Immunomodulators and immunomodulator conjugates

Abstract

The present disclosure provides a compound of formula I: TIFF2024508426000121.tif47165 Pharmaceutically acceptable salts thereof, conjugates thereof, and methods of synthesizing such compounds and uses in methods of treating pathological conditions, for example, in subjects are provided. The compounds described herein have immune-modulating properties and can interact with Toll-like receptors as described herein. In some embodiments, TLR-modulating compounds are disclosed that can induce a more desirable ratio of pro-inflammatory cytokines to anti-inflammatory cytokines.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 152,003, filed February 22, 2021, and U.S. Provisional Application No. 63 / 273,081, filed October 28, 2021, which are incorporated by reference in their entireties herein.

[0002] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in this specification. [Background technology]

[0003] Toll-like receptor (TLR) modulators can be used in various therapeutic settings, for example, as vaccine adjuvants. However, many factors have limited the effectiveness of TLR-modulating compounds (such as imiquimod). For one, such compounds can induce proinflammatory cytokines, but they can also induce significant levels of anti-inflammatory cytokines (such as IL-10). Thus, there is an unmet need to develop TLR-modulating compounds that can induce a more desirable ratio of proinflammatory cytokines to anti-inflammatory cytokines. Summary of the Invention [Means for solving the problem]

[0004] In some embodiments, TLR modulating compounds are disclosed that can induce a more desirable ratio of pro-inflammatory to anti-inflammatory cytokines. In some instances, such TLR modulating compounds are compounds of formula I: [ka] [In the formula, The fused ring A is [ka] selected from the group consisting of; R 1 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n NC(=O)-, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from halo, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, NR u R v aryl optionally substituted by alkyl substituted by aryl, carboxy substituted aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, OR z , -N(H)S(O)R r , R s C(=O)O-, -SR w , -NR x R y , (C1-C6)alkoxycarbonyl, and carboxy; R 2 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R nis NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R 3 is H, halo, hydroxy, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n is NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R 4 is R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(Re )-, R e S(O)2NR f - or R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(R e )- or R e S(O)2NR f - is 1-ethylene substituted at the 2-position with R a is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, or heteroaryl, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, and heteroaryl are hydroxy, halo, -SH, cyano, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R b is H or XY; Each R c and R d are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R eis H, (C1-C6) alkyl, or R aa and; R f is H or (C1-C6)alkyl; Each R g and R h are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R k is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, trifluoromethyl, aryl, or aryl(C1-C6)alkyl, each (C1-C6)alkyl can be optionally substituted with one or more halo, (C1-C6)alkanoyloxy, (C1-C6)alkoxy, (C3-C8)cycloalkyl; Each R m and R n are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; X is a linking group; Y is a peptide, protein, or maleimide; Ring B and ring C in formula I are selected from halo, hydroxy, nitro, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkanoyloxy, (C1-C6) alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, cyano, and NR p R q may be optionally further substituted on one or more carbons with one or more groups independently selected from the group consisting of: Each R p and R q are independently H or (C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R r is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; R s is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; Each R u and R v are independently H or (C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R w is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; Each R x and R yare independently H or (C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R z is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; R aa is aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halo, nitro, cyano, (C1-C6)alkoxy, and (C1-C6)alkyl optionally substituted with one or more halo; or a pharma- ceutically acceptable salt thereof It could be.

[0005] In some embodiments, Y is an antigen.

[0006] The disclosure also provides a pharmaceutical composition comprising a compound of formula I, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable diluent and / or carrier.

[0007] Further provided herein is a method of treating a pathological condition in an animal (e.g., a viral infection, a bacterial infection, or cancer) comprising administering to the animal (e.g., a mammal such as a human) a compound of formula I or a pharma- ceutically acceptable salt thereof and / or a pharmaceutical composition comprising such a compound.

[0008] Further provided herein is a method of stimulating an immune response in an animal (e.g., a mammal such as a human), comprising administering to the animal a compound of formula I or a pharma- ceutically acceptable salt thereof and / or a pharmaceutical composition comprising such a compound.

[0009] Further provided herein is a compound of formula I or a pharma- ceutically acceptable salt thereof for use in the prophylactic and / or therapeutic treatment of a pathological condition (e.g., viral infection, bacterial infection, or cancer) in an animal (e.g., a mammal, such as a human). Further provided herein is a compound of formula I or a pharma- ceutically acceptable salt thereof for use in medical therapy. The present disclosure also provides the use of a compound of formula I or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament useful for the treatment of a pathological condition (e.g., viral infection, bacterial infection, or cancer) in an animal (e.g., a mammal, such as a human).

[0010] The present disclosure further provides processes and intermediates disclosed herein that are useful for preparing compounds of Formulas I-IV, or pharma- ceutically acceptable salts thereof.

[0011] Further provided herein are methods of synthesizing compounds of Formulae I-IV and intermediates thereof, comprising carrying out the reactions according to any one of Reaction Schemes 1-5. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] I. Introduction The present disclosure provides compounds (e.g., those of formulas I-IV) that can interact with one or more Toll-like receptors (TLRs) (e.g., TLR-7, TLR-8, or a combination thereof). In some embodiments, the compounds of the present disclosure are agonists for one or more TLRs. Thus, in some embodiments, the compounds provided herein can initiate an immune response in a subject, which can be used to treat a disease or pathological condition in a subject. Further provided herein are conjugates that can include a compound of the present disclosure (e.g., one of formulas I-IV) coupled to another molecule. Such other molecules can be small molecules, peptides, proteins, or nucleic acids. In some cases, the conjugates herein include a compound of any one of formulas I-IV coupled to a peptide or protein. As further described herein, the compound can be coupled (e.g., covalently coupled) to a peptide or protein via a linker.

[0013] Numerical ranges should be understood as being inclusive, i.e., including the lower and upper limits set forth. Furthermore, the term "about," as used herein, and unless expressly indicated otherwise, generally refers to and encompasses the set forth numerical value(s) plus or minus 10%. For example, "about 10%" indicates a range of 9% to 11%, and "about 1" may encompass a range of 0.9 to 1.1.

[0014] It is noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to a "compound" includes a plurality of such compounds and equivalents thereof known to those of skill in the art, and so forth. Similarly, the terms "a" (or "an"), "one or more," and "at least one" may be used interchangeably herein. It is also noted that the terms "comprising," "including," and "having" may be used interchangeably.

[0015] As used herein, "comprising" is synonymous with "including," "containing," or "characterized by" and is inclusive or open-ended and does not exclude additional unrecited elements or method steps. As used herein, "consisting of" excludes any element, step, or ingredient not specified in the claim element. As used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim.

[0016] The term "subject" as used herein generally refers to an individual to whom a compound described herein or a conjugate containing such a compound is administered. Examples of "subject" include, but are not limited to, mammals such as humans, rats, mice, guinea pigs, non-human primates, pigs, goats, cows, horses, dogs, cats, birds, and poultry. Typically, the subject is a rat, mouse, dog, non-human primate, or human. In some embodiments, the subject is a human.

[0017] The term "antibody" as used herein covers intact monoclonal, polyclonal, monospecific, and multispecific antibodies (e.g., bispecific antibodies), including intact antibodies and antigen-binding antibody fragments, as well as reduced forms thereof in which one or more of the interchain disulfide bonds may be broken, which exhibit the desired biological activity, provided that the antigen-binding antibody fragments have the required number of desired number of binding sites for the groups to which they are attached (such as linker moieties described herein), if applicable. In embodiments involving compounds attached to antibodies via linkers, such linkers may be attached to the sulfur atoms of cysteine ​​residues of the interchain disulfide bonds reduced via succinimide or hydrolyzed succinimide and / or cysteine ​​residues of those introduced by genetic engineering. The native form of an antibody is a tetramer, consisting of two identical pairs of immunoglobulin chains, each pair having one light chain and one heavy chain. In each pair, the light and heavy chain variable domains (VL and VH) together are primarily responsible for binding to the antigen. The light and heavy chain variable domains consist of framework regions interrupted by three hypervariable regions (also called "complementarity determining regions" or "CDRs"). The light and heavy chains also contain constant regions that can be recognized by and interact with the immune system. The antibody can be derived from any suitable species. In some embodiments, the antibody is of human or murine origin, and in some embodiments, the antibody is a human antibody, a humanized antibody, or a chimeric antibody. The antibody can be fucosylated or defucosylated to varying degrees.

[0018] An "antigen" is an entity to which an antibody specifically binds. Generally, "antigen" as used herein includes any substance that causes an animal's immune system to produce antibodies or antigen-specific T cells against the substance. The term also includes haptans. An antigen can be a foreign substance from the environment, such as a chemical, a bacterium, a virus, or pollen. An antigen can also be formed within the body, such as by bacterial toxins, tissue cells, or tumor cells. An antigen is a molecular structure encoded by a substance, such as a pathogen or tumor, against which an immune response is directed. Examples of antigens can come from pathogens, such as bacteria or viruses (e.g., influenza, HIV, or HCV). Alternatively, antigens can come from tumor cells or tumor cell lysates or synthetic peptides derived from tumors or infectious organisms. In one embodiment, the antigen comprises a peptide sequence containing cysteine ​​or lysine.

[0019] All terms, chemical names, expressions, and designations have their usual meanings known to those skilled in the art. When a group of substituents is disclosed herein, it is understood that all individual members of the group and all subgroups (including any isomers, enantiomers, and diastereomers of the group members) are separately disclosed. When Markush groups or other groupings are used herein, all individual members of the group, as well as all possible combinations and subcombinations of the group, are intended to be individually included in the disclosure. When a compound is described herein such that a specific isomer, enantiomer, or diastereomer of the compound is not specified, for example, by formula or chemical name, the description is intended to include each isomer and enantiomer of the compound described individually or in any combination. Additionally, unless otherwise specified, all isotopic variants of the compounds disclosed herein are intended to be covered by the disclosure. The specific names of the compounds are intended to be exemplary, as it is known that one skilled in the art may name the same compound differently.

[0020] The term "optionally substituted" refers to the indicated group being either substituted or unsubstituted. As used herein, the term "substituted" refers to a compound in which a hydrogen is replaced by another reactive functional group or atom, as described herein (e.g., an alkyl chain).

[0021] As used herein, the term "group" may refer to a reactive functional group of a chemical compound. A group of the present compound refers to an atom or a collection of atoms that is part of the compound. The groups of the present disclosure may be bonded to other atoms of the compound through one or more covalent bonds. Groups may also be characterized in terms of their valence state. The present disclosure encompasses groups that are characterized as monovalent, divalent, trivalent, etc.

[0022] As used herein, dashed lines in chemical structures may be used to indicate a bond to the remainder of the molecule. For example, [ka] In [ka] is used to designate the 1-position as the point of attachment of 1-methylcyclopentate to the rest of the molecule. Alternatively, e.g. [ka] In [ka] may be used to indicate that a given moiety (a cyclohexyl moiety in this example) is attached to a molecule via a bond that is "capped" by a wavy line.

[0023] The following definitions are used unless otherwise stated: Halo is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, alkenyl, alkynyl, etc. refer to both straight chain and branched chain groups, although references to individual radicals (e.g., propyl) encompass only the straight chain radical; the branched chain isomer (e.g., isopropyl) is specifically referred to. Aryl refers to a phenyl group or an ortho-fused bicyclic carbocyclic radical having about 9-10 ring atoms in which at least one ring is aromatic. Heteroaryl encompasses monocyclic aromatic ring radicals containing 5 or 6 ring atoms consisting of carbon and 1-4 heteroatoms (each selected from the group consisting of nonperoxygen, sulfur, and N(X), where X is absent or is H, O, (C1-C4)alkyl, phenyl, or benzyl), and ortho-fused bicyclic heterocycle radicals of about 8-10 ring atoms containing 1-4 heteroatoms (each selected from the group consisting of nonperoxygen, sulfur, and N(X).

[0024] It will be recognized by those skilled in the art that compounds of the present disclosure having chiral centers can exist in and be isolated in optically active racemic forms. Some compounds may exhibit polymorphism. It should be understood that the present disclosure covers any racemic, optically active, polymorphic, or stereoisomer of the compounds of the present disclosure, or mixtures thereof, that retain the useful properties described herein, and methods for preparing optically active forms are well known in the art (e.g., by resolution of racemic forms by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using chiral stationary phases).

[0025] Specific values ​​listed below for radicals, substituents, and ranges are for illustration only, and they do not exclude other defined values ​​or other values ​​within defined ranges for radicals and substituents.

[0026] Specifically, (C1-C6)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl; (C3-C6)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (C3-C6)cycloalkyl(C1-C6)alkyl can be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclopropylethyl, 2-cyclobutylmethyl, 2-cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclohexylethyl ... -cyclobutylethyl, 2-cyclopentylethyl, or 2-cyclohexylethyl; (C1-C6)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; (C2-C6)alkenyl can be vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,-pentenyl, 2-pentenyl, 3-pentenyl, 4- pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl; (C2-C6)alkynyl can be ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl; (C1-C6)alkanoyl can be acetyl, propanoyl, or butanoyl. (C1-C6)alkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentaoxycarbonyl, or hexyloxycarbonyl; (C2-C6)alkanoyloxy can be acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy, pentanoyloxy, or hexanoyloxy; aryl can be phenyl, indenyl, or naphthyl;Heteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazolyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl (or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or its N-oxide), or quinolyl (or its N-oxide);

[0027] The term "alkyl" refers to an unsubstituted straight or branched chain saturated hydrocarbon having the indicated number of carbon atoms (e.g., "C1-C4 alkyl," "C1-C6 alkyl," "C1-C8 alkyl," or "C1-C 10 "Alkyl" has 1-4, 1-6, 1-8, or 1-10 carbon atoms, respectively, and is derived by the removal of one hydrogen atom from a parent alkane. Representative straight chain "C1-C8 alkyl" groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl, while branched C1-C8 alkyls include, but are not limited to, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and 2-methylbutyl.

[0028] The term "alkylene" refers to a divalent unsubstituted saturated branched or straight chain hydrocarbon of the stated number of carbon atoms (e.g., C1-C6 alkylene has 1-6 carbon atoms) with two monovalent centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. Alkylene groups can be substituted with 1-6 fluoro groups, for example on the carbon backbone (as -CHF- or -CF2-) or on the terminal carbons of a straight or branched alkylene (such as -CHF2 or -CF3). Alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), n-propylene (-CH2CH2CH2-), n-butylene (-CH2CH2CH2CH2-), difluoro-methylene (-CF2-), tetrafluoroethylene (CF2CF2), and the like.

[0029] The term "alkenyl" refers to an unsubstituted straight or branched chain hydrocarbon having at least one carbon-carbon double bond and the indicated number of carbon atoms (e.g., "C2-C8 alkenyl" or "C2-C 10 "Alkenyl" has 2 to 8 or 2 to 10 carbon atoms, respectively. If the number of carbon atoms is not specified, the alkenyl group has 2 to 6 carbon atoms.

[0030] The term "heteroalkyl" refers to a stable straight or branched chain saturated hydrocarbon having the stated number of all atoms and at least one (e.g., 1-15) heteroatom selected from the group consisting of O, N, Si, and S. The carbon atoms and heteroatoms of the heteroalkyl group can be oxidized (e.g., to form ketones, N-oxides, sulfones, and the like) and the nitrogen atom can be quaternized. The heteroatom(s) can be located at any interior position of the heteroalkyl group and / or at any terminal position of the heteroalkyl group (including the terminal end of a branched heteroalkyl group) and / or at the position at which the heteroalkyl group is attached to the remainder of the molecule. The heteroalkyl group can be substituted with 1-6 fluoro groups, for example on the carbon backbone (as -CHF- or -CF2-) or on the terminal carbon of a straight or branched chain heteroalkyl (such as -CHF2 or -CF3). Examples of heteroalkyl groups include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)2, -C(=O)-NH-CH2-CH2-NH-CH3, -C(=O)-N(CH3)-CH2-CH2-N(CH3)2, -C(=O)-NH-CH2-CH2-NH-C(=O)-CH2-CH3, -C(=O)-N(CH3)-CH2-CH2-N(CH3)-C(=O)-CH2-CH3, -O-CH2-CH2-CH2-NH(CH3), -O-CH2-CH2-CH2-N(CH3)2, -O-CH2-CH2-CH2-NH-C(=O)-CH2-C H3, -O-CH2-CH2-CH2-N(CH3)-C(=O)-CH2-CH3, -CH2-CH2-CH2-NH(CH3), -O-CH2-CH2-CH2-N(CH3)2, -CH2-CH2-CH2-NH-C(=O)-CH2-CH3, -CH2-CH2-CH2-N(CH3)-C(=O)-CH2-CH3, -CH2-CH2-CH2-N(CH3)-C(=O)-CH2-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -NH-CH2-CH2-NH-C(=O)-CH2-CH3, -CH2-CH2-S(O)2-CH3, -CH2-CH2-O-CF3, and -Si(CH3)3. Up to two heteroatoms may be consecutive (eg, -CH2-NH-OCH3 and -CH2O-Si(CH3)3).A terminal polyethylene glycol (PEG) moiety is one type of heteroalkyl group.

[0031] The term "alkynyl" refers to an unsubstituted straight or branched chain hydrocarbon having at least one carbon-carbon triple bond and the indicated number of carbon atoms (e.g., "C2-C8 alkynyl" or "C2-C 10 "Alkynyl" has 2 to 8 or 2 to 10 carbon atoms, respectively. If the number of carbon atoms is not specified, the alkynyl group has 2 to 6 carbon atoms.

[0032] The term "acyl" refers to an alkyl, haloalkyl, alkenyl, alkynyl, arylcycloalkyl, heteroaryl, or heterocyclyl group, as defined herein, connected to the remainder of the compound by a C=O (carbonyl) group.

[0033] The term "carboxamide" refers to the group -C(=O)NRR', where R and R' are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, arylcycloalkyl, heteroaryl, and heterocyclyl, as defined herein.

[0034] The term "heteroalkylene" refers to a divalent unsubstituted straight or branched chain group derived from heteroalkyl (e.g., as defined herein). Examples of heteroalkylene groups include -CH-CH-O-CH-, -CH-CH-O-CF-, -CH-CH-NH-CH-, -C(=O)-NH-CH-CH-NH-CH-, -C(=O)-N(CH3)-CH-CH-N(CH3)-CH-, -C(=O)-NH-CH-CH-NH-C(=O)-CH-CH-, -C(=O)-N(CH3)-CH-CH-N(CH3)-C(=O)-CH-CH-, -O-CH-CH-CH-NH-CH-, -O-CH-CH-CH-CH- N(CH3)-CH2-, -O-CH2-CH2-CH2-NH-C(=O)-CH2-CH2-, -O-CH2-CH2-CH2-N(CH3)-C(=O)-CH2-CH2-, -CH2-CH2-CH2-NH-CH2-, -CH2-CH2-CH2-N(CH3) -CH2-, -CH2-CH2-CH2-NH-C(=O)-CH2-CH2-, -CH2-CH2-CH2-N(CH3)-C(=O)-CH2-CH2-, -CH2-CH2-NH-C(=O)-, -CH2-CH2-N(CH3)-CH2-, -CH2-CH2-N + These include, but are not limited to, (CH3)2-, -NH-CH2-CH2(NH2)-CH2-, and -NH-CH2-CH2(NHCH3)-CH2-. A divalent polyethylene glycol (PEG) moiety is a type of heteroalkylene group.

[0035] The term "alkoxy" refers to an alkyl group (as defined herein) that is attached to a molecule via an oxygen atom. For example, alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and n-hexoxy.

[0036] The term "alkylthio" refers to an alkyl group (as defined herein) that is attached to a molecule via a sulfur atom. For example, alkythio groups include, but are not limited to, thiomethyl, thioethyl, thio-n-propyl, thio-iso-propyl, and the like.

[0037] The term "haloalkyl" refers to an unsubstituted straight or branched chain saturated hydrocarbon having the indicated number of carbon atoms (e.g., "C1-C4 alkyl," "C1-C6 alkyl," "C1-C8 alkyl," or "C1-C 10 "Alkyl" has 1 to 4, 1 to 6, 1 to 8, or 1 to 10 carbon atoms, respectively, where at least one hydrogen atom of the alkyl group is replaced by a halogen (e.g., fluoro, chloro, bromo, or iodo). When the number of carbon atoms is not indicated, haloalkyl groups have 1 to 6 carbon atoms. Representative C 1-6 Haloalkyl groups include, but are not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, and 1-chloroisopropyl.

[0038] The term "cycloalkyl" refers to a cyclic, saturated or partially unsaturated hydrocarbon having the indicated number of carbon atoms (e.g., "C 3-8 Cycloalkyl" or "C 3-6 "Cycloalkyl" has 3 to 8 or 3 to 6 carbon atoms, respectively. If the number of carbon atoms is not indicated, the cycloalkyl group has 3 to 6 carbon atoms. Cycloalkyl groups include bridged, fused, and spiro ring systems, as well as bridged bicyclic systems in which one ring is aromatic and the other is unsaturated. Representative "Cycloalkyl" groups include aryl, aryl, and aryl. 3-6 "Cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0039] The term "aryl" refers to an unsubstituted monovalent carbocyclic aromatic hydrocarbon group of 6 to 10 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, biphenyl, and the like.

[0040] The term "heterocycle" refers to a saturated or partially unsaturated ring or polycondensed ring system, including bridged, fused and spiro ring systems. Heterocycles may be described by the total number of atoms in the ring system, for example, a 3-10 membered heterocycle has 3-10 total ring atoms. The term encompasses single saturated or partially unsaturated rings (e.g., 3-, 4-, 5-, 6-, or 7-membered rings) from about 1-6 carbon atoms and about 1-3 ring heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The ring may be substituted by one or more (e.g., 1, 2, or 3) oxo groups, and the sulfur and nitrogen atoms may also be present in their oxidized forms. Such rings include, but are not limited to, azetidinyl, tetrahydrofuranyl, and piperidinyl. The term "heterocycle" also encompasses polycondensed ring systems (e.g., ring systems containing 2, 3, or 4 rings) in which a single heterocyclic ring (as defined above) can be fused with one or more heterocycles (e.g., decahydronapthyridinyl), carbocycles (e.g., decahydroquinolyl), or aryls. The rings of a polycondensed ring system can be connected to each other through fused bonds, spiro bonds, and bridged bonds, where valence requirements permit. It will be understood that the point of attachment of a polycondensed ring system (for a heterocycle as defined above) can be at any position of the polycondensed ring system, including the heterocyclic, aryl, and carbocyclic portions of the ring. It will also be understood that the point of attachment of a heterocycle or heterocyclic polycondensed ring system can be at any suitable atom of the heterocycle or heterocyclic polycondensed ring system, including carbon atoms and heteroatoms (e.g., nitrogen). Exemplary heterocycles include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, and 1,4-benzodioxanyl.

[0041] The term "heteroaryl" refers to an aromatic hydrocarbon ring system with at least one heteroatom in a single ring or fused ring system selected from the group consisting of O, N, and S. When all atoms contributing to the conjugated π system are in the same plane, the ring or ring system has 4n +2 electrons in the conjugated π system. In some embodiments, the heteroaryl group has 5-10 total ring atoms and 1, 2, or 3 heteroatoms (referred to as "5-10 membered heteroaryl"). Heteroaryl groups include, but are not limited to, imidazole, triazole, thiophene, furan, pyrrole, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine, and indole.

[0042] The term "hydroxyl" refers to the -OH group. The term "cyano" refers to the -CN group. The term "carboxy" refers to the -C(=O)OH group. The term "oxo" refers to the =O group.

[0043] The term "alkanoyl" refers to an alkyl group, as defined herein, connected to the remainder of the molecule by a -C(=O) group. Exemplary alkanoyl groups include, but are not limited to, acetyl, n-propanoyl, and n-butanoyl.

[0044] The term "alkanoyloxy" refers to an alkyl group, as defined herein, connected to the remainder of the molecule by an -OC(=O) group. Exemplary alkanoyloxy groups include, but are not limited to, acetoxy, n-propanoyloxy, and n-butanoyloxy.

[0045] The term "alkoxycarbonyl" refers to an alkoxy group, as defined herein, attached through the oxygen atom of the alkoxy to a C(=O)-alkyl group (ie, an alkyl ester group).

[0046] The terms "arylalkyl" and "cycloalkylalkyl" refer to an aryl group or a cycloalkyl group (as defined herein) connected to the remainder of the molecule by an alkyl group, as defined herein. Exemplary arylalkyl groups include, but are not limited to, benzyl and phenethyl. Exemplary cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, and cyclohexylethyl.

[0047] With respect to any of the above groups containing one or more substituents, it is understood that such groups do not contain substitutions or substitution patterns that are sterically impractical and / or synthetically impractical. In addition, as further described herein, the compounds of the present disclosure may include all stereochemical isomers (and racemic mixtures) resulting from the substitution of these compounds.

[0048] The term "amino acid" as used herein includes naturally occurring amino acid residues in either D- or L-form (e.g., Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Hyl, Hyp, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val), as well as unnatural amino acids (e.g., phosphoserine, phosphothreonine, phosphotyrosine, hydroxyproline, gamma carboxyglutamic acid; hippuric acid, octahydroindole 2-carboxylic acid, statins, 1,2,3,4,tetrahydroisoquinoline-3 carboxylic acid, penicillamine, ornithine, citruline, alpha methylalanine, parabenzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, and tert butylglycine). The term also includes natural and unnatural amino acids bearing conventional amino protecting groups (e.g., acetyloxycarbonyl or benzyloxycarbonyl), and natural and unnatural amino acids protected at the carboxy terminus (e.g., as (C1-C6) alkyl, phenyl, or benzyl esters or amides; or as α-methylbenzyl amides). Other suitable amino- and carboxy-protecting groups are known to those of skill in the art (see, for example, TW Greene, Protecting Groups In Organic Synthesis; Wiley: New York, 1981, and references cited therein). The amino acid may be linked to the remainder of the compound of Formula I through the carboxy terminus, the amino terminus, or any other convenient point of attachment (e.g., through the sulfur of cysteine, etc.).

[0049] The term "peptide" as used herein describes a sequence of at least about 2 and not more than about 25 amino acids and / or peptidyl residues. The peptide sequence may be linear or cyclic. As an example, cyclic peptides may be prepared or may result from the formation of disulfide bridges between two cysteine ​​residues in the sequence. The peptide may be linked to the remainder of the compound of formula I via the carboxy terminus, amino terminus, or other convenient attachment point (e.g., via the sulfur of cysteine, etc.). In some cases, the peptides herein contain 3-25, 5-21, or 10-25 amino acids. Peptide derivatives may be prepared as disclosed in U.S. Pat. Nos. 4,612,302; 4,853,371; and 4,684,620. The peptide sequences specifically recited herein are written with the amino terminus on the left and the carboxy terminus on the right. "Protein," as used herein, generally refers to a molecule that contains a sequence of at least about 25 amino acids and / or peptidyl residues (e.g., from about 25 to about 750, from about 50 to about 500, from about 100 to about 500, or from about 100 to about 1000).

[0050] As used herein, the term "free drug" refers to a biologically active drug molecule (e.g., one of formulas I-IV) that is not covalently bound to another moiety (such as a peptide or protein). Thus, free drug refers to a compound that is present immediately upon cleavage from a conjugate (e.g., a drug-peptide conjugate or a drug-protein conjugate as described herein). The release mechanism may be via a cleavable linker in the conjugate, or via intracellular transformation or metabolism of the conjugate. In some embodiments, the free drug may be protonated and / or may exist as a charged moiety. The free drug is a pharmacologically active species that is capable of exerting a particular biological effect. In some embodiments, the pharmacologically active species is the parent drug alone. In some embodiments, the pharmacologically active species is the parent drug bound to another molecule, for example, in a conjugate.

[0051] The term "treat" or "treatment", unless otherwise indicated or implied by the context, refers to therapeutic treatment and prophylactic measures to prevent recurrence, the purpose being to inhibit undesired physiological changes or disorders (such as the onset or spread of cancer). For purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, whether detectable or undetectable, reduction in the extent of disease, stabilized (e.g., not worsening) disease state, delayed or slowed disease progression, amelioration or palliation of disease state, and remission (whether partial or complete). "Treatment", in some embodiments, also encompasses prolonging the survival of a subject compared to expected survival in the absence of treatment.

[0052] In the context of cancer, the term "treatment" includes any or all of the following: inhibiting the growth of cancer cells or tumors, inhibiting the replication of cancer cells, reducing the overall tumor burden or number of cancer cells, and ameliorating one or more symptoms associated with the disease.

[0053] II.TLR modulating compounds In some embodiments, provided herein are Toll-like receptor (TLR) modulating compounds that can induce a more desirable ratio of pro-inflammatory to anti-inflammatory cytokines. In some instances, the compounds of the present disclosure can interact with and / or modulate TLR-7, TLR-8, or a combination of such receptors.

[0054] Compound structure In some instances, a compound of formula I capable of modulating a TLR: [ka] [In the formula, The fused ring A is [ka] selected from the group consisting of; R 1is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n NC(=O)-, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from halo, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, NR u R v aryl optionally substituted by alkyl substituted by aryl, carboxy substituted aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, OR z , -N(H)S(O)R r , R s C(=O)O-, -SR w , -NR x R y , (C1-C6)alkoxycarbonyl, and carboxy; R 2 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R nis NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R 3 is H, halo, hydroxy, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n is NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R 4 is R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(Re )-, R e S(O)2NR f - or R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(R e )- or R e S(O)2NR f - is 1-ethylene substituted at the 2-position with R a is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, or heteroaryl, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, and heteroaryl are hydroxy, halo, -SH, cyano, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R b is H or XY; Each R c and R d are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R eis H, (C1-C6) alkyl, or R aa and; R f is H or (C1-C6)alkyl; Each R g and R h are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R k is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, trifluoromethyl, aryl, or aryl(C1-C6)alkyl, each (C1-C6)alkyl can be optionally substituted with one or more halo, (C1-C6)alkanoyloxy, (C1-C6)alkoxy, (C3-C8)cycloalkyl; Each R m and R n are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; X is a linking group; Y is a peptide, protein, or maleimide; Ring B and ring C in formula I are selected from halo, hydroxy, nitro, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkanoyloxy, (C1-C6) alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, cyano, and NR p R q may be optionally further substituted on one or more carbons with one or more groups independently selected from the group consisting of: Each R p and R q are independently H or (C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R r is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; R s is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; Each R u and R v are independently H or (C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R w is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; Each R x and R yare independently H or (C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R z is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; R aa is aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halo, nitro, cyano, (C1-C6)alkoxy, and (C1-C6)alkyl optionally substituted with one or more halo; or a pharma- ceutically acceptable salt thereof is provided herein.

[0055] In some instances, a compound of formula I capable of modulating a TLR: [ka] [In the formula, The fused ring A is [ka] selected from the group consisting of; R 1 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R nNC(=O)-, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from halo, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, NR u R v aryl optionally substituted by alkyl substituted by aryl, carboxy substituted aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, OR z , -N(H)S(O)R r , R s C(=O)O-, -SR w , -NR x R y , (C1-C6)alkoxycarbonyl, and carboxy; R 2 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n is NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R 3is H, halo, hydroxy, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n is NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R 4 is R w S(O)2NR f - and; R a is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, or heteroaryl, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, and heteroaryl are hydroxy, halo, -SH, cyano, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R b is H or XY; Each Rc and R d are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R e is H, (C1-C6) alkyl, or R aa and; R f is H or (C1-C6)alkyl; Each R g and R h are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R k is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, trifluoromethyl, aryl, or aryl(C1-C6)alkyl, each (C1-C6)alkyl can be optionally substituted with one or more halo, (C1-C6)alkanoyloxy, (C1-C6)alkoxy, (C3-C8)cycloalkyl; Each R m and R nare independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; X is a linking group; Y is a peptide, protein, or maleimide; Ring B and ring C in formula I are selected from halo, hydroxy, nitro, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkanoyloxy, (C1-C6) alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, cyano, and NR p R q may be optionally further substituted on one or more carbons with one or more groups independently selected from the group consisting of: Each R p and R q are independently H or (C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R r is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; R s is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; Each R u and R vare independently H or (C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R w is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; Each R x and R y are independently H or (C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R z is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; R aa is aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halo, nitro, cyano, (C1-C6)alkoxy, and (C1-C6)alkyl optionally substituted with one or more halo; or a pharma- ceutically acceptable salt thereof is provided herein.

[0056] In some instances, a compound of formula I capable of modulating a TLR: [ka] [In the formula, The fused ring A is [ka] selected from the group consisting of; R 1is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n NC(=O)-, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from halo, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, NR u R v aryl optionally substituted by alkyl substituted by aryl, carboxy substituted aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, OR z , -N(H)S(O)R r , R s C(=O)O-, -SR w , -NR x R y , (C1-C6)alkoxycarbonyl, and carboxy; R 2 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R nis NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R 3 is H, halo, hydroxy, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n is NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R 4 is R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(Re )-, or R e S(O)2NR f - is 1-ethylene substituted at the 2-position with R a is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, or heteroaryl, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, and heteroaryl are hydroxy, halo, -SH, cyano, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R b is H or XY; Each R c and R d are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R e is H, (C1-C6) alkyl, or R aa and; R f is H or (C1-C6)alkyl; Each R g and R hare independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R k is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, trifluoromethyl, aryl, or aryl(C1-C6)alkyl, each (C1-C6)alkyl can be optionally substituted with one or more halo, (C1-C6)alkanoyloxy, (C1-C6)alkoxy, (C3-C8)cycloalkyl; Each R m and R n are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; X is a linking group; Y is a peptide, protein, or maleimide; Ring B and ring C in formula I are selected from halo, hydroxy, nitro, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkanoyloxy, (C1-C6) alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, cyano, and NR p R q may be optionally further substituted on one or more carbons with one or more groups independently selected from the group consisting of: Each Rp and R q are independently H or (C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R r is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; R s is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; Each R u and R v are independently H or (C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R w is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; Each R x and R y are independently H or (C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R z is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; R aais aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halo, nitro, cyano, (C1-C6)alkoxy, and (C1-C6)alkyl optionally substituted with one or more halo; or a pharma- ceutically acceptable salt thereof is provided herein.

[0057] In some instances, a compound of formula I capable of modulating a TLR: [ka] [In the formula, The fused ring A is [ka] and; R 2 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n is NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R 4 is R k -C(=O)-, R k -OC(=O)-, R k-S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(R e )-, R e S(O)2NR f - or R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(R e )- or R e S(O)2NR f - is 1-ethylene substituted at the 2-position with R a is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, or heteroaryl, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, and heteroaryl are hydroxy, halo, -SH, cyano, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R b is H or XY; Each R g and R hare independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R k is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, trifluoromethyl, aryl, or aryl(C1-C6)alkyl, each (C1-C6)alkyl can be optionally substituted with one or more halo, (C1-C6)alkanoyloxy, (C1-C6)alkoxy, (C3-C8)cycloalkyl; X is a linking group; Y is a peptide, a protein, or a maleimide. is provided herein.

[0058] In some instances, a compound of formula I capable of modulating a TLR: [ka] [In the formula, The fused ring A is [ka] and; R 2 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R nis NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R 4 is R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(R e )-, R e S(O)2NR f - or R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(R e )- or R e S(O)2NR f - is 1-ethylene substituted at the 2-position with R ais H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, or heteroaryl, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, and heteroaryl are hydroxy, halo, -SH, cyano, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R b is H or XY; Each R g and R h are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R k is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, trifluoromethyl, aryl, or aryl(C1-C6)alkyl, each (C1-C6)alkyl can be optionally substituted with one or more halo, (C1-C6)alkanoyloxy, (C1-C6)alkoxy, (C3-C8)cycloalkyl; X is a linking group; Y is a peptide, a protein, or a maleimide. is provided herein.

[0059] In some instances, a compound of formula I capable of modulating a TLR: [ka] [In the formula, The fused ring A is [ka] and; R 2 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n is NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R 4 is R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(R e )-, R e S(O)2NR f - or R k -C(=O)-, R k -OC(=O)-, Rk -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(R e )- or R e S(O)2NR f - is 1-ethylene substituted at the 2-position with R a is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, or heteroaryl, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, and heteroaryl are hydroxy, halo, -SH, cyano, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R b is H or XY; Each R g and R h are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R kis H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, trifluoromethyl, aryl, or aryl(C1-C6)alkyl, each (C1-C6)alkyl can be optionally substituted with one or more halo, (C1-C6)alkanoyloxy, (C1-C6)alkoxy, (C3-C8)cycloalkyl; X is a linking group; Y is a peptide, a protein, or a maleimide. is provided herein.

[0060] In some instances, a compound of formula I capable of modulating a TLR: [ka] [In the formula, The fused ring A is [ka] and; R 1 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n NC(=O)-, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from halo, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, NR u R v aryl optionally substituted by alkyl substituted by aryl, carboxy substituted aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, ORz , -N(H)S(O)R r , R s C(=O)O-, -SR w , -NR x R y , (C1-C6)alkoxycarbonyl, and carboxy; R 2 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n is NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R 3 is H, halo, hydroxy, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R nis NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R 4 is R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(R e )-, R e S(O)2NR f - or R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(R e )- or R e S(O)2NR f - is 1-ethylene substituted at the 2-position with R ais H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, or heteroaryl, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, and heteroaryl are hydroxy, halo, -SH, cyano, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R b is H or XY; Each R c and R d are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R e is H, (C1-C6) alkyl, or R aa and; R f is H or (C1-C6)alkyl; Each R g and R hare independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R k is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, trifluoromethyl, aryl, or aryl(C1-C6)alkyl, each (C1-C6)alkyl can be optionally substituted with one or more halo, (C1-C6)alkanoyloxy, (C1-C6)alkoxy, (C3-C8)cycloalkyl; Each R m and R n are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; X is a linking group; Y is a peptide, protein, or maleimide; Ring B and ring C in formula I are selected from halo, hydroxy, nitro, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkanoyloxy, (C1-C6) alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, cyano, and NR p R q may be optionally further substituted on one or more carbons with one or more groups independently selected from the group consisting of: Each Rp and R q are independently H or (C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R r is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; R s is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; Each R u and R v are independently H or (C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R w is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; Each R x and R y are independently H or (C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R z is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; R aais aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halo, nitro, cyano, (C1-C6)alkoxy, and (C1-C6)alkyl optionally substituted with one or more halo; or a pharma- ceutically acceptable salt thereof is provided herein.

[0061] In some instances, the compounds of formula I provided herein have the structure of formula III or IV: [ka] or a pharma- ceutically acceptable salt thereof [In the formula, R 1 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n NC(=O)-, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from halo, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, NR u R v aryl optionally substituted by alkyl substituted by aryl, carboxy substituted aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, OR z , -N(H)S(O)R r , R s C(=O)O-, -SR w , -NR x R y, (C1-C6)alkoxycarbonyl, and carboxy; R 2 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n is NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R 4 is R k -C(=O)-, R k -OC(=O)- or R k -S(O)2-O-; R a is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, or heteroaryl, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, and heteroaryl are hydroxy, halo, -SH, cyano, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NRg R h optionally substituted with one or more groups independently selected from the group consisting of: R b is H or XY; Each R g and R h are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R k is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, trifluoromethyl, aryl, or aryl(C1-C6)alkyl, each (C1-C6)alkyl can be optionally substituted with one or more halo, (C1-C6)alkanoyloxy, (C1-C6)alkoxy, (C3-C8)cycloalkyl; X is a linking group; Y is a peptide, a protein, or a maleimide. Includes.

[0062] In some instances, a compound of formula I capable of modulating a TLR: [ka] [In the formula, The fused ring A is [ka] selected from the group consisting of; R 1is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n NC(=O)-, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from halo, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, NR u R v aryl optionally substituted by alkyl substituted by aryl, carboxy substituted aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, OR z , -N(H)S(O)R r , R s C(=O)O-, -SR w , -NR x R y , (C1-C6)alkoxycarbonyl, and carboxy; R 2 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R nis NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R 3 is H, halo, hydroxy, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n is NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R 4 is R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(Re )-, R e S(O)2NR f - or R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(R e )- or R e S(O)2NR f - is 1-ethylene substituted at the 2-position with R a is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, or heteroaryl, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, and heteroaryl are hydroxy, halo, -SH, cyano, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R b is H or XY; Each R c and R d are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R eis H, (C1-C6) alkyl, or R aa and; R f is H or (C1-C6)alkyl; Each R g and R h are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R k is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, trifluoromethyl, aryl, or aryl(C1-C6)alkyl, each (C1-C6)alkyl can be optionally substituted with one or more halo, (C1-C6)alkanoyloxy, (C1-C6)alkoxy, (C3-C8)cycloalkyl; Each R m and R n are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; X is a linking group; Y is a peptide, protein, or maleimide; Ring B and ring C in formula I are selected from halo, hydroxy, nitro, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkanoyloxy, (C1-C6) alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, cyano, and NR p R q may be optionally further substituted on one or more carbons with one or more groups independently selected from the group consisting of: Each R p and R q are independently H or (C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R r is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; R s is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; Each R u and R v are independently H or (C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R w is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; Each R x and R yare independently H or (C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R z is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; R aa is aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halo, nitro, cyano, (C1-C6)alkoxy, and (C1-C6)alkyl optionally substituted with one or more halo; or a pharma- ceutically acceptable salt thereof is provided herein.

[0063] In some instances, a compound of formula I capable of modulating a TLR: [ka] [In the formula, The fused ring A is [ka] selected from the group consisting of; R 1 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, heterocycle, NR g R h , or R m R nNC(=O)-, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, and heterocycles are selected from halo, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, NR u R v aryl optionally substituted by alkyl substituted by aryl, carboxy substituted aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, OR z , -N(H)S(O)R r , R s C(=O)O-, -SR w , -NR x R y , (C1-C6)alkoxycarbonyl, and carboxy; R 2 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n is NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R 3is H, halo, hydroxy, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n is NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R 4 is R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e S(O)2NR f - or R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(R e )- or R e S(O)2NR f - is 1-ethylene substituted at the 2-position with R ais H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, or (C1-C6)alkoxycarbonyl, and any of the (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, and (C1-C6)alkoxycarbonyl are selected from the group consisting of hydroxy, halo, -SH, cyano, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R b is H or XY; Each R c and R d are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R e is H, (C1-C6) alkyl, or R aa and; R f is H or (C1-C6)alkyl; Each R g and R h are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R kis H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, trifluoromethyl, aryl, or aryl(C1-C6)alkyl, each (C1-C6)alkyl can be optionally substituted with one or more halo, (C1-C6)alkanoyloxy, (C1-C6)alkoxy, (C3-C8)cycloalkyl; Each R m and R n are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; X is a linking group; Y is a peptide, protein, or maleimide; Ring B and ring C in formula I are selected from halo, hydroxy, nitro, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkanoyloxy, (C1-C6) alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, cyano, and NR p R q may be optionally further substituted on one or more carbons with one or more groups independently selected from the group consisting of: Each R p and R q are independently H or (C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R r is H, aryl, or optionally substituted with halo or aryl (C1-C10 ) alkyl; R s is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; Each R u and R v are independently H or (C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R w is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; Each R x and R y are independently H or (C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R z is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; R aa is aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halo, nitro, cyano, (C1-C6)alkoxy, and (C1-C6)alkyl optionally substituted with one or more halo; or a pharma- ceutically acceptable salt thereof is provided herein.

[0064] In some embodiments, the compound of formula I has the structure of formula (Ia) or formula (Ib): [ka] Includes.

[0065] In some embodiments, the compound of formula I has the structure of formula (Ia): [ka] Includes.

[0066] In some embodiments, the compound of formula I has the structure of formula (Ib): [ka] Includes.

[0067] In some embodiments, the fused ring A is [ka] is selected from the group consisting of:

[0068] In some embodiments, the fused ring A is [ka] is selected from the group consisting of:

[0069] In some embodiments, the fused ring A is [ka] is selected from the group consisting of:

[0070] In some embodiments, the fused ring A is [ka] is selected from the group consisting of:

[0071] In some embodiments, the fused ring A is [ka] is selected from the group consisting of:

[0072] In some embodiments, the fused ring A is [ka] is selected from the group consisting of:

[0073] In some embodiments, the fused ring A is [ka] is selected from the group consisting of:

[0074] In some embodiments, the fused ring A is [ka] is selected from the group consisting of:

[0075] In some embodiments, the fused ring A is [ka] In some embodiments, the fused ring A is [ka] In some embodiments, the fused ring A is [ka] In some embodiments, the fused ring A is [ka] In some embodiments, the fused ring A is [ka] In some embodiments, the fused ring A is [ka] It is.

[0076] In some embodiments, R 1 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, heterocycle, NR g R h , or R m R n NC(=O)-, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, and heterocycles are selected from halo, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, NR u R v aryl optionally substituted by alkyl substituted by aryl, carboxy substituted aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, OR z , -N(H)S(O)R r , R s C(=O)O-, -SR w , -NR x R y , (C1-C6)alkoxycarbonyl, and carboxy.

[0077] In some embodiments, R 1 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, heterocycle, NR g R h , or R m R nNC(=O)-, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, and heterocycles are selected from halo, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, NR u R v aryl optionally substituted by alkyl substituted by aryl, carboxy substituted aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, OR z , -N(H)S(O)R r , R s C(=O)O-, -SR w , -NR x R y , (C1-C6)alkoxycarbonyl, and carboxy.

[0078] In some embodiments, R 1 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, or -NR g R h and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, and (C1-C6)alkoxycarbonyl is selected from the group consisting of halo, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, NR u R v aryl optionally substituted by alkyl substituted by aryl, carboxy substituted aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, OR z , -N(H)S(O)R r , R s C(=O)O-, -SR w , -NR x R y, (C1-C6)alkoxycarbonyl, and carboxy.

[0079] In some embodiments, R 1 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, or -NR g R h wherein any of the (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, and (C1-C6)alkoxycarbonyl are optionally substituted with one or more groups independently selected from the group consisting of halo, cyano, oxo, oxiranyl, and (C3-C8)cycloalkyl.

[0080] In some embodiments, R 1 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, or -NR g R h wherein any of the (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl are optionally substituted with one or more groups independently selected from the group consisting of halo, cyano, oxo, oxiranyl, and (C3-C8)cycloalkyl.

[0081] In some embodiments, R 1 R is H or (C1-C6)alkyl optionally substituted with one or more groups independently selected from the group consisting of halo and cyano. 1 is H or (C1-C6)alkyl.

[0082] In some embodiments, R 1 is H. In some embodiments, R 1 is not H.

[0083] In some embodiments, R 2But NR g R h If R 1 is R c R d NS(O)2- or R e S(O)2NR f In some cases, R 2 is (C1-C6)alkyl substituted with one or more (C1-C6)alkylthio; 1 is R c R d NS(O)2- or R e S(O)2NR f -It is.

[0084] In some embodiments, R 2 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, or -NR g R h and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, and (C1-C6)alkoxycarbonyl is selected from the group consisting of hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h and optionally substituted with one or more groups independently selected from the group consisting of:

[0085] In some embodiments, R 2 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, or -NR g R h and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, and (C1-C6)alkoxycarbonyl is selected from halo, -SH, cyano, (C3-C8)cycloalkyl, and NR gR h and optionally substituted with one or more groups independently selected from the group consisting of:

[0086] In some embodiments, R 2 is H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl, and any of the (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl are selected from the group consisting of halo, -SH, cyano, (C3-C8)cycloalkyl, and NR g R h and optionally substituted with one or more groups independently selected from the group consisting of:

[0087] In some embodiments, R 2 is (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl, and any of the (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl are selected from the group consisting of halo, -SH, cyano, (C3-C8)cycloalkyl, and NR g R h and optionally substituted with one or more groups independently selected from the group consisting of:

[0088] In some embodiments, R 2 is H, or halo, -SH, cyano, and NR g R h and (C1-C6) alkyl optionally substituted with one or more groups independently selected from the group consisting of:

[0089] In some embodiments, R 2 R is H or (C1-C6) alkyl 2 It is.

[0090] In some embodiments, R 2 is H. In some embodiments, R 2 is not H.

[0091] In some embodiments, R3 is H, halo, hydroxy, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, or NR g R h and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, and (C1-C6)alkoxycarbonyl is selected from the group consisting of hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h and optionally substituted with one or more groups independently selected from the group consisting of:

[0092] In some embodiments, R 3 is H, halo, hydroxy, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, or NR g R h and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, and (C1-C6)alkoxycarbonyl is selected from halo, -SH, cyano, (C3-C8)cycloalkyl, and NR g R h and optionally substituted with one or more groups independently selected from the group consisting of:

[0093] In some embodiments, R 3 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, or NR g R h and any of (C1-C6) alkyl, (C2-C6) alkenyl, and (C2-C6) alkynyl is selected from halo, -SH, and cyano, and (C3-C8) cycloalkyl and NR g R hand optionally substituted with one or more groups independently selected from the group consisting of:

[0094] In some embodiments, R 3 is H, or halo, -SH, cyano, (C3-C8)cycloalkyl, and NR g R h and (C1-C6) alkyl optionally substituted with one or more groups independently selected from the group consisting of:

[0095] In some embodiments, R 3 is H or (C1-C6)alkyl.

[0096] In some embodiments, R 3 is H. In some embodiments, R 3 is not H.

[0097] In some embodiments, R 4 is R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e S(O)2NR f - or R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(R e )- or R e S(O)2NR f - is 1-ethylene substituted at the 2-position by

[0098] In some embodiments, R 4 is R k-C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(R e )-, or R e S(O)2NR f - is 1-ethylene substituted at the 2-position by

[0099] In some embodiments, R 4 is R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NS(O)2-, R e S(O)2NR f - or R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NS(O)2- or R e S(O)2NR f - is 1-ethylene substituted at the 2-position by

[0100] In some embodiments, R 4 is R k -C(=O)-, R k -OC(=O)- or R k -C(=O)-, R k It is 1-ethylene substituted at the 2-position with -O-C(=O)-.

[0101] In some embodiments, R 4 is R k -S(O)2-O-, R c R d NS(O)2-, R e S(O)2NR f - or R k -S(O)2-O-, R c Rd NS(O)2- or R e S(O)2NR f - is 1-ethylene substituted at the 2-position by

[0102] In some embodiments, R 4 is R k -C(=O)- or R k -OC(=O)-.

[0103] In some instances, the compound of formula I, 4 is R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(R e )-, or R e S(O)2NR f In such a case, R 4 is R e S(O)2NR f - may be R e is R w In another embodiment, R 4 is R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(R e )-, or R e S(O)2NR f - is a 1-ethylene substituted at the 2-position with -. The compounds of formula I herein are b In other cases, R bis XY. In such cases, X can be (C1-C6) alkyl, (C2-C6) alkenyl, or (C1-C6) alkynyl, which (C1-C6) alkyl, (C2-C6) alkenyl, or (C1-C6) alkynyl is optionally substituted with oxo.

[0104] In some embodiments, R a is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, or (C1-C6)alkoxycarbonyl, and any of the (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, and (C1-C6)alkoxycarbonyl are selected from the group consisting of hydroxy, halo, -SH, cyano, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h and optionally substituted with one or more groups independently selected from the group consisting of:

[0105] In some embodiments, R a is H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl, and any of the (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl is selected from the group consisting of halo, -SH, cyano, oxiranyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h and optionally substituted with one or more groups independently selected from the group consisting of:

[0106] In some embodiments, R a is H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl, and any of the (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl groups is selected from the group consisting of halo, -SH, cyano, and NR g R hand optionally substituted with one or more groups independently selected from the group consisting of:

[0107] In some embodiments, R a is H, or halo, -SH, cyano, and NR g R h and (C1-C6) alkyl optionally substituted with one or more groups independently selected from the group consisting of:

[0108] In some embodiments, R a is H or (C1-C6)alkyl.

[0109] In some embodiments, R a is H. In some embodiments, R a is not H.

[0110] In some embodiments, the compound of formula I, Ring A is selected from the group consisting of rings i, j, k, l, u, and w; R 1 , R 2 , and R 3 can independently be H or optionally substituted (C1-C6)alkyl; R 4 is R k -C(=O)-, R k -OC(=O)- or R k -S(O)2-O-; R k is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, trifluoromethyl, aryl, or aryl(C1-C6)alkyl, each (C1-C6)alkyl can be optionally substituted with one or more halo, (C1-C6)alkanoyloxy, (C1-C6)alkoxy, (C3-C8)cycloalkyl; X is a linking group; Y is a peptide, a protein, or a maleimide. is provided herein.

[0111] In some embodiments, ring A is [ka] [In the formula, R 2 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n is NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h and optionally substituted with one or more groups independently selected from the group consisting of Provided herein is a compound of formula I, selected from the group consisting of: 2 is H or an optionally substituted (C1-C6)alkyl. In some embodiments, ring A is ring i. In some embodiments, ring A is ring j. In some embodiments, ring A is ring k. In some embodiments, ring A is ring l.

[0112] In instances where ring A is ring j, the compound has formula II: [ka] or a pharma- ceutically acceptable salt thereof [In the formula, R2 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n is NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R 4 is R k -C(=O)-, R k -OC(=O)- or R k -S(O)2-O-; R a is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, or heteroaryl, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, and heteroaryl are hydroxy, halo, -SH, cyano, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: Rb is H or XY; Each R g and R h are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R k is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, trifluoromethyl, aryl, or aryl(C1-C6)alkyl, each (C1-C6)alkyl can be optionally substituted with one or more halo, (C1-C6)alkanoyloxy, (C1-C6)alkoxy, (C3-C8)cycloalkyl; X is a linking group; Y is a peptide, a protein, or a maleimide. It could be.

[0113] In some embodiments, the compound of formula II: [ka] or a pharma- ceutically acceptable salt thereof [In the formula, R 2 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R nis NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R 4 is R k -C(=O)- or R k -OC(=O)-; R a is H or optionally substituted (C1-C6)alkyl; R b is H or XY; Each R g and R h are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R k is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, trifluoromethyl, aryl, or aryl(C1-C6)alkyl, each (C1-C6)alkyl can be optionally substituted with one or more halo, (C1-C6)alkanoyloxy, (C1-C6)alkoxy, (C3-C8)cycloalkyl; X is a linking group; Y is a peptide, a protein, or a maleimide. It is of the following.

[0114] In some embodiments, the compound of formula II, R 2 is H or optionally substituted (C1-C6)alkyl; R 4 is R k -C(=O)- or R k -OC(=O)-; R a is H or optionally substituted (C1-C6)alkyl; R b is H or XY; R k is H or optionally substituted (C1-C6)alkyl; X is a linking group; Y is an antigen or a maleimide. is provided herein.

[0115] In some embodiments, with reference to Formula II, R 2 is an optionally substituted (C-C) alkyl; R k -OC(=O)- is R k is optionally substituted (C-C)alkyl; R a is H;R b is H or XY, where X is a linking group and Y is an antigen or a maleimide.

[0116] Thus, in some embodiments, Compound 1 has the following structure: [ka] Provided herein are compounds of Formula I or II having the formula:

[0117] In some embodiments, ring A is [ka] [In the formula, R 1 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n NC(=O)-, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from halo, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, NR u R v aryl optionally substituted by alkyl substituted by aryl, carboxy substituted aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, OR z , -N(H)S(O)R r , R s C(=O)O-, -SR w , -NR x R y , (C1-C6)alkoxycarbonyl, and carboxy; R 2 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R nis NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R 3 is H, halo, hydroxy, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n is NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h and is as described herein for formula I, optionally substituted with one or more groups independently selected from the group consisting of: Provided herein are compounds of formula I,

[0118] Thus, in the same embodiment, compounds of formula III and IV, respectively: [ka] [In the formula, R 1 , R 2 , and R 3 can be independently H or (C1-C6)alkyl, which can be optionally substituted with (C1-C3)alkyl, substituted or unsubstituted (C3-C8)cycloalkyl, or substituted or unsubstituted aryl; R 4 is R k -C(=O)-, R k -OC(=O)- or R k -S(O)2-O-; R k is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, trifluoromethyl, aryl, or aryl(C1-C6)alkyl, each (C1-C6)alkyl can be optionally substituted with one or more halo, (C1-C6)alkanoyloxy, (C1-C6)alkoxy, (C3-C8)cycloalkyl; R a is H or optionally substituted (C1-C6)alkyl; R b is H or XY; X is a linking group; Y is an antigen or a maleimide. is provided herein.

[0119] Thus, in some embodiments, the compounds herein are [ka] is selected from the group consisting of:

[0120] In some embodiments, a compound of the present disclosure (e.g., a compound of any one of Formulas I-IV) may be capable of binding to a Toll-like receptor (TLR). In some embodiments, binding of such a compound to a TLR may exert an agonistic effect on the TLR. In some embodiments, binding of a compound to a TLR may exert an immunostimulatory effect.

[0121] Compound synthesis A process for preparing compounds of formulae I-IV is provided as a further embodiment of the present disclosure and is illustrated by the following procedure, in which the general radical meanings are as given above unless otherwise limited. Certain compounds of formulae I-IV may be useful as intermediates for preparing other compounds of formulae I-IV. In cases where the compounds are sufficiently basic or acidic, pharma- ceutically acceptable salts of compounds of formulae I-IV may be useful as intermediates for the isolation or purification of compounds of formulae I-IV.

[0122] Conventional synthetic approaches to tricyclic ABC heterocycles may be based on substituted quinoline scaffolds, as shown in Formulae I-IV. However, such routes may be limited in their ability to generate versatile functional group patterns on tricyclic ABC heterocycles due to the harsh reaction conditions that may be required. Furthermore, conventional synthetic approaches may not lead to 5N-oxide intermediates in the presence of electron-withdrawing groups, as shown further below.

[0123] Thus, in some embodiments, various substituents (e.g., R 4 Provided herein is an improved synthetic route to such tricyclic ABC heterocycles (such as thiazoquinolines) as shown in Formulae I-IV, which may enable the introduction of

[0124] In various embodiments, the substituted quinoline compounds of the present disclosure (including those of Formulas I-IV) can be produced according to Scheme 1 below. [ka] During the ceremony, Z is S, O, or -NR f and; R 2is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n is NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R 4 is R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(R e )-, R e S(O)2NR f - or R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(R e )- or R e S(O)2NR f - is 1-ethylene substituted at the 2-position with Each R c and Rd are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R e is H, (C1-C6) alkyl, or R aa and; R f is H or (C1-C6)alkyl; Each R g and R h are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R k is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, trifluoromethyl, aryl, or aryl(C1-C6)alkyl, each (C1-C6)alkyl can be optionally substituted with one or more halo, (C1-C6)alkanoyloxy, (C1-C6)alkoxy, (C3-C8)cycloalkyl; Each R m and R nare independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R aa is aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halo, nitro, cyano, (C1-C6)alkoxy, and (C1-C6)alkyl optionally substituted with one or more halo.

[0125] Scheme 2 below shows a variation on Scheme 1 above, encompassing alternative compound substitutions. [ka] During the ceremony, W is N or CH; Z is S, O, or -NR f and; R 2 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R nis NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R 4 is R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(R e )-, R e S(O)2NR f - or R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(R e )- or R e S(O)2NR f - is 1-ethylene substituted at the 2-position by Each R c and R dare independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R e is H, (C1-C6) alkyl, or R aa and; R f is H or (C1-C6)alkyl; Each R g and R h are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R k is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, trifluoromethyl, aryl, or aryl(C1-C6)alkyl, each (C1-C6)alkyl can be optionally substituted with one or more halo, (C1-C6)alkanoyloxy, (C1-C6)alkoxy, (C3-C8)cycloalkyl; Each R m and R nare independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R aa is aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halo, nitro, cyano, (C1-C6)alkoxy, and (C1-C6)alkyl optionally substituted with one or more halo.

[0126] In some embodiments, according to Reaction Scheme 1 and Scheme 2 above, R 2 is (C1-C6) alkyl.

[0127] In some embodiments, according to Reaction Scheme 1 and Scheme 2 above, R 4 is aryl, (C2-C6)alkynyl, vinyl, cyano, R k -C(=O)-, R m R n NC(=O)- or R k -OC(=O)-; R k is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, trifluoromethyl, aryl, or aryl(C1-C6)alkyl, each (C1-C6)alkyl can be optionally substituted with one or more halo, (C1-C6)alkanoyloxy, (C1-C6)alkoxy, (C3-C8)cycloalkyl; Each R m and R nare independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which can be optionally substituted with one or more (C1-C6)alkyl.

[0128] Alternatively, the 7-bromo-3-nitroquinolin-4(1H)-one in Scheme 1 above can be synthesized as shown in Scheme 3 below. [ka]

[0129] In some embodiments, a procedure is provided herein that can start with the introduction of a bromo group into a thiazoloquinoline using a modified Niementowski reaction to produce the desired 3-amino-4-hydroxy-7-bromoquinoline. Cyclization to such 7-bromo-thiazoloquinoline can then be provided by first forming a primary amide at the 3-amino position, followed by dehydration using phosphorus pentasulfide in pyridine. Oxidation of the N5 position using 3-chloroperbenzoic acid in dichloromethane in the presence of a C7 bromo group can then provide the N5 oxide in good yield (e.g., >70%). In such instances, the N3 oxidation product will be absent or present in very small amounts. The 4-amino group can then be introduced as a benzamide surrogate via a 1,3-dipolar cycloaddition reaction using the dipolarophile benzoyl isocyanate with carbon dioxide being released as a by-product. The final product can then be obtained in a two-step process using Pd2(dba)3 with a catalyst (e.g. XPhos) for alkoxycarbonylation to generate the C7-phenyl ester, followed by acid-catalyzed hydrolysis and transesterification to give the target thiazoquinoline compound as shown.

[0130] Further provided herein, in some embodiments, are synthetic methods for various substituted quinolines capable of interacting with one or more TLRs, such as TLR-7 and / or TLR-8. In some aspects, provided herein are synthetic routes for substituted pyrroloquinolines, such as those shown in Scheme 4. [ka] During the ceremony, R 1 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n NC(=O)-, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from halo, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, NR u R v aryl optionally substituted by alkyl substituted by aryl, carboxy substituted aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, OR z , -N(H)S(O)R r , R s C(=O)O-, -SR w , -NR x R y , (C1-C6)alkoxycarbonyl, and carboxy; R 4 is R k -C(=O)-, R k -OC(=O)-, R k-S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(R e )-, R e S(O)2NR f - or R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(R e )- or R e S(O)2NR f - is 1-ethylene substituted at the 2-position with Each R c and R d are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R e is H, (C1-C6) alkyl, or R aa and; R f is H or (C1-C6)alkyl; Each R g and R hare independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R k is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, trifluoromethyl, aryl, or aryl(C1-C6)alkyl, each (C1-C6)alkyl can be optionally substituted with one or more halo, (C1-C6)alkanoyloxy, (C1-C6)alkoxy, (C3-C8)cycloalkyl; Each R m and R n are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R r is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; R s is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; Each R u and R vare independently H or (C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R w is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; Each R x and R y are independently H or (C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R z is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; R aa is aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halo, nitro, cyano, (C1-C6)alkoxy, and (C1-C6)alkyl optionally substituted with one or more halo.

[0131] Other embodiments of the present disclosure provide synthetic routes to substituted furoquinolines, for example as shown in Scheme 5. [ka] During the ceremony, R 2 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m Rn is NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R 4 is R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(R e )-, R e S(O)2NR f - or R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(R e )- or R e S(O)2NR f - is 1-ethylene substituted at the 2-position with Each R c and R dare independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R e is H, (C1-C6) alkyl, or R aa and; R f is H or (C1-C6)alkyl; Each R g and R h are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R k is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, trifluoromethyl, aryl, or aryl(C1-C6)alkyl, each (C1-C6)alkyl can be optionally substituted with one or more halo, (C1-C6)alkanoyloxy, (C1-C6)alkoxy, (C3-C8)cycloalkyl; Each R m and R nare independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R aa is aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halo, nitro, cyano, (C1-C6)alkoxy, and (C1-C6)alkyl optionally substituted with one or more halo.

[0132] In some embodiments, the substituent R 1 , R 2 , and R 4 are independently selected from the group consisting of H, (C1-C6)alkyl, aryl, heteroaryl, and (C3-C8)cycloalkyl, all of which (except H) may be optionally substituted with (C1-C3)alkyl, substituted or unsubstituted (C3-C8)cycloalkyl, or substituted or unsubstituted aryl. In some embodiments, Schemes 1-5 can be used to synthesize compounds of Formulas I-IV (e.g., compounds 1-26, either as intermediates or final products).

[0133] III. Linker In some embodiments, provided herein are molecules that may include a compound of any one of formulas I-IV and a linker. In such cases, a linking group X, for example of formula I herein, may tether the remainder of a compound of formulas I-IV to another molecule Y. Such other molecules Y may include or consist of small molecules, peptides, proteins, nucleic acids, or combinations thereof. In some cases, XY may include a maleimide moiety coupled to antigen Y. In various embodiments, the nature of the linking group X may not be important, provided that the resulting antigen conjugate retains the biological properties of the unconjugated antigen.

[0134] In some embodiments, the linker X can have a molecular weight of about 20 daltons to about 20,000 daltons, about 20 daltons to about 5,000 daltons, about 20 daltons to about 1,000 daltons, or about 20 daltons to about 200 daltons. In some cases, the length of X is about 5 angstroms to about 60 angstroms. In some embodiments, the linker X separates the antigen from the remainder of the compound of Formula I-IV by a length of about 5 angstroms to about 40 angstroms, inclusive.

[0135] The linker moiety X of the present disclosure may comprise or consist of a divalent branched or unbranched, saturated or unsaturated hydrocarbon chain having from about 2 to about 25 carbon atoms, where one or more (e.g., 1, 2, 3, or 4) of the carbon atoms are optionally replaced by (-O-), and the chain is optionally substituted on the carbon by one or more (e.g., 1, 2, 3, or 4) substituents selected from the group consisting of (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio, azido, cyano, nitro, halo, hydroxy, oxo (=O), carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy. In another embodiment, the linker X comprises or consists of a polyethyleneoxy chain. Such polyethyleneoxy chains may comprise or consist of 2, 3, 4, 5, 6, 7, 8, 9, or 10 repeating ethyleneoxy units.

[0136] In some instances, the linker moiety X can be a divalent radical formed from a protein. In some instances, the linker moiety X can be a divalent radical formed from a peptide. In some instances, the linker moiety X can be a divalent radical formed from an amino acid.

[0137] In some embodiments, the linker moiety X is [ka] [Wherein, n is 2, 3, 4, 5, or 6; R bb is an amino acid side chain] The compound may comprise or consist of a molecule selected from the group consisting of:

[0138] In some embodiments, the linker moiety X is [ka]

[0023] wherein n is 2, 3, 4, 5, or 6. The compound may comprise or consist of a molecule selected from the group consisting of:

[0139] In some embodiments, the linker moiety X is [ka] The compound may comprise or consist of a molecule selected from the group consisting of:

[0140] IV. Conjugates The present disclosure further provides conjugates comprising one or more compound(s) of any one of Formulas I-IV coupled to another molecule Y.

[0141] As described herein, in some cases, such one or more compound(s) of any one of formulae I-IV can be coupled to another molecule Y via a linker. In some cases, the other molecule Y can be a biomolecule such as a peptide or protein (e.g., an antibody or an antigen-binding fragment thereof). Such a conjugate can be a molecule of formula V, which is represented by R b is XY, where X is a linking group and Y is a peptide, protein, or maleimide.

[0142] In some instances, the compounds of formulas I-IV herein are coupled to a biomolecule Y (such as a peptide or protein). In some cases, the biomolecule Y is an antibody. In other cases, the biomolecule Y is an antigen. Thus, provided herein are conjugates comprising one or more compounds of any one of formulas I-IV coupled to an antigen Y via a linker X as described herein.

[0143] V. Pharmaceutical Compositions Pharmaceutical compositions comprising one or more compounds of formula I-IV and / or one or more conjugates according to the present disclosure are provided herein. In some instances, administration of the compounds of formula I as pharma-ceutically acceptable acid salts or base salts may be appropriate. Examples of pharma-ceutically acceptable salts are organic acid addition salts formed with acids that form physiologically acceptable anions (e.g., tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, and α-glycerophosphate). Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate.

[0144] Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art (e.g., by sufficiently reacting a basic compound, such as an amine, with a suitable acid to provide a physiologically acceptable anion.) Alkali metal (e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids can also be made.

[0145] The compound(s) of formula I can be formulated as pharmaceutical compositions and administered to a mammalian host (such as a human patient) in a variety of forms adapted to the chosen route of administration (e.g., by oral or parenteral, intravenous, intramuscular, topical, or subcutaneous routes). Thus, the compounds of the present disclosure can be administered systemically (e.g., orally) in combination with a pharmaceutically acceptable vehicle (such as an inert diluent or an assimilable edible carrier). They can be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or directly incorporated into the patient's diet. For oral therapeutic administration, the active compound can be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations can contain at least 0.1% of the active compound. The percentage of the compositions and preparations may be varied and may conveniently be between about 2% to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions will be such that an effective dosage level will be obtained (e.g., as measured systemically and / or locally after administration).

[0146] Tablets, troches, pills, capsules, and the like, containing one or more compounds of formula I, may further contain the following: binding agents (such as tragacanth gum, acacia, corn starch, or gelatin); excipients (such as dicalcium phosphate); disintegrating agents (such as corn starch, potato starch, alginic acid, and the like); lubricants (such as magnesium stearate); and sweeteners (such as sucrose, fructose, lactose, or aspartame) or flavoring agents (such as peppermint, methyl salicylate, or cherry flavoring), which may be added. When the unit dosage form is a capsule, the capsule may contain a liquid carrier (such as vegetable oil or polyethylene glycol) in addition to the above types of materials. Various other materials may be present as coatings of the solid unit dosage form or to otherwise modify the physical form of the form. For example, tablets, pills, or capsules may be coated with gelatin, wax, shellac, or sugar, and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetener, methylparaben and propylparaben as preservatives, a dye, and a flavoring agent (such as cherry or orange flavoring). In general, any material used in preparing any unit dosage form should be pharma-ceutically acceptable and substantially non-toxic in the amounts used. In addition, the active compound may be incorporated into sustained release preparations and devices.

[0147] The compounds of the present disclosure (e.g., any one of formulas I-IV) may be administered intravenously or intraperitoneally by infusion or injection. Solutions of such compounds(s) or their pharma-ceutically acceptable salts may be prepared in water, optionally mixed with a non-toxic surfactant. Dispersions may also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof, and oils. Under ordinary conditions of storage and use, these preparations contain preservatives to prevent the growth of microorganisms. Pharmaceutical dosage forms suitable for injection or infusion include sterile aqueous solutions or dispersions, or sterile powders, containing the active ingredient, which are suitable for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, and are optionally encapsulated in liposomes. In all cases, the final dosage form must be sterile, liquid, and stable under the conditions of manufacture and storage. The liquid carrier or vehicle may be a solvent or liquid dispersion medium, including, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol, and the like), vegetable oils, non-toxic glyceryl esters, and suitable mixtures thereof. Proper fluidity may be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions, or by the use of surfactants. Prevention of the action of microorganisms may be brought about by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like). In many cases, it will be preferable to include an isotonic agent (e.g., sugar, buffer, or sodium chloride). Prolonged absorption of the injectable compositions may be brought about by the use in the composition of agents delaying absorption (e.g., aluminum monostearate and gelatin).

[0148] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in a suitable solvent, optionally with various other ingredients listed above, followed by sterilization by filtration. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred method of preparation is vacuum drying and freeze-drying techniques, which result in a powder of the active ingredient and any additional desired ingredients that are present in a solution that has previously been sterilized by filtration. For topical administration, the compound can be applied in pure form, for example when it is a liquid. However, it will generally be desired to administer the compound to the skin as a composition or formulation in combination with a dermatologically acceptable carrier, which can be solid or liquid. Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, and the like. Useful liquid carriers include water, alcohol, or glycol, or water-alcohol / glycol mixtures, in which the compound can be dissolved or dispersed at effective levels, optionally with the aid of a non-toxic surfactant. Adjuvants (such as fragrances and additional antimicrobial agents) can be added to optimize the properties for a given use. The resulting liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers. Viscosity-increasing substances (such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified cellulose, or modified mineral materials) can also be used with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for direct application to the user's skin. Examples of useful dermatological compositions that can be used to deliver the compound(s) of formula I to the skin are known in the art, see, for example, Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157), and Wortzman (U.S. Pat. No. 4,820,508). Useful dosages of the compound(s) of formula I can be determined by comparing in vitro activity and in vivo activity in animal models.Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see US Pat. No. 4,938,949.

[0149] The amount of the compound disclosed herein, or active substance pharma- ceutically acceptable salt or derivative thereof for use in treatment may vary depending not only on the specific salt selected, but also on the route of administration, the nature of the pathology being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attending physician or clinician.The desired dose can conveniently be provided in a single dose or as a divided dose administered at appropriate intervals (e.g., as 2, 3, 4 or more subdoses per day).The subdose itself can be further divided, for example, into multiple discrete loosely spaced administrations (such as by multiple inhalations from an insufflator or by applying multiple drops to the eye).

[0150] Provided herein are pharmaceutical compositions comprising one or more compounds of formula I and / or conjugate(s) thereof, as described herein, prepared for therapeutic and prophylactic use in mammals (e.g., humans). In some cases, such pharmaceutical compositions are formulated into oral dosage forms or dosage forms for injection. Exemplary dosage forms are shown below in Table 1. [Table 1]

[0151] Compositions containing the compounds of Formula I-IV, conjugates, and / or pharma- ceutically acceptable salts thereof may be formulated in unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually from about 100 mg to about 500 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human and other subjects, each unit containing a predetermined amount of the active material (i.e., a compound of Formula I-IV or a pharma- ceutically acceptable salt thereof) calculated to produce a desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0152] An effective amount of the active material (i.e., a compound or conjugate of Formula I-IV, or a pharma- ceutically acceptable salt of any of the above) is usually supplied at a dosage level of about 0.01 mg / kg to about 1000 mg / kg body weight per day, or any range therein. In some cases, the range is about 0.05 to about 500 mg / kg body weight per day, or any range therein. In some cases, the range is about 0.1 to about 250 mg / kg body weight per day, or any range therein. In some cases, the range is about 0.1 to about 100 mg / kg body weight per day, or any range therein. In one example, the range can be about 0.1 to about 50.0 mg / kg body weight per day, or any amount or range therein. In another example, the range can be about 0.01 to about 15.0 mg / kg body weight per day, or any range therein. In yet another example, the range may range from about 0.05 to about 7.5 mg / kg body weight per day, or any amount therein. In yet another example, the range may range from about 0.1 to about 5.0 mg / kg body weight per day, or any amount therein. Pharmaceutical compositions containing a compound of Formula I-IV, or any pharma- ceutically acceptable salt thereof, may be administered on a regimen of 1-4 times per day or in a single daily dose.

[0153] VI.How to use Provided herein are methods of using one or more compounds of Formula I-IV, and / or conjugate(s) thereof, pharmaceutical compositions comprising such compounds, for the treatment of a disease or pathological condition in a subject in need thereof. In some embodiments, such methods may include administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I-IV of the present disclosure, a conjugate, or a pharmaceutical composition, thereby treating such disease or condition in the subject. In some cases, the subject is a mammal, such as a human or a rodent. Diseases and / or conditions that may be treated using the compounds of the present disclosure include, but are not limited to, cancer, viral infection, or bacterial infection.

[0154] Cancer (including but not limited to tumors, metastases, or other diseases or disorders characterized by abnormal cells, in some embodiments characterized by uncontrolled cell proliferation) is treated or inhibited by administration of the disclosed compounds, or conjugates thereof, as disclosed herein. In some embodiments, the subject has previously been treated for cancer. In some embodiments, the prior treatment is surgery, radiation therapy, administration of one or more anti-cancer agents, or any combination of the above.

[0155] In any of the methods described herein, the cancer is selected from the group consisting of adenocarcinoma, adrenal cortical carcinoma, adrenal neuroblastoma, anal squamous cell carcinoma, appendix adenocarcinoma, bladder urothelial carcinoma, bile duct adenocarcinoma, bladder carcinoma, bladder urothelial carcinoma, bone chordoma, myeloid leukemia (chronic lymphocytic), myeloid leukemia (non-lymphocytic acute myeloid), myeloproliferative disorders, multiple myeloma, osteosarcoma, brain astrocytoma, brain glioblastoma, brain medulloblastoma, brain meningioma, brain oligodendroglioma, breast adenoid cystic carcinoma, breast cancer, ductal carcinoma in situ, invasive ductal carcinoma, invasive lobular carcinoma of the breast, breast metaplastic carcinoma, cervical neuroendocrine tumor, cervical squamous cell carcinoma, colon Adenocarcinoma, colon carcinoid tumor, duodenal adenocarcinoma, endometriotic tumor, esophageal adenocarcinoma, esophageal and gastric cancer, intraocular melanoma, intraocular squamous cell carcinoma, lacrimal duct carcinoma, fallopian tube serous carcinoma, gallbladder adenocarcinoma, glomus tumor of the gallbladder, gastroesophageal junction adenocarcinoma, head and neck adenoid cystic carcinoma, head and neck cancer, head and neck neuroblastoma, head and neck squamous cell carcinoma, renal chromophobe carcinoma, renal medullary carcinoma, renal cell carcinoma, papillary renal cell carcinoma, renal sarcomatoid carcinoma, renal and urothelial carcinoma, kidney cancer, lymphocytic leukemia, chronic lymphocytic leukemia, intrahepatic cholangiocarcinoma, intrahepatic hepatocellular carcinoma, liver cancer, lung adenocarcinoma, lung adenosquamous carcinoma, lung atypical carcinoid, lung carcinosarcoma, lung large cell neuroendocrine tumor, lung non-small cell lung cancer, lung Sarcoma, pulmonary sarcomatoid carcinoma, small cell lung carcinoma, small cell undifferentiated lung carcinoma, lung squamous cell carcinoma, upper aerodigestive tract squamous cell carcinoma, upper aerodigestive tract carcinoma, lymphadenopathy lymphoma (diffuse large B cell), lymphadenopathy lymphoma (follicular lymphoma), lymphadenopathy lymphoma (mediastinal B cell), lymphadenopathy lymphoma (plasmablastic lung adenocarcinoma), lymphoma (follicular lymphoma), lymphoma (non-Hodgkin's), nasopharyngeal and paranasal sinus undifferentiated carcinoma, ovarian cancer, ovarian carcinosarcoma, ovarian clear cell carcinoma, ovarian epithelial carcinoma, ovarian granulosa cell tumor, ovarian serous carcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma, pancreatic neuroendocrine tumor, peritoneal mesothelioma, peritoneal serous carcinoma, placental choriocarcinoma, pleural mesothelioma tumor, prostatic acinar adenocarcinoma, prostate cancer, rectal adenocarcinoma, rectal squamous cell carcinoma, skin adnexal carcinoma, cutaneous basal cell carcinoma, cutaneous melanoma, cutaneous Merkel cell carcinoma, cutaneous squamous cell carcinoma, small intestinal adenocarcinoma, small intestinal gastrointestinal stromal tumor (GIST), large intestine / colon cancer, large intestine adenocarcinoma, soft tissue angiosarcoma, soft tissue Ewing's sarcoma, soft tissue hemangioendothelioma, soft tissue inflammatory myofibroblastic tumor, soft tissue leiomyosarcoma, soft tissue liposarcoma, soft tissue neuroblastoma, soft tissue paraganglioma, soft tissue perivascular epithelioid cell tumor, soft tissue sarcoma, soft tissue synovial sarcoma, gastric adenocarcinoma, gastric adenocarcinoma (diffuse type), gastric adenocarcinoma (intestinal type), gastric adenocarcinoma (intestinal type),Selected from the group consisting of gastric squamous myosarcoma, thymic carcinoma, thymic lymphocytic thymoma, papillary thyroid carcinoma, adenocarcinoma of unknown primary source, carcinoma of unknown primary source, malignant neoplasm of unknown primary source, lymphoid neoplasm, melanoma of unknown primary source, sarcomatoid carcinoma of unknown primary source, squamous cell carcinoma of unknown primary source, undifferentiated neuroendocrine carcinoma of unknown etiology, undifferentiated small cell carcinoma of unknown primary source, uterine carcinosarcoma, endometrial adenocarcinoma, endometrial adenocarcinoma (endometrioid), endometrial adenocarcinoma (papillary serous), and uterine leiomyosarcoma.

[0156] Methods provided herein include methods of treating one or more disease(s) in a subject in need thereof. Some embodiments provide a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I-IV, a pharma-ceutically acceptable salt thereof, a conjugate thereof, or a pharmaceutical composition thereof. Some embodiments provide a method of inducing an anti-tumor immune response in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I-IV, a pharma-ceutically acceptable salt thereof, a conjugate thereof, or a pharmaceutical composition thereof.

[0157] Some embodiments herein provide a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I-IV, or a pharma- ceutically acceptable salt thereof, or a conjugate thereof, in combination with another anti-cancer therapy (e.g., surgery and radiation therapy) and / or an anti-cancer agent (e.g., an immunotherapy such as nivolumab or pembrolizumab). The compound of Formula I-IV or its conjugate(s) may be administered to the subject before, during, or after administration of the anti-cancer therapy and / or anti-cancer agent. In some embodiments, the compound of Formula I-IV described herein may be administered to the subject following treatment with radiation and / or after surgery.

[0158] Some embodiments provide a method of delaying or preventing acquired resistance to an anti-cancer drug comprising administering a therapeutically effective amount of a compound of Formula I-IV, a pharma- ceutically acceptable salt thereof, or a conjugate thereof to a patient subject at risk for developing or having acquired resistance to an anti-cancer drug. In some embodiments, the patient is administered a dose of the anti-cancer drug (e.g., administered to the patient substantially simultaneously with a dose of a compound of Formula I-IV, a pharma- ceutically acceptable salt thereof, or a conjugate thereof).

[0159] Some embodiments provide a method of delaying and / or preventing the development of cancer resistant to an anti-cancer drug in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula I-IV, a pharma- ceutically acceptable salt thereof, or a conjugate thereof, prior to, during, or after administration of a therapeutically effective amount of an anti-cancer drug.

[0160] The compounds of Formulae I-IV and / or conjugates thereof are useful for inhibiting the proliferation of cancer cells, inducing apoptosis of cancer cells, increasing phagocytosis of cancer cells, and / or treating cancer in a subject in need thereof. In some embodiments, the cancer is as described herein. In some embodiments, the subject has previously been treated for cancer. In some embodiments, the prior treatment is surgery, radiation therapy, administration of one or more anti-cancer agents, or any combination of the above. In some embodiments, the subject has discontinued a prior treatment, e.g., due to unacceptable or intolerable side effects, the toxicity of the prior treatment was too high, or the subject developed resistance to the prior treatment. Some embodiments provide a method of delaying or preventing a disease or disorder, comprising administering a therapeutically effective amount of a compound of Formulae I-IV or a pharma- ceutically acceptable salt thereof, and a vaccine against the disease or disorder to a patient subject at risk for developing the disease or disorder. In some embodiments, the disease or disorder is a cancer as described herein. In some embodiments, the disease or disorder is a viral pathogen. In some embodiments, the vaccine is administered subcutaneously. In some embodiments, the vaccine is administered intramuscularly. In some embodiments, the compound of Formula I-IV, a pharma- ceutically acceptable salt thereof, or a conjugate thereof, and the vaccine are administered via the same route (e.g., both the compound of Formula I-IV or a pharma- ceutically acceptable salt thereof, and the vaccine are administered subcutaneously). In some embodiments, the compound of Formula I-IV, a pharma- ceutically acceptable salt thereof, or a conjugate thereof, and the vaccine are administered via different routes. In some embodiments, the vaccine and the compound of Formula I-IV or a pharma- ceutically acceptable salt thereof are provided in a single formulation. In some embodiments, the vaccine and the compound of Formula I-IV or a pharma- ceutically acceptable salt thereof are provided in separate formulations. In some embodiments, the compounds of Formula I-IV described herein are present in the form of a salt when used for treatment.In some embodiments, the salt is a pharma- ceutically acceptable salt.

[0161] VII. Compound Activity and Testing Various experimental procedures for synthesizing, evaluating, and using the compounds (eg, those of Formulas I-IV) and conjugates of the present disclosure are provided herein.

[0162] Screening for binding ability of compounds to TLR-7 / 8 expressing cells: Toll-like receptor (TLR)-7 positive cell lines or TLR-8 positive cell lines and HEK-Blue TLR cells can be used in the screening assay. HEK-Blue TLR cells can be engineered HEK293 cells stably expressing TLR genes and inducibly expressing NF-kB-SEAP (secreted embryonic alkaline phosphase) reporter gene. Binding of ligand(s) (e.g., compounds of formulas I-IV) by TLR in HEK-Blue cells can induce SEAP (pNPP as a substrate for phosphase) to turn blue. In some cases, compounds of the present disclosure, for example at a concentration of about 20 nmol / ml or about 5.2 nmol / ml, can be added in triplicate to HEK-Blue-TLR7 or HEK-Blue-TLR8 cells cultured at 37° C. and 5% CO2. After a period of time (e.g., 24 hours), a volume (e.g., 5 μL) of each experimental supernatant can be mixed with about 200 μl of detection medium containing pNPP. After 1 hour, SEAP activity can be read as OD at 650 nm in a microplate reader to determine the binding affinity of the tested compounds.

[0163] TLR7 / 8 Modulator NF-κB Reporter Assay: Human embryonic kidney (HEK) cells stably transfected with human TLR-7 or TLR-8 and NF-κB-responsive secreted embryonic alkaline phosphatase (SEAP) gene (HEK-TLR-7 and -HEK-TLR-8) can be purchased and then stimulated with 30 μM of compound (e.g., compound of Formula I-IV) in DMEM containing 10% FBS and 0.01% Normocin (InvivoGen) in a 96-well plate for about 24 hours. Subsequently, a volume (e.g., about 20 μL) of supernatant from each well can be incubated with Quanti-blue substrate solution (InvivoGen) for about 1 hour at 37° C., and absorbance can be read at a wavelength of 650 nm.

[0164] Measurement of proinflammatory cytokines by cytometric bead assay: Bone marrow-derived dendritic cells (BMDCs) can be generated by isolating a single cell suspension of bone marrow from the femurs of C57BL / 6 mice (6-8 weeks old). Red blood cells can then be lysed with 0.83% NH4Cl, 0.1% KHCO3, and 0.009%. Five million cells can be seeded into each well of a 6-well plate in complete RPMI medium (Invitrogen, Grand Island, NY) supplemented with 20 ng / ml mouse granulocyte-macrophage colony-stimulating factor (PeproTech, Rocky Hill, NJ). After several days of culture, BMDCs can be stimulated with 30 μM of a compound (e.g., a compound of Formula I-IV) for 3 days. A volume of approximately 25 μL of supernatant can then be removed and assayed for TNFα, IL-12p40, IL-1β, and IL-10 using flow cytometry bead arrays according to the manufacturer's instructions (e.g., BD Bioscience, San Jose, Calif.). Controls can be performed using the addition of media and carrier without drug.

[0165] Assessment of effects on human monocyte-derived dendritic cells (MoDCs): MoDCs can be plated into 96-well plates and stimulated with multiple (e.g., 5 or more) different concentrations of one or more compounds of formula I at various concentrations (e.g., about 0.3, 0.5, 1.3, 5.2, and 20 nmol per ml of cell culture medium) for about 48 hours, performed in triplicate. For immunostaining and flow cytometry analysis, after about 48 hours of stimulation, cells can be stained with anti-HLA-DR, anti-CD11c, anti-CD-86, anti-CD80, anti-CD83, anti-CD8a, anti-CD123, combinations thereof, and relevant isotype controls, followed by analysis including cytokine analysis.

[0166] In vivo assessment of IL-6 levels: TLR7 mutant mice and C57BL / 6j mice (8-12 weeks old) can be used to introduce the TLR7 mutant gene into 129S1 / Sv derived from CJ7 embryonic stem cells. The cell line can be backcrossed 10 times to C57BL / 6Ncr, and no TLR7 RNA expression can be detected in bone marrow-derived macrophages. Single cell suspensions of splenocytes from C57BL / 6j or TLR7 mutant mice can then be isolated. Splenocytes in culture medium can be treated in triplicate with one or more compounds of the present disclosure at various concentrations. Supernatants from culture medium can be collected, for example, after 12 and 24 hours of treatment. Cytometric bead arrays (BD Biosciences, San Jose, CA) can be used for measurement of IL-6 levels.

[0167] Proliferation of pmel CD8 and IFNγ production: Single cell suspensions of BMDC cells from C56BL / 6j mice and splenocytes from pmel mice can be treated in triplicate with about 3.5 μg of human gp100 peptide (gp100 peptide sequence: CALLAVGATKVPR-NQDWLGVSRQLRTK, GenScript, Piscataway, NJ) per well and a test compound (e.g., compound of formula I) at a concentration of about 10.4 nmol / ml. The BMDC cells can then be washed twice with complete RPMI medium and subsequently co-cultured with pmel CD8 splenocytes that have been CFSE-labeled and isolated from pmel splenocytes with a CD8+ T Cell isolation Kit at a DC / CD8 ratio of 1:3. After 4 days of co-culture, the supernatant can be collected and IFNγ can then be measured. The cell pellet can be washed and stained with fluorocore-labeled antibodies.

[0168] IL-2 production of OT-I cells after stimulation with compounds of formulas I-IV: Single cell suspensions of C57BL / 6j can be treated in triplicate with a test compound (e.g., of formula I) at a concentration of about 20.8 nmol / ml, with and without 15 μg ovalbumin per well. After 4 days, cells can be washed twice with complete RPMI medium and cultured with isolated OT-I CD8 T cells. After 4 days of co-culture, supernatants can be collected and detected. CBA can be performed for IL-2 production.

[0169] Embodiment For further illustration, additional non-limiting embodiments of the present disclosure are described below.

[0170] Embodiment P1: A compound of formula I: [ka] [In the formula, The fused ring A is [ka] selected from the group consisting of; R 1is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n NC(=O)-, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from halo, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, NR u R v aryl optionally substituted by alkyl substituted by aryl, carboxy substituted aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, OR z , -N(H)S(O)R r , R s C(=O)O-, -SR w , -NR x R y , (C1-C6)alkoxycarbonyl, and carboxy; R 2 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R nis NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R 3 is H, halo, hydroxy, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n is NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R 4 is R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(Re )-, R e S(O)2NR f - or R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(R e )- or R e S(O)2NR f - is 1-ethylene substituted at the 2-position with R a is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, or heteroaryl, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, and heteroaryl are hydroxy, halo, -SH, cyano, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R b is H or XY; Each R c and R d are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R eis H, (C1-C6) alkyl, or R aa and; R f is H or (C1-C6)alkyl; Each R g and R h are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R k is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, trifluoromethyl, aryl, or aryl(C1-C6)alkyl, each (C1-C6)alkyl can be optionally substituted with one or more halo, (C1-C6)alkanoyloxy, (C1-C6)alkoxy, (C3-C8)cycloalkyl; Each R m and R n are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; X is a linking group; Y is a peptide, protein, or maleimide; Ring B and ring C in formula I are selected from halo, hydroxy, nitro, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkanoyloxy, (C1-C6) alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, cyano, and NR p R q may be optionally further substituted on one or more carbons with one or more groups independently selected from the group consisting of: Each R p and R q are independently H or (C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R r is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; R s is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; Each R u and R v are independently H or (C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R w is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; Each R x and R yare independently H or (C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R z is H, aryl, or optionally substituted with halo or aryl (C1-C 10 ) alkyl; R aa is aryl optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halo, nitro, cyano, (C1-C6)alkoxy, and (C1-C6)alkyl optionally substituted with one or more halo; or a pharma- ceutically acceptable salt thereof.

[0171] Embodiment P2:R 4 But R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(R e )-, or R e S(O)2NR f The compound of embodiment P1, wherein

[0172] Embodiment P3:R 4 But R e S(O)2NR f - and R e But R w The compound of embodiment P1 or P2, wherein

[0173] Embodiment P4:R 4 But R k -C(=O)-, R k -OC(=O)- or R k The compound of embodiment P1 or P2, wherein the compound is -S(O)2-O-.

[0174] Embodiment P5:R 4 But R k -C(=O)-, R k -OC(=O)-, R k -S(O)2-O-, R c R d NC(=O)-, R c R d NS(O)2-, R e C(=O)N(R e )-, or R e S(O)2NR f The compound of embodiment P1, wherein R is 1-ethylene substituted at the 2-position with -.

[0175] Embodiment P6:R k The compound of any one of embodiments P1, P2, P4, or P5, wherein is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, trifluoromethyl, aryl, or aryl(C1-C6)alkyl, each (C1-C6)alkyl optionally substituted with one or more halo, (C1-C6)alkanoyloxy, (C1-C6)alkoxy, or (C3-C8)cycloalkyl.

[0176] Embodiment P7: The fused ring A is [ka] The compound of any one of embodiments P1 to P6 selected from the group consisting of:

[0177] Embodiment P8:R 1 and R 3 A compound of embodiment P7, wherein each is independently H or optionally substituted (C1-C6)alkyl.

[0178] Embodiment P9:R 2is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n NC(═O)—, and any of the (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycles are selected from the group consisting of hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h The compound of embodiment 7P or P8, optionally substituted with one or more groups independently selected from the group consisting of:

[0179] Embodiment P10: The fused ring A is [ka] The compound of any one of embodiments P1 to P9 selected from the group consisting of:

[0180] Embodiment P11:R 2 A compound of any one of embodiments P1 through P10, wherein is H or optionally substituted (C1-C6)alkyl.

[0181] Embodiment P12: Ring A is [ka] The compound of any one of embodiments P9 to P11, wherein

[0182] Embodiment P13: Ring A is [ka] The compound of any one of embodiments P9 to P11, wherein

[0183] Embodiment P14: Ring A is [ka] The compound of any one of embodiments P9 to P11, wherein

[0184] Embodiment P15: Ring A is [ka] The compound of any one of embodiments P9 to P11, wherein

[0185] Embodiment P16: Compound of formula II: [ka] or a pharma- ceutically acceptable salt thereof [In the formula, R 2 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n is NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R hoptionally substituted with one or more groups independently selected from the group consisting of: R 4 is R k -C(=O)-, R k -OC(=O)- or R k -S(O)2-O-; R a is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, or heteroaryl, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, and heteroaryl are hydroxy, halo, -SH, cyano, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R b is H or XY; Each R g and R h are independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R kis H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, trifluoromethyl, aryl, or aryl(C1-C6)alkyl, each (C1-C6)alkyl can be optionally substituted with one or more halo, (C1-C6)alkanoyloxy, (C1-C6)alkoxy, (C3-C8)cycloalkyl; X is a linking group; Y is a peptide, protein, or maleimide.

[0186] Embodiment P17:R 2 A compound of embodiment P16, wherein is H or optionally substituted (C1-C6)alkyl.

[0187] Embodiment P18:R 4 But R k -C(=O)- or R k The compound of embodiment P16 or P17, wherein the compound is -OC(=O)-.

[0188] Embodiment P19:R k A compound of embodiment P18, wherein is H or optionally substituted (C1-C6)alkyl.

[0189] Embodiment P20:R a The compound of any one of embodiments P16 through P19, wherein is H or optionally substituted (C1-C6)alkyl.

[0190] Embodiment P21:R b The compound of any one of embodiments P16 to P20, wherein is H or XY.

[0191] Embodiment P22: [ka] The compound of any one of embodiments P16 to P21, having

[0192] Embodiment P23: Ring A is [ka] [In the formula, R 1 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n NC(=O)-, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from halo, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, NR u R v aryl optionally substituted by alkyl substituted by aryl, carboxy substituted aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, OR z , -N(H)S(O)R r , R s C(=O)O-, -SR w , -NR x R y , (C1-C6)alkoxycarbonyl, and carboxy; R 2 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R nis NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R 3 is H, halo, hydroxy, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n is NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h and optionally substituted with one or more groups independently selected from the group consisting of The compound of any one of embodiments P1 to P7, wherein

[0193] Embodiment P24: A compound of formula III or formula IV: [ka] or a pharma- ceutically acceptable salt thereof [In the formula, R 1 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n NC(=O)-, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from halo, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, NR u R v aryl optionally substituted by alkyl substituted by aryl, carboxy substituted aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, OR z , -N(H)S(O)R r , R s C(=O)O-, -SR w , -NR x R y , (C1-C6)alkoxycarbonyl, and carboxy; R 2 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy, (C3-C6) cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R nis NC(═O)—, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are selected from hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R 4 is R k -C(=O)-, R k -OC(=O)- or R k -S(O)2-O-; R a is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, or heteroaryl, and any of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C3-C6)cycloalkyl, aryl, and heteroaryl are hydroxy, halo, -SH, cyano, oxiranyl, (C3-C8)cycloalkyl, aryl, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, and NR g R h optionally substituted with one or more groups independently selected from the group consisting of: R b is H or XY; Each R g and R hare independently H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C1-C6)alkyl; R k is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, trifluoromethyl, aryl, or aryl(C1-C6)alkyl, each (C1-C6)alkyl can be optionally substituted with one or more halo, (C1-C6)alkanoyloxy, (C1-C6)alkoxy, (C3-C8)cycloalkyl; X is a linking group; Y is a peptide, protein, or maleimide.

[0194] Embodiment P25:R 1 and R 2 is independently H or (C1-C6)alkyl, which may be optionally substituted with (C1-C3)alkyl, substituted or unsubstituted (C3-C8)cycloalkyl, or substituted or unsubstituted aryl.

[0195] Embodiment P26:R 4 But R k -OC(=O)- or R k The compound of embodiment P24 or P25, wherein the compound is -S(O)2-O-.

[0196] Embodiment P27: [ka] The compound of embodiment P24 or P25, selected from the group consisting of:

[0197] Embodiment P28: A compound of any one of embodiments P1 to P21 or P23 to P26 wherein X is (C1-C6)alkyl, (C2-C6)alkenyl, or (C1-C6)alkynyl, which (C1-C6)alkyl, (C2-C6)alkenyl, or (C1-C6)alkynyl is optionally substituted with oxo.

[0198] Embodiment P29: X is [ka]

[0023] wherein n is 2, 3, 4, 5, or 6. The compound of any one of embodiments P1 to P21 or P23 to P26 selected from the group consisting of:

[0199] Embodiment P30: The compound of any one of embodiments P1-P21, P23-P26, or P28-P29 wherein Y is maleimide.

[0200] Embodiment P31: The compound of any one of embodiments P1 to P21, P23 to P26, or P28 to P29, wherein Y is an antigen.

[0201] Embodiment P32: The compound of embodiment P31, wherein said antigen is associated with a bacterium or a virus, said virus being selected from the group consisting of influenza virus, HIV, and HCV.

[0202] Embodiment P33: The compound of any one of embodiments P1 to P21, P23 to P26, or P28 to P29, wherein Y is an antigen associated with a tumor cell or a tumor cell lysate.

[0203] Embodiment P34: The compound of any one of embodiments P31 to P33, wherein Y is an antigen comprising a peptide sequence containing cysteine, lysine, or both.

[0204] Embodiment P35: The compound of any one of embodiments P1 to P34, wherein said compound is compound 1 or any one of 22 to 26.

[0205] Embodiment P36: A pharmaceutical composition comprising a compound according to any one of embodiments P1 to P35 and a pharma- ceutically acceptable diluent or carrier.

[0206] Embodiment P37: A method for treating a pathological condition in an animal comprising administering to said animal a compound according to any one of embodiments P1 to P35, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment P36.

[0207] Embodiment P38: A method of stimulating an immune response in an animal comprising administering to the animal a compound according to any one of embodiments P1 to P35, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment P36.

[0208] Embodiment P39: A method of treating cancer in an animal comprising administering to the animal a compound according to any one of embodiments P1 to P35, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment P36.

[0209] Embodiment P40: A method of synthesizing a compound of any one of embodiments P1 to P35, comprising carrying out a reaction according to any one of reaction schemes 1 to 5. EXAMPLES

[0210] The following examples are given for the purpose of illustrating various embodiments of the present disclosure, and are not meant to limit the present disclosure in any manner.These examples, together with the methods described herein, are representative of some embodiments herein, are illustrative, and are not intended as limitations on the scope of the present disclosure.Those skilled in the art will be able to come up with variations thereof and other uses that are covered within the spirit of the present disclosure as defined by the scope of the claims.

[0211] Example 1 General synthetic procedure This example demonstrates the synthesis of compounds of Formulas I and II.

[0212] General experimental conditions: All solvents were used as received from commercial vendors, except DMF, which was purified by passing through two alumina columns in a solvent purification system. 2-Amino-4-bromobenzoic acid was purchased from AstaTech. Pd2(dba)3 and triethylamine were purchased from Chem-Impex. XPhos was purchased from TCI America. Phosphorus pentasulfide was purchased from Acros Organics. All other common chemicals were purchased from Sigma-Aldrich, Macron, Alfa Aesar, Fisher Chemical, or synthesized using cited literature protocols. Thin-layer chromatography (TLC) was performed on 0.25 mm hard-layer silica G plates, and the developed plates were visualized by a handheld UV lamp. The silica used for chromatography was SiliaFlash® P60 from Silicycle. 1 H NMR spectrum and 13 C NMR spectra were recorded on a Varian 600 MHz or Varian 400 MHz spectrometer in the solvents indicated and peaks are reported as chemical shifts (multiplicity, J coupling in Hz, number of protons). High-resolution mass spectra were obtained on an Agilent TOF II TOF / MS instrument equipped with an ESI or APCI interface.

[0213] Example 2 Synthesis of 4-bromo-2-((2-nitroethylidene)amino)benzoic acid (3) [ka] 2-Amino-4-bromobenzoic acid (2, 3.0 g, 13.89 mmol, 1 equiv.) was dissolved in a 1:1 mixture of water:dioxane (90 mL) at 50° C. Addition of methazoic acid (40 mL, ca. 28 mmol, ca. 2 equiv.) resulted in the immediate precipitation of an off-white solid. The solution was allowed to cool to 25° C. and stirred for 18 h. The pale yellow precipitate was filtered and rinsed with water until the filtrate was clear. The filtered solid was dried to constant weight in a vacuum oven. This crude yellow solid 3 was carried forward without characterization.

[0214] Example 3 Synthesis of methazonic acid Sodium hydroxide (6.72 g, 168 mmol) was dissolved in water (12 mL) and maintained at 25° C. To this aqueous sodium hydroxide solution, nitromethane (3 mL, 56 mmol) was added dropwise with rapid stirring and heated to 35° C. for 10 minutes. The reaction was cooled to 25° C. and another portion of nitromethane (3 mL, 56 mmol) was added while carefully maintaining the temperature below 35° C. After 10 minutes of rapid stirring, the reaction was heated to 50° C. for 5 minutes and then allowed to cool to 25° C. for 10 minutes. The reaction mixture was poured into cold water (50 mL) and then concentrated hydrochloric acid was added. Additional water was added until the total volume was 80 mL. The crude methazonic acid solution was used immediately in the next step or frozen (−20° C.) and then carefully thawed just prior to use in the reaction shown in Example 2.

[0215] Example 4 Synthesis of 7-bromo-3-nitroquinolin-4-ol (4) [ka] Crude 4-bromo-2-((2-nitroethylidene)amino)benzoic acid (3, 0.45 g, 1.57 mmol, 1 equiv.) was added to a flask containing a stir bar and acetic anhydride (5 mL). The suspension was heated to 100° C. for 45 min or until completely dissolved. Anhydrous sodium acetate was added to the reaction in one portion with vigorous stirring. The reaction was heated to reflux for 2 h and then allowed to cool to 25° C. The contents of the flask were diluted with cold 80% aqueous acetic acid and the solid was filtered. The solid was rinsed with acetic acid until the filtrate was clear. The solid was dried in a vacuum oven at 45° C. overnight to give a light brown powder that easily peeled off the filter paper. The crude solid 4 has limited solubility in most solvents and was therefore carried forward without characterization.

[0216] Example 5 Synthesis of 3-amino-7-bromo-4-hydroxyquinoline (5) [ka] To a solution of crude 7-bromo-3-nitroquinolin-4-ol (0.34 g, 1.26 mmol) in anhydrous DMF (16 mL) was added sodium dithionite (1.0 g). The reaction mixture was stirred at 25° C. under N2 for 18 h. DMF was removed under vacuum and the crude solid was suspended in ethyl acetate (15 mL) and then washed with hot water (35 mL). The mixture was stirred and heated with saturated aqueous sodium carbonate (10 mL) until all remaining sodium dithionite was decomposed. The organics were separated from the aqueous layer and extracted with ethyl acetate (4×10 mL). The organics were combined and concentrated under vacuum. The crude compound was purified by silica column with 85:9:3:3 EtOAc:MeOH:H2O:Et3N to give an off-white solid in 24.8% yield. 1 H NMR ((CD3)2SO, 400 MHz) δ 11.48 (br s, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.68 (s, 1H), 7.55 (s, 1H), 7.29 (d, J = 8.8 Hz, 1H), 4.72 (br s, 2H).

[0217] Example 6 Synthesis of 7-bromo-2-butylthiazolo[4,5-c]quinoline (6) [ka] To a solution of 3-amino-7-bromo-4-hydroxyquinoline (0.07 g, 0.29 mmol, 1 equiv) in anhydrous pyridine (3.4 mL) purged with N2, valeryl chloride (0.044 g, 0.37 mmol, 1.25 equiv) was added and heated to 60° C. in a pressure vessel for 2 h. The reaction was cooled to 25° C. and placed under N2 again. Phosphorus pentasulfide (0.14 g, 0.32 mmol, 1.1 equiv) was added and the reaction was heated to 105° C. in a pressure vessel for 18 h. The reaction was cooled to 25° C. and aqueous sodium carbonate (10 mL) and ethyl acetate (10 mL) were added. The mixture was separated and the aqueous layer was extracted with ethyl acetate (2×5 mL) (caveat, there is a trace of hydrogen sulfide in the organics, which will usually be removed with mild vacuum with some gentle heating for 2 h). The combined organics were concentrated in vacuo and purified by silica column with 1:99 MeOH:DCM to give a yellow waxy solid in 86.1% yield. 1 H NMR (CDCl3, 400 MHz) δ 9.43 (s, 1H), 8.43 (d, J = 1.6 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.73 (dd, J = 8.4, 1.6 Hz, 1H), 3.23 (t, J = 7.6 Hz, 2H), 1.94 (quintet, J = 7.6 Hz, 2H), 1.51 (apparent sextet, J = 7.6, 7.2 Hz, 2H), 1.01 (t, J = 7.2 Hz, 3H).

[0218] Example 7 Synthesis of 7-bromo-2-butylthiazolo[4,5-c]quinoline 5-oxide (7) [ka] To a solution of 7-bromo-2-butylthiazolo[4,5-c]quinoline (0.075 g, 0.23 mmol, 1 equiv) in dichloromethane (3 mL) was added 53% m-chloroperoxybenzoic acid (0.27 g, 0.82 mmol, 3.5 equiv). This was stirred at 25° C. for 15 h. TLC showed a nearly complete reaction. The reaction mixture was washed with saturated aqueous sodium carbonate (10 mL), diluted with additional portions of dichloromethane (10 mL) and water (10 mL), the mixture was separated, the aqueous layer was extracted with DCM (2×10 mL), and the organics were combined and concentrated under vacuum. The crude solid was purified by silica column with 1:99 to 2:98 MeOH:DCM (linear gradient) to give a white powder in 92.7% yield. 1 H NMR (CDCl3, 400 MHz) δ 9.19 (s, 1H), 9.11 (s, 1H), 7.84 (s, 2H), 3.20 (t, J = 7.6 Hz, 2H), 1.92 (quintet, J = 7.6 Hz, 2H), 1.51 (sextet, J = 7.6, 2H), 1.00 (t, J = 7.6 Hz, 3H).

[0219] Example 8 Synthesis of N-(7-bromo-2-butylthiazolo[4,5-c]quinolin-4-yl)benzamide (8) [ka] To a solution of 7-bromo-2-butylthiazolo[4,5-c]quinoline 5-oxide (0.073 g, 0.22 mmol, 1 equiv.) in dichloromethane (8 mL) was added benzoyl isocyanate (0.127 g, 0.86 mmol, 4 equiv.). The solution turned pale yellow after the benzoyl isocyanate was completely dissolved and was stirred at 25 °C for 18 h. The reaction mixture was concentrated under vacuum and purified by silica column with 0:100 to 1:99 MeOH:DCM (linear gradient) to give a white solid in 73.4% yield. 1H NMR (CDCl3, 400 MHz) δ 9.69 (br s, 1H), 8.41 (s, 1H), 8.08 (s, 1H), 8.06 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.65 - 7.53 (m, 4H), 3.21 (t, J = 7.6 Hz, 2H), 1.92 (quintet, J = 7.6 Hz, 2H), 1.53 (apparent sextet, J = 7.6, 7.2 Hz, 2H), 1.02 (t, J = 7.2 Hz, 3H). 13 C{ 1 H} NMR (CDCl3, 600 MHz) δ 173.0, 164.6, 145.4, 144.3, 140.7, 139.3, 134.7, 132.4,132.2, 129.2, 128.9, 127.7, 125.5, 122.9, 120.2, 34.0, 31.9, 22.3, 13.8. (ESI+): Calculated value C 21 H 18 BrN3OS [M + H]+ 440.0427, found 440.0437 (error 2.3 ppm).

[0220] Example 9 Synthesis of N-(2-butyl-7-phenoxycarbonylthiazolo[4,5-c]quinolin-4-yl)benzamide (9) [ka] A solution of formic acid (2 mL) in acetic anhydride (5 mL) was stirred for 1 h at 35° C. to generate acetic formic anhydride. N-(7-bromo-2-butylthiazolo[4,5-c]quinolin-4-yl)benzamide (0.07 g, 0.16 mmol, 1 equiv.), phenol (0.061 g, 0.65 mmol, 4.1 equiv.), tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3] (0.015 g, 0.016 mmol, 10 mol%), and 9,9-dimethyl-9H-xanthene-4,5-diylbis(diphenylphosphane) [XPhos] (0.021 g, 0.037 mmol, 23 mol%) were added to a flask and suspended in toluene (4 mL) under a stream of N2. The mixture was stirred for 1 min and then pre-made acetic formic anhydride (75 μL, 0.95 mmol, 6 equiv) was added in one portion with stirring, followed immediately by triethylamine (100 μL, 0.72 mmol, 4.5 equiv). The flask was capped with a septum and stirred for 2 min. An additional portion of triethylamine (100 μL) (1.44 mmol, 9 equiv total) was then added, followed by an additional portion of acetic formic anhydride (30 μL) (1.33 mmol, 8.3 equiv total). The reaction was stirred and heated to 85° C. for 18 h, then cooled to 25° C. and diluted with ethyl acetate (5 mL). The crude reaction mixture was filtered through a small silica plug, concentrated under vacuum, and purified by silica column from 1:99 MeOH:DCM to 4:96 MeOH:DCM to give an off-white solid in 15.7% yield. 1 H NMR (CDCl3, 600 MHz) δ 9.76 (br s, 1H), 9.17 (s, 1H), 8.25 (dd, J = 8.4, 1.8 Hz, 1H), 8.09 (d, J = 7.8 Hz, 2H), 7.94 (d, J = 8.4 Hz, 1H), 7.65 - 7.43 (m, 5H), 7.35 - 7.75 (m, 3H), 3.25 (t, J = 7.8 Hz, 2H), 1.95 (quintet, J = 7.8 Hz, 2H), 1.54 (apparent sextet, J = 7.8, 7.2 Hz, 2H), 1.03 (t, J = 7.2 Hz, 3H). 13C{ 1 H} NMR (CDCl3, 600 MHz) δ 174.4, 164.7, 164.4, 151.0, 145.4, 143.1, 140.3, 140.2, 134.6, 132.4, 129.9, 129.6, 129.51, (ESI+): Calculated value C 28 H 23 N3O3S [M + H]+ 482.1533, found 482.1572 (error 8.1 ppm).

[0221] Example 10 Synthesis of 4-amino-2-butyl-7-methoxycarbonylthiazolo[4,5-c]quinoline (1) [ka] N-(2-Butyl-7-phenoxycarbonylthiazolo[4,5-c]quinolin-4-yl)benzamide (0.010 g, 0.020 mmol) was added to a small vial and suspended in anhydrous methanol (3 mL). The mixture was sonicated for 1 min to break up any large solid clumps. Under a stream of N2, concentrated sulfuric acid (3 drops, approximately 125 mg) was added, which quickly dissolved the fine suspended solids. The vial was capped, stirred, and heated at 60° C. for 15 h. The reaction was cooled to 25° C., neutralized with solid sodium carbonate powder, diluted with ethyl acetate (5 mL) and water (5 mL), and stirred for 10 min. The mixture was concentrated under vacuum and redissolved in equal amounts of ethyl acetate and water. The mixture was separated and the aqueous layer was extracted with ethyl acetate (3×5 mL). The organics were combined and concentrated under vacuum. The crude was purified by silica column with 25:75 EtOAc:Hexs to give the final product as a white solid in 68.7% yield. 1H NMR (CDCl3, 600 MHz) δ 8.53 (d, J = 1.2 Hz, 1H), 8.03 (dd, J = 8.4, 1.2 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 6.86 (br s, 2H), 3.98 (s, 3H), 3.20 (t, J = 7.8 Hz, 2H), 1.91 (apparent-quintet, J = 7.8, 7.2 Hz, 2H), 1.51 (sextet, J = 7.2 Hz, 2H), 1.01 (t, J = 7.2 Hz, 3H). 13 C{ 1 H} NMR (CDCl3, 600 MHz) δ 174.5, 166.2, 151.0, 141.5, 138.7, 138.1, 131.5, 125.5, 125.2, 124.6, 121.5, 52.6, 33.9, 31.8, 22.2, 13.7. (APCI+): calcd. 16 H 17 N3O2S [M + H]+ 316.1114, measured value 316.1108 (error 1.9 ppm).

[0222] This synthetic route provides a superior route to allow for more versatile substitution at the C7 position of 4-amino-quinolines, as demonstrated by the synthesis of 4-amino-2-butyl-7-methoxycarbonylthiazolo[4,5-c]quinoline 1. The approach overcomes the limitations of previous routes, which require the formation of a 5N-oxide intermediate that is incompatible with the electron-withdrawing group at the C7 position. Instead, it has been unexpectedly found that a d-catalyzed carbonylation reaction allows for the design and efficient and scalable synthesis of substituted quinoline nucleoside base analogues and highly substituted isoquinolines.

[0223] Example 11 Synthesis of 4-amino-2-butyl-7-methoxycarbonylthiazolo[4,5-c]quinoline (1) Compound 1 was synthesized according to the following reaction conditions. [ka]

[0224] Example 12 Heterocyclic Compounds of the Disclosure The compounds in Table 2 were prepared using the synthetic methods described in Examples 1-11 and Reaction Schemes 1-5. [Table 2-1] [Table 2-2]

[0225] Example 13 Testing compounds using the TLR7 / 8-NF-κB reporter assay Human embryonic kidney (HEK) cells stably transfected with human TLR-7 or TLR-8 and NF-κB-responsive secreted embryonic alkaline phosphatase (SEAP) gene (HEK-TLR-7 and -HEK-TLR-8) are purchased from InvivoGen (San Diego, CA). HEK-TLR7 / 8 cells are stimulated with 30 μM of compound in DMEM containing 10% FBS and 0.01% Normocin (InvivoGen) in 96-well plates for 24 hours. 20 μL of supernatant from each well is incubated with Quanti-blue substrate solution (InvivoGen) for 1 hour at 37° C., and absorbance is read at 650 nm using a Synergy plate reader (Biotek, Winooski, VT).

[0226] Example 14 Measurement of proinflammatory cytokines by cytometric bead assay Bone marrow derived dendritic cells (BMDCs) are generated by isolating a single cell suspension of bone marrow from the femurs of C57BL / 6 mice (6-8 weeks old). Red blood cells are then lysed with 0.83% NH4Cl, 0.1% KHCO3, and 0.009%. Five million cells are seeded into each well of a 6-well plate in complete RPMI medium (Invitrogen, Grand Island, NY) supplemented with 20 ng / ml mouse granulocyte macrophage colony stimulating factor (PeproTech, Rocky Hill, NJ). After approximately 6 days of culture, BMDCs are stimulated with 30 μM of compound for 3 days. A volume of approximately 25 μL of supernatant is then removed and assayed for TNFα, IL-12p40, IL-1β, and IL-10 using flow cytometry bead arrays according to the manufacturer's instructions (BD Bioscience, San Jose, CA). Controls are performed using the addition of medium and carrier without drug. Flow cytometry is performed on a FACS canto-II (BD Bioscience) and data are analyzed using Flowjo software (Tree Star, Inc. Ashland, OR).

[0227] Example 15 Measurement of proinflammatory cytokines by cytometric bead assay Dendritic cells are generated from peripheral blood monocytes as described (Brossart P, et al. Blood. 1998;92:4238-4247). Briefly, CD14 positive monocytes are from healthy human peripheral blood mononuclear cells (PBMCs) obtained via isolation with Lymphocyte Separation Medium (Mediatech, Inc, Manassas, VA) and after purification with CD14 microbeads from Miltenyi Biotec Inc (Aubun, CA). CD14 positive monocytes (>95% CD14) are cultured into immature monocyte-derived dendritic cells (MoDCs) by further culture with GM-CSF (100 ng / ml) and IL-4 (100 ng / ml) (R&D, MN) for 6 days.

[0228] Approximately 100,000 MoDC cells are plated into 96-well plates and stimulated in triplicate with five different concentrations of the TLR-modulating compounds of the present disclosure at concentrations of 0, 0.325, 1.3, 5.2, and 20.8 nmol / ml for 48 hours. For immunostaining and flow cytometry analysis, cells are stained with anti-HLA-DR, anti-CD11c, anti-CD-86, anti-CD80, anti-CD83, anti-CD8a, anti-CD123, and relevant isotype controls (eBioscience, San Diego, CA) after stimulation with compounds for approximately 48 hours. Cells are loaded onto a FACS-canto II and analyzed by FACSDiva and Flowjo. For cytometric bead assay (CBA), supernatants are collected 48 hours after stimulation with TLR-modulating compounds. Inflammatory cytokine levels are identified by CBA according to the manufacturer's instructions (BD, San Jose, CA).

[0229] Example 16 Assessment of IL-6 levels following stimulation with compounds of the present disclosure TLR7 mutant and C57BL / 6j mice (8-12 weeks old) are obtained from Jackson Lab (Bar Harbor, Maine). The TLR7 mutant gene is introduced into 129S1 / Sv derived from CJ7 embryonic stem cells. The cell line is backcrossed 10 times to C57BL / 6Ncr. TLR7 RNA expression is not detectable in bone marrow-derived macrophages. Homozygous TLR7 mutant mice are generated from backcrossing heterozygous mutant mice with wild-type C57BL / 6j.

[0230] Single cell suspensions of splenocytes from C57BL / 6j or TLR7 mutant mice are isolated after squeezing the whole spleen through a 70 μm cell strainer and red blood cell lysis process. Splenocytes are pulsed in triplicate with 2.08 nmol / ml or 20.8 nmol / ml imiquimod (IMQ), hydroxylimiquimod (IMQ-OH), or 10 μg / ml CpG685 in complete RPMI-1640 medium (10% heat-inactivated FBS, glutamine, 1% penicillin / streptomycin, 55 nmol 2-ME, 10 mmol HEPES). Supernatants from culture medium are collected 12 and 24 hours after pulsing and frozen at -80°C until analysis. Cytometric bead arrays (BD Biosciences, San Jose, CA) are used for measurement of IL-6 levels according to the manufacturer's instructions. Analysis is performed on a FACScantoII machine with FACSAria II software and further analyzed with Flowjo software (Tree Star, Inc, Ashland, Oreg.) A standard curve and negative control (PBS) are included in the samples for calculation of cytokine concentrations.

[0231] Example 17 Screening of in vitro binding ability to TLR7 / 8 expressing cells A TLR-7 or TLR-8 positive cell line, such as HEK-Blue TLR cells (Invivogen, San Diego, CA), is used for this screening assay. HEK-Blue TLR cells are engineered HEK293 cells. Such cells stably express TLR genes and inducibly express the NF-kB-SEAP (secreted embryonic alkaline phosphase) reporter gene. Binding of a ligand (e.g., a compound of this disclosure) by TLR in HEK-Blue cells induces SEAP to produce blue color. The screening assay is performed according to the manufacturer's instructions. A concentration of 20.8 nmol / ml or 5.2 nmol / ml of TLR-targeting compounds is added in triplicate to HEK-Blue-TLR7 or HEK-Blue-TLR8 cells cultured at 37°C and 5% CO2. After 24 hours, 5 μl of culture supernatant is mixed with 200 μl of detection medium containing pNPP. After 1 hour, SEAP activity is read as OD at 650 nm in a microplate reader (BioTek Synergy 2, Vermont).

[0232] Example 18 Inflammatory cytokine detection in BMDCs and splenocytes Bone marrow cells are collected from femurs and tibiae of C57BL / 6j mice. After removing red blood cells with ammonium chloride-potassium buffer, bone marrow cells are cultured with complete RPMI-1640 medium and 2ng / ml granulocyte macrophage colony stimulating factor (GM-CFS) at 5% CO2 and 37°C for 6 days. Medium is changed twice during the 6-day culture. Single cell suspensions of splenocytes are prepared as described herein. BMDCs or splenocytes are stimulated in triplicate with various concentrations of test compounds of formula I, 20.8nmol / ml, 5.2nmol / ml, 1.3nmol / ml, 0.325nmol / ml, and 0nmol / ml. After 48 hours of stimulation, supernatants are collected and frozen at -80°C until analysis. Cytometric bead array (CBA, BD Bioscience) is performed for inflammatory cytokines according to the manufacturer's instructions. 500 events are collected. Analysis of all samples is performed on a FACScanto-II machine with software and further analyzed by Flowjo. Standard curves and negative controls (PBS) are included in the samples for each cytokine for calculation of cytokine concentrations.

[0233] Detection of costimulatory substance levels in BMDCs. After 2 days of stimulation with test compounds of formula I, BMDCs are triple stained with different fluorocore-labeled antibodies obtained from eBioscience (San Diego, CA). The antibodies include anti-MHC-II (IA / IE, clone M5 / 114.15.2), anti-CD86 (clone GL1), anti-CD80 (clone 16-10A1), anti-CD8α (clone 53-6.7), anti-CD11b (clone, M1 / 70), anti-CD-205 (clone 205yekta), anti-CD3 (clone 17A2), and anti-CD11c (clone N418). All samples are captured on a FACSCanto II flow cytometer (BD Biosciences, San Jose, CA). 50,000 to 100,000 events are collected. All data are analyzed by Flowjo software (Tree Star, Inc, Ashland, Oreg.) Gates are based on the CD3-CD11c+ population.

[0234] Proliferation and IFNγ production of pmel CD8 after cross-presentation. BMDCs from C56BL / 6j mice and pmel mice (human gp100 25-33 Single cell suspensions of splenocytes from T cell receptor transgenic mice containing H2Db specific receptors (Jackson Lab) are prepared as described above in this example. BMDCs are pulsed in triplicate for 48 hours with 3.5 μg per well of human gp100 peptide (peptide sequence: CALLAVGATKVPRNQDWLGVSRQLRTK, GenScript, Piscataway, NJ) and a test compound of formula I at a concentration of 10.4 nmol / ml, as well as hgp100 peptide control and PBS negative control. BMDCs are washed twice with complete RPMI medium and then co-cultured with pmel CD8 splenocytes that are CFSE-labeled and isolated from pmel splenocytes by CD8+ T Cell isolation Kit (Miltenyi Biotec, Auburn, CA) at a DC / CD8 ratio of 1:3. After 4 days of co-culture, the supernatants are collected and frozen at -80°C until detection of INFγ by CBA kit. CBA for IFNγ measurement is performed according to the manufacturer's instructions. Cell pellets are washed and stained with fluorocore-labelled antibodies (all from eBioscience): anti-CD3 (clone 17A2) and anti-CD8α (clone 53-6.7). Flow cytometry data is captured from stained samples on a FACSCanto II flow cytometer and analyzed by Flowjo software. Gates are from the CD3+CD8+ population.

[0235] IL-2 production of OT-I cells after stimulation with new TLR7 ligands from IMQ. Single bone marrow cell suspensions from C57BL / 6j mice are prepared as described previously in this example. Cells are pulsed in triplicate with test compounds of formula I at a concentration of 20.8 nmol / ml, with and without 15 μg ovalbumin (Sigma-Aldrich, St. Louis, MO) per well. After 4 days, cells are washed twice with complete RPMI medium and cultured with OT-I CD8 T cells isolated using a CD8+ isolation Kit (Miltenyl Biotec and Auburn, CA). After 4 days of co-culture, supernatants are collected and detected. CBA is performed for IL-2 production according to the instructions of BD Bioscience. Data is captured on a FACSCantoII flow cytometer, 500 events are collected, and analyzed by Flowjo software.

[0236] The terms and expressions used herein are used as terms of description, not as terms of limitation, and the use of such terms and expressions is not intended to exclude any equivalents or portions of the features shown and described, but it is recognized that various modifications are possible within the scope of the disclosure as claimed. Thus, although the present invention has been specifically disclosed by some embodiments, exemplary embodiments, and optional features, it should be understood that modifications and variations of the concepts disclosed herein may be used by those skilled in the art, and that such modifications and variations are deemed to be within the scope of the disclosure as defined by the appended claims. The specific embodiments provided herein are examples of useful embodiments of the disclosure, and it will be apparent to those skilled in the art that the disclosure can be implemented using numerous variations of the devices, device components, and method steps described in this description. As will be apparent to those skilled in the art, the methods and devices useful for the present methods may include numerous optional compositions and processing elements and steps.

Claims

1. Compounds of Formula I: 【Chemistry 104】 [In the formula, The fused ring A is 【Chemistry 105】 selected from the group consisting of: R １ is H, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, (C １ -C ６ ) alkanoyl, (C １ -C ６ ) alkoxycarbonyl, (C １ -C ６ ) alkanoyloxy, (C ３ -C ６ ) cycloalkyl, aryl, heteroaryl, heterocycle, NR ｇ R ｈ , or R ｍ R ｎ NC(=O)-, and any (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, (C １ -C ６ ) alkanoyl, (C １ -C ６ ) alkoxycarbonyl, (C １ -C ６ ) alkanoyloxy, (C ３ -C ６ ) Cycloalkyl, aryl, heteroaryl, and heterocycles are selected from halo, cyano, oxo, oxiranyl, (C ３ -C ８ ) cycloalkyl, NR ｕ R ｖ aryl optionally substituted by alkyl substituted by aryl, aryl substituted by carboxy, heteroaryl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) alkylthio, OR ｚ , -N(H)S(O) ２ R ｒ , R ｓ C(=O)O-, -SR ｗ , -NR ｘ R ｙ , (C １ -C ６ ) optionally substituted with one or more groups independently selected from the group consisting of alkoxycarbonyl, and carboxy; R ２ is H, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, (C １ -C ６ ) alkanoyl, (C １ -C ６ ) alkoxycarbonyl, (C １ -C ６ ) alkanoyloxy, (C ３ -C ６ ) cycloalkyl, aryl, heteroaryl, heterocycle, NR ｇ R ｈ , or R ｍ R ｎ NC(=O)-, and any (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, (C １ -C ６ ) alkanoyl, (C １ -C ６ ) alkoxycarbonyl, (C １ -C ６ ) alkanoyloxy, (C ３ -C ６ Cycloalkyl, aryl, heteroaryl, and heterocycles are hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C ３ -C ８ ) cycloalkyl, aryl, heteroaryl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) alkylthio, and NR ｇ R ｈ optionally substituted with one or more groups independently selected from the group consisting of: R ３ is H, halo, hydroxy, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, (C １ -C ６ ) alkanoyl, (C １ -C ６ ) alkoxycarbonyl, (C １ -C ６ ) alkanoyloxy, (C ３ -C ６ ) cycloalkyl, aryl, heteroaryl, heterocycle, NR ｇ R ｈ , or R ｍ R ｎ NC(=O)-, and any (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, (C １ -C ６ ) alkanoyl, (C １ -C ６ ) alkoxycarbonyl, (C １ -C ６ ) alkanoyloxy, (C ３ -C ６ Cycloalkyl, aryl, heteroaryl, and heterocycles are hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C ３ -C ８ ) cycloalkyl, aryl, heteroaryl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) alkylthio, and NR ｇ R ｈ optionally substituted with one or more groups independently selected from the group consisting of: R ４ is R ｋ -C(=O)-, R ｋ -O-C(=O)-, R ｋ -S (O) ２ -O-, R ｃ R ｄ NC(=O)-, R ｃ R ｄ N.S. (O) ２ -, R ｅ C(=O)N(R ｅ ) -, R ｅ S (O) ２ N.R. ｆ - or R ｋ -C(=O)-, R ｋ -O-C(=O)-, R ｋ -S (O) ２ -O-, R ｃ R ｄ NC(=O)-, R ｃ R ｄ N.S. (O) ２ -, R ｅ C(=O)N(R ｅ ) - or R ｅ S (O) ２ N.R. ｆ - is 1-ethylene substituted at the 2-position by -; R ａ is H, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, (C １ -C ６ ) alkanoyl, (C １ -C ６ ) alkoxycarbonyl, (C ３ -C ６ ) cycloalkyl, aryl, or heteroaryl; １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, (C １ -C ６ ) alkanoyl, (C １ -C ６ ) alkoxycarbonyl, (C ３ -C ６ ) Cycloalkyl, aryl, and heteroaryl are hydroxy, halo, -SH, cyano, oxiranyl, (C ３ -C ８ ) cycloalkyl, aryl, heteroaryl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) alkylthio, and NR ｇ R ｈ optionally substituted with one or more groups independently selected from the group consisting of: R ｂ is H or X-Y; Each R ｃ and R ｄ are independently H, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ３ -C ８ ) cycloalkyl, (C ３ -C ８ ) Cycloalkyl(C １ -C ６ ) alkyl, aryl, aryl (C １ -C ６ ) alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, said ring being １ -C ６ ) optionally substituted with alkyl; R ｅ is H, (C １ -C ６ ) alkyl, or R ａａ and R ｆ is H or (C １ -C ６ ) alkyl; Each R ｇ and R ｈ are independently H, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ３ -C ８ ) cycloalkyl, (C ３ -C ８ ) Cycloalkyl(C １ -C ６ ) alkyl, aryl, aryl (C １ -C ６ ) alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, said ring being １ -C ６ ) optionally substituted with alkyl; R ｋ is H, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, (C ３ -C ８ ) cycloalkyl, trifluoromethyl, aryl, or aryl (C １ -C ６ ) alkyl, each (C １ -C ６ ) alkyl is one or more halo, (C １ -C ６ ) alkanoyloxy, (C １ -C ６ ) alkoxy, (C ３ -C ８ ) optionally substituted with cycloalkyl; Each R ｍ and R ｎ are independently H, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ３ -C ８ ) cycloalkyl, (C ３ -C ８ ) Cycloalkyl(C １ -C ６ ) alkyl, aryl, aryl (C １ -C ６ ) alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, said ring being １ -C ６ ) optionally substituted with alkyl; X is a linking group; Y is a peptide, protein, or maleimide; Rings B and C in formula I are halo, hydroxy, nitro, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkenyl, (C １ -C ６ ) alkynyl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) alkanoyl, (C １ -C ６ ) alkanoyloxy, (C １ -C ６ ) alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, cyano, and NR ｐ R ｑ may be optionally further substituted on one or more carbons with one or more groups independently selected from the group consisting of: Each R ｐ and R ｑ are independently H or (C １ -C ６ ) alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, said ring being １ -C ６ ) optionally substituted with alkyl; R ｒ is optionally substituted with H, aryl, or halo or aryl (C １ -C １０ ) alkyl; R ｓ is optionally substituted with H, aryl, or halo or aryl (C １ -C １０ ) alkyl; Each R ｕ and R ｖ are independently H or (C １ -C ６ ) alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, said ring being １ -C ６ ) optionally substituted with alkyl; R ｗ is optionally substituted with H, aryl, or halo or aryl (C １ -C １０ ) alkyl; Each R ｘ and R ｙ are independently H or (C １ -C ６ ) alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, said ring being １ -C ６ ) optionally substituted with alkyl; R ｚ is optionally substituted with H, aryl, or halo or aryl (C １ -C １０ ) alkyl; R ａａ is hydroxy, halo, nitro, cyano, (C １ -C ６ ) alkoxy, and (C １ -C ６ ) aryl optionally substituted with one or more groups independently selected from the group consisting of alkyl; or a pharma- ceutically acceptable salt thereof.

2. Compounds of Formula I: 【Chemistry 106】 [In the formula, The fused ring A is 【Chemistry 107】 selected from the group consisting of: R １ is H, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, (C １ -C ６ ) alkanoyl, (C １ -C ６ ) alkoxycarbonyl, (C １ -C ６ ) alkanoyloxy, (C ３ -C ６ ) cycloalkyl, heterocycle, NR ｇ R ｈ , or R ｍ R ｎ NC(=O)-, and any (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, (C １ -C ６ ) alkanoyl, (C １ -C ６ ) alkoxycarbonyl, (C １ -C ６ ) alkanoyloxy, (C ３ -C ６ ) Cycloalkyl and heterocycles include halo, cyano, oxo, oxiranyl, (C ３ -C ８ ) cycloalkyl, NR ｕ R ｖ aryl optionally substituted by alkyl substituted by aryl, aryl substituted by carboxy, heteroaryl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) alkylthio, OR ｚ , -N(H)S(O) ２ R ｒ , R ｓ C(=O)O-, -SR ｗ , -NR ｘ R ｙ , (C １ -C ６ ) optionally substituted with one or more groups independently selected from the group consisting of alkoxycarbonyl, and carboxy; R ２ is H, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, (C １ -C ６ ) alkanoyl, (C １ -C ６ ) alkoxycarbonyl, (C １ -C ６ ) alkanoyloxy, (C ３ -C ６ ) cycloalkyl, aryl, heteroaryl, heterocycle, NR ｇ R ｈ , or R ｍ R ｎ NC(=O)-, and any (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, (C １ -C ６ ) alkanoyl, (C １ -C ６ ) alkoxycarbonyl, (C １ -C ６ ) alkanoyloxy, (C ３ -C ６ Cycloalkyl, aryl, heteroaryl, and heterocycles are hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C ３ -C ８ ) cycloalkyl, aryl, heteroaryl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) alkylthio, and NR ｇ R ｈ optionally substituted with one or more groups independently selected from the group consisting of: R ３ is H, halo, hydroxy, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, (C １ -C ６ ) alkanoyl, (C １ -C ６ ) alkoxycarbonyl, (C １ -C ６ ) alkanoyloxy, (C ３ -C ６ ) cycloalkyl, aryl, heteroaryl, heterocycle, NR ｇ R ｈ , or R ｍ R ｎ NC(=O)-, and any (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, (C １ -C ６ ) alkanoyl, (C １ -C ６ ) alkoxycarbonyl, (C １ -C ６ ) alkanoyloxy, (C ３ -C ６ Cycloalkyl, aryl, heteroaryl, and heterocycles are hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C ３ -C ８ ) cycloalkyl, aryl, heteroaryl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) alkylthio, and NR ｇ R ｈ optionally substituted with one or more groups independently selected from the group consisting of: R ４ is R ｋ -C(=O)-, R ｋ -O-C(=O)-, R ｋ -S (O) ２ -O-, R ｃ R ｄ NC(=O)-, R ｃ R ｄ N.S. (O) ２ -, R ｅ S (O) ２ N.R. ｆ - or R ｋ -C(=O)-, R ｋ -O-C(=O)-, R ｋ -S (O) ２ -O-, R ｃ R ｄ NC(=O)-, R ｃ R ｄ N.S. (O) ２ -, R ｅ C(=O)N(R ｅ ) - or R ｅ S (O) ２ N.R. ｆ - is 1-ethylene substituted at the 2-position by -; R ａ is H, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, (C １ -C ６ ) alkanoyl, or (C １ -C ６ ) alkoxycarbonyl, and any (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, (C １ -C ６ ) alkanoyl, and (C １ -C ６ ) Alkoxycarbonyl is hydroxy, halo, -SH, cyano, oxiranyl, (C ３ -C ８ ) cycloalkyl, aryl, heteroaryl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) alkylthio, and NR ｇ R ｈ optionally substituted with one or more groups independently selected from the group consisting of: R ｂ is H or X-Y; Each R ｃ and R ｄ are independently H, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ３ -C ８ ) cycloalkyl, (C ３ -C ８ ) Cycloalkyl(C １ -C ６ ) alkyl, aryl, aryl (C １ -C ６ ) alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, said ring being １ -C ６ ) optionally substituted with alkyl; R ｅ is H, (C １ -C ６ ) alkyl, or R ａａ and R ｆ is H or (C １ -C ６ ) alkyl; Each R ｇ and R ｈ are independently H, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ３ -C ８ ) cycloalkyl, (C ３ -C ８ ) Cycloalkyl(C １ -C ６ ) alkyl, aryl, aryl (C １ -C ６ ) alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, said ring being １ -C ６ ) optionally substituted with alkyl; R ｋ is H, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, (C ３ -C ８ ) cycloalkyl, trifluoromethyl, aryl, or aryl (C １ -C ６ ) alkyl, each (C １ -C ６ ) alkyl is one or more halo, (C １ -C ６ ) alkanoyloxy, (C １ -C ６ ) alkoxy, (C ３ -C ８ ) optionally substituted with cycloalkyl; Each R ｍ and R ｎ are independently H, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ３ -C ８ ) cycloalkyl, (C ３ -C ８ ) Cycloalkyl(C １ -C ６ ) alkyl, aryl, aryl (C １ -C ６ ) alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, said ring being １ -C ６ ) optionally substituted with alkyl; X is a linking group; Y is a peptide, protein, or maleimide; Rings B and C in formula I are halo, hydroxy, nitro, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkenyl, (C １ -C ６ ) alkynyl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) alkanoyl, (C １ -C ６ ) alkanoyloxy, (C １ -C ６ ) alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, cyano, and NR ｐ R ｑ may be optionally further substituted on one or more carbons with one or more groups independently selected from the group consisting of: Each R ｐ and R ｑ are independently H or (C １ -C ６ ) alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, said ring being １ -C ６ ) optionally substituted with alkyl; R ｒ is optionally substituted with H, aryl, or halo or aryl (C １ -C １０ ) alkyl; R ｓ is optionally substituted with H, aryl, or halo or aryl (C １ -C １０ ) alkyl; Each R ｕ and R ｖ are independently H or (C １ -C ６ ) alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, said ring being １ -C ６ ) optionally substituted with alkyl; R ｗ is optionally substituted with H, aryl, or halo or aryl (C １ -C １０ ) alkyl; Each R ｘ and R ｙ are independently H or (C １ -C ６ ) alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, said ring being １ -C ６ ) optionally substituted with alkyl; R ｚ is optionally substituted with H, aryl, or halo or aryl (C １ -C １０ ) alkyl; R ａａ is hydroxy, halo, nitro, cyano, (C １ -C ６ ) alkoxy, and (C １ -C ６ ) aryl optionally substituted with one or more groups independently selected from the group consisting of alkyl; or a pharma- ceutically acceptable salt thereof.

3. The compound of formula I, wherein the compound has the structure of formula (Ia): 【Chemistry 117】 wherein the fused ring A is 【Chemistry 118】 3. The compound of claim 1 or 2, selected from the group consisting of:

4. The fused ring A is 【Chemistry 119】 The compound according to any one of claims 1 to 3, selected from the group consisting of:

5. The compound of formula I, wherein the compound has the structure of formula (Ia): 【Chemistry 120】 wherein the fused ring A is 【Chemistry 121】 3. The compound of claim 2, selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

6. The fused ring A is 【Chemistry 122】 3. The compound of claim 2, selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

7. R 3 is H, halo, hydroxy, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) alkanoyl, (C 1 -C 6 ) alkoxycarbonyl, or NR g R h , and any of the (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) alkanoyl, and (C 1 -C 6 ) alkoxycarbonyl is hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C 3 -C 8 ) cycloalkyl, aryl, heteroaryl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 5. The compound of claim 1, optionally substituted with one or more groups independently selected from the group consisting of NR g R h , or a pharma- ceutically acceptable salt thereof.

8. R 3 is H, halo, hydroxy, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) alkanoyl, (C 1 -C 6 ) alkoxycarbonyl, or NR g R h , and any of the (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) alkanoyl, and (C 1 -C 6 ) alkoxycarbonyl is halo, --SH, cyano, (C 3 -C 8 ) cycloalkyl, and NR g R h .

5. The compound of any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more groups independently selected from the group consisting of:

9. The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein R3 is H or (C1-C6)alkyl optionally substituted with one or more groups independently selected from the group consisting of halo, -SH, cyano, (C3-C8)cycloalkyl, and NRgRh.

10. The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein R3 is H or (C1-C6) alkyl.

11. R １ But, H, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, (C １ -C ６ ) alkanoyl, (C １ -C ６ ) alkoxycarbonyl, or -NR ｇ R ｈ and any (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, (C １ -C ６ ) alkanoyl, and (C １ -C ６ ) alkoxycarbonyl is halo, cyano, oxo, oxiranyl, (C ３ -C ８ ) cycloalkyl, NR ｕ R ｖ aryl optionally substituted by alkyl substituted by aryl, aryl substituted by carboxy, heteroaryl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) alkylthio, OR ｚ , -N(H)S(O) ２ R ｒ , R ｓ C(=O)O-, -SR ｗ , -NR ｘ R ｙ , (C １ -C ６ 11. The compound of any one of claims 1 to 5 or 7 to 10, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more groups independently selected from the group consisting of alkoxycarbonyl, and carboxy.

12. R １ But, H, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, or -NR ｇ R ｈ and any (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, and (C ２ -C ６ ) alkynyl is halo, cyano, oxo, oxiranyl, (C ３ -C ８ 11. The compound of any one of claims 1 to 5 or 7 to 10, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more groups independently selected from the group consisting of: 1) cycloalkyl;

13. R １ is H or (C １ -C ６ 11. The compound according to any one of claims 1 to 5 or 7 to 10, or a pharma- ceutically acceptable salt thereof, wherein: R is 1 or 2; and R is 3 or 4.

14. R １ The compound according to any one of claims 1 to 5 or 7 to 10, wherein is H, or a pharma- ceutically acceptable salt thereof.

15. R ２ But, H, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, (C １ -C ６ ) alkanoyl, (C １ -C ６ ) alkoxycarbonyl, or -NR ｇ R ｈ and any (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, (C １ -C ６ ) alkanoyl, and (C １ -C ６ ) alkoxycarbonyl is hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C ３ -C ８ ) cycloalkyl, aryl, heteroaryl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) alkylthio, and NR ｇ R ｈ 15. The compound of any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more groups independently selected from the group consisting of:

16. R ２ But, H, (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, (C １ -C ６ ) alkanoyl, (C １ -C ６ ) alkoxycarbonyl, or -NR ｇ R ｈ and any (C １ -C ６ ) alkyl, (C ２ -C ６ ) alkenyl, (C ２ -C ６ ) alkynyl, (C １ -C ６ ) alkanoyl, and (C １ -C ６ ) alkoxycarbonyl is halo, -SH, cyano, (C ３ -C ８ ) cycloalkyl, and NR ｇ R ｈ 15. The compound of any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, optionally substituted with one or more groups independently selected from the group consisting of:

17. R ２ is H, or halo, -SH, cyano, and NR ｇ R ｈ (C １ -C ６ 15. The compound of any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, wherein: R is 1 or 2; and R is 3 or 4.

18. R ２ is H or (C １ -C ６ 15. The compound of any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, wherein: R is 1 or 2; and R is 3 or 4.

19. R ２ The compound according to any one of claims 1 to 14, wherein is H, or a pharma- ceutically acceptable salt thereof.

20. R ４ But, R ｋ -C(=O)-, R ｋ -O-C(=O)-, R ｋ -S (O) ２ -O-, R ｃ R ｄ N.S. (O) ２ -, R ｅ S (O) ２ N.R. ｆ - or R ｋ -C(=O)-, R ｋ -O-C(=O)-, R ｋ -S (O) ２ -O-, R ｃ R ｄ N.S. (O) ２ - or R ｅ S (O) ２ N.R. ｆ 20. The compound of any one of claims 1 to 19, which is 1-ethylene substituted at the 2-position with -, or a pharma- ceutically acceptable salt thereof.

21. R ４ But, R ｋ -C(=O)-, R ｋ -O-C(=O)- or R ｋ -C(=O)-, R ｋ 20. The compound according to any one of claims 1 to 19, which is 1-ethylene substituted at the 2-position with -O-C(=O)-, or a pharma- ceutically acceptable salt thereof.

22. R ４ But, R ｋ -C(=O)- or R ｋ The compound according to any one of claims 1 to 19, which is -O-C(=O)-, or a pharma- ceutically acceptable salt thereof.

23. The compound of formula I, wherein the compound has the structure of formula (Ia) or (Ib): 【Chemistry 108】 3. The compound of claim 1 or 2, comprising:

24. The compound of formula I, wherein the compound has the structure of formula (Ia): 【Chemistry 109】 23. The compound of any one of claims 1 to 22, comprising:

25. R ａ is H, or halo, -SH, cyano, and NR ｇ R ｈ (C １ -C ６ 25. The compound of any one of claims 1 to 24, or a pharma- ceutically acceptable salt thereof, wherein: R is 1 or 2; and R is 2 or 3.

26. R ａ is H or (C １ -C ６ 25. The compound of any one of claims 1 to 24, or a pharma- ceutically acceptable salt thereof, wherein: R is 1 or 2; and R is 2 or 3.

27. ​​The fused ring A is 【Chemistry 110】 3. The compound of claim 1 or 2, selected from the group consisting of:

28. The fused ring A is 【Chemistry 111】 3. The compound of claim 1 or 2, selected from the group consisting of:

29. The fused ring A is 【Chemistry 112】 6. The compound of claim 1, 2, or 5, selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

30. The fused ring A is 【Chemistry 113】 3. The compound of claim 2, wherein:

31. The fused ring A is 【Chemistry 114】 3. The compound of claim 2, selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

32. A compound of formula II: 【Chemistry 99】 or a pharma- ceutically acceptable salt thereof. [In the formula, R 2 is H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, (C 3 -C 6 )cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n NC(═O)—, with any of (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, (C (C 3 -C 6 )cycloalkyl, aryl, heteroaryl, and heterocycle are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C 3 -C 8 )cycloalkyl, aryl, heteroaryl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, and NR g R h ; R 4 is R k -C(═O)- or R k -O-C(═O)-; R a is H or optionally substituted (C 1 -C 6 )alkyl; R b is H or X—Y; each R g and R h is independently H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C 1 -C 6 )alkyl; R k is H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 8 )cycloalkyl, trifluoromethyl, aryl, or aryl(C 1 -C 6 )alkyl, each (C 1 -C 6 )alkyl can be optionally substituted with one or more halo, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyl; each R m and R n is independently H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C 1 -C 6 )alkyl; X is a linking group; Y is a peptide, protein, or maleimide.

33. Formula: 【Chemistry 100】 33. The compound of claim 32, having the formula: or a pharma- ceutically acceptable salt thereof.

34. A compound of formula III or formula IV: 【Chemistry 101】 or a pharma- ceutically acceptable salt thereof [In the formula, R 1 is H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, (C 3 -C 6 )cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n NC(═O)—, with any of (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, (C (3-C6)cycloalkyl, aryl, heteroaryl, and heterocycle are optionally substituted with one or more groups independently selected from the group consisting of halo, cyano, oxo, oxiranyl, (C3-C8)cycloalkyl, aryl optionally substituted with alkyl substituted by NRuRv, aryl substituted with carboxy, heteroaryl, (C1-C6)alkoxy, (C1-C6)alkylthio, ORz, -N(H)S(O)2Rr, RsC(=O)O-, -S-Rw, -NRxRy, (C1-C6)alkoxycarbonyl, and carboxy; R 2 is H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, (C 3 -C 6 )cycloalkyl, aryl, heteroaryl, heterocycle, NR g R h , or R m R n NC(═O)—, with any of (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, (C (C 3 -C 6 )cycloalkyl, aryl, heteroaryl, and heterocycle are optionally substituted with one or more groups independently selected from the group consisting of hydroxy, halo, -SH, cyano, oxo, oxiranyl, (C 3 -C 8 )cycloalkyl, aryl, heteroaryl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, and NR g R h ; R 4 is R k -C(═O)-, R k -O-C(═O)-, or R k -S(O) 2 -O-; R a is H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 3 -C 6 )cycloalkyl, aryl, or heteroaryl, with any of the (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 3 -C 6 )cycloalkyl, aryl, and heteroaryl being hydroxy, halo, -SH, cyano, oxiranyl, (C 3 -C 8 )cycloalkyl, aryl, heteroaryl, (C 1 -C 6 ) optionally substituted with one or more groups independently selected from the group consisting of alkoxy, (C 1 -C 6 )alkylthio, and NR g R h ; R b is H or X—Y; each R g and R h is independently H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C 1 -C 6 )alkyl; R k is H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 8 )cycloalkyl, trifluoromethyl, aryl, or aryl(C 1 -C 6 )alkyl, each (C 1 -C 6 )alkyl can be optionally substituted with one or more halo, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyl; each R m and R n is independently H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C 1 -C 6 )alkyl; X is a linking group; Y is a peptide, protein, or maleimide; R r is H, aryl, or (C 1 -C 10 )alkyl optionally substituted with halo or aryl; R s is H, aryl, or (C 1 -C 10 )alkyl optionally substituted with halo or aryl; each R u and R v is independently H or (C 1 -C 6 )alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C 1 -C 6 )alkyl; R w is H, aryl, or (C 1 -C 10 )alkyl optionally substituted with halo or aryl; each R x and R y is independently H or (C 1 -C 6 )alkyl; or together with the nitrogen to which they are attached form an aziridino, azetidino, morpholino, piperazino, pyrrolidino, or piperidino ring, which may be optionally substituted with one or more (C 1 -C 6 )alkyl; R z is H, aryl, or (C 1 -C 10 )alkyl optionally substituted with halo or aryl. 【Request 35】 【Chemical 123】 35. The compound of claim 34, selected from the group consisting of: or a pharma- ceutically acceptable salt thereof.

36. X is 【Chemistry 103】 wherein n is 2, 3, 4, 5, or 6.

35. The compound of any one of claims 1 to 32 or 34, selected from the group consisting of:

37. 【Catalogue 124】 A compound selected from the group consisting of:

38. The compound according to any one of claims 1 to 33, 34, or 36, or a pharma- ceutically acceptable salt thereof, wherein R b is X—Y.

39. The compound of any one of claims 1 to 32, 34, 36, or 38, or a pharma- ceutically acceptable salt thereof, wherein Y is an antibody.

40. A pharmaceutical composition comprising a compound according to any one of claims 1 to 39, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable diluent or carrier.

41. A composition comprising a compound according to any one of claims 1 to 39 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 40, for use in therapy.

42. A composition comprising a compound according to any one of claims 1 to 39 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 40, for use in a method of stimulating an immune response in an animal.

43. A composition comprising a compound according to any one of claims 1 to 39 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 40, for use in a method for treating cancer.

44. 40. A method of synthesizing a compound of any one of claims 1 to 39, or a pharma- ceutically acceptable salt thereof, comprising carrying out a reaction according to any one of Reaction Schemes 1 to 5.

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