Compounds and methods for the treatment, remission, or prevention of arthritis

Abstract

This disclosure describes compounds containing an asialoglycoprotein receptor (ASGPR) binding moiety and an anti-CCP (anti-cyclic citrullinated peptide binding moiety) in a non-limiting context. When administered in therapeutically effective doses, these compounds are useful in the prevention, treatment, and / or remission of various types of arthritis, including rheumatoid arthritis (RA), in subjects. TIFF2026508972000542.tif85170

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority under U.S. Provisional Patent Application No. 63 / 482,486, entitled “COMPOUNDS, COMPOUNDS, AND METHODS FOR TREATING, AMELIORATING, OR PREVENTING ARTHRITIS,” filed on 31 January 2023, and U.S. Provisional Patent Application No. 63 / 606,161, entitled “COMPOUNDS AND METHODS FOR TREATING, AMELIORATING, OR PREVENTING ARTHRITIS,” filed on 5 December 2023, the disclosures thereof incorporated herein by reference in their entirety.

[0002] Description of research funded by the federal government. This invention was created with government support under GM067543, awarded by the National Institutes of Health. The government has certain rights in this invention.

[0003] Incorporation of documents submitted as text files via the electronic filing system. The present invention includes one or more sequences in computer-readable format in an attached text file named "047162-7400WO1(02160)Sequence Listing ST_26.xml", which was created on January 29, 2024, and whose contents are incorporated herein by reference in their entirety. [Background technology]

[0004] background In rheumatoid arthritis (RA), the body's immune system attacks its own tissues, including the joints, and eventually the internal organs. RA affects the synovial membrane of the joints, causing painful hypertrophy. Long-term inflammation associated with RA can lead to bone erosion and joint deformities. Existing treatments for RA, such as methotrexate and adalimumab (HUMIRA®), are associated with serious undesirable side effects, including but not limited to loss of appetite, stomatitis, diarrhea, headache, and / or hair loss.

[0005] Therefore, there is a continuing need for more selective, rapid, and effective treatments for rheumatoid arthritis (RA). This disclosure addresses this need. [Overview of the Initiative]

[0006] Structure in various situations: Compounds of formula II having TIFF2026508972000002.tif17128, or pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs thereof, are provided herein. During the ceremony, PBM is the antibody-binding site for anti-cyclic citrullinated peptides (anti-CCP); CON and linker-2 appear independently in each instance, as follows: (a) In the above formula, TIFF2026508972000003.tif20128, R 1 Each occurrence is independently either H or C1-C3 alkyl; Each occurrence of n'' is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; or (b) In the above formula, TIFF2026508972000004.tif15128 Each occurrence of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25; Each occurrence of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25; Each occurrence of n'' is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; or (c) In the above formula, TIFF2026508972000005.tif6128 Z and Z' are each independently a bond, -(CH2) i 0 -O-, -(CH2) i -S-, -(CH2) i -N(R)-, In TIFF2026508972000006.tif27128; R 2 Each occurrence of is independently H or C1 - C3 alkyl; Each occurrence of Y is independently a bond, -O-, -S-, or -N(R)-; Each occurrence of i is independently an integer in the range of 0 - 100; D is -(CH2) i -Y-C(=O)-Y-(CH2) i -, -(CH2) m' -, -[(CH2) n -X 1 j -, or a bond, provided that Z, Z', and D are not bonds simultaneously; j is an integer in the range of 1 - 100; m' is an integer in the range of 1 - 100; n is an integer in the range of​​​​​​​​​​​​​​In each occurrence, -CH2-, -O-, -S-, and -N(R) appear independently. 4 )-, -C(O)-, -S(O)-, -S(O)2-, -S(O)2O-, -OS(O)2-, or -OS(O)2O-; X 3 In each occurrence, -O-, -S-, or -N(R 4 )-and; R 4 In each occurrence, it is independently H, C1-C3 alkyl, C1-C3 alkanol, or -C(O)(C1-C3 alkyl). structure; or (e)C 6~18 Ariel, C 3~18 Heterocyclyl, C 6~18 Viaryl, or C 6~18 A heterobiaryl which may be substituted with 1 to 6 substituents selected from the group consisting of F, Cl, Br, I, O(RG), O(O)N(RG)2, CN, NO, NO2, ONO2, CF3, OCF3, -(RG), N(RG)2, S(RG), SO(RG), SO2(RG), SO2N(RG)2, and SO3(RG), where each occurrence of RG may be independently substituted with H, or C 1~10 Alkyl, possibly substituted C 3~10 Cycloalkyl, may be substituted C 6~18 Aryl, or possibly substituted C 5~18 C is a heteroaryl. 6~18 Ariel, C 3~18 Heterocyclyl, C 6~18 Viaryl, or C 6~18 Heterobiaryl and; CRBM is structured as follows: Having TIFF2026508972000008.tif15128, in the above formula, Each RG 1 Independently The filename is TIFF2026508972000009.tif7128; Each occurrence of XG is independently selected from the group consisting of -CH2-, -C(=O)-, -NH-, and -O-; Each occurrence of ZG is independently selected from the group consisting of -CH2-, -C(=O)-, -NH-, and -O-; AG is independent in each appearance The filename is TIFF2026508972000010.tif21128; RG 2 and RG 3 In each instance, independently, hydrogen and halogen, and possibly substituted C, are present. 1~10 Alkyl, possibly substituted C 1~10 Alkoxy, C may be substituted. 1~10 Selected from the group consisting of aminoalkyl groups and combinations thereof, and -C(=O)R groups which may be substituted with 1 to 5 groups selected from the group consisting of aminoalkyl groups and combinations thereof, or RG 2 and RG 3 These, together with the nitrogen atom to which they are bonded, may be substituted C 1~10 Alkyl, possibly substituted C 1~10 Alkoxy, C may be substituted. 1~10 aminoalkyl, optionally substituted C 6~10 Aryl, C may be substituted. 5~10 It forms a C5 heterocycle which may be substituted with 1 to 5 substituents selected from the group consisting of heteroaryls, halogens, and combinations thereof; Each occurrence of R is independent of H, and C may be substituted. 1~10 Alkyl, possibly substituted C 3~10 Cycloalkyl, may be substituted C 6~18 Aryl, or possibly substituted C 5~18 It is a heteroaryl, Each occurrence of m is independently 2, 3, 4, 5, 6, 7, 8, 9, or 10; Each occurrence of n is an integer in the range of 1 to 100, independently; Each occurrence p is an independent integer in the range of 1 to 50; k' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; j' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; h and h' are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; i L is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; However, h, h', and i L At least one of them is at least 1.

[0007] Structure in various situations: Compounds of formula Ia having TIFF2026508972000011.tif35128, or pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs thereof, are provided herein. During the ceremony, TIFF2026508972000012.tif2128 is a single or double bond between carbon atoms; A may be substituted with 1 to 6 substituents selected from the group consisting of F, Cl, Br, I, O(RG), O(O)N(RG)2, CN, NO, NO2, ONO2, CF3, OCF3, -(RG), N(RG)2, S(RG), SO(RG), SO2(RG), SO2N(RG)2, and SO3(RG), C 6~18 Ariel, C 6~18 Heterocyclyl, C 6~18 Biaryl, or C 6~18 It is a heterobiaryl; L A Structure: This is an ASGPR coupling portion containing TIFF2026508972000013.tif15128; L B Structure: It is an anti-CCP1 binding moiety having TIFF2026508972000014.tif20128; AA is an amino acid sequence that is at least 80% homologous to SEQ ID NO:1; RG 1 Each appearance is independently of hydrogen or The filename is TIFF2026508972000015.tif7128; AG is an amino sugar; Each occurrence of RG is independently H, and C may be substituted. 1~10 Alkyl, possibly substituted C 3~10 Cycloalkyl, may be substituted C 6~18 Aryl, or possibly substituted C 5~18 It is a heteroaryl; Each occurrence of XG is independently selected from the group consisting of -CH2-, -C(=O)-, -NH-, and -O-; Each occurrence of ZG is independently selected from the group consisting of -CH2-, -C(=O)-, -NH-, and -O-; m is 2, 3, 4, 5, 6, 7, 8, 9, or 10; n is an integer in the range of 1 to 100; p is an integer in the range of 1 to 50.

[0008] The compounds of formulas Ia, II, and IIb, and any other compounds described herein, are useful in methods for the prevention, treatment, and / or remission of arthritis in subjects where such treatment is needed. The method comprises the step of administering to a subject a therapeutically effective amount of the compounds of formulas Ia, II, and IIb, or any other compounds described herein, in various aspects, wherein the compounds may optionally be formulated as a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier or excipient. [Brief explanation of the drawing]

[0009] The drawings are not for limitation, but rather to illustrate various aspects of the present application as a whole. [Figure 1]This is a schematic diagram of one mode of action of the compound of formula I in various forms. Although we do not wish to be constrained by theory, the mode of action of the compound here is at least partially as follows: Step 1: MoDE-A binds to the target protein of interest; Step 2: The MoDE-A / protein complex binds to ASGPR (asiaroglycoprotein receptor) on hepatocytes; Step 3: The ASGPR / MoDE-A / protein ternary complex is taken up by hepatocytes by endocytosis; Step 4: The ternary complex dissociates; Step 5: The taken-uptaken target protein is degraded by endocytosis; Step 6: ASGPR and MoDE-A return to the extracellular space and are reused. [Figure 2A] Several embodiments of ASGPR-binding fragments are shown. [Figure 2B] The structure of formula I is shown in several forms. [Figure 3A] Figures 3A to 3D collectively show schemes for synthesizing compound target A0001A in several embodiments. Figure 3A shows schemes for synthesizing PEGylated sugar 4 in several embodiments. [Figure 3B] Figures 3A-3D collectively show schemes for synthesizing compound target A0001A in several embodiments. Figure 3B shows schemes for synthesizing tricarboxylic acid 8 in various embodiments. [Figure 3C] Figures 3A to 3D collectively show schemes for synthesizing compound target A0001A in several embodiments. Figure 3C shows schemes for synthesizing asialoclycoprotein-binding substance 10 in several embodiments. [Figure 3D] Figures 3A to 3D collectively show schemes for synthesizing compound target A0001A in several embodiments. Figure 3D shows the synthesis of compound target A0001A in several embodiments. [Figure 4A] Figures 4A to 4C collectively show schemes for synthesizing the compound of formula I, CCP1-GN4, in several embodiments. Figure 4A shows the synthesis of the peptide intermediate Int-00002. [Figure 4B]Figures 4A-4C collectively show schemes for synthesizing the compound CCP1-GN4 of formula I in several embodiments. Figure 4B shows the synthesis of an alkynyl derivative of compound target A0001A in several embodiments. [Figure 4C] Figures 4A to 4C collectively show schemes for synthesizing the compound of formula I, CCP1-GN4, in several embodiments. Figure 4C shows the synthesis of CCP1-GN4 in several embodiments. [Figure 5A] The anti-CCP1 SPR (surface plasmon resonance) coupling data for the compound CCP1-GN4 in several embodiments are shown. The KD (anti-CCP) for CCP1-GN4 was 75 nM. [Figure 5B] ASGPR SPR binding data for compound CCP1-GN4 in several embodiments are shown. The KD(ASGPR) for CCP1-GN4 was 1.92 nM. [Figure 6] Figure 6A shows plasma stability data for CCP1-GN4 in mice, rats, and humans in several embodiments. All T1 / 2 values ​​were longer than 290 minutes. Figure 6B shows plasma protein binding data for CCP1-GN4 in mice, rats, and humans. [Figure 7] We present data on the internal translocation of anti-CCP1 into ASGPR+HEK-293 cells mediated by CCP1-GN4 in several aspects. [Figure 8] Figure 8A shows data on anti-CCP1 depletion by CCP1-GN4 compared to a control, in several embodiments. Figure 8B shows AUC (Area Under Curve) data for CCP1-GN4 compared to a control, for the depletion studies shown in Figure 8A, in several embodiments. [Modes for carrying out the invention]

[0010] Detailed explanation Herein, certain aspects of the disclosed subject matter are given detailed reference, with examples partially illustrated in the accompanying drawings. The disclosed subject matter is described in conjunction with the enumerated claims, but it should be understood that the illustrated subject matter is not intended to limit the claims to the disclosed subject matter.

[0011] Throughout this book, values ​​expressed in range form should be interpreted flexibly to include not only the numerical limits explicitly stated as range limits, but also all individual numerical values ​​or subranges contained within that range, as if each numerical value and subrange were explicitly stated. For example, the range "approximately 0.1% to approximately 5%" or "approximately 0.1% to approximately 5%" should be interpreted to include not only approximately 0.1% to approximately 5%, but also the individual values ​​within the indicated range (e.g., 1%, 2%, 3%, and 4%) and subranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%). The notation "approximately X to Y" is equivalent to "approximately X to approximately Y" unless otherwise indicated. Similarly, the notation "approximately X, Y, or approximately Z" is equivalent to "approximately X, approximately Y, or approximately Z" unless otherwise indicated.

[0012] In this text, the terms “a,” “an,” or “the” are used to include one or more unless the context explicitly indicates otherwise. The term “or” is used to refer to a non-exclusive “or” unless otherwise indicated. The phrases “at least one of A and B” or “at least one of A or B” are synonymous with “A, B, or A and B.” Furthermore, it should be understood that any usage or terminology used herein, unless otherwise defined, is for explanatory purposes only, not limitation. The use of section headings is for the purpose of aiding the reading of the document and should not be interpreted as limitation; information related to a section heading may exist within or outside that particular section. All publications, patents, and patent documents mentioned herein are incorporated herein in whole by reference, as they are incorporated individually by reference.

[0013] In the methods described herein, the actions may be performed in any order unless the time or order of operations is explicitly stated. Furthermore, the specified actions may be performed simultaneously unless the terms of the claims explicitly state that they are performed separately. For example, the action of doing X as described in the claims and the action of doing Y as described in the claims may be performed simultaneously in a single operation, and the resulting process falls within the literal scope of the process described in the claims.

[0014] definition The term “approximately” as used herein may allow some degree of variability in a value or range, for example, within 10%, 5%, or 1% of the limit of the stated value or range, and includes the exact stated value or range.

[0015] The term “substantially” means, as used herein, a majority or majority, for example, at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. The term “substantially absent” as used herein may mean having none at all or having trace amounts of a material, for example, that the amount of material present does not affect the material properties of the composition containing that material, for example, that the composition contains about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than about 4.5 wt%, equal to about 4.5 wt%, or greater than about 4.5 wt%, or 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less. The term "substantially absent" may mean having trace amounts, for example, that the composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than about 4.5 wt%, equal to about 4.5 wt%, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less, or about 0 wt%.

[0016] The term “organic group” as used herein refers to any carbon-containing functional group. Examples include oxygen-containing groups, e.g., alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups; carboxyl groups, e.g., carboxylic acids, carboxylates, and carboxylate esters; sulfur-containing groups, e.g., alkyl sulfide groups and aryl sulfide groups; and other heteroatom-containing groups. Non-restrictive examples of organic groups include OR, OOR, OC(O)N(R)2, CN, CF3, OCF3, R, C(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OCO(O)R, C(O)N(R)2, OCO(O)N(R)2, C(S)N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2 N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R )C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, C(=NOR)R, and substituted or unsubstituted (C1~C 100 ) contains hydrocarbyl, where R may be hydrogen (in examples containing other carbon atoms) or a carbon-based portion, and the carbon-based portion may be substituted or unsubstituted.

[0017] The term “substituted” means, as used herein, a state in which one or more hydrogen atoms contained therein have been replaced with one or more non-hydrogen atoms, together with the molecules or organic groups as defined herein. The terms “functional group” or “substituent” mean, as used herein, a group that can be substituted for or is substituted for a molecule or organic group. Examples of substituents or functional groups include, but are not limited to, halogens (e.g., F, Cl, Br, and I); oxygen atoms in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups, e.g., carboxylic acids, carboxylates, and carboxylate esters; sulfur atoms in groups such as thiol groups, alkyl sulfide groups, aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; nitrogen atoms in groups such as amines, hydroxyamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that may be bonded to the substituted carbon (or other) atom include F, Cl, Br, I, OR, OCO(O)N(R)2, CN, NO, NO2, ONO2, azide, CF3, OCF3, R, O(oxo), S(thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OCO(O)R, C(O)N(R)2, OCO(O)N(R)2, C(S)N(R)2, (CH2) 0~2 N(R)C(O)R, (CH2) 0~2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, and C(=NOR)R included, where R may be a hydrogen or carbon-based part; for example, R may be hydrogen, (C1~C 100 ) may be hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl; or two R groups bonded to a nitrogen atom or an adjacent nitrogen atom may form a heterocyclyl with the nitrogen atom.

[0018] The term "alkyl" as used herein refers to linear and branched alkyl and cycloalkyl groups having 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbon atoms, or, in some embodiments, 1 to 8 carbon atoms. Examples of linear alkyl groups include those having 1 to 8 carbon atoms, such as the methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, and n-octyl group. Examples of branched alkyl groups include, but are not limited to, the isopropyl group, isobutyl group, sec-butyl group, t-butyl group, neopentyl group, isopentyl group, and 2,2-dimethylpropyl group. As used herein, the term "alkyl" encompasses n-alkyl groups, isoalkyl groups, and anteisoalkyl groups, as well as other branched alkyl groups. Typical substituted alkyl groups may be substituted once or more times with any of the groups described herein, such as amino groups, hydroxyl groups, cyano groups, carboxyl groups, nitro groups, thio groups, alkoxy groups, and halogen groups.

[0019] The term "aminoalkyl" as used herein refers to an alkyl group as defined herein, wherein at least one hydrogen atom in the alkyl group is replaced with nitrogen, and by nitrogen substitution, a primary amine, secondary amine, or tertiary amine is formed. Furthermore, an aminoalkyl group may have one or more nitrogen atoms between any two carbon atoms in the alkyl chain, and by nitrogen substitution, a secondary amine or tertiary amine may be formed.

[0020] The term “alkenyl” as used herein refers to a linear alkyl group, branched alkyl group, and cyclic alkyl group as defined herein, except that there is at least one double bond between two carbon atoms. Thus, an alkenyl group has 2 to 40 carbon atoms, or 2 to about 20 carbon atoms, or 2 to 12 carbon atoms, or in some embodiments, 2 to 8 carbon atoms. Examples include, but are not limited to, vinyl, -CH=C=CCH2, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl.

[0021] The term "alkynyl" as used herein refers to linear alkyl groups and branched alkyl groups, except that they have at least one triple bond between two carbon atoms. Thus, alkynyl groups have 2 to 40 carbon atoms, 2 to about 20 carbon atoms, or 2 to 12 carbon atoms, or in some embodiments, 2 to 8 carbon atoms. Examples include, but are not limited to, -C≡CH, -C≡C(CH3), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3).

[0022] The term "acyl" as used herein refers to a group containing a carbonyl moiety, bonded via a carbonyl carbon atom. The carbonyl carbon atom is bonded to a hydrogen atom to form a "formyl" group, or to another carbon atom which may be part of an alkyl group, aryl group, aralkylcycloalkyl group, cycloalkylalkyl group, heterocyclyl group, heterocyclylalkyl group, heteroaryl group, heteroarylalkyl group, etc. The acyl group may contain 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bonded to the carbonyl group. The acyl group may contain a double or triple bond as defined herein. The acryloyl group is an example of an acyl group. The acyl group may contain a heteroatom as defined herein. The nicotinoyl group (pyridyl-3-carbonyl) is an example of an acyl group as defined herein. Other examples include the acetyl group, benzoyl group, phenylacetyl group, pyridylacetyl group, cinnamoyl group, and acryloyl group. When a group containing a carbon atom bonded to a carbonyl carbon atom also contains a halogen, that group is called a "haloacyl group." One example is the trifluoroacetyl group.

[0023] The term "cycloalkyl" as used herein refers to cyclic alkyl groups, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, cycloalkyl groups may have 3 to about 8 to 12 ring members, while in other embodiments, the number of ring carbon atoms is in the range of 3 to 4, 5, 6, or 7. Cycloalkyl groups may further include polycyclic cycloalkyl groups, such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and calenyl groups, as well as fused rings, such as, but not limited to, dekalinyl. Cycloalkyl groups also include rings substituted with linear or branched alkyl groups as defined herein. Typical substituted cycloalkyl groups may be monosubstituted or polysubstituted, and may include, for example, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexyl groups, or monosubstituted, disubstituted, or trisubstituted norbornyl or cycloheptyl groups, which may be substituted with, for example, amino, hydroxyl, cyano, carboxyl, nitro, thio, alkoxy, or halogen groups. The term "cycloalkenyl," alone or in combination, refers to a cyclic alkenyl group.

[0024] The term "aryl" as used herein refers to a cyclic aromatic hydrocarbon group that does not contain heteroatoms in the ring. Thus, aryl groups include, but are not limited to, phenyl, azlenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenantrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain about 6 to about 14 carbon atoms in the ring portion of the group. Aryl groups may be unsubstituted or substituted as defined herein. Typical substituted aryl groups may be monosubstituted or multisubstituted, and may, for example, be a phenyl group substituted at one or more of the 2, 3, 4, 5, or 6 positions of the phenyl ring, or a naphthyl group substituted at one or more of the 2 to 8 positions.

[0025] The term "aralkyl" as used herein refers to an alkyl group as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced by a bond to an aryl group as defined herein. Typical aralkyl groups include the benzyl group and the phenylethyl group, as well as condensed (cycloalkylaryl) alkyl groups, such as 4-ethyl-indanyl. An aralkenyl group is an alkenyl group as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced by a bond to an aryl group as defined herein.

[0026] The term "heterocyclyl," as used herein, refers to aromatic and non-aromatic cyclic compounds containing three or more ring members, where one or more of the ring members are heteroatoms, e.g., N, O, and S, for example. Thus, heterocyclyls can be cycloheteroalkyl, heteroaryl, or, in the case of polycyclic compounds, any combination thereof. In some embodiments, heterocyclyl groups contain 3 to about 20 ring members, although some such groups have 3 to about 15 ring members. The term heterocyclyl includes rings in which one or more CH2 groups within the ring are replaced by one or more C=O groups, as found in cyclic ketones, lactones, and lactams. Examples of heterocyclyl groups containing C=O groups include, but are not limited to, β-propiolactams, γ-butyrolactams, δ-valerolactams, and ε-caprolactams, as well as their corresponding lactones. A heterocyclyl group, denoted as C2-heterocyclyl, may be a five-ring having two carbon atoms and three heteroatoms, a six-ring having two carbon atoms and four heteroatoms, etc. Similarly, a C4-heterocyclyl may be a five-ring having one heteroatom, a six-ring having two heteroatoms, etc. The sum of the number of carbon atoms and the number of heteroatoms is equal to the total number of ring atoms. A heterocyclyl ring may contain one or more double bonds. A heteroaryl ring is one embodiment of a heterocyclyl group. The term "heterocyclyl group" includes fused ring species, such as those containing fused aromatic and non-aromatic groups. For example, the dioxolanyl ring system and the benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups in the sense of this specification. This term also includes polycyclic ring systems containing heteroatoms, such as, but not limited to, quinuclidyls. The heterocyclyl group may be unsubstituted or substituted as described herein.Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, prinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Typical substituted heterocyclyl groups may be monosubstituted or multisubstituted, and may, for example, be a piperidinyl group or quinolinyl group that is 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted, with groups such as those described herein, though not limited to these.

[0027] The term "heteroaryl," as used herein, refers to an aromatic cyclic compound containing five or more ring members, where one or more of the ring members are heteroatoms, e.g., N, O, and S; for example, a heteroaryl ring may have five to about eight to twelve ring members. A heteroaryl group is a type of heterocyclyl group that possesses an aromatic electronic structure. A heteroaryl group denoted as C2-heteroaryl may be a five-ring with two carbon atoms and three heteroatoms, a six-ring with two carbon atoms and four heteroatoms, etc. Similarly, a C4-heteroaryl may be a five-ring with one heteroatom, a six-ring with two heteroatoms, etc. The sum of the number of carbon atoms and the number of heteroatoms is equal to the total number of ring atoms. x~y A heterocyclyl ring, as denoted, contains "x" members to "y" members, including all intermediate integers from "x" to "y", and may be any ring containing one or more heteroatoms as defined herein.x~y In the ring denoted as shown, all members other than the heteroatoms are carbon. x~y The heterocyclyl ring indicated as such may be a polycyclic ring system, such as a bicyclic or tricyclic ring system. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, prinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl. The heteroaryl group may be unsubstituted or substituted with any of the groups described herein. Typical substituted heteroaryl groups may be substituted once or multiple times with any of the groups described herein.

[0028] Further examples of aryl and heteroaryl groups include phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, and be Nzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrrolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl) Pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyridinyl, 4-pyridinyl, 5-pyridinyl, 6-pyridinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl) ), benzo[b]furanil (2-benzo[b]furanil, 3-benzo[b]furanil, 4-benzo[b]furanil, 5-benzo[b]furanil, 6-benzo[b]furanil, 7-benzo[b]furanil), 2,3-dihydro-benzo[b]furanil (2-(2,3-dihydro-benzo[b]furanil), 3-(2,3-dihydro-benzo[b]furanil), 4-(2,3-dihydro-benzo[b]furanil), 5-(2,3-dihydro-benzo[b]furanil), 6-(2,3-dihydro-benzo[b]furanil), 7-(2,3-Dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3-dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl) 6-(2,3-dihydro-benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indazolyl, 2-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl) Zolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepine-1-yl, 5H-dibenz[b,f]azepine-2-yl, 5 H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl), 10,11-dihydro-5H-dibenz[b,f]azepine (10,11-dihydro-5H-dibenz[b,f]azepine-1-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-3-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-4-yl, 10,11-dihydro-5H-dibenz[b,This includes, but is not limited to, azepine-5-yl (f), etc.

[0029] The term "heterocyclylalkyl" as used herein refers to an alkyl group as defined herein, in which a hydrogen or carbon bond of the alkyl group as defined herein is replaced by a bond to a heterocyclyl group as defined herein. Typical heterocyclylalkyl groups include, but are not limited to, furan-2-ylmethyl, furan-3-ylmethyl, pyridine-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indole-2-ylpropyl.

[0030] The term "heteroarylalkyl" means, as used herein, an alkyl group in which a hydrogen or carbon bond of the alkyl group is replaced by a bond to a heteroaryl group as defined herein.

[0031] The term "alkoxy," as used herein, refers to an alkyl group, including a cycloalkyl group, to which an oxygen atom is bonded, as defined herein. Examples of linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, and hexyloxy. Examples of branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, and isohexyloxy. Examples of cyclic alkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. An alkoxy group may contain about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to the oxygen atom, and may further contain double or triple bonds, and may contain heteroatoms. For example, the allyloxy group or the methoxyethoxy group are alkoxy groups in the sense defined herein, as are the methylenedioxy group when two adjacent atoms in a structure are substituted with them.

[0032] The term "amine," as used herein, refers to, for example, primary, secondary, and tertiary amines having formula N(group)3, where each group may independently be H or other than H, such as alkyl or aryl. Amines include, but are not limited to, R-NH2, e.g., alkylamines, arylamines, alkylarylamines; R2NH, where each R is independently selected, e.g., dialkylamines, diarylamines, aralkylamines, heterocyclylamines, etc.; and R3N, where each R is independently selected, e.g., trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, etc. The term "amine," as used herein, also includes the ammonium ion.

[0033] The term "amino group" as used herein refers to -NH2, -NHR, -NR2, -NR3+ Substituents in the form of (wherein each R is independently selected), and non-protonable -NR3 + This refers to each protonation form, excluding those specified. Therefore, any compound substituted with an amino group can be considered an amine. In the sense of this specification, "amino group" can be a primary amino group, a secondary amino group, a tertiary amino group, or a quaternary amino group. The "alkylamino" group includes monoalkylamino groups, dialkylamino groups, and trialkylamino groups.

[0034] The terms “halo,” “halogen,” or “halide” groups, either alone or as part of other substituents, mean, as used herein, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, unless otherwise noted.

[0035] The term "haloalkyl" group, as used herein, includes monohalogen alkyl groups, polyhalogen alkyl groups in which all halogen atoms may be the same or different, and perhalogen alkyl groups in which all hydrogen atoms are replaced by halogen atoms, such as fluorocarbons. Examples of haloalkyl groups include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, and perfluorobutyl.

[0036] The term "monovalent," as used herein, refers to a substituent that is connected to the molecule being substituted via a single bond. When a substituent is monovalent, for example, F or Cl, it is bonded to the atom being substituted by a single bond.

[0037] The terms "hydrocarbon" or "hydrocarbyl" refer to molecules or functional groups containing carbon and hydrogen atoms, as used herein. These terms may also refer to molecules or functional groups that typically contain both carbon and hydrogen atoms, but in which all hydrogen atoms are substituted with other functional groups.

[0038] As used herein, the term "hydrocarbyl" refers to a functional group derived from a linear, branched, or cyclic hydrocarbon, which may be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, acyl, or any combination thereof. The hydrocarbyl group is (C a ~C b ) may be expressed as hydrocarbyl, where a and b are integers and mean having any number of carbon atoms from a to b. For example, (C1~C4) hydrocarbyl means that the hydrocarbyl group can be methyl (C1), ethyl (C2), propyl (C3), or butyl (C4), and (C0~C b )Hydrocarbyl means that, in a certain manner, the hydrocarbyl group is absent.

[0039] The term "solvent," as used herein, refers to a liquid capable of dissolving solids, liquids, or gases. Non-limiting examples of solvents include silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids.

[0040] The term “more independently selected” refers to the group of mentioned, which may be the same, different, or a mixture thereof, unless the context explicitly indicates otherwise, as used herein. Therefore, in this definition, “X 1 , X 2 , and X 3 The phrase "is selected independently from noble gases" includes, for example, X 1 , X 2 , and X 3 If all of them are the same, X 1 , X 2 , and X 3 If all of them are different, X 1 and X 2 Although they are the same, X 3 This includes cases where the values ​​are different, as well as other similar permutations.

[0041] The term "room temperature" as used herein refers to a temperature of approximately 15°C to 28°C.

[0042] The term "standard temperature and pressure" means 20°C and 101 kPa as used herein.

[0043] As used herein, the terms “composition” or “pharmaceutical composition” refer to a mixture of at least one compound described herein and a pharmaceutically acceptable carrier. Pharmaceutical compositions facilitate the administration of compounds to a patient or subject. Multiple techniques for administering compounds exist in the art, including, but not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0044] A "disease" is a state of animal health in which the animal is unable to maintain homeostasis and, if the disease does not go into remission, the animal's health continues to deteriorate.

[0045] In contrast, "disorder" in animals refers to a state of health where the animal can maintain homeostasis, but its health is not as good as when it is not disordered. Leaving a disorder untreated does not necessarily lead to a further deterioration of the animal's health.

[0046] As used herein, the terms “effective dose,” “pharmaceutically effective dose,” and “therapeutically effective dose” refer to a non-toxic but sufficient amount of an active substance to provide the desired biological outcome. This outcome may be the reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired modification of a biological system. The appropriate therapeutic dose in any individual case can be determined by those skilled in the art using routine experimental methods.

[0047] As used herein, the term "efficacy" refers to the maximum effect (Emax) achieved in the assay.

[0048] As used herein, the term “pharmaceutically acceptable” means a material, such as a carrier or diluent, that does not impair the biological activity or properties of a compound and is relatively non-toxic, i.e., the material can be administered to an individual without causing undesirable biological effects and without harmful interaction with any of the components of the composition in which it is contained.

[0049] As used herein, the term “pharmaceutically acceptable salt” means a salt, solvate, hydrate, or clathrate of the compound to be administered, prepared from a pharmaceutically acceptable, non-toxic acid or base, including inorganic or organic acids or bases.

[0050] Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid (including sulfates and bisulfates), and phosphoric acid (including hydrogen phosphates and dihydrogen phosphates). Suitable organic acids can be selected from aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic acid class, and sulfonic acid class organic acids, examples of which include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, malonic acid, saccharin, fumaric acid, pyruvate, aspartic acid, glutamic acid, benzoic acid, and antacid. It contains lanyl acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid, and galacturonic acid.

[0051] Suitable pharmaceutically acceptable base addition salts of the compounds described herein include, for example, ammonium salts, alkali metal salts, alkaline earth metal salts, and metal salts including transition metal salts, such as calcium salts, magnesium salts, potassium salts, sodium salts, and zinc salts. Also included are organic salts made from basic amines, such as N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. All of these salts can be prepared from the corresponding compounds, for example, by reacting the compounds with a suitable acid or base.

[0052] As used herein, the terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” mean a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid extender, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that is involved in the transport or delivery of the compounds described herein to a patient in a manner that enables it to perform its intended function. Typically, such constructs are transported or delivered from one organ or part of the body to another organ or part of the body. Each carrier must be compatible with the other components of the formulation containing the compounds described herein and must be “acceptable” in the sense that it is not harmful to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include sugars, e.g., lactose, glucose, and sucrose; starches, e.g., corn starch and potato starch; cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients, e.g., cocoa butter and suppository wax; oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, e.g., propylene glycol; polyols, e.g., glycerin, sorbitol, mannitol, and polyethylene glycol; esters, e.g., ethyl oleate and ethyl laurate; agar; buffers, e.g., magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solution; and other non-toxic and suitable substances used in pharmaceutical formulations. As used herein, “pharmaceutically acceptable carrier” includes the activity and compatibility of the compounds described herein, and any coatings, antimicrobial and antifungal agents, as well as absorption retarders, etc., that are physiologically acceptable to the patient. Supplementary active compounds may be incorporated into the composition. “pharmaceutically acceptable carrier” may further include pharmaceutically acceptable salts of the compounds described herein.Other additional components that may be included in pharmaceutical compositions used in conjunction with the methods or compounds described herein are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0053] The terms “patient,” “subject,” or “individual” are used interchangeably herein and refer to any animal, or its cells, which may be in vitro or in situ, that accept the methods described herein. In a non-limiting embodiment, patient, subject, or individual is human.

[0054] As used herein, the term “potency” means the dose (ED) required to produce half of the maximum response. 50 ) refers to.

[0055] A "therapeutic" treatment is a procedure administered to a subject exhibiting signs of pathology with the aim of reducing or eliminating those signs.

[0056] As used herein, the terms “treatment” or “to treat” are defined as the application or administration of a therapeutic agent, i.e., one of the compounds described herein (alone or in combination with other agents), to a patient having the condition or symptoms of the condition intended herein, for the purpose of curing, restoring, alleviating, reducing, modifying, correcting, relieving, improving, or influencing the condition or symptoms of the condition intended herein, or to the application or administration of a therapeutic agent to tissue or cell lines isolated from the patient (e.g., for diagnostic or ex vivo application). Such treatments may be specifically modified or adapted based on knowledge derived from the field of pharmacogenomics.

[0057] As used herein, the term "cell receptor binding moiety" (CRBM) refers to the moiety of the compounds described herein that binds to receptors on cells capable of degrading circulating proteins in a subject. The CRBM can be a moiety that binds to receptors present on hepatocytes. For example, the CRBM can be an asialoglycoprotein receptor (ASGPR), LRPR, LDLR (low density lipoprotein receptor), RcγRI, FcRN, transferrin receptor, macrophage scavenger receptor (e.g., the membrane receptor for degraded cells), and the like.

[0058] Compound The compounds of formula I or other compounds described herein can be prepared by the general schemes described herein using synthetic methods known to those of skill in the art. The following examples illustrate non-limiting aspects of the compounds described herein and their preparation.

[0059] In various aspects, a compound of formula I or a pharmaceutically acceptable salt or N-oxide thereof is provided and has the structure: TIFF2026508972000016.tif26128. In various aspects, CON represents from 1 to 15 independently selected groups as defined herein for [CON] or [Linker-2] that form a linker connecting L A and L B and L is covalently bonded to the open valence in CON. In various aspects, L A and L B are covalently bonded to the open valence in CON. In various aspects, L A is a cell receptor binding moiety (CRBM). In various aspects, L B is an anti-CCP1 (anti-cyclic citrullinated peptide) binding moiety.

[0060] In various aspects, the compound of formula I is L A -[CON] w -L B can also be represented, w is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, and each [CON] is independently selected from any [CON] group or [linker-2] group described herein.

[0061] Autoantibodies are known to play a role in rheumatoid arthritis. Treatment with rituximab is more effective in patients with anti-citrullinated protein antibodies (ACPA), and serum reactivity to cyclic citrullinated peptides (CCP) is used as a diagnostic tool for RA. Recently, several groups have developed improved CCPs with higher specificity and sensitivity for the diagnosis of RA, and there is a growing expectation that these peptides will be used to neutralize pathogenic autoantibodies as a treatment.

[0062] In various embodiments, the compounds described herein can target CCP1 peptides, CCP2 peptides, and CCP3 peptides. In various embodiments, L B is an anti-CCP1 binding moiety. In various embodiments, L B is an anti-CCP2 binding moiety. In various embodiments, L B is an anti-CCP3 binding moiety. In various embodiments, L B can bind to autoantibodies involved in autoimmune arthritis and related autoimmune diseases.

[0063] In addition to the neutralization strategies described above, there are several strategies for treating, remitting, and / or preventing autoimmune diseases by depleting autoantibodies. Total IgG depletion by apheresis (plasmapheresis) or immunotherapy (rituximab) can lead to the treatment, remission, and / or prevention of autoimmune diseases, but is associated with immunosuppression resulting from the depletion of the healthy antibody repertoire.

[0064] A. Structure of the CON linker In various embodiments, each CON is independently a cyclic or acyclic moiety, as follows: (a) In the above formula, TIFF2026508972000017.tif21128, R 1 Each occurrence is independently either H or C1-C3 alkyl; Each occurrence of n'' is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; or (b) In the above formula, TIFF2026508972000018.tif15128, Each occurrence of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25; Each occurrence of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25; Each occurrence of n'' is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; or (c) In the above formula, TIFF2026508972000019.tif6128 Z and Z' are joined independently, -(CH2) i -O-, -(CH2) i -S-, -(CH2) i -N(R)-, The filename is TIFF2026508972000020.tif27128; R 2 Each occurrence is independently either H or C1-C3 alkyl; Each occurrence of Y is independently a combination, -O-, -S-, or -N(R)-; Each occurrence of i is an independent integer in the range of 0 to 100; D is -(CH2) i -YC(=O)-Y-(CH2) i -,-(CH2) m' -,-[(CH2) n -X 1 ]j - or combination, except that Z, Z', and D are not combined simultaneously; j is an integer in the range of 1 to 100; m' is an integer in the range of 1 to 100; n is an integer in the range of 1 to 100; X 1 is -O-, -S-, or -N(R)-; Each R is independently a C1-C3 alkyl group which may be substituted with H or 1-3 hydroxyl groups; or (d) A structure selected from the group consisting of TIFF2026508972000021.tif51132, in the above formula, X 2 In each occurrence, -CH2-, -O-, -S-, and -N(R) appear independently. 4 )-, -C(O)-, -S(O)-, -S(O)2-, -S(O)2O-, -OS(O)2-, or -OS(O)2O-; X 3 In each occurrence, -O-, -S-, or -N(R 4 )-and; R 4 In each occurrence, it is independently H, C1-C3 alkyl, C1-C3 alkanol, or -C(O)(C1-C3 alkyl). structure; or (e)C 6~18 Ariel, C 3~18 Heterocyclyl, C 6~18 Viaryl, or C 6~18 A heterobiaryl which may be substituted with 1 to 6 substituents selected from the group consisting of F, Cl, Br, I, O(RG), O(O)N(RG)2, CN, NO, NO2, ONO2, CF3, OCF3, -(RG), N(RG)2, S(RG), SO(RG), SO2(RG), SO2N(RG)2, and SO3(RG), where each occurrence of RG may be independently substituted with H, or C 1~10 Alkyl, possibly substituted C 3~10 Cycloalkyl, may be substituted C 6~18Aryl, or possibly substituted C 5~18 C is a heteroaryl. 6~18 Ariel, C 3~18 Heterocyclyl, C 6~18 Viaryl, or C 6~18 Heterobiaryl It is possible.

[0065] B.L. A Structure In various forms, L A This is the cell receptor binding site (CRBM). For example, non-limitingly, the CRBM is as follows: (a) Amino acid sequence: LRP1 (low-density lipoprotein receptor-related protein 1) binding site having TIFF2026508972000022.tif51128; or (b) Amino acid sequence: An LDLR (low-density lipoprotein receptor) binding moiety having TIFF2026508972000023.tif171128, wherein any of the LDLR binding moieties containing two cysteine ​​residues or a cysteine ​​residue and a penicillamine residue (Pen) may form a cyclic disulfide bond; or (c) Amino acid sequence: An FcγRI binding moiety according to TIFF2026508972000024.tif111128, wherein any of the FcγRI binding moieties containing two cysteine ​​residues may form a cyclic disulfide bond; or (d) Amino acid sequence: An FcRN binding moiety having TIFF2026508972000025.tif11130 or succinic anhydride NN dimerized SYN1327 (each cyclized CC), wherein any of the two cysteine ​​residues in the FcRN binding moiety may form a cyclic disulfide bond; or (e) Amino acid sequence: Transferrin receptor binding group by TIFF2026508972000026.tif51128; or (f) Amino acid sequence: Macrophage scavenger receptor binding site having TIFF2026508972000027.tif37128; or (g) Structure: A base having TIFF2026508972000028.tif84128; or (h) Structure: A base having TIFF2026508972000029.tif21128; or (i) Structure: It has TIFF2026508972000030.tif15128, and in the formula, RG 1' teeth The filename is TIFF2026508972000031.tif6128; RG 1 Each appearance is independently of hydrogen or The filename is TIFF2026508972000032.tif7128; Each occurrence of XG is independently selected from the group consisting of -CH2-, -C(=O)-, -NH-, and -O-; Each occurrence of ZG is independently selected from the group consisting of -CH2-, -C(=O)-, -NH-, and -O-; n is an integer in the range of 1 to 100; p is an integer in the range of 1 to 50; AG is a monosaccharide, disaccharide, or oligosaccharide consisting of up to 20 monosaccharide units as defined herein. base It is possible.

[0066] Appropriate monosaccharides include, Aldoses, for example, aldtriose, D-glyceraldehyde, etc. Aldotetroses, for example, D-erythrose, D-threose, etc. Aldopentoses, such as D-ribose, D-arabinose, D-xylose, D-lyxose, etc. Aldohexoses, such as D-allose, D-altrose, D-glucose, D-mannose, D-glucose, D-idose, D-galactose, and D-talose; Ketotrioses, such as dihydroxyacetone; Ketotetrose, for example, D-erythritolose; Ketopentoses, such as D-ribeye, D-xylulose, etc. Ketohexoses, such as D-psicone, D-fructose, D-sorbose, D-tagatose, etc. Amino sugars, such as galactoseamine, sialic acid, and N-acetylglucosamine; Sulfosaccharides, for example, sulfoquinovose, etc. It includes.

[0067] Suitable disaccharides include sucrose, lactose, maltose, trehalose, cellobiose, kordibiose, nigerose, isomaltose, β,β-trehalose, sophorose, laminaribiose, gentiobiose, turanose, maltulose, palatinose, gentiobiluose, mannobiose, melibiose, melibiulose, rutinose, rutinulose, and xylobiose.

[0068] In any monosaccharide, disaccharide, or oligosaccharide described herein, one or more hydroxyl (OH) groups within a particular sugar are NRG 2 RG 3 It's fine if it's been replaced with the base, and here, RG 2 and RG 3 Each of these independently consists of hydrogen and a halogen, and may be substituted with C. 1~10 Alkyl, possibly substituted C 1~10 Alkoxy, C may be substituted. 1~10 Selected from the group consisting of aminoalkyl groups and combinations thereof, and -C(=O)R groups which may be substituted with 1 to 5 groups, or RG 2 and RG3 These, together with the nitrogen atom to which they are bonded, may be substituted C 1~10 Alkyl, possibly substituted C 1~10 Alkoxy, C may be substituted. 1~10 aminoalkyl, optionally substituted C 6~10 Aryl, C may be substituted. 5~10 It forms a C5 heterocycle which may be substituted with 1 to 5 substituents selected from the group consisting of heteroaryls, halogens, and combinations thereof. RG 2 and RG 3 Each occurrence of R in this expression is independent of H and C, which may be substituted. 1~10 Alkyl, possibly substituted C 3~10 Cycloalkyl, may be substituted C 6~18 Aryl, or possibly substituted C 5~18 It is a heteroaryl compound.

[0069] In any monosaccharide, disaccharide, or oligosaccharide described herein, The sugars (AG) in TIFF2026508972000033.tif7128 are connected through the anomeric carbons of the sugars.

[0070] In some embodiments, AG has the following structure: TIFF2026508972000034.tif20128 is available, (ZG) p teeth, It has the structure TIFF2026508972000035.tif37138.

[0071] In some embodiments, AG has the following structure: TIFF2026508972000036.tif16128 is available, (ZG) p teeth, It has the structure TIFF2026508972000037.tif37138.

[0072] In various forms, (XG) nThese are -O-(CH2)3-, -NH-(CH2CH2O)3-CH2-, and =N * (C=O)(CH2)2C(=O)NHCH2CH2-(OCH2CH2)4-(in the formula, =N * (where is a cyclic nitrogen in a heterocyclic system), or has a structure selected from the group consisting of combinations of groups (a) to (i).

[0073] In various ways, L A Structure: This is an ASGPR coupling portion having TIFF2026508972000038.tif15128; each RG 1 teeth The filename is TIFF2026508972000039.tif7128; below: (i)L A Each AG within The filename is TIFF2026508972000040.tif20128; (ii)L A Two of the AGs inside TIFF2026508972000041.tif20128, L A One of the AGs inside The filename is TIFF2026508972000042.tif16128; (iii)L A One of the AGs inside TIFF2026508972000043.tif20128, L A Two of the AGs inside It is TIFF2026508972000044.tif16128; or (iv)L A Each AG within, The filename is TIFF2026508972000045.tif16128; One of these applies.

[0074] In various forms, L A Alternatively, CRBM has the following structure: It has TIFF2026508972000046.tif15128, During the ceremony, Each occurrence of XG is independently selected from the group consisting of -CH2-, -C(=O)-, -NH-, and -O-; Each RG 1 teeth The filename is TIFF2026508972000047.tif7128; n is an integer in the range of 1 to 100; AG is independent in each appearance The filename is TIFF2026508972000048.tif21128; RG 2 and RG 3 In each instance, independently, hydrogen and halogen, and possibly substituted C, are present. 1~10 Alkyl, possibly substituted C 1~10 Alkoxy, C may be substituted. 1~10 Selected from the group consisting of aminoalkyl groups and combinations thereof, and -C(=O)R groups which may be substituted with 1 to 5 groups selected from the group consisting of aminoalkyl groups and combinations thereof, or RG 2 and RG 3 These, together with the nitrogen atom to which they are bonded, may be substituted C 1~10 Alkyl, possibly substituted C 1~10 Alkoxy, C may be substituted. 1~10 aminoalkyl, optionally substituted C 6~10 Aryl, C may be substituted. 5~10 It forms a C5 heterocycle which may be substituted with 1 to 5 substituents selected from the group consisting of heteroaryls, halogens, and combinations thereof; Each occurrence of R is independent of H, and C may be substituted. 1~10 Alkyl, possibly substituted C 3~10 Cycloalkyl, may be substituted C 6~18 Aryl, or possibly substituted C 5~18 It is a heteroaryl compound.

[0075] In the amino acid sequences described herein, non-standard amino acids are defined as follows: TIFF2026508972000049.tif158146

[0076] C. L B Structure In various forms, L B Structure: This is an anti-CCP1 (anti-cyclic citrullinated peptide) antibody binding moiety having TIFF2026508972000050.tif20128, In the formula, AA is SEQ ID NO:1. The amino acid sequence is at least 80% homologous to TIFF2026508972000051.tif4128, where m is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0077] At least 80% homology means an amino acid sequence having an anti-CCP1 antibody-binding region that is 80% homologous to SEQ ID NO:1, even if the amino acid sequence contains more residues than SEQ ID NO:1, such as synthetically modified residues. This definition of homology applies to all sequences described as homologous in this specification.

[0078] In some embodiments, SEQ ID NO:1 is a (3,16) cyclic peptide having a disulfide bond between Cys3 and Cys16. B The binding site of the amino acid residue in AA that is directly bonded to the carbonyl group within is, in various embodiments, a free bonding valency at the NH of the amino acid residue's backbone, which allows for the formation of an amide bond.

[0079] "Cit" has the following structure: This is the α-amino acid citrulline, which has the IP address TIFF2026508972000052.tif22128.

[0080] In various forms, L B Structure: TIFF2026508972000053.tif20128 or its enantiomer: This is the anti-CCP1 (anti-cyclic citrullinated peptide) antibody binding site, which contains TIFF2026508972000054.tif20128.

[0081] In various forms, L B Structure: It has TIFF2026508972000055.tif28143, In the formula, the bond connecting the cysteine ​​residues represents a disulfide bond.

[0082] In various embodiments, the anti-CCP antibody binding moiety has a sequence that is at least 80, 85, 90, or 95% homologous to any of the sequences in Table A. In various embodiments, the anti-CCP antibody binding moiety has a sequence that is any of the sequences in Table A.

[0083] (Table A) Additional anti-CCP antibody binding subarray (L B (AA inside) TIFF2026508972000056.tif69146

[0084] In various embodiments, a disulfide bond exists between Cys2 and Cys14 in any of the sequences SEQ ID NO:69 to SEQ ID NO:73. In various embodiments, sequences SEQ ID NO:69 to SEQ ID NO:73 are cyclic peptides. The sequences in Table A have L in any of the residues within the sequence. B The components may be covalently bonded within the portion, and such bonds are intended herein as to be shown independently and completely. In various embodiments, the sequences in Table A have L at the first residue in the sequence, for example, H (histidine) in SEQ ID NO:69. B They are covalently bonded within the part.

[0085] In various embodiments, the anti-CCP antibody binding portion is an anti-CCP1 antibody binding portion, an anti-CCP2 antibody binding portion, and / or an anti-CCP3 antibody binding portion. In various embodiments, the anti-CCP antibody binding portion L B (IC) 50 or EC 50 (Measured by) Having in vitro or in vivo potency. Anti-CCP antibody binding moiety L B In various embodiments, against anti-CCP antibodies, such as anti-CCP1 antibody, anti-CCP2 antibody, and / or anti-CCP3 antibody, the concentrations are approximately 900, 800, 700, 600, 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.1, 0.05, or less than approximately 0.01 nM, at least approximately 900, 800, 700, 600, 500, 400, 3 00, 200, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.1, 0.05, or approximately 0.01 nM, or approximately 900, 800, 700, 600, 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.1, 0.05, or approximately 0.01 nM, (IC 50 or EC 50 It has in vitro or in vivo potency (measured by...). In vitro or in vivo potency may be determined (in vitro) in clinically or experimentally appropriate cell lines, or (in vivo) in the desired organism, such as a mouse, rat, cat, dog, pig, rabbit, or human. In various embodiments, in vitro potency is determined in human cell lines. In various embodiments, in vivo potency is determined in humans.

[0086] In various forms, L B The AA within is an amino acid sequence containing 5 to 40 amino acid residues, of which 1 to 5 are citrulline residues, and optionally, at least 2 of the residues in AA are cysteine ​​residues that form disulfide (-SS-) bonds, making AA a cyclic peptide. In various embodiments, the non-citrulline amino acid residues in AA are any naturally occurring amino acids (L-amino acids) or their D-amino acid isomers. In various embodiments, L B The AA within is an amino acid sequence containing 5 to 40 amino acid residues and 1 citrulline residue. In various embodiments, L B The AA within is an amino acid sequence containing 5 to 40 amino acid residues and 2 citrulline residues. In various embodiments, L B The AA within is an amino acid sequence containing 5 to 40 amino acid residues and 3 citrulline residues. In various embodiments, L B The AA within is an amino acid sequence containing 10 to 40 amino acid residues and 4 citrulline residues. In various embodiments, L B The AA within the sequence is an amino acid sequence containing 10 to 40 amino acid residues and 5 citrulline residues. If there are at least two cysteine ​​residues in the amino acid sequence, they are separated by at least two non-cysteine ​​amino acid residues.

[0087] In various embodiments, the compound of formula I has the structure: It has TIFF2026508972000057.tif35128, During the ceremony, TIFF2026508972000058.tif2128 is a single or double bond between carbon atoms; A may be substituted with 1 to 6 substituents selected from the group consisting of F, Cl, Br, I, ORG, OCO(O)N(RG)2, CN, NO, NO2, ONO2, CF3, OCF3, RG, N(RG)2, SR, SORG, SO2RG, SO2N(RG)2, and SO3RG, C 6~18 Ariel, C 3~18 Heterocyclyl, C 6~18 Biaryl, or C 6~18 It is a heterobiaryl; L A Structure: It is an asial glycoprotein receptor (ASGPR) binding site containing TIFF2026508972000059.tif15128; L B Structure: It is an anti-CCP1 binding moiety having TIFF2026508972000060.tif20128; AA is an amino acid sequence that is at least 80% homologous to SEQ ID NO:1; RG 1 'teeth The filename is TIFF2026508972000061.tif7128; RG 1 Each appearance is independently of hydrogen or The filename is TIFF2026508972000062.tif7128; (ZG) p Structure: It has TIFF2026508972000063.tif16128, In the above equation, p is 2, 4, 6, or 8.

[0088] In various embodiments, p is 2. In various embodiments, p is 4. In various embodiments, p is 6. In various embodiments, p is 8.

[0089] In various ways, (XG) n These are -O-(CH2)3-, -NH-(CH2CH2O)3-CH2-, and =N *It has a structure selected from the group consisting of (C=O)(CH2)2C(=O)NHCH2CH2-(OCH2CH2)4-, where =N * It is a cyclic nitrogen in a heterocyclic system; AG is an amino sugar; Each occurrence of RG is independently H, and C may be substituted. 1~10 Alkyl, possibly substituted C 3~10 Cycloalkyl, may be substituted C 6~18 Aryl, or possibly substituted C 5~18 It is a heteroaryl; Each occurrence of XG is independently selected from the group consisting of -CH2-, -C(=O)-, -NH-, and -O-; Each occurrence of ZG is independently selected from the group consisting of -CH2-, -C(=O)-, -NH-, and -O-; m is 2, 3, 4, 5, 6, 7, 8, 9, or 10; n is an integer in the range of 1 to 100; p is an integer in the range of 1 to 50.

[0090] In the compounds of formula Ia, A is a ring, or a ring system that may contain multiple rings. Therefore, A may be a ring system containing two, three, four, or more rings that are condensed or bonded together, such as a biaryl ring system. The heterocyclyl A ring may be aromatic, or it may contain aliphatic carbon or nitrogen atoms in part of the ring within A.

[0091] In various embodiments, m is 2. In various embodiments, m is 3.

[0092] In various configurations, AA is an array: The molecule has the name TIFF2026508972000064.tif4128, where the cysteine ​​residues in SEQ ID NO:1 may optionally combine with each other to form disulfide (-SS-) bonds.

[0093] The asialoclycoprotein receptor (ASGPR1) binds to asialoclycoproteins and other glycoproteins in which sialic acid has been removed and galactose residues are exposed. In various embodiments, L B Structure: It has TIFF2026508972000065.tif20128.

[0094] In various embodiments, AG has a structure: It has TIFF2026508972000066.tif21128, During the ceremony, RG 2 and RG 3 Each of these independently consists of hydrogen and a halogen, and may be substituted with C. 1~10 Alkyl, possibly substituted C 1~10 Alkoxy, C may be substituted. 1~10 Selected from the group consisting of aminoalkyl groups and combinations thereof, and -C(=O)R groups which may be substituted with 1 to 5 groups selected from the group consisting of aminoalkyl groups and combinations thereof, or RG 2 and RG 3 These, together with the nitrogen atom to which they are bonded, may be substituted C 1~10 Alkyl, possibly substituted C 1~10 Alkoxy, C may be substituted. 1~10 aminoalkyl, optionally substituted C 6~10 Aryl, C may be substituted. 5~10 It forms a C5 heterocycle which may be substituted with 1 to 5 substituents selected from the group consisting of heteroaryls, halogens, and combinations thereof. In various embodiments, RG 2 It is hydrogen, RG 3 It is C(=O)CH3.

[0095] In a particular embodiment, each occurrence of R may be independently substituted with H and C. 1~10 Alkyl, possibly substituted C 3~10 Cycloalkyl, may be substituted C 6~18Aryl, or possibly substituted C 5~18 It is a heteroaryl compound.

[0096] AG includes other galactosyl analogs that bind to ASGR in various embodiments.

[0097] In various embodiments, AG has a structure: It has TIFF2026508972000067.tif20128.

[0098] In various embodiments, AG has a structure: It has TIFF2026508972000068.tif16128.

[0099] In various forms, (Z) p Structure: It has TIFF2026508972000069.tif37140.

[0100] In various forms, (XG) n These are -O-(CH2)3-, -NH-(CH2CH2O)3-CH2-, and =N * It has a structure selected from the group consisting of (C=O)(CH2)2C(=O)NHCH2CH2-(OCH2CH2)4-, where =N * This is the cyclic nitrogen within A.

[0101] In various embodiments, AA is a (3,16) cyclic peptide in which the cysteine ​​residues at positions 3 and 16 form a disulfide bond. In various embodiments, AA is at least 95% homologous to SEQ ID NO:1. In various embodiments, AA is the amino acid sequence of SEQ ID NO:1.

[0102] In various embodiments, the compound of formula Ia has the structure: It has TIFF2026508972000070.tif29128.

[0103] In various embodiments, the compound of formula Ia has the structure: It has TIFF2026508972000071.tif71143.

[0104] In various embodiments, the compound is of formula IIb: It is a compound of TIFF2026508972000072.tif25128, During the ceremony, L A and L B This is defined herein as: L A Structure: Having TIFF2026508972000073.tif15128, in the above formula, Each RG 1 teeth The filename is TIFF2026508972000074.tif7128; Each occurrence of XG is independently selected from the group consisting of -CH2-, -C(=O)-, -NH-, and -O-; Each occurrence of ZG is independently selected from the group consisting of -CH2-, -C(=O)-, -NH-, and -O-; AG is independent in each appearance The filename is TIFF2026508972000075.tif21128; RG 2 and RG 3 In each instance, independently, hydrogen and halogen, and possibly substituted C, are present. 1~10 Alkyl, possibly substituted C 1~10 Alkoxy, C may be substituted. 1~10 Selected from the group consisting of aminoalkyl groups and combinations thereof, and -C(=O)R groups which may be substituted with 1 to 5 groups selected from the group consisting of aminoalkyl groups and combinations thereof, or RG 2 and RG 3 These, together with the nitrogen atom to which they are bonded, may be substituted C 1~10 Alkyl, possibly substituted C 1~10 Alkoxy, C may be substituted. 1~10 aminoalkyl, optionally substituted C 6~10Aryl, C may be substituted. 5~10 It forms a C5 heterocycle which may be substituted with 1 to 5 substituents selected from the group consisting of heteroaryls, halogens, and combinations thereof; Each occurrence of R is independent of H, and C may be substituted. 1~10 Alkyl, possibly substituted C 3~10 Cycloalkyl, may be substituted C 6~18 Aryl, or possibly substituted C 5~18 It is a heteroaryl; L B Structure: The anti-CCP binding portion has TIFF2026508972000076.tif20128, and in the above formula, AA is an amino acid sequence that is at least 80% homologous to an amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:69~SEQ ID NO:76, and SEQ ID NO:77; m is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0105] In various embodiments, in the compounds of formula I or IIb, AA is a (3,16)cyclic peptide. In various embodiments, in the compounds of formula I or IIb, AA is at least 95% homologous to SEQ ID NO:1. In various embodiments, in the compounds of formula I or IIb, AA is the amino acid sequence of SEQ ID NO:1. In various embodiments, in the compounds of formula I or IIb, m is 2.

[0106] In various embodiments, in compounds of formula I or IIb, (ZG) p is -CH2-(O-CH2-CH2)2-NH(C=O)CH2CH2-. In various embodiments, in compounds of formula I or IIb, RG 1 and / or RG 1' Each of them is, The filename is TIFF2026508972000077.tif12128.

[0107] In various embodiments, in compounds of formula I or formula IIb, L A Structure: It has TIFF2026508972000078.tif30128.

[0108] In various embodiments, in compounds of formula I or formula IIb, (XG) n The group is selected from the group consisting of -CH2-(OCH2CH2)2-, -CH2-(OCH2CH2)3-, -CH2-(OCH2CH2)4-, and -CH2-(OCH2CH2)5-. In various embodiments, in compounds of formula I or IIb, (XG) n It is -CH2-(OCH2CH2)4-.

[0109] In various embodiments, in compounds of formula I or formula IIb, RG 1 Each AG within is, The filename is TIFF2026508972000079.tif20128.

[0110] In various embodiments, in compounds of formula I or formula IIb, RG 2 is H. In various embodiments, in compounds of formula I or formula IIb, RG 3 It is -C(=O)CH3.

[0111] In various embodiments, in compounds of formula I or formula IIb, RG 1 Each AG within is, The filename is TIFF2026508972000080.tif30128.

[0112] In various embodiments, in compounds of formula I or formula IIb, RG 1 Each AG within is, The filename is TIFF2026508972000081.tif16128.

[0113] In various embodiments, in compounds of formula I or formula IIb, RG 1 Each AG within is, The filename is TIFF2026508972000082.tif16128.

[0114] In various embodiments, in compounds of formula I or formula IIb, RG 1 Each AG within is, The filename is TIFF2026508972000083.tif22128.

[0115] In various forms, L in equation IIb A Alternatively, CRBM in Equation II is The filename is TIFF2026508972000084.tif46140.

[0116] In various embodiments, in compounds of formula I or formula IIb, L B Structure: It has TIFF2026508972000085.tif28143.

[0117] In various embodiments, compounds of formula II or IIb have the following structure: It has TIFF2026508972000086.tif189143.

[0118] Additional galactose-based and talose-based ASGPR binding moieties In some embodiments, this disclosure relates to a useful method for removing disease-related circulating proteins in a patient or subject, formula II: This concerns the compound based on its overall chemical structure in TIFF2026508972000087.tif17128.

[0119] The term “extracellular protein targeting ligand” is used interchangeably with the term PBM (protein binding moiety) as used herein. In various embodiments, both “extracellular protein targeting ligand” and PBM refer not only to targetable proteins found in intracellular and extracellular fluids, but also to membrane-bound proteins present on the cell surface, including, for example, soluble proteins (e.g., antibodies) and membrane-bound proteins for degradation, such as immune checkpoints (e.g., PD1, PD-L1, etc.). Therefore, the terms “extracellular protein targeting ligand” and PBM are not limited to cellular proteins.

[0120] In various embodiments, PBM is an anti-CCP1 binding moiety. In various embodiments, PBM is an anti-CCP2 binding moiety. In various embodiments, PBM is an anti-CCP3 binding moiety. In various embodiments, PBM can bind to autoantibodies involved in autoimmune arthritis and related autoimmune diseases. In various embodiments, PBM is any L described herein. B It has the same structure as the other part.

[0121] The term "ASGPR ligand" is used interchangeably with the asial glycoprotein receptor (ASGPR) binding moiety as defined herein, as used herein.

[0122] In the compound of formula II, each [CON] is an optional connector chemical part that, if present, is directly connected to [PBM] or [CRBM], or connects [linker-2] to [PBM] or [CRBM].

[0123] In the compound of formula II or its pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs, [Linker-2] is a chemical moiety having a bonding value of 1 to 15, optionally covalently bonded to one or more [CRBM] groups and / or [PBM] groups via a [CON] containing a [MULTICON] group, and [Linker-2] may optionally contain one or more [CON] groups or [MULTICON] groups itself; k' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; j' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; h and h' are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; i L is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; However, h, h', and i L At least one of them is at least 1. .

[0124] In various configurations, k' is 1 and j' is 1.

[0125] The [MULTICON] group can connect one or more [CRBM] or [PBM] groups to one or more [linker-2] groups. In various embodiments, the [linker-2] groups have a bonding value of 1 to 10. In various embodiments, the [linker-2] groups have a bonding value of 1 to 5. In various embodiments, the [linker-2] groups have a bonding value of 1, 2, or 3. In various embodiments, in the compound of formula II, the [linker-2] groups are the linkers as defined herein. A Linker B Linker C Linker D , and / or one or more combinations thereof.

[0126] In certain embodiments of compounds of formula II as illustrated elsewhere herein, R 3In each occurrence, independently, hydrogen, alkyl, heteroalkyl, haloalkyl (e.g., -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CH2F, and -CF2CF3), arylalkyl, heteroarylalkyl, alkenyl, alkynyl, and heteroaryl, heterocyclic, -OR 8 , and -NR 8 R 9 More likely to be selected.

[0127] In certain embodiments of compounds of formula II as illustrated elsewhere herein, R 4 In each occurrence, the elements are independently hydrogen, heteroalkyl, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, and -OR. 6 , -NR 6 R 7 More selected, In certain embodiments of compounds of formula II as illustrated elsewhere herein, R 6 and R 7 In each occurrence, independently, hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, and haloalkyl, heteroaryl, heterocyclic, -alkyl-OR 8 , -alkyl-NR 8 R 9 , C(O)R 3 , S(O)R 3 , C(S)R 3 , and S(O)2R 3 More selected; and In certain embodiments of compounds of formula II as illustrated elsewhere herein, R 8 and R 9 Each instance is independently selected from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclic.

[0128] A. Galactose-based ASGPR-binding cell receptor binding portion of Equation II In a particular embodiment, the compounds of formula II are selected from the following: TIFF2026508972000088.tif232113TIFF2026508972000089.tif164128TIFF202 6508972000090.tif173128TIFF2026508972000091.tif206107TIFF2026508972 000092.tif150128TIFF2026508972000093.tif92128TIFF2026508972000094.t if213111TIFF2026508972000095.tif93128TIFF2026508972000096.tif132128T IFF2026508972000097.tif137128TIFF2026508972000098.tif150128TIFF2026 508972000099.tif161128TIFF2026508972000100.tif148128TIFF202650897200 0101.tif160129TIFF2026508972000102.tif196108TIFF2026508972000103.ti f171128TIFF2026508972000104.tif169128TIFF2026508972000105.tif126128.

[0129] In some embodiments, the compound of formula II has the following structure: It has one of the following: TIFF2026508972000106.tif116128.

[0130] In various embodiments, ASGPR ligand is C 1 or C 5 (R 1 or R 5 They are linked at any of the ) positions to form a decomposition compound. In various embodiments, the ASGPR ligand is C 6 They are linked at a certain position to form a decomposition compound. For example, the ASGPR ligand If the filename is TIFF2026508972000107.tif17128, non-limiting examples of ASGPR-binding compounds of formula II include: This includes TIFF2026508972000108.tif50128 or its disubstituted or trisubstituted versions, or pharmaceutically acceptable salts thereof, where disubstituted or trisubstituted means the number of additional galactose derivatives bound to the linker moiety.

[0131] In any embodiment of this specification, where the ASGPR ligand is described for use in a degrading agent, the ASGPR ligand is typically C 5 Position (for example, this is adjacent to C 6 The linker is linked to the extracellular protein targeting ligand via a carbon hydroxyl (which can refer to any other functional moiety that may be used for linking purposes). 1 When connected through a position, the carbon is appropriately functionalized for linkage with, for example, a hydroxyl group, an amino group, an allyl group, an alkyne group, or a hydroxyl-allyl group.

[0132] In various configurations, C 3 Position or C 4 Because these positions chelate with calcium for ASGPR binding in the liver, ASGPR ligands are not bound at these positions. In certain embodiments, ASGPR ligands useful for incorporation into compounds of formula II are selected from the following: TIFF2026508972000109.tif68128TIFF2026508972000110.tif133128TIFF2026508972000111.tif198112T IFF2026508972000112.tif217124TIFF2026508972000113.tif213125TIFF2026508972000114.tif154128T IFF2026508972000115.tif180128TIFF2026508972000116.tif173128TIFF2026508972000117.tif146128T IFF2026508972000118.tif155128TIFF2026508972000119.tif156128TIFF2026508972000120.tif131128.

[0133] In a particular embodiment, the compounds of formula II are selected from the following: TIFF2026508972000121.tif43128TIFF2026508972000122.tif140129TIFF20265089720 00123.tif89128TIFF2026508972000124.tif189128TIFF2026508972000125.tif121128.

[0134] B. The talose-based ASGPR-binding cell receptor binding portion of formula II. In a particular embodiment, the compounds of formula II are selected from the following: TIFF2026508972000126.tif68128TIFF2026508972000127.tif188128TIFF2026508972000128.tif170128TIFF2026508972000129.tif182128TIFF2026508972000130.tif183128TIFF2026508972000131.tif145128TIFF2026508972000132.tif186128TIFF2026508972000133.tif190128TIFF2026508972000134.tif214112TIFF2026508972000135.tif156128TIFF2026508972000136.tif203108TIFF2026508972000137.tif160128TIFF2026508972000138.tif99128TIFF2026508972000139.tif134128TIFF2026508972000140.tif137128TIFF2026508972000141.tif201133TIFF2026508972000142.tif100128TIFF2026508972000143.tif216131TIFF2026508972000144.tif214123TIFF2026508972000145.tif22586TIFF2026508972000146.tif208107TIFF2026508972000147.tif212123TIFF2026508972000148.tif181128TIFF2026508972000149.tif193114TIFF2026508972000150.tif177128TIFF2026508972000151.tif222120TIFF2026508972000152.tif127128TIFF2026508972000153.tif167128TIFF2026508972000154.tif168128TIFF2026508972000155.tif198104TIFF2026508972000156.tif210103TIFF2026508972000157.tif128128TIFF2026508972000158.tif156128TIFF2026508972000159.tif156128TIFF2026508972000160.tif168128TIFF202650 8972000161.tif148128TIFF2026508972000162.tif144128TIFF2026508972000163.tif69128. .

[0135] In some embodiments, the compound of formula II is an extracellular proteolytic compound in which the ASGPR ligand is one of the ligands described herein. TIFF2026508972000164.tif50128

[0136] In some embodiments, in compounds of formula II, the ASGPR ligand is C1 or C5(R 1 or R 5 It is linked at any of the ) positions to form a decomposition compound. In some embodiments, in the compound of formula II, the ASGPR ligand is linked at C6. In various embodiments, the ASGPR ligand is If the filename is TIFF2026508972000165.tif17128, non-limiting examples of ASGPR-binding compounds of formula II include: This includes TIFF2026508972000166.tif110128 or its disubstituted or trisubstituted versions, or pharmaceutically acceptable salts thereof, where disubstituted or trisubstituted means the number of additional galactose derivatives bonded to the linker moiety. In certain embodiments, the compound of formula II is Selected from TIFF2026508972000167.tif146128, where, in a particular embodiment, R 2 -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), R 2Each of the groups may be substituted with one, two, three, or four independent substituents described herein, for example, one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0137] In a certain aspect, the compound of formula II is Selected from TIFF2026508972000168.tif141128 and TIFF2026508972000169.tif146128, where, in a particular embodiment, R 2 -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), R 2 Each of the groups may be substituted with one, two, three, or four independent substituents described herein, for example, one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0138] In a certain aspect, the compound of formula II is Selected from TIFF2026508972000170.tif140128 and TIFF2026508972000171.tif145128, where, in a particular embodiment, R 2 -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), R 2 Each of the groups may be substituted with one, two, three, or four independent substituents described herein, for example, one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0139] In a certain aspect, the compound of formula II is Selected from TIFF2026508972000172.tif140128 and TIFF2026508972000173.tif146128, where, in a particular embodiment, R 2 -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), R 2 Each of the groups may be substituted with one, two, three, or four independent substituents described herein, for example, one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0140] In a certain aspect, the compound of formula II is Selected from TIFF2026508972000174.tif140128 and TIFF2026508972000175.tif145128, where, in a particular embodiment, R 2 -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), R 2 Each of the groups may be substituted with one, two, three, or four independent substituents described herein, for example, one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0141] In a certain aspect, the compound of formula II is Selected from TIFF2026508972000176.tif140128 and TIFF2026508972000177.tif146128, where, in a particular embodiment, R 2 -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), R 2Each of the groups may be substituted with one, two, three, or four independent substituents described herein, for example, one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0142] In a certain aspect, the compound of formula II is Selected from TIFF2026508972000178.tif140128 and TIFF2026508972000179.tif145128, where, in a particular embodiment, R 2 -NR 6 COR 3 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), R 2 Each of the groups may be substituted with one, two, three, or four independent substituents described herein, for example, one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0143] In a certain aspect, the compound of formula II is Selected from TIFF2026508972000180.tif139128 and TIFF2026508972000181.tif145128, where, in a particular embodiment, R 2 -NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), R 2 Each of the groups may be substituted with one, two, three, or four independent substituents described herein, for example, one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0144] In a certain aspect, the compound of formula II is Selected from TIFF2026508972000182.tif152128 and TIFF2026508972000183.tif145128, where, in a particular embodiment, R 2 -NR b COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), R 2 Each of the groups may be substituted with one, two, three, or four independent substituents described herein, for example, one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0145] In a certain aspect, the compound of formula II is Selected from TIFF2026508972000184.tif153128, TIFF2026508972000185.tif147128, and TIFF2026508972000186.tif145128, where, in a particular embodiment, R 2 -NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), R 2 Each of the groups may be substituted with one, two, three, or four independent substituents described herein, for example, one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0146] In a certain aspect, the compound of formula II is Selected from TIFF2026508972000187.tif152128 and TIFF2026508972000188.tif145128, where, in a particular embodiment, R 2 -NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), R2 Each of the groups may be substituted with one, two, three, or four independent substituents described herein, for example, one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0147] In a certain aspect, the compound of formula II is Selected from TIFF2026508972000189.tif152128 and TIFF2026508972000190.tif145128, where, in a particular embodiment, R 2 -NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), R 2 Each of the groups may be substituted with one, two, three, or four independent substituents described herein, for example, one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0148] In a certain aspect, the compound of formula II is Selected from TIFF2026508972000191.tif154128 and TIFF2026508972000192.tif145128, where, in a particular embodiment, R 2 -NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), R 2 Each of the groups may be substituted with one, two, three, or four independent substituents described herein, for example, one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0149] In a certain aspect, the compound of formula II is Selected from TIFF2026508972000193.tif152128 and TIFF2026508972000194.tif146128, where, in a particular embodiment, R 2 -NR 6 COR 10 , -NR 6 -(5-membered heteroaryl), and -NR 6 -Selected from (6-membered heteroaryl), R 2 Each of the groups may be substituted with one, two, three, or four independent substituents described herein, for example, one, two, three, or four substituents independently selected from F, Cl, Br, haloalkyl, or alkyl.

[0150] In a particular embodiment, the compounds of formula II are selected from the following: TIFF2026508972000195.tif152128TIFF2026508972000196.tif164128TIFF2026508972000197.t if202112TIFF2026508972000198.tif202112TIFF2026508972000199.tif198128TIFF20265089720 00200.tif164128TIFF2026508972000201.tif200112TIFF2026508972000202.tif202112TIFF202 6508972000203.tif203112TIFF2026508972000204.tif195130TIFF2026508972000205.tif72128.

[0151] In a particular embodiment, ASGPR ligands useful for incorporation into the compound of formula II are selected from the following: TIFF2026508972000206.tif60128TIFF2026508972000207.tif151128TIFF2026508972000208.tif112128T IFF2026508972000209.tif157128TIFF2026508972000210.tif133128TIFF2026508972000211.tif162128T IFF2026508972000212.tif139129TIFF2026508972000213.tif192128TIFF2026508972000214.tif189128T IFF2026508972000215.tif216127TIFF2026508972000216.tif211122TIFF2026508972000217.tif197129.

[0152] C. ASGPR ligand / binding site in the compound of formula II In a particular embodiment, in a compound of formula II, R 1 It is hydrogen.

[0153] In a particular embodiment, in a compound of formula II, R 1 teeth, The filename is TIFF2026508972000218.tif5128.

[0154] In a particular embodiment, in a compound of formula II, R 1 teeth, The filename is TIFF2026508972000219.tif5128.

[0155] In a particular embodiment, in a compound of formula II, R 1 teeth, The filename is TIFF2026508972000220.tif5128.

[0156] In a particular embodiment, in a compound of formula II, R 1 teeth, The filename is TIFF2026508972000221.tif5128.

[0157] In a particular embodiment, in a compound of formula II, R 1 teeth, The filename is TIFF2026508972000222.tif5128.

[0158] In a particular embodiment, in a compound of formula II, R 1 teeth, The filename is TIFF2026508972000223.tif5128.

[0159] In a particular embodiment, in a compound of formula II, R 1 This is a C0-C6 alkyl-cyano which may be substituted with 1, 2, 3, or 4 substituents.

[0160] In a particular embodiment, in a compound of formula II, R 1 This is an alkyl which may be substituted with 1, 2, 3, or 4 substituents.

[0161] In a particular embodiment, in a compound of formula II, R 1 is an alkenyl which may be substituted with 1, 2, 3, or 4 substituents. In a particular embodiment, in the compound of formula II, R 1 is an alkynyl which may be substituted with 1, 2, 3, or 4 substituents. In a particular embodiment, in the compound of formula II, R 1 is a haloalkyl which may be substituted with 1, 2, 3, or 4 substituents. In a particular embodiment, in the compound of formula II, R 1 It is F.

[0162] In a particular embodiment, in a compound of formula II, R 1 It is Cl.

[0163] In a particular embodiment, in a compound of formula II, R 1 It is Br.

[0164] In a particular embodiment, in a compound of formula II, R 1 is an aryl which may be substituted with 1, 2, 3, or 4 substituents.

[0165] In a particular embodiment, in a compound of formula II, R 1 This is an arylalkyl which may be substituted with 1, 2, 3, or 4 substituents.

[0166] In a particular embodiment, in a compound of formula II, R 1 This is a heteroaryl compound which may be substituted with 1, 2, 3, or 4 substituents.

[0167] In a particular embodiment, in a compound of formula II, R 1 This is a heteroarylalkyl which may be substituted with 1, 2, 3, or 4 substituents.

[0168] In a particular embodiment, in a compound of formula II, R 1 This is a heterocycle that may be substituted with 1, 2, 3, or 4 substituents.

[0169] In a particular embodiment, in a compound of formula II, R 1 This is a heterocycloalkyl which may be substituted with 1, 2, 3, or 4 substituents.

[0170] In a particular embodiment, in a compound of formula II, R 1 This is a haloalkoxy which may be substituted with 1, 2, 3, or 4 substituents.

[0171] In a particular embodiment, in a compound of formula II, R 1 -O-alkenyl, -O-alkynyl, C0-C6 alkyl-OR may be substituted with 1, 2, 3, or 4 substituents, respectively. 6 C0-C6 alkyl-SR 6 C0-C6 alkyl-NR 6 R 7C0-C6 alkyl-C(O)R 3 C0-C6 alkyl-S(O)R 3 C0-C6 alkyl-C(S)R 3 C0~C6 alkyl-S(O)2R 3 , C 0~ C6alkyl-N(R 8 )-C(O)R 3 , C0~C6 alkyl-N(R 8 )-S(O)R 3 , C0~C6 alkyl-N(R 8 )-C(S)R 3 , C0~C6 alkyl-N(R 8 )-S(O)2R 3 , C 0~ C6 alkyl-OC(O)R 3 C0-C6 alkyl-OS(O)R 3 C0-C6 alkyl-OC(S)R 3 -N=S(O)(R 3 )2, C0-C6 alkyl N3, or C0-C6 alkyl-OS(O)2R 3 That is the case.

[0172] In a particular embodiment, in a compound of formula II, R 2 is an aryl which may be substituted with 1, 2, 3, or 4 substituents.

[0173] In a particular embodiment, in a compound of formula II, R 2 This is a heterocycle that may be substituted with 1, 2, 3, or 4 substituents.

[0174] In a particular embodiment, in a compound of formula II, R 2 This is a heteroaryl compound containing one or two heteroatoms independently selected from N, O, and S, which may be substituted with one, two, three, or four substituents.

[0175] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000224.tif37128.

[0176] In a particular embodiment, in a compound of formula II, R 2 This is a heterocycle that may be substituted with 1, 2, 3, or 4 substituents.

[0177] In a particular embodiment, in a compound of formula II, R 2 may be substituted with 1, 2, 3, or 4 substituents -NR 8 -S(O)-R 3 That is the case.

[0178] In a particular embodiment, in a compound of formula II, R 2 may be substituted with 1, 2, 3, or 4 substituents -NR 8 -C(S)-R 3 That is the case.

[0179] In a particular embodiment, in a compound of formula II, R 2 may be substituted with 1, 2, 3, or 4 substituents -NR 8 -S(O)(NR 6 )-R 3 That is the case.

[0180] In a particular embodiment, in a compound of formula II, R 2 -N=S(O)(R 3 )2.

[0181] In a particular embodiment, in a compound of formula II, R 2 may be substituted with 1, 2, 3, or 4 substituents -NR 8 C(O)NR 9 S(O)2R 3 That is the case.

[0182] In a particular embodiment, in a compound of formula II, R 2may be substituted with 1, 2, 3, or 4 substituents -NR 8 -S(O)2-R 10 That is the case.

[0183] In a particular embodiment, in a compound of formula II, R 2 may be substituted with 1, 2, 3, or 4 substituents -NR 8 -C(NR 6 )-R 3 That is the case.

[0184] In a particular embodiment, in a compound of formula II, R 2 It is hydrogen.

[0185] In a particular embodiment, in a compound of formula II, R 2 is R 10 That is the case.

[0186] In a particular embodiment, in a compound of formula II, R 2 is alkyl-C(O)-R 3 That is the case.

[0187] In a particular embodiment, in a compound of formula II, R 2 -C(O)-R 3 That is the case.

[0188] In a particular embodiment, in a compound of formula II, R 2 It is alkyl.

[0189] In a particular embodiment, in a compound of formula II, R 2 It is a haloalkyl.

[0190] In a particular embodiment, in a compound of formula II, R 2 -OC(O)R 3 That is the case.

[0191] In a particular embodiment, in a compound of formula II, R 2 -NR 8 -C(O)R 10That is the case.

[0192] In a particular embodiment, in a compound of formula II, R 2 is an alkenyl which may be substituted with 1, 2, 3, or 4 substituents.

[0193] In a particular embodiment, in a compound of formula II, R 2 This is an allele that may be substituted with 1, 2, 3, or 4 substituents.

[0194] In a particular embodiment, in a compound of formula II, R 2 This is an alkynyl which may be substituted with 1, 2, 3, or 4 substituents.

[0195] In a particular embodiment, in a compound of formula II, R 2 may be substituted with 1, 2, 3, or 4 substituents -NR 6 -It is Alkenil.

[0196] In a particular embodiment, in a compound of formula II, R 2 is an -O-alkenyl which may be substituted with 1, 2, 3, or 4 substituents.

[0197] In a particular embodiment, in a compound of formula II, R 2 may be substituted with 1, 2, 3, or 4 substituents -NR 6 - It is Alkinil.

[0198] In a particular embodiment, in a compound of formula II, R 2 may be substituted with 1, 2, 3, or 4 substituents -NR 6 -It is a heteroaryl compound.

[0199] In a particular embodiment, in a compound of formula II, R 2 may be substituted with 1, 2, 3, or 4 substituents -NR 6 - It is Ariel.

[0200] In a particular embodiment, in a compound of formula II, R 2 It is an -O-heteroaryl which may be substituted with 1, 2, 3, or 4 substituents.

[0201] In a particular embodiment, in a compound of formula II, R 2 is an -O-aryl which may be substituted with 1, 2, 3, or 4 substituents.

[0202] In a particular embodiment, in a compound of formula II, R 2 is an -O-alkynyl which may be substituted with 1, 2, 3, or 4 substituents.

[0203] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000225.tif10128.

[0204] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000226.tif17129.

[0205] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000227.tif97128, where R is an optional substituent as defined herein.

[0206] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000228.tif41128.

[0207] In a particular embodiment, in a compound of formula II, R 2A teeth, Selected from TIFF2026508972000229.tif99128, where R is an optional substituent as defined herein.

[0208] In a particular embodiment, in a compound of formula II, R 2A teeth, Selected from TIFF2026508972000230.tif43128.

[0209] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000231.tif138128.

[0210] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000232.tif134136.

[0211] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000233.tif8128.

[0212] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000234.tif8128.

[0213] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000235.tif37128.

[0214] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000236.tif37128.

[0215] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000237.tif18128.

[0216] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000238.tif14128.

[0217] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000239.tif41128.

[0218] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000240.tif41128.

[0219] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000241.tif11128.

[0220] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000242.tif11128.

[0221] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000243.tif38128.

[0222] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000244.tif35128.

[0223] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000245.tif57128.

[0224] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000246.tif57128.

[0225] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000247.tif31128.

[0226] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000248.tif31128.

[0227] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000249.tif69128.

[0228] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000250.tif69128.

[0229] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000251.tif22128.

[0230] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000252.tif22128.

[0231] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000253.tif22128.

[0232] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000254.tif22128.

[0233] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000255.tif18128.

[0234] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000256.tif18128.

[0235] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000257.tif19128.

[0236] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000258.tif20128.

[0237] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000259.tif91128.

[0238] In a particular embodiment, in a compound of formula II, R 2 or R 2A teeth, Selected from TIFF2026508972000260.tif94128.

[0239] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000261.tif26128.

[0240] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000262.tif25128.

[0241] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000263.tif9128.

[0242] In a particular embodiment, in a compound of formula II, R 2 teeth, Selected from TIFF2026508972000264.tif9128.

[0243] In a particular embodiment, in a compound of formula II, R 2 This is more likely to be chosen.

[0244] In a particular embodiment, in a compound of formula II, R 2 This is a spirocyclic heteroalgebra, for example, not limited to, The filename is TIFF2026508972000265.tif11128.

[0245] In a particular embodiment, in a compound of formula II, R 2 This refers to silicon-containing heterocycles, for example, not limited to, The filename is TIFF2026508972000266.tif14128.

[0246] In a particular embodiment, in a compound of formula II, R 2 It has been replaced with SF5, for example, indefinitely, The filename is TIFF2026508972000267.tif20128.

[0247] In a particular embodiment, in a compound of formula II, R 2 It is substituted with a sulfoxime, for example, not limited to, The filename is TIFF2026508972000268.tif20128.

[0248] In a particular embodiment, in a compound of formula II, R 10 It is selected from biring complex algebras.

[0249] In a particular embodiment, in a compound of formula II, R 10 It is selected from spirocyclic heteroalgebras.

[0250] In a particular embodiment, in a compound of formula II, R 10 -NR 6 - Selected from a complex algebra.

[0251] In a particular embodiment, in a compound of formula II, R 10 teeth, Selected from TIFF2026508972000269.tif12128.

[0252] In a particular embodiment, in a compound of formula II, R 10 teeth, Selected from TIFF2026508972000270.tif38128.

[0253] In a particular embodiment, in a compound of formula II, R 10 teeth, Selected from TIFF2026508972000271.tif18128.

[0254] In a particular embodiment, in a compound of formula II, R 10 teeth, Selected from TIFF2026508972000272.tif30128.

[0255] In a particular embodiment, in a compound of formula II, the ring is Selected from TIFF2026508972000273.tif126128.

[0256] In a particular embodiment, in a compound of formula II, R 30 teeth, Selected from TIFF2026508972000274.tif31128.

[0257] In a particular embodiment, in a compound of formula II, R 200 teeth, The filename is TIFF2026508972000275.tif13128.

[0258] In a particular embodiment, in a compound of formula II, R 200 teeth, The filename is TIFF2026508972000276.tif11128.

[0259] In a particular embodiment, in a compound of formula II, R 200 teeth, The filename is TIFF2026508972000277.tif13128.

[0260] In a particular embodiment, in a compound of formula II, R 200 teeth, The filename is TIFF2026508972000278.tif11128.

[0261] In a particular embodiment, in a compound of formula II, R 200 teeth, The filename is TIFF2026508972000279.tif13128.

[0262] In a particular embodiment, in a compound of formula II, R 200 teeth, The filename is TIFF2026508972000280.tif13128.

[0263] In a particular embodiment, in a compound of formula II, R 200 teeth, The filename is TIFF2026508972000281.tif13128.

[0264] In a particular embodiment, in a compound of formula II, R 200 teeth, The filename is TIFF2026508972000282.tif13128.

[0265] In a particular embodiment, in a compound of formula II, R 200 teeth, The filename is TIFF2026508972000283.tif11128.

[0266] In a particular embodiment, in a compound of formula II, R 200 teeth, The filename is TIFF2026508972000284.tif11128.

[0267] In a particular embodiment, in a compound of formula II, R 200 teeth, The filename is TIFF2026508972000285.tif11128.

[0268] In a particular embodiment, in a compound of formula II, R 200 teeth, The filename is TIFF2026508972000286.tif11128.

[0269] Linker In a non-limiting embodiment, in a compound of formula II, a linker A and linker B teeth, Selected independently from TIFF2026508972000287.tif11128, During the ceremony, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , and R 20 In each occurrence, R 21 The bonds, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR may each be substituted with one, two, three, or four substituents selected more independently. 6 -, -NR 6 C(O)-, -O-, -S-, -NR 6 -, -C(R 21 R 21 )-,-P(O)(R 3 )O-, -P(O)(R 3 )-, divalent residues of natural or unnatural amino acids, alkenyls, alkynyls, haloalkyls, alkoxys, and heterocyclics, heteroaryls, -CH2CH2-[O-(CH2)2] n -O-, CH2CH2-[O-(CH2)2] n -NR 6 -, -CH2CH2-[O-(CH2)2] n -,-[-(CH2)2-O-] n -,-[O-(CH2)2] n -,-[O-CH(CH3)C(O)] n -,-[C(O)-CH(CH3)-O] n -,-[O-CH2C(O)] n -,-[C(O)-CH2-O] n - Selected from the group consisting of divalent residues of fatty acids, unsaturated or saturated monocarboxylic acids, or divalent residues of dicarboxylic acids; n is independently selected in each case from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; R 21 In each appearance, independently, hydrogen, alkyl, alkenyl, alkynyl, F, Cl, Br, I, hydroxyl, alkoxy, azide, amino, cyano, -NR 6 R 7 , -NR 8 SO2R 3 , -NR 8 S(O)R 3 Selected from the group consisting of haloalkyl, heteroalkyl, heteroaryl, and heterocyclic compounds; The remaining variables are as defined herein.

[0270] In some embodiments, in a compound of formula II, a linker A It is a bond, a linker B teeth The filename is TIFF2026508972000288.tif9128.

[0271] In some embodiments, in a compound of formula II, a linker B It is a bond, a linker A teeth The filename is TIFF2026508972000289.tif9128.

[0272] In some embodiments, in the compound of formula II, the divalent amino acid residue is Selected from TIFF2026508972000290.tif175128, in the formula, the amino acids may be oriented in any direction, and the amino acids may be L-forms, D-forms, or mixtures thereof.

[0273] In some embodiments, in compounds of formula II, the divalent residue of the dicarboxylic acid undergoes a nucleophilic addition reaction: It is generated from TIFF2026508972000291.tif19128.

[0274] Non-limiting embodiments of the divalent residues of dicarboxylic acids produced from nucleophilic addition reactions include: This includes TIFF2026508972000292.tif48128.

[0275] In some embodiments, in the compound of formula II, the divalent residue of the dicarboxylic acid undergoes a condensation reaction: It is generated from TIFF2026508972000293.tif19128.

[0276] Non-limiting embodiments of the divalent residues of the dicarboxylic acid produced from condensation include: This includes TIFF2026508972000294.tif49128.

[0277] Non-limiting embodiments of the divalent residue of saturated dicarboxylic acid include: This includes TIFF2026508972000295.tif44128.

[0278] Non-limiting embodiments of the divalent residue of saturated dicarboxylic acid include: This includes TIFF2026508972000296.tif21128.

[0279] Non-limiting embodiments of the divalent residues of saturated monocarboxylic acids include butyric acid (-OC(O)(CH2)2CH2-), caproic acid (-OC(O)(CH2)4CH2-), caprylic acid (-OC(O)(CH2)5CH2-), capric acid (-OC(O)(CH2)8CH2-), and lauric acid (-OC(O)(CH2) 10 CH2-), myristic acid (-OC(O)(CH2) 12 CH2-), pentadecanoic acid (-OC(O)(CH2) 13 CH2-), palmitic acid (-OC(O)(CH2) 14 CH2-), stearic acid (-OC(O)(CH2) 16 CH2-), behenic acid (-OC(O)(CH2) 20 CH2-), and lignoceric acid (-OC(O)(CH2) 22 Selected from CH2-).

[0280] Non-limiting embodiments of divalent fatty acid residues include residues selected from linoleic acid, palmitoleic acid, vaccenic acid, pauric acid, oleic acid, elaidic acid, gondic acid, gadrenic acid, nervonic acid, myristoleic acid, and erucic acid: TIFF2026508972000297.tif87134.

[0281] Non-limiting embodiments of the divalent residues of fatty acids include linoleic acid (-C(O)(CH2)7(CH)2CH2(CH)2(CH2)4CH2-), docosahexaenoic acid (-C(O)(CH2)2(CHCHCH2)6CH2-), eicosapentaenoic acid (-C(O)(CH2)3(CHCHCH2)5CH2-), α-linolenic acid (-C(O)(CH2)7(CHCHCH2)3CH2-), stearidonic acid (-C(O)(CH2)4(CHCHCH2)4CH2-), γ-linolenic acid (-C(O)(CH2)4(CHCHCH2)3(CH2)3CH2-), and arachidonic acid (-C(O)(CH2) 3, (CHCHCH2)4(CH2)4CH2-), docosatetraenoic acid (-C(O)(CH2)5(CHCHCH2)4(CH2)4CH2-), palmitoleic acid (-C(O)(CH2)7CHCH(CH2)5CH2-), vaccenic acid (-C(O)(CH2)9CHCH(CH2)5CH2-), pauric acid (-C(O)(CH2) 11 CHCH(CH2)5CH2-), oleic acid (-C(O)(CH2)7CHCH(CH2)7CH2-), elaidic acid (-C(O)(CH2)7CHCH(CH2)7CH2-), gondic acid (-C(O)(CH2)9CHCH(CH2)7CH2-), gadolic acid (-C(O)(CH2)7CHCH(CH2)9CH2-), nervonic acid (-C(O)(CH2) 13 CHCH(CH2)3CH2-), Mead acid (-C(O)(CH2)3(CHCHCH2)3(CH2)6CH2-), Myristoleic acid (-C(O)(CH2)7CHCH(CH2)3CH2-), and Erucic acid (-C(O)(CH2) 11 Selected from CHCH(CH2)7CH2-).

[0282] In a particular embodiment, in a compound of formula II, a linker C teeth, Selected from TIFF2026508972000298.tif26128, During the ceremony, R 22 In each occurrence, R 21 Alkyl, -C(O)N-, -NC(O)-, -N-, -C(R 21 )-, -P(O)O-, -P(O)-, -P(O)(NR 6 R 7 Selected from the group consisting of N-, alkenyl, haloalkyl, aryl, heterocyclic, and heteroaryl; The remaining variables are as defined herein.

[0283] In a particular embodiment, in a compound of formula II, a linker D teeth, Selected from TIFF2026508972000299.tif38128, During the ceremony, R 32 In each occurrence, R 21 Alkyl, N, which may each be substituted with 1, 2, 3, or 4 substituents selected more independently. + Selected from the group consisting of X-, -C-, alkenyl, haloalkyl, aryl, heterocyclic, and heteroaryl; X- represents an anionic group, such as Br- or Cl-. - and; All other variables are as defined herein.

[0284] In a particular embodiment, in a compound of formula II, a linker A teeth, Selected from TIFF2026508972000300.tif20128, In the formula, each heteroaryl, heterocyclic, cycloalkyl, and aryl may be substituted with one, two, three, or four of any combination of halogens, alkyls, haloalkyls, and heteroaryls, heterocyclics, or cycloalkyls, as permitted by the bond valency.

[0285] In a particular embodiment, in a compound of formula II, a linker A teeth, Selected from TIFF2026508972000301.tif80128, In the formula, each heteroaryl, heterocyclic, and cycloalkyl group may be substituted with one, two, three, or four of any combination of halogens, alkyls, haloalkyls, aryls, heteroaryls, heterocyclics, or cycloalkyl groups, as permitted by the bond valency.

[0286] In a particular embodiment, in a compound of formula II, a linker B teeth, Selected from TIFF2026508972000302.tif67128.

[0287] In a particular embodiment, in a compound of formula II, a linker B teeth, Selected from TIFF2026508972000303.tif171128.

[0288] In a particular embodiment, in a compound of formula II, a linker B Linker C , or linker D teeth, Selected from TIFF2026508972000304.tif83128, In the formula, tt is independently selected from 1, 2, or 3, and ss is 3 minus tt (3-tt).

[0289] In a particular embodiment, in a compound of formula II, a linker B Linker C , or linkerD teeth, Selected from TIFF2026508972000305.tif36128, In the formula, tt and ss are as defined herein.

[0290] In a particular embodiment, in a compound of formula II, a linker B Linker C , or linker D teeth, Selected from TIFF2026508972000306.tif136128TIFF2026508972000307.tif170128TIFF2026508972000308.tif170128TIFF2026508972000309.tif21692 In the formulas, heteroaryl, heterocyclic, cycloalkyl, and aryl may each be substituted with one, two, three, or four of any combination of halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocyclic, or cycloalkyl, as permitted by the bond valency; tt and ss are as defined herein.

[0291] In a particular embodiment, in a compound of formula II, a linker B Linker C , or linker D teeth, Selected from TIFF2026508972000310.tif121128 and TIFF2026508972000311.tif156128 In the formula, heteroaryl, heterocyclic, cycloalkyl, and aryl may each be substituted with one, two, three, or four of any combination of halogen, alkyl, haloalkyl, and heteroaryl, heterocyclic, or cycloalkyl, as permitted by the bond valency; tt and ss are as defined herein.

[0292] In a particular embodiment, in a compound of formula II, a linker B Linker C, or linker D teeth, Selected from TIFF2026508972000312.tif52128 In the formula, heteroaryl and aryl may each be substituted with one, two, three, or four of any combination of halogens, alkyls, haloalkyls, aryls, heteroaryls, heterocyclics, or cycloalkyls, as permitted by the bond valency; tt and ss are as defined herein.

[0293] In a particular embodiment, in a compound of formula II, a linker A teeth, Selected from TIFF2026508972000313.tif47128.

[0294] In a particular embodiment, in a compound of formula II, a linker A teeth, Selected from TIFF2026508972000314.tif60128.

[0295] In a particular embodiment, in a compound of formula II, a linker A teeth, Selected from TIFF2026508972000315.tif49128.

[0296] In a particular embodiment, in a compound of formula II, a linker A teeth, Selected from TIFF2026508972000316.tif50128.

[0297] In a particular embodiment, in a compound of formula II, a linker B teeth, Selected from TIFF2026508972000317.tif79128.

[0298] In a particular embodiment, in a compound of formula II, a linker B teeth, Selected from TIFF2026508972000318.tif67128.

[0299] In a particular embodiment, in a compound of formula II, a linker B teeth, Selected from TIFF2026508972000319.tif167128.

[0300] In a particular embodiment, in a compound of formula II, a linker B teeth, Selected from TIFF2026508972000320.tif69128 and TIFF2026508972000321.tif157128.

[0301] In a particular embodiment, in a compound of formula II, a linker C teeth, Selected from TIFF2026508972000322.tif29128.

[0302] In a particular embodiment, in a compound of formula II, a linker C teeth, Selected from TIFF2026508972000323.tif87128.

[0303] In a particular embodiment, in a compound of formula II, a linker C teeth, Selected from TIFF2026508972000324.tif116128.

[0304] In a particular embodiment, in a compound of formula II, a linker C teeth, Selected from TIFF2026508972000325.tif58128.

[0305] In a particular embodiment, in a compound of formula II, a linker C teeth, Selected from TIFF2026508972000326.tif125128.

[0306] In a particular embodiment, in a compound of formula II, a linker C teeth, Selected from TIFF2026508972000327.tif63132.

[0307] In a particular embodiment, in a compound of formula II, a linker C teeth, Selected from TIFF2026508972000328.tif122128.

[0308] In a particular embodiment, in a compound of formula II, a linker C teeth, Selected from TIFF2026508972000329.tif140128.

[0309] In a particular embodiment, in a compound of formula II, a linker D teeth, Selected from TIFF2026508972000330.tif118128.

[0310] In a particular embodiment, in a compound of formula II, a linker D teeth, Selected from TIFF2026508972000331.tif159128.

[0311] In a particular embodiment, in a compound of formula II, linker D is Selected from TIFF2026508972000332.tif87128.

[0312] In a particular embodiment, in a compound of formula II, a linker D teeth, Selected from TIFF2026508972000333.tif180128.

[0313] In a particular embodiment, in a compound of formula II, a linker D teeth, Selected from TIFF2026508972000334.tif58128.

[0314] In a particular embodiment, in a compound of formula II, a linker D teeth, Selected from TIFF2026508972000335.tif115128.

[0315] In a particular embodiment, in a compound of formula II, a linker D teeth, Selected from TIFF2026508972000336.tif191128.

[0316] In a particular embodiment, in a compound of formula II, a linker A teeth, Selected from TIFF2026508972000337.tif22128.

[0317] In a particular embodiment, in a compound of formula II, a linker A teeth, Selected from TIFF2026508972000338.tif13128.

[0318] In a particular embodiment, in a compound of formula II, a linker A teeth, Selected from TIFF2026508972000339.tif96128.

[0319] In a certain manner, linker A R 21 Each of the substituents may be substituted with one, two, three, or four more selected substituents. Selected from TIFF2026508972000340.tif136128.

[0320] In a particular embodiment, in a compound of formula II, a linker A teeth, Selected from TIFF2026508972000341.tif16128.

[0321] In a particular embodiment, in a compound of formula II, a linker A teeth, Selected from TIFF2026508972000342.tif33128.

[0322] In a particular embodiment, in a compound of formula II, a linker A teeth, Selected from TIFF2026508972000343.tif33128.

[0323] In a particular embodiment, in a compound of formula II, a linker A teeth, Selected from TIFF2026508972000344.tif34128.

[0324] In a particular embodiment, in a compound of formula II, a linker A teeth, Selected from TIFF2026508972000345.tif46128.

[0325] In a particular embodiment, in a compound of formula II, a linker A teeth, Selected from TIFF2026508972000346.tif14128.

[0326] In a particular embodiment, in a compound of formula II, a linker A This is more likely to be chosen.

[0327] In a particular embodiment, in a compound of formula II, a linker A teeth, Selected from TIFF2026508972000347.tif136128 and TIFF2026508972000348.tif136128.

[0328] In a particular embodiment, in a compound of formula II, a linker A teeth, Selected from TIFF2026508972000349.tif92128.

[0329] In a particular embodiment, in a compound of formula II, a linker A teeth, Selected from TIFF2026508972000350.tif130136.

[0330] In a particular embodiment, in a compound of formula II, a linker A teeth, Selected from TIFF2026508972000351.tif38128.

[0331] In a particular embodiment, in a compound of formula II, a linker A teeth, Selected from TIFF2026508972000352.tif34128.

[0332] In a particular embodiment, in a compound of formula II, a linker A teeth, Selected from TIFF2026508972000353.tif68128.

[0333] In a particular embodiment, in a compound of formula II, a linker A teeth, Selected from TIFF2026508972000354.tif56128.

[0334] In a particular embodiment, in a compound of formula II, a linker A teeth, Selected from TIFF2026508972000355.tif67128.

[0335] In a particular embodiment, in a compound of formula II, a linker B teeth, Selected from TIFF2026508972000356.tif30128.

[0336] In a particular embodiment, in a compound of formula II, a linker B teeth, Selected from TIFF2026508972000357.tif12128.

[0337] In a particular embodiment, in a compound of formula II, a linker B teeth, Selected from TIFF2026508972000358.tif40128.

[0338] In a particular embodiment, in a compound of formula II, a linker B R 21 Selected from those which may be substituted with one, two, three, or four further selected substituents.

[0339] In a particular embodiment, in a compound of formula II, a linker B teeth, Selected from TIFF2026508972000359.tif57128.

[0340] In a particular embodiment, in a compound of formula II, a linker B teeth, Selected from TIFF2026508972000360.tif21128.

[0341] In a particular embodiment, in a compound of formula II, a linker B teeth, Selected from TIFF2026508972000361.tif26128.

[0342] In a particular embodiment, in a compound of formula II, a linker B teeth, Selected from TIFF2026508972000362.tif34128.

[0343] In a particular embodiment, in a compound of formula II, a linker B teeth, Selected from TIFF2026508972000363.tif55128.

[0344] In a particular embodiment, in a compound of formula II, a linker B teeth, Selected from TIFF2026508972000364.tif43128.

[0345] In a particular embodiment, in a compound of formula II, a linker B teeth, Selected from TIFF2026508972000365.tif108128.

[0346] In a particular embodiment, in a compound of formula II, a linker B teeth, Selected from TIFF2026508972000366.tif60128.

[0347] In a particular embodiment, in a compound of formula II, a linker B - Linker A teeth, Selected from TIFF2026508972000367.tif18128.

[0348] In a particular embodiment, in a compound of formula II, a linker B - Linker A teeth, Selected from TIFF2026508972000368.tif37128.

[0349] In a particular embodiment, in a compound of formula II, a linker C teeth, Selected from TIFF2026508972000369.tif38128.

[0350] In a particular embodiment, in a compound of formula II, a linkerC teeth, Selected from TIFF2026508972000370.tif59128.

[0351] In a particular embodiment, in a compound of formula II, a linker C teeth, Selected from TIFF2026508972000371.tif38128.

[0352] In a particular embodiment, in a compound of formula II, a linker C teeth, Selected from TIFF2026508972000372.tif87128.

[0353] In a particular embodiment, in a compound of formula II, a linker C teeth, Selected from TIFF2026508972000373.tif48128.

[0354] In a particular embodiment, in a compound of formula II, a linker C teeth, Selected from TIFF2026508972000374.tif75128.

[0355] In a particular embodiment, in a compound of formula II, a linker C teeth, Selected from TIFF2026508972000375.tif86128, TIFF2026508972000376.tif163128, and TIFF2026508972000377.tif49128.

[0356] In a particular embodiment, in a compound of formula II, a linker C R 21 Selected from those which may be substituted with one, two, three, or four further selected substituents.

[0357] In a particular embodiment, in a compound of formula II, a linker Cteeth, Selected from TIFF2026508972000378.tif66128.

[0358] In a particular embodiment, in a compound of formula II, a linker C teeth, Selected from TIFF2026508972000379.tif20128.

[0359] In a particular embodiment, in a compound of formula II, a linker C teeth, Selected from TIFF2026508972000380.tif20128.

[0360] In a particular embodiment, in a compound of formula II, a linker C teeth, Selected from TIFF2026508972000381.tif41128.

[0361] In a particular embodiment, in a compound of formula II, a linker C teeth, Selected from TIFF2026508972000382.tif41128.

[0362] In a particular embodiment, in a compound of formula II, a linker C teeth, Selected from TIFF2026508972000383.tif30128.

[0363] In a particular embodiment, in a compound of formula II, a linker C teeth, Selected from TIFF2026508972000384.tif45128.

[0364] In a particular embodiment, in a compound of formula II, a linker C teeth, Selected from TIFF2026508972000385.tif74128.

[0365] In a particular embodiment, in a compound of formula II, a linker C -(Linker A )2 is, Selected from TIFF2026508972000386.tif63128.

[0366] In a particular embodiment, in a compound of formula II, a linker C -(Linker A )2 is, Selected from TIFF2026508972000387.tif115128.

[0367] In a particular embodiment, in a compound of formula II, a linker C -(Linker A )2 is, Selected from TIFF2026508972000388.tif24128.

[0368] In a particular embodiment, in a compound of formula II, a linker C -(Linker A )2 is, Selected from TIFF2026508972000389.tif185128.

[0369] In a particular embodiment, in a compound of formula II, a linker D teeth, Selected from TIFF2026508972000390.tif45128.

[0370] In a particular embodiment, in a compound of formula II, a linker D R 21 Each of the substituents may be substituted with one, two, three, or four more selected substituents. Selected from TIFF2026508972000391.tif81128.

[0371] In a particular embodiment, in a compound of formula II, a linker B -(Linker A)teeth, Selected from TIFF2026508972000392.tif60128.

[0372] In a particular embodiment, in a compound of formula II, a linker C -(Linker A )teeth, Selected from TIFF2026508972000393.tif164128.

[0373] In a particular embodiment, in a compound of formula II, a linker D -(Linker A )teeth, Selected from TIFF2026508972000394.tif88128.

[0374] Various modes of transport, R 4 In each occurrence, the elements are independently hydrogen, heteroalkyl, alkyl, haloalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, and -OR. 6 , -NR 6 R 7 , C(O)R 3 , S(O)R 3 , C(S)R 3 , and S(O)2R 3 More likely to be selected.

[0375] In various embodiments, in the compound of formula II, R 5 is hydrogen, heteroalkyl, TIFF2026508972000395.tif19128, C0~C6 alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocycloalkyl, haloalkoxy, -O-alkenyl, -O-alkynyl, C0~C6 alkyl-OR 6 C0-C6 alkyl-SR 6 C0-C6 alkyl-NR 6 R 7C0-C6 alkyl-C(O)R 3 C0-C6 alkyl-S(O)R 3 C0-C6 alkyl-C(S)R 3 C0~C6 alkyl-S(O)2R 3 , C0~C6 alkyl-N(R 8 )-C(O)R 3 , C0~C6 alkyl-N(R 8 )-S(O)R 3 , C0~C6 alkyl-N(R 8 )-C(S)R 3 , C0~C6 alkyl-N(R 8 )-S(O)2R 3 , C 0~ C6 alkyl-OC(O)R 3 C0-C6 alkyl-OS(O)R 3 C0-C6 alkyl-OC(S)R 3 -N=S(O)(R 3 )2, C0-C6 alkyl N3, and C0-C6 alkyl-OS(O)2R 3 These can be selected more independently, and each of them may be substituted with one, two, three, or four substituents.

[0376] In various embodiments, in the compound of formula II, R 6 and R 7 In each occurrence, independently, hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, and haloalkyl, heteroaryl, heterocyclic, -alkyl-OR 8 , -alkyl-NR 8 R 9 , C(O)R 3 , S(O)R 3 , C(S)R 3 , and S(O)2R 3 More likely to be selected.

[0377] In various embodiments, in the compound of formula II, R 8 and R 9Each instance is independently selected from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclic.

[0378] In various embodiments, the compound of formula II has the structure of formula II-A.

[0379] In various embodiments, in the compound of formula II-A, L B This is as defined herein.

[0380] This disclosure concerns the structure: We provide a compound of formula II-A having TIFF2026508972000396.tif17128, or a salt, stereoisomer, or solvate thereof. During the ceremony, L B This is, for example, an anti-CCP1 (anti-cyclic citrullinated peptide) binding moiety as described elsewhere in this specification. [ASGPBM] is The asialoglycoprotein receptor binding moiety has a structure selected from TIFF2026508972000397.tif220113; Each [CON] is an optional connector chemical part that connects [LIN] to [PBM] or [ASGPBM], if present; [LIN] is a [linker] or [linker-2], which is a chemical moiety having a bond value of 1 to 15, optionally covalently bonded to one or more [ASGPBM] or [PBM] groups via [CON], and [LIN] may optionally contain one or more [CON] groups itself; Z B (CH2) IM , C(O)-(CH2) IM -, or C(O)-(CH2) IM -NR M and; R Mis a C1-C3 alkyl group which may be substituted with H or one or two hydroxyl groups; R2 is The file is TIFF2026508972000398.tif15128, where R AM C1-C4 alkyl, -(CH2) which may be substituted with H, up to 3 halo groups and 1 or 2 hydroxyl groups. K COOH may be substituted with 1 to 3 halo groups - (CH2) K C(O)O-(C1~C4 alkyl), -OC(O)-(C1~C4 alkyl) which may be substituted with 1 to 3 halo groups, -C(O)-(C1~C4 alkyl) which may be substituted with 1 to 3 halo groups, or -(CH2) K -NR N3 R N4 is; or R 2 teeth, The file is TIFF2026508972000399.tif14128, and here, R TA H, CN, NR N1 R N2 ,-(CH2) K OH may be substituted with 1 to 3 halo groups - (CH2) K O(C1-C4 alkyl), C1-C4 alkyl which may be substituted with 1-3 halo groups, -(CH2) K COOH may be substituted with 1 to 3 halo groups - (CH2) K C(O)O-(C1~C4 alkyl), -OC(O)-(C1~C4 alkyl) which may be substituted with 1 to 3 halo groups, or -C(O)-(C1~C4 alkyl) which may be substituted with 1 to 3 halo groups, or R TA is C3~C 10 A 3- to 10-membered heteroaryl group containing aryl or up to 5 heteroaryl atoms, wherein each of the aryl or heteroaryl group contains up to 3 CN, NR N1 R N2 ,-(CH2) KOH may be substituted with 1 to 3 halo groups - (CH2) K O(C1-C4 alkyl), C1-C3 alkyl which may be substituted with 1-3 halo groups or 1-2 hydroxyl groups, -O-(C1-C3-alkyl), -(CH2) K COOH may be substituted with 1 to 3 halo groups - (CH2) K C(O)O-(C1-C4 alkyl), OC(O)-(C1-C4 alkyl) which may be substituted with 1-3 halo groups, or -(CH2) which may be substituted with 1-3 halo groups. K It may be substituted with C(O)-(C1~C4 alkyl), or R TA It may be substituted with up to 3 halo groups or up to 3 C1-C3 alkyl groups. Is it TIFF2026508972000400.tif48128; or R TA teeth The filename is TIFF2026508972000401.tif57128; R N , R N1 , R N2 , R N3 , R N4 Each is independently a C1-C3 alkyl group which may be substituted with H, or 1-3 halo groups or 1-2 hydroxyl groups, and each is -(CH2) K The group may be substituted with 1 to 3 fluoro groups or 1 to 2 hydroxyl groups, or it may be substituted with 1 to 4 C1-C3 alkyl groups; IM is an integer in the range of 0 to 6, independently in each occurrence; K is an integer in the range of 0 to 4, independently in each occurrence; k' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; j' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; h and h' are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; i L is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; However, h, h', and i L At least one of them is at least 1.

[0381] In various embodiments, in the compound of formula II-A, R2 is -NC(=O)CH3.

[0382] D. Other base ASGPR coupling parts Furthermore, the ASGPR activity is indicated by Reshitko,GS,et al.,"Synthesis and Evaluation of New Trivalent Ligands for Hepatocyte Targeting via the Asialoglycoprotein Receptor,"Bioconjugate Chem,doi:10.1021 / acs.bioconjchem.0C00202;Majouga,AG,et al.,"Identification of Novel Small-Molecule ASGP-R Ligands,"Current Drug Delivery,2016,13,1303-1312,doi:10.2174 / 1567201813666160719144651;Olshanova,AS,et al.,"Synthesis of a new betulinic acid glycoconjugate with N-acetyl-D-galactosamine for the targeted delivery to hepatocellular carcinoma." cells,"Russian Chemical Bulletin,International Edition,Vol.69,No.1,pp.158-163,January 2020;Yamansarov,E.Yu.,et al.,"New ASGPR-targeted ligands based on glycoconjugated natural triterpenoids,"Russian Chemical Bulletin,Int Edition,Vol.68,No.12,pp.2331-2338,Dec.2019;Congdon,MD,et al.,"Enhanced Binding and Reduced Immunogenicity of Glycoconjugates Prepared via Solid-State Photoactivation of Aliphatic Diazirine Carbohydrates,"Bioconjugate Chem,doi:10.1021 / acs.This may be any portion of the following: bioconjchem.0c00555; and Dhawan, V., et al., "Polysaccharide conjugates surpass monosaccharide ligands in hepatospecific targeting - Synthesis and comparative in silico and in vitro assessment," Carbohydrate Research 509(2021)108417, doi:10.1016 / j.carres.2021.108417. The following ASGPR binding moieties are illustrative and not limiting.

[0383] 1. GalNAc-tyrosine-based portion In some embodiments, the ASGPR binding moiety may be a moiety having the structure M1, M2, M3, or M4, or a combination thereof. In the structures M1, M2, M3, and M4, X is independently O, NH, or S in each occurrence. In various embodiments, the compound of formula I or formula II is M1, M2, M3, or M4: It may have one, two, or three ASGPR binding sites having the structure of TIFF2026508972000402.tif85128.

[0384] In various embodiments, the ASGPR binding portions M1-M4 may be conjugated to any suitable [CON], [linker], or [linker-2] as described herein and Congdon, MD, et al., "Enhanced Binding and Reduced Immunogenicity of Glycoconjugates Prepared via Solid-State Photoactivation of Aliphatic Diazirine Carbohydrates," Bioconjugate Chem, doi:10.1021 / acs.bioconjchem.0c00555.

[0385] 2. Trivalent triazole-based portion In some embodiments, the ASGPR coupling portion is M5: This may be a part having the structure of TIFF2026508972000403.tif38128.

[0386] In structure M5, each R is independently R1 or R2 in each occurrence: The filename is TIFF2026508972000404.tif48128.

[0387] In various embodiments, the compound of formula I or formula II contains an ASGPR binding moiety having the structure of M5. In various embodiments, each R in M5 is R1. In various embodiments, each R in M5 is R2.

[0388] In various embodiments, the ASGPR binding moiety M5 may be conjugated / bound to any suitable [CON], [linker], or [linker-2] as described herein and Reshitko, GS, et al., "Synthesis and Evaluation of New Trivalent Ligands for Hepatocyte Targeting via the Asialoglycoprotein Receptor," Bioconjugate Chem, doi:10.1021 / acs.bioconjchem.0C00202.

[0389] 3. Behenate ester portion derived from galactose and agarose In various embodiments, the ASGPR binding moiety is derived from moiety M7 of galactose behenate ester. It could be TIFF2026508972000405.tif26128.

[0390] In structure M7, Y is either OH or NHAc.

[0391] In various embodiments, the ASGPR binding moiety is derived from moiety M8 of agarose behenate: It could be TIFF2026508972000406.tif62128.

[0392] In various embodiments, the ASGPR binding moieties M7 and M8 may be conjugated to any suitable [CON], [linker], or [linker-2] as described herein and in Dhawan, V., et al., "Polysaccharide conjugates surpass monosaccharide ligands in hepatospecific targeting - Synthesis and comparative in silico and in vitro assessment," Carbohydrate Research 509(2021)108417, doi:10.1016 / j.carres.2021.108417.

[0393] 4. Other small molecule ASGPR binding sites In various embodiments, the ASGPR binding moiety is one of the following compounds 2-18: It could be any of the files in TIFF2026508972000407.tif203151.

[0394] In various embodiments, in compounds 15 and 16, R is CH2OAc, COOH, or CH2OH. Compounds 2-18 are described herein and Majouga, A G., et al., "Identification of Novel Small-Molecule ASGP-R Ligands," Current Drug Delivery, 2016, 13, 1303-1312, doi:10.2174 / 1567201813666160719144651; Olshanova, A.S., et al. al.,"Synthesis of a new betulinic acid glycoconjugate with N-acetyl-D-galactosamine for the targeted delivery to hepatocellular carcinoma cells,"Russian Chemical Bulletin,International Edition,Vol.69,No.1,pp.158-163,January 2020;Yamansarov,E.Yu.,et al.,"New ASGPR-targeted ligands based on conjugated natural triterpenoids,"Russian Chemical Bulletin,International Compounds 2-18 may be conjugated / bonded to any suitable [CON], [Linker], or [Linker-2] as described in Edition, Vol. 68, No. 12, pp. 2331-2338, December 2019. Compounds 2-18 may be bonded through any suitable reactive group contained therein. Non-limitingly, compounds 2-13 may be bonded to [CON], [Linker], or [Linker-2] through or by reaction with at least one OH, NH, vinyl, alkynyl, amide, acid, ester, ketone, or aromatic halogen contained in compounds 2-18.Suitable reaction modes for attaching compounds 2-18 to [CON], [Linker], or [Linker-2] as described herein include, but are not limited to, substitution (e.g., alkylation of OH or NH groups), esterification (esterification), amidation (amide formation), transesterification (exchange of one ester with another), amide exchange (exchange of one amide with another), azide-alkyne cycloaddition, and other reactions that can form CC, NC, or OC bonds with vinyl and alkynyl groups, such as cycloaddition, amination, oxidation, alkylation, and rearrangement reactions (e.g., Claisen, Cope, etc.).

[0395] The compounds described herein may possess one or more stereocenters, each stereocenter independently existing in either the (R) or (S) configuration. In certain embodiments, the compounds described herein exist as optically active or racemic compounds. It should be understood that the compounds described herein encompass racemic compounds, optically active compounds, positional isomers, and stereoisomers, or combinations thereof, possessing the therapeutically useful properties described herein. Preparation of optically active compounds is achieved in any suitable manner, including, but not limited to, separation of racemic compounds by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In certain embodiments, a mixture of one or more isomers is used as a therapeutic compound described herein. In other embodiments, the compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis, and / or separation of mixtures of enantiomers and / or diastereomers. The separation of compounds and their isomers can be achieved by any means, including, but not limited to, chemical processes, enzymatic processes, fractional recrystallization, distillation, and chromatography.

[0396] The methods and formulations described herein include the use of N-oxides (where appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of any compound having the structure of any compound described herein, as well as metabolites and active metabolites of these compounds having the same type of activity. Solvates include solvates of water, ethers (e.g., tetrahydrofuran, methyl tert-butyl ether), or alcohols (e.g., ethanol), acetates, etc. In certain embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents, e.g., water and ethanol. In other embodiments, the compounds described herein exist in non-solvated forms.

[0397] In certain embodiments, the compounds described herein may exist as tautomers. All tautomers fall within the range of compounds presented herein.

[0398] In all compounds described herein, the variable position is selected such that a stable compound is produced. In various embodiments, a stable compound is a compound that is formulated or can be formulated according to at least one formulation or pharmaceutical composition described herein and is administered or can be administered to a subject by at least one route of administration described herein in order to achieve at least one therapeutic effect described herein.

[0399] In certain embodiments, the compounds described herein are prepared as prodrugs. “Prodrug” means an agent that is converted to a parent drug in vivo. In certain embodiments, by in vivo administration, the prodrug is chemically converted to a biological, pharmaceutically, or therapeutically active form of the compound. In other embodiments, the prodrug is enzymatically metabolized to a biological, pharmaceutically, or therapeutically active form of the compound by one or more steps or processes.

[0400] In certain embodiments, for example, the aromatic ring portion of the compounds described herein is sensitive to various metabolic reactions. The incorporation of appropriate substituents into the aromatic ring structure can reduce, minimize, or eliminate these metabolic pathways. In certain embodiments, appropriate substituents for reducing or eliminating the sensitivity of the aromatic ring to metabolic reactions include, but are not limited to, deuterium, halogens, or alkyl groups.

[0401] The compounds described herein include isotope-labeled compounds in which one or more atoms have the same atomic number but their atomic mass or mass number differs from those commonly found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include: 2 H, 3 H, 11 C, 13 C, 14 C, 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, and 35 While S is included, it is not limited to these. In certain embodiments, isotope-labeled compounds are useful in tissue distribution studies of drugs and / or substrates. In other embodiments, substitution with heavier isotopes, e.g., deuterium, provides greater metabolic stability (e.g., increased in vivo half-life or reduced required dose). In yet another embodiment, positron-emitting isotopes, e.g., 11 C, 18 F, 15 O, and 13 Substitution with nitrogen is useful in positron emission tomography (PET) studies to investigate the receptor occupation of substrates. Isotope-labeled compounds are prepared by any suitable method, or by a process in which a suitable isotope-labeled reagent is used instead of the unlabeled reagent used in other cases.

[0402] In certain embodiments, the compounds described herein may be labeled by means of other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0403] The compounds described herein, and other related compounds having different substituents, are described herein, for example, in Fieser & Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4. th The compounds are synthesized using the techniques and materials described in Ed., (Wiley 1992); Carey & Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green & Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosures). The general methods for preparing the compounds described herein are modified by the use of appropriate reagents and conditions to introduce the various parts found in the formulas provided herein.

[0404] The compounds described herein are synthesized using any suitable method starting from commercially available compounds, or prepared using the methods described herein.

[0405] In certain embodiments, reactive functional groups, such as hydroxyl groups, amino groups, imino groups, thio groups, or carboxyl groups, are protected to avoid unwanted involvement in the reaction. Protecting groups are used to block some or all of the reactive moiety, preventing such groups from participating in the chemical reaction until the protecting group is removed. In other embodiments, each protecting group can be removed by different means. Protecting groups that are cleaved under entirely different reaction conditions satisfy the requirement of differential removal.

[0406] In certain embodiments, protecting groups are removed by acids, bases, reductive conditions (e.g., hydrolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal, and t-butyldimethylsilyl are used to protect carboxyl and hydroxyl reactive moieties in the presence of amino groups protected with a Cbz group, which is unstable in acid and can be removed by hydrolysis, and an Fmoc group, which is unstable in basic conditions. Carboxylic acid and hydroxyl reactive moieties are blocked with basic unstable groups, such as methyl, ethyl, and acetyl, in the presence of amines that are blocked with acid-unstable groups, such as t-butylcarbamates, or carbamates that are stable in both acidic and basic conditions but can be removed by hydrolysis.

[0407] In certain embodiments, the carboxylic acid and hydroxyl-reactive moieties are blocked with a protecting group that can be removed by hydrolysis, such as a benzyl group, while the amine group that can hydrogenate with an acid is blocked with a basic and unstable group, such as Fmoc. The carboxylic acid-reactive moiety is protected by conversion to simple ester compounds as exemplified herein, including conversion to alkyl esters, or blocked with a protecting group that can be removed oxidatively, such as 2,4-dimethoxybenzyl, while the coexisting amino group is blocked with a fluoride-unstable silylcarbamate.

[0408] Allyl blocking groups are useful in the presence of acid and base protecting groups because they are stable and can be subsequently removed by metal or π-acid catalysts. For example, allyl-blocked carboxylic acids are deprotected by palladium-catalyzed reactions in the presence of acidically unstable t-butylcarbamate or basicly unstable acetateamine protecting groups. Yet another type of protecting group is a resin to which a compound or intermediate is bound. As long as the residue is bound to the resin, its functional group is blocked and does not react. Once released from the resin, the functional group becomes available for reaction.

[0409] Typically, blocking / protecting groups are Selected from TIFF2026508972000408.tif76128.

[0410] Further descriptions of other protecting groups, as well as techniques applicable to the fabrication and removal of protecting groups, are provided in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thiem VerLAg, New York, NY, 1994, which are incorporated herein by reference for such disclosures.

[0411] composition Compositions containing the compounds described herein include pharmaceutical compositions comprising at least one compound described herein and at least one pharmaceutically acceptable carrier. In certain embodiments, compositions are formulated for oral or parenteral administration, for example, percutaneous, transmucosal (e.g., sublingual, tongue, (trans) buccal, (trans) urethral, ​​vagina (e.g., transvaginal and perival), nasal (intra) and (trans) rectal, intrabladder, intrapulmonary, intraduodenal, intragastric, subarachnoid, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration. 。

[0412] Methods of treatment, prevention, and / or remission This disclosure includes methods for preventing, treating, and / or relieving arthritis using compounds contemplated herein. Non-limiting examples of arthritis include rheumatoid arthritis, lupus erythematosus, psoriatic arthritis, ankylosing spondylitis, and axial spondyloarthritis. The methods may be used to treat, relieve, and / or prevent other types of arthritis or inflammatory diseases that are or are caused by autoimmune responses / disorders. The methods include the step of administering a compound contemplated herein to a subject in need thereof, wherein the compound may be administered as a pharmaceutical composition further comprising optionally at least one pharmaceutically acceptable excipient or carrier. In various embodiments, arthritis is rheumatoid arthritis.

[0413] In various embodiments, the compound / composition is administered by a route selected from the group consisting of oral, transdermal, transmucosal, nasal (intra)catheter, rectal, intrabladder, intrapulmonary, intraduodenal, intragastric, subarachnoid, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical.

[0414] In various aspects, the subject is a mammal. In various aspects, the subject is a human.

[0415] The methods described herein optionally include the step of administering to a subject a therapeutically effective amount of at least one compound described herein, which may be formulated as a pharmaceutical composition. In various embodiments, the therapeutically effective amount of at least one compound described herein present in the pharmaceutical composition is the only therapeutically active compound in the pharmaceutical composition. In certain embodiments, the method further includes the step of administering to a subject an additional therapeutic agent for treating arthritis or other autoimmune disorders.

[0416] In certain embodiments, administering the compounds described herein to a subject allows for the administration of a lower dose of the additional therapeutic agent compared to the dose of the additional therapeutic agent alone required to achieve similar results in the treatment of arthritis in the subject. For example, in certain embodiments, the compounds described herein enhance the activity of the additional therapeutic agent, thereby allowing for a lower dose of the additional therapeutic agent to provide the same effect.

[0417] In certain embodiments, the compounds and therapeutic agents described herein are administered simultaneously to a subject. In other embodiments, the compounds and therapeutic agents described herein are combined into a single agent and administered simultaneously to a subject.

[0418] In one particular aspect, the subject is a mammal. In another aspect, the mammal is a human.

[0419] Combination therapy Compounds useful in the methods described herein may be used in combination with one or more additional therapeutic agents useful for treating, relieving, and / or preventing arthritis or other autoimmune disorders. These additional therapeutic agents may include commercially available compounds or compounds that are available by synthesis to those skilled in the art. These additional therapeutic agents are known to treat, prevent, and / or alleviate the symptoms of arthritis.

[0420] In various embodiments, synergistic effects are observed when the compounds described herein are administered together with one or more additional therapeutic agents or compounds. These synergistic effects are observed, for example, by appropriate means, e.g., sigmoid E maxThe effects can be calculated using the following equations: the equation (Holford & Scheiner, 1981, Clin. Pharmacokinet. 6:429-453), the Loewe additivity equation (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114:313-326), and the median-effect equation (Chou & TaLALAy, 1984, Adv. Enzyme Regul. 22:27-55). Each of the above equations can be applied to experimental data to generate corresponding graphs to aid in evaluating the effects of drug combinations. The corresponding graphs associated with the above equations are the concentration-effect curve, the isobologram curve, and the combination exponential curve, respectively.

[0421] In various embodiments, the method includes the step of administering one or more additional therapeutic agents useful for treating, relieving, and / or preventing arthritis or other autoimmune disorders, such as disease-modifying antirheumatic drugs (DMARDs), glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), and analgesics. The additional therapeutic agents may be administered in any of the doses and routes of administration described herein. In various embodiments, the additional therapeutic agents may be administered sequentially or concurrently with the compounds. Sequential administration may, in various embodiments, be 1 minute to 12 hours before or after the administration of the compound of formula I, formula Ia, formula II, or formula IIb, or any other compound described herein that conjugates to an anti-CCP antibody.

[0422] Non-exclusive examples of disease-modifying antirheumatic drugs include hydroxychloroquine sulfate, leflunomide, methotrexate, tofacitinib, baricitinib, sulfasalazine, upadacitinib, abatacept, adalimumab, adalimumab-atto, anakinra, etanercept, etanercept-szzs, infliximab, infliximab-dyyb, infliximab-abda, infliximab-dyyb, rituximab, rituximab-abbs, golimumab, certolizumab pegol, tocilizumab, and sarilumab.

[0423] Non-specific examples of glucocorticoids include betamethasone, prednisone, and methylprednisolone.

[0424] Non-steroidal anti-inflammatory drugs (NSAIDs) include non-specific examples such as celecoxib, diclofenac sodium, and ibuprofen.

[0425] Non-specific examples of analgesics include acetaminophen, tramadol, oxycodone, and hydrocodone.

[0426] Dosage / Prescription The administration plan may influence what constitutes the effective dose. The therapeutic formulation may be administered to the subject before or after the onset of arthritis. Furthermore, several divided doses and staggered doses may be administered daily or continuously, or the dose may be administered by continuous infusion or bolus injection. In addition, the dose of the therapeutic formulation may be increased or decreased proportionally as indicated by the urgency of the therapeutic or prophylactic situation.

[0427] The compositions described herein may be administered to patients, preferably mammals, more preferably humans, using known methods, in doses and durations effective for treating arthritis in patients. The effective amount of the therapeutic compound required to achieve a therapeutic effect may vary depending on factors such as the patient's state of disease or disability; the patient's age, sex, and weight; and the therapeutic compound's ability to treat arthritis in patients. The administration plan may be adjusted to provide an optimal therapeutic response. For example, several divided doses may be administered daily, or the dose may be reduced proportionally as indicated by the urgency of the treatment situation. A non-limiting example of the effective dose range of the therapeutic compounds described herein is approximately 1 to 5,000 mg / kg body weight per day. Those skilled in the art can study the relevant factors and make determinations regarding the effective amount of the therapeutic compound without excessive experimental methods.

[0428] The actual dose levels of the active ingredients in the pharmaceutical compositions described herein may be varied to obtain an amount of the active ingredient that is effective in achieving a desired therapeutic response for a particular patient, composition, and mode of administration, without toxicity to the patient.

[0429] Specifically, the selected dosage level depends on a variety of factors, including well-known medical factors such as the activity of the specific compound used, the time of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds, or materials used in combination with the compound, and the age, sex, weight, condition, overall health status, and medical history of the patient receiving treatment.

[0430] A physician with ordinary skill in the art, such as an internist or veterinarian, can easily determine and prescribe the effective amount of the required pharmaceutical composition. For example, an internist or veterinarian can start the dose of the compound described herein used in the pharmaceutical composition at a level lower than the level required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

[0431] In specific embodiments, it is particularly advantageous to formulate compounds as dosage units for ease of administration and uniformity of dosage. A dosage unit, as used herein, refers to a physically discontinuous unit suitable as a unit dose for a patient receiving treatment, each unit containing a predetermined amount of the therapeutic compound calculated to produce the desired therapeutic effect, along with the required pharmaceutical medium. The dosage unit forms of compounds described herein are designated and directly depend on (a) the unique characteristics of the therapeutic compound and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the art of formulation / manufacturing such therapeutic compounds.

[0432] In certain embodiments, the compositions described herein are formulated using one or more pharmaceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of the compound described herein and a pharmaceutically acceptable carrier.

[0433] The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Appropriate fluidity can be maintained, for example, by the use of coatings such as lecithin, maintaining the required particle size in the case of dispersion, and the use of surfactants. Prevention of microbial action can be achieved by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferable to include isotonic agents, such as sugars, sodium chloride, or polyhydric alcohols, such as mannitol and sorbitol, in the composition. Long-term absorption of the injectable composition can be achieved by including absorption-delaying agents, such as aluminum monostearate or gelatin, in the composition.

[0434] In certain embodiments, the compositions described herein are administered to a patient in doses ranging from one to five times a day or more. In other embodiments, the compositions described herein are administered to a patient in doses including, but not limited to, once a day, every two days, every three days to once a week, and once every two weeks. It will be readily apparent to those skilled in the art that the frequency of administration of the various combination compositions described herein will vary from individual to individual due to many factors, including, but not limited to, age, disease or disorder to be treated, sex, overall health, and other factors. Therefore, the administration of the compounds and compositions described herein should not be construed as being limited to a specific dosing plan, and the exact dosage and composition to be administered to any patient will be determined by the attending physician, taking into account all other factors concerning that patient.

[0435] The compounds described herein for administration are approximately 1 μg to 10,000 mg, approximately 20 μg to 9,500 mg, approximately 40 μg to 9,000 mg, approximately 75 μg to 8,500 mg, approximately 150 μg to 7,500 mg, approximately 200 μg to 7,000 mg, approximately 350 μg to 6,000 mg, approximately 500 μg to 5,000 mg, approximately 750 μg to 4,000 mg, and approximately 1 mg to 5,000 mg. This can range from 3,000 mg, approximately 10 mg to approximately 2,500 mg, approximately 20 mg to approximately 2,000 mg, approximately 25 mg to approximately 1,500 mg, approximately 30 mg to approximately 1,000 mg, approximately 40 mg to approximately 900 mg, approximately 50 mg to approximately 800 mg, approximately 60 mg to approximately 750 mg, approximately 70 mg to approximately 600 mg, approximately 80 mg to approximately 500 mg, and any full or partial increase in between. In various embodiments, the compound of formula I is administered in doses of 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg / kg.

[0436] In some embodiments, the dose of the compound described herein is about 1 mg to about 2,500 mg. In some embodiments, the dose of the compound described herein used in the composition described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, the dose of the second compound described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any all full or partial increases thereof.

[0437] In a particular embodiment, the composition described herein is a packaged pharmaceutical composition comprising a container for holding a therapeutically effective amount of the compound described herein, either alone or in combination with a second agent, and instructions for the use of the compound to treat, prevent, or alleviate one or more symptoms of arthritis in a patient.

[0438] The formulations may be used in combination with conventional excipients known in the art, i.e., pharmaceutically acceptable organic or inorganic carriers, suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration. The pharmaceutical preparations may be sterilized and, if desired, mixed with adjuvants, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts to affect osmotic pressure, buffers, colorants, flavoring agents, and / or aromatics. They may also be combined, if desired, with other active substances, such as other analgesics.

[0439] The routes of administration for any of the compositions described herein include oral, nasal, rectal, vaginal, parenteral, buccal, sublingual, or topical. Compounds for use in the compositions described herein may be formulated for administration by any suitable route, e.g., oral or parenteral, e.g., percutaneous, transmucosal (e.g., sublingual, tongue, (trans) buccal, (trans) urethral, ​​vagina (e.g., transvaginal and transperipheral), nasal (intra) and (trans) rectal), intravesical, intrapulmonary, intraduodenal, intragastric, subarachnoid, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration. In various embodiments, compounds of formula I are administered by intravenous administration.

[0440] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel capsules, lozenges, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magma, lozenges, creams, pastes, ointments, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powders or aerosolized formulations for inhalation, compositions and formulations for intravesical administration, etc. It should be understood that the formulations and compositions described herein are not limited to the specific formulations and compositions described herein.

[0441] Oral administration Tablets, sugar-coated tablets, liquids, drops, suppositories, or capsules, caplets, and gel capsules are particularly suitable for oral administration. Compositions for oral use may be prepared according to any method known in the art, and such compositions may contain one or more active substances selected from the group consisting of inert, non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. Such excipients include, for example, inert diluents, e.g., lactose; granulators and disintegrants, e.g., corn starch; binders, e.g., starch; and lubricants, e.g., magnesium stearate. Tablets may be uncoated or coated by known techniques for improved appearance or to delay the release of the active ingredient. Formulations for oral use may be presented as hard gelatin capsules in which the active ingredient is mixed with an inert diluent.

[0442] For oral administration, the compounds described herein may be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients, such as binders (e.g., polyvinylpyrrolidone, hydroxypropylcellulose, or hydroxypropylmethylcellulose); bulking agents (e.g., corn starch, lactose, crystalline cellulose, or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). Optionally, tablets may be coated using appropriate methods and coating materials, such as the OPADRY® film coating system available from Colorcon (West Point, Pa.) (e.g., OPADRY® OY type, OYC type, organic enteric OY-P type, aqueous enteric OY-A type, OY-PM type, and OPADRY® White, 32K18400). Liquid preparations for oral administration may be in the form of solutions, syrups, or suspensions. Liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives, such as suspending agents (e.g., sorbitol syrup, methylcellulose, or hydrogenated edible fat); emulsifiers (e.g., lecithin or gum arabic); non-aqueous media (e.g., almond oil, oily ester, or ethyl alcohol); and preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, or sorbic acid).

[0443] The compositions described herein may be prepared, packaged, or sold as formulations suitable for oral or buccal administration. Tablets containing the compounds described herein may be prepared, for example, by compressing or molding the active ingredient together with one or more additional ingredients, optionally. Compressed tablets may be prepared by compressing a highly fluid form of the active ingredient, such as a powder or granular preparation, which may optionally be mixed with one or more of the following: binders, lubricants, excipients, surfactants, and dispersants, in a suitable device. Molded tablets may be prepared by molding a mixture of the active ingredient, a pharmaceutically acceptable carrier, and at least enough liquid to moisten the mixture, in a suitable device. Pharmaceutically acceptable excipients used in the manufacture of tablets include, but are not limited to, inert diluents, granulators and disintegrants, dispersants, surfactants, disintegrants, binders, and lubricants.

[0444] Suitable dispersants include, but are not limited to, potato starch, sodium starch glycolate, poloxamer 407, or poloxamer 188. One or more dispersants may be present in the composition individually in an amount of about 0.01% w / w to about 90% w / w relative to the weight of the dosage form. One or more dispersants, individually, in amounts of at least about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w of the weight of the dosage form, or about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20% It may be present in the composition in amounts greater than %, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or in amounts less than approximately 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%.

[0445] Surfactants include cationic, anionic, or nonionic surfactants, or combinations thereof. Suitable surfactants include behentrimonium chloride, benzalkonium chloride, benzethonium chloride, benzododecinium bromide, carbebendecinium bromide, cetalkonium chloride, cetrimonium bromide, cetylpyridine chloride, didecyldimethylammonium chloride, dimethyldioctadecylammonium bromide, dimethyldioctadecylammonium chloride, domifen bromide, and laurylmethylgluceth-10 hydroxypropyldimonium chloride. Lido, tetramethylammonium hydroxide, tonzonium bromide, stearalkonium chloride, octenidine dihydrochloride, olaflur, N-oleyl-1,3-propanediamine, 2-acrylamido-2-methylpropanesulfonic acid, alkylbenzene sulfonate, ammonium lauryl sulfate, ammonium perfluorononanoate, doxate, disodium cocoamphodiaacetate, magnesium laureth sulfate, perfluorobutanesulfonic acid, perfluorononanoic acid, perfluorooctanesulfonic acid, perfluorooctanoic acid, potassium lauryl sulfate, sodium alkyl sulfate, sodium dodecyl sulfate, sodium laurate, sodium laureth sulfate, sodium lauroyl sarcosinate, sodium myreth sulfate, sodium nonanoyloxybenzenesulfonate, sodium pareth sulfate, sodium stearate, sodium sulfosuccinate, cetomacrogol 1000, cetostearyl alcohol, cetyl alcohol, cocamide diethanolamine, cocamide monoethanolamine, decyl Luglucoside, decyl polyglucose, glycerol monostearate, octylphenoxypolyethoxyethanol CA-630, isoceteth-20, lauryl glucoside, octylphenoxypolyethoxyethanol P-40, nonoxynol-9, nonoxynol, nonylphenoxypolyethoxyethanol (NP-40), octaethylene glycol monododecyl ether, N-octyl β-D-thioglucopyranoside, octyl glucoside, oleyl alcohol, PEG-10 sunflower glyceride,This list includes, but is not limited to, pentaethylene glycol monododecyl ether, polidocanol, poloxamer, poloxamer 407, polyethoxylated beef tallow amine, polyglycerol polyricinoleate, polysorbate, polysorbate 20, polysorbate 80, sorbitan, sorbitan monolaurate, sorbitan monostearate, sorbitan tristearate, stearyl alcohol, surfactin, Triton X-100, and Tween 80. One or more surfactants may be present in the composition individually in amounts ranging from about 0.01% w / w to about 90% w / w relative to the weight of the dosage form. One or more surfactants, individually, in amounts of at least about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w of the weight of the dosage form, or about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, It may be present in the composition in amounts greater than 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or in amounts less than approximately 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%.

[0446] Suitable diluents include, but are not limited to, calcium carbonate, magnesium carbonate, magnesium oxide, sodium carbonate, lactose, crystalline cellulose, calcium phosphate, calcium hydrogen phosphate, and sodium phosphate, Cellactose® 80 (75% α-lactose monohydrate and 25% cellulose powder), mannitol, pregelatinized starch, starch, sucrose, sodium chloride, talc, anhydrous lactose, and granulated lactose. One or more diluents may be present in the composition individually in an amount of about 0.01% w / w to about 90% w / w relative to the weight of the dosage form. One or more diluents, each individually, may be present in amounts of at least about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w relative to the weight of the dosage form, or about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%. It may be present in the composition in amounts greater than %, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or in amounts less than approximately 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%.

[0447] Suitable granulators and disintegrants include, but are not limited to, sucrose, copovidone, corn starch, crystalline cellulose, methylcellulose, sodium starch glycolate, pregelatinized starch, povidone, sodium carboxymethylcellulose, sodium alginate, citric acid, sodium croscarmellose, cellulose, calcium carboxymethylcellulose, colloidal silicon dioxide, crospovidone, and alginic acid. One or more granulators or disintegrants may be present in the composition individually in amounts ranging from about 0.01% w / w to about 90% w / w relative to the weight of the dosage form. One or more granulating agents or disintegrants, individually, may be present in amounts of at least about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w of the weight of the dosage form, or about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, or 15%. It may be present in the composition in amounts greater than 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or in amounts less than approximately 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%.

[0448] Suitable binders include, but are not limited to, gelatin, gum arabic, pregelatinized corn starch, polyvinylpyrrolidone, anhydrous lactose, lactose monohydrate, hydroxypropyl methylcellulose, methylcellulose, povidone, polyacrylamide, sucrose, dextrose, maltose, gelatin, and polyethylene glycol. One or more binders may be present in the composition individually in amounts ranging from about 0.01% w / w to about 90% w / w relative to the weight of the dosage form. One or more binders, individually, in amounts of at least about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w of the weight of the dosage form, or about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20% It may be present in the composition in amounts greater than %, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or in amounts less than approximately 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%.

[0449] Suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, hydrogenated castor oil, glyceryl monostearate, glyceryl behenate, mineral oil, polyethylene glycol, poloxamer 407, poloxamer 188, sodium laureth sulfate, sodium benzoate, stearic acid, sodium stearyl fumarate, silica, and talc. One or more lubricants may be present in the composition individually in amounts ranging from about 0.01% w / w to about 90% w / w relative to the weight of the dosage form. One or more lubricants, individually, in amounts of at least about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% w / w of the weight of the dosage form, or about 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20% It may be present in the composition in amounts greater than %, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%, or in amounts less than approximately 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%.

[0450] The tablets may be uncoated or coated using known methods to achieve delayed disintegration in the target gastrointestinal tract, thereby providing sustained release and absorption of the active ingredient. For example, materials such as glyceryl monostearate or glyceryl distearate may be used to coat the tablets. Furthermore, for example, the tablets may be coated using the methods described in U.S. Patents 4,256,108; 4,160,452; and 4,265,874 to form osmotic release controlled tablets. The tablets may further contain sweeteners, flavorings, colorings, preservatives, or combinations thereof to provide a pharmaceutically appealing and palatable preparation.

[0451] The tablets may be enterically coated so that the coating dissolves at a specific pH, for example, about pH 5.0 to about pH 7.5, thereby beginning to release the compounds described herein. The coating may contain, for example, EUDRAGIT® L, S, FS, and / or E polymers having acidic or alkaline groups to enable the release of the compounds described herein at a specific location, for example, in any desired area of ​​the intestine. The coating may also contain, for example, EUDRAGIT® RL and / or RS polymers having cationic or neutral groups to enable control of the release time of the compounds described herein by pH-independent swelling.

[0452] Parenteral administration For parenteral administration, the compounds described herein may be formulated for injection or infusion, e.g., intravenous, intramuscular, or subcutaneous injection or infusion, or for administration in bolus doses and / or for continuous infusion. Suspensions, solutions, or emulsions in oily or aqueous media may be used, which may optionally contain other formulation agents, e.g., suspending agents, stabilizers, and / or dispersants.

[0453] The sterile injectable forms of the compositions described herein may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using appropriate dispersants or wetting and suspending agents. The sterile injectable preparations may also be sterile injectable solutions or suspensions with non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable media and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solutions. Sterile non-volatile oils have conventionally been used as solvents or suspension media. For this purpose, any non-irritating non-volatile oil, such as synthetic monoglycerides or diglycerides, may be used. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are naturally pharmaceutically acceptable oils, such as olive oil or castor oil, and especially their polyoxyethylated versions. These oily solutions or suspensions may contain a diluent or dispersant for long-chain alcohols, such as lauryl alcohol, stearyl alcohol, or oleyl alcohol, or a similar alcohol.

[0454] Additional dosage forms Appropriate additional dosage forms for use with the compounds and compositions described herein include those described in U.S. Patent Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Appropriate additional dosage forms for use with the compounds and compositions described herein also include those described in U.S. Patent Applications Nos. 20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Appropriate additional dosage forms for use with the compounds and compositions described herein also include those described in PCT applications WO 03 / 35041;WO 03 / 35040;WO 03 / 35029;WO 03 / 35177;WO 03 / 35039;WO 02 / 96404;WO 02 / 32416;WO 01 / 97783;WO 01 / 56544;WO 01 / 32217;WO 98 / 55107;WO 98 / 11879;WO 97 / 47285;WO 93 / 18755; and WO 90 / 11757.

[0455] Controlled-release formulations and drug delivery systems In certain embodiments, the formulations described herein may be short-acting, rapid-offset, and controlled-release formulations, such as sustained-release, delayed-release, and pulsed-release formulations, but are not limited to these.

[0456] The term "sustained-release" is used in its original sense to refer to a drug formulation that provides a gradual release of the drug over a long period, which may, but may not necessarily, result in a substantially constant blood level of the drug over that period. This period can be about one month or longer, and should be longer than the release of the same amount of drug administered in bolus form.

[0457] For sustained release, the compound may be formulated with a suitable polymer or hydrophobic material that provides the compound with sustained-release properties. Therefore, the compound for use in the methods described herein may be administered in the form of microparticles, for example, by injection, or in the form of wafers or disks, by implantation.

[0458] In some cases, the dosage form used may provide a desired release profile at a variable rate, for example, by using hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres, or combinations thereof, as a sustained release or controlled release of one or more active ingredients therein. Suitable controlled-release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the pharmaceutical compositions described herein. Accordingly, single-unit dosage forms suitable for oral administration and adapted for controlled release, such as tablets, capsules, gel capsules, and caplets, are included in the compositions and dosage forms described herein.

[0459] Most controlled-release pharmaceutical products share the common goal of improving drug therapy beyond what is achieved by their uncontrolled counterparts. Ideally, the use of optimally designed controlled-release preparations in medical treatment is characterized by the use of minimal active pharmaceutical ingredients to cure or control a condition in the shortest possible time. Advantages of controlled-release formulations include prolonged drug activity, reduced administration frequency, and improved patient compliance. Furthermore, controlled-release formulations can be used to influence the time of onset of action or other characteristics, such as the blood level of the drug, and thus the occurrence of side effects.

[0460] Most controlled-release formulations are designed to release an initial amount of the drug to rapidly produce the desired therapeutic effect, and then gradually and continuously release other amounts of the drug to maintain this level of therapeutic effect over a longer period. To maintain this constant drug level in the body, the drug must be released from the formulation at a rate that replaces the amount of drug that is metabolized and excreted from the body.

[0461] The control of the release of the active ingredient can be stimulated by various inducers, such as pH, temperature, enzymes, water, or other physiological conditions or compounds. The term "controlling-release component" is defined herein as a compound, including but not limited to polymers, polymer matrices, gels, permeable membranes, liposomes, or microspheres, or combinations thereof, that facilitate the control of the release of the active ingredient. In some embodiments, the compounds described herein are administered to a patient, either alone or in combination with other agents, using sustained-release formulations.

[0462] The term "delayed release" is used herein in its conventional sense to refer to a drug formulation that provides an initial release of the drug after some delay following administration, which may include, but is not necessarily, a delay of about 10 minutes to about 12 hours.

[0463] The term "pulsed release" is used herein in its conventional sense to refer to a drug formulation that provides a drug release such that a pulsed plasma profile of the drug occurs after drug administration.

[0464] The term "immediate release" is used in its traditional sense to refer to a drug formulation that provides drug release immediately after administration.

[0465] As used herein, short-term means any period of time including, up to about 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 1 hour, 40 minutes, 20 minutes, or 10 minutes after drug administration, and any or all of its full or partial increments.

[0466] As used herein, rapid offset means any period of time including, up to about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes after drug administration, and any full or partial increment thereof.

[0467] Administration The therapeutically effective amount or dose of the compounds described herein depends on the patient's age, sex, and weight, the patient's current medical condition, and the progression of arthritis in the patient receiving treatment. Those skilled in the art can determine the appropriate dosage based on these and other factors.

[0468] Appropriate doses of the compounds described herein may range from approximately 0.01 mg to approximately 5,000 mg per day, for example, from approximately 0.1 mg to approximately 1,000 mg per day, for example, from approximately 1 mg to approximately 500 mg, for example, from approximately 5 mg to approximately 250 mg. The dose may be administered as a single dose or as multiple doses, for example, 1 to 4 times or more per day. When multiple doses are used, the amount of each dose may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses with a dose interval of approximately 12 hours.

[0469] It is understood that the daily dose of the compound may be administered daily, every other day, every two days, every three days, every four days, or every five days, as an example of non-limiting administration. For example, in every-other-day administration, a dose of 5 mg per day is started on Monday, followed by the first dose of 5 mg per day on Wednesday, followed by the second dose of 5 mg per day on Friday, and so on.

[0470] If the patient's condition improves, the administration of the compounds described herein may, at the discretion of the physician, be optionally continued; alternatively, the dose of the drug being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug-free period”). The length of the drug-free period may, at will, vary from 2 days to 1 year, and may, for example, be 2, 3, 4, 5, 6, 7, 10, 12, 15, 20, 28, 35, 50, 70, 100, 120, 150, 180, 200, 250, 280, 300, 320, 350, or 365 days. Dose reductions during drug-free periods range from 10% to 100%, and include, for example, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0471] If the patient's condition improves, a maintenance dose is administered as needed. Subsequently, the dose, frequency, or both are reduced to a level that maintains the improved disease. In certain embodiments, the patient requires long-term, intermittent treatment in the event of relapses of symptoms and / or infection.

[0472] The compounds described herein may be formulated in unit dosage forms. The term "unit dosage form" refers to a physically discontinuous unit appropriate as a unit dose for a patient receiving treatment, each unit containing, optionally, a predetermined amount of the active material calculated to produce the desired therapeutic effect, along with an appropriate pharmaceutical carrier. A unit dosage form may be for once-daily administration or for one dose of multiple daily administrations (e.g., approximately 1 to 4 times or more per day). If multiple daily doses are used, the unit dosage form may be the same or different for each dose.

[0473] The toxicity and therapeutic efficacy of such treatment plans may be optionally determined in cell cultures or experimental animals, and the LD (Low-Dose) 50(Lethal dose in 50% of the population) and ED 50 This includes, but is not limited to, determining the therapeutically effective dose (LD) for 50% of the population. The dose-to-toxicity ratio is the therapeutic index, and the LD is the dose-to-toxicity ratio. 50 and ED 50 It is expressed as a ratio to [amount]. Data obtained from cell culture assays and animal studies may optionally be used in determining the range of doses for use in humans. The dose of such compounds is preferably ED with minimal toxicity. 50 The circulating concentration is within the range of [the specified concentration]. The dosage may vary within this range depending on the dosage form used and the route of administration utilized. [Examples]

[0474] Various aspects of this application can be better understood by referring to the following exemplary examples. The scope of this application is not limited to the examples given herein.

[0475] material and method Abbreviations used DCM = Dichloromethane; EA = Ethyl acetate; DCE = 1,2-Dichloroethane; PE = Petroleum ether; TFA = Trifluoroacetic acid; HOBt = 1-Hydroxybenzotriazole; DCC = N,N'-Dicyclohexylcarbodiimide; EDCI = 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide; DIPEA / DIEA = N,N-Diisopropylethylamine; HOAt = 1-Hydroxy-7-Azabenzotriazole; Fmoc = Fluorenylmethoxycarbonyl; DIC = N,N'-Diisopropylcarbodiimide; HATU = Hexafluorophosphate azabenzotriazole tetramethyluronium.

[0476] Spectroscopic and coupling assays Referring to Figure 5A, the binding of CCP1-GN4 was evaluated using surface plasmon resonance (SPR) in a Biacore S200 instrument. Prior to the binding study, 20 μg / mL mouse anti-citrullinated epitope recombinant antibody clone 12G1 (anti-CCP1) (Creative Biolabs) was immobilized on a Series S sensor chip CM5 using amine coupling with a target of 1,000 response units (RUs) in 10 mM sodium acetate buffer pH 5.5. In parallel, a normal human IgG isotype control (R&D Systems) was immobilized under the same conditions as a reference minus control. The sensor chip and reagents required for amine coupling were purchased from Cytiva.

[0477] CCP1-GN4 was serially diluted with 100% DMSO and transferred to a 96-well microplate. The samples were diluted to the final test concentrations (1000 nM, 250 nM, 62.5 nM, 15.6 nM, 3.9 nM, 1 nM) in 1% DMSO by adding 1× HBS-P buffer (Cytiva). A solution of 1× HBS-P (Cytiva) containing 1% DMSO was prepared as a running buffer immediately before the binding experiment.

[0478] The sample was injected onto the sensor tip at 25°C with a contact time of 300 seconds, a dissociation time of 600 seconds, and a flow rate of 30 μL / min. Between injections, any remaining bound analytes were washed from the sensor tip surface using a solution containing 50% DMSO in 1×HBS-P buffer.

[0479] The reactions of CCP1-GN4 at various test concentrations were fitted using a steady-state affinity model in Biacore Insight Evaluation software (Cytiva) to obtain measured dissociation constants (KD).

[0480] Referring to Figure 5B, binding to ASGPR1 was characterized by surface plasmon resonance (SPR) in a Biacore 8K instrument. Prior to binding measurement, recombinant biotin-ASGPR1 (Viva Biotech) was diluted to a concentration of 2 μg / mL in a buffer containing 20 mM Tris pH 8.0, 200 mM NaCl, 1 mM TCEP, 2 mM CaCl2, and 0.01% Tween 20. After conditioning the sensor tip SA (Cytiva) by three injections of 1 M NaCl in 50 mM NaOH, 2 μg / mL of ASGPR was captured on the sensor tip surface. Capture was performed at a target level of 1000 RU and a flow rate of 5 μL / min. CCP1-GN4 was serially diluted to 10 final test concentrations (25 nM, 8.3 nM, 2.8 nM, 0.93 nM, 0.3 nM, 0.1 nM, 0.03 nM, 0.01 nM, 0.004 nM, 0.0013 nM) in a buffer solution consisting of a final solvent composition of 20 mM Tris pH 8.0, 200 mM NaCl, 1 mM TCEP, 2 mM CaCl2, 0.01% Tween 20, and 3% DMSO.

[0481] The sample was injected onto the sensor chip surface with an addition time of 180 seconds, a dissociation time of 600 seconds, a flow rate of 40 μL / min, and a temperature of 25°C. Using Biacore Insight Evaluation software, the data files were fitted to multi-cycle dynamics and steady-state models to determine dynamics and affinity coupling parameters.

[0482] Referring to Figures 6A and 6B, the plasma stability (PBS) of CCP1-GN4 was measured at WuXi Biologics. The compound was incubated in human, rat, or mouse plasma at 37°C for 2 hours. Aliquots were taken at various time points, and the residual percentage of CCP1-GN4 was quantified by LC-MS. For plasma protein binding (PPB), the compound (CCP1-GN4) was incubated with human, rat, or mouse plasma proteins, and the degree of plasma protein binding was determined by ultracentrifugation and LC-MS.

[0483] Referring to Figure 7, HEK-293-ASGPR cells were collected by acutase, filtered through a 40 μm cell strainer, and confirmed viability. Cells were seeded in complete medium containing 2 μg / mL poly-D-lysine at 30 k / 100 μL per well. Anti-CCP1 antibody (12G1) and goat anti-mouse antibody (Jackson 115-546-071) AF488 were pre-incubated at 37°C for 30 minutes (final concentrations of 100 nM and 34 nM, respectively). The cell medium was removed, and then a mixture of BH5553 and CCP1 antibody (12G1) and goat anti-mouse antibody AF488 was added to the cells (total volume of 100 μL per well). The cells were then incubated at 37°C for 20 hours. Cell fluorescence was quantified over time using Incucyte.

[0484] Referring to Figures 8A and 8B, CD-1 mice (n=3 in each group) were administered anti-CCP1 antibody (2 mpk, IV) at time point -1h. Blood samples were collected at time points 0, 0.08, 0.25, 0.5, 2, 4, and 8h. Following the initial blood collection, CCP1-GN4 (1.21 and 0.24 mpk) and peptide control BH5638 (1.21 mpk eq) were administered at time point 0h. Anti-CCP1 concentrations at various time points were determined by MSD assay. CCP1-Gn4 PK was determined by LC-MS at Touchstone Biosciences.

[0485] Synthesis method General chemical methods Flash chromatography was performed on a CombiFlash NEXTGEN 300+ system using Teledyne ISCO running software version 5.0.62. Separation was achieved using RediSep Rf high-performance gold C18 columns (reverse phase) and RediSep Rf flash columns (normal phase). HPLC purification of the compounds was performed using a Shimadzu chromatography system with Waters SunFire C18 OBD Prep columns (10 mm × 150 mm) and LabSolutions software version 5.92. NMR analysis was performed using Agilent DD2 400 MHz and Agilent DD2 600 MHz NMR spectrometers. The 600 MHz instrument was equipped with a C[H] cryogenic probe. HRMS analysis was performed on a Shimadzu 9030 quadrupole time-of-flight LC-MS system after separation using a Shim-pack Scepter C18-120 1.9 μm (2.1 × 50 mm) reversed-phase chromatography column. Separation was performed using a gradient of water with 0.1% formic acid added to acetonitrile. Infrared (IR) spectra were collected using neat samples and recorded using a Thermo Nicolet 6700 equipped with a diamond ATR cell. Selected νma was cm -1 The data is reported as follows. Optical rotation was recorded with a Rudolph Autopol IV polarimeter. Chemicals were purchased from Sigma Aldrich, Fisher, and Carbosynth. Solvents were purchased from Fisher and Macron.

[0486] Example of synthesis Compound 1(48) 2-(2-(2-hydroxyethoxy)ethoxy)ethyl 4-methylbenzene sulfonate Triethylene glycol (17.5 mL, 19.7 g, 131 mmol, 5 equivalents) was dissolved in dichloromethane (150 mL) and triethylamine (5.48 mL, 3.98 g, 1.5 equivalents) and cooled to 0°C. Then, p-toluenesulfonyl chloride (5.00 g, 26.2 mmol, 1.00 equivalent) was added, and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then diluted in dichloromethane and washed with water (3 times) and brine (1 time). The organic layer was dried over sodium sulfate and concentrated under vacuum to obtain compound 1 (6.89 g, 22.6 mmol) as a pale yellow oily substance in 85% yield, which was used without further purification. The spectrum was consistent with previously reported characterization data.

[0487] Compound 2(48) 2-(2-(2-azidoethoxy)ethoxy)ethane-1-ol Tosylate 1 (2.00 g, 6.57 mmol) and sodium azide (0.470 g, 7.23 mmol, 1.1 equivalents) were dissolved in dimethylformamide (40 mL) and stirred overnight at 60°C. The volume was reduced by approximately half by rotary evaporation at 70°C, the resulting mixture was diluted with water, and extracted with ethyl acetate (twice). The combined organic layer was washed with brine (three times), dried over sodium sulfate, and evaporated to obtain azide 2 as a colorless oily substance (932 mg, 5.32 mmol) in 81% yield, which was used without further purification.

[0488] Compound 3(49) TIFF2026508972000411.tif20128(5R,6R,7R,7aR)-5-(acetoxymethyl)-2-methyl-3a,6,7,7a-tetrahydro-5H-pyrano[3,2-d]oxazole-6,7-diyldiaacetate D-galactosamine pentaacetate (100 mg, 0.257 mmol) was dissolved in dichloroethane (1.0 mL), stirred at room temperature under a nitrogen atmosphere, and then trimethylsilyltrifluoromethanesulfonate (70.0 μL, 86.0 mg, 0.387 mmol, 1.50 equivalents) was added. The reaction mixture was stirred at 50°C for 90 minutes, then cooled to room temperature and stirred for a further 12 hours. The reaction mixture was then injected into ice-cold saturated sodium bicarbonate aqueous solution and extracted with dichloromethane. The organic layer was washed with water (twice), then dried over sodium sulfate and evaporated to obtain compound 3 (236 mg, 77.7 mmol, 92%) as a dark, rubbery substance, which was used without further purification.

[0489] Compound 4(50) (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)tetrahydro-2H-pyran-3,4-diyldiacetate Compound 3 (200 mg, 0.607 mmol) and Compound 2 (160 mg, 0.913 mmol, 1.50 equivalents) were dissolved in 1,2-dichloroethane (5 mL). A 4 Å molecular sieve was then added, and the reaction mixture was stirred for 30 minutes. Trimethylsilyltrifluoromethanesulfonate (55.0 μL, 67.5 mg, 0.304 mmol, 0.5 equivalents) was then added to the mixture, and the reaction mixture was stirred overnight. The reaction mixture was then diluted in dichloromethane, washed with 1 M sodium bicarbonate (once) and water (once), dried over magnesium sulfate, and concentrated. The crude oily substance was purified with silica gel (50-100% ethyl acetate in dichloromethane) to obtain compound 4 (245 mg, 0.486 mmol) as a white solid in 80.1% yield. The spectrum was consistent with previously reported characterization data.

[0490] Compound 5(50) (2R,3R,4R,5R,6R)-5-acetamide-2-(acetoxymethyl)-6-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)tetrahydro-2H-pyran-3,4-diyldiacetate Compound 4 (1.80 g, 3.57 mmol) was dissolved in tetrahydrofuran (35 mL). Then, triphenylphosphine (1.40 g, 5.35 mmol, 1.5 equivalents) and water (257 μL, 14.28 mmol, 4 equivalents) were added, and the reaction mixture was stirred at room temperature under nitrogen for 36 hours. The solvent was removed, and the crude product, a colorless oily substance, was used in the next step without further purification.

[0491] Compound 6(51) 3,3'-((2-amino-2-((2-cyanoethoxy)methyl)propane-1,3-diyl)bis(oxy))dipropanenitrile Tris(hydroxymethyl)aminomethane (1.00 g, 8.25 mmol, 1.00 equivalent) was dissolved in dioxane (50 mL), and aqueous KOH (40% w / v, 1 mL) was added dropwise. Acrylonitrile (6.45 mL, 5.22 g, 25.2 mmol, 3.05 equivalents) was then added dropwise, and the reaction was stirred overnight. Dioxane was removed under vacuum, and the resulting aqueous solution was extracted with dichloromethane (3 times). The combined organic layer was then washed with brine (1 time), dried over sodium sulfate, and evaporated to obtain compound 6 as a colorless oily substance (1.12 g, 4.04 mmol) in 48.5% yield, which was used in further steps without purification. The spectrum was consistent with previously reported characterization data.

[0492] Compound 7(52) Dimethyl 3,3'-((2-amino-2-((3-methoxy-3-oxopropoxy)methyl)propane-1,3-diyl)bis(oxy))dipropionate Compound 6 (710 mg, 2.50 mmol) was dissolved in methanol (30 mL) and sulfuric acid (2.8 mL) and heated under reflux for 24 hours. The solution was then cooled to 0°C, neutralized with saturated sodium bicarbonate solution, and extracted with dichloromethane (three times). The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified over silica gel (0-10% methanol in dichloromethane) to obtain compound 7 as a colorless oily substance (656 mg, 1.73 mmol) in 69.0% yield. The spectrum was consistent with previously reported characterization data.

[0493] compound 8 Methyl 8,8-bis((3-methoxy-3-oxopropoxy)methyl)-3,6-dioxo-1-phenyl-2,10-dioxa-4,7-diazatridecane-13-oate Compound 7 (723 mg, 1.90 mmol) was dissolved in acetonitrile (25 mL). Then, 1-hydroxybenzotriazole hydrate (291 mg, 1.90 mmol, 1 equivalent), N-carbobenzyloxyglycine (397 mg, 1.90 mmol, 1.00 equivalent), and N,N'-dicyclohexylcarbodiimide (392 mg, 1.90 mmol, 1.00 equivalent) were added, and the reaction mixture was stirred overnight. Then, the acetonitrile was evaporated, and the residue was adsorbed onto silica and purified using a gradient of 0-75% ethyl acetate in hexane. Compound 8 (866 mg, 1.52 mmol) was recovered as a colorless oily substance in 80% yield.

[0494] compound 9 8,8-Bis((2-carboxyethoxy)methyl)-3,6-dioxo-1-phenyl-2,10-dioxa-4,7-diazatridecane-13-acid Compound 8 (100 mg, 0.175 mmol) was dissolved in dioxane (2 mL) and aqueous NaOH solution (2 M, 2 mL). The reaction mixture was stirred for 3 hours, then acidified to approximately pH 3 with 6 M hydrochloric acid and extracted twice with ethyl acetate. The organic fraction was washed with 1 M HCl, then dried over sodium sulfate and evaporated to obtain compound 9 as a white solid, which was used in further steps without purification.

[0495] compound 10 Compound 9 (372 mg, 0.704 mmol, 1 equivalent) was dissolved in dimethylformamide (40 mL) and diisopropylethylamine (981 μL, 728 mg, 5.63 mmol, 8.00 equivalents). Then, N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (HBTU) (1.01 g, 2.67 mmol, 3.8 equivalents) was added, and the reaction mixture was stirred at room temperature for 10 minutes, after which Compound 5 (1.28 g, 2.67 mmol, 3.8 equivalents) was added. The reaction mixture was stirred for 2 hours, then diluted with dichloromethane and washed with aqueous phosphoric acid solution (1 M, once), aqueous sodium bicarbonate solution (1 M, once), and brine (once). The organic layer was dried over sodium sulfate and evaporated over silica. The residue was purified (0-20% methanol in dichloromethane) to obtain compound 10 (831 mg, 0.436 mmol) as a light brown solid in 62% yield.

[0496] compound 11 Compound 10 (710 mg, 0.372 mmol) was dissolved in anhydrous methanol (90 mL) and cooled to 0°C under nitrogen. Palladium carbon (71.0 mg, 10% w / w) was then added, and the reaction was stirred at 0°C under a hydrogen atmosphere (1 atm) for 16 hours. After completion, the reaction was filtered through Celite, and the methanol was evaporated to obtain the intermediate amine (657 mg, 0.370 mmol) in 99.5% yield, which was used without further purification. The amine (441 mg, 0.248 mmol) was dissolved in methanol (15 mL) and cooled to 0°C. Then, sodium methoxide solution (400 μL, 5.4 M in MeOH) was added to remove the O-acetyl group, and the reaction was stirred for 30 minutes. Next, Dowex 50WX8 was added until the solution became weakly acidic. The resin was filtered and thoroughly washed with methanol. The combined methanol fraction was evaporated under reduced pressure to obtain compound 11 (274 mg, 0.196 mmol) as a colorless oily substance in 79.0% yield. Compound 11 was used in further steps without purification.

[0497] compound 12 Benzyl(1-hydroxy-15,15-bis(14-hydroxy-5-oxo-2,9,12-trioxa-6-azatetradecyl)-10,17-dioxo-3,6,13-trioxa-9,16-diazaoctadecane-18-yl)carbamate Compound 9 (302 mg, 0.572 mmol, 1 equivalent) was dissolved in dichloromethane (25 mL) and triethylamine (480 μL, 3.431 mmol, 6.00 equivalents). Then, 1-hydroxybenzotriazole hydrate (350 mg, 2.28 mmol, 4 equivalents) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (417 mg, 2.17 mmol, 3.80 equivalents) were added, followed by the addition of 2-[2-(2-aminoethoxy)ethoxy]ethanol (300 mg, 2.01 mmol, 3.80 equivalents). The reaction mixture was then stirred overnight. The solvent was evaporated, and the crude material was purified by reverse-phase chromatography without workup using a gradient of 5–35% acetonitrile in water with 0.1% formic acid added. Compound 12 was recovered as a colorless oily substance (345 mg, 0.372 mmol) in 65% yield.

[0498] compound 13 3,3'-((2-(2-aminoacetamide)-2-(14-hydroxy-5-oxo-2,9,12-trioxa-6-azatetradecyl)propane-1,3-diyl)bis(oxy))bis(N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)propanamide) Compound 12 (345 mg, 0.374 mmol, 1.00 equivalent) was dissolved in methanol (15 mL). The solution was purged under a nitrogen stream for 5 minutes. Then, 10% Pd / C (5% w / w, 17.3 mg) was added under a nitrogen stream. The mixture was purged with hydrogen gas for 5 minutes and then stirred under a hydrogen atmosphere for 2 hours. The mixture was then filtered through a Celite bed, and the filtrate was vacuum concentrated to obtain compound 13 as a colorless oily substance in 96% yield (282 mg, 0.359 mmol). Compound 13 was used in further steps without purification.

[0499] Compound 14(53) Ethyl 4-((2-chloroquinoline-6-yl)oxy)butanoate TIFF2026508972000422.tif161282-chloroquinoline-6-ol (1.00 g, 5.57 mmol) and potassium carbonate (1.53 g, 11.1 mmol, 2.0 equivalents) were dissolved in dimethylformamide (20 mL). Then, ethyl bromobutyrate (1.63 g, 1.2 mL, 8.35 mmol, 1.5 equivalents) was added, and the mixture was stirred at 80°C for 12 hours. The reaction product was diluted with ethyl acetate and washed with water (twice) and brine (three times). The organic layer was dried over sodium sulfate and evaporated to obtain compound 14 as a pale yellow solid, which was used in the next step without further purification. The spectrum was consistent with previously reported characterization data.

[0500] Compound 15(53) Ethyl 4-((2-((trimethylsilyl)ethynyl)quinoline-6-yl)oxy)butanoate Compound 14 (1.52 g, 5.17 mmol) was dissolved in tetrahydrofuran (20 mL) and triethylamine (2.88 mL, 20.7 mmol, 4 equivalents). Then, copper(I) iodide (49.0 mg, 0.258 mmol, 0.050 equivalents), bis(triphenylphosphine)palladium(II) dichloride (181 mg, 0.258 mmol, 0.050 equivalents), and trimethylsilylacetylene (1.07 mL, 762 mg, 7.75 mmol, 1.50 equivalents) were added, and the reaction mixture was stirred in a pressurized vessel at 65°C for 16 hours. The reaction mixture was then cooled and filtered through Celite. The Celite was thoroughly washed with ethyl acetate, and the combined organic fraction was evaporated. The residue was purified with silica (0-50% ethyl acetate in hexane) to obtain compound 15 as a pale yellow solid in 81% yield (1.49 g, 4.19 mmol). The spectrum was consistent with previously reported characterization data.

[0501] Compound 16(53) Ethyl 4-((2-ethynylquinoline-6-yl)oxy)butanoate Compound 15 (1.57 g, 4.42 mmol) was dissolved in dichloromethane (45 mL), and tetrabutylammonium fluoride (5.30 mL, 1.00 M in THF, 5.30 mmol, 1.20 equivalents) was added dropwise. After stirring for 1 minute, 10% citric acid (50 mL) was added, and the reaction mixture was stirred for 30 minutes. The organic phase was washed with water (once), dried, and evaporated to obtain compound 16 as a pale yellow solid, which was used in the next step without further purification. The spectrum was consistent with previously reported characterization data.

[0502] Compound 17(53) Ethyl 4-((2-(1-(3-fluoro-4-hydroxyphenyl)-1H-1,2,3-triazole-4-yl)quinoline-6-yl)oxy)butanoate TIFF2026508972000425.tif241282-Fluoro-4-iodophenol (126 mg, 0.529 mmol) and sodium azide (38 mg, 0.528 mmol, 1.0 equivalent) were dissolved in DMSO (2.5 mL) and stirred at 70°C for 2 hours. Then, compound 32 (150 mg, 0.529 mmol, 1 equivalent), trans-N,N'-dimethylcyclohexane-1,2-diamine (11 mg, 0.079 mmol, 0.15 equivalents), sodium ascorbate (10 mg, 0.053 mmol, 0.1 equivalent), copper(I) iodide (15 mg, 0.079 mmol, 0.15 equivalents), and H2O (2.5 mL) were added, and the mixture was stirred overnight at 70°C. The reaction mixture was diluted with ethyl acetate and washed once with water and once with brine. The organic layer was dried over sodium sulfate, evaporated, and purified with silica (0-100% ethyl acetate in dichloromethane) to obtain compound 17 as an off-white solid. The spectrum was consistent with previously reported characterization data.

[0503] Compound 18(53) 4-((2-(1-(3-fluoro-4-hydroxyphenyl)-1H-1,2,3-triazole-4-yl)quinoline-6-yl)oxy)butanoic acid Compound 17 (90.0 mg, 0.206 mmol) was dissolved in dioxane (6.00 mL) and 2 M NaOH (3.00 mL). The reaction mixture was stirred at room temperature for 2.5 hours, then diluted with water and the pH was adjusted to 3 with 1 M HCl. The mixture was cooled to 4°C and filtered to obtain compound 18 as a brown powder, which was used without further purification.

[0504] Compound 19(54) 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl 4-methylbenzene sulfonate TIFF2026508972000427.tif9128 Tetraethylene glycol (50.0 g, 258 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0°C, and stirred. Then, sodium hydroxide (1.68 g, 41.3 mmol, 1.60 equivalents) in water (10 mL) was added, followed by the dropwise addition of p-toluenesulfonyl chloride (5.00 g, 25.8 mmol, 1.00 equivalent) in tetrahydrofuran (3 mL). The reaction mixture was stirred at 0°C for 4 hours and then diluted with dichloromethane. The organic layer was washed with ice-cold water (twice) and brine (once), and then dried over sodium sulfate to obtain compound 19 (8.84 g, 25.4 mmol, 99.0% yield) as a pale yellow oily substance, which was used in further steps without purification.

[0505] Compound 20(54) 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethane-1-ol Compound 19 (8.84 g, 25.4 mmol) was dissolved in 100% ethanol (200 mL), and sodium azide (4.128 g, 63.5 mmol, 2.50 equivalents) was added. The reaction mixture was heated under reflux for 16 hours, then cooled to room temperature, and water (150 mL) was added. The ethanol was then evaporated under reduced pressure, and the aqueous layer was extracted with ethyl acetate (twice). The organic layer was washed with water (once) and brine (once), dried over sodium sulfate, and evaporated to obtain compound 20 (4.82 g, 22.1 mmol) as a yellow oily substance in 87.0% yield. The spectrum was consistent with previously reported characterization data.

[0506] Compound 21(55) 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)acetic acid Ice-cold Jones' reagent was prepared separately by mixing chromium trioxide (1.37 g, 13.68 mmol, 3.00 equivalents), H2SO4 (2.38 mL), and water (26.2 mL) at 0°C. The Jones' reagent was then added dropwise to an ice-cold solution of compound 20 (1.00 g, 4.56 mmol, 1 equivalent) in acetone (20 mL). The reaction mixture was then heated to room temperature and stirred for 16 hours. The excess Jones' reagent was quenched by adding isopropanol (30 mL) and the reaction mixture was concentrated. The aqueous residue was then extracted with dichloromethane (4 times). The organic layers were combined, dried over sodium sulfate, and concentrated to obtain compound 21 (851 mg, 3.65 mmol) as a colorless oily substance in 80% yield, which was used in further steps without purification.

[0507] Compound 22(56) 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)acetic acid Compound 21 (2.4 g, 10.3 mmol) was dissolved in methanol and the atmosphere was flushed with N2. Palladium carbon (240 mg, 10% w / w) was added, and the flask was again purged with nitrogen. The flask was then purged with H2 gas and stirred under an H2 atmosphere for 16 hours. The reaction product was then filtered through Celite and concentrated to obtain compound 22 (2.13 g, 10.3 mmol) as a colorless oily substance in quantitative yield. Compound 22 was used in further steps without purification.

[0508] compound 23 2-(2-(2-(2-((2,4-dinitrophenyl)amino)ethoxy)ethoxy)ethoxy)acetic acid TIFF2026508972000431.tif151281-Chloro-2,4-dinitrobenzene (52.8 mg, 0.261 mmol, 1.00 equivalent), compound 22 (75.5 mg, 0.365 mmol, 1.40 equivalent), and sodium bicarbonate (65.7 mg, 0.782 mmol, 3.00 equivalent) were dissolved in water (2 mL) in a round-bottom flask. A reflux condenser was then attached to the flask, and the mixture was stirred at 95°C for 16 hours. The reaction mixture was then cooled, diluted in saturated sodium bicarbonate solution (10 mL), and then washed with dichloromethane. The aqueous solution was then treated with concentrated hydrochloric acid until the pH of the solution was less than 2. The aqueous layer was then extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to obtain compound 23 (86.8 mg, 0.232 mmol) as a bright yellow oily substance in 89% yield, which was used without further purification.

[0509] Compound 24 (D-MoDE-A) Compound 23 (75.1 mg, 0.201 mmol, 1.5 equivalents) was dissolved in dichloromethane (7 mL) and diisopropylethylamine (26 mg, 0.201 mmol, 1.5 equivalents). Then, 1-hydroxybenzotriazole hydrate (34.9 mg, 0.2278 mmol, 1.7 equivalents) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (41.0 mg, 0.214 mmol, 1.6 equivalents) were added and the mixture was stirred for 10 minutes. Deprotected amine 9-OAc (238 mg, 0.134 mmol, 1 equivalent) with Cbz was added and the reaction mixture was stirred overnight. The mixture was diluted in dichloromethane (50 mL) and washed with water (twice) and brine (once). The organic layer was dried over sodium sulfate and concentrated. The residue was dissolved in methanol (3.5 mL) and cooled to 0°C. Then, sodium methoxide solution (5.4 M in methanol, 292 μL) was added, and the reaction was stirred at 0°C for 30 minutes. It was then neutralized with Dowex 50WX8. The reaction was filtered and concentrated. The residue was directly purified by HPLC (0-30% acetonitrile in water, +0.1% formic acid) to obtain compound 24 as a bright yellow powder in 18.6% yield (0.0249 mmol, 43.7 mg).

[0510] Compound 25 (M-MoDE-A) TIFF2026508972000433.tif102128 Compound 18 (23.5 mg, 0.0575 mmol, 1.1 equivalents) and (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (20.0 mg, 0.0522 mmol, 1 equivalent) in anhydrous dimethylformamide (5 mL) and diisopropylethylamine ( Compound 11 (73.0 mg, 0.0522 mmol) was dissolved in 23.3 μL of water and stirred at room temperature for 10 minutes. Compound 11 was then added and the reaction mixture was stirred for 30 minutes. The mixture was loaded directly into an HPLC and purified (20-30% acetonitrile in water, + 0.3% trifluoroacetic acid) to obtain Compound 25 (12 mg, 0.0067 mmol) as an off-white powder in 12.8% yield.

[0511] Compound 26 (DNP-OH3) 3,3'-((2-(14-((2,4-dinitrophenyl)amino)-4-oxo-6,9,12-trioxa-3-azatetradecanamide)-2-(14-hydroxy-5-oxo-2,9,12-trioxa-6-azatetradecyl)propane-1,3-diyl)bis(oxy))bis(N-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)propanamide) Compound 13 (234 mg, 0.297 mmol, 1 equivalent) was dissolved in dimethylformamide (5 mL) and triethylamine (83 μL, 0.594 mmol, 2 equivalents). Compound 23 (110.9 mg, 0.297 mmol, 1 equivalent) and 1-hydroxybenzotriazole hydrate (59 mg, 0.386 mmol, 1.3 equivalents) were then added, followed by the addition of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (68.3 mg, 0.356 mmol, 1.2 equivalents). The reaction mixture was stirred overnight and then evaporated under a stream of nitrogen. The product was directly purified via reverse-phase HPLC (0-30% acetonitrile in water + 0.1% formic acid) to obtain compound 26 (178 mg, 0.155 mmol) as a bright yellow powder in 52.3% yield.

[0512] General synthesis methods for CCP1-GN3 compounds The skeletons of TIFF2026508972000435.tif29145 and TIFF2026508972000436.tif4145 were synthesized according to standard Fmoc-based SPPS conditions. The peptide was cleaved from the resin for 3 hours using 95% TFA, 2.5% TIS, and 2.5% H2O. The linear peptide was then resuspended in DMSO / MeCN / H2O (1:1:1) and stirred for 48 hours to facilitate disulfide formation. The peptide was then purified by HPLC (0-80% MeCN + 0.1% TFA, 30 minutes) to obtain compound 100.

[0513] Compound 11 (NH2GN3) was dissolved in DMF, followed by the addition of DBCO-PEG4-NHS ester (CAS#1427004-19-0) (1.5 equivalents) and DIEA (5 equivalents). The reaction mixture was stirred overnight in RT, diluted with H2O + 0.1% TFA, and purified by HPLC (MeCN / H2O + 0.1% TFA, 0-80% MeCN) to obtain compound 101.

[0514] Compound 12 (NH2OH3) was dissolved in DMF, followed by the addition of DBCO-PEG4-NHS ester (CAS#1427004-19-0) (1.5 equivalents) and DIEA (5 equivalents). The reaction mixture was stirred overnight in RT, diluted with H2O + 0.1% TFA, and purified by HPLC (MeCN / H2O + 0.1% TFA, 0-80% MeCN) to obtain compound 102.

[0515] Compound 100 (1 equivalent) and compound 101 (1.5 equivalents) were dissolved in H2O / MeCN (1:1 v / v) and stirred overnight at room temperature. The crude mixture was then purified by HPLC (MeCN / H2O + 0.1% TFA, 0-80% MeCN) to obtain CCP-MoDE-A (CCP1-GN3).

[0516] The terms and expressions used herein are for illustrative purposes only, not limitation, and in using such terms and expressions, there is no intention to exclude the shown and described features or their equivalents, and it should be recognized that various modifications are possible within the scope of the embodiments of this application. Accordingly, although this application describes specific embodiments and optional features, it should be understood that modifications and variations of the compositions, methods, and concepts disclosed herein may be adopted by those skilled in the art, and such modifications and variations should be considered within the scope of the embodiments of this application.

[0517] Method for preparing intermediate A001A Referring to Figures 3A to 3D, a synthesis scheme for synthesizing the intermediate target A001A is provided.

[0518] Preparation of intermediate 2: To a solution of 1a (60.0 g, 400 mmol, 2.00 equivalents) in 2-methyltetrahydrofuran (450 mL), 1 (34.2 g, 200 mmol, 1.00 equivalent) in 2-methyltetrahydrofuran (160 mL) was added at 0°C. The mixture was stirred at 25°C for 2 hours. TLC (DCM:MeOH = 20:1, R f A reading of 0.70 (=0.70) indicated that the reaction was complete, and one major new spot with lower polarity was detected. HCl / EA (ethyl acetate) (1N, 27.0 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes. The white precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain intermediate 2 (crude, 105.0 g, 370.6 mmol) as a yellow oily substance. LCMS: RT=0.797 min, MS calculated value: 283.14, measured value: [M+Na] + = 306.1. TIFF2026508972000441.tif18145

[0519] Preparation of intermediate 3: TIFF2026508972000442.tif29151 A solution of 2a (100.0 g, 257 mmol, 1.00 equivalent) in DCE (1,2-dichloroethane) (500 mL) was mixed with TMSOTf (85.6 g, 385 mmol, 1.50 equivalent) and stirred at 60°C for 2 hours. The reaction mixture was then cooled to room temperature (25°C) and stirred for another hour. A mixture of intermediate 2 (80.0 g, 282 mmol, 1.10 equivalent) in DCE (500 mL) and 4 Å powdered molecular sieve (50.0 g) was added to the reaction mixture. The resulting mixture was stirred under an N2 atmosphere for 30 minutes. A solution of intermediate 2a (100.0 g, 257 mmol, 1.00 equivalent) in DCE was then added dropwise to the mixture at 0°C. The mixture was stirred at 25°C for 16 hours under an N2 atmosphere. TLC (DCM:MeOH = 10:1, R f The value (=0.42) indicates that intermediate 2a was completely consumed, and one major new spot with greater polarity was detected.

[0520] The reaction mixture was filtered and washed with saturated NaHCO3 (500 mL), water (500 mL), and brine (500 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, PE (petroleum ether):EA (ethyl acetate) = 3:1 to 1:6, then DCM:MeOH = 20:1) to obtain intermediate 3 (90.0 g, 146.9 mmol, 91.6% purity, 57.2% yield) as a yellow oily substance. LCMS: RT = 0.860 min, MS calculated value: 612.25, measured value: [M+H] + = 613.2. TIFF2026508972000443.tif25151

[0521] Preparation of intermediate 4: TIFF2026508972000444.tif28150 In a reaction bottle (purged three times with Ar), Pd / C (9.00 g, 10% purity) was gradually added with THF (180 mL), and then a solution of TFA (16.7 g, 147 mmol, 1.00 equivalent) and intermediate 3 (90.0 g, 147.0 mmol, 1.00 equivalent) in THF (720 mL) was gradually added to the reactant under N2. The reactant was degassed, purged three times with N2 and H2, and then stirred at 25°C for 3 hours under an H2 atmosphere (40 psi). TLC (DCM:MeOH = 10:1, R f A reading of 0.20 (=0.20) indicated that intermediate 3 was completely consumed, and one major new spot with greater polarity was detected. The reaction mixture was dissolved in THF (100 mL), carefully filtered through siliceous earth under an N2 atmosphere, washed the cake with THF (100 mL, twice), and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was diluted with water (1000 mL), washed with DCM (300 mL, three times), and the aqueous layer was freeze-dried to obtain intermediate 4 (80.0 g, 139.0 mmol, 95.1% purity, 91.8% yield, TFA salt) as a white solid. LCMS: RT=0.484 min, MS calculated value: 478.22, measured value: [M+H] + = 478.9. TIFF2026508972000445.tif24143

[0522] Preparation of intermediate 6: To a mixture of 5 (60.0 g, 495.0 mmol, 1.00 equivalent) in DMSO (166 mL), NaOH aqueous solution (5.0 M, 9.91 mL, 0.10 equivalent) was added dropwise at 0-15°C for at least 5 minutes. After addition, the mixture was stirred at 0-15°C for 5 minutes, and then 5a (254.0 g, 1.98 mol, 287 mL, 4.00 equivalent) was added dropwise to the reaction mixture at 20°C. The resulting mixture was stirred at 25°C for 16 hours. TLC (DCM:MeOH = 10:1, R f A value of 0.7) indicated that compound 5 was completely consumed, and one major new spot with lower polarity was detected. The resulting reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was dissolved in siRNA (400 mL), quenched by adding water (400 mL), and extracted with siRNA (400 mL, 3 times). The combined organic layer was washed with brine (300 mL, 2 times), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain intermediate 6 (100.0 g, 197.8 mmol, 96.0% purity, 40.0% yield) as a colorless oily substance. TIFF2026508972000447.tif18141

[0523] Preparation of intermediate 7: To a solution of intermediate 6 (40.0 g, 79.1 mmol, 1.00 equivalent) in MeCN (400 mL), HOBt (10.7 g, 79.1 mmol, 1.00 equivalent) was added. Then, 6a (16.5 g, 79.1 mmol, 1.00 equivalent) and DCC (16.3 g, 79.1 mmol, 1.00 equivalent) were added. The reaction mixture was stirred at 25°C for 16 hours. TLC (PE:EA = 1:1, R fA value of 0.80 indicated that intermediate 6 was completely consumed, and one major new spot with lower polarity was detected. The MeCN was evaporated to obtain the residue. The residue was purified by column chromatography (SiO2, PE:EA = 10:1~1:1) to obtain intermediate 7 (40.0 g, 57.4 mmol, 82.9% purity, 72.5% yield) as a white solid. LCMS: RT = 1.151 min, MS calculated value: 696.38, measured value: [M+H] + =697.3, [M+Na] + = 719.3. TIFF2026508972000449.tif11130

[0524] Preparation of intermediate 8: A solution of intermediate 7 (30.0 g, 43.0 mmol, 1.00 equivalent) in HCOOH (300 mL) was stirred at 25°C for 16 hours. TLC (PE:EA = 1:1, R f A value of 0.04 indicated that intermediate 7 was completely consumed, and one major new spot with greater polarity was detected. The solvent was evaporated under reduced pressure, then co-evaporated with toluene (50 mL, 3 times) under reduced pressure, and dried under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (A: 0.1% FA conditions / H2O, B: MeCN) to obtain intermediate 8 (20.0 g, 37.8 mmol, 98.2% purity, 87.9% yield). TIFF2026508972000451.tif24145

[0525] Preparation of intermediate 9: Intermediate 8 (20.0 g, 37.8 mmol, 1.00 equivalent) and intermediate 4 (78.5 g, 132 mmol, 3.50 equivalent, TFA salt) were stirred in 400 mL of DMF, to which HOBt (20.4 g, 151 mmol, 4.00 equivalent), EDCI (29.0 g, 151 mmol, 4.00 equivalent), and DIPEA (22.0 g, 170 mmol, 4.50 equivalent) were subsequently added. The reaction mixture was stirred at 25°C for 2 hours. TLC (DCM:MeOH = 10:1, R f A value of 0.4) indicated that intermediate 8 was completely consumed, and one major new spot with greater polarity was detected. The reaction mixture was gradually injected into a stirred-cold 0.5 mol / L HCl solution (900 mL) and stirred for 10 minutes. A white precipitate formed, which was filtered, and the aqueous phase was extracted twice with DCM (600 mL, twice). The combined organic layers were washed with 5% NaHCO3 (450 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, DCM:MeOH = 100:1~5:1) to obtain intermediate 9 (58.0 g, 30.4 mmol, 82.7% purity, 80.3% yield) as a white solid. TIFF2026508972000453.tif45145

[0526] Preparation of intermediate 10: A 500 mL round-bottom flask was purged three times with Ar gas, and anhydrous Pd / C (1.50 g, 1.41 mmol, 10% purity, 1.00 equivalent) was carefully added. Then, under an Ar atmosphere, THF (150.0 mL) was added to completely permeate the Pd / C, followed by the gradual addition of a solution of intermediate 9 (15.0 g, 7.85 mmol, 1.00 equivalent) and TFA (895 mg, 7.85 mmol, 583 μL, 1.00 equivalent) in THF (75 mL). The resulting mixture was degassed, purged three times with H2, and then stirred at 25°C for 3 hours under an H2 atmosphere (15 psi). The reaction was monitored by LC-MS, which showed the desired mass (one main peak with the desired mass was detected). The reaction mixture was carefully filtered through siliceous soil under an N2 atmosphere, and the cake was washed with THF (100 mL, twice). Water was then immediately added to the filtered cake. The organic layer was concentrated under reduced pressure to obtain intermediate 10 (13.0 g, 6.54 mmol, 83.2% yield, 99.7% purity, TFA salt) as a white solid. TIFF2026508972000455.tif31145

[0527] Preparation of Intermediate Objective A001A: To a solution of intermediate 10 (12.0 g, 6.35 mmol, 1.00 equivalent, TFA) in MeOH (120.0 mL), NaOMe (5.4 M, 5.01 mL, 4.26 equivalents) was added at 0°C. The mixture was stirred at 0°C for 0.5 hours. The reaction was monitored by LC-MS, which showed the desired mass (one main peak containing the desired mass was detected). 10.0 mL of 1.0 M HCl solution was added to the reaction mixture until the pH became 6. The mixture was diluted with H2O (75.0 mL) and extracted by DCM (120 mL, 3 times). The mixture was lyophilized to obtain target A001A (9.0 g, 5.96 mmol, 93.9% yield, >95% purity, HCl) as a white solid. TIFF2026508972000457.tif38141

[0528] Preparation of peptide intermediate Int-00002 Referring to Figure 4A, a synthesis scheme for synthesizing the intermediate target Int-0002 is provided.

[0529] Preparation of Int-00002: Peptides were synthesized using standard Fmoc chemistry (Fmoc-Ser(tBu)-Wang resin).

[0530] Resin preparation: While bubbling with N2 for 30 minutes, 600 mL of DMF was added to a container containing Fmoc-Ser(tBu)-Wang resin (15.0 mmol, 41.4 g, sub=0.361 mmol / g, 1.00 equivalent). The resin was washed with 600 mL of DMF five times, followed by the addition of 20% piperidine in 400 mL of DMF, and then bubbling with N2 at 25°C for 30 minutes. The mixture was filtered, the resin was washed with 600 mL of DMF five times, and then the process proceeded to the next step.

[0531] Coupling: A solution of Fmoc-Gly-OH (13.3 g, 45.0 mmol, 3.00 equivalents) and HOAt (6.12 g, 3.00 equivalents) in DMF (400 mL) was added to the resin while bubbling with N2. Then, DIC (3.00 equivalents) was added dropwise to the mixture, and N2 bubbling was performed at 25°C for 30 minutes. The coupling reaction was monitored by a ninhydrin test, and if it was colorless, the coupling was complete. The resin was then washed five times with DMF (600 mL).

[0532] Deprotection: 20% piperidine in DMF (400 mL) was added to the resin, and the mixture was bubbling with N2 at 25°C for 30 minutes. The resin was then washed five times with DMF (600 mL). The deprotection reaction was monitored by a ninhydrin test; if it showed a blue or brownish-red color, the reaction was complete.

[0533] Steps 2 and 3 were repeated for the following amino acid elongation: numbers #2 to #21, Table 1.

[0534] After the final positioning was complete, the resin was then washed five times with DMF (600 mL) and five times with MeOH (600 mL), and dried under reduced pressure to obtain intermediate 11 (resin to which the peptide was bound, 15.0 mmol).

[0535] (Table 1) List of amino acids and corresponding reagents used in SPPS TIFF2026508972000458.tif205147

[0536] Peptide cleavage and disulfide formation: Cutting: Intermediate 11 (105 g, resin) was stirred in a solution of TFA / 3-MPA / Tis / H2O (92.5 / 2.5 / 2.5 / 2.5, v / v / v / v, 1050 mL) at 25°C for 2 hours. The mixture was precipitated with isopropyl ether (cold, 10 L). After filtration, the solid was washed twice more with isopropyl ether (cold, 10 L) and dried under reduced pressure for 2 hours to obtain intermediate 12 (30.0 g, crude) as a white solid. TIFF2026508972000459.tif11128

[0537] Disulfide formation: Intermediate 12 (30.0 g, crude) was dissolved in H2O (12 L) and MeCN (3 L) at 25°C. Then, 0.1 M I2 / AcOH was added dropwise to the mixture until the yellow color persisted, and the mixture was stirred at 25°C for 5 minutes. After filtration, the filtrate was directly purified by preparative HPLC (A: 0.075% TFA / H2O, B: MeCN) to obtain Int-00002 (3.97 g, 9.68% yield, 90.25% purity) as a white solid. TIFF2026508972000460.tif11128

[0538] Preparation of target A001A-PEG4-alkyne Referring to Figure 4B, a synthesis scheme for synthesizing the intermediate target A001A-PEG4-alkyne is provided.

[0539] Preparation of intermediate 14: TIFF2026508972000461.tif44128 Intermediate 13 (600 mg, 2.31 mmol, 1.00 equivalent) and 13a (2.30 g, 13.8 mmol, 6.00 equivalent) were dissolved in DMF (6 mL) and EDCI (1.33 g, 6.92 mmol, 3.00 equivalent) was added at 0°C. The mixture was stirred at 0°C for 1 hour. The mixture was directly purified by preparative HPLC (TFA conditions) to obtain intermediate 14 (800 mg, 83.4% yield, 98.2% purity) as a yellow oily substance. TIFF2026508972000462.tif4136

[0540] Preparation of target A001A-PEG4-alkyne: TIFF2026508972000463.tif58150 Intermediate 14 (276 mg, 676 μmol, 1.05 equivalents) and target A001A (1.00 g, 644 μmol, 1.00 equivalent) were dissolved in DMF (0.25 mL) and DIEA (166 mg, 230 μL, 2.00 equivalents) was added. The mixture was stirred at 25 °C for 12 hours. The mixture was diluted with MeCN / H2O (cold, v / v, 3 / 3, 10 mL) and then dried by lyophilization to remove DMF. The residue was directly purified by preparative HPLC (AcOH conditions) to obtain target A001A-PEG4-alkyne (0.60 g, 93.5% purity, 56.8% yield) as a colorless oily substance. TIFF2026508972000464.tif17141

[0541] Preparation of CCP1-GN4: Referring to Figure 4C, a synthesis scheme for synthesizing CCP1-GN4 is provided.

[0542] To a solution of Int-00002 (750 mg, 303 μmol, 1.10 equivalents) and target A001A-PEG4-alkyne (453 mg, 276 μmol, 1.00 equivalent) in DMF (7.5 mL), solutions of CuSO4 (0.4 M, 690 μL, 1.00 equivalent), sodium L-ascorbate (0.4 M, 2.76 mL, 4.00 equivalents), and ammonium bicarbonate (0.2 M, 2.09 mL, 1.51 equivalents) were added at 25°C. The mixture was stirred at 25°C for 1 hour under an N2 atmosphere. The residue was directly purified by preparative HPLC (AcOH conditions) to obtain CCP1-GN4 (412 mg, 93.6 μmol, 33.8% yield, 93.14% purity) as a white solid. TIFF2026508972000465.tif11134

[0543] List of types The following enumerated aspects are provided, and their numbering is not intended to be interpreted as indicating a level of importance. Appearance 1: Structure: A compound of formula II having TIFF2026508972000466.tif17128, or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, During the ceremony, PBM is the antibody-binding site for anti-cyclic citrullinated peptides (anti-CCP); CON and linker-2 appear independently in each instance, as follows: (a) In the above formula, TIFF2026508972000467.tif21128 R 1 Each occurrence is independently either H or C1-C3 alkyl; Each occurrence of n'' is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; or (b) In the above formula, TIFF2026508972000468.tif15128 Each occurrence of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25; Each occurrence of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25; Each occurrence of n'' is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; or (c) In the above formula, TIFF2026508972000469.tif6128 Z and Z' are joined independently, -(CH2) i -O-, -(CH2) i -S-, -(CH2) i -N(R)-, The filename is TIFF2026508972000470.tif27128; R 2 Each occurrence is independently either H or C1-C3 alkyl; Each occurrence of Y is independently a combination, -O-, -S-, or -N(R)-; Each occurrence of i is an independent integer in the range of 0 to 100; D is -(CH2) i -YC(=O)-Y-(CH2) i -,-(CH2) m' -,-[(CH2) n -X 1 ] j - or combination, except that Z, Z', and D are not combined simultaneously; j is an integer in the range of 1 to 100; m' is an integer in the range of 1 to 100; n is an integer in the range of 1 to 100; X 1 is -O-, -S-, or -N(R)-; Each R is independently a C1-C3 alkyl group which may be substituted with H or 1-3 hydroxyl groups; or (d) A structure selected from the group consisting of TIFF2026508972000471.tif50132, in the above formula, X 2 In each occurrence, -CH2-, -O-, -S-, and -N(R) appear independently. 4 )-, -C(O)-, -S(O)-, -S(O)2-, -S(O)2O-, -OS(O)2-, or -OS(O)2O-; X 3 In each occurrence, -O-, -S-, or -N(R 4 )-and; R 4 In each occurrence, it is independently H, C1-C3 alkyl, C1-C3 alkanol, or -C(O)(C1-C3 alkyl). The structure; or (e)C 6~18 Ariel, C 3~18 Heterocyclyl, C 6~18 Viaryl, or C 6~18 A heterobiaryl which may be substituted with 1 to 6 substituents selected from the group consisting of F, Cl, Br, I, O(RG), O(O)N(RG)2, CN, NO, NO2, ONO2, CF3, OCF3, -(RG), N(RG)2, S(RG), SO(RG), SO2(RG), SO2N(RG)2, and SO3(RG), where each occurrence of RG may be independently substituted with H, or C 1~10 Alkyl, possibly substituted C 3~10 Cycloalkyl, may be substituted C 6~18 Aryl, or possibly substituted C 5~18 The C is a heteroaryl compound. 6~18 Ariel, C 3~18 Heterocyclyl, C 6~18 Viaryl, or C 6~18 Heterobiaryl and; CRBM has a structure: It has TIFF2026508972000472.tif15128, In the above formula, Each RG 1 Independently TIFF2026508972000473.tif is 7128; Each occurrence of XG is independently selected from the group consisting of -CH2-, -C(=O)-, -NH-, and -O-; Each occurrence of ZG is independently selected from the group consisting of -CH2-, -C(=O)-, -NH-, and -O-; AG is independently at each occurrence TIFF2026508972000474.tif is 21128; RG 2 and RG 3 are, independently at each occurrence, hydrogen, and one to five groups independently selected from the group consisting of halogen, optionally substituted C 1~10 alkyl, optionally substituted C 1~10 alkoxy, optionally substituted C 1~10 aminoalkyl, and combinations thereof, or is selected from the group consisting of -C(=O)R optionally substituted with one to five groups selected from the group consisting of RG 2 and RG 3 together with the nitrogen atom to which they are attached, form a C5 heterocycle optionally substituted with one to five substituents selected from the group consisting of optionally substituted C 1~10 alkyl, optionally substituted C 1~10 Each occurrence of R is independently H, optionally substituted C 1~10 alkyl, optionally substituted C 3~10 cycloalkyl, optionally substituted C 6~18 aryl, or optionally substituted C 5~18 heteroaryl; Each occurrence of m is independently 2, 3, 4, 5, 6, 7, 8, 9, or 10; Each occurrence of n is independently an integer in the range of 1 to 100; ​​​​​​​Each occurrence p is an independent integer in the range of 1 to 50; k' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; j' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; h and h' are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; i L is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; However, h, h', and i L At least one of them is at least 1. The compound, or its pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs. Embodiment 2: The compound of Embodiment 1, wherein k' is 1 and j' is 1. Appearance 3: Formula IIb: The formula has the expression TIFF2026508972000475.tif25128, During the ceremony, L A Structure: It has TIFF2026508972000476.tif15128, In the above formula, Each RG 1 Independently The filename is TIFF2026508972000477.tif7128; Each occurrence of XG is independently selected from the group consisting of -CH2-, -C(=O)-, -NH-, and -O-; Each occurrence of ZG is independently selected from the group consisting of -CH2-, -C(=O)-, -NH-, and -O-; AG is independent in each appearance The filename is TIFF2026508972000478.tif21128; RG 2 and RG 3 In each instance, independently, hydrogen and halogen, and possibly substituted C, are present. 1~10 Alkyl, possibly substituted C1~10 Alkoxy, C may be substituted. 1~10 Selected from the group consisting of aminoalkyl groups and combinations thereof, and -C(=O)R groups which may be substituted with 1 to 5 groups selected from the group consisting of aminoalkyl groups and combinations thereof, or RG 2 and RG 3 These, together with the nitrogen atom to which they are bonded, may be substituted C 1~10 Alkyl, possibly substituted C 1~10 Alkoxy, C may be substituted. 1~10 aminoalkyl, optionally substituted C 6~10 Aryl, C may be substituted. 5~10 It forms a C5 heterocycle which may be substituted with 1 to 5 substituents selected from the group consisting of heteroaryls, halogens, and combinations thereof; Each occurrence of R is independent of H, and C may be substituted. 1~10 Alkyl, possibly substituted C 3~10 Cycloalkyl, may be substituted C 6~18 Aryl, or possibly substituted C 5~18 It is a heteroaryl; L B Structure: This is an anti-CCP binding portion having TIFF2026508972000479.tif20128, In the above formula, AA is an amino acid sequence that is at least 80% homologous to an amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:69~SEQ ID NO:76, and SEQ ID NO:77; m is 2, 3, 4, 5, 6, 7, 8, 9, or 10. A compound according to embodiment 1 or 2. Embodiment 4: The compound of Embodiment 3, wherein AA is a (3,16)cyclic peptide. Embodiment 5: The compound of Embodiment 3 or 4, wherein AA is at least 95% homologous to SEQ ID NO:1. Embodiment 6: A compound according to any one of Embodiments 3 to 5, wherein AA is the amino acid sequence of SEQ ID NO:1. Embodiment 7: A compound from any one of Embodiments 3 to 6, wherein m is 2. Appearance 8: (ZG) p A compound in any one of embodiments 1 to 6, wherein the parent compound is -CH2-(O-CH2-CH2)2-NH(C=O)CH2CH2-. Appearance 9: Each RG 1 but A compound according to any one of embodiments 1 to 6, which is TIFF2026508972000480.tif10128. Embodiment 10: L A Or CRBM, structure: A compound having TIFF2026508972000481.tif27128, one of any one of embodiments 1 to 6. Appearance 11: (XG) n However, one compound selected from the group consisting of -CH2-(OCH2CH2)2-, -CH2-(OCH2CH2)3-, -CH2-(OCH2CH2)4-, and -CH2-(OCH2CH2)5-, which is any one of embodiments 1 to 6. Appearance 12: (XG) n The compound of embodiment 11, wherein the compound is -CH2-(OCH2CH2)4-. Appearance 13: RG 1 Each AG within A compound according to any one of embodiments 1 to 12, which is TIFF2026508972000482.tif20128. Appearance 14: RG 2 A compound according to embodiment 13, wherein the compound is hydrogen. Appearance 15: RG 3 A compound according to embodiment 13, wherein -C(=O)CH3. Appearance 16: RG 1 Each AG within A compound according to any one of embodiments 1 to 15, which is TIFF2026508972000483.tif30128. Appearance 17: L A Or CRBM A compound according to any one of embodiments 1 to 16, which is TIFF2026508972000484.tif42131. Appearance 18: A compound according to any one of embodiments 1 to 17, which is TIFF2026508972000485.tif180140. Appearance 19: Structure: A compound of formula Ia having TIFF2026508972000486.tif30128, or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, During the ceremony, TIFF2026508972000487.tif2128 is a single or double bond between carbon atoms; A may be substituted with 1 to 6 substituents selected from the group consisting of F, Cl, Br, I, O(RG), O(O)N(RG)2, CN, NO, NO2, ONO2, CF3, OCF3, -(RG), N(RG)2, S(RG), SO(RG), SO2(RG), SO2N(RG)2, and SO3(RG), C 6~18 Ariel, C 6~18 Heterocyclyl, C 6~18 Biaryl, or C 6~18 It is a heterobiaryl; L A Structure: This is an ASGPR junction containing TIFF2026508972000488.tif15128; L B Structure: It is an anti-CCP1 binding moiety having TIFF2026508972000489.tif20128; AA is an amino acid sequence that is at least 80% homologous to SEQ ID NO:1; RG 1 Each appearance is independently of hydrogen or The filename is TIFF2026508972000490.tif7128; AG is an amino sugar; Each occurrence of RG is independently H, and C may be substituted. 1~10 Alkyl, possibly substituted C 3~10 Cycloalkyl, may be substituted C 6~18 Aryl, or possibly substituted C 5~18 It is a heteroaryl; Each occurrence of XG is independently selected from the group consisting of -CH2-, -C(=O)-, -NH-, and -O-; Each occurrence of ZG is independently selected from the group consisting of -CH2-, -C(=O)-, -NH-, and -O-; m is 2, 3, 4, 5, 6, 7, 8, 9, or 10; n is an integer in the range of 1 to 100; p is an integer in the range of 1 to 50, the compound, or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof. Aspect 20: Each AG independently has the structure: TIFF2026508972000491.tif20128, wherein, RG 2 and RG 3 are each independently hydrogen, and a group of 1 to 5 substituents selected from the group consisting of halogen, optionally substituted C 1~10 alkyl, optionally substituted C 1~10 alkoxy, optionally substituted C 1~10 aminoalkyl, and combinations thereof, or optionally substituted -C(=O)R selected from the group consisting of; or RG 2 and RG 3 together with the nitrogen atom to which they are attached, form a C5 heterocycle optionally substituted with 1 to 5 substituents selected from the group consisting of optionally substituted C 1~10 alkyl, optionally substituted C 1~10 alkoxy, optionally substituted C 1~10 aminoalkyl, optionally substituted C 6~10 aryl, optionally substituted C 5~10 heteroaryl, halogen, and combinations thereof; Each occurrence of R is independently H, optionally substituted C 1~10 alkyl, optionally substituted C 3~10 cycloalkyl, optionally substituted C 6~18 aryl, or optionally substituted C 5~18It is a heteroaryl. Compound according to embodiment 19. Appearance 21: RG 2 It is hydrogen, and RG 3 A compound according to embodiment 19 or 20, wherein is C(=O)CH3. Embodiment 22: AG has structure: A compound according to embodiment 19 or 20, having TIFF2026508972000492.tif20128. Embodiment 23: AG has structure: A compound according to embodiment 19 or 20, having TIFF2026508972000493.tif16128. Appearance 24: (ZG) p Each occurrence is independently structured: It has TIFF2026508972000494.tif14128, In the formula, p is 2, 4, 6, or 8. A compound according to any one of embodiments 19 to 23. Appearance 25: (XG) n However, -O(CH2)3-, -NH-(CH2CH2O)3-CH2-, and =N * Selected from the group consisting of (C=O)(CH2)2C(=O)NHCH2CH2-(OCH2CH2)4-, where in the formula, =N * A is a ring nitrogen within A, and is one of any one of the compounds in embodiments 19 to 24. Embodiment 26: Any one of the compounds from Embodiments 19 to 25, wherein AA is a (3,16)cyclic peptide. Embodiment 27: Any one of the compounds from Embodiments 19 to 26, wherein AA is at least 95% homologous to SEQ ID NO:1. Embodiment 28: A compound according to any one of Embodiments 19 to 27, wherein AA is the amino acid sequence of SEQ ID NO:1. Appearance 29: L A However, the structure: This is an ASGPR coupling portion containing TIFF2026508972000495.tif15128; Each RG 1 but The filename is TIFF2026508972000496.tif7128; Below:(i)L A Each AG within TIFF2026508972000497.tif20128; (ii)L A Two of the AGs inside TIFF2026508972000498.tif20128, L A One of the AGs inside TIFF2026508972000499.tif16128; (iii)L A One of the AGs inside TIFF2026508972000500.tif20128, L A Two of the AGs inside TIFF2026508972000501.tif16128; or (iv)L A Each AG within The file is TIFF2026508972000502.tif16128; one of the following conditions applies: A compound from any one of embodiments 19 to 28. Apparatus 30: Structure: A compound according to any one of embodiments 19 to 29, having TIFF2026508972000503.tif29128. Embodiment 31: A pharmaceutical composition comprising one compound from Embodiments 1 to 30 and at least one pharmaceutically acceptable carrier or excipient. Embodiment 32: A method for preventing, treating, and / or relieving arthritis in a person in need thereof, The method comprises the step of administering a therapeutically effective amount of any one compound of embodiments 1 to 30 to a subject, wherein the compound is optionally formulated as a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier or excipient. Embodiment 33: The method of Embodiment 32, wherein the arthritis is selected from the group consisting of rheumatoid arthritis, lupus erythematosus, psoriatic arthritis, ankylosing spondylitis, and axial spondyloarthritis. Embodiment 34: The method of Embodiment 33, wherein the arthritis is rheumatoid arthritis. Embodiment 35: Any one of Embodiments 32 to 34, wherein the compound is administered by a route selected from the group consisting of oral, transdermal, transmucosal, nasal (intra)nasal, (trans)rectal, intrabladder, intrapulmonary, intraduodenal, intragastric, subarachnoid, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical. Embodiment 36: Any one of Embodiments 32 to 34, wherein the compound is administered intravenously or orally. Embodiment 37: Any one of Embodiments 32 to 36, wherein the compound is administered in a dose of approximately 0.01 mg / kg to approximately 20 mg / kg. Embodiment 38: Any one of embodiments 32 to 37, wherein the subject is a mammal. Embodiment 39: Any one of embodiments 32 to 38, wherein the subject is a human. Embodiment 40: Any one of embodiments 32 to 39, further comprising the step of administering at least one additional therapeutic agent selected from the group consisting of disease-modifying antirheumatic drugs, glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), and analgesics. Embodiment 41: The method of Embodiment 40, wherein the at least one additional therapeutic agent is administered sequentially or simultaneously with the compound, and optionally, the at least one additional therapeutic agent and the compound are combined into a compound. Embodiment 42 is the PBM or L B The present invention provides compounds according to embodiments 1 to 30, which include a peptide containing 5 to 40 amino acid residues, of which 1 to 5 are citrulline residues, and optionally, at least 2 of the residues in the peptide are cysteine ​​residues that form a disulfide (-SS-) bond.

[0544] The terms and expressions used herein are for illustrative purposes only, not limitation, and in using such terms and expressions, there is no intention to exclude the shown and described features or their equivalents, and it should be recognized that various modifications are possible within the scope of the embodiments of this application. Accordingly, although this application describes specific embodiments and optional features, it should be understood that modifications and variations of the compositions, methods, and concepts disclosed herein may be adopted by those skilled in the art, and such modifications and variations should be considered within the scope of the embodiments of this application.

Claims

1. structure: A compound of formula II having, or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, During the ceremony, PBM is the antibody-binding site for anti-cyclic citrullinated peptides (anti-CCPs); CON and linker-2 appear independently in each instance, as follows: （a） In the above formula, R 1 Each occurrence is independently H or C 1 ~C 3 It is alkyl; Each occurrence of n'' is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; or （b） In the above formula, Each occurrence of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25; Each occurrence of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25; Each occurrence of n'' is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; or （c） In the above formula, Z and Z' are each independently a bond, -(CH 2 ) i -O-, -(CH 2 ) i -S-, -(CH 2 ) i -N(R)-, And; R 2 Each occurrence is independently H or C 1 ~C 3 It is alkyl; Each occurrence of Y is independently a combination, -O-, -S-, or -N(R)-; Each occurrence of i is an independent integer in the range of 0 to 100; D is -(CH 2 ) i -YC(=O)-Y-(CH 2 ) i -,-(CH 2 ) m' -,-[(CH 2 ) n -X 1 ] j -, or combination, except that Z, Z', and D are not combined simultaneously; j is an integer in the range of 1 to 100; m' is an integer in the range of 1 to 100; n is an integer in the range of 1 to 100; X 1 is -O-, -S-, or -N(R)-; Each R can independently be substituted with H, or C may be substituted with 1 to 3 hydroxyl groups. 1 ~C 3 It is alkyl; or （d） A structure selected from the group consisting of the above formula, X 2 Each occurrence is independently -CH 2 -, -O-, -S-, -N(R 4 )-, -C(O)-, -S(O)-, -S(O) 2 -, -S(O) 2 O-, -OS(O) 2 -, or -OS(O) 2 It is O-; X 3 In each occurrence, -O-, -S-, or -N(R 4 )-and; R 4 In each occurrence, H and C are independent. 1 ~C 3 Alkyl, C 1 ~C 3 Alkanol, or -C(O)(C 1 ~C 3 It is alkyl. The structure; or (e) C 6～18 Ariel, C 3～18 Heterocyclyl, C 6～18 Viaryl, or C 6～18 A heterobiaryl, consisting of F, Cl, Br, I, O(RG), O(O)N(RG) 2 , CN, NO, NO 2 ONO 2 , CF 3 OCF 3 ,-(RG),N(RG) 2 S(RG), SO(RG), SO 2 (RG), SO 2 N(RG) 2 , and SO 3 Each of the substituents may be substituted with 1 to 6 substituents selected from the group consisting of (RG), where each occurrence of RG is independently substituted with H, or C. 1～10 Alkyl, possibly substituted C 3～10 Cycloalkyl, may be substituted C 6～18 Aryl, or possibly substituted C 5～18 The C is a heteroaryl compound. 6～18 Ariel, C 3～18 Heterocyclyl, C 6～18 Viaryl, or C 6～18 Heterobiaryl And; CRBM has the following structure: It has, In the above formula, Each RG 1 Independently And; Each XG occurrence is independent of -CH 2 Selected from the group consisting of -, -C(=O)-, -NH-, and -O-; Each appearance of ZG is independent of -CH 2 Selected from the group consisting of -, -C(=O)-, -NH-, and -O-; AG is independent in each appearance And; RG 2 and RG 3 In each instance, independently, hydrogen and halogen, and possibly substituted C, are present. 1～10 Alkyl, possibly substituted C 1～10 Alkoxy, C may be substituted. 1～10 Selected from the group consisting of aminoalkyl groups and combinations thereof, and -C(=O)R groups which may be substituted with 1 to 5 groups selected from the group consisting of aminoalkyl groups and combinations thereof, or RG 2 and RG 3 These, together with the nitrogen atom to which they are bonded, may be substituted C 1～10 Alkyl, possibly substituted C 1～10 Alkoxy, C may be substituted. 1～10 aminoalkyl, optionally substituted C 6～10 Aryl, C may be substituted. 5～10 It forms a C5 heterocycle which may be substituted with 1 to 5 substituents selected from the group consisting of heteroaryls, halogens, and combinations thereof; Each occurrence of R is independent of H, and C may be substituted. 1～10 Alkyl, possibly substituted C 3～10 Cycloalkyl, may be substituted C 6～18 Aryl, or possibly substituted C 5～18 It is a heteroaryl; Each occurrence of m is independently 2, 3, 4, 5, 6, 7, 8, 9, or 10; Each occurrence of n is an integer in the range of 1 to 100, independently; Each occurrence p is an independent integer in the range of 1 to 50; k' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; j' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; h and h' are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; i L is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; However, h, h', and i L At least one of them is at least 1. The compound, or its pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs.

2. The compound according to claim 1, wherein k' is 1 and j' is 1.

3. Equation IIb: The formula is During the ceremony, L A Structure: It has, In the above formula, Each RG 1 Independently And; Each XG occurrence is independent of -CH 2 Selected from the group consisting of -, -C(=O)-, -NH-, and -O-; Each appearance of ZG is independent of -CH 2 Selected from the group consisting of -, -C(=O)-, -NH-, and -O-; AG is independent in each appearance And; RG 2 and RG 3 is, independently at each occurrence, hydrogen, and from the group consisting of halogen, optionally substituted C 1～10 alkyl, optionally substituted C 1～10 alkoxy, optionally substituted C 1～10 aminoalkyl, and optionally substituted with 1 to 5 groups selected from the group consisting of combinations thereof -C(=O)R selected from the group consisting of, or RG 2 and RG 3 together with the nitrogen atom to which they are attached form a C5 heterocycle optionally substituted with 1 to 5 substituents selected from the group consisting of optionally substituted C 1～10 alkyl, optionally substituted C 1～10 alkoxy, optionally substituted C 1～10 aminoalkyl, optionally substituted C 6～10 aryl, optionally substituted C 5～10 heteroaryl, halogen, and combinations thereof; Each occurrence of R is independent of H, and C may be substituted. 1～10 Alkyl, possibly substituted C 3～10 Cycloalkyl, may be substituted C 6～18 Aryl, or possibly substituted C 5～18 It is a heteroaryl; L B Structure: It is an anti-CCP binding moiety having, In the above formula, AA is an amino acid sequence that is at least 80% homologous to an amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:69 to SEQ ID NO:76, and SEQ ID NO:77; m is 2, 3, 4, 5, 6, 7, 8, 9, or 10. The compound according to claim 1.

4. The compound according to claim 3, wherein AA is a (3,16)cyclic peptide.

5. The compound according to claim 4, wherein AA is at least 95% homologous to SEQ ID NO:

1.

6. The compound according to claim 4, wherein AA is the amino acid sequence of SEQ ID NO:

1.

7. The compound according to any one of claims 3 to 6, wherein m is 2.

8. (ZG) p ga-CH 2 -(O-CH 2 -CH 2 ) 2 -NH(C=O)CH 2 CH 2 - The compound according to any one of claims 1 to 6.

9. Each RG 1 but The compound according to any one of claims 1 to 6.

10. L A Or CRBM, structure: A compound according to any one of claims 1 to 6, having the following characteristics.

11. (XG) n However, -CH 2 -(OCH 2 CH 2 ) 2 -, -CH 2 -(OCH 2 CH 2 ) 3 -, -CH 2 -(OCH 2 CH 2 ) 4 -, and -CH 2 -(OCH 2 CH 2 ) 5 A compound according to any one of claims 1 to 6, selected from the group consisting of -.

12. (XG) n ga-CH 2 -(OCH 2 CH 2 ) 4 - The compound according to claim 11.

13. RG 1 Each AG within The compound according to any one of claims 1 to 12.

14. RG 2 The compound according to claim 13, wherein is hydrogen.

15. RG 3 -C(=O)CH 3 The compound according to claim 13.

16. RG 1 Each AG within The compound according to any one of claims 1 to 15.

17. L A Or CRBM The compound according to any one of claims 1 to 16.

18. The compound according to any one of claims 1 to 17.

19. structure: A compound of formula Ia having, or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, During the ceremony, is a single or double bond between carbon atoms; A is F, Cl, Br, I, O(RG), OC(O)N(RG) 2 , CN, NO, NO 2 ONO 2 , CF 3 OCF 3 ,-(RG),N(RG) 2 S(RG), SO(RG), SO 2 (RG), SO 2 N(RG) 2 , and SO 3 Each of the following substituents may be substituted with one to six substituents selected from the group consisting of (RG): C 6～18 Ariel, C 6～18 Heterocyclyl, C 6～18 Biaryl, or C 6～18 It is a heterobiaryl; L A Structure: It is an ASGPR coupling portion having; L B Structure: It is an anti-CCP1 binding moiety having; AA is an amino acid sequence that is at least 80% homologous to SEQ ID NO:1; RG 1 Each appearance is independently of hydrogen or And; AG is an amino sugar; Each occurrence of RG is independently H, and C may be substituted. 1～10 Alkyl, possibly substituted C 3～10 Cycloalkyl, may be substituted C 6～18 Aryl, or possibly substituted C 5～18 It is a heteroaryl; Each XG occurrence is independent of -CH 2 Selected from the group consisting of -, -C(=O)-, -NH-, and -O-; Each appearance of ZG is independent of -CH 2 Selected from the group consisting of -, -C(=O)-, -NH-, and -O-; m is 2, 3, 4, 5, 6, 7, 8, 9, or 10; n is an integer in the range of 1 to 100; p is an integer in the range of 1 to 50. The compound, or its pharmaceutically acceptable salts, stereoisomers, solvates, or polymorphs.

20. Each AG is structured independently: It has, During the ceremony, RG 2 and RG 3 Each of these independently consists of hydrogen and a halogen, and may be substituted with C. 1～10 Alkyl, possibly substituted C 1～10 Alkoxy, C may be substituted. 1～10 Selected from the group consisting of aminoalkyl groups and combinations thereof, and -C(=O)R groups which may be substituted with 1 to 5 groups selected from the group consisting of aminoalkyl groups and combinations thereof, or RG 2 and RG 3 These, together with the nitrogen atom to which they are bonded, may be substituted C 1～10 Alkyl, possibly substituted C 1～10 Alkoxy, C may be substituted. 1～10 aminoalkyl, optionally substituted C 6～10 Aryl, C may be substituted. 5～10 It forms a C5 heterocycle which may be substituted with 1 to 5 substituents selected from the group consisting of heteroaryls, halogens, and combinations thereof; Each occurrence of R is independent of H, and C may be substituted. 1～10 Alkyl, possibly substituted C 3～10 Cycloalkyl, may be substituted C 6～18 Aryl, or possibly substituted C 5～18 It is a heteroaryl. The compound according to claim 19.

21. RG 2 It is hydrogen, and RG 3 is C(=O)CH 3 The compound according to claim 19 or 20.

22. AG is structured as follows: The compound according to claim 19 or 20, having the following characteristics.

23. AG is structured as follows: The compound according to claim 19 or 20, having the following characteristics.

24. (ZG) p Each occurrence is independently structured: It has, In the formula, p is 2, 4, 6, or 8. The compound according to any one of claims 19 to 23.

25. (XG) n However, -O(CH 2 ) 3 -, -NH-(CH 2 CH 2 O) 3 -CH 2 -, and =N * (C=O)(CH 2 ) 2 C(=O)NHCH 2 CH 2 -(OCH 2 CH 2 ) 4 - Selected from the group consisting of, where in the formula, =N * The compound according to any one of claims 19 to 24, wherein is a ring nitrogen in A.

26. The compound according to any one of claims 19 to 25, wherein AA is a (3,16) cyclic peptide.

27. The compound according to any one of claims 19 to 26, wherein AA is at least 95% homologous to SEQ ID NO:

1.

28. The compound according to any one of claims 19 to 27, wherein AA is the amino acid sequence of SEQ ID NO:

1.

29. L A However, the structure: It is an ASGPR coupling portion having; Each RG 1 but And; below: (i) L A Each AG within It is; (ii) L A Two of the AGs inside And L A One of the AGs inside It is; (iii) L A One of the AGs inside And L A Two of the AGs inside is; or (iv) L A Each AG within It is; One of the following applies: The compound according to any one of claims 19 to 28.

30. structure: A compound according to any one of claims 19 to 29, having the following characteristics.

31. A pharmaceutical composition comprising a compound according to any one of claims 1 to 30 and at least one pharmaceutically acceptable carrier or excipient.

32. A method for preventing, treating, and / or relieving arthritis in a person who needs it, A method comprising the step of administering a therapeutically effective amount of a compound according to any one of claims 1 to 30 to a subject, wherein the compound is optionally formulated as a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier or excipient.

33. The method according to claim 32, wherein the arthritis is selected from the group consisting of rheumatoid arthritis, lupus erythematosus, psoriatic arthritis, ankylosing spondylitis, and axial spondyloarthritis.

34. The method according to claim 33, wherein the arthritis is rheumatoid arthritis.

35. The method according to any one of claims 32 to 34, wherein the compound is administered by a route selected from the group consisting of oral, transdermal, transmucosal, nasal (intra)nasal, (trans)rectal, intrabladder, intrapulmonary, intraduodenal, intragastric, subarachnoid, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical.

36. The method according to any one of claims 32 to 34, wherein the compound is administered intravenously or orally.

37. The method according to any one of claims 32 to 36, wherein the compound is administered in a dose of about 0.01 mg / kg to about 20 mg / kg.

38. The method according to any one of claims 32 to 37, wherein the subject is a mammal.

39. The method according to any one of claims 32 to 38, wherein the subject is a human.

40. The method according to any one of claims 32 to 39, further comprising the step of administering at least one additional therapeutic agent selected from the group consisting of disease-modifying antirheumatic drugs, glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), and analgesics.

41. The method according to claim 40, wherein the at least one additional therapeutic agent is administered sequentially or simultaneously with the compound, and optionally, the at least one additional therapeutic agent and the compound are in a combination.

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