Compounds and methods for treating, ameliorating or preventing arthritis

Abstract

The present disclosure describes compounds that contain, in a non-limiting aspect, an asialoglycoprotein receptor (ASGPR) binding moiety and an anti-CCP (anti-cyclic citrullinated peptide binding moiety). These compounds are useful for preventing, treating and / or ameliorating various types of arthritis, including rheumatoid arthritis (RA), in a subject when administered in therapeutically effective amounts.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 482,486, filed January 31, 2023, entitled “Compounds and methods for treating, improving or preventing arthritis”, and U.S. Provisional Patent Application No. 63 / 606,161, filed December 5, 2023, entitled “Compounds and methods for treating, improving or preventing arthritis”, the entire disclosure of which is incorporated herein by reference.

[0003] Statement regarding federally funded research

[0004] This invention was developed with government support under Project GM067543, granted by the National Institutes of Health in the United States. The government holds certain rights to this invention.

[0005] By incorporating the material submitted as a text file via the Patent Office's electronic submission system.

[0006] This invention includes one or more sequences in a computer-readable format entitled “047162-7400WO1(02160)SequenceListing ST_26.xml” in an accompanying text file, which is 112KB in size and was created on January 29, 2024, the contents of which are incorporated herein by reference in their entirety. Background Technology

[0007] In rheumatoid arthritis (RA), the body's immune system attacks its own tissues, including the joints, and eventually internal organs. RA affects the inner lining of the joints, causing painful swelling. Over long periods, the inflammation associated with RA can lead to bone erosion and joint deformities. Existing treatments for RA include methotrexate and adalimumab. These are associated with serious adverse side effects, including but not limited to loss of appetite, oral pain, diarrhea, headache, and / or hair loss.

[0008] Therefore, there is a current need for more selective and rapid-acting RA treatments. This disclosure addresses this need. Summary of the Invention

[0009] In all respects, this article provides compounds of formula II or pharmaceutically acceptable salts, stereoisomers, solvates or polymorphs thereof having the following structures:

[0010]

[0011] in:

[0012] PBM is the binding site of anti-cyclic citrullinated peptide (anti-CCP) antibodies;

[0013] CON and LINKER-2 are independent each time they appear:

[0014] a) in:

[0015] R 1 Each occurrence of is independently H or C1-C3 alkyl; and

[0016] 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

[0017] b) in:

[0018] 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;

[0019] 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;

[0020] 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

[0021] c) in:

[0022] Z and Z' are each an independent bond, -(CH2) i -O-、-(CH2) i -S-、-(CH2) i -N(R)-、

[0023] R 2 Each occurrence of is independently H or C1-C3 alkyl;

[0024] Each occurrence of Y is a key independently, -O-, -S-, or -N(R)-;

[0025] Each occurrence of i is an independent integer from 0 to 100;

[0026] D stands for -(CH2) i -YC(=O)-Y-(CH2) i -、-(CH2)m’ -、-[(CH2) n -X 1 ] j - OR key, provided that Z, Z' and D are not all keys at the same time;

[0027] j is an integer from 1 to 100;

[0028] m' is an integer from 1 to 100;

[0029] n is an integer from 1 to 100;

[0030] X 1 It is -O-, -S-, or -N(R)-;

[0031] Each R is independently H or a C1-C3 alkyl group optionally substituted with 1-3 hydroxyl groups; or d) a structure selected from the following:

[0032]

[0033] in

[0034] X 2 Each occurrence is independently -CH2-, -O-, -S-, -N(R) 4 )-, -C(O)-, -S(O)-, -S(O)2-, -S(O)2O-, -OS(O)2- or -OS(O)2O-;

[0035] X 3 Each occurrence is independently -O-, -S-, or -N(R) 4 )-;

[0036] R 4 Each time it appears, it is independently H, C1-C3 alkyl, C1-C3 alkanol, or -C(O)(C1-C3 alkyl); or e)C 6-18 Aryl, C 3-18 Heterocyclic group, C 6-18 Biaryl or C 6-18 The heteroaryl groups are each optionally substituted with 1-6 substituents selected from F, Cl, Br, I, O(RG), OC(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).

[0037] Each occurrence of RG is independently H, with optional substitution of C. 1-10 Alkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 6-18aryl or optionally substituted C 5-18 Mixed aromatics;

[0038] The structure of CRBM is as follows:

[0039] in

[0040] Each RG 1 Independently

[0041] Each occurrence of XG is independently selected from -CH2-, -C(=O)-, -NH-, and -O-;

[0042] Each occurrence of ZG is independently selected from -CH2-, -C(=O)-, -NH-, and -O-;

[0043] Each occurrence of AG is independent.

[0044]

[0045] RG 2 and RG 3 Each time it appears, it is independently selected from hydrogen and -C(=O)R, which is optionally replaced by 1-5 Cs selected from halogens and optionally substituted. 1-10 Alkyl, optionally substituted C 1-10 Alkoxy, optional substituted C 1-10 aminoalkyl groups and combinations thereof are substituted, or

[0046] RG 2 and RG 3 Together with the nitrogen atoms to which they are attached, they form a C5 heterocycle, which is optionally substituted by 1-5 substituents selected from the optionally substituted C atoms. 1-10 Alkyl, optionally substituted C 1-10 Alkoxy, optional substituted C 1-10 Aminoalkyl, optionally substituted C 6-10 aryl, optionally substituted C 5-10 heteroaryl groups, halogens and their combinations;

[0047] Each occurrence of R is independently of H, and the C is arbitrarily substituted. 1-10 Alkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 6-18 aryl or optionally substituted C 5-18 Mixed aromatics;

[0048] Each occurrence of m is independently 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0049] Each occurrence of n is an integer from 1 to 100 independently;

[0050] Each occurrence of p is an integer from 1 to 50 independently;

[0051] k' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15;

[0052] j' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15;

[0053] h and h' are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15;

[0054] i L The digits are 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; and

[0055] The conditions are h, h', and i L At least one of them is at least 1.

[0056] In various respects, this paper provides Equation I with the following structure a The compound or its pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph:

[0057]

[0058] in:

[0059] It is a carbon-carbon single or double bond;

[0060] A is C 6-18 Aryl, C 6-18 Heterocyclic group, C 6-18 Biaryl or C 6-18 Heteroaryl groups, each optionally substituted by 1-6 substituents selected from F, Cl, Br, I, O(RG), OC(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);

[0061] L A It is the ASGPR bonding part, which has a structure

[0062] L B It is the anti-CCP1 binding part, with structure

[0063] AA is an amino acid sequence that is at least 80% homologous to SEQ ID NO:1;

[0064] RG 1 Each occurrence is independently of hydrogen or

[0065] AG is an amino sugar;

[0066] Each occurrence of RG is independently H, with optional substitution of C. 1-10 Alkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 6-18 aryl or optionally substituted C 5-18 Mixed aromatics;

[0067] Each occurrence of XG is independently selected from -CH2-, -C(=O)-, -NH-, and -O-;

[0068] Each occurrence of ZG is independently selected from -CH2-, -C(=O)-, -NH-, and -O-;

[0069] m is 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0070] n is an integer from 1 to 100; and

[0071] p is an integer from 1 to 50.

[0072] Methods for the prevention, treatment, and / or improvement of arthritis in a subject of need, using compounds of formula Ia, II, IIb, or any other compounds described herein. In various aspects, the method comprises administering to a subject a therapeutically effective amount of a compound of formula Ia, II, IIb, or any other compound described herein, wherein said compound is optionally formulated as a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier or excipient. Attached Figure Description

[0073] The accompanying drawings illustrate various embodiments of this application by way of example rather than limitation.

[0074] Figure 1 This is a schematic diagram of one mode of action of the compound of formula I according to various embodiments. Not wishing to be bound by theory, the mechanism of action of the compound is described below in at least part: Step 1: MoDE-A binds to the target protein of interest; Step 2: The MoDE-A / protein complex binds to ASGPR (desialylglycoprotein receptor) on hepatocytes; Step 3: The ASGPR / MoDE-A / protein ternary complex is internalized into the hepatocytes; Step 4: The ternary complex dissociates; Step 5: The intracellular target protein is degraded; and Step 6: ASGPR and MoDE-A are reabsorbed extracellularly.

[0075] Figure 2AAn ASGPR binding fragment according to some implementations is shown.

[0076] Figure 2B The structure of Formula I according to some embodiments is shown.

[0077] Figures 3A-3D Together, a scheme for synthesizing compound Target A0001A according to some embodiments is shown. Figure 3A A scheme for synthesizing PEGylated sugar 4 according to some embodiments is shown. Figure 3B Schemes for synthesizing tricarboxylic acid 8 according to various embodiments are shown. Figure 3C A scheme for synthesizing desialyl glycoprotein binder 10 according to some embodiments is shown. Figure 3D The synthesis of compound Target A0001A according to some embodiments is shown.

[0078] Figures 4A-4C Together, a scheme for synthesizing compound CCP1-GN4 of formula I according to some embodiments is shown. Figure 4A The synthesis of peptide intermediate Int-00002 is shown. Figure 4B The synthesis of an alkynyl derivative of compound Target A0001A according to some embodiments is shown. Figure 4C The synthesis of CCP1-GN4 according to some embodiments is shown.

[0079] Figure 5A The data on the resistance to CCP1 SPR (surface plasmon resonance) binding of compound CCP1-GN4 according to some embodiments are shown. KC of CCP1-GN4 D (Anti-CCP) is 75 nM.

[0080] Figure 5B The ASGPRSPR binding data of compound CCP1-GN4 according to some embodiments are shown. K of CCP1-GN4 D (ASGPR) is 1.92 nM.

[0081] Figure 6A Plasma stability data for CCP1-GN4 in mice, rats, and humans are shown according to some implementation methods. All T 1 / 2 All are longer than 290 minutes.

[0082] Figure 6B Plasma protein binding data for CCP1-GN4 in mice, rats, and humans are shown.

[0083] Figure 7 This demonstrates, according to some implementations, CCP1-GN4-mediated anti-CCP1 internalization into ASGPR.+ Data from HEK-293 cells.

[0084] Figure 8A Data on CCP1 depletion resistance of CCP1-GN4 compared to a control according to some embodiments are shown.

[0085] Figure 8B This illustrates, according to some implementation methods, reference Figure 8A The exhaustion study shown is an AUC (area under the curve) data for CCP1-GN4 compared to the control. Detailed Implementation

[0086] Reference will now be made in detail to certain embodiments of the disclosed subject matter, some of which are illustrated in the accompanying drawings. While the disclosed subject matter will be described in conjunction with the listed claims, it is to be understood that the illustrative subject matter is not intended to limit the claims to the disclosed subject matter.

[0087] Values ​​expressed in range format throughout this document should be interpreted flexibly to include not only the values ​​explicitly stated as range boundaries, but also all individual values ​​or subranges included within that range, as if each value and subrange were explicitly stated. For example, the range “about 0.1% to about 5%” or “about 0.1% to 5%” should be interpreted to include not only about 0.1% to about 5%, but also individual values ​​(e.g., 1%, 2%, 3%, and 4%) and subranges within the specified range (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%). Unless otherwise stated, the statement “about X to Y” has the same meaning as “about X to about Y”. Similarly, unless otherwise stated, the statement “about X, Y, or about Z” has the same meaning as “about X, about Y, or about Z”.

[0088] In this document, unless the context clearly specifies otherwise, the terms “a,” “an,” or “the” are used to include one or more. Unless otherwise stated, the term “or” is used to refer to a non-exclusive “or.” The expressions “at least one of A and B” or “at least one of A or B” have the same meaning as “A, B, or A and B.” Furthermore, it should be understood that the wording or terminology used herein, unless otherwise defined, is descriptive and not restrictive. Section headings are used to aid reading and should not be construed as limiting; information relating to a section heading may appear within or outside that particular section. All publications, patents, and patent documents cited in this document are incorporated herein by reference in their entirety as if individually cited.

[0089] In the methods described herein, actions may be performed in any order unless the timing or sequence of operations is explicitly stated. Furthermore, specified actions may be performed simultaneously unless the language of the claim specifies that they should be performed separately. For example, the claimed action of performing X and the claimed action of performing Y may be performed simultaneously in a single step, and the resulting method will fall within the literal scope of the claimed method.

[0090] definition

[0091] The term “about” as used herein may allow for a degree of variation in the value or range, for example, within 10%, 5%, or 1% of the specified limit of the specified value or range, and includes the exact specified value or range.

[0092] As used herein, the term "substantially" means the majority or the vast majority, such as 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%. As used herein, the term "substantially free of" may mean that it contains no or only a very small amount of material such that the amount of material present does not affect the material properties of the composition comprising the material, such that the material in the composition is about 0 wt% to about 5 wt%, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to 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. The term "substantially free" can mean having a negligible amount such that the material in the composition is about 0 wt% to about 5 wt%, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to 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%.

[0093] As used herein, the term "organic group" refers to any carbon-containing functional group. Examples may include oxygen-containing groups, such as alkoxy, aryloxy, aralkyloxy, and oxo (carbonyl) groups; carboxyl groups, including carboxylic acids, carboxylates, and carboxylic esters; sulfur-containing groups, such as alkyl and aryl thioether groups; and other heteroatom-containing groups. Non-limiting 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, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, and (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 R can be a hydrocarbon group, wherein R can be hydrogen (in instances including other carbon atoms) or a carbonyl moiety, and wherein the carbonyl moiety can be substituted or unsubstituted.

[0094] The term “substituted” as used herein in conjunction with the molecule or organic group as defined herein means a state in which one or more hydrogen atoms are replaced by one or more non-hydrogen atoms. The terms “functional group” or “substituent” as used herein refer to a group that can be or is substituted onto 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 the following groups: hydroxyl, alkoxy, aryloxy, aralkyloxy, oxo (carbonyl) groups, carboxyl groups (including carboxylic acids, carboxylates, and carboxyl esters); sulfur atoms in the following groups: thiols, alkyl and aryl thioether groups, sulfoxides, sulfones, sulfonyl groups, and sulfonamides; nitrogen atoms in the following groups: amines, hydroxyamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that can bond with substituted carbon (or other) atoms include F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO, NO2, ONO2, azide, CF3, OCF3, R, O (oxo), S (thiocarbonyl), 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, OC(O)R, C(O)N(R)2, OC(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)CO R, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R and C(=NOR)R, wherein R can be a hydrogen or carbonyl moiety; for example, R can be hydrogen, (C1-C100) hydrocarbon, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclic, heteroaryl or heteroarylalkyl; or wherein two R groups bonded to a nitrogen atom or an adjacent nitrogen atom may together with one or more nitrogen atoms form a heterocyclic group.

[0095] As used herein, the term "alkyl" refers to straight-chain and branched alkyl and cycloalkyl groups having 1 to 40 carbon atoms, 1 to 20 carbon atoms, 1 to 12 carbon atoms, or, in some embodiments, 1 to 8 carbon atoms. Examples of straight-chain alkyl groups include those having 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. Examples of branched alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl. As used herein, the term "alkyl" includes n-alkyl, isoalkyl, and anteisoalkyl, as well as other branched forms of alkyl. Representative substituted alkyl groups may be substituted once or multiple times with any group listed herein, such as amino, hydroxyl, cyano, carboxyl, nitro, thio, alkoxy, and halogen groups.

[0096] As used herein, the term "aminoalkyl" means an alkyl group as defined herein, wherein at least one hydrogen atom in the alkyl group is substituted with nitrogen, forming a primary, secondary, or tertiary amine depending on the substitution of nitrogen. Furthermore, an aminoalkyl group may have one or more nitrogen atoms between any two carbon atoms in the alkyl chain, forming a secondary or tertiary amine depending on the substitution of nitrogen.

[0097] As used herein, the term "alkenyl" refers to straight-chain, branched, and cyclic alkyl groups as defined herein, distinguished by the presence of at least one double bond between two carbon atoms. Thus, alkenyl groups have 2 to 40 carbon atoms, or 2 to approximately 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, etc.

[0098] As used herein, the term "alkynyl" refers to both straight-chain and branched alkyl groups, distinguished by the presence of at least one triple bond between two carbon atoms. Thus, an alkynyl group has 2 to 40 carbon atoms, 2 to approximately 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).

[0099] As used herein, the term "acyl" refers to a group containing a carbonyl moiety, wherein the group is bonded via a carbonyl carbon atom. The carbonyl carbon atom bonds with hydrogen to form a "formyl" group, or bonds with another carbon atom, which may be part of an alkyl, aryl, aralkylcycloalkyl, cycloalkylalkyl, heterocyclic, heterocyclic, heteroaryl, heteroaryl, or heteroarylalkyl group. An acyl group may include 0 to about 12, 0 to about 20, or 0 to about 40 additional carbon atoms bonded to the carbonyl group. An acyl group may include double or triple bonds as defined herein. Acryloyl is an example of an acyl group. An acyl group may also include heteroatoms as defined herein. Nicotinyl (pyridyl-3-carbonyl) is an example of an acyl group as defined herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl. When a group containing a carbon atom bonded to a carbonyl carbon atom contains a halogen, the group is called a "haloacyl" group. The example is trifluoroacetyl.

[0100] As used herein, the term "cycloalkyl" refers to a cyclic alkyl group, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the cycloalkyl group may have 3 to about 8-12 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 4, 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups, such as, but not limited to, norbornel, adamantyl, bornel, camphenyl, isocamphenyl, and carenyl, as well as fused rings, such as, but not limited to, decalinyl. Cycloalkyl groups also include rings substituted with straight-chain or branched alkyl groups as defined herein. Representative substituted cycloalkyl groups can be monosubstituted or polysubstituted, such as, but not limited to, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexyl groups or mono, di, or trisubstituted norbornyl or cycloheptyl groups, which can be substituted by, for example, amino, hydroxyl, cyano, carboxyl, nitro, thio, alkoxy, and halogen groups. The term "cycloalkenyl" alone or in combination refers to cyclic alkenyl groups.

[0101] As used herein, the term "aryl" refers to a cyclic aromatic hydrocarbon group that does not contain heteroatoms in its ring. Therefore, aryl includes, but is not limited to, phenyl, azulel, hepta-enyl, biphenyl, indole-3-yl, fluorenyl, phenanthrene, triphenylene, pyrene, and naphthacenyl. The aryl group can be chrysenyl, biphenyl, anthraceneyl, or naphthyl. In some embodiments, the aryl group contains about 6 to about 14 carbons in the ring portion of the group. As defined herein, the aryl group can be unsubstituted or substituted. Representative substituted aryl groups can be monosubstituted or polysubstituted, such as, but not limited to, phenyl groups substituted at any one or more of the 2-, 3-, 4-, 5-, or 6-positions of the benzene ring, or naphthyl groups substituted at any one or more of the 2- to 8-positions of the benzene ring.

[0102] As used herein, the term "aralkyl" means an alkyl group as defined herein, wherein the hydrogen or carbon bonds of the alkyl group are replaced by bonds attached to an aryl group as defined herein. Representative aralkyl groups include benzyl, phenethyl, and fused (cycloalkylaryl) alkyl groups, such as 4-ethylindenyl. Arylene is an alkenyl group as defined herein, wherein the hydrogen or carbon bonds of the alkyl group are replaced by bonds attached to an aryl group as defined herein.

[0103] As used herein, the term "heterocyclyl" refers to an aromatic or non-aromatic cyclic compound containing three or more ring members, wherein one or more of the ring members are heteroatoms, such as, but not limited to, N, O, and S. Thus, a heterocyclyl group can be a cycloheteroalkyl or heteroaryl group, or, if polycyclic, any combination thereof. In some embodiments, a heterocyclyl group comprises 3 to about 20 ring members, while other such groups have 3 to about 15 ring members. The term heterocyclyl includes a ring in which the CH2 group is replaced by one or more C=O groups, such as those found in cyclic ketones, lactones, and lactams. Examples of heterocyclyl groups containing C=O groups include, but are not limited to, β-propiolactam, γ-butyrolactam, δ-valprolactam, and ε-caprolactam, and the corresponding lactones. A heterocyclyl group named C2-heterocyclyl can be a pentaneous ring having two carbon atoms and three heteroatoms, a hexane ring having two carbon atoms and four heteroatoms, etc. Similarly, a C4-heterocyclyl group can be a pentaneous ring having one heteroatom, a hexane ring having two heteroatoms, etc. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. Heterocyclic rings may also include one or more double bonds. Heteroaryl rings are an embodiment of heterocyclic groups. The phrase "heterocyclic group" includes fused rings, including those fused with aromatic and non-aromatic groups. For example, dioxolane and the benzodioxolane system (methylenedioxanone system) are both heterocyclic groups within the meaning of this document. The phrase also includes polycyclic ring systems containing heteroatoms, such as, but not limited to, quinuclidyl. Heterocyclic groups may be unsubstituted or may be substituted as discussed herein. Heterocyclic groups include, but are not limited to, pyrrolyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, phenylthio, benzobenzylthio, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridyl, isoxazolylpyridinyl, thianaphthyl, purine, xanthine, adenine, guanidine, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl. Representative substituted heterocyclic groups can be monosubstituted or multiple substituted, such as, but not limited to, piperidinyl or quinolinyl, which are 2-, 3-, 4-, 5- or 6-substituted, or disubstituted by those groups listed herein.

[0104] As used herein, the term "heteroaryl" refers to an aromatic ring compound containing five or more ring members (one or more of which are heteroatoms, such as, but not limited to, N, O, and S); for example, a heteroaryl ring can have 5 to about 8-12 ring members. Heteroaryls are various heterocyclic groups having aromatic electronic structures. A heteroaryl named C2-heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms, etc. Similarly, a C4-heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, etc. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. A heteroaryl named C... x-y The heterocyclic base ring can be any ring containing 'x' to 'y' members, including all intermediate integers between 'x' and 'y', and contains one or more heteroatoms as defined herein. In the name C... x-y In the ring, all non-heteroatom members are carbon. It is named C. x-y The heterocyclic ring can also be a polycyclic ring system, such as a bicyclic or tricyclic ring system. Heteroaryl groups include, but are not limited to, the following groups: pyrrole, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, phenylthio, benzobenzylthio, benzofuranyl, indolyl, azaindolyl, indolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridyl, isoxazolpyridyl, thianaphthyl, purine, xanthine, adenine, guanidinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl. Heteroaryl groups can be unsubstituted or substituted with groups discussed herein. Representative substituted heteroaryl groups can be substituted once or multiple times with groups listed herein.

[0105] Other examples of aryl and heteroaryl groups include, but are not limited to, phenyl, biphenyl, indole, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazole, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracene (1-anthrayl, 2-anthrayl, 3-anthrayl), phenylthio (2-phenylthio, 3-phenylthio), furanyl (2-furanyl, 3-furanyl), indole, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthyl, isoindanyl, diphenylmethyl, acridineyl, thiazolyl, pyrroleyl (2-pyrroleyl), pyrazolyl (3-pyrazolyl), 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), pyridinyl (2-pyridinyl, 3-pyridinyl, 4-pyridinyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolinyl (2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl, 8-quinolinyl), isoquinolinyl (1... -Isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl, 5-isoquinolinyl, 6-isoquinolinyl, 7-isoquinolinyl, 8-isoquinolinyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), Hydrogen-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl), benzo[b]phenylthio (2-benzo[b]phenylthio, 3-benzo[b]phenylthio, 4-benzo[b]phenylthio, 5-benzo[b]phenylthio, 6-benzo[b]phenylthio, 7-benzo[b]phenylthio), 2,3-dihydro-benzo[b]phenylthio, (2-(2,3-dihydro-benzo[b]phenylthio), 3-(2,3-dihydro-benzo[b]phenylthio), 4-(2,3-dihydro-benzo[b]phenylthio), 5-(2,3-dihydro-benzo[b]phenylthio), 6-(2,3-dihydro-benzo[b]phenylthio), 7-(2,3-Dihydro-benzo[b]phenylthio), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazole, 3-indazole, 4-indazole, 5-indazole, 6-indazole, 7-indazole), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl) (e.g., imidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazole (1-carbazole, 2-carbazole, 3-carbazole, 4-carbazole), 5H-dibenzo[b,f]aza, (5H-dibenzo[b,f]aza) -1-yl,5H-dibenzo[b,f]aza -2-yl,5H-dibenzo[b,f]aza -3-yl,5H-dibenzo[b,f]aza -4-yl,5H-dibenzo[b,f]aza -5-yl), 10,11-dihydro-5H-dibenzo[b,f]aza (10,11-dihydro-5H-dibenzo[b,f]aza) -1-yl, 10,11-dihydro-5H-dibenzo[b,f]aza -2-yl, 10,11-dihydro-5H-dibenzo[b,f]aza -3-yl, 10,11-dihydro-5H-dibenzo[b,f]aza -4-yl, 10,11-dihydro-5H-dibenzo[b,f]aza -5-base, etc.

[0106] As used herein, the term "heterocyclylalkyl" means an alkyl group as defined herein, wherein the hydrogen or carbon bonds of the alkyl group as defined herein are replaced by bonds attached to a heterocyclic group as defined herein. Representative heterocyclyl groups include, but are not limited to, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indole-2-ylpropyl.

[0107] As used herein, the term “heteroarylalkyl” means an alkyl group as defined herein, wherein the hydrogen or carbon bonds of the alkyl group are replaced by bonds attached to the heteroaryl group as defined herein.

[0108] As used herein, the term "alkoxy" refers to an oxygen atom bonded to an alkyl group (including cycloalkyl groups) as defined herein. Examples of straight-chain alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, and hexoxy. Examples of branched-chain alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, and isohexoxy. Examples of cyclic alkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. An alkoxy group may include about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to an oxygen atom, and may further include double or triple bonds, and may also include heteroatoms. For example, allyloxy or methoxyethoxy are also alkoxy groups within the meaning of this document, as is methylenedioxy when two adjacent atoms of the structure are substituted with it.

[0109] As used herein, the term "amine" refers to primary, secondary, and tertiary amines having, for example, the formula N(group)3, where each group may be independently H or non-H, such as alkyl, aryl, etc. Amines include, but are not limited to, R-NH2, such as alkylamines, arylamines, and alkylarylamines; R2NH, where each R is independently chosen, such as dialkylamines, diarylamines, arylamines, heterocyclic amines, etc.; and R3N, where each R is independently chosen, such as trialkylamines, dialkylarylamines, alkyldiarylamines, and triarylamines, etc. The term "amine" also includes, as used herein, the ammonium ion.

[0110] As used in this article, the term "amino group" refers to -NH2, -NHR, -NR2, and -NR3. + (where each R is independently chosen) form, and except -NR3 + The protonated form of each substituent other than (which cannot be protonated). Therefore, any compound substituted with an amino group can be considered an amine. "Amino" as used herein can refer to primary, secondary, tertiary, or quaternary amino groups. "Alkylamino" includes monoalkylamino, dialkylamino, and trialkylamino groups.

[0111] As used herein, unless otherwise stated, the terms “halo,” “halogen,” or “halide” refer to a fluorine, chlorine, bromine, or iodine atom, either on its own or as part of another substituent.

[0112] As used herein, the term "haloalkyl" includes monohaloalkyl, polyhaloalkyl (where all halogen atoms may be the same or different), and perhaloalkyl (where all hydrogen atoms are replaced by halogen atoms, such as fluorine atoms). Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3-difluoropropyl, perfluorobutyl, etc.

[0113] As used in this article, the term "monovalent" refers to a substituent that is bonded to the substituted molecule via a single bond. When a substituent is monovalent, such as F or Cl, it is bonded to the substituted atom via a single bond.

[0114] As used herein, the terms "hydrocarbon" or "hydrocarbyl" refer to a molecule or functional group that comprises carbon and hydrogen atoms. The term can also refer to a molecule or functional group that typically comprises carbon and hydrogen atoms but in which all hydrogen atoms are replaced by other functional groups.

[0115] As used herein, the term "hydrocarbyl" refers to a functional group derived from a straight-chain, branched, or cyclic hydrocarbon, and can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, acyl, or any combination thereof. Hydrocarbyl groups can be represented as (C... a -C b (C1-C4) hydrocarbon group, where a and b are integers and mean having any number of carbon atoms from a to b. For example, (C1-C4) hydrocarbon group means that the hydrocarbon group can be methyl (C1), ethyl (C2), propyl (C3), or butyl (C4). In some embodiments, (C0-C4) hydrocarbon group... b The presence of a hydrocarbon group means that there is no hydrocarbon group.

[0116] As used herein, the term "solvent" refers to a liquid that can dissolve solids, liquids, or gases. Non-limiting examples of solvents include silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids.

[0117] Unless the context clearly indicates otherwise, the term "independently selected from" as used herein means that the mentioned groups are the same, different, or a mixture thereof. Therefore, according to this definition, the phrase "X" 1 X 2 and X 3 "Independently selected from inert gases" will include, for example, X. 1 X 2 and X 3 All are the same, among which X 1 X 2 and X 3 All are different, among which X1 and X 2 Same but X 3 Unlike other similar arrangements.

[0118] The term "room temperature" as used in this article refers to a temperature of approximately 15°C to 28°C.

[0119] The term "standard temperature and pressure" as used in this article refers to 20°C and 101 kPa.

[0120] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound described herein with a pharmaceutically acceptable carrier. Pharmaceutical compositions facilitate the administration of the compound to a patient or subject. Various techniques for administering compounds exist in the art, including but not limited to intravenous injection, oral administration, aerosol, parenteral administration, ocular, pulmonary, and topical administration.

[0121] "Disease" refers to a state of health in an animal in which the animal is unable to maintain homeostasis, and if the disease is not treated, the animal's health will continue to deteriorate.

[0122] In contrast, an animal's "disorder" is a state of health in which the animal is able to maintain homeostasis, but its health is worse than when it is not in a state of disorder. Without treatment, a disorder does not necessarily lead to further deterioration of the animal's health.

[0123] As used herein, the terms "effective amount," "pharmaceutically effective amount," and "therapeutically effective amount" refer to a non-toxic but sufficient quantity of a drug to provide the desired biological outcome. This outcome may be a reduction and / or alleviation of the symptoms, signs, or cause of a disease, or any other desired alteration of a biological system. Those skilled in the art can determine the appropriate therapeutic amount for any individual case through routine laboratory testing.

[0124] As used in this article, the term "efficacy" refers to the maximum effect (Emax) achieved in a trial.

[0125] As used herein, the term "pharmaceutically acceptable" means a material, such as a carrier or diluent, that does not diminish the biological activity or properties of a compound and is relatively non-toxic, i.e., that the material can be administered to an individual without causing adverse biological effects or interacting with any component contained in the composition in a harmful manner.

[0126] As used herein, the term “pharmaceutically acceptable salt” refers to a salt of an applied compound prepared from a pharmaceutically acceptable, non-toxic acid or base (including inorganic acids or bases, organic acids or bases, their solutions, hydrates, or inclusion complexes).

[0127] 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 hydrogen sulfates), and phosphoric acid (including hydrogen phosphates and dihydrogen phosphates). Suitable organic acids can be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic, and sulfonic acid 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, saccharinic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, pamoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, p-aminobenzenesulfonic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactopyric acid, and galacturonic acid.

[0128] Suitable pharmaceutically acceptable base addition salts of the compounds described herein include, for example, ammonium salts and metal salts, including alkali metal salts, alkaline earth metal salts, and transition metal salts, such as calcium, magnesium, potassium, sodium, and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts derived from basic amines, such as N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-meglumine), and procaine. All these salts can be prepared from the respective compounds by reacting them with, for example, a suitable acid or base.

[0129] As used herein, the terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refer to a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that participates in carrying or transporting the compounds described herein into or to a patient so that they can perform their intended function. Typically, such a construct is carried or transported from one organ or site of the body to another. Each carrier must be "acceptable" in the sense that it is compatible with other components of the formulation, including one or more of the compounds described herein, and will not cause harm to the patient. Examples of materials that can be used as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth gum; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; ethylene glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic and compatible substances used in pharmaceutical formulations. As used herein, "pharmaceuticalally acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, absorption delay agents, etc., that are compatible with the activity of one or more of the compounds described herein and are physiologically acceptable to patients. Additional active compounds may also be added to the composition. "Pharmaceutically acceptable carrier" may also include pharmaceutically acceptable salts of one or more of the compounds described herein. Other additional ingredients that may be included in the pharmaceutical composition and used with the methods or compounds described herein are known in the art and have been described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0130] The terms “patient,” “subject,” or “individual” are used interchangeably herein and refer to any animal or its in vitro or in situ cells to which the methods described herein are applicable. In a non-limiting embodiment, the patient or individual is a human being.

[0131] As used herein, the term "potency" refers to the production of half the maximum response (ED). 50 The required dose.

[0132] "Therapeutic" treatment refers to treatment administered to subjects exhibiting pathological symptoms in order to alleviate or eliminate those symptoms.

[0133] As used herein, the terms "treatment" or "treating" are defined as the application or administration of a therapeutic agent, namely one or more compounds described herein (alone or in combination with another pharmaceutical agent), to a patient suffering from the condition or symptoms of the condition considered herein (e.g., for diagnostic or in vitro application), with the aim of curing, restoring, alleviating, relieving, altering, remedying, improving, modifying, or influencing the condition or symptoms of the condition considered herein. Such treatments can be specifically tailored or modified based on knowledge gained from the field of pharmacogenomics.

[0134] As used herein, the term "cell receptor-binding moiety" (CRBM) refers to the portion of the compound described herein that binds to a receptor on a cell capable of degrading circulating proteins of the subject. A CRBM can be a portion that binds to a receptor present within or on hepatocytes. For example, a CRBM can be an asialic acid glycoprotein receptor (ASGPR), LRPR, LDLR (low-density lipoprotein receptor), RcγRI, FcRN, transferrin receptor, macrophage scavenger receptors (e.g., membrane receptors that degrade cells), etc.

[0135] compound

[0136] Compounds of Formula I or other compounds described herein can be prepared using synthetic methods known to those skilled in the art through the general procedures described herein. The following examples illustrate non-limiting embodiments of the compounds described herein and their preparation.

[0137] In various embodiments, a compound of formula I or a pharmaceutically acceptable salt or N-oxide thereof is provided, having the following structure:

[0138]

[0139] In various embodiments, CON represents 1 to 15 independently selected groups, such as [CON] or [LINKER-2] as defined herein, which are in L A and L B Connecting groups are formed between them, and L A and L BThe open valence is covalently bonded to CON. In various implementations, L A It is the cell receptor-binding moiety (CRBM). In various embodiments, L B It is the anti-CCP1 (anti-cyclic citrullinated peptide) binding moiety.

[0140] In various embodiments, the compound of formula I can also be represented as:

[0141] L A —[CON] w —L B ,

[0142] Where 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] or [LINKER-2] group described herein.

[0143] Autoantibodies are known to play a role in rheumatoid arthritis (RA). Rituximab is more effective in treating patients with anti-citrullinated protein antibodies (ACPA), and serum reactivity to cyclic citrullinated peptides (CCPs) has been used as a diagnostic tool for RA. Recently, several groups have developed modified CCPs that are more specific and sensitive for RA diagnosis, and there is a growing call to utilize these peptides to neutralize pathogenic autoantibodies as a treatment approach.

[0144] In various embodiments, the compounds described herein can target CCP1, CCP2, and CCP3 peptides. In various embodiments, L B It is the anti-CCP1 binding part. In various implementations, L B It is the anti-CCP2 binding part. In various implementations, L B It is the anti-CCP3 binding part. In various implementations, L B It can bind to autoantibodies associated with autoimmune arthritis and related autoimmune diseases.

[0145] In addition to the neutralization strategies mentioned above, there are several existing strategies for treating, improving, and / or preventing autoimmune diseases by depleting autoantibodies. In vitro depletion of whole IgG (plasma exchange) or depletion through immunotherapy (rituximab) can lead to the treatment, improvement, and / or prevention of autoimmune diseases, but this is associated with immunosuppression caused by the depletion of the healthy antibody pool.

[0146] A. Structure of the CON linker group

[0147] In various implementations, each CON is independently a ring-shaped or non-ring-shaped portion, and can be:

[0148] a) in:

[0149] R 1 Each occurrence of is independently H or C1-C3 alkyl; and

[0150] 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

[0151] b) in:

[0152] 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;

[0153] 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;

[0154] 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

[0155] c) in:

[0156] Z and Z' are each an independent bond, -(CH2) i -O-、-(CH2) i -S-、-(CH2) i -N(R)-、

[0157]

[0158] R 2 Each occurrence of is independently H or C1-C3 alkyl;

[0159] Each occurrence of Y is a key independently, -O-, -S-, or -N(R)-;

[0160] Each occurrence of i is an independent integer from 0 to 100;

[0161] D stands for -(CH2) i -YC(=O)-Y-(CH2) i -、-(CH2) m '-、-[(CH2) n -X 1 ] j- OR key, provided that Z, Z' and D are not all keys at the same time;

[0162] j is an integer from 1 to 100;

[0163] m' is an integer from 1 to 100;

[0164] n is an integer from 1 to 100;

[0165] X 1 It is -O-, -S-, or -N(R)-;

[0166] Each R is independently H or a C1-C3 alkyl group optionally substituted with 1-3 hydroxyl groups; or d) a structure selected from the following:

[0167] in

[0168] X 2 Each occurrence is independently -CH2-, -O-, -S-, -N(R) 4 )-, -C(O)-, -S(O)-, -S(O)2-, -S(O)2O-, -OS(O)2- or -OS(O)2O-;

[0169] X 3 Each occurrence is independently -O-, -S-, or -N(R) 4 )-;

[0170] R 4 Each time it appears, it is independently H, C1-C3 alkyl, C1-C3 alkanol, or -C(O)(C1-C3 alkyl); or e)C 6-18 Aryl, C 3-18 Heterocyclic group, C 6-18 Biaryl or C 6-18 The heteroaryl groups are each optionally substituted with 1-6 substituents selected from F, Cl, Br, I, O(RG), OC(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).

[0171] Each occurrence of RG is independently H, with optional substitution of C. 1-10 Alkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 6-18 aryl or optionally substituted C 5-18 Mixed aromatic compounds.

[0172] BL A Structure

[0173] In various implementations, L A It is the cell receptor-binding moiety (CRBM). For example, but not limited to, the CRBM can be: a) the LRP1 (low-density lipoprotein receptor-associated protein 1) binding moiety, which has the following amino acid sequence:

[0174] Ac-VKFNKPFVFLNleIEQNTK-NH2 (SEQ ID NO:2),

[0175] VKFNKPFVFLMIEQNTK(SEQ ID NO:3),

[0176] TWPKHFDKHTFYSILKLGKH-OH(SEQ ID NO:4),

[0177] TFFYGGSRGKRNNFKTEEY-OH(SEQ ID NO:5),

[0178] LRKLRKRLLRDADDLLRKLRKRLLRDADDL (SEQ ID NO: 6),

[0179] TEELRVRLASHLRKLRKRLL(SEQ ID NO:7),

[0180] EAKIEKHNHYQKQLEIAHEKLR(SEQ ID NO:8), or

[0181] TFFYGGSRGKRNNFKTEEY (SEQ ID NO:9); or b) the LDLR (low-density lipoprotein receptor) binding moiety, which has the following amino acid sequence:

[0182] CM-Thz-RLRG-Pen (cyclized c-Pen) (SEQ ID NO:10)

[0183] CMPRLRGC (cyclized CC) (SEQ ID NO:11)

[0184] HLDCMPRGCFRN (cyclized CC) (SEQ ID NO:12)

[0185] CQVKSMPRC (cycloated CC) (SEQ ID NO:13),

[0186] CTTPMPRLC (cycloated CC) (SEQ ID NO:14)

[0187] CKAPQMPRC (Cycated CC) (SEQ ID NO:15)

[0188] CLNPSMPRC (Cycated CC) (SEQ ID NO:16)

[0189] CLVSSMPRC (Cycated CC) (SEQ ID NO:17)

[0190] CLQPMPRLC (cycloated CC) (SEQ ID NO:18)

[0191] CPVSSMPRC (Cycated CC) (SEQ ID NO:19)

[0192] CQSPMPRLC (cycloated CC) (SEQ ID NO:20)

[0193] CLTPMPRLC (cycloated CC) (SEQ ID NO:21),

[0194] DSGLCMPRLRGCDPR(SEQ ID NO:22),

[0195] TPSAHAMALQSLSVG(SEQ ID NO:23),

[0196] Ac-DSGLLCMPRLRGCDPR-NH2 (SEQ ID NO:24),

[0197] Pr VH434: Pr-CMPRLRGC-NH2 (SEQ ID NO: 25),

[0198] Pr-CMPRLRGC-NH2(cyclized CC) (SEQ ID NO:26),

[0199] Pr-CMThzRLRG-Pen-NH2 (cyclized C-Pen) (SEQ ID NO:27)

[0200] Ac-CMPRLGC-NH2(cycloated CC) (SEQ ID NO:28)

[0201] Ac-CMPRLRGC-NH2(cyclized CC) (SEQ ID NO:29),

[0202] Ac-D-Pen-M-Thz-RLRGC-NH2 (cyclized Pen-C) (SEQ ID NO: 30),

[0203] Pr-CM-Thz-RLRG-Pen-NH2 (cyclized c-Pen) (SEQ ID NO:31)

[0204] Pr-CM-Thz-RLR-Sar-Pen-NH2 (cyclized C-Pen) (SEQ ID NO: 32),

[0205] Pr-CM-Pip-RLR-Sar-C-NH2(cyclized CC) (SEQ ID NO:33),

[0206] Pr-CM-Pip-RLRG-Pen-NH2 (cyclized c-Pen) (SEQ ID NO:34), or

[0207] Pr-CM-Pip-RLR-Sar-Pen-+-NH2 (cyclized c-Pen) (SEQ ID NO: 35),

[0208] Any LDLR binding moiety containing two cysteine ​​residues or cysteine ​​and penicillamine residues (Pen) optionally forms a cyclic disulfide bond; or

[0209] c) Based on the FcγRI binding region of the following amino acid sequence:

[0210] TDT C LMLPLLLG C DEE (cyclized CC) (SEQ ID NO:36)

[0211] DPI C WYFPRLLG C TTL (Cyclized CC) (SEQ ID NO:37),

[0212] WYP C YIYPRLLG C DGD (cyclized CC) (SEQ ID NO: 38),

[0213] GNI C MLIPGLLG C SYE (cyclized CC) (SEQ ID NO: 39),

[0214] VNS C LLLPNLLG C GDD (cycloated CC) (SEQ ID NO:40)

[0215] TPV C ILLPSLLG C DTQ (cyclized CC) (SEQ ID NO: 41),

[0216] TVL C SLWPELLG C PPE (cyclocarboxylated CC) (SEQ ID NO:42)

[0217] TFS C LMWPWLLG C ESL (cyclized CC) (SEQ ID NO:43)

[0218] FGT C YTWPWLLG C EGF (cyclized CC) (SEQ ID NO:44),

[0219] SLF C RLLLTPVG C VSQ (cyclized CC) (SEQ ID NO:45)

[0220] HLL V LPRGLLG C TTLA (cyclized CC) (SEQ ID NO:46)

[0221] TSL C SMFPDLLG C FNL (cycloated CC) (SEQ ID NO:47)

[0222] SHP C GRLPMLLG C AES (cyclized CC) (SEQ ID NO:48)

[0223] TST C SMVPGPLGAV STW (cycloated CC) (SEQ ID NO:49)

[0224] KDP C TRWAMLLG C DGE (cyclized CC) (SEQ ID NO:50),

[0225] IMT C SVYPFLLG C VDK (cyclized CC) (SEQ ID NO:51), or

[0226] IHS C AHVMRLLG C WSR (cycloated CC) (SEQ ID NO:52)

[0227] Any FcγRI binding moiety containing two cysteine ​​residues may optionally form a cyclic disulfide bond; or d) an FcRN binding moiety according to the following amino acid sequence:

[0228] Ac-NH-QRFCTGHFGGLYPCNGP-CONH2(cyclized CC) (SEQ ID NO:53),

[0229] Ac-NH-RF-Pen-TGHFG-Sar-NMeLeu-YPC-CONH2 (cyclized CC) (SEQ ID NO:54), or succinic anhydride NN dimer SYN1327 (each cyclized CC),

[0230] Any FcRN binding moiety containing two cysteine ​​residues may optionally form a cyclic disulfide bond; or e) a transferrin receptor binding group according to the following amino acid sequence:

[0231] CGGGPFWWWP(SEQ ID NO:55),

[0232] CGGGHKYLRW (SEQ ID NO:56),

[0233] CGGGKRIFMV(SEQ ID NO:57),

[0234] CGGGKWHYLR (SEQ ID NO:58),

[0235] THRPPMWSPVWP(SEQ ID NO:59),

[0236] HAIYPRH (SEQ ID NO:60),

[0237] THRPPMWSPVWP (SEQ ID NO:61), or

[0238] THRPPMWSPVWP (SEQ ID NO:62); or f) a macrophage scavenger receptor binding moiety having the following amino acid sequence:

[0239] LSLERFLRCWSDAPA(SEQ ID NO:63),

[0240] LERFLRCWSDAPA(SEQ ID NO:64),

[0241] RFLRCWSDAPA(SEQ ID NO:65),

[0242] LRCWSDAPA (SEQ ID NO:66),

[0243] CWSDAPA (SEQ ID NO:67), or

[0244] DWFKAFYDKVAEKFKEAF(SEQ ID NO:68);

[0245] g) Groups having the following structures:

[0246] or

[0247] h) Groups having the following structures:

[0248] Or i) Groups having the following structures:

[0249] in

[0250] RG 1’ yes

[0251] RG1 Each occurrence is independently of hydrogen or

[0252] Each occurrence of XG is independently selected from -CH2-, -C(=O)-, -NH-, and -O-;

[0253] Each occurrence of ZG is independently selected from -CH2-, -C(=O)-, -NH-, and -O-;

[0254] n is an integer from 1 to 100;

[0255] p is an integer from 1 to 50; and

[0256] AG is an oligosaccharide, a disaccharide, or up to 20 of any monosaccharide units described herein.

[0257] Suitable monosaccharides include:

[0258] Aldose, such as propionaldehyde, D-glyceraldehyde, etc.;

[0259] Butylacetose, such as D-erythrose, D-threose, etc.;

[0260] Pentoses, such as D-ribose, D-arabinose, D-xylose, D-lythose, etc.;

[0261] Aldehydes, such as D-aloose, D-azurose, D-glucose, D-mannose, D-gulose, D-idolose, D-galactose, and D-tarose, etc.

[0262] Pyruvose, such as dihydroxyacetone;

[0263] Butylulose, such as D-erythritolose, etc.;

[0264] Pentoketoses, such as D-ribulose and D-xylitolose;

[0265] Hexyloses, such as D-allulose, D-fructose, D-sorbose, D-tagatose, etc.;

[0266] Amino sugars, such as galactosamine, sialic acid, N-acetylglucosamine, etc.;

[0267] Sulfosyl sugars, such as sulfoquinolones.

[0268] Suitable disaccharides include: sucrose, lactose, maltose, trehalose, cellobiose, kojibiose, aspergillus niger, isomaltose, β,β-trehalose, sophorose, kelp disaccharide, gentiobiose, pinebiose, maltulose, paragine, gentiobiose, mannobiose, melibiose, melibiose, rutinose, rutinulose, xylobiose, etc.

[0269] In any monosaccharide, disaccharide, or oligosaccharide described herein, one or more hydroxyl (OH) groups in a particular sugar can be NRG. 2 RG 3 Group substitution, wherein RG 2 and RG 3 Each is independently selected from hydrogen and -C(=O)R, and is optionally replaced by 1-5 C atoms selected from halogens and optionally substituted. 1-10 Alkyl, optionally substituted C 1-10 Alkoxy, optional substituted C 1-10 Substitution of aminoalkyl groups and combinations thereof, or RG 2 and RG 3 Together with the nitrogen atoms to which they are attached, they form a C5 heterocycle, which is optionally substituted with 1-5 C atoms selected from the optionally substituted C atoms. 1-10 Alkyl, optionally substituted C 1-10 Alkoxy, optional substituted C 1-10 Aminoalkyl, optionally substituted C 6-10 aryl, optionally substituted C 5-10 Heteroaryl, halogen, and their combined substitutions. R in RG 2 and RG 3 Each occurrence of H in the text is independently represented by an arbitrarily substituted C. 1-10 Alkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 6-18 aryl or optionally substituted C 5-18 Mixed aromatic compounds.

[0270] Of any monosaccharides, disaccharides, or oligosaccharides described herein The sugar (AG) in the sugar is linked by anomeric carbons on the sugar.

[0271] In some implementations, the AG has the following structure:

[0272]

[0273] And (ZG) p It has the following structure:

[0274]

[0275] In some implementations, the AG has the following structure:

[0276]

[0277] And (ZG) p It has the following structure:

[0278]

[0279] In various embodiments, (XG)n has a structure selected from -O-(CH2)3-, -NH-(CH2CH2O)3-CH2- and =N*(C=O)(CH2)2C(=O)NHCH2CH2-(OCH2CH2)4-, wherein =N* is a cyclic nitrogen in a heterocyclic system; or a combination of groups a) to i).

[0280] In various implementation methods

[0281] L A It is the ASGPR bonding part, and its structure is as follows:

[0282] Each RG 1 yes and

[0283] One of the following is true:

[0284] i)L A Each AG in is

[0285] ii)L A The two AGs in the middle are And L A One of the AGs is

[0286] iii)L A One of the AGs is And L A The two AGs in the middle are or

[0287] iv)L A Each AG in is

[0288] In various implementations, L A Alternatively, CRBM may have the following structure:

[0289] in

[0290] Each occurrence of XG is independently selected from -CH2-, -C(=O)-, -NH-, and -O-;

[0291] Each RG 1 yes

[0292] n is an integer from 1 to 100;

[0293] AG is independent each time it appears.

[0294] RG 2 and RG 3Each time it appears, it is independently selected from hydrogen and -C(=O)R, which is optionally replaced by 1-5 Cs selected from halogens and optionally substituted. 1-10 Alkyl, optionally substituted C 1-10 Alkoxy, optional substituted C 1-10 aminoalkyl groups and combinations thereof are substituted, or

[0295] RG 2 and RG 3 Together with the nitrogen atoms to which they are attached, they form a C5 heterocycle, which is optionally substituted by 1-5 substituents selected from the optionally substituted C atoms. 1-10 Alkyl, optionally substituted C 1-10 Alkoxy, optional substituted C 1-10 Aminoalkyl, optionally substituted C 6-10 aryl, optionally substituted C 5-10 heteroaryl groups, halogens and their combinations;

[0296] Each occurrence of R is independently of H, and the C is arbitrarily substituted. 1-10 Alkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 6-18 aryl or optionally substituted C 5-18 Mixed aromatic compounds.

[0297] In the amino acid sequence of this article, non-standard amino acids are defined as follows:

[0298]

[0299]

[0300] CL B Structure

[0301] In various implementations, L B It is an anti-CCP1 (anti-cyclic citrullinated peptide) antibody-binding moiety with the following structure.

[0302]

[0303] Wherein AA is an amino acid sequence that is at least 80% homologous to SEQ ID NO:1, HQCHQESTCitGRSRGRCGRSGS-OH (SEQ ID NO:1), and m is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0304] At least 80% homology means that the amino acid sequence of the anti-CCP1 antibody binding region is 80% homologous to SEQ ID NO:1, even if that amino acid sequence contains more residues than SEQ ID NO:1, including synthetically modified residues. The definition of homology applies to all sequences described herein as homologous.

[0305] In some embodiments, SEQ ID NO:1 is a (3,16) cyclic peptide having a disulfide bond between Cys3 and Cys16. In various embodiments, AA is directly bonded to L. B The attachment site of the carbonyl amino acid residue is the free valence of the NH backbone in the amino acid residue, thus forming an amide bond.

[0306] “Cit” is the α-amino acid citrulline, with the following structure:

[0307]

[0308] In various implementations, L B It is an anti-CCP1 (anti-cyclic citrullinated peptide) antibody-binding moiety with the following structure.

[0309] or its enantiomers

[0310] In various implementations, L B It has the following structure:

[0311]

[0312] The bonds connecting cysteine ​​residues are disulfide bonds.

[0313] 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 of any of the sequences in Table A. Table A: Additional anti-CCP antibody binding moiety sequences (L B (AA)

[0314] The sequence of AA (X = Cit) Serial Number HCHQESTXGRSRGCG SEQ ID NO:69 HCHQESTXGPSRGCG SEQ ID NO:70 HCHQESTXGRARGCG SEQ ID NO:71 HCHQESTXGRSPGCG SEQ ID NO:72 HCHQESTXGPAPGCG SEQ ID NO:73 SHQESTXGXSXGRSGRSGS SEQ ID NO:74 TXGRS SEQ ID NO:75 TXGXS SEQ ID NO:76 TRGXS SEQ ID NO:77

[0315] In various embodiments, a disulfide bond exists between Cys2 and Cys14 in any of 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 can be covalently attached to L... B On any residue in the partial sequence, and each such attachment is considered independently herein, as if fully listed. In various embodiments, the sequences in Table A are covalently attached to L B On the first residue in a partial sequence, such as H (histidine) in SEQ ID NO:69.

[0316] 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 Having an in vitro or in vivo potency (e.g., as indicated by IC50) of less than, at least or equal to about 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2 or about 1 μM for anti-CCP antibodies (including anti-CCP1, CCP2 and / or CCP3 antibodies). 50 or EC 50 (Measured). In various embodiments, the anti-CCP antibody binding portion L B The efficacy of anti-CCP antibodies against CCP1, CCP2, and / or CCP3, whether in vitro or in vivo (via IC50), is demonstrated. 50 or EC 50 The measured value is less than, at least, or equal to about 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 about 0.01 nM. In vitro or in vivo potency can be determined in clinically or experimentally suitable cell lines (in vitro) or desired organisms (in vivo) such as mice, rats, cats, dogs, pigs, rabbits, or humans. In various embodiments, in vitro potency is determined in human cell lines. In various embodiments, in vivo potency is determined in humans.

[0317] In various implementations, L B The AA in AA is an amino acid sequence containing five (5) to forty (40) amino acid residues, of which one to five residues are citrulline residues, and optionally, at least two residues in AA are cysteine ​​residues that form a disulfide (-SS-) bond, making AA a cyclic peptide. In various embodiments, the non-citrulline amino acid residues in AA are any naturally occurring amino acid (L-amino acid) or its D-amino acid isomer. In various embodiments, L... B AA in the text is an amino acid sequence containing five (5) to forty (40) amino acid residues and one citrulline residue. In various embodiments, L... B AA in the text is an amino acid sequence containing five (5) to forty (40) amino acid residues and two citrulline residues. In various embodiments, L... B AA in the formula is an amino acid sequence containing five (5) to forty (40) amino acid residues and three citrulline residues. In various embodiments, L... B AA in the text is an amino acid sequence containing ten (10) to forty (40) amino acid residues and four citrulline residues. In various embodiments, L... BAA in the sequence is an amino acid sequence containing ten (10) to forty (40) amino acid residues and five citrulline residues. If at least two cysteine ​​residues are present, they are separated in the amino acid sequence by at least two non-cysteine ​​amino acid residues.

[0318] In various embodiments, the compound of formula I has the following structure:

[0319]

[0320] in:

[0321] It is a carbon-carbon single or double bond;

[0322] A is C 6-18 Aryl, C 3-18 Heterocyclic group, C 6-18 Biaryl or C 6-18 Heteroaryl groups, each optionally substituted by 1-6 substituents selected from F, Cl, Br, I, ORG, OC(O)N(RG)2, CN, NO, NO2, ONO2, CF3, OCF3, RG, N(RG)2, SR, SORG, SO2RG, SO2N(RG)2 and SO3RG;

[0323] L A It is the desialyl glycoprotein receptor (ASGPR) binding site, with a structural... in

[0324] L B It is the anti-CCP1 binding part, with structure

[0325] AA is an amino acid sequence that is at least 80% homologous to SEQ ID NO:1;

[0326] RG 1’ for

[0327] RG 1 Each occurrence is independently of hydrogen or

[0328] (ZG) p It has the following structure:

[0329]

[0330] Where p is 2, 4, 6, or 8.

[0331] In various implementations, p is 2. In various implementations, p is 4. In various implementations, p is 6. In various implementations, p is 8.

[0332] In various embodiments, (XG)n has a structure selected from -O-(CH2)3-, -NH-(CH2CH2O)3-CH2- and =N*(C=O)(CH2)2C(=O)NHCH2CH2-(OCH2CH2)4-, wherein =N* is a cyclic nitrogen in the heterocyclic system.

[0333] AG is an amino sugar;

[0334] Each occurrence of RG is independently H, with optional substitution of C. 1-10 Alkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 6-18 aryl or optionally substituted C 5-18 Mixed aromatics;

[0335] Each occurrence of XG is independently selected from -CH2-, -C(=O)-, -NH-, and -O-;

[0336] Each occurrence of ZG is independently selected from -CH2-, -C(=O)-, -NH-, and -O-;

[0337] m is 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0338] n is an integer from 1 to 100; and

[0339] p is an integer from 1 to 50.

[0340] In compounds of formula Ia, A is a ring or ring system that can contain multiple rings. Therefore, A can be a ring system containing two, three, four, or more rings fused together or bonded together, such as a diaryl ring system. The heterocyclic A ring can be aromatic, or some portions of one or more rings in A may contain aliphatic carbon or nitrogen atoms.

[0341] In various implementations, m is 2. In various implementations, m is 3.

[0342] In various embodiments, AA has the sequence HQCHQESTCitGRSRGRCGRSGS (SEQ ID NO:1), wherein the cysteine ​​residues in SEQ ID NO:1 optionally bind to each other to form a disulfide (-SS-) bond.

[0343] The desialyl glycoprotein receptor (ASGPR1) binds to desialyl proteins and other sialyl-removing glycoproteins, exposing galactose residues. In various embodiments, L B It has the following structure:

[0344]

[0345] In various implementations, the AG has the following structure:

[0346]

[0347] Among them RG 2 and RG 3 Each is independently selected from hydrogen and -C(=O)R, and is optionally replaced by 1-5 C atoms selected from halogens and optionally substituted. 1-10 Alkyl, optionally substituted C 1-10 Alkoxy, optional substituted C 1-10 aminoalkyl groups and combinations thereof are substituted, or

[0348] RG 2 and RG 3 Together with the nitrogen atoms to which they are attached, they form a C5 heterocycle, which is optionally divided into five C atoms selected from the optionally substituted C atoms. 1-10 Alkyl, optionally substituted C 1-10 Alkoxy, optional substituted C 1-10 Aminoalkyl, optionally substituted C 6-10 aryl, optionally substituted C 5-10 Heteroaryl, halogen, and combinations thereof are substituted. In various embodiments, RG 2 It's hydrogen, RG 3 It is C(=O)CH3.

[0349] In some implementations, each occurrence of R is independently of 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 Mixed aromatic compounds.

[0350] In various embodiments, AG includes other galactosyl analogs that bind to ASGR.

[0351] In various implementations, the AG has the following structure:

[0352]

[0353] In various implementations, the AG has the following structure:

[0354]

[0355] In various implementations, (Z) p It has the following structure:

[0356]

[0357] In various embodiments, (XG)n has a structure selected from -O-(CH2)3-, -NH-(CH2CH2O)3-CH2- and =N*(C=O)(CH2)2C(=O)NHCH2CH2-(OCH2CH2)4-, wherein =N* is the cyclic nitrogen in A.

[0358] In various embodiments, AA is a (3, 16) cyclic peptide, wherein the cysteine ​​residues at positions 3 and 16 of AA form a disulfide bond. In various embodiments, AA has at least 95% homology with SEQ ID NO:1. In various embodiments, AA is the amino acid sequence of SEQ ID NO:1.

[0359] In various embodiments, the compound of formula Ia has the following structure:

[0360]

[0361] In various embodiments, the compound of formula Ia has the following structure:

[0362]

[0363] In various embodiments, the compound is a compound of formula IIb:

[0364]

[0365] Where L A and L B As defined in this article:

[0366] L A Having structure in

[0367] Each RG 1 for

[0368] Each occurrence of XG is independently selected from -CH2-, -C(=O)-, -NH-, and -O-;

[0369] Each occurrence of ZG is independently selected from -CH2-, -C(=O)-, -NH-, and -O-;

[0370] AG independently for each occurrence

[0371]

[0372] RG 2 and RG 3 Each time it appears, it is independently selected from hydrogen and -C(=O)R, which is optionally replaced by 1-5 Cs selected from halogens and optionally substituted. 1-10Alkyl, optionally substituted C 1-10 Alkoxy, optional substituted C 1-10 aminoalkyl groups and combinations thereof are substituted, or

[0373] RG 2 and RG 3 Together with the nitrogen atoms to which they are attached, they form a C5 heterocycle, which is optionally substituted by 1-5 substituents selected from the optionally substituted C atoms. 1-10 Alkyl, optionally substituted C 1-10 Alkoxy, optional substituted C 1-10 Aminoalkyl, optionally substituted C 6-10 aryl, optionally substituted C 5-10 heteroaryl groups, halogens and their combinations;

[0374] Each occurrence of R is independently of H, and the C is arbitrarily substituted. 1-10 Alkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 6-18 aryl or optionally substituted C 5-18 Mixed aromatics;

[0375] L B It is the anti-CCP binding part, which has a structure in:

[0376] AA is an amino acid sequence that is at least 80% homologous to the amino acid sequences selected from SEQ ID NO:1, SEQ ID NO:69-SEQ ID NO:76 and SEQ ID NO:77; and

[0377] m is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0378] In various embodiments, in the compound of formula I or formula IIb, AA is a (3,16) cyclic peptide. In various embodiments, in the compound of formula I or formula IIb, AA has at least 95% homology with SEQ ID NO:1. In various embodiments, in the compound of formula I or formula IIb, AA is the amino acid sequence of SEQ ID NO:1. In various embodiments, in the compound of formula I or formula IIb, m is 2.

[0379] In various embodiments, in compounds of formula I or IIb, (ZG) p It is -CH2-(O-CH2-CH2)2-NH(C=O)CH2CH2-. In various embodiments, in compounds of formula I or IIb, each RG 1 and / or RG 1’ for

[0380]

[0381] In various embodiments, in compounds of formula I or IIb, L A It has the following structure:

[0382]

[0383] In various embodiments, in compounds of formula I or IIb, (XG)n is selected from -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 n It is -CH2-(OCH2CH2)4-.

[0384] In various embodiments, in compounds of formula I or IIb, RG 1 Each AG in is

[0385] In various embodiments, in compounds of formula I or IIb, RG 2 It is H. In various embodiments, in compounds of formula I or IIb, RG 3 It is -C(=O)CH3.

[0386] In various embodiments, in compounds of formula I or IIb, RG 1 Each AG in is

[0387] In various embodiments, in compounds of formula I or IIb, RG 1 Each AG in is

[0388] In various embodiments, in compounds of formula I or IIb, RG 1 Each AG in is

[0389] In various embodiments, in compounds of formula I or IIb, RG 1 Each AG in is

[0390] In various implementations, L in formula IIb A Or, in Equation II, CRBM is:

[0391]

[0392] In various embodiments, in compounds of formula I or IIb, L BIt has the following structure:

[0393] In various embodiments, the compound of formula II or IIb has the following structure:

[0394]

[0395] The other ASGPR binding component based on galactose and taro sugar

[0396] In some embodiments, the present invention relates to compounds of general chemical structure according to Formula II for removing circulating proteins associated with a disease state or symptom in a patient or subject:

[0397]

[0398] The term "extracellular protein-targeting ligand" as used herein is interchangeable with the term PBM (protein-binding moiety). In various embodiments, both "extracellular protein-targeting ligand" and PBM refer to targetable proteins found intracellularly or in extracellular fluid, as well as membrane-bound proteins present on the cell surface, including, for example, soluble proteins (such as antibodies) and membrane-bound proteins such as immune checkpoints for degradation (such as PD1, PD-L1, etc.). Therefore, the terms "extracellular protein-targeting ligand" and PBM are not limited to cellular proteins.

[0399] In various embodiments, the PBM is an anti-CCP1 binding portion. In various embodiments, the PBM is an anti-CCP2 binding portion. In various embodiments, the PBM is an anti-CCP3 binding portion. In various embodiments, the PBM can bind to autoantibodies associated with autoimmune arthritis and related autoimmune diseases. In various embodiments, the PBM has any of the L... described herein. B Some of the structures are the same.

[0400] The term “ASGPR ligand” as used herein is interchangeable with the desialylate glycoprotein receptor (ASGPR) binding portion as defined herein.

[0401] In the compound of formula II, each [CON] is an optional linking chemical moiety, which, when present, is directly linked to [PBM] or [CRBM], or links [LINKER-2] to [PBM] or [CRM].

[0402] In the compound of formula II:

[0403] [LINKER-2] is a chemical moiety with a valence of 1 to 15, which is covalently attached to one or more [CRBM] and / or [PBM] groups, optionally via [CON], including [MULTICON] groups, wherein [LINKER-2] itself optionally contains one or more [CON] or [MULTICON] groups;

[0404] k' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15;

[0405] j' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15;

[0406] h and h' are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15;

[0407] i L The digits are 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0408] The conditions are h, h', and i L At least one of them is at least 1.

[0409] Or its pharmaceutically acceptable salts, stereoisomers, solvates or polymorphs.

[0410] In various implementations, k' is 1 and j' is 1.

[0411] The [MULTICON] group may attach one or more of [CRBM] or [PBM] to one or more of [LINKER-2]. In various embodiments, the valence of [LINKER-2] is from 1 to 10. In various embodiments, the valence of [LINKER-2] is from 1 to 5. In various embodiments, the valence of [LINKER-2] is 1, 2, or 3. In various embodiments, in the compound of formula II, [LINKER-2] includes a linking group as defined herein. A Linking groups B Linking groups C Linking groups D One or more of the following: and / or combinations thereof.

[0412] In some embodiments of the compounds of formula II illustrated elsewhere in this document, R 3Each time it appears, it is independently selected from hydrogen, alkyl, heteroalkyl, haloalkyl (including -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CH2F and -CF2CF), aralkyl, heteroaryl, alkenyl, ynyl and heteroaryl, heterocyclic, -OR 8 and -NR 8 R 9 .

[0413] In some embodiments of the compounds of formula II illustrated elsewhere in this document, R 4 Each time it appears, it is independently selected from hydrogen, heteroalkyl, alkyl, haloalkyl, aralkyl, heteroaryl, alkenyl, ynyl, aryl, heteroaryl, heterocyclic, and -OR. 6 -NR 6 R 7 ,

[0414] In some embodiments of the compounds of formula II illustrated elsewhere in this document, R 6 and R 7 Each time it appears, it is independently selected from hydrogen, heteroalkyl, alkyl, aralkyl, heteroaralkyl, alkenyl, ynyl, 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 ;and

[0415] In some embodiments of the compounds of formula II illustrated elsewhere in this document, R 8 and R 9 Each time it appears, it is independently selected from hydrogen, heteroalkyl, alkyl, aralkyl, heteroaralkyl, alkenyl, ynyl, aryl, heteroaryl, and heterocyclic.

[0416] A. The galactose-based ASGPR-binding cell receptor-binding moiety of Formula II

[0417] In some embodiments, the compound of formula II is selected from:

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436] In some embodiments, the compound of formula II has one of the following structures:

[0437]

[0438]

[0439] In various implementations, the ASGPR ligand is in C 1 Or C 5 (R 1 Or R 5 ) positional linkage to form degradation compounds. In various embodiments, the ASGPR ligand is located at C 6 Positional linkages are used to form degradation compounds. For example, when the ASGPR ligand is...

[0440] hour,

[0441] Non-limiting examples of ASGPR-binding compounds of formula II include:

[0442]

[0443] Or a di- or tri-substituted version thereof or a pharmaceutically acceptable salt thereof, wherein di- or tri-substituted means the number of additional galactose derivatives attached to the linking group portion.

[0444] In any implementation of the use of ASGPR ligands for degradation products described herein, the ASGPR ligands are typically in C 5 The linker group is attached to an extracellular protein-targeting ligand (e.g., it may refer to an adjacent C6 carbon hydroxyl group or other functional part that can be used for the purpose of linking). When the linker group and the extracellular protein-targeting ligand are linked through the C1 position, the carbon is appropriately functionalized for linking, for example, by linking with a hydroxyl, amino, allyl, alkyne, or hydroxy-allyl group.

[0445] In various implementations, the ASGPR ligand is not in C 3 Or C 4 These sites are linked because they are associated with calcium chelation for ASGPR binding in the liver. In some embodiments, the ASGPR ligands that can be used with compound II are selected from:

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457] In some embodiments, the compound of formula II is selected from:

[0458]

[0459]

[0460]

[0461]

[0462]

[0463] B. The taro-based ASGPR-binding cell receptor-binding moiety of Formula II: In some embodiments, the compound of Formula II is selected from:

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507] In some embodiments, the compound of formula II is an extracellular protein degradation compound, wherein the ASGPR ligand is the ligand described herein.

[0508]

[0509] In some embodiments, in compounds of formula II, the ASGPR ligand is linked at the C1 or C5 (R1 or R5) position to form a degradation compound. In some embodiments, in compounds of formula II, the ASGPR ligand is linked at the C6 position. In various embodiments, when the ASGPR ligand is

[0510]

[0511] Non-limiting examples of ASGPR-binding compounds of formula II include:

[0512]

[0513] Or its di- or tri-substituted form or a pharmaceutically acceptable salt, wherein di- or tri-substituted refers to the number of additional galactose derivatives attached to the linking site. In some embodiments, the compound of formula II is selected from:

[0514]

[0515] In some implementations, R 2 Selected from -NR 6 COR 3 -NR 6 -(5-heteroaryl) and -NR 6 -(6-heteroaryl), in each of which R 2 The group is optionally substituted by one, two, three or four independent substituents as described herein, for example, one, two, three or four substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0516] In some embodiments, the compound of formula II is selected from:

[0517]

[0518]

[0519] In some implementations, R 2 Selected from -NR 6 COR 3 -NR 6 -(5-heteroaryl) and -NR 6 -(6-heteroaryl), in each of which R 2 The group is optionally substituted by one, two, three or four independent substituents as described herein, for example, one, two, three or four substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0520] In some embodiments, the compound of formula II is selected from:

[0521]

[0522]

[0523] In some implementations, R 2 Selected from -NR 6 COR 3 -NR 6 -(5-heteroaryl) and -NR 6 -(6-heteroaryl), in each of which R 2 The group is optionally substituted by one, two, three or four independent substituents as described herein, for example, one, two, three or four substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0524] In some embodiments, the compound of formula II is selected from:

[0525]

[0526]

[0527] In some implementations, R 2 Selected from -NR 6 COR 3 -NR 6 -(5-heteroaryl) and -NR 6 -(6-heteroaryl), in each of which R 2 The group is optionally substituted by one, two, three or four independent substituents as described herein, for example, one, two, three or four substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0528] In some embodiments, the compound of formula II is selected from:

[0529]

[0530]

[0531] In some implementations, R 2 Selected from -NR 6 COR 3 -NR 6 -(5-heteroaryl) and -NR 6 -(6-heteroaryl), in each of which R 2 The group is optionally substituted by one, two, three or four independent substituents as described herein, for example, one, two, three or four substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0532] In some embodiments, the compound of formula II is selected from:

[0533]

[0534]

[0535] In some implementations, R 2 Selected from -NR 6 COR 3 -NR 6 -(5-heteroaryl) and -NR 6 -(6-heteroaryl), in each of which R 2 The group is optionally substituted by one, two, three or four independent substituents as described herein, for example, one, two, three or four substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0536] In some embodiments, the compound of formula II is selected from:

[0537]

[0538]

[0539] In some implementations, R 2 Selected from -NR 6 COR 3 -NR 6 -(5-heteroaryl) and -NR 6 -(6-heteroaryl), in each of which R 2 The group is optionally substituted by one, two, three or four independent substituents as described herein, for example, one, two, three or four substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0540] In some embodiments, the compound of formula II is selected from:

[0541]

[0542]

[0543] In some implementations, R 2 Selected from -NR 6 COR 10 -NR 6 -(5-heteroaryl) and -NR 6 -(6-heteroaryl), in each of which R 2The group is optionally substituted by one, two, three or four independent substituents as described herein, for example, one, two, three or four substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0544] In some embodiments, the compound of formula II is selected from:

[0545]

[0546]

[0547] In some implementations, R 2 Selected from -NR 6 COR 10 -NR 6 -(5-heteroaryl) and -NR 6 -(6-heteroaryl), in each of which R 2 The group is optionally substituted by one, two, three or four independent substituents as described herein, for example, one, two, three or four substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0548] In some embodiments, the compound of formula II is selected from:

[0549]

[0550]

[0551] In some implementations, R 2 Selected from -NR 6 COR 10 -NR 6 -(5-heteroaryl) and -NR 6 -(6-heteroaryl), in each of which R 2 The group is optionally substituted by one, two, three or four independent substituents as described herein, for example, one, two, three or four substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0552] In some embodiments, the compound of formula II is selected from:

[0553]

[0554]

[0555] In some implementations, R 2 Selected from -NR 6 COR 10 -NR 6 -(5-heteroaryl) and -NR 6-(6-heteroaryl), in each of which R 2 The group is optionally substituted by one, two, three or four independent substituents as described herein, for example, one, two, three or four substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0556] In some embodiments, the compound of formula II is selected from:

[0557]

[0558]

[0559] In some implementations, R 2 Selected from -NR 6 COR 10 -NR 6 -(5-heteroaryl) and -NR 6 -(6-heteroaryl), in each of which R 2 The group is optionally substituted by one, two, three or four independent substituents as described herein, for example, one, two, three or four substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0560] In some embodiments, the compound of formula II is selected from:

[0561]

[0562]

[0563] In some implementations, R 2 Selected from -NR 6 COR 10 -NR 6 -(5-heteroaryl) and -NR 6 -(6-heteroaryl), in each of which R 2 The group is optionally substituted by one, two, three or four independent substituents as described herein, for example, one, two, three or four substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0564] In some embodiments, the compound of formula II is selected from:

[0565]

[0566]

[0567] In some implementations, R 2 Selected from -NR 6 COR 10 -NR 6-(5-heteroaryl) and -NR 6 -(6-heteroaryl), in each of which R 2 The group is optionally substituted by one, two, three or four independent substituents as described herein, for example, one, two, three or four substituents independently selected from F, Cl, Br, haloalkyl or alkyl.

[0568] In some embodiments, the compound of formula II is selected from:

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581] In some embodiments, the ASGPR ligands that can be used in fused II compounds are selected from:

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596] C. ASGPR ligands / binding sites in compounds of formula II

[0597] In some embodiments, in the compound of formula II, R 1 It is hydrogen.

[0598] In some embodiments, in the compound of formula II, R 1 yes

[0599] In some embodiments, in the compound of formula II, R 1 yes

[0600] In some embodiments, in the compound of formula II, R 1 yes

[0601] In some embodiments, in the compound of formula II, R 1 yes

[0602] In some embodiments, in the compound of formula II, R 1 yes

[0603] In some embodiments, in the compound of formula II, R 1 yes

[0604] In some embodiments, in the compound of formula II, R 1 It is a C0-C6 alkyl-cyano group that is optionally substituted with 1, 2, 3 or 4 substituents.

[0605] In some embodiments, in the compound of formula II, R 1 It is an alkyl group that is optionally substituted with 1, 2, 3 or 4 substituents.

[0606] In some embodiments, in the compound of formula II, R1 It is an alkenyl group optionally substituted with 1, 2, 3, or 4 substituents. In some embodiments, in compounds of formula II, R 1 It is an alkynyl group optionally substituted with 1, 2, 3, or 4 substituents. In some embodiments, in compounds of formula II, R 1 It is a haloalkyl group optionally substituted with 1, 2, 3, or 4 substituents. In some embodiments, in compounds of formula II, R 1 It is F.

[0607] In some embodiments, in the compound of formula II, R 1 It is Cl.

[0608] In some embodiments, in the compound of formula II, R 1 It is Br.

[0609] In some embodiments, in the compound of formula II, R 1 It is an aryl group that is optionally substituted with 1, 2, 3 or 4 substituents.

[0610] In some embodiments, in the compound of formula II, R 1 It is an aralkyl group that is optionally substituted with 1, 2, 3 or 4 substituents.

[0611] In some embodiments, in the compound of formula II, R 1 It is a heteroaryl group that is optionally substituted with 1, 2, 3 or 4 substituents.

[0612] In some embodiments, in the compound of formula II, R 1 It is a heteroaryl group that is optionally substituted with 1, 2, 3 or 4 substituents.

[0613] In some embodiments, in the compound of formula II, R 1 It is a heterocycle that is optionally substituted with 1, 2, 3 or 4 substituents.

[0614] In some embodiments, in the compound of formula II, R 1 It is a heterocyclic alkyl group that is optionally substituted with 1, 2, 3 or 4 substituents.

[0615] In some embodiments, in the compound of formula II, R 1 It is a haloalkoxy group that is optionally substituted with 1, 2, 3 or 4 substituents.

[0616] In some embodiments, in the compound of formula II, R 1 It is -O-alkenyl, -O-ynyl, C0-C6 alkyl-OR 6 C0-C6 alkyl-SR 6C0-C6 alkyl-NR 6 R 7 C0-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 C0-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 Each of these is optionally substituted by 1, 2, 3 or 4 substituents.

[0617] In some embodiments, in the compound of formula II, R 2 It is an aryl group that is optionally substituted with 1, 2, 3 or 4 substituents.

[0618] In some embodiments, in the compound of formula II, R 2 It is a heterocycle that is optionally substituted with 1, 2, 3 or 4 substituents.

[0619] In some embodiments, in the compound of formula II, R 2 It is a heteroaryl group containing one or two heteroatoms independently selected from N, O and S, which are optionally substituted with 1, 2, 3 or 4 substituents.

[0620] In some embodiments, in the compound of formula II, R 2 Selected from

[0621]

[0622] In some embodiments, in the compound of formula II, R 2 It is a heterocycle that is optionally substituted with 1, 2, 3 or 4 substituents.

[0623] In some embodiments, in the compound of formula II, R2 -NR is optionally substituted by 1, 2, 3 or 4 substituents. 8 -S(O)-R 3 .

[0624] In some embodiments, in the compound of formula II, R 2 -NR is optionally substituted by 1, 2, 3 or 4 substituents. 8 -C(S)-R 3 .

[0625] In some embodiments, in the compound of formula II, R 2 -NR is optionally substituted by 1, 2, 3 or 4 substituents. 8 -S(O)(NR 6 )-R 3 .

[0626] In some embodiments, in the compound of formula II, R 2 -N=S(O)(R is optionally substituted with 1, 2, 3 or 4 substituents. 3 )2.

[0627] In some embodiments, in the compound of formula II, R 2 -NR is optionally substituted by 1, 2, 3 or 4 substituents. 8 C(O)NR 9 S(O)2R 3 .

[0628] In some embodiments, in the compound of formula II, R 2 -NR is optionally substituted by 1, 2, 3 or 4 substituents. 8 -S(O)2-R 10 .

[0629] In some embodiments, in the compound of formula II, R 2 -NR is optionally substituted by 1, 2, 3 or 4 substituents. 8 -C(NR 6 )-R 3 .

[0630] In some embodiments, in the compound of formula II, R 2 It is hydrogen.

[0631] In some embodiments, in the compound of formula II, R 2 It is R 10 .

[0632] In some embodiments, in the compound of formula II, R 2 It is an alkyl-C(O)-R3 .

[0633] In some embodiments, in the compound of formula II, R 2 It is -C(O)-R 3 .

[0634] In some embodiments, in the compound of formula II, R 2 It is an alkyl group.

[0635] In some embodiments, in the compound of formula II, R 2 It is a haloalkyl group.

[0636] In some embodiments, in the compound of formula II, R 2 It is -OC(O)R 3 .

[0637] In some embodiments, in the compound of formula II, R 2 Yes -NR 8 -C(O)R 10 .

[0638] In some embodiments, in the compound of formula II, R 2 It is an alkenyl group that is optionally substituted with 1, 2, 3 or 4 substituents.

[0639] In some embodiments, in the compound of formula II, R 2 It is an allyl group that is optionally substituted with 1, 2, 3 or 4 substituents.

[0640] In some embodiments, in the compound of formula II, R 2 It is an alkynyl group that is optionally substituted with 1, 2, 3 or 4 substituents.

[0641] In some embodiments, in the compound of formula II, R 2 -NR is optionally substituted by 1, 2, 3 or 4 substituents. 6 -Alkenyl.

[0642] In some embodiments, in the compound of formula II, R 2 It is an -O-alkenyl group that is optionally substituted with 1, 2, 3 or 4 substituents.

[0643] In some embodiments, in the compound of formula II, R 2 -NR is optionally substituted with 1, 2, 3 or 4 substituents. 6 -Alkyne group.

[0644] In some embodiments, in the compound of formula II, R 2-NR is optionally substituted by 1, 2, 3 or 4 substituents. 6 - Mixed aromatic compounds.

[0645] In some embodiments, in the compound of formula II, R 2 -NR is optionally substituted by 1, 2, 3 or 4 substituents. 6 -Aryl.

[0646] In some embodiments, in the compound of formula II, R 2 It is an -O-heteroaryl group that is optionally substituted with 1, 2, 3 or 4 substituents.

[0647] In some embodiments, in the compound of formula II, R 2 It is an -O-aryl group that is optionally substituted with 1, 2, 3 or 4 substituents.

[0648] In some embodiments, in the compound of formula II, R 2 It is an -O-ynyl group that is optionally substituted with 1, 2, 3 or 4 substituents.

[0649] In some embodiments, in the compound of formula II, R 2 Selected from

[0650]

[0651] In some embodiments, in the compound of formula II, R 2 Selected from

[0652]

[0653] In some embodiments, in the compound of formula II, R 2 Selected from

[0654]

[0655] Where R is an optional substituent as defined in this paper.

[0656] In some embodiments, in the compound of formula II, R 2 Selected from

[0657]

[0658] In some embodiments, in the compound of formula II, R 2A Selected from

[0659]

[0660] Where R is an optional substituent as defined in this paper.

[0661] In some embodiments, in the compound of formula II, R 2A Selected from

[0662]

[0663] In some embodiments, in the compound of formula II, R 2 Selected from

[0664]

[0665] In some embodiments, in the compound of formula II, R 2 Selected from

[0666]

[0667] In some embodiments, in the compound of formula II, R 2 Selected from

[0668] In some embodiments, in the compound of formula II, R 2 Selected from In some embodiments, in the compound of formula II, R 2 Selected from

[0669]

[0670] In some embodiments, in the compound of formula II, R 2 Selected from

[0671]

[0672] In some embodiments, in the compound of formula II, R 2 Selected from In some embodiments, in the compound of formula II, R 2 Selected from In some embodiments, in the compound of formula II, R 2 Selected from

[0673]

[0674] In some embodiments, in the compound of formula II, R 2 Selected from

[0675]

[0676] In some embodiments, in the compound of formula II, R 2 Selected from

[0677]

[0678] In some embodiments, in the compound of formula II, R 2 Selected from

[0679]

[0680] In some embodiments, in the compound of formula II, R 2 Selected from

[0681]

[0682] In some embodiments, in the compound of formula II, R 2 Selected from

[0683]

[0684] In some embodiments, in the compound of formula II, R 2 Selected from

[0685]

[0686] In some embodiments, in the compound of formula II, R 2 Selected from

[0687]

[0688] In some embodiments, in the compound of formula II, R 2 Selected from

[0689]

[0690] In some embodiments, in the compound of formula II, R 2 Selected from

[0691]

[0692] In some embodiments, in the compound of formula II, R 2 Selected from

[0693]

[0694] In some embodiments, in the compound of formula II, R 2 Selected from

[0695]

[0696] In some embodiments, in the compound of formula II, R 2 Selected from

[0697]

[0698] In some embodiments, in the compound of formula II, R 2 Selected from

[0699]

[0700] In some embodiments, in the compound of formula II, R 2 Selected from

[0701]

[0702] In some embodiments, in the compound of formula II, R 2 Selected from

[0703]

[0704] In some embodiments, in the compound of formula II, R 2 Selected from In some embodiments, in the compound of formula II, R 2 Selected from

[0705]

[0706] In some embodiments, in the compound of formula II, R 2 Selected from

[0707] In some embodiments, in the compound of formula II, R 2 Selected from In some embodiments, in the compound of formula II, R 2 Selected from

[0708]

[0709] In some embodiments, in the compound of formula II, R 2 Or R 2A Selected from

[0710]

[0711] In some embodiments, in the compound of formula II, R 2 Selected from

[0712]

[0713] In some embodiments, in the compound of formula II, R 2 Selected from

[0714]

[0715] In some embodiments, in the compound of formula II, R 2 Selected from

[0716] In some embodiments, in the compound of formula II, R 2 Selected from

[0717] In some embodiments, in the compound of formula II, R 2 Selected from

[0718] In some embodiments, in the compound of formula II, R 2 It is a spirocyclic heterocyclic ring, such as, but not limited to, In some embodiments, in the compound of formula II, R 2 It contains silicon heterocyclic compounds, such as, but not limited to, In some embodiments, in the compound of formula II, R 2 Replaced by SF5, for example, but not limited to,

[0719]

[0720] In some embodiments, in the compound of formula II, R 2 Replaced by sulfoxime, for example, but not limited to,

[0721]

[0722] In some embodiments, in the compound of formula II, R 10 Selected from bicyclic heterocyclic compounds. In some embodiments, in compounds of formula II, R 10 Selected from spirocyclic heterocycles. In some embodiments, in compounds of formula II, R 10 Selected from -NR 6 - Heterocyclic ring. In some embodiments, in compounds of formula II, R 10 Selected from

[0723] In some embodiments, in the compound of formula II, R 10 Selected from

[0724]

[0725] In some embodiments, in the compound of formula II, R 10 Selected from

[0726]

[0727] In some embodiments, in the compound of formula II, R 10 Selected from

[0728]

[0729] In some embodiments, in the compound of formula II, the cyclization is selected from...

[0730]

[0731]

[0732] In some embodiments, in the compound of formula II, R 30 Selected from

[0733]

[0734] In some embodiments, in the compound of formula II, R 200 yes

[0735] In some embodiments, in the compound of formula II, R 200 yes

[0736] In some embodiments, in the compound of formula II, R 200 yes In some embodiments, in the compound of formula II, R 200 yes In some embodiments, in the compound of formula II, R 200 yes

[0737] In some embodiments, in the compound of formula II, R 200 yes

[0738] In some embodiments, in the compound of formula II, R 200 yes

[0739] In some embodiments, in the compound of formula II, R 200 yes

[0740] In some embodiments, in the compound of formula II, R 200 yes

[0741] In some embodiments, in the compound of formula II, R 200 yes

[0742] In some embodiments, in the compound of formula II, R 200 yes

[0743] In some embodiments, in the compound of formula II, R 200 yes

[0744] Linking group

[0745] In a non-limiting embodiment, in the compound of formula II, the linking group A and linking groups B Selected independently from:

[0746]

[0747] in:

[0748] R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 and R 20 Each time it appears, it is independently selected from the following: bond, alkyl group, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR. 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 non-natural amino acids, alkenyl, alkynyl, haloalkyl, alkoxy, heterocyclic, heteroaryl, -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 - A divalent residue of a fatty acid, an unsaturated or saturated monocarboxylic acid or a dicarboxylic acid; wherein each is independently selected from R 21 The 1, 2, 3 or 4 substituents may be optionally substituted;

[0749] n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 each time it appears;

[0750] R 21 Each time it appears, it is independently selected from 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 , haloalkyl, heteroalkyl, heteroaryl, and heterocyclic;

[0751] And the remaining variables are as defined in this article.

[0752] In one embodiment, in the compound of formula II, the linking group A It is a bond and a linking group B yes

[0753]

[0754] In one embodiment, in the compound of formula II, the linking group B It is a bond and a linking group A yes

[0755]

[0756] In one embodiment, in the compound of formula II, the divalent residues of the amino acid are selected from...

[0757]

[0758]

[0759] The amino acids can be oriented in either direction, and the amino acids can be in L- or D- form or a mixture thereof.

[0760] In one embodiment, in the compound of formula II, the divalent residue of the dicarboxylic acid is generated by a nucleophilic addition reaction:

[0761]

[0762] Non-limiting embodiments of divalent residues of dicarboxylic acids generated by nucleophilic addition reactions include:

[0763]

[0764] In one embodiment, in the compound of formula II, a divalent residue of a dicarboxylic acid is generated by a condensation reaction:

[0765]

[0766] Non-limiting embodiments of the divalent residues of the dicarboxylic acid generated by condensation include:

[0767]

[0768] Non-limiting embodiments of the divalent residues of saturated dicarboxylic acids include:

[0769] Non-limiting embodiments of the divalent residues of saturated dicarboxylic acids include:

[0770]

[0771] Non-limiting embodiments of the divalent residues of saturated monocarboxylic acids are selected from butyric acid (-OC(O)(CH2)2CH2-), hexanoic acid (-OC(O)(CH2)4CH2-), octanoic acid (-OC(O)(CH2)5CH2-), decanoic 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-), benzolic acid (-OC(O)(CH2)) 20 CH2-) and tetracosanoic acid (-OC(O)(CH2)) 22 CH2-);

[0772] Non-limiting embodiments of divalent residues in fatty acids include residues selected from linoleic acid, palmitoleic acid, isoleic acid, paucilinic acid, oleic acid, eliadic acid, gondooic acid, gadoleic acid, nervonic acid, myristoleic acid, and erucic acid.

[0773]

[0774] Non-limiting embodiments of the divalent residues of fatty acids are selected from 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-), linolenic acid (-C(O)(CH2)4(CHCHCH2)4CH2-), γ- Linolenic acid (-C(O)(CH2)4(CHCHCH2)3(CH2)3CH2-), 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-), isoleic acid (-C(O)(CH2)9CHCH(CH2)5CH2-), eicosenoic acid (-C(O)(CH2) 11 CHCH(CH2)5CH2-), oleic acid (-C(O)(CH2)7CHCH(CH2)7CH2-), transoleic acid (-C(O)(CH2)7CHCH(CH2)7CH2-), eicosanoic acid (-C(O)(CH2)9CHCH(CH2)7CH2-), eicosanoic acid (-C(O)(CH2)7CHCH(CH2)9CH2-), tetracosanoic acid (-C(O)(CH2)5CH2-), ole ... 13 CHCH(CH2)3CH2-), eicosuritrienoic acid (-C(O)(CH2)3(CHCHCH2)3(CH2)6CH2-), myristone acid (-C(O)(CH2)7CHCH(CH2)3CH2-), and erucic acid (-C(O)(CH2) 11 CHCH(CH2)7CH2-).

[0775] In some embodiments, in the compound of formula II, the linking group C Selected from:

[0776]

[0777] in:

[0778] R 22 Each time it appears, it is independently selected from alkyl, -C(O)N-, -NC(O)-, -N-, -C(R) 21 )-, -P(O)O-, -P(O)-, -P(O)(NR 6 R 7 N-, alkenyl, haloalkyl, aryl, heterocyclic, and heteroaryl, wherein each is optionally independently selected from R 21 The 1, 2, 3 or 4 substituents are substituted;

[0779] And the remaining variables are as defined in this article.

[0780] In some embodiments, in the compound of formula II, the linking group D Selected from:

[0781]

[0782] in:

[0783] R 32 Each time it appears, it is independently selected from alkyl, N + X-, -C-, alkenyl, haloalkyl, aryl, heterocyclic, and heteroaryl, wherein each is optionally independently selected from R 21 The 1, 2, 3 or 4 substituents are substituted;

[0784] X- is an anionic group, such as Br- or Cl-. - ;and

[0785] All other variables are as defined in this document.

[0786] In some embodiments, in the compound of formula II, the linking group A Selected from:

[0787]

[0788] Each of the heteroaryl, heterocyclic, cycloalkyl, and aryl groups may optionally be substituted by one, two, three, or four or any combination of halogens, alkyl groups, haloalkyl groups, and heteroaryl, heterocyclic, or cycloalkyl groups, as permitted by the valence.

[0789] In some embodiments, in the compound of formula II, the linking group A Selected from:

[0790]

[0791] Each of the heteroaryl, heterocyclic, and cycloalkyl groups may optionally be substituted by one, two, three, or four or any combination of halogens, alkyl groups, haloalkyl groups, aryl groups, heteroaryl groups, heterocyclic groups, or cycloalkyl groups, as permitted by the valence.

[0792] In some embodiments, in the compound of formula II, the linking group B Selected from:

[0793]

[0794] In some embodiments, in the compound of formula II, the linking group B Selected from:

[0795]

[0796] In some embodiments, in the compound of formula II, the linking group B Linking groups C or linking groups D Selected from:

[0797]

[0798] Where tt is independently selected from 1, 2 or 3 and ss is 3 minus tt (3-tt).

[0799] In some embodiments, in the compound of formula II, the linking group B Linking groups C or linking groups D Selected from:

[0800]

[0801] tt and ss are defined as in this article.

[0802] In some embodiments, in the compound of formula II, the linking group B Linking groups C or linking groups D Selected from:

[0803]

[0804]

[0805]

[0806]

[0807]

[0808] Each of the heteroaryl, heterocyclic, cycloalkyl, and aryl groups may optionally be substituted by one, two, three, or four or any combination of halogens, alkyl, haloalkyl, aryl, heteroaryl, heterocyclic, or cycloalkyl groups, as permitted by the valence; and tt and ss are as defined herein.

[0809] In some embodiments, in the compound of formula II, the linking group B Linking groups C or linking groups D Selected from:

[0810]

[0811]

[0812] Each of the heteroaryl, heterocyclic, cycloalkyl, and aryl groups may optionally be substituted by one, two, three, or four or any combination of halogens, alkyl, haloalkyl, heteroaryl, heterocyclic, or cycloalkyl groups, as permitted by the valence: and tt and ss are as defined herein.

[0813] In some embodiments, in the compound of formula II, the linking group B, linking group C, or linking group D is selected from:

[0814]

[0815] Each of the heteroaryl and aryl groups may optionally be substituted by any combination of 1, 2, 3 or 4 of a halogen, alkyl, haloalkyl, aryl, heteroaryl, heterocyclic or cycloalkyl group, as permitted by the valence; and tt and ss are as defined herein.

[0816] In some embodiments, in the compound of formula II, the linking group A Selected from:

[0817]

[0818] In some embodiments, in the compound of formula II, the linking group A Selected from:

[0819]

[0820] In some embodiments, in the compound of formula II, the linking group A Selected from:

[0821]

[0822] In some embodiments, in the compound of formula II, the linking group A Selected from:

[0823]

[0824] In some embodiments, in the compound of formula II, the linking group B is selected from:

[0825]

[0826] In some embodiments, in the compound of formula II, the linking group B Selected from:

[0827]

[0828] In some embodiments, in the compound of formula II, the linking group B Selected from:

[0829]

[0830]

[0831] In some embodiments, in the compound of formula II, the linking group B Selected from:

[0832]

[0833]

[0834] In some embodiments, in the compound of formula II, the linking group C Selected from:

[0835]

[0836] In some embodiments, in the compound of formula II, the linking group C Selected from:

[0837]

[0838] In some embodiments, in the compound of formula II, the linking group C Selected from:

[0839]

[0840]

[0841] In some embodiments, in the compound of formula II, the linking group C Selected from:

[0842]

[0843] In some embodiments, in the compound of formula II, the linking group C Selected from:

[0844]

[0845] In some embodiments, in the compound of formula II, the linking group C Selected from:

[0846]

[0847] In some embodiments, in the compound of formula II, the linking group C Selected from:

[0848]

[0849] In some embodiments, in the compound of formula II, the linking group C is selected from:

[0850]

[0851] In some embodiments, in the compound of formula II, the linking group D Selected from:

[0852]

[0853] In some embodiments, in the compound of formula II, the linking group D Selected from:

[0854]

[0855]

[0856] In some embodiments, in the compound of formula II, the linking group D Selected from:

[0857]

[0858] In some embodiments, in the compound of formula II, the linking group D Selected from:

[0859]

[0860] In some embodiments, in the compound of formula II, the linking group D Selected from:

[0861]

[0862] In some embodiments, in the compound of formula II, the linking group DSelected from:

[0863]

[0864] In some embodiments, in the compound of formula II, the linking group D Selected from:

[0865]

[0866] In some embodiments, in the compound of formula II, the linking group A Selected from:

[0867]

[0868] In some embodiments, in the compound of formula II, the linking group A Selected from:

[0869]

[0870] In some embodiments, in the compound of formula II, the linking group A Selected from:

[0871]

[0872] In some embodiments, the linking group A Selected from

[0873]

[0874]

[0875] Each of these is arbitrarily selected from R 21 The compound may be substituted with one, two, three, or four substituents. In some embodiments, in compounds of formula II, the linking group... A Selected from:

[0876]

[0877] In some embodiments, in the compound of formula II, the linking group A Selected from

[0878]

[0879] In some embodiments, in the compound of formula II, the linking group A Selected from

[0880]

[0881] In some embodiments, in the compound of formula II, the linking group ASelected from

[0882]

[0883] In some embodiments, in the compound of formula II, the linking group A Selected from

[0884]

[0885] In some embodiments, in the compound of formula II, the linking group A Selected from

[0886]

[0887] In some embodiments, in the compound of formula II, the linking group A Selected from

[0888] In some embodiments, in the compound of formula II, the linking group A Selected from

[0889]

[0890]

[0891] In some embodiments, in the compound of formula II, the linking group A Selected from

[0892]

[0893]

[0894] In some embodiments, in the compound of formula II, the linking group A Selected from

[0895]

[0896]

[0897] In some embodiments, in the compound of formula II, the linking group A Selected from

[0898]

[0899] In some embodiments, in the compound of formula II, the linking group A Selected from

[0900]

[0901] In some embodiments, in the compound of formula II, the linking groupA Selected from

[0902]

[0903]

[0904] In some embodiments, in the compound of formula II, the linking group A Selected from

[0905]

[0906] In some embodiments, in the compound of formula II, the linking group A Selected from

[0907]

[0908] In some embodiments, in the compound of formula II, the linking group B Selected from

[0909]

[0910] In some embodiments, in the compound of formula II, the linking group B Selected from

[0911]

[0912] In some embodiments, in the compound of formula II, the linking group B Selected from

[0913]

[0914] In some embodiments, in the compound of formula II, the linking group B Selected from, wherein each is optionally selected from R 21 It can be substituted with 1, 2, 3 or 4 substituents.

[0915] In some embodiments, in the compound of formula II, the linking group B Selected from:

[0916]

[0917] In some embodiments, in the compound of formula II, the linking group B Selected from:

[0918]

[0919] In some embodiments, in the compound of formula II, the linking group B Selected from:

[0920]

[0921] In some embodiments, in the compound of formula II, the linking group B Selected from:

[0922]

[0923] In some embodiments, in the compound of formula II, the linking group B Selected from:

[0924]

[0925] In some embodiments, in the compound of formula II, the linking group B Selected from:

[0926]

[0927] In some embodiments, in the compound of formula II, the linking group B Selected from:

[0928]

[0929] In some embodiments, in the compound of formula II, the linking group B Selected from:

[0930]

[0931] In some embodiments, in the compound of formula II, the linking group B - Linking group A Selected from:

[0932]

[0933] In some embodiments, in the compound of formula II, the linking group B - Linking group A Selected from:

[0934] In some embodiments, in the compound of formula II, the linking group C Selected from:

[0935]

[0936] In some embodiments, in the compound of formula II, the linking group C Selected from:

[0937]

[0938] In some embodiments, in the compound of formula II, the linking group C Selected from:

[0939]

[0940] In some embodiments, in the compound of formula II, the linking group C Selected from:

[0941]

[0942] In some embodiments, in the compound of formula II, the linking group C Selected from:

[0943]

[0944] In some embodiments, in the compound of formula II, the linking group C Selected from:

[0945]

[0946] In some embodiments, in the compound of formula II, the linking group C Selected from:

[0947]

[0948]

[0949] In some embodiments, in the compound of formula II, the linking group C Selected from: where each is optionally selected from R 21 It can be substituted with 1, 2, 3 or 4 substituents.

[0950] In some embodiments, in the compound of formula II, the linking group C Selected from:

[0951]

[0952] In some embodiments, in the compound of formula II, the linking group C Selected from:

[0953]

[0954] In some embodiments, in the compound of formula II, the linking group C Selected from:

[0955]

[0956] In some embodiments, in the compound of formula II, the linking groupC Selected from:

[0957]

[0958] In some embodiments, in the compound of formula II, the linking group C Selected from:

[0959]

[0960] In some embodiments, in the compound of formula II, the linking group C Selected from:

[0961]

[0962] In some embodiments, in the compound of formula II, the linking group C Selected from:

[0963]

[0964] In some embodiments, in the compound of formula II, the linking group C Selected from:

[0965]

[0966] In some embodiments, in the compound of formula II, the linking group C -(linking group) A )2 is selected from:

[0967]

[0968] In some embodiments, in the compound of formula II, the linking group C -(linking group) A )2 is selected from:

[0969]

[0970] In some embodiments, in the compound of formula II, the linking group C -(linking group) A )2 is selected from:

[0971]

[0972] In some embodiments, in the compound of formula II, the linking group C -(linking group) A )2 is selected from:

[0973]

[0974] In some embodiments, in the compound of formula II, the linking group D Selected from:

[0975]

[0976] In some embodiments, in the compound of formula II, the linking group D Selected from:

[0977]

[0978] Each of these is arbitrarily selected from R 21 It can be substituted with 1, 2, 3 or 4 substituents.

[0979] In some embodiments, in the compound of formula II, the linking group B -(linking group) A (Selected from)

[0980]

[0981] In some embodiments, in the compound of formula II, the linking group C -(linking group) A (Selected from)

[0982]

[0983]

[0984] In some embodiments, in the compound of formula II, the linking group D -(linking group) A (Selected from)

[0985]

[0986] In various implementations, R 4 Each time it appears, it is independently selected from hydrogen, heteroalkyl, alkyl, haloalkyl, aralkyl, heteroaryl, alkenyl, ynyl, 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 .

[0987] In various embodiments, in the compound of formula II, R 5 Independently selected from hydrogen, heteroalkyl, C0-C6 alkyl-cyano, alkyl, alkenyl, alkynyl, haloalkyl, F, Cl, Br, I, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic alkyl, haloalkoxy, -O-alkenyl, -O-alkynyl, C0-C6 alkyl-OR 6 C0-C6 alkyl-SR 6 C0-C6 alkyl-NR 6 R 7 C0-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 C0-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 Each of these is optionally substituted by 1, 2, 3 or 4 substituents.

[0988] In various embodiments, in the compound of formula II, R 6 and R 7 Each time it appears, it is independently selected from hydrogen, heteroalkyl, alkyl, aralkyl, heteroaralkyl, alkenyl, ynyl, 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 .

[0989] In various embodiments, in the compound of formula II, R 8 and R 9 Each time it appears, it is independently selected from hydrogen, heteroalkyl, alkyl, aralkyl, heteroaralkyl, alkenyl, ynyl, aryl, heteroaryl, and heterocyclic.

[0990] In various embodiments, the compound of formula II has the structure of formula II-A.

[0991] In various embodiments, in compounds of formula II-A, L B As defined in this article.

[0992] This invention provides a compound of formula II-A, the structure of which is as follows:

[0993]

[0994] in:

[0995] L B It is the anti-CCP1 (anti-cyclic citrullinated peptide) binding moiety, for example, as described elsewhere in this article.

[0996] [ASGPBM] is the desialyl glycoprotein receptor-binding moiety, and its structure is selected from...

[0997]

[0998]

[0999] Each [CON] is an optional linker chemical portion that, when present, links [LIN] to [PBM] or [ASGPBM];

[1000] [LIN] is [LINKER] or [LINKER-2], each of which is a chemical moiety with a valence of 1 to 15, which is covalently attached to one or more [ASGPBM] or [PBM] groups, optionally via [CON], wherein [LIN] itself optionally contains one or more [CON] groups;

[1001] Z B It does not exist (CH2). IM C(O)-(CH2) IM -or C(O)-(CH2) IM -NR M ;

[1002] R M It is an H or a C1-C3 alkyl group optionally substituted with one or two hydroxyl groups;

[1003] R2 is

[1004] Where R AM It is a C1-C4 alkyl group, optionally substituted with up to 3 halogenated groups and 1 or 2 hydroxyl groups, or -(CH2). KCOOH, or -(CH2) optionally substituted with 1-3 halogroups. K C(O)O-(C1-C4 alkyl), -OC(O)-(C1-C4 alkyl) optionally substituted with 1-3 halogen groups, -C(O)-(C1-C4 alkyl) or -(CH2) optionally substituted with 1-3 halogen groups K -NR N3 R N4 ,or

[1005] R2 is

[1006] in

[1007] R TA It is H, CN, NR N1 R N2 -(CH2) K OH, or -(CH2) optionally substituted with 1-3 halogroups. K O (C1-C4 alkyl), C1-C4 alkyl optionally substituted with 1-3 halogroups, -(CH2) K COOH, or -(CH2) optionally substituted with 1-3 halogroups. K C(O)O-(C1-C4 alkyl), -OC(O)-(C1-C4 alkyl) optionally substituted with 1-3 halogen groups, or -C(O)-(C1-C4 alkyl) optionally substituted with 1-3 halogen groups, or

[1008] R TA It is C3-C 10 The aryl group or a tri- to deca-aryl group containing up to five heteroaryl atoms, each aryl or heteroaryl group optionally substituted by up to three of the following groups: CN, NR. N1 R N2 -(CH2) K OH, or -(CH2) optionally substituted with 1-3 halogroups. K O (C1-C4 alkyl), C1-C3 alkyl optionally substituted with 1-3 halogroups or 1-2 hydroxyl groups, -O-(C1-C3-alkyl) optionally substituted with 1-3 halogroups, -(CH2)KCOOH, -(CH2) optionally substituted with 1-3 halogroups. K C(O)O-(C1-C4 alkyl), OC(O)-(C1-C4 alkyl) optionally substituted with 1-3 halogen groups, or -(CH2) optionally substituted with 1-3 halogen groups. K C(O)-(C1-C4 alkyl), or

[1009] R TA yes It is optionally substituted with up to three C1-C3 alkyl groups, which are optionally substituted with up to three halogenated groups; or

[1010] R TA yes

[1011] R N R N1 R N2 R N3 R N4 Each is independently H or a C1-C3 alkyl group optionally substituted with 1 to 3 halogen groups or 1 or 2 hydroxyl groups, and each -(CH2) K The group is optionally substituted with 1-4 C1-C3 alkyl groups, and these C1-C3 alkyl groups are optionally substituted with 1-3 fluorine groups or 1-2 hydroxyl groups;

[1012] IM is an integer from 0 to 6 each time it appears;

[1013] K is an integer from 0 to 4, which appears independently each time.

[1014] K' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15;

[1015] J' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15;

[1016] h and h' are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15;

[1017] i L The digits are 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[1018] The conditions are h, h', and i L At least one of them is at least 1.

[1019] Or its salts, stereoisomers or solvates.

[1020] In various embodiments, in compounds of formula II-A, R2 is -NC(=O)CH3.

[1021] D. Based on other ASGPR combination parts

[1022] In some embodiments, the ASGPR binding portion can be any of the portions described in the following: 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 betulinicacid glycoconjugate with N-acetyll-D-galactosamine for the targeted delivery to hepatocellular carcinoma cells”, Russian Chemicals. 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, International Edition, Vol. 68, No. 12, pp. 2331-2338, December 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.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 portion is illustrative and not intended to be restrictive.

[1023] 1. GalNAc-tyrosine based portion

[1024] In some embodiments, the ASGPR binding moiety may be a moiety having an M1, M2, M3, or M4 structure, or a combination thereof. In the structures M1, M2, M3, and M4, X is independently O, NH, or S each time it appears. In various embodiments, the compound of formula I or formula II may have one, two, or three ASGPR binding moieties having an M1, M2, M3, or M4 structure.

[1025]

[1026]

[1027] In various embodiments, the ASGPR binding portions M1 to M4 can be conjugated with any suitable [CON], [LINKER], or [LINKER-2] as described herein and in 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.

[1028] 2. Partially based on trivalent triazoles

[1029] In some implementations, the ASGPR bonding portion may be a portion having an M5 structure:

[1030]

[1031] In structure M5, each R is either R1 or R2 independently each time it appears.

[1032]

[1033] In various embodiments, the compound of formula I or formula II contains an ASGPR binding moiety having an M5 structure. In various embodiments, each R in M5 is R1. In various embodiments, each R in M5 is R2.

[1034] In various implementations, the ASGPR binding portion M5 can be conjugated / bonded with any suitable [CON], [LINKER], or [LINKER-2] as described herein and in 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.

[1035] 3. Gaussate fractions derived from galactose and agarose

[1036] In various embodiments, the ASGPR binding portion can be a galactosyl behenate-derived portion M7:

[1037]

[1038] In structure M7, Y is OH or NHAc.

[1039] In various embodiments, the ASGPR binding portion can be the agarose behenate-derived portion M8:

[1040]

[1041] In various embodiments, the ASGPR binding portions M7 and M8 can be conjugated with 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.

[1042] 4. Other small molecule ASGPR binding sites

[1043] In various embodiments, the ASGPR binding moiety can be any of the following compounds 2-18:

[1044]

[1045]

[1046] In various embodiments, in compounds 15 and 16, R is CH2OAc, COOH, or CH2OH. Compounds 2-18 are comparable to those described in this paper and in the following studies: Majoruga, AG et al., “Identification of Novel Small-Molecule ASGP-RLigands”, Current Drug Delivery, 2016, 13, 1303-1312, doi: 10.2174 / 1567201813666160719144651; Olshanova, AS et al., “Synthesis of a new betulinicacid 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; and Yamansarov, E.Yu et al., “New ASGPR-targeted ligands based on glycoconjugated natural triterpenoids”, Russian Chemical. Bulletin, International Edition, Vol. 68, No. 12, pp. 2331-2338, December 2019, any suitable [CON], [LINKER], or [LINKER-2] conjugation / bonding described herein. Compounds 2-18 may be attached by any suitable reactive group contained therein. Without limitation, compounds 2-13 may be attached to [CON], [LINKER], or [LINKER-2] by or through 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 the [CON], [LINKER], or [LINKER-2] described herein include, but are not limited to, substitution (e.g., alkylation of OH or NH groups), esterification (formation of esters), amidation (formation of amides), ester transfer (exchanging one ester for another), transamidation (exchanging one amide for another), azide-alkynyl cycloaddition, and other reactions capable of forming CC, NC, or OC bonds with vinyl and alkynyl groups, such as cycloaddition, amination, oxidation, alkylation, rearrangement (e.g., Claisen, Cope, etc.).

[1047] The compounds described herein may have one or more stereocenters, and each stereocenter may exist independently in an (R) or (S) configuration. In some embodiments, the compounds described herein exist in an optical or racemic form. It should be understood that the compounds described herein include racemic, optical, regioisomeric, and stereoisomeric forms or combinations thereof having the therapeutically useful properties described herein. Preparation of the optical form is achieved in any suitable manner, including, as a non-limiting example, by resolution of the racemic form using recrystallization, synthesis from optically active raw materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In some embodiments, a mixture of one or more isomers is used as the 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. Resolution of the compounds and their isomers can be achieved by any means, including but not limited to chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

[1048] The methods and formulations described herein include N-oxides (if appropriate), crystalline forms (also called polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of compounds having the structure of any one or more compounds described herein, as well as metabolites and active metabolites of these compounds having the same type of activity. Solvates include water, ether (e.g., tetrahydrofuran, methyl tert-butyl ether), or alcohol (e.g., ethanol) solvates, acetates, etc. In some embodiments, the compounds described herein are present in a solvated form with pharmaceutically acceptable solvents such as water and ethanol. In other embodiments, the compounds described herein are present in a non-solvated form.

[1049] In some embodiments, one or more of the compounds described herein may be present as tautomers. All tautomers are included within the scope of the compounds presented herein.

[1050] Of all the compounds described herein, variable positions are selected to obtain stable compounds. In various embodiments, a stable compound refers to a compound formulated according to or according to at least one formulation or pharmaceutical composition described herein, and administered to a subject via or through at least one route of administration described herein to achieve at least one therapeutic effect described herein.

[1051] In some embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" is a pharmaceutical preparation that is converted into a parent drug in vivo. In some embodiments, after administration in vivo, the prodrug is chemically converted into a biologically, pharmaceutically, or therapeutically active form of the compound. In other embodiments, the prodrug is enzymatically metabolized into a biologically, pharmaceutically, or therapeutically active form of the compound through one or more steps or processes.

[1052] In some embodiments, such as those described herein, sites on the aromatic ring moiety are susceptible to various metabolic reactions. Adding appropriate substituents to the aromatic ring structure can reduce, minimize, or eliminate such metabolic pathways. In some embodiments, by way of example only, appropriate substituents that reduce or eliminate the sensitivity of the aromatic ring to metabolic reactions are deuterium, halogens, or alkyl groups.

[1053] The compounds described herein also include isotopically labeled compounds, wherein one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from those commonly found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include, but are not limited to, those... 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 S. In some embodiments, the isotope-labeled compound can be used for drug and / or substrate tissue distribution studies. In other embodiments, substitution with a heavier isotope, such as deuterium, provides greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirement). In still other embodiments, positron-emitting isotopes, such as... 11 C 18 F, 15 O and 13 Nitrogen substitution is useful in positron emission tomography (PET) studies to examine substrate-acceptor occupancy. Isotope-labeled compounds are prepared by any suitable method or by a process that uses a suitable isotope-labeled reagent instead of an otherwise unlabeled reagent.

[1054] In some embodiments, the compounds described herein are labeled in other ways, including but not limited to using chromophores or fluorescent moieties, bioluminescent labeling, or chemiluminescent labeling.

[1055] The compounds described herein and other related compounds with different substituents are used in, for example, 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 Supplements (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, 4th Edition (Wiley 1992); Carey & Sundberg, Advanced Organic Chemistry, 4th Edition, Volumes A and B (Plenum 2000, 2001); and Green & Wuts, Protective Groups in Organic Synthesis, 3rd Edition (Wiley 1992). The compounds are synthesized using the techniques and materials described in (1999) (all of which are incorporated herein by reference). General methods for preparing compounds as described herein are modified by using suitable reagents and conditions to introduce the various parts present in the formulas provided herein.

[1056] The compounds described herein can be synthesized from commercially available compounds or prepared using any suitable procedure described herein.

[1057] In some embodiments, reactive functional groups, such as hydroxyl, amino, imino, thio, or carboxyl groups, are protected to prevent them from undesirably participating in the reaction. Protecting groups are used to block some or all of the reactive portions and prevent these groups from participating in the chemical reaction until the protecting groups are removed. In other embodiments, each protecting group can be removed in a different manner. Protecting groups cleaved under entirely different reaction conditions satisfy the requirement of differential removal.

[1058] In some embodiments, the protecting group is removed by acid, base, reducing conditions (e.g., hydrogenolysis), and / or oxidizing conditions. Groups such as triphenylmethyl, dimethoxytriphenylmethyl, acetal, and tert-butyldimethylsilyl are acid-labile and are used to protect the carboxyl and hydroxyl reactive moieties in the presence of an amino group protected by a Cbz group that can be removed by hydrogenolysis and a base-labile Fmoc group. In the presence of an amine blocked by an acid-labile group (e.g., tert-butyl carbamate) or an acid- and base-stable but hydrolyzable urethane ester, the carboxylic acid and hydroxyl reactive moieties are blocked by a base-labile group (e.g., but not limited to methyl, ethyl, and acetyl).

[1059] In some embodiments, the reactive moiety of the carboxylic acid and hydroxyl group is blocked by a hydrolyzable protecting group such as a benzyl group, while the amine group capable of forming hydrogen bonds with acids is blocked by a base-unstable group such as Fmoc. The reactive moiety of the carboxylic acid is protected by conversion to the simple ester compounds illustrated herein, including conversion to alkyl esters or blocking with an oxidically removable protecting group such as a 2,4-dimethoxybenzyl group, while the coexisting amine group is blocked with a fluoride-unstable silyl carbamate.

[1060] Allyl blocking groups are useful in the presence of acidic and basic protecting groups, as the former are stable and subsequently removed by metal or π-acid catalysts. For example, allyl-blocked carboxylic acids can be deprotected by palladium-catalyzed reactions in the presence of acid-instable tert-butyl carbamate or base-instable amine acetate protecting groups. Another form of protecting group is that which is attached to a resin or intermediate. As long as the residue is attached to the resin, the functional group is blocked and will not react. Once released from the resin, the functional group can react.

[1061] Typically, the blocking / protecting groups can be selected from:

[1062]

[1063] Other protecting groups, and detailed descriptions of techniques applicable to the generation and removal of protecting groups, are described in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, New York, NY, 1999 and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, the disclosures of which are incorporated herein by reference.

[1064] Composition

[1065] Compositions containing one or more of the compounds described herein include pharmaceutical compositions comprising at least one of the compounds described herein and at least one pharmaceutically acceptable carrier. In some embodiments, the composition is formulated for administration via routes such as oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, oral, urethral, ​​vaginal (e.g., vaginal and perivasal), nasal (internal) and rectal (internal), bladder, lung, duodenum, stomach, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical application.

[1066] Methods of treatment, prevention and / or improvement

[1067] This invention includes methods for preventing, treating, and / or improving arthritis using the compounds described herein. Non-limiting examples of arthritis include rheumatoid arthritis, lupus erythematosus, psoriatic arthritis, ankylosing spondylitis, and axial spondylitis. This method can be used to treat, improve, and / or prevent other forms of arthritis or inflammatory diseases caused by or resulting from an autoimmune response / disorder. The method includes administering the compounds described herein to a subject in need, wherein the compounds are optionally administered as a pharmaceutical composition further comprising at least one pharmaceutically acceptable excipient or carrier. In various embodiments, the arthritis is rheumatoid arthritis.

[1068] In various embodiments, the compound / composition is administered via a route selected from oral, transdermal, mucosal, nasal, rectal, bladder, lung, duodenum, stomach, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical routes.

[1069] In various implementations, the subject is a mammal. In various implementations, the subject is a human.

[1070] The methods described herein include administering to a subject a therapeutically effective amount of at least one compound described herein, optionally formulated in a pharmaceutical composition. In various embodiments, the at least one compound described herein present in a therapeutically effective amount in the pharmaceutical composition is the only therapeutically active compound in the pharmaceutical composition. In some embodiments, the method further includes administering to the subject an additional therapeutic agent for treating arthritis or other autoimmune disorders.

[1071] In some embodiments, the compound described herein may be administered to a subject at a lower dose than the dose required to achieve a similar effect in treating the subject's arthritis when administered alone. For example, in some embodiments, the compound described herein may enhance the activity of the additional therapeutic compound, thereby allowing the use of a lower dose of the additional therapeutic compound to provide the same effect.

[1072] In some embodiments, the compounds and therapeutic agents described herein are administered together to the subject. In other embodiments, the compounds and therapeutic agents described herein are co-formulated and co-administered to the subject.

[1073] In some implementations, the subject is a mammal. In other implementations, the mammal is a human.

[1074] combination therapy

[1075] The useful compounds described herein can be used in combination with one or more additional therapeutic agents for treating, improving, and / or preventing arthritis or another autoimmune disease. These additional therapeutic agents may include compounds that are commercially available or synthetically available to those skilled in the art. These additional therapeutic agents are known to treat, prevent, or alleviate the symptoms of arthritis.

[1076] In various embodiments, synergistic effects have been observed when the compound described herein is administered in combination with one or more other therapeutic agents or compounds. For example, suitable methods, such as Sigmoid-E, can be used. max Synergistic effects were calculated using equations (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 equations mentioned above can be applied to experimental data to generate corresponding curves to help evaluate the effects of drug combinations. The corresponding curves associated with the equations mentioned above are concentration-effect curves, equivalence plots, and combination exponent curves, respectively.

[1077] In various embodiments, the method includes administering one or more additional therapeutic agents that can be used to treat, improve, and / or prevent arthritis or another autoimmune disease, including disease-modifying antirheumatic drugs (DMARDs), glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), and analgesics. The additional therapeutic agents can be administered at any dosage and via any route of administration as described herein. In various embodiments, the additional therapeutic agents can be administered sequentially or simultaneously with the compounds. In various embodiments, sequential administration can occur from 1 minute to 12 hours before or after administration of a compound of formula I, Ia, II, or IIb, or any other compound described herein that binds to an anti-CCP antibody.

[1078] Non-restrictive 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.

[1079] Non-restricted examples of glucocorticoids include betamethasone, prednisone, and methylprednisolone.

[1080] Non-limiting examples of nonsteroidal anti-inflammatory drugs include celecoxib, diclofenac sodium, ibuprofen, etc.

[1081] Non-limiting examples of analgesics include acetaminophen, tramadol, oxycodone, hydrocodone, etc.

[1082] Application / Dosage / Formulation

[1083] Administration regimens may affect the composition of the effective dose. The therapeutic agent may be administered to the subject before or after the onset of arthritis. Furthermore, several separate doses may be administered daily or sequentially, as well as alternating doses, or the dose may be administered continuously by infusion or by bolus injection. Additionally, the dose of the therapeutic agent may be increased or decreased proportionally depending on the urgency of the treatment or prevention situation.

[1084] The compositions described herein can be administered to patients, preferably mammals, more preferably humans, at doses and times that are effective in treating arthritis in the patient, using known procedures. The effective amount of the therapeutic compound required to achieve a therapeutic effect can vary depending on factors such as the patient's disease or disorder state; the patient's age, sex, and weight; and the ability of the therapeutic compound to treat the arthritis in the patient. Dosing regimens can be adjusted to provide an optimal therapeutic response. For example, several separate doses can be administered daily, or the dose can be proportionally reduced as indicated by the urgency of the treatment situation. Non-limiting examples of the effective dose range of the therapeutic compounds described herein are between about 1 and 5,000 mg / kg body weight / day. Those skilled in the art can investigate the relevant factors and determine the effective amount of the therapeutic compound without the need for inappropriate experiments.

[1085] The actual dosage level of the active ingredient in the pharmaceutical composition described herein can be altered to obtain an amount of active ingredient that effectively achieves the therapeutic response required for a particular patient, composition, and route of administration, without being toxic to the patient.

[1086] Specifically, the chosen dose level depends on a variety of factors, including the activity of the particular compound used, the timing of administration, the excretion rate of the compound, the duration of treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health status and medical history of the patient being treated, and similar factors well known in the medical field.

[1087] A physician with ordinary skills in the art, such as an internist or veterinarian, can easily determine and prescribe the effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian may begin with a dose of the compound described herein used in the pharmaceutical composition that is below the dose required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

[1088] In certain embodiments, it is particularly advantageous to formulate the compound into dosage units to facilitate administration and uniformity of dosage. As used herein, dosage units refer to physically discontinuous units suitable as a unit dose for a patient to be treated; each unit contains a calculated predetermined quantity of the therapeutic compound to bind with a desired drug carrier to produce the intended therapeutic effect. The dosage unit form of one or more compounds described herein is determined by and directly depends on (a) the unique properties of the therapeutic compound and the specific therapeutic effect to be achieved, and (b) the inherent limitations in the technology of compounding / formulating such a therapeutic compound.

[1089] In some embodiments, the compositions described herein are formulated using one or more pharmaceutically acceptable excipients or carriers. In some embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of the compound described herein and a pharmaceutically acceptable carrier.

[1090] The carrier can 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. For example, appropriate flowability can be maintained in the dispersed state by using a coating such as lecithin, maintaining the desired particle size, and by using surfactants. Antimicrobial activity can be achieved using various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, isotonic agents, such as sugars, sodium chloride, or polyols, such as mannitol and sorbitol, are preferably included in the composition. The absorption time of injectable compositions can be prolonged by including agents that delay absorption, such as aluminum monostearate or gelatin.

[1091] In some embodiments, the compositions described herein are administered to a patient at doses of 1 to 5 times or more per day. In other embodiments, the compositions described herein are administered to a patient at dose ranges including, but not limited to, once daily, once every two days, once every three days to once weekly, and once every two weeks. It will be apparent to those skilled in the art that the frequency of administration of the various combinations described herein varies from person to person and depends on many factors, including but not limited to age, the 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 limited to any particular dosing regimen, and the precise dose and composition administered to any patient shall be determined by the attending physician after taking into account all other factors of the patient.

[1092] The compounds (one or more) described herein for application may be administered in doses of about 1 μg to about 10,000 mg, about 20 μg to about 9,500 mg, about 40 μg to about 9,000 mg, about 75 μg to about 8,500 mg, about 150 μg to about 7,500 mg, about 200 μg to about 7,000 mg, about 350 μg to about 6,000 mg, about 500 μg to about 5,000 mg, or about 750 μg to about 4,000 mg. The range of about 1 mg to about 3,000 mg, about 10 mg to about 2,500 mg, about 20 mg to about 2,000 mg, about 25 mg to about 1,500 mg, about 30 mg to about 1,000 mg, about 40 mg to about 900 mg, about 50 mg to about 800 mg, about 60 mg to about 750 mg, about 70 mg to about 600 mg, about 80 mg to about 500 mg, and any and all whole or part of the increments therein. In various embodiments, the compound of formula I is administered at a dose 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.

[1093] In some embodiments, the dosage of the compound described herein is between about 1 mg and about 2,500 mg. In some embodiments, the dosage of the compound described herein used in the compositions 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 and all of its whole or partial increments.

[1094] In some embodiments, the composition described herein is a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of the compound described herein, alone or in combination with a second agent; and instructions for using the compound to treat, prevent, or alleviate one or more symptoms of arthritis in a patient.

[1095] The formulations can be mixed with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteric, or any other suitable route of administration known in the art. Pharmaceutical formulations can be sterilized and, if desired, mixed with excipients such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts affecting osmotic pressure buffers, colorants, flavoring agents, and / or aromatic substances. They can also be combined with other active agents, such as other analgesics, when needed.

[1096] The routes of administration for any of the compositions described herein include the mouth, nose, rectum, vagina, parenteral, oral cavity, sublingual, or topical. The compounds used in the compositions described herein can be formulated for administration via any suitable route, such as oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, tongue, oral cavity, urethra, vagina (e.g., vagina and periavaginal), nasal (internal), and transrectal), intrabladder, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical application. In various embodiments, the Formula I compound is administered via intravenous administration.

[1097] Suitable compositions and dosage forms include, for example, tablets, capsules, pouches, pills, gel capsules, lozenges, dispersants, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, pastes, sugar tablets, emulsions, ointments, plasters, lotions, tinctures, suppositories, liquid sprays for nasal or oral administration, dry powders or aerosols for inhalation, and compositions and formulations for intravesical administration. It should be understood that the formulations and compositions described herein are not limited to the specific formulations and compositions described herein.

[1098] Oral administration

[1099] For oral administration, tablets, lozenges, liquids, drops, suppositories, capsules, pouches, and gel capsules are particularly suitable. Compositions intended for oral use can be prepared according to any method known in the art, and such compositions may comprise one or more formulations selected from the group of inert, non-toxic pharmaceutical excipients suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as lactose; granulating and disintegrants such as corn starch; binders such as starch; and lubricants such as magnesium stearate. Tablets may be uncoated or may be coated using known techniques to achieve a refined effect or delay the release of the active ingredient. Formulations for oral use may also be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert diluent.

[1100] For oral administration, the compounds (one or more) described herein may be in the form of tablets or capsules prepared by conventional methods using pharmaceutically acceptable excipients such as binders (e.g., polyvinylpyrrolidone, hydroxypropyl cellulose, or hydroxypropyl methylcellulose); fillers (e.g., corn starch, lactose, microcrystalline cellulose, or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., sodium starch saccharide); or wetting agents (e.g., sodium dodecyl sulfate). If desired, the tablets may be coated using suitable methods and coating materials, such as OPADRY, available from Colorcon, West Point, Pa. TM Film coating systems (e.g., OPADRY) TM OY type, OYC type, organic enteric-coated OY-P type, water-based enteric-coated OY-A type, OY-PM type and OPADRY TM White, 32K18400). Liquid formulations for oral administration may be in the form of solutions, syrups, or suspensions. Liquid formulations may be prepared by conventional methods with pharmaceutically acceptable additives, such as suspensions (e.g., sorbitol syrup, methylcellulose, or hydrogenated edible fats); emulsifiers (e.g., lecithin or gum arabic); non-aqueous media (e.g., almond oil, oily esters, or ethanol); and preservatives (e.g., methylparaben, propylparaben, or sorbic acid).

[1101] The compositions described herein can be prepared, packaged, or marketed in formulations suitable for oral or oral administration. For example, tablets containing the compounds described herein can be made by compressing or molding the active ingredient, optionally with the addition of one or more other ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granule formulation, in a suitable apparatus, optionally mixed with one or more binders, lubricants, excipients, surfactants, and dispersants. Molded tablets can be prepared by molding a mixture of the active ingredient, a pharmaceutically acceptable carrier, and at least sufficient liquid to wet the mixture in a suitable apparatus. Pharmaceutically acceptable excipients for manufacturing tablets include, but are not limited to, inert diluents, granulators and disintegrants, dispersants, surfactants, disintegrants, binders, and lubricants.

[1102] Suitable dispersants include, but are not limited to, potato starch, sodium starch glycolate, poloxamer 407, or poloxamer 188. One or more dispersants may each be present in the composition alone in an amount from about 0.01% w / w to about 90% w / w relative to the weight of the dosage form. One or more dispersants may each be present in the composition alone in an amount of at least, greater than, or less than 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.

[1103] Surfactants include cationic, anionic, or nonionic surfactants, or combinations thereof. Suitable surfactants include, but are not limited to, behenyltrimethylammonium chloride, benzalkonium chloride, phenethylammonium chloride, benzalkonium bromide, carbon bromide n-decanoic acid, cetylamine chloride, cetrimonium bromide, cetylpyridine chloride, dialcyldimethylammonium chloride, dimethyloctadecylammonium bromide, dimethyloctadecylammonium chloride, domiphen bromide, dodecylmethylglucose-10-hydroxypropyl diammonium chloride, tetramethylammonium hydroxide, toluene bromide, octadecylammonium chloride, octeneamine hydrochloride, and olafluridine. N-Oleoyl-1,3-Propanediamine, 2-Acrylamide-2-methylpropanesulfonic acid, Alkylbenzenesulfonate, Ammonium dodecyl sulfate, Ammonium perfluorononanoate, Dococuronate, Sodium cocoamide diacetate, Magnesium lauryl ether sulfate, Perfluorobutyric acid, Perfluorononanoic acid, Perfluorooctane sulfonic acid, Perfluorooctanoic acid, Potassium lauryl sulfate, Sodium alkyl sulfate, Sodium dodecyl sulfate, Sodium lauryl ether sulfate, Sodium lauroyl sarcosinate, Sodium myristyl ether sulfate, Sodium nonanoyloxybenzenesulfonate, Alkyl alcohol polyether Sodium sulfate, sodium stearate, sodium sulfosuccinate, cetyl alcohol polyether 1000, cetearyl alcohol, cetyl alcohol, cocoyl diethanolamine, cocamide monoethanolamine, decyl glucoside, decyl polydextrose, glyceryl monostearate, octylphenoxy polyethoxyethanol CA-630, isohydroxyethyl-20, lauryl glucoside, octylphenoxy polyethoxyethanol P-40, nonylphenol polyol-9, nonylphenol polyether, nonylphenoxy polyethoxyethanol (NP-40), octaethylene glycol monostearate Dodecyl ether, N-octylβ-D-thiopyranoside, octyl glucoside, oleyl alcohol, PEG-10 sunflower glyceryl ester, pentaethylene glycol monododecyl ether, polydextrose, poloxamer, poloxamer 407, polyethoxylated tallow amine, polyglycerol polyricinoleate, polysorbate, polysorbate 20, polysorbate 80, dehydrated sorbitol, sorbitol monolaurate, sorbitan monostearate, sorbitan tristearate, stearyl alcohol, surfactant, Triton X-100, and Tween 80. One or more surfactants may each be present in the composition alone in an amount from about 0.01% w / w to about 90% w / w relative to the weight of the dosage form. One or more surfactants may each be present in the composition in an amount of at least, greater than or less than 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.

[1104] Suitable diluents include, but are not limited to, calcium carbonate, magnesium carbonate, magnesium oxide, sodium carbonate, lactose, microcrystalline cellulose, calcium phosphate, dicalcium phosphate, and sodium phosphate. The composition contains 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 each be present in the composition alone 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 may each be present in the composition alone in an amount of at least, greater than, or less than 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.

[1105] Suitable granulating agents and disintegrants include, but are not limited to, sucrose, copovidone, corn starch, microcrystalline cellulose, methylcellulose, sodium starch glycolate, pregelatinized starch, povidone, sodium carboxymethyl cellulose, sodium alginate, citric acid, croscarmellose sodium, cellulose, calcium carboxymethyl cellulose, colloidal silica, croscarmellose, and alginate. One or more granulating agents and disintegrants may each be present alone in the composition in an amount from about 0.01% w / w to about 90% w / w relative to the weight of the dosage form. One or more granulating agents and disintegrants may each be present in the composition in an amount of at least, greater than or less than 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.

[1106] 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, glucose, maltose, gelatin, and polyethylene glycol. One or more binders may each be present in the composition alone in an amount from about 0.01% w / w to about 90% w / w relative to the weight of the dosage form. One or more binders may each be present in the composition alone in an amount of at least, greater than, or less than 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.

[1107] 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 lauryl ether sulfate, sodium benzoate, stearic acid, sodium stearoyl fumarate, silica, and talc. One or more lubricants may each be present in the composition alone in an amount from about 0.01% w / w to about 90% w / w relative to the weight of the dosage form. One or more lubricants may each be present in the composition in an amount of at least, greater than or less than 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.

[1108] Tablets may be uncoated or coated using known methods to achieve delayed disintegration in the gastrointestinal tract of the subject, thereby providing sustained release and absorption of the active ingredient. For example, materials such as glyceryl monostearate or glyceryl distearate can be used for coated tablets. Further, as an example, tablets may be coated using the methods described in U.S. Patent Nos. 4,256,108, 4,160,452, and 44,265,874 to form osmotic controlled-release tablets. Tablets may also contain sweeteners, flavoring agents, coloring agents, preservatives, or some combination thereof to provide a pharmaceutically palatable formulation.

[1109] Tablets can also be enteric-coated, allowing the coating to dissolve at a specific pH value, such as from about pH 5.0 to about pH 7.5, thereby releasing the compounds described herein. The coating may contain, for example, compounds having acidic or basic groups. L, S, FS, and / or E polymers are used to allow the release of the compounds described herein at specific sites, including any desired site in the intestine. The coating may also contain, for example, polymers with cationic or neutral groups. RL and / or RS polymers are used to achieve time-controlled release of the compounds described herein through pH-independent swelling.

[1110] External application

[1111] For parenteral administration, the compounds described herein can be formulated for injection or infusion, for example, intravenous, intramuscular, or subcutaneous injection or infusion, or administered at a bolus dose and / or via continuous infusion. Suspensions, solutions, or emulsions in oily or aqueous media may be used, optionally containing other formulations such as suspending agents, stabilizers, and / or dispersants.

[1112] The aseptic injectable form of the compositions described herein may be an aqueous or oil-based suspension. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Aseptic injectable formulations may also be as sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions of 1,3-butanediol. Acceptable media and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Sterile fixed oils are commonly used as solvents or suspension media. For this purpose, any bland fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glycerol derivatives, may be used to prepare injectable formulations, as may pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylene form. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as lauryl alcohol, stearyl alcohol, or oleyl alcohol or similar alcohols.

[1113] Other forms of application

[1114] Additional dosage forms suitable for use with the compounds (one or more) 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. Further dosage forms suitable for use with the compounds (one or more) and compositions described herein include those described in U.S. Patent Application Nos. 20030147952, 20030104062, 20030104053, 20030044466, 20030039688, and 20020051820. Other dosage forms suitable for use with the compounds (one or more) and compositions described herein 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.

[1115] Controlled-release formulations and drug delivery systems

[1116] In some embodiments, the formulations described herein may be, but are not limited to, short-term, rapid-compensation, and controlled formulations such as sustained-release, delayed-release, and pulsatile-release formulations.

[1117] The term sustained release, in its conventional sense, refers to a pharmaceutical preparation that releases the drug gradually over an extended period of time, although not necessarily, but which results in a substantially constant blood level of the drug over that extended period. This period can be as long as a month or longer, and should be longer than the release achieved by administering the same amount via bolus injection.

[1118] For sustained release, the compound can be formulated with a suitable polymer or hydrophobic material that provides sustained release properties. Thus, the compound used in one or more of the methods described herein can be administered in particulate form by, for example, injection, or in wafer or disc form by implantation.

[1119] In some cases, the dosage form to be used may be provided for sustained or controlled release of one or more active ingredients using, for example, hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, permeation systems, multilayer coatings, microparticles, liposomes, or microspheres, or combinations thereof, thereby providing the desired release profile in different proportions. Suitable controlled-release formulations known to those skilled in the art, including those described herein, can be readily selected for use in the pharmaceutical compositions described herein. Therefore, single-unit dosage forms suitable for oral administration, such as tablets, capsules, gel capsules, and sac tablets, are included in the compositions and dosage forms described herein.

[1120] Most controlled-release pharmaceutical products share the common goal of improving therapeutic efficacy relative to their non-controlled-release counterparts. Ideally, the optimal design of controlled-release formulations in medical treatment is characterized by the use of the least amount of drug substance to cure or control the condition in the shortest possible time. The advantages of controlled-release formulations include prolonged drug activity, reduced dosing frequency, and improved patient compliance. Furthermore, controlled-release formulations can be used to influence the onset time of a drug or other properties, such as blood drug concentration, and thus can affect the occurrence of side effects.

[1121] Most controlled-release formulations are designed to first release a certain amount of drug to rapidly produce the desired therapeutic effect, and then gradually and continuously release additional amounts of drug to maintain this level of therapeutic effect over an extended period of time. To maintain this constant drug level in the body, the drug must be released from the dosage form at a rate that replaces the amount metabolized and excreted.

[1122] Controlled 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 "controlled-release component" is defined herein as one or more compounds, including but not limited to polymers, polymer matrices, gels, permeable membranes, liposomes, or microspheres, or combinations thereof, that promote the controlled release of the active ingredient. In some embodiments, a sustained-release formulation is used to administer one or more of the compounds described herein, alone or in combination with another pharmaceutical formulation, to a patient.

[1123] The term delayed release, in its conventional sense, refers to a pharmaceutical preparation that provides the initial release of the drug after a certain delay following drug administration, and although not mandatory, may range from about 10 minutes to about 12 hours.

[1124] In its conventional sense, the term pulsed release refers to a pharmaceutical formulation that delivers drug release in a manner that produces a pulsed plasma distribution after drug administration.

[1125] The term immediate release, in its conventional sense, refers to a pharmaceutical preparation that delivers the drug immediately after administration.

[1126] As used herein, "short term" means any time period following drug administration, up to and including approximately 8 hours, approximately 7 hours, approximately 6 hours, approximately 5 hours, approximately 4 hours, approximately 3 hours, approximately 2 hours, approximately 1 hour, approximately 40 minutes, approximately 20 minutes, or approximately 10 minutes after drug administration, and any or all of these whole or partial increments.

[1127] As used herein, rapid compensation refers to any time period following drug administration, up to and including approximately 8 hours, approximately 7 hours, approximately 6 hours, approximately 5 hours, approximately 4 hours, approximately 3 hours, approximately 2 hours, approximately 1 hour, approximately 40 minutes, approximately 20 minutes, or approximately 10 minutes, as well as any full and partial increments thereof.

[1128] Dosage

[1129] The therapeutically effective amount or dosage of the compounds described herein depends on the patient's age, sex, weight, current medical condition, and the progression of arthritis in the patient being treated. Technicians are able to determine the appropriate dosage based on these and other factors.

[1130] Suitable doses of the compounds described herein can range from about 0.01 mg to about 5,000 mg per day, for example, from about 0.1 mg to about 1,000 mg, or from about 1 mg to about 500 mg per day, or from about 5 mg to about 250 mg per day. Dosage can be administered as a single dose or multiple doses, for example, one to four or more times per day. When multiple doses are used, the amount of each dose can be the same or different. For example, a daily dose of 1 mg can be administered as two 0.5 mg doses, with an interval of about 12 hours between each dose.

[1131] It is understood that, in non-limiting instances, the amount of compound administered daily may be daily, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, in the case of administration every other day, a dose of 5 mg daily may be started on Monday, followed by the first dose of 5 mg daily on Wednesday, and the second dose of 5 mg daily on Friday, etc.

[1132] If the patient's condition does improve, the compound(s) described herein may be administered continuously, at the physician's discretion; alternatively, the dosage may be temporarily reduced or suspended for a period of time (i.e., a "withdrawal period"). The length of the withdrawal period may vary between 2 days and 1 year, and includes, for example, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during the withdrawal period includes 10%-100%, and for example only, includes 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[1133] Once the patient's condition improves, a maintenance dose will be administered if necessary. Subsequently, the dose or frequency of administration, or both, will be reduced to a level that maintains the improvement in the disease. In some implementations, the patient will require intermittent treatment on a long-term basis in case of any recurrence of symptoms and / or infection.

[1134] The compounds described herein can be formulated into unit dosage forms. The term "unit dosage form" refers to a physically discontinuous unit suitable as a unit dose for a patient receiving treatment, each unit containing a calculated predetermined amount of active substance to produce the desired therapeutic effect, optionally used with a suitable drug carrier. This unit dosage form can be used for either a single-day dose or a multi-day dose (e.g., about 1 to 4 times or more daily). When multiple daily doses are used, the unit dosage form for each dose can be the same or different.

[1135] The toxicity and efficacy of this treatment regimen may optionally be determined in cell cultures or laboratory animals, including but not limited to determining the LD50. 50 (A dose that is lethal to 50% of the population) and ED 50 (The dose that has a therapeutic effect on 50% of the population). The dose ratio between toxicity and efficacy is the therapeutic index, expressed as LD50. 50 and ED 50 The ratio between [specific values]. Data obtained from cell culture experiments and animal studies may optionally be used to determine the dosage range for human use. The dosage of this compound is preferably within the cyclic concentration range, which includes the ED (expiratory power source) with minimal toxicity. 50 Optionally, within this range, the dosage may vary depending on the dosage form and route of administration used.

[1136] Example

[1137] Various embodiments of this application can be better understood by referring to the following examples, which are provided by way of illustration. The scope of this application is not limited to the embodiments given herein.

[1138] Materials and Methods

[1139] abbreviations used

[1140] 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 = fluorenemethoxycarbonyl; DIC = N,N'-diisopropylcarbodiimide; HATU = hexafluorophosphate azabenzotriazole tetramethylurea.

[1141] Spectroscopy and binding analysis

[1142] Reference Figure 5AThe binding of CCP1-GN4 was assessed using surface plasmon resonance (SPR) on a Biacore S200 instrument. Prior to the binding study, 20 μg / mL of the mouse anti-citrulline epitope recombinant antibody clone 12G1 (anti-CCP1) (Creative BioLabs) was immobilized onto the S-series sensor chip CM5 and amine-conjugated to a target of 1000 reaction units (RU) in 10 mM sodium acetate buffer at pH 5.5. Simultaneously, a normal human IgG isotype control (R&D System) was immobilized as a reference subtraction control under the same conditions. The sensor chip and reagents required for amine conjugation were purchased from Cytiva.

[1143] CCP1-GN4 was serially diluted in 100% DMSO and transferred to 96-well microplates. 1X HBS-P buffer (Cytiva) was added to dilute the samples to the final test concentrations in 1% DMSO (1000 nM, 250 nM, 62.5 nM, 15.6 nM, 3.9 nM, 1 nM). Immediately prior to the binding assay, a 1X HBS-P (Cytiva) solution containing 1% DMSO was prepared as a run buffer.

[1144] Samples were injected into the sensor chip at a flow rate of 30 μL / min with a contact time of 300 seconds, a dissociation time of 600 seconds, and at 25 °C. Between injections, any remaining bound analytes were washed from the sensor chip surface using a solution of 50% DMSO in 1X HBS-P buffer.

[1145] The steady-state affinity model was used to fit the response of CCP1-GN4 at different test concentrations in Biacore Insight Evaluation software (Cytiva) to obtain the measured value of the dissociation constant (KD).

[1146] Reference Figure 5BThe binding of ASGPR1 to the target was characterized by surface plasmon resonance (SPR) on a Biacore 8K instrument. Prior to binding measurements, recombinant biotin-ASGPR1 (Viva Biotech) was diluted to a concentration of 2 μg / mL in a buffer solution containing 20 mM Tris pH 8.0, 200 mM NaCl, 1 mM TCEP, 2 mM CaCl2, and 0.01% Tween-20. Before capturing 2 μg / mL ASGPR on the sensor chip surface, the sensor chip SA (Cytiva) was conditioned with three injections of 1 M NaCl in 50 mM NaOH. Capture was performed at a flow rate of 5 μL / min at a target level of 1000 RU. CCP1-GN4 was serially diluted to the final test concentration (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) at 10 sites in a buffer solution consisting of 20 mM Tris pH 8.0, 200 mM NaCl, 1 mM TCEP, 2 mM CaCl2, 0.01% Tween-20 and 3% DMSO.

[1147] Samples were injected into the sensor chip surface at a contact time of 180 seconds, a dissociation time of 600 seconds, a flow rate of 40 μL / min, and a temperature of 25 °C. The data files were fitted into multi-cycle dynamics and steady-state models using Biacore Insight Evaluation software to determine the kinetic and affinity binding parameters.

[1148] Reference Figure 6A and 6B The plasma stability (PBS) of CCP1-GN4 was determined at WuXi Biologics. The compound was incubated in human, rat, or mouse plasma at 37°C for 2 hours. Aliquots were taken at different time points, and the remaining percentage of CCP1-GN4 was quantified by LCMS. For plasma protein binding (PPB), the compound (CCP1-GN4) was incubated with human, rat, or mouse plasma proteins, and the degree of protein binding was determined by ultracentrifugation and LCMS.

[1149] Reference Figure 7HEK-293-ASGPR cells were harvested with acutase, filtered through a 40 μm cell filter, and their viability was confirmed. Cells were seeded at 30 kJ / 100 μL per well in complete medium containing 2 μg / mL poly-D-lysine. Anti-CCP1 antibody (12G1) and goat anti-mouse (Jackson 115-546-071) AF488 were pre-incubated at 37°C for 30 min (final concentrations of 100 nM and 34 nM, respectively). The cell culture medium was removed, and a mixture of BH5553, CCP1 antibody (12G1), and goat anti-mouse AF488 was added to the cells (total volume 100 μL per well). The cells were then incubated at 37°C for 20 h. Cell fluorescence was quantified using Incucyte over time.

[1150] Reference Figure 8A and 8B CD1 mice (n=3 per group) were administered anti-CCP1 antibody (2 mpk, IV) at time 1 h. Blood samples were collected at time 0, 0.08, 0.25, 0.5, 2, 4, and 8 h. CCP1-GN4 (1.21 and 0.24 mpk) and peptide control BH5638 (1.21 mpk eq) were administered at time 0 h after the first blood sample. Anti-CCP1 concentrations at different time points were determined by MSD assay. CCP1-Gn4 pk was measured by LCMS at Touchstone Biosciences.

[1151] Synthesis method

[1152] General chemical methods

[1153] Rapid chromatography was performed on a CombiFlash NEXTGEN 300+ system using Teledyne ISCO software version 5.0.62. Separations were performed on RediSep Rf high-performance gold C18 columns (reversed phase) and RediSep Rf flash columns (normal phase). HPLC purification of the compounds was performed using a Shimadzu chromatographic system with a Waters SunFire C18 OBD preparative column (10 mm x 150 mm) and LabSolutions software version 5.92. NMR analysis was performed on an Agilen DD2 400 MHz and Agilen DD 2 600 MHz NMR spectrometer. The 600 MHz instrument was equipped with a C[H] cold probe. HRMS analysis was performed on a Shimadzu 9030 quadrupole time-of-flight LC-MS system after separation on a Shim-pack Scepter C18-120 1.9 μm (2.1 x 50 mm) reversed-phase column. Separation was performed using a gradient of water and acetonitrile with the addition of 0.1% formic acid. Infrared (IR) spectra were collected using pure samples and recorded using a Thermo Nicolet 6700 equipped with a diamond ATR cell. (Report selection ν) ma The unit is cm. -1 Optical rotation was recorded using a Rudolph Autopol IV polarimeter. Chemicals were purchased from Sigma-Aldrich, Fisher, and Carbosynth. Solvents were purchased from Fisher and Macron.

[1154] Synthesis Examples

[1155] Compound 1 (48)

[1156] 2-(2-(2-hydroxyethoxy)ethoxy)ethyl ester of 4-methylbenzenesulfonic acid

[1157]

[1158] Triethylene glycol (17.5 mL, 19.7 g, 131 mmol, 5 eq) was dissolved in dichloromethane (150 mL) and triethylamine (5.48 mL, 3.98 g, 1.5 eq) and cooled to 0 °C. Then, p-toluenesulfonyl chloride (5.00 g, 26.2 mmol, 1.00 eq) 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 (3x) and brine (1x). The organic layer was dried over sodium sulfate and concentrated under vacuum to give compound 1 (6.89 g, 22.6 mmol) in a pale yellow oil in 85% yield, which was ready for use without further purification. The spectra matched the previously reported characteristic data.

[1159] Compound 2(48)

[1160] 2-(2-(2-azidoethoxy)ethoxy)ethanol

[1161]

[1162] Toluenesulfonate 1 (2.00 g, 6.57 mmol) and sodium azide (0.470 g, 7.23 mmol, 1.1 eq) were dissolved in dimethylformamide (40 mL) and stirred overnight at 60 °C. The volume was reduced by about half by rotary evaporation at 70 °C. The resulting mixture was diluted in water and extracted with ethyl acetate (2x). The combined organic layers were washed with brine (3x), dried over sodium sulfate, and evaporated to give a colorless oily azide 2 (932 mg, 5.32 mmol) in 81% yield, which was ready for use without further purification.

[1163] Compound 3(49)

[1164]

[1165] (5R,6R,7R,7aR)-5-(acetoxymethyl)-2-methyl-3a,6,7,7a-tetrahydro-5H-pyrano[3,2-d]oxazol-6,7-dimethyldiacetate

[1166] D-galactosamine pentaacetate (100 mg, 0.257 mmol) was dissolved in dichloroethane (1.0 mL) and stirred at room temperature under a nitrogen atmosphere. Trimethylsilyl trifluoromethanesulfonate (70.0 μL, 86.0 mg, 0.387 mmol, 1.50 eq) was then added. The reaction mixture was stirred at 50 °C for 90 min, then cooled to room temperature and stirred for another 12 h. The mixture was then poured into an ice-cold saturated aqueous solution of sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with water (2x), dried over sodium sulfate, and evaporated to give compound 3 (236 mg, 77.7 mmol, 92%) as a dark gel, which was ready for use without further purification.

[1167] Compound 4 (50)

[1168] (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-[2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy]tetrahydro-2H-pyran-3,4-dimethyldiacetate

[1169]

[1170] Compound 3 (200 mg, 0.607 mmol) and compound 2 (160 mg, 0.913 mmol, 1.50 eq) were dissolved in 1,2-dichloroethane (5 mL). Then, [the following was added] Molecular sieves were used, and the reaction mixture was stirred for 30 minutes. Trimethylsilyl trifluoromethanesulfonate (55.0 μL, 67.5 mg, 0.304 mmol, 0.5 eq) 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 (1x) and water (1x), dried over magnesium sulfate, and concentrated. The crude oil was purified on silica gel (50–100% ethyl acetate in dichloromethane solution) to give compound 4 (245 mg, 0.486 mmol) as a white solid in 80.1% yield. The spectra matched the previously reported characteristic data.

[1171] Compound 5(50)

[1172] (2R,3R,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-[2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy]tetrahydro-2H-pyran-3,4-dimethyldiacetate

[1173]

[1174] Compound 4 (1.80 g, 3.57 mmol) was dissolved in tetrahydrofuran (35 mL). Then, triphenylphosphine (1.40 g, 5.35 mmol, 1.5 eq) and water (257 μL, 14.28 mmol, 4 eq) were added, and the reaction mixture was stirred at room temperature under nitrogen for 36 hours. The solvent was removed, and the colorless, oily crude product was used for subsequent steps without further purification.

[1175] Compound 6(51)

[1176] 3,3'-((2-amino-2-((2-cyanoethoxy)methyl)propane-1,3-diyl)bis(oxy))dipropionitrile

[1177]

[1178] Tris(hydroxymethyl)aminomethane (1.00 g, 8.25 mmol, 1.00 eq) was dissolved in dioxane (50 mL), and an aqueous solution of KOH (40% w / v, 1 mL) was added dropwise. Acrylonitrile (6.45 mL, 5.22 g, 25.2 mmol, 3.05 eq) was then added dropwise, and the reaction mixture was stirred overnight. Dioxane was removed under vacuum, and the resulting aqueous solution was extracted with dichloromethane (3x). The combined organic layers were then washed with brine (1x), dried over sodium sulfate, and evaporated to give a colorless oily compound 6 (1.12 g, 4.04 mmol) in 48.5% yield, which could be used directly in subsequent steps without purification. The spectra matched the previously reported characteristic data.

[1179] Compound 7(52)

[1180] 3,3'-((2-amino-2-((3-methoxy-3-oxopropoxy)methyl)propane-1,3-diyl)bis(oxo))dipropionate dimethyl ester

[1181]

[1182] 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 into dichloromethane (3x). The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified on silica gel (0–10% methanol in dichloromethane solution) to give compound 7 (656 mg, 1.73 mmol) as a colorless oil in 69.0% yield. The spectra matched the previously reported characteristic data.

[1183] Compound 8

[1184] 8,8-Bis[(3-methoxy-3-oxopropoxy)methyl]-3,6-dioxo-1-phenyl-2,10-dioxa-4,7-diazatriadecane-13-carboxylic acid methyl ester

[1185]

[1186] Compound 7 (723 mg, 1.90 mmol) was dissolved in acetonitrile (25 mL), followed by the sequential addition of 1-hydroxybenzotriazole hydrate (291 mg, 1.90 mmol, 1 eq), N-benzyloxycarbonylglycine (397 mg, 1.90 mmol, 1.00 eq), and N,N'-dicyclohexylcarbodiimide (392 mg, 1.90 mmol, 1.00 eq). The reaction mixture was stirred overnight at room temperature. The acetonitrile was then evaporated, and the residue was purified by adsorption onto silica gel using a gradient of 0-75% ethyl acetate in hexane. This yielded a colorless oily compound 8 (866 mg, 1.52 mmol) in 80% yield.

[1187] Compound 9

[1188] 8,8-Bis[(2-Carboxyethoxy)methyl]-3,6-dioxo-1-phenyl-2,10-dioxa-4,7-diazatridecan-13-carboxylic acid

[1189]

[1190] Compound 8 (100 mg, 0.175 mmol) was dissolved in dioxane (2 mL) and NaOH aqueous solution (2 M, 2 mL). The reaction mixture was stirred for 3 hours, then acidified to pH 3 with 6 M hydrochloric acid and extracted twice with ethyl acetate. The organic fraction was washed with 1 M HCl, dried over sodium sulfate, and evaporated to give compound 9 as a white solid, which could be used in subsequent steps without purification.

[1191] Compound 10

[1192]

[1193] Compound 9 (372 mg, 0.704 mmol, 1 eq) was dissolved in dimethylformamide (40 mL) and diisopropylethylamine (981 μL, 728 mg, 5.63 mmol, 8.00 eq). Then, N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)ureonium hexafluorophosphate (HBTU) (1.01 g, 2.67 mmol, 3.8 eq) was added, and the reaction mixture was stirred at room temperature for 10 minutes, followed by the addition of compound 5 (1.28 g, 2.67 mmol, 2.67 mmol, 3.8 eq). The reaction mixture was stirred for two hours, then diluted in dichloromethane and washed with aqueous solutions of phosphoric acid (1 M, 1 x), sodium bicarbonate (1 M, 1 x), and brine (1 x). The organic layer was dried on sodium sulfate and evaporated onto silica. The residue was purified (0-20% methanol in dichloromethane) to give compound 10 as a light brown solid (831 mg, 0.436 mmol) in 62% yield.

[1194] Compound 11

[1195]

[1196] 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 mixture was stirred for 16 hours under a hydrogen atmosphere (1 atm) at 0 °C. After the reaction was complete, the mixture was filtered through diatomaceous earth, and methanol was evaporated to give the intermediate amine (657 mg, 0.370 mmol) in 99.5% yield, which was ready for use without further purification. The amine (441 mg, 0.248 mmol) was dissolved in methanol (15 mL) and cooled to 0 °C. Sodium methoxide solution (400 μL, 5.4 M MeOH solution) was then added to remove the O-acetyl group, and the reaction mixture was stirred for 30 minutes. Dowex 50WX8 was then added until the solution was weakly acidic. The mixture was filtered through resin and thoroughly washed with methanol. The combined methanol fractions were evaporated under reduced pressure to give a colorless oily compound 11 (274 mg, 0.196 mmol) in 79.0% yield. Compound 11 was used in subsequent steps without purification.

[1197] Compound 12

[1198] (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) benzyl carbamate

[1199]

[1200] Compound 9 (302 mg, 0.572 mmol, 1 eq) was dissolved in dichloromethane (25 mL) and triethylamine (480 μL, 3.431 mmol, 6.00 eq). Then, 1-hydroxybenzotriazole hydrate (350 mg, 2.28 mmol, 4 eq) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (417 mg, 2.17 mmol, 3.80 eq) were added, followed by 2-[2-(2-aminoethoxy)ethoxy]ethanol (300 mg, 2.01 mmol, 3.80 eq). The reaction mixture was then stirred overnight. The solvent was evaporated, and the crude substance was purified by reversed-phase chromatography without post-treatment using a gradient of 5–35% acetonitrile in water with the addition of 0.1% formic acid. Compound 12 (345 mg, 0.372 mmol) was recovered in 65% yield as a colorless oil.

[1201] Compound 13

[1202] 3,3'-((2-(2-aminoacetamido)-2-(14-hydroxy-5-oxo-2,9,12-trioxa-6-azatetradecyl)propane-1,3-diyl)bis(oxy))bis(N-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)propionamide)

[1203]

[1204] Compound 12 (345 mg, 0.374 mmol, 1.00 eq) was dissolved in methanol (15 mL). The solution was purged under a nitrogen stream for five minutes. Then, 10% Pd / C (5% w / w, 17.3 mg) was added under a nitrogen stream. The mixture was purged with hydrogen for 5 minutes, and then stirred under a hydrogen atmosphere for 2 hours. The mixture was then filtered through a diatomaceous earth bed, and the filtrate was concentrated under vacuum to give a colorless oily compound 13 (282 mg, 0.359 mmol) in 96% yield. Compound 13 was used in subsequent steps without purification.

[1205] Compound 14(53)

[1206] 4-((2-chloroquinoline-6-yl)oxy)ethyl butyrate

[1207]

[1208] 2-Chloroquinoline-6-ol (1.00 g, 5.57 mmol) and potassium carbonate (1.53 g, 11.1 mmol, 2.0 eq) were dissolved in dimethylformamide (20 mL). Ethyl bromobutyrate (1.63 g, 1.2 mL, 8.35 mmol, 1.5 eq) was then added, and the mixture was stirred at 80 °C for 12 hours. The reactant was diluted in ethyl acetate and washed with water (2x) and brine (3x). The organic layer was dried over sodium sulfate and evaporated to give compound 14 as a pale yellow solid, which was used in subsequent steps without further purification. The spectra matched the previously reported characteristic data.

[1209] Compound 15(53)

[1210] 4-((2-((trimethylsilyl)ethynyl)quinoline-6-yl)oxy)ethyl butyrate

[1211]

[1212] Compound 14 (1.52 g, 5.17 mmol) was dissolved in tetrahydrofuran (20 mL) and triethylamine (2.88 mL, 20.7 mmol, 4 eq). Copper iodide (I) (49.0 mg, 0.258 mmol, 0.050 eq), bis(triphenylphosphine)palladium (II) dichloride (181 mg, 0.258 mmol, 0.050 equivalent) and trimethylsilylacetylene (1.07 mL, 762 mg, 7.75 mmol, 1.50 eq) were then added, and the reaction mixture was stirred in a pressurized vessel at 65 °C for 16 h. The reaction mixture was then cooled and filtered through diatomaceous earth. The diatomaceous earth was thoroughly washed with ethyl acetate, and the combined organic fractions were evaporated. The residue was purified on silica (0–50% ethyl acetate in hexane) to give compound 15 (1.49 g, 4.19 mmol) as a pale yellow solid in 81% yield. The spectra matched the previously reported characteristic data.

[1213] Compound 16(53)

[1214] 4-((2-ethynylquinoline-6-yl)oxy)ethyl butyrate

[1215]

[1216] Compound 15 (1.57 g, 4.42 mmol) was dissolved in dichloromethane (45 mL), and tetrabutylammonium fluoride (5.30 mL, 1.00 M THF solution, 5.30 mmol, 1.20 eq) was added dropwise. After stirring for 1 min, 10% citric acid (50 mL) was added, and the reaction mixture was stirred for 30 min. The organic phase was washed with water (1 x), dried, and evaporated to give a pale yellow solid, compound 16, which could be used in subsequent steps without further purification. The spectrum matched the previously reported characteristic data.

[1217] Compound 17(53)

[1218] 4-((2-(1-(3-fluoro-4-hydroxyphenyl)-1H-1,2,3-triazol-4-yl)quinoline-6-yl)oxy)ethyl butyrate

[1219]

[1220] 2-Fluoro-4-iodophenol (126 mg, 0.529 mmol) and sodium azide (38 mg, 0.528 mmol, 1.0 eq) were dissolved in DMSO (2.5 mL) and stirred at 70 °C for 2 hours. Then, compound 32 (150 mg, 0.529 mmol, 1 eq), trans-N,N'-dimethylcyclohexane-1,2-diamine (11 mg, 0.079 mmol, 0.15 eq), sodium ascorbate (10 mg, 0.053 mmol, 0.1 eq), copper iodide (I) (15 mg, 0.079 mmol, 0.15 eq), and H₂O (2.5 mL) were added, and the mixture was stirred at 70 °C overnight. The reaction mixture was diluted with ethyl acetate and washed with water (1 x) and brine (1 x). The organic layer was dried with sodium sulfate, evaporated, and purified over silica (0-100% ethyl acetate in dichloromethane solution) to give a grayish-white solid, compound 17. The spectrum matched the previously reported characteristic data.

[1221] Compound 18(53)

[1222] 4-((2-(1-(3-fluoro-4-hydroxyphenyl)-1H-1,2,3-triazol-4-yl)quinoline-6-yl)oxy)butyric acid

[1223]

[1224] 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, during which time the mixture was diluted with water and the pH was adjusted to 3 with 1 M HCl. The mixture was cooled to 4 °C and filtered to give compound 18 as a brown powder, which could be used without further purification.

[1225] Compound 19(54)

[1226] 2-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl ester of 4-methylbenzenesulfonic acid

[1227]

[1228] Tetraethylene glycol (50.0 g, 258 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0 °C, and stirred. A solution of sodium hydroxide (1.68 g, 41.3 mmol, 1.60 eq) in water (10 mL) was then added, followed by dropwise addition of p-toluenesulfonyl chloride (5.00 g, 25.8 mmol, 1.00 eq) in tetrahydrofuran (3 mL). The reaction mixture was stirred at 0 °C for 4 hours and then diluted in dichloromethane. The organic layer was washed with ice-cold water (2x) and brine (1x), and then dried over sodium sulfate to give a pale yellow oily compound 19 (8.84 g, 25.4 mmol, 99.0% yield), which could be used in subsequent steps without purification.

[1229] Compound 20(54)

[1230] 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethanol-1-ol

[1231]

[1232] 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 eq) was added. The reaction mixture was heated under reflux for 16 hours, then cooled to room temperature before adding water (150 mL). The ethanol was then evaporated under reduced pressure, and the aqueous layer was extracted into ethyl acetate (2x). The organic layer was washed with water (1x) and brine (1x), dried over sodium sulfate, and evaporated to give a yellow oily compound 20 (4.82 g, 22.1 mmol) in 87.0% yield. The spectra matched the previously reported characteristic data.

[1233] Compound 21(55)

[1234] 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)acetic acid

[1235]

[1236] A chilled Jones reagent was prepared separately by mixing chromium trioxide (1.37 g, 13.68 mmol, 3.00 eq), H₂SO₄ (2.38 mL), and water (26.2 mL) at 0 °C. The Jones reagent was then added dropwise to a chilled solution of compound 20 (1.00 g, 4.56 mmol, 1 eq) in acetone (20 mL). The reaction mixture was then heated to room temperature and stirred for 16 hours. Excess Jones reagent was quenched by adding isopropanol (30 mL), and the reaction mixture was concentrated. The aqueous residue was then extracted with dichloromethane (4x). The combined organic layers were dried over sodium sulfate and concentrated to give a colorless oily compound 21 (851 mg, 3.65 mmol) in 80% yield, which was ready for subsequent steps without purification.

[1237] Compound 22(56)

[1238] 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)acetic acid

[1239]

[1240] Compound 21 (2.4 g, 10.3 mmol) was dissolved in methanol, and the atmosphere was purged with N2. Palladium / carbon (240 mg, 10% w / w) was added, and the flask was purged again with nitrogen. The flask was then purged with H2 and stirred for 16 hours under H2 atmosphere. The reaction mixture was then filtered through diatomaceous earth and concentrated to give a colorless oily compound 22 (2.13 g, 10.3 mmol) in quantitative yield. Compound 22 was used in subsequent steps without purification.

[1241] Compound 23

[1242] 2-(2-(2-((2,4-dinitrophenyl)amino)ethoxy)ethoxy)ethoxy)acetic acid

[1243]

[1244] 1-Chloro-2,4-dinitrobenzene (52.8 mg, 0.261 mmol, 1.00 eq), compound 22 (75.5 mg, 0.365 mmol, 1.40 eq), and sodium bicarbonate (65.7 mg, 0.782 mmol, 3.00 eq) were dissolved in water (2 mL) in a round-bottom flask. The flask was then fitted with a reflux condenser, and the mixture was stirred at 95 °C for 16 hours. The reaction mixture was then cooled and diluted to a saturated sodium bicarbonate solution (10 mL), followed by washing with dichloromethane. The aqueous solution was then treated with concentrated hydrochloric acid until the pH of the solution was below 2. The aqueous layer was then extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to give compound 23 (86.8 mg, 0.232 mmol) in 89% yield, which was ready for use without further purification.

[1245] Compound 24 (D-MoDE-A)

[1246]

[1247] Compound 23 (75.1 mg, 0.201 mmol, 1.5 eq) was dissolved in dichloromethane (7 mL) and diisopropylethylamine (26 mg, 0.201 mmol, 1.5 eq). Then, 1-hydroxybenzotriazole hydrate (34.9 mg, 0.2278 mmol, 1.7 eq) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (41.0 mg, 0.214 mmol, 1.6 eq) were added, and the mixture was stirred for 10 minutes. Cbz-deprotected amine 9-OAc (238 mg, 0.134 mmol, 1 eq) was added, and the reaction mixture was stirred overnight. The mixture was diluted in dichloromethane (50 mL) and washed with water (2x) and brine (1x). 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 methanol solution, 292 μL) was added, and the reaction mixture was stirred at 0 °C for 30 min. The mixture was then neutralized with a Dowex 50WX8. The reaction mixture was filtered and concentrated. The residue was purified directly by HPLC (0–30% acetonitrile aqueous solution, +0.1% formic acid) to give compound 24 as a bright yellow powder in 18.6% yield (0.0249 mmol, 43.7 mg).

[1248] Compound 25 (M-MoDE-A)

[1249]

[1250] Compound 18 (23.5 mg, 0.0575 mmol, 1.1 eq) 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 eq) were dissolved in anhydrous dimethylformamide (5 mL) and diisopropylethylamine (23.3 μL, 16.9 mg, 0.131 mmol, 2.5 eq), and stirred at room temperature for 10 min. Then, compound 11 (73.0 mg, 0.0522 mmol) was added, and the reaction mixture was stirred for 30 min. The mixture was directly loaded onto HPLC and purified (20–30% aqueous acetonitrile solution, +0.3% trifluoroacetic acid) to give compound 25 (12 mg, 0.0067 mmol) as a grayish-white powder in 12.8% yield.

[1251] Compound 26(DNP-OH3)

[1252] 3,3'-(2-(14-((2,4-dinitrophenyl)amino)-4-oxo-6,9,12-trioxa-3-azatetradecanoamide)-2-(14-hydroxy-5-oxo-2,9,12-trioxa-6-azatetradecyl)propane-1,3-diyl)bis(oxy))bis(N-(2-(2-(2-(2-hydroxyethoxy)ethoxyethyl)propionamide)

[1253]

[1254] Compound 13 (234 mg, 0.297 mmol, 1 eq) was dissolved in dimethylformamide (5 mL) and triethylamine (83 μL, 0.594 mmol, 2 eq). Then, compound 23 (110.9 mg, 0.297 mmol, 1 eq) and 1-hydroxybenzotriazole hydrate (59 mg, 0.386 mmol, 1.3 eq) were added, followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (68.3 mg, 0.356 mmol, 1.2 eq). The reaction mixture was stirred overnight and then evaporated under a nitrogen atmosphere. The product was directly purified by reversed-phase HPLC (0-30% acetonitrile aqueous solution + 0.1% formic acid) to give compound 26 (178 mg, 0.155 mmol) as a bright yellow powder, in a yield of 52.3%.

[1255] General Synthetic Methods of CCP1-GN3 Compounds

[1256]

[1257] The backbone of N3CCP1 (azidohomoalinine)-HQCHQESTCitGRSRGRCGRSGS) was synthesized under 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 promote disulfide formation. The peptide was then purified by HPLC (0 to 80% MeCN + 0.1% TFA over 30 minutes) to give compound 100.

[1258]

[1259] Compound 11 (NH2GN3) was dissolved in DMF, followed by the addition of DBCO-PEG4-NHS ester (CAS#1427004-19-0) (1.5 eq) and DIEA (5 eq). The reaction mixture was stirred overnight at room temperature, diluted in H2O + 0.1% TFA, and purified by HPLC (MeCN / H2O + 0.1% TFA, 0-80% MeCN) to obtain 101.

[1260]

[1261] Compound 12 (NH2OH3) was dissolved in DMF, followed by the addition of DBCO-PEG4-NHS ester (CAS#1427004-19-0) (1.5 eq) and DIEA (5 eq). The reaction mixture was stirred overnight at room temperature, diluted in H2O + 0.1% TFA, and purified by HPLC (MeCN / H2O + 0.1% TFA, 0-80% MeCN) to give 102.

[1262]

[1263] Compound 100 (1 eq) and compound 101 (1.5 eq) 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 give CCP-MoDE-A (CCP1-GN3).

[1264] The terms and expressions used herein are descriptive rather than limiting, and their use is not intended to exclude any equivalents of the shown and described features or portions thereof. However, it should be understood that various modifications can be made within the scope of embodiments of this application. Therefore, it should be understood that although this application describes specific embodiments and optional features, modifications and variations can be made to the compositions, methods, and concepts disclosed herein by those skilled in the art, and such modifications and variations are considered to be within the scope of embodiments of this application.

[1265] Preparation procedure of intermediate A001A

[1266] Reference Figures 3A-3D A synthetic scheme for synthesizing the intermediate target A001A is provided.

[1267] Preparation of intermediate 2:

[1268]

[1269] At 0 °C, 1 (34.2 g, 200 mmol, 1.00 equivalent) of 2-methyltetrahydrofuran (450 mL) solution was added to 1a (60.0 g, 400 mmol, 2.00 equivalent). The mixture was stirred at 25 °C for 2 hours. TLC (DCM:MeOH = 20:1, R f =0.70) indicated the reaction was complete, and a new major spot of low polarity was detected. HCl / EA (ethyl acetate) (1 N, 27.0 mL) was added to the reaction mixture and stirred for 30 minutes. The white precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure to give a yellow oily intermediate 2 (crude product, 105.0 g, 370.6 mmol). LCMS: RT = 0.797 min, MS cal.: 283.14, observed mass: [M+Na] + =306.1. 1 H NMR (400MHz, DMSO-d6) δppm 7.23-7.41 (m, 5H), 5.01 (s, 2H), 4.60 (br s, 1H), 3.45-3.52 (m, 6H), 3.38-3.43 (m, 5h), 3.14 (q, J = 5.94Hz, 2H) and 2.53-2.55 (m, 1H).

[1270] Preparation of intermediate 3:

[1271]

[1272] TMSOTf (85.6 g, 385 mmol, 1.50 equivalent) was added to a 500 mL solution of DCE (1,2-dichloroethane) containing 2a (100.0 g, 257 mmol, 1.00 equivalent), and the mixture was stirred at 60 °C for 2 hours. The reaction mixture was then cooled to room temperature (25 °C) and stirred for another 1 hour. Intermediate 2 (80.0 g, 282 mmol, 1.10 equivalent) was added to the reaction mixture. A mixture of powdered molecular sieve (50.0 g) and DCE (500 mL) was prepared. The mixture was stirred for 30 minutes under a N2 atmosphere. Then, a DCE solution of intermediate 2a (100.0 g, 257 mmol, 1.00 equivalent) was added dropwise to the mixture at 0 °C. The mixture was stirred at 25 °C for 16 hours under a N2 atmosphere. TLC (DCM:MeOH = 10:1, R f =0.42) indicates that intermediate 2a has been completely consumed and a major new spot with high polarity was detected.

[1273] 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 give 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 give a yellow oily intermediate 3 (90.0 g, 146.9 mmol, 91.6% purity, 57.2% yield). LCMS: RT = 0.860 min, MS cal.: 612.25, observed mass: [M+H] + =613.2. 1 H NMR (400MHz, DMSO-d6) δppm 7.80 (d, J=9.03Hz, 1H), 7.24-7.39 (m, 6H), 5.22 (d, J=3.51Hz, 1H), 4.95-5 .05(m, 3H), 4.53-4.59(m, 1H), 3.99-4.06(m, 3H), 3.84-3.92(m, 1H), 3.73 -3.82(m, 1H), 3.55-3.61(m, 1H), 3.45-3.53(m, 7H), 3.41(t, J=5.90Hz, 2H ), 3.11-3.18(m, 3H), 2.10(s, 3H), 1.99(s, 3H), 1.89(s, 3H), 1.77(s, 3H).

[1274] Preparation of intermediate 4:

[1275]

[1276] Slowly add 180 mL of THF to the Pd / C (9.00 g, 10% purity) solution (purged three times with Ar) in the reaction flask. Then, under N2, slowly add 720 mL of THF solution of TFA (16.7 g, 147 mmol, 1.00 equivalent) and intermediate 3 (90.0 g, 147.0 mmol, 1.00 equivalent) to the reaction mixture. Degas the reactants, purge three times with N2 and H2, and then stir at 25 °C for 3 hours under H2 atmosphere (40 psi). TLC (DCM:MeOH = 10:1, R f =0.20) indicates that intermediate 3 has been completely consumed, and a major new spot with high polarity was detected. The reaction mixture was dissolved in THF (100 mL), carefully filtered through silica at N2 atmosphere, the filter cake was washed with THF (100 mL x 2), and the filtrate was concentrated under reduced pressure to give the residue. The residue was diluted with water (1000 mL), washed with DCM (300 mL x 3), and the aqueous layer was lyophilized to give white solid intermediate 4 (80.0 g, 139.0 mmol, 95.1% purity, 91.8% yield, TFA salt). LCMS: RT = 0.484 min, MS cal.: 478.22, observed mass: [M+H] + =478.9. 1 H NMR (400MHz, DMSO-d6) δppm 7.91 (br t, J=9.03Hz, 4H), 5.21 (d, J=3.26Hz, 1H), 4.96 (dd, J=11.17, 3.39Hz, 1H), 4.54 (d , J=8.53Hz, 1H), 3.98-4.08(m, 3H), 3.85-3.93(m, 1H), 3.75-3.84(m, 1H), 3.59(br t, J=5.14Hz, 3H), 3.50-3.56 (m, 6H), 2.98 (br s, 2H), 2.10 (s, 3H), 2.00 (s, 3H), 1.89 (s, 3H), 1.78 (s, 3H).

[1277] Preparation of intermediate 6:

[1278]

[1279] Add NaOH aqueous solution (5.0 M, 9.91 mL, 0.10 equivalent) dropwise to a mixture of 5 (60.0 g, 495.0 mmol, 1.00 equivalent) of DMSO (166 mL) for 5 minutes at 0–15 °C. After addition, stir the mixture at 0–15 °C for 5 minutes, and then add 5a (254.0 g, 1.98 mol, 287 mL, 4.00 equivalent) dropwise to the reaction mixture at 20 °C. Stir the resulting mixture at 25 °C for 16 hours. TLC (DCM:MeOH = 10:1, R f =0.7) indicates that compound 5 has been completely consumed, and a major new spot of low polarity was detected. The resulting reaction mixture was concentrated under reduced pressure to give the residue. The residue was dissolved in EtOAc (400 mL), quenched with water (400 mL), and extracted with EtOAc (400 mL x 3). The combined organic layers were washed with brine (300 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give colorless oily intermediate 6 (100.0 g, 197.8 mmol, 96.0% purity, 40.0% yield). 1 H NMR (400MHz, DMSO-d6) δppm 3.51-3.61 (m, 7H), 3.17 (s, 5H), 2.39 (t, J=6.02Hz, 6H), 1.40 (s, 27H).

[1280] Preparation of intermediate 7:

[1281]

[1282] HOBt (10.7 g, 79.1 mmol, 1.00 equivalent) was added to a MeCN (400 mL) solution of intermediate 6 (40.0 g, 79.1 mmol, 1.00 equivalent). Then 6a (16.5 g, 79.1 mmol, 1.00 equivalent) and DCC (16.3 g, 79.1 mmol, 1.0 equivalent) were added. The reaction mixture was stirred at 25 °C for 16 hours. TLC (PE:EA = 1:1, R f =0.80) indicates that intermediate 6 has been completely consumed, and a major new spot of low polarity was detected. Evaporation of MeCN yielded the residue. The residue was purified by column chromatography (SiO2, PE:EA = 10:1 to 1:1) to give a white solid intermediate 7 (40.0 g, 57.4 mmol, 82.9% purity, 72.5% yield). LCMS:RT = 1.151 min, MS cal.: 696.38, observed mass: [M+H] + =697.3, [M+Na] + =719.3. 1H NMR (400MHz, DMSO-d6) δppm 7.26-7.40 (m, 6H), 7.06 (s, 1H), 5.03 (s, 2H), 3.49-3.61 (m, 14H), 2.39 (br t, J=6.02Hz, 6H), 1.40 (s, 27H).

[1283] Preparation of intermediate 8:

[1284]

[1285] A solution of intermediate 7 (30.0 g, 43.0 mmol, 1.00 equivalent) in 300 mL of HCOOH was stirred at 25 °C for 16 h. TLC (PE:EA = 1:1, Rf = 0.04) showed that intermediate 7 was completely consumed and a major new spot with high polarity was detected. The solvent was evaporated under reduced pressure, and then co-evaporated with toluene (50 mL x 3) under reduced pressure and dried under reduced pressure to give the residue. The residue was purified by preparative HPLC (A: 0.1% FA conditions / H2O, B: MeCN) to give intermediate 8 (20.0 g, 37.8 mmol, 98.2% purity, 87.9% yield). 1 ¹H NMR (400 MHz, DMSO-d⁶) δppm 12.17 (br s, 3H), 7.26–7.43 (m, 6H), 7.06 (s, 1H), 5.02 (s, 2H), 3.49–3.65 (m, 14H), 2.42 (br t, J = 6.27 Hz, 6H). LCMS: RT = 0.790 min, MS cal.: 528.20, observed mass: [M+H] + =529.2.

[1286] Preparation of intermediate 9:

[1287]

[1288] To a stirred solution of intermediate 8 (20.0 g, 37.8 mmol, 1.00 equivalent) and intermediate 4 (78.5 g, 132 mmol, 3.50 equivalent, TFA salt) in DMF (400 mL), 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 added sequentially. The reaction mixture was stirred at 25 °C for 2 hours. TLC (DCM:MeOH = 10:1, R f=0.4) indicates that intermediate 8 has been completely consumed, and a major new spot with high polarity was detected. The reaction mixture was slowly poured into a stirred, cold 0.5 mol / L HCl solution (900 mL) and stirred for 10 minutes. A white precipitate formed and was filtered. The aqueous phase was extracted twice with DCM (600 mL x 2). The combined organic layers were washed with 5% NaHCO3 (450 mL), dried over Na2SO4, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, DCM:MeOH = 100:1 to 5:1) to give a white solid intermediate 9 (58.0 g, 30.4 mmol, 82.7% purity, 80.3% yield). 1 H NMR (400MHz, DMSO-d6) δppm 7.92 (br t, J=5.14Hz, 3H), 7.81 (d, J=9.03Hz, 3H), 7.28-7.39 (m, 6H), 7.13 (s, 1H), 5.21 (d, J=3.26Hz, 3H), 5.02 (s, 2H), 4.97 (dd, J= 11.17, 3.39Hz, 3H), 4.54 (d, J=8.53Hz, 3H), 4.03 (s, 9H), 3.84-3.92 (m, 3H), 3.75-3.81 (m, 3H), 3.45-3.61 (m, 37H), 3.39 (br 3.18–3.23 (m, 6H), 2.30 (br t, J = 6.15 Hz, 6H), 2.10 (s, 9H), 2.00 (s, 9H), 1.89 (s, 9H), 1.77 (s, 9H). LCMS: RT = 3.455 min, MS cal.: 1908.81, observed mass: [M+2H] 2+ =955.7.

[1289] Preparation of intermediate 10:

[1290]

[1291] A 500 mL round-bottom flask was purged three times with Ar gas, and dry Pd / C (1.50 g, 1.41 mmol, 10% purity, 1.00 equivalent) was carefully added. THF (150.0 mL) was then added to completely permeate the Pd / C, followed by the slow addition of intermediate 9 (15.0 g, 7.85 mmol, 1.00 equivalent) and TFA (895 mg, 7.85 mmol / L, 583 μL, 1.00 equivalent) in 75 mL of THF under Ar atmosphere. The resulting mixture was degassed and purged three times with H2, and then stirred at 25 °C for 3 hours under H2 atmosphere (15 psi). The reaction was monitored by LCMS, which showed the desired mass (a main peak with the desired mass was detected). The reaction mixture was carefully filtered through silica at N2 atmosphere, and the filter cake was washed with THF (100 mL x 2). Water was then immediately added to the filter cake. The organic layer was concentrated under reduced pressure to give intermediate 10 (13.0 g, 6.54 mmol, 83.2% yield, 99.7% purity, TFA salt) as a white solid. 1 H NMR (400MHz, DMSO-d6) δppm 7.89-7.99(m, 5H), 7.82(d, J=9.3Hz, 3H), 7.74(s, 1H), 7.14-7.28(m, 1H), 5 .22 (d, J=3.3Hz, 3H), 4.97 (dd, J=11.3, 3.4Hz, 3H), 4.54 (d, J=8.5Hz, 3H), 3 .84-3.93(m, 3H), 3.76-3.82(m, 3H), 3.47-3.61(m, 43H), 3.21(q, J=5.8Hz, 6H), 2.29-2.34(m, 6H), 2.10(s, 9H), 2.00(s, 9H), 1.89(s, 8H), 1.77(s, 9H). LCMS: RT=1.333min, MS cal.: 1774.7, Found: [M+2H] 2+ =888.6.

[1292] Preparation of intermediate target A001A:

[1293]

[1294] At 0 °C, NaOMe (5.4 M, 5.01 mL, 4.26 equivalents) was added to a methanol (120.0 mL) solution of intermediate 10 (12.0 g, 6.35 mmol, 1.00 equivalent, TFA). The mixture was stirred at 0 °C for 0.5 h. The reaction was monitored by LCMS, and the desired mass was observed (a main peak with the desired mass was detected). 1.0 M HCl solution (10.0 mL) was added to the reaction mixture until pH = 6. The mixture was diluted with H2O (75.0 mL) and extracted with DCM (120 mL x 3). The mixture was freeze-dried to give a white solid target A001A (9.0 g, 5.96 mmol, 93.9% yield, >95% purity, HCl). 1 H NMR (400MHz, DMSO-d6) δppm 7.96 (br t, J=5.4Hz, 3H), 7.67 (d, J=8.9Hz, 3H), 7.51 (s, 1H), 4.27 (d, J=8.4Hz, 3H), 3.75-3.80 (m, 6H), 3.70 (br d, J=10.0Hz, 6H), 3.49 (br d, J=4.0Hz, 31H), 3.37-3.42 (m, 12H), 3.30 (br d, J=6.1Hz, 4H), 3.20 (br d, J=5.8Hz, 6H), 2.99 (s, 2H), 2.30 (br t, J=6.4Hz, 6H), 1.80 (s, 9H). LCMS: RT = 0.966 min, MS cal.: 1396.6, Findings: [M+2H] 2+ =699.1.

[1295] Preparation of peptide intermediate Int-00002

[1296] Reference Figure 4A A synthesis scheme for synthesizing intermediate targets.

[1297] Preparation of Int-00002:

[1298] Peptides were synthesized using standard Fmoc chemistry (Fmoc-Ser(tBu)-Wang resin).

[1299] Resin preparation: DMF (600 mL) 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), and bubbled with N2 for 30 minutes. The resin was washed with DMF (600 mL x 5), and then 20% piperidine was added to DMF (400 mL), and bubbled with N2 for 30 minutes at 25 °C. The mixture was filtered, and the resin was washed with DMF (600 mL x 5) before proceeding to the next step.

[1300] Coupling: Under bubbling N2, a DMF solution (400 mL) containing Fmoc-Gly-OH (13.3 g, 45.0 mmol, 3.00 equivalent) and HOAt (6.12 g, 3.00 equivalent) was added to the resin. Then, DIC (3.00 equivalent) was added dropwise to the mixture, and the mixture was bubbled with N2 at 25 °C for 30 minutes. The coupling reaction was monitored by a ninhydrin test; if a colorless result was observed, the coupling was complete. The resin was then washed with 5 x 600 mL DMF.

[1301] Deprotection: Add a 20% piperidine solution in DMF (400 mL) to the resin and bubble the mixture with N2 at 25 °C for 30 minutes. Then wash the resin with DMF (600 mL) x 5. Monitor the deprotection reaction by the ninhydrin test; if a blue or brownish-red color appears, the reaction is complete.

[1302] Repeat steps 2 and 3 to extend the following amino acids: numbered #2-21, Table 1.

[1303] After completing the last position, the resin was washed with 5 x DMF (600 mL) and 5 x MeOH (600 mL) and dried under reduced pressure to obtain intermediate 11 (peptide-binding resin, 15.0 mmol).

[1304] Table 1: List of amino acids and corresponding reagents used in SPPS.

[1305] # Material Coupling reagents 1 Fmoc-Gly-OH (3.00 equivalents) DIC (3.00 equivalent) and HOAt (3.00 equivalent) 2 Fmoc-Ser(Trt)-OH (3.00 equivalents) DIC (3.00 equivalent) and HOAt (3.00 equivalent) 3 Fmoc-Arg(Pbf)-OH (3.00 equivalents) DIC (3.00 equivalent) and HOAt (3.00 equivalent) 4 Fmoc-Gly-OH (3.00 equivalents) DIC (3.00 equivalent) and HOAt (3.00 equivalent) 5 Fmoc-Cys(Trt)-OH (3.00 equivalents) DIC (3.00 equivalent) and HOAt (3.00 equivalent) 6 Fmoc-Arg(Pbf)-OH (3.00 equivalents) DIC (3.00 equivalent) and HOAt (3.00 equivalent) 7 Fmoc-Gly-OH (3.00 equivalents) DIC (3.00 equivalent) and HOAt (3.00 equivalent) 8 Fmoc-Arg(Pbf)-OH (3.00 equivalents) DIC (3.00 equivalent) and HOAt (3.00 equivalent) 9 Fmoc-Ser(tBu)-OH (2.00 equivalents) DIC (3.00 equivalent) and HOAt (3.00 equivalent) 10 Fmoc-Arg(Pbf)-OH (3.00 equivalents) DIC (3.00 equivalent) and HOAt (3.00 equivalent) 11 Fmoc-Gly-OH (3.00 equivalents) DIC (3.00 equivalent) and HOAt (3.00 equivalent) 12 Fmoc-Cit-OH (1.50 equivalents) DIC (1.50 equivalent) and HOAt (1.50 equivalent) 13 Fmoc-Thr(tBu)-OH (3.00 equivalents) HATU (2.85 equivalent) and DIEA (6.00 equivalent) 14 Fmoc-Ser(tBu)-OH (3.00 equivalents) HATU (2.85 equivalent) and DIEA (6.00 equivalent) 15 Fmoc-Glu(OtBu)-OH (3.00 equivalents) HATU (2.85 equivalent) and DIEA (6.00 equivalent) 16 Fmoc-Gln(Trt)-OH (3.00 equivalents) HATU (2.85 equivalent) and DIEA (6.00 equivalent) 17 Fmoc-His(Trt)-OH (3.00 equivalents) HATU (2.85 equivalent) and DIEA (6.00 equivalent) 18 Fmoc-Cys(Trt)-OH (3.00 equivalents) HATU (2.85 equivalent) and DIEA (6.00 equivalent) 19 Fmoc-Gln(Trt)-OH (3.00 equivalents) HATU (2.85 equivalent) and DIEA (6.00 equivalent) 20 Fmoc-His(Trt)-OH (3.00 equivalents) HATU (2.85 equivalent) and DIEA (6.00 equivalent) 21 <![CDATA[Fmoc-Dab(N3)-OH (1.50 equivalents)]]> DIC (1.50 equivalent) and HOAt (1.50 equivalent)

[1306] Peptide cleavage and disulfide formation:

[1307] Pyrolysis: Intermediate 11 (105 g, resin) was stirred for 2 hours at 25 °C in a TFA / 3-MPA / Tis / H2O solution (92.5 / 2.5 / 2.5 / 2.5, v / v / v / v, 1050 mL). The mixture was precipitated with isopropyl ether (cold, 10 L). After filtration, the solid was washed twice with isopropyl ether (cold, 10 L) and dried under reduced pressure for 2 hours to give a white solid intermediate 12 (30.0 g, crude product). LCMS: RT = 0.310 min, calculated MS: Mav =2469.60, observed mass: [M+2H] 2+ =1235.5, [M+3H] 3+ =824.2.

[1308] 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 a 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 give a white solid Int-00002 (3.97 g, 9.68% yield, 90.25% purity). LC-MS: RT = 1.214 min, calculated MS: M av =2467.58, observed mass: [M+2H] 2+ =1234.3, [M+3H] 3+ =823.4.

[1309] Preparation of target A001A-PEG4-alkyne

[1310] Reference Figure 4B Synthesis scheme for synthesizing intermediate targets

[1311] A001A-PEG4-acetylene is available.

[1312] Preparation of intermediate 14:

[1313]

[1314] At 0 °C, EDCI (1.33 g, 6.92 mmol, 3.00 equivalent) was added to a DMF (6 mL) solution of intermediates 13 (600 mg, 2.31 mmol, 1.00 equivalent) and 13a (2.30 g, 13.8 mmol, 6.00 equivalent). The mixture was stirred at 0 °C for 1 hour. The mixture was directly purified by preparative HPLC (TFA conditions) to give a yellow oily intermediate 14 (800 mg, 83.4% yield, 98.2% purity). LCMS: RT = 1.430 min, calculated MS: Mav = 408.34, observed mass: [M+Na] + =431.0.

[1315] Preparation of target A001A-PEG4-alkyne:

[1316]

[1317] DIEA (166 mg, 230 μL, 2.00 equivalent) was added to a DMF (0.25 mL) solution of intermediate 14 (276 mg, 676 μmol, 1.05 equivalent) and target A001A (1.00 g, 644 μmol, 1.00 equivalent). The mixture was stirred at 25 °C for 12 h. The mixture was diluted with MeCN / H2O (cold, v / v, 3 / 3, 10 mL) and then lyophilized to remove DMF. The residue was directly purified by preparative HPLC (AcOH conditions) to give a colorless oily target A001A-PEG4-acetylene (0.60 g, 93.5% purity, 56.8% yield). LCMS: RT = 0.368 min, calculated MS: Mav = 1639.74, observed mass: [M+H] + =1639.8, [M-sugar + H] + =1426.6, [M - 2x sugar + H] + =1233.6, [M - 3x sugar + H] + =1030.3, [M+2H] 2+ =820.6.

[1318] Preparation of CCP1-GN4:

[1319] Reference Figure 4C It provides a synthesis scheme for synthesizing CCP1-GN4.

[1320] At 25 °C, a solution of CuSO4 (0.4 M, 690 μL, 1.00 equivalent), sodium L-ascorbate (0.4 M, 2.76 mL, 4.00 equivalent), and ammonium bicarbonate (0.2 M, 2.09 mL, 1.51 equivalent) was added to a DMF (7.5 mL) solution of Int-00002 (750 mg, 303 μmol, 1.10 equivalent) and target A001A-PEG4-alkyne (453 mg, 276 μmol, 1.00 equivalent). The mixture was stirred at 25 °C for 1 hour under a N2 atmosphere. The residue was directly purified by preparative-HPLC (AcOH conditions) to give a white solid CCP1-GN4 (412 mg, 93.6 μmol, 33.8% yield, 93.14% purity). LCMS: RT=1.295min, MS cal.:Mav=4107.32, [2*M+5H] 5+ =1643.7, [M+3H] 3+ =1369.9, [M+4H] 4+ =1027.6, [M-sugar + 4H] 4+ =976.4, [M+5H] 5+ =822.3.

[1321] List of implementation methods

[1322] The following implementation methods are provided, and their numbers should not be interpreted as indicating a level of importance:

[1323] Implementation Method 1: A compound of Formula II or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, having the following structure:

[1324]

[1325] in:

[1326] PBM is the binding site of anti-cyclic citrullinated peptide (anti-CCP) antibodies;

[1327] CON and LINKER-2 are independent each time they appear:

[1328] a) in:

[1329] R 1 Each occurrence of is independently H or C1-C3 alkyl; and

[1330] 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

[1331] b) in:

[1332] 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;

[1333] 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;

[1334] 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

[1335] c) in:

[1336] Z and Z' are each an independent bond, -(CH2) i -O-、-(CH2) i -S-、-(CH2) i -N(R)-、

[1337] R 2 Each occurrence of is independently H or C1-C3 alkyl;

[1338] Each occurrence of Y is independently a key, -O-, -S-, or -N(R)-;

[1339] Each occurrence of i is an independent integer from 0 to 100;

[1340] D stands for -(CH2) i -YC(=O)-Y-(CH2) i -、-(CH2) m’ -、-[(CH2) n -X 1 ] j - OR key, provided that Z, Z' and D are not all keys at the same time;

[1341] j is an integer from 1 to 100;

[1342] m' is an integer from 1 to 100;

[1343] n is an integer from 1 to 100;

[1344] X 1 It is -O-, -S-, or -N(R)-;

[1345] Each R is independently H or a C1-C3 alkyl group optionally substituted with 1-3 hydroxyl groups; or

[1346] d) Choose from the following structures:

[1347]

[1348]

[1349] in

[1350] X 2 Each occurrence is independently -CH2-, -O-, -S-, -N(R) 4 )-, -C(O)-, -S(O)-, -S(O)2-, -S(O)2O-, -OS(O)2- or -OS(O)2O-;

[1351] X 3 Each occurrence is independently -O-, -S-, or -N(R) 4 )-;

[1352] R 4Each time it appears, it is independently H, C1-C3 alkyl, C1-C3 alkanol, or -C(O)(C1-C3 alkyl); or e)C 6-18 Aryl, C 3-18 Heterocyclic group, C 6-18 Biaryl or C 6-18 The heteroaryl groups are each optionally substituted with 1-6 substituents selected from F, Cl, Br, I, O(RG), OC(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).

[1353] Each occurrence of RG is independently H, with optional substitution of C. 1-10 Alkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 6-18 aryl or optionally substituted C 5-18 Mixed aromatics;

[1354] The structure of CRBM is as follows: in

[1355] Each RG 1 Independently

[1356] Each occurrence of XG is independently selected from -CH2-, -C(=O)-, -NH-, and -O-;

[1357] Each occurrence of ZG is independently selected from -CH2-, -C(=O)-, -NH-, and -O-;

[1358] AG independently for each occurrence

[1359]

[1360] RG 2 and RG 3 Each time it appears, it is independently selected from hydrogen and -C(=O)R, which is optionally replaced by 1-5 Cs selected from halogens and optionally substituted. 1-10 Alkyl, optionally substituted C 1-10 Alkoxy, optional substituted C 1-10 aminoalkyl groups and combinations thereof are substituted, or

[1361] RG 2 and RG 3 Together with the nitrogen atoms to which they are attached, they form a C5 heterocycle, which is optionally substituted by 1-5 substituents selected from the optionally substituted C atoms. 1-10 Alkyl, optionally substituted C 1-10Alkoxy, optional substituted C 1-10 Aminoalkyl, optionally substituted C 6-10 aryl, optionally substituted C 5-10 heteroaryl groups, halogens and their combinations;

[1362] Each occurrence of R is independently of H, and the C is arbitrarily substituted. 1-10 Alkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 6-18 aryl or optionally substituted C 5-18 Mixed aromatics;

[1363] Each occurrence of m is independently 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[1364] Each occurrence of n is an integer from 1 to 100 independently;

[1365] Each occurrence of p is an integer from 1 to 50 independently;

[1366] k' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15;

[1367] j' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15;

[1368] h and h' are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15;

[1369] i L It can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; and

[1370] The conditions are h, h', and i L At least one of them is at least 1.

[1371] Implementation Method 2: The compound according to Implementation Method 1, wherein k' is 1 and j' is 1.

[1372] Embodiment 3: The compound according to Embodiment 1 or 2 has the formula IIb

[1373] in:

[1374] L A It has the following structure in

[1375] Each RG 1 Independently

[1376] Each occurrence of XG is independently selected from -CH2-, -C(=O)-, -NH-, and -O-;

[1377] Each occurrence of ZG is independently selected from -CH2-, -C(=O)-, -NH-, and -O-;

[1378] AG independently for each occurrence

[1379]

[1380] RG 2 and RG 3 Each time it appears, it is independently selected from hydrogen and -C(=O)R, which is optionally replaced by 1-5 Cs selected from halogens and optionally substituted. 1-10 Alkyl, optionally substituted C 1-10 Alkoxy, optional substituted C 1-10 aminoalkyl groups and combinations thereof are substituted, or

[1381] RG 2 and RG 3 Together with the nitrogen atoms to which they are attached, they form a C5 heterocycle, which is optionally substituted by 1-5 substituents selected from the optionally substituted C atoms. 1-10 Alkyl, optionally substituted C 1-10 Alkoxy, optional substituted C 1-10 Aminoalkyl, optionally substituted C 6-10 aryl, optionally substituted C 5-10 heteroaryl groups, halogens and their combinations;

[1382] Each occurrence of R is independently of H, and the C is arbitrarily substituted. 1-10 Alkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 6-18 aryl or optionally substituted C 5-18 Mixed aromatics;

[1383] L B It is the anti-CCP binding part, which has a structure in:

[1384] AA is an amino acid sequence that is at least 80% homologous to the amino acid sequences selected from SEQ ID NO:1, SEQ ID NO:69-SEQ ID NO:76 and SEQ ID NO:77; and

[1385] m is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[1386] Implementation Method 4: The compound according to Implementation Method 3, wherein AA is a (3,16) cyclic peptide.

[1387] Implementation Method 5: The compound according to Implementation Method 3 or 4, wherein AA has at least 95% homology with SEQ ID NO:1.

[1388] Embodiment 6: The compound according to any one of Embodiments 3-5, wherein AA is the amino acid sequence of SEQ ID NO:1.

[1389] Example 7: The compound according to any one of embodiments 3-6, wherein m is 2.

[1390] Embodiment 8: The compound according to any one of Embodiments 1-6, wherein (ZG)p is -CH2-(O-CH2-CH2)2-NH(C=O)CH2CH2-.

[1391] Embodiment 9: The compound according to any one of Embodiments 1-6, wherein each RG 1 for

[1392]

[1393] Embodiment 10: The compound according to any one of Embodiments 1-6, wherein L A Or CRBM has a structure:

[1394] Embodiment 11: The compound according to any one of Embodiments 1-6, wherein (XG)n is selected from -CH2-(OCH2CH2)2-, -CH2-(OCH2CH2)3-, -CH2-(OCH2CH2)4- and -CH2-(OCH2CH2)5-.

[1395] Embodiment 12: The compound according to Embodiment 11, wherein (XG) n It is -CH2-(OCH2CH2)4-.

[1396] Embodiment 13: The compound according to any one of Embodiments 1-12, wherein RG 1 Each AG in is

[1397] Embodiment 14: The compound according to Embodiment 13, wherein RG 2 It is hydrogen.

[1398] Embodiment 15: The compound according to Embodiment 13, wherein RG 3 It is -C(=O)CH3.

[1399] Embodiment 16: The compound according to any one of Embodiments 1-15, wherein RG 1Each AG in is

[1400] Embodiment 17: The compound according to any one of Embodiments 1-16, wherein L A Or CRBM is

[1401]

[1402] Embodiment 18: The compound according to any one of Embodiments 1-17 is:

[1403]

[1404] Implementation Method 19: A compound of Formula Ia or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, having the following structure:

[1405] in:

[1406] It is a carbon-carbon single or double bond;

[1407] A is C 6-18 Aryl, C 6-18 Heterocyclic group, C 6-18 Biaryl or C 6-18 Heteroaryl groups, each optionally substituted by 1-6 substituents selected from F, Cl, Br, I, O(RG), OC(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);

[1408] L A It is the ASGPR bonding part, which has a structure

[1409] L B It is the anti-CCP1 binding part, with structure

[1410] AA is an amino acid sequence that is at least 80% homologous to SEQ ID NO:1;

[1411] RG 1 Each occurrence is independently of hydrogen or

[1412] AG is an amino sugar;

[1413] Each occurrence of RG is independently H, with optional substitution of C. 1-10 Alkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C6-18 aryl or optionally substituted C 5-18 Mixed aromatics;

[1414] Each occurrence of XG is independently selected from -CH2-, -C(=O)-, -NH-, and -O-;

[1415] Each occurrence of ZG is independently selected from -CH2-, -C(=O)-, -NH-, and -O-;

[1416] m is 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[1417] n is an integer from 1 to 100; and

[1418] p is an integer from 1 to 50.

[1419] Embodiment 20: The compound according to Embodiment 19, wherein each AG independently has the following structure:

[1420] in:

[1421] RG 2 and RG 3 Each is independently selected from hydrogen and -C(=O)R, and is optionally replaced by 1-5 C atoms selected from halogens and optionally substituted. 1-10 Alkyl, optionally substituted C 1-10 Alkoxy, optional substituted C 1-10 aminoalkyl groups and combinations thereof are substituted, or

[1422] RG 2 and RG 3 Together with the nitrogen atoms to which they are attached, they form a C5 heterocycle, which is optionally substituted by 1-5 substituents selected from the optionally substituted C atoms. 1-10 Alkyl, optionally substituted C 1-10 Alkoxy, optional substituted C 1-10 Aminoalkyl, optionally substituted C 6-10 aryl, optionally substituted C 5-10 heteroaryl groups, halogens and their combinations;

[1423] Each occurrence of R is independently of H, and the C is arbitrarily substituted. 1-10 Alkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 6-18 aryl or optionally substituted C 5-18 Mixed aromatics;

[1424] Embodiment 21: The compound according to Embodiment 19 or 20, wherein RG 2 It's hydrogen, RG 3 It is C(=O)CH3.

[1425] Embodiment 22: The compound according to Embodiment 19 or 20, wherein AG has the following structure:

[1426] Embodiment 23: The compound according to Embodiment 19 or 20, wherein AG has the following structure:

[1427] Embodiment 24: The compound according to any one of Embodiments 19-23, wherein each occurrence of (ZG)p independently has the following structure:

[1428] Where p is 2, 4, 6 or 8.

[1429] Embodiment 25: The compound according to any one of Embodiments 19-24, wherein (XG)n is selected from -O-(CH2)3-, -NH-(CH2CH2O)3-CH2- and =N*(C=O)(CH2)2C(=O)NHCH2CH2-(OCH2CH2)4-, wherein =N* is the cyclic nitrogen in A.

[1430] Embodiment 26: The compound according to any one of Embodiments 19-25, wherein AA is a (3,16) cyclic peptide.

[1431] Example 27: The compound according to any one of Examples 19-26, wherein AA has at least 95% homology with SEQ ID NO:1.

[1432] Embodiment 28: The compound according to any one of Embodiments 19-27, wherein AA is the amino acid sequence of SEQ ID NO:1.

[1433] Embodiment 29: The compound according to any one of Embodiments 19-28, wherein L A It is the ASGPR bonding part, which has a structure

[1434] Each RG 1 yes and

[1435] One of the following is true:

[1436] i)L A Each AG in is ii)L A The two AGs in the middle are And L A One of the AGs is iii)L A One of the AGs is And L A The two AGs in the middle are or iv)L A Each AG in is

[1437] Embodiment 30: The compound according to any one of Embodiments 19-29 has the following structure:

[1438] Embodiment 31: A pharmaceutical composition comprising the compound of any one of Embodiments 1-30 and at least one pharmaceutically acceptable carrier or excipient.

[1439] Implementation Method 32: A method for preventing, treating and / or improving arthritis in a subject in need, the method comprising: administering to the subject a therapeutically effective amount of any one of Implementation Methods 1-30, optionally wherein the compound is formulated as a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier or excipient.

[1440] Implementation Method 33: The method according to Implementation Method 32, wherein the arthritis is selected from rheumatoid arthritis, lupus erythematosus, psoriatic arthritis, ankylosing spondylitis and axial spondylitis.

[1441] Implementation 34: The method according to implementation 33, wherein the arthritis is rheumatoid arthritis.

[1442] Embodiment 35: The method according to any one of Embodiments 32-34, wherein the compound is administered via a route selected from oral, transdermal, mucosal, nasal, rectal, bladder, lung, duodenum, stomach, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, bronchial, inhalation, and local routes.

[1443] Embodiment 36: The method according to any one of Embodiments 32-34, wherein the compound is administered intravenously or orally.

[1444] Embodiment 37: The method according to any one of Embodiments 32-36, wherein the compound is administered at a dose of about 0.01 mg / kg to about 20 mg / kg.

[1445] Implementation method 38: The method according to any one of implementation methods 32-37, wherein the subject is a mammal.

[1446] Implementation method 39: The method according to any one of implementation methods 32-38, wherein the subject is a human.

[1447] Implementation method 40: The method according to any one of implementation methods 32-39 further includes administering at least one additional therapeutic agent selected from disease-modifying antirheumatic drugs, glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), and analgesics.

[1448] Embodiment 41: The method according to Embodiment 40, wherein the at least one additional therapeutic agent is administered sequentially or simultaneously with the compound, optionally wherein the at least one additional therapeutic agent and the compound are co-formulated.

[1449] Embodiment 42 provides the compounds described in Embodiments 1-30, wherein the PBM or L B The peptide comprises a peptide having five (5) to forty (40) amino acid residues, wherein one to five residues are citrulline residues, and optionally, at least two residues in the peptide are cysteine ​​residues that form a disulfide (-SS-) bond.

[1450] The terms and expressions used herein are descriptive rather than limiting, and their use is not intended to exclude any equivalents of the shown and described features or portions thereof. However, it should be understood that various modifications can be made within the scope of embodiments of this application. Therefore, it should be understood that although this application describes specific embodiments and optional features, modifications and variations can be made to the compositions, methods, and concepts disclosed herein by those skilled in the art, and such modifications and variations are considered to be within the scope of embodiments of this application.

Claims

1. A compound of formula II or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof, having the following structure: in: PBM is the binding site of anti-cyclic citrullinated peptide (anti-CCP) antibodies; CON and LINKER-2 are independent each time they appear: a) in: R 1 Each occurrence of is independently H or C1-C3 alkyl; and 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: 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: Z and Z' are each an independent bond, -(CH2) i -O-、-(CH2) i -S-、-(CH2) i -N(R)-、 R 2 Each occurrence of is independently H or C1-C3 alkyl; Each occurrence of Y is independently a key, -O-, -S-, or -N(R)-; Each occurrence of i is an independent integer from 0 to 100; D stands for -(CH2) i -YC(=O)-Y-(CH2) i -、-(CH2) m’ -、-[(CH2) n -X 1 ] j - OR key, provided that Z, Z' and D are not all keys at the same time; j is an integer from 1 to 100; m' is an integer from 1 to 100; n is an integer from 1 to 100; X 1 It is -O-, -S-, or -N(R)-; Each R is independently H or a C1-C3 alkyl group optionally substituted with 1-3 hydroxyl groups; or d) Selected from the following structures: in X 2 Each occurrence is independently -CH2-, -O-, -S-, -N(R) 4 )-, -C(O)-, -S(O)-, -S(O)2-, -S(O)2O-, -OS(O)2- or -OS(O)2O-; X 3 Each occurrence is independently -O-, -S-, or -N(R) 4 )-; R 4 Each time it appears, it is independently H, C1-C3 alkyl, C1-C3 alkanol, or -C(O)(C1-C3 alkyl); or e)C 6-18 Aryl, C 3-18 Heterocyclic group, C 6-18 Biaryl or C 6-18 The heteroaryl groups are each optionally substituted with 1-6 substituents selected from F, Cl, Br, I, O(RG), OC(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). Each time RG appears, it is independently H and an arbitrarily substituted C. 1-10 Alkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 6-18 aryl or optionally substituted C 5-18 Mixed aromatics; The structure of CRBM is as follows: in Each RG 1 Independently Each occurrence of XG is independently selected from -CH2-, -C(=O)-, -NH-, and -O-; Each occurrence of ZG is independently selected from -CH2-, -C(=O)-, -NH-, and -O-; Each occurrence of AG is independent. RG 2 and RG 3 Each time it appears, it is independently selected from hydrogen and -C(=O)R, which is optionally replaced by 1-5 Cs selected from halogens and optionally substituted. 1-10 Alkyl, optionally substituted C 1-10 Alkoxy, optional substituted C 1-10 aminoalkyl groups and combinations thereof are substituted, or RG 2 and RG 3 Together with the nitrogen atoms to which they are attached, they form a C5 heterocycle, which is optionally substituted by 1-5 substituents selected from the optionally substituted C atoms. 1-10 Alkyl, optionally substituted C 1-10 Alkoxy, optional substituted C 1-10 Aminoalkyl, optionally substituted C 6-10 aryl, optionally substituted C 5-10 heteroaryl groups, halogens and their combinations; Each occurrence of R is independently of H, and the C is arbitrarily substituted. 1-10 Alkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 6-18 aryl or optionally substituted C 5-18 Mixed aromatics; Each occurrence of m is independently 2, 3, 4, 5, 6, 7, 8, 9 or 10; Each occurrence of n is an integer from 1 to 100 independently; Each occurrence of p is an integer from 1 to 50 independently; k' is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; j' can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; h and h' are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; i L The digits are 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; and The conditions are h, h', and i L At least one of them is at least 1.

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

3. The compound according to claim 1, having formula IIb in: L A Having structure in Each RG 1 Independently Each occurrence of XG is independently selected from -CH2-, -C(=O)-, -NH-, and -O-; Each occurrence of ZG is independently selected from -CH2-, -C(=O)-, -NH-, and -O-; AG independently for each occurrence RG 2 and RG 3 Each time it appears, it is independently selected from hydrogen and -C(=O)R, which is optionally replaced by 1-5 Cs selected from halogens and optionally substituted. 1-10 Alkyl, optionally substituted C 1-10 Alkoxy, optional substituted C 1-10 aminoalkyl groups and combinations thereof are substituted, or RG 2 and RG 3 Together with the nitrogen atoms to which they are attached, they form a C5 heterocycle, which is optionally substituted by 1-5 substituents selected from the optionally substituted C atoms. 1-10 Alkyl, optionally substituted C 1-10 Alkoxy, optional substituted C 1-10 Aminoalkyl, optionally substituted C 6-10 aryl, optionally substituted C 5-10 heteroaryl groups, halogens and their combinations; Each occurrence of R is independently of H, and the C is arbitrarily substituted. 1-10 Alkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 6-18 aryl or optionally substituted C 5-18 Mixed aromatics; L B It is the anti-CCP binding part, which has a structure in: AA is an amino acid sequence that is at least 80% homologous to the amino acid sequences selected from SEQ ID NO:1, SEQ ID NO:69-SEQ ID NO:76 and SEQ ID NO:77; and m is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

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

5. The compound according to claim 4, wherein AA has at least 95% homology with 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 3-6, wherein m is 2.

8. The compound according to any one of claims 1-6, wherein (ZG)p is -CH2-(O-CH2-CH2)2-NH(C=O)CH2CH2-.

9. The compound according to any one of claims 1-6, wherein each RG 1 for 10. The compound according to any one of claims 1-6, wherein L A Alternatively, CRBM may have the following structure:

11. The compound according to any one of claims 1-6, wherein, (XG)n is selected from -CH2-(OCH2CH2)2-, -CH2-(OCH2CH2)3-, -CH2-(OCH2CH2)4- and -CH2-(OCH2CH2)5-.

12. The compound according to claim 11, wherein (XG) n It is -CH2-(OCH2CH2)4-.

13. The compound according to any one of claims 1-12, wherein RG 1 Each AG in is 14. The compound according to claim 13, wherein RG 2 It is hydrogen.

15. The compound according to claim 13, wherein RG 3 It is -C(=O)CH3.

16. The compound according to any one of claims 1-15, wherein RG 1 Each AG in the array is 17. The compound according to any one of claims 1-16, wherein L A Or CRBM is 18. The compound according to any one of claims 1-17, wherein it is:

19. A compound of formula Ia or a pharmaceutically acceptable salt, stereoisomer, solvate, or polymorph thereof having the following structure: in: It is a carbon-carbon single or double bond; A is C 6-18 Aryl, C 6-18 Heterocyclic group, C 6-18 Biaryl or C 6-18 Heteroaryl groups, each optionally substituted by 1-6 substituents selected from F, Cl, Br, I, O(RG), OC(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); L A It is the ASGPR bonding part, which has a structure L B It is the anti-CCP1 binding part, with structure AA is an amino acid sequence that is at least 80% homologous to SEQ ID NO:1; RG 1 Each occurrence is independently of hydrogen or AG is an amino sugar; Each occurrence of RG is independently H, with optional substitution of C. 1-10 Alkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 6-18 aryl or optionally substituted C 5-18 Mixed aromatics; Each occurrence of XG is independently selected from -CH2-, -C(=O)-, -NH-, and -O-; Each occurrence of ZG is independently selected from -CH2-, -C(=O)-, -NH-, and -O-; m is 2, 3, 4, 5, 6, 7, 8, 9 or 10; n is an integer from 1 to 100; and p is an integer from 1 to 50.

20. The compound according to claim 19, wherein each AG independently has the following structure: in: RG 2 and RG 3 Each is independently selected from hydrogen and -C(=O)R, and is optionally replaced by 1-5 C atoms selected from halogens and optionally substituted. 1-10 Alkyl, optionally substituted C 1-10 Alkoxy, optional substituted C 1-10 aminoalkyl groups and combinations thereof are substituted, or RG 2 and RG 3 Together with the nitrogen atoms to which they are attached, they form a C5 heterocycle, which is optionally substituted by 1-5 substituents selected from the optionally substituted C atoms. 1-10 Alkyl, optionally substituted C 1-10 Alkoxy, optional substituted C 1-10 Aminoalkyl, optionally substituted C 6-10 aryl, optionally substituted C 5-10 heteroaryl groups, halogens and their combinations; Each occurrence of R is independently of H, and the C is arbitrarily substituted. 1-10 Alkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 6-18 aryl or optionally substituted C 5-18 Mixed aromatics; 21. The compound according to claim 19 or 20, wherein RG 2 It's hydrogen, RG 3 It is C(=O)CH3.

22. The compound according to claim 19 or 20, wherein AG has the following structure:

23. The compound according to claim 19 or 20, wherein AG has the following structure:

24. The compound according to any one of claims 19-23, wherein each occurrence of (ZG)p independently has the following structure: Where p is 2, 4, 6 or 8.

25. The compound according to any one of claims 19-24, wherein (XG)n is selected from -O-(CH2)3-, -NH-(CH2CH2O)3-CH2- and =N*(C=O)(CH2)2C(=O)NHCH2CH2-(OCH2CH2)4-, wherein =N* is the cyclic nitrogen in A.

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

27. The compound according to any one of claims 19-26, wherein AA has at least 95% homology with SEQ ID NO:

1.

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

1.

29. The compound according to any one of claims 19-28, wherein L A It is the ASGPR bonding part, which has a structure Each RG 1 yes and One of the following is true: i)L A Each AG in is ii)L A The two AGs in the middle are And L A One of the AGs is iii)L A One of the AGs is And L A The two AGs in the middle are or iv)L A Each AG in is 30. The compound according to any one of claims 19-29, having the following structure:

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

32. A method for preventing, treating, and / or improving arthritis in subjects in need, the method comprising: The subject is given a therapeutically effective amount of any one of claims 1-30, optionally wherein the compound is formulated as a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier or excipient.

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

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

35. The method according to any one of claims 32-34, wherein the compound is administered via a route selected from oral, transdermal, mucosal, nasal, rectal, bladder, lung, duodenum, stomach, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, bronchial, inhalation, and local routes.

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

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

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

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

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

41. The method of claim 40, wherein the at least one additional therapeutic agent is administered sequentially or simultaneously with the compound, optionally wherein the at least one additional therapeutic agent and the compound are co-formulated.

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