Steroidal compounds and protein-conjugates thereof

Abstract

Protein steroid conjugates are described in which a glucocorticoid compound is conjugated to a binding agent, preferably an antibody. These protein steroid conjugates are useful, for example, for targeted delivery of a glucocorticoid (GC) to a cell.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 62 / 508,317, filed May 18, 2017, and U.S. Provisional Patent Application No. 62 / 419,365, filed November 8, 2016, the entire contents of which are incorporated herein by reference in their entirety for all purposes. Invention Field

[0003] The present invention provides novel steroid compounds, their protein conjugates, and methods for treating diseases, symptoms, and conditions, including the administration of said steroid compounds and conjugates. Background of the Invention

[0005] Antibody-drug conjugates (ADCs) are antibodies covalently linked to bioactive small molecule drugs, thus combining the targeting specificity of the antibody with the mode of action and potency of the small molecule drug. The therapeutic effects of ADCs have been validated in cancer treatment and remain a major and ongoing focus of research. ADCETRIS ® (brentuximab vedotin) and KADCYLA ® (ado-trastuzumab emtansine conjugate) is an ADC approved for the treatment of certain types of cancer, and at least forty ADCs are currently in clinical development.

[0006] Glucocorticoids (GCs) are small-molecule steroid compounds that bind to glucocorticoid receptors (GRs) and are used in anti-inflammatory and immunosuppressive therapies. However, because glucocorticoid receptors are widely expressed in many cell types, glucocorticoid therapy is subject to toxicity in most organ systems. Therefore, there is a need for novel glucocorticoids and new therapies that minimize the side effects caused by glucocorticoid administration, particularly those caused by activation of glucocorticoid receptors in non-target cells. This invention provides solutions to the above-mentioned needs and other unmet needs in the field to which this invention pertains. The invention includes antibody-drug conjugates containing a glucocorticoid payload. Invention Abstract

[0007] This invention provides compounds and methods for treating various diseases, symptoms, or conditions. In some aspects, the compounds have the structure shown in formula (A):

[0008]

[0009] (A);

[0010] Or its pharmaceutically acceptable salts, solvates, stereoisomers, or derivatives.

[0011] in:

[0012] R 1 and R 2 Each is independently -H, alkyl, alkyl-C(O)-O-, -OH, or halogen; or R 1 and R 2 Together ,

[0013] Where R 4 It is an alkyl, aryl, arylalkyl, or N-containing heterocyclic alkyl group.

[0014] The alkyl, aryl, arylalkyl, and N-containing heterocyclic alkyl groups mentioned above are, in each case, optionally, independently -NR. a R b replace;

[0015] R 3 It is -OH, R Z -C(O)-X-, heteroalkyl, piperidinyl, -NR a R b ,-oxyaryl-NR a R b 、or -ZA(R P ) t ;

[0016] R 5 In each case, it is independently -OH, halogen, alkyl, or arylalkyl;

[0017] R Z It is an alkyl group;

[0018] X is O or NR a ;

[0019] Z is S, S(O), S(O)2, SO2NR a O, C(O)NR a C(O), or NR a ;

[0020] A is aryl, arylalkyl, or heteroaryl;

[0021] R P In each case, it is independently a halogen, an optionally substituted alkyl group, -OH, or -NR. a R b ;

[0022] R a and R bIn each case, it is independently -H, an optionally substituted alkyl group, or an optionally substituted aryl group;

[0023] n is an integer from 0 to 19; and

[0024] t is an integer from 1 to 3;

[0025] The conditions are:

[0026] 1) (a) When R 1 When it is –OH or (b) when R 1 and R 2 Together , where R 4 It is C 1-9 alkyl or At that time, R 3 Not -OH, and

[0027] 2) R 3 Not for .

[0028] In some respects, the compound is a protein-drug conjugate, such as an antibody-drug conjugate, which contains an antigen-binding protein, such as an antibody, and the compound shown in formula (A).

[0029] In some respects, the compound is a protein-drug conjugate, such as an antibody-drug conjugate, which comprises an antigen-binding protein, such as an antibody, the compound shown in formula (A), and a cyclodextrin moiety.

[0030] Brief description of the attached figures

[0031] Figure 1 The sequences for synthesizing certain steroid compounds described in this invention are shown.

[0032] Figure 2 The sequence showing the position of the primary alcohol modifying budesonide is shown.

[0033] Figure 3 The sequence of the primary alcohol position modified by flumethasone is shown.

[0034] Figure 4 The sequence of the primary alcohol position modified by dexamethasone is shown.

[0035] Figure 5 Compound 7-1 in Table 1 is shown. R Two-dimensional nuclear Overhauser effect (NOE) magnetic resonance spectroscopy (hereinafter referred to as "2D-NOESY").

[0036] Figure 6Compound 7-1 in Table 1 is shown. S 2D–NOESY.

[0037] Figure 7 Table 1 shows 11-5 R 2D–NOESY spectrum.

[0038] Figure 8 Compounds 11-5 in Table 1 are shown. S 2D–NOESY spectrum.

[0039] Figure 9 A general method for synthesizing certain linker-payload pairs is shown.

[0040] Figure 10 The sequence of the synthesized DIBAC-Suc-NHS (compound (V)) is shown.

[0041] Figure 11 The sequence for synthesizing DIBAC-Suc-PEG4-acid / NHS (compound (VI)) is shown.

[0042] Figure 12 The sequence of the synthesized BCN-PEG4-acid (compound (VII)) is shown.

[0043] Figure 13 The sequence of the synthesized DIBAC–Suc–PEG4–VC–pAB–PNP (compound (VIII)) is shown.

[0044] Figure 14 The sequence of the synthetic linker-payload 1 (LP1) is shown.

[0045] Figure 15 The sequences of the synthetic linker-payload 2 (LP2) and linker-payload 3 (LP3) are shown.

[0046] Figure 16 The sequence of the synthetic linker-payload 4-11 (LP4-LP11) is shown.

[0047] Figure 17 The sequence of the synthetic linker-payload 12 (LP12) is shown.

[0048] Figure 18 The synthetic sequences for preparing linker-load 12 (LP13) and linker-load 14 (LP14) are shown.

[0049] Figure 19 A general synthetic method for ADC coupling via a [2+3] click reaction with LP4 is shown.

[0050] Figure 20 The following are examples of Coomassie-stained SDS-PAGE gels of anti-PRLR antibody, azide-functionalized anti-PRLR antibody, and anti-PRLR antibody-LP4 conjugate as described in Example 59.

[0051] Figure 21 Volume exclusion chromatography (SEC) of the anti-PRLR antibody, the azide-functionalized antibody, and the 4DAR anti-PRLR-LP4 conjugate as described in Example 59 is shown.

[0052] Figure 22 ESI-MS of the anti-PRLR antibody, the azide-functionalized anti-PRLR antibody, and the anti-PRLR antibody-LP4 conjugate as described in Example 59 are shown.

[0053] Figure 23 illustrates the use of steroid ADCs and budesonide controls in 293 / PRLR / GRE-Luc cells as described in Example 64. Figure 23A ) and 293 / MMTV-Luc cells ( Figure 23B Selective GR activation in ).

[0054] Figure 24 The contributions of steroid ADCs and budesonide controls to GR-activated linker-load are shown in 293 / PRLR / GRE-Luc cells as described in Example 65.

[0055] Figure 25 illustrates the activation of glucocorticoid receptors by budesonide, 11-5 from Table 1, and anti-IL2Rγ ncADC in the HEK293 / MMTV-luc / IL-2R / IL7R cell line at 24, 48, or 72 hours, as described in Example 66.

[0056] Figure 26 The sequence of the synthetic linker-payload (LP7) is shown.

[0057] Figure 27 A method for synthesizing compound (27b) is shown.

[0058] Figure 28 The sequences of the synthetic linker-payload (LP15 and LP16) are shown.

[0059] Figure 29 A general synthetic method for coupling an ADC via a [2+3] click reaction with a cyclodextrin-linker-load is shown.

[0060] Figure 30 This shows the relationship between relative light units (RLU) and log.10 The [M] relationship diagram shows the biological activity of steroid ADCs with and without cyclodextrin linkers.

[0061] Figure 31 The sequences for synthesizing certain steroid compounds (effective load 1 to 6) described in this invention are shown.

[0062] Figure 32 The sequences for synthesizing certain linker-steroid compounds (LP101 to LP116) are shown.

[0063] Figure 33 A general synthetic method for ADC coupling via [2+3] click reaction is shown.

[0064] Figure 34 ESI-MS results for anti-PRLR Ab, anti-PRLR Ab-N3, and anti-PRLR-LP are shown.

[0065] Figure 35 ESI-MS results for anti-Fel d1 Ab, anti-Fel d1 Ab-PEG3-N3, and anti-Fel d1 Ab-LP are shown.

[0066] Figure 36 shows the relative light unit (RLU) and log 10 In the [M] relationship diagram, antigen-positive cells (293_PRLR_PBind GR / UAS-Luc cells) are shown. Figure 36A ) and antigen-negative cells (293_PBind GR / UAS-Luc cells, Figure 36B The biological activity of steroid ADCs in ).

[0067] Figure 37A The mean blood concentration-time of compounds 4b and 6-I is shown.

[0068] Figure 37B The levels of TNF-α in blood samples with payloads of 4b and 6-I as described in Examples 120-121 are shown. Invention Details

[0070] A. Definition

[0071] In this invention, "alkyl" refers to a monovalent and saturated hydrocarbon group. Alkyl groups are optionally substituted and can be straight-chain, branched, or cyclic, i.e., cycloalkyl. Alkyl groups include, but are not limited to, those having 1-20 carbon atoms, i.e., C1. 1-20 Alkyl group; 1-12 carbon atoms, i.e., C 1-12 Alkyl group; 1-8 carbon atoms, i.e., C64. 1-8 Alkyl group; 1-6 carbon atoms, i.e., C64 1-6 Alkyl group; and 1-3 carbon atoms, i.e., C1-3 Alkyl groups. Examples of alkyl moiety include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, pentyl moiety, hexyl moiety, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. "Alkylene" refers to a divalent alkyl group.

[0072] The term "halogenated alkyl" as used in this invention refers to an alkyl group as defined above, wherein the alkyl group includes at least one substituent selected from halogens such as F, Cl, Br or I.

[0073] In this invention, "alkenyl" refers to a monovalent hydrocarbon group moiety comprising at least two carbon atoms and one or more non-aromatic carbon-carbon double bonds. The alkenyl group is optionally substituted and can be straight-chain, branched, or cyclic. Alkenyl groups include, but are not limited to, those having 2-20 carbon atoms, i.e., C1... 2-20 Alkenyl group; 2-12 carbon atoms, i.e., C 2-12 Alkenyl group; 2-8 carbon atoms, i.e., C 2-8 Alkenyl group; 2-6 carbon atoms, i.e., C 2-6 Alkenyl group; and 2-4 carbon atoms, i.e., C 2-4 Those with an alkenyl group. Examples of alkenyl group moiety include, but are not limited to, vinyl, propenyl, butenyl, and cyclohexenyl. "Alkenyl" is a divalent alkenyl group.

[0074] In this invention, "alkynyl" refers to a monovalent hydrocarbon group moiety containing at least two carbon atoms and one or more carbon-carbon triple bonds. The alkynyl group is optionally substituted and can be straight-chain, branched, or cyclic. Alynyl groups include, but are not limited to, those having 2-20 carbon atoms, i.e., C1... 2-20 Alkynyl group; 2-12 carbon atoms, i.e., C 2-12 Alkynyl group; 2-8 carbon atoms, i.e., C64. 2-8 Alkynyl group; 2-6 carbon atoms, i.e., C64. 2-6 Alkyne group; and 2-4 carbon atoms, i.e., C 2-4 Those with an alkynyl group. Examples of alkynyl group moiety include, but are not limited to, ethynyl, propynyl, and butynyl. "Imyynyl" is a divalent alkynyl group.

[0075] As used in this invention, "alkoxy" refers to a monovalent and saturated hydrocarbon group moiety, wherein the hydrocarbon comprises a single bond connected to an oxygen atom, and wherein the free radical is located on an oxygen atom, such as ethoxy CH3CH2–O·. Alkoxy substituents are linked to compounds in which they are substituted by the oxygen atom of the alkoxy substituent. Alkoxy groups are optionally substituted and can be straight-chain, branched, or cyclic, i.e., cycloalkoxy. Alkoxy groups include, but are not limited to, those having 1-20 carbon atoms, i.e., C1. 1-20 Alkyl group; 1-12 carbon atoms, i.e., C 1-12 Alkyl group; 1-8 carbon atoms, i.e., C 1-8Alkyl group; 1-6 carbon atoms, i.e., C 1-6 Alkyl group; and 1-3 carbon atoms, i.e., C 1-3 Those with alkoxy groups. Examples of alkoxy group moiety include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, isobutoxy, pentoxy group moiety, hexoxy group moiety, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy.

[0076] The term "haloalkoxy" as used in this invention refers to an alkoxy group as defined above, wherein the alkoxy group includes at least one substituent selected from halogens such as F, Cl, Br or I.

[0077] In this invention, "aryl" refers to a monovalent group moiety, which is a radical in aromatic compounds, wherein all ring atoms are carbon atoms. The aryl group is optionally substituted and can be monocyclic or polycyclic, such as bicyclic or tricyclic. Examples of aryl group moiety include, but are not limited to, having 6 to 20 ring carbon atoms, i.e., C64 ... 6-20 Aryl group; 6 to 15 ring carbon atoms, i.e., C 6-15 aryl group, and 6 to 10 ring carbon atoms, i.e., C 6-10 Those with aryl groups. Examples of aryl group moiety include, but are not limited to, phenyl, naphthyl, fluorenyl, azulel, anthracel, phenanthryl, and pyrene.

[0078] In this invention, "arylalkyl" refers to the monovalent group portion of an alkyl compound, wherein the alkyl compound is substituted with an aromatic substituent, i.e., the aromatic compound includes a single bond linked to the alkyl group, and wherein the free radical is located on the alkyl group. The arylalkyl group is linked to the illustrated chemical structure via the alkyl group. Arylalkyl can be represented by the following structures, for example, Where B is an aromatic group moiety, such as phenyl. The arylalkyl group is optionally substituted, meaning that the aryl group and / or the alkyl group can be substituted as described in this invention. Examples of arylalkyl groups include, but are not limited to, benzyl.

[0079] As used in this invention, "aryloxy group" refers to the monovalent group portion of an aromatic compound, wherein all ring atoms are carbon atoms, and wherein the ring is substituted with an oxygen atom, i.e., the aromatic compound includes a single bond connected to an oxygen atom, and wherein the free radical is located on an oxygen atom, such as a phenoxy group. The aryloxy group is linked to the compound through which it is substituted by this oxygen atom. The aryloxy group is optionally substituted. Aryloxy groups include, but are not limited to, those having 6 to 20 ring carbon atoms, i.e., C646. 6-20 Aryloxy group; 6 to 15 ring carbon atoms, i.e., C 6-15 Aryloxy group, and 6 to 10 ring carbon atoms, i.e., C 6-10Those with aryloxy groups. Examples of aryloxy groups include, but are not limited to, phenoxy, naphthoxy, and anthraceneoxy groups.

[0080] The “R” used in this invention a R b "N-Aryloxy" refers to the monovalent group portion of an aromatic compound, wherein all ring atoms are carbon atoms, and the ring is surrounded by R... a R b N-substituents and oxy-substituents, i.e., the aromatic compounds include those with R a R b N-substituent-linked single bonds and single bonds linked to oxygen atoms, wherein the free radical is located on the oxygen atom, for example... R a R b The N-aryloxy substituent is linked to the compounds in which it is substituted by this oxygen atom. R a R b The N-aryloxy group is optionally substituted. R a R b N-aryloxy groups include, but are not limited to, those having 6 to 20 ring carbon atoms, 6 to 15 ring carbon atoms, and 6 to 10 ring carbon atoms. R a R b Examples of the N-aryloxy group moiety include, but are not limited to, 4–(dimethyl-amino)-phenoxy. .

[0081] As used in this invention, "arylene" refers to the divalent group moiety of an aromatic compound, wherein the ring atom is only a carbon atom. The arylene group is optionally substituted and can be monocyclic or polycyclic, such as bicyclic or tricyclic. Examples of arylene group moiety include, but are not limited to, having 6 to 20 ring carbon atoms, i.e., C1... 6-20 arylene; 6 to 15 ring carbon atoms, i.e., C 6-15 arylene; and 6 to 10 ring carbon atoms, i.e., C 6-10 Those from Aromatica.

[0082] As used in this invention, "heteroalkyl" refers to an alkyl group in which one or more carbon atoms are replaced by heteroatoms. "Heteroalkenyl" as used in this invention refers to an alkenyl group in which one or more carbon atoms are replaced by heteroatoms. "Heteroyneyl" as used in this invention refers to an alkynyl group in which one or more carbon atoms are replaced by heteroatoms. Suitable heteroatoms include, but are not limited to, nitrogen, oxygen, and sulfur atoms. Heteroalkyl groups are optionally substituted. Examples of heteroalkyl group moieties include, but are not limited to, aminoalkyl, sulfonylalkyl, and sulfinylalkyl. Examples of heteroalkyl group moieties also include, but are not limited to, methylamino, methanesulfonyl, and methylsulfinyl.

[0083] As used in this invention, "heteroaryl" refers to the monovalent group portion of an aromatic compound, wherein the ring atom comprises a carbon atom and at least one oxygen, sulfur, nitrogen, or phosphorus atom. Examples of heteroaryl group portions include, but are not limited to, those having 5 to 20 ring atoms, 5 to 15 ring atoms, and 5 to 10 ring atoms. The heteroaryl group may be optionally substituted.

[0084] As used in this invention, "heteroaryl" refers to an aryl group in which one or more ring atoms of the aromatic ring are replaced by oxygen, sulfur, nitrogen, or phosphorus atoms. The substitution of the heteroaryl group is optional.

[0085] "Heterocyclic alkyl" refers to a cycloalkyl group in which one or more carbon atoms are replaced by heteroatoms. Suitable heteroatoms include, but are not limited to, nitrogen, oxygen, and sulfur atoms. Heterocyclic alkyl groups are optionally substituted. Examples of heterocyclic alkyl group moiety include, but are not limited to, morpholino, piperidinyl, tetrahydropyranyl, pyrrolidinyl, imidazoalkyl, oxazolidinyl, thiazoalkyl, dioxopentyl, dithioheteropentyl, oxacyclopentyl, or thioheteropentyl.

[0086] As used in this invention, "N-containing heterocyclic alkyl" refers to a cycloalkyl group in which one or more carbon atoms are replaced by heteroatoms, and where at least one heteroatom is a nitrogen atom. Suitable heteroatoms include, but are not limited to, oxygen and sulfur atoms in addition to nitrogen atoms. The N-containing heterocyclic alkyl group is optionally substituted. Examples of the N-containing heterocyclic alkyl group moiety include, but are not limited to, morpholino, piperidinyl, pyrrolyl, imidazoalkyl, oxazolyl, or thiazoalkyl.

[0087] The term "optionally substituted" as used in this invention, when describing a group moiety such as an optionally substituted alkyl group, means that this group moiety is optionally attached to one or more substituents. Examples of such substituents include, but are not limited to, halogens, cyano groups, nitro groups, haloalkyl groups, azide groups, epoxy groups, optionally substituted heteroaryl groups, and optionally substituted heterocyclic alkyl groups. , where R A R B and R C Each time it appears, it is independently a hydrogen atom, alkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, heteroalkyl, heteroaryl, or heterocycloalkyl, or R. A and R BTogether with the atoms attached to them, they form saturated or unsaturated carbocyclic rings, wherein the rings are optionally substituted, and one or more ring atoms are optionally substituted with heteroatoms. In some embodiments, when the group is optionally substituted with an optionally substituted heteroaryl group, an optionally substituted heterocyclic alkyl group, or an optionally substituted saturated or unsaturated carbocyclic ring, the substituents on the optionally substituted heteroaryl group, optionally substituted heterocyclic alkyl group, or optionally substituted saturated or unsaturated carbocyclic ring, if they are substituted, are not substituted by substituents that are further optionally substituted by other substituents. In some embodiments, when the group described in this invention is optionally substituted, unless otherwise stated, the substituents attached to the group are unsubstituted.

[0088] As used in this invention, "binding agent" refers to any molecule capable of specifically binding to a given binding partner. In some embodiments, the binding agent is an antibody or an antigen-binding fragment thereof.

[0089] The term "linker" as used in this invention refers to the divalent group portion that covalently links the binder to the steroid described in this invention.

[0090] The term "amide synthesis conditions" as used in this invention refers to reaction conditions suitable for promoting the formation of amides, for example, by reacting a carboxylic acid, an activated carboxylic acid, or an acyl halide with an amine. In some embodiments, "amide synthesis conditions" refers to reaction conditions suitable for promoting the formation of an amide bond between a carboxylic acid and an amine. In some of these embodiments, the carboxylic acid is first converted to an activated carboxylic acid before the activated carboxylic acid reacts with the amine to form an amide. Suitable conditions for amide formation include, but are not limited to, those that utilize reagents to achieve reactions between carboxylic acids and amines, including but not limited to, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinylphosphonium hexafluorophosphate (PyBOP), (7-azobenzotriazol-1-yloxy)tripyrrolidinylphosphonium hexafluorophosphate (PyAOP), tripyrrolidinylphosphonium hexafluorophosphate (PyBrOP), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HBTU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluoroborate (TBTU), 1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4,5-] bPyridinium 3-oxyhexafluorophosphate (HATU), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 2-chloro-1,3-dimethylimidazolium hexafluorophosphate (CIP), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), and carbonyldiimidazole (CDI). In some embodiments, the carboxylic acid is first converted to an activated carboxylic acid ester, and then reacted with an amine to form an amide bond. In some embodiments, the carboxylic acid reacts with a reagent. The reagent activates the carboxylic acid by deprotonating it, and then the deprotonated carboxylic acid forms a product complex with the protonated carboxylic acid due to nucleophilic attack on the protonating reagent. For some carboxylic acids, the activated ester is more susceptible to nucleophilic attack by the amine than before the carboxylic acid is converted to an activated ester. This results in amide bond formation. Therefore, the carboxylic acid is described as activated. Exemplary reagents include DCC and DIC.

[0091] The term "therapeuticly effective amount" as used in this invention refers to an amount of (a compound) sufficient to provide therapeutic benefit when a patient treats or controls a disease or condition, or delays or minimizes one or more symptoms associated with the disease or condition.

[0092] As used in this invention, "pharmaceuticalally acceptable derivative" refers to any form of the compound, such as an ester or prodrug of the compound, which provides the compound when administered to a patient.

[0093] The term "pharmaceutically acceptable salt" as used in this invention refers to any salt suitable for administration to a patient. Suitable salts include, but are not limited to, those found in Berge. et al ., "Pharmaceutical Salts", J. Pharm. Sci Those disclosed in , 1977, 66:1, are incorporated herein by reference. Examples of salts include, but are not limited to, acid-derived, base-derived, organic, inorganic, amine, and alkali metal or alkaline earth metal salts, including but not limited to calcium salts, magnesium salts, potassium salts, sodium salts, hydrochlorides, hydrobromic acid salts, sulfates, nitrates, phosphates, acetates, propionates, glycolates, pyruvates, oxalates, maleates, malonates, succinates, fumarates, tartrates, citrates, benzoates, cinnamates, mandelates, methanesulfonates, ethanesulfonates, p-toluenesulfonates, and salicylates, etc.

[0094] Certain groups, molecule / group moieties, substituents, and atoms are described with wavy lines intersecting the bonds to indicate the atoms through which the groups, molecule / group moieties, substituents, and atoms are connected. For example, a phenyl group substituted with a propyl group can be represented as:

[0095]

[0096] It has the following structure:

[0097] The illustrations used in this invention of substituents connected to cyclic groups (e.g., aromatic rings, heteroaromatic rings, fused rings, and saturated or unsaturated cycloalkyl or heterocycloalkyl groups) via bonds between ring atoms are intended to show that, unless otherwise stated, cyclic groups can be substituted with substituents at any ring position of the cyclic group or on any ring of the fused ring group, according to the techniques set forth in this invention or those disclosed immediately relating to techniques known in the art. For example, the group The subscript q is an integer from 0 to 4, and the substituent R is... 1 The position is generally described as not being directly connected to any vertex of the bond line structure, i.e., a specific ring carbon atom, including the following, where the substituent R 1 Non-limiting examples of groups attached to specific ring carbon atoms:

[0098]

[0099] Additionally, for example, the group... The subscript n is an integer from 0 to 19, and the substituent R is... 5 The position is generally described, that is, depicted as not directly connected to any vertex of the bond line structure, including non-limiting examples of the following groups, where the substituent R 5 Linked to a specific ring carbon atom:

[0100] .

[0101] The phrase "active (reactive) linker" or the abbreviation "RL" refers to a monovalent group that contains both an active (reactive) group and a linking group, such as... As shown, RG is the active group and L is the linker group. The linker group is any divalent group portion that bridges the active group to the payload. The active linker (RL), together with the payload to which they are linked, forms an intermediate (“linker-payload”) that can be used as a synthetic precursor for preparing the antibody-steroid conjugate of the present invention. The active linker contains an active group (“RG”), which is a functional group or group portion that reacts with the active portion of an antibody, a modified antibody, or an antigen-binding fragment thereof. The group portion resulting from the reaction of the active group with the antibody, the modified antibody, or an antigen-binding fragment thereof, together with the linker group, forms the “binding linker” (“BL”) portion of the conjugate of the present invention. In some embodiments, the “active group” is a functional group or group portion (e.g., maleimide or NHS ester) that reacts with cysteine ​​or lysine residues of an antibody or an antigen-binding fragment thereof. In some embodiments, the “active group” is a functional group or group portion capable of undergoing click chemistry. In some embodiments of the click chemistry reaction, the active group is an alkyne capable of undergoing a 1,3-cycloaddition reaction with an azide. Suitable active groups include, but are not limited to, strained alkynes, such as those suitable for strain-promoted cycloaddition of alkynes-azidoides (SPAAC), cyclic alkynes, such as cyclooctynes, benzocycloalkynes, and alkynes capable of undergoing a 1,3-cycloaddition reaction with an azide without a copper catalyst. Suitable alkynes also include, but are not limited to, DIBAC, DIBO, BARAC, DIFO, substituted alkynes such as fluorinated alkynes, aza-cyclic alkynes, BCN, and their derivatives. Linker-loads containing such active groups can be used to couple antibodies already functionalized with an azide group. Such functionalized antibodies include antibodies functionalized with an azide-polyethylene glycol group. In some embodiments, such functionalized antibodies are obtained by reacting an antibody containing at least one glutamine residue (e.g., heavy chain Q295 (EU number)) with a compound of the formula H2N–LL–N3 in the presence of an enzyme transglutaminase, wherein LL is a divalent polyethylene glycol group.

[0102] In some embodiments, the active group is an alkyne, for example... It can be achieved through click chemistry with azides (e.g. ) reaction to form click chemical products, such as Its regioisomers, or mixtures thereof. In some embodiments, the active group is an alkyne, for example... or It can be achieved through click chemistry with azides (e.g. ) reaction to form click chemical products, such as In some embodiments, the active group is an alkyne, for example... It can be achieved through click chemistry with azides (e.g. ) reaction to form click chemical products, such as Its regioisomers, or mixtures thereof. In some embodiments, the active group is a functional group, such as... It reacts with cysteine ​​residues on the antibody or its antigen-binding fragment to form a bond, for example... Where Ab refers to an antibody or its antigen-binding fragment, and S refers to the S atom on a cysteine ​​residue, the functional group binding to Ab through the S atom on this cysteine ​​residue. In some embodiments, the active group is a functional group, for example... It reacts with lysine residues on antibodies or their antigen-binding fragments to form bonds, for example... In this context, Ab refers to an antibody or its antigen-binding fragment, and N refers to the N atom on a lysine residue. The functional group binds to Ab through the N atom on this lysine residue.

[0103] As used in this invention, the phrase "binding linker" or "BL" refers to any divalent group or group portion of a binding agent (e.g., an antibody or its antigen-binding fragment) and the payload compound (e.g., a steroid) described in this invention. Generally, suitable binding linkers for the antibody conjugates described in this invention are those that are stable enough to utilize the cyclic half-life of the antibody and simultaneously capable of releasing their payload upon antigen-mediated internalization of the conjugate. Linkers can be cleavable or non-cleavable. Cleavable linkers are those that are cleaved by intracellular metabolism after internalization, for example, by hydrolysis, reduction, or enzymatic reactions. Non-cleavable linkers are those that release the attached payload through lysosomal degradation of the antibody after internalization. Suitable linkers include, but are not limited to, acid-labile linkers, hydrolyzably unstable linkers, enzymatically cleavable linkers, reductively unstable linkers, self-sacrificing linkers, and non-cleavable linkers. Suitable linkers also include, but are not limited to, glucuronic acid derivatives, succinimide-thioether derivatives, polyethylene glycol (PEG) units, hydrazones, ε-hexanoyl units, and disulfide units (e.g., –S–S–, –S–C(R)). 1 R 2 ) –, where R 1 and R 2These can be independently hydrogen or hydrocarbon groups, carbamate units, p-aminobenzyl units (PAB), phosphate units such as mono-, di-, or tri-phosphate units, and peptide units such as peptide units containing 2, 3, 4, 5, 6, 7, 8, or more amino acids, including but not limited to those containing valine-citrulline units. In some embodiments, the binder linker (BL) comprises a group portion formed by reacting the active group (RG) of the active linker (RL) with the active portion of the binder (e.g., an antibody, a modified antibody, or an antigen-binding fragment thereof).

[0104] In some embodiments, the BL comprises the following group moiety: Its regioisomers, or mixtures thereof, wherein It is a bond connected to the binder. In some embodiments, the BL comprises the following group moiety: Its regioisomers, or mixtures thereof, wherein It is a bond connected to the binder. In some embodiments, the BL comprises the following group moiety: Its regioisomers, or mixtures thereof, wherein It is a bond connected to the binder. In some embodiments, the BL comprises the following group moiety: Its regioisomers, or mixtures thereof, wherein It is a bond connected to the binder. In some embodiments, the BL comprises the following group moiety: ,in It is a bond linked to the cysteine ​​residue of the antibody or its antigen-binding fragment. In some embodiments, the BL comprises the following group moiety: ,in It is a bond linked to the lysine residue of the antibody or its antigen-binding fragment. In these embodiments, the bond linked to the binder is either a direct link or a linker. In a particular embodiment, the binder is modified with an azide to facilitate linking to BL. Examples are described below.

[0105] B. Steroid compounds

[0106] This invention provides compounds having the structure shown in formula (A):

[0107]

[0108] (A);

[0109] Or its pharmaceutically acceptable salts, solvates, stereoisomers, or derivatives.

[0110] in:

[0111] R 1 and R 2 Each is independently -H, alkyl, alkylene-C(O)-O-, -OH, or halogen; or R 1 and R 2 Together ,

[0112] Where R 4 It is an alkyl, aryl, arylalkyl, or N-containing heterocyclic alkyl group.

[0113] The alkyl, aryl, arylalkyl, and N-containing heterocyclic alkyl groups mentioned above are, in each case, optionally, independently -NR. a R b replace;

[0114] R 3 It is -OH, R Z -C(O)-X-, heteroalkyl, piperidinyl, -NR a R b ,-oxyaryl-NR a R b 、or -ZA(R P ) t ;

[0115] R 5 In each case, it is independently -OH, halogen, alkyl, or arylalkyl;

[0116] R Z It is an alkyl group;

[0117] X is O or NR a ;

[0118] Z is S, S(O), S(O)2, SO2NR a O, C(O)NR a C(O), or NR a ;

[0119] A is aryl or heteroaryl;

[0120] R P In each case, it is independently a halogen, an optionally substituted alkyl group, -OH, or -NR. a R b ;

[0121] R a and R b In each case, it is independently -H, or optionally substituted alkyl;

[0122] n is an integer from 0 to 19; and

[0123] t is an integer from 1 to 3;

[0124] The conditions are: (1) (a) When R 1 When it is –OH, or (b) when R 1 and R 2 Together , where R 4 It is C 1-9 alkyl or At that time, R 3 Not –OH, and (2) R 3 Not for .

[0125] In some embodiments, the compound shown in formula (A) has the formula (A) 1 The structure of )

[0126]

[0127] (A 1 )

[0128] Where R 1 -R 3 Both have the definitions described above, and R 5A and R 5B Each is an independent halogen or hydrogen atom.

[0129] In formula (A) 1 In some embodiments of the compound shown, R 5A and R 5B All are hydrogen atoms. In formula (A) 1 In some embodiments of the compound shown, R 5A and R 5B Both are fluorine. In formula (A) 1 In some embodiments of the compound shown, R 5A It is a hydrogen atom, and R 5B It's fluorine.

[0130] In formula (A) 1 In some embodiments of the compound shown, R 1 It is an alkylene group -C(O)-O– or –OH, and R 2 It is an alkyl group.

[0131] In formula (A) 1 In some embodiments of the compound shown, R 1 and R 2 Together , where R 4 It is an aryl, arylalkyl, or alkyl group, wherein the aryl, arylalkyl, and alkyl groups are optionally –NR a R bReplacement. In some implementations, R 4 It is – aryl-NR a R b In some implementation schemes, R 4 It is –phenyl-NR a R b .

[0132] In formula (A) 1 In some embodiments of the compound shown, R 1 and R 2 Together , where R 4 yes .

[0133] In formula (A) 1 In some embodiments of the compound shown, R 3 It is –OH, –NR a R b R Z -C(O)-X–, or , where R P It is a halogen, t is an integer from 0 to 2, R a It is H, R b It is H or alkyl, X is O or NH, and R Z It is an alkyl group.

[0134] In formula (A) 1 In some embodiments of the compound shown, R 3 It is –OH, –NH2, –NHCH3, –N(CH3)2, .

[0135] In formula (A) 1 In some embodiments of the compound shown, R 1 and R 2 Together , where R 4 It is an aryl, arylalkyl, or alkyl group, wherein the aryl, arylalkyl, and alkyl groups are optionally –NR a R b Replace; R 3 It is –OH, –NR a R b R Z -C(O)-X–, or , where R P It is a halogen, t is an integer from 0 to 2, R a It is H, R b It is H or alkyl, X is O or NH, and R Z It is an alkyl group; and R 5In each case, it is independently either a fluorine or a hydrogen atom.

[0136] The present invention also provides formula (A) 2 The compound shown is:

[0137]

[0138] (A 2 )

[0139] Where n is an integer from 0 to 4, and R 3 Is it –OH or R? Z -C(O)-O–; where R Z It is an alkyl group. In some embodiments, n is 0 or 1.

[0140] The present invention also provides formula (A) 3 The compound shown is:

[0141]

[0142] (A 3 )

[0143] Where n is an integer from 1 to 4, and R 3 Is it –OH or R? Z -C(O)-O–; where R Z It is an alkyl group. In some embodiments, n is 2.

[0144] The present invention also provides formula (A) 4 The compound shown is:

[0145]

[0146] (A 4 )

[0147] Where R 3 Yes – NR a R b , and R 4 It is an alkyl group, wherein R a and R b Each is independently a hydrogen atom or an alkyl group, or R a and R b Together they form a ring of 3-7 atoms. In some implementations, R 4 It is C 1-4 Alkyl group. In some embodiments, R 4 It is propyl. In some implementations, R 3 It is –NH2, –NHCH3, or –N(CH3)2.

[0148] The present invention also provides formula (A) 5The compound shown is:

[0149]

[0150] (A 5 )

[0151] Where R 4 It is an alkyl group, R P1 It is a halogen or hydrogen atom, and R P2 Yes – NR a R b Or –OH, where R a and R b Each is independently a hydrogen atom or an alkyl group. In some embodiments, R 4 It is C 1-4 Alkyl groups, and R P2 It is –NH2.

[0152] The present invention also provides formula (A) 6 The compound shown is:

[0153]

[0154] (A 6 )

[0155] Where R 3 yes R Z C(O)X–、 , or NR a R b Where X is O or NR a , It is aryl or heteroaryl, R P It is a halogen, t is an integer from 0 to 2, R a and R b Each is independently a hydrogen atom or an alkyl group, R Z It is an alkyl group, and R Q It is an alkoxy group, and R 4 It is an alkyl group. In some embodiments, R 3 yes .

[0156] The present invention also relates to formula (A) 7 The compound shown is:

[0157]

[0158] (A 7 )

[0159] Where R 3 yes Where X is O or NR a , It is aryl or heteroaryl, R P It is a halogen, t is an integer from 0 to 2, R a and R b Each is independently a hydrogen atom or an alkyl group, R 5A It is a hydrogen atom or fluorine, and R 5B It is fluorine. In some implementations, R 3 yes .

[0160] In some embodiments, the present invention provides compounds having the structure shown in formula (I):

[0161]

[0162] (I)

[0163] Or its pharmaceutically acceptable salts, solvates, stereoisomers, or derivatives.

[0164] in:

[0165] R 1 and R 2 Each is independently -H, alkyl, alkyl-C(O)-O-, -OH, or halogen; or R 1 and R 2 Together ,

[0166] Where R 4 It is an alkyl, aryl, arylalkyl, or N-containing heterocyclic alkyl group.

[0167] The alkyl, aryl, arylalkyl, and N-containing heterocyclic alkyl groups mentioned above are, in each case, optionally, independently -NR. a R b replace;

[0168] R 3 It is -OH, alkyl-C(O)-O-, heteroalkyl, -NR a R b -NR a R b –Oxyaryl, or R a R b N–aryloxy–, wherein the alkyl-C(O)-O-, heteroalkyl, -NR a R b and R a R b N-aryloxy group is optionally substituted with a halogen;

[0169] R 5 In each case, it is independently -OH, halogen, alkyl, or arylalkyl;

[0170] R a and R b In each case, it is independently H or alkyl; and

[0171] n is an integer from 0 to 19;

[0172] The condition is: when (a) or (b): (a) R 1 Is –OH, or (b) when R 1 and R 2 Together , and R 4 It is C 1-9 alkyl or Then R 3 Not –OH.

[0173] In some of these embodiments, R 1 and R 2 The components are independently selected from –H, alkyl, alkyl-C(O)-O-, –OH, and halogens. In some other embodiments, R 1 and R 2 Together In some embodiments, R 1 Yes – H. In some other embodiments, R 1 It is an alkyl group. In some embodiments, R 1 It is an alkyl–C(O)–O–. In some other embodiments, R 1 It is –OH. In some embodiments, R 1 It is a halogen. In some other embodiments, R 1 Yes –F. In some embodiments, R 1 Yes –Cl. In some other embodiments, R 1 Yes –Br. In some embodiments, R 1 Yes – I. In some other embodiments, R 2 It is –OH. In some embodiments, R 2 It is a halogen. In some other embodiments, R 2 Yes – F. In some embodiments, R 2 Yes – Cl. In some other embodiments, R 2 Yes –Br. In some embodiments, R 2 Yes-I.

[0174] In some embodiments, in formula (I), R 5 It is –OH. In some embodiments, R 5 It is a halogen, such as, but not limited to, –F, –Cl, –Br, or –I. In some embodiments, R 5 Yes –F. In some embodiments, R 5 Yes –Cl. In some embodiments, R5 Yes –Br. In some embodiments, R 5 Yes – I. In some embodiments, R 5 It is an alkyl group, such as, but not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or nonyl. In some embodiments, R 5 It is benzyl.

[0175] In some embodiments, in formula (I), R 3 Selected from –OH, alkyl –C(O)–O–, and R a R b N-aryloxy. In some of these examples, alkyl-C(O)-O- or R a R b The N-aryloxy group is optionally substituted with a halogen. In some embodiments, R 3 It is –OH. In some embodiments, R 3 It is an alkyl group –C(O)–O–. In some embodiments, R 3 It is R a R b N-aryloxy group. In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes .

[0176] In some embodiments of equation (I), R 3 It is –OH, alkyl –C(O)–O–, heteroalkyl, –NR a R b 、or R a R b N-aryloxy, of which alkyl-C(O)-O-, heteroalkyl, -NR a R b 、or R a R b N-aryloxy group is optionally substituted with a halogen. R a and R b In each case, it is independently –H or alkyl.

[0177] In some embodiments, R 3 It is R a R b N-aryloxy group, where R a and R bIn each case, it is independently –H or alkyl.

[0178] In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes .

[0179] In some embodiments, R 3 It is R a R b N-aryloxy group, where R a and R b In each case, it is independently –H or alkyl.

[0180] In some embodiments, in formula (I), R 4 It is selected from the group consisting of alkyl, aryl, arylalkyl, and N-containing heterocyclic alkyl groups. In some of these embodiments, the alkyl, aryl, arylalkyl, or N-containing heterocyclic alkyl group is optionally -NR. a R b Replacement. In some embodiments, R 4 It is an alkyl group, such as, but not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or nonyl. In some embodiments, R 4 It is methyl. In some embodiments, R 4 It is ethyl. In some embodiments, R 4 It is n-propyl. In some embodiments, R 4 It is isopropyl. In some embodiments, R 4 It is n-butyl. In some embodiments, R 4 It is isobutyl. In some embodiments, R 4 It is tert-butyl. In some embodiments, R 4 It is sec-butyl. In some embodiments, R 4It is pentyl. In some embodiments, R 4 It is self-based. In some embodiments, R 4 It is heptyl. In some embodiments, R 4 It is octyl or nonyl. In some embodiments, R 4 It is an aryl group, such as, but not limited to, phenyl or naphthyl. In some embodiments, R 4 It is phenyl. In some instances, R 4 It is a naphthyl group. In some embodiments, R 4 It is an aralkyl group, such as, but not limited to, benzyl. In some embodiments, R 4 It is an N-containing heterocyclic alkyl group, such as, but not limited to, piperidinyl. In some embodiments, R 4 It is 4-amino-phenyl. In some embodiments, R 4 It is a 4-aminophenyl that is optionally substituted with a halogen.

[0181] In some embodiments, R 4 yes , where R a and R b In each case, it is independently H or alkyl.

[0182] In some embodiments, R 4 yes .

[0183] In some embodiments, R 4 yes .

[0184] In some embodiments, R 4 yes .

[0185] In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R4 yes .

[0186] In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes .

[0187] In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes .

[0188] In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes .

[0189] In some embodiments, R 4 It is an alkyl group substituted with an amino group, such as, but not limited to, methyl-amino, ethyl-amino, propyl-amino, butyl-amino, pentyl-amino, hexyl-amino, heptyl-amino, octyl-amino, or nonyl-amino. In some embodiments, R 4 It is methyl-amino. In some embodiments, R 4 It is ethyl-amino. In some embodiments, R 4 It is n-propyl-amino. In some embodiments, R 4 It is isopropyl-amino. In some embodiments, R 4 It is n-butyl-amino. In some embodiments, R 4 It is isobutyl-amino. In some embodiments, R 4 It is tert-butyl-amino. In some embodiments, R 4 It is pentyl-amino. In some embodiments, R 4 It is hexyl-amino. In some embodiments, R 4 It is heptylated-amino. In some embodiments, R 4 It is octyl-amino. In some embodiments, R 4 It is nonyl-amino.

[0190] In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes .

[0191] In some embodiments, in this invention, R a and R bIn each case, the components are independently selected from H or alkyl groups. In some embodiments, R... a and R b All are H. In some embodiments, R a and R b All are methyl groups. In some embodiments, R a and R b All are ethyl. In some embodiments, R a and R b All are propyl. In some embodiments, R a or R b One of them is -H, and the other is an alkyl group. In some embodiments, R a or R b One of them is -H, and the other is methyl. In some embodiments, R a or R b One of them is -H, and the other is ethyl. In some embodiments, R a or R b One of them is -H, and the other is propyl.

[0192] In some embodiments, n is an integer from 0 to 19. In some embodiments, n is 0. In some other embodiments, n is 1. In some embodiments, n is 2. In some other embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some other embodiments, n is 6. In some embodiments, n is 7. In some other embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some other embodiments, n is 11. In some embodiments, n is 12. In some other embodiments, n is 13. In some embodiments, n is 14. In some embodiments, n is 15. In some other embodiments, n is 16. In some embodiments, n is 17. In some other embodiments, n is 18. In some embodiments, n is 19.

[0193] In some embodiments, in equation (I), when R 1 When it is –OH, R 3 Not –OH.

[0194] In some embodiments, in equation (I), when R 1 and R 2 Together , where R 4 It is C 1-9 When alkyl or 4–(dimethyl-amino)–phenyl, R 3 Not –OH.

[0195] In some embodiments, the present invention provides a compound of formula (I), wherein R 1 and R 2 Together In some of these embodiments, R 4 It is an alkyl, aryl, arylalkyl, or N-containing heterocyclic alkyl group. In some embodiments, the alkyl, aryl, heteroaryl, arylalkyl, and N-containing heterocyclic alkyl groups are optionally prefixed with -NR. a R b Replacement. In some of these embodiments, R 4 It is an alkyl group. In some of these examples, R 4 It is an aryl group. In some of these embodiments, R 4 It is an arylalkyl group. In some of these examples, R 4 It is an N-containing heterocyclic alkyl group. In some embodiments, R 4 It is an alkyl group, such as, but not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or nonyl. In some embodiments, R 4 It is methyl. In some embodiments, R 4 It is ethyl. In some embodiments, R 4 It is n-propyl. In some embodiments, R 4 It is isopropyl. In some embodiments, R 4 It is n-butyl. In some embodiments, R 4 It is isobutyl. In some embodiments, R 4 It is tert-butyl. In some embodiments, R 4 It is sec-butyl. In some embodiments, R 4 It is pentyl. In some embodiments, R 4 It is self-based. In some embodiments, R 4 It is heptyl. In some embodiments, R 4 It is octyl or nonyl. In some embodiments, R 4 It is an aryl group, such as, but not limited to, phenyl or naphthyl. In some embodiments, R 4 It is phenyl. In some embodiments, R 4 It is a naphthyl group. In some embodiments, R 4 It is a heteroaryl group, such as, but not limited to, thiophene or phenol. In some embodiments, R 4 It is an arylalkyl group, such as, but not limited to, benzyl. In some embodiments, R 4 It is an N-containing heterocyclic alkyl group, such as, but not limited to, piperidinyl. In some embodiments, R 4 It is 4-amino-phenyl. In some embodiments, R 4 It is a 4-aminophenyl that is optionally substituted with a halogen.

[0196] In some embodiments, the present invention provides a compound of formula (I), wherein R 1 and R 2 Together , where R 4It is selected from the group consisting of alkyl, aryl, arylalkyl, and N-containing heterocyclic alkyl; and wherein the alkyl, aryl, arylalkyl, or N-containing heterocyclic alkyl is optionally –NR a R b Substitution; and the stereochemistry of the carbon represented by * is R configuration.

[0197] In some embodiments, the present invention provides a compound of formula (I), wherein R 1 and R 2 Together , where R 4 It is selected from the group consisting of alkyl, aryl, arylalkyl, and N-containing heterocyclic alkyl; and wherein the alkyl, aryl, arylalkyl, or N-containing heterocyclic alkyl is optionally –NR a R b Substitution; and the stereochemistry of the carbon represented by * is S configuration.

[0198] In some embodiments, the present invention provides compounds of formula (I), wherein the compounds have the structure of formula (PIa):

[0199]

[0200] (PIa).

[0201] In some of these embodiments, R 1 and R 2 Each is independently selected from -H, alkyl, alkyl-C(O)-O-, -OH, or halogen. In some other embodiments, R 1 and R 2 Together In some embodiments, R 1 Yes – H. In some other embodiments, R 1 It is an alkyl group. In some embodiments, R 1 It is an alkyl–C(O)–O–. In some other embodiments, R 1 It is –OH. In some embodiments, R 1 It is a halogen. In some other embodiments, R 1 Yes – F. In some embodiments, R 1 Yes –Cl. In some other embodiments, R 1 Yes –Br. In some embodiments, R 1 Yes – I. In some other embodiments, R 2 It is –OH. In some embodiments, R 2 It is a halogen. In some other embodiments, R 2 Yes – F. In some embodiments, R 2 Yes – Cl. In some other embodiments, R 2Yes –Br. In some embodiments, R 2 Yes – I.

[0202] In some embodiments, in formula (PIa), R 5 It is –OH. In some embodiments, R 5 It is a halogen, such as, but not limited to, –F, –Cl, –Br, or –I. In some embodiments, R 5 Yes –F. In some embodiments, R 5 Yes –Cl. In some embodiments, R 5 Yes –Br. In some embodiments, R 5 Yes – I. In some embodiments, R 5 It is an alkyl group, such as, but not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or nonyl.

[0203] In some embodiments, in formula (PIa), R 3 Selected from –OH, alkyl –C(O)–O–, and R a R b N-aryloxy. In some of these examples, alkyl-C(O)-O- or R a R b The N-aryloxy group is optionally substituted with a halogen. In some embodiments, R 3 It is –OH. In some embodiments, R 3 It is an alkyl group –C(O)–O–. In some embodiments, R 3 It is R a R b N-aryloxy-. In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 It is R a R b N-aryloxy-. In some embodiments, R 3 Yes -NR a R b –Oxyaryl.

[0204] In some embodiments, in formula (PIa), R 4It is selected from the group consisting of alkyl, aryl, arylalkyl, and N-containing heterocyclic alkyl groups. In some of these embodiments, the alkyl, aryl, arylalkyl, or N-containing heterocyclic alkyl group is optionally replaced by –NR. a R b Replacement. In some embodiments, R 4 It is an alkyl group, such as, but not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or nonyl. In some embodiments, R 4 It is methyl. In some embodiments, R 4 It is ethyl. In some embodiments, R 4 It is n-propyl. In some embodiments, R 4 It is isopropyl. In some embodiments, R 4 It is n-butyl. In some embodiments, R 4 It is isobutyl. In some embodiments, R 4 It is tert-butyl. In some embodiments, R 4 It is pentyl. In some embodiments, R 4 It is self-based. In some embodiments, R 4 It is heptyl. In some embodiments, R 4 It is octyl or nonyl. In some embodiments, R 4 It is an aryl group, such as, but not limited to, phenyl or naphthyl. In some embodiments, R 4 It is phenyl. In some embodiments, R 4 It is a naphthyl group. In some embodiments, R 4 It is an arylalkyl group – such as, but not limited to, benzyl. In some embodiments, R 4 It is an N-containing heterocyclic alkyl group, such as, but not limited to, piperidinyl. In some embodiments, R 4 It is 4-amino-phenyl. In some embodiments, R 4 It is a 4-aminophenyl that is optionally substituted with a halogen.

[0205] In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes .

[0206] In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes .

[0207] In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes .

[0208] In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes .

[0209] In some embodiments, R 4 It is an alkyl group substituted with an amino group, such as, but not limited to, methyl-amino, ethyl-amino, propyl-amino, butyl-amino, pentyl-amino, hexyl-amino, heptyl-amino, octyl-amino, or nonyl-amino. In some embodiments, R 4 It is methyl-amino. In some embodiments, R 4 It is ethyl-amino. In some embodiments, R 4 It is n-propyl-amino. In some embodiments, R 4 It is isopropyl-amino. In some embodiments, R 4 It is n-butyl-amino. In some embodiments, R 4 It is isobutyl-amino. In some embodiments, R 4 It is tert-butyl-amino. In some embodiments, R 4 It is pentyl-amino. In some embodiments, R 4 It is hexyl-amino. In some embodiments, R 4 It is heptylated-amino. In some embodiments, R 4 It is octyl-amino. In some embodiments, R 4 It is nonyl-amino.

[0210] In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes .

[0211] In some embodiments, in this invention, Ra and R b In each case, it is independently selected from H or alkyl groups. In some embodiments, R a and R b All are –H. In some embodiments, R a and R b All are methyl groups. In some embodiments, R a and R b All are ethyl. In some embodiments, R a and R b All are propyl. In some embodiments, R a or R b One of them is -H, and the other is an alkyl group. In some embodiments, R a or R b One of them is -H, and the other is methyl. In some embodiments, R a or R b One of them is -H, and the other is ethyl. In some embodiments, R a or R b One of them is -H, and the other is propyl.

[0212] In some embodiments, n in formula (PIa) is an integer from 0 to 19. In some embodiments, n is 0. In some other embodiments, n is 1. In some embodiments, n is 2. In some other embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some other embodiments, n is 6. In some embodiments, n is 7. In some other embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some other embodiments, n is 11. In some embodiments, n is 12. In some other embodiments, n is 13. In some embodiments, n is 14. In some embodiments, n is 15. In some other embodiments, n is 16. In some embodiments, n is 17. In some other embodiments, n is 18. In some embodiments, n is 19.

[0213] In some embodiments, in formula (PIa), when R 1 When it is –OH, R 3 Not –OH.

[0214] In some embodiments, in formula (PIa), when R 1 and R 2 Together , where R 4 It is C 1-9 When alkyl or 4–(dimethyl-amino)–phenyl, R 3 Not –OH. In some embodiments, R 4 yes In some embodiments, R4 yes .

[0215] In some embodiments, the present invention provides compounds of formula (PIa), wherein the compounds have the structures of formula (PIb–1) or (PIb–2):

[0216] .

[0217] In some embodiments, the present invention provides compounds of formula (PIa), wherein the compounds have the structures of formula (PIc–1) or (PIc–2):

[0218] .

[0219] In some embodiments, the present invention provides compounds of formula (PIa), wherein the compounds have the structures of formula (PId–1) or (PId–2):

[0220] .

[0221] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0222] In some embodiments, the present invention provides compounds of formula (I), wherein the compounds have the structures of formula (PIe–1) or (PIe–2):

[0223]

[0224] (PIe–1) (PIe–2).

[0225] In some embodiments, the present invention provides compounds of formula (PIa), (PIb–1), (PIb–2), (PIc–1), (PIc–2), (PId–1), (PId–2), (PIe–1), or (PIe–2), wherein R 3 Selected from alkyl–C(O)–O– or R a R b N–aryloxy–; wherein alkyl–C(O)–O– or R– a R b N-aryloxy- is optionally substituted with a halogen.

[0226] In some embodiments, the present invention provides compounds of formula (PIa), (PIb–1), (PIb–2), (PIc–1), (PIc–2), (PId–1), (PId–2), (PIe–1), or (PIe–2), wherein R 3 It is an alkyl group –C(O)–O– that is optionally substituted with a halogen.

[0227] In some embodiments, the present invention provides compounds of formula (PIa), (PIb–1), (PIb–2), (PIc–1), (PIc–2), (PId–1), (PId–2), (PIe–1), or (PIe–2), wherein R 3 yes .

[0228] In some embodiments, the present invention provides compounds of formula (PIa), (PIb–1), (PIb–2), (PIc–1), (PIc–2), (PId–1), (PId–2), (PIe–1), or (PIe–2), wherein R 3 R is optionally replaced by halogen a R b N-aryloxy-.

[0229] In some embodiments, the present invention provides compounds of formula (PIa), (PIb–1), (PIb–2), (PIc–1), (PIc–2), (PId–1), (PId–2), (PIe–1), or (PIe–2), wherein R 3 yes .

[0230] In some embodiments, the present invention provides compounds of formula (PIa), (PIb–1), (PIb–2), (PIc–1), (PIc–2), (PId–1), (PId–2), (PIe–1), or (PIe–2), wherein R 3 yes .

[0231] In some embodiments, the present invention provides compounds of formula (PIa), (PIb–1), (PIb–2), (PIc–1), (PIc–2), (PId–1), (PId–2), (PIe–1), or (PIe–2), wherein R 3 Selected from –OH, alkyl –C(O)–O–, and R a R b N-aryloxy-. In some of these examples, alkyl-C(O)-O- or R a R b N-aryloxy- is optionally substituted with a halogen. In some embodiments, R 3 It is –OH. In some embodiments, R 3 It is an alkyl group –C(O)–O–. In some embodiments, R 3 It is R a R b N-aryloxy-. In some embodiments, R3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 It is R a R b N-aryloxy-. In some embodiments, R 3 Yes -NR a R b –Oxyaryl.

[0232] In some embodiments, the present invention provides compounds of formula (PIa), (PIb–1), (PIb–2), (PIc–1), (PIc–2), (PId–1), (PId–2), (PIe–1), or (PIe–2), wherein R 3 It is R a R b N–aryloxy–, where R a and R b In each case, it is independently H or alkyl.

[0233] In some embodiments, the present invention provides compounds of formula (PIa), (PIb–1), (PIb–2), (PIc–1), (PIc–2), (PId–1), (PId–2), (PIe–1), or (PIe–2), wherein R 4 It is selected from the group consisting of alkyl, aryl, arylalkyl, and N-containing heterocyclic alkyl groups. In some of these embodiments, the alkyl, aryl, arylalkyl, or N-containing heterocyclic alkyl group is optionally replaced by –NR. a R b Replacement. In some embodiments, R 4 It is an alkyl group, such as, but not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or nonyl. In some embodiments, R 4 It is methyl. In some embodiments, R 4 It is ethyl. In some embodiments, R 4 It is n-propyl. In some embodiments, R 4 It is isopropyl. In some embodiments, R 4 It is n-butyl. In some embodiments, R 4 It is isobutyl. In some embodiments, R 4 It is tert-butyl. In some embodiments, R 4 It is pentyl. In some embodiments, R4 It is self-based. In some embodiments, R 4 It is heptyl. In some embodiments, R 4 It is octyl or nonyl. In some embodiments, R 4 It is an aryl group, such as, but not limited to, phenyl or naphthyl. In some embodiments, R 4 It is phenyl. In some embodiments, R 4 It is a naphthyl group. In some embodiments, R 4 It is an arylalkyl group – such as, but not limited to, benzyl. In some embodiments, R 4 It is an N-containing heterocyclic alkyl group, such as, but not limited to, piperidinyl. In some embodiments, R 4 It is 4-amino-phenyl. In some embodiments, R 4 It is a 4-aminophenyl that is optionally substituted with a halogen.

[0234] In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes .

[0235] In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes .

[0236] In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes .

[0237] In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes .

[0238] In some embodiments, the present invention provides compounds of formula (PIa), (PIb–1), (PIb–2), (PIc–1), (PIc–2), (PId–1), (PId–2), (PIe–1), or (PIe–2), wherein R 4 It is an alkyl group substituted with an amino group, such as, but not limited to, methyl-amino, ethyl-amino, propyl-amino, butyl-amino, pentyl-amino, hexyl-amino, heptyl-amino, octyl-amino, or nonyl-amino. In some embodiments, R 4 It is methyl-amino. In some embodiments, R 4 It is ethyl-amino. In some embodiments, R 4 It is n-propyl-amino. In some embodiments, R 4 It is isopropyl-amino. In some embodiments, R 4 It is n-butyl-amino. In some embodiments, R 4 It is isobutyl-amino. In some embodiments, R 4 It is tert-butyl-amino. In some embodiments, R 4 It is pentyl-amino. In some embodiments, R 4 It is hexyl-amino. In some embodiments, R 4 It is heptylated-amino. In some embodiments, R 4 It is octyl-amino. In some embodiments, R 4 It is nonyl-amino.

[0239] In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes .

[0240] The compound shown in formula (I) is not one of the following compounds:

[0241] .

[0242] In some embodiments, the present invention provides compounds of formula (I), wherein the compounds have the structure of formula (PII):

[0243]

[0244] (PII).

[0245] In formula (PII), R 3 Selected from –OH, alkyl –C(O)–O–, and R a R bN-aryloxy. In some of these examples, alkyl-C(O)-O- or R a R b The N-aryloxy group is optionally substituted with a halogen. In some embodiments, R 3 It is –OH. In some embodiments, R 3 It is an alkyl group –C(O)–O–. In some embodiments, R 3 It is R a R b N-aryloxy-. In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 It is R a R b N-aryloxy-.

[0246] In some embodiments, in formula (PII), R 4 It is selected from the group consisting of alkyl, aryl, arylalkyl, and N-containing heterocyclic alkyl groups. In some of these embodiments, the alkyl, aryl, arylalkyl, or N-containing heterocyclic alkyl group is optionally replaced by –NR. a R b Replacement. In some embodiments, R 4 It is an alkyl group, such as, but not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or nonyl. In some embodiments, R 4 It is methyl. In some embodiments, R 4 It is ethyl. In some embodiments, R 4 It is n-propyl. In some embodiments, R 4 It is isopropyl. In some embodiments, R 4 It is n-butyl. In some embodiments, R 4 It is isobutyl. In some embodiments, R 4 It is tert-butyl. In some embodiments, R 4 It is sec-butyl. In some embodiments, R 4 It is pentyl. In some embodiments, R 4 It is self-based. In some embodiments, R 4 It is heptyl. In some embodiments, R 4 It is octyl or nonyl. In some embodiments, R 4 It is an aryl group, such as, but not limited to, phenyl or naphthyl. In some embodiments, R4 It is phenyl. In some embodiments, R 4 It is a naphthyl group. In some embodiments, R 4 It is an arylalkyl group – such as, but not limited to, benzyl. In some embodiments, R 4 It is an N-containing heterocyclic alkyl group, such as, but not limited to, piperidinyl. In some embodiments, R 4 It is 4-amino-phenyl. In some embodiments, R 4 It is a 4-aminophenyl that is optionally substituted with a halogen.

[0247] In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes .

[0248] In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R4 yes .

[0249] In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes .

[0250] In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes .

[0251] In some embodiments, R 4 It is an alkyl group substituted with an amino group, such as, but not limited to, methyl-amino, ethyl-amino, propyl-amino, butyl-amino, pentyl-amino, hexyl-amino, heptyl-amino, octyl-amino, or nonyl-amino. In some embodiments, R4 It is methyl-amino. In some embodiments, R 4 It is ethyl-amino. In some embodiments, R 4 It is n-propyl-amino. In some embodiments, R 4 It is isopropyl-amino. In some embodiments, R 4 It is n-butyl-amino. In some embodiments, R 4 It is isobutyl-amino. In some embodiments, R 4 It is tert-butyl-amino. In some embodiments, R 4 It is pentyl-amino. In some embodiments, R 4 It is hexyl-amino. In some embodiments, R 4 It is heptylated-amino. In some embodiments, R 4 It is octyl-amino. In some embodiments, R 4 It is nonyl-amino.

[0252] In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes .

[0253] In some embodiments, in this invention, R a and R b In each case, the components are independently selected from H or alkyl groups. In some embodiments, R... a and R b All are H. In some embodiments, R a and R b All are methyl groups. In some embodiments, R a and R b All are ethyl. In some embodiments, R a and R b All are propyl. In some embodiments, R a or R b One of them is -H, and the other is an alkyl group. In some embodiments, R a or R b One of them is -H, and the other is methyl. In some embodiments, R a or R b One of them is -H, and the other is ethyl. In some embodiments, R a or R b One of them is -H, and the other is propyl.

[0254] In some embodiments, n in formula (PII) is an integer from 0 to 19. In some embodiments, n is 0. In some other embodiments, n is 1. In some embodiments, n is 2. In some other embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some other embodiments, n is 6. In some embodiments, n is 7. In some other embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some other embodiments, n is 11. In some embodiments, n is 12. In some other embodiments, n is 13. In some embodiments, n is 14. In some embodiments, n is 15. In some other embodiments, n is 16. In some embodiments, n is 17. In some other embodiments, n is 18. In some embodiments, n is 19.

[0255] In some embodiments, the present invention provides compounds of formula (I), wherein the compounds have the structures of formula (PIIa) or (PIIb):

[0256] .

[0257] In some embodiments, the present invention provides compounds of formula (PIIa) or (PIIb), wherein R 4 Selected from 4-amino-phenyl, 4-amino-1-methyl-phenyl, 2-amino-ethyl, piperidinyl, or propyl. In some embodiments, R 4 It is 4-amino-phenyl. In some embodiments, R 4 It is 4-amino-1-methyl-phenyl. In some embodiments, R 4 It is 2-amino-ethyl. In some embodiments, R 4 It is piperidinyl. In some embodiments, R 4 It is propyl. In some embodiments, R 4 It is n-propyl. In some embodiments, R 4 It is isopropyl.

[0258] In some embodiments, the present invention provides compounds of formula (PIIa) or (PIIb), wherein R 3 Selected from alkyl–C(O)–O– or R a R b N-aryloxy; wherein alkyl-C(O)-O-, or R- a R b The N-aryloxy group may optionally be substituted with a halogen.

[0259] In some embodiments, the present invention provides compounds of formula (PIIa) or (PIIb), wherein R 3 yes .

[0260] In some embodiments, the present invention provides compounds of formula (PIIa) or (PIIb), wherein R 3 yes .

[0261] In some embodiments, the present invention provides compounds of formula (PIIa) or (PIIb), wherein R 3 yes .

[0262] In some embodiments, the present invention provides compounds of formula (PIIa) or (PIIb), wherein the compounds have the structure of formula (PIII):

[0263] .

[0264] In equation (PIII), R 9 Selected from H or –NR a R b In some embodiments, R 9 It is H. In some other embodiments, R 9 Yes – NR a R b R 4 R 4 The subscript n has the definition described in Equation I or the definition described above.

[0265] In equation (PIII), R 10 and R 11 In each case, the choice is made independently of H, F, or –NR. a R b .

[0266] In some embodiments, the present invention provides compounds of formula (III), wherein the compounds have the structures of formula (PIIIa) or (PIIIb):

[0267] .

[0268] In some embodiments, the present invention provides compounds of formula (I), wherein the compounds have the structure of formula (PIV):

[0269] .

[0270] In equation (PIV), –NR a R b R 4 R 5 The subscript n has the definition described in Equation I or the definition described above.

[0271] In some embodiments, the present invention provides compounds of formula (I), wherein the compounds have the structure of formula (PV):

[0272] .

[0273] In equation (PV), –NR a R b R 4 R 4 The subscript n has the definition described in Equation I or the definition described above.

[0274] In some embodiments, the present invention provides compounds of formula (PV), wherein the compounds have structures of formula (PVa) or (PVb):

[0275] .

[0276] In some embodiments, the present invention provides compounds of formula (I), wherein the compounds have the structure of formula (PVI):

[0277] .

[0278] In equation (PVI), R 3 Selected from alkyl–C(O)–O– or R a R b N-aryloxy, wherein the alkyl group is –C(O)–O– or –NR. a R b –Oxyaryl groups may optionally be substituted with halogens.

[0279] In some embodiments, in formula (PVI), R 4 Selected from –H, –OH, halogen, or alkyl. In some embodiments, R 4 It is a halogen, such as, but not limited to, –F, –Cl, –Br, or –I. In some embodiments, R 4 Yes –F. In some embodiments, R 4 Yes –Cl. In some embodiments, R 4 Yes –Br. In some embodiments, R 4 Yes – I. In some embodiments, R 4It is an alkyl group, such as, but not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or nonyl. The subscript n is an integer from 0 to 19. In some embodiments, n is 0. In some other embodiments, n is 1. In some embodiments, n is 2. In some other embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some other embodiments, n is 6. In some embodiments, n is 7. In some other embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some other embodiments, n is 11. In some embodiments, n is 12. In some other embodiments, n is 13. In some embodiments, n is 14. In some embodiments, n is 15. In some other embodiments, n is 16. In some embodiments, n is 17. In some other embodiments, n is 18. In some embodiments, n is 19.

[0280] In some embodiments, in formula (PVI), R 3 Selected from –OH, alkyl –C(O)–O–, –NR a R b , or NR a R b –Aryloxy. In some of these examples, alkyl–C(O)–O– or R a R b The N-aryloxy group is optionally substituted with a halogen. In some embodiments, R 3 It is –OH. In some embodiments, R 3 It is an alkyl group –C(O)–O–. In some embodiments, R 3 It is R a R b N-aryloxy group.

[0281] In some embodiments, R 3 Yes – NR a R b In some embodiments, R 3 It is –NH2. In some embodiments, R 3 It is –NH(CH3).

[0282] In some embodiments, R 3 It is R a R b N-aryloxy group.

[0283] In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes .

[0284] In some embodiments, the present invention provides compounds of formula (I), wherein the compounds have the structure of formula (PVII):

[0285] .

[0286] In equation (PVII), R 3 Selected from alkyl–C(O)–O– or R a R b N-aryloxy, wherein alkyl-C(O)-O-, or NR a R b –The aryloxy group may optionally be replaced by a halogen.

[0287] In some embodiments, in formula (PVII), R 4 Selected from –H, –OH, halogen, or alkyl. In some embodiments, R 4 It is a halogen, such as, but not limited to, –F, –Cl, –Br, or –I. In some embodiments, R 4 Yes –F. In some embodiments, R 4 Yes –Cl. In some embodiments, R 4 Yes –Br. In some embodiments, R 4 Yes – I. In some embodiments, R 4It is an alkyl group, such as, but not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or nonyl. The subscript n is an integer from 0 to 19. In some embodiments, n is 0. In some other embodiments, n is 1. In some embodiments, n is 2. In some other embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some other embodiments, n is 6. In some embodiments, n is 7. In some other embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some other embodiments, n is 11. In some other embodiments, n is 12. In some other embodiments, n is 13. In some other embodiments, n is 14. In some embodiments, n is 15. In some other embodiments, n is 16. In some embodiments, n is 17. In some other embodiments, n is 18. In some embodiments, n is 19. In some embodiments, in formula (PVII), R 3 Selected from –OH, alkyl –C(O)–O–, –NR a R b , or NR a R b –Aryloxy. In some of these examples, alkyl–C(O)–O– or R a R b The N-aryloxy group is optionally substituted with a halogen. In some embodiments, R 3 It is –OH. In some embodiments, R 3 It is an alkyl group –C(O)–O–. In some embodiments, R 3 It is R a R b N-aryloxy group.

[0288] In some embodiments, R 3 Yes – NR a R b In some embodiments, R 3 It is –NH2. In some embodiments, R 3 It is –NH(CH3).

[0289] In some embodiments, R 3 It is R a R b N-aryloxy group.

[0290] In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes .

[0291] In some embodiments, the present invention provides compounds of formula (PVII), wherein the compounds have the structure of formula (PVIIa):

[0292]

[0293] (PVIIa).

[0294] In some embodiments, the present invention provides compounds of formula (PVII), wherein the compounds have the structure of formula (PVIIb):

[0295]

[0296] (PVIIb).

[0297] In some embodiments, the present invention provides compounds of formula (PVII), (PVIIa) or (PVIIb), wherein R 3 It is arbitrarily replaced by halogens. or R a R b N-aryloxy-.

[0298] In some embodiments, the present invention provides compounds of formula (PVII), (PVIIa) or (PVIIb), wherein R 3 yes .

[0299] In some embodiments, the present invention provides compounds of formula (PVII), (PVIIa) or (PVIIb), wherein R 3 yes .

[0300] In some embodiments, the present invention provides compounds of formula (PVII), wherein the compounds have the structures of formula (PVIIb–1) or (PVIIb–2):

[0301] .

[0302] In some embodiments, the present invention provides compounds of formula (PVII), (PVIIa), (PVIIb), (PVIIb–1), or (PVIIb–2), wherein R 3 It is an alkyl–C(O)–O– or R a R b N-aryloxy group.

[0303] In some embodiments, the present invention provides compounds of formula (I), wherein the compounds have the structure of formula (PVIII):

[0304]

[0305] (PVIII).

[0306] In some embodiments, in any of the formulas (PI), (PIa), (PIb–1), (PIb–2), (PIc–1), (PIc–2), (PId–1), (PId–2), (PIe–1), (PIe–2), (PII), (PIIa), (PIIb), (PIIIa), (PIIIb), (PIV), (PV), (PVa), (PVb), (PVI), (PVII), (PVIIa), (PVIIb), (PVIIb–1), or (PVIIb–2), the halogen, when present, is fluorine.

[0307] In some embodiments of the compound shown in formula (I), R 1 and R 2 Each is independently selected from –H, alkyl, alkyl-C(O)-O-, –OH, or halogen. In some other embodiments, R 1 and R 2 Together In some embodiments, R 1 Yes – H. In some other embodiments, R 1 It is an alkyl group. In some embodiments, R 1 It is an alkyl–C(O)–O–. In some other embodiments, R 1 It is –OH. In some embodiments, R 1 It is a halogen. In some other embodiments, R 1 Yes –F. In some embodiments, R 1 Yes –Cl. In some other embodiments, R 1 Yes –Br. In some embodiments, R 1 Yes – I. In some other embodiments, R 2 It is –OH. In some embodiments, R 2 It is a halogen. In some other embodiments, R2 Yes – F. In some embodiments, R 2 Yes – Cl. In some other embodiments, R 2 Yes –Br. In some embodiments, R 2 Yes – I.

[0308] In some embodiments, in formula (I), R 5 In each case, it is independently selected from –OH, halogen, alkyl, or arylalkyl. In some embodiments, R 5 It is –OH. In some embodiments, R 5 It is a halogen, such as, but not limited to, –F, –Cl, –Br, or –I. In some embodiments, R 5 Yes –F. In some embodiments, R 5 Yes –Cl. In some embodiments, R 5 Yes –Br. In some embodiments, R 5 Yes – I. In some embodiments, R 5 It is an alkyl group, such as, but not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or nonyl. In some embodiments, R 5 It is benzyl.

[0309] In some embodiments, in formula (I), R 4 It is selected from the group consisting of alkyl, aryl, arylalkyl, and N-containing heterocyclic alkyl groups. In some of these embodiments, the alkyl, aryl, arylalkyl, or N-containing heterocyclic alkyl group is optionally replaced by –NR. a R b Replacement. In some embodiments, R 4 It is an alkyl group, such as, but not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or nonyl. In some embodiments, R 4 It is methyl. In some embodiments, R 4 It is ethyl. In some embodiments, R 4 It is n-propyl. In some embodiments, R 4 It is isopropyl. In some embodiments, R 4 It is n-butyl. In some embodiments, R 4 It is isobutyl. In some embodiments, R 4 It is tert-butyl. In some embodiments, R 4 It is sec-butyl. In some embodiments, R 4 It is pentyl. In some embodiments, R 4 It is self-based. In some embodiments, R 4 It is heptyl. In some embodiments, R 4 It is octyl or nonyl. In some embodiments, R 4 It is an aryl group, such as, but not limited to, phenyl or naphthyl. In some embodiments, R4 It is phenyl. In some embodiments, R 4 It is a naphthyl group. In some embodiments, R 4 It is an arylalkyl group – such as, but not limited to, benzyl. In some embodiments, R 4 It is an N-containing heterocyclic alkyl group, such as, but not limited to, piperidinyl. In some embodiments, R 4 It is 4-amino-phenyl. In some embodiments, R 4 It is a 4-aminophenyl that is optionally substituted with a halogen.

[0310] In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes .

[0311] In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes .

[0312] In some embodiments, R 4 It is an alkyl group substituted with an amino group, such as, but not limited to, methyl-amino, ethyl-amino, propyl-amino, butyl-amino, pentyl-amino, hexyl-amino, heptyl-amino, octyl-amino, or nonyl-amino. In some embodiments, R 4 It is methyl-amino. In some embodiments, R 4 It is ethyl-amino. In some embodiments, R 4 It is n-propyl-amino. In some embodiments, R 4 It is isopropyl-amino. In some embodiments, R 4 It is n-butyl-amino. In some embodiments, R 4 It is isobutyl-amino. In some embodiments, R 4 It is tert-butyl-amino. In some embodiments, R 4 It is sec-butyl-amino. In some embodiments, R 4 It is pentyl-amino. In some embodiments, R 4 It is hexyl-amino. In some embodiments, R 4 It is heptylated-amino. In some embodiments, R 4 It is octyl-amino. In some embodiments, R 4 It is nonyl-amino.

[0313] In some embodiments, R 4 yes In some embodiments, R 4 yes In some embodiments, R 4 yes .

[0314] In some embodiments, in this invention, R a and R b In each case, it is independently selected from H or alkyl groups. In some embodiments, R a and R b All are H. In some embodiments, R a and R b All are methyl groups. In some embodiments, R a and R b All are ethyl. In some embodiments, R a and R b All are propyl. In some embodiments, R a or R b One of them is -H, and the other is an alkyl group. In some embodiments, R a or R bOne of them is -H, and the other is methyl. In some embodiments, R a or R b One of them is -H, and the other is ethyl. In some embodiments, R a or R b One of them is -H, and the other is propyl.

[0315] In some embodiments, n in equation (I) is an integer from 0 to 19. In some embodiments, n is 0. In some other embodiments, n is 1. In some embodiments, n is 2. In some other embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some other embodiments, n is 6. In some embodiments, n is 7. In some other embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some other embodiments, n is 11. In some embodiments, n is 12. In some other embodiments, n is 13. In some embodiments, n is 14. In some embodiments, n is 15. In some other embodiments, n is 16. In some embodiments, n is 17. In some other embodiments, n is 18. In some embodiments, n is 19.

[0316] In some embodiments, in equation (I), when R 1 When it is –OH, R 3 Not –OH.

[0317] In some embodiments, in equation (I), when R 1 and R 2 Together , where R 4 It is C 1-9 When alkyl or 4–(dimethyl-amino)–phenyl, R 3 Not –OH.

[0318] In some embodiments, the present invention provides a compound of formula (I), wherein R 1 and R 2 Together In some of these embodiments, R 4 It is an alkyl, aryl, arylalkyl, or N-containing heterocyclic alkyl group. In some embodiments, the alkyl, aryl, arylalkyl, or N-containing heterocyclic alkyl group is optionally prefixed with -NR. a R b Replacement. In some of these embodiments, R 4 It is an alkyl group. In some of these examples, R 4 It is an aryl group. In some of these embodiments, R 4 It is an arylalkyl group. In some of these examples, R 4 It is an N-containing heterocyclic alkyl group. In some embodiments, R 4It is an alkyl group, such as, but not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or nonyl. In some embodiments, R 4 It is methyl. In some embodiments, R 4 It is ethyl. In some embodiments, R 4 It is n-propyl. In some embodiments, R 4 It is isopropyl. In some embodiments, R 4 It is n-butyl. In some embodiments, R 4 It is isobutyl. In some embodiments, R 4 It is tert-butyl. In some embodiments, R 4 It is sec-butyl. In some embodiments, R 4 It is pentyl. In some embodiments, R 4 It is self-based. In some embodiments, R 4 It is heptyl. In some embodiments, R 4 It is octyl. In some embodiments, R 4 It is nonylene. In some embodiments, R 4 It is an aryl group, such as, but not limited to, phenyl or naphthyl. In some embodiments, R 4 It is phenyl. In some embodiments, R 4 It is a naphthyl group. In some embodiments, R 4 It is an arylalkyl group, such as, but not limited to, benzyl. In some embodiments, R 4 It is an N-containing heterocyclic alkyl group, such as, but not limited to, piperidinyl. In some embodiments, R 4 It is 4-amino-phenyl. In some embodiments, R 4 It is a 4-aminophenyl that is optionally substituted with a halogen.

[0319] In some embodiments, the present invention provides a compound of formula (I), wherein R 1 and R 2 Together , where R 4 It is selected from the group consisting of alkyl, aryl, arylalkyl, and N-containing heterocyclic alkyl; and wherein the alkyl, aryl, arylalkyl, or N-containing heterocyclic alkyl is optionally –NR a R b Substitution; and the stereochemistry of the carbon represented by * is R configuration.

[0320] In some embodiments, the present invention provides a compound of formula (I), wherein R 1 and R 2 Together , where R 4 It is selected from the group consisting of alkyl, aryl, arylalkyl, and N-containing heterocyclic alkyl; and wherein the alkyl, aryl, arylalkyl, or N-containing heterocyclic alkyl is optionally –NRa R b Substitution; and the stereochemistry of the carbon represented by * is S configuration.

[0321] In equation (I), when R 1 When it is –OH, or when R 1 and R 2 Together , where R 4 It is C 1-9 When alkyl or 4–(dimethyl-amino)–phenyl, R 3 Not –OH.

[0322] In some embodiments, the payload of the present invention is a derivative or analogue of budesonide or diflorasone. In some embodiments, the derivative is an amine- or aniline-containing molecule with a structure related to budesonide or diflorasone. As described in the present invention, based on the methods described in the present invention, the payload of the present invention, as well as other steroid compounds, can be conjugated to an antibody or its antigen-binding fragment. As described in the present invention, based on the methods described in the present invention, the payload of the present invention, as well as other steroid compounds, can be conjugated to an antibody or its antigen-binding fragment, and also to a cyclodextrin moiety. As taught in the present invention, stable linker-payloads can be used with these conjugation methods to generate antibody-steroid-conjugates. In some embodiments, the antibody-steroid-conjugate further includes a cyclodextrin moiety.

[0323] In some embodiments, the present invention provides formula (I) 1 The compound shown is:

[0324]

[0325] (I 1 );

[0326] Or its pharmaceutically acceptable salts, solvates, stereoisomers, or derivatives.

[0327] in:

[0328] R 1 and R 2 Each is independently -H, alkyl, alkyl-C(O)-O-, -OH, or halogen; or R 1 and R 2 Together ,

[0329] Where R 4 It is an alkyl, aryl, arylalkyl, or N-containing heterocyclic alkyl group.

[0330] The alkyl, aryl, arylalkyl, and N-containing heterocyclic alkyl groups mentioned above are, in each case, optionally, independently -NR. a R b replace;

[0331] R 5 In each case, it is independently -OH, halogen, alkyl, or arylalkyl;

[0332] R 3 It is -OH, alkyl-C(O)-O-, or –X-aryl-NR a R b X is selected from S, S(O), S(O)2, SO2NR a CONR a C(O), or NR a The alkyl–C(O)–O– and –X–aryl–NR a R b It can be optionally replaced by halogen or prodrug.

[0333] R a and R b In each case, it is independently H, alkyl, or aryl;

[0334] R c It is –H or alkyl; and

[0335] n is an integer from 0 to 19;

[0336] The condition is: when (a) or (b): (a) R 1 Is it –OH, or (b) R 1 and R 2 Together , and R 4 It is C 1-9 alkyl or When, then R 3 Not –OH.

[0337] In some of these embodiments, alkyl–C(O)–O– or –X–aryl–NR a R b Optionally replaced by halogen. In some embodiments, R 3 It is –OH. In some embodiments, R 3 It is an alkyl group –C(O)–O–. In some embodiments, R 3 It is R a R b N-aryloxy group. In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes .

[0338] In some embodiments, R 3 It is –X–aryl–NR a R b .

[0339] In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes .

[0340] In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes .

[0341] In some embodiments, R 3yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes .

[0342] In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes .

[0343] In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes .

[0344] In some embodiments, the present invention provides a compound of formula (I), wherein R 3 A structure having one of the following structural formulas:

[0345] .

[0346] In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In these embodiments, q is an integer from 0 to 5.

[0347] In some embodiments, the present invention provides a compound of formula (I), wherein R 3 A structure having one of the following structural formulas:

[0348] .

[0349] In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In these embodiments, q is an integer from 0 to 5.

[0350] In some embodiments, the present invention provides a compound of formula (I), wherein R 3 A structure having one of the following structural formulas:

[0351] .

[0352] In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes .

[0353] In some embodiments, the present invention provides compounds of formula (I), wherein the compounds have the structure of formula 1000:

[0354] 1000

[0356] Or a pharmaceutically acceptable salt, solvate, stereoisomer, or derivative thereof. In Formula 1000, R 1 and R 2 Each of the following groups is independently selected from: -H, -OH, alkyl, -OC(O)-alkyl, and halogen; or R 1 and R 2 Together , where R 4 It is selected from alkyl, aryl, alkylaryl, arylalkyl, heteroaryl, -alkylene-NR a R b -X-Asaryl-Y-NR a R b -X-heteroaryl-Y-NR a R b The group consisting of N-containing heterocyclic alkyl groups; wherein X is absent, or X is -N-, -CH2-, or -O-; wherein Y is absent, or Y is -CH2-. R 3 It is selected from -OH, -OC(O)-alkyl, -O-aryl, and -NR. a R b ,-alkylene-NR a R b -X-Asaryl-Y-NR a R b -X-heteroaryl-Y-NR a R b The group consisting of N-containing heterocyclic alkyl groups; wherein X is absent, or X is -N-, -CH2-, or -O-; wherein Y is absent, or Y is -CH2-. R 5 In each case, substituents are independently selected from the group consisting of -OH, halogens, and alkyl groups; n is an integer from 0 to 19; and each R 5 Located on any ring atom. R a and R bIn each case, the group consisting of -H and alkyl groups is selected independently; or R a and R b Cyclization forms a cyclohexaalkyl group having 3 to 6 ring atoms, including a heteroatom, which is the N atom attached to it. R a and R b In each case, it is independently and optionally substituted by at least one substituent selected from the group consisting of -OH, -PO4H, NH2, -C(O)OH, and -C(O)CH3.

[0357] In some embodiments, the present invention provides a compound of formula 1000, wherein R 3 It is selected free-alkylene-NR a R b -X-Asaryl-Y-NR a R b -X-heteroaryl-Y-NR a R b The group consisting of N-containing heterocyclic alkyl groups; wherein X is absent, or X is -N-, -CH2-, or -O-; wherein Y is absent, or Y is -CH2-; and R 4 It is selected from alkyl, aryl, alkylaryl, arylalkyl, heteroaryl, -alkylene-NR a R b -X-Asaryl-Y-NR a R b -X-heteroaryl-Y-NR a R b The group consisting of N-containing heterocyclic alkyl groups; wherein X is absent, or X is -N-, -CH2-, or -O-; wherein Y is absent, or Y is -CH2-.

[0358] In some embodiments, the present invention provides a compound of formula 1000, wherein R 3 It is selected from -OH, -OC(O)-alkyl, -O-aryl, and -NR. a R b ,-alkylene-NR a R b -X-Asaryl-Y-NR a R b -X-heteroaryl-Y-NR a R b The group consisting of N-containing heterocyclic alkyl groups; wherein X is absent, or X is -N-, -CH2-, or -O-; wherein Y is absent, or Y is -CH2-; and R 4 It is selected free-alkylene-NR a R b -X-Asaryl-Y-NRa R b -X-heteroaryl-Y-NR a R b The group consisting of N-containing heterocyclic alkyl groups; wherein X is absent, or X is -N-, -CH2-, or -O-; wherein Y is absent, or Y is -CH2-.

[0359] In some embodiments, the present invention provides a compound of formula 1000, R 3 Yes -NR a R b ; and R 4 It is an alkyl group. In some embodiments, R 3 It is –NH2. In some implementations, R 4 It is n-propyl. In some implementations, R 3 It is –NH2, and R 4 It's n-propyl.

[0360] In some embodiments, the compound shown in Formula 1000 has the structure shown in Formula 1010, 1020, 1030, or 1040:

[0361]

[0362] Or its pharmaceutically acceptable salt, solvate, or stereoisomer.

[0363] In some embodiments, the compound shown in Formula 1000 has the structure shown in Formula 1110, 1120, 1130, or 1140:

[0364]

[0365]

[0366] Or its pharmaceutically acceptable salt, solvate, or stereoisomer.

[0367] In certain embodiments according to any of formulas 1000-1140, R 3 It is -OH or -OC(O)-alkyl; and R 4 It is -alkylene-NR a R b -X-alynyl-NR a R b -X-heteroaryl-NR a R b Or a heterocyclic alkyl group containing N; wherein X is absent, or X is -CH2-. In some embodiments, R 4 It is -alkylene-NH2, -C6H5-NH2 or -CH2-C6H5-NH2.

[0368] In certain embodiments according to any of formulas 1000-1140, R 3 It is -O-aryl, -NR a R b ,-alkylene-NR a R b -X-Asaryl-Y-NR a R b -X-heteroaryl-Y-NR a R b or N-containing heterocyclic alkyl groups; wherein X is absent, or X is -N-, -CH2-, or -O-; wherein Y is absent, or Y is -CH2-; and R 4 It is alkyl, aryl, alkylaryl, or arylalkyl. In some embodiments, R 3 It is -O-aryl-NR a R b , or -O-heteroaryl-NR a R b ; wherein the aryl or heteroaryl group is optionally substituted with a halogen, deuterium, hydroxyl, or methoxy group. In some embodiments, R 3 It is -O-phenyl-NR a R b , or -O-heteroaryl-NR a R b ; wherein the phenyl or heteroaryl group is optionally substituted with a halogen or deuterium. In some embodiments according to this paragraph, R 4 It's n-propyl.

[0369] In some embodiments, the present invention provides compounds represented by any of formulas 1000-1140, wherein R 3 Yes -NR a R b ; and R 4 It is an alkyl group. In some embodiments, R 3 It is –NH2. In some implementations, R 4 It is n-propyl. In some implementations, R 3 It is –NH2, and R 4 It's n-propyl.

[0370] In any of equations 1000-1140, R 3 It can be any specific R provided above. 3 In a specific implementation scheme, R 3 It is -NH2, -N(H)CH3, -N(CH3)2, or In a specific implementation scheme, R 3 yes In a specific implementation scheme, R 3 yes In a specific implementation scheme, R 3 yes .

[0371] In any of equations 1000-1140, R 4 It can be any specific R provided above. 4 In a specific implementation scheme, R 4 Selected from -CH2-CH2-NH2, In a specific implementation scheme, R 4 It's n-propyl.

[0372] The present invention also provides compounds having the following structures:

[0373]

[0374]

[0375]

[0376] Or its pharmaceutically acceptable salt, solvate, or stereoisomer.

[0377] Included within the scope of this invention are pharmaceutically acceptable salts, solvates, crystalline forms, amorphous forms, polymorphic forms, regioisomers, stereoisomers, prodrugs such as phosphatase prodrugs, glucose-prodrugs, ester prodrugs, etc., metabolites, and steroid active loads as described in this invention (including formula (I), (I... I ) and (A 1 )-(A 7 The physiological adducts shown in the figure.

[0378] C. Protein steroid conjugates

[0379] This invention provides protein conjugates of the steroidal compounds described herein. Such conjugates include proteins, such as antibodies or antigen-binding fragments thereof, which are, for example, bound by a binding linker described herein to compounds described in Section B above (e.g., formula (A), (A...). 1 ), (A 2 ), (A 3 ), (A 4 ), (A 5 ), (A 6 ), (A 7 ), (I), (I) 1(PIa), (PIb–1), (PIb–2), PIc–1), (PIc–2), (PId–1), (PId–2), (PIe–1), (PIe–2), (PII), (PIIa), (PIIb), (PIII), (PIIIa), (PIIIb), (PIV), (PV), (PVa), (PVb), (PVI), (PVII), (PVIIa), (PVIIb), (PVIIb–1), (PVIIb–2), (PVIII), and (1000)-(1140) compounds) covalently linked.

[0380] The binder linker can be linked to the steroid of the present invention at any suitable portion or location of the steroid, including, for example, via amides, ethers, esters, carbamates, or amines. For example, the binder linker can be of formula (A) 1 R shown 1 R 3 or R 4 Or, a hydroxyl group may be attached to the compound:

[0381]

[0382] (A 1 ).

[0383] In some embodiments, the steroid compound of the present invention is attached to the binder linker by reacting the amino or hydroxyl groups of the steroid with suitable active groups present on the linker. In some embodiments, the binder linker further includes a cyclodextrin moiety. For example, the cyclodextrin moiety may be attached to the chemical backbone structure of the binder linker.

[0384] In some embodiments, the present invention provides compounds having the following structural formula:

[0385] BA-(L-PAY) x

[0386] Wherein BA is a binder as described in this invention; L is an optional linker as described in this invention; PAY is a steroid compound as described in this invention; and x is an integer from 1 to 30. In a particular embodiment, each PAY is selected from formulas (A), (A... 1 ), (A 2 ), (A 3 ), (A 4 ), (A 5 ), (A 6 ), (A 7 ), (I), (I) 1The compounds represented by the general formulas of the group consisting of (PIa), (PIb–1), (PIb–2), PIc–1), (PIc–2), (PId–1), (PId–2), (PIe–1), (PIe–2), (PII), (PIIa), (PIIb), (PIII), (PIIIa), (PIIIb), (PIV), (PV), (PVa), (PVb), (PVI), (PVII), (PVIIa), (PVIIb), (PVIIb–1), (PVIIb–2), (PVIII), and (1000)-(1140) have atoms, such as hydrogen atoms, removed from the compounds to obtain the groups. Examples of such compounds will be described in detail below.

[0387] In some embodiments, the present invention provides compounds having the structure shown in formula (III):

[0388]

[0389] (III);

[0390] Either (a) or (b):

[0391] (a) R 3 Is it –BL–, –BL–X–, or ;

[0392] R 1 and R 2 Each is independently –H, alkyl, alkyl-C(O)-O-, –OH, or halogen; or R 1 and R 2 Together , where R 4 It is an alkyl, aryl, arylalkyl, or N-containing heterocyclic alkyl; wherein the alkyl, aryl, arylalkyl, and N-containing heterocyclic alkyl are optionally –NR a R b Replace; or

[0393] (b) R 3 It is –OH, alkyl –C(O)–O–, heteroalkyl, –NR a R b Or aryloxy group, wherein the alkyl –C(O)–O–, heteroalkyl, or aryloxy group is optionally –NR a R b -NR a R b –Aryloxy or halogen substitution, and R 1 and R 2 Together , where R 4 It is –BL– , Or –BL–Y, where Y is a divalent heterocycle containing N;

[0394] –BL– is a divalent binder linker;

[0395] R 5 In each case, it is independently –OH, halogen, alkyl, or arylalkyl;

[0396] R a and R b In each case, it is independently –H or alkyl;

[0397] R P In each case, it is halogen independently;

[0398] BA is a binder connected to –BL–;

[0399] X is independently NR in each case. a Or O;

[0400] It is aryl or heteroaryl;

[0401] t is an integer from 0 to 2;

[0402] x is an integer from 1 to 30; and

[0403] n is an integer from 0 to 19.

[0404] In some embodiments, the subscript x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In some embodiments, the subscript x is 0. In some embodiments, the subscript x is 1. In some embodiments, the subscript x is 2. In some embodiments, the subscript x is 3. In some embodiments, the subscript x is 4. In some embodiments, the subscript x is 5. In some embodiments, the subscript x is 6. In some embodiments, the subscript x is 7. In some embodiments, the subscript x is 8. In some embodiments, the subscript x is 9. In some embodiments, the subscript x is 10. In some embodiments, the subscript x is 11. In some embodiments, the subscript x is 12. In some embodiments, the subscript x is 13. In some embodiments, the subscript x is 14. In some embodiments, the subscript x is 15. In some embodiments, the subscript x is 16. In some embodiments, the subscript x is 17. In some embodiments, the subscript x is 18. In some embodiments, the subscript x is 19. In some embodiments, the subscript x is 20. In some embodiments, the subscript x is 21. In some embodiments, the subscript x is 22. In some embodiments, the subscript x is 23. In some embodiments, the subscript x is 24. In some embodiments, the subscript x is 25. In some embodiments, the subscript x is 26. In some embodiments, the subscript x is 27. In some embodiments, the subscript x is 28. In some embodiments, the subscript x is 29. In some embodiments, the subscript x is 30.

[0405] In some embodiments of formula (III), R 1 and R 2 Each is independently –H, alkyl, or –OH. In some embodiments of formula (III), R 1 or R 2 One of them is –H, alkyl, or –OH. In some embodiments of formula (III), R 1 and R 2 All are -H, alkyl, or -OH.

[0406] In some embodiments of formula (III), R 1 and R 2 Together In some embodiments, R 4 Yes – RL. In some embodiments, R 4 It is RL–NR a –Aryl. In some other embodiments, R 4 It is an alkyl group. In some embodiments, R 4 It is an arylalkyl group. In some embodiments, R 4 It is aryl. In other embodiments, R 4It is an N-containing heterocyclic alkyl group. In some of these examples, the alkyl, aryl, arylalkyl, or N-containing heterocyclic alkyl group is optionally substituted.

[0407] In some embodiments of formula (III), R 5 It is –H or halogen. In some embodiments of formula (II), R 5 It is –H or fluorine. In some embodiments of formula (III), R 5 One of them is –H or a halogen. In some embodiments of formula (III), R 5 It is –H or halogen, and n is 2. In some embodiments of formula (III), R 5 It is –F, and n is 1. In some embodiments of equation (II), R 5 It is –F, and n is 2.

[0408] In some embodiments of formula (III), R 3 It is BL. In some embodiments of formula (III), R 3 It is RL–NR a –Aryloxy–. In some other embodiments of formula (III), R 3 It is –OH. In some other embodiments of formula (III), R 3 It is an alkyl–C(O)–O–. In some other embodiments of formula (III), R 3 It is a heteroalkyl group. In some other embodiments of formula (III), R 3 It is –N–R a R b In some other embodiments of equation (III), R 3 It is an aryl group. In some other embodiments of formula (III), R 3 It is an aryloxy group. In some other embodiments of formula (III), the alkyl–C(O)–O–, heteroalkyl, or aryloxy group is optionally replaced by –NR. a R b Or halogen substitution.

[0409] In some embodiments of formula (II), R 3 It is –OH. In some embodiments of formula (III), R 3 It is an alkyl group –C(O)–O–. In some embodiments, R 3 yes In some embodiments of formula (III), R 3 It is a heteroalkyl group. In some embodiments, R 3 yes In some embodiments of formula (III), R 3 yes or In some embodiments of formula (III), R 3 Yes – NR a R b In some embodiments, R 3 Yes -NR a R b –Oxyaryl. In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 It is an aryloxy group. In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes .

[0410] In equation (III), the subscript n is an integer from 0 to 19. In some embodiments, n is 0. In some other embodiments, n is 1. In some embodiments, n is 2. In some other embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some other embodiments, n is 6. In some embodiments, n is 7. In some other embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some other embodiments, n is 11. In some embodiments, n is 12. In some other embodiments, n is 13. In some embodiments, n is 14. In some embodiments, n is 15. In some other embodiments, n is 16. In some embodiments, n is 17. In some other embodiments, n is 18. In some embodiments, n is 19.

[0411] In some embodiments, the present invention provides compounds having the structure shown in formula (IIIa):

[0412]

[0413] (IIIa);

[0414] in:

[0415] BA is a binder;

[0416] R 5 In each case, it is independently –OH, halogen, or alkyl;

[0417] R 3 Selected from –OH, alkyl –C(O)–O–, heteroalkyl, –NR a R b -NR a R b –aryloxy, or aryloxy group, wherein the alkyl –C(O)–O–, heteroalkyl, or aryloxy group is optionally –NR a R b Or halogen substitution;

[0418] BL is a binder linker;

[0419] R a and R b In each case, the components are independently selected from H, alkyl, and alkyl–C(O);

[0420] n is an integer from 0 to 19; and

[0421] x is an integer from 1 to 30.

[0422] In some embodiments, the present invention provides compounds having the structure shown in formula (IIIa2):

[0423]

[0424] (IIIa2);

[0425] in:

[0426] BA is a binder;

[0427] R 5 In each case, it is independently –OH, halogen, or alkyl;

[0428] R 3 Selected from –OH, alkyl –C(O)–O–, heteroalkyl, –NR a R b -NR a R b–O-aryl, or aryloxy, wherein the alkyl –C(O)–O–, heteroalkyl, or aryloxy group is optionally –NR a R b Or halogen substitution.

[0429] BL is a binder linker;

[0430] R a and R b In each case, the components are independently selected from H, alkyl, and alkyl–C(O);

[0431] n is an integer from 0 to 19; and

[0432] x is an integer from 0 to 30.

[0433] In some embodiments of formula (IIIa2), R 3 It is –OH. In some embodiments of formula (IIIa2), R 3 It is an alkyl group –C(O)–O–. In some embodiments, R 3 yes In some embodiments of formula (IIIa2), R 3 It is a heteroalkyl group. In some embodiments, R 3 yes In some embodiments of formula (IIIa2), R 3 Yes – NR a R b In some embodiments, R 3 yes In some embodiments, R 3 It is an aryloxy group. In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes In some embodiments, R 3 yes .

[0434] In some embodiments, the compound represented by formula (IIIa2) has the following structure:

[0435]

[0436] in:

[0437] BA is a binder;

[0438] R 3 It is –OH or alkyl –C(O)–O–;

[0439] R 5a and R 5b Each can be either –F or H independently;

[0440] BL is a binder linker; and

[0441] x is an integer from 1 to 30.

[0442] In some embodiments, the present invention provides compounds having the structure shown in formula (IIIb):

[0443]

[0444] (IIIb);

[0445] in:

[0446] BA is a binder;

[0447] R 5 In each case, it is independently –OH, halogen, or alkyl;

[0448] R 4 Selected from alkyl, aryl, arylalkyl, or N-containing heterocyclic alkyl groups, wherein the alkyl, aryl, arylalkyl, or N-containing heterocyclic alkyl group is optionally –NR a R b replace;

[0449] BL is a binder linker;

[0450] R a and R b In each case, the components are independently selected from H, alkyl, and alkyl-C(O);

[0451] n is an integer from 0 to 19; and

[0452] x is an integer from 0 to 30.

[0453] In some embodiments of formula (IIIb), R 5 It is –H or halogen. In some embodiments of formula (IIIb), R 5 It is fluorine. In some embodiments of formula (IIIb), n is at least 2, R 5 Two of them are halogens. In some embodiments of formula (IIIb), R 5 It is –F, and n is 1. In some embodiments of equation (IIIb), R 5 Yes –F.

[0454] In some embodiments of formula (IIIb), R 4 It is an alkyl group. In some embodiments of formula (IIb), R 4 It is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, pentyl moiety, hexyl moiety, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments of formula (IIIb), R 4 It's n-propyl.

[0455] In some embodiments, the compound shown in formula (IIIb) has the following structure:

[0456]

[0457] in:

[0458] BA is a binder;

[0459] R 4 It is an alkyl group;

[0460] R 5a and R 5b Each can be either –F or H independently;

[0461] BL is a binder linker; and

[0462] x is an integer from 1 to 30.

[0463] In some embodiments, the present invention provides compounds having the structure shown in formula (IIIc):

[0464]

[0465] (IIIc);

[0466] in:

[0467] BA is a binder;

[0468] R 1 and R 2 Each can be independently –H, alkyl, alkyl-C(O)-O-, –OH, or halogen;

[0469] R 5 In each case, it is independently selected from –OH, halogen, or alkyl;

[0470] BL is a binder linker;

[0471] n is an integer from 0 to 19; and

[0472] x is an integer from 1 to 30.

[0473] In some embodiments of formula (IIIc), R5 It is a halogen. In some embodiments of formula (IIIc), R 5 It is fluorine. In some embodiments of formula (IIIc), R 5 One of them is a halogen. In some embodiments of formula (IIIc), R 5 Two of them are halogens. In some embodiments of formula (IIIc), R 5 It is –F, and n is 2.

[0474] In some embodiments of formula (IIIc), R 1 It is CH3.

[0475] In other embodiments of formula (IIIc), R 1 It is OH.

[0476] In some other embodiments of formula (IIIc), R 1 It is H.

[0477] In some embodiments of formula (IIIc), R 2 It is CH3.

[0478] In other embodiments of formula (IIIc), R 2 It is OH.

[0479] In some other embodiments of formula (IIIc), R 2 It is H.

[0480] In some embodiments of formula (IIIc), R 1 It is CH3, and R 2 It is CH3.

[0481] In other embodiments of formula (IIIc), R 1 It is CH3, and R 2 It is OH.

[0482] In some embodiments of formula (IIIc), R 1 It is CH3, and R 2 It is H.

[0483] In some other embodiments of formula (IIIc), R 1 It is OH, and R 2 It is CH3.

[0484] In other embodiments of formula (IIIc), R 1 It is OH, and R 2 It is OH.

[0485] In some embodiments of formula (IIIc), R 1 It's H, and R 2It is H.

[0486] In some other embodiments of formula (IIIc), R 1 It's H, and R 2 It is OH.

[0487] In other embodiments of formula (IIIc), R 1 It's H, and R 2 It is H.

[0488] In some embodiments, the compound shown in formula (IIIc) has the following structure:

[0489]

[0490] (IIIc)

[0491] in:

[0492] BA is a binder;

[0493] R 2 It is methyl;

[0494] R 5a and R 5b Each can be either –F or H independently;

[0495] BL is a binder linker; and

[0496] x is an integer from 0 to 30.

[0497] In some embodiments, the compound shown in formula (IIIc) has the following structure:

[0498] ;

[0499] BA is a binder;

[0500] RG is an active group residue;

[0501] CD is cyclodextrin;

[0502] SP 1 It is a spacer group;

[0503] AA 4 They are amino acid residues;

[0504] AA 5 It is a dipeptide residue;

[0505] PEG stands for polyethylene glycol;

[0506] m is an integer from 0 to 4;

[0507] x is an integer from 0 to 30;

[0508] R 4 It is an alkyl, aryl, arylalkyl, or N-containing heterocyclic alkyl; wherein the alkyl, aryl, arylalkyl, and N-containing heterocyclic alkyl are optionally prefixed with -NR. a R b replace;

[0509] R a and R b In each case, it is independently -H or alkyl;

[0510] BA is a binder connected to –BL–;

[0511] SP 1 and SP 2 In each case, either independently absent, or independently a spacer group residue, and wherein SP... 1 Includes trivalent linkers; AA 4 It is a trivalent linker containing amino acid residues; AA 5 It is a dipeptide residue; PEG is a polyethylene glycol residue; wherein... The symbol represents the atom by which the chemical group shown in the general formula is connected to the adjacent group, CD is independently absent or independently a cyclodextrin residue in each case, wherein at least one CD is present, and the subscript m is an integer from 0 to 5; in these embodiments, the subscript m is 0, 1, 2, 3, 4, or 5. In some embodiments, the subscript m is 0. In some embodiments, the subscript m is 1. In some embodiments, the subscript m is 2. In some embodiments, the subscript m is 3. In some embodiments, the subscript m is 4. In some embodiments, the subscript m is 5. In some embodiments, AA 4 Or AA 5 Each of these, in each case, independently comprises an amino acid selected from alanine, valine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or citrulline, their derivatives, or combinations thereof. In some embodiments, AA 4 It is an amino acid selected from alanine, valine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or citrulline, their derivatives, or combinations thereof. In some embodiments, AA 4 It is lysine. In some implementations, AA 4 It is lysine or a derivative of lysine. In some embodiments, AA 5 It is valine-citrulline. In some implementations, AA 5It is citrulline-valine. In some implementations, AA 5 It is valine-alanine. In some implementations, AA 5 It is alanine-valine. In some implementations, AA 5 It is valine-glycine. In some implementations, AA 5 It is glycine-valine. In some implementations, AA 5 It is glutamic acid-valine-citrulline. In some implementation schemes, AA 5 It is glutamine-valine-citrulline. In some implementation schemes, AA 5 It is lysine-valine-alanine. In some implementation schemes, AA 5 It is lysine-valine-citrulline. In some implementation schemes, AA 5 It is glutamic acid-valine-citrulline. In some embodiments, SP 1 In each case, C is chosen independently. 1-6 Alkylene, -NH-, -C(O)-, (-CH2-CH2-O) e -NH-CH2-CH2-(-O-CH2-CH2) e -C(O)-, -C(O)-(CH2) u -C(O)-, -C(O)-NH-(CH2) v - A group consisting of elements and their combinations, where subscript e is an integer from 0 to 4, subscript u is an integer from 1 to 8, and subscript v is an integer from 1 to 8. In some embodiments, SP 2 In each case, C is chosen independently. 1-6 Alkylene, -NH-, -C(O)-, (-CH2-CH2-O) e -NH-CH2-CH2-(-O-CH2-CH2) e -C(O)-, -C(O)-(CH2) u -C(O)-, -C(O)-NH-(CH2) v - A group consisting of elements and their combinations, where subscript e is an integer from 0 to 4, subscript u is an integer from 1 to 8, and subscript v is an integer from 1 to 8.

[0512] The present invention also provides formula (B) 2 The compound shown is:

[0513]

[0514] (B 2 )

[0515] Where n is an integer from 0 to 4, R 3 Is it –OH or R?Z -C(O)-O–; where R Z n is an alkyl group, BL is a binder linker, BA is a binder, and x is an integer from 1 to 30. In some embodiments, n is 0 or 1, and x is an integer from 1 to 6. In some embodiments, x is 4.

[0516] The present invention also provides formula (B) 3 The compound shown is:

[0517]

[0518] (B 3 )

[0519] Where n is an integer from 1 to 4, R 3 Is it –OH or R? Z -C(O)-O–; where R Z n is an alkyl group, BL is a binder linker, BA is a binder, and x is an integer from 1 to 30. In some embodiments, n is 2, and x is an integer from 1 to 6. In some embodiments, x is 4.

[0520] The present invention also provides formula (B) 4 The compound shown is:

[0521]

[0522] (B 4 )

[0523] Where R 4 It is an alkyl group, wherein R a It is a hydrogen atom or an alkyl group; BL is a binder linker, and BA is a binder. In some embodiments, R 4 It is C 1-4 Alkyl group. In some embodiments, R 4 It is propyl. In some implementations, R 3 It is –NH2, –NHCH3, or –N(CH3)2. In some implementations, x is an integer from 1 to 6. In some implementations, x is 4.

[0524] The present invention also provides formula (B) 5 The compound shown is:

[0525]

[0526] (B 5 )

[0527] Where R 4 It is an alkyl group, R P1 It is a halogen or hydrogen atom, and X is NR. aOr O, where R a It is a hydrogen atom or an alkyl group, BL is a binder linker, BA is a binder, and x is an integer from 1 to 30. In some embodiments, R 4 It is C 1-4 Alkyl group, X is NH, and x is an integer from 1 to 6. In some embodiments, x is 4.

[0528] The present invention also provides formula (B) 6A The compound shown is:

[0529]

[0530] (B 6A )

[0531] Where X is O or NR a , It is aryl or heteroaryl, R P It is a halogen, t is an integer from 0 to 2, R a It is a hydrogen atom or alkyl group, BL is a binder linker, BA is a binder, and x is an integer from 1 to 30, and R 4 It is an alkyl group. In some embodiments, X is O, and R is... 4 It is an alkyl group, and x is an integer from 1 to 6. In some embodiments, x is 4.

[0532] The present invention also relates to formula (B) 6B The compound shown is:

[0533]

[0534] (B 6B )

[0535] Where R a It is a hydrogen atom or an alkyl group, BL is a binder linker, BA is a binder, and x is an integer from 1 to 30. In some embodiments, x is an integer from 1 to 6. In some embodiments, x is 4.

[0536] As used in this invention, the phrase "binding linker" or "BL" refers to any divalent group or group portion of a binding agent (e.g., an antibody or its antigen-binding fragment) that links, conjugates, or binds to the payload compound (e.g., a steroid) described in this invention. Generally, suitable binding linkers for antibody conjugates described in this invention are those that are stable enough to utilize the cyclic half-life of the antibody and simultaneously capable of releasing their payload upon antigen-mediated internalization of the conjugate. Linkers can be cleavable or non-cleavable. Cleavable linkers are those that are cleaved by intracellular metabolism after internalization, such as by hydrolysis, reduction, or enzymatic reactions. Non-cleavable linkers are those that release the attached payload through lysosomal degradation of the antibody after internalization. Suitable linkers include, but are not limited to, acid-labile linkers, hydrolyzably unstable linkers, enzymatically cleavable linkers, reductively unstable linkers, self-sacrificing linkers, and non-cleavable linkers. Suitable linkers also include, but are not limited to, glucuronic acid derivatives, succinimide-thioether derivatives, polyethylene glycol (PEG) units, carbamate derivatives, hydrazones, ε-hexanoyl units, and disulfide units (e.g., –S–S–, –SSC(R)). 1 (R) 2 )–, where R 1 and R 2 These can be categorized independently as hydrogen or hydrocarbon groups, p-aminobenzyl (PAB) units, phosphate ester units such as mono-, di-, or tri-phosphate ester units, and peptide units such as peptide units containing 2, 3, 4, 5, 6, 7, 8, or more amino acid units, including but not limited to valine-citrulline units, valine-alanine units, valine-arginine units, valine-lysine units, -lysine-valine-citrulline units, and -lysine-valine-alanine units. In some embodiments, the binding linker group of the conjugate described in this invention is derived from the reaction of the linker-loaded "active linker" group of this invention with the active portion of the antibody. The active linker group (RL) refers to a monovalent group containing both an active group and a linker group, such as... As shown, RG is the active group, L is the linking group, and the wavy line represents the bond connected to the payload. The linking group is any divalent group portion that bridges the active group to the payload. The linking group can also be any trivalent group portion that bridges the active group, the payload, and the cyclodextrin portion. In some embodiments, the linking group is trivalent and includes a cyclodextrin portion connected to a trivalent group (e.g., a lysine residue) in the linking group. The active linker (RL), together with the payload to which they are connected, constitutes an intermediate (“linker-payload”) that can be used as a synthetic precursor for preparing the antibody-steroid conjugate of the present invention. The active linker contains an active group (RG), which is a functional group or group portion that reacts with the active portion of an antibody, a modified antibody, or an antigen-binding fragment thereof. The group portion obtained by reacting the active group (RG) with an antibody, a modified antibody, or an antigen-binding fragment thereof, together with the linking group (L), constitutes the “binding linker” (BL) portion of the conjugate of the present invention. Therefore, in some embodiments, the BL has the following structure:

[0537]

[0538] in It is the bond connected to the binder, RG N It is a group portion obtained by reacting the active group of the linker-effectively loaded with the active part of the binder, where L is the linker group, and... It is the key that connects to the payload.

[0539] In some implementations, RG N A reaction derived from RG with cysteine ​​or lysine residues of an antibody or its antigen-binding fragment. In some embodiments, RG N Derived from click chemistry. In some embodiments of the click chemistry, RG N Derived from the 1,3-cycloaddition reaction between alkynes and azides. This type of RG... N Non-limiting examples include those derived from strained alkynes, such as those suitable for strain-promoted alkyne-azide cycloaddition (SPAAC), cycloalkynes such as cyclooctynes, benzocyclocyclized alkynes, and alkynes capable of 1,3-cycloaddition with azides in the absence of a copper catalyst. Suitable RG N This also includes, but is not limited to, those derived from DIBAC, DIBO, BARAC, DIFO, and substituted alkynes such as fluorinated alkynes, azacyclic alkynes, BCN, and their derivatives. RG containing such alkynes... NThe conjugate of the group can be derived from an antibody functionalized with an azide group. Such functionalized antibodies include those functionalized with an azide-polyethylene glycol group. In some embodiments, such functionalized antibodies are obtained by reacting an antibody containing at least one glutamine residue with a compound of the formula H2N–LL–N3 (where LL is a divalent polyethylene glycol group) in the presence of an enzymatic transglutaminase (e.g., microbial transglutaminase). Suitable glutamine residues for the antibody include Q295, or those derived through insertion or mutation (e.g., the N297Q mutation).

[0540] In some embodiments, the BA of the conjugate described in this invention is an antibody or its antigen-binding fragment. In some embodiments, the conjugate described in this invention is derived from an azide-functionalized antibody. In some embodiments, the BA of the conjugate described in this invention is:

[0541]

[0542] Where Ab is the antibody or its antigen-binding fragment, n is an integer from 1 to 10, w is the number of linker payloads, and It is a bond connected to a single linker (BL), for example, a bond connected to a group portion derived from a 1,3-cycloaddition reaction between an alkyne and an azide. In some embodiments, w is 3. In some embodiments, w is 2 or 4, that is, the coupling comprises 2 or 4 linker loading portions.

[0543] In some implementation schemes, BL is the formula ((BL) A The divalent group portion shown in the diagram;

[0544] –RG N –(SP 1 ) q –(A) z –(NR a ) s –(B) t –(CH2) u –(O) v –( SP 2 ) w –

[0545] (BL A );

[0546] Among them RG N It has the definition described in this invention;

[0547] A is an amino acid or peptide;

[0548] R a It is H or alkyl;

[0549] B is an aryl, heteroaryl, or heterocyclic alkyl group, wherein the aryl, heteroaryl, or heterocyclic alkyl group is optionally surrounded by an alkyl group, –OH, or –NR. a R b replace;

[0550] SP 1 and SP 2 Each is an independent spacer group; and q, z, s, t, u, v, and w are each independently 0 or 1 in each case.

[0551] In some other implementations, BL is a formula (BL B The trivalent group portion shown in the diagram;

[0552] –RG N –(SP 1 ) q –(A) z –(NR a ) s –(B) t –(CH2) u –(O) v –( SP 2 ) w –

[0553] (BL B );

[0554] Among them RG N It has the definition described in this invention;

[0555] A is a tripeptide, wherein at least one amino acid in the tripeptide is directly or indirectly linked to the cyclodextrin moiety;

[0556] R a It is H or alkyl;

[0557] B is an aryl, heteroaryl, or heterocyclic alkyl group, wherein the aryl, heteroaryl, or heterocyclic alkyl group is optionally surrounded by an alkyl group, –OH, or –NR. a R b replace;

[0558] SP 1 and SP 2 Each is an independent spacer group; and q, z, s, t, u, v, and w are each independently 0 or 1 in each case.

[0559] In some embodiments, the cyclodextrin (CD) is directly linked to an amino acid residue, such as a lysine amino acid residue. This means that the CD is located one bond position away from the lysine amino acid covalent linker. In some of these embodiments, the covalent linker is also directly linked to the payload portion. This means that the covalent linker is located one bond position away from the payload (e.g., but not limited to the steroid payload described herein). In some of these embodiments, the covalent linker is also directly linked to the CD portion. This means that the covalent linker is located one bond position away from the CD (e.g., the CD described herein). In some of these embodiments, the covalent linker is a lysine amino acid or a derivative thereof.

[0560] In some embodiments, the CD is indirectly linked to a covalent linker in a linking group (e.g., BL). This means that the CD is located away from the covalent linker by more than one bond position. It also means that the CD is linked to the covalent linker via another group portion. For example, the CD may be linked to a maleimide group, which in turn is linked to a polyethylene glycol group, which is then linked to the covalent linker. In some of these embodiments, the covalent linker is also indirectly linked to the effective load portion. This means that the covalent linker is located away from the effective load (e.g., but not limited to, the steroid effective load of the present invention) by more than one bond position. It also means that the covalent linker is linked to the effective load via another group portion. For example, the covalent linker may be linked to a dipeptide, such as, but not limited to, Val-Ala or Val-Cit, which may be linked to p-aminobenzoyl, which may be linked to the effective load. In some of these embodiments, the covalent linker is also indirectly linked to a cyclodextrin portion. This means that the covalent linker is located away from the cyclodextrin (e.g., the cyclodextrin described in this invention) by more than one bond position. It also means that the covalent linker is connected to the cyclodextrin via another functional group. For example, the covalent linker may be connected to a polyethylene glycol group, which may be connected to an active group, which may be connected to the cyclodextrin. In some of these embodiments, the covalent linker is a lysine amino acid or a derivative thereof.

[0561] In some implementations, BL is –RG N –(SP 1 ) q –(A) z –. In some implementations, BL is –RG N –(SP 1 ) q –(A)2–. In some implementations, BL is the formula (BL A1 The group portion shown is:

[0562]

[0563] (BL A1 )

[0564] Where R AA1 and R AA2 Each is an independent amino acid side chain. In formula RL A1 In some embodiments, SP 1 It is a divalent polyethylene glycol group, and RG N It is a 1,3-cycloaddition adduct resulting from the reaction between alkynes and azides.

[0565] In some implementations, BL is –RG N –(SP 1 ) q –(A) z –. In some implementations, BL is –RG N –(SP 1 ) q –(A)2–. In some implementations, BL is the formula (BL B1 The group portion shown is:

[0566]

[0567] (BL B1 ).

[0568] Where R AA1 and R AA2 Each is an independent amino acid side chain. R AA3 These are amino acid side chains directly or indirectly linked to the cyclodextrin moiety. (In formula RL) B1 In some embodiments, SP 1 It is a divalent polyethylene glycol group, and RG N It is a 1,3-cycloaddition adduct resulting from the reaction between alkynes and azides.

[0569] In some implementations, BL has the following structure:

[0570] –RG N –(SP 1 )q–Z 1 –Z 2 –Z 3 0–1 –

[0571] in:

[0572] RG N and SP 1 All have the definitions described in this invention;

[0573] q is 0 or 1;

[0574] Z 1 It is polyethylene glycol or hexanoyl group;

[0575] Z 2 It is a dipeptide or tripeptide; and

[0576] Z 3 It is a PAB group.

[0577] In some implementation schemes, RG N Derived from click chemically active groups, and Z 1 It is a polyethylene glycol group. In some embodiments, RG N -(SP 1 )qZ 1 -yes:

[0578] , or mixtures thereof; or In some embodiments, the dipeptide is valine-citrulline or valine-alanine.

[0579] In some embodiments, the BL is linked to the payload via a tertiary amine. For example, if the steroid is a compound such that: Then the RL can be connected to the tertiary amine as follows:

[0580] .

[0581] In some embodiments, the present invention provides the following compounds:

[0582] ,

[0583] in:

[0584] BL is a binder linker having the above definition;

[0585] R a and R b In each case, it is independently –H or alkyl.

[0586] In some embodiments, the RG of the present invention N Derived from click-chemically active groups. In some embodiments, RG N yes:

[0587] or mixtures thereof;

[0588] ;or

[0589] or mixtures thereof; wherein It is a bond that connects to the binder.

[0590] In some other embodiments, the RG of the present invention N Groups selected from those that react with cysteine ​​or lysine residues on the antibody or its antigen-binding fragment. In some embodiments, RG N yes ;in It is a bond linked to a cysteine ​​residue in a binding agent (such as an antibody). In some embodiments, RG N yes .

[0591] In some implementation schemes, SP 1 Selected from:

[0592] .

[0593] In some embodiments, SP 1 yes In some other embodiments, SP 1 yes In other embodiments, SP 1 yes In other embodiments, SP 1 yes In some other embodiments, SP 1 yes In any of the above embodiments, the subscripts a, b, and c are independently integers from 1 to 20 in each case.

[0594] In some implementation schemes, R AA3 Selected from Where CD is the cyclodextrin moiety. In some implementations, R AA3 Selected from .

[0595] In any of the compounds represented by formula (II), (IIa), (IIb), or (IIc), SP 1 Selected from:

[0596] .

[0597] In some embodiments, SP 1 yes In some embodiments, SP 1 yes In some embodiments, SP 1 yes In some embodiments, SP 1 yes In some embodiments, SP 1 yes .

[0598] In some embodiments, SP 1 yes In some embodiments, SP 1 yes In some embodiments, SP 1 yes In some embodiments, SP 1 yes In some embodiments, SP 1 yes In some embodiments, SP 1 yes .

[0599] In some implementation schemes, BL–SP 1 yes:

[0600]

[0601] or mixtures thereof;

[0602]

[0603] or mixtures thereof;

[0604]

[0605] or mixtures thereof;

[0606] or In some of these embodiments, the subscripts b, c, and d are, in each case, independent integers from 1 to 20.

[0607] In any of the compounds shown in formula (II), (IIa), (IIb), or (IIc), BL–SP 1 Selected from:

[0608] .

[0609] In some implementations, A is a peptide selected from valine-citrulline, citrulline-valine, lysine-phenylalanine, phenylalanine-lysine, valine-asparagine, asparagine-valine, threonine-asparagine, asparagine-threonine, serine-asparagine, asparagine-serine, phenylalanine-asparagine, asparagine-phenylalanine, leucine-asparagine, asparagine-leucine, isoleucine-asparagine, asparagine-isoleucine, glycine-asparagine, asparagine-glycine, glutamic acid-asparagine, asparagine-glutamic acid, citrulline-asparagine, asparagine-citrulline, alanine-asparagine, or asparagine-alanine.

[0610] In some embodiments, A is valine-citrulline, or citrulline-valine.

[0611] In some embodiments, A is valine-alanine, or alanine-valine.

[0612] In some embodiments, A is lysine-valine-alanine, or alanine-valine-lysine.

[0613] In some embodiments, A is lysine-valine-citrulline, or citrulline-valine-lysine.

[0614] In some embodiments, A is valine.

[0615] In some embodiments, A is alanine.

[0616] In some embodiments, A is citrulline.

[0617] In some embodiments, A is In some of these embodiments, R AA1 It is an amino acid side chain, and R in it AA2 It is an amino acid side chain.

[0618] In some embodiments, A is In some of these embodiments, R AA1 It is an amino acid side chain, R AA2 It is an amino acid side chain, and R AA3 It is an amino acid side chain that is directly or indirectly linked to the cyclodextrin moiety.

[0619] In some embodiments, A is .

[0620] In some embodiments, A is .

[0621] In some embodiments, A is ,in This indicates a bond that is directly or indirectly connected to the cyclodextrin moiety.

[0622] In some embodiments, including any of the foregoing embodiments, the CD is independently selected from:

[0623]

[0624] .

[0625] In some embodiments, the CD is .

[0626] In some embodiments, the CD is .

[0627] In some embodiments, the CD is .

[0628] In some embodiments, the CD is .

[0629] In some embodiments, the CD is .

[0630] In some embodiments, the CD is .

[0631] In some embodiments, A is .

[0632] In some embodiments, R a It is H.

[0633] In some embodiments, R a It is an alkyl group.

[0634] In some embodiments, R a It is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, or pentyl.

[0635] In some implementations, B is aryl.

[0636] In some embodiments, B is phenyl.

[0637] In some embodiments of the compounds shown in formula (II), (IIa), (IIb), or (IIc), B is phenyl or pyridyl.

[0638] In some embodiments of the present invention, B is:

[0639] .

[0640] In these embodiments, R 10 It includes alkyl, alkenyl, alkynyl, alkoxy, aryl, alkylaryl, arylalkyl, halogen, haloalkyl, haloalkoxy, heteroaryl, heterocyclic alkyl, hydroxyl, cyano, nitro. Or azide group. In these embodiments, the subscripts p and m are independently selected from integers from 0 to 4 in each case.

[0641] In some embodiments of the present invention, B is: .

[0642] In these embodiments, p is 0, 1, 2, 3, or 4. In some of these embodiments, R 1 In each case, it is independently alkyl, alkoxy, haloalkyl, or halogen. In some embodiments, R 1It is an alkyl group. In some embodiments, R 1 It is an alkoxy group. In some embodiments, R 1 It is a haloalkyl group. In some embodiments, R 1 It is halogen.

[0643] In formula (BL) A In some implementations of ), the –(NR) a ) s –(B) t –(CH2) u –(O) v –( SP 2 ) w yes:

[0644] .

[0645] This invention provides antibody-steroid conjugates having the following general formula:

[0646]

[0647]

[0648]

[0649]

[0650]

[0651] Or its pharmaceutically acceptable salts or solvates;

[0652] Where BA is a binding agent, and x is an integer from 1 to 30. In a particular embodiment, BA is an antibody. In some embodiments, x is an integer from 1 to 4. In some embodiments, x is 4. In some embodiments, x is 2.

[0653] This invention provides an antibody-steroid conjugate of Formula 1200:

[0654] 1200

[0656] Or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: BA is a binding agent; each L is an optional linker; BA or L and R 3 or R 4 Covalent connection; and x is an integer from 1 to 30. Those skilled in the art will recognize that, when L exists, L is covalent to R. 3 or R 4 Connection; when L does not exist, BA and R 3 or R 4Connection. The group R will be described in detail below. 3 or R 4 In a particular implementation, BA is an antibody. In some implementations, x is an integer from 1 to 4. In some implementations, x is 4. In some implementations, x is 2.

[0657] In some implementations of formula 1200, R 1 and R 2 Each of the following groups is independently selected from: -H, -OH, alkyl, -OC(O)-alkyl, and halogen; or R 1 and R 2 Together In some implementations, R 3 It is selected free-alkylene-NR a R b -X-Asaryl-Y-NR a R b -X-heteroaryl-Y-NR a R b The group consisting of N-containing heterocyclic alkyl groups; wherein X is absent, or X is -N-, -CH2-, or -O-; wherein Y is absent, or Y is -CH2-; and R 4 It is selected from alkyl, aryl, alkylaryl, arylalkyl, heteroaryl, -alkylene-NR a R b -X-Asaryl-Y-NR a R b -X-heteroaryl-Y-NR a R b The group consisting of N-containing heterocyclic alkyl groups; wherein X is absent, or X is -N-, -CH2-, or -O-; wherein Y is absent, or Y is -CH2-.

[0658] In some embodiments of formula 1200, R 3 It is selected from -OH, -OC(O)-alkyl, -O-aryl, and -NR. a R b ,-alkylene-NR a R b -X-Asaryl-Y-NR a R b -X-heteroaryl-Y-NR a R b The group consisting of N- and N-containing heterocyclic alkyl groups; wherein X is absent, or X is -N-, -CH2-, or -O-; wherein Y is absent, or Y is -CH2-; R 4 It is selected free-alkylene-NR a R b -X-Asaryl-Y-NRa R b -X-heteroaryl-Y-NR a R b The group consisting of N-containing heterocyclic alkyl groups; wherein X is absent, or X is -N-, -CH2-, or -O-; wherein Y is absent, or Y is -CH2-.

[0659] In some embodiments of formula 1200, R 3 Yes -NR a R b ; and R 4 It is an alkyl group.

[0660] In each embodiment of Formula 1200, BA or L is related to R 3 or R 4 Functional group connections in R. For example, if R 3 or R 4 If an amino group is included, then BA or L can be attached to the amino group, replacing a hydrogen atom. In each embodiment, R 5 In each case, substituents are independently selected from the group consisting of –OH, halogens, and alkyl groups; n is an integer from 0 to 19; and each R 5 Located on any ring atom. In each embodiment, R a and R b In each case, the group consisting of -H and alkyl groups is selected independently; or R a and R b Cyclization forms a cyclohexaalkyl group having 3 to 6 ring atoms, including a heteroatom, which is the N atom attached to it. In a particular embodiment, BA is an antibody. In some embodiments, x is an integer from 1 to 4. In some embodiments, x is 4. In some embodiments, x is 2.

[0661] This invention provides antibody-steroid conjugates of formula 1210, 1220, 1230, or 1240:

[0662]

[0663] Or its pharmaceutically acceptable salt, solvate, or stereoisomer; wherein R 3 Covalently bonded to L or BA.

[0664] In some embodiments of formulas 1210, 1220, 1230, or 1240, R 1 and R 2 Each of the following groups is independently selected from: -H, -OH, alkyl, -OC(O)-alkyl, and halogen; or R 1 and R 2 Together In some implementations, R 3 It is selected free-alkylene-NR a R b -X-Asaryl-Y-NR a R b -X-heteroaryl-Y-NR a R b The group consisting of N-containing heterocyclic alkyl groups; wherein X is absent, or X is -N-, -CH2-, or -O-; wherein Y is absent, or Y is -CH2-; and R 4 It is selected from alkyl, aryl, alkylaryl, arylalkyl, heteroaryl, -alkylene-NR a R b -X-Asaryl-Y-NR a R b -X-heteroaryl-Y-NR a R b The group consisting of N-containing heterocyclic alkyl groups; wherein X is absent, or X is -N-, -CH2-, or -O-; wherein Y is absent, or Y is -CH2-. In some embodiments, R 3 Yes -NR a R b ; and R 4 It is an alkyl group. In each embodiment, BA or L is associated with R. 3 The amino group in R is linked, for example, replacing a hydrogen atom. a and R b In each case, the group consisting of -H and alkyl groups is selected independently; or R a and R b Cyclization forms a cyclohexaalkyl group having 3 to 6 ring atoms, including a heteroatom, which is the N atom attached to it. In a particular embodiment, BA is an antibody. In some embodiments, x is an integer from 1 to 4. In some embodiments, x is 4. In some embodiments, x is 2.

[0665] This invention provides antibody-steroid conjugates of formula 1310, 1320, 1330, or 1340:

[0666]

[0667] Or its pharmaceutically acceptable salt, solvate, or stereoisomer; wherein R 4 Covalently bonded to L or BA.

[0668] In some embodiments of formulas 1310, 1320, 1330, or 1340, R 3It is selected from -OH, -OC(O)-alkyl, -O-aryl, and -NR. a R b ,-alkylene-NR a R b -X-Asaryl-Y-NR a R b -X-heteroaryl-Y-NR a R b The group consisting of N-containing heterocyclic alkyl groups; wherein X is absent, or X is -N-, -CH2-, or -O-; wherein Y is absent, or Y is -CH2-; and R 4 It is selected free-alkylene-NR a R b -X-Asaryl-Y-NR a R b -X-heteroaryl-Y-NR a R b The group consisting of N-containing heterocyclic alkyl groups; wherein X is absent, or X is -N-, -CH2-, or -O-; wherein Y is absent, or Y is -CH2-. In each embodiment, BA or L is with R. 4 The amino group in R is linked, for example, replacing a hydrogen atom. a and R b In each case, the group consisting of -H and alkyl groups is selected independently; or R a and R b Cyclization forms a cyclohexaalkyl group having 3 to 6 ring atoms, including a heteroatom, which is the N atom attached to it. In a particular embodiment, BA is an antibody. In some embodiments, x is an integer from 1 to 4. In some embodiments, x is 4. In some embodiments, x is 2.

[0669] The present invention also provides antibody-steroid conjugates having the structure shown in the following general formula:

[0670]

[0671] or mixtures thereof;

[0672]

[0673] or mixtures thereof;

[0674]

[0675] or mixtures thereof;

[0676]

[0677] or mixtures thereof;

[0678]

[0679] or mixtures thereof;

[0680]

[0681] or mixtures thereof;

[0682]

[0683] or mixtures thereof;

[0684]

[0685] or mixtures thereof;

[0686]

[0687] or mixtures thereof;

[0688]

[0689] or mixtures thereof;

[0690]

[0691] or mixtures thereof;

[0692] Where Ab is the antibody, and x is an integer from 1 to 30. In some implementations, x is an integer from 1 to 4. In some implementations, x is 4. In some implementations, x is 2.

[0693] The present invention also provides antibody-steroid conjugates having the structure shown in the following general formula:

[0694]

[0695] Or a mixture thereof.

[0696] In a particular implementation, Ab is an antibody, and x is an integer from 1 to 30. In some implementations, x is an integer from 1 to 4. In some implementations, x is 4. In some implementations, x is 2.

[0697] The present invention also provides antibody-steroid conjugates having the structure shown in the following general formula:

[0698] .

[0699] The present invention also provides antibody-steroid conjugates having the structure shown in the following general formula:

[0700]

[0701] or mixtures thereof;

[0702]

[0703]

[0704] or mixtures thereof;

[0705]

[0706] or mixtures thereof;

[0707]

[0708] or mixtures thereof;

[0709] ,

[0710] ,

[0711] or mixtures thereof;

[0712] ,

[0713]

[0714] or mixtures thereof;

[0715]

[0716] or mixtures thereof;

[0717]

[0718] or mixtures thereof;

[0719]

[0720]

[0721] or mixtures thereof;

[0722]

[0723] or mixtures thereof;

[0724]

[0725]

[0726] Or a mixture thereof.

[0727] In a particular implementation, Ab is an antibody, and x is an integer from 1 to 30. In some implementations, x is an integer from 1 to 4. In some implementations, x is 4. In some implementations, x is 2.

[0728] The present invention also provides binder conjugates of budesonide or difluralasone.

[0729] Suitable binders for any conjugates provided in this invention include, but are not limited to, antibodies, lymphokines, hormones, growth factors, viral receptors, interleukins, or any other cell-binding molecules or peptide-binding molecules or substances.

[0730] In some embodiments, the binding agent is an antibody. As used herein, the term "antibody" refers to any antigen-binding molecule or molecular complex containing at least one complementarity-determining region (CDR) that specifically binds to or interacts with a particular antigen. The term "antibody" also includes immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, and their polymers (e.g., IgM). Each heavy chain contains a heavy chain variable region (abbreviated herein as HCVR or V). H ) and the heavy chain constant region. The heavy chain constant region contains three structural domains, C H 1. C H 2 and C H 3. Each light chain contains a light chain variable region (abbreviated as LCVR or V in this invention). L ) and the light chain constant region. The light chain constant region contains a structural domain (C L 1). The V H and V L The region can be further subdivided into high-variability regions, called complementary determinant regions (CDRs), and interspersed with more conservative regions, called framing regions (FRs). Each V H and V L It consists of three CDRs and four FRs, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the FRs of the antibody (or its antigen-binding portion) may be identical to human germline sequences, or may be natural or artificially modified. A common amino acid sequence can be defined based on a side-by-side analysis of two or more CDRs.

[0731] The term "antibody" as used in this invention also includes the antigen-binding fragment of a complete antibody molecule. The terms "antigen-binding portion" and "antigen-binding fragment" of an antibody, as used in this invention, encompass any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. The antigen-binding fragment of an antibody can be derived from a complete antibody molecule, for example, using any suitable standard technique, such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding variable and optionally constant domains of the antibody. Such DNA is known and / or readily available from, for example, commercial sources, DNA libraries (including, for example, phage-antibody libraries), or can be synthesized. The DNA can be sequenced and chemically manipulated or manipulated using molecular biology techniques, for example, arranging one or more variable and / or constant domains into a suitable conformation, or introducing codons, generating cysteine ​​residues, modifying, adding, or deleting amino acids, etc.

[0732] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues mimicking the hypervariable region of an antibody (e.g., a separated complementarity-determining region (CDR), such as a CDR3 peptide) or a constrained FR3-CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single-domain antibodies, domain-deficient antibodies, chimeric antibodies, CDR-grafted antibodies, biantibodies, triantibodies, tetraantibodies, microantibodies, nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also included in the expression of “antigen-binding fragments” as used in this invention.

[0733] Antibody antigen-binding fragments typically contain at least one variable domain. The variable domain can have any size or amino acid composition and typically contains at least one core-drag domain (CDR), which is adjacent to or within one or more frame sequences. In the presence of V... L V related to the structural domain H In the antigen-binding fragment of the structural domain, the V H and V L The structural domains can be positioned relative to each other in any suitable arrangement. For example, the variable region can be dimer and contain V. H -V H V H -V L or V L -V LDimer. Alternatively, the antigen-binding fragment of the antibody may contain monomer V. H or V L Structural domain.

[0734] In some embodiments, the antigen-binding fragment of the antibody may include at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of the variable and constant domains that may be found within the antigen-binding fragment of the antibody disclosed in this invention include: (i) V H -C H 1; (ii) V H -C H 2; (iii) V H -C H 3; (iv) V H -C H 1-C H 2; (v) V H -C H 1-C H 2-C H 3; (vi) V H -C H 2-C H 3; (vii) V H -C L (viii) V L -C H 1; (ix) V L -C H 2; (x) V L -C H 3;(xi) V L -C H 1-C H 2;(xii) V L -C H 1-C H 2-C H 3; (xiii) V L -C H 2-C H 3; and (xiv) V L -C LIn any configuration of the variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be directly connected to each other or may be connected via complete or partial hinge or linker regions. The hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids, which result in flexible or semi-flexible connections between adjacent variable and / or constant domains in a single polypeptide molecule. Furthermore, the antigen-binding fragment of the antibody disclosed in this invention may comprise homodimers or heterodimers (or other multimers) of any of the variable and constant domains listed above, which are non-covalently bound to each other and / or connected to a monomer having one or more V H or V L The structural domains are non-covalently bonded (e.g., via disulfide bonds).

[0735] Like intact antibody molecules, antigen-binding fragments can be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding fragments of antibodies typically contain at least two distinct variable domains, each capable of specifically binding to a single antigen or binding to different epitopes on the same antigen. Any form of multispecific antibody, including the exemplary bispecific antibody forms disclosed herein, can be adapted to antigen-binding fragments of the antibodies disclosed herein using conventional techniques available in the art.

[0736] The antibodies described in this invention can act via complement-dependent cytotoxicity (CDC) or antibody-dependent cell-mediated cytotoxicity (ADCC). "Complement-dependent cytotoxicity" (CDC) refers to the lysis of cells expressing antigens by the antibodies of this invention in the presence of complement. "Antibody-dependent cell-mediated cytotoxicity" (ADCC) refers to a cell-mediated reaction in which non-specific cytotoxic cells expressing Fc receptors (FcRs) (e.g., natural killer (NK) cells, neutrophils, and macrophages) recognize binding antibodies on target cells, thereby causing target cell lysis. CDC and ADCC can be measured using assays well-known and available in the art. (See, for example, U.S. Patent Nos. 5,500,362 and 5,821,337, and Clynes...) et al. (1998) Proc. Natl. Acad. Sci. (USA) 95 (652-656). The constant region of an antibody is important in its ability to fix complement and mediate cell-dependent cytotoxicity. Therefore, antibody isotypes can be selected based on whether the antibody needs to mediate cytotoxicity.

[0737] Antibodies that can be used with the compounds of this invention include human antibodies. The term "human antibody" as used herein is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Human antibodies may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutations in vivo), such as in CDRs, particularly in CDR3. However, the term "human antibody" as used herein is not intended to include antibodies in which a germline CDR sequence derived from another mammalian species (e.g., mouse) has been grafted onto a human frame sequence. The term "human antibody" does not include naturally occurring molecules that are typically present in naturally occurring, unmodified organisms without modification or human intervention / manipulation.

[0738] In some embodiments, the antibody may be a recombinant human antibody. The term "recombinant human antibody" as used herein is intended to include all human antibodies prepared, expressed, generated, or isolated via a recombinant process, such as antibodies expressed using a recombinant expression vector transfected into host cells (further described below); antibodies isolated from recombinant, combined human antibody libraries (further described below); and antibodies isolated from animals (e.g., mice) that are transgenic animals carrying human immunoglobulin genes (see, for example, Taylor). et al. (1992) Nucl. Acids Res. 20:6287-6295); or antibodies prepared, expressed, produced, or isolated by any other method involving splicing a human immunoglobulin gene sequence into another DNA sequence. Such recombinant human antibodies possess variable and constant regions derived from human germline immunoglobulin sequences. However, in some embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when using animals with transgenic human Ig sequences, in vivo somatic cell mutagenesis), and thus the V of the recombinant antibody... H and V L The amino acid sequence of the region is derived from human lineage V. H and V L The sequence and related sequences may not naturally exist in the human antibody germline library in vivo.

[0739] Human antibodies can exist in two forms associated with hinge heterogeneity. In one form, the immunoglobulin molecule comprises a stable four-chain construct of approximately 150-160 kDa, where dimers are linked together by interchain heavy-chain disulfide bonds. In the second form, the dimers are not linked by interchain disulfide bonds and form a molecule of approximately 75-80 kDa, consisting of covalently coupled light and heavy chains (half-antibodies). These forms are extremely difficult to separate even after affinity purification.

[0740] The frequency of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with the hinge region isotype of the antibody. A single amino acid substitution in the hinge region of the human IgG4 hinge can significantly increase the likelihood of the second form (Angal). et al. The presence of (1993) Molecular Immunology 30:105) decreased to levels typically observed using human IgG1 hinges. This invention disclosure includes hinges, C H 2 or C H The antibody has one or more mutations in region 3, which may be required, for example, in production, to increase the yield of the desired antibody form.

[0741] The antibodies that can be used with the compounds of this invention can be isolated antibodies. As used in this invention, "isolated antibody" refers to an antibody that has been identified and isolated and / or recovered from at least one component of its natural environment. For example, for the purposes of this invention, an antibody that has been isolated or removed from at least one component of an organism or from tissues or cells in which antibodies are naturally present or produced is a "isolated antibody". Isolated antibodies also include in situ antibodies within recombinant cells. Isolated antibodies are antibodies that have undergone at least one purification or isolation step. According to some embodiments, isolated antibodies may be substantially free of other cellular material and / or chemicals.

[0742] Compared to the corresponding germline sequences of derived antibodies, antibodies usable with the compounds of this invention may contain one or more amino acid substitutions, insertions, and / or deletions in the frame and / or CDR regions of the heavy and light chain variable domains. Such mutations can be readily identified by comparing the amino acid sequences disclosed herein with germline sequences available from, for example, public antibody sequence databases. This invention includes antibodies and antigen-binding fragments derived from any amino acid sequence of this invention, wherein one or more amino acids in one or more frame and / or CDR regions are mutated to corresponding residues of the germline sequence of the derived antibody, or mutated to corresponding residues of another human germline sequence, or mutated to conserved amino acid substitutions of the corresponding germline residues (such sequence changes are collectively referred to as "germline mutations" in this invention). Those skilled in the art can readily generate numerous antibody and antigen-binding fragments containing one or more individual germline mutations or combinations thereof, starting from the heavy and light chain variable region sequences disclosed herein. In some embodiments, V H and / or V LAll frame and / or CDR residues within the domain are mutated back to residues found in the original germline sequence of the derived antibody. In other embodiments, only certain residues are mutated back to the original germline sequence, for example, mutated residues found only in the first 8 amino acids of FR1 or the last 8 amino acids of FR4, or mutated residues found only in CDR1, CDR2, or CDR3. In other embodiments, one or more frame and / or CDR residues are mutated to corresponding residues of a different germline sequence (i.e., a germline sequence different from the germline sequence of the originally derived antibody). Furthermore, the antibody of the present invention may comprise any combination of two or more germline mutations within the frame and / or CDR regions, for example, wherein certain individual residues are mutated to corresponding residues of a specific germline sequence, while certain other residues different from the original germline sequence remain or are mutated to corresponding residues of a different germline sequence. Once obtained, the antibody containing one or more germline mutations and the antigen-binding fragment can be readily tested for one or more desired properties, such as improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as applicable), reduced immunogenicity, etc.

[0743] In some embodiments, the antibody is a monoclonal antibody, a polyclonal antibody, an antibody fragment (Fab, Fab', and F(ab)2, a microantibody, a biantibody, a triantibody, etc.), or a bispecific antibody. The antibodies described in this invention can be humanized using the methods described in U.S. Patent No. 6,596,541 and U.S. Publication No. 2012 / 0096572, each of which is incorporated herein by reference in its entirety.

[0744] When the binder is an antibody, it binds as an antigen-binding partner of the polypeptide and can be a transmembrane molecule (e.g., a receptor) or a growth factor that can be glycosylated or phosphorylated.

[0745] Suitable targets for binding to the conjugate include any target requiring steroid delivery. In some embodiments, the conjugate is an antibody, a modified antibody, or an antigen-binding fragment thereof, which binds to targets selected from: AXL, BAFFR, BCMA, BCR-list components, BDCA2, BDCA4, BTLA, BTNL2, BTNL3, BTNL8, BTNL9, C10orf54, CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, CCR9, CCR10, CD11c, CD137, CD138, CD14, CD168, CD177, CD19, CD20, CD209, CD209L, CD22, CD226, CD248, CD25, CD27, CD2 74, CD276, CD28, CD30, CD300A, CD33, CD37, CD38, CD4, CD40, CD44, CD45, CD46, CD47, CD48, CD5 , CD52, CD55, CD56, CD59, CD62E, CD68, CD69, CD70, CD74, CD79a, CD79b, CD8, CD80, CD86, CD90.2. CD96, CLEC12A, CLEC12B, CLEC7A, CLEC9A, CR1, CR3, CRTAM, CSF1R, CTLA4, CXCR1 / 2, CXCR4, CXCR5, D DR1, DDR2, DEC–205, DLL4, DR6, FAP, FCamR, FCMR, FcR’s, Fire, GITR, HHLA2, HLA Class II, HVEM, ICOSLG, IF NLR1, IL10R1, IL10R2, IL12R, IL13RA1, IL13RA2, IL15R, IL17RA, IL17RB, IL17RC, IL17RE, IL20R1, IL 20R2, IL21R, IL22R1, IL22RA, IL23R, IL27R, IL29R, IL2Rg, IL31R, IL36R, IL3RA, IL4R, IL6R, IL5R, IL7 R, IL9R, Integrins, LAG3, LIFR, MAG / Siglec-4, MMR, MSR1, NCR3LG1, NKG2D, NKp30, NKp46, PDCD1, PROKR1, PVR, PVRIG, PVRL2, PVRL3, RELT, SIGIRR, Siglec-1 (sialic acid-binding immunoglobulin-like lectin-1), Siglec-10, Siglec-5, Siglec-6, Siglec-7, Siglec-8, Siglec-9, SIRPA, SLAMF7, TACI, TCR-list components / assoc, PTCRA, TCRb, CD3z, CD3, TEK, TGFBR1, TGFBR2, TGFBR3, TIGIT, TLR2, TLR4, TROY, TSLPR, TYRO, VLDLR, VSIG4, and VTCN1.

[0746] The binder linker can be attached to the binder (e.g., an antibody or antigen-binding molecule) via attachment to a specific amino acid site within the antibody or antigen-binding molecule. Exemplary amino acid attachments that may be used in the context of this aspect of the invention include, for example, lysine (see, for example, US 5,208,020; US 2010 / 0129314; Hollander). et al. , Bioconjugate Chem.,2008, 19:358–361; WO 2005 / 089808; US 5,714,586; US 2013 / 0101546; and US 2012 / 0585592), cysteine ​​(see, for example, US 2007 / 0258987; WO2013 / 055993; WO2013 / 055990; WO 2013 / 053873; WO 2013 / 053872; WO 2011 / 130598; US 2013 / 0101546; and US 7,750,116), selenocysteine ​​(see, for example, WO 2008 / 122039; and Hofer et al ., Proc.Natl. Acad. Sci., USA, 2008, 105 :12451–12456), formylglycine (see, for example, Carrico et al ., Nat. Chem . Biol. , 2007, 3:321–322; Agarwal et al ., Proc. Natl. Acad. Sci., USA, 2013, 110 :46–51, and Rabuka et al ., Nat. Protocols , 2012 , 10 :1052–1067), non-natural amino acids (see, for example, WO 2013 / 068874 and WO 2012 / 166559), and acidic amino acids (see, for example, WO 2012 / 05982). Linkers can be coupled via glutamine through transglutaminase-based chemical-enzymatic coupling (see, for example, Dennler et al., Bioconjugate Chem (2014, 25, 569–578). Linkers can also be connected to carbohydrates (see, for example, US 2008 / 0305497, WO 2014 / 065661, and Ryan). et al ., Food& Agriculture Immunol. , 2001, 13 :127–130) and the attachment of disulfide linkages (see, for example, WO 2013 / 085925, WO 2010 / 010324, WO 2011 / 018611, WO2014 / 197854, and Shaunak et al ., Nat. Chem. Biol. , 2006, 2 (312–313) and coupled to an antigen-binding protein. In some embodiments, the binding agent is an antibody, and the antibody is linked to the linker via a lysine residue. In some embodiments, the antibody is linked to the linker via a cysteine ​​residue.

[0747] D. Methods for preparing compounds

[0748] The conjugates described in this invention can be obtained by conjugating the linker-load described in this invention with a binder (e.g., an antibody under standard conjugation conditions) (see, for example, Drug Deliv 2016 Jun;23(5):1662-6; AAPS Journal , Vol. 17, No. 2, March 2015; and Int.J. Mol. Sci 2016, 17, 561 (the entire contents of which are incorporated herein by reference). A linker-load is a synthetic intermediate comprising a target load and a linker moiety, which ultimately serves as a group portion (or a portion thereof) connecting the binder to the load. The linker-load contains an active group that reacts with the binder to form the conjugate described herein. When the binder is an antibody, the antibody can be conjugated to the linker-load via one or more cysteine, lysine, or other residues of the antibody. The linker-load can be conjugated to cysteine ​​residues, for example, by subjecting the antibody to a reducing agent (e.g., dithiotheritol) to cleave the disulfide bonds of the antibody, such as by purifying and reducing the antibody by gel filtration, and subsequently reacting the antibody with a linker-load containing an active group moiety (e.g., a maleimide group). Suitable solvents include, but are not limited to, water, DMA, DMF, and DMSO. Linker-loads containing active groups (e.g., activated ester or acyl halide groups) can be coupled to lysine residues. Suitable solvents include, but are not limited to, water, DMA, DMF, and DMSO. Known protein techniques, including, for example, volume exclusion chromatography, dialysis, and ultrafiltration / percolation, can be used to purify the conjugates.

[0749] The linker, such as an antibody, can also be coupled via click chemistry. In some embodiments of the click chemistry, the linker-load comprises an active group, such as an alkyne capable of 1,3-cycloaddition with an azide. Suitable active groups include, but are not limited to, strained alkynes, such as those suitable for strain-promoted cycloaddition of alkynes-azidoides (SPAAC), cyclic alkynes, such as cyclooctynes, benzocyclocyclic alkynes, and alkynes capable of 1,3-cycloaddition with an azide in the absence of a copper catalyst. Suitable alkynes also include, but are not limited to, DIBAC, DIBO, BARAC, DIFO, substituted alkynes such as fluorinated alkynes, aza-cyclic alkynes, BCN, and their derivatives. Linker-loads containing such active groups can be used to couple antibodies already functionalized with an azide group. Such functionalized antibodies include antibodies functionalized with an azide-polyethylene glycol group. In some embodiments, such functionalized antibodies are obtained by reacting an antibody containing at least one glutamine residue (e.g., heavy chain Q295) with a compound of formula H2N–LL–N3 (where LL is a divalent polyethylene glycol group) in the presence of transglutaminase. For convenience, in some general formulas of the present invention, the antibody Ab is a modified antibody having one or more covalently linked –LL–N3 groups or residues thereof. Preferably, each –LL–N3 is covalently linked to an amino acid side chain of a glutamine residue of the antibody. More preferably, the –LL–N3 is an active group RG or can react with the active group RG to form a covalent bond with the linker-load. Again, for convenience, the –LL–N3 group is explicitly shown in some general formulas of the present invention.

[0750] This invention provides a method for synthesizing the conjugates described herein, the method comprising contacting a binding agent (e.g., an antibody) with a linker-load described herein. In some embodiments, the linker-load comprises a cyclodextrin moiety.

[0751] In some embodiments, the linker's effective load is the compound shown in formula (II):

[0752]

[0753] (II)

[0754] (a) R 3 Is it RL–, RL–X–, or ;

[0755] R 1 and R 2 Each is independently -H, alkyl, alkyl-C(O)-O-, -OH, or halogen; or R 1 and R 2 Together , where R 4 It is an alkyl, aryl, arylalkyl, or N-containing heterocyclic alkyl; wherein the alkyl, aryl, arylalkyl, and N-containing heterocyclic alkyl are optionally prefixed with -NR. a R b Replace; or

[0756] (b) R 3 It is -OH, alkyl –C(O)–O–, heteroalkyl, –NR a R b Or aryloxy group, wherein the alkyl –C(O)–O–, heteroalkyl, or aryloxy group is optionally –NR a R b Or halogen substitution, and R 1 and R 2 Together , where R 4 It is –RL–, Or RL–Y, where Y is a divalent heterocycle containing N;

[0757] RL is an active linker;

[0758] R 5 In each case, it is independently -OH, halogen, alkyl, or arylalkyl;

[0759] R a and R b In each case, it is independently -H or alkyl;

[0760] R P In each case, it is halogen independently;

[0761] X is independently NR in each case. a Or O;

[0762] It is aryl or heteroaryl; and

[0763] n is an integer from 0 to 19.

[0764] The compounds shown in formula (II) are linker-loads that can be used as synthetic intermediates for synthesizing the conjugates described in this invention. These linker-loads contain active groups that can react with antibodies to form the conjugates described in this invention.

[0765] In some embodiments of formula (II), R 1 and R 2 Each is independently -H, alkyl, or -OH. In some embodiments of formula (II), R 1 or R 2One of them is -H, alkyl, or -OH. In some embodiments of formula (II), R 1 and R 2 All are -H, alkyl, or -OH.

[0766] In some embodiments of formula (II), R 1 and R 2 Together In some embodiments, R 4 Yes – RL. In some embodiments, R 4 It is RL–NR a –Aryl. In some other embodiments, R 4 It is an alkyl group. In some embodiments, R 4 It is an arylalkyl group. In some embodiments, R 4 It is aryl. In other embodiments, R 4 It is an N-containing heterocyclic alkyl group. In some of these embodiments, the alkyl, aryl, arylalkyl, or N-containing heterocyclic alkyl group may optionally be substituted.

[0767] In some embodiments of formula (II), R 5 It is a halogen. In some embodiments of formula (II), R 5 It is fluorine. In some embodiments of formula (II), R 5 One of them is a halogen. In some embodiments of formula (II), R 5 It is a halogen, and n is 2. In some embodiments of formula (II), R 5 It is –F, and n is 1. In some embodiments of equation (II), R 5 It is –F, and n is 2.

[0768] In some embodiments of formula (II), R 3 It is RL. In some embodiments of equation (II), R 3 It is RL–NR a –Aryloxy–. In some other embodiments of formula (II), R 3 It is –OH. In some other embodiments of formula (II), R 3 It is an alkyl group –C(O)–O–. In some other embodiments of formula (II), R 3 It is a heteroalkyl group. In some other embodiments of formula (II), R 3 It is –N–R a R b In some other embodiments of equation (II), R 3 It is aryl. In some other embodiments of formula (II), R 3It is an aryloxy group. In some other embodiments of formula (II), the alkyl–C(O)–O–, heteroalkyl, or aryloxy group is optionally replaced by –NR. a R b Or halogen substitution.

[0769] In some embodiments of formula (II), R 3 It is –OH. In some embodiments of formula (II), R 3 It is an alkyl group –C(O)–O–. In some embodiments of formula (II), R 3 yes In some embodiments of formula (II), R 3 It is a heteroalkyl group. In some embodiments of formula (II), R 3 yes In some embodiments of formula (II), R 3 yes In some embodiments of formula (II), R 3 Yes – NR a R b In some embodiments of formula (II), R 3 yes In some embodiments of formula (II), R 3 yes In some embodiments of formula (II), R 3 yes In some embodiments of formula (II), R 3 It is an aryloxy group. In some embodiments of formula (II), R 3 yes In some embodiments of formula (II), R 3 yes In some embodiments of formula (II), R 3 yes In some embodiments of formula (II), R 3 yes In some embodiments of formula (II), R 3 yes In some embodiments of formula (II), R 3 yes In some embodiments of formula (II), R 3 yes In some embodiments of formula (II), R 3 yes In some embodiments of formula (II), R 3 yes In some embodiments of formula (II), R 3 yes .

[0770] In equation (II), the subscript n is an integer from 0 to 19. In some embodiments, n is 0. In some other embodiments, n is 1. In some embodiments, n is 2. In some other embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some other embodiments, n is 6. In some embodiments, n is 7. In some other embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some other embodiments, n is 11. In some embodiments, n is 12. In some other embodiments, n is 13. In some embodiments, n is 14. In some embodiments, n is 15. In some other embodiments, n is 16. In some embodiments, n is 17. In some other embodiments, n is 18. In some embodiments, n is 19.

[0771] In some embodiments, the present invention provides compounds having the structure shown in formula (IIa):

[0772] ;

[0773] in:

[0774] R 5 In each case, it is independently –OH, halogen, or alkyl;

[0775] R 3 Selected from –OH, alkyl –C(O)–O–, heteroalkyl, –NR a R b Or aryloxy group, wherein the alkyl –C(O)–O–, heteroalkyl, or aryloxy group is optionally –NR a R b Or halogen substitution;

[0776] RL is an active linker;

[0777] R a and R b In each case, the components are independently selected from H, alkyl, and alkyl–C(O); and

[0778] n is an integer from 0 to 19.

[0779] In some embodiments, the present invention provides compounds having the structure shown in formula (IIa2):

[0780]

[0781] (IIa2);

[0782] in:

[0783] R 5In each case, it is independently –OH, halogen, or alkyl;

[0784] R 3 It is –OH, alkyl –C(O)–O–, heteroalkyl, –NR a R b Or aryloxy group, wherein the alkyl –C(O)–O–, heteroalkyl, or aryloxy group is optionally –NR a R b Or halogen substitution;

[0785] RL is an active linker;

[0786] R a and R b In each case, it is independently selected from H, alkyl, or alkyl–C(O); and

[0787] n is an integer from 0 to 19.

[0788] In some embodiments of formula (IIa2), R 3 It is –OH. In some embodiments of formula (IIa2), R 3 It is an alkyl group –C(O)–O–. In some embodiments, R 3 yes In some embodiments of formula (IIa2), R 3 It is a heteroalkyl group. In some embodiments, R 3 yes In some embodiments of formula (IIa2), R 3 Yes – NR a R b In some embodiments, R 3 yes In some embodiments of formula (IIa2), R 3 It is an aryloxy group. In some embodiments of formula (IIa2), R 3 yes In some embodiments of formula (IIa2), R 3 yes In some embodiments of formula (IIa2), R 3 yes In some embodiments of formula (IIa2), R 3 yes In some embodiments of formula (IIa2), R 3 yes .

[0789] In some embodiments, the compound shown in formula (IIa2) has the following structure:

[0790]

[0791] in:

[0792] R 3 It is –OH or alkyl –C(O)–O–;

[0793] R 5a and R 5b Each is independently –F or H; and

[0794] RL is an active linker.

[0795] In some embodiments, the present invention provides compounds having the structure shown in formula (IIb):

[0796]

[0797] (IIb);

[0798] in:

[0799] R 5 In each case, it is independently –OH, halogen, or alkyl;

[0800] R 4 Selected from alkyl, aryl, arylalkyl, or N-containing heterocyclic alkyl groups, wherein the alkyl, aryl, arylalkyl, or N-containing heterocyclic alkyl group is optionally –NR a R b replace;

[0801] RL is an active linker;

[0802] R a and R b In each case, the components are independently selected from H, alkyl, and alkyl–C(O); and

[0803] n is an integer from 0 to 19.

[0804] In some embodiments of formula (IIb), R 5 It is a halogen. In some embodiments of formula (IIb), R 5 It is fluorine. In some embodiments of formula (IIb), n is at least 2, and R 5 Two of them are halogens. In some embodiments of formula (IIb), R 5 F is 1, and n is 1. In some embodiments of equation (IIb), R 5 Yes –F.

[0805] In some embodiments of formula (IIb), R 4 It is an alkyl group. In some embodiments of formula (IIb), R 4It is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, pentyl moiety, hexyl moiety, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments of formula (IIb), R 4 It's n-propyl.

[0806] In some embodiments, the compound shown in formula (IIb) has the following structure:

[0807]

[0808] in:

[0809] R 4 It is an alkyl group;

[0810] R 5a and R 5b Each is independently –F or H; and

[0811] RL is an active linker.

[0812] In some embodiments, the present invention provides compounds having the structure shown in formula (IIc):

[0813]

[0814] in:

[0815] R 1 and R 2 Each can be independently -H, alkyl, alkyl-C(O)-O-, -OH, or halogen;

[0816] R 5 In each case, it is independently selected from -OH, halogen, or alkyl;

[0817] RL is an active linker; and

[0818] n is an integer from 0 to 19.

[0819] In some embodiments of formula (IIc), R 5 It is a halogen. In some embodiments of formula (IIc), R 5 It is fluorine. In some embodiments of formula (IIc), R 5 One of them is a halogen. In some embodiments of formula (IIc), R 5 Two of them are halogens. In some embodiments of formula (IIc), R 5 It is –F, and n is 2.

[0820] In some embodiments of formula (IIc), R 1 It is CH3.

[0821] In other embodiments of formula (IIc), R 1 It is OH.

[0822] In some other embodiments of formula (IIc), R 1 It is H.

[0823] In some embodiments of formula (IIc), R 2 It is CH3.

[0824] In other embodiments of formula (IIc), R 2 It is OH.

[0825] In some other embodiments of formula (IIc), R 2 It is H.

[0826] In some embodiments of formula (IIc), R 1 It is CH3, and R 2 It is CH3.

[0827] In other embodiments of formula (IIc), R 1 It is CH3, and R 2 It is OH.

[0828] In some embodiments of formula (IIc), R 1 It is CH3, and R 2 It is H.

[0829] In some other embodiments of formula (IIc), R 1 It is OH, and R 2 It is CH3.

[0830] In some other embodiments of formula (IIc), R 1 It is OH, and R 2 It is OH.

[0831] In some embodiments of formula (IIc), R 1 It's H, and R 2 It is H.

[0832] In some other embodiments of formula (IIc), R 1 It's H, and R 2 It is OH.

[0833] In other embodiments of formula (IIc), R 1 It's H, and R 2 It is H.

[0834] In some embodiments, the compound shown in formula (IIc) has the following structure:

[0835]

[0836] in:

[0837] R 2 It is methyl;

[0838] R 5a and R 5b Each is independently –F or H; and

[0839] RL is an active linker.

[0840] In some embodiments, the present invention provides compounds having the structure shown in formula (III-R):

[0841]

[0842] in:

[0843] R 3 yes ;

[0844] R 1 and R 2 Each is independently -H, alkyl, alkyl-C(O)-O-, -OH, or halogen; or R 1 and R 2 Together , where R 4 It is an alkyl, aryl, arylalkyl, or N-containing heterocyclic alkyl; wherein the alkyl, aryl, arylalkyl, and N-containing heterocyclic alkyl are optionally prefixed with -NR. a R b replace;

[0845] R 5 In each case, it is independently -OH, halogen, alkyl, or arylalkyl;

[0846] R a and R b In each case, it is independently -H or alkyl;

[0847] R P In each case, it is halogen independently;

[0848] It is aryl or heteroaryl;

[0849] t is an integer from 0 to 2;

[0850] x is an integer from 1 to 30; and where:

[0851] RL is the active linker, defined as follows; SP 1 and SP 2In each case, either independently absent, or independently spacer group residues, and wherein SP... 1 Includes trivalent linkers; AA 1 It is a trivalent linker containing amino acid residues; AA 2 It is a dipeptide residue; PEG is a polyethylene glycol residue; wherein... The symbol represents the atom connected to the adjacent group in the general formula. CD, in each case, is either independently absent or independently a cyclodextrin residue, wherein at least one CD is present. The subscript m is an integer from 0 to 5. In these embodiments, the subscript m is 0, 1, 2, 3, 4, or 5. In some embodiments, the subscript m is 0. In some embodiments, the subscript m is 1. In some embodiments, the subscript m is 2. In some embodiments, the subscript m is 3. In some embodiments, the subscript m is 4. In some embodiments, the subscript m is 5. In some embodiments, AA 1 Or AA 2 Each of these, in each case, independently comprises an amino acid selected from alanine, valine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or citrulline, their derivatives, or combinations thereof. In some embodiments, AA 1 It is an amino acid selected from alanine, valine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or citrulline, their derivatives, or combinations thereof. In some embodiments, AA 1 It is lysine. In some implementations, AA 1 It is lysine or a derivative of lysine. In some embodiments, AA 2 It is valine-citrulline. In some implementation schemes, AA 2 It is citrulline-valine. In some implementation schemes, AA 2 It is valine-alanine. In some implementation schemes, AA 2 It is alanine-valine. In some implementation schemes, AA 2 It is valine-glycine. In some implementation schemes, AA 2 It is glycine-valine. In some implementation schemes, AA 2 It is glutamic acid-valine-citrulline. In some implementation schemes, AA 2 It is glutamine-valine-citrulline. In some implementation schemes, AA 2 It is lysine-valine-alanine. In some implementation schemes, AA 2It is lysine-valine-citrulline. In some implementation schemes, AA 2 It is glutamic acid-valine-citrulline. In some embodiments, SP 1 In each case, C is chosen independently. 1-6 Alkylene, -NH-, -C(O)-, (-CH2-CH2-O) e -NH-CH2-CH2-(-O-CH2-CH2) e -C(O)-, -C(O)-(CH2) u -C(O)-, -C(O)-NH-(CH2) v - A group consisting of elements and their combinations, where subscript e is an integer from 0 to 4, subscript u is an integer from 1 to 8, and subscript v is an integer from 1 to 8. In some embodiments, SP 2 In each case, C is chosen independently. 1-6 Alkylene, -NH-, -C(O)-, (-CH2-CH2-O) e -NH-CH2-CH2-(-O-CH2-CH2) e -C(O)-, -C(O)-(CH2) u -C(O)-, -C(O)-NH-(CH2) v - A group consisting of elements and their combinations, where subscript e is an integer from 0 to 4, subscript u is an integer from 1 to 8, and subscript v is an integer from 1 to 8.

[0852] In some embodiments, the present invention provides compounds having the structure shown in formula (IIIc-R):

[0853] ;

[0854] Formula (IIIc-R)

[0855] RL is an active linker;

[0856] CD is cyclodextrin;

[0857] SP 1 It is a spacer group;

[0858] AA 4 They are amino acid residues;

[0859] AA 5 It is a dipeptide residue;

[0860] PEG stands for polyethylene glycol;

[0861] m is an integer from 0 to 4;

[0862] x is an integer from 0 to 30;

[0863] R 4 It is an alkyl, aryl, arylalkyl, or N-containing heterocyclic alkyl; wherein the alkyl, aryl, arylalkyl, and N-containing heterocyclic alkyl are optionally –NR a R b replace;

[0864] R a and R b In each case, it is independently –H or alkyl;

[0865] SP 1 and SP 2 In each case, either independently absent, or independently spacer group residues, and wherein SP... 1 Includes trivalent linkers; AA 4 It is a trivalent linker containing amino acid residues; AA 5 It is a dipeptide residue; PEG is a polyethylene glycol residue; wherein... The symbol represents the atom connected to the adjacent group in the general formula. CD, in each case, is either independently absent or independently a cyclodextrin residue, wherein at least one CD is present. The subscript m is an integer from 0 to 5. In these embodiments, the subscript m is 0, 1, 2, 3, 4, or 5. In some embodiments, the subscript m is 0. In some embodiments, the subscript m is 1. In some embodiments, the subscript m is 2. In some embodiments, the subscript m is 3. In some embodiments, the subscript m is 4. In some embodiments, the subscript m is 5. In some embodiments, AA 4 Or AA 5 Each of these, in each case, independently comprises an amino acid selected from alanine, valine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or citrulline, their derivatives, or combinations thereof. In some embodiments, AA 4 It is an amino acid selected from alanine, valine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or citrulline, their derivatives, or combinations thereof. In some embodiments, AA 4 It is lysine. In some implementations, AA 4 It is lysine or a derivative of lysine. In some embodiments, AA 5 It is valine-citrulline. In some implementation schemes, AA 5 It is citrulline-valine. In some implementation schemes, AA 5It is valine-alanine. In some implementation schemes, AA 5 It is alanine-valine. In some implementation schemes, AA 5 It is valine-glycine. In some implementation schemes, AA 5 It is glycine-valine. In some implementation schemes, AA 5 It is glutamic acid-valine-citrulline. In some implementation schemes, AA 5 It is glutamine-valine-citrulline. In some implementation schemes, AA 5 It is lysine-valine-alanine. In some implementation schemes, AA 5 It is lysine-valine-citrulline. In some implementations, AA 5 It is glutamic acid-valine-citrulline. In some embodiments, SP 1 In each case, C is chosen independently. 1-6 Alkylene, -NH-, -C(O)-, (-CH2-CH2-O) e -NH-CH2-CH2-(-O-CH2-CH2) e -C(O)-, -C(O)-(CH2) u -C(O)-, -C(O)-NH-(CH2) v - A group consisting of elements and their combinations, where subscript e is an integer from 0 to 4, subscript u is an integer from 1 to 8, and subscript v is an integer from 1 to 8. In some embodiments, SP 2 In each case, C is chosen independently. 1-6 Alkylene, -NH-, -C(O)-, (-CH2-CH2-O) e -NH-CH2-CH2-(-O-CH2-CH2) e -C(O)-, -C(O)-(CH2) u -C(O)-, -C(O)-NH-(CH2) v - A group consisting of elements and their combinations, where subscript e is an integer from 0 to 4, subscript u is an integer from 1 to 8, and subscript v is an integer from 1 to 8.

[0866] The phrase "active linker" or its abbreviation "RL" used in this invention refers to a monovalent group containing an active group and a linker group, denoted as... The active linker (RG) is the active group, and the linker (L) is the connecting group. The linker is any divalent group portion that bridges the active group to the payload. The linker also includes any trivalent group portion that bridges the active group, the cyclodextrin portion, and the payload. The active linker (RL), together with the payload to which they are linked, constitutes an intermediate (“linker-payload”) that can be used as a synthetic precursor for preparing the antibody-steroid conjugate of the present invention. The active linker contains an active group (“RG”), which is a functional group or group portion that reacts with the active portion of an antibody, a modified antibody, or an antigen-binding fragment thereof. The group portion resulting from the reaction of the active group with the antibody, a modified antibody, or an antigen-binding fragment thereof, together with the linker, constitutes the “binding linker” (“BL”) portion of the conjugate of the present invention. In some embodiments, the “active group” is a functional group or group portion (e.g., maleimide or NHS ester) that reacts with cysteine ​​or lysine residues of an antibody or an antigen-binding fragment thereof. In some embodiments, the “active group” is a functional group or group portion capable of undergoing click chemistry. In some embodiments of the click chemistry, the active group is an alkyne capable of undergoing a 1,3-cycloaddition reaction with an azide. Suitable active groups of this kind include, but are not limited to, strained alkynes, such as those suitable for strain-promoted cycloaddition of alkynes-azides (SPAAC), cyclic alkynes, such as cyclooctynes, benzocycloalkynes, and alkynes capable of undergoing a 1,3-cycloaddition reaction with an azide without a copper catalyst. Suitable alkynes also include, but are not limited to, DIBAC, DIBO, BARAC, substituted alkynes such as fluorinated alkynes, aza-cyclic alkynes, BCN and its derivatives. Linker-loads containing such active groups can be used to couple antibodies already functionalized with an azide group. Such functionalized antibodies include antibodies functionalized with an azide-polyethylene glycol group. In some embodiments, such functionalized antibodies are obtained by reacting an antibody containing at least one glutamine residue (e.g., heavy chain Q295) with a compound of formula H2N–LL–N3 in the presence of transglutaminase, wherein LL is, for example, a divalent polyethylene glycol group, or wherein LL is a trivalent group comprising polyethylene glycol and a cyclodextrin moiety. In some embodiments, the antibody is a functionalized antibody having the following structure:

[0867]

[0868] Where Ab is an antibody, R is a hydrocarbon group, n is an integer from 1 to 10, and w is an integer from 1 to 10. In some embodiments, R is ethylene. In some embodiments, n is 3. In some embodiments, w is 2 or 4.

[0869] In some embodiments, the active group is an alkyne, for example... It can be achieved through click chemistry with azides, such as The reaction forms click chemical products, such as Its regioisomers, or mixtures thereof. In some embodiments, the active group is an alkyne, for example... It can be achieved through click chemistry with azides, such as The reaction forms click chemical products, such as In some embodiments, the active group is an alkyne, for example... It can be achieved through click chemistry with azides, such as The reaction forms click chemical products, such as Its regioisomers, or mixtures thereof. In some embodiments, the active group is a functional group, such as... It reacts with cysteine ​​residues on the antibody or its antigen-binding fragment to form a bond, for example... Where Ab refers to an antibody or its antigen-binding fragment, and S refers to the S atom on a cysteine ​​residue, the functional group binding to Ab through the S atom on this cysteine ​​residue. In some embodiments, the active group is a functional group, for example... It reacts with lysine residues on antibodies or their antigen-binding fragments to form bonds, for example... Where Ab refers to an antibody or its antigen-binding fragment, and –NH- refers to the terminus on a lysine residue, through which the functional group binds to Ab. In some embodiments, the N atom on the lysine residue to which the functional group is attached is represented in this invention by the letter N above the bond, for example, .

[0870] In some implementations, RL is the formula (RL) A The monovalent group portion shown in the diagram;

[0871] RG–(SP 1 ) q –(A) z –(NR a ) s –(B) t –(CH2) u –(O) v –( SP 2 ) w –(RL A );

[0872] Wherein, RG is the active group;

[0873] A is an amino acid or peptide;

[0874] R a It is H or alkyl;

[0875] B is an aryl, heteroaryl, or heterocyclic alkyl group, wherein the aryl, heteroaryl, or heterocyclic alkyl group is optionally surrounded by an alkyl group, –OH, or –N–R. a R b replace;

[0876] SP 1 and SP 2 Each is an independent spacer group; and q, z, s, t, u, v and w are independently 0 or 1 in each case.

[0877] In some implementations, RL is RG–(SP 1 ) q –(A) z –. In some implementations, RL is RG–(SP 1 ) q –(A)2–. In some implementations, RL is the formula (RL) A1 The group portion shown is:

[0878]

[0879] (RL A1 )

[0880] Where R AA1 and R AA2 Each is an independent amino acid side chain. In formula RL A1 In some embodiments, SP 1 It is a divalent polyethylene glycol group, and RG is a group containing an alkyne that can undergo a 1,3-cycloaddition reaction with an azide.

[0881] In some implementations, RL has the following structures:

[0882] RG–(SP 1 )q–Z 1 –Z 2 –Z 3 0–1 –

[0883] in:

[0884] RG, SP 1 Both and q have the definition described in this invention;

[0885] Z 1 It is a polyethylene glycol group or a hexanoyl group;

[0886] Z 2 It is a dipeptide; and

[0887] Z 3 It is a PAB group.

[0888] In some other implementations, BL is a formula (BL B The trivalent group portion shown in the diagram;

[0889] –RG N –(SP 1 ) q –(A) z –(NR a ) s –(B) t –(CH2) u –(O) v –( SP 2 ) w –(BL B );

[0890] Among them RG N It has the definition described in this invention;

[0891] A is a tripeptide, wherein at least one of the amino acids in the tripeptide is directly or indirectly linked to the cyclodextrin moiety;

[0892] R a It is H or alkyl;

[0893] B is an aryl, heteroaryl, or heterocyclic alkyl group, wherein the aryl, heteroaryl, or heterocyclic alkyl group is optionally surrounded by an alkyl group, –OH, or –NR. a R b replace;

[0894] SP 1 and SP 2 Each is an independent spacer group; and q, z, s, t, u, v and w are independently 0 or 1 in each case.

[0895] In some embodiments, the cyclodextrin (CD) is directly linked to an amino acid residue, such as a lysine amino acid residue. This means that the CD is located one bond position away from the lysine amino acid covalent linker. In some of these embodiments, the covalent linker is also directly linked to the payload portion. This means that the covalent linker is located one bond position away from the payload (e.g., but not limited to the steroid payload described herein). In some of these embodiments, the covalent linker is also directly linked to the CD portion. This means that the covalent linker is located one bond position away from the CD (e.g., the CD described herein). In some of these embodiments, the covalent linker is a lysine amino acid or a derivative thereof.

[0896] In some embodiments, the CD is indirectly linked to a covalent linker in a linking group (e.g., BL). This means that the CD is located away from the covalent linker by more than one bond position. It also means that the CD is linked to the covalent linker via another group portion. For example, the CD may be linked to a maleimide group, which in turn is linked to a polyethylene glycol group, which is then linked to the covalent linker. In some of these embodiments, the covalent linker is also indirectly linked to the effective load portion. This means that the covalent linker is located away from the effective load (e.g., but not limited to, the steroid effective load of the present invention) by more than one bond position. It also means that the covalent linker is linked to the effective load via another group portion. For example, the covalent linker may be linked to a dipeptide, such as, but not limited to, Val-Ala or Val-Cit, which may be linked to p-aminobenzoyl, which may be linked to the effective load. In some of these embodiments, the covalent linker is also indirectly linked to a cyclodextrin portion. This means that the covalent linker is located away from the cyclodextrin (e.g., the cyclodextrin described in this invention) by more than one bond position. It also means that the covalent linker is connected to the cyclodextrin via another functional group. For example, the covalent linker may be connected to a polyethylene glycol group, which may be connected to an active group, which may be connected to the cyclodextrin. In some of these embodiments, the covalent linker is a lysine amino acid or a derivative thereof.

[0897] In some implementations, BL is –RG N –(SP 1 ) q –(A) z –. In some implementations, BL is –RG N –(SP 1 ) q –(A)2–. In some implementations, BL is the formula (BL B1 The group portion shown is:

[0898]

[0899] (BL B1 )

[0900] Where R AA1 and R AA2 Each is an independent amino acid side chain. R AA3 These are amino acid side chains directly or indirectly linked to the cyclodextrin moiety. (In formula RL) B1 In some embodiments, SP 1 It is a divalent polyethylene glycol group, and RG N It is a 1,3-cycloaddition adduct formed by the reaction between alkynes and azides.

[0901] In some embodiments, A is In some of these embodiments, R AA1 It is an amino acid side chain, R AA2 It is an amino acid side chain, and R AA3 It is an amino acid side chain that is directly or indirectly connected to the cyclodextrin moiety.

[0902] In some embodiments, A is ,in This indicates a bond that is directly or indirectly connected to the cyclodextrin moiety.

[0903] In some embodiments, including any of the foregoing embodiments, CD is independently selected from:

[0904] .

[0905] In some embodiments, the CD is .

[0906] In some embodiments, the CD is .

[0907] In some embodiments, the CD is .

[0908] In some embodiments, the CD is .

[0909] In some embodiments, the CD is .

[0910] In some embodiments, the CD is .

[0911] In some embodiments, A is .

[0912] In some embodiments, the RL is linked to a tertiary amine. For example, if the steroid is a compound such that: Then the RL can be connected to the tertiary amine as follows:

[0913] .

[0914] In some embodiments, the present invention provides the following compounds:

[0915] ,

[0916] in:

[0917] RL is an active linker as defined above;

[0918] R a and Rb In each case, it is independently –H or alkyl.

[0919] In some embodiments, the RG of the present invention is selected from click-chemically active groups.

[0920] In some other embodiments, the RG of the present invention is selected from groups that react with cysteine ​​or lysine residues on an antibody or its antigen-binding fragment.

[0921] In some implementation schemes, RG is:

[0922] .

[0923] In some embodiments, RG is In other embodiments, RG is In some other embodiments, RG is In some embodiments, RG is In other embodiments, RG is In other embodiments, RG is .

[0924] In some implementation schemes, SP 1 Optional from:

[0925] .

[0926] In some embodiments, SP 1 yes In some other embodiments, SP 1 yes In other embodiments, SP 1 yes In other embodiments, SP 1 yes In some other embodiments, SP 1 yes .

[0927] In any of the above embodiments, the subscripts a, b, and c are, in each case, independent integers from 1 to 20.

[0928] In any of the compounds shown in formula (II), (IIa), (IIb), or (IIc), SP 1 Optional from:

[0929] .

[0930] In some embodiments, SP 1 yes In some embodiments, SP 1 yes , In some embodiments, SP 1 yes In some embodiments, SP 1 yes In some embodiments, SP 1 yes .

[0931] In some embodiments, SP 1 yes In some embodiments, SP 1 yes In some embodiments, SP 1 yes In some embodiments, SP 1 yes In some embodiments, SP 1 yes In some embodiments, SP 1 yes .

[0932] In some implementation schemes, RL–SP 1 The following groups can be freely selected:

[0933] In some of these embodiments, the subscripts b, c, and d are, in each case, independent integers from 1 to 20.

[0934] In some embodiments, RL–SP 1 -yes In some embodiments, RL–SP 1 yes In some embodiments, RL–SP 1 yes In some embodiments, RL–SP 1 yes In some embodiments, RL–SP 1 yes In some embodiments, RL–SP 1 yes .

[0935] In any of the compounds shown in formula (II), (IIa), (IIb), or (IIc), RL–SP 1 Selected from:

[0936]

[0937] .

[0938] In some implementations, A is a peptide selected from valine-citrulline, citrulline-valine, lysine-phenylalanine, phenylalanine-lysine, valine-asparagine, asparagine-valine, threonine-asparagine, asparagine-threonine, serine-asparagine, asparagine-serine, phenylalanine-asparagine, asparagine-phenylalanine, leucine-asparagine, asparagine-leucine, isoleucine-asparagine, asparagine-isoleucine, glycine-asparagine, asparagine-glycine, glutamic acid-asparagine, asparagine-glutamic acid, citrulline-asparagine, asparagine-citrulline, alanine-asparagine, or asparagine-alanine.

[0939] In some embodiments, A is valine-citrulline, or citrulline-valine.

[0940] In some embodiments, A is valine-alanine, or alanine-valine.

[0941] In some embodiments, A is valine.

[0942] In some embodiments, A is alanine.

[0943] In some embodiments, A is citrulline.

[0944] In some embodiments, A is In some of these embodiments, R AA1 It is an amino acid side chain, and R in it AA2 It is an amino acid side chain.

[0945] In some embodiments, A is .

[0946] In some embodiments, A is .

[0947] In some embodiments, R a It is H.

[0948] In some embodiments, R a It is an alkyl group.

[0949] In some embodiments, R a It is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, or pentyl.

[0950] In some implementations, B is aryl.

[0951] In some embodiments, B is phenyl.

[0952] In some embodiments of the compounds shown in formula (II), (IIa), (IIb), or (IIc), B is phenyl or pyridyl.

[0953] In some embodiments of the present invention, B is:

[0954] .

[0955] In these embodiments, R 10 It includes alkyl, alkenyl, alkynyl, alkoxy, aryl, alkylaryl, arylalkyl, halogen, haloalkyl, haloalkoxy, heteroaryl, heterocyclic alkyl, hydroxyl, cyano, nitro. NR a R b Or azide group. In these embodiments, the subscripts p and m are each independently selected from integers from 0 to 4. In some embodiments of the invention, B is: In these embodiments, p is 0, 1, 2, 3, or 4. In some of these embodiments, R 1 In each case, it is independently alkyl, alkoxy, haloalkyl, or halogen. In some embodiments, R 1 It is an alkyl group. In some embodiments, R 1 It is an alkoxy group. In some embodiments, R 1 It is a haloalkyl group. In some embodiments, R 1 It is halogen.

[0956] In formula (RL) A In some implementations of ), the –(NR) a ) s –(B) t –(CH2) u –(O) v –( SP 2 ) w yes:

[0957] .

[0958] The present invention also provides a connector-load for budesonide or diflubenzuron. In some embodiments, the present invention provides a connector-load having the following structure:

[0959]

[0960] RL stands for active linker.

[0961] Examples of a connector-payload include, but are not limited to:

[0962]

[0963]

[0964]

[0965]

[0966]

[0967]

[0968] And its salt.

[0969] E. Pharmaceutical compositions and treatment methods

[0970] This invention includes methods for treating diseases, conditions, or illnesses (e.g., inflammatory diseases and autoimmune diseases) or controlling their symptoms, comprising administering a therapeutically effective amount of one or more compounds disclosed herein. This includes any disease, condition, or illness related to glucocorticoid receptors, glucocorticoid binding, and / or glucocorticoid receptor signaling. Such methods include administering to a patient the steroid payload or protein conjugate thereof described herein. Therefore, what is included in this invention is a method for treating diseases, conditions, or illnesses related to glucocorticoid receptors, comprising administering formula (I), (I) to a patient suffering from said disease, condition, or illness. 1 The present invention provides a method for treating diseases, conditions, or illnesses associated with glucocorticoid receptors, including administration of compounds selected from formula (A), (A... 1 ), (A 2 ), (A 3 ), (A 4 ), (A 5 ), (A 6 ), (A 7 ), (I), (I) 1 Protein conjugates of compounds comprising the group consisting of (PIa), (PIb–1), (PIb–2), (PIc–1), (PIc–2), (PId–1), (PId–2), (PIe–1), (PIe–2), (PII), (PIIa), (PIIb), (PIII), (PIIIa), (PIIIb), (PIV), (PV), (PVa), (PVb), (PVI), (PVII), (PVIIa), (PVIIb), (PVIIb–1), (PVIIb–2), (PVIII), and combinations thereof.

[0971] In some implementations, the disease, condition, or illness is an allergic state, including but not limited to asthma, atopic dermatitis, contact dermatitis, drug allergic reactions, perennial or seasonal allergic rhinitis, and serum sickness; skin diseases, including but not limited to bullous herpetic dermatitis, exfoliative erythroderma, mycosis fungoides, pemphigus, and erythema multiforme severe (Stevens-Johnson syndrome); endocrine disorders, including but not limited to primary or secondary adrenal insufficiency, congenital adrenal hyperplasia, cancer-related hypercalcemia, and non-suppurative thyroiditis; gastrointestinal diseases; hematologic disorders, including but not limited to acquired (autoimmune) hemolytic anemia, congenital (erythroid) dysplastic anemia (Diamond-Blackfan anemia), adult idiopathic thrombocytopenic purpura, pure red cell aplasia, and secondary thrombocytopenia; trichinosis; tuberculous meningitis with or about to be blocked subarachnoid space; neoplastic diseases, Including but not limited to leukemia and lymphoma; neurological disorders, including but not limited to acute exacerbations of multiple sclerosis, cerebral edema associated with primary or metastatic brain tumors, craniotomy, or head injury; ophthalmic disorders, including but not limited to sympathetic ophthalmia, temporal arteritis, uveitis, and ocular inflammation unresponsive to topical corticosteroids; renal disorders, including but not limited to diuresis or proteinuria relief induced by idiopathic nephrotic syndrome or lupus erythematosus; respiratory disorders, including but not limited to beryllium poisoning, fulminant or disseminated pulmonary tuberculosis when used concurrently with appropriate anti-tuberculosis chemotherapy, idiopathic eosinophilic pneumonia, symptomatic sarcoidosis; and rheumatic disorders, including but not limited to adjunctive treatment for acute gouty arthritis, acute rheumatic carditis, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, including juvenile rheumatoid arthritis (to help patients get through acute attacks or exacerbations), and for dermatomyositis, polymyositis, and systemic lupus erythematosus.

[0972] In some embodiments, the present invention provides a method for treating a disease, symptom, or condition selected from autoimmune diseases, allergies (hypersensitivity reactions), arthritis, asthma, respiratory disorders, blood disorders, cancer, collagen diseases, connective tissue diseases, skin diseases, eye diseases, endocrine problems, immune diseases, inflammatory diseases, intestinal diseases, gastrointestinal diseases, neurological diseases, organ transplant conditions, rheumatoid diseases, skin diseases, swelling conditions, wound healing conditions, and combinations thereof, including the administration of the steroid payload or conjugates described in the present invention.

[0973] In some embodiments, the autoimmune disease is selected from multiple sclerosis, autoimmune hepatitis, herpes zoster, systemic lupus erythematosus (i.e., lupus), myasthenia gravis, Duchenne muscular dystrophy, and sarcoidosis. In some embodiments, the respiratory disorder is selected from asthma, chronic obstructive pulmonary disease, bronchitis, and acute bronchitis. In some embodiments, the cancer is selected from leukemia, lymphocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), and multiple myeloma. In some embodiments, the collagen disease is systemic lupus erythematosus. In some embodiments, the eye disease is keratitis. In some embodiments, the endocrine problem is selected from Addison's disease, adrenal insufficiency, adrenal cortex hyperplasia, and congenital adrenal hyperplasia. In some embodiments, the inflammatory disease is selected from joint inflammation, tendinitis, bursitis, epicondylitis, Crohn's disease, inflammatory bowel disease, lipopneumonia-thyroiditis, urticaria, pericarditis, nephrotic syndrome, and uveitis. In some embodiments, the intestinal disease is selected from ulcerative colitis, Crohn's disease, and inflammatory bowel disease. In some embodiments, the rheumatoid disease is selected from rheumatoid arthritis, polymyalgia rheumatica, psoriatic arthritis, ankylosing spondylitis, and systemic lupus erythematosus. In some embodiments, the skin disease is selected from psoriasis, eczema, and poisonivy caused by contact with toxic lacquer. In some embodiments, the neurological disease is chronic inflammatory demyelinating polyradiculoneuropathy.

[0974] In some embodiments, the compounds of the present invention are administered to patients to treat acute inflammatory events, including but not limited to shock, cerebral edema, and graft-versus-host disease. In some embodiments, the compounds of the present invention are administered to treat lympholysis, including but not limited to those associated with hematologic malignancies such as leukemia, lymphoma, and myeloma.

[0975] In some embodiments, the present invention provides a method for reducing inflammation in a subject with this need, comprising administering a therapeutically effective amount of the steroid or its conjugate described herein to the subject with this need. In some embodiments, the present invention provides a method for modulating the immune system of a subject with this need, comprising administering a therapeutically effective amount of the steroid or its conjugate described herein to the subject with this need. In some embodiments, the present invention provides a method for modulating cortisol levels in a subject with this need, comprising administering a therapeutically effective amount of the steroid or its conjugate described herein to the subject with this need. In some embodiments, the present invention provides a method for reducing lymphocyte migration in a subject with this need, comprising administering a therapeutically effective amount of the steroid or its conjugate described herein to the subject with this need. In some embodiments, the present invention provides a method for treating hypercalcemia caused by cancer, Meniere's disease, migraine, cluster headache, severe aphthous ulcers, laryngitis, severe tuberculosis, Herxheimer's reaction to syphilis, decompensated heart failure, allergic rhinitis, or nasal polyps, comprising administering to a subject in need of the steroid payload or a conjugate thereof described herein. In some embodiments, the compounds disclosed herein may be used to treat inflammatory bowel disease, Crohn's disease, or ulcerative colitis. In some embodiments, the disease, condition, or ailment is a chronic inflammatory disease, including but not limited to asthma, skin infections, and eye infections. In some embodiments, the compounds described herein are used for immunosuppression in patients undergoing organ transplantation.

[0976] In some embodiments, the steroid payload and its conjugates described in this invention are administered to patients to treat neurological disorders related to GR signaling, including but not limited to mental illnesses such as schizophrenia, drug addiction, post-traumatic stress disorder (PTSD), mood disorders, substance abuse, stress, and anxiety. In some embodiments, the steroid payload and its conjugates described in this invention are administered to patients to treat visual system disorders, including but not limited to ocular inflammation (e.g., conjunctivitis, keratitis, uveitis), macular edema, and macular degeneration. In some embodiments, the steroid payload and its conjugates described in this invention are administered to patients to treat cardiovascular diseases. In some embodiments, the steroid payload and its conjugates described in this invention are administered to patients to treat glucose and / or liver metabolic disorders. In some embodiments, the steroid payload and its conjugates described in this invention are administered to patients to treat musculoskeletal system disorders. In some embodiments, the steroid payload and its conjugates described in this invention are administered to patients to treat inflammatory skin conditions such as eczema and psoriasis.

[0977] The protein conjugates described in this invention provide a means of targeted delivery of their steroid payload to specific cellular or organ systems, thereby reducing or preventing side effects caused by the administration of free, unconjugated steroid payloads. Therefore, this invention provides a method for treating diseases, conditions, or illnesses related to glucocorticoid receptors, comprising using formula (I) or (I...). 1 The conjugate is administered to a patient suffering from the aforementioned disease, condition, or symptom, wherein the side effects associated with the free steroid payload of the conjugate are reduced. Furthermore, the present invention provides for the use of formula (I) or (I...). 1 A method for delivering a compound to cells, comprising reacting the cells with a compound of formula (I) or (I) 1 The compound is contacted with a protein conjugate, wherein the protein conjugate comprises an antibody or an antigen-binding fragment thereof that binds to the cell surface antigen.

[0978] The compounds described in this invention can be administered alone or in combination with one or more adjunctive therapeutic agents. The one or more adjunctive therapeutic agents may be administered before, concurrently with, or shortly after administration of the compounds described in this invention. This invention also includes pharmaceutical compositions comprising any of the compounds described in this invention in combination with one or more adjunctive therapeutic agents, and methods of treatment comprising administering such combinations to patients in need.

[0979] Suitable adjunctive therapies include, but are not limited to, secondary glucocorticoids, autoimmune therapies, hormones, biologics, or monoclonal antibodies. Suitable therapies also include, but are not limited to, any pharmaceutically acceptable salts, acids, or derivatives of the compounds described herein.

[0980] The compounds described in this invention can also be used in combination with or in combination with antiviral agents, antibiotics, analgesics, corticosteroids, steroids, oxygen molecules, antioxidants, COX inhibitors, cardioprotective agents, metal chelating agents, IFN-γ, and / or NSAIDs, and / or be formulated together.

[0981] In some embodiments of the method described in this invention, multiple doses of the compound of the invention (or a pharmaceutical composition comprising a combination of the compound of the invention with any additional therapeutic agents mentioned in this invention) may be administered to a subject over a predetermined period of time. The method of this aspect of the invention comprises sequentially administering multiple doses of the compound of the invention to a subject. As used in this invention, "sequential administration" means administering each dose of the compound to a subject at different time points, for example, on different numbers of days separated by predetermined intervals (e.g., hours, days, weeks, or months). The invention includes a method comprising sequentially administering a single initial dose of the compound of the invention to a patient, followed by one or more second doses of the compound, and optionally one or more subsequent third doses of the compound.

[0982] The terms “initial dose,” “second dose,” and “third dose” refer to the order of administration of the compounds described in this invention. Thus, the “initial dose” is the dose administered at the start of a treatment regimen (also known as the “baseline dose”); the “second dose” is the dose administered after the initial dose; and the “third dose” is the dose administered after the second dose. The initial, second, and third doses may all contain the same amount of the compounds of this invention, but may generally differ from each other in terms of administration frequency. In some embodiments, the amount of the compound contained in the initial, second, and / or third doses varies from one another during treatment (e.g., adjusted upwards or downwards as appropriate). In some embodiments, at the start of a treatment regimen, two or more doses (e.g., 2, 3, 4, or 5) are administered as a “loading dose,” followed by subsequent doses (e.g., a “maintenance dose”) administered less frequently.

[0983] In some exemplary embodiments of the present invention, each second and / or third dose is administered for 1 to 26 weeks immediately following the aforementioned dose (e.g., 1, 1½, 2, 2½, 3, 3½, 4, 4½, 5, 5½, 6, 6½, 7, 7½, 8, 8½, 9, 9½, 10, 10½, 11, 11½, 12, 12½, 13, 13½, 14, 14½, 15, 15½, 16, 16½, 17, 17½, 18, 18½, 19, 19½, 20, 20½, 21, 21½, 22, 22½, 23, 23½, 24, 24½, 25, 25½, 26, 26½, or more). The phrase “immediately following the aforementioned dose” as used herein refers to administering the dose of the compound of the present invention to the patient in a sequence of multiple doses, prior to the administration of the next dose, in a sequence in which no interventional dose is present.

[0984] The method of this aspect of the invention may comprise administering any number of two and / or three doses of the compound of the invention to a patient. For example, in some embodiments, only a single two-dose is administered to the patient. In other embodiments, two or more two-dose doses (e.g., 2, 3, 4, 5, 6, 7, 8 or more) are administered to the patient. Similarly, in some embodiments, only a single three-dose dose is administered to the patient. In other embodiments, two or more three-dose doses (e.g., 2, 3, 4, 5, 6, 7, 8 or more) are administered to the patient. The dosing regimen may be continued indefinitely for the lifespan of a particular subject, or until such treatment is no longer necessary or advantageous.

[0985] In embodiments involving multiple secondary doses, each secondary dose can be administered / dosed at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient 1 to 2 weeks or 1 to 2 months immediately following the aforementioned dose. Similarly, in embodiments involving multiple tertiary doses, each tertiary dose can be administered / dosed at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the patient 2 to 12 weeks immediately following the aforementioned dose. In some embodiments of the invention, the frequency of administering secondary and / or tertiary doses to the patient may vary during the treatment regimen. The dosing frequency may also be adjusted by the physician during treatment based on the individual patient's needs following clinical examination.

[0986] The present invention includes a dosing regimen in which a patient is given two to six loading doses at a first frequency (e.g., once a week, once every two weeks, once every three weeks, once a month, once every two months, etc.), followed by two or more maintenance doses administered to the patient in a less frequent manner. For example, according to this aspect of the invention, if the loading dose is administered once a month, then the maintenance dose may be administered once every six weeks, once every two months, once every three months, etc.

[0987] This invention includes pharmaceutical compositions of compounds and / or conjugates of formulas (I) and (II) as described herein, for example, compositions comprising the compounds described herein, their salts, stereoisomers, polymorphs, and pharmaceutically acceptable carriers, diluents, and / or excipients. Examples of suitable carriers, diluents, and excipients include, but are not limited to: buffers for maintaining a suitable pH of the composition (e.g., citrate buffer, succinate buffer, acetate buffer, phosphate buffer, lactate buffer, oxalate buffer, etc.), carrier proteins (e.g., human serum albumin), nanoparticles, saline solutions, polyols (e.g., trehalose, sucrose, xylitol, sorbitol, etc.), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxolate, etc.), antimicrobial agents, and antioxidants.

[0988] In some embodiments, the present invention provides a method for treating a disease, symptom, or condition, comprising administering a therapeutically effective amount of a compound of formula I, III, or a pharmaceutical composition thereof to a patient suffering from said symptom.

[0989] In some embodiments, the present invention provides a method for treating a disease, symptom, or condition, comprising administering a therapeutically effective amount of the compound or pharmaceutical composition thereof described in the present invention to a patient suffering from said symptom.

[0990] In some embodiments, the present invention provides a method for treating diseases, symptoms, or conditions selected from the group consisting of immune diseases, autoimmune diseases, inflammation, asthma, or inflammatory bowel disease, Crohn's disease, and ulcerative colitis.

[0991] In some embodiments, the present invention provides a method for treating a disease, symptom, or condition by targeting an antigen (e.g., an antigen expressing a cell surface), wherein steroid administration can achieve therapeutic benefits, including the administration of the conjugates described in the present invention. In some embodiments, the antigen is AXL, BAFFR, BCMA, BCR – list components, BDCA2, BDCA4, BTLA, BTNL2, BTNL3, BTNL8, BTNL9, C10orf54, CCR1, CCR3. CCR4, CCR5, CCR6, CCR7, CCR9, CCR10, CD11c, CD137, CD138, CD14, CD168, CD177, CD19, CD20, CD209, CD209L, CD22, CD226, CD248, CD25, CD27, CD274, CD276, CD28, CD30 , CD300A, CD33, CD37, CD38, CD4, CD40, CD44, CD45, CD47, CD46, CD48, CD5, CD52, CD55, CD56, CD59, CD62E, CD68, CD69, CD70, CD74, CD79a, CD79b, CD8, CD80, CD86, CD90.2. CD96, CLEC12A, CLEC12B, CLEC7A, CLEC9A, CR1, CR3, CRTAM, CSF1R, CTLA4, CXCR1 / 2, CXCR4, CXCR5, DDR1, DDR2, DEC–205, DLL4, DR6, FAP, FCamR, FCMR, FcR's, Fire, GITR, HHLA2, HLA Class II, HVEM, ICOSLG, IFNLR1, IL10R1, IL10R2, IL12R, IL13RA1, IL13RA2, IL15R, IL17RA, IL17RB, IL17RC, IL17RE, IL20R1, IL20R2, IL21R, IL22R1, IL22RA , IL23R, IL27R, IL29R, IL2Rg, IL31R, IL36R, IL3RA, IL4R, IL6R, IL5R, IL7R, IL9R, Integrins, LAG3, LIFR, MAG / Siglec–4, MMR, MSR1, NCR3LG1, NKG2 D, NKp30, NKp46, PDCD1, PROKR1, PVR, PVRIG, PVRL2, PVRL3, RELT, SIGIRR, Siglec-1, Siglec-10, Siglec-5, Siglec-6, Siglec-7, Siglec-8, Siglec-9, SIRPA, SLAMF7, TACI, TCR-list components / assoc, PTCRA, TCRb, CD3z, CD3, TEK, TGFBR1, TGFBR2, TGFBR3, TIGIT, TLR2, TLR4, TROY, TSLPR, TYRO, VLDLR, VSIG4, or VTCN1. In some embodiments, the antigen is IL2R-γ.

[0992] In some embodiments, the present invention provides methods for treating diseases, symptoms, or conditions selected from immune diseases, autoimmune diseases, inflammatory diseases, skin diseases, or gastrointestinal diseases.

[0993] In some embodiments, the disease is Crohn's disease, ulcerative colitis, Cushing's syndrome, adrenal insufficiency, or congenital adrenal hyperplasia.

[0994] In some embodiments, the disease is inflammation, asthma, or inflammatory bowel disease.

[0995] In some embodiments, the disease is an autoimmune disease selected from multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, psoriasis, or eczema.

[0996] In some embodiments, the present invention provides a method for reducing or improving the side effects of chemotherapy, wherein the method comprises administering a therapeutically effective amount of the compound or composition of the present invention to a patient suffering from the condition.

[0997] In some embodiments, the present invention provides a method for reducing or improving the side effects of immunosuppressive therapy, wherein the method comprises administering a therapeutically effective amount of the compound or composition of the present invention to a patient suffering from said condition.

[0998] In some embodiments, the present invention provides a method for treating cancer, wherein the method comprises administering a therapeutically effective amount of the compound or composition of the present invention to a patient suffering from said disease. In some embodiments, said cancer is selected from acute lymphoblastic leukemia, chronic lymphoblastic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma (NHL), or multiple myeloma, and others.

[0999] F. Example

[1000] The following non-limiting examples illustrate certain implementation schemes.

[1001] Unless otherwise expressly stated, reagents and solvents are derived from commercial sources such as Sinopharm Chemical Reagent Co. (SCRC), Sigma-Aldrich, Alfa, or other suppliers.

[1002] Recorded on Bruker AVIII 400 or Bruker AVIII 500 1 ¹H NMR and other NMR spectra. Data were processed using Nuts or MestReNova software, and the proton shift in parts per million (ppm) under a low magnetic field with internal standard tetramethylsilane was determined.

[1003] HPLC-MS determinations were performed on an Agilent 1200 HPLC / 6100 SQ system under the following conditions:

[1004] Method A for HPLC-MS determination consisted of the following mobile phases: A: water (0.01% trifluoroacetic acid, TFA) and B: acetonitrile (0.01% TFA). A gradient phase of 5% B was used, which was increased to 95% B at a flow rate of 1.0 mL / min over a 15-minute (min) time interval. A SunFire C18 column, 4.6 x 50 mm, 3.5 µm, was used. The column temperature was 50 ºC. Detectors included an analog-to-digital converter (ADC-ELSD), a diode array detector (214 nm and 254 nm), and electrospray ionization-atmospheric pressure ionization (ES-API).

[1005] Method B for HPLC-MS determination consisted of the following mobile phases: A: water (10 mM NH4HCO3) and B: acetonitrile. A gradient phase of 5% B was used, which was increased to 95% B at a flow rate of 1.0 mL / min over a 15-minute (min) time interval. An XBridge C18 column, 4.6 x 50 mm, 3.5 µm, was used. The column temperature was 50ºC. Detectors included an ADC ELSD, a DAD (214 nm and 254 nm), and a mass detector (MSD ES-API).

[1006] LC-MS determinations were performed on an Agilent 1200 HPLC / 6100 SQ system under the following conditions:

[1007] Method A for LC-MS determination was performed on a WATERS 2767 instrument. The columns were Shimadzu Shim-Pack, PRC-ODS, 20 x 250 mm, 15 μm, two connected in series. The mobile phases were A: water (0.01% TFA) and B: acetonitrile (0.01% TFA). The gradient phase was 5% B, which was increased to 95% B over a 3-minute time interval at a flow rate of 1.8–2.3 mL / min. The column used was a SunFire C18, 4.6 x 50 mm, 3.5 μm. The column temperature was 50 ºC. Detectors included an analog-to-digital converter (ELSD, evaporative light scattering detector), a diode array detector (DAD) (214 nm and 254 nm), and an ES-API.

[1008] Method B for LC-MS determination was performed on a Gilson GX-281 instrument. The column was an Xbridge PrepC18 10 μm OBD, 19 x 250 mm. The mobile phase was A: water (10 mM NH4HCO3) and B: acetonitrile. The gradient phase was 5% B, which was increased to 95% B over a 3-minute time interval at a flow rate of 1.8–2.3 mL / min. The column used was an XBridge C18, 4.6 x 50 mm, 3.5 µm. The column temperature was 50ºC. Detectors included an ADC ELSD, a DAD (214 nm and 254 nm), and a mass-selective detector (MSD) (ES-API).

[1009] Preparative high-performance liquid chromatography (preparative HPLC) was performed on a Gilson GX-281 instrument. Two solvent systems were used, one acidic and one basic. The acidic solvent system consisted of a Waters SunFire 10 µm C18 column (100 Å, 250 x 19 mm). Solvent A for the preparative HPLC was an aqueous solution of 0.05% TFA, and solvent B was acetonitrile. Elution conditions were a linear gradient, increasing from 5% solvent B to 100% solvent B at a flow rate of 30 mL / min over a 20-minute time period. The basic solvent system consisted of a Waters Xbridge 10 µm C18 column (100 Å, 250 x 19 mm). Solvent A for the preparative HPLC was an aqueous solution of 10 mM ammonium bicarbonate (NH4HCO3), and solvent B was acetonitrile. The elution conditions were a linear gradient, which increased from 5% solvent B to 100% solvent B at a flow rate of 30 mL / min over a 20-minute period.

[1010] Rapid chromatography was performed on the Biotage instrument using the Agela Flash Column silica-CS. Unless otherwise explicitly stated, reversed-phase rapid chromatography was performed on the Biotage instrument using the Boston ODS or Agela C18.

[1011] The following abbreviations are used in the embodiments and throughout the specification:

[1012]

[1013]

[1014]

[1015]

[1016]

[1017]

[1018] Preparation method

[1019] Example 1

[1020] This embodiment illustrates a method for preparing a material with properties in C 22 A method for positional stereochemical control of desonide chemical derivatives. Figure 1 and 2 In the C of compounds 7, 8 and 11 22 Positions are indicated by an asterisk (*). According to... Figure 1 and 2 The synthetic route shown is for C 22 The location of steroidal compounds with stereochemical control is synthesized.

[1021] Make Dyned (1), whose common name is (1 S ,2 S 4 R 8 S 9 S ,11 S ,12 S ,13 R )–11–hydroxy–8–(2–hydroxyacetyl)–6,6,9,13–tetramethyl–5,7–dioxapentane [10.8.0.0] 2,9 .0 4,8 .0 13,18 Eicosane-14,17-dien-16-one, reacted with isobutyric anhydride (compound 2) to esterify the primary alcohol position of compound 1, yielding intermediate 3. Compound 3 was then transacetylated with a series of aldehydes (4-1; 4-2; 4-3; and 4-4, each distinguished relative to the R-CHO group indicated to the right of these numerical designations) under strong acid HClO4 conditions to yield alcohol 5 and ester 6. Figure 1 As shown, these aldehyde compounds are relative to Figure 1 The R groups shown are different from each other.

[1022] Alcohol 5 and ester 6 were both separated by column chromatography.

[1023] Each alcohol 5 or ester 6 reacts with diethylamine to remove the Fmoc- group or with Fe. / The NH4Cl reaction reduces the nitro group, thereby providing the nitro group at C10 and C20 respectively. 22 The diastereomers 7 and 8 have R / S stereochemistry.

[1024] As described below, the R and S epimers are separated and their characteristics are identified. R -andS - Configuration. Separate, for example Figure 1 R-epimeters of compounds 7 and 8, and through 1 ¹H NMR confirmed that it comprised over 90% of the majority of stereoisomers. 2D-NOESY spectroscopy determined the Ci of each epimer. 22 Configuration.

[1025] Table 1 below shows the steroid compounds prepared using the method described in this invention.

[1026] Table 1 - Structural formulas and chemiphysical properties of the compounds

[1027]

[1028]

[1029]

[1030]

[1031] Table 2 below shows the steroid compounds prepared using the method described in this invention.

[1032] Table 2 - Structural formulas and chemiphysical properties of compounds

[1033]

[1034]

[1035]

[1036] Table 3 below shows the effective load of the connector obtained using the method described in this invention.

[1037] Table 3. Examples of Connectors-Payloads

[1038]

[1039]

[1040]

[1041]

[1042] Table 4 below shows the effective load of the connector obtained using the method described in this invention.

[1043] Table 4. Examples of Connectors-Payloads

[1044]

[1045]

[1046]

[1047]

[1048] Example 2

[1049] This embodiment illustrates a method for preparing chemical derivatives of budesonide, dexamethasone, and flumethasone. Typically, as... Figure 2 , 3 Figures 4 and 4 illustrate these methods.

[1050] like Figure 2 As shown, budesonide (9) or its difluoro analogue (9B) methanesulfonate analogues react with alkylamine compounds or substituted phenolic compounds (10) to give compounds (11) containing aniline or amine, such as Figure 2 Compounds 11-1 to 11-23 in the group.

[1051] like Figure 3 As shown, the methanesulfonate analogue of dexamethasone (12) reacts with alkylamine compounds or substituted phenolic compounds (10) to give Figure 3 Compounds containing aniline or amine (14) or (15).

[1052] like Figure 4 As shown, the methanesulfonate analogue of flumethasone (13) reacts with alkylamine compounds or substituted phenolic compounds (10) to obtain Figure 4 Compounds containing aniline or amine (16).

[1053] As described below, 11-5 in Table 1 S and 11-5 R Stereochemically pure epimers were obtained by chiral separation from a mixture of their respective R / S isomers. The absolute stereochemistry of each compound was determined by 2D-NOESY. 2D-NOESY spectra are shown in 11-5. R H 22 and H 18 Related, and in 11-5 S H 22 and H 18 There is no correlation between them. Similarly, compound 7-1 in Table 1 was identified by 2D-NOESY. S 7-1 R 7-4 R 8-1 R 11-6 S11-6 R 11-7 R 11-8 R 11-12 R 11-13 R 、and 11-19 R C 22 The chiral center of position.

[1054] Example 3

[1055] This example illustrates the preparation of compound 7-1 in Table 1. S and 7-1 R The method. This embodiment relates to... Figure 1 The numbered compounds in the list.

[1056] 2–[(1 S ,2 S 4 R 8 S 9 S ,11 S ,12 S ,13 R )–11–hydroxy–9,13–dimethyl–6–(4–nitrophenyl)–16–oxy–5,7–dioxapentane [10.8.0.0] 2,9 .0 4,8 .0 13,18 [eicosyl-14,17-dien-8-yl]-2-oxoethyl 2-methylpropionate (5-1) and

[1057] (1 S ,2 S 4 R 8 S 9 S ,11 S ,12 S ,13 R )–11–hydroxy–8–(2–hydroxyacetyl)–9,13–dimethyl–6–(4–nitrophenyl)–5,7–dioxapentane [10.8.0.0] 2,9 .0 4,8 .0 13,18 [Eicosane–14,17–diene–16–one (6–1)]

[1058] Step 1: Compound 3 was synthesized by reacting desonide (1) with isobutyric acid in acetone according to the method in US2007 / 135398, the entire contents of which are incorporated herein by reference for all purposes.

[1059] Step 2: At 0°C, an aqueous solution of perchloric acid (70%, 1.90 g, 1.33 mmol) was added dropwise to a nitropropane (20 mL) solution of compound 3 (320 mg, 0.657 mmol), followed by the addition of 4-nitrobenzaldehyde (4-1, 151 mg, 1.00 mmol). The resulting mixture was stirred overnight at room temperature and then diluted with ethyl acetate (80 mL). The resulting mixture was washed with saturated sodium bicarbonate aqueous solution (30 mL x 3) and then with brine (30 mL x 2). The resulting solution was then dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by rapid chromatography, eluting with a petroleum ether solution of 0-35% ethyl acetate, to give compound (5-1) as a yellow solid (120 mg, yield 32%), which is based on... 1 The ratio of H NMR is 3 / 1 of 5 R / 5 S A mixture of epimers was further eluted with a petroleum ether solution of 60-70% ethyl acetate to give compound (6-1) as a yellow solid (150 mg, yield 36%), which is based on... 1 The ratio of H NMR is 5 / 1 of 6 R / 6 S A mixture of epimers (R / S not determined).

[1060] Compound (5–1): ESI m / z: 580 (M + H) + . 1 H NMR (CDCl3, 400 MHz, epimers A and B, ratio = 3) δ 8.27 and 8.25 (d, J = 8.8 Hz, 2H), 7.62 and 7.55 (d, J = 8.8 Hz, 2H), 7.28–7.21 (m, 1H), 6.33–6.23 (m, 1H), 6.03 and 6.05 (s, 1H), 5.62 and 6.16 (s, 1H), 5.12 and 5.43 (d, 2H) J = 5.4 Hz, 1H), 4.97 and 4.77 (d, J = 17.6 Hz, 1H), 4.88 and 4.33 (d, J=17.6 Hz, 1H), 4.52 (br s, 1H), 2.80–2.50 (m, 2H), 2.44–2.29 (m, 1H), 2.29–2.05 (m, 3H), 2.01–1.84 (m, 2H), 1.80–1.67 (m, 2H), 1.51 and 1.59 (br s, 1H), 1.46 and 1.48 (s, 3H), 1.29–1.07 (m, 7H), 1.03 and 1.05 (s, 3H) ppm.

[1061] Compound 6–1: ESI m / z: 510 (M + H) + . 1 H NMR (DMSO d6 400 MHz, epimers A and B, with a ratio of 5) δ 8.26 and 8.24 (d, J = 8.8 Hz, 2H), 7.77 and 7.57 (d, J = 8.8 Hz, 2H), 7.32(d, J = 10.0 Hz, 1H), 6.17 and 6.18 (dd, J = 10.0 Hz, 1.8 Hz, 1H), 5.93 and 5.95 (s, 1H), 5.63 and 6.28 (s, 1H), 5.14 and 5.03 (t, J = 6.0 Hz, 1H), 4.99 and 5.35 (d, J = 6.3Hz, 1H), 4.82 (d, J = 3.2 Hz, 1H), 4.64–4.13 (m, 3H), 2.64–2.51 (m, 1H), 2.37–2.24 (m, 1H), 2.20–1.99 (m, 2H), 1.94–1.57 (m, 5H), 1.40 (s, 3H), 1.14–0.98 (m, 2H), 0.88 (s, 3H) ppm.

[1062] Step 3: Prepare the (1) in Table 1 S ,2 S 4 R 6 R 8 S 9 S ,11 S ,12 S ,13 R)–6–(4–aminophenyl)–11–hydroxy–8–(2–hydroxyacetyl)–9,13–dimethyl–5,7–dioxapentane [10.8.0.0] 2,9 .0 4,8 .0 13,18 [Eicosane-14,17-diene-16-one (7-1)] R ) and (1) in Table 1 S ,2 S 4 R 6 S 8 S 9 S ,11 S ,12 S ,13 R )–6–(4–aminophenyl)–11–hydroxy–8–(2–hydroxyacetyl)–9,13–dimethyl–5,7–dioxapentane [10.8.0. 0] 2,9 .0 4,8 .0 13,18 [Eicosane-14,17-diene-16-one (7-1)] S ).

[1063] Iron powder (56.0 mg, 1.00 mmol) and ammonium chloride (53.5 mg, 1.00 mmol) were simultaneously added to a mixed solution of compound 5-1 (51.0 mg, 0.100 mmol) in 3 mL of ethanol and 0.5 mL of water. The suspension was stirred at 80 °C for 1 hour and filtered through diatomaceous earth to remove solids. The filtrate was concentrated under vacuum, and the residue was purified by preparative HPLC (Method B) to give compound 7-1. R (30 mg, yield 63%) is a white solid, and compound 7-1 S (8 mg, yield 17%) is a white solid.

[1064] 2D-NOESY spectroscopy was used to determine compound 7-1 R and compound 7-1 S The stereochemical configuration of the chiral center. 2D-NOESY spectroscopy confirms the stereochemical configuration of compound 7-1. R H 22 and H 21 There is a correlation between them, which indicates that they have R Configurational chiral center. And in compound 7-1 S H 22 and H 21 No correlation was observed between them, indicating that they have S Configurational chiral center. NMR studies also indicate that compound 7-1 R H 22The displacement (5.33 ppm) was much higher than that of compound 7-1. S H 22 The shift (6.01 ppm) indicates that compound 7-1 R H 22 It faces greater obstacles. Compound 7-1-22 R and compound 7-1-22 S 2D-NOESY spectrum as Figure 5 and Figure 6 As shown.

[1065] Compound 7-1 in Table 1 R ESI m / z: 480 (M + H) + . 1 H NMR (MeOD d4 , 400 MHz) δ 7.46(d, J = 10.1 Hz, 1H), 7.17 (d, J = 8.4 Hz, 2H), 6.67 (d, J = 8.4 Hz, 2H), 6.27 (dd, J = 10.1, 1.8 Hz, 1H), 6.04 (s, 1H), 5.33 (s, 1H), 5.00 (d, J = 5.4 Hz, 1H), 4.61 (d, J = 19.4 Hz, 1H), 4.50–4.39 (m, 1H), 4.31 (d, J = 19.4 Hz, 1H), 2.78–2.61 (m, 1H), 2.47–2.35 (m, 1H), 2.35–2.22 (m, 1H), 2.22–2.10 (m, 1H), 2.04–1.94 (m,1H), 1.91–1.66 (m, 4H), 1.51 (s, 3H), 1.25–1.11 (m, 1H), 1.07 (dd, J =11.2 Hz, 3.5 Hz, 1H), 0.99 (s, 3H) ppm.

[1066] Compound 7-1 in Table 1 S ESI m / z: 480 (M + H) + . 1 H NMR (MeOD d4 , 400 MHz) δ 7.47(d,J = 10.1 Hz, 1H), 7.02 (d, J = 8.4 Hz, 2H), 6.65 (d, J = 8.5 Hz, 2H), 6.27 (dd, J = 10.1, 1.8 Hz, 1H), 6.03 (s, 1H), 6.01 (s, 1H), 5.36 (d, J = 6.2 Hz, 1H),4.46–4.31 (m, 2H), 4.12 (d, J = 19.2 Hz, 1H), 2.75–2.61 (m, 1H), 2.47–2.35 (m,1H), 2.27–2.11 (m, 2H), 2.08–1.97 (m, 1H), 1.96–1.73 (m, 4H), 1.51 (s, 3H),1.33–1.17 (m, 2H),1.17–1.09 (m, 1H), 1.01 (s, 3H) ppm.

[1067] Example 4

[1068] This embodiment illustrates the preparation of compounds (8-1) in Table 1. R / S ) and compounds (8-1 R The method of ). This embodiment relates to Figure 1 The numbered compounds in the list.

[1069] 2–[(1 S ,2 S 4 R 8 S 9 S ,11 S ,12 S ,13 R )–6–(4–aminophenyl)–11–hydroxy–9,13–dimethyl–16–oxy–5,7–dioxapentane [10.8.0.0] 2,9 .0 4,8 .0 13,18 [eicosyl-14,17-diene-8-yl]-2-oxoethyl 2-methylpropionate (8-1 R ).

[1070] Iron powder (56.0 mg, 1.00 mmol) and ammonium chloride (53.5 mg, 1.00 mmol) were simultaneously added to a mixed solution of compound (6-1) (58.0 mg, 0.100 mmol) in ethanol (3 mL) and water (1 mL). The resulting suspension was stirred at 80 °C for 1 hour and filtered through diatomaceous earth to remove solids. The filtrate was concentrated under vacuum, and the residue was purified by preparative HPLC (Method B) to obtain compound (8-1). R ) and its enantiomers (i.e., C 22 (S stereochemical) (26 mg, yield 45%) was a white solid. It was determined by HPLC and... 1 H NMR determined that the ratio of the R-diamer to the S-diamer was 4:1. ESI m / z: 550 (M+H) + .

[1071] Further separation yielded R -Iconomers, and their configurations were determined by 2D NMR.

[1072] Compound (8–1) R ESI m / z: 550 (M + H) + . 1 H NMR (MeOD d4 , 500 MHz) δ 7.46 (d, J =10.0 Hz, 1H), 7.19 (d, J = 8.5 Hz, 2H), 6.69 (d, J = 8.4 Hz, 2H), 6.27 (dd, J =10.0 Hz, 2.0 Hz, 1H), 6.05 (s, 1H), 5.44 (s, 1H), 5.07 (d, J = 17.5 Hz, 1H), 4.96 (d, J = 5.5 Hz, 1H), 4.88 (d, J= 17.5 Hz, 1H), 4.48–4.44 (m, 1H), 2.73–2.64(m, 2H), 2.42–2.39 (m, 1H), 2.32–2.24 (m, 1H), 2.19–2.15 (m, 1H), 2.03–1.99(m,1H), 1.95–1.92 (m, 1H), 1.90–1.83 (m, 2H), 1.76–1.69 (m, 1H), 1.52 (s,3H), 1.27–1.12 (m, 7H), 1.09–1.05 (m, 1H), 1.02 (s, 3H) ppm.

[1073] Example 5

[1074] This example illustrates the preparation of compounds (7–2) in Table 1. R / S The method of ). This embodiment relates to Figure 1 The numbered compounds in the list.

[1075] Step 1: (1 S ,2 S 4 R 8 S 9 S ,11 S ,12 S ,13 R )–11–hydroxy–8–(2–hydroxyacetyl)–9,13–dimethyl–6–[(4–nitrophenyl)methyl]–5,7–dioxapentane[10.8.0.0] 2,9 .0 4,8 .0 13,18 [Eicosane–14,17–diene–16–one (5–2)]

[1076] according to SynthesisThe synthetic method described in 2011, 18, 2935–2940 (the entire contents of which are incorporated herein by reference in their entirety for all purposes) was performed by adding dropwise an aqueous solution of perchloric acid (70%, 985 mg, 6.90 mmol) to a solution of compound (3) (226 mg, 0.464 mmol) in nitropropane (10 mL) at 0 °C, followed by the addition of 2–(4-nitrophenyl)acetaldehyde (4-2, 115 mg, 0.696 mmol). The resulting mixture was stirred overnight at room temperature and then diluted with ethyl acetate (60 mL). The resulting mixture was washed with saturated aqueous sodium bicarbonate solution (50 mL x 3), followed by washing with brine (50 mL x 3), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by rapid chromatography, eluting with a petroleum ether solution of 0–35% ethyl acetate, to give compound (6-2) as a brown solid (95 mg, yield 34%), comprising... 1 22% of H NMR determined ratios >10 / 1 R / S The diastereomer was further eluted with a petroleum ether solution of 60-70% ethyl acetate to give compound (5-2) (145 mg, yield 60%) as a brown solid.

[1077] Compound (5–2): ESI m / z: 524 (M + H) + . 1 H NMR (CDCl3, 400 MHz) δ 8.09 (d, J =8.7 Hz, 2H), 7.39 (d, J = 8.7 Hz, 2H), 7.17 (d, J = 10.1 Hz, 1H), 6.31 (dd, J =10.1 Hz, 1.8 Hz, 1H), 6.02 (s, 1H), 4.92 (d, J = 5.3 Hz, 1H), 4.86 (t, J = 3.6Hz, 1H), 4.52–4.39 (m, 2H), 4.28–4.17 (m, 1H), 3.08 (d, J = 3.5 Hz, 2H), 2.96(t, J= 4.9 Hz, 1H), 2.53–2.40 (m, 1H), 2.32–2.19 (m, 1H), 2.04–1.95 (m, 1H), 1.95–1.82 (m, 2H), 1.60–1.46 (m, 3H), 1.38 (s, 3H), 1.34 (br s, 1H), 0.91–0.77 (m, 4H), 0.76–0.62 (m, 2H) ppm.

[1078] Step 2: (1) S ,2 S 4 R 8 S 9 S ,11 S ,12 S ,13 R )–6–[(4–aminophenyl)methyl]–11–hydroxy–8–(2–hydroxyacetyl)–9,13–dimethyl–5,7–dioxapentane[10.8.0.0] 2,9 .0 4,8 .0 13,18 [Eicosane–14,17–diene–16–one (7–2)] R / S )

[1079] Iron powder (78.0 mg, 1.40 mmol) and ammonium chloride (75.0 mg, 1.40 mmol) were simultaneously added to a mixed solution of compound (5-2) (75.0 mg, 0.143 mmol) in ethanol (4 mL) and water (0.5 mL). The suspension was stirred at 80 °C for 1.5 hours and filtered through diatomaceous earth to remove solids. The filtrate was concentrated under vacuum, and the residue was purified by preparative HPLC (Method B) to give compound (7–2). R / S (26 mg, 37% yield) is a white solid. ESI m / z: 494 (M + H) + . 1 H NMR (MeOD) d4 , 400 MHz) δ 7.44 (d, J = 10.1 Hz, 1H), 6.93 (d, J = 8.3 Hz, 2H), 6.48 (d, J =8.3 Hz, 2H), 6.30 (dd, J = 10.1 Hz, 1.9 Hz, 1H), 6.07 (s, 1H), 4.85–4.77 (m,2H), 4.51 (d, J= 19.4 Hz, 1H), 4.35–4.29 (m, 1H), 4.24 (d, J = 19.4 Hz, 1H),2.87–2.72 (m, 2H), 2.62–2.47 (m, 1H), 2.38–2.28 (m, 1H),2.08–1.93 (m, 1H),1.90–1.78 (m, 2H), 1.67–1.58 (m, 1H), 1.53–1.37 (m, 5H), 0.91–0.77 (m, 5H), 0.74 (dd, J = 11.2 Hz, 3.4 Hz, 1H) ppm.

[1080] Example 6

[1081] This example illustrates the preparation of compounds (8–2) in Table 1. R / S The method of ). This embodiment relates to Figure 1 The numbered compounds in the list.

[1082] Step 1: 2–[(1S,2S,4R,8S,9S,11S,12S,13R)–11–hydroxy–9,13–dimethyl–6–[(4–nitrophenyl)methyl]–16–oxy–5,7–dioxapentane [10.8.0.0] 2,9 .0 4,8 .0 13,18 [Eicosane-14,17-diene-8-yl]-2-oxoethyl 2-methylpropionate (6-2)

[1083] The synthesis of compound 6-2 was as described in Example 5 above. Compound 6-2: ESI m / z: 594 (M + H) + . 1 HNMR (CDCl3, 400 MHz) δ 8.15 (d, J = 8.7 Hz, 0.1H) and 8.09 (d, J = 8.7 Hz, 1.9H), 7.40(d, J = 8.6 Hz, 2H), 7.20 (d, J = 10.1 Hz, 1H), 6.31 (dd, J = 10.1 Hz, 1.8 Hz, 1H), 6.02 (s, 1H), 4.94 (t, J = 3.6 Hz, 1H), 4.87 (d, J= 5.1 Hz, 1H), 4.81 (d, J = 17.6Hz, 1H), 4.71 (d, J = 17.6 Hz, 1H), 4.46 (s, 1H), 3.09 (d, J = 3.5 Hz, 2H), 2.73–2.61 (m, 1H), 2.53–2.41 (m, 1H), 2.31–2.21 (m, 1H), 2.07–1.96 (m, 1H), 1.94–1.84 (m, 2H), 1.84–1.76 (m, 1H),1.63–1.43 (m, 3H), 1.39 (s, 3H), 1.22 (t, J =7.0 Hz, 6H), 0.92–0.82 (m, 4H), 0.76–0.61 (m, 2H) ppm.

[1084] Step 2: 2–[(1 S ,2 S 4 R 8 S 9 S ,11 S ,12 S ,13 R )–6–[(4–aminophenyl)methyl]–11–hydroxy–9,13–dimethyl–16–oxy–5,7–dioxapentane[10.8.0.0] 2,9 .0 4,8 .0 13,18 [eicosyl-14,17-diene-8-yl]-2-oxoethyl 2-methylpropionate (8-2 R / S )

[1085] Iron powder (61.0 mg, 1.09 mmol) and ammonium chloride (58.4 mg, 1.09 mmol) were simultaneously added to a mixed solution of compound 6-2 (65.0 mg, 0.109 mmol) in ethanol (5 mL) and water (1 mL). The suspension was stirred at 80 °C for 1 hour and filtered through diatomaceous earth to remove solids. The filtrate was concentrated under vacuum, and the residue was purified by preparative HPLC (Method B) to give compound (8–2). R / S (30 mg, yield 49%) is a white solid. ESI m / z: 564 (M + H) + . 1 H NMR (CDCl3, 400 MHz) δ 7.25 (d, J= 10.2 Hz, 1H), 6.95 (d, J = 8.3 Hz, 2H), 6.44 (d, J = 8.3 Hz, 2H), 6.31 (dd, J = 10.1, 1.8 Hz, 1H), 6.05 (s, 1H), 4.92–4.84 (m, 2H), 4.80 (d, J = 5.2 Hz, 1H), 4.73 (d, J = 17.7 Hz, 1H), 4.41 (s, 1H), 3.48 (br s, 1H), 2.85(d, J = 2.7 Hz, 2H), 2.75–2.62 (m, 1H), 2.56–2.41 (m, 1H), 2.31–2.19 (m, 1H), 2.05–1.91 (m, 2H), 1.88–1.80 (m, 1H), 1.77–1.70 (m, 1H), 1.55–1.41 (m, 3H), 1.39 (s, 3H), 1.29–1.18 (m, 8H), 0.91–0.74 (m, 5H) ppm.

[1086] Example 7

[1087] This example illustrates the preparation of compounds (8–3) in Table 1. R / S The method of ). This embodiment relates to Figure 1 The numbered compounds in the list.

[1088] Step 1: 2–[(1 S ,2 S 4 R 8 S 9 S ,11 S ,12 S ,13 R )–6–(2–{[(9 H –fluorene-9-ylmethoxy)carbonyl]amino}ethyl)–11–hydroxy–9,13–dimethyl–16–oxy–5,7–dioxapentane [10.8.0.0] 2,9 .0 4,8 .0 13,18 [Eicosane-14,17-diene-8-yl]-2-oxoethyl-2-methylpropionate (6-3)

[1089] according to J. Am. Chem. Soc.The synthetic method described in 2006, 128 (12), 4023–4034 (the entire contents of which are incorporated herein by reference in their entirety for all purposes) was performed by adding dropwise an aqueous solution of perchloric acid (70%, 214 mg, 1.49 mmol) to a nitrobanane (5 mL) solution of compound 3 (240 mg, 0.493 mmol) at 0 °C, followed by the addition of Fmoc-3-amino-1-propanal (4-3, 236 mg, 0.799 mmol). The resulting mixture was stirred overnight at room temperature and then diluted with ethyl acetate (80 mL). The mixture was washed with saturated aqueous sodium bicarbonate solution (50 mL x 3), then with water (50 mL x 2), and finally with brine (50 mL), then dried over sodium sulfate and concentrated under vacuum. The residue was purified by preparative TLC (silica gel, methanol / dichloromethane, v / v = 1 / 25) to give compound (6-3) (200 mg, yield 56%). R / 6 S The epimer is a grayish-white solid. ESI m / z: 724 (M + H) + . 1 H NMR (CDCl3, 400 MHz) δ 7.76 (d, J = 7.6 Hz, 2H), 7.56 (d, J = 7.2 Hz, 2H), 7.40 (d, J = 7.2 Hz, 1H), 7.32–7.20 (m,3H), 6.28–6.25(m, 2H), 6.00 (s, 1H), 5.28–5.04 (m, 2H), 4.87–4.76 (m, 1H), 4.46–4.35 (m,3H), 4.18 (t, J = 6.8 Hz, 1H), 3.49 (s, 1H), 3.39–3.24 (m, 2H), 2.77–2.49 (m,2H), 2.37–2.26 (m, 1H), 2.23–1.96 (m, 3H), 1.96–1.47 (m,6H), 1.45–1.41 (m,3H), 1.28–1.06 (m, 10H), 1.02–0.94 (m, 3H) ppm.

[1090] Step 2: 2–[(1 S ,2 S 4 R 8 S 9 S ,11 S,12 S ,13 R )–6–(2–aminoethyl)–11–hydroxy–9,13–dimethyl–16–oxy–5,7–dioxapentane [10.8.0.0] 2,9 .0 4,8 .0 13,18 [eicosyl-14,17-diene-8-yl]-2-oxoethyl 2-methylpropionate (8-3) R / S )

[1091] A solution of compound (6-3) (40.0 mg, 55.3 μmol) in diethylamine (1 mL) and dichloromethane (1 mL) was stirred overnight at room temperature. The volatiles were removed by vacuum concentration, and the residue was purified by preparative HPLC (Method B) followed by preparative TLC (thin-layer chromatography) (silica gel, dichloromethane / methanol, v / v = 75 / 10) to give compound (8–3). R / S (3 mg, yield 11%) is a grayish-white solid. ESI m / z: 502 (M + H) + . 1 H NMR (MeOD d4 , 400 MHz) δ 7.36 (d, J =10.1 Hz, 1H), 6.16 (dd, J = 10.1 Hz, 1.8 Hz, 1H), 5.91 (s, 1H), 5.23 (t, J = 4.4Hz, 1H), 5.08–4.90 (m, 1H), 4.75–4.65 (m, 1H), 4.38–4.28 (m, 1H), 2.83–2.50 (m, 2H), 2.33–2.23 (m, 1H), 2.13–2.00 (m, 2H), 1.90–1.46 (m,6H), 1.39 (s,3H), 1.24–1.12 (m, 2H), 1.23–0.78 (m, 11H) ppm.

[1092] Example 8

[1093] This example illustrates the preparation of compounds 7–4 in Table 1. R The method. This embodiment relates to... Figure 1 The numbered compounds in the list.

[1094] (1 S ,2 S 4 R 6 R 8S 9 S ,11 S ,12 S ,13 R )–11–hydroxy–8–(2–hydroxyacetyl)–9,13–dimethyl–6–(piperidin–4–yl)–5,7–dioxapentane [10.8.0.00] 2,9 .0 4,8 .0 13,18 [Eicosane–14,17–diene–16–one (7–4)] R ).

[1095] At 0 °C, a solution of desonide (1, 0.10 g, 0.25 mmol) in nitropropane (5 mL) was added dropwise with an aqueous solution of perchloric acid (70%, 0.11 g, 0.75 mmol), followed by the addition of 1–Boc–4–piperidinecarbaldehyde (4–4, 64 mg, 0.30 mmol). After stirring overnight at room temperature, the suspension was concentrated under vacuum. The resulting residue was alkalized with a methanol solution of ammonia (7 M, 10 mL). The resulting mixture was concentrated under vacuum, and the crude product was purified twice by preparative HPLC (Method B) to give compound 7–4. R (15 mg, yield 13%) is a white solid. ESI m / z: 472 (M + H) + . 1 H NMR (MeOD d4 , 500 MHz) δ 7.47 (d, J = 10.0 Hz, 1H), 6.27 (dd, J = 10.0 Hz, 2.0 Hz, 1H), 6.03 (s, 1H), 4.90(d, J = 4.0 Hz, 1H), 4.50 (d, J = 19.0 Hz, 1H), 4.46–4.43 (m, 1H), 4.41 (d, J = 4.0Hz, 1H), 4.29 (d, J= 19.0 Hz, 1H), 3.13–3.09 (m, 2H), 2.71–2.60 (m, 3H), 2.42–2.38 (m, 1H), 2.27–2.13 (m, 2H), 1.99–1.96 (m, 1H), 1.85–1.64 (m, 7H), 1.52 (s, 3H), 1.51–1.38 (m, 2H), 1.14–0.99 (m, 2H), 0.96 (s, 3H) ppm. Compounds 7–4 R Stereochemistry R - The configuration was confirmed by 2D NMR.

[1096] Example 9

[1097] This example illustrates the preparation of compounds (11-1) in Table 1. R / S The method is typically as follows: Figure 2 As shown.

[1098] Step 1: 2–[(1 S ,2 S 4 R 8 S 9 S ,11 S ,12 S ,13 R )–11–hydroxy–9,13–dimethyl–16–oxo–6–propyl–5,7–dioxapentane [10.8. 00] 2,9 .0 4,8 .0 13,18 [Eicosane-14,17-dien-8-yl]-2-oxoethyl methanesulfonate (9)

[1099] A general method for synthesizing methanesulfonate compounds from alcohols: Add triethylamine or 4-dimethylaminopyridine (2 equivalents) and methanesulfonyl chloride (1.2 equivalents) to a solution of alcohol (1.0 equivalent) in DCM (10 mL / g starting material). Stir at 0°C for half an hour, or until the starting material is exhausted as determined by TLC, then add silica gel (100-200 mesh) to the reaction mixture and concentrate under vacuum. Purify the residue containing silica gel by silica gel column chromatography (0-50% ethyl acetate in petroleum ether solution) to obtain the methanesulfonate product. Alternatively, wash the mixture with diluted aqueous hydrochloric acid (1N), then with brine, dry over sodium sulfate, and concentrate. Purify the crude product by rapid chromatography (0-2% MeOH in DCM solution) to obtain the corresponding methanesulfonate product.

[1100] Another method for preparing compound 9: At 0 °C, 4-dimethylaminopyridine (0.16 g, 1.3 mmol) was added dropwise to a pyridine (5 mL) solution of budesonide (0.28 mg, 0.65 mmol), followed by the addition of methanesulfonyl chloride (0.11 g, 0.97 mmol). After stirring at room temperature for 2 hours, the resulting mixture was poured into ethyl acetate (100 mL). The mixture was washed with diluted aqueous hydrochloric acid (1 N), then with brine, dried over sodium sulfate, and concentrated. The crude product was purified by rapid chromatography (0-1% methanol in dichloromethane solution) to give compound (9) (0.26 g, 85% yield) as a white solid. ESI m / z: 509 (M + H) + . 1 1H NMR (CDCl3, 400 MHz) (including epimers) δ 7.25 and 7.22 (d, J = 2.0 Hz, 1H), 6.30–6.27 (m, 1H), 6.03–6.02 (m, 1H), 5.17–5.11 (m, 1.5H), 5.06–4.96 (m, 1.5H), 4.87–4.86 (m, 0.5 H), 4.59 (d, J = 4.5 Hz, 0.5 H), 4.52–4.50 (m, 1 H), 3.24(s, 3H), 2.60–2.53 (m, 1H), 2.36–2.33 (m, 1H), 2.24–2.00 (m, 3H), 1.86–1.62(m, 4H), 1.53–1.33 (m, 8H), 1.21–1.09 (m, 2 H), 1.02–0.96 (m, 3H), 0.94–0.91 (m, 3H) ppm.

[1101] Step 2: (1) S ,2 S 4 R 8 S 9 S ,11 S ,12 S ,13 R )–8–(2–aminoacetyl)–11–hydroxy–9,13–dimethyl–6–propyl–5,7–dioxapentane [10.8.0.0] 2,9 .0 4,8 .0 13,18 [Eicosane-14,17-diene-16-one (11-1)] R / S )

[1102] Compound 9 (0.10 g, 0.20 mmol) was added to a solution of ammonia in MeOH (7 M, 15 mL) at room temperature. The resulting solution was sealed and stirred overnight at 40 °C. The volatiles were removed by vacuum concentration, and the crude product was purified by preparative HPLC (Method B) to give compound (11-1). R / S (8.0 mg, 9% yield) is a grayish-white solid. ESI m / z: 429.9 (M + H) + . 1 HNMR (MeOD d4 , 400 MHz) δ 7.46 (d, J = 10.0 Hz, 1H), 6.26 (d, J = 10.0 Hz, 1H), 6.02 (s, 1H), 5.22–5.15 (m, 1.5 H), 4.88 (m, 0.6H), 4.58 (m, 0.5H), 4.42 (m, 1H), 3.96–3.81 (m, 0.7H), 3.50–3.41 (m, 0.7H), 2.70–2.63 (m, 1H), 2.40–2.37 (m, 1H), 2.22–1.94 (m, 3H), 1.87–1.25 (m, 11H), 1.17–0.80 (8H) ppm. Analytical HPLC: >95%, retention time: 7.63 min (Method B).

[1103] Example 10

[1104] This example illustrates the preparation of compounds 11-2 in Table 1. R / S The method. This embodiment relates to... Figure 2 The numbered compounds in the list.

[1105] (1S,2S,4R,8S,9S,11S,12S,13R)–11–hydroxy–9,13–dimethyl–8–[2–(methylamino)acetyl]–6–propyl–5,7–dioxapentane[10.8.0.0] 2,9 .0 4,8 .0 13,18 [Eicosane-14,17-diene-16-one (11-2)] R / S )

[1106] A solution of compound 9 (51 mg, 0.10 mmol) in methylamine (2 M THF solution, 0.5 mL) was placed in a sealed tube and stirred at 20–25 °C for 4 hours, followed by stirring at 40 °C overnight. The volatiles were removed by vacuum concentration, and the residue was purified by preparative HPLC (Method A) and then by preparative HPLC (Method B) to obtain compound (11–2). R / S (15 mg, 33% yield) is a white solid. ESI m / z: 444.3 (M + H) + . 1 H NMR (CDCl3, 400 MHz) δ 7.26–7.23 (d, J =10.8 Hz, 1H), 6.30–6.26 (m, 1H), 6.03–6.02 (m, 1H), 5.20–5.16 (m, 1H), 4.90–4.89 (d, J = 4.8 Hz, 0.5 H), 4.69–4.66 (t, J = 4.8 Hz, 0.5H), 4.49–4.51 (m, 1H), 3.50–3.29 (m, 2H), 2.61–2.52 (m, 1H), 2.37–2.32 (m, 1H), 2.17–2.16 (d, J = 3.6Hz, 3H), 2.14–2.08 (m, 3H), 1.86–1.74 (m, 3H), 1.59–1.48 (m, 2H), 1.45(s,3H), 1.42–0.89 (m, 12H) ppm.

[1107] Example 11

[1108] This example illustrates the preparation of compounds 11-3 in Table 1. R / S The method. This embodiment relates to... Figure 2 The numbered compounds in the list.

[1109] (1 S ,2 S 4 R 8 S 9 S ,11 S ,12 S ,13 R )–8–[2–(dimethylamino)acetyl]–11–hydroxy–9,13–dimethyl–6–propyl–5,7–dioxapentane[10.8.0.0] 2,9 .0 4,8 .013,18 [Eicosane-14,17-diene-16-one (11-3)] R / S )

[1110] At room temperature, a solution of dimethylamine in THF (2 M, 0.75 mL, 1.5 mmol) was added dropwise to a solution of compound 9 (51 mg, 0.10 mmol) in THF (3 mL). The reaction mixture was stirred overnight at 50 °C. The reaction mixture was concentrated, and the crude product was purified by preparative HPLC (Method B) to give compound 11-3. R / S (15 mg, 33% yield) It is a white solid. ESI m / z: 458.2 (M + H) + . 1 H NMR (MeOD d4 , 400 MHz) δ 7.46 (d, J = 10.4 Hz, 1H), 6.26 (d, J =10.0 Hz, 1H), 6.02 (s, 1H), 5.21 (t, J = 4.8 Hz, 0.6H), 5.17 (d, J = 7.2 Hz, 0.6H), 4.58 (d, J = 4.4 Hz, 0.4H), 4.44–4.41 (m, 1H), 3.80–3.57 (m, 1H), 3.26(d, J = 18.8 Hz, 0.7H), 3.08–2.91 (m, 0.7H), 2.70–2.61 (m, 1H), 2.49–2.33 (m, 7H), 2.26–2.11 (m, 2H), 2.02–1.95 (m, 1H), 1.85–1.55 (m, 5H), 1.49 (s, 3H), 1.49–1.30 (m, 3H), 1.09–1.00 (m, 2H), 0.98–0.90 (m, 6H) ppm. Analytical HPLC: >95%, retention time: 8.34 min (Method B).

[1111] Example 12

[1112] This example illustrates the preparation of compounds 11-5 in Table 1. R / S The method. This embodiment relates to... Figure 2 The numbered compounds in the list.

[1113] (1 S ,2S 4 R 8 S 9 S ,11 S ,12 S ,13 R )–8–[2–(4–aminophenoxy)acetyl]–11–hydroxy–9,13–dimethyl–6–propyl–5,7–dioxapentane[10.8.00] 2,9 .0 4,8 .0 13,18 Eicosane–14,17–diene–16–one (11-5) R / S )

[1114] General method B for preparing substituted phenolic ethers from their methanesulfonate precursors: Add the methanesulfonate precursor (1 equivalent), the substituted phenol (2.0-2.5 equivalents), and potassium carbonate or cesium carbonate (2.0-3.0 equivalents) to hot acetonitrile or acetone (60-65°C). Reflux the resulting suspension for 2-3 hours and monitor the reaction by LCMS and / or TLC. After cooling the reaction to room temperature, concentrate under vacuum to remove volatiles, and add water to the resulting residue. Extract the aqueous mixture with ethyl acetate. Wash the combined organic solutions with water and brine, dry over sodium sulfate, and concentrate under vacuum. The resulting crude product can be used directly in the next step or purified by rapid chromatography or preparative HPLC.

[1115] Step 1: A mixed solution of compound 9 (0.13 g, 0.26 mmol), 4-nitrophenol (10⁻⁵, 72 mg, 0.52 mmol), and potassium carbonate (72 mg, 0.52 mmol) in acetone (10 mL) was refluxed (60 °C) overnight. After filtering to remove the solids, the filtrate was concentrated under vacuum. The crude product was purified by rapid chromatography (0-1% methanol in dichloromethane solution) to give a nitro-intermediate (0.11 g, 77% yield) as a brown oil. ESIm / z: 552 (M + H) + . 1 1H NMR (CDCl3, 500 MHz) (including epimers) δ 8.23–8.15 (m, 2.4H), 7.26–7.23 (m, 1H), 6.97–6.91 (m, 2.4H), 6.31–6.28 (m, 1H), 6.05–6.04 (m, 1H), 5.22–5.18 (m, 1.4H), 5.10–5.07 (m, 0.6H),4.93 (d, J = 5.0 Hz, 0.6H), 4.83–4.77 (m, 1H), 4.67 (d, J= 5.0 Hz, 0.6H), 4.56–4.53 (m, 1H), 2.62–2.55 (m, 1H), 2.38–2.5 (m, 1H), 2.24–2.07 (m, 3H), 1.88–1.56 (m, 5H), 1.46–1.40 (m, 6H), 1.20–1.13 (m, 2H), 1.05–0.99 (m, 3H), 0.97–0.94 (m, 3H) ppm.

[1116] Step 2: Iron powder (0.10 g, 1.9 mmol) and ammonium chloride (0.10 g, 1.9 mmol) were simultaneously added to a mixed solution of nitro-intermediate (0.10 g, 0.19 mmol) in 20 mL of ethanol and 2 mL of water. The suspension was stirred at 80 °C for 2 hours and filtered through diatomaceous earth to remove inorganic salts. The filtrate was concentrated under vacuum, and the residue was purified by preparative HPLC (Method B) to obtain compound (11-5). R / S (50 mg, 50% yield) is a white solid. ESI m / z: 522 (M + H) + . 1 H NMR (MeOD) d4 500 MHz (including epimers) δ 7.47 (d, J = 10.0 Hz, 1H), 6.78–6.70 (m, 4H), 6.29–6.26 (m, 1H), 6.04 (br s, 1H), 5.25 (t, J = 5.0 Hz, 0.4H), 5.20 (d, J = 7.0Hz, 0.4H), 5.06 (d, J =18.0 Hz, 0.4H), 4.98 (d, J=18.0 Hz, 0.6H), 4.90–4.87 (m,0.6 H), 4.75–4.66 (m, 1.6H), 4.46–4.44 (m, 1H), 2.71–2.64 (m, 1H), 2.42–2.38(m, 1H),2.28–2.18 (m, 2H), 2.06–2.00 (m, 1H), 1.87–1.83 (m, 1H), 1.76–1.73(m, 1H), 1.69–1.61 (m, 3H), 1.55–1.38 (m, 3H), 1.51 (s, 3H), 1.20–1.02 (m,3H),0.98–0.92 (m, 5H) ppm.

[1117] Compound 11-5 in Table 1 was separated by chiral HPLC. R and compound 11-5 S A mixture of two epimers (0.30 g, 0.58 mmol) was prepared using a mobile phase of hexane (0.1% DEA) / ethanol (0.1% DEA) = 70 / 30 at a flow rate of 60 mL / min, and detected at 214 nm. The resulting solution was concentrated to obtain compounds 11-5. S (30 mg, 10% yield) and compounds 11-5 R (50 mg, 17% yield) is a white solid. Compound 11-5 S and compound 11-5 R The structure was confirmed using 2D-NOESY.

[1118] (1 S ,2 S 4 R 8 S 9 S ,11 S ,12 S ,13 R )–8–[2–(4–aminophenoxy)acetyl]–11–hydroxy–9,13–dimethyl–6–propyl–5,7–dioxapentane[10.8.0.0² ,9 .0 4,8 0¹³ , ¹ 8 Eicosane–14,17–diene–16–one (11-5) S (): First peak value in HPLC; ESI m / z: 522 (M + H) +Retention time in HPLC (Method A): 7.54 min; Chiral SFC (CC4): Retention time 4.71 min, 99.5% % 1 H NMR (400 MHz, CDCl3) δ 7.21 (d, J = 10.1 Hz, 1H), 6.77 (d, J = 8.8 Hz, 2H), 6.63 (d, J = 8.8 Hz, 2H), 6.24 (dd, J =10.1, 1.6 Hz, 1H), 6.02 (s, 1H), 5.20 (d, J = 6.8 Hz, 1H), 5.18 (t, J = 4.8 Hz, 1H), 4.99 (d, J = –17.9 Hz, 1H), 4.61 (d, J = –17.9 Hz, 1H), 4.43 (s, 1H), 3.46(s, 2H), 2.57 (td, J = 13.2, 4.4 Hz, 1H), 2.34 (dd, J = 13.4, 3.2 Hz, 1H), 2.16–2.01 (m, 4H), 1.85–1.68 (m, 3H), 1.59–1.49 (m, 3H), 1.44 (s, 3H),1.44–1.26(m, 2H), 1.18–1.09 (2H), 1.00 (s, 3H), 0.91 (t, J = 7.3 Hz, 3H) ppm. 13 C NMR (100MHz, CDCl3) δ 204.0, 186.7, 170.0, 156.3, 151.4, 141.0, 127.9, 122.6, 116.5,116.4, 108.4, 98.6, 83.2, 72.6, 69.8, 55.3,53.0, 47.2, 44.2, 41.5, 37.3,34.1, 33.0, 32.0, 31.1, 21.2, 17.9, 17.7, 14.1 ppm.

[1119] (1 S ,2 S 4 R 8S 9 S ,11 S ,12 S ,13 R )–8–[2–(4–aminophenoxy)acetyl]–11–hydroxy–9,13–dimethyl–6–propyl–5,7–dioxapentane[10.8.0.0² ,9 .0 4,8 0¹³ , ¹ 8 Eicosane–14,17–diene–16–one (11-5) R (): Second peak in HPLC; ESI m / z: 522 (M + H) + Retention time in HPLC (Method A): 7.58 min; Chiral SFC (CC4): Retention time 3.80 min, 98.1% % 1 H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 10.1 Hz, 1H), 6.79 (dd, J = 8.8 Hz, 2H), 6.65 (d, J = 8.8 Hz, 2H), 6.27 (dd, J =10.1, 1.7 Hz, 1H), 6.04 (s, 1H), 4.94 (d, J = 4.4 Hz, 1H), 4.89 (d, J = –18.0 Hz, 1H), 4.65 (d, J = –18.0 Hz, 1H), 4.61 (t, J = 4.4 Hz, 1H), 4.48 (d, J = 2.1 Hz,1H), 3.51 (s, 2H), 2.58 (td, J = 13.3, 4.9 Hz, 1H), 2.35 (dd, J = 13.4, 2.8 Hz,1H), 2.23–1.99 (m, 4H), 1.79–1.61 (m, 6H), 1.46–1.38 (m, 2H), 1.44 (s, 3H),1.23–1.09 (m, 2H),0.95 (s, 3H), 0.93 (t, J = 7.3 Hz, 3H) ppm. 13C NMR (101 MHz, CDCl3) δ 204.9, 186.6, 170.0, 156.2, 151.2, 141.0, 127.9, 122.5, 116.3, 116.3,104.5, 97.6, 81.9, 72.6, 69.9, 55.1, 49.8, 45.7, 44.0, 41.1, 35.0, 34.0,33.3,31.9, 30.3, 21.1, 17.5, 17.1, 14.0 ppm.

[1120] Example 13

[1121] This example illustrates the preparation of compounds 11-5 in Table 1. S and (11-5) R The method described in this embodiment involves... Figure 2 The numbered compounds in the list.

[1122] According to the general method A described in Example 9, respectively by ( R Compound 9 was prepared by budesonide. R , and by ( S Compound 9 was prepared by budesonide. S Using the same method as described in Example 12, compounds (9) were respectively... S The reaction of compound (10-12) with compound (11-5) yields compound (11-5). S ), and compounds (9) R The reaction of compound (10-9) with compound (11-5) yields compound (11-5). R A representative procedure is as follows. To compound (9) R ) or compound (9 S Compound 10-9 (2 equivalents) and Cs₂CO₃ (2 equivalents) were simultaneously added to a 10 mL solution of acetone (100 mg). The mixture was refluxed for 2 hours, and the crude product was post-processed as follows: acetone was removed by vacuum concentration, the crude product was extracted with ethyl acetate, inorganic salts were washed with water, and the obtained product was purified by chromatography (0-50% ethyl acetate in petroleum ether solution) to obtain compound 11-5. R Or compound 11-5 S (25-60% yield) It is a pale yellow solid. ESI m / z: 522 (M + H) + Analytical HPLC: 98%. Compounds 11-5 R and compound 11-5 S 2D-NOESY spectrum as Figure 7 and 8 As shown.

[1123] Example 14

[1124] This example illustrates the preparation of compounds 11-6 in Table 1. S and 11-6 R The method. This embodiment relates to... Figure 2 The numbered compounds in the list.

[1125] (1 S ,2 S 4 R 6 S 8 S 9 S ,11 S ,12 S ,13 R )–8–[2–(4–amino–3–fluorophenoxy)acetyl]–11–hydroxy–9,13–dimethyl–6–propyl–5,7–dioxapentane[10.8.0.0² ,9 .0 4,8 0¹³ , ¹ 8 Eicosane–14,17–diene–16–one (11-6) S ) and (1 S ,2 S 4 R 6 R 8 S 9 S ,11 S ,12 S ,13 R )–8–[2–(4–amino–3–fluorophenoxy)acetyl]–11–hydroxy–9,13–dimethyl–6–propyl–5,7–dioxapentane[10.8.0.0² ,9 .0 4,8 0¹³ , ¹ 8 Eicosane–14,17–diene–16–one (11-6) R ).

[1126] The racemic mixture of compounds 11–6R / S was prepared according to the method described in Example 12. The racemic products were separated by chiral SFC (see Section 2.3) to obtain compounds 11–6R / S. S (Second peak) and compound 11-6 R (The first peak value) is a grayish-white solid.

[1127] Compound 11-6 S (30 mg, 7.9% yield). ESI m / z: 540.2 (M + H)+ . 1 H NMR (500 MHz, DMSO) d6 ) δ 7.32 (d, J = 10.1 Hz, 1H), 6.71–6.62 (m, 2H), 6.49 (dd, J = 8.5, 2.0 Hz,1H), 6.19–6.16 (m, 1H), 5.93 (s, 1H), 5.21 (t, J = 4.8 Hz, 1H), 5.10 (d, J = 7.3Hz, 1H), 5.02 (d, J = 18.1 Hz, 1H), 4.69 (dd, J = 58.9, 28.6 Hz, 4H), 4.31 (s,1H), 2.56–2.51 (m, 1H), 2.29 (d, J = 10.6 Hz, 1H), 2.06–1.97 (m, 3H), 1.89 (s, 2H), 1.79–1.72 (m, 1H), 1.30 (m, 10H), 0.88–0.85 (m, 6H) ppm. Retention time: 2.94 min, 98% in chiral SFC (AD). Analytical HPLC: >96.94%, retention time: 7.94 min (Method B).

[1128] Compound 11-6 R (28 mg, 7.4% yield). ESI m / z: 540.3 (M + H) + . 1 H NMR (500 MHz, DMSO) d6 ) δ 7.32 (d, J = 10.1 Hz, 1H), 6.72–6.68 (m, 2H), 6.52 (dd, J = 8.6, 2.1 Hz, 1H), 6.18 (d, J = 10.1 Hz, 1H), 5.93 (s, 1H), 5.01 (d, J = 18.3 Hz, 1H), 4.77(dd, J = 12.9, 3.3 Hz, 2H), 4.71 (s, 2H), 4.65 (t, J= 4.3 Hz, 1H), 4.32 (s, 1H), 3.17 (d, J = 5.2 Hz, 1H), 2.57–2.51 (m, 1H), 2.30 (d, J = 10.5 Hz, 1H), 2.10 (d, J 0.87 (t, J = 7.4 Hz, 3H), 0.83 (s, 3H)ppm. Retention time: 2.25 min, 100% in chiral SFC (AD). Analytical HPLC: >98.50%, retention time: 8.01 min (Method B).

[1129] Example 15

[1130] This example illustrates the preparation of compounds 11-7 in Table 1. R The method. This embodiment relates to... Figure 2 The numbered compounds in the list.

[1131] (1 S ,2 S 4 R 8 S 9 S ,11 S ,12 S ,13 R )-8-[2-(4-amino-3-fluorophenoxy)acetyl]-11-hydroxy-9,13-dimethyl-6-propyl-5,7-dioxapentane[10.8.0.0² ,9 .0 4,8 0¹³ , ¹ 8 Eicosane-14,17-dien-16-one (11-7) S and 11-7 R )

[1132] A racemic mixture of steroid compounds 11–7–22R / S was prepared according to the method described in Example 12. The racemic product was separated by chiral SFC (see Section 2.3) to obtain compound 11–7. S (Second peak) and compounds 11-7 R (First peak).

[1133] Compound 11-7 R ESI m / z: 540.2 (M + H) + . 1 H NMR (500 MHz, CDCl3) δ 7.25 (d, J =10.1 Hz, 1H), 6.87 (dt, J = 15.5, 7.7 Hz, 1H), 6.47 (dd, J = 12.8, 2.4 Hz, 1H), 6.37 (d, J = 8.7 Hz, 1H), 6.29 (dd, J = 9.9, 4.4 Hz, 1H), 6.04 (s, 1H), 5.22–4.49(m, 5H), 3.61 (s, 2H), 2.58 (td, J = 13.5, 4.9 Hz, 1H), 2.36 (d, J = 10.3 Hz, 1H), 2.19–2.03 (m, 3H), 1.87–1.72 (m, 2H), 1.67–1.55 (m, 3H), 1.51–1.33 (m, 7H), 1.21–1.11 (m, 2H), 1.00–0.90 (m, 6H). Analytical HPLC: >62.24%, 36.49%, retention times: 7.78, 7.86 min (Method B).

[1134] Example 16

[1135] This example illustrates the preparation of compounds 11-8 in Table 1. R The method. This embodiment relates to... Figure 2 The numbered compounds in the list.

[1136] (1 S ,2 S 4 R 6 R 8 S 9 S ,11 S ,12 S ,13 R )–11–hydroxy–9,13–dimethyl–8–{2–[4–(methylamino)phenoxy]acetyl}–6–propyl–5,7–dioxapentane–[10.8.0.0² ,9 .0 4,8 0¹³ , ¹ 8[Eicosane-14,17-diene-16-one (11-8)] R )

[1137] Steroid 11-8 was prepared according to the method described in Example 13.

[1138] Compound (11-8) was obtained R It was a white solid (14 mg, 54% yield). ESI m / z: 525.3 (M + H) + . 1 HNMR (500 MHz, MeOD d4 ) δ 7.47 (d, J = 10.1 Hz, 1H), 6.83–6.80 (m, 2H), 6.65–6.62(m, 2H), 6.28 (dd, J = 10.1, 1.9 Hz, 1H), 6.04 (s, 1H), 4.99 (d, J = 18.2 Hz, 1H), 4.90 (d, J = 4.8 Hz, 1H), 4.74 (d, J = 18.1 Hz, 1H), 4.66 (t, J = 4.5 Hz, 1H), 4.46 (d, J = 3.0 Hz, 1H), 2.75 (s, 3H), 2.67 (td, J = 13.6, 5.2 Hz, 1H), 2.40(dd, J = 13.5, 2.7 Hz, 1H), 2.30–2.22 (m, 1H), 2.16–2.12 (m, 1H), 2.02 (dd, J =13.7, 3.3 Hz, 1H), 1.85 (dd, J = 13.7, 2.6 Hz, 1H), 1.76 (d, J = 6.9 Hz, 1H),1.67–1.63 (m, 4H), 1.51 (s, 3H), 1.48–1.44 (m, 2H), 1.17–1.08 (m, 1H),1.05(dd, J = 11.2, 3.5 Hz, 1H), 0.98–0.94 (m, 6H) ppm. Analytical HPLC: 100%, retention time: 7.56 min (Method A).

[1139] Example 17

[1140] This example illustrates the preparation of compounds (11-10) in Table 1. R / S The method described in this embodiment involves... Figure 2 The numbered compounds in the list.

[1141] (1 S ,2 S 4 R 6 R 8 S 9 S ,11 S ,12 S ,13 R )–8–[2–(4–fluorophenoxy)acetyl]–11–hydroxy–9,13–dimethyl–6–propyl–5,7–dioxapentane[10.8.0.0² ,9 .0 4,8 0¹³ , ¹ 8 [Eicosane-14,17-diene-16-one (11-10)] R / S ).

[1142] Steroid compounds 11-10 R / S It was prepared according to the method described in Example 13.

[1143] Compounds 11-10 were obtained. R / S It is a white solid (14 mg, 54% yield). ESI m / z: 525.2 (M + H) + . 1 HNMR (400 MHz, MeOD d4 ) δ 7.47 (d, J = 10.1 Hz, 1H), 7.02 (t, J = 8.7 Hz, 2H), 6.94–6.90 (m, 2H), 6.27 (dd, J = 10.1, 1.8 Hz, 1H), 6.03 (s, 1H), 5.06 (d, J = 18.1Hz, 1H), 4.90–4.88 (m, 1H), 4.82 (d, J = 18.1 Hz, 1H), 4.69 (t, J = 4.4 Hz, 1H), 4.46 (d, J= 2.8 Hz, 1H), 2.71–2.63 (m, 1H), 2.42–2.38 (m, 1H), 2.30–2.11 (m, 2H), 2.05–2.01 (m, 1H), 1.89–1.84 (m, 1H), 1.77–1.63 (m, 5H), 1.51–1.41 (m, 5H), 1.18–1.02 (m, 2H), 0.97–0.93 (m, 6H) ppm. Analytical HPLC: 100%, retention time: 9.94 min (Method A).

[1144] Example 18

[1145] This example illustrates the preparation of compounds 11-11 in Table 1. R / S The method. This embodiment relates to... Figure 2 The numbered compounds in the list.

[1146] N –(4–{2–[(1 S ,2 S 4 R 6 R 8 S 9 S ,11 S ,12 S ,13 R )–11–hydroxy–9,13–dimethyl–16–oxy–6–propyl–5,7–dioxapentane [10.8.0.0²] ,9 .0 4,8 0¹³ , ¹ 8 [eicosyl-14,17-diene-8-yl]-2-oxoethoxy}phenyl)acetamide (11-11) R / S )

[1147] Steroid compounds 11-11 R / S It was prepared according to the method described in Example 13.

[1148] Compound 11-11 was obtained R / S It is a white solid (25 mg, 46% yield). ESI m / z: 564.3 (M + H) + . 1 HNMR (500 MHz, MeOD d4 ) δ 7.49–7.45 (m, 3H), 6.89 (d, J = 9.0 Hz, 2H), 6.28 (d, J=10.2 Hz, 1H), 6.04 (s, 1H), 5.09 (d, J = 18.1 Hz, 1H), 4.91–4.89 (m, 1H), 4.83(d, J = 18.1 Hz, 1H), 4.70 (t, J = 4.3 Hz, 1H), 4.47 (d, J = 3 Hz, 1H), 2.72–2.65 (m, 1H), 2.43–2.39 (m, 1H), 2.30–2.22 (m, 1H), 2.18–2.12 (n, 4H), 2.06–2.03 (m, 1H), 1.90–1.86 (m, 1H), 1.77–1.65 (m, 5H), 1.48 (m, 5H), 1.18–1.09 (m, 1H), 1.07–1.04 (m, 1H), 0.99–0.95 (m, 6H) ppm. Analytical HPLC: 100%, retention time: 7.33 min (Method B).

[1149] Example 19

[1150] This example illustrates the preparation of compounds 11-12 in Table 1. R / S The method. This embodiment relates to... Figure 2 The numbered compounds in the list.

[1151] (1 S ,2 S 4 R 8 S 9 S ,11 S ,12 R ,13 S ,19 S )–8–[2–(4–aminophenoxy)acetyl]–12,19–difluoro–11–hydroxy–9,13–dimethyl–6–propyl–5,7–dioxapentane[10.8.0.0²] ,9 .0 4,8 0¹³ , ¹ 8 [Eicosane-14,17-diene-16-one (11-12)] R / S )

[1152] Step 1: Compound (9B) was prepared according to general method A as described in Example 9. Triethylamine (34 mg, 0.34 mmol) and methanesulfonyl chloride (30 mg, 0.26 mmol) were added dropwise to a solution of (6S,9R)2F-budesonide (80 mg, 0.17 mmol) in DCM (1 mL) at 0 °C. The mixture was stirred at this temperature for half an hour until (6S,9R)2F-budesonide was depleted as monitored by TLC. The reaction mixture was then diluted with DCM (100 mL) and quenched with a saturated aqueous solution of ammonium chloride (30 mL). The organic solution was washed with a saturated aqueous solution of ammonium chloride, then with brine, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by rapid chromatography (0–2% MeOH in DCM solution) to give the corresponding methanesulfonate product (9B).

[1153] Step 2: Dissolve compound 9B in acetone (0.5 mL). Add 4-aminophenol (10⁻⁹, 37 mg, 0.34 mmol) and cesium carbonate (0.11 g, 0.34 mmol) to the resulting solution. Reflux the reaction mixture for 1.5 hours, or until (9B) is completely depleted as determined by TLC and LCMS. Then dilute the mixture with ethyl acetate and filter. Concentrate the filtrate under vacuum, and purify the residue by preparative HPLC (Method B) to give compounds 11-12. R / S (6.0 mg, yield 6.3% starting from (6S,9R)2F-budesonide) is a white solid. ESI m / z: 558 (M + H) + . 1 H NMR (500 MHz, MeOD d4 ) δ 7.34 (d, J = 10.0 Hz, 1H), 6.78–6.71 (m, 4H), 6.37–6.33 (m, 2H), 5.63–5.49 (m, 1H), 5.10–4.99 (m, 1H), 4.77–4.63 (m, 2H), 4.33 (d, J = 9.1 Hz, 1H), 2.74–2.57 (m, 1H), 2.39–2.13 (m, 3H), 1.98–1.31 (m, 12H), 1.03–0.93 (m, 6H) ppm. Analytical HPLC: purity 97.4%, retention time: 7.55 min (Method B).

[1154] (1 S ,2 S 4 R 6 R 8S 9 S ,11 S ,12 R ,13 S ,19 S )-8-[2-(4-aminophenoxy)acetyl]-12,19-difluoro-11-hydroxy-9,13-dimethyl-6-propyl-5,7-dioxapentane[10.8.0.0²] ,9 .0 4,8 0¹³ ,18 Eicosane-14,17-dien-16-one (11-12) R )

[1155] Compound 9B was prepared according to general method A as described in Example 9. R Compound 9B R (0.90 g, 1.7 mmol) was reacted with 4-aminophenol (0.20 g, 1.8 mmol) and cesium carbonate (1.1 g, 3.4 mmol) in acetonitrile (20 mL), and then purified by silica gel column chromatography (50-80% ethyl acetate in petroleum ether solution) to obtain (11-12) R (0.20 g, 54% yield) is a yellow oily substance. ESI m / z: 558 (M / +H) + . 1 H NMR (500 MHz, DMSO d6 ) δ 7.26 (d, J =10.5 Hz, 1H), 6.64 (d, J = 5.0 Hz, 2H), 6.50 (d, J = 5.0 Hz, 2H), 6.30 (dd, J = 10Hz, 2 Hz, 1H), 6.11 (s, 1H), 5.72-5.65 (m, 0.5H), 5.62-5.55 (m, 0.5H), 5.52-5.48 (m, 1H), 5.0 (s, 0.5H), 4.95 (s, 0.5H), 4.80-4.78 (m, 1H), 4.75-4.65 (m,1H), 4.24-4.16 (m, 1H), 2.70-2.52 (m, 1H), 2.30-2.21 (m, 1H), 2.11-2.00 (m,2H), 1.77 (d, J=13.0Hz, 1H), 1.61-1.54 (m, 4H), 1.49 (s, 3H), 1.36 (q, J = 7.5Hz, 3H), 1.23 (s, 1H), 0.87 (d, J = 7.5 Hz, 3H), 0.83 (s, 3H) ppm. Analytical HPLC: 100%, retention time: 8.44 min (Method B).

[1156] Example 20

[1157] This example illustrates the preparation of compounds 11-13 in Table 1. R The method. This embodiment relates to... Figure 2 The numbered compounds in the list.

[1158] (1S,2S,4R,6R,8S,9S,11S,12R,13S,19S)-8-[2-(3-aminophenoxy)acetyl]-12,19-difluoro-11-hydroxy-9,13-dimethyl-6-propyl-5,7-dioxapentane[10.8.0.0²] ,9 .0 4,8 0¹³ ,18 Eicosane-14,17-dien-16-one (11-13) R ).

[1159] Steroids 11-13 R It was prepared according to the method described in Example 19.

[1160] After purification by preparative HPLC (Method A), compound (11-13) was obtained. R It is a light orange solid (9.0 mg, 44% yield). ESIm / z: 558 (M + H) + . 1 H NMR (500 MHz, MeOD d4 ) δ 7.35 (dd, J = 10.1, 1.3 Hz, 1H), 7.29 (t, J = 8.1 Hz, 1H), 6.76-6.70 (m, 3H), 6.40-6.29 (m, 2H), 5.66-5.48(m, 1H), 5.14(d, J = 18.1 Hz, 1H), 4.93-4.91 (m, 1H), 4.90-4.87 (m, 1H), 4.77(t, J= 4.3 Hz, 1H), 4.35 (d, J = 9.3 Hz, 1H), 2.76-2.62 (m, 1H), 2.41-2.18 (m,3H), 1.83-1.56 (m, 9H), 1.50 (dt, J = 15.4, 7.6 Hz, 2H), 0.99–0.96 (m, 6H) ppm. Analytical HPLC: 100%, retention time: 7.77 min (Method A).

[1161] Example 21

[1162] This example illustrates the preparation of compounds 11-14 in Table 1. R / S The method. This embodiment relates to... Figure 2 The numbered compounds in the list.

[1163] (1 S ,2 S 4 R 8 S 9 S ,11 S ,12 R ,13 S ,19 S )-8-[2-(4-amino-3-fluorophenoxy)acetyl]-12,19-difluoro-11-hydroxy-9,13-dimethyl-6-propyl-5,7-dioxapentane[10.8.0.0²] ,9 .0 4,8 0¹³ ,18 Eicosane-14,17-dien-16-one (11-14) R / S ).

[1164] At room temperature, 4-amino-3-fluorophenol (10⁻¹⁴, 0.25 g, 2.0 mmol) and potassium hydroxide (0.11 g, 2.0 mmol) were added to a DMSO (3 mL) solution of (9B) (0.20 g, 0.37 mmol). The resulting mixture was stirred at 60 °C for 1 hour under nitrogen protection until the reaction was complete, and the reaction was monitored by TLC and LCMS. After cooling the reaction mixture to room temperature and filtering through a membrane, the reaction solution was directly purified by preparative HPLC (Method A) to give compounds 11-14. R / S (40 mg, 19% yield) It is a grayish-white solid. ESI m / z: 576 (M + H) + . 1 H NMR (500 MHz, MeOD d4 ) δ7.40-7.31 (m, 1H), 7.20 (td, J = 9.1, 1.9 Hz, 1H), 6.91-6.84 (m, 1H), 6.80-6.76 (m, 1H), 6.40-6.30 (m, 2H), 5.57 (ddd, J = 48.6, 9.7, 6.8 Hz, 1H), 5.15 (d, J = 18.1 Hz,1H), 4.90-4.79 (m, 2H), 4.75 (t, J = 4.3 Hz, 1H), 4.41-4.28 (m, 1H), 2.78-2.57 (m, 1H), 2.40-2.12 (m, 3H), 1.98-1.39 (m, 11H), 1.07-0.92 (m, 6H) ppm. Analytical HPLC: 100%, retention time: 8.10 min (Method A).

[1165] Example 22

[1166] This example illustrates the preparation of compounds 11-15 in Table 1. R / S The method. This embodiment relates to... Figure 2 The numbered compounds in the list.

[1167] tert-butyl N -[(4-{2-[(1 S ,2 S 4 R 8 S 9 S ,11 S ,12 R ,13 S ,19 S )-12,19-difluoro-11-hydroxy-9,13-dimethyl-16-oxo-6-propyl-5,7-dioxapentane [10.8.0.0²] ,9 .0 4,8 0¹³ ,18 [eicosyl-14,17-dien-8-yl]-2-oxoethoxy[phenyl]methyl]carbamate ( N -Boc-11-15 R / S ).

[1168] Step 1: At room temperature, Boc₂O (2.4 g, 11 mmol) was added dropwise to a solution of 4-(aminomethyl)phenol (1.2 g, 10 mmol) in methanol (70 mL) and water (5 mL) using a syringe. The resulting mixture was stirred at room temperature for 1 hour until the 4-(aminomethyl)phenol was completely consumed, and the mixture was monitored by LCMS and TLC. The volatiles were removed by vacuum concentration, and the residue was dissolved in ethyl acetate (150 mL). The solution was washed with saturated citric acid aqueous solution (50 mL x 2), then washed with brine, dried over sodium sulfate, and concentrated under vacuum to obtain... N -Boc-4-aminomethylphenol (2.1 g, 94% yield) is a brown oily substance. ESI m / z: 246 (M + Na) + . 1 H NMR (500 MHz, CDCl3) δ 7.12 (d, J = 7.8 Hz, 2H), 6.82-6.71 (m,2H), 4.84 (s, 1H), 4.23 (d, J = 5.3 Hz, 2H), 1.46 (s, 9H) ppm.

[1169] Step 2: Prepare compound (N-Boc-11-15) according to the method described in Example 19. R / S ).

[1170] (1 S ,2 S 4 R 8 S 9 S ,11 S ,12 R ,13 S ,19 S )-8-{2-[4-(aminomethyl)phenoxy]acetyl}-12,19-difluoro-11-hydroxy-9,13-dimethyl-6-propyl-5,7-dioxapentane[10.8.0.0² ,9 .0 4,8 0¹³ ,18 Eicosane-14,17-dien-16-one (11-15) R / S )

[1171] At 0°C, via syringe, inject (N-Boc-11-15) R / STFA (0.4 mL) was added dropwise to a 2 mL solution of DCM (30 mg, 45 μmol). The resulting mixture was stirred at room temperature for 1 hour until Boc was completely removed, and the reaction was monitored by LCMS. The volatiles were removed by vacuum concentration, and the residue was purified by preparative HPLC (Method A) to give compounds (11-15). R / S (15 mg, 49% yield) is a white solid. ESI m / z: 572 (M + H) + . 1 H NMR (500 MHz, MeOD d4 ) δ 7.45-7.32(m, 3H), 7.01-6.96 (m, 2H), 6.41-6.30 (m, 2H), 5.57 (ddd, J = 18.2, 10.4, 7.3Hz, 1H), 5.21 (dd, J = 19.7 Hz, 1H), 4.93-4.91 (m, 1H), 4.85 (d, J = 18.0 Hz, 1H), 4.77 (t, J = 4.3 Hz, 1H), 4.37-4.32 (m, 1H), 4.07 (s, 2H), 2.75-2.58 (m, 1H), 2.40-2.15 (m, 3H), 1.86-1.40 (m, 11H), 1.08-0.92 (m, 6H) ppm. Analytical HPLC: 100%, retention time: 7.47 min (Method A).

[1172] Example 23

[1173] This example illustrates the preparation of compounds 11-16 in Table 1. R / S The method. This embodiment relates to... Figure 2 The numbered compounds in the list.

[1174] (1 S ,2 S 4 R 6 R 8 S 9 S ,11 S ,12 S ,13 R )-11-hydroxy-8-[2-(4-hydroxyphenoxy)acetyl]-9,13-dimethyl-6-propyl-5,7-dioxapentane[10.8.0.0² ,9 .0 4,8 0¹³, ¹ 8 Eicosane-14,17-dien-16-one (11-16) R / S )

[1175] Compounds 11-16 were prepared according to the method described in Example 12. R / S .

[1176] After purification by preparative HPLC (Method A), compounds 11-16 were obtained. R / S (20 mg, 38% yield) It is a brownish-brown solid. ESIm / z: 523.2 (M + H) + . 1 H NMR (500 MHz, MeOD d4 ) δ 7.47 (d, J = 10.1 Hz, 1H),6.82-6.77 (m, 2H), 6.75-6.70 (m, 2H), 6.28 (dd, J = 10.1, 1.8 Hz, 1H), 6.04 (s,1H), 5.00 (d, J = 18.1 Hz, 1H), 4.91-4.89 (m, 1H), 4.75 (d, J = 18.1 Hz, 1H), 4.67 (t, J = 4.5 Hz, 1H), 4.46 (d, J = 3.1 Hz, 1H), 2.68 (td, J = 13.6, 5.8 Hz, 1H), 2.40 (dd, J = 13.5, 2.8 Hz, 1H), 2.31-2.21 (m, 1H), 2.17-2.13 (m, 1H), 2.02 (dd, J = 13.7, 3.3 Hz, 1H), 1.86 (dd, J = 13.7, 2.6 Hz, 1H), 1.80-1.58 (m, 5H), 1.53-1.40 (m, 5H), 1.18-0.93 (m, 8H) ppm. Preparative HPLC: 100%, retention time: 8.92 min (Method A).

[1177] Example 24

[1178] This example illustrates the preparation of compounds 11-17 in Table 1. R / SThe method. This embodiment relates to... Figure 2 The numbered compounds in the list.

[1179] (1 S ,2 S 4 R 8 S 9 S ,11 S ,12 R ,13 S ,19 S )-8-{2-[(6-aminopyridin-2-yl)oxy]acetyl}-12,19-difluoro-11-hydroxy-9,13-dimethyl-6-propyl-5,7-dioxapentane[10.8.0.0] 2,9 .0 4,8 .0 13,18 Eicosane-14,17-dien-16-one (11-17) R / S )

[1180] Compounds 11-17 were prepared according to the method described in Example 19. R / S .

[1181] After purification by rapid chromatography (10-50% ethyl acetate in petroleum ether solution), compounds 11-17 were obtained. R / S (50 mg, 24% yield) is a white solid. ESI: 559 (M + H) + . 1 H NMR (500 MHz, DMSO d6 ) δ 7.35-7.31 (m, 2H), 6.31 (d, J = 11.5 Hz, 1H), 6.13 (s, 1H), 6.03 (d, J = 8.0 Hz, 1H), 5.98 (d, J = 7.5 Hz, 1H), 5.84-5.82 (m, 1H), 5.68-5.56 (m, 3H), 5.25-4.72 (m, 4H), 4.29 (br s, 1H), 2.66-2.57 (m, 1H), 2.28-2.05 (m, 4H), 1.63-1.58 (m, 4H), 1.50-1.30 (m, 6H), 0.95-0.87 (m, 6H) ppm. Analytical HPLC: 100%, retention time: 8.65 min (Method A).

[1182] Example 25

[1183] This embodiment illustrates a method for preparing compounds 11-19 in Table 1. This embodiment relates to... Figure 2 The numbered compounds in the list.

[1184] (1 S ,2 S 4 R 8 S 9 S ,11 S ,12 R ,13 S ,19 S )-8-(2-azidoacetyl)-12,19-difluoro-11-hydroxy-9,13-dimethyl-6-propyl-5,7-dioxapentane [10.8.0.0²] ,9 .0 4,8 0¹³ ,18 Eicosane-14,17-dien-16-one (11-19)

[1185] Step 1: A suspension of compound 9B (1.0 g, 1.8 mmol) and sodium azide (1.2 g, 18 mmol) in acetone (15 mL) was stirred overnight at 50 °C. The reaction was confirmed to be complete by LC-MS. After cooling, the reaction mixture was poured into cold water (80 mL). The aqueous mixture was extracted with ethyl acetate (50 mL x 3). The combined organic solutions were washed with brine (30 mL), dried over sodium sulfate, and concentrated under vacuum to give (11-19) R / S The crude azide precursor (0.90 g, >99% yield) was a yellow solid and could be used in the next step without further purification. ESI m / z: 492 (M + H) + .

[1186] (1 S ,2 S 4 R 6 R 8 S 9 S ,11 S ,12 R ,13 S ,19 S )-8-(2-aminoacetyl)-12,19-difluoro-11-hydroxy-9,13-dimethyl-6-propyl-5,7-dioxapentane [10.8.0.0²] ,9 .0 4,8 0¹³ ,18 Eicosane-14,17-dien-16-one trifluoroacetate (11-19) R / S )

[1187] Step 2: Add compounds 11-19 R / S The precursor (0.85 g, 1.7 mmol) was added to a THF (20 mL) solution in 1 N, 10 mL aqueous hydrochloric acid solution. The mixture was stirred at 28–32 °C until it became clear, and then triphenylphosphine (0.68 g, 2.6 mmol) was added at this temperature. The resulting clear yellow solution was stirred at 28–32 °C for 18 hours, and the reaction was confirmed to be complete by TLC and LCMS. The mixture was concentrated under vacuum, and the residue was purified by reversed-phase rapid chromatography (0–50% acetonitrile in TFA (0.05%) aqueous solution) to give compounds 11–19. R / S (0.56 g, 57% yield, TFA salt) is a grayish-white solid. ESIm / z: 466 (M + H) + . 1 H NMR (400 MHz, MeOD d4 ) δ 7.33 (d, J = 9.9 Hz, 1H), 6.40-6.29(m, 2H), 5.69-5.45 (m, 1H), 4.93-4.92 (m, 1H), 4.71 (t, J = 4.3 Hz, 1H), 4.35-4.27 (m, 2H), 3.90-3.84 (m, 1H), 2.81-2.54 (m, 1H), 2.42-2.06 (m, 3H), 1.82-1.32 (m, 11H), 1.09-0.87 (m, 6H)ppm. 19 F NMR (376 MHz, MeOD d4 ) δ -77.01, -166.24, -166.92, -188.81, -188.83 ppm. Analytical HPLC: 100%, retention time: 6.86 min (Method A).

[1188] (1 S ,2 S 4 R 6 R 8 S 9 S ,11 S ,12 R ,13 S ,19 S )-8-(2-aminoacetyl)-12,19-difluoro-11-hydroxy-9,13-dimethyl-6-propyl-5,7-dioxapentane [10.8.0.0²] ,9.0 4,8 0¹³ ,18 Eicosane-14,17-dien-16-one trifluoroacetate (11-19) R )

[1189] Step 1: Using the same method as above, after purification by rapid chromatography (0-50% ethyl acetate in petroleum ether solution), the compound (9B) was obtained. R (11-19) were prepared. R The azide-based precursor (0.12 g, 87% yield) was a white solid. ESIm / z: 492 (M + H) + . 1 H NMR (500 MHz, CDCl3) δ 7.10 (dd, J = 10.2, 1.3 Hz, 1H), 6.44(s, 1H), 6.38 (dd, J = 10.2, 1.8 Hz, 1H), 5.48-5.31 (m, 1H), 4.92 (d, J = 5.4 Hz, 1H), 4.62 (t, J = 4.4 Hz, 1H), 4.43 (dd, J = 5.6, 2.7 Hz, 1H), 4.22 (d, J = 18.7Hz, 1H), 3.94 (d, J = 18.7 Hz, 1H), 2.56-2.39 (m, 2H), 2.32-2.18 (m, 2H), 1.85-1.71 (m, 3H), 1.67-1.54 (m, 7H), 1.46-1.37 (m, 2H),0.97-0.90 (m, 6H)ppm.

[1190] Step 2: Using the same method as above, after purification by preparative HPLC (Method A), compounds 11-19 were obtained. R (30 mg, 66% yield) It is a white solid. ESI m / z: 466 (M + H) + . 1 H NMR (500 MHz, MeOD d4 ) δ 7.34(d, J= 10.0 Hz, 1H), 6.40-6.30 (m, 2H), 5.65-5.46 (m, 1H), 4.94-4.91 (m, 1H), 4.72 (t, J = 4.3 Hz, 1H), 4.34-4.28 (m, 2H), 3.88 (d, J = 18.8 Hz, 1H), 2.78-2.60 (m, 1H), 2.39-2.34 (m, 1H), 2.33-2.18 (m, 2H), 1.77-1.54 (m, 9H), 1.53-1.40 (m, 2H), 0.99-0.95 (m, 6H) ppm. Analytical HPLC: 100%, retention time: 6.85 min (Method A).

[1191] Example 26

[1192] This example illustrates the preparation of compounds 11-20 in Table 1. R / S The method. This embodiment relates to... Figure 2 The numbered compounds in the list.

[1193] (1 S ,2 S 4 R 8 S 9 S ,11 S ,12 R ,13 S ,19 S )-12,19-difluoro-11-hydroxy-8-(2-{[(4-methoxyphenyl)methyl](methyl)amino}acetyl)-9,13-dimethyl-6-propyl-5,7-dioxapentane[10.8.0.0² ,9 .0 4 ,8 0¹³ ,18 Eicosane-14,17-dien-16-one trifluoroacetic acid (11-20) R / S )

[1194] At room temperature, add sequentially to a 10 mL solution of acetonitrile containing compound 9B (0.54 g, 1.0 mmol) N -PMB-methylamine (0.30 g, 2.0 mmol) and potassium carbonate (0.28 g, 2.0 mmol). The reaction mixture was stirred overnight at 70 °C. After cooling, the mixture was diluted with DCM and filtered. The filtrate was concentrated under vacuum, and the residue was purified by rapid chromatography (10-90% ethyl acetate in petroleum ether solution) to give the crude compound (11-20). R / S (0.20 g, 33% yield) was a white solid. The crude product (30 mg) was further purified by preparative HPLC (Method A) to give pure compound (11-20 g). R / S It is a white solid (12 mg, 13% yield). ESI m / z: 600 (M + H) + . 1 H NMR (500 MHz, MeOD d4 ) δ 7.50-7.43 (m, 2H), 7.34 (d, J = 10.1 Hz, 1H), 7.07 (d, J = 8.5 Hz, 2H), 6.39-6.30 (m, 2H), 5.56(ddd, J = 48.5, 10.7, 6.5 Hz, 1H), 5.24-5.21 (m, 1H), 4.94-4.92 (m, 1H), 4.64-4.53 (m, 1H), 4.38-4.16 (m, 4H), 3.86 (s, 3H), 2.92-2.91 (m, 3H), 2.76-2.56(m, 1H), 2.39-2.31 (m, 1H), 2.28-2.09 (m, 2H), 1.97 (td, J = 13.2, 7.8 Hz, 1H), 1.78–1.23 (m, 10H), 1.08–0.88 (m, 6H) ppm. Analytical HPLC: 100%, retention time: 7.81 min (Method A).

[1195] Example 27

[1196] This example illustrates the preparation of compounds 11-21 in Table 1. R / S The method. This embodiment relates to... Figure 2 The numbered compounds in the list.

[1197] (1 S ,2 S 4 R 8 S 9 S ,11 S ,12 R ,13 S ,19 S )-12,19-difluoro-11-hydroxy-9,13-dimethyl-8-[2-(methylamino)acetyl]-6-propyl-5,7-dioxapentane[10.8.0.0²,9 .0 4,8 0¹³ ,18 Eicosane-14,17-dien-16-one trifluoroacetic acid (11-21) R / S )

[1198] To compounds 11-20 R / S 1 drop of 1-chloroethyl chloroformate and 0.4 mL of chloroform were added to a 4 mL screw-cap vial containing 30 mg (0.053 mmol). The mixture was stirred at 70 °C for 2 hours until the starting material was exhausted as monitored by TLC. After cooling to room temperature, methanol (1.5 mL) was added to the mixture. The mixture was stirred at 70 °C for 1 hour until the reaction was complete, monitored by TLC and LCMS. The volatiles were removed by vacuum concentration, and the residue was purified by preparative HPLC (Method A) to give compound 11-21. R / S (8.0 mg, 28% yield) It is a white solid. ESIm / z: 480 (M + H) + . 1 H NMR (400 MHz, MeOD) d4 ) δ 7.34 (d, J = 10.1 Hz, 1H), 6.41-6.26 (m, 2H), 5.56 (ddd, J = 48.7, 10.0,6.8 Hz, 1H), 5.28 (t, J = 4.9 Hz, 1H), 5.23 (d, J = 7.4 Hz, 1H), 4.47-4.41 (m,1H), 4.34-4.30 (m, 1H), 4.07-4.00 (m, 1H), 2.82-2.54 (m, 4H), 2.43-2.09 (m,3H), 1.96 (td, J = 13.6, 7.9 Hz, 1H), 1.81-1.34 (m, 10H), 1.10-0.85 (m, 6H)ppm. 19 F NMR (376 MHz, MeOD d4 ) δ -76.96, -166.28, -166.95, -188.80, -188.83 ppm. Analytical HPLC: 99%, retention time: 6.97 min (Method A).

[1199] Example 28

[1200] This example illustrates a method for preparing compound 14-2 in Table 1. This example relates to... Figure 3 The numbered compounds in the list.

[1201] (1R,2S,8S,10S,11S,13S,14R,15S,17S)–1,8–difluoro–17–hydroxy–2,13,15–trimethyl–14–[2–(methylamino)acetyl]–5–oxotetracyclo[8.7.0.0²] ,7 .0¹¹ ,15 Heptadecane-3,6-diene-14-ylpropionate (14-2)

[1202] The synthesis report of flumethasone mesylate (12) is in Bioorg. Med. Chem. Lett. In 2015, 25, 2837–2843, the entire contents of this document are incorporated herein by reference in their entirety for all purposes.

[1203] 12 mg (82 mg crude) of methylamine (2 M THF solution, 1.5 mL, 3,000 mmol) was placed in a sealed tube and stirred overnight at room temperature. The mixture was then heated at 60 °C for 3 hours until the reaction was complete. The solution was concentrated under vacuum, and the residue was purified by preparative HPLC (0-80% acetonitrile aqueous solution containing 10 mM NH₄HCO₃) to give compound 14-2 (8 mg, 11% yield in two steps) as a white solid. ESI m / z: 480.2 (M+H). 1 H NMR (DMSO–d6, 400 MHz) δ7.27–7.25 (d, J=10.4 Hz, 1H), 6.30–6.27 (dd, J=10.4, 2.0 Hz, 1 H), 6.10 (s,1H), 5.73–5.56 (m, 1H), 5.43–5.32 (m, 2H), 4.62–4.42 (m, 1H), 4.25–4.18 (m,1H), 4.15 (brs, 1H), 2.87 (s, 2H), 2.70 (s, 1H), 2.60–2.56 (m, 1H), 2.36–1.90(m, 7H), 1.49–1.35 (m, 5H), 1.10–0.91 (m, 10H).

[1204] Example 29

[1205] This embodiment illustrates a method for preparing compounds 15-5 in Table 1. This embodiment relates to... Figure 3 The numbered compounds in the list.

[1206] (1 R,2 S 8 S 10 S ,11 S ,13 R ,14 R 15 S 17 S )–14–[2–(4–aminophenoxy)acetyl]–1,8–difluoro–14,17–dihydroxy–2,13,15–trimethyltetracyclo[8.7.0.0] 2,7 .0 11,15 Heptadecane–3,6-diene–5-one (15-5)

[1207] Step 1: A mixture of compound (12) (0.16 g, 0.33 mmol), 4-nitrophenol (10⁻⁵, 92 mg, 0.67 mmol), and potassium carbonate (92 mg, 0.67 mmol) in acetone (15 mL) was refluxed (60 °C) for 18 hours. After cooling the reaction mixture to room temperature, the volatiles were removed by vacuum concentration. The residue was purified by rapid chromatography (0-1% ethyl acetate in petroleum ether) to give a nitro-intermediate (0.14 g, 79% yield) as a white solid. ESI m / z: 532 (M + H) + . 1 H NMR (CDCl3, 400 MHz) δ 8.20 (d, J = 9.0 Hz, 2H), 7.10 (d, J = 10.5 Hz, 1H), 6.94 (d, J = 9.0 Hz,2H), 6.43 (br s, 1H), 6.39–6.37 (m, 1H), 5.45–5.32 (m, 1H), 5.26 (d, J = 18.0Hz, 1H), 4.85 (d, J = 18.0 Hz, 1H), 4.43–4.40 (m, 1H), 3.21–3.16 (m, 1H), 2.60 (s, 1H), 2.52–2.40 (m, 2H), 2.30–2.20 (m, 2H), 2.06–1.99 (m, 1H),1.86–1.68(m, 3H), 1.53–1.48 (m, 2H), 1.09 (s, 3H), 0.99 (d, J = 7.0 Hz, 3H) ppm.

[1208] Step 2: Iron powder (0.14 g, 2.5 mmol) was added to a mixed solution of ethanol (20 mL) and water (2 mL) containing the nitro-intermediate (0.13 g, 0.25 mmol), followed by ammonium chloride (0.14 g, 2.5 mmol). After stirring at 80 °C for 2 hours, the suspension was cooled to room temperature and filtered through diatomaceous earth to remove inorganic salts. The filtrate was concentrated under vacuum, and the residue was purified by preparative HPLC (Method B) to give compound 15-5 (90 mg, 70% yield) as a white solid. ESI m / z: 502 (M + H) + . 1 H NMR (D...

Claims

1. The compound represented by formula (1000): 1000； Or its pharmaceutically acceptable salts or stereoisomers. in: R 1 and R 2 Together , Or (a) or (b): (a) R 3 Yes - OC 6-10 Aromatic-NR a R b C 6-10 The aryl group can be substituted by a halogen and R a and R b Independently -H or C in each case 1-6 Alkyl; and R 4 It is C 1-6 alkyl; or (b) R 3 Yes -NR a R b , where R a and R b Independently for -H and C in each case. 1-6 Alkyl, or optionally amino-substituted C 6-10 Aryl; and R 4 It is C 1-6 alkyl; R 5 In each case, it is independently -OH, halogen, or C. 1-6 Alkyl groups and each R 5 Located on any ring atom; and n is an integer from 0 to 16.

2. The compound according to claim 1, wherein the compound of formula (1000) has the formula (A) 1 The structure of ) (A 1 ) Where R 1 -R 3 All as defined in claim 1, and R 5A and R 5B Each is an independent halogen or hydrogen atom.

3. The compound according to any one of claims 1-2, wherein R 3 Yes -NR a R b R a It's H, and R b Is it H or C? 1-6 alkyl.

4. The compound according to claim 1, having the formula (A) 4 The structure shown is as follows: (A 4 ) Where R 3 Yes – NR a R b , and R 4 It is C 1-6 Alkyl, wherein R a and R b Each is independently a hydrogen atom or a carbon atom. 1-6 alkyl.

5. The compound according to claim 4, wherein R 4 It is C 1-4 alkyl.

6. The compound according to claim 4 or 5, wherein R 3 It is -NH2, -NHCH3, or -N(CH3)2.

7. The compound according to claim 1, having the formula (A) 5 The structure shown is as follows: (A 5 ) Where R 4 It is C 1-6 Alkyl, R P1 It is a hydrogen atom, and R P2 Yes – NR a R b , where R a and R b Each is independently a hydrogen atom or a carbon atom. 1-6 alkyl.

8. The compound according to claim 1, having the formula (A) 6 The structure shown is as follows: (A 6 ) Where R 3 It is NR a R b , where R a and R b Each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl groups, and R 4 It is C 1-6 alkyl.

9. The compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, in: R 1 and R 2 Together , R 3 Yes -NR a R b ; R 4 It is C 1-6 alkyl; R 5 In each case, the choice is independent of -OH, halogen, and C. 1-6 Substituents in the group consisting of alkyl groups; n is an integer from 0 to 16; and each R 5 Located on any ring atom; and R a and R b In each case, H and C are chosen independently. 1-6 A group composed of alkyl groups.

10. The compound according to claim 9, wherein R 3 It is -NH2.

11. The compound according to claim 9, having a structure shown in formula 1110, 1120, 1130, or 1140: Or its pharmaceutically acceptable salts or stereoisomers.

12. The compound according to claim 11, wherein, R 3 Yes -NR a R b ;and R 4 It's n-propyl.

13. The compound according to claim 12, having the structure shown in formula 1120.

14. The compound according to claim 11, wherein, R 3 Yes - OC 6-10 Aromatic-NR a R b .

15. The compound according to claim 14, wherein R 3 It is -NH2, -N(H)CH3 or -N(CH3)2.

16. The compound according to claim 14, wherein R 3 Yes - OC 6-10 Aromatic-NR a R b ; wherein C 6-10 The aryl group can be optionally replaced by a halogen.

17. The compound according to claim 14, wherein R 3 It is -O-phenyl-NR a R b The phenyl group is optionally replaced by a halogen.

18. The compound according to claim 14, wherein R 3 yes , , , ,or .

19. The compound according to claim 14, wherein R 3 yes .

20. The compound according to any one of claims 14-19, wherein R 4 It's n-propyl.

21. A compound selected from: Or its pharmaceutically acceptable salts or stereoisomers.

22. A compound comprising a binder coupled to a compound of any one of claims 1-21, wherein the binder is an antibody or an antigen-binding fragment thereof.

23. A compound comprising a binding agent conjugated with the compound of any one of claims 1-22 and cyclodextrin CD, wherein the binding agent is an antibody or an antigen-binding fragment thereof.

24. The compound of claim 23, wherein CD is selected from the group consisting of: in This indicates the bond connecting the CD to the protein-steroid conjugate.

25. A compound having the structure shown in Formula 1200: 1200 Or its pharmaceutically acceptable salts or stereoisomers. in: R 1 and R 2 Together , Or (a) or (b): (a) R 3 Yes - OC 6-10 Aromatic-NR a R b ;and R 4 It is C 1-6 alkyl; or (b) R 3 Yes -NR a R b ;and R 4 It is C 1-6 alkyl; R 5 In each case, the choice is independent of -OH, halogen, and C. 1-6 Substituents in the group consisting of alkyl groups; n is an integer from 0 to 16; and each R 5 Located on any ring atom; R a and R b In each case, H and C are chosen independently. 1-6 Groups composed of alkyl groups; BA is a binder; Each L is an optional connector; BA or L and R 3 or R 4 Covalent bonding; and x is an integer from 1 to 30.

26. The compound according to claim 25, having a structure shown in formula 1210, 1220, 1230, or 1240: Or its pharmaceutically acceptable salts or stereoisomers; Where R 3 Covalently bonded to L or BA.

27. The compound according to claim 25, having a structure shown in formula 1310, 1320, 1330, or 1340: Or its pharmaceutically acceptable salts or stereoisomers; Where R 4 Covalently bonded to L or BA.

28. The compound according to claim 25, wherein the compound is selected from the group consisting of: Or its pharmaceutically acceptable salts or stereoisomers; Each L is an optional connector; Each BA is a binder; and Each x is an integer from 1 to 30.

29. The compound according to claim 25, wherein the compound is selected from the group consisting of: Where x is an integer from 1 to 30; Or its pharmaceutically acceptable salts or stereoisomers.

30. Use of the compound according to any one of claims 1-29 in the preparation of a medicament for treating diseases, symptoms or conditions related to glucocorticoid receptor signaling.

31. The use according to claim 30, wherein, The disease, symptom, or condition mentioned is an inflammatory disease, symptom, or condition.

32. Use of the compound of any one of claims 10-13 in the preparation of a medicament for treating diseases, symptoms or conditions related to glucocorticoid receptor signaling.

33. The use according to claim 32, wherein, This reduces the side effects associated with the administration of the uncoupled steroid payload of the compound.

34. An in vitro method for delivering the compound of claim 1 to cells, comprising contacting the cells with a protein steroid conjugate of the compound, wherein the protein conjugate comprises an antibody or an antigen-binding fragment thereof, the antibody or the antigen-binding fragment thereof binding to a surface antigen of the cells.

35. A linker-load comprising a compound of any one of claims 1-21, optionally linked to an active group via a linker.

36. A linker-load comprising, optionally, a compound of claim 35 linked to an active group via a linker, wherein the linker-load is selected from the group consisting of: 。 37. The compound according to claim 21, wherein the compound is: ， Or its pharmaceutically acceptable salts or stereoisomers.

38. The compound according to claim 21 or 37, wherein the compound is: Or its pharmaceutically acceptable salts or stereoisomers.

39. The compound according to claim 28, wherein it is , where x is an integer from 1 to 6; , where x is an integer from 1 to 6; , where x is an integer from 1 to 6; , where x is an integer from 1 to 6; or , where x is an integer from 1 to 6.

40. The compound according to claim 39, wherein x is 2 or 4.

41. The compound according to claim 39 or 40, wherein... BA is an antibody having a glutamine residue at position 295 according to EU number, wherein L is bonded to said glutamine residue, or BA is an antibody having a glutamine residue at position 295 according to EU number and a glutamine residue at position 297 according to EU number, wherein L is bonded to the glutamine residue at position 295 or 297.

42. The compound according to claim 29, which is or ， Where x is an integer from 1 to 6; or or ， Where x is an integer from 1 to 6; or or Where x is an integer from 1 to 6; or or ， Where x is an integer from 1 to 6; or or ， Where x is an integer from 1 to 6.

43. The compound according to claim 42, wherein x is 2 or 4.

44. The compound according to claim 42 or 43, wherein Ab is an antibody having a glutamine residue at position 295 according to EU number, wherein the terminal –NH group is bonded to said glutamine residue, or Ab is an antibody having a glutamine residue at position 295 according to EU number and a glutamine residue at position 297 according to EU number, wherein the terminal –NH group is bonded to the glutamine residue at position 295 or 297.

45. The compound according to claim 36, wherein it is 、 、 、 or 。 46. ​​The compound according to claim 1 or 21, wherein the compound is: Or, or its pharmaceutically acceptable salt or stereoisomer.

47. The compound according to claim 1, 21, or 46, wherein the compound is: Or, or its pharmaceutically acceptable salt or stereoisomer.

48. The compound according to claim 29, wherein the compound is or , where x is an integer from 1 to 30; Or its pharmaceutically acceptable salts or stereoisomers.

49. The compound according to claim 1 or 21, wherein the compound is: Or, or its pharmaceutically acceptable salt or stereoisomer.

50. The compound according to claim 1 or 21, wherein the compound is: or Or, or its pharmaceutically acceptable salt or stereoisomer.

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