Peptide-drug conjugates for targeted therapy of kidney disease

Abstract

The present invention provides compounds of Formula I: # imgabs0 # or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as therapeutic or anticancer agents, pharmaceutical compositions comprising them, methods of their use, and methods of making these compounds.

Description

Technical Field

[0001] The present invention provides novel bioactive compounds for the treatment of inflammation-related kidney diseases, pharmaceutical compositions thereof, methods of use thereof, and methods of preparation thereof. These novel drugs and compositions thereof have therapeutic activity in the treatment of inflammation-related kidney diseases, particularly chronic kidney disease (CKD), systemic lupus erythematosus (SLE), diabetic nephropathy, chronic glomerulonephritis, and acute kidney injury (AKI). Background Art

[0002] Kidney disease includes a variety of serious kidney diseases and has a significant impact on global human health. Renal inflammation may be caused by a variety of exogenous and endogenous factors, including exposure to nephrotoxic substances, surgery (such as kidney transplantation), chemotherapy (treatment of cancer, diabetes or infection), infection (such as urinary tract infection and pyelonephritis) and certain chronic diseases. Among them, acute and chronic kidney disease, such as CKD, has been reported to have reached epidemic levels worldwide (e.g., Levey et al. in Kidney Int., 2005, pp.2089-2100 and Stenvinkel et al. in J. Intern. Med. 2010, 268, pp.456-467). Unfortunately, the long-term treatment of CKD required for the management of this disease state is often accompanied by serious adverse reactions, resulting in unsatisfactory treatment results and insufficient patient compliance.

[0003] Systemic lupus erythematosus (SLE) is another common chronic inflammatory disease that often affects the kidneys (e.g., reviewed by Almaani et al., Clin. J. Am. Soc. Nephrol. 2017, 12, pp. 825–835). SLE can lead to the debilitating condition lupus nephritis (LN), which must be treated with high-dose corticosteroids, toxic cyclophosphamide, or potent immunosuppressants such as cyclosporine. However, the use of such chemotherapy is often limited by the severe adverse effects of these drugs.

[0004] Furthermore, developing new and improved therapies for such kidney diseases is very difficult. For example, several drug candidates have failed in clinical trials due to safety issues and / or poor efficacy, including those for the treatment of CKD, autosomal dominant polycystic kidney disease (ADPKD), and diabetic nephropathy (reviewed by Wischnjow et al., Bioconjugate Chemistry, 2016, pp. 1050-1057).

[0005] Importantly, many of the adverse reactions that limit the use of current drugs and the development of new drugs are related to excessively extensive systemic exposure of these bioactive molecules. In other words, a bioactive drug for kidney disease, administered orally or intravenously, must first circulate in the bloodstream of the mammal or patient in need of such treatment before reaching the kidneys. This undesirable but unavoidable distribution of bioactive molecules to various body parts and organs beyond the kidneys can lead to off-target effects, which often manifest as adverse events.

[0006] Therefore, compared with traditional treatments (which can lead to drug exposure to other organs and potentially cause adverse reactions in non-renal areas), kidney-targeted drug delivery systems (including the selective transport of bioactive molecules to the kidneys) are a better choice. This will allow the biological activity of the drug to act directly on the site of renal disease, thereby expanding the drug's therapeutic window, reducing systemic adverse reactions, and improving the efficiency of this therapy.

[0007] A variety of renal drug delivery systems that direct structures to renal tissue (also known as renal targeting or molecular guidance systems) have been described. For example, in Molecular Therapy, 2007, pp. 1647-1654, Bioconjugate Chem. 2012, pp. 1200-1210, Bioconjugate Chemistry, 2016, pp. 1050-1057, and in U.S. Pat. Peptide carrier structures are described in 10,413,614. Other molecular delivery systems for kidney targeting include macromolecules such as polyvinylpyrrolidone (Nat. Biotechnol. 2003, pp. 399-404), chitosan (J. Drug Target, 2007, pp. 269-278), glucosamine (Controlled Release, 2013, pp. 148-156), and proteins (as reviewed in J. Med. Chem., 1992, pp. 1246-1259 and Int. J. Nanomedicine, 2017, pp. 673-5686).

[0008] A separate class of drugs for targeted treatment of kidney disease includes prodrugs, which can selectively release the bioactive drug structure by kidney-associated enzymes (eg, see J. Controlled Release, 2013, pp. 148-156; and RSC Adv. 4, 2014, pp. 50828-50831).

[0009] Among serious kidney diseases, CKD is recognized as a global public health problem. Over time, this chronic disease may develop into end-stage renal disease, which is debilitating. Ultimately, the option of maintaining life will be limited to time-consuming and expensive kidney dialysis and / or kidney transplantation. In many parts of the world, the lack or scarcity of dialysis stations has exacerbated this severe situation. Therefore, there is an urgent need for a CKD treatment method that can prevent end-stage renal disease by improving treatment and disease management (for example, by Erico et al. in Kidney Int. 2005, 68, Suppl. 98, pp. S21-S24).

[0010] CKD is a complex disease associated with a variety of pathogenic factors. One of the main factors is inflammation, which is usually caused by the overexpression of proinflammatory mediators, such as endothelin-1, monocyte chemoattractant protein-1, normal T cells and osteopontin (Perico et al., described in Kidney Int. 2005, 68, Suppl. 98, pp. S21-S24). Acute kidney injury (AKI) is another risk factor associated with CKD (campbell et al., described in J. Clin. Hypertension, 2015, 17, pp. 514–527). In addition, AKI may also occur independently of CKD, for example, due to exposure to nephrotoxic substances (such as nephrotoxic proinflammatory substances). In kidney transplantation, renal ischemia-reperfusion injury is the main cause of AKI. Similar to the etiology of CKD, renal inflammation plays a major role in the pathophysiology of ischemic AKI (eg, as described by Bonventre and Zuk in Kidney Int. 2004, 66, pp. 480-485).

[0011] Subsequently, certain anti-inflammatory drugs have been used to treat CKD and AKI. For example, Moonen et al. described anti-inflammatory treatment using the corticosteroid dexamethasone in BMC Neurology. 2018, 19:343.

[0012] Separately, adjuvant anti-inflammatory therapy is also often used during cancer treatment: for example, to reduce the toxic effects of anticancer drugs (e.g., as described by Shih et al. in J. Pain Palliative Care Pharmacother. 2007, 21 pp. 69-76, and by Vogelzang et al. in J. Clin. Oncol. 2003, 21, pp. 2636-2644), or to induce beneficial immunomodulatory effects (e.g., see Cook et al. Oncoimmunology, 2016, 5, e1066062).

[0013] However, long-term exposure to most anti-inflammatory drugs, such as steroids and nonsteroidal anti-inflammatory drugs (NSAIDs), is associated with serious adverse effects, including bone loss, cataracts, or muscle weakness. Therefore, safer and more effective drugs are needed to treat CKD, SLE, LN, AKI, and various other inflammation-related kidney diseases or kidney damage. These therapies must have improved selectivity, directing the drug's biological activity directly to the site of disease, thereby minimizing or eliminating adverse effects caused by off-target toxicity due to exposure of healthy tissues and organs to the drug.

[0014] A recent approach to improving drug selectivity is to target highly active drugs directly to the kidneys (e.g., as reviewed by Wischnjow et al. in Bioconjugate Chemistry, 2016, pp. 1050-1057). In this approach, an active drug (e.g., an antibacterial drug) is linked (or bound) to a targeting moiety that has a high affinity for kidney cells. Thus, the active drug or drugs are selectively delivered to the organ in need of treatment.

[0015] The present invention provides unique conjugates of certain anti-inflammatory drugs with acyclic and cyclic peptides (cyclopeptides), suitable for the targeted treatment of various kidney diseases. By carefully designing appropriate linking groups (linkers) and additional structural elements (such as spacers that alter connectivity), the covalent binding of the bioactive drug to the peptide is achieved to maximize targeted delivery and therapeutic bioactivity. The drugs provided by the present invention are particularly suitable for the treatment of CKD, AKI, and other non-cancerous kidney diseases.

[0016] A variety of cyclic peptides have been described, for example, WO 2019136298, WO 2016 / 083531, WO 2015 / 149131, WO 2015 / 135976, US 2015 / 0031602, WO 2014 / 188178, WO 2014 / 108469, CN 103923190, US 2014 / 0162937, WO 2014 / 028087, WO 2013 / 112548, CN 103130876, WO 2013 / 072695, WO 2012 / 168820, WO 2012051663, US 2012 / 0316105, US2012 / 0283176, US2010 / 0160215, US2009 / 0215677, WO 2008 / 017734, WO 2006 / 045156, US2006 / 0004185, US 6380356 and US3450687. For example, in US10413614, certain conjugates of non-cyclic peptide structures for kidney-targeted delivery of protective agents to counteract nephrotoxic substances are described. None of these references specifically describes or generally contemplates the combinations provided herein. Summary of the Invention

[0017] Provided herein are novel compounds and compositions for the targeted treatment of inflammation-related kidney diseases.

[0018] These novel compounds exhibit a surprising ability to target renal tissue, particularly renal cells affected by inflammation, including inflammation caused by overexpression of innate pro-inflammatory mediators, inflammation induced by exogenous nephrotoxic substances, or inflammation caused by other therapeutic drugs (such as cytotoxic anticancer drugs or nephrotoxic antibacterial drugs). The unique affinity of the compositions provided herein for renal tissue affected by renal disease enables these molecules to be selectively delivered and accumulated at the site of disease, with minimal or no accumulation in other tissues not affected by the disease.

[0019] Thus, a selective and overall safer kidney treatment is achieved that significantly reduces adverse effects on other normal organs in treated mammals compared to current standard treatments for inflammation-related kidney disease, such as corticosteroids and nonsteroidal anti-inflammatory drugs.

[0020] In one aspect of the invention, the therapeutic effect of the compound is achieved by releasing one or more anti-inflammatory components (biologically active payloads and / or drugs) incorporated into such designed molecules. The active payload (drug) may comprise a steroid structure, a nonsteroidal anti-inflammatory drug (NSAID) structure, or an immunomodulatory structure. These components are, for example, selected from biologically active structures that have the ability to inhibit or counteract inflammation (e.g., inflammation caused by AKI or in transplant surgery, or inflammation induced by cytokines) or have a similar ability to activate an immunomodulatory therapeutic anti-inflammatory response.

[0021] Typically, the compounds provided herein are composed of a peptide, cyclic peptide, or another "targeting tracker" (ligand) structure with high affinity (capable of binding) to kidney cells, and an active drug substructure, which together constitute a single conjugate molecule. The active drug (payload) is connected to the kidney affinity structure through a uniquely designed linker and spacer framework. This unique design enables the active drug (payload) to be released directly into the kidney tissue, thereby producing a therapeutic anti-inflammatory effect.

[0022] In another aspect, the composition has anti-inflammatory properties in the form of a complete conjugate molecule without releasing the active drug payload (contained in the structure) at the site of kidney inflammation. After accumulating at the site of kidney inflammation, the compound directly exerts its anti-inflammatory effect. In a related aspect, the conjugate, after exerting its desired biologically active effect, decomposes into generally non-toxic metabolites.

[0023] In yet another aspect, the anti-inflammatory effect is achieved through the combined effects of (i) direct anti-inflammatory effects of the compound and (ii) release of the active drug payload contained within the structure (upon accumulation at the cancer site).

[0024] In another aspect, the intact conjugate itself and / or the drug released from the conjugate in the kidney exhibits a protective effect against nephrotoxic substances (eg, cytotoxic anticancer drugs).

[0025] Surprisingly, some of the compounds and combinations provided herein lack significant antibacterial and / or other biological activity, exerting only the desired anti-inflammatory effects on kidneys affected by renal disease.

[0026] Furthermore, although some of the combinations provided herein contain cyclic peptide groups (structures) from chemical classes generally considered to cause nephrotoxicity (e.g., polymyxins), the therapeutic compounds of the present invention exhibit little or no nephrotoxicity at therapeutic dose levels required to treat inflammation-associated kidney disease.

[0027] Those skilled in the art will readily appreciate that not every molecular construct that combines an anti-inflammatory component (payload) with a "hot chaser" affinity structure (ligand targeting kidney cells) through an appropriate linker and a carefully positioned spacer (strategically placed between the ligand and the biologically active payload) is suitable for use as a therapeutic drug. Surprisingly, the compounds and combinations provided herein have good pharmacological properties, have appropriate stability in plasma, can prevent premature biological activity, and are able to preferentially accumulate in kidney cells, or accumulate in the kidneys affected by inflammation-related kidney diseases.

[0028] Even more surprising is that some compounds provided herein are delivered by self-targeting, directly into the kidney cells affected by inflammation, or only in the vicinity of the inflammation-affected tissue, to exert their biological activity. To a certain extent, this combination comprises a class of molecules that can specifically release anti-inflammatory payloads (contained in their structures) in the kidney cells affected by inflammation by metabolic cleavage of a specific class of enzymes. These enzymes may be specific to kidney cells or overexpressed (enriched) in the kidney cells affected by inflammation, such as known enzymes such as cathepsins, glutaminases, glutathione transferases, peptide deformylases (or PDFs), peptidases, and reductases.

[0029] In addition to metabolic degradation by enzymes overexpressed in inflammatory renal cells (e.g., cathepsins, glutaminases, peptide deformylases (PDFs), or similar enzymes), some compounds provided herein can also be degraded in vivo by chemical cleavage, such as the known pH-dependent autocleavage, which occurs on molecules that have both a cleavable group (e.g., an ester, amide, or carbonate group) and a free nucleophilic group (e.g., an amine, alcohol, or thiol group). When the two cleavable groups and the nucleophilic group are spatially close to each other and the nucleophilic group is essentially free (e.g., a free amine group at neutral, alkaline, or physiological pH), the nucleophilic group may be acylated by the ester group, resulting in the transfer of the acyl group to the nucleophilic atom (e.g., the nitrogen atom in the amine group). As an alternative to or concurrently with the above process, the free amine may activate the amide functional group adjacent to the carbamate group, thereby inducing the carbamate to react with the latter, converting the original amide into a diacylated imide group. In certain combinations of the present application, cleavage of the chemically designed linker occurs after initial enzymatic metabolism of the auxiliary enzyme-cleavable linker (e.g., peptide substructure or analog) to generally achieve release of the anti-inflammatory payload in kidney tissue.

[0030] In one aspect, the present application provides a compound of formula I: or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein: R 1 is connected to X 1 residues, by removing from the parent or precursor structure R 1 H is formed by removing one H atom from any of the following hydrogen-containing groups NH2, NH, OH and SH independently selected; and wherein R 1 H is selected from compounds that have the ability to modulate glucocorticoid receptor (GR) activity or have the ability to induce the regulation of GR activity; X connected together 1 、X 2 and X 3 The sequence formed -X 1 -X 2 -X 3 - comprising a cleavable linker, wherein: X 1 Missing or selected from -CH2NH-, -C(=O)NHC(=O)C 1-6 Alkylene NH-, A group consisting of 1 The left side of the group is connected to R 1 ; X 2 is missing or contains an amino acid residue or a peptide residue consisting of 1 to 6 amino acids selected from α-, β- or γ-amino acids that are unsubstituted or substituted at any N atom, Phe, Gly, Val, Lys, Cit, Ser, Ala, Glu, Gln, Asp, D-Phe, D-Val, D-Lys, D-Cit, D-Ser, D-Ala, D-Glu, D-Gln and D-Asp; wherein X 2 The carbonyl end of the group is connected to X 1 or R 1 (If X 1 missing); X 3 Selected from -C(=O)-, -C(=O)-R 2 -C(=O)- and -C(=O)OR 2 -C(=O)-; wherein X 3 The left side of the group is connected to X 1 (If X 2 missing) or X 2 ; R 2 Selected from the group consisting of: substituted or unsubstituted C 1-6 Alkylene, C 3-10 Cycloalkylene, heteroarylene, C 3-10 Cycloalkylene C 1-3Alkylene, C 1-3 Alkylene C 3-10 Cycloalkylene, C 1-3 Alkylene C 3-10 Cycloalkylene C 1-3 Alkylene, heteroarylene C 1-3 Alkylene, C 1-3 Alkylene heteroarylene, C 1-3 Alkylene heteroarylene C 1-3 Alkylene, C 1-6 Alkylene NHC(=O)C 1-6 Alkylene, and -R 3 -R 4 -R 5 -R 6 -(S) p -R 13 -; Among them, when R 2 is unsubstituted C 1-6 When alkylene, X 1 or X 2 Not missing; or when R 2 is substituted C 1-6 When alkylene, R 2 One to four R 14 replace; R 3 Deletion or selection of NH, N(C 1-6 Alkylene), and C 1-6 a group consisting of an alkylene group; R 4 Missing or selected from arylene, heteroarylene, -C(C 3-10 Cycloalkylene)2-, C 3-10 Cycloalkylene, heterocycloalkylene, and -(OCH2CH2O) q - the group formed; R 5 Missing or C 1-6 alkylene; R 6 Missing or selected by OC 1-6 Alkylene and the group formed; R 13 Missing or selected from C 1-12 Alkylene, C 3-10 Cycloalkylene, C 3-10 Cycloalkylene C 1-6 The group consisting of alkylene, heterocycloalkylene, heteroarylene and arylene; wherein R 13 Optionally one to four R 15 replace; R 14 Independently selected from -C 0-3Alkylene-polyvinyl alcohol, halogen, OH, NH2, SH, CN, C 3-10 Cycloalkyl, C 1-8 the group consisting of alkoxy, aryl, and heteroaryl; R 15 Independently selected from halogen, OH, NH2, SH, C 3-10 the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; A 8 To A 11 is an optional amino acid residue selected from the group consisting of α-, β-, or γ-amino acids, unsubstituted or substituted at any N atom, Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, L-homoserine, Thr, Trp, Tyr, Val, D-Ala, D-Arg, D-Asn, D-Asp, D-Cys, D-Gl u, D-Gln, D-His, D-Ile, D-Leu, D-Lys, D-Met, D-Phe, D-Pro, D-Ser, D-homoserine, D-Thr, D-Trp, D-Tyr, D-Val, 3-aminoproline, 4-aminoproline, biphenylalanine (Bip), D-Bip, 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), 2,5-diaminopentanoic acid, nitrogen heterocycle butane-2-carboxylic acid, azetidine-3-carboxylic acid, piperidine-2-carboxylic acid, 6-aminopiperidine-2-carboxylic acid, 5-aminopiperidine-2-carboxylic acid, 4-aminopiperidine-2-carboxylic acid, 3-aminopiperidine-2-carboxylic acid, piperidine-3-carboxylic acid, 6-aminopiperidine-3-carboxylic acid, 5-aminopiperidine-3-carboxylic acid, 4-aminopiperidine-3-carboxylic acid, piperazine-2-carboxylic acid, 6-aminopiperazine-2-carboxylic acid, 8-azabicyclo[3.2.1]octane-2-carboxylic acid, 4-aminopiperidine-2-carboxylic acid 4-amino-3-arylbutanoic acid, 4-amino-3-(3-chlorophenyl)butanoic acid; and 5-amino-4-arylpentanoic acid; R a 、R b and R c represents the side chain of an amino acid independently selected from serine, threonine, leucine, phenylalanine, norleucine, norvaline, or tert-butylglycine; Integers h, i, j and k are independently selected from 0, 1 and 2; The integer q is selected from 1 to 10; The integers x, y, z and p are independently selected from 1 and 2.

[0031] In another aspect, the present application provides a compound of formula Ia: or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein: R a is CH2CH(CH3)2 or CH2Ph; The integer f is 1 or 2.

[0032] In another aspect, the present application provides a compound of formula Ib: or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein: R a It is CH2CH(CH3)2 or CH2Ph.

[0033] In another aspect, the present application provides a drug-linker intermediate compound represented by the following formula: 1 -X 1 -X 2 -X 3 -OH, where: R 1 is connected to X 1 residues, by removing from the parent or precursor structure R 1 H is formed by removing one H atom from any of the following hydrogen-containing groups NH2, NH, OH and SH independently selected; and wherein R 1 H is selected from compounds having the activity of regulating glucocorticoid receptor (GR) activity or the activity of inducing regulation of glucocorticoid receptor (GR) activity and X connected together 1 、X 2 and X 3 The sequence formed -X 1 -X 2 -X 3 - comprising a cleavable linker, wherein: X 1 Missing or selected from -CH2NH-, -C(=O)NHC(=O)C 1-6 Alkylene NH-, A group consisting of 1 The left side of the group is connected to R 1 ; X 2is missing or contains an amino acid residue or a peptide residue consisting of 1 to 6 amino acids selected from α-, β- or γ-amino acids that are unsubstituted or substituted at any N atom, Phe, Gly, Val, Lys, Cit, Ser, Ala, Glu, Gln, Asp, D-Phe, D-Val, D-Lys, D-Cit, D-Ser, D-Ala, D-Glu, D-Gln and D-Asp; wherein X 2 The carbonyl end of the group is connected to X 1 or R 1 (If X 1 missing); X 3 Selected from -C(=O)-, -C(=O)-R 2 -C(=O)- and -C(=O)OR 2 -C(=O)-; wherein X 3 The left side of the group is connected to X 1 (If X 2 missing) or X 2 ; R 2 Selected from the group consisting of: substituted or unsubstituted C 1-6 Alkylene, C 3-10 Cycloalkylene, heteroarylene, C 3-10 Cycloalkylene C 1-3 Alkylene, C 1-3 Alkylene C 3-10 Cycloalkylene, C 1-3 Alkylene C 3-10 Cycloalkylene C 1-3 Alkylene, heteroarylene C 1-3 Alkylene, C 1-3 Alkylene heteroarylene, C 1-3 Alkylene heteroarylene C 1-3 Alkylene, C 1-6 Alkylene NHC(=O)C 1-6 Alkylene, and -R 3 -R 4 -R 5 -R 6 -(S) p -R 13 -; Among them, when R 2 is unsubstituted C 1-6 When alkylene, X 1 or X 2 Not missing; or when R 2 is substituted C 1-6 When alkylene, R 2 One to four R 14 replace; R 3 Deletion or selection of NH, N(C 1-6 Alkylene), and C 1-6 a group consisting of an alkylene group; R 4 Missing or selected from arylene, heteroarylene, -C(C 3-10 Cycloalkylene)2-, C 3-10 Cycloalkylene, heterocycloalkylene, and -(OCH2CH2O) q - the group formed; R 5 Missing or C 1-6 alkylene; R 6 Missing or selected by OC 1-6 Alkylene and the group formed; R 13 Missing or selected from C 1-12 Alkylene, C 3-10 Cycloalkylene, C 3-10 Cycloalkylene C 1-6 The group consisting of alkylene, heterocycloalkylene, heteroarylene and arylene; wherein R 13 Optionally one to four R 15 replace; R 14 Independently selected from -C 0-3 Alkylene-polyvinyl alcohol, halogen, OH, NH2, SH, CN, C 3-10 Cycloalkyl, C 1-8 the group consisting of alkoxy, aryl, and heteroaryl; R 15 Independently selected from halogen, OH, NH2, SH, C 3-10 the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; The integer q is selected from 1 to 10; The integer p is selected from 1 and 2.

[0034] In another aspect, the present application provides a linker represented by the following formula: -X 1 -X 2 -X 3 - It is used to obtain a peptide-drug conjugate, wherein the drug (preferably, the drug is dexamethasone or a derivative thereof) is coupled to the peptide (preferably, the peptide is PMBN, PMBH or a derivative thereof) through a linker, wherein: X 1 Missing or selected from -CH2NH-, -C(=O)NHC(=O)C 1-6 Alkylene NH-, A group consisting of 1 The left side of the group is connected to R 1 ; X 2 is missing or contains an amino acid residue or a peptide residue consisting of 1 to 6 amino acids selected from α-, β- or γ-amino acids that are unsubstituted or substituted at any N atom, Phe, Gly, Val, Lys, Cit, Ser, Ala, Glu, Gln, Asp, D-Phe, D-Val, D-Lys, D-Cit, D-Ser, D-Ala, D-Glu, D-Gln and D-Asp; wherein X 2 The carbonyl end of the group is connected to X 1 ; X 3 Selected from -C(=O)-, -C(=O)-R 2 -C(=O)- and -C(=O)OR 2 -C(=O)-; wherein X 3 The left side of the group is connected to X 1 (If X 2 missing) or X 2 ; R 2 Selected from the group consisting of: substituted or unsubstituted C 1-6 Alkylene, C 3-10 Cycloalkylene, heteroarylene, C 3-10 Cycloalkylene C 1-3 Alkylene, C 1-3 Alkylene C 3-10 Cycloalkylene, C 1-3 Alkylene C 3-10 Cycloalkylene C 1-3 Alkylene, heteroarylene C 1-3 Alkylene, C 1-3 Alkylene heteroarylene, C 1-3 Alkylene heteroarylene C 1-3 Alkylene, C 1-6 Alkylene NHC(=O)C 1-6 Alkylene, and -R 3 -R 4 -R 5 -R 6 -(S) p -R 13 -; Among them, when R 2 is unsubstituted C 1-6 When alkylene, X 1 or X 2 Not missing; or when R 2 is substituted C1-6 When alkylene, R 2 One to four R 14 replace; R 3 Deletion or selection of NH, N(C 1-6 Alkylene), and C 1-6 a group consisting of an alkylene group; R 4 Missing or selected from arylene, heteroarylene, -C(C 3-10 Cycloalkylene)2-, C 3-10 Cycloalkylene, heterocycloalkylene, and -(OCH2CH2O) q - the group formed; R 5 Missing or C 1-6 alkylene; R 6 Missing or selected by OC 1-6 Alkylene and the group formed; R 13 Missing or selected from C 1-12 Alkylene, C 3-10 Cycloalkylene, C 3-10 Cycloalkylene C 1-6 The group consisting of alkylene, heterocycloalkylene, heteroarylene and arylene; wherein R 13 Optionally one to four R 15 replace; R 14 Independently selected from -C 0-3 Alkylene-polyvinyl alcohol, halogen, OH, SH, CN, C 3-10 Cycloalkyl, C 1-8 the group consisting of alkoxy, aryl, and heteroaryl; R 15 Independently selected from halogen, OH, NH2, SH, C 3-10 the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; The integer q is selected from 1 to 10; The integer p is selected from 1 and 2.

[0035] On the other hand, X 2 The amino acid or peptide residue is missing or comprises an amino acid or peptide residue selected from the group consisting of Gly-Phe-Gly-Gly, Gly-Phe-Gly, Cit-Val, Cit, Glu, Glu-Gly, Asp-Val-Glu-Asp, Ala-Ala-Gly and Ala-Ala.

[0036] On the other hand, X 2The amino acid or peptide residue is missing or comprises an amino acid or peptide residue selected from the group consisting of Gly-Phe-Gly-Gly, Gly-Phe-Gly, Cit-Val, Cit, Glu, Ala-Ala-Gly and Ala-Ala.

[0037] On the other hand, R 2 Selected from the group consisting of: substituted or unsubstituted C 1-6 Alkylene, C 4-7 Cycloalkylene, -heteroarylene-C 1-3 Alkylene-, -C 1-3 Alkylene-heteroarylene-C 1-3 Alkylene-, -C 1-6 Alkylene-(2,5-dioxopyrrolidine-1,3-diyl)-SC 1-3 Alkylene-CH(NH2)-, -C 1-6 Alkylene-(2,5-dioxopyrrolidine-1,3-diyl)-SC 1-12 Alkylene-, -C 1-6 Alkylene-(2,5-dioxopyrrolidine-1,3-diyl)-SC 3-6 Cycloalkylene-, -C 1-6 Alkylene-(OCH2CH2O) q -C 1-6 Alkylene-R 6 -SR 13 -、-C 1-6 Alkylene-arylene-SSR 13 -, -arylene-C 1-6 Alkylene-SSR 13 -、-N(C 1-6 Alkylene)-arylene-C 1-6 Alkylene-SSC 2-6 Alkylene-, -N(C 1-6 Alkylene)-arylene-C 1-6 Alkylene-SSC 3-10 Cycloalkylene C 1-6 Alkylene-, -N(C 1-6 Alkylene)-arylene-SSC(CH3)2-C 1-3 Alkylene-, -N(C 1-6 Alkylene)-arylene-SSC 3-10 Cycloalkylene C 1-6 Alkylene-, -N(C 1-6 Alkylene)-C 1-6 Alkylene-SSC 1-3 Alkylene-C(NH2)-, -N(C 1-6 Alkylene)-C 1-6Alkylene-SSC 2-6 Alkylene-, -N(C 1-6 Alkylene)-OC 1-6 Alkylene-SSR 13 -、-C 2-6 Alkylene-SSC 3-10 Cycloalkylene C 1-6 Alkylene-, -C 3-6 Alkylene-SSC 1-6 Alkylene-, -C 3-6 Cycloalkylene-SSC 1-6 Alkylene-, -C 1-6 Alkylene-SSC 3-6 Cycloalkylene-, and -C 3-6 Cycloalkylene-SSC 3-6 Cycloalkylene-.

[0038] On the other hand, R 14 Selected from the group consisting of: -C 0-3 Alkylene-polyvinyl alcohol, C 0-3 Alkylene NHC(=O)CH(NH2)C 1-6 Alkylene C(=O)OH, halogen, OH, SH, CN, C 3-10 Cycloalkyl, C 1-8 Alkoxy, aryl and heteroaryl.

[0039] On the other hand, X 3Selected from the group consisting of: -C(=O)-, -C(=O)CH2C(=O)-, -C(=O)CH2CH2C(=O)-, -C(=O)OCH2CH(CH3)-SS-CH2C(=O)-, -C(=O)CH2CH2NHC(=O)CH2CH2C(=O)-, -C(=O)CH(NH2)CH2CH2C(=O)-, -C(=O)cyclobutylC(=O)-, -(C=O)SS (C=O)-, -(C=O)CH2-SSC(CH3)2(C=O)-, -(C=O)CH2-SSC(cyclopropyl)2(C=O)-, -(C=O)C(CH3)2-SS-CH2(C=O)-, -(C=O)C(cyclopropyl)2-SS-CH2(C=O)-, -(C=O)NHCH2CH2-SSC(CH3)2CH2C(=O)-, -(C=O)NHCH2C(CH3)2-SSC (CH3)2CH2C(=O)-, -C(=O)NHCH2CH2-SSC(cyclopropyl)2-, -(C=O)OCH2CH2-SSC(CH3)2CH2C(=O)-, -(C=O)OCH2C(CH3)2-SSC(CH3)2CH2C(=O)-, -C(=O)OCH2CH2-SSC(cyclopropyl)2-, -(C=O)CH2CH2-(2,5-dioxopyrrolidine-1,3-diyl) -S-CH2CH2C(=O)-、-(C=O)CH2CH2-(2,5-dioxopyrrolidine-1,3-diyl)-S-CH2CH(NH2)C(=O)-、-(C=O)CH2-(2,5-dioxopyrrolidine-1,3-diyl)-S-CH2CH2C(=O)-、-(C=O)CH2-(2,5-dioxopyrrolidine-1,3-diyl)-S-CH2CH(NH2)C(=O)-、-(C=O)CH2-(2,5-dioxopyrrolidine-1,3-diyl) 1-6 Alkylene-(2,5-dioxopyrrolidine-1,3-diyl)-SC(CH3)2CH2-C(=O)-, -(C=O)C 1-6 Alkylene-(2,5-dioxopyrrolidine-1,3-diyl)-SC(CH3)2C(CH3)2-C(=O)-,

[0040] On the other hand, -X 1 -X 2 -X 3 - independently selected from the following structures:

[0041] On the other hand, -X 1 -X 2 -X 3 - independently selected from the following structures:

[0042] On the other hand, -X 1 -X 2 -X 3 -The left side is connected to R 1 .

[0043] On the other hand, R 1 H is represented by formula II: in: R 8 and R 9 Independently selected from H, C 1-12 Alkyl, C 1-12 the group consisting of alkyl C(=O)O-, -OH and halogen; or R 8 and R 9 Formed together wherein E is independently selected from CH2 and O; When E is CH2, then G is N; or when E is O, then G is CH or C(C 1-6 alkyl); R 11 WYZR 12 or -WYZC 1-6 Alkylene-R 12 ; R 7 Independently selected from -C 1-6 Alkylene-NR i R j 、-C 1-6 Alkylene-OH, -C 1-6 Alkylene-halogen, -SC 1-6 Alkylene-halogen, -C 1-6 Alkylene-TWYZR 12 , and -C 1-6 Alkylene-TWYZC 1-6 Alkylene-R 12 the group formed; R 12 Each occurrence is independently selected from H, NR i Rj , OH, and SH; T is selected from S(=O), S(=O)2, S(=O)2NR i 、O、S、C(=O)NR i , C(=O) and NR i the group formed; W and Z are independently absent at each occurrence or independently selected from the group consisting of alkylene, arylene, heteroarylene, cycloalkylene, and heterocycloalkylene; each of these groups may be replaced by 1 to 4 -CH i R j 、F、Cl、Br、I、-C 0-6 Alkylene-OH, or -C 0-6 Alkylene-NR i R j replace; Each occurrence of Y is independently missing, or independently selected from -C 0-6 Alkylene-CR i R j -C 0-6 Alkylene-, -C 0-6 Alkylene-OC 0-6 Alkylene-, -C 0-6 Alkylene-SC 0-6 Alkylene-, -C 0-6 Alkylene-NR i -C 0-6 Alkylene-, -C 0-6 Alkylene-S(=O)-C 0-6 Alkylene-, -C 0-6 Alkylene-S(=O)2-C 0-6 Alkylene-, -C 0-6 Alkylene-S(=O)2NR i ,-C 0-6 Alkylene-, -C 0-6 Alkylene-C(=O)NR i -C 0-6 Alkylene-, -C 0-6 Alkylene-C(=O)-C 0-6 Alkylene-, -C 0-6 Alkylene-CR i =CR i -C 0-6 Alkylene-, and -C 0-6 Alkylene -C≡CC 0-6 Alkylene - a group consisting of; R 10 is independently selected at each occurrence from the group consisting of OH, halogen, alkyl, =0, and arylalkyl; Ri and R j Each occurrence is independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; The keys with dotted lines represents a single bond or a double bond; n is an integer selected from 0-19.

[0044] On the other hand, according to formula II, R 1 H is represented by Formula IIa, Formula IIb, Formula IIc or Formula IId:

[0045] On the other hand, R 1 is from R 1 It is obtained by removing H from the primary alcohol CH2OH group, phenylene-OH group or NH2 group in the H structure.

[0046] In another aspect, a compound of Formula I, Ia or Ib is provided, which releases a bioactive agent R after administration to a mammal. 1 H exerts a therapeutic effect.

[0047] In another aspect, a compound of Formula I, Ia or Ib is provided, which has anti-inflammatory activity or a therapeutic effect on kidney disease, which is determined by (i) reducing or slowing the release of renal cytokines such as TNF-α, IL-6, IL-12; (ii) reducing one or more biomarkers, optionally, wherein the one or more biomarkers are selected from protein levels, blood urea nitrogen and serum creatinine; or (iii) improving the condition of a patient in need of treatment or a mammal in an animal test.

[0048] In another aspect, a compound of Formula I, Ia or Ib is provided, which has anti-inflammatory activity, wherein the anti-inflammatory activity is to treat inflammatory diseases in kidney inflammation, kidney damage or dysfunction, or inflammation induced by nephrotoxic substances, such as drug nephrotoxic substances, such as anti-cancer, anti-diabetic, anti-infective or other chemotherapeutic substances.

[0049] In another aspect, a compound of Formula I, Ia or Ib is provided which is combined with a similar dose of free agent or drug HR incorporated into the compound. 1 have enhanced anti-inflammatory, immunomodulatory or renoprotective effects compared to the control, as determined by in vitro or in vivo assays for anti-inflammatory, immunomodulatory or renoprotective activity.

[0050] In yet another aspect, provided is a compound of Formula I, Ia, or Ib that, when administered to a mammal, exhibits preferential accumulation in the kidney with a ratio of molar concentration in the kidney to molar concentration in the blood of between about 5 and 500.

[0051] In yet another aspect, provided is a compound of Formula I, Ia, or Ib that, when administered to a mammal, exhibits preferential accumulation in the kidney, with a ratio of molar concentration in the kidney to molar concentration in the blood of at least about 20.

[0052] In yet another aspect, there is provided a compound of Formula I, Ia or Ib, when reacted with an amount equal to that of the reagent HR 1 The standard therapeutic dose (in moles) of the drug HR is the same as the free drug HR when administered to mammals. 1 The compound showed a significant HR in the kidney compared to the standard treatment dose. 1 The drug loading (tissue concentration) and / or drug exposure (area under the curve, AUC) is approximately 1.5 to 15 times that of the dose of the active ingredient.

[0053] In yet another aspect, there is provided a compound of Formula I, Ia or Ib, when reacted with an amount equal to that of the reagent HR 1 The standard therapeutic dose (in moles) of the dose (expressed in moles) when administered to a mammal, with the agent HR 1 The invention also provides a novel therapeutic agent that exhibits approximately 1.5-15 times greater efficacy compared to a standard therapeutic dose of a conventional steroid, wherein the therapeutic effect is determined as slowing, halting, or reversing progression of inflammation (as determined by changes in cytokine release and / or by using biochemical biomarkers for disease monitoring or similar methods).

[0054] In yet another aspect, there is provided a compound of Formula I, Ia or Ib, when reacted with an amount equal to that of the reagent HR 1 The standard therapeutic dose (molar amount) is a dose (expressed in moles) when administered to a mammal, with the reagent HR 1 The invention provides a method for treating renal insufficiency of the kidney and showing at least 2-fold greater efficacy compared to a standard treatment dose of the kidney, wherein the therapeutic effect is determined as slowing, halting or reversing the progression of inflammation or renal damage (as determined by cytokine release levels and / or by using biochemical biomarkers for inflammation monitoring, or by radiography, or by magnetic resonance imaging, or the like).

[0055] In yet another aspect, there is provided a compound of Formula I, Ia or Ib, when reacted with an amount equal to that of the reagent HR 1 The standard therapeutic dose (in moles) of 1The invention further provides for a therapeutic agent that exhibits at least a 2-fold reduction in the rate of adverse reactions and / or off-target toxicities compared to a standard therapeutic dose of the drug, as determined by medical observation, blood cell counts, tissue biopsy, and / or analysis of biochemical biomarkers or similar methods in the mammal being treated.

[0056] In yet another aspect, a compound of Formula I, Ia or Ib is provided for use in treating renal inflammation, wherein the renal inflammation is chronic kidney disease (CKD), systemic lupus erythematosus (SLE), nephritis, acute kidney injury (AKI), or inflammation in renal transplant surgery.

[0057] In yet another aspect, provided is a method for treating inflammation-related kidney disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of Formula I, Ia, or Ib.

[0058] In yet another aspect, a compound of Formula I, Ia or Ib is provided, which has enhanced in vivo efficacy against inflammation-related kidney diseases compared to the related (parent) anti-inflammatory, immunomodulatory or tubular protective moiety (compound) conjugated to the compound, as determined by in vivo experiments in animal models of these kidney diseases, wherein the compound and the related free drug (conjugated in the compound provided herein) are administered at the same molar dose.

[0059] In another aspect, a pharmaceutical composition is provided, comprising a compound of Formula I, Ia or Ib, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a pharmaceutically acceptable carrier.

[0060] In another aspect, provided is a method for treating inflammation in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of Formula I, Ia or Ib, or a pharmaceutically acceptable salt, solvate or hydrate thereof, or the pharmaceutical composition.

[0061] In another aspect, a method for treating inflammation-related kidney disease in humans or other warm-blooded animals is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, Ia or Ib, or a pharmaceutically acceptable salt, prodrug, solvate or hydrate thereof, or said pharmaceutical composition.

[0062] The compound of Formula I, Ia or Ib or a pharmaceutically acceptable salt, solvate or hydrate thereof, or the pharmaceutical composition is administered to a mammal as a pharmaceutical composition by parenteral, transdermal, oral, intranasal, topical, rectal or intratumoral administration.

[0063] In another aspect, the renal inflammation is chronic kidney disease (CKD), systemic lupus erythematosus (SLE), nephritis, acute kidney injury (AKI), diabetic nephropathy, chronic glomerulonephritis, or inflammation in renal transplant surgery.

[0064] In yet another aspect, novel intermediates and methods for preparing compounds of Formula I, Ia, or Ib are provided.

[0065] In another aspect, a compound of formula II is provided: or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein: R 8 and R 9 Independently selected from H, C 1-12 Alkyl, C 1-12 the group consisting of alkyl C(=O)O-, -OH and halogen; or R 8 and R 9 Formed together wherein E is independently selected from CH2 and O; When E is CH2, then G is N; or when E is O, then G is CH or C(C 1-6 alkyl); R 11 WYZR 12 or -WYZC 1-6 Alkylene-R 12 ; R 7 Independently selected from -C 1-6 Alkylene-NR i R j 、-C 1-6 Alkylene-OH, -C 1-6 Alkylene-halogen, -SC 1-6 Alkylene-halogen, -C 1-6 Alkylene-TWYZR 12 , and -C 1-6 Alkylene-TWYZC 1-6 Alkylene-R 12 the group formed; R 12 Each occurrence is independently selected from H, NR i R j , OH, and SH; T is selected from S(=O), S(=O)2, S(=O)2NR i 、O、S、C(=O)NRi , C(=O) and NR i the group formed; W and Z are independently absent at each occurrence or independently selected from the group consisting of alkylene, arylene, heteroarylene, cycloalkylene, and heterocycloalkylene; each of these groups may be replaced by 1 to 4 -CH i R j 、F、Cl、Br、I、-C 0-6 Alkylene-OH, or -C 0-6 Alkylene-NR i R j replace; Each occurrence of Y is independently missing, or independently selected from -C 0-6 Alkylene-CR i R j -C 0-6 Alkylene-, -C 0-6 Alkylene-OC 0-6 Alkylene-, -C 0-6 Alkylene-SC 0-6 Alkylene-, -C 0-6 Alkylene-NR i -C 0-6 Alkylene-, -C 0-6 Alkylene-S(=O)-C 0-6 Alkylene-, -C 0-6 Alkylene-S(=O)2-C 0-6 Alkylene-, -C 0-6 Alkylene-S(=O)2NR i ,-C 0-6 Alkylene-, -C 0-6 Alkylene-C(=O)NR i -C 0-6 Alkylene-, -C 0-6 Alkylene-C(=O)-C 0-6 Alkylene-, -C 0-6 Alkylene-CR i =CR i -C 0-6 Alkylene-, and -C 0-6 Alkylene -C≡CC 0-6 Alkylene - a group consisting of; R 10 is independently selected at each occurrence from the group consisting of OH, halogen, alkyl, =0, and arylalkyl; R i and R j Each occurrence is independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; The keys with dotted lines Indicates a single bond or a double bond; n is an integer selected from 0-19.

[0066] On the other hand, R 8 and R 9 Formed together wherein E is independently selected from CH2 and O; When E is CH2, G is N, R 11 Selected from -Z-NR i R j , -Z-OH, and -WYZR 12 , R 7 Choose Free-C 1-6 Alkylene-OH, -C 1-6 Alkylene-NH2, -C 1-6 Alkylene-TWYZR 12 、-C 1-6 Alkylene-TZ-NR i R j , and -C 1-6 a group consisting of alkylene-TZ-OH; Or when E is O, then G is CH, R 11 Selected from alkyl, R 7 -C 1-6 Alkylene-T-heteroarylene-NR i R j ; Or when E is O, then G is CH, R 11 Selected from -heteroarylene-NR i R j ,-arylene-heteroarylene-NR i R j , -Z-OH, -WYZ-SH, and -WYZ-OH; R 7 -C 1-6 Alkylene-OH; Or when E is O, then G is CH, R 11 Choose from -Z-NR i R j , -Z-OH and -WYZR 12 Group composed of R 7 Choose Free-C 1-6 Alkylene-TWYZR 12 、-C 1-6 Alkylene-TZ-OH, -C 1-6 Alkylene-TZ-NRi R j , and -C 1-6 a group consisting of an alkylene group -NH2; R 12 Each occurrence is independently selected from H, NR i R j , OH, and SH; T is selected from S(=O), S(=O)2, S(=O)2NR i 、O、S、C(=O)NR i , C(=O) and NR i the group formed; W is selected from the group consisting of arylene, heteroarylene, cycloalkylene, and heterocycloalkylene; Z, at each occurrence, is independently selected from the group consisting of arylene, heteroarylene, cycloalkylene, and heterocycloalkylene; Y is C 1-6 Alkylene, O or S; R 10 Each occurrence is independently selected from the group consisting of OH, halogen, alkyl, and arylalkyl; R i and R j Each occurrence is independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; The keys with dotted lines represents a single bond or a double bond; n is an integer selected from 0-19.

[0067] In another aspect, the compound according to formula II is represented by formula IIa, formula IIb, formula IIc or formula IId:

[0068] In another aspect, W is selected from:

[0069] In another aspect, each occurrence of Z is independently selected from:

[0070] In another aspect, the compound of formula II is selected from the following structures: DETAILED DESCRIPTION

[0071] Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

[0072] The carbon atom content of various hydrocarbon-containing groups is represented by a prefix that indicates the minimum and maximum number of carbon atoms in the group, i.e., the prefix C i-j = means that the group contains from integer "i" to integer "j" carbon atoms. Thus, for example, C 1-14 Alkyl refers to an alkyl group containing one to fourteen carbon atoms.

[0073] The term alkyl refers to straight and branched chain saturated hydrocarbon groups. References to individual groups (e.g., "propyl") include only straight chain groups, while branched chain isomers (e.g., "isopropyl") are specifically mentioned. Unless otherwise specified, "alkyl" contains 1-12 carbon atoms. In addition to any groups specifically recited in any embodiment or claim, alkyl is optionally substituted by one, two, three, or four radicals selected from halogen, hydroxy, cyano, C 1-12 Alkyl, C 3-7 Substituents of cycloalkyl, aryl, biaryl, heterocyclyl and heteroaryl (Het) are substituted. In some embodiments, alkyl includes but is not limited to difluoromethyl, 2-fluoroethyl, trifluoroethyl, (adamantan-1-yl)methyl, 3-(cyclohexyl)propyl, 4-propylcyclohexyl, -CH=CH-aryl, -CH=CH-Het 1 , -CH2-phenyl, biphenylmethyl, etc. In some embodiments, the alkyl group is unsubstituted. 1 " or "alkyl 2 "alkyl" refers to independently selected alkyl groups that may be different from each other or independently the same as each other. If the term "alkyl" is used more than once in the same group, each "alkyl" is independent of the other "alkyl" at each occurrence.

[0074] The term "Alk" refers to an alkyl group as defined herein.

[0075] The term "alkylene" refers to a divalent alkyl group. Unless otherwise specified, an "alkylene" group contains 1-12 carbon atoms. An alkylene group is optionally substituted as described for an alkyl group. In some embodiments, an alkylene group is unsubstituted. A distinction is made between "alkylene" and "alkylene" groups. 1 " or "alkylene 2 " refers to independently selected alkylene groups that are different from each other or independently equal to each other. Wherein C0 alkylene represents a vacancy.

[0076] The term "alkenyl" refers to straight and branched hydrocarbon groups containing at least one double bond, in some embodiments 1, 2 or 3 double bonds. Unless otherwise specified, an "alkenyl" group contains 2 to 12 carbon atoms. In addition to any groups specifically recited in any embodiment or claim, an alkenyl group is optionally substituted with one, two or three alkyl radicals selected from halogen, C 1-12 Alkyl, C 3-7Cycloalkyl, aryl, biaryl and Het 1 In some embodiments, the alkenyl group is unsubstituted.

[0077] The term "alkenylene" refers to a divalent alkenyl group. Unless otherwise specified, an "alkenylene" group contains 2-12 carbon atoms. An alkenylene group is optionally substituted as described for an alkenyl group. In some embodiments, an alkenylene group is unsubstituted.

[0078] The term "cycloalkyl" or "carbocyclyl" refers to a saturated or partially unsaturated monocyclic, fused bicyclic, bridged polycyclic, or spirocyclic ring structure containing from 3 to 12, from 3 to 10, or from 3 to 7 ring atoms, or the specified number of atoms. Examples of monocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Bicyclic and polycyclic structures include, for example, norbornane, decalin, and adamantyl. For example, C3-C8 cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and norbornane. These include fused ring structures. As used herein, the term "fused" refers to two or more rings that have at least two atoms and one bond in common, such as two cyclohexane rings sharing a carbon-carbon bond. As used herein, the term "bridged polycyclic" refers to compounds in which non-adjacent atoms in the cycloalkyl group are connected by one or more atoms. As used herein, the term "spirocycle" (or "spiro") refers to two rings having only one atom in common and no bridge connecting the two rings. Examples of fused cycloalkyl groups include decahydronaphthyl, dodecahydro-1H-phenanthrenyl, and tetradecahydroanthracenyl; examples of bridged cycloalkyl groups include bicyclo[1.1.1]pentyl, adamantyl, and norbornyl; examples of spirocycloalkyl groups include spiro[3.3]heptane and spiro[4.5]decane. In addition to any groups specifically mentioned in any embodiment or claim, the cycloalkyl group may be optionally substituted with one, two, or three substituents selected from halogen, C 1-12 Alkyl, C 3-7 In certain embodiments, the cycloalkyl group is unsubstituted.

[0079] The term "cycloalkylene" refers to a cycloalkyl group as described above, connected to at least two other groups, i.e., a divalent hydrocarbon group. The two moieties connected to the cycloalkylene can be connected to the same atom or different atoms of the cycloalkylene. Cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, and cyclooctylene. Except for any groups specifically mentioned in any embodiment or claim, the cycloalkylene group can be arbitrarily substituted as described for cycloalkyl. In certain embodiments, the cycloalkylene is unsubstituted. In certain or any embodiments, the cycloalkylene group represented by R 4 to R 10 Any two of the C 3-6The cycloalkylene group may be optionally substituted with one or two substituents independently selected from C 1-6 Alkyl and aryl groups.

[0080] The term "heterocycloalkyl" refers to a cycloalkyl group as described above containing from 1 to 5 heteroatoms, such as N, O, and S. These heteroatoms may also be substituted with oxo groups, such as, but not limited to, -S(O)- and -S(O)2-. For example, heterocycles include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, morpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, piperidinyl, indolinyl, quinuclidinyl, and 1,4-dioxa-8-azaspiro[4.5]decan-8-yl.

[0081] The term "heterocycloalkylene" refers to a heterocycloalkyl group as described above, linked to at least two other groups. The two moieties linked to the heterocycloalkylene may be linked to the same atom or different atoms of the heterocycloalkylene.

[0082] The term "heteroalkyl" refers to an alkyl or cycloalkyl group as described above having a substituent containing a heteroatom selected from N, O and S(O) n , wherein n is an integer from 0 to 2, in certain embodiments, the substituent includes hydroxyl (OH), C 1-4 Alkoxy, amino, mercapto (-SH) and the like. The heteroatom may be embedded in any portion of the heteroalkyl group [e.g., the heteroalkyl group may be C 1-4 Alkyl C(=O)OC 3-6 cycloalkylNH2], or containing a heterocyclic substituent [for example, the heteroalkyl group can be 2-(4-morpholinyl)ethyl]. In certain embodiments, the substituent includes -NR a R b 、-OR a , and -S(O) n R c , where each R a are independently hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic or -C(O)R (where R is C 1-4 alkyl); each R b are independently hydrogen, C 1-4 Alkyl, -SO2R (where R is C 1-4 Alkyl or C 1-4 Hydroxyalkyl), -SO2NRR' (wherein R and R' are independently hydrogen or C 1-4 alkyl), or -CONR'R" (wherein R and R" are independently hydrogen or C 1-4 alkyl); n is an integer from 0 to 2; each R c are independently hydrogen, C1-4 Alkyl, C 3-6 Cycloalkyl, optionally substituted aryl, or NR a R b , where R a and R b As described above, in some embodiments, heteroalkyl groups include, but are not limited to, 2-methoxyethyl (—CH2CH2OCH3), 2-hydroxyethyl (—CH2CH2OH), hydroxymethyl (—CH2OH), 2-aminoethyl (—CH2CH2NH2), 2-methylaminoethyl (—CH2CH2NHCH3), benzyloxymethyl, 2-thienylthiomethyl, and the like.

[0083] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0084] The term "aryl" refers to a monocyclic or fused bicyclic, tricyclic or larger aromatic ring system containing 6 to 16 ring carbon atoms. For example, aryl can be phenyl, benzyl or naphthyl, preferably phenyl. Aryl groups can include fused polycyclic ring systems in which only one ring is aromatic. Aryl groups can be mono-, di- or tri-substituted by one, two or three substituents. Preferred aryl groups are naphthyl, phenyl or phenyl mono- or di-substituted by alkoxy, phenyl, halogen, alkyl or trifluoromethyl, particularly phenyl or phenyl mono- or di-substituted by alkoxy, halogen or trifluoromethyl, especially phenyl. In addition to any groups specifically mentioned in any embodiment or claim, aryl can be optionally substituted by 1 to 3 substituents independently selected from halogen, -C 1-12 Alkyl (unsubstituted or substituted, in one embodiment with 1, 2 or 3 halogens), aryl, -OH, -OC 1-12 Alkyl, -S(O) n C 1-4 Alkyl (wherein n is 0, 1 or 2), -C 1-4 Alkyl NH2, -NHC 1-4 Alkyl, -C(=O)H, C(=O)OR a 、OC(=O)R a 、OC(=O)NR a R c , OC(=O)heteroaryl, OC(=O)(heterocyclyl) and -C=N-OR d (where R d is hydrogen or -C 1-4 Two adjacent substituents on an aryl group may be linked to form a C 4-7 A cycloalkyl group or a 4- to 7-membered heterocyclic group is fused to the aryl group. Two adjacent substituents in the aryl group may be linked to form a C fused to the aryl group. 4-7Cycloalkyl or 4 to 7 membered heterocyclic group. 1 " or "aryl 2 "Aryl" refers to independently selected aryl groups that may be different from each other or independently the same as each other. If the term "aryl" is used more than once in the same group, each occurrence of each "aryl" is independent of the other "aryl".

[0085] The term "arylene" refers to an aryl group as described above, connected to at least two other groups. The two moieties connected to the arylene group are connected to different atoms in the arylene group. Arylene groups include, but are not limited to, phenylene.

[0086] The term "arylalkyl" refers to an alkyl group substituted with an aryl group, each as defined herein, including groups wherein the aryl and alkyl groups are optionally substituted as described in their respective definitions.

[0087] The term "arylheteroaryl" refers to an aryl group substituted by a heteroaryl group, each as defined herein, including groups wherein the aryl and heteroaryl groups are optionally substituted as described in their respective definitions.

[0088] The term "heteroarylaryl" refers to a heteroaryl group substituted by an aryl group, each as defined herein, including groups wherein the aryl and heteroaryl groups are optionally substituted as described in their respective definitions.

[0089] The term "biaryl" refers to an aryl group, as defined herein, substituted by another aryl group, as defined herein, including wherein the aryl groups are independently optionally substituted as described in the definitions herein.

[0090] The term "biarylalkyl" refers to an alkyl group substituted with an aryl group, which is substituted with another aryl group, each as defined herein, including wherein each aryl group is independently and the alkyl group is optionally substituted as described in its respective definition.

[0091] The terms "heterocyclic ring", "heterocyclic ring" and "heterocycle" refer to monocyclic or bicyclic aromatic rings, or saturated or unsaturated non-aromatic monocyclic or bicyclic rings, which contain 3 to 12 carbon atoms and 1 to 4 groups independently selected from oxygen, nitrogen, P(=O) and S(O) in the ring. m wherein m is an integer from 0 to 2. In addition to any groups specifically recited in any embodiment or claim, the heterocycle is optionally substituted with one, two or three substituents selected from halogen, C(=O)OR a 、OC(=O)R a 、OC(=O)NR a R b 、-C 1-20 Alkyl, -OH, -NH2, -OC1-20 Alkyl, -S(O) m C 1-20 Alkyl (wherein m is 0, 1, or 2), -C 1-20 Alkyl-NH2, -NHC 1-4 Alkyl, -C(=O)H, or -C=N-OR d1 , where R a 、R b and R d are independently hydrogen or C 1-20 In some or any embodiments, the heterocycle is unsubstituted. 5 to R 10 Any two of which are formed and / or consist of R 11 and R 12 Formed and / or by R 4 and R 11 Formed and / or by R 6 and R 12 The 4 to 7 membered or 5 to 7 membered ring formed is optionally as described for heterocycle and optionally substituted by one or two independently selected C 1-6 Alkyl and aryl groups are substituted.

[0092] Het 1 is independently at each occurrence a C-linked 5- or 6-membered heterocyclic ring having 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring.

[0093] The term "unsaturated" in the context of the terms cycloalkyl, cycloalkylene and heterocycle refers to a ring that is partially unsaturated but not aromatic.

[0094] In some embodiments, heterocycles include but are not limited to azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pterin, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, isoxolinone, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiadiazole tetrazole, thiazolidine, thia phene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also known as thiomorpholinyl), piperidinyl, pyrrolidine, tetrahydrofuranyl, 1,3-benzoxazine, 1,4-oxazin-3-one, 1,3-benzoxazin-4-one, pyrrolidine, pyrrolidin-2-one, oxazolidin-2-one, azapine, perhydroazepine, perhydroazepine-2-one, perhydro-1,4-oxazacyclooxane, perhydro-1,-4-oxazacyclooxane-2-one, perhydro-1,4-oxazacyclooxane-3-one, perhydro-1,3-oxazacyclooxane-2-one, azabicyclo[3.1.0]hexane, and the like, and N-oxides of said nitrogen heterocycles. In addition to any groups specifically recited in any embodiment or claim, heterocycles also include substituted and unsubstituted rings, including those selected from C(=O)OR a 、OC(=O)R a 、OC(=O)NR a R b A group in which R a and R b are independently hydrogen or C 1-6 alkyl.

[0095] The term "heteroaryl" refers to a five (5) or six (6) membered C- or N-linked heterocyclic ring optionally fused to benzene or another heterocyclic ring (at least one of which is aromatic). A heterocyclic ring fused to a benzene ring is also referred to as a benzoheterocyclyl. In some embodiments, heteroaryl includes, but is not limited to, pyridine, thiophene, furan, pyrazole, indole, benzimidazole, quinoline, pyrimidine, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazinyl, 4-oxo-2-imidazolyl, 2-imidazolyl, 4-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl, 4-pyrazolyl, 5- Pyrazolyl, 2-oxazolyl, 4-oxazolyl, 4-oxo-2-oxazolyl, 5-oxazolyl, 1,2,3-oxathiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazole, 4-isothiazole, 5-isothiazole, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3 -Isopyrrolyl, 4-isopyrrolyl, 5-isopyrrolyl, 1,2,3,-oxathiazol-1-oxo, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 5-oxo-1,2,4-oxadiazol-3-yl, 1,2,4-thiadiazol-3-yl, 1,2,5-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 3-oxo-1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 2-oxo-1,3,4-thiadiazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3,4-tetrazol-5-yl, 5-oxazolyl, 3-isothiazolyl, 4-isothiazolyl and 5-isothiazolyl, 1,3,4,-oxadiazole, 4-oxo-2-thiazolyl, or 5-methyl-1,3,4-thiadiazol-2-yl, thiazoldione, 1,2,3,4-thiatriazole and 1,2,4-dithiazolone. In addition to any groups specifically listed in any embodiment or claim, heteroaryl also includes substituted and unsubstituted rings, including those selected from C(=O)OR a 、OC(=O)R a , and OC(=O)NR a R b Those rings substituted with groups wherein each R a and R b are independently hydrogen or C 1-6 In some embodiments, the heteroaryl group is unsubstituted. 1 " or "heteroaryl 2"Heteroaryl" refers to independently selected heteroaryl groups that may be different from each other or independently identical to each other. If the term "heteroaryl" is used more than once in the same group, each "heteroaryl" may be independent of the other "heteroaryl" at each occurrence. The term "heteroarylene" is a divalent group based on the above-mentioned heteroaryl groups.

[0096] The term "heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group, each as defined herein.

[0097] The term "monosubstituted" refers to a group having at least one substituent in the group, excluding the point of attachment of the group to the main structure or general formula. The term "polysubstituted" refers to a group having at least two substituents in the group, excluding the point of attachment of the group to the main structure or general formula.

[0098] Unless otherwise specified, a "carbon atom" refers to a carbon atom optionally replaced by H, halogen, NR a R b 、C 1-12 Alkyl, C 3-7 Cycloalkyl, aryl, heteroaryl or heterocyclic substituted carbon atoms include atoms having sp3, sp2 and sp electron hybridization.

[0099] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "aryl optionally mono- or disubstituted with alkyl" means that alkyl may but need not be present, and that the description includes instances where aryl is mono- or disubstituted with alkyl and instances where it is not substituted with alkyl.

[0100] Compounds that have the same molecular formula but differ in the nature or order of bonding of their atoms, or in the arrangement of their atoms in space, are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0101] Stereoisomers that are not mirror images of one another are termed "diastereomers," while those that are non-superimposable mirror images of one another are termed "enantiomers." For example, when a compound has an asymmetric center, it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center, and described by the R- and S-sequencing rules of Cahn and Prelog, or by the way that the molecule rotates the plane of polarized light, and designated as right- or left-handed (i.e., (+) or (-)-isomers, respectively). A chiral compound can exist as either an individual enantiomer or as a mixture thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0102] The compounds provided herein may have one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include all individual enantiomers and any mixtures thereof, racemic, partially racemic or otherwise. Methods for determining stereochemistry and resolving stereoisomers are well known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition J. March, John Wiley and Sons, New York, 1992).

[0103] The substitution of hydrogen (H), carbon (C) or nitrogen (N) in the compounds of formula I-IV described herein includes substitution with any isotope of the corresponding atom. Thus, substitution of hydrogen (H) includes 1 H. 2 H (deuterium) or 3 H (tritium) isotope substitution may be desirable, for example, for specific therapeutic or diagnostic treatments, metabolic research applications, or stability enhancement. Alternatively, the compounds described herein may incorporate radioactive isotopes (radioactive isotopes or radioisotopes) known in the art, such as any number of 3 H. 15 O. 12 C or 13 N isotopes to provide the corresponding radiolabeled compounds of Formula I-IV as those described herein.

[0104] "Pharmaceutically acceptable carrier" refers to a carrier that can be used to prepare a pharmaceutical composition, is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes carriers that can be used in veterinary and human medicine. "Pharmaceutically acceptable carrier" as used in the specification and claims includes one or more such carriers.

[0105] A "pharmaceutically acceptable salt" of a compound is a salt that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include: (1) Acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxybenzoyl)benzoic acid, 1,2-ethanedisulfonic ... Ethylenesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptanoic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or (2) Salts formed when the acidic protons present in the parent compound are replaced by metal ions, such as alkali metal ions, alkaline earth ions or aluminum ions; or when coordinated with organic bases such as ethanolamine, diethanolamine, triethanolamine, butanetriolamine, N-methylglucamine, etc.

[0106] “Treating,” “treatment,” or “therapy” for a disease includes: (1) preventing the disease, that is, preventing the clinical symptoms of the disease from developing in a mammal that may be exposed to or susceptible to the disease but does not yet experience or display symptoms of the disease, (2) inhibit the disease, i.e., prevent or reduce the development of the disease or its clinical symptoms, or (3) Relieve the disease, that is, cause the disease or its clinical symptoms to disappear.

[0107] "Therapeutically effective amount" refers to the amount of a compound that is sufficient to affect the treatment of a disease when administered to a mammal. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc. of the mammal to be treated.

[0108] "Leaving group" has the meaning usually associated with it in synthetic organic chemistry, i.e., an atom or group capable of being displaced by a nucleophile, including halogens, C 1-4 Alkylsulfonyloxy, ester or amino groups, such as chloro, bromo, iodo, formyloxy, toluoyloxy, trifluorosulfonyloxy, methoxy, N,O-dimethylhydroxyamino and the like.

[0109] "Prodrug" refers to any compound that releases an active parent drug in vivo according to the compound provided herein when the prodrug is administered to a mammalian subject. The prodrug of the compound provided herein is prepared by modifying the functional group present in the compound provided herein, and the modification can be cleaved in vivo to release the parent compound. Prodrugs include compounds provided herein, wherein the hydroxyl, sulfhydryl, amide or amino group in the compound is combined with any group that can be cleaved in vivo to regenerate free hydroxyl, amide, amino or sulfhydryl groups. Examples of prodrugs include, but are not limited to, esters (such as acetate, formate, benzoate, phosphate or phosphonate derivatives) of the hydroxyl functional group in the compound provided herein, carbamates (such as N, N dimethylaminocarbonyl) and the like. The prodrug of the compound provided herein can be used for specific therapeutic applications, such as for pulmonary delivery of an aerosol containing the prodrug of this compound, or for improving tolerance to the same agent. For example, the mesylate prodrug form of the polymyxin drug colistin (e.g., as described by Bergen et al. in Antimicrob. Agents Chemother. 2006, vol. 50, p. 1953) is used to reduce the neurotoxic effects of colistin and is used for aerosol administration of the drug. This and other known forms of prodrugs can also be used to further improve the pharmaceutical properties of the compounds provided herein.

[0110] The term "mammal" refers to all mammals, including humans, livestock, and companion animals (pets).

[0111] The compounds described herein are generally named according to the IUPAC or CAS nomenclature system. Abbreviations well known to those of ordinary skill in the art can be used (e.g., "Ph" for phenyl, "Me" for methyl, "Et" for ethyl, "h" for hours or hours, and "rt" for room temperature). Illustrative Embodiments

[0112] Certain compounds of Formula I may be preferred within the broadest definition of the present application. Specific and preferred values for radicals, substituents, and ranges listed herein are for illustration only; they do not exclude other defined values for radicals and substituents or other values within the defined ranges.

[0113] In some preferred compounds described in this application, C 1-14 The alkyl group may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, octyl, nonyl, decyl and isomeric forms thereof.

[0114] In some preferred compounds described in this application, C 2-12 Alkenyl may be ethenyl, propenyl, allyl, butenyl and isomeric forms thereof (including cis and trans isomers).

[0115] In some preferred compounds described in this application, C 3-7 The cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and isomeric forms thereof.

[0116] In some preferred compounds described in this application, C 1-14 The heteroalkyl group may be hydroxymethyl, hydroxyethyl, 2-(N,N-dimethylamino)ethyl, 2-(4-morpholinyl)ethyl, and 2-methoxyethyl.

[0117] In some preferred compounds described herein, the halogen may be fluorine (F) or chlorine (Cl).

[0118] Those skilled in the art will also understand that the compounds described herein may have additional chiral centers and be separated in optically active and racemic forms. The present application includes any racemic, optically active, tautomer, geometric or stereoisomeric form or mixtures thereof of the compounds described herein.

[0119] Any embodiment described in this application may be combined with any other embodiment described in this application.

[0120] In a preferred embodiment, R 1 The parent (precursor) structure of is selected from the following structures.

[0121] In a preferred embodiment, R 1 The parent (precursor) structure is selected from the following structures:

[0122] The following are some preferred compounds of formula I, including any salt form thereof, such as hydrochloride, sulfate or other pharmaceutically acceptable salts:

[0123] In a preferred embodiment, a compound of Formula I, Ia, or Ib, or any embodiment thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is provided that has anti-inflammatory activity; or a therapeutic effect on kidney disease, as determined by reducing or slowing the release of renal cytokines such as TNF-α, IL-6, or IL-12; or reducing biomarkers such as protein levels, blood urea nitrogen, and serum creatinine, or by improving the condition of a patient in need of treatment or a mammal in an animal test.

[0124] In a preferred embodiment, a compound of Formula I, Ia, or Ib, or any embodiment thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is provided for use in treating inflammation, wherein the inflammation is renal inflammation, or an inflammatory disease in renal injury or dysfunction, or inflammation induced by a nephrotoxic substance, including a pharmaceutical nephrotoxic substance, such as an anti-cancer, anti-diabetic, anti-infective, or other chemotherapeutic substance.

[0125] In some or any embodiments, there is provided a compound of Formula I, Ia, or Ib, or any embodiment thereof, which, when combined with a similar dose of free agent or drug HR in said compound, 1 In some or any embodiments, the compound of formula IP-1, IP-2 or II-P-1, or any of its embodiments, has an enhanced anti-inflammatory, immunomodulatory or renal protective effect compared to a similar dose of the free agent or drug HR incorporated into the compound. 1 have enhanced anti-inflammatory, immunomodulatory or renoprotective effects compared to the control, as determined by in vitro or in vivo assays for anti-inflammatory, immunomodulatory or renoprotective activity.

[0126] In some or any embodiments, when administered to a mammal, a compound of Formula I, Ia, or Ib, or any embodiment thereof, exhibits preferential accumulation in the kidney, with a ratio of molar concentration in the kidney to molar concentration in the blood of between about 5 and 50.

[0127] In some or any embodiments, when administered to a mammal, a compound of Formula I, Ia, or Ib, or any embodiment thereof, exhibits preferential accumulation in the kidney, with a ratio of its molar concentration in the kidney to its molar concentration in the blood of at least about 20.

[0128] In some or any embodiments, when the reagent HR is equal to 1 When a dose (expressed in moles) of a standard therapeutic dose (in moles) of the free drug HR1 is administered to a mammal, the compound of Formula I, Ia, or Ib, or any embodiment thereof, exhibits an effect in the kidney on the HR1 activity of the free drug HR1. 1 The drug loading (tissue concentration) and / or drug exposure (area under the curve, AUC) is approximately 1.5 to 15 times that of the dose of the active ingredient.

[0129] In some or any embodiments, when the reagent HR is equal to 1 The standard therapeutic dose (in molar amounts) of the dose (expressed in molar amounts) when administered to a mammal, with the agent HR 1 The compounds of Formula I, Ia, or Ib, or any embodiment thereof, exhibit about 1.5-15 fold greater efficacy compared to a standard therapeutic dose of 1,000 mg / kg ...

[0130] In some or any embodiments, when the reagent HR is equal to 1 The standard therapeutic dose (molar amount) is a dose (expressed in moles) when administered to a mammal, with the reagent HR 1 The compounds of Formula I, Ia, or Ib, or any embodiment thereof, exhibit at least 2-fold greater efficacy compared to a standard therapeutic dose of 1,000 mg / kg of 1,000 mg / kg of renal tissue, wherein the therapeutic effect is determined as slowing, halting, or reversing progression of inflammation or renal damage (as determined by cytokine release levels and / or by using biochemical biomarkers for inflammation monitoring, or by radiography, or by magnetic resonance imaging, or the like).

[0131] In some or any embodiments, the HR of the reagent 1 The standard therapeutic dose (in moles) of a dose (expressed in moles) when administered to a mammal is comparable to HR 1The compound of Formula I, Ia, or Ib, or any embodiment thereof, exhibits at least a 2-fold reduction in adverse reactions and / or off-target toxicities compared to a standard therapeutic dose of at least 100 mg / dL, as determined by medical observation, blood cell count, tissue biopsy, and / or analysis of biochemical biomarkers or the like in the mammal being treated.

[0132] In some embodiments and aspects, the compounds provided herein can be used in combination with adjuvants to synergize and / or enhance the therapeutic effect of the compound itself or the adjuvant, or both. Such adjuvants include other anticancer or immunomodulatory agents, such as monoclonal antibody agents, or another anti-inflammatory agent, or other anticancer or antibacterial agents, or humanized antibodies.

[0133] In one such aspect, the compounds provided herein have modest or no anti-inflammatory activity in vitro, but exhibit high anti-inflammatory efficacy when administered to a mammal in need of such treatment.

[0134] In some or any embodiments, a pharmaceutical composition is provided, comprising a therapeutically effective amount of a compound of Formula I, Ia, or Ib, or any embodiment thereof, and a pharmaceutically acceptable carrier. General synthetic method

[0135] The compounds described herein can be prepared according to one or more methods, for example, as described in the following references. General syntheses of certain relevant starting materials have been described in the literature. For example, O'Dowd et al. describe the preparation of Boc-protected polymyxin B nonapeptides in Tetrahedron Lett. 2007, vol. 48, p. 2003. Additional protected polymyxin B nonapeptides and colistin nonapeptide derivatives can be prepared as described in Okimura et al. in Chem. Pharm. Bull. 2007, vol. 55, pp. 1724-1730. Similarly, general peptide acylation chemistry is described in Tetrahedron Lett. 2007, vol. 48, pp. 2003-2005.

[0136] Other general methods suitable for preparing compounds of formula I-III are described in the following publications: WO 2016 / 083531, WO 2015 / 149131, WO 2015 / 135976, US2015 / 0031602, WO 2014 / 188178, WO 2014 / 108469, CN 103923190, US2014 / 0162937, WO 2014 / 028087、WO 2013 / 112548, CN 103130876, WO 2013 / 072695, WO 2012 / 168820, WO 2012051663, US 2012 / 0316105, US2012 / 0283176, US2010 / 0160215, US2009 / 0215677, WO 2008 / 017734, WO 2006 / 045156, US2006 / 0004185, US 6380356, and US 3450687.

[0137] Suitable methods for incorporating suitable enzymatically and / or chemically cleavable groups X, Y and Z (and the same additional spacers / linkers) into compounds of Formula I-III have been described in general related synthetic techniques for preparing ADCs and other reagents, for example, as reported in the following publications: US20170355769; J.Am.Chem.Soc.018, vol.140, p.1617; Bioconjugate Chem.2016, vol.27, p.1606; Bioconjugate Chem.2016, vol.27, p.1645; Bioconjugate Chem.2015, vol.26, p.919; Mol.Pharmaceutics2015, vol.12, p.1813; ACS Med.Chem.Lett.2017, vol.8, p.1037; ACS Med.Chem.Lett.2016, vol.7, p.983; Org.Process Res.Dev.2019, vol.23, p.2647; Bioconjugate Chem.2016, vol.27, p.1880; Bioconjugate Chem.2017, vol.28, p.620; Org.Process Res.Dev.2018, vol.22, p.286; Bioconjugate Chem.2015, vol.26, p.2216; J.Med.Chem.2014, vol.57, p.6949; Bioconjugate Chem.2018, vol.29, p.1155; J.Am.Chem.Soc.2015, vol.137, p.3229; Mol.Pharmaceutics 2018, vol.15, p.2384; ACS Med.Chem.Lett.2016, vol.7, p.988; Chem.Biodiversity 2019, vol.16, e1800520; Nature Commun.|2018, vol.9, p.2512; Mol.Pharmaceutics 2011, vol.8, p.901; ACS Med.Chem.Lett.2019, vol.10, p.1393; J.Nat.Prod.2017, vol.80, p.2447; ACS Med.Chem.Lett.2019, vol.10, p.1674; Pharmaceutics 2013, vol.5, p.220; and other references cited in the publications.

[0138] It will be apparent to one skilled in the art of synthetic organic chemistry that the specific methods, amino acid reagents, and linker / spacer structures described in the above references are directly adaptable to prepare compounds of Formulas I-III by straightforward variation of the specific reagents and protection / deprotection schemes.

[0139] Additional syntheses of specific compounds described herein are illustrated by various synthetic schemes in the following examples, which are also applicable to the preparation of other compounds provided herein. Example

[0140] The embodiments described in this application are described in the following examples, which are intended to illustrate but not to limit the scope of the present disclosure. Common abbreviations familiar to those of ordinary skill in the art of synthesis are used throughout; abbreviation: NMR: 400 MHz in D2O 1 H NMR spectra (δ, ppm), unless otherwise specified; LCMS: liquid chromatography-mass spectrometry; MS: mass spectral data of positive ionization method (m / z); Chromatography: Unless otherwise specified, chromatography on silica gel with organic solvents was used; TLC: thin layer chromatography; HPLC: reversed-phase high performance chromatography using a commercial C18 column; TES: Et3SiH; TFA: CF3COOH; TCFH: N,N,N',N'-tetramethylchloroformamidomethylammonium hexafluorophosphate; EA: EtOAc; ACN:MeCN; DMF: N,N-dimethylformamide; DCC: N,N'-dicyclohexylcarbodiimide; DCE: 1,2-dichloroethane; NMP: N-methylpyrrolidone; NsCl: 4-nitrobenzenesulfonyl chloride; PE: hexane or light petroleum ether; C18 chromatography: Reversed phase chromatography using a gradient of 0.1% TFA in water and acetonitrile (ACN); PMBN(Boc)4 is the same as PMBNBoc4: H-Thr-Dab(Boc)-cyclo[Dab-Dab(Boc)-D-Phe-Leu-Dab(Boc)-Dab(Boc)-Thr]; PMBH(Boc)3 is the same as PMBNBoc3: cyclo[Dab-Dab(Boc)-D-Phe-Leu-Dab(Boc)-Dab(Boc)-Thr]; Other reagent abbreviations are the same as those used in common synthetic literature, including the American Chemical Society abbreviation list, such as in the Journal of Organic Chemistry; or the Journal of Peptide Chemistry. Unless otherwise specified, all reagents were either from commercial sources or prepared by conventional methods described in the existing literature.

[0141] Example 1 Synthesis of the compound of Example 1:

[0142] Intermediate 1: DIEA (247 mg, 1.91 mmol) and TBTU (404 mg, 1.26 mmol) were added to a solution of Fmoc-Glu(OtBu)-OH (542 mg, 1.27 mmol) in DMF (5.00 mL) at 25°C and stirred at 25°C for 10 minutes. Subsequently, a solution of dexamethasone (500 mg, 1.26 mmol) and DIEA (247 mg, 1.91 mmol) in DMF (5.00 mL) was added to the mixture at 25°C and stirred at 25°C for 12 hours. The crude product was diluted with methanol (1 mL) and purified by HPLC (Phenomenex Luna C18 75×30 mm×3 μm, water-FA / ACN) to give 600 mg of white solid Intermediate 1. MS: 800.6 [M+H] + .

[0143] Intermediate 2: To a solution of Intermediate 1 (100 mg, 0.125 mmol) in dichloromethane (DCM, 1.00 mL) was added trifluoroacetic acid (TFA, 0.200 mL, 2.61 mmol) at 25°C and stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to give crude Intermediate 2 as a yellow oil. LCMS: 744.5 [M+H] + .

[0144] Intermediate 3: PMBN-Boc4 (50.0 mg, 0.037 mmol), DIEA (23.9 mg, 0.185 mmol) and HATU (20.9 mg, 0.055 mmol) were added to a solution of intermediate 2 (50.5 mg, 0.041 mmol) in DMF (1.00 mL) at 0° C., and the mixture was stirred at 25° C. for 12 hours. The crude product was diluted with DMF (1 mL) and purified by HPLC (Phenomenex Luna C18 75×30 mm×3 μm, water-FA / ACN gradient elution) to give 30.0 mg of intermediate 3 as a light yellow solid.

[0145] Compound of Example 1: A solution of intermediate 3 (20 mg, 0.010 mmol) in dichloromethane (DCM, 0.50 mL) was mixed with diethylamine (0.001 mL, 0.005 mmol) at 25° C. and stirred at 25° C. for 2 hours. Subsequently, the reaction mixture was adjusted to pH 1 with TFA at 0° C., and then TFA (0.300 mL) was added to the mixture at 25° C. and stirring was continued at 25° C. for 2 hours. The crude product was diluted with MeCN (1 mL) and purified by HPLC (Phenomenex Luna 80×30 mm×3 μm, water (containing TFA)-ACN) to give 18.16 mg of the compound of Example 1 as a white solid. MS: 1467.05 [M+H] + . 1 H NMR (400MHz, CD3OD): 7.41(d,J=10.1Hz,1H),7.33-7.20(m,5H),6.29(dd,J=1.9,10.1Hz,1H),6.09(s,1H),5.16(d,J =4.6Hz,2H),4.62-4.39(m,4H),4.38-4.23(m,6H),4.21-4.02(m,3H),3.68-3.52(m,1H),3.17-2.90(m,13H),2.88-2 .65(m,3H),2.51-2.06(m,14H),2.04-1.95(m,2H),1.92-1.84(m,1H),1.80-1.64(m,2H),1.59(s,3H),1.56-1.47(m, 2H),1.46-1.34(m,2H),1.27-1.16(m,6H),1.02(s,3H),0.87(d,J=7.4Hz,3H),0.80-0.72(m,3H),0.71-0.64(m,3H).

[0146] Example 2 Synthesis of the compound of Example 2:

[0147] Intermediate 5: A solution of dexamethasone (1 g, 2.5 mmol), 4-nitrobenzenesulfonyl chloride (1.13 g, 5.1 mmol) and TEA (1.06 mL, 7.6 mmol) in dichloromethane (DCM, 10 mL) was stirred at room temperature under argon for 16 hours. After completion of the reaction, the reaction mixture was extracted with dichloromethane (80 mL), washed sequentially with saturated sodium bicarbonate solution (2 × 10 mL) and saturated brine (10 mL), dried, and concentrated to give 1.1 g of crude intermediate 5. MS: 411.19 [M+H] + .

[0148] Intermediate 6: A mixture of intermediate 5 (crude product 1.1 g, 2.5 mmol) and sodium azide (NaN3, 1.6 g, 25 mmol) in acetone (15 mL) was stirred at 50°C under argon protection for 16 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate (EtOAc, 80 mL) and washed with saturated brine (10 mL x 2). After drying and concentration, the mixture was purified by silica gel column chromatography (EtOAc / PE = 0-100%) to obtain 0.9 g of intermediate 6. MS: 418.22 [M+H] + .

[0149] Intermediate 7: A mixture of intermediate 6 (417 mg, 1 mmol), 1M HCl (2 mL) and triphenylphosphine (PPh3, 394 mg, 1.5 mmol) in tetrahydrofuran (THF, 10 mL) was stirred at room temperature under argon for 16 hours. After completion of the reaction, the mixture was purified by C18 column chromatography (ACN / H2O=0-80%) to give 265 mg of intermediate 7. MS: 392.32 [M+H] + .

[0150] Intermediate 9: A solution of Boc-L-Ala-L-Ala-OMe (823 mg, 3 mmol) and trifluoroacetic acid (TFA, 2 mL) in dichloromethane (DCM, 6 mL) was stirred at room temperature under argon for 3 hours. The solvent was then removed to give 1.1 g of crude intermediate 9. MS: 175.19 [M+H] + .

[0151] Intermediate 10: A mixture of intermediate 9 (crude product 1.1 g, 3 mmol), (tert-butoxycarbonyl)glycine (552 mg, 3.15 mmol), HATU (1.25 g, 3.3 mmol) and DIEA (1.5 mL, 9 mmol) in DMF (10 mL) was stirred at room temperature under argon for 5 hours. After completion of the reaction, the mixture was extracted with ethyl acetate (EtOAc, 50 mL) and washed sequentially with 1 M HCl (2 × 15 mL), 0.5 M NaOH (2 × 5 mL) and saturated brine (5 mL). After drying and concentration, 0.8 g of intermediate 10 was obtained. MS: 332.05 [M+H] + .

[0152] Intermediate 11: A mixture of intermediate 10 (0.8 g) and trifluoroacetic acid (TFA, 1 mL) in dichloromethane (DCM, 3 mL) was stirred at room temperature under argon for 3 hours. After removing the solvent, 0.9 g of crude intermediate 11 was obtained. MS: 232.12 [M+H] + .

[0153] Intermediate 12: A mixture of PMBN-Boc4 (500 mg, 0.37 mmol) and succinic anhydride (48 mg, 0.48 mmol) in a mixed solvent of acetonitrile (ACN, 5 mL) and water (1 mL) was stirred at room temperature under argon protection for 16 hours. After the reaction was completed, the mixture was extracted with ethyl acetate (EtOAc, 50 mL) and washed with 1M HCl (2×5 mL) and saturated brine (2×5 mL) in sequence. After drying and concentration, 560 mg of intermediate 12 was obtained. MS: 1463.55 [M+H] + .

[0154] Intermediate 13: A mixture of intermediate 12 (530 mg, 0.36 mmol), intermediate 11 (312 mg, 0.91 mmol), HATU (344 mg, 0.91 mmol) and DIEA (0.24 mL, 1.45 mmol) in DMF (5 mL) was stirred at room temperature under argon for 3 hours. After completion of the reaction, the mixture was extracted with ethyl acetate (EA, 60 mL), washed sequentially with 1 M HCl (2×10 mL) and saturated brine (10 mL). After drying and concentration, the product was purified by C18 column chromatography (ACN / H2O gradient elution = 0-90%) to give 450 mg of intermediate 13. MS: 1676.56 [M+H] + .

[0155] Intermediate 14: A mixture of intermediate 13 (430 mg, 0.256 mmol), LiOH.H2O (22 mg, 0.513 mmol) and water (1 mL) in tetrahydrofuran (THF, 4 mL) was stirred at room temperature under argon for 4 hours. After completion of the reaction, the mixture was extracted with ethyl acetate (EA, 60 mL) and washed sequentially with 1M HCl (10 mL) and saturated brine (10 mL). After drying and concentration, the mixture was purified by C18 column chromatography (ACN / H2O = 0-90%) to give 305 mg of intermediate 14. MS: 1662.59 [M+H] + .

[0156] Intermediate 15: A mixture of intermediate 14 (265 mg, 0.16 mmol), HATU (73 mg, 0.19 mmol) and DIEA (0.066 mL, 0.4 mmol) in DMF (3 mL) was stirred at room temperature under argon for 0.5 h, followed by the addition of intermediate 17 (105 mg, 0.21 mmol) and continued stirring at room temperature under argon for 1 h. After completion of the reaction, the mixture was extracted with ethyl acetate (EA, 60 mL), washed sequentially with 1 M HCl (2 x 8 mL) and saturated brine (8 mL). After drying and concentration, the mixture was purified by C18 column chromatography (ACN / H2O = 0-90%) to afford 178 mg of intermediate 15. MS: 1018.72 [M+H].

[0157] Compound of Example 2: A mixture of Intermediate 15 (150 mg, 0.07 mmol) and trifluoroacetic acid (TFA, 0.5 mL) in dichloromethane (DCM, 1.5 mL) was stirred at room temperature under argon for 1 hour. After removing the solvent, the mixture was purified by C18 column chromatography (ACN / H2O = 0-60%) to obtain 62.4 mg of the compound of Example 2. MS: 1635.93 [M+H] + . 1H NMR:7.46(d,J=10.0Hz,1H),7.33(t,J=7.4Hz,2H),7.28(t,J=7.3Hz,1H),7.20(d, J=7.5Hz,2H),6.35(d,J=10.1Hz,1H),6.16(s,1H),4.54(t,J=8.2Hz,1H),4.40(dt ,J=15.7,8.9Hz,2H),4.34–4.12(m,13H),3.91–3.81(m,2H),3.27(dt,J=14.6,7.8 Hz,1H),3.11–2.92(m,10H),2.61(s,6H),2.54–2.38(m,2H),2.18(ddt,J=24.0,14. 8,8.0Hz,5H),2.12–2.02(m,3H),1.85(d,J=53.6Hz,5H),1.74(q,J=12.2Hz,1H),1 .64(d,J=14.0Hz,1H),1.48(s,3H),1.37(dd,J=7.3,2.2Hz,4H),1.33(t,J=7.3Hz, 3H),1.20(s,1H),1.16(dd,J=6.4,2.1Hz,3H),1.13(d,J=6.2Hz,3H),0.89(d,J=4. 6Hz, 3H), 0.80 (dd, J = 7.4, 2.3Hz, 3H), 0.72 (d, J = 6.6Hz, 3H), 0.65 (d, J = 6.5Hz, 3H).

[0158] Example 3: Synthesis of the compound of Example 3:

[0159] Intermediate 16: PMBHBoc3 (127.2 mg, 0.12 mmol), succinic anhydride (18.01 mg, 0.18 mmol), 4-dimethylaminopyridine (DMAP, 43.96 mg, 0.36 mmol) and water / ACN (5 mL / 5 mL) were added to a 25 mL reaction flask. The reaction mixture was then stirred at room temperature for 12 hours. After completion of the reaction, the mixture was concentrated and purified by C18 column chromatography (ACN / water, containing 0.05% TFA, gradient 0-100%) to give 182.2 mg of Intermediate 16 as a white solid. MS: 1162.26 [M+H] + .

[0160] Intermediate 17: A mixture of triamcinolone (800 mg, 2.0 mmol), tert-butyl (4-formaldehyde phenyl) carbamate (496 mg, 2.2 mmol) and MgSO4 (1.2 g, 10 mmol) in ACN (15 mL) was stirred at room temperature for 15 minutes, followed by the addition of HClO4 (0.856 mL) and continued stirring at room temperature overnight. After completion of the reaction, the mixture was extracted with EtOAc and washed sequentially with aqueous sodium bicarbonate solution and saturated brine. After drying and concentration, 840 mg of the crude product, Intermediate 17, was obtained as a white solid. MS: 498.16 [M+H] + .

[0161] Intermediate 18: A mixture of intermediate 17 (crude product 780 mg, 1.56 mmol), Boc-Val-Cit-OH (586 mg, 1.56 mmol), HATU (711 mg, 1.87 mmol) and DIEA (0.5 mL, 3.12 mmol) in DMF (5 mL) was stirred at room temperature under argon for 5 hours. After completion of the reaction, the mixture was extracted with EtOAc (50 mL) and washed sequentially with 1 M HCl (2×15 mL), 0.5 M NaOH (2×5 mL) and saturated brine (5 mL). After drying over MgSO₄ and concentration, the mixture was purified by C₁₈ column chromatography to give 0.3 g of intermediate 18.

[0162] Intermediate 19: A mixture of Intermediate 18 (0.15 g) and TFA (1 mL) in dichloromethane (DCM, 5 mL) was stirred at room temperature under argon for 3 hours. After removing the solvent, 0.17 g of crude Intermediate 19 was obtained.

[0163] Intermediate 20: A mixture of Intermediate 19 (crude product 114 mg, 0.19 mmol), Intermediate 16 (224 mg, 0.21 mmol), HATU (289 mg, 0.76 mmol) and DIEA (0.25 mL, 1.52 mmol) in DMF (5 mL) was stirred at room temperature under argon for 5 hours. After completion of the reaction, the mixture was extracted with EtOAc (50 mL) and washed sequentially with 1 M HCl (2×15 mL), 0.5 M NaOH (2×5 mL) and saturated brine (5 mL). After drying and concentration, the residue was purified by C18 column chromatography (ACN / water containing 0.05% TFA, gradient 0-100%) to give 60.8 mg of Intermediate 20 as a white solid. MS: 1897.61 [M+H] + .

[0164] Compound of Example 3: To a 25 mL reaction flask, intermediate 29 (60.8 mg, 0.032 mmol), TFA (0.5 mL), and dichloromethane (DCM, 2.5 mL) were added under air. The reaction mixture was then stirred at room temperature for 3 hours. Volatiles were removed under vacuum, and the residue was purified by C18 column chromatography (ACN / water containing 0.05% TFA, gradient 0-100%) to afford 33.6 mg of compound of Example 3 as a white solid. MS: 1597.8 [M+H] + . 1H NMR(600MHz, DMSO-d6):8.79(d,J=6.4Hz,1H),8.44(d,J=8.4Hz,1H),8.34–8.22(m,2H),7.94–7.89(m,3H),7.87(dq,J=10 .1,5.0Hz,3H),7.83–7.79(m,4H),7.76(s,1H),7.62(dd,J=12.2,8.4Hz,2H),7.36(dd,J=8.7,3.2Hz,1H),7.34–7.29(m,2H ),7.29–7.25(m,3H),7.24(d,J=17.8Hz,1H),7.22–7.16(m,1H),6.24(dt,J=10.2,2.1Hz,1H),6.12–6.05(m,1H),6.04(d,J =3.5Hz,1H),5.50(s,2H),5.43(s,1H),4.94(d,J=4.9Hz,1H),4.55–4.49(m,2H),4.38(q,J=7.5Hz,2H),4.22(dt,J=19.2,9 .4Hz,6H),4.01(s,1H),3.94(t,J=5.9Hz,1H),3.01(s,1H),2.95(dq,J=13.3,6.5,5.8Hz,3H),2.87(q,J=8.7,7.6Hz,4H), 2.80(s,1H),2.76(d,J=15.3Hz,1H),2.66(d,J=15.4Hz,2H),2.58(s,1H),2.46–2.41(m,2H),2.39–2.31(m,3H),2.16(td,J =11.9,6.4Hz,2H),2.06–1.92(m,5H),1.87–1.82(m,2H),1.69(q,J=8.4,7.1Hz,4H),1.59(d,J=16.0Hz,2H),1.50(s,3H),1 .44(s,1H),1.34(d,J=12.3Hz,2H),1.11(s,1H),1.05(d,J=6.2Hz,3H),0.90–0.81(m,9H),0.81–0.73(m,5H),0.72(s,2H).

[0165] Example 4: Synthesis of the compound of Example 4:

[0166] Intermediate 21: Fluocinolone acetonide (1.22 g, 2.7 mmol) and HBF4 (40% aqueous solution, 25 mL) were added to a 100 mL reaction flask. The reaction mixture was stirred at room temperature for 12 hours. The white precipitate was collected by filtration, washed with water, and dried under high vacuum to give 965.9 mg of crude Intermediate 21 as a white solid. MS: 413.11 [M+H] + .

[0167] Intermediate 22: In a 100 mL reaction flask were added intermediate 21 (965.9 mg, 2.342 mmol), butyraldehyde (0.227 mL, 2.6 mmol), HClO4 (70%, 980 μL, 11.7 mmol), MgSO4 (1.41 g, 11.7 mmol) and ACN (25 mL). Subsequently, the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was filtered through a celite pad, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in EtOAc, washed with saturated sodium bicarbonate solution and saturated brine, dried over Na2SO4, filtered, concentrated under reduced pressure, and dried under high vacuum to obtain 1.18 g of white solid intermediate 22. MS: 467.22 [M+H] + .

[0168] Intermediate 23: To a 100 mL reaction flask were added intermediate 22 (932.4 mg, 2 mmol), 4-nitrobenzenesulfonyl chloride (664.8 mg, 1.5 mmol), TEA (0.834 mL, 6 mmol) and DCM (30 mL). Subsequently, the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution and the DCM layer was separated. The aqueous layer was extracted twice with DCM. The combined DCM layers were washed with saturated sodium bicarbonate solution and saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 943.5 mg of an off-white solid intermediate 23. MS: 652.20 [M+H] + .

[0169] Intermediate 24: In a 25 mL reaction flask, intermediate 23 (629 mg, 0.963 mmol), tert-butyl N-(4-hydroxyphenyl)carbamate (222.3 mg, 1.063 mmol), potassium carbonate (K2CO3, 400.5 mg, 2.898 mmol) and DMF (12 mL) were added. The reaction system was carried out under an N2 atmosphere. The reaction mixture was then stirred at room temperature for 12 hours. Purification by C18 column chromatography (ACN / water, containing 0.05% TFA, gradient 0-100%) gave 103.8 mg of off-white solid intermediate 24. MS: 658.32 [M+H] + .

[0170] Intermediate 25: In a 25 mL reaction vial, intermediate 24 (103.8 mg, 0.158 mmol), TFA (0.5 mL), and DCM (2.5 mL) were added. The reaction mixture was then stirred at room temperature for 12 hours. The volatile components were removed under reduced pressure to give 116.2 mg of crude intermediate 25 as an off-white solid. MS: 558.32 [M+H] + .

[0171] Intermediate 26: To a 25 mL reaction vial were added Intermediate 25 (crude product 116.2 mg, 0.158 mmol), Fmoc-Val-Cit-OH (86.3 mg, 0.174 mmol), HATU (66.1 mg, 0.174 mmol), DIEA (81 μL, 0.474 mmol), and DMF (5 mL). The reaction mixture was then stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc, washed sequentially with saturated ammonium chloride solution and saturated brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by C18 column chromatography (ACN / water with 0.05% TFA, gradient 0-100%) to afford 23.1 mg of Intermediate 26 as a white solid. MS: 1036.27 [M+H] + .

[0172] Intermediate 27: In a 10 mL reaction vial, intermediate 26 (23.1 mg, 0.0223 mmol), DEA (0.2 mL) and methanol (MeOH, 1 mL) were added. The reaction mixture was then stirred at room temperature for 12 hours. The volatile components were removed under reduced pressure and dried under high vacuum to give 32.4 mg of intermediate 27 as a white solid. MS: 814.32 [M+H] + .

[0173] Intermediate 28: To a 25 mL reaction vial were added Intermediate 27 (32.4 mg, 0.0233 mmol), Intermediate 16 (40.6 mg, 0.035 mmol), TCFH (17.5 mg, 0.0699 mmol), N-methylimidazole (NMI, 1.91 mg, 0.0233 mmol), and dry ACN (2.5 mL). The reaction was carried out under N2 protection. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, washed sequentially with saturated ammonium chloride solution and saturated brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by C18 column chromatography (ACN / water containing 0.05% TFA, gradient 0-100%) to give 20.6 mg of Intermediate 28 as a white solid. MS: 1958.18 [M+H] + .

[0174] Example 4: To a 25 mL reaction flask, intermediate 37 (20.6 mg, 0.01 mmol), TFA (0.5 mL), and DCM (2.5 mL) were added, and the reaction system was carried out under Ar protection. The reaction mixture was then stirred at room temperature for 12 hours. The volatile components were removed under reduced pressure, and the residue was purified by C18 column chromatography (ACN / water, containing 0.05% TFA, gradient 0-100%) to obtain 14.2 mg of Example 4 as a white solid. MS: 1529.72 [M+H] + . 1H NMR:7.42(d,J=10.1Hz,1H),7.29(t,J=7.4Hz,2H),7.24(t,J=7.3Hz,1H),7.18–7.14(m,2H),6.3 2(dd,J=10.1,1.9Hz,1H),6.13(s,1H),4.94(d,J=15.3Hz,2H),4.48–4.40(m,2H),4.30(d,J=10.5 Hz,1H),4.21(dt,J=13.5,6.3Hz,2H),4.13–4.04(m,4H),3.33(dt,J=14.4,7.3Hz,1H),3.05–2.99 (m,4H),2.99–2.88(m,3H),2.83–2.74(m,1H),2.70(dt,J=12.5,7.6Hz,1H),2.66–2.59(m,1H),2. 42(dt,J=11.5,6.1Hz,2H),2.37(d,J=12.7Hz,1H),2.25(s,1H),2.19(s,1H),2.13(d,J=14.3Hz,3 H),2.02(q,J=12.9,12.3Hz,4H),1.90–1.81(m,5H),1.72(q,J=12.0Hz,2H),1.61(d,J=14.3Hz,1H ),1.45(s,3H),1.39(d,J=12.5Hz,2H),1.36(s,3H),1.31(q,J=11.7,9.7Hz,2H),1.18(d,J=12.6H z,1H),1.10(d,J=6.3Hz,3H),0.87(s,3H),0.77(d,J=7.3Hz,3H),0.66(s,3H),0.62–0.56(m,3H).

[0175] Example 5: Synthesis of the compound of Example 5:

[0176] Intermediate 29: In a 100 mL reaction flask, intermediate 21 (1102.8 mg, 2.67 mmol), tert-butyl (4-formaldehyde phenyl) carbamate (650.8 mg, 2.94 mmol), HClO4 (70%, 1.123 mL, 13.35 mmol), MgSO4 (1.607 g, 13.35 mmol) and ACN (25 mL) were added. The reaction mixture was then stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The crude product was purified by C18 column chromatography (ACN / water, containing 0.05% TFA, gradient 0-100%) to give 528.1 mg of intermediate 29 as a yellow solid. MS: 616.22 [M+H] + .

[0177] Intermediate 30: In a 25 mL reaction vial, intermediate 29 (528.1 mg, 0.86 mmol), TFA (1 mL), and DCM (5 mL) were added. The reaction mixture was then stirred at room temperature for 12 hours. The volatile components were removed under reduced pressure to give 306.1 mg of intermediate 30 as a yellow solid. MS: 516.21 [M+H] + .

[0178] Intermediate 31: To a 50 mL reaction flask were added Intermediate 30 (crude product 306.1 mg, 0.594 mmol), Boc-Ala-Ala-OH (154.5 mg, 0.594 mmol), HATU (248.3 mg, 0.653 mmol), DIEA (204 μL, 1.188 mmol), and DMF (6 mL). The reaction mixture was then stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc, washed sequentially with saturated ammonium chloride solution and saturated brine, and dried over Na2SO4. The crude product was purified by C18 column chromatography (ACN / water with 0.05% TFA, gradient 0-100%) to afford 267.8 mg of Intermediate 31 as a yellow solid. MS: 758.27 [M+H] + .

[0179] Intermediate 32: In a 25 mL reaction vial, intermediate 31 (267.8 mg, 0.353 mmol), TFA (0.5 mL), and DCM (2.5 mL) were added. The reaction mixture was then stirred at room temperature for 12 hours. The volatile components were removed under reduced pressure to give 413.6 mg of intermediate 32 as a yellow solid. MS: 658.21 [M+H] + .

[0180] Intermediate 33: To a 100 mL reaction flask were added Intermediate 32 (crude product 413.6 mg, 0.353 mmol), Boc-glycine (61.9 mg, 0.353 mmol), HATU (147.9 mg, 0.389 mmol), DIEA (121 μL, 0.707 mmol), and DMF (8 mL). The reaction mixture was then stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc, washed sequentially with saturated ammonium chloride solution and saturated brine, and dried over Na2SO4. The crude product was purified by C18 column chromatography (ACN / water with 0.05% TFA, gradient 0-100%) to afford 119.9 mg of Intermediate 33 as a yellow solid. MS: 815.23 [M+H] + .

[0181] Intermediate 34: In a 25 mL reaction vial, intermediate 33 (119.9 mg, 0.147 mmol), TFA (0.5 mL), and DCM (2.5 mL) were added. The reaction mixture was then stirred at room temperature for 12 hours. The volatile components were removed under reduced pressure to give 192.3 mg of intermediate 34 as a yellow solid. MS: 715.21 [M+H] + .

[0182] Intermediate 35: To a 25 mL reaction vial were added Intermediate 16 (147.2 mg, 0.1267 mmol), Intermediate 34 (90.5 mg, 0.1267 mmol), HATU (53.1 mg, 0.1394 mmol), DIEA (65 μL, 0.3801 mmol), and dry DMF (2.5 mL). The reaction mixture was then stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc, washed sequentially with saturated ammonium chloride solution and saturated brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by C18 column chromatography (ACN / water with 0.05% TFA, gradient 0-100%) to afford 124.1 mg of Intermediate 35 as a white solid. MS: 1858.29 [M+H] + .

[0183] Compound of Example 5: Intermediate 35 (124.1 mg, 0.0668 mmol), TFA (0.5 mL), and DCM (2.5 mL) were added to a 25 mL reaction flask. The reaction mixture was then stirred at room temperature for 12 hours. The volatile components were removed under reduced pressure, and the residue was purified by C18 column chromatography (ACN / water containing 0.05% TFA, gradient 0-100%) to give 32.6 mg of Compound of Example 5 as a white solid. MS: 1557.77 [M+H] + , 1H NMR:7.41(d,J=4.2Hz,1H),7.36(d,J=10.1Hz,1H),7.27(d,J=6.4Hz,1H),7. 21(s,4H),7.15(s,0H),7.08(s,1H),6.73(d,J=8.3Hz,1H),6.35(d,J=20.8H z,2H),5.59(s,0H),5.55(s,0H),5.50(s,1H),5.04(s,0H),4.46(t,J=13.2H z,1H),4.38–4.22(m,4H),4.20(d,J=19.7Hz,2H),4.11(s,3H),3.81(d,J=17. 9Hz,1H),3.65–3.60(m,0H),3.50–3.43(m,0H),3.29(s,0H),3.00(s,6H),2. 69(s,3H),2.48(d,J=30.8Hz,3H),2.36(s,0H),2.14(s,4H),1.90(s,0H),1. 76(s,3H),1.46(s,2H),1.42–1.35(m,1H),1.31(d,J=7.2Hz,3H),1.09(d,J= 6.6Hz, 2H), 0.85 (d, J = 5.0Hz, 2H), 0.66 (d, J = 17.9Hz, 3H), 0.60–0.53 (m, 2H).

[0184] Example 6: Synthesis of the compound of Example 6: Intermediate 36: To a round-bottom flask were added tert-butyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (4.47 g, 14 mmol), 4-bromomethylbenzaldehyde (4.17 g, 21.2 mmol), potassium carbonate (9.7 g, 70 mmol), and PdCl(dppf)·DCM (0.40 g, 4.9 mmol). Anhydrous THF (90 mL) was added to the flask, which was then fitted with a reflux condenser and heated to 85°C for 16 hours. 9 mL of H2O was then added, and stirring continued for 18 hours. The reaction mixture was cooled, diluted with water (200 mL), transferred to a separatory funnel, and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with saturated brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (gradient elution, 0-80% EA-PE) to give 3.2 g of the title compound as a clear oil which crystallized upon standing overnight. 1HNMR(400MHz, CDCl3):9.97(s,1H),7.80(d,J=5.2Hz,2H),7.35(d,J=5.2Hz,2H),7.28(br s,1H),7.18-7.23(m,2H),6.85(d,J=4.8Hz,1H),6.47(brs,1H),4.02(s,2H),1.50(s,9H). Compound of Example 6: In a round-bottom flask, 16-α-hydroxyprednisolone (2.02 g, 5.38 mmol), intermediate 36 (3.02 g, 9.68 mmol), and MgSO4 (1.98 g, 16.4 mmol) were added. The mixture was suspended in acetonitrile (80 mL) and cooled to 0°C. Trifluoromethanesulfonic acid (2.35 mL, 26.8 mmol) was then added dropwise and stirred for 1 hour. The mixture was poured into 100 mL of aqueous sodium bicarbonate solution and extracted with EtOAc (100 mL x 1, 50 mL x 2). The combined organic layers were washed with saturated brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography using EtOAc / petroleum ether = 0-100% to give 5.7 g of an off-white solid. 1.06 g of the crude product was further purified by reverse phase C18 column chromatography (CH3CN / water = 0-65%, containing 0.1% TFA) to obtain 340 mg of the target compound as a white powder. MS: 570.25 [M+H] + . The following compounds were prepared using the method described in Example 6.

[0185] Example 14: Synthesis of the compound of Example 14: Intermediate 37: To a solution of dexamethasone (200 mg, 0.510 mmol) in ethyl acetate were added tert-butyl (4-chlorosulfonyl)carbamate (223 mg, 0.765 mmol) and triphenylphosphine (601 mg, 62.5 mmol). The mixture was heated to 50°C and stirred for 1 hour. DIPEA (10.0 g, 2.295 mmol) was then added and stirring continued at 50°C for 1 hour. The reaction was quenched with water and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The product was purified by column chromatography to yield 283.2 mg of the target compound as a yellow solid. MS: 600.35 [M+H] + . Compound of Example 14: To a solution of Intermediate 37 (52 mg, 0.087 mmol) in DCM (1 mL) was added TFA (0.3 mL). The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated to afford 41.2 mg of the title compound as a white powder. MS: 500.02 [M+H] + . The following compounds were prepared using the method described in Example 3. The following compounds were prepared using the method described in Example 4.

[0186] Example 21: Synthesis of the compound of Example 21:

[0187] Intermediate 38: At 0°C and N2 protection, to a THF (2.00 mL) solution of PMBH(Boc)3 (100 mg, 0.094 mmol) was added 3-mercaptopropionic acid (13.0 mg, 0.120 mmol), DIEA (51.1 mg, 0.360 mmol), HOBt (19.0 mg, 0.140 mmol) and EDCI (27.0 mg, 0.140 mmol) in sequence. Subsequently, the mixture was stirred at 25°C for 12 hours. The residue was purified by preparative thin layer chromatography (prep-TLC, EA) to give 50 mg of intermediate 38 as a white solid.

[0188] Intermediate 39: To a solution of Intermediate 38 (110 mg, 0.096 mmol) in DCM (2.00 mL) was added TFA (0.400 mL) and stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to give 130 mg of crude Intermediate 39 as a yellow solid. MS: 850.7 [M+H] + .

[0189] Intermediate 40: To a solution of Fmoc-Gly-Gly-OH (50.0 g, 141 mmol) in dioxane (500 mL) was added HOSu (20.0 g, 169 mmol) and DCC (35.0 g, 169 mmol) at 25°C and stirred for 12 hours. Water (300 mL) was then added, followed by L-phenylalanine (23.0 g, 141 mmol) and NaHCO₃ (15.0 g, 183 mmol) at 25°C, and stirring was continued for 4 hours. The reaction mixture was concentrated under reduced pressure to remove the dioxane. The residue was washed with ethyl acetate (100 mL x 3), and the aqueous phase was acidified to pH = 4 with 2M HCl and extracted with DCM (200 mL x 3). The combined organic layers were washed with saturated brine, dried over Na₂SO₄, and concentrated to give 53 g of crude Intermediate 40 as a pale yellow oil. MS: 502.2 [M+H] + .

[0190] Intermediate 41: Intermediate 40 (52.0 g, 104 mmol) was dissolved in THF (500 mL), followed by the addition of HOSu (12.0 g, 104 mmol) and DCC (21 g, 104 mmol) at 25°C and stirring for 12 hours. H2O (300 mL) was then added, followed by the addition of 2-[(2-aminoacetyl)amino]acetic acid (14.0 g, 104 mmol) and NaHCO3 (10.0 g, 114 mmol) at 25°C, and stirring continued for 12 hours. The reaction mixture was concentrated under reduced pressure to remove THF. The residue was purified by HPLC (column: Phenomenex Luna C18, 250×70 mm, 15 μm; elution gradient: 0.2% formic acid in water (eluent A) to 0.2% formic acid in acetonitrile (eluent B), 30% to 60%) to afford 20 g of Intermediate 41 as a white solid. MS:616.3[M+H] + .

[0191] Intermediate 42: To a solution of intermediate 41 (10.0 g, 16.0 mmol) in AcOH (20.0 mL) and DMF (160 mL) was added lead tetraacetate (17.0 g, 16 mmol) at 25°C under N2 protection. The mixture was then stirred at 50°C for 5 hours. The reaction mixture was concentrated under reduced pressure to remove DMF and AcOH. The reaction residue was poured into EtOAc. The reaction mixture was filtered, the filter cake was washed with EtOAc (100 mL), and the filtrate was concentrated under vacuum to give 5.7 g of intermediate 42 as a white solid.

[0192] Intermediate 43: To a solution of intermediate 42 (6.00 g, 9.50 mmol) in DCM (600 mL) was added dexamethasone (5.60 g, 14.0 mmol) and TFA (3.60 mL, 48.0 mmol) at 25°C. Subsequently, the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove DCM and TFA. The crude product was purified by flash column chromatography (gradient elution, DCM / MeOH from 50 / 1 to 10 / 1) to give 4.4 g of intermediate 43 as a white solid.

[0193] Intermediate 44: To a solution of Intermediate 43 (4.40 g, 4.60 mmol) in DCM (30.0 mL) was added diethylamine (15.0 mL) at 25°C. The mixture was then stirred at 25°C for 12 hours. The reaction mixture was concentrated under vacuum. The residue was purified by HPLC (column: Welch Xtimate C18, 250×100 mm, particle size 10 μm; mobile phase: [A: water (containing 10 mM NH4HCO3); B: ACN]; B%: 25%-55%, 18.00 min) to give 400 mg of Intermediate 44 as a white solid. MS: 740.4 [M+H] + .

[0194] Intermediate 45: To a solution of Intermediate 44 (250 mg, 0.270 mmol) in DMF (3.00 mL) was added 1-{3-[(2,5-dioxotetrahydro-1H-pyrrol-1-yl)oxy]-3-oxopropyl}pyrrole-2,5-dione (72.0 mg, 0.270 mmol) and DIEA (105 mg, 0.810 mmol) at 25°C, and the mixture was stirred for 12 hours. The residual mixture was purified by HPLC (column: Phenomenex Luna C18, 100 × 40 mm × 3 μm; mobile phase: [A: water (containing 0.2% FA); B: ACN]; B%: 30.00%-60.00%, 8.00 min) to give 120 mg of Intermediate 45 as a white solid. MS: 891.3 [M+H] + .

[0195] Compound of Example 21: To a solution of Intermediate 39 (70.0 mg, 0.073 mmol) in H2O (1.50 mL) and ACN (1.50 mL) was added Intermediate 45 (26.0 mg, 0.029 mmol) and NaHCO3 (18.0 mg, 0.22 mmol) at 0°C and stirred for 2 hours. The residue was purified by HPLC (column: Phenomenex Luna C18, 75×30 mm×3 μm; elution gradient: 0.2% formic acid in water (eluent A) to 0.2% formic acid in acetonitrile (eluent B), 30%-60%) to afford 32 mg of Compound of Example 21 as a white solid. MS: 871.3 [M+2H] + / 2.1H NMR (400MHz, MeOD): 8.63-8.43 (m, 2H), 7.41-7.18 (m, 11H), 6.24 (dd, J = 10. 1,1.8Hz,1H),6.08(s,1H),4.77(d,J=10.6Hz,2H),4.73-4.66(m,2H),4.63( d,J=1.4Hz,1H),4.60-4.51(m,2H),4.40-4.32(m,3H),4.31-4.24(m,2H),4. 23-4.18(m,1H),4.15-4.05(m,2H),4.02-3.98(m,1H),3.95-3.74(m,8H),3. 70(dd,J=14.1,6.8Hz,1H),3.26-3.21(m,1H),3.20-2.87(m,14H),2.78-2.3 5(m,9H),2.31-2.19(m,2H),2.16-2.07(m,3H),2.00-1.84(m,4H),1.80-1.6 4(m,1H),1.62-1.55(m,4H),1.54-1.44(m,2H),1.34-1.25(m,1H),1.24-1.1 2(m,4H),1.01(s,3H),0.86(d,J=7.3Hz,3H),0.71(brs,3H),0.65(brs,3H).

[0196] Example 22: Synthesis of the compound of Example 22:

[0197] Intermediate 46: To a solution of Intermediate 17 (1 g, mmol) and imidazole (683.8 mg, 10.05 mmol) in DCM (25 mL) was added TBDMSCl (904 mg, 6.03 mmol) at 0°C, followed by stirring at room temperature for 2 hours. The reaction mixture was washed with water (15 mL) and saturated brine (15 mL), dried over Na2SO4, filtered, and concentrated to afford Intermediate 46.

[0198] Intermediate 47: To a solution of Boc-Gly-Gly-Phe-Gly-OH (100 mg, 0.229 mmol), HATU (96 mg, 0.252 mmol) and DIPEA (89 mg, 0.688 mmol) in DMF (2 mL) was added Intermediate 46 (140 mg, 0.229 mmol). The resulting mixture was stirred at room temperature overnight, then quenched with H2O and extracted with EtOAc. The organic layer was washed with saturated brine, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase HPLC to give 120 mg of Intermediate 47 as a colorless oil. MS: 1030.20 [M+H] + .

[0199] Intermediate 48: To a solution of Intermediate 47 (120 mg, 0.117 mmol) in DCM (1 mL) was added TFA (0.45 mL) The resulting mixture was stirred at room temperature for 2 hours, and then the reaction mixture was concentrated to give the crude Intermediate 48 as a white powder (110 mg).

[0200] Intermediate 49: Intermediate 48 (80 mg, 0.098 mmol) was added to a DMF (2 mL) solution containing Intermediate 16 (114 mg, 0.098 mmol), HATU (41 mg, 0.108 mmol) and DIPEA (38 mg, 0.294 mmol). The resulting mixture was stirred at room temperature overnight. Subsequently, the reaction mixture was quenched with H2O and extracted with EtOAc. The organic layer was washed with saturated brine, dried over Na2SO4, filtered and evaporated. The residue was purified by reverse phase HPLC to give Intermediate 49 (80 mg) as a white solid. MS: 1960.24 [M+H] + . Compound of Example 22: To a solution of Intermediate 49 (80 mg, 0.041 mmol) in DCM (1.3 mL) was added TFA (0.5 mL) at room temperature. The mixture was stirred at room temperature for 2 hours and then concentrated. The crude product was dissolved in water and then freeze-dried to afford Compound of Example 22 (75.7 mg) as a white powder. MS: 1660.85 [M+H] + .1 H NMR(400MHz,DMSO-d6):10.04(s,1H),8.78-8.82(m,1H),8.45(s,1H),8.07- 8.34(m,1H),8.19(m,77.59-7.83(m,12H),7.18-7.38(m,14H),6.22(dd,J=10 .0Hz,2.0Hz,1H),6.03(s,1H),5.42-5.47(m,2H),4.93(d,J=4.4Hz,1H),3.5 8-4.54(m,31H),2.66-3.18(m,13H),1.67-2.38(m,23H),0.74-1.50(m,28H).

[0201] Example 23: Synthesis of the compound of Example 23:

[0202] Intermediate 50: The compound of Example 7 (100 mg, 0.165 mmol) was added to a DMF (2 mL) solution containing Boc-Ala-Ala-OH (43 mg, 0.165 mmol), HATU (69 mg, 0.182 mmol) and DIPEA (64 mg, 0.496 mmol). The resulting mixture was stirred at room temperature overnight. Subsequently, the reaction mixture was quenched with H2O and extracted with EtOAc. The organic layer was washed with saturated brine, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase C18 column (gradient of 0.05% TFA in ACN-water from 0 to 100%) to give Intermediate 50 (76 mg) as a white powder. MS: 848.12 [M+H] + .

[0203] Intermediate 51. To a solution of Intermediate 50 (76 mg, 0.079 mmol) in DCM (1.0 mL) was added TFA (0.3 mL). The resulting mixture was stirred at room temperature for 2 hours, and then the reaction mixture was concentrated under reduced pressure to give Intermediate 51 (65 mg) as a white powder. MS: 748.28 [M+H] + .

[0204] Intermediate 52: Intermediate 51 (65 mg, 0.087 mmol) was added to a DMF (2 mL) solution containing intermediate 16 (100 mg, 0.087 mmol), HATU (34 mg, 0.096 mmol) and DIPEA (33 mg, 0.261 mmol). The resulting mixture was stirred at room temperature overnight. Subsequently, the reaction mixture was quenched with H2O and extracted with EtOAc. The organic layer was washed with saturated brine, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase C18 column (ACN-water gradient ratio from 0 to 100%, containing 0.05% TFA) to give intermediate 52 (66 mg) as a white powder. MS: 1891.12 [M+H] + . Compound of Example 23: To a solution of Intermediate 52 (66 mg, 0.035 mmol) in DCM (1.0 mL) was added TFA (0.3 mL) at room temperature. The mixture was stirred at room temperature for 2 hours and then concentrated. The residue was dissolved in water and freeze-dried to afford Compound of Example 23 (53 mg) as a white powder. MS: 1591.97 [M+H] + . 1 H NMR(400MHz, DMSO-d6):9.81(d,J=1.6Hz,1H),8.77-8.81(m,1H),8.07-8.34(m,7H),7.71-7 .94(m,14H),7.19-7.50(m,15H),6.90-6.98(m,1H),6.29(dd,J=6.4Hz,1.2Hz,1H),6.13(s, 1H),5.32-5.70(m,4H),4.94(d,J=3.6Hz,1H),3.88-4.52(m,35H),2..80-3.16(m,10H),1.5 7-2.38(m,24H),1.50(s,3H),1.18-1.27(m,13H),1.04(d,J=3.6Hz,3H),0.71-0.91(m,12H).

[0205] Example 24: Synthesis of the compound of Example 24:

[0206] Intermediate 53. To a solution of the compound of Example 6 (175 mg, 0.31 mmol) and Fmoc-Asp(OBu-t)-OH (152 mg, 0.37 mmol) in DMF (10.0 mL) was added HATU (175 mg, 0.46 mmol) and 2,6-lutidine (99 mg, 0.92 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours. Subsequently, the reaction mixture was diluted with EA (30 mL), washed with water (3×15 mL) and saturated brine (15 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by reverse phase HPLC (ACN-water gradient from 0 to 100% with 0.1% TFA) to give Intermediate 53 (236 mg) as a white solid. MS: 963.42 [M+H] + .

[0207] Intermediate 54: To a solution of Intermediate 53 (270 mg, 0.2804 mmol) in MeOH (10.0 mL) was added DEA (2 mL) at room temperature. The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by reverse phase C18 column (gradient elution with CH3CN in water (containing 0.1% TFA) from 0% to 100%) to give Intermediate 54 (53 mg) as a white solid. MS: 741.41 [M+H] + .

[0208] Intermediate 55: L-Valine benzyl ester hydrochloride (200 mg, 0.821 mmol) and Fmoc-Glu(OtBu)-OH (384 mg, 0.903 mmol) were dissolved in DMF (6.0 mL), followed by the addition of HATU (467 mg, 1.231 mmol) and DIEA (317 mg, 2.462 mmol) at room temperature. The mixture was stirred at room temperature for 4 hours. After completion of the reaction, the mixture was diluted with EA (20 mL), washed with water (2×15 mL) and saturated brine (15 mL), dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by reverse phase HPLC (ACN-water gradient from 0 to 100% with 0.1% TFA) to afford Intermediate 55 (470 mg) as a white solid. MS: 615.20 [M+H] + .

[0209] Intermediate 56: To a solution of Intermediate 55 (470 mg, 0.7646 mmol) in MeOH (15.0 mL) was added DEA (3 mL) at room temperature. The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by reverse phase C18 column (ACN-water gradient from 0 to 100%, containing 0.1% TFA) to give Intermediate 56 (265 mg) as a pale yellow solid. MS: 393.36 [M+H] + .

[0210] Intermediate 57: To a solution of Intermediate 56 (265 mg, 0.6752 mmol) and Fmoc-Asp(OBu-t)-OH (305 mg, 0.7427 mmol) in DMF (5.0 mL) was added HATU (384 mg, 1.0127 mmol) and DIEA (261 mg, 2.0255 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours. Subsequently, the reaction mixture was diluted with EA (30 mL), washed with water (2×15 mL) and saturated brine (15 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by C₁₈ column (ACN-water gradient from 0 to 100% with 0.1% TFA) to afford Intermediate 57 (350 mg) as a white solid. MS: 786.33 [M+H] + .

[0211] Intermediate 58: To a solution of Intermediate 57 (350 mg, 0.4453 mmol) in MeOH (15.0 mL) was added DEA (3 mL) at room temperature. The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by C18 column (ACN-water gradient from 0 to 100%, containing 0.1% TFA) to give Intermediate 58 (222 mg) as a pale yellow solid. MS: 564.80 [M+H] + .

[0212] Intermediate 59: To a solution of Intermediate 58 (222 mg, 0.39 mmol) and Fmoc-glycine (129 mg, 0.43 mmol) in DMF (5.0 mL) was added HATU (224 mg, 0.59 mmol) and DIEA (152 mg, 1.18 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. Subsequently, the reaction mixture was diluted with EA (30 mL), washed with water (2×15 mL) and saturated brine (15 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by C₁₈ column (ACN-water gradient from 0 to 100% with 0.1% TFA) to afford Intermediate 59 (217 mg) as a white solid. MS: 843.22 [M+H]+ .

[0213] Intermediate 60: To a solution of Intermediate 59 (217 mg, 0.2574 mmol) in MeOH (10.0 mL) was added DEA (2 mL) at room temperature. The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by C18 column (ACN-water gradient from 0 to 100%, containing 0.1% TFA) to give Intermediate 60 (92 mg) as a white solid. MS: 621.38 [M+H] + .

[0214] Intermediate 61: To a solution of Intermediate 16 (48 mg, 0.0413 mmol) in DMF (2.0 mL) was added HATU (23 mg, 0.0620 mmol), DIEA (16 mg, 0.1239 mmol) and Intermediate 60 (25 mg, 0.0413 mmol) at room temperature. The mixture was stirred at room temperature for 4 hours. Subsequently, the reaction mixture was diluted with EA (15 mL), washed with water (2×10 mL) and saturated brine (10 mL), dried over Na₂SO₄, filtered and concentrated. The residue was purified by C18 column (ACN-water gradient from 0 to 100% with 0.1% TFA) to give Intermediate 61 (38 mg) as a white solid. MS: 1765.71 [M+H] + .

[0215] Intermediate 62: To a solution of Intermediate 61 (38 mg, 0.0215 mmol) in MeOH (4 mL) was added 10% Pd / C (6 mg) at room temperature. The mixture was stirred under an H2 atmosphere for 4 hours. Subsequently, the reaction mixture was filtered and concentrated. The residue was purified by C18 column (ACN-water gradient from 0 to 100%, containing 0.1% TFA) to give the crude product of Intermediate 62 as a white solid (35 mg). MS: 1675.54 [M+H] + .

[0216] Intermediate 63: To a solution of Intermediate 62 (35 mg, 0.022 mmol) in DMF (2.0 mL) was added HATU (12 mg, 0.032 mmol), DIEA (8 mg, 0.066 mmol) and Intermediate 54 (17 mg, 0.024 mmol) at room temperature. The mixture was stirred at room temperature for 4 hours. Subsequently, the reaction mixture was diluted with EA (15 mL), washed with water (2×8 mL) and saturated brine (8 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by C18 column (ACN-water gradient from 0 to 100% with 0.1% TFA) to give Intermediate 63 (25 mg) as a white solid. MS: 1199.31 [M+2H] + / 2. Compound of Example 24: To a solution of intermediate 63 (25 mg, 0.0104 mmol) in DCM (2.5 mL) was added TFA (0.5 mL) at room temperature. The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was purified by C18 column (ACN-water gradient from 0 to 100% with 0.1% TFA) to afford the compound of Example 24 (6.7 mg) as a white solid. MS:1929.70.1HNMR(600MHz,DMSO):12.22(s,3H),9.84(s,1H),8.78(s,1H),8.32-8.23(m,5H),8.11(m,2 H),8.02(d,J=7.6Hz,2H),7.79-7.62(m,11H),7.44-7.41(m,2H),7.38(d,J=7.9Hz,2H),7.32-7.19(m,12H ),6.89(d,J=7.6Hz,1H),6.16(d,J=10.2Hz,1H),5.93(s,1H),5.39(s,1H),5.09(s,1H),4.92(d,J=5.4Hz ,1H),4.86(s,1H),4.78(d,J=3.5Hz,1H),4.67-4.58(m,2H),4.51-4.48(m,2H),4.40(d,J=7.2Hz,1H),4.2 8-4.13(m,9H),3.97(d,J=7.5Hz,2H),3.88(s,2H),3.71(s,2H),3.16(s,1H),2.98-2.95(m,2H),2.85-2. 80(m,4H),2.77-2.71(m,2H),2.67(s,1H)2.57-2.54(m,2H),2.39(s,4H),2.31(d,J=11.3Hz,1H),2.00(s, 1H),1.92(s,5H),1.80-1.70(m,8H),1.75-1.66(m,2H),1.43(d,J=9.4Hz,1H),1.39(s,3H),1.38-1.32(m ,1H),1.20(s,1H),1.07-0.99(m,5H),0.87(d,J=14.8Hz,3H),0.84-0.78(m,10H),0.74(dd,J=6.6Hz,4H).

[0217] Example 25: Synthesis of the compound of Example 25:

[0218] Intermediate 64: The compound of Example 6 (300 mg, 0.53 mmol), Fmoc-L-glutamic acid 5-tert-butyl ester (255 mg, 0.60 mmol), HATU (285 mg, 0.75 mmol), and 2,6-lutidine (144 μL, 1.23 mmol) were dissolved in DMF (4.5 mL), and the mixture was stirred at room temperature for 16 hours. Subsequently, the mixture was extracted with EA (3 times), and the combined organic layers were washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (EA-PE 0-90% gradient) to give Intermediate 64 (372 mg) as a white powder. MS: 977.47 [M+H] + .

[0219] Intermediate 65: DEA (400 μL) was added to a solution of intermediate 64 (315 mg, 0.32 mmol) in ACN (4 mL) and stirred at room temperature for 2 hours. The mixture was then concentrated and the residue was purified by flash column chromatography (MeOH in DCM gradient 0-10%) to give intermediate 65 (89 mg) as a white powder. MS: 755.61 [M+H] + .

[0220] Intermediate 66: PMBH(Boc)3 (850 mg, 0.80 mmol), Fmoc-L-glutamic acid 5-tert-butyl ester (408 mg, 0.96 mmol), HATU (459 mg, 1.21 mmol) and lutidine (221 μL, 1.87 mmol) were dissolved in DMF (9 mL), and the mixture was stirred at room temperature overnight. The mixture was then diluted with EtOAc, and the organic layer was washed three times with saturated brine and concentrated. The residue was purified by reverse phase HPLC (ACN-water gradient from 0 to 100%, containing 0.1% TFA) to give Intermediate 66 (843 mg) as a white powder. MS: 1469.38 [M+H] + .

[0221] Intermediate 67: Intermediate 66 (843 mg, 0.57 mmol) was dissolved in MeOH (9 mL) and DEA (900 μL) was added and stirred at room temperature for 6 hours. The mixture was then concentrated. The residue was purified by column chromatography (MeOH in DCM gradient 0-15%) to give Intermediate 67 (521 mg) as a white powder. MS: 1248.99 [M+H] + .

[0222] Intermediate 68: To a solution of Intermediate 67 (521 mg, 0.42 mmol) in ACN (6 mL) and H2O (3 mL) was added succinic anhydride (114 mg, 1.14 mmol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was then concentrated. The residue was purified by reverse phase HPLC (ACN-water gradient from 30 to 100%, containing 0.1% TFA) to give Intermediate 68 (461 mg) as a white powder. MS: 1346.11 [M+H] + .

[0223] Intermediate 69: Intermediate 68 (461 mg, 0.34 mmol), benzoylglycine hydrochloride (55 mg, 0.33 mmol), HATU (168 mg, 0.44 mmol) and 2,6-lutidine (81 μL, 0.69 mmol) were dissolved in DMF (5.5 mL), and the mixture was stirred at room temperature overnight. Subsequently, the mixture was diluted with EtOAc, washed with saturated brine (3 times), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (ACN-water gradient ratio from 0 to 100%) to give Intermediate 69 (295.8 mg) as a white powder. MS: 1495.16 [M+H] + .

[0224] Intermediate 70. To a solution of Intermediate 69 (295 mg, 0.20 mmol) in MeOH (5 mL) was added 10% Pd / C (29 mg), and the mixture was stirred at room temperature under a H2 atmosphere for 2 hours. Subsequently, the mixture was filtered through Celite, and the filtrate was evaporated under vacuum to give the crude product of Intermediate 70 (272 mg) as a white solid, which was used directly in the next reaction. MS: 1403.22 [M+H].

[0225] Intermediate 71: Intermediate 70 (198 mg, 0.14 mmol), Intermediate 65 (89 mg, 0.12 mmol), HATU (68 mg, 0.18 mmol) and 2,5-lutidine (33 μL, 0.11 mmol) were dissolved in DMF (3 mL), and the mixture was stirred at room temperature for 6 hours. Subsequently, the mixture was diluted with EA, washed three times with saturated brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (0-10% MeOH / DCM) to give Intermediate 71 (58 mg) as a white powder. MS: 1071.06 [M+H] + . Compound of Example 25: Intermediate 71 (58 mg, 0.027 mmol) was dissolved in DCM (2.5 mL) and TFA (625 μL) was added and stirred at room temperature for 1 hour. The mixture was then concentrated. The residue was purified by flash column chromatography (0-50% acetonitrile / water with 0.1% TFA) to provide the compound of Example 25 (14 mg) as a white powder. MS: 1729.88 [M+H] + .

[0226] Example 26: Synthesis of the compound of Example 26: Compound of Example 26: The synthesis method of the compound of Example 26 is similar to that of the compound of Example 21, and is carried out according to the above route. MS: 1690.57 [M+H] + .

[0227] Example 27: Synthesis of the compound of Example 27: Compound of Example 27: The synthesis method of the compound of Example 27 is similar to that of the compound of Example 21, and is carried out according to the above route. MS: 1630.64 [M+H] + .

[0228] Example 28: Synthesis of the compound of Example 28: Compound of Example 28: The synthesis method of the compound of Example 28 is similar to that of the compound of Example 21, and is carried out according to the above route. MS: 1557.78 [M+H] + . Utility and testing

[0229] The compounds provided herein show strong in vivo efficacy against a variety of inflammatory-related kidney diseases, including CKD and AKI, postoperative inflammation (such as in kidney transplant surgery), or inflammation induced by anticancer or antibacterial therapy or in the treatment of diabetes, or inflammation caused by exposure to nephrotoxic substances in the environment. Therefore, these agents can be used to treat such kidney diseases.

[0230] The in vitro activity of the compounds provided herein can be assessed by using standard bioassay testing procedures for assessing binding (conjugation) to the active entities (payloads) in the combinations provided herein. The choice of a specific assessment is determined based on the known or expected mode of action of the payload structure. For example, a conjugate conjugated to an anti-inflammatory vanin-1 inhibitor can be tested in a human vanin-1 enzyme assay, such as disclosed in PCT WO 20040504. As described in 2020 / 114943.

[0231] The preferential renal targeting of the compounds provided herein to the kidney (or at sites of renal injury) can be assessed by pharmacokinetic (PK) testing, for example, in standard rodent PK testing. PK data are often used to establish key parameters for predicting therapeutic outcomes. Thus, the drug concentration (C) at a given time point, the drug concentration in the target tissue (C) Target ), monitoring the area under the curve (AUC) of a plot of systemic drug concentration over time, and other parameters can often predict treatment efficacy. For example, drug concentrations in organs affected by cancer are important for the effective action of anticancer agents (e.g., as described by Zhang et al. in Drug Metabolism and Disposition. 2019, vol. 47, p. 1122).

[0232] Representative compounds provided herein were tested in an intravenously administered rodent PK model using methods similar to those described in the monograph Current Protocols in Pharmacology, 2005, 7.1.1-7.1.26, John Wiley & Sons, Inc. Illustrative mouse PK data for the compounds of Examples 3, 5, and 15 are summarized below in Table 1. As is clear from these data, these compounds exhibit a surprising ability to target the kidney, as evidenced by the high levels of preferential concentrations in renal tissue, the organ of interest for therapeutic targeting. Table 1: Effect of exemplary compounds of the invention on enhancing the delivery of anti-inflammatory and immunomodulatory agents (drug levels in the kidney at T = 0.5 h). a The drug was administered by injection into the tail vein of mice. b The dose is 1 mg / kg, expressed as μmol / kg with a molecular weight (MW) of 392 Daltons. c For the compound of Example 3, the dose was 4 mg / kg, expressed as μmol / kg based on a molecular weight of 1,939 Daltons (3TFA). d For the compound of Example 5, the dose was 4 mg / kg, expressed as μmol / kg based on a molecular weight of 1,900 Daltons (3TFA). e For the compound of Example 15, the dose was 2.5 mg / kg, expressed as μmol / kg based on a molecular weight of 2,012 Daltons (3TFA).

[0233] The in vivo efficacy was evaluated in a lipopolysaccharide (LPS) mouse model, as described by Chen et al. in PLoS One 2015, 10(7), e013465. A brief introduction is as follows: Male ICR mice weighing 23-25 g were selected and randomly divided into groups of 10 mice. They were fasted for 12 hours before the test, but had free access to water. Each group of mice was given the test drug and solvent by intravenous injection. One hour later, the mice were intraperitoneally injected with 15 mg / kg of LPS. After 18 hours, blood was collected from each group of mice, and after standing for 3 hours, serum was separated by centrifugation at 10,000 rpm for 3 minutes. Serum creatinine (CREA) was determined using the standard procedure of a biochemical analyzer. The results shown in Table 2 show that the compounds of the present invention can significantly reduce the serum creatinine level induced by LPS. This indicates that the compounds of the present invention can significantly reduce the level of renal inflammation (damage) induced by LPS toxin. Table 2: Serum creatinine test results in the LPS mouse model. a At the time of administration, the dose of dexamethasone was 2.5 mg / kg (6.4 μmol / kg), which is approximately 5 times the active glucocorticoid dose in the compound of Example 3 (dose of 2.5 mg / kg or 1.3 μmol / kg), the compound of Example 15 (2.5 mg / kg or 1.2 μmol / kg), and the compound of Example 26 (2.5 mg / kg or 1.3 μmol / kg). In a separate test of the compound of Example 26, the creatinine (CREA) data of dexamethasone (2.5 mg / kg) were 45.6 ± 19.3.

[0234] It is noteworthy that the active glucocorticoid receptor agonist in the compounds of Examples 3, 5 and 15, administered in the novel conjugated form, has drug levels in the kidney (measured as concentrations in renal tissue) that are approximately 5-6 times higher than the dexamethasone renal levels achieved by injecting the (unconjugated) drug form of dexamethasone. Since the level of a drug at the site of disease impact directly affects the therapeutic effect (in vivo activity) of the drug, the data shown in Table 1 indicate that the novel combination provided by the present invention has significantly enhanced in vivo therapeutic potential.

[0235] The data shown in Table 1 demonstrate that less frequent dosing of this agent is feasible compared to standard dosing of dexamethasone. Based on this data, the compounds of Examples 3 and 5 can be administered much less frequently, for example, once daily, once weekly, etc. This advantage greatly benefits patients in need of such treatment. Furthermore, this useful feature provides significant pharmaceutical economic benefits by reducing the number of medical procedures required in hospitals providing treatment.

[0236] The data in Table 2 show that dexamethasone plays a renal protective effect in a dose-dependent manner, which is consistent with the expected effect of the drug. Surprisingly, at a much lower molar amount than dexamethasone, the compound of Example 3, Example 15 and Example 26 significantly reduces the renal injury induced by lipopolysaccharide (LPS), and this result is determined by using serum creatinine (CREA) biomarker experiments (reported as acute kidney injury in the literature, the key parameter of AKI performance). In terms of the active glucocorticoid of equivalent dose, the compound of Example 3, Example 15 and Example 26 is surprisingly better than the dexamethasone control group. This is consistent with the drug exposure in the kidney enhanced in the pharmacokinetic study results of exemplary compounds of the present invention, including AUC and active residence time.

[0237] The in vivo activity of the compounds provided herein can also be evaluated by similar test procedures, for example, the method described by Chen et al. in Inflammopharmacology, 201826, pp.1331-1338 for evaluating the anti-inflammatory and immunomodulatory effects of corticosteroid drugs; or in rodent models of non-diabetic and diabetic chronic kidney disease described in Perico et al. Kidney International, 2005, vol.68, Supplement 98, pp.S21-S24 and Remuzzi et al. Kidney International, 2002, vol.62, pp.885-894, as well as other test methods in the references cited therein.

[0238] Surprisingly, certain compounds provided herein, when tested in rodent models of kidney inflammation and kidney disease, were administered by intravenous injection at a dose (molar amount) equal to the standard therapeutic dose (molar amount) of dexamethasone or other corticosteroids, or nonsteroidal anti-inflammatory drugs (e.g., naproxen, or Vasin-1 inhibitors), and exhibited a therapeutic effect that was 2-fold or higher than the standard therapeutic dose of such drugs. The therapeutic effect was determined to be slowing, stopping, or reversing the progression of kidney inflammation or kidney disease (including, for example, nephropathy or acute kidney injury caused by chemicals or cytotoxic drugs (e.g., anticancer chemotherapy drugs), or in transplant surgery).

[0239] Surprisingly, despite their high efficacy in mammals, the compounds provided herein exhibit little or no toxicity to normal kidney cells, both in vitro (e.g., in human kidney cell HK-2 assays) and in vivo mammalian models, such as rodent models.

[0240] The safety profile of the compounds of the present invention can be further established by detecting biomarkers that predict nephrotoxicity. Such detection methods (including NGAL detection) have been described, for example, by Keirstead et al. Toxicol.Sci. Relevant description is given in 2014, vol. 137, pp. 278-291.

[0241] Surprisingly, certain compounds provided herein, when administered to a mammal at a standard therapeutic dose (expressed on a molar basis) equivalent to that of dexamethasone or other corticosteroids, or non-steroidal anti-inflammatory drugs (e.g., naproxen, or Vasin-1 inhibitors), exhibit at least a 2-fold reduction in the incidence (frequency or rate) of adverse reactions and / or manifestations of non-target toxicity (e.g., bone marrow suppression or bone marrow toxicity), as determined, for example, by platelet counts and other blood cell counts, compared to a standard therapeutic dose of axitinib, brivanib, pazopanib, or sunitinib.

[0242] Therefore, certain compounds of the present application show highly effective therapeutic effects in treating kidney diseases associated with inflammation, but will not limit the standard treatment of such diseases due to excessive non-target toxicity.

[0243] Therefore, the novel compounds and combinations provided herein are expected to provide a long-awaited, safer and more effective targeted treatment option for kidney disease and kidney injury (including CKD, AKI and other kidney injuries encountered in kidney transplantation). Administration and drug formulation

[0244] Typically, the compound provided herein can be administered in a therapeutically effective amount by any acceptable mode of administration of a reagent for similar purposes. For example, the compound provided herein can be administered orally, parenterally, transdermally, topically, rectally or intranasally, or by intratumoral administration. The actual amount of the compound provided herein (i.e., active ingredient) will depend on many factors, such as the severity of the disease to be treated (i.e., infection), the age and relative health of the subject, the effectiveness of the compound used, route of administration and form and other factors, all of which are within the scope of the attending clinician.

[0245] The data obtained from cell culture assays and animal studies can be used to formulate a range of dosages for use in humans. The dosage of such compounds is preferably within a range of circulating concentrations that include therapeutic efficacy with little or no toxicity. The dosage can vary within this range, depending on the dosage form used and the route of administration used. For any compound used in the methods provided herein, the therapeutically effective dose can be initially estimated from animal models. The dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC determined in cell culture. 50 (ie, the concentration of the test compound that achieves a half-maximal inhibition of symptoms.) Such information can be used to more accurately determine useful doses in humans.

[0246] When used as a drug, the compounds provided herein are generally administered in the form of a pharmaceutical composition. These compounds can be administered by a variety of routes, including oral, parenteral, transdermal, topical, rectal, and intranasal administration.

[0247] The compounds provided herein are effective as injectable, oral, inhalable, topical or intratumoral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and contain at least one active compound.

[0248] The present invention also includes pharmaceutical compositions, which contain one or more compounds provided above as active ingredients, and pharmaceutically acceptable carriers. When preparing the compositions of the present invention, the active ingredient is typically mixed with an excipient, diluted with an excipient, or enclosed in such a carrier, which can be in the form of a capsule, pouch, paper, or other container. When an excipient is used as a diluent, it can be a solid, semisolid, or liquid material that acts as a solvent, carrier, or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, pouches, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0249] The compositions are preferably formulated in unit dosage form, each dosage containing from about 0.1 to about 2000 mg, more usually from about 1 to about 900 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unit dosages for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect in combination with a suitable pharmaceutical excipient. Preferably, the compound provided above is used in an amount not exceeding about 20% by weight of the pharmaceutical composition, more preferably not exceeding about 15% by weight, the remainder being pharmaceutically inert carriers.

[0250] The active compound is effective over a wide dosage range and is generally administered in a pharmaceutically or therapeutically effective amount. However, it should be understood that the actual amount of compound administered can be determined by the physician based on relevant circumstances, including the condition to be treated, the severity of the bacterial infection being treated, the selected route of administration, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0251] In therapeutic use for treating or combating bacterial infections in warm-blooded animals, the compounds or pharmaceutical compositions thereof can be administered orally, topically, transdermally, and / or parenterally in a dosage to achieve and maintain a concentration, i.e., an amount, or blood level of the active ingredient in the animal being treated, which will be antibacterially effective. Typically, such an antibacterial or therapeutically effective dose (i.e., effective dose) of the active ingredient will be in the range of about 0.1 mg / kg to about 250 mg / kg body weight / day, more preferably about 1.0 mg / kg to about 50 mg / kg body weight / day.

[0252] In order to prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a uniform mixture of the compound described herein. When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is evenly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. The solid preformulation is then subdivided into a unit dosage form of the above type containing, for example, 0.1 to approximately 500 mg of the active ingredient described herein.

[0253] Tablet described in the present application or pill can coating or otherwise compound, to provide the dosage form with prolongation advantage.For example, tablet or pill can comprise inner dosage and outer dosage component, and the latter is the envelope form on the former.These two kinds of compositions can be separated by enteric layer, and enteric layer is used for resisting the disintegration in the stomach, and allows inner component to enter duodenum or delay release intactly.Multiple materials can be used for this enteric layer or coating, and this material comprises the mixture of multiple polymeric acid and polymeric acid and the material such as shellac, spermol and cellulose acetate.

[0254] Liquid forms of the novel compositions described herein that can be used for oral or parenteral administration include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils, such as corn oil, cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical carriers.

[0255] Additionally, liposomal formulations of the compounds described herein can be used, for example, to enhance the therapeutic efficacy of certain infections, such as pneumonia or lung infections.

[0256] The compounds provided herein are administered intratumorally using solutions or gels prepared in appropriate aqueous solutions containing appropriate excipient additives (such as glucose, polyethylene glycol, polyoxyethylene castor oil, cyclodextrin, etc.).

[0257] Compositions for inhalation or insufflation include pharmaceutically acceptable solutions and suspensions, aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the compositions are administered via the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents can be aerosolized using an inert gas. Aerosolized solutions can be inhaled directly from the aerosolizing device, or the aerosolizing device can be connected to a mask tent or intermittent positive pressure breathing apparatus. Solution, suspension, or powder compositions can be administered from a device that delivers the formulation in an appropriate manner, preferably orally or nasally.

[0258] Available at Remington's Pharmaceutical Sciences, Mace Publishing Company, Other suitable formulations can be found in Pharmacopoeia, Philadelphia, PA, 17th ed. (1985).

[0259] Alternatively, the compounds described herein may be co-administered with other drugs, including antioxidants, such as ascorbic acid, or megalin receptor inhibitors generally known to mitigate the adverse effects of polymyxin drugs.

[0260] As mentioned above, the compounds described herein are suitable for use in various drug delivery systems. In addition, in order to improve the serum half-life in vivo of the administered compound, the compound can be encapsulated, introduced into the lumen of the liposome, prepared as a colloid, or other conventional techniques for providing extended serum half-life of the compound can be used. Various methods can be used to prepare liposomes, as described in, for example, U.S. Patents 4,235,871, 4,501,728, and 4,837,028 to Szoka et al., each of which is incorporated herein by reference. Alternatively, the compounds described herein can be administered as nanomicelles or nanomaterial-encapsulated compositions, as described by Taki et al. in Pharmaceut., 2012, vol. 3, p. 1092.

[0261] As described above, the compound administered to the patient is in the form of a pharmaceutical composition as described above. These compositions can be sterilized by conventional sterilization techniques or can be sterile filtered. The resulting aqueous solution can be packaged for use as is or lyophilized, and the lyophilized formulation can be combined with a sterile aqueous carrier prior to administration. The pH of the compound formulation is generally between 3 and 11, more preferably between 5 and 9, and most preferably between 7 and 8. It will be understood that the use of some of the above-mentioned excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.

[0262] The disclosures of each patent, patent application, and publication (e.g., journal, article, and / or textbook) cited in this application are incorporated herein by reference in their entirety. In addition, as used in this application and the appended claims, singular articles such as "a," "an," and "one" are intended to refer to the singular or plural. Although this application describes the present invention in conjunction with preferred aspects, those of ordinary skill in the art, after reading the foregoing description, may affect changes, equivalent substitutions, and other types of changes to the invention described in this application. Each aspect described above may also include or incorporate such changes or aspects disclosed with respect to any or all other aspects. The content of the present invention is also not limited to the specific aspects described in this application, which are intended to serve as a single illustration of the various aspects provided by this application. Without departing from the spirit and scope of this disclosure, many modifications and variations may be made to the present invention, which will be apparent to those skilled in the art. In addition to the methods listed in this application, functionally equivalent methods within the scope of this disclosure will be apparent to those skilled in the art from the foregoing description. It should be understood that this disclosure is not limited to specific methods, reagents, process conditions, materials, etc., and, of course, these methods, reagents, and materials may vary. It should also be understood that the terminology used in this application is for the purpose of describing particular aspects only and is not intended to be limiting. Therefore, this description is to be regarded as illustrative.

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein: R 1 is connected to X 1 residues, by removing from the parent or precursor structure R 1 H is formed by removing one H atom from any of the following hydrogen-containing groups NH2, NH, OH and SH independently selected; and wherein R 1 H is selected from compounds that modulate glucocorticoid receptor (GR) activity or can induce glucocorticoid receptor (GR) activity; X connected together 1 、X 2 and X 3 The sequence formed -X 1 -X 2 -X 3 - comprising a cleavable linker, wherein: X 1 Missing or selected from -CH2NH-, -C(=O)NHC(=O)C 1-6 Alkylene NH-, A group consisting of 1 The left side of the group is connected to R 1 ; X 2 The peptide residue is missing or contains an amino acid residue or a peptide residue consisting of 1 to 6 amino acids, wherein the amino acid is selected from α-, β- or γ-amino acids that are unsubstituted or substituted on any N atom, Phe, Gly, Val, Lys, Cit, Ser, Ala, Glu, Gln, Asp, D-Phe, D-Val, D-Lys, D-Cit, D-Ser, D-Ala, D-Glu, D-Gln and D-Asp; where X 2 The carbonyl end of the group is connected to X 1 or R 1 (If X 1 missing); X 3 Selected from -C(=O)-, -C(=O)-R 2 -C(=O)- and -C(=O)OR 2 -C(=O)-; wherein X 3 The left side of the group is connected to X 1 (If X 2 missing) or X 2 ; R 2 Selected from the group consisting of: substituted or unsubstituted C 1-6 Alkylene, C 3-10 Cycloalkylene, heteroarylene, C 3-10 Cycloalkylene C 1-3 Alkylene, C 1-3 Alkylene C 3-10 Cycloalkylene, C 1-3 Alkylene C 3-10 Cycloalkylene C 1-3 Alkylene, heteroarylene C 1-3 Alkylene, C 1-3 Alkylene heteroarylene, C 1-3 Alkylene heteroarylene C 1-3 Alkylene, C 1-6 Alkylene NHC(=O)C 1-6 Alkylene, and -R 3 -R 4 -R 5 -R 6 -(S) p -R 13 -; Among them, when R 2 is unsubstituted C 1-6 When alkylene, X 1 or X 2 Not missing; or when R 2 is substituted C 1-6 When alkylene, R 2 One to four R 14 replace; R 3 Deletion or selection of NH, N(C 1-6 Alkylene), and C 1-6 a group consisting of an alkylene group; R 4 Missing or selected from arylene, heteroarylene, -C(C 3-10 Cycloalkylene)2-, C 3-10 Cycloalkylene, heterocycloalkylene, and -(OCH2CH2O) q - the group formed; R 5 Missing or C 1-6 alkylene; R 6 Missing or selected by OC 1-6 Alkylene and the group formed; R 13 Missing or selected from C 1-12 Alkylene, C 3-10 Cycloalkylene, C 3-10 Cycloalkylene C 1-6 The group consisting of alkylene, heterocycloalkylene, heteroarylene and arylene; wherein R 13 Optionally one to four R 15 replace; R 14 Independently selected from -C 0-3 Alkylene-polyvinyl alcohol, halogen, OH, NH2, SH, CN, C 3-10 Cycloalkyl, C 1-8 the group consisting of alkoxy, aryl, and heteroaryl; R 15 Independently selected from halogen, OH, NH2, SH, C 3-10 the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; A 8 To A 11 is an optional amino acid residue selected from the group consisting of unsubstituted or substituted α-, β-, or γ-amino acids, Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, L-homoserine, Thr, Trp, Tyr, Val, D-Ala, D-Arg, D-Asn, D-Asp, D-Cys, D-Gl u, D-Gln, D-His, D-Ile, D-Leu, D-Lys, D-Met, D-Phe, D-Pro, D-Ser, D-homoserine, D-Thr, D-Trp, D-Tyr, D-Val, 3-aminoproline, 4-aminoproline, biphenylalanine (Bip), D-Bip, 2,3-diaminopropionic acid (Dap), 2,4-diaminobutyric acid (Dab), 2,5-diaminopentanoic acid, nitrogen heterocycle butane-2-carboxylic acid, azetidine-3-carboxylic acid, piperidine-2-carboxylic acid, 6-aminopiperidine-2-carboxylic acid, 5-aminopiperidine-2-carboxylic acid, 4-aminopiperidine-2-carboxylic acid, 3-aminopiperidine-2-carboxylic acid, piperidine-3-carboxylic acid, 6-aminopiperidine-3-carboxylic acid, 5-aminopiperidine-3-carboxylic acid, 4-aminopiperidine-3-carboxylic acid, piperazine-2-carboxylic acid, 6-aminopiperazine-2-carboxylic acid, 8-azabicyclo[3.2.1]octane-2-carboxylic acid, 4-aminopiperidine-2-carboxylic acid 4-amino-3-arylbutanoic acid, 4-amino-3-(3-chlorophenyl)butanoic acid; and 5-amino-4-arylpentanoic acid; R a 、R b and R c represents the side chain of an amino acid independently selected from serine, threonine, leucine, phenylalanine, norleucine, norvaline, or tert-butylglycine; Integers h, i, j and k are independently selected from 0, 1 and 2; The integer q is selected from 1 to 10; The integers x, y, z and p are independently selected from 1 and 2.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof, characterized in that: Has the following formula Ia: R a is CH2CH(CH3)2 or CH2Ph; The integer f is 1 or 2.

3. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof, characterized in that: Has the following formula Ib: R a It is CH2CH(CH3)2 or CH2Ph.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, solvate or hydrate thereof, characterized in that X 2 The amino acid or peptide residue is missing or comprises an amino acid or peptide residue selected from the group consisting of Gly-Phe-Gly-Gly, Gly-Phe-Gly, Cit-Val, Cit, Glu, Glu-Gly, Asp-Val-Glu-Asp, Ala-Ala-Gly and Ala-Ala.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate or hydrate thereof, characterized in that: R 2 Selected from the group consisting of: substituted or unsubstituted C 1-6 Alkylene, C 4-7 Cycloalkylene, -heteroarylene-C 1-3 Alkylene-, -C 1-3 Alkylene-heteroarylene-C 1-3 Alkylene-, -C 1-6 Alkylene-(2,5-dioxopyrrolidine-1,3-diyl)-SC 1-3 Alkylene-CH(NH2)-, -C 1-6 Alkylene-(2,5-dioxopyrrolidine-1,3-diyl)-SC 1-12 Alkylene-, -C 1-6 Alkylene-(2,5-dioxopyrrolidine-1,3-diyl)-SC 3-6 Cycloalkylene-, -C 1-6 Alkylene-(OCH2CH2O) q -C 1-6 Alkylene-R 6 -SR 13 -、-C 1-6 Alkylene-arylene-SSR 13 -, -arylene-C 1-6 Alkylene-SSR 13 -、-N(C 1-6 Alkylene)-arylene-C 1-6 Alkylene-SSC 2-6 Alkylene-, -N(C 1-6 Alkylene)-arylene-C 1-6 Alkylene-SSC 3-10 Cycloalkylene C 1-6 Alkylene-, -N(C 1-6 Alkylene)-arylene-SSC(CH3)2-C 1-3 Alkylene-, -N(C 1-6 Alkylene)-arylene-SSC 3-10 Cycloalkylene C 1-6 Alkylene-, -N(C 1-6 Alkylene)-C 1-6 Alkylene-SSC 1-3 Alkylene-C(NH2)-, -N(C 1-6 Alkylene)-C 1-6 Alkylene-SSC 2-6 Alkylene-, -N(C 1-6 Alkylene)-OC 1-6 Alkylene-SSR 13 -、-C 2-6 Alkylene-SSC 3-10 Cycloalkylene C 1-6 Alkylene-, -C 3-6 Alkylene-SSC 1-6 Alkylene-, -C 3-6 Cycloalkylene-SSC 1-6 Alkylene-, -C 1-6 Alkylene-SSC 3-6 Cycloalkylene-, and -C 3-6 Cycloalkylene-SSC 3-6 Cycloalkylene-.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate or hydrate thereof, characterized in that: X 3 Selected from the group consisting of: -C(=O)-, -C(=O)CH2C(=O)-, - C(=O)CH2CH2C(=O)-,-C(=O)OCH2CH(CH3)-SS-CH2C(=O)-,- C(=O)CH2CH2NHC(=O)CH2CH2C(=O)-, -C(=O)CH(NH2)CH2CH2C(=O)-, -C(=O)cyclobutyl C(=O)-、-(C=O)SS(C=O)-、-(C=O)CH2-SSC(CH3)2(C=O)-、-(C=O)CH2-SSC(cyclopropyl cyclopropyl)2-SS-CH2(C=O)-, -(C=O)C(CH3)2-SS-CH2(C=O)-, -(C=O)C(cyclopropyl)2-SS-CH2(C=O)-, - (C=O)NHCH2CH2-SSC(CH3)2CH2C(=O)-、-(C=O)NHCH2C(CH3)2-SSC(CH3)2CH2C(=O)-、-C(=O)NHCH2CH2-SSC(cyclopropyl)2-、-(C=O)OCH2CH2-SSC(CH3)2CH2C(=O)-、-(C=O)OCH2C(CH3)2-SSC(CH3)2CH2C(=O)-、-C(=O)OCH2CH2-SSC(cyclopropyl)2-、- (C=O)CH2CH2-(2,5-dioxopyrrolidine-1,3-diyl)-S-CH2CH2C(=O)-、-(C=O)CH2CH2-(2,5-dioxopyrrolidine-1,3-diyl)-S-CH2CH(NH2)C(=O)-、-(C=O)CH2-(2,5-dioxopyrrolidine-1,3-diyl)-S-CH2CH2C(=O)-、-(C=O)CH2-(2,5-dioxopyrrolidine-1,3-diyl)-S-CH2CH(NH2)C(=O)-、- (C=O)C 1-6 Alkylene-(2,5-dioxopyrrolidine-1,3-diyl)-SC(CH3)2CH2-C(=O)-, -(C=O)C 1-6 Alkylene-(2,5-dioxopyrrolidine-1,3-diyl)-SC(CH3)2C(CH3)2-C(=O)-, 7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate or hydrate thereof, characterized in that: -X 1 -X 2 -X 3 - is independently selected from the following structures, wherein -X 1 -X 2 -X 3 -The left side is connected to R 1 :

8. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, solvate or hydrate thereof, characterized in that: R 1 H is represented by formula II: in: R 8 and R 9 Independently selected from H, C 1-12 Alkyl, C 1-12 the group consisting of alkyl C(=O)O-, -OH and halogen; or R 8 and R 9 Together wherein E is independently selected from CH2 and O; When E is CH2, then G is N; or when E is O, then G is CH or C(C 1-6 alkyl); R 11 WYZR 12 or -WYZC 1-6 Alkylene-R 12 ; R 7 Independently selected from -C 1-6 Alkylene-NR i R j 、-C 1-6 Alkylene-OH, -C 1-6 Alkylene-halogen, -SC 1-6 Alkylene-halogen, -C 1-6 Alkylene-TWYZR 12 , and -C 1-6 Alkylene-TWYZC 1-6 Alkylene-R 12 the group formed; R 12 Each occurrence is independently selected from H, NR i R j , OH, and SH; T is selected from S(=O), S(=O)2, S(=O)2NR i 、O、S、C(=O)NR i , C(=O) and NR i the group formed; W and Z are independently absent at each occurrence or independently selected from the group consisting of alkylene, arylene, heteroarylene, cycloalkylene, and heterocycloalkylene; each of these groups may be replaced by 1 to 4 -CH i R j 、F、Cl、Br、I、-C 0-6 Alkylene-OH, or -C 0-6 Alkylene-NR i R j replace; Each occurrence of Y is independently missing, or independently selected from -C 0-6 Alkylene-CR i R j -C 0-6 Alkylene-, -C 0-6 Alkylene-OC 0-6 Alkylene-, -C 0-6 Alkylene-SC 0-6 Alkylene-, -C 0-6 Alkylene-NR i -C 0-6 Alkylene-, -C 0-6 Alkylene-S(=O)-C 0-6 Alkylene-, -C 0-6 Alkylene-S(=O)2-C 0-6 Alkylene-, -C 0-6 Alkylene-S(=O)2NR i ,-C 0-6 Alkylene-, -C 0-6 Alkylene-C(=O)NR i -C 0-6 Alkylene-, -C 0-6 Alkylene-C(=O)-C 0-6 Alkylene-, -C 0-6 Alkylene-CR i =CR i -C 0-6 Alkylene-, and -C 0-6 Alkylene -C≡CC 0-6 Alkylene - a group consisting of; R 10 is independently selected at each occurrence from the group consisting of OH, halogen, alkyl, =0, and arylalkyl; R i and R j Each occurrence is independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; The dotted bonds represent single or double bonds; n is an integer selected from 0-19.

9. The compound according to claim 8 or a pharmaceutically acceptable salt, solvate or hydrate thereof, characterized in that: According to formula II, R 1 H is represented by Formula IIa, Formula IIb, Formula IIc or Formula IId:

10. The compound according to claim 8 or 9, or a pharmaceutically acceptable salt, solvate or hydrate thereof, characterized in that: R 1 H is selected from the following structures:

11. The compound according to claim 10 or a pharmaceutically acceptable salt, solvate or hydrate thereof, characterized in that: R 1 is from R 1 It is obtained by removing H from the primary alcohol CH2OH group, phenylene-OH group or NH2 group in the H structure.

12. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof, characterized in that: Selected from the following structures:

13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, solvate or hydrate thereof, characterized in that: Possesses anti-inflammatory activity or a therapeutic effect on kidney disease, which is determined by (i) reducing or slowing the release of renal cytokines such as TNF-α, IL-6, and IL-12; (ii) reducing one or more biomarkers, optionally, wherein the one or more biomarkers are selected from protein levels, blood urea nitrogen, and serum creatinine; or (iii) improving the condition of a patient in need of treatment or a mammal in an animal test.

14. The compound according to claim 13, or a pharmaceutically acceptable salt, solvate or hydrate thereof, characterized in that: The anti-inflammatory activity is in the treatment of inflammatory diseases in kidney inflammation, kidney damage or dysfunction, or inflammation induced by nephrotoxic substances, including drug nephrotoxic substances, such as anti-cancer, anti-diabetic, anti-infective or other chemotherapeutic substances.

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, solvate or hydrate thereof, characterized in that: HR of free agent or drug at similar doses as those incorporated into the compound 1 have enhanced anti-inflammatory, immunomodulatory or renoprotective effects compared to the control, as determined by in vitro or in vivo assays for anti-inflammatory, immunomodulatory or renoprotective activity.

16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, solvate or hydrate thereof, characterized in that When administered to a mammal, the compound exhibits preferential accumulation in the kidney, with the ratio of its molar concentration in the kidney to its molar concentration in the blood being between about 5 and 50.

17. The compound according to claims 1-16, or a pharmaceutically acceptable salt, solvate or hydrate thereof, characterized in that: When administered to a mammal, the compound exhibits preferential accumulation in the kidney, with a ratio of molar concentration in the kidney to molar concentration in the blood of at least about 20.

18. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, solvate or hydrate thereof, characterized in that: When the reagent HR 1 The standard therapeutic dose (in moles) of the drug HR is the same as the free drug HR when administered to mammals. 1 The compound showed a significant HR in the kidney compared to the standard treatment dose. 1 The drug loading (tissue concentration) and / or drug exposure (area under the curve, AUC) is approximately 1.5 to 15 times that of the dose of the active ingredient.

19. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, solvate or hydrate thereof, characterized in that: When the reagent HR 1 The standard therapeutic dose (in molar amounts) of the dose (expressed in molar amounts) when administered to a mammal, with the agent HR 1 The invention also provides a novel therapeutic agent that exhibits approximately 1.5-15 times greater efficacy compared to a standard therapeutic dose of a conventional steroid, wherein the therapeutic effect is determined as slowing, halting, or reversing progression of inflammation (as determined by changes in cytokine release and / or by using biochemical biomarkers for disease monitoring or similar methods).

20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate or hydrate thereof, characterized in that: When the reagent HR 1 The standard therapeutic dose (molar amount) is a dose (expressed in moles) when administered to a mammal, with the reagent HR 1 The invention provides a method for treating renal insufficiency of the kidney and showing at least 2-fold greater efficacy compared to a standard treatment dose of the kidney, wherein the therapeutic effect is determined as slowing, halting or reversing the progression of inflammation or renal damage (as determined by cytokine release levels and / or by using biochemical biomarkers for inflammation monitoring, or by radiography, or by magnetic resonance imaging, or the like).

21. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, solvate or hydrate thereof, characterized in that: When the reagent HR 1 The standard therapeutic dose (in moles) of a dose (expressed in moles) when administered to a mammal is comparable to HR 1 The invention further provides for a therapeutic agent that exhibits at least a 2-fold reduction in the rate of adverse reactions and / or off-target toxicities compared to a standard therapeutic dose of the drug, as determined by medical observation, blood cell counts, tissue biopsy, and / or analysis of biochemical biomarkers or similar methods in the mammal being treated.

22. A pharmaceutical composition, characterized in that Comprising a therapeutically effective amount of the compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and a pharmaceutically acceptable carrier.

23. A method for treating kidney inflammation in a mammal, characterized in that: The method comprises administering to a mammal a therapeutically effective amount of the compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt, solvate or hydrate thereof, or the pharmaceutical composition according to claim 22.

24. The method according to claim 23, wherein The compound or its pharmaceutically acceptable salt, solvate or hydrate, or the pharmaceutical composition is administered to a mammal as a pharmaceutical composition by parenteral, transdermal, oral, intranasal, topical, rectal or intratumoral administration.

25. The method according to claim 23 or 24, characterized in that The kidney inflammation is chronic kidney disease (CKD), systemic lupus erythematosus (SLE), nephritis, acute kidney injury (AKI), diabetic nephropathy, chronic glomerulonephritis or inflammation in kidney transplant surgery.

26. A compound of formula II: or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein: R 8 and R 9 Together wherein E is independently selected from CH2 and O; When E is CH2, G is N, R 11 Selected from -Z-NR i R j , -Z-OH, and -WYZR 12 , R 7 Choose Free-C 1-6 Alkylene-OH, -C 1-6 Alkylene-NH2, -C 1-6 Alkylene-TWYZR 12 、-C 1-6 Alkylene-TZ-NR i R j , and -C 1-6 a group consisting of alkylene-TZ-OH; Or when E is O, then G is CH, R 11 Selected from alkyl, R 7 -C 1-6 Alkylene-T-heteroarylene-NR i R j ; Or if E is O, then G is CH, R 11 Selected from -heteroarylene-NR i R j ,-arylene-heteroarylene-NR i R j , -Z-OH, -WYZ-SH, and -WYZ-OH; R 7 -C 1-6 Alkylene-OH; Or if E is O, then G is CH, R 11 Choose from -Z-NR i R j , -Z-OH and -WYZR 12 Group composed of R 7 Choose Free-C 1-6 Alkylene-TWYZR 12 、-C 1-6 Alkylene-TZ-OH, -C 1-6 Alkylene-TZ-NR i R j , and -C 1-6 a group consisting of an alkylene group -NH2; R 12 Each occurrence is independently selected from H, NR i R j , OH, and SH; T is selected from S(=O), S(=O)2, S(=O)2NR i 、O、S、C(=O)NR i , C(=O) and NR i the group formed; W is selected from the group consisting of arylene, heteroarylene, cycloalkylene, and heterocycloalkylene; Z is independently selected from the group consisting of arylene, heteroarylene, cycloalkylene, and heterocycloalkylene at each occurrence; Y is C 1-6 Alkylene, O or S; R 10 Each occurrence is independently selected from the group consisting of OH, halogen, alkyl, and arylalkyl; R i and R j Each occurrence is independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; The dotted bonds represent single or double bonds; n is an integer selected from 0-19.

27. The compound according to claim 26, characterized in that The compound is represented by formula IIa, formula IIb, formula IIc or formula IId:

28. The compound according to claim 26 or 27, characterized in that W is selected from:

29. The compound according to any one of claims 26 to 28, characterized in that Each occurrence of Z is independently selected from:

30. The compound according to any one of claims 26 to 29, characterized in that Selected from the following compounds:

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