu121, Asn122, Cys137, Thr138, Cys139, Leu145, Asn148, Glu149, and / or Cys150 of SEQ ID NO:1) mediates a non-covalent interaction with a compound as described herein. In some embodiments, a residue of the TNFR1 binding pocket (e.g., Ser118, Leu119, Cys120, Leu121, Asn122, Cys137, Thr138, Cys139, Leu145, Asn148, Glu149, and / or Cys150 of SEQ ID NO:1) mediates a lipophilic interaction and / or hydrophobic interaction with a compound as described herein. In some embodiments, a residue of the TNFR1 binding pocket (e.g., Ser118, Leu119, Cys120, Leu121, Asn122, Cys137, Thr138, Cys139, Leu145, Asn148, Glu149, and / or Cys150 of SEQ ID NO:1) mediates an electrostatic interaction with a compound as described herein. In some embodiments, a residue of the TNFR1 binding pocket (e.g., Ser118, Leu119, Cys120, Leu121, Asn122, Cys137, Thr138, Cys139, Leu145, Asn148, Glu149, and / or Cys150 of SEQ ID NO:1) mediates an ionic interaction with a compound as described herein. In some embodiments, a residue of the TNFR1 binding pocket (e.g., Ser118, Leu119, Cys120, Leu121, Asn122, Cys137, Thr138, Cys139, Leu145, Asn148, Glu149, and / or Cys150 of SEQ ID NO:1) mediates an H-bond interaction with a compound as described herein. In some embodiments, a residue of the TNFR1 binding pocket (e.g., Ser118, Leu119, Cys120, Leu121, Asn122, Cys137, Thr138, Cys139, Leu145, Asn148, Glu149, and / or Cys150 of SEQ ID NO:1) mediates a Van der Waals interaction with a compound as described herein. In some embodiments, a residue of the TNFR1 binding pocket (e.g., Ser118, Leu119, Cys120, Leu121, Asn122, Cys137, Thr138, Cys139, Leu145, Asn148, Glu149, and / or Cys150 NAI-1542604160v1Attorney Ref. No.14463-061-228 of SEQ ID NO:1) mediates a Van der Waals interaction (e.g., a dipole-dipole interaction; dipole- induced dipole interaction; or London dispersion force) with a compound as described herein. In some embodiments, a residue of the TNFR1 binding pocket (e.g., Ser118, Leu119, Cys120, Leu121, Asn122, Cys137, Thr138, Cys139, Leu145, Asn148, Glu149, and / or Cys150 of SEQ ID NO:1) mediates a pi-effect interaction (e.g., a pi-pi interaction; CH-pi interaction; cation-pi interaction; anion-pi interaction; or polar-pi interaction) with a compound as described herein. In some embodiments of the methods disclosed herein, a residue of the TNFR1 binding pocket (e.g., Ser118, Leu119, Cys120, Leu121, Asn122, Cys137, Thr138, Cys139, Leu145, Asn148, Glu149, and / or Cys150 of SEQ ID NO:1) mediates an interaction with a compound as described herein via a bridging a water molecule. In some embodiments, a residue of the TNFR1 binding pocket (e.g., Ser118, Leu119, Cys120, Leu121, Asn122, Cys137, Thr138, Cys139, Leu145, Asn148, Glu149, and / or Cys150 of SEQ ID NO:1) mediates more than one non-covalent interaction as described herein, which may be of different types.

[0085] In some embodiments of the methods disclosed herein, residues of the TNFR1 binding pocket may mediate an H-bond interaction between the TNFR1 and a compound as described herein, either directly or indirectly through a bridging water.

[0086] In some embodiments of the methods disclosed herein, residue Asn134 of the TNFR1 mediates one or two H-bond interactions between the TNFR1 and a compound as described herein. In certain embodiments, residue Cys137 of SEQ ID NO:1 mediates one or two H-bond interactions between the TNFR1 and a compound as described herein. In certain embodiments, residue Asn148 of SEQ ID NO:1 mediates one or two H-bond interactions between the TNFR1 and a compound as described herein. In certain embodiments, residue Asn148 of SEQ ID NO:1 mediates one or two H-bond interactions between the TNFR1 and a compound as described herein. In certain embodiments, one or two of the H-bond interactions between the TNFR1 and a compound are via a bridging water. In certain embodiments, residue Thr135 of SEQ ID NO:1 mediates one or two H-bond interactions between the TNFR1 and a compound as described herein.

[0087] In some embodiments of the methods disclosed herein, the binding interactions between the TNFR1 and compound as described herein are as depicted in any one of figures disclosed herein. 7.3. Methods

[0088] The present disclosure provides a method of inhibiting TNFR1-mediated activity, comprising selectively contacting the TNFR1 with a compound as disclosed herein, such as in Section 7.4, that binds to TNFR1 at a binding pocket between CRD3 and CRD4 of the TNFR1, NAI-1542604160v1Attorney Ref. No.14463-061-228 wherein the binding pocket is defined according to any embodiment as disclosed herein, such as in Section 7.2.1. In some embodiments, the compound is a compound of Formula (II), SEQ ID NOs:6, 7, 8, 9, Compounds A, B, C, D, or a pharmaceutically acceptable salt of any of the foregoing.

[0089] In another aspect, the present disclosure provides a method of inhibiting oligomerization of two or more TNFR1 receptor species comprising contacting the TNFR1 with a compound disclosed herein, such as in Section 7.4, that competes for binding to the TNFR1 at a binding pocket between CRD3 and CRD4 of the TNFR1, wherein the binding pocket is defined according to any embodiment as disclosed herein, such as in Section 7.2.1. In some embodiments, the compound is a compound of Formula (II), SEQ ID NOs:6, 7, 8, 9, Compound A, B, C, D, or a pharmaceutically acceptable salt of any of the foregoing.

[0090] In another aspect, the present disclosure provides a method of inhibiting oligomerization of two or more TNFR1 receptor species comprising contacting the TNFR1 with a first compound that competes with a second compound for binding to the TNFR1 at a binding pocket between CRD3 and CRD4 of the TNFR1. In a specific embodiment, the second compound is any compound disclosed herein, such as in Section 7.4. In a specific embodiment, the binding pocket is defined according to any embodiment as disclosed herein, such as in Section 7.2.1. In some embodiments, the second compound is a compound of Formula (II), SEQ ID NOs:6, 7, 8, 9, Compound A, B, C, D, or a pharmaceutically acceptable salt of any of the foregoing.

[0091] In another aspect, the present disclosure provides method of inhibiting a TNFR1- mediated activity comprising contacting a first TNFR1 with a compound as disclosed herein, such as in Section 7.4, that inhibits interaction with a second TNFR1 with the first TNFR1. In some embodiments, the first TNFR1 is TNFL-bound TNFR1. In some embodiments, the secondTNFR1 is TNFL-bound TNFR1. In some embodiments, the TNFL is TNF .

[0092] In another aspect, the present disclosure provides method of inhibiting a TNFR1- mediated activity comprising contacting a first TNFR1 with a first compound that competes with a second compound for binding to the TNFR1 at a binding pocket between CRD3 and CRD4 of the TNFR1. In a specific embodiment, the second compound is any compound disclosed herein, such as in Section 7.4. In a specific embodiment, the binding pocket is defined according to any embodiment as disclosed herein, such as in Section 7.2.1. In some embodiments, the second compound is a compound of Formula (II), SEQ ID NOs:6, 7, 8, 9, Compound A, B, C, D, or a pharmaceutically acceptable salt of any of the foregoing. In certain embodiments, the first compound inhibits interaction of a second TNFR1 with the first TNFR1. In some embodiments, NAI-1542604160v1Attorney Ref. No.14463-061-228 the first TNFR1 is TNFL-bound TNFR1. In some embodiments, the second TNFR1 is TNFL-bound TNFR1. In some embodiments, the TNFL is TNF .

[0093] In another aspect, the present disclosure provides method of inhibiting a TNFL- mediated activity comprising contacting a TNFR1 with a compound as disclosed herein, such as in Section 7.4, that inhibits interaction with a second TNFR1 with the first TNFR1. In some embodiments, the first TNFR1 is TNFL-bound TNFR1. In some embodiments, the secondTNFR1 is TNFL-bound TNFR1. In some embodiments, the TNFL is TNF .

[0094] In another aspect, the present disclosure provides method of inhibiting a TNFL- mediated activity comprising contacting a first TNFR1 with a first compound that competes with a second compound for binding to the TNFR1 at a binding pocket between CRD3 and CRD4 of the TNFR1. In a specific embodiment, the second compound is any compound disclosed herein, such as in Section 7.4. In a specific embodiment, the binding pocket is defined according to any embodiment as disclosed herein, such as in Section 7.2.1. In some embodiments, the second compound is a compound of Formula (II), SEQ ID NOs:6, 7, 8, 9, Compound A, B, C, D, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the TNFL isTNF .

[0095] In another aspect, the present disclosure provides a method of inhibiting oligomerization of two or more TNFR1 receptor species comprising contacting a first TNFR1 with a compound, with a compound as disclosed herein, such as in Section 7.4, that inhibits the interaction of the first TNFR1 with a second TNFR1. In some embodiments, the first TNFR1 is TNFL-bound TNFR1. In some embodiments, the second TNFR1 is TNFL-bound TNFR1. Insome embodiments, the TNFL is TNF .

[0096] In another aspect, the present disclosure provides a method of inhibiting oligomerization of two or more TNFR1 receptor species comprising contacting a first TNFR1 with a first compound that competes with a second compound for binding to the TNFR1 at a binding pocket between CRD3 and CRD4 of the TNFR1. In a specific embodiment, the second compound is any compound disclosed herein, such as in Section 7.4. In a specific embodiment, the binding pocket is defined according to any embodiment as disclosed herein, such as in Section 7.2.1. In some embodiments, the second compound is a compound of Formula (II), SEQ ID NOs:6, 7, 8, 9, Compound A, B, C, D, or a pharmaceutically acceptable salt of any of the foregoing. In certain embodiments, the first compound inhibits interaction of a second TNFR1 with the first TNFR1. In some embodiments, the first TNFR1 is TNFL-bound TNFR1. In some embodiments, the second TNFR1 is TNFL-bound TNFR1. In some embodiments, the TNFL is NAI-1542604160v1Attorney Ref. No.14463-061-228TNF . In some embodiments, the first TNFR1 is TNFL-bound TNFR1. In some embodiments,the second TNFR1 is TNFL-bound TNFR1. In some embodiments, the TNFL is TNF .

[0097] As used herein, TNFR1-mediated activity refers to any downstream biologicalactivity of TNFR1 activation by any TNFL (including TNF ) including, but not limited to,inflammation, cytokine signaling, apoptosis, cell proliferation, cell survival, cell differentiation,MAPK signaling, NF- B signaling, and any combination thereof. As used herein, reference tothe compound binding to TNFR1 also encompasses binding to sTNFR1.

[0098] In certain embodiments, the compound binds the TNFR1 at a binding pocket, wherein the binding of the compound to the binding pocket blocks the TNFR1-mediated activity. In certain embodiments, the compound binds to the extracellular domain of TNFR1. In certain embodiments, the compound binds to sTNFR1. In certain embodiments, the compoundor does not bind to TNFR1 in the binding pocket specific for the ligand of TNFR1 (e.g., TNF ).In certain embodiments, the compound binds to the TNFR1 at a region distinct from where theligand of TNFR1 (e.g., TNF ) binds. In certain embodiments, the binding of the compound tothe TNFR1 is non-competitive with the binding of the ligand of TNFR1 (e.g., TNF ). In certainembodiments, the compound binds to TNFR1 at an interface of a first TNFR1 that interacts with a second TNFR1 once each of the first and second TNFR1 is bound by a ligand of TNFR1 (e.g.,TNF ). In certain embodiments, the interface is a clustering interface. In certain embodiments,the compound blocks a second TNFL-bound TNFR1 from binding to or interacting with the first TNFL-bound TNFR1. In some embodiments, the compound binds to a binding pocket located between CRD3 and CRD4 of TNFR1. In some embodiments, the binding of the compound to the TNFR1 at the binding pocket inhibits oligomerization or clustering of TNFR1. In certain embodiments, the compound binds to a binding pocket as disclosed in Section 7.2.1 herein.

[0099] In certain embodiments, binding of the compound as disclosed herein to TNFR1 disrupts the interaction between TNFL-bound TNFR1 receptor species. In certain embodiments, binding of the compound as disclosed herein to TNFR1 inhibits the interaction between TNFL- bound TNFR1 monomers. In certain embodiments, binding of the compound as disclosed herein to TNFR1 prevents interaction between TNFL-bound TNFR1 receptor species. In some embodiments, binding of the compound as disclosed herein to TNFR1 prevents oligomerization of TNFR1 upon binding by a TNFL to the TNFR1.

[0100] In some embodiments of the methods described herein, the compound is a compound as disclosed herein, such as in Section 7.4. In some embodiments, the compound is a compound of Formula (II), SEQ ID NOs:6, 7, 8, 9, Compound A, B, C, D, or a pharmaceutically acceptable salt of any of the foregoing. NAI-1542604160v1Attorney Ref. No.14463-061-228 7.4. Compounds that Bind to TNFR1

[0101] In certain aspects of the various methods provided herein, the present disclosure compounds are provided that bind to a binding pocket of the TNFR1. Exemplary compounds are described in any embodiment in Section 7.2.1. In certain embodiments, the compound does notbind to TNFR1 in the binding pocket specific for ligand of TNFR1 (e.g., TNF ). In certainembodiments, the compound does not bind to a binding pocket of TNFR1 located between cysteine rich domain 2 (CRD2) and CRD3. In certain embodiments, the compound binds to an interface, for example, a clustering interface, of TNFR1. In certain embodiments, the compound binds to TNFR1 between CRD3 and CRD4 of TNFR1. In certain embodiments, the TNFR1 binding pocket is defined by amino acid residues Asn134, Thr135, Cys137, and Asn148 of SEQ ID NO:1. In certain embodiments, the TNFR1 binding pocket is defined or further defined by amino acid residues Ser118 through Asn122, Cys137 through Cys139, and Asn148 through Cys150 of SEQ ID NO:1. In certain embodiments, the TNFR1 binding pocket is defined or further defined by amino acid residues Cys137 through Cys139, Leu145, and Asn148 through Cys150 of SEQ ID NO:1. In certain embodiments, the TNFR1 binding pocket is defined or further by amino acid residues Cys137 through Cys139 and Asn148 through Cys150 of SEQ ID NO:1. In certain embodiments, the TNFR1 binding pocket is defined or further defined by amino acid residues Ser118 through Asn122, Cys137 through Cys139, Leu145, and Asn148 through Cys150 of SEQ ID NO:1. In certain embodiments, the compound binds to TNFR1 at one or more of residues Asn134, Thr135, Cys137, and Asn148 of SEQ ID NO:1. In certain embodiments, the compound binds to TNFR1 at two or more of residues Asn134, Thr135, Cys137, and Asn148 of SEQ ID NO:1. In certain embodiments, the compound binds to TNFR1 at three or more of residues Asn134, Thr135, Cys137, and Asn148 of SEQ ID NO:1. In certain embodiments, the compound binds to TNFR1 at each of residues Asn134, Thr135, Cys137, and Asn148 of SEQ ID NO:1.

[0102] In some embodiments of the methods disclosed herein, a compound as described herein inhibits oligomerization of a TNFL-bound TNFR1, which inhibits one or more biological functions of the TNFR1. In some embodiments, a compound as described herein blocks the interface of a first TNFL-bound TNFR1 at which a second TNFL-bound TNFR1 would otherwise bind to form an oligomeric TNFR1 cluster, which inhibits one or more biological functions of one or both of the first and second TNFL-bound TNFR1. In some embodiments, the blocking is a steric blocking. In some embodiments, a compound as described herein binds to a first TNFL-bound TNFR1 between CRD3 and CRD4, which blocks an interface of the first TNFL-bound TNFR1 at which a second TNFL-bound TNFR1 would otherwise bind to form an o NAliIg-1o5m426e0r4i1c60 Tv1NFR1 cluster, and in turn, inhibits one or more biological functions of TNFR1. InAttorney Ref. No.14463-061-228 some embodiments, the biological function of TNFR1 is inflammation (e.g., in a subject). In some embodiments, the biological function of TNFR1 is cytokine signaling. In some embodiments, the biological function of TNFR1 is apoptosis. In some embodiments, the biological function of TNFR1 is necroptosis. In some embodiments, the biological function of TNFR1 is cell proliferation. In some embodiments, the biological function of TNFR1 is cell survival. In some embodiments, the biological function of TNFR1 is cell differentiation. In some embodiments, the biological function of TNFR1 is MAPK signaling. In some embodiments, thebiological function of TNFR1 is NF- B signaling.

[0103] In certain embodiments of the methods provided herein, the compound that binds to TNFR1 as disclosed herein comprises a peptide. In certain embodiments, the compound that binds to TNFR1 as disclosed herein is a peptide. In some embodiments, the compound is cyclic. In certain embodiments, the compound is a cyclic peptide.

[0104] In certain embodiments of the methods provided herein, the cyclic peptide comprises or consists of an amino acid sequence having a length of from 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 comprises or consists of an amino acid sequence having a length of from 10 to 24 amino acid residues. In some embodiments, the cyclic peptide comprises or consists of an amino acid sequence having a length of from 11 to 20 amino acid residues. In some embodiments, the cyclic peptide comprises or consists of an amino acid sequence having a length of from 11 to 18 amino acid residues. In some embodiments, the cyclic peptide comprises or consists of an amino acid sequence having a length of from 11 to 17 amino acid residues. In some embodiments, the cyclic peptide comprises or consists of an amino acid sequence having a length of from 12 to 16 amino acid residues. In some embodiments, the cyclic peptide comprises or consists of an amino acid sequence having a length of from 13 to 15 amino acid residues. In some embodiments, the cyclic peptide comprises or consists of an amino acid sequence having a length of 12 amino acids. In some embodiments, the cyclic peptide comprises or consists of an amino acid sequence having a length of 13 amino acids. In some embodiments, the cyclic peptide comprises or consists of an amino acid sequence having a length of 14 amino acids. In certain embodiments, the cyclic peptide comprises or consists of an amino acid sequence having a length of 15 amino acids. In some embodiments, the cyclic peptide comprises or consists of an amino acid sequence having a length of 16 amino acids. In certain embodiments, the compound further comprises a non-peptidic linker.

[0105] In certain embodiments of the methods provided herein, the compound is a macrocyclic peptide. In some embodiments, the macrocyclic peptide comprises or consists of an NAI-1542604160v1Attorney Ref. No.14463-061-228 amino acid sequence having a length of from 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 comprises or consists of an amino acid sequence having a length of from 10 to 24 amino acid residues. In some embodiments, the macrocyclic peptide comprises or consists of an amino acid sequence having a length of from 11 to 20 amino acid residues. In some embodiments, the macrocyclic peptide comprises or consists of an amino acid sequence having a length of from 12 to 16 amino acid residues. In some embodiments, the macrocyclic peptide comprises or consists of an amino acid sequence having a length of from 13 to 15 amino acid residues. In some embodiments, the macrocyclic peptide comprises or consists of an amino acid sequence having a length of 12 amino acids. In some embodiments, the macrocyclic peptide comprises or consists of an amino acid sequence having a length of 13 amino acids. In some embodiments, the macrocyclic peptide comprises or consists of an amino acid sequence having a length of 14 amino acids. In certain embodiments, the macrocyclic peptide comprises or consists of an amino acid sequence having a length of 15 amino acids. In some embodiments, the macrocyclic peptide comprises or consists of an amino acid sequence having a length of 16 amino acids. In certain embodiments, the compound further comprises a non-peptidic linker.

[0106] In some embodiments, the compound is a compound as described herein. In some embodiments, a compound as described herein that binds to TNFR1 at a binding pocket as described herein is a lipophilic compound comprising one or more lipophilic moieties. In some embodiments, a compound as described herein that binds to TNFR1 at a binding pocket as described herein is hydrophobic compound comprising one or more hydrophobic moieties.

[0107] In certain embodiments of the methods provided herein, the compound that binds to TNFR1 as disclosed herein has a molecular weight of from about 1200 Da to about 3000 Da. In certain embodiments, the compound has a molecular weight of from about 1200 Da to about 2500 Da. In certain embodiments, the compound has a molecular weight of from about 1200 Da to about 2250 Da. In certain embodiments, the compound has a molecular weight of from about from about 1500 Da to 2250 Da. In certain embodiments, the compound has a molecular weight of from about from about 1500 Da to 2500 Da. In certain embodiments, the compound has a molecular weight of from about from about 1500 Da to 3000 Da. In certain embodiments, the compound has a molecular weight of from about 1750 Da to about 3000 Da. In certain embodiments, the compound has a molecular weight of from about 1750 Da to about 2500 Da. In certain embodiments, the compound has a molecular weight of from about 1750 Da to about 2250 Da. NAI-1542604160v1Attorney Ref. No.14463-061-228

[0108] In certain embodiments of the methods provided herein, the compound that binds to TNFR1 as disclosed herein comprises one or more moieties selected from: (a) an H-bond interaction moiety capable of accepting an H-bond from the side chain of residue Asn148 of the TNFR1; (b) an H-bond interaction moiety capable of donating an H-bond to the side chain of residue Asn148 of the TNFR1; (c) an H-bond interaction moiety capable of accepting an H-bond from the backbone of residue Cys137 of the TNFR1; and (d) an H-bond interaction moiety capable of donating an H-bond to the backbone of residue Cys137 of the TNFR1.

[0109] In certain embodiments of the methods provided herein, the compound that binds to TNFR1 as disclosed herein comprises one or more moieties selected from: (a) an H-bond interaction moiety capable of donating an H-bond to the backbone of residue Thr135 of the TNFR1; and (b) an H-bond interaction moiety capable of accepting an H-bond from the sidechain residue Asn134 of the TNFR1.

[0110] In certain embodiments of the methods provided herein, the compound that binds to TNFR1 as disclosed herein comprises an H-bond interaction moiety capable of accepting an H- bond from the side chain of residue Asn134 (e.g., the side chain amine of residue Asn134) of SEQ ID NO:1. In certain embodiments, the compound comprises an H-bond interaction moiety capable of donating an H-bond to the side chain of residue Asn134 (e.g., the side chain aminocarbonyl oxygen of residue Asn134 of TNFR1) of SEQ ID NO:1.

[0111] In certain embodiments, the compound comprises an H-bond interaction moiety capable of donating an H-bond to the backbone of residue Thr135 (e.g., the carbonyl oxygen of the backbone of residue Thr135 of TNFR1) of SEQ ID NO:1.

[0112] In certain embodiments, the compound comprises an H-bond interaction moiety capable of accepting an H-bond from the backbone of residue Cys137 (e.g., the amide nitrogen of the backbone of residue Cys137 of TNFR1) of SEQ ID NO:1. In certain embodiments, the compound comprises an H-bond interaction moiety capable of donating an H-bond to the backbone of residue Cys137 (e.g., the carbonyl oxygen of the backbone of residue Cys137 of TNFR1) of SEQ ID NO:1.

[0113] In certain embodiments of the methods provided herein, the compound that binds to TNFR1 as disclosed herein comprises an H-bond interaction moiety capable of accepting an H- bond from the side chain of residue Asn148 (e.g., the side chain amine of residue Asn148 of NAI-1542604160v1Attorney Ref. No.14463-061-228 TNFR1) of SEQ ID NO:1. In certain embodiments, the compound comprises an H-bond interaction moiety capable of donating an H-bond to the side chain of residue Asn148 (e.g., the side chain aminocarbonyl oxygen of residue Asn148 of TNFR1) of SEQ ID NO:1.

[0114] In certain embodiments of the methods provided herein, the compound comprises two or more of the H-bond interaction moieties described above. In certain embodiments of the methods provided herein, the compound comprises three or more of the H-bond interaction moieties described above. In certain embodiments of the methods provided herein, the compound comprises four or more of the H-bond interaction moieties described above. In certain embodiments of the methods provided herein, the compound comprises five or more of the H-bond interaction moieties described above. In certain embodiments of the methods provided herein, the compound comprises six or more of the H-bond interaction moieties described above. In certain embodiments of the methods provided herein, the compound comprises all of the H-bond interaction moieties described above.

[0115] As used herein, the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, and thirteenth amino acids of the compound are as depicted with reference to Formula (II) in FIG.2.

[0116] In certain embodiments of the methods provided herein, the compound binds to the TNFR1 binding pocket according to any embodiment disclosed herein via an aliphatic or aliphatic-aryl (e.g., alkyl or aryl-alkyl) side chain on the first amino acid residue of the compound. In certain embodiments, the compound binds to the TNFR1 binding pocket according to any embodiment disclosed herein via a bicyclic aryl or heteroaryl moiety of an eighth amino acid of the compound. In certain embodiments, the compound binds to the TNFR1 binding pocket according to any embodiment disclosed herein via an hydroxymethyl moiety of a ninth amino acid of the compound. In certain embodiments, the compound binds to the TNFR1 binding pocket according to any embodiment disclosed herein via two or three moieties selected from the group consisting of an aliphatic (e.g., alkyl) or aliphatic-aryl (e.g., aryl-alkyl) side chain on the first amino acid residue of the compound, a bicyclic aryl or heteroaryl moiety of the eighth amino acid of the compound, a hydroxymethyl moiety of the ninth amino acid of the compound, and an aryl moiety of the tenth amino acid of the compound.

[0117] In certain embodiments of the methods provided herein, the H-bond interaction moiety capable of accepting an H-bond from the amino hydrogen of the backbone of residue Cys137 of TNFR1 is present on the backbone or side chain of the eighth amino acid of the compound. In certain embodiments, the H-bond interaction moiety capable of donating an H- bond to the carbonyl oxygen of the backbone of residue Cys137 of TNFR1 is present on the NAI-1542604160v1Attorney Ref. No.14463-061-228 backbone or side chain of the eighth amino acid of the compound. In certain embodiments, the eighth amino acid of the compound is 3-(2-naphthyl)-L-alanine (2Nal), (S)-2-amino-3-(7-chloro- 1H-indol-3-yl)propanoic acid (Trp7Cl), or L-tryptophan (W).

[0118] In certain embodiments of the methods provided herein, the H-bond interaction moiety capable of accepting an H-bond from the side chain of residue Asn134 of the TNFR1 is present on the backbone or side chain of the tenth amino acid of the compound. In certain embodiments, the H-bond interaction moiety capable of accepting an H-bond from the side chain of residue Asn134 of the TNFR1 is a carbonyl moiety. In certain embodiments, the H- bond interaction moiety capable of accepting an H-bond from the side chain of residue Asn134 of the TNFR1 is a carboxylate-substituted or hydroxy-substituted phenyl moiety. In certain embodiments, the tenth amino acid of the compound is L-tyrosine (Y) or L-phenylalanine-4- carboxylic acid (Phe4COOH).

[0119] In certain embodiments of the methods provided herein, the H-bond interaction moiety capable of accepting an H-bond from the side chain of residue Asn148 of the TNFR1 is present on the backbone or side chain of the third amino acid of the compound. In certain embodiments, the H-bond interaction moiety capable of donating an H-bond to the side chain of residue Asn148 of the TNFR1 is present on the backbone or side chain of the third amino acid of the compound. In certain embodiments, the H-bond interaction moiety capable of donating an H-bond to Asn148 comprises a hydroxyl moiety or an amine moiety. In certain embodiments, the H-bond interaction moiety capable of donating an H-bond to Asn148 comprises an hydroxyalkyl moiety. In certain embodiments, the third amino acid of the compound is (S)- piperazine-2-carboxylic acid (Pip2c), (S)-piperidine-2-carboxylic acid (Pip), or L-serine (S).

[0120] In certain embodiments of the methods provided herein, an H-bond interaction moiety capable of donating an H-bond to the backbone of residue Thr135 of SEQ ID NO:1 is present on the backbone or side chain of the ninth amino acid of the compound. In certain embodiments, the H-bond interaction moiety capable of donating an H-bond to the carbonyl oxygen of the backbone of residue Thr135 of SEQ ID NO:1 comprises a hydroxyl moiety. In certain embodiments, the H-bond interaction moiety capable of donating an H-bond to the carbonyl oxygen of the backbone of residue Thr135 of SEQ ID NO:1 comprises an hydroxyalkyl moiety, for example an hydroxymethyl moiety. In certain embodiments, the ninth amino acid of the compound is -methyl-L-serine (aMeS) or L-serine (S).

[0121] In certain embodiments, the thirteenth amino acid of the compound is -methyl-L- tryptophan (aMeW), L-tryptophan (W), or (2S,3S)-2-amino-3-(7-methoxy-1H-indol-3- yl)butanoic acid (SbMeW7OMe). NAI-1542604160v1Attorney Ref. No.14463-061-228

[0122] In certain embodiments of the methods provided herein, the first amino acid comprises an aliphatic side chain or aryl-containing side chain. In certain embodiments, the first amino acid comprises a C1-6 alkyl side chain or a C1-3 alkylaryl side chain. In certain embodiments, the first amino acid comprises a methyl, ethyl, propyl, butyl moiety. In certain embodiments, the side chain of the first amino acid is propyl. In certain embodiments, the side chain of the first amino acid is butyl. In certain embodiments, the side chain of the first amino acid is substituted with a monocyclic aryl moiety (e.g., phenyl). In certain embodiments, the side chain of the first amino acid is phenyl. In certain embodiments, the first amino acid of the compound is L-norleucine (Nle), L-phenylalanine (F), or (S)-2-(amino)heptanoic acid (Ahp).

[0123] In certain embodiments of the methods provided herein, the eighth amino acid comprises a side chain comprising an optionally substituted bicyclic aryl or heteroaryl moiety. In certain embodiments, the eighth amino acid comprises a side chain comprising an optionally substituted indolyl or naphthyl moiety. In certain embodiments, the eighth amino acid of the compound is L-tryptophan (W), 3-(2-naphthyl)-L-alanine (2Nal), or (S)-2-amino-3-(7-chloro- 1H-indol-3-yl)propanoic acid (Trp7Cl).

[0124] In certain embodiments, the tenth amino acid comprises a side chain comprising substituted or unsubstituted benzyl. In certain embodiments, the side chain of the tenth amino acid comprises benzyl substituted with a carboxylic acid (–COOH) moiety. In certain embodiments, the side chain of the tenth amino acid comprises benzyl para-substituted with a carboxylic acid (–COOH) moiety. In certain embodiments, the side chain of the tenth amino acid comprises benzyl substituted with a hydroxyl (–OH) moiety. In certain embodiments, the side chain of the tenth amino acid comprises benzyl para-substituted with a hydroxyl (–OH) moiety. In certain embodiments, the tenth amino acid of the compound is L-tyrosine (Y), or (S)- 4-(2-amino-2-carboxyethyl)benzoic acid (Phe4COOH).

[0125] Without being bound by theory, it is believed that binding of the compounds to TNFR1 leads to a conformational change of an interface of a first TNFL-bound TNFR1 trimer:trimer complex at which a second TNFL-bound TNFR1 trimer:trimer complex would otherwise bind or interact to form an oligomeric TNFL-bound TNFR1 cluster. For example, such conformational changes can lead to steric inhibition of the binding of the second TNFL- bound TNFR1 trimer:trimer complex to the first TNFL-bound TNFR1. This conformational change effectively inhibits oligomerization of the first and second TNFR1 receptor species. Inhibition of oligomerization, in turn, inhibits TNFR1-mediated activity that would otherwise occur if the TNFR1 monomers had proceeded to oligomerize. In some embodiments, TNFR1- mediated activity is inflammation, cytokine signaling, apoptosis, necroptosis, cell proliferation, NAI-1542604160v1Attorney Ref. No.14463-061-228cell survival, cell differentiation, MAPK signaling, NF- B signaling, or any combinationthereof. In some embodiments, TNFR1-mediated activity is inflammation. In some embodiments, TNFR1-mediated activity is cytokine signaling. In some embodiments, TNFR1- mediated activity is apoptosis. In some embodiments, TNFR1-mediated activity is necroptosis. In some embodiments, TNFR1-mediated activity is cell proliferation. In some embodiments, TNFR1-mediated activity is cell survival. In some embodiments, TNFR1-mediated activity is cell differentiation. In some embodiments, TNFR1-mediated activity is MAPK signaling. Insome embodiments, TNFR1-mediated activity is NF- B signaling, or any combination thereof.

[0126] In certain embodiments of the methods provided herein, the compound that binds to TNFR1 comprises an amino acid sequence, wherein the first amino acid in the sequence comprises an aliphatic or aryl-alkyl moiety. In certain embodiments, the third amino acid in the sequence comprises a hydroxyl moiety or an amine moiety. In certain embodiments, the eighth amino acid in the sequence comprises an optionally substituted bicyclic aryl or heteroaryl moiety. In certain embodiments, the ninth amino acid in the sequence comprises an hydroxymethyl moiety. In certain embodiments, the tenth amino acid in the sequence comprises an optionally substituted aryl moiety.

[0127] In certain embodiments of the methods provided herein, the compound that binds to TNFR1 comprises an amino acid sequence, wherein: the first amino acid in the sequence comprises an alkyl or aryl-alkyl moiety; the third amino acid in the sequence comprises a hydroxyl moiety or an amine moiety; the eighth amino acid in the sequence comprises a bicyclic aryl or bicyclic heteroaryl moiety; the ninth amino acid in the sequence comprises a hydroxymethyl moiety; and the tenth amino acid in the sequence comprises an aryl-methyl moiety.

[0128] In certain embodiments of the methods provided herein, the compound that binds to TNFR1 comprises an amino acid sequence, wherein: the first amino acid in the sequence comprises a C1-6 alkyl or aryl(C0-3 alkyl) moiety (e.g., pentyl, butyl or benzyl); the third amino acid in the sequence comprises an hydroxymethyl moiety, a piperidinyl moiety, or a piperazinyl moiety; the eighth amino acid in the sequence comprises a naphthyl, indolyl, naphthylmethyl or indolylmethyl moiety; the ninth amino acid in the sequence comprises an hydroxymethyl moiety; and NAI-1542604160v1Attorney Ref. No.14463-061-228 the tenth amino acid in the sequence comprises a substituted benzyl moiety (e.g., phenyl substituted (e.g., para-substituted) with a hydroxyl moiety or a carboxylic acid moiety).

[0129] In certain embodiments of the methods provided herein, the compound that binds to TNFR1 comprises an amino acid sequence, wherein: the first amino acid in the sequence comprises (S)-2-aminoheptanoic acid, L-norleucine, or L-phenylalanine; the third amino acid in the sequence comprises (S)-piperazine-2-carboxylic acid, (S)- piperidine-2-carboxylic acid, or L-serine; the eighth amino acid in the sequence comprises 3-(2-naphthyl)-L-alanine, (S)-2-amino- 3-(7-chloro-1H-indol-3-yl)propanoic acid, or L-tryptophan; the ninth amino acid in the sequence comprises -methyl-L-serine or L-serine; and the tenth amino acid in the sequence comprises L-tyrosine or L-phenylalanine-4- carboxylic acid.

[0130] In certain embodiments of the methods provided herein, the compound that binds to TNFR1 comprises an amino acid sequence according to SEQ ID NO:6: ClAc*-Ahp-4Pal-S- SbMeW-dP-N-Phe4COOH-2Nal-aMeS-Phe4COOH-H-Sar-aMeW-C*-NH2 (SEQ ID NO:6) or pharmaceutically acceptable salt thereof, wherein * indicates attachment to form a cyclic peptide, and where each moiety is described herein, e.g., in Table 1.

[0131] In certain embodiments of the methods provided herein, the compound that binds to TNFR1 comprises an amino acid sequence according to SEQ ID NO:7: Nle*-4Pal-Pip2c-W- NMeE-N-Phe4COOH-Trp7Cl-aMeS-Phe4COOH-Y-Sar-SbMeW7OMe-bhcLeu* (SEQ ID NO:7) or pharmaceutically acceptable salt thereof, wherein * indicates attachment to form a cyclic peptide, and where each moiety is described herein, e.g., in Table 1.

[0132] In certain embodiments of the methods provided herein, the compound that binds to TNFR1 comprises an amino acid sequence according to SEQ ID NO:8: Nle*-4Pal-Pip-W- NMeE-N-4Pal-Trp7Cl-aMeS-Phe4COOH-Phe3CONH2-Sar-SbMeW7OMe-bhcLeu* (SEQ ID NO:8) or pharmaceutically acceptable salt thereof, wherein * indicates attachment to form a cyclic peptide, and where each moiety is described herein, e.g., in Table 1.

[0133] In certain embodiments of the methods provided herein, the compound that binds to TNFR1 comprises an amino acid sequence according to SEQ ID NO:9: ClAc*-F-Y-S-W-Sar-N- Y-W-S-Y-Y-Sar-W-C*-G-E-E-NH2 (SEQ ID NO:9) or pharmaceutically acceptable salt thereof, wherein * indicates attachment to form a cyclic peptide, and where each moiety is described herein, e.g., in Table 1. NAI-1542604160v1Attorney Ref. No.14463-061-228

[0134] In certain embodiments of the methods provided herein, the compound is a compound of Formula (I) or a pharmaceutically acceptable salt thereof:is selected from hydrogen, C1-10 alkyl, (C1-6 alkyl)0-2 amino(C0-10 alkyl), (C1-6 alkyl)0-2amino(C0-10alkyl)oxy(C0-6alkyl), (C1-6alkyl)3N+(C0-6alkyl), aryl(C0-10alkyl), heteroaryl(C0-10alkyl), (C3-12)cycloalkyl(C0-10alkyl), heterocycloalkyl(C0-10alkyl), C1-10fluoroalkyl, C2-10alkenyl, (C0-6alkyl)carbonylamino(C0-6alkyl), (C0-6alkyl)0-2aminocarbonyl(C0-6alkyl), (C1-6alkyl)0-2 aminocarbonylamino(C0-6alkyl), arylcarbonylamino(C0-6alkyl), arylaminocarbonyl(C0-6alkyl), heteroarylcarbonylamino(C0-6alkyl), heteroarylaminocarbonyl(C0-6alkyl), C1-6alkyloxy, (C1-6alkyl)oxy(C0-6alkyl), ((C3-12)cycloalkyl)oxy(C0-6alkyl), ((C3-12)cycloalkyl C0-6alkyl)oxy(C0-6alkyl), (C0-6alkyl)carboxy(C0-6alkyl), N-=N+=N–(C0-6alkyl), and H2N– C(=NH)NH–(C0-6alkyl),wherein R1is substituted by 0, 1, 2, 3, or 4 R1asubstituents each independently selectedfrom C1-6alkyl,cyano, halo,and C1-6alkyloxy; each R2ais independently selected from hydrogen, hydroxy, C1-4 alkyl, fluoro, and C1-4alkyloxy; R2bis selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein saidheteroaryl contains at least one nitrogen atom, wherein R2bis substituted by 0, 1, or 2 R2cindependently selected from C1-6 alkyl,amino(C0-6alkyl), (C1-6alkyl)0-2 amino(C0-6alkyl), (C1-6alkyl)3N+(C0-6alkyl), aminocarbonyl(C0-6alkyl), (C1-6alkyl)0-2 aminocarbonyl(C0-6alkyl), hydroxy, C1-6alkyloxy, halo, (C1-6alkyl)0-2 NAI-1542604160v1Attorney Ref. No.14463-061-228 amino(C0-6alkyloxy), (C1-6alkyl)3N+(C0-6alkyloxy), (C1-6alkyloxy)carbonyl(C0-6alkyl), carboxy(C0-6alkyl), carboxy(C1-6alkyl)oxy(C0-6alkyl), C1-6haloalkyl, C1-6haloalkyloxy, and C1-6alkyloxy; R3ais selected from hydrogen, hydroxy, hydroxy(C1-6 alkyl), amino, amino(C1-6 alkyl),C1-10alkyl, (C3-12)cycloalkyl(C0-10alkyl), (C0-6alkyl)thio(C1-6alkyl), and carboxy(C1-6alkyl),wherein R3amay be substituted by 0, 1, or 2 R3csubstituents;R3bis selected from hydrogen, C1-10 alkyl, hydroxy(C1-6 alkyl), amino(C1-10 alkyl), (C1-6alkyl)0-2 amino(C1-10alkyl), (C1-6alkyl)3N+(C1-6alkyl), C1-6haloalkyl, aryl(C0-10alkyl), heteroaryl(C0-10alkyl), (C3-12)cycloalkyl(C0-10alkyl), heterocycloalkyl(C0-10alkyl), (C1-6alkyl)oxy(C1-6alkyl), (C3-12)cycloalkyloxy(C1-6alkyl), carboxy(C1-6alkyl), aminocarbonyl(C1-6alkyl), (C1-6alkyl)0-2 aminocarbonyl(C1-6alkyl), aminocarbonylamino(C1-6alkyl), (C1-6alkyl)0-2 aminocarbonylamino(C1-6alkyl), (C0-6alkyl)thio(C1-6alkyl), (C1-6alkyl)SO2(C1-6alkyl), and (C1-6alkyl)sulfinyl(C1-6 alkyl), wherein R3bmay be substituted by 0, 1, or 2 R3csubstituents;each R3cis independently selected from halo, C1-6 alkyl, amino, (C1-6 alkyl)0-2 amino(C0-6alkyl), (C1-3N+–, (C1-6alkyl)SO2(C0-6alkyl), cyano, cyano(C1-6alkyl), hydroxy, hydroxy(C1-6alkyl), (C1-6alkyl)oxy(C0-6alkyl), aminocarbonyl(C0-6alkyl), and (C0-6)carboxy(C0-6alkyl); and wherein R3aand R3b, together with the atoms to which they are attached, may forma saturated ring system, wherein said saturated ring system may be substituted by 0, 1, or 2 R3csubstituents; R4ais selected from hydrogen, C1-6 alkyl, hydroxy, C1-4 alkyloxy, and fluoro;R4bis selected from bicyclic heteroaryl(C0-3 alkyl), and bicyclic aryl(C0-3 alkyl),wherein R4bis substituted with 0, 1, or 2 R4csubstituents each independently selectedfrom halo, hydroxy, cyano, nitro, carboxy, carboxy(C1-6alkyl), (C1-6alkyloxy)carbonyl(C0-6alkyl), C1-6alkyloxy, (C1-6alkyl)oxy(C1-6alkyl), C1-6alkyl, and C1-6haloalkyl; R5ais selected from hydrogen, C1-10C1-10 fluoroalkyl, carboxy(C1-10 alkyl),hydroxy, hydroxy(C1-10alkyl), cyano(C1-10alkyl), heterocycloalkyl(C0-10alkyl), aminocarbonyl(C1-6alkyl), (C1-6alkyl)0-2aminocarbonyl(C1-6alkyl), (carboxy(C1-10alkyl))oxy (C1-6alkyl), aryl(C0-6alkyl), (C3-12)cycloalkyl(C0-6alkyl), heteroaryl(C0-6alkyl), (C1-6alkyl) oxy(C1-6alkyl), (C1-6alkyloxy)carbonyl(C0-6alkyl), amino, amino(C1-6alkyl), (C1-6alkyl)0-2 NAI-1542604160v1Attorney Ref. No.14463-061-228 amino(C0-6alkyl), amino(C1-6alkyl)carbonylamino(C1-6alkyl), (C1-6alkyl)0-2 amino(C1-6alkyl)carbonylamino(C1-6alkyl), (C1-6alkyl)3N+(C2-10alkyl), (C1-6alkyl)3N+(C1-6alkyl)carbonylamino(C1-6 alkyl), and C1-10 fluoroalkyl, and wherein R5ais substituted by 0, 1, or2 R5dsubstituents;R5bis selected from hydrogen, C1-10 alkyl, hydroxy(C1-10 alkyl), carboxy(C1-6 alkyl), (C1-6alkyl)oxy(C1-6alkyl), aminocarbonyl(C1-6alkyl), (C1-6alkyl)0-2aminocarbonyl(C1-6alkyl), carboxy(C1-10alkyl)oxy(C1-6alkyl), cyano(C1-10alkyl), amino(C1-6alkyl), (C1-6alkyl)0-2 amino(C1-6alkyl), amino(C1-6alkyl)carbonylamino(C1-6alkyl), (C1-6alkyl)0-2 amino(C1-6alkyl)carbonylamino(C1-6alkyl), (C1-6alkyl)3N+(C2-6alkyl)oxy(C1-6alkyl), (C1-6alkyl)3N+(C1-6alkyl)carbonylamino(C1-6alkyl), (C1-6alkyl)3N+(C1-6alkyl), (heterocycloalkyl(C0-10alkyl), (C3-12)cycloalkyl(C0-10 alkyl), and C1-10 haloalkyl, wherein R5bis substituted by 0, 1, 2, or 3 R5esubstituents, wherein R5aand R5b, together with the atoms to which they are attached, form asaturated mono- or bi-cyclic ring, wherein said mono- or bi-cyclic ring is substituted with 0, 1,2, or 3 R5dand 0, 1, 2, or 3 R5esubstituents;each R5dis independently selected from selected from halo, hydroxy, hydroxy(C1-10alkyl), C1-10alkyl, carboxy, carboxy(C1-6alkyl), C1-6alkyloxy, (C1-6alkyl)oxy(C1-6alkyl), amino, amino(C1-6alkyl), (C1-6alkyl)0-2amino(C0-6alkyl), amino(C1-6alkyl)carbonylamino(C0-6alkyl), (C1-6alkyl)0-2amino(C1-6alkyl)carbonylamino(C0-6alkyl), (C1-6alkyl)3N+(C0-6alkyl), (C1-6alkyl)3N+(C2-6alkyl)oxy(C0-6alkyl), (C1-6alkyl)3N+(C1-6alkyl)carbonylamino(C0-6alkyl), (carboxy(C1-6alkyl))oxy(C1-6alkyl), cyano(C0-6alkyl), tetrazolyl(C0-6alkyl), and C1-6haloalkyl,and two R5dsubstituents together with the atom they are attached to may join together to form asaturated ring; each R5eis independently selected from halo, hydroxy, hydroxy(C1-10 alkyl), C1-10 alkyl,carboxy, carboxy(C1-6alkyl), C1-6alkyloxy, (C1-6alkyl)oxy(C1-6alkyl), amino, amino(C1-6alkyl), (C1-6alkyl)0-2 amino(C0-6alkyl), amino(C1-6alkyl)carbonylamino(C0-6alkyl), (C1-6alkyl)0-2 amino(C1-6alkyl)carbonylamino(C0-6alkyl), (C1-6alkyl)3N+(C0-6alkyl), (C1-6alkyl)3N+(C2-6alkyl)oxy(C0-6alkyl), (C1-6alkyl)3N+(C1-6alkyl)carbonylamino(C0-6alkyl), (carboxy(C1-6alkyl))oxy(C1-6 alkyl), cyano(C0-6 alkyl), tetrazolyl(C0-6 alkyl), and C1-6 haloalkyl, and two R5esubstituents together with the atom they are attached to may join together to form a saturated ring; NAI-1542604160v1Attorney Ref. No.14463-061-228 R5cis hydrogen, C1-4 alkyl, hydroxy(C1-4 alkyl), C1-4 alkyloxy, or (C1-4 alkyl)oxy(C1-4alkyl); R6ais selected from hydrogen, hydroxy, amino, C1-4 alkyloxy, and C1-6 alkyl;R6bis selected from hydrogen, C1-6 alkyl, hydroxy, C1-4 alkyloxy, and fluoro;R6cis selected from C1-10 6 alkyloxy, (C1-6 alkyl)oxy(C1-6 alkyl), C1-10 haloalkyl,aryl(C0-6alkyl), heteroaryl(C0-10alkyl),6alkyl)SO2(C0-6alkyl), hydroxy, hydroxy(C1-6alkyl),amino(C0-6alkyl), (C1-6alkyl)0-2amino6alkyl), aminocarbonyl(C0-6alkyl), (C1-6alkyl)0-2aminocarbonyl(C0-6alkyl), (C1-6alkyl)carbonylamino(C0-6alkyl), (C1-6alkyl)0-2 aminocarbonylamino(C0-6alkyl), and carboxy(C0-6alkyl); R7ais selected from hydrogen, C1-6 alkyl, hydroxy, C1-4 alkyloxy, and fluoro;R7bis selected from aryl(C0-6 alkyl), heteroaryl(C0-6 alkyl), and (C3-12)cycloalkyl(C0-6alkyl), wherein R7bis substituted by 0, 1, 2, or 3 R7csubstituents each independently selectedfrom C1-6alkyl, C1-10fluoroalkyl, C1-10fluoroalkyloxy, (C1-6alkyl)0-2 amino(C0-5alkyl), (C1-6alkyl)3N+(C0-5alkyl), carboxy(C0-6alkyl), (C1-6alkyloxy)carbonyl(C0-6alkyl), carboxy(C1-6alkyl)oxy(C0-6alkyl), aminocarbonyl(C0-6alkyl), (C1-6alkyl)0-2aminocarbonyl(C0-6alkyl), hydroxy, hydroxy(C1-6alkyl), halo, –(C0-5alkyl)–(S(=O)2OH), –(C0-5alkyl)–(S(=O)2NH2), amino(C0-6alkyl)oxy(C0-6alkyl), (C1-6alkyl)0-2 amino(C0-6alkyl)oxy(C0-6alkyl), (C1-6alkyl)3N+(C0-6alkyl)oxy(C0-6alkyl), aminocarbonylamino(C0-6alkyl), (C1-6alkyl)0-2aminocarbonylamino(C0-6alkyl), C1-10haloalkyl, C1-10haloalkyloxy, and (C1-6alkyl)oxy(C0-6alkyl); R8ais selected from hydrogen, C1-6 alkyl, hydroxy, C1-4 alkyloxy, C1-6 fluoroalkyl, C1-4fluoroalkyloxy, and halo;R8bis selected from bicyclic aryl(C0-3 alkyl) and bicyclic heteroaryl(C0-3 alkyl), whereinR8bis by 0, 1, or 2 R8csubstituents each independently selected from C1-4 alkyl,halo, cyano, nitro, carboxy, amino, hydroxy, C1-6fluoroalkyl, C1-6fluoroalkyloxy, C1-6alkyloxy, amino(C1-3alkyl), and hydroxy(C1-6alkyl); R9is selected from hydrogen, and C1-4 alkyl;R10ais selected from hydrogen, hydroxy, C1-6 alkyl, C1-4 alkyloxy, and fluoro;NAI-1542604160v1Attorney Ref. No.14463-061-228 R10bis selected from (C3-12)cycloalkyl(C0-3 alkyl), aryl(C0-3 alkyl), and heteroaryl(C0-3alkyl), wherein said heteroaryl contains 1, 2, or 3 nitrogen atoms, wherein R10bis substitutedby 0, 1, or 2 R10cwherein each R10cis independently selected from C1-10 C1-10fluoroalkyl, C1-6haloalkyl, C1-10fluoroalkyloxy, amino, amino(C1-6alkyl), (C1-6alkyl)0-2amino(C0-6alkyl), (C1-6alkyl)3N+(C0-6alkyl), hydroxy, hydroxy(C1-6alkyl), cyano, halo, aminocarbonyl, aminocarbonyl(C1-6alkyl), (C1-6alkyl)0-2aminocarbonyl(C0-6alkyl), (C1-6alkyl)0-2 aminocarbonylamino(C0-6alkyl), (C1-6alkyl)carbonylamino(C0-6alkyl), carboxy(C0-6alkyl), (C1-6alkoxy)carbonyl(C0-6alkyl), carboxy(C1-6alkyl)oxy(C0-6alkyl), –(C0-5alkyl)–(S(=O)2OH), –(C0-5alkyl)–(S(=O)2NH2), amino(C0-6alkyl)oxy(C0-6alkyl), (C1-6alkyl)0-2amino(C0-6alkyl)oxy(C0-6alkyl), (C1-6alkyl)3N+(C0-6alkyl)oxy(C0-6alkyl), (C1-6alkyl)oxy(C0-6alkyl), C1-6haloalkyloxy, (C3-12)cycloalkyl(C0-6alkyl), and heterocycloalkyl(C0-6alkyl); R11ais selected from hydrogen, hydroxy, C1-6 alkyl, C1-4 alkyloxy, and fluoro;selected from aryl(C0-3 alkyl), heteroaryl(C0-3 alkyl), wherein said heteroarylcontains 1, 2, or 3 nitrogen atoms, and H2N–C(=NH)NH–(C1-6 alkyl), wherein R11bissubstituted by 0, 1, 2, 3, or 4 R11csubstituents each independently selectedC1-6 alkyl,amino, amino(C1-6alkyl), (C1-6alkyl)0-2 amino(C0-6alkyl), (C1-6alkyl)3N+(C0-6alkyl), hydroxy, hydroxy(C1-6alkyl), cyano, halo, aminocarbonyl, aminocarbonyl(C1-6alkyl), (C1-6alkyl)0-2aminocarbonyl(C0-6alkyl), carboxy(C0-6alkyl), carboxy(C1-6alkyl)oxy(C0-6alkyl), amino(C0-6alkyl)oxy(C0-6alkyl), (C1-6alkyl)0-2 amino(C0-6alkyl)oxy(C0-6alkyl), (C1-6alkyl)3N+(C0-6alkyl)oxy(C0-6alkyl), (C1-6alkyl)oxy(C0-6alkyl), C1-6haloalkyloxy, C1-6haloalkyl, (C3-12)cycloalkyl(C0-6alkyl), heterocycloalkyl(C0-6alkyl), ((C1-6alkyl)carbonyl)heterocycloalkyl (C0-10alkyl), and ((C1-6alkyl)carbonyloxy)heterocycloalkyl(C0-10alkyl); R12ais selected from hydrogen, hydroxy, amino, C1-10 alkyl, and (C3-12)cycloalkyl(C0-6alkyl); R12bis selected from hydrogen, C1-10 alkyl, and (C3-12)cycloalkyl(C0-6 alkyl); whereinR12atogether with the atoms to which they are attached, may form a saturated ring;R13ais selected from hydrogen, hydroxy, C1-6 alkyl, C1-4 alkyloxy, and fluoro;selected from hydrogen, and C1-4 alkyl;R13cis selected from a bicycliccontaining heteroaryl having 1 or 2 nitrogenand bicyclic-aryl and wherein R13cis substituted independently by 0, 1, or 2 R13dsubstituentsNAI-1542604160v1Attorney Ref. No.14463-061-228 each independently selected from halo, C1-6alkyl, carboxy(C0-4alkyl), C1-4haloalkyloxy, and C1-4alkyloxy; is selected from ,alkyloxy; m is selected from 1, 2, 3, or 4; n is selected from 1, 2, 3, or 4; and R14bis selected from hydrogen, C1-8 alkyl, aryl(C0-6 alkyl), and heteroaryl(C0-6alkyl), wherein R14bis substituted by 0, 1, 2, or 3 halo groups.

[0135] In aembodiment of the invention, R1is selected from aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, phenyl, phenylmethyl, phenylethyl, phenylpropyl, styryl, biphenyl, naphthyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, imidazolyl, pyrazolyl, NAI-1542604160v1Attorney Ref. No.14463-061-228 furyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, biphenylmethyl, naphthylmethyl, pyridylmethyl, pyridazinylmethyl, pyrimidylmethyl, pyrazinylmethyl, imidazolylmethyl, pyrazolylmethyl, furylmethyl, thiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, oxadiazolylmethyl, bicyclo[1.1.1.]pentyl, (bicyclo[1.1.1.]pentyl)methyl, phenylcarbonylaminoethyl, aminocarbonylmethyl, aminocarbonylethyl, aminocarbonylpropyl, aminocarbonylisopropyl, aminocarbonylbutyl, aminocarbonylaminomethyl, aminocarbonylaminoethyl, aminocarbonylaminopropyl, aminocarbonylaminobutyl, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, adamantyl, carboxy, carboxymethyl, carboxyethyl, azidomethyl, azidoethyl, azidopropyl, phenylaminocarbonylmethyl, pyridylaminocarbonylmethyl, (pyridylcarbonylamino)methyl, guanidino, guanidinomethyl, guanidinoethyl, guanidinopropyl, guanidinobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, pentafluoroethyl, fluoropropyl, difluoropropyl, trifluoropropyl, pentafluoropropyl, heptafluoropropyl, trifluorobutyl, N,N,N-trimethylmethylammonium, N,N,N-trimethyleth-1- ylammonium, N,N,N-trimethylpropan-1-ylammonium, N,N,N-trimethylbut-1-ylammonium, methylamino, methylaminomethyl, methylaminoethyl, methylaminopropyl, methylaminobutyl, dimethylamino, dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, dimethylaminobutyl, ethylamino, ethylaminomethyl, ethylaminoethyl, ethylaminopropyl, ethylaminobutyl, diethylamino, diethylaminomethyl, diethylaminoethyl, diethylaminopropyl, diethylaminobutyl, aminoethoxy, aminoethoxymethyl, isoxazolylcarbonylaminomethyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, cyclopropoxymethyl, cyclopropylmethoxy, cyclopropylmethoxymethyl, cyclopropylmethoxyethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, vinyl, prop-2-enyl, but-3-enyl, and pent-4-enyl, and the other groups are as provided in the general Formula (I) above.

[0136] In a second embodiment of the invention, R1is selected from 3-aminopropyl, 4-aminobutyl, phenyl, phenylmethyl, bicyclo[1.1.1.]pentyl, phenylcarbonylaminoethyl, aminocarbonylmethyl, aminocarbonylaminoethyl, n-propyl, n-butyl, isobutyl, isopentyl, n- pentyl, n-hexyl, 1-azidoethyl, 2-azidoethyl, azidopropyl, 3-azidopropyl, pyridylaminocarbonylmethyl, 3-guanidinopropyl, 2,2-difluoropropyl, 4,4,4-trifluorobutyl, N,N,N-trimethylpropan-1-ylammonium, methylaminopropyl, dimethylaminopropyl, isoxazolylcarbonylaminomethyl, ethoxy, methoxymethyl, prop-2-enyl, cyclopropylmethoxy, NAI-1542604160v1Attorney Ref. No.14463-061-228 and aminoethoxy, and the other groups are as provided in the general Formula (I) above or as in the first embodiment.

[0137] In a third embodiment of the invention, R1asubstituents are each independentlyselected from C1-6alkyl, amino, cyano, halo, and hydroxy, and the other groups are as providedin the general Formula (I) above or as in the first second embodiments.

[0138] In a fourth embodiment of the invention, each R2ais independently selected fromhydrogen, hydroxy, methyl, ethyl, methoxy, ethoxy, fluoro, and the other groups are as provided in the general Formula (I) above, or as in the first through third embodiments.

[0139] In a fifth embodiment of the invention, each R2ais independently selected fromhydrogen, hydroxy, and methyl, and the other groups are as provided in the general Formula (I) above, or as in the first through fourth embodiments.

[0140] In a sixth embodiment of the invention, R2bis selected from phenyl, benzyl,biphenyl, naphthyl, pyridyl, pyridazinylpyrimidyl, pyrazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, and bicyclo[1.1.1]pentyl, and the other groups are as provided in the general Formula (I) above, or as in the first through fifth embodiments.

[0141] In a seventh embodiment, R2bis selected from phenyl, pyridyl, pyrimidyl,pyridazinyl, imidazolyl, and bicyclopentyl, and the other groups are as provided in the general Formula (I) above, or as in the first through sixth embodiments.

[0142] In an eighth embodiment, each R2cis independently selected from aminomethyl,hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, tert- butyl, fluoro, chloro, bromo, iodo, aminoethoxy, N-methylaminoethoxy, N-ethylaminoethoxy, N,N- , carboxy, carboxymethoxy, (carboxymethoxy)methyl,dimethylaminocarbonyl, and aminocarbonylmethyl, and the other groups are as provided in the general Formula (I) above, or as in the first through seventh embodiments.

[0143] In a ninth embodiment, each R2cis independently selected from aminomethyl,hydroxy, methoxy, fluoro, carboxy,and the other groups are as provided in the general Formula (I) above, or as in the first through eighth embodiments.

[0144] In a tenth embodiment of the invention, R3ais selected from hydrogen, methyl,ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl, cyclobutyl, cyclobutylmethyl, cyclobutylethyl, aminoethyl, aminopropyl, NAI-1542604160v1Attorney Ref. No.14463-061-228 aminobutyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxymethyl, carboxyethyl,carboxypropyl, carboxybutyl, thioethyl, and thiopropyl, wherein R3amay be substituted by 0, 1,or 2 R3csubstituents each independently selected from fluoro, methyl, ethyl, n-propyl,isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, amino, N-methylamino, N- methylaminomethyl, N-ethylamino, N-ethylaminomethyl, N,N-dimethylamino, N,N- dimethylaminomethyl, N,N-diethylamino, N,N-diethylaminomethyl, N,N,N-trimethylammonium, N,N,N-trimethylmethylammonium, hydroxy, hydroxymethyl, –SO2CH3, –CH2SO2CH3, – CH2CH2SO2CH3, cyano, cyanomethyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, carboxy, carboxymethyl, and carboxyethyl, and the other groups are as provided in the general Formula (I) above, or as in the first through nineth embodiments.

[0145] In a eleventh embodiment of the invention, R3ais selected from hydrogen, methyl,ethyl, propyl, 2-methylpropyl, butyl, aminoethyl, 2-aminoethyl, aminopropyl, 3-aminopropyl, hydroxyethyl, 2-hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl,carboxyethyl, 2-carboxyethyl, and thioethyl, wherein R3amay be substituted by 0, 1, or 2 R3csubstituents each independently selected from methyl, isopropyl, cyclopropyl, amino, N- methylamino, hydroxy,–SO2CH3, –CH2SO2CH3, cyano, methoxy, and carboxy, and the other groups are as provided in the general Formula (I) above, or as in the first through tenth embodiments.

[0146] In a twelfth embodiment of the invention, R3bis selected from hydrogen, methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-tert-butyl, n-pentyl, isopentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmetyl, cyclopentylmethyl, cyclohexylmethyl, bicyclo[1.1.1]pentylmethyl, hydroxymethyl, 1- hydroxyethyl, 2-hydroxyethyl, hydroxypropyl, 3-hydroxypropyl, 1-methyl-1-hydroxyethyl, hydroxyisopropyl, hydroxybutyl, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, aminomethyl, 2-aminoethyl, N-methylaminomethyl, N,N-dimethylaminomethyl, N- methylaminoethyl, N,N-dimethylaminoethyl, N-methylaminopropyl, N,N-dimethylaminopropyl, 1-aminopropyl, 2-aminopropyl, 3-aminopropyl, 2-aminoprop-2-yl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, benzyl, 3- pyridinylmethyl, 4-pyridinylmethyl, imidazolylmethyl, thiazolylmethyl, oxazolylmethyl, thiophenylmethyl, furanylmethyl, pyrazolylmethyl, N-pyrazolylmethyl, 1-phenylethyl, 1-(4- pyridinyl)ethyl, aminocarbonylmethyl, aminocarbonylethyl, aminocarbonylpropyl, (N,N- dimethyl)aminocarbonylmethyl, (N,N-dimethyl)aminocarbonylethyl, thiomethyl, thioethyl, thiopropyl, –CH2CH2SO2CH3, carboxymethyl, carboxyethyl, 2-carboxyethyl, carboxypropyl, 3- carboxypropyl, carboxybutyl, 4-carboxybutyl, piperazinylmethyl, morpholinomethyl, NAI-1542604160v1Attorney Ref. No.14463-061-228 piperidinylmethyl, azetidinylmethyl, tetrahydropyranylmethyl, aminocarbonylaminomethyl, aminocarbonylaminoethyl, aminocarbonylaminopropyl, and aminocarbonylaminobutyl, whereinR3bmay be substituted by 0, 1, or 2 R3csubstituents each independently selected from fluoro,chloro, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, amino, aminomethyl, N-N-ethylamino, N-ethylaminomethyl, N,N- dimethylamino, N,N-dimethylaminomethyl, N,N-diethylamino, N,N-diethylaminomethyl, N,N,N- trimethylammonium, N,N,N-trimethylmethylammonium, hydroxy, hydroxymethyl, –SO2CH3, – CH2SO2CH3, –CH2CH2SO2CH3, cyano, cyanomethyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, carboxy, carboxymethyl, and carboxyethyl, and the other groups are as provided in the general Formula (I) above, or as in the first through eleventh embodiments.

[0147] In a thirteenth embodiment of the invention, R3bis selected from hydrogen, methyl,ethyl, n-propyl, isopropyl, isobutyl, n-butyl, cyclopropyl, cyclobutyl, hydroxymethyl, 1- hydroxyethyl, 2-hydroxyethyl, hydroxypropyl, 3-hydroxypropyl, 1-methyl-1-hydroxyethyl, methoxyethyl, aminomethyl, 2-aminoethyl, N-methylaminomethyl, 1-methyl-1-aminoethyl, 2- aminoprop-2-yl, 1-phenylmethyl, benzyl, imidazolylmethyl, thiazolylmethyl, aminocarbonylmethyl, aminocarbonylethyl, thiomethyl, –CH2CH2SO2CH3, carboxymethyl, 2- carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, piperazinylmethyl, andaminocarbonylaminopropyl, wherein R3bmay be substituted by 0, 1, or 2 R3csubstituents eachindependently selected from methyl, isopropyl, cyclopropyl, amino, N-methylamino, hydroxy,

[0148] –SO2CH3, –CH2SO2CH3, cyano, methoxy, and carboxy, and the other groups are as provided in the general Formula (I) above, or as in the first through twelfth embodiments.

[0149] In a fourteenth embodiment of the invention, R3aand R3b, together with the atomsto which they are attached, form a saturated ringby 0, 1, or 2, R3csubstituents and the ring system is selected from: ,NAI-1542604160v1Attorney Ref. No.14463-061-228 ,

[0150] In a fifteenth embodiment of the invention, and together with the atoms towhich they are attached, form a saturated ring system0, 1, or 2, R3csubstituentsand the ring system is selected from: ,, and the other groups are as provided in the general Formula (I) above, or as infourteenth embodiments.

[0151] In a sixteenth embodiment of the invention, R4ais selected from hydrogen, methyl,ethyl, propyl, hydroxy, methoxy, and fluoro, and thegroups are as provided in the general Formula (I) above, or as in the first through fifteenth embodiments. NAI-1542604160v1Attorney Ref. No.14463-061-228

[0152] In a seventeenth embodiment of the invention, R4ais hydrogen or methyl, and theother groups are as provided in the general Formula (I) above, or as in the first through sixteenth embodiments.

[0153] In an eighteenth embodiment of the invention, R4bis selected from indolyl,naphthyl, quinolinyl, pyrrolo[2,3-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyridine, 1H-pyrazolo[3,4-b] benzothiazolyl, and wherein R4bsubstituted with 0, 1,or 2 R4csubstituents each independently selected from fluoro, bromo, iodo, cyano, nitro,hydroxy, methyl, ethyl, propyl, isopropyl, carboxy, carboxymethyl, and carboxyethyl, and the other groups are as provided in the general Formula (I) above, or as in the first through seventeenth embodiments.

[0154] In a nineteenth embodiment of the invention, R4bis selected from indolyl, naphthyl,quinolinyl, pyrrolo[2,3-b]pyridinyl, 1H-pyrazolo[3,4-4band indazolyl, wherein Rsubstituted with 0, 1, or 2 R4csubstituents each independently selected from fluoro, chloro,methyl, and carboxymethyl, and the other groups are as provided in the general Formula (I) above, or as in the first through eighteenth embodiments.

[0155] In a twentieth embodiment of the invention, R5ais selected from hydrogen, methyl,ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, cyclopentyl, cyclobutyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, phenyl, benzyl, phenylethyl, phenylpropyl, oxazolylmethyl, thiazolylmethyl, imidazolylmethyl, triazolylmethyl, oxadiazolylmethyl, thiadiazolylmethyl, oxazolylethyl, thiazolylethyl, imidazolylethyl, triazolylethyl, oxadiazolylethyl, thiadiazolylethyl, oxazolylpropyl, thiazolylpropyl, imidazolylpropyl, triazolylpropyl, oxadiazolylpropyl, thiadiazolylpropyl, azetidinylmethyl, azetidinylethyl, oxetanylmethyl, oxetanylmethyl, pyrrolidinylmethyl, pyrrolidinylethyl, tetrahydrofuranylmethyl, tetrahydrofuranylethyl, piperidinylmethyl, piperidinylethyl, piperazinylmethyl, piperazinylethyl, tetrahydropyranylmethyl, tetrahydropyranylmethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl, 3- hydroxy-2,2-dimethylpropyl, cyclopropylmethyl, 1-hydroxypropan-2-yl, 2-hydroxyethyl, 3- hydroxypropyl, 2-hydroxyisopropyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, cyanomethyl, cyanoethyl, cyanopropyl, cyanobutyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2- aminoethyl, 3-aminopropyl, 3-amino-2,2-dimethylpropyl, cyclopropylmethyl, 4-aminobutyl, aminomethylcarbonylaminoethyl, aminoethylcarbonylaminoethyl, NAI-1542604160v1Attorney Ref. No.14463-061-228 aminomethylcarbonylaminopropyl, aminoethylaminocarbonylmethyl, aminoethylaminocarbonylethyl, aminoethylaminocarbonylpropyl, aminohexylcarbonylaminoethyl, aminohexylcarbonylaminoethyl, (N-methylamino)ethyl, (N- methylamino)propyl, (N-ethylamino)ethyl, (N,N-diethylamino)propyl, (N,N- dimethylamino)ethyl, (N,N-dimethylamino)propyl, (N,N-diethylamino)ethyl, (N,N- diethylamino)propyl, (N,N,N-trimethylammonium)ethyl, (N,N,N-trimethylammonium)propyl, (N,N,N-triethylammonium)ethyl, (N,N,N-triethylammonium)propyl, (N- methylamino)methylcarbonylaminoethyl, (N-methylamino)ethylcarbonylaminoethyl, (N- methylamino)methylcarbonylaminopropyl, (N-ethylamino)methylcarbonylaminoethyl, (N- ethylamino)ethylcarbonylaminoethyl, (N-ethylamino)methylcarbonylaminopropyl, (N- methylamino)pentylcarbonylaminoethyl, (N-methylamino)pentylcarbonylaminoethyl, (N- methylamino)pentylcarbonylaminopropyl, (N,N-dimethylamino)methylcarbonylaminoethyl, (N,N-dimethylamino)ethylcarbonylaminoethyl, (N,N- dimethylamino)methylcarbonylaminopropyl, (N,N-diethylamino)methylcarbonylaminoethyl, (N,N-diethylamino)ethylcarbonylaminoethyl, (N,N-diethylamino)methylcarbonylaminopropyl, (N,N-dimethylamino)pentylcarbonylaminoethyl, (N,N- dimethylamino)pentylcarbonylaminoethyl, (N,N-dimethylamino)pentylcarbonylaminopropyl, N,N,N-trimethyl-ethan-1-ammonium, N,N,N-trimethyl-propan-1-ammonium, (N,N,N- trimethylammonium)methylcarbonylaminoethyl, (N,N,N- trimethylammonium)ethylcarbonylaminoethyl, (N,N,N- trimethylammonium)methylcarbonylaminopropyl, (N,N,N- trimethylammonium)ethylcarbonylaminopropyl, (N,N,N- trimethylammonium)pentylcarbonylaminoethyl,trimethylammonium)pentylcarbonylaminopropyl, (carboxymethyl)oxyethyl, and(carboxymethyl)oxypropyl, wherein R5ais substituted by 0, 1, 2, or 3 R5dsubstituents eachindependently selected from chloro, fluoro, hydroxy, hydroxymethyl, hydroxyethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, carboxy, carboxymethyl, carboxyethyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, methoxypropyl, amino, aminomethyl, aminoethyl, N-methylamino, (N-methylamino)methyl, (N- methylamino)ethyl, N,N-dimethylamino, (N,N-dimethylamino)methyl, (N,N- dimethylamino)ethyl, N,N-diethylamino, (N,N-diethylamino)methyl, (N,N-diethylamino)ethyl, aminomethylcarbonylamino, aminoethylcarbonylamino, aminopentylcarbonylamino, aminomethylcarbonylaminomethyl, aminoethylcarbonylaminomethyl, (N- methylamino)methylcarbonylamino, (N-methylamino)ethylcarbonylamino, (N- NAI-1542604160v1Attorney Ref. No.14463-061-228 methylamino)methylcarbonylaminomethyl, (N-methylamino)ethylcarbonylaminomethyl, (N,N- dimethylamino)methylcarbonylamino, (N,N-dimethylamino)ethylcarbonylamino, (N,N- dimethylamino)methylcarbonylaminomethyl, (N,N-dimethylamino)ethylcarbonylaminomethyl, (N,N-diethylamino)methylcarbonylamino, (N,N-diethylamino)ethylcarbonylamino, (N,N- diethylamino)methylcarbonylaminomethyl, (N,N-diethylamino)ethylcarbonylaminomethyl, N,N,N-trimethylammonium, (N,N,N-trimethylammonium)methyl, (N,N,N- trimethylammonium)ethyl, (N,N,N-trimethylammonium)ethoxy, (N,N,N- trimethylammonium)ethoxymethyl, (N,N,N-trimethylammonium)methylcarbonylamino, (N,N,N- triethylammonium)methylcarbonylamino, (N,N,N-trimethylammonium)ethylcarbonylamino, (N,N,N-trimethylammonium)pentylcarbonylamino, (N,N,N- trimethylammonium)methylcarbonylaminomethyl, (N,N,N- trimethylammonium)ethylcarbonylaminomethyl, cyano, cyanomethyl, cyanoethyl, tetrazoyl, tetrazoylmethyl, tetrazoylethyl, carboxymethoxy, carboxyethoxy, carboxymethoxymethyl, and carboxyethoxymethyl, and the other groups are as provided in the general Formula (I) above, or as in the first through nineteenth embodiments.

[0156] In a twenty-first embodiment of the invention, R5ais selected from hydrogen,methyl, ethyl, n-propyl, cyclopropylmethyl, (1,3,4-2-yl)ethyl, 2-hydroxyethyl, 3- hydroxypropyl, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 2-hydroxyethyl, 2-hydroxy-1- methylethyl, hydroxypropyl, 3-hydroxy-2,2-dimethylpropyl, methoxyethyl, methoxypropyl, aminocarboxyethyl, 2-fluoroethyl, 2,2-difluoroethyl, carboxymethoxyethyl, 2-aminoethyl, 3- aminopropyl, (N,N-dimethylamino)ethyl, N,N,N-trimethyl-ethan-1-ammonium, (N,N,N- trimethylammonium)ethoxyethyl, (N,N,N-trimethylammonium)methylcarbonylaminoethyl, and(carboxymethyl)oxyethyl, wherein R5ais substituted by 0, 1, 2, or 3 R5dsubstituents eachindependently selected from fluoro, hydroxy, hydroxymethyl, methyl, carboxy, carboxymethyl, methoxy, amino, N,N-dimethylamino, N,N,N-trimethylammonium, (N,N,N- trimethylammonium)ethoxy, (N,N,N-trimethylammonium)methylcarbonylamino, cyano, tetrazoyl, and carboxymethoxy, and the other groups are as provided in the general Formula (I) above, or as in the first through twentieth embodiments.

[0157] In a twenty-second embodiment of the invention, R5bis selected from hydrogen,methyl, ethyl, isopropyl, n-propyl, cyclopropyl, isobutyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclopropylmethyl, oxetanylmethyl, tetrahydrofurylmethyl, tetrahydropyranylmethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, methoxypropyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, (carboxymethoxy)methyl, (carboxymethoxy)ethyl, (carboxyethoxy)methyl, NAI-1542604160v1Attorney Ref. No.14463-061-228 (carboxyethoxy)ethyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, (N- methylamino)methyl, (N-methylamino)ethyl, (N-methylamino)propyl, (N-methylamino)butyl, (N,N-dimethylamino)methyl, (N,N-dimethylamino)ethyl, (N,N-dimethylamino)propyl, (N,N- dimethylamino)butyl, (N,N-diethylamino)methyl, (N,N-diethylamino)ethyl, (N,N- diethylamino)propyl, (N,N-diethylamino)butyl, N,N,N-trimethylmethan-1-ylammonium, N,N,N- trimethylethan-1-ylammonium, N,N,N-triethylethan-1-ylammonium, N,N,N-trimethylpropan-1- ylammonium, N,N,N-trimethylbutan-1-ylammonium, (N,N,N- trimethylammonium)ethoxymethyl, (N,N,N-trimethylammonium)ethoxyethyl, (N,N,N- triethylammonium)ethoxyethyl, (N,N,N-trimethylammonium)ethoxypropyl, (N,N,N- trimethylammonium)ethoxybutyl, aminocarbonylmethyl, aminocarbonylethyl, aminocarbonylpropyl, aminocarbonylbutyl, (N-methylamino)carbonylmethyl, (N- methylamino)carbonylethyl, (N-methylamino)carbonylpropyl, (N-methylamino)carbonylbutyl, (N,N-dimethylamino)carbonylmethyl, (N,N-dimethylamino)carbonylethyl, (N,N- dimethylamino)carbonylpropyl, (N,N-dimethylamino)carbonylbutyl, aminomethylcarbonylaminoethyl, aminomethylcarbonylaminopropyl, aminoethylcarbonylaminoethyl, aminoethylcarbonylaminopropyl, (N,N- dimethylamino)methylcarbonylaminoethyl, (N,N-dimethylamino)methylcarbonylaminopropyl, (N,N-dimethylamino)ethylcarbonylaminoethyl, (N,N-dimethylamino)ethylcarbonylaminopropyl, (N,N,N-trimethylammonium)methylcarbonylaminoethyl, (N,N,N- triethylammonium)methylcarbonylaminoethyl, (N,N,N- trimethylammonium)methylcarbonylaminopropyl, (N,N,N- trimethylammonium)ethylcarbonylaminoethyl, (N,N,N- trimethylammonium)ethylcarbonylaminopropyl, (N,N,N-trimethylammonium)ethoxyethyl, (N,N,N-trimethylammonium)ethoxypropyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyanomethyl, cyanoethyl, cyanopropyl, cyanoisopropyl, and cyanobutyl,wherein R5bis substituted by 0, 1, 2, or 3 R5esubstituents each independently selected fromchloro, hydroxy, hydroxymethyl, hydroxyethyl, methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, carboxy, carboxymethyl, carboxyethyl, methoxy, ethoxy, methoxymethyl, methoxyethyl, methoxypropyl, amino, aminomethyl, aminoethyl, N-methylamino, (N-methylamino)methyl, (N-methylamino)ethyl, N,N-dimethylamino, (N,N-dimethylamino)methyl, (N,N-dimethylamino)ethyl, N,N- diethylamino, (N,N-diethylamino)methyl, (N,N-diethylamino)ethyl, aminomethylcarbonylamino, aminoethylcarbonylamino, aminopentylcarbonylamino, aminomethylcarbonylaminomethyl, aminoethylcarbonylaminomethyl, (N-methylamino)methylcarbonylamino, (N- NAI-1542604160v1Attorney Ref. No.14463-061-228 methylamino)ethylcarbonylamino, (N-methylamino)methylcarbonylaminomethyl, (N- methylamino)ethylcarbonylaminomethyl, (N,N-dimethylamino)methylcarbonylamino, (N,N- dimethylamino)ethylcarbonylamino, (N,N-dimethylamino)methylcarbonylaminomethyl, (N,N- dimethylamino)ethylcarbonylaminomethyl, (N,N-diethylamino)methylcarbonylamino, (N,N- diethylamino)ethylcarbonylamino, (N,N-diethylamino)methylcarbonylaminomethyl, (N,N- diethylamino)ethylcarbonylaminomethyl, N,N,N-trimethylammonium, (N,N,N- trimethylammonium)methyl, (N,N,N-trimethylammonium)ethyl, (N,N,N- trimethylammonium)ethoxy, (N,N,N-trimethylammonium)ethoxymethyl, (N,N,N- trimethylammonium)methylcarbonylamino, (N,N,N-triethylammonium)methylcarbonylamino, (N,N,N-trimethylammonium)ethylcarbonylamino, (N,N,N- trimethylammonium)pentylcarbonylamino, (N,N,N- trimethylammonium)methylcarbonylaminomethyl, (N,N,N- trimethylammonium)ethylcarbonylaminomethyl, cyano, cyanomethyl, cyanoethyl, tetrazoyl, tetrazoylmethyl, tetrazoylethyl, carboxymethoxy, carboxyethoxy, carboxymethoxymethyl, and carboxyethoxymethyl, and the other groups are as provided in the general Formula (I) above, or as in the first through twenty-first embodiments.

[0158] In a twenty-third embodiment of the invention, R5bis selected from hydrogen,methyl, ethyl, n-propyl, cyclopropylmethyl, hydroxymethyl, 2-hydroxyethyl, 2-carboxyethyl, 3- carboxypropyl, 2-aminoethyl, (N,N-dimethylamino)ethyl, 2-methoxyethyl, N,N,N- trimethylethan-1-ammonium, (N,N,N-trimethyl-ammonium)methylcarbonylaminoethyl, (N,N,N- trimethyl-ammonium)ethoxyethyl, 2-fluoroethyl, 2,2-difluoroethyl, and (carboxymethoxy)ethyl,wherein R5bis substituted by 0, 1, 2, or 3 R5esubstituents each independently selected fromfluoro, hydroxy, hydroxymethyl, methyl, carboxy, carboxymethyl, methoxy, amino, N,N- dimethylamino, N,N,N-trimethylammonium, (N,N,N-trimethylammonium)ethoxy, (N,N,N- trimethylammonium)methylcarbonylamino, cyano, tetrazoyl, and carboxymethoxy, and the other groups are as provided in the general Formula (I) above, or as in the first through twenty- second embodiments.

[0159] In a twenty-fourth embodiment of the invention, R5cis hydrogen, methyl, or ethyl,and the other groups are as provided in the general Formula (I) above, or as in the first through twenty-third embodiments.

[0160] In a twenty-fifth embodiment of the invention, R5cis hydrogen, or methyl, and theother groups are as provided in the general Formula (I) above, or as in the first through twenty- fourth embodiments. NAI-1542604160v1Attorney Ref. No.14463-061-228

[00161] In a twenty-sixth embodiment of the inventio, R5aand R5b, together with the atomsto which they are attached, form a saturated mono- or bi-cyclic ring system substituted with 0, 1, 2, or 3 R5dand 0, 1, 2, or 3 R5esubstituents, wherein said mono- or bi-cyclic ring system isselected from: , ,Attorney Ref. No.14463-061-228 inthrough the twenty-fifth embodiments.

[00162] In a twenty-seventh embodiment of the invention, R5aand R5b, together with theatoms to which they are attached, form a saturated mono- orcyclic ring system substituted with 0, 1, 2, or 3 R5dand 0, 1, 2, or 3 R5esubstituents, wherein said mono- or bi-cyclic ringsystem is selected from: ,NAI-1542604160v1Attorney Ref. No.14463-061-228 ,the other groups are as provided in the general the sixteenth and the twenty-first through the

[00163] In a twenty-eighth embodiment, R6ais selected from hydrogen, hydroxy, methyl,ethyl, propyl, and methoxy, and the other groups are as provided in the general Formula (I) above, or as in the first through the twenty-seventh embodiments.

[00164] In a twenty-nineth embodiment, R6ais selected from hydrogen and methyl, and theother groups are as provided in the general(I) above, or as in the first through the twenty-eighth embodiments.

[00165] In a thirtieth embodiment, R6bis selected from hydrogen, hydroxy, methyl, ethyl,propyl, methoxy, and ethoxy, and the other groups are as provided in the general Formula (I) above, or as in the first through the twenty-nineth embodiments.

[00166] In a thirty-first embodiment, R6bis selected from hydrogen, hydroxy, and methyl,and the other groups are as provided in the general Formula (I) above, or as in the first through the thirtieth embodiments.

[00167] In a thirty-second embodiment, R6cis selected from aminocarbonyl,(aminocarbonyl)methyl, (aminocarbonyl)ethyl, (aminocarbonyl)propyl, (N- methylamino)carbonyl, (N-methylamino)carbonylmethyl, (N-methylamino)carbonylethyl, (N- methylamino)carbonylpropyl, (N,N-dimethylamino)carbonyl, (N,N- dimethylamino)carbonylmethyl, (N,N-dimethylamino)carbonylethyl, (N,N- dimethylamino)carbonylpropyl, (N,N-diethylamino)carbonyl, (N,N- diethylamino)carbonylmethyl, (N,N-diethylamino)carbonylethyl, (N,N- diethylamino)carbonylpropyl, aminocarbonylamino, (aminocarbonylamino)methyl, (aminocarbonylamino)ethyl, (aminocarbonylamino)propyl, methoxy, methoxymethyl, methoxyethyl, ethoxy, ethoxymethyl, ethoxyethyl, methylsulfonyl, (methylsulfonyl)methyl, NAI-1542604160v1Attorney Ref. No.14463-061-228 (methylsulfonyl)ethyl, (methylsulfonyl)propyl, amino, aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, aminobutyl, carboxy, carboxymethyl, carboxyethyl, hydroxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, sec-butyl, isobutyl, tert-butyl, phenyl, and benzyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the thirty-first embodiments.

[0168] In a thirty-third embodiment, R6cis selected from aminocarbonyl,(aminocarbonyl)methyl, (N,N-dimethylamino)carbonylmethyl, aminocarbonylamino, (aminocarbonylamino)ethyl, methoxymethyl, (methylsulfonyl)methyl, hydroxy, and methyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the thirty-second embodiments.

[0169] In a thirty-fourth embodiment, R7ais selected from hydrogen, methyl, ethyl,hydroxy, methoxy, and ethoxy, and the other groups are as provided in the general Formula (I) above, or as in the first through the thirty-third embodiments.

[0170] In a thirty-fifth embodiment, R7ais selected from hydrogen, methyl, and hydroxy,and the other groups are as provided in the general Formula (I) above, or as in the first through the thirty-fourth embodiments.

[0171] In a thirty-sixth embodiment, R7bis selected from phenyl, biphenyl, naphthyl,pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, imidazolyl, pyrazolyl, furyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, 3-oxoisoindolinyl, and bicyclo[1.1.1]pentyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the thirty-fifth embodiments.

[0172] In a thirty-seventh embodiment, R7bis selected from phenyl, pyridyl, pyrimidyl,furyl, thiazolyl, and 3-oxoisoindolinyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the thirty-sixth embodiments.

[0173] In a thirty-eighth embodiment of the invention, R7cis selected from fluoro, chloro,bromo, iodo, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, carboxy, carboxymethyl, methoxycarbonyl, methoxycarbonylmethyl, ethoxycarbonyl, carboxymethoxy, carboxyethoxy, carboxymethoxymethyl, aminocarbonyl, aminocarbonylmethyl, (N,N- dimethylamino)carbonyl, (N,N-dimethylamino)carbonylmethyl, amino, aminomethyl, N,N- dimethylamino, (N,N-dimethylamino)methyl, (N,N-diethylamino)methyl, N,N,N- trimethylammonium, N,N,N-trimethylmethylammonium, N,N,N-triethylmethylammonium, methyl, ethyl, propyl, isopropyl, difluoromethyl, trifluoromethyl, –SO2OH,–CH2SO2OH, – S NAOI-21N54H2620,41 –6C0vH12SO2NH2, aminoethoxy, aminoethoxymethyl, (N,N-dimethylamino)ethoxy,Attorney Ref. No.14463-061-228 N,N,N-trimethyleth-1-oxy-ammonium, aminocarbonylamino, and aminocarbonylaminomethyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the thirty-seventh embodiments.

[0174] In a thirty-nineth embodiment of the invention, R7cis selected from hydroxy,carboxymethoxy, fluoro, chloro, methoxy, carboxy, methoxycarbonyl, aminocarbonyl, aminomethyl, –SO2OH, –SO2NH2, aminoethoxy, and aminocarbonylamino, and the other groups are as provided in the general Formula (I) above, or as in the first through the thirty-eighth embodiments.

[0175] In a fortieth embodiment, R8ais selected from hydrogen, methyl, ethyl, hydroxy,methoxy, and ethoxy, and the other groups are as provided in the general Formula (I) above, or as in the first through the thirty-nineth embodiments.

[0176] In a forty-first embodiment, R8ais selected from hydrogen, and methyl, and theother groups are as provided in the general Formula (I) above, or as in the first through the fortieth embodiments.

[0177] In a forty-second embodiment of the invention, R8bis selected from indolyl,naphthyl, indolylmethyl, naphthylmethyl, quinolinyl, [2,3-b]pyridinyl, indazolyl,benzothiazolyl, and benzothiophenyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the forty-first embodiments.

[0178] In a forty-third embodiment of the invention, R8bis selected from indolyl, naphthyl,and pyrrolo[2,3-b]pyridinyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the forty-second embodiments.

[0179] In a forty-fourth embodiment of the invention, each R8cindependently is selectedfrom methyl, ethyl, isopropyl, fluoro, chloro, bromo, iodo,amino, aminomethyl, nitro, hydroxy, hydroxymethyl, carboxy, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, methoxy, ethoxy, and trifluoromethoxy, and the other groups are as provided in the general Formula (I) above, or as in the first through the forty-third embodiments.

[0180] In a forty-fifth embodiment of the invention, each R8cindependently is selectedfrom fluoro, chloro, bromo, and cyano, and the other groups are as provided in the general Formula (I) above, or as in the first through the forty-fourth embodiments.

[0181] In a forty-sixth embodiment of the invention, R9is selected from hydrogen, methyl,ethyl, and propyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the forty-fifth embodiments. NAI-1542604160v1Attorney Ref. No.14463-061-228

[0182] In a forty-seventh embodiment of the invention, R9is hydrogen or methyl, and theother groups are as provided in the general Formula (I) above, or as in the first through the forty- sixth embodiments.

[0183] In a forty-eighth embodiment of the invention, R10ais selected from hydrogen,hydroxy, methyl, ethyl, propyl, methoxy, ethoxy, and propoxy, and the other groups are as provided in the general Formula (I) above, or as in the first through the forty-seventh embodiments.

[0184] In a forty-nineth embodiment of the invention, R10ais selected from hydrogen, andhydroxy, and the other groups are as provided in the general Formula (I) above, or as in the first through the forty-eighth embodiments.

[0185] In a fiftieth embodiment of the invention, R10bis selected from phenyl, benzyl,biphenyl, biphenylmethyl, pyridyl, pyridylmethyl, pyridazinyl, pyrimidyl, pyrazinyl, imidazolyl, imidazolylmethyl, pyrazolyl, furyl, furylmethyl, oxazolyl, oxazolylmethyl, thiazolyl, indolyl, [1,2,4]triazolo[1,5-a]pyridine, and bicyclo[1.1.1]pentyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the forty-nineth embodiments.

[0186] In a fifty-first embodiment of the invention, R10bis selected from phenyl, andpyrimidyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the fiftieth embodiments.

[0187] In a fifty-second embodiment, each R10cis independently selected from methyl,ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2- trifluoroethyl, trifluoromethoxy, 2,2,2-trifluoroethoxy, fluoro, chloro, bromo, iodo, hydroxy, hydroxymethyl, hydroxyethyl, cyano, amino, aminomethyl, aminoethyl, N-methylamino, (N- methylamino)methyl, (N-methylamino)ethyl, N,N-dimethylamino, (N,N-dimethylamino)methyl, (N,N-dimethylamino)ethyl, N,N,N-trimethylammonium, N,N,N-trimethylmethan-ylammonium, aminocarbonyl, aminocarbonylmethyl, aminocarbonylethyl, (N-methylamino)carbonyl, (N- methylamino)carbonylmethyl, (N,N-dimethylamino)carbonyl, (N,N- dimethylamino)carbonylmethyl, aminocarbonylamino,methylcarbonylamino, methylcarbonylaminomethyl, carboxy, carboxymethyl, carboxyethyl, methoxycarboxy, carboxymethoxy, carboxyethoxy, carboxymethoxymethyl, carboxyethoxymethyl, –S(=O)2OH, –CH2(S(=O)2OH), –S(=O)2NH2, –CH2(S(=O)2NH2), aminoethoxy, aminopropoxy, (N-methylamino)ethoxy, (N-ethylamino)ethoxy, (N,N- d NAimI-1e5t4h26y0l4a1m60vin1o)ethoxy, (N,N-diethylamino)ethoxy, (N,N,N-trimethylammonium)ethoxy,Attorney Ref. No.14463-061-228 methoxy, ethoxy, methoxymethyl, ethoxymethyl, difluoromethoxy, trifluoromethoxy, and 2,2,2- trifluoroethoxy, and the other groups are as provided in the general Formula (I) above, or as in the first through the fifty-first embodiments.

[0188] In a fifty-third embodiment, each R10cis independently selected from fluoro,carboxy, carboxymethyl, (carboxymethyl)oxy, aminocarbonyl, amino, aminomethyl, –SO2OH, – SO2NH2, hydroxy, and aminocarbonylamino, and the other groups are as provided in the general Formula (I) above, or as in the first through the fifty-second embodiments.

[0189] In a fifty-fourth embodiment of the invention, R11ais selected from hydrogen,hydroxy, methyl, ethyl, methoxy, and ethoxy, and the are as provided in the generalFormula (I) above, or as in the first through the fifty-

[0190] In a fifty-fifth embodiment of the invention, R11ais selected from hydrogen, andhydroxy, and the other groups are as provided in theFormula (I) above, or as in the first through the fifty-fourth embodiments.

[0191] In a fifty-sixth embodiment, R11bis selected from (H2N–C(=NH)–NH)methyl,(H2N–C(=NH)–NH)ethyl, (H2N–C(=NH)–NH)propyl, (H2N–C(=NH)–NH)butyl, phenyl, benzyl, pyridinyl, pyridinylmethyl, indolyl, indolylmethyl, pyridazinyl, pyridazinylmethyl, pyrimidyl, pyrimidylmethyl, pyrazinyl, pyrazinylmethyl, imidazolyl, imidazolylmethyl, pyrazolyl, pyrazolylmethyl, [1,2,4]triazolo[1,5-a]pyridine, oxazolyl, oxazolylmethyl, thiazolyl, and thiazolylmethyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the fifty-fifth embodiments.

[0192] In a fifty-seventh embodiment, R11bis selected from phenyl, (H2N–C(=NH)–NH)ethyl, pyridinyl, indolyl, andthe other groups are as provided in the general Formula (I) above, or as in the first through the fifty-sixth embodiments.

[0193] In a fifty-eighth embodiment of the invention, each R11cis independently selectedfrom fluoro, chloro, bromo, iodo, (carboxymethyl)oxy,oxymethyl, (carboxyethyl)oxy, hydroxy, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, carboxy, carboxymethyl, aminocarbonyl, aminocarbonylmethyl, (N- methylamino)carbonyl, (N-methylamino)carbonylmethyl, (N,N-dimethylamino)carbonyl, (N,N- dimethylamino)carbonylmethyl, amino, N-methylamino, N,N-dimethylamino, N,N- diethylamino, aminomethyl, (N,N-dimethylamino)methyl, (N,N-diethylamino)methyl, N,N,N- trimethylammonium, N,N,N-trimethylmeth-1-yl-ammonium, N,N,N-triethylammonium, N,N,N- triethylmeth-1-yl-ammonium, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, difluoromethyl, trifluoromethyl, aminoethoxy, aminopropoxy, aminoethoxymethyl, (N,N-dimethylamino)ethoxy, NAI-1542604160v1Attorney Ref. No.14463-061-228 N,N,N-trimethyleth-1-yloxy-ammonium, cyano, and methylcarbonylpiperazyl [(N- acetyl)piperazyl], and the other groups are as provided in the general Formula (I) above, or as in the first through the fifty-seventh embodiments.

[0194] In a fifty-nineth embodiment of the invention, each R11cis independently selectedfrom (carboxymethyl)oxy, fluoro, chloro, hydroxy, methoxy, trifluoromethoxy, carboxy, carboxymethyl, aminocarbonyl, aminocarbonylmethyl, aminomethyl, aminoethoxy, (N,N- dimethylamino)ethoxy, and methylcarbonylpiperazyl , and the other groups are as provided in the general (I) above, or the fifty-eighth embodiments.

[0195] In a sixtieth embodiment of the invention, R12ais selected from hydrogen, methyl,ethyl, propyl, cyclopropyl, and isopropyl, and the are as provided in the generalFormula (I) above, or as in the first through the fifty-nineth embodiments.

[0196] In a sixty-first embodiment of the invention, R12ais selected from hydrogen,methyl, ethyl, and n-propyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the sixtieth embodiments.

[0197] In a sixty-second embodiment, R12bis selected from hydrogen, methyl, ethyl, andpropyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the sixty-first embodiments.

[0198] In a sixty-third embodiment, R12bis selected from hydrogen, and methyl, and theother groups are as provided in the(I) above, or as in the first through the sixty- second embodiments.

[0199] In a sixty-forth embodiment of the invention, R12aand R12b, together with theatoms to which they are attached form a saturated ring ,and , and the other groups are as provided in the general Formula (I) above, or as in the first through the sixty-third embodiments. NAI-1542604160v1Attorney Ref. No.14463-061-228

[0200] In a sixty-fifth embodiment of the invention, R12aand R12b, together with theatoms to which they are attached the other groups are as provided in the general Formula (I) above, or as in sixty-fourth embodiments.

[0201] In a sixty-sixthmethyl, or propyl, and the othergroups are as provided in the general Formula (I) above, or as in the first through the sixty-fifthembodiments.

[0202] In a sixty-seventh embodiment, R13bis hydrogen or methyl, and the other groupsare as provided in the general Formula (I) above, or as in the first through the sixty-sixth embodiments.

[0203] In a sixty-eighth embodiment, R13cis selected from indolyl, pyrrolo[2,3-b]pyridinyl,quinolinyl, indazolyl, and naphthyl, groups are as provided in the general Formula(I) above, or as in the first through the sixty-seventh embodiments.

[0204] In a sixty-nineth embodiment, R13cis selected from indolyl, and pyrrolo[2,3-b]pyridinyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the sixty-eighth embodiments.

[0205] In a seventieth embodiment, each R13dindependently is selected from fluoro,chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, carboxy, carboxymethyl, methoxy, difluoromethoxy, trifluoromethoxy, and ethoxy, and the other groups are as provided in the general Formula (I) above, or as in the first through the sixty-nineth embodiments.

[0206] In a seventy-first embodiment, each R13dindependently is selected from methyl,chloro, and methoxy, and the other groups arein the general Formula (I) above, or as in the first through the seventieth embodiments.

[0207] In a seventy-second embodiment, each R14aindependently is selected from amino,hydroxy, N-methylamino, N,N-dimethylamino, N-ethylamino, methoxy, and ethoxy, and the other groups are as provided in the general Formula (I) above, or as in the first through the seventy-first embodiments.

[0208] In a seventy-third embodiment, each R14aindependently is amino, and the othergroups are as provided in the general Formula (I) above, or as in the first through the seventy- second embodiments.

[0209] In a seventy-fourth embodiment, each R14bindependently is selected fromhydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, n-pentyl, isopentyl, NAI-1542604160v1Attorney Ref. No.14463-061-228 neopentyl, trifluoromethyl, trifluoroethyl, phenyl, benzyl, chlorophenyl, dichlorophenyl, fluorophenyl, difluorophenyl, bromophenyl, iodophenyl, chlorobenzyl, dichlorobenzyl, fluorobenzyl, difluorobenzyl, bromobenzyl, iodobenzyl, naphthyl, naphthylmethyl, pyrazolyl, pyrazolylmethyl, indolyl, indolylmethyl, imidazolyl, imidazolylmethyl, pyridyl, and pyridylmethyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the seventy-third embodiments.

[0210] In a seventy-fifth embodiment, each R14bindependently is selected from hydrogen,methyl, ethyl, and phenyl, and the other groups are as provided in the general Formula (I) above, or as in the first through the seventy-fourth embodiments.

[0211] In certain embodiments of the methods provided herein, the compound is a compound of Formula (II) or a pharmaceutically acceptable salt thereof: ,R1'is hydrogen, C1-10 alkyl, monocycloalkyl, monoheterocycloalkyl, monocyclic aryl, or monocyclic heteroaryl; R2'is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R3'ais hydrogen or C1-3alkyl; R3'bis hydroxy(C1-6 alkyl); R3'aand R3'btogether with the carbon and nitrogen atom to which they are attached form a 5- or 6-membered heterocycloalkyl; R3'cis hydrogen or C1-3alkyl; R4'is hydrogen or C1-6 alkyl; NAI-1542604160v1Attorney Ref. No.14463-061-228 R5'ais hydrogen or C1-6 alkyl; R5'bis hydrogen or carboxy(C1-6alkyl); or R5'aand R5'btogether with the carbon and nitrogen atom to which they are attached form a 5- or 6-membered heterocycloalkyl; R7'is monocyclic aryl or monocyclic heteroaryl; R8'is bicyclic aryl or bicyclic heteroaryl; R9'is hydrogen or C1-4 alkyl; R10'is hydrogen, C1-6alkyl, –OH, or –COOH; R11'is monocyclic aryl or monocyclic heteroaryl; R13'ais hydrogen or C1-6 alkyl; R13'bis hydrogen or C1-4 alkyl; R13'cis hydrogen, C1-6 alkyl, C1-6 alkoxy; and the linkeror,(*) represents attachment to the compound at the carbonyl carbon bound to the linker, wherein the wavy line ( ) represents attachment to the nitrogen boundto the linker; and wherein: m is selected from 1 to 4; n is selected from 1 to 4; wherein each of the C1-3alkyl, C1-4alkyl, C1-6alkyl, C1-6alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl are optionally substituted with 0, 1, or 2 halo, hydroxyl, carboxy (–COOH), or aminocarbonyl (–CONH2) groups.

[0212] In Formula (II), R1'may be, in any embodiment of any method disclosed herein, hydrogen, C1-10alkyl, C3-6monocycloalkyl, C3-5monoheterocycloalkyl, C5-6monocyclic aryl, or C5-6 monocyclic heteroaryl. In certain embodiments, R1'is C1-6 alkyl or C5-6 monocyclic aryl. In certain embodiments, R1'is C2-4alkyl or optionally substituted phenyl. In certain embodiments, R1'is propyl, butyl, or phenyl. NAI-1542604160v1Attorney Ref. No.14463-061-228

[0213] In some embodiments of the method disclosed herein, the linker of the compound of N Formula (II)H. In some embodiments of the methods disclosed herein, thetoa , or or phenyl. In certain embodiments, R2'is substituted or unsubstituted 4-pyridinyl or phenyl. In some embodiments, R2'is 4-pyridinyl. In certain embodiments, R2'is hydroxy-substituted phenyl. In certain embodiments, R2'is 4-hydroxy-phenyl.

[0215] In certain embodiments of the methods disclosed herein, the compound that binds to TNFR1 is a compound of Formula (II), wherein R3'bis hydroxy(C1-6alkyl). In certain embodiments, R3bis hydroxymethyl.

[0216] In certain embodiments of the methods disclosed herein, the compound that binds to TNFR1 is a compound of Formula (II), wherein R3'aand R3'btogether with the carbon and nitrogen atom to which they are attached form an optionally substituted 5- or 6-membered heterocycloalkyl having 0 or 1 additional heteroatoms selected from the group consisting of N, O, and S. In certain embodiments, R3'aand R3'btogether with the carbon and nitrogen atom to which they are attached form an optionally substituted 5- or 6-membered heterocycloalkyl, wherein the an optionally substituted 5- or 6-membered heterocycloalkyl is or ,wherein the wavy line ( ) represents attachment to adjacent atoms in the

[0217] In certain embodiments of the methods disclosed herein, the compound that binds to TNFR1 is a compound of Formula (II), wherein R4'is hydrogen or C1-6 alkyl. In certain NAI-1542604160v1Attorney Ref. No.14463-061-228 embodiments, R4'is hydrogen or C1-3 alkyl. In certain embodiments, R4'is hydrogen or methyl. In certain embodiments, R4'is hydrogen. In certain embodiments, R4'is methyl.

[0218] In certain embodiments of the methods disclosed herein, the compound that binds to TNFR1 is a compound of Formula (II), wherein R5'ais hydrogen or C1-6alkyl. In certain embodiments, R5'ais hydrogen or methyl. In certain embodiments, R5'ais methyl.

[0219] In certain embodiments of the methods disclosed herein, the compound that binds to TNFR1 is a compound of Formula (II), wherein R5'bis hydrogen or carboxy(C1-6 alkyl). In certain embodiments, R5'bis carboxy(C1-3alkyl). In certain embodiments, R5'bis hydrogen or – (CH2)2COOH. In certain embodiments, R5'bis hydrogen. In certain embodiments, R5'bis – (CH2)2COOH.

[0220] In certain embodiments of the methods disclosed herein, the compound that binds to TNFR1 is a compound of Formula (II), wherein R5'aand R5'btogether with the carbon and nitrogen atom to which they are attached form an optionally substituted 5- or 6-membered heterocycloalkyl having 1 or 2 heteroatoms selected from the group consisting of N, O, and S. In certain embodiments, R5'aand R5'btogether with the carbon and nitrogen atom to which they are attached form an optionally substituted 5-membered heterocycloalkyl. In certain embodiments, R5'aand R5'btogether with atoms to which they are attached form a 5- or 6-membered heterocycloalkyl which , wherein the wavy line ( ) represents attachment tothe adjacent atoms of

[0221] In certain embodiments of the methods disclosed herein, the compound that binds to TNFR1 is a compound of Formula (II), wherein R7'is substituted or unsubstituted pyridinyl or phenyl. In certain embodiments, R7'is substituted or unsubstituted 4-pyridinyl or phenyl. In some embodiments, R7'is 4-pyridinyl. In certain embodiments, R7'is hydroxy-substituted phenyl. In certain embodiments, R7'is 4-hydroxy-phenyl. In certain embodiments, R7'is carboxy-substituted phenyl. In certain embodiments, R7'is 4-carboxy-phenyl.

[0222] In Formula (II), R8'may be, in any embodiment of any method disclosed herein, substituted, or unsubstituted C8-10bicyclic aryl or 8-, 9-, or 10-membered bicyclic heteroaryl. In some embodiments of the methods disclosed herein, R8'is substituted or unsubstituted naphthyl. In certain embodiments, R8'is substituted or unsubstituted indolyl. In certain embodiments, R8'isAttorney Ref. No.14463-061-228

[0223] In certain embodiments of the methods disclosed herein, the compound that binds to TNFR1 is a compound of Formula (II), wherein R9'is hydrogen or C1-4alkyl. In certain embodiments, R9'is hydrogen. In certain embodiments, R9'is C1-4 alkyl. In certain embodiments, R9'is methyl.

[0224] In certain embodiments of the methods disclosed herein, the compound that binds to TNFR1 is a compound of Formula (II), wherein R10'is hydrogen, C1-6alkyl, –OH, or –COOH. In certain embodiments, R10'is –OH or –COOH. In certain embodiments, R10'is –OH. In certain embodiments, R10'is –COOH.

[0225] In certain embodiments of the methods disclosed herein, the compound that binds to TNFR1 is a compound of Formula (II), R11'is monocyclic aryl or heteroaryl. In certain embodiments, R11'is substituted monocyclic aryl. In certain embodiments, R11'is unsubstituted monocyclic aryl. In certain embodiments, R11'is substituted monocyclic heteroaryl. In certain embodiments, R11'is unsubstituted monocyclic heteroaryl. In certain embodiments, R11'is substituted or unsubstituted imidazolyl or phenyl. In certain embodiments, R11'is substituted with hydroxyl and –CONH2. In certain embodiments, R11'or.embodiments of the methods disclosed herein, the compound that binds to TNFR1 is a compound of Formula (II), wherein R13'ais hydrogen or C1-3 alkyl. In certain embodiments, R13'ais hydrogen or methyl. In certain embodiments, R13'ais hydrogen. In certain embodiments, R13'ais methyl.

[0227] In certain embodiments of the methods disclosed herein, the compound that binds to TNFR1 is a compound of Formula (II), wherein R13'bis hydrogen or C1-4 alkyl. In certain embodiments, R13'bis hydrogen or C1-4alkyl. In certain embodiments, R13'bis C1-4alkyl. In certain embodiments, R13'bis methyl. In certain embodiments, R13'bis hydrogen.

[0228] In certain embodiments of the methods disclosed herein, the compound that binds to TNFR1 is a compound of Formula (II), wherein R13'cis hydrogen or C1-6 alkoxy. In certain embodiments, R13'cis hydrogen or methoxy. In certain embodiments, R13'cis hydrogen. In certain embodiments, R13'cis methoxy.

[0229] In certain embodiments of the methods disclosed herein, the compound that binds to TNFR1 is a compound of Formula (II): R1'is propyl, butyl, or phenyl; NAI-1542604160v1Attorney Ref. No.14463-061-228 R3'ais hydrogen; R3'bis hydroxymethyl; or R3'aand R3'btogether with the carbon and nitrogen atom to which they are attached form a 6-membered heterocycloalkyl; R8'is substituted or unsubstituted naphthyl or indolyl; R9'is H or methyl; and R10is –OH or –COOH.

[0230] In certain embodiments of the methods disclosed herein, the compound that binds to TNFR1 is a compound of Formula (II), wherein each of the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl may be optionally and independently substituted with one or more of halo, hydroxyl, carboxy (–COOH), or aminocarbonyl (–CONH2) groups.

[0231] In certain embodiments of the methods disclosed herein, the compound that binds to TNFR1 is Compound A:or a pharmaceutically acceptable salt thereof. As will be recognized by one of skill in the art, Compound A may also be described by SEQ ID NO:6.

[0232] In certain embodiments of the methods disclosed herein, the compound that binds to TNFR1 is Compound B: NAI-1542604160v1Attorney Ref. No.14463-061-228or a pharmaceutically acceptable salt thereof. As will be recognized by one of skill in the art, Compound B may also be described by SEQ ID NO:7.

[0233] In certain embodiments of the methods disclosed herein, the compound that binds to TNFR1 is Compound C:NAI-1542604160v1Attorney Ref. No.14463-061-228 or a pharmaceutically acceptable salt thereof. As will be recognized by one of skill in the art, Compound C may also be described by SEQ ID NO:8.

[0234] In certain embodiments of the methods disclosed herein, the compound that binds to TNFR1 is Compound D:or a pharmaceutically acceptable salt thereof. As will be recognized by one of skill in the art, Compound D may also be described by SEQ ID NO:9.

[0235] The mechanism of action (MOA) of anti-TNF biologics such as infliximab,adalimumab, golimumab and certolizumab, involves binding to the cytokine TNF and thus,inhibition of engagement with both TNFR1 and tumor-necrosis factor receptor 2 (TNFR2). While not being bound by any specific theory, the compounds that bind to the TNFR1 binding pocket as provided herein selectively inhibit TNFR1 to specifically attenuate theproinflammatory activities of TNF -mediated TNFR1 signaling, and to spare / passively enableTNF –TNFR2 pro-homeostatic signaling, which may confer better therapeutic efficacy than thestandard of care anti-TNF biologics. Accordingly, provided herein, in certain aspects, arecompounds and compositions comprising the same that bind to the TNFR1 binding pocket NAI-1542604160v1Attorney Ref. No.14463-061-228 provided herein. Also provided are methods of modulating TNFR1-mediated biological activity in subject, such as inflammation, apoptosis, necroptosis, cell differentiation, cell survival, and cell proliferation. 8. EXAMPLES 8.1. EXAMPLE 1: METHODS OF SYNTHESIS 8.1.1. General Procedures to Access Building Blocks and Monomers

[0236] The compounds of the present invention can be prepared according to the procedures of the following schemes and specific examples, or modifications thereof, using readily available starting materials, appropriate materials and reagents and conventional synthetic procedures and are further exemplified by the following specific examples. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art but are not mentioned in greater detail. The general procedures for making the compounds claimed in this invention can be readily understood and appreciated by one skilled in the art from viewing the following schemes. The examples also include methods for testing such compounds in biophysical, biochemical, and cellular assays. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the disclosure.

[0237] Unless otherwise specifically indicated, all reagents are commercially available, known in the literature, or readily synthesized by one skilled in the art. The general route applied to the synthesis of compounds of Formula (II) (e.g., Compounds A, B, C, D) is described in the Schemes that follow. In some instances, the order of carrying out the reaction steps in the schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. Additionally, various protecting group strategies familiar to one skilled in the art of organic synthesis and solid phase peptide synthesis may be employed to facilitate the reaction, to improve yield and purity, or to avoid unwanted reaction products.

[0238] All reagents and solvents were purchased from commercial sources and used without further purification unless otherwise noted. All temperatures are in degrees Celsius (°C), and ambient temperature or room temperature (RT) is 20 °C. Most compounds were purified by reversed-phase preparative high-performance liquid chromatography (HPLC) or medium- pressure liquid chromatography (MPLC) on silica gel. The course of the reactions was followed by liquid chromatography / mass spectrometry (LC-MS) or Ultra performance liquid chromatography / mass spectrometry (UPLC-MS); electrospray ionization (ESI); UV detection at 254 nm). Proton, fluorine, and carbon magnetic resonance (1H,19F and13C NMR) spectra were recorded on a 300, 400, 500, or 600 MHz Varian or Bruker spectrometer, and chemical shifts are NAI-1542604160v1Attorney Ref. No.14463-061-228 reported in parts per million (ppm) relative to tetramethylsilane and referenced to residual solvent. Coupling constants are reported in hertz.1H NMR data are reported as given here: chemical shift (multiplicity [singlet (s), doublet (d), triplet (t), quartet (q), doublet of doublets (dd), doublet of triplets (dt), triplet of doublets (td), triplet of triplets (tt), doublet of doublet of doublets (ddd), multiplet (m), and broad singlet (br. s)], coupling constant [Hz] and integration). Reactions sensitive to moisture or air were performed under nitrogen or argon using anhydrous solvents and reagents. The progress of reactions was determined by either analytical thin layer chromatography (TLC) usually performed with pre-coated TLC plates (E. Merck, Darmstadt, Germany), silica gel 60F-254, layer thickness 0.25 mm or liquid chromatography-mass spectrometry (LC-MS).

[0239] Unless otherwise indicated, when ratios of compounds (such as for examples solvents) are given, the ratio is on a volume-to-volume basis. For example, solvent gradient ranging from 100% hexanes to 50% EtOAc / hexanes means a gradient starting from a mixture of 100 parts by volume of hexanes varying to mixture of 50 parts by volume ethyl acetate to 50 parts by volume of hexanes.

[0240] The term “w / w” means weight of compound to total weight. For example, NaH 60% w / w means 60 parts by weight NaH to 100 parts total weight.

[0241] The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way. Wherein a racemic mixture is produced, the enantiomers may be separated using SFC reverse or normal phase chiral resolution conditions either after isolation of the final product or at a suitable Intermediate, followed by processing of the single isomers individually. It is understood that alternative methodologies may also be employed in the synthesis of these key intermediates and examples. Asymmetric methodologies (e.g., chiral catalysis, auxiliaries, biocatalytic process) may be used where possible and appropriate. The exact choice of reagents, solvents, temperatures, and other reaction conditions depends upon the nature of the intended product.

[0242] The amino acids used to synthesize the Final Compounds as described herein may be prepared by the following methods and are also commercially available. NAI-1542604160v1Attorney Ref. No.14463-061-228 8.1.2. Intermediates and Monomers Syntheses Synthetic Scheme 13- yl)butanoic acid (Fmoc-SbMeW-OH):

[0243] Step 1: Into a 500 mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed DMSO (20 mL, 4 V), indole (5.00 g, 42 mmol), (2S,3R)-2-amino-3-hydroxybutanoic acid (10.17 g, 85 mmol, 2 equiv), 0.2 M potassium phosphate buffer (230 mL, 46 V, pH = 8.0). The resulting solution was stirred at 65 °C. PLP (46 mg, 0.18 mmol, 0.0041 equiv) in H2O (2 mL) and PfTrpB 7E6 (1.00 g, 20 wt. %) in 0.2 M potassium phosphate buffer (2 mL, pH = 8) was added into the solution. The resulting solution was stirred for 18 h at 65 °C. The reaction progress was monitored by LC-MS. Upon completion, the resulting solution was used directly in next step.

[0244] Step 2: Into the solution was added Na2CO3(9.05 g, 85.3 mmol, 2.0 equiv), Fmoc- OSu (21.58 g, 64.0 mmol, 1.5 equiv) and THF (100 mL) at 0 °C. The resulting solution was stirred for 3 h at RT. The solution was adjusted to pH = 3 with aq.6 N HCl. The mother liquor was collected by filtration and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with DI water (2 × 400 mL) and brine (400 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was triturated with (DCM / n-heptane = 1:1; v / v), and the solids were collected by filtration to afford (2S,3S)-2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-3-(1H-indol-3-yl)butanoic acid. MS ESI calculated for C27H24N2O4[M + H]+441, found 441.1H NMR (400 MHz, DMSO-d6): 10.88 (s, 1H), 7.87 (d, J = 7.5 Hz, 2H), 7.69–7.56 (m, 3H), 7.39 (t, J = 7.4 Hz, 2H), 7.38–7.21 (m, 4H), 7.18 (d, J = 2.1 Hz, 1H), 7.05 (ddd, J = 8.1, 6.9, 1.2 Hz,, 6.96 (td, J = 7.4, 7.0, 1.1 Hz, 1H), 4.43–4.32 (m, NAI-1542604160v1Attorney Ref. No.14463-061-228 1H), 4.21 (d, J = 10.0 Hz, 1H), 4.16 (t, J = 5.3 Hz, 2H), 3.50 (q, J = 7.1 Hz, 1H), 1.33 (d, J = 7.1 Hz, 3H). Synthetic Scheme 2- - 1H-indol-3-yl)butanoic acid (Fmoc-SbMeW7OMe-OH):

[0245] Step 1: Into a 5 L 4-necked round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed DMSO (640 mL, 4 V), 7-methoxy-1H-indole (50 g, 0.34 mol, 1 equiv), (2S,3R)-2-amino-3-hydroxybutanoic acid (81 g, 0.68 mol, 2 equiv) and 0.2 M potassium phosphate buffer (2300 mL, pH = 8.0, 46 V). The resulting solution was heated to 65 °C. PLP (5 g, 0.02 mol, 0.056 equiv) and PfTrpB 7E6 (50 g, 100 wt. %) were added into the solution. The reaction mixture was stirred overnight at 65 °C. Upon completion, the reaction mixture was used directly in the next step.

[0246] Step 2: Into the reaction mixture were added Na2CO3 (72 g, 0.68 mol, 2.0 equiv), Fmoc-OSu (230 g, 0.68 mol, 2 equiv), and THF (500 mL) at 0 °C. The reaction was stirred for 3 h at RT. The solution was then adjusted to pH = 5-6 with an aq.6 N HCl solution. The mixture was then filtered, and the filtrate was extracted with EtOAc (3 × 1 L). The combined organic layers were washed with DI water (2 × 1 L) and brine (1 L), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by trituration with DCM / heptane (5 V:5 V) for 1 h to yield (2S,3S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(7-methoxy-1H- indol-3-yl)butanoic acid. MS ESI calculated for C28H26N2O5 [M + H]+471, found 471.1H NMR (400 MHz, DMSO-d6): 12.63 (s, 1H), 10.95 (d, J = 2.6 Hz, 1H), 7.87 (dt, J = 7.6, 1.0 Hz, 2H), 7.68–7.61 (m, 2H), 7.40 (tt, J = 7.5, 1.1 Hz, 2H), 7.28 (tdd, J = 7.5, 3.4, 1.1 Hz, 3H), 7.20 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 2.5 Hz, 1H), 6.89 (t, J = 7.8 Hz, 1H), 6.66–6.59 (m, 1H), 4.36 (dd, J = 8.5, 7.2 Hz, 1H), 4.27–4.07 (m, 3H), 3.89 (s, 3H), 3.44 (q, J = 7.1 Hz, 1H), 1.33 (d, J = 7.1 Hz, 3H). NAI-1542604160v1Attorney Ref. No.14463-061-228 8.1.3. Preparation of Final Compounds A. Generalized Procedure for Synthesizing Linear Peptide Precursors

[0247] Peptides in Tables 1 and 2 were synthesized using standard solid-phase synthesis using Fmoc / tBu chemistry as exemplified in Chan, W.C.; White, P.D. “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, N.L. “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.

[0248] During peptide chain elongation, the -amino group of each amino acid was protected with a 9H-fluoren-9-ylmethoxycarbonyl group (Fmoc). To avoid any side reactions during the chain elongation steps, any reactive amino acid side chains also carry acid-labile protecting groups, effectively masking the reactive groups until removal upon treatment with strong acid. After 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 the coupling of the subsequent Fmoc-protected amino acid derivative.

[0249] The side chain protecting groups used were: 1. tert-butyl (tBu) for -Me-L-Ser (aMeS), L-Ser (S), L-Tyr, (Y) Phe4COOH, N-Me-L-Glu (NMeE); 2. trityl (Trt) for L-Asn (N), L-Cys (C); 3. tert-butoxy-carbonyl (Boc) for L-Trp (W), -Me-L-Trp (aMeW), L-His (H), Pip2c.

[0250] Fmoc-protected amino acids were typically obtained from vendors such as Sigma- Aldrich®(Millipore Sigma, St. Louis, MO), Novabiochem®(Millipore Sigma, St. Louis, MO), Chem-Impex (Wood Dale, IL), Combi-Blocks (San Diego, CA), Ambeed (Arlington Hts, IL), AstaTech Inc. (Bristol, PA), Iris Biotech (Marktredwitz, Germany), Acrotein BioChem Inc (Hoover, AL), Amatek (Berwyn, PA), ChemScene LLC (Monmouth Junction, NJ), BLD Pharmatech Co., Limited (Cincinnati, OH), AchemBlock (Hayward, CA), AA Blocks LLC (San Diego, CA), abcr GmbH (Karlsruhe, Germany), Enamine Ltd. (Kyiv, Ukraine), Chem Shuttle (Burlingame, CA), or PharmaBlock (USA), Inc. (Hatfield, PA). NAI-1542604160v1Attorney Ref. No.14463-061-228 B. Synthetic Procedures used to Prepare Thioether Cyclic Peptides Synthetic Scheme 3

[0251] Peptides were synthesized on a Liberty Blue™ synthesizer from CEM Corporation (Matthews, NC), using standard solid-phase synthesis using Fmoc / tBu chemistry as summarized above in Synthetic Scheme 3.

[0252] Reactions were typically performed at a 50 μmol scale using Rink Amide MBHA LL resin (100–200 mesh, 0.4 mmol / g loading, 1% DVB cross-linked polystyrene, Novabiochem®). All the amino acids were dissolved at a 0.2 M concentration in anh. DMF or NMP. The amino acids were activated with equimolar amounts of Oxyma Pure solution (0.5 M in anh. DMF), and a 2-fold molar excess of DIC solution (0.5 M in anh. DMF).

[0253] Every synthesis cycle included: (1) Fmoc amino acid deprotection by 20% v / v piperidine or N-methylmorpholine (NMM) in anh. DMF (90 °C microwave assisted heating, 1 min); (2) Coupling (potentially repeated twice for difficult couplings) with Fmoc-protected amino acid / DIC / Oxyma (5, 5, and 10 equiv, respectively; 90 °C microwave assisted heating, 2 or 4 min). Cycles of Fmoc deprotection and Fmoc-protected amino acid coupling were repeated with the desired monomers until the full linear peptide was formed; (3) The peptide N-terminus was eventually capped with the required 2-chloroacetyl acetyl moiety by coupling with chloroacetic acid and DIC (5 and 10 equiv, respectively; 90 °C microwave assisted heating, 2 min; repeated twice). NAI-1542604160v1Attorney Ref. No.14463-061-228 b) Cleavage and Deprotection

[0254] After completion of the synthesis, the linear resin-bound peptide was transferred into a fritted plastic column. The resin was washed with DCM then dried under negative pressure on a Razor®peptide cleavage system from CEM Corporation (Matthews, NC). The peptide was deprotected and cleaved from the solid support by treatment with TFA / H2O / TIS / DODT (92.5:2.5:2.5:2.5, v / v / v / v; 10 mL) at 38 °C for 30 min. The solution was collected into a 50 mL centrifuge tube. The resin washed with TFA (2 × 2 mL). The cleavage solution was partially concentrated to a volume of ~5 mL under vacuum. The crude linear peptide was precipitated from the TFA cleavage solution using chilled tert-butyl methyl ether (MTBE; 40 mL) and collected by centrifugation (4000 rpm). The supernatant was removed. Additional cold MTBE (30 mL) was added to the peptide pellet and clarified by centrifugation. The resulting crude peptide pellet was blown dried by a stream of nitrogen gas. c) Peptide Cyclization

[0255] The crude solids were dissolved in 1:1 (v / v) mixture of DI water / MeCN (15 mL). The pH was adjusted to pH 8 by addition of an aq.0.2 M ammonium bicarbonate solution (3 mL). The solution was shaken at RT for approximately 2 h and monitored by UPLC-MS. After the reaction was complete, the reaction solution was quenched by addition of TFA (200 μL), frozen and lyophilized. d) HPLC Purification

[0256] The crude residue was then dissolved in DMSO and purified by preparative reversed- phase high performance liquid chromatography on a Waters™ SunFire Prep C18 OBD column (100Å, 5 μm, column size 19 × 150 mm, Milford, MA) using an Agilent MS-Directed Preparative HPLC-MS system. Mobile phase: (A) 0.1% TFA in HPLC-grade water and (B) 0.1% TFA in HPLC-grade acetonitrile; flow rate: 35 mL / min; UV wavelength = 215 nm; gradient: gradient: 0.5%B / min for 40 min starting at 5%B less than the calculated %B required for compound elution. In some instances, better separation was obtained by 0.1% NH4OH as modifier.

[0257] UV absorbing fractions containing the target m / z ions were collected and the fractions containing the desired product were combined, concentrated in vacuo, and freeze-dried to afford the cyclized peptide as a solid.

[0258] Confirmation of identity and purity assessment of final compounds were performed by UPLC-MS, which was measured by a reverse phase Waters™ ACQUITY UPLC-MS system. Column: Waters™ Cortecs C18+ Column (90 Å, 1.6 μm, column size 2.1 × 100 mm). Mobile phase: (A) 0.1% TFA in HPLC-grade water and (B) 0.1% TFA in HPLC-grade acetonitrile; NAI-1542604160v1Attorney Ref. No.14463-061-228 injection volume: 0.5 μL; flow rate: 0.7 mL / min; Column Temperature: 60 °C; UV wavelength = 215 nm; gradient: 2–35% in 9.1 min. Synthetic Scheme 4 STrt Solid-phase peptide synthesis Oa) Solid Phase Synthesis of Peptides (SPPS)

[0259] Peptides were synthesized on a Biotage®Syro II peptide synthesizer (Biotage Corporation, Boston, MA) using standard solid-phase synthesis using Fmoc / tBu chemistry as summarized above in Synthetic Scheme 6.

[0260] Reactions were typically performed at the 10 μmol or 25 μmol scale using Rink Amide MBHA LL resin (100–200 mesh, 0.4 mmol / g loading, Novabiochem®). Solutions of the reagents and amino acid monomers were prepared as follows: Fmoc-protected amino acids (0.2 M or 0.4 M in anh. DMF, NMP, or DMSO), HATU (0.5 M in anh. DMF), DIPEA (2.0 M in anh. NMP), (ClAc)2O (0.4 M in anh. DMF), 4-methylpiperidine (20% v / v in anh. DMF).

[0261] Every synthesis cycle included: (1) Single or double coupling with Fmoc-protected amino acid / HATU / DIPEA (4, 4 and 8 equiv, respectively; at 50 °C or 75°C; 15 min for single coupling or 15 min + 30 min for double coupling). After the coupling reaction was complete the mixture was filtered, and the peptidyl resin was washed with DMF; (2) Fmoc deprotection (repeated three times) using 20% (v / v) 4-methylpiperidine in DMF (RT; 3 min). The mixture was filtered, and the peptidyl resin was washed with DMF. Cycles of Fmoc deprotection and Fmoc-protected amino acid coupling were repeated with the desired monomers until the full linear peptide was formed; (3) The peptide N-terminus was capped by the addition of (ClAc)2O and DIPEA (10 and 20 equiv, respectively; repeated twice) in anh. DMF, then the peptidyl resin was washed with DCM. NAI-1542604160v1Attorney Ref. No.14463-061-228 b) Cleavage and Deprotection

[0262] After completion of the synthesis, the linear resin-bound peptide was washed with DCM then dried under positive nitrogen pressure on a peptide cleavage system from Biotage Corporation, Boston, MA.

[0263] The peptide was deprotected and cleaved from the solid support by treatment with TFA / H2O / TIS / DODT (92.5:2.5:2.5:2.5, v / v / v / v; 2 mL) at RT for 1 h. The solution was collected into a 50 mL centrifuge tube. The resin washed with TFA (1 mL). The crude linear peptide was precipitated from the TFA cleavage solution using chilled Et2O (30 mL) and collected by centrifugation (4000 rpm). The supernatant was removed. Additional cold Et2O (30 mL) was added to the peptide pellet and clarified by centrifugation. The resulting crude peptide pellet was blown dried by a stream of nitrogen gas. c) Peptide Cyclization

[0264] The crude solids were re-dissolved in DMSO (1.5 mL). The pH was adjusted by addition of 2.0 M DIPEA in NMP solution (0.5 mL). The solution was shaken at RT for approximately 12 h and monitored by UPLC-MS. After the reaction was complete, the cyclization mixture was acidified by the addition of 40 L glacial acetic acid and the resulting solutions were filtered and submitted for RP-purification. d) HPLC Purification

[0265] Purification was performed by preparative reversed-phase high performance liquid chromatography (RP-HPLC) on Waters™ X-Bridge Prep C18 OBD Prep column (130 Å, 5 pm, column size 19 × 100 mm) using a Waters™ MS-Directed AutoPurification HPLC-MS system. Mobile phase: (A) 0.16% TFA in HPLC-grade water and (B) 0.16% TFA in HPLC-grade acetonitrile; flow rate: 25 mL / min; UV wavelength = 215 nm; gradient: 25–50% B over 5 min. Alternatively purification was performed on Waters™ CSH-C18 Column (19 × 250 mm, 5 m) using an Agilent, with 1290 infinity II preparative LC system and LC-MSD XT mass spectrometer. Mobile phase: (A) 0.1% formic acid in HPLC-grade water and (B) 0.1% formic acid in HPLC-grade acetonitrile; flow rate: 25 mL / min; UV wavelength = 215 nm; gradient: 20% B over 2.5 min, then increasing to 55% B over the next 17.5 min. UV absorbing fractions containing the target m / z ions were collected and the fractions containing product were confirmed by LC-MS.

[0266] Confirmation of identity and purity assessment of final compounds were performed by UPLC-MS, which was measured by a reverse phase Waters™ ACQUITY UPLC-MS system. Column: Waters™ XSelect CSH C18 Column (130 Å, 2.5 μm, column size 2.1 × 50 mm). Mobile phase: (A) 0.05% TFA in HPLC-grade water and (B) 0.05% TFA in HPLC-grade NAI-1542604160v1Attorney Ref. No.14463-061-228 acetonitrile; injection volume: 1 μL; flow rate: 1 mL / min; UV wavelength = 215 nm; gradient: 5–100% B in 5 min. Lyophilization of combined fractions containing pure peptide resulted in the final cyclized product as a powder. C. Synthetic Procedures used to Prepare Macrolactam Cyclic Peptides Synthetic Scheme 53.a) Solid Phase Synthesis of Peptides (SPPS)

[0267] Peptides were synthesized on a Liberty Blue™ synthesizer from CEM Corporation, using standard solid-phase synthesis using Fmoc / tBu chemistry as summarized above in Synthetic Scheme 9.

[0268] Reactions were typically performed at a 100 μmol scale using 2-chlorotrityl chloride resin (100–200 mesh, 1% DVB, 1.71 mmol / g loading, Novabiochem®) or 2-chlorotrityl chloride resin preloaded with the starting amino acid (0.66 mmol / g loading, Novabiochem®), based on the synthetic strategy.

[0269] The loading of the initial C-terminal amino acid to the 2CTC resin was performed in a fritted plastic syringe by treating with 1.0 millimolar excess of Fmoc-protected amino acid solution (0.2 M in a 4:1 (v / v) DCM / NMP mixture) and 5-fold molar excess of DIPEA at RT for 45 min. MeOH (0.4 mL) was added and the slurry was shaken for 15 min at RT. The resin was drained and washed with DMF. The Fmoc-protecting group was removed by treating with piperidine (20% v / v in DMF) at RT for 10 min. This process was repeated once more (twice total). The resin was washed with DMF, MeOH and DCM and dried under vacuum. NAI-1542604160v1Attorney Ref. No.14463-061-228

[0270] Every synthesis cycle included: (1) Fmoc amino acid deprotection by 20% v / v piperidine in anh. DMF (50 °C microwave assisted heating, 10 min; repeated twice); (2) Coupling (potentially repeated twice for difficult couplings) with Fmoc-protected amino acid / HATU / DIPEA (5, 5, and 10 equiv, respectively; 50 °C microwave assisted heating, 10 min). Cycles of Fmoc deprotection and Fmoc-protected amino acid coupling were repeated with the desired monomers until the full linear protected peptide was formed; (3) The peptide N- terminus was deprotected using 20% v / v piperidine in DMF (50 °C microwave assisted heating, 10 min; repeated twice). b) Cleavage of Protected Linear Peptide

[0271] After completion of the synthesis, the linear resin-bound peptide was transferred into a fritted plastic column. The resin was washed with DCM then the linear peptide was cleaved off the solid support by treatment with HFIP / DCM (3:7, v / v; 5 mL) at RT for 5 min. The solution was collected into a round bottom flask. This process was repeated twice more (three times total), and the cleavage solution was combined. The solvents were removed under reduced pressure. c) Solution Phase Macrolactamization

[0272] The crude protected linear peptide was resuspended in anh. THF (1.5 mg / mL). Anhydrous DMF (500 L) was added. DIPEA (5 equiv), HOAt (0.8 equiv) and HATU (1.2 equiv) were added to the peptide solution and the solution stirred at RT. The reaction was monitored by UPLC-MS and stopped after complete conversion of the starting material. The reaction solution was then concentrated under reduced pressure to dryness. d) Deprotection of the Protected Cyclic Peptide

[0273] The cyclic peptide was deprotected by treatment with TFA / H2O / TIS / Phenol (90:2:4:4, v / v / v / w; 15 mL) at RT for 1 h. The crude cyclic peptide was precipitated from the TFA cleavage solution using chilled MTBE (50 mL) and collected by centrifugation. The supernatant was removed. Additional cold MTBE (40 mL) was added to the peptide pellet and clarified by centrifugation. This process was repeated once more (twice total). The resulting crude peptide pellet was dissolved in 1:1 (v / v) mixture of DI water / MeCN (10 mL) and 5% (v / v) of TFA was added to the solution to remove the tryptophan adduct. The solution was frozen and lyophilized. e) HPLC Purification

[0274] The crude residue was then dissolved in DMSO and purified by preparative reversed- phase high performance liquid chromatography on a Waters™ Xbridge Protein BEH C4 OBD prep column (300Å, 5 μm, column size 30 × 250 mm) using a Waters™ 2545 HPLC system NAI-1542604160v1Attorney Ref. No.14463-061-228 equipped with Waters™ 2489 UV / Visible detector. Mobile phase: (A) 0.1% TFA in HPLC- grade water and (B) 0.1% TFA in HPLC-grade acetonitrile; flow rate: 50 mL / min; UV wavelength = 214 nm; gradient: 0.5%B / min starting at 5% B less than the calculated %B required for compound elution over 20 min. UV absorbing fractions containing the target were collected and the fractions containing the desired product were combined, concentrated in vacuo and freeze-dried to afford the cyclized peptide as a solid.

[0275] Confirmation of identity and purity assessment of final compounds were performed by UPLC-MS, which was measured by a reverse phase Waters™ ACQUITY UPLC-MS system. Column: Waters™ ACQUITY UPLC Protein BEH C4 (300 Å, 1.7 μm, column size 2.1 × 100 mm, Milford, MA). Mobile phase: (A) 0.1% TFA in HPLC-grade water and (B) 0.1% TFA in HPLC-grade acetonitrile; injection volume: 0.5 μL; flow rate: 0.4 mL / min; Column Temperature: 45 °C; UV wavelength = 214 nm; gradient: 20–20% B in 1 min and 20–40% in 3 min. Synthetic Scheme 6NAI-1542604160v1Attorney Ref. No.14463-061-228 D. Synthesis of Specific Compounds SEQ ID NO:4K(biotin)-NH2; SEQ ID NO:4) was prepared using Synthetic Procedure A starting with Fmoc- Lys(biotin)-OH (Novabiochem®, cat. # 852097) and adding a Gly–Aea spacer (SEQ ID NO:5) attached to the carboxy moiety of the C-terminal cysteine. MS ESI calculated for C121H145ClN25O28S2[M + 2H]2+1231.51, found 1231.5. 8.2. EXAMPLE 2: BIOLOGICAL ASSAYS 8.2.1. Procedure For Human STNFR1-Peptide Displacement Assay

[0277] The affinity was determined using LanthaScreen Eu-based time-resolved fluorescence resonance energy transfer (TR-FRET)–based binding assay.

[0278] A TR-FRET assay measuring the displacement of biotinylated peptide SEQ ID NO:4 from human sTNFR1 in a pre-formed complex by a macrocyclic peptide yields the affinity (Kdapp) of the cyclic peptide for sTNFR1. The reagents for the assay include: the C’- terminally 6His-tagged sTNFR1 (residues 1-211) protein purified from a Sf21 baculovirus expression system, the biotin-tagged B0372 peptide described in section “Preparation of Final Compounds”, part E, the LanthaScreen™ anti-His Tag Europium donor (Life Technologies Corporation (San Diego, CA), cat. # PV5597), and a streptavidin-conjugate Alexa Fluor™ 647 acceptor (Invitrogen (Waltham, MA), cat. # S32357). Time-resolved TR-FRET is achieved NAI-1542604160v1Attorney Ref. No.14463-061-228 when sTNFR1 is bound to biotinylated peptide SEQ ID NO:4 through coupling of the donor and acceptor FRET pair.

[0279] 100 nM biotinylated peptide SEQ ID NO:4 and 0.25 nM sTNFR1-6His are added to a binding buffer (1× DPBS, Gibco™, cat. # 20012-027 with 0.1% BSA and 0.05% Tween® 20) to form the protein-peptide complex.100 nM biotinylated peptide SEQ ID NO:4 was chosen as it reflects the ~Kdfor this complex. After 30 min at ambient temperature, each test peptide (2 mM stock in DMSO) is titrated in a 20 point, ~3-fold discrete dose-response using an acoustic- dispense liquid handler. Specifically, 80 nL of peptide / DMSO is transferred into a ProxiPlate- 384 Plus 384-well assay plate (PerkinElmer, cat. # 6008289). To this plate, 8 μL of the previously formed sTNFR1– biotinylated peptide SEQ ID NO:4 complex is added and allowed to reach binding equilibrium with the test peptide at ambient temperature for 90 min. For TR- FRET detection, 8 μL of 0.25 nM of LanthaScreen™ anti-His Tag Europium and 25 nM of streptavidin-conjugate Alexa Fluor™ 647 in the same binding buffer are added to the assay plate and read on an EnVision®plate reader (PerkinElmer (Boston, MA)) after a 90 min final incubation.

[0280] The TR-FRET signal is measured with the following EnVision®settings: excitation laser at 337 nm; emission1 = 615 nm, emission2 = 665 nm, LANCE / DELFIA dichroic mirror, delay time = 100 ms. The signal of each well is determined as the ratio of the emission at 665 nm to that at 615 nm. Percent displacement is determined by normalization to control wells containing DMSO (0%) or a saturating concentration of a displaceable peptide (100%). The %– effect as a function of peptide concentration is fit to a five-parameter logistic fitMorrison equation to account for tight binding kinetics. The inflection point of the 5-parameter fit is the measured Kdappreported in Table 3. It should be noted that peptides with weaker binding affinity where tight binding was not observed under these assay conditions were titrated with 10 pts titration range and dose-response curves were analyzed using a 4-parameter logistic model to calculate IC50 values (Table 3). sTNFR1 sequence (SEQ ID NO:15): LVPHLGDREKRDSVCPQGKYIHPQNNSICCTKCHKGTYLYNDCPGPGQDTDCRECESGSFTASENHL RHCLSCSKCRKEMGQVEISSCTVDRDTVCGCRKNQYRHYWSENLFQCFNCSLCLNGTVHLSCQEKQN TVCTCHAGFFLRENECVSCSNCKKSLECTKLCLPQIENVKGTEDSGTTGGGLNDIFEAQKIEWHELE VLFQGPHHHHHHGSWSHPQFEK 8.2.2. Procedure for Binding Affinity and Selectivity Measured by SPR

[0281] Affinity and selectivity for hTNFR1 and TNFR2 was determined using SPR. Human TNFR1 or TNFR2 genes (extracellular domain only) were synthesized with a C-terminal Avi- NAI-1542604160v1Attorney Ref. No.14463-061-228 tag, HRV 3C protease cleavage site followed by a 6His-tag for affinity purification. The final gene product was cloned into pBAC™-1 vector (Millipore Sigma) for expression testing in insect cells. Constructs were transfected into Sf21 cells for baculovirus generation followed by protein expression analysis in Sf21 and Tni cell lines. Large scale expression in Sf21 cells was performed using baculovirus infected insect cells (BIICs) infected at a MOI = 2.0 grown for 72 h. Target proteins secreted into the media were harvested via centrifugation and concentrated using diafiltration. TNFR was purified by immobilized metal ion affinity chromatography (IMAC) using a Ni-Sepharose HisTrap™ column (Cytiva™). Isolated TNFR had His tag removed using HRV 3C protease followed by additional purification using Ni-NTA chromatography. Biotinylation was performed on Ni-NTA flow-through fractions concentratedto 45 M and treated with BirA ligase (1:100, g / g ratio) in 50 mM Tris pH 7.5, 150 mMNaCl, 50 μM biotin, 10 mM magnesium acetate, 10 mM ATP at 4 °C for 20 h. Final purification of biotin-TNFR and buffer exchange into 20 mM HEPES pH 7.5, 150 mM NaCl was performed using a HiLoad® Superdex® 20026 / 60 column (Cytiva™). Highly purified protein was aliquoted and stored at -80 °C. Human TNFR1 construct sequence (SEQ ID NO:16): MGLSTVPDLLLPLVLLELLVGIYPSGVIGLVPHLGDREKRDSVCPQGKYIHPQNNSICCTKCHKGTY LYNDCPGPGQDTDCRECESGSFTASENHLRHCLSCSKCRKEMGQVEISSCTVDRDTVCGCRKNQYRH YWSENLFQCFNCSLCLNGTVHLSCQEKQNTVCTCHAGFFLRENECVSCSNCKKSLECTKLCLPQIEN VKGTEDSGTTGGGLNDIFEAQKIEWHELEVLFQGPHHHHHHGSWSHPQFEK Human TNFR2 construct sequence (SEQ ID NO:17): MAPVAVWAALAVGLELWAAAHALPAQVAFTPYAPEPGSTCRLREYYDQTAQMCCSKCSPGQHAKVFC TKTSDTVCDSCEDSTYTQLWNWVPECLSCGSRCSSDQVETQACTREQNRICTCRPGWYCALSKQEGC RLCAPLRKCRPGFGVARPGTETSDVVCKPCAPGTFSNTTSSTDICRPHQICNVVAIPGNASMDAVCT STSPTRSMAPGAVHLPQPVSTRSQHTQPTPEPSTAPSTSFLLPMGPSPPAEGSTGDGGGLNDIFEAQ KIEWHELEVLFQGPHHHHHHGSWSHPQFEK

[0282] The SPR assay uses a Cytiva™ 8K or 8K+ biosensor instrument to measure the kinetics of peptide analytes binding to captured human TNFR1 extracellular domain (ECD) protein; peptide analytes are also evaluated for any off-target binding to human TNFR2 ECD protein in parallel. Recombinant human TNFR1 ECD and human TNFR2 ECD proteins, biotinylated via engineered C-terminal avi-tags, are immobilized to a regenerable streptavidin biosensor chip surface (Cytiva™ Biotin CAPture kit, Series S; cat. # 28920234). Peptide analytes binding to immobilized human TNFR1 ECD protein and their subsequent dissociation are conducted in a buffer of 10 mM HEPES pH 7.4, 150 mM NaCl, 3 mM EDTA, 0.05% P20, 2% DMSO under laminar flow conditions and measured in response units (RU), which are NAI-1542604160v1Attorney Ref. No.14463-061-228 directly proportional to the accumulated mass on the surface of the biosensor chip; the biosensor chip surface is regenerated via Cytiva™ proprietary methods between the evaluation of each peptide analyte. The binding and dissociation of peptide analytes are displayed as sensorgrams in real time and recorded for subsequent determination of binding kinetics. The SPR assay determines the association and dissociation rate constants, kon and koff, for each peptide analyte and, from these values, calculates the binding affinity, Kd,reported in Table 3. 8.2.3. Procedure for THP-1 Lucia NF- B cells

[0283] The inhibition of TNF -induced NF- B signal transduction pathways was evaluatedin THP-1 cells. THP-1 cells harboring NF- B-inducible Lucia™ reporter gene (InvivoGen, cat.# thp1-nfkb) designed for monitoring NF- B signal transduction pathway was employed toassess the inhibitory effect macrocyclic peptides on TNFR1 signaling. The cells were cultured in media containing RPMI 1640, 2 mM L-glutamine, 25 mM HEPES, 10% heat-inactivated fetal bovine serum with appropriate selection antibiotics. Assays were performed in media that was devoid of selection antibiotics. For profiling, 125 nL of peptides in DMSO (10 mM) were dispensed into Falcon® 384-well Optilux white / clear flat bottom TC-treated microtest microplate (Corning, cat. # 353963) using Echo® 555. The peptides were tested in a dose response to determine EC50’s [10 or 1 μM top concentration and 1:3 dilutions]. A suspension of 1 million cells / mL was dispensed at 20 μL / well in a 384-well plate to a density of 20,000 cells / well and pre-incubated with peptides at 37 °C for 1 h. Subsequently, 5 μL of TNFcontaining media (recombinant human TNF ; R&D Systems USA, cat. # 210-TA-005 / CF) orTNF-free media (for controls) was added to the wells. The final concentration of TNF in theassay in 10 ng / mL. After overnight incubation at 37 °C (16–18 h), 5 μL of supernatant was aspirated and transferred to a 384-well microplate (PerkinElmer, cat. # 6007680) for measurement of secreted luciferase activity with 25 μL of QUANTI-Luc™ luminescence assay reagent (InvivoGen, cat. # rep-qlc1) in each well. The luminescence was measured in EnVision® Multimode Plate Reader (PerkinElmer). Dose response curves were analyzed using a 4-parameter logistic model to calculate IC50 values, reported in Table 3, using TIBCO® Spotfire® software employing appropriate Minimum and Maximum controls.

[0284] The amino acid sequences, synthetic procedure used to synthesize and purify the macrocyclic peptides, calculated monoisotopic masses, molecular formulas, calculated molecular weights and mass spectral data for Compounds A-D (SEQ ID NOS: 6, 7, 8, and 9) are provided below in Table 2. NAI-1542604160v1de+v2 ++2+ren ] ] ]2]o HHH H sI2+2 2M2H H06 6 110 0 1C1 1 1C C C .ltoh)gl2io286078m.3.6.9 3.4Me / 2 9 7 6Wg(02020222erudecB C C A orP- - - )c- 2 -Y-p -- N- E9- -SH 6-lOH-2piPH- Hi l -)P-C7-r-aG :saPOH OH-lO a OO Oe la prH-ra ) S- -)C Oe 4-C4eON-Nc ) PC4CM OP4-T-lOS-eW- -nph hC4C 4-e eh 4e7elaO C2M OS-W- 2DeAP-eh - lNP- hP WeN- P4- 4eH N7YraH Iuq-cN- P-We -u N-SMueNhOWe-FS- N- QeSAl Pd SeMe -Eeb L-PcE-SC -3McY- EESC ((-oMa-rLcheMaS--rhb e e eh bSAlY- Dl-cWea-l aS bM (NlCaS(oM NMa PC( S- AycMba osSN2l-cW7plrcy- ol Wc Wcy-dyc T cY nuoQ pE D.IO N6 7 8 9mSoCd1v06:n2u1e o4l p0A B C D62bam4o51-IT C A N

[0285] The biological activities (binding IC50and Kdappin the displacement assay, affinity KD, and cell activity in THP-1 cells) of Compounds A-D (SEQ ID NOS: 6, 7, 8, and 9 as disclosed herein) are provided below in Table 3. Table 3: Biological Activities of Compounds Nos. A-D (SEQ ID NOs: 6-9) TR- TR- SEQ IFRET, FRET, SPR, SPR, THP-1, CompoundDhTNFR1 hTNFR2 IC50R18.3.1. Expression And Purification of TNFR1 and TNFAlpha

[0286] Various constructs of the extracellular domain of TNFR1 or complexedTNF / extracellular domain of TNFR1 were recombinantly expressed and purified bychromatography. TNFR1_V7 was expressed using Baculovirus cells and purified from the growth medium by nickel-affinity chromatography followed by size exclusion chromatography. Pure protein was concentrated to 6 mg / mL. TNFR1_V14, V1 and V10 were expressed using E. coli cells, the protein was solubilized and isolated from the inclusion bodies, refolded and purified by Ion-exchange and size exclusion chromatography. Pure protein was concentrated to18 mg / mL. Human TNF was expressed and purified from E. coli cells with an N-terminal HIS-tag. The protein was purified by affinity and size exclusion chromatography steps including r NeAmI-1o5v42a6l04 o1f60 tvh1e HIS-tag. 8.3.2. Crystallography Protocol

[0287] Co-crystals were grown by the hanging drop method of vapor diffusion in 96-well format. Crystallization trials were set up for each of the peptides at a protein:peptide molar ratio 1:1.5 at both 4 and 18°C using the respective constructs. Broad screening of crystallization conditions was performed using commercially available screens. Screening set-up was performed using a Mosquito (TTP Labtech) dispensing 200 nL of sample solution in two separate sub-wells, to which 100-200 nL of precipitant solution was added. The mixture was incubated at 18 °C in a Rockimager (Formulatrix). Crystals appeared between a period of 2 to 45 days. For flash- freezing and data collection, a cryoprotectant solution at a pH and a precipitant concentration matching the crystallization conditions and augmented with 20% v / v glycerol was added to theAttorney Ref. No.14463-061-228 crystallization drop. The crystals were then harvested with a LithoLoop (Molecular Dimensions) and flash-frozen in liquid nitrogen.

[0288] The X-ray data sets were collected at a wavelength of 1 Å either at the Industrial Macromolecular Consortium Association (IMCA) beamline at the Advanced Photon Source (APS), or at the macromolecular crystallography beam line at the Canadian Light Source (CLS). Data sets were indexed and scaled using the autoPROC (Global Phasing) software with calls to XDS, POINTLESS (CCP4) and STARANISO (Global Phasing) for integration, space group determination and scaling, respectively. The structure was solved by molecular replacement using the MOLREP program (CCP4). Structures were refined using COOT (CCP4) and autoBUSTER (Global Phasing). The constructs that were co-crystallized with each compound is shown below in Table 4. Table 4: TNFR1 Constructs for Crystallization Studies Compound Binding Compound TNFR1 Construct Amino Acid Sequence MECESGSFTA SENHLRHCLS CSKCRKEMGQAttorney Ref. No.14463-061-228 Compound TNFR1 Construct Amino Acid Sequence MDSVCPQGKY IHPQNNSICC TKCHKGTYLY NDCPGPGQDT DCRECESGSF TASENHLRHC125 mM zinc chloride solution was added to one of the aliquots to a final concentration of 1 mM. Broad screening of crystallization conditions was performed using commercially available screens at 18 °C. Screening set-up was performed using a Mosquito (TTP Labtech) dispensing 200 nL of sample solution with or without exogenous zinc in two separate sub-wells, to which 100-200 nL of precipitant solution was added. The mixture was incubated at 18 °C in a RockImager (Formulatrix). Crystals appeared between a time period of 2 to 45 days. For flash- freezing and data collection, a cryoprotectant solution at a pH and a precipitant concentration matching the crystallization conditions and augmented with 20% v / v glycerol was added to the crystallization drop. The crystals were then harvested with a LithoLoop (Molecular Dimensions) and flash-frozen in liquid nitrogen.

[0290] Data collection was performed either at the Industrial Macromolecular Consortium Association (IMCA) beamline at the Advanced Photon Source (APS), or at the macromolecular crystallography beam line at the Canadian Light Source (CLS). Data were processed using the autoPROC (Global Phasing) software with calls to XDS, POINTLESS (CCP4) and STARANISO (Global Phasing) for integration, space group determination and scaling, respectively. The structure was solved by molecular replacement using the MOLREP program (CCP4). Structures were refined using COOT (CCP4) and autoBUSTER (Global Phasing). 8.3.3. Cryo-EM Grid Preparation and Data Collection

[0291] TNF , TNFR_V7 construct, and Compound B were mixed in the final buffercomposition was 20 mM Tris, pH 8.0, and 100 mM NaCl at a molar ratio of 1:3:6 and incubatedfor an hour in ice. Aliquots (3 L) of purified complex were applied to glow-discharged (20 s oncarbon side) C-flat 20 nm thickness holey carbon-on-gold grids (300 mesh, R1.2 / 1.3). The gridswere blotted for 3 s at 95% humidity and plunge-frozen into liquid ethane using a Vitrobot MarkIV (Thermo Fisher Scientific). Grids were imaged on a 300 keV Titan Krios cryo-electronmicroscope (Thermo Fisher Scientific) equipped with an energy filter (Gatan GIF BioQuantum) and a post-GIF Gatan K3 Summit direct electron detector. Images were taken on the K3 camerain dose-fractionation mode at a calibrated magnification of 105000, corresponding to 0.84 Å perphysical pixel (0.42 Å per super-resolution pixel). The dose fractionation on the specimen was setAttorney Ref. No.14463-061-228 to be 1.0625 electrons per Å2 per frame and the total number of frames was 40, resulting in atotal dose of 42.5 electrons per Å2. An energy slit with a width of 20 eV was used during datacollection. Fully automated data collection was carried out using Latitude in Gatan Imaging Suite(Gatan Inc.) with a nominal defocus range set from -0.6 to -2.0 m. Image Shift was used withnine exposure groups per stage shift to improve the throughput of data collection. A total of 12000 movies were collected for the sample. 8.3.4. Cryo-EM Data Processing

[0292] The cryoSPARC Live application of cryoSPARC v2 (Structura Biotechnology) was used to streamline the movie processing, CTF estimation, particle picking, and 2D classification. Preprocessing involved anisotropic motion correction and local CTF estimation. The data werecurated by keeping only data with better than 6 Å determined by CTF fit resolution. Particlepicking started with blob picking ~150 Å in diameter. Once a small set of particles was extractedand 2D class averages were obtained, the good 2D classes were used as templates for picking on the entire dataset. Then ab initio 3D reconstruction was carried out in cryoSPARC v2. Homogenous refinement coupled with nonuniform and global CTF refinements gave the final 3Dreconstructions at 3.2 Å. The structure was built starting from atomic models of close homologs.Manual adjustments to the models were performed using Coot and automated refinement was performed using Phenix. Coordinates and restraints for peptides were generated using Grade (Global Phasing Ltd.) and was manually fitted into the density using real-space refinement in Coot and further refined using Phenix. Model quality was assessed using Molprobity as implemented in Phenix.

[0293] FIGs.3A-3B depict two-dimensional representations of a fragment of Compound B bound in the binding pocket of the TNFR1 showing interactions between the compound and the pocket. FIGs.4A-4B depict (A) a three-dimensional top view and (B) a three-dimensional bottom view of the TNFR1 binding pocket when bound to Compound A, Compound B, Compound C, and Compound D of the disclosure, as determined by X-ray crystallography and presented as an overlay. A three-dimensional cartoon representation of Compound B bound in the binding pocket of the TNFR1 is shown in FIGs.5A (binding pocket not shown) and 5B (binding pocket shown). FIG.6 is a superimposed imaged depicting the displacement of the CDR4 of the TNFR1 upon binding of Compound B. The green portion of FIG.6 represent the unbound TNFR1 and red represents TNFR1 bound to Compound B. This displacement is seen with each of Compounds A, B, C, and D as disclosed herein.

Claims

Attorney Ref. No.14463-061-228 CLAIMS What is claimed is:

1. A method of inhibiting a tumor necrosis factor receptor 1 (TNFR1)-mediated activity comprising contacting a TNFR1 with a compound that binds to TNFR1 at a binding pocket between CRD3 and CRD4 of TNFR1.

2. The method of claim 1 or 2, wherein the TNFR1 is a membrane-bound TNFR1.

3. The method of any one of claims 1-3, wherein the TNFR1 comprises an amino acid sequence according to SEQ ID NO:

1.

4. The method of any one of claims 1-3, wherein the binding pocket of the TNFR1 comprises amino acid residues Asn134, Thr135, Cys137, and Asn148 of SEQ ID NO:

1.

5. The method of any one of claims 1-4, wherein the binding pocket of the TNFR1 comprises or further comprises one or more of amino acid residues Ser118, Leu119, Cys120, Leu121, and Asn122 of SEQ ID NO:

1.

6. The method of any one of claims 1-5, wherein the binding pocket of the TNFR1 comprises or further comprises one or more of amino acid residues Thr 138, Cys 139, Leu145, Asn148, Glu149, and Cys150 of SEQ ID NO:

1.

7. The method of any one of claims 1-6, wherein the binding pocket of the TNFR1 is defined by amino acid residues Ser118, Leu119, Cys120, Leu121, Asn122, Cys137, Thr138, Cys139, Leu145, Asn148, Glu149, and Cys150 of SEQ ID NO:

1.

8. The method of any one of claims 1-7, wherein the compound binds to the TNFR1 at one or more of residues Asn134, Thr135, Cys137, and Asn148 of SEQ ID NO:

1.

9. The method of any one of claims 1-8, wherein the compound comprises at least one moiety selected from: a) an H-bond interaction moiety capable of donating an H-bond to residue Asn148 of the TNFR1; b) an H-bond interaction moiety capable of accepting an H-bond from residue Cys137 of the TNFR1; andAttorney Ref. No.14463-061-228 c) an H-bond interaction moiety capable of donating an H-bond to residue Cys137 of the TNFR1.

10. The method of claim 9, wherein the compound further comprises at least one moiety selected from: a) an H-bond interaction moiety capable of donating an H-bond to residue Thr135 of the TNFR1; and b) an H-bond interaction moiety capable of accepting an H-bond from residue Asn134 of the TNFR1.

11. The method of any one of claims 1-10, wherein the compound comprises a peptide.

12. The method of claim 11, wherein the compound is a cyclic peptide.

13. The method of claim 12, wherein the compound comprises 12-18 amino acid residues.

14. The method of any one of claims 1-13, wherein the compound comprises an amino acid sequence, and wherein the compound binds to the binding pocket of TNFR1 via an aliphatic side chain on the first amino acid in the sequence.

15. The method of any one of claims 1-14, wherein the compound comprises an amino acid sequence, and wherein the compound binds or further binds to the binding pocket of TNFR1 via a bicyclic aryl or heteroaryl moiety on the eighth amino acid in the sequence.

16. The method of claim 15, wherein the bicyclic aryl or heteroaryl moiety is naphthyl or indolyl.

17. The method of any one of claims 1-16, wherein the compound comprises an amino acid sequence, and wherein the compound binds or further binds to the binding pocket of TNFR1 via a monocyclic aryl moiety on the tenth amino acid of the sequence.

18. The method of claim 17, wherein the monocyclic aryl moiety is phenyl.

19. The method of claims 1-18, wherein the compound comprises an amino acid sequence, and wherein the compound binds or further binds to the binding pocket of TNFR1 via a hydroxyl moiety or an amine moiety on the third amino acid in the sequence.Attorney Ref. No.14463-061-228 20. The method of claim 19, wherein the hydroxyl moiety or an amine moiety is comprised within an hydroxymethyl moiety, a piperidinyl moiety, or a piperazinyl moiety.

21. The method of claims 1-20, wherein the compound comprises an amino acid sequence, and wherein the compound binds or further binds to the binding pocket of TNFR1 via a hydroxyl moiety on the ninth amino acid in the sequence.

22. The method of claim 21, wherein the hydroxyl moiety is comprised within an hydroxymethyl moiety.

23. The method of any one of claims 14-21, wherein the eighth amino acid binds to Cys137 of the TNFR1 of SEQ ID NO:

1.

24. The method of any one of claims 14-23, wherein the tenth amino acid binds to Asn134 of the TNFR1 of SEQ ID NO:

1.

25. The method of any one of claims 14-24, wherein the third amino acid binds to Asn148 of the TNFR1 of SEQ ID NO:

1.

26. The method of any one of claims 14-24, wherein the ninth amino acid binds to Thr135 of the TNFR1 of SEQ ID NO:

1.

27. The method of any one of claims 14-26, wherein the first amino acid is (S)-2- aminoheptanoic acid (Ahp), L-norleucine (Nle), or L-phenylalanine (F).

28. The method of any one of claims 14-27, wherein the third amino acid is (S)-piperazine-2- carboxylic acid (Pip2c), (S)-piperidine-2-carboxylic acid (Pip), or L-serine (S).

29. The method of any one of claims 14-28, wherein the eighth amino acid is 3-(2-naphthyl)- L-alanine (2Nal), (S)-2-amino-3-(7-chloro-1H-indol-3-yl)propanoic acid (Trp7Cl), or L- tryptophan (W).

30. The method of any one of claims 14-29, wherein the ninth amino acid is -methyl-L- serine (aMeS) or L-Serine (S).

31. The method of any one of claims 14-30, wherein the tenth amino acid is L-tyrosine (Y) orL-phenylalanine-4-carboxylic acid (Phe4COOH).Attorney Ref. No.14463-061-228 32. The method of any one of claims 1-31, wherein the compound has a molecular weight of from about 1200 Da to about 3000 Da, from about 1500 Da to 2500 Da, or from about 1750 Da to about 2250 Da.

33. A method of inhibiting a TNFR1-mediated activity, comprising contacting the TNFR1 with a first compound that competes with a second compound for binding to TNFR1 at a binding pocket between CRD3 and CRD4 of TNFR1, wherein the second compound comprises or consists of a sequence selected from: a) ClAc*-Ahp-4Pal-S-SbMeW-dP-N-Phe4COOH-2Nal-aMeS-Phe4COOH-H-Sar- aMeW-C*-NH2(SEQ ID NO:6); b) Nle*-4Pal-Pip2c-W-NMeE-N-Phe4COOH-Trp7Cl-aMeS-Phe4COOH-Y-Sar- SbMeW7OMe-bhcLeu* (SEQ ID NO:7); c) Nle*-4Pal-Pip-W-NMeE-N-4Pal-Trp7Cl-aMeS-Phe4COOH-Phe3CONH2-Sar- SbMeW7OMe-bhcLeu* (SEQ ID NO:8); or d) ClAc*-F-Y-S-W-Sar-N-Y-W-S-Y-Y-Sar-W-C*-G-E-E-NH2(SEQ ID NO:9); or a pharmaceutically acceptable salt thereof, wherein * indicates attachment to form a cyclic peptide.

34. A method of inhibiting a TNFR1-mediated activity, comprising contacting the TNFR1 with a first compound that competes with a second compound for binding to TNFR1 at a binding pocket between CRD3 and CRD4 of TNFR1, wherein the second compound is Compound A, B, C, or D:Attorney Ref. No.14463-061-228 ,Attorney Ref. No.14463-061-228 ,Attorney Ref. No.14463-061-228 HO 2 ,or a pharmaceutically acceptable salt thereof.

35. The method of any one of claims 1-34, wherein the TNFR1-mediated activity is selected from the group consisting of inflammation, cytokine signaling, apoptosis, necroptosis, cell proliferation, cell survival, cell differentiation, MAPK signaling, NF- B signaling,and any combination thereof.